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BACKGROUND OF THE INVENTION
The use of sweeping jet fluidic oscillators for defrosting/defogging operation of automobile windshields is disclosed in Kakei et al. U.S. Pat. Nos. 3,832,939 and 3,745,906, and Stouffer U.S. Pat. No. 4,250,799 (and divisions thereof). In Kakei et al., several forms of sweeping jet oscillators for defrost purposes are disclosed, one of which included a fluidic oscillator in which a pair of crossed feedback pipes received portions of air issuing from the outlet downstream of the throat and returned same to a pair of control ports. In the Stouffer patent, a vibrating reed oscillator is utilized which significantly reduced the amount of space under the dash but the movement of the weighted end of the vibrated reed through the jet or air stream created a swishing sound noticable to passengers in the close confined space of an automobile. The use of electromagnets to control the valving of the control ports for switching purposes has been suggested for use in cars but this invites an unnecessary complexity and requires a fluid logic element of at least 5W in length to get adequate sweeping angles where W is the width of the power nozzle. Fluidic oscillators based on an continuous passage or loop interconnecting the pair of control ports of the fluidic element are known in the art as disclosed in Van Nostrand's Scientific Encyclopedia (6th Edition) page 1235, for example. Izumi et al. U.S. Pat. Nos. 4,416,192, 4,407,186 and 4,393,898 disclose use of fluidics with electromagnetic control in directional control of air in automobiles.
DESCRIPTION OF THE PRESENT INVENTION
The basic fluidic oscillator of the present invention has several features which make it ideal as a defroster outlet for motor vehicles. The oscillator portion itself can be made relatively short, under, for example, about 2W where W is the width of the power nozzle, so that, with the use of sweep angle enhancers as disclosed herein, the fluidic sweep angle can be designed to cover angles up to about 180 degrees with about 120 degrees being typical. This gives the fluidic nozzle the flexibility to defrost any windshield configuration from a single outlet source located near the center line of the windshield. However, it is within the contemplation of this invention that instead of a single oscillator, one fluidic oscillator can be utilized for the passenger side as well as one for the driver side. The sweep angle referred to above is measured from the center line of the emerging air jet at each extreme position of sweep in the oscillator. The actual extent of the oscillation is slightly larger than the fan angle and is measured from the extremes of the jet profile. The frequency of oscillation can be controlled to provide excellent distribution over the windshield and minimum mixing with ambient air. This is achieved by designing the fluidic oscillator's wavelength to be greater than the distance from the fluidic outlet to the upper corners of the windshield all as described in Stouffer U.S. Pat. No. 4,250,799 (and division thereof). Under this condition, air exiting from the fluidic oscillator during each cycle has ample time to cover the windshield with a coherent jet. The wavelength of the fluidic is constant for any supply pressure (i.e., the blower setting), thus yielding consistent distribution and minimum ambient mixing in all defrost modes. The fluidic sweep angle and the frequency, which in the preferred embodiment is below 12 Hz, and the angle of attack relative to the windshield more efficiently clear the passenger and driver side as called for in the Federal Motor Vehicle Standard Specifications (FMVSS103). However, the invention also provides great flexibility in the design to change the defroster clearing patterns and in this respect, one factor governing defrost pattern development is the aiming angle or angle of attack relative to the windshield. Controlling the angle of attack is achieved by element positioning (taking into account the space available under the dash) and/or the outlet control vane adjustment. For any sweep angle, low angles of attack (flow more parallel to the windshield), the defrost pattern growth is faster from base to the top of the windshield. For large angles of attack (flow more perpendicular to the windshield), the pattern growth is faster from the windshield center line to the sides.
While in the preferred embodiment, the sweep angle enhancing vanes are shown as having parallel axes, it is contemplated that there may be instances where the curvature of the windshield is such that the sweep angle enhancing vanes be set at angles to better accomodate such curvature and direct the blast of air at an angle of attack commensurate with the windshield curvature or, when two nozzles are used to direct some defrost air to side windows at the ends of the sweep.
Significantly, the oscillator utilized in the present invention mates with existing blower systems without reducing the blower output so that the fluidic oscillator itself can be sized to deliver the same volumetric flow rate as in the current defrost system using wide diffuser vane and diverging funnel. Thus, the fluidic oscillator utilized on a defroster outlet offers essentially the same impedance to the blower system as a conventional diffuser vane diverging funnel arrangement. While the two systems offer similar impedance, the controlling restriction for the fluidic oscillator according to the present invention in a typical example is about 3.75 square inches as compared to about 14.6 square inches for conventional production type systems.
According to this invention, underdash volumetric space occupied by the defrost system is reduced by the fluidic oscillator is made relatively short and is of the type having a power nozzle, a pair of control ports immediately adjacent to and downstream of the power nozzle and a continuous inertance loop interconnecting the control ports. In the preferred embodiment, a pair of relatively short sidewalls are provided along with one or more sweep angle enhancers. While the diverging sidewalls can obviously be made longer, in the preferred embodiment the downstream edges of the diverging walls are made less than twice the width of the power nozzle (2W). In addition, since the air flow from the blower to the fluidic oscillator itself is controlled by the channeling and duct work in the vehicle, flow straighteners are preferrably utilized just at the manifolding of the oscillator to the duct work to thereby reduce the length of ducting to the power nozzle and thereby assure more uniform and symetrical velocity of profile of the air stream entering the power nozzle. Fluid inertance is a measure of the pressure required to accelerate a mass of fluid in a passageway and thus is associated with flow through a tube or passage and is a function of the length and cross-sectional area thereof. Since the fluidic oscillator utilized is more sensitive to the inertance loop's cross-sectional area than to its length, that is, the fluidic is sensitive to abrupt changes in cross-section or particularly sudden reductions cross-sectional area of the continuous inertance loop, an important feature of the invention is the avoidance of abrupt changes in cross-section in direction or cross-sectional area of fluid flow in the continuous inertance loop. The inertance loop is coupled to the control ports via entry ways.
With appropriate inertance loop cross-sectional area, the fluidic oscillates over a large range of lengths and feed pressures. With the oscillator exemplary dimensions given herein, for lengths of 3/4 inch (approximately internal diameter tubing which have equivalent square or rectangular cross-sections), for passageway or loop lengths about 15-18 inches a 3/4 inch internal diameter inertance tube gives consistantly low standard deviation although other inertance tube cross-sections operated well within the scope of this invention. According to this invention, the length and cross-sectional area of the inertance loop tube is chosen so as to assure that the frequency of oscillation is below about 12 Hz so that the inertance loop will be large. The invention provides a solution to the problem of packaging large inertance loops. In addition, the inertance loop itself is shaped or "packaged" so as to reduce the volmetric space required. Thus, the inertance loop can be a sinuous or serpentine path formed on one of the walls or disposed in part of the duct work leading to the fluidic oscillator or it can be formed or "wrapped" in a helical fashion around the fluidic oscillator itself. In any case, the above noted criteria of no sharp reductions in cross-sectional area or sharp turns are avoided so as to not effect the inertance quality, is required.
The worst type of flow with respect to good oscillation is one where, just upstream of the power nozzle of the fluidic oscillator there is a large velocity gradient from one side of the feed channel to the other. In a preferred embodiment several flow straighteners in the upstream portion of the feed are used to assure a symmetrical and more uniform velocity profile and prevent air from piling up on one side of the flow of air to the power nozzle. If underdash space was not a factor then a straight feed tube or duct (about 6W long where "W" is the width of the power nozzle) can be used in place of or in addition to flow straightners.
Thus, flow variations and problems with flow are solved preferably using flow straighteners and not inertanence or control port manipulation. In one operating embodiment as disclosed herein, the height of the unit e.g., from floor to ceiling as opposed to width is about one and one half inches when the width of the power nozzle is about 2.5 inches.
The fluidic units are not as sensitive to flow problems from floor to ceiling. If the flow is "stacked" on the ceiling, placing the inertance inlet near the ceiling solved the problem. The inertance loop can be round or square in configuration and for form factor purposes this may be preferred.
It is the object of the present invention to provide an improved defrost/defog system for motor vehicles which is compact, has no moving parts, rapidly cleans a surface of frost or fog, is of relatively low cost, which can eliminate one defrost nozzle and reduce the underdash space required for defrost systems.
BRIEF DESCRIPTION OF THE DRAWINGS
The above and other objects, advantages and features of the invention will become more apparent when considered with the following specification and accompanying drawings wherein:
FIG. 1 is an exploded isometric view of a defrost/defog nozzle as installed in a dashboard to defrost/defog a windshield of a vehicle and incorporating the invention,
FIG. 2 is a plan view of the silhouette of the fluidic oscillator with exemplary dimensions thereon,
FIG. 3 is a side sectional view showing one angular relationship of the nozzle to the windshield,
FIG. 4 illustrates diagrammatically the operation of the fluidic in relation to the windshield and the wavelength thereof,
FIGS. 5 and 6 are diagrammatic illustrations showing the effect of the angle of attack and the defrost pattern formed on the windshield,
FIG. 7 is a diagrammatic illustration showing the adjustment of the oscillator relative to adjust the angle of attack relative to a windshield,
FIG. 8 is a diagrammatic illustration of the fluidic oscillator with a helical wind or wrap of the continuous inertance loop,
FIG. 9 is a diagrammatic illustration of a fluidic oscillator with a sinuous or serepentine path for the continuous inertance loop and flow straighteners therein.
DETAILED DESCRIPTION OF THE INVENTION
Referring now to FIG. 1, the fluidic oscillator nozzle N is shown installed in a dash D of an automobile or other vehicle for projecting defrost/defog air in a sweeping pattern upon the windshield W of the automobile. Nozzle N is comprised of a fluidic oscillator 10 which receives defrost/defog air under pressure from a supply (not shown) coupled via passage or duct 11. A coupling member 12 is constituted by a generally rectangular frame 13 which, as will be described more fully hereafter, may be used to house or "package" a portion of inertance loop 14 and thus improve the form factor and reduce underdash volumetric space required by the unit. Fluidic oscillator 10 comprises a power nozzle 15 having a width W, a pair of rectangular control ports 16L, 16R and a pair of short diverging wall elements 17L, 17R and in the preferred embodiment, the length of short wall elements 17L and 17R is such that the distance from the power nozzle to the outer edge 18 of the oscillator is less than 2W. Control ports 16L and 16R are connected by a continuous inertance loop 14 which, in this embodiment enters or is coupled to the upstream side 19UL and 20UL of cylindrical structures 21L and 21R forming the control port structures 16L and 16R. In this embodiment the conttrol ports 16L and 16R per se are rectangular in cross-section. The upper and lower cover plates 22 and 23, respectively are parallel to one another and spaced apart a distance D. The power nozzle aspect ratio is defined as the power nozzle width divided by the power nozzle depth (W/D). When several aspect ratios are plotted with respect to feed pressure and frequency, it was found that the higher the aspect ratio (short, wide jet), the higher the frequency. With respect to their respective frequencies at constant pressure, it was found that doubling the aspect ratio approximately doubled the frequency at constant inertance. The general relation between frequency and power nozzle area at constant inertance is the smaller the area the higher the frequency.
The distance from the power nozzle throat 25 upstream to the coupling unit 12 is made as short as possible when the flow straighteners described later herein are used. It should be noted that while the power nozzle is comprised of a pair of converging sidewalls 27 and 28 straight sidewalls could be used. The downstream edges of the control structures 21L and 21R are set back a short distance for reasons to be described more fully hereafter. The angular relationship of the sidewalls 17L and 17R can be varied. In the following, wall exit angles are measured relative to the set back point. A wall angle of 0 degrees is parallel to the flow and an angle of 90 degrees is perpendicular to the flow. In tests, the length of the wall elements 17L and 17R were varied from about 1/2 inches to 3 inches. The minimum wall angle for oscillation is about 5 degrees for both wall length and between 5 degrees and 20 degrees, the shorter wall had a higher frequency.
As shown in FIGS. 1 and 2, the outer most ends of the short wall elements are provided with convexly curved segments 31L and 31R which in conjunction with sweep angle enhancers 32, 33, 34 and 35, cause a greatly enhanced sweep angle. That is, a larger sweep angle for a given fluidic oscillator. In other words, the sweep angle is enlarged or made much larger than would normally be the case without the sweep angle enhancers. While the number and angulation of the sweep angle enhancers can be uniform that is, one or more on each side, and each of the same length and angularity, it will be appreciated as shown in FIGS. 1 and 2 that the angles of the sweep angle enhancers 32-35 can be adjusted to accomodate the position and angularity of the windshield and other dashboard topographical features. In fact, one sweep angle enhancer can be incorporated into a nozzle outlet so that the sweep will be greater on one side, for example the left side towards the left side or driver's side as opposed to the right side if this be desired. In addition, the sweep angle enhancers can be adjusted in length in the direction of flow to provide more or less of sweep angle enhancement effects. In some cases, where two oscillating nozzles are used, it may be desirable to have the nozzle on the passenger side direct more defrost air toward the left driver's side to assure that the driver side clears faster and is maintained clear for safety reasons.
A feature of the invention is the form factor of the inertance loop so as to reduce the volumetric space occupied by the oscillator. In the embodiment shown in FIG. 1, inertance loop 14 is coupled at one end 14-1 into the upstream side 19UL of the cylindrical structure 21L forming the coupling to left control port 16L and extends rearwardly or upstream wise into the rectangular box like structure 13 forming the coupling or fitting 12 to the plenum 11. The inertance loop 14 forms a first loop portion 14-2 extending in a left rearward direction in FIG. 1 and then a second loop portion 14L-3 extending transversely of the flow path and then a third loop portion 14L-4 which extends upwardly and then extends outside box 12, towards the upstream side 20UL of the cylindrical structure 21R where end 14-5 couples inertance loop flow to the right control port 16R. Ends 14-1 and 14-5 of the inertance loop can be impedance matching horn elements to enhance the effect of flow in the inertance loop on the air stream issuing through the power nozzle and enhance the switching effect. This can, for example, be curved in the form of a ram's horn thereby avoiding sharp turns and gradually increasing in cross-section to approach matching the cross-section of the control ports 16L and 16R.
Flow straighteners 40, 41, 42 and 43 are provided in the preferred embodiment so as to avoid problems caused by effects of turbulence and non-uniformity in the velocity profile in the flow of the air jet from the supply to the power nozzle 15 and prevents air from piling up on one side of the unit. It will be appreciated that if form is not significant and more volumetric space is provided under the dash for this defrost system, there is no need to design the inertance loop for any consideration other than the criteria mentioned above namely, uniform cross-sectional area and no sharp corners or bends that would effect the inertance property thereof. As shown in FIG. 8, the inertance loop 14' has one end 14'-1 coupled to a port 16P at the upper end of the cylindrical structure 21L and is wound in helical fashion about the oscillator and ends up in a second port 16PR in the end of the cylindrical structure 21R. It will be appreciated that the inertance loop 14' can be formed with passages molded or otherwise formed as an integral part of the external surfaces of the oscillator to thus improve the form factor. As indicated in FIG. 9, the inertance loop is in the form of a serepentine or sinuous path molded or otherwise formed on one of the top and bottom walls 22 and 23 of the fluidic oscillator 10. However, it will be appreciated that the loop 14S can be formed half on one surface 22 and the other half on surface 23, due regard being had for the effect of surface friction on the flow properties of the smaller sectioned loops. A plurality of parallel paths which satisfy the basic inertance requirements for this oscillator can be utilized to improve the form factor in some situations.
As shown in FIG. 2, in the defroster disclosed herein, the control port width is about 0.8 and the set back width is about 2.260 inches. The unit is sensitive to moving the set back. The unit is less sensitive to widening the set backs. In general, if you open the set back you must open the control ports and vice versa.
The forces needed to induce oscillation arises from the differential pressure across the control ports 16L and 16R which, in this embodiment, are rectangular openings. The pressure in the control port varies from atmospheric to some negative pressure. During oscillation this pressure oscillates about a negative biased level. The maximum pressure differential occurs when the jet attaches to one of the outlet walls 31L or 31R and dwells there for a (relatively short) period of time. (In installations where a single defrost nozzle is centrally located, the dwell at the ends provides heavy ended sweep which better defrosts the driver and passenger sides. This heavy endedness, wherein a larger volume of defrost air flows than during the regular sweeping motion can be designed to catch side windows when one defrost nozzle is used, When the control port pressure is plotted against the feed pressure it was found that a straight line curve resulted. Both control ports are at a pressure which is less than atmospheric however the control port nearest the jet is always at a lower pressure. Tests indicate that the control port differential pressure increases in a linear fashion with increasing feed pressure. The magnitude of the pressure differential is not only controlled by the feed pressure (or velocity) but also by the control port width, set back width, distance from power nozzle to set backs. The interrelationship of these parameters is not fully understood at this time so these relationships hold for constant fluidic geometry. In the disclosed embodiment, during oscillation, the control port pressure never reaches maximum static pressure. A short inertance at low feed pressure and a long inertance at high feed pressure yielding the same frequency have the same ratio of dynamic/static pressure in the control port. In the embodiment shown in FIG. 2, the range of stable oscillation was seen to be between about 60 percent and 10 percent of the maximum static control port pressure. Larger inertance values have higher control port differentials at the same feed pressure. Having a large differential seem to yield good oscillation until reaching about 60 percent of the static pressure where notable hesitation occurs from, it is believed, wall attachment and excessive flow delays in the inertance.
The power nozzle aspect ratio is defined as the power nozzle width/power nozzle depth. When several aspect ratios are plotted with respect to feed pressure and frequency, it was found that the higher the aspect ratio (short, wide jet), the higher the frequency. At constant pressure, doubling the aspect ratio approximately doubled the frequency at constant inertance. This holds true only if the power nozzle areas are held constant and other fluidic geometry is held constant. The general relationship between frequency and power nozzle area at constant inertance is: the smaller the area, the higher the frequency.
In FIG. 3, the dash D and windshield W are at angles 0 determined by the car manufacturer. In this situation, air sweeping from the fluidic oscillator 10 passes through a grill G which is substantially completely open and is of low impedance so as to not adversely affect operation of the oscillator. The angle of attack can be adjusted by various design paramaters regarding the fluidic oscillator as described above. Thus, the frequency of oscillation can be controlled to provide excellent distribution over the windshield and minimum mixing with the ambient air. As noted above, this is achieved by designing the fluidic oscillator's wavelength to be greater than the distance from the fluidic outlet to the upper corners of the windshield (see FIG. 4). Under this condition, air exiting from the fluidic during each cycle has ample time to cover the windshield with a coherent jet. The wavelenth of the fluidic is a constant (for any supply pressure (i.e., blower setting) thus yielding consistant distribution and minimum ambient mixing in all defrost/defog modes. In this invention, the dominant factor governing defrost pattern development is the aiming angle (or angle of attack) relative to the windshield as is shown in FIG. 7. Control of the angle of attack is achieved by the positioning of the fluidic oscillator (in the volumetric space available therefor as provided by the car manufacturer). In FIG. 7, the fluidic element 10 is shown as being adjustable laterally, towards and away from the windshield and rotated about an arc. However, these are design adjustments and not intended to reflect adjustments of the unit in use.
For any sweep angle, low angles of attack (more flow parallel to the windshield), the defrost pattern growth as shown in FIG. 5 is faster from the base to the top of the windshield. For large angles of attack (flow more perpendicular to the windshield), the pattern of growth is faster from the windshield center line to the sides (see FIG. 6).
While there has been disclosed and described preferred embodiments of the invention, it is to be noted that various changes and modifications will be apparent to those skilled in the art and it is intended that such changes and modifications be encompassed and included within the scope and the spirit off the claims appended hereto. | A defrost/defog air supply system for issuing a sweeping jet of air upon a windshield or other surface to be defrosted or defogged comprises a fluidic oscillator having a power nozzle coupled to receive the defrost/defog air and an outlet for issuing a sweeping stream of defrost/defog air onto the surface. The fluidic oscillator is short in length (in the preferred embodiment the distance from the power nozzle to the end of the outlet is less than twice the width of the power nozzle) and has a pair of control ports immediately adjacent the downstream side of the power nozzle of the fluidic and a continuous inertance loop interconnecting the control ports with the continuous inertance loop being of a length and cross-section such as to maintain the frequency of oscillation below about 12 Hz to thereby avoid mixing with ambient air prior to impingement upon the surface to be defrost. The downstream edges of the control ports are set back to permit ambient air to enter the control port when the defrost-defog air issuing from the nozzle is at the opposite sides. Flow straighteners are provided upstream of the power nozzle and just as the air exits from the manifold or supply to assure uniform and symmetrical flow velocity profile in the power nozzle. Sweep angle enhancers are provided at the outlet so that very short diverging sidewalls reduce the amount of underdash space required. | 1 |
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is the National Phase of International Application PCT/US2009/057422 filed Sep. 18, 2009 which designated the U.S. and which claims priority to U.S. Provisional App. Ser. No. 61/099,726 filed Sep. 24, 2008. The noted applications are incorporated herein by reference. U.S. Pat. Nos. 6,046,343 and 6,300,505 are hereby incorporated by reference in their entireties.
BACKGROUND OF THE INVENTION
1. Field of the Invention
Embodiments of the present invention generally relate to temperature control of a reactor using probability distribution of temperature measurements.
2. Description of the Related Art
Maleic anhydride is of significant commercial interest throughout the world. It is used alone or in combination with other acids in the manufacture of alkyd and polyester resins. It is also a versatile intermediate for chemical synthesis.
Maleic anhydride is conventionally manufactured by passing a gas comprising a hydrocarbon having at least four carbon atoms in a straight chain and oxygen through a catalyst bed, typically a fixed catalyst bed tubular plug flow reactor, containing a catalyst including mixed oxides of vanadium and phosphorus. The catalyst employed may further comprise promoters, activators or modifiers such as iron, lithium, zinc, molybdenum, chromium, uranium, tungsten, and other metals, boron and/or silicon. The product gas exiting the reactor typically contains maleic anhydride together with oxidation by-products such as carbon monoxide, carbon dioxide, water vapor, acrylic and acetic acids and other by-products, along with inert gases present in air when air is used as the source of molecular oxygen.
Because the reaction is highly exothermic, the reactor must be cooled during operation. Typically, a shell and tube heat exchanger is used as a reactor with the catalyst packed in the tubes through which the hydrocarbon and oxygen gases are passed. A cooling fluid, often a molten salt, flows over and cools the outside of the tubes. Because the length of the tubes is generally much greater than the diameter of the tubes, the reaction system approaches plug flow.
While the cooling capacity is substantially uniform throughout the reactor, the rate of reaction varies widely with the concentration of the hydrocarbon reactant and the temperature of the reaction zone. Because the reactant gases are generally at a relatively low temperature when they are introduced into the catalyst bed, the reaction rate is low in the region immediately adjacent the inlet of the reactor. Once the reaction begins, however, it proceeds rapidly with the rate of reaction further increasing as the reaction zone temperature increases from the heat released by the reaction. The reaction zone temperature continues to increase with distance along the length of the reactor tube until the depletion of the hydrocarbon causes the rate of reaction to decrease thereby decreasing the temperature of the reaction zone through transfer of heat to the cooling fluid, and allowing the remaining portion of the reactor tube to operate at a lower temperature differential. In practice, commercial reactors are configured so that a number of tubes, typically 50-100+, are equipped with a longitudinal thermocouple in the center of the tube, inserted to a tube depth (distance from the top or bottom tubesheet) where maximum temperatures are expected. Of these multiple measurement locations, the location with the highest temperature is generally referred to as the “hot spot”.
If the temperature distribution in the reactor increases, reactor performance, catalyst activity, and the integrity of the reactor vessel may deteriorate. Generally, the selectivity of the catalyst varies inversely with the reaction temperature while the rate of reaction varies directly with the reaction temperature. Higher reaction zone temperatures result in lower catalyst selectivity and favor the complete oxidation of the hydrocarbon feedstock to carbon dioxide and water instead of maleic anhydride. As the temperature distribution in the reactor increases, the amount of the hydrocarbon feedstock consumed by the reaction increases but the decreased selectivity of the catalyst can result in a decreased yield of maleic anhydride. In addition, exposure of the catalyst bed to excessive temperatures may degrade the catalyst activity and cause and excessive rate of corrosion of the reactor tubes. Such degradation of the catalyst activity generally reduces the productivity of the operation and may also reduce the selectivity of the catalyst at a given temperature. The higher heat of reaction released by the conversion of the hydrocarbon feedstock to carbon dioxide and water further compounds this problem. An excessive rate of corrosion of the reactor tubes will lead to premature failure of individual tubes or of the entire reactor.
Typically, the catalyst bed temperature is continuously monitored at 50-100+ tubes via a single thermocouple at each location. The bulk of the catalyst bed is maintained below an upper temperature limit by reducing the feed rate of the limiting reactant (i.e., air or butane) if the “hot spot” is above the specified upper temperature limit.
SUMMARY OF THE INVENTION
Embodiments of the present invention generally relate to temperature control of a reactor using probability distribution of temperature measurements. In one embodiment, a method of controlling a temperature of a chemical reaction includes injecting a reactant stream into a reactor and through a catalyst bed of the reactor. The reactant stream includes a hydrocarbon and oxygen. Injection of the reactant stream into the catalyst bed causes an exothermic chemical reaction. The method further includes circulating a coolant through the reactor, thereby removing heat from the catalyst bed. The method further includes measuring temperature at a plurality of locations in the catalyst bed. The method further includes calculating a fraction of the catalyst bed greater than a predetermined maximum temperature limit using a probability distribution generated using the temperature measurements.
In another embodiment, a chemical reactor includes a tubular shell having an inlet and an outlet, each formed through a wall thereof. The reactor further includes three or more tubes disposed in the shell, made from a thermally conductive material, and containing catalyst. The reactor further includes first and second tube sheets, each tube sheet fixed to each of the tubes and coupled to the shell, thereby isolating bores of the tubes from a chamber of the reactor. The reactor further includes first and second heads coupled to the shell, each head having an inlet and an outlet formed through a wall thereof. The reactor further includes two or more temperature sensors, each temperature sensor disposed through the shell, into the bores of respective tubes, and in communication with the catalyst. The reactor further includes a controller in communication with the temperature sensors and configured to perform an operation. The operation includes inputting temperature measurements from the temperature sensors, and calculating a fraction of the catalyst greater than a predetermined maximum temperature limit using a probability distribution generated using the temperature measurements.
BRIEF DESCRIPTION OF THE DRAWINGS
So that the manner in which the above recited features of the present invention can be understood in detail, a more particular description of the invention, briefly summarized above, may be had by reference to embodiments, some of which are illustrated in the appended drawings. It is to be noted, however, that the appended drawings illustrate only typical embodiments of this invention and are therefore not to be considered limiting of its scope, for the invention may admit to other equally effective embodiments.
FIG. 1 is a cross-section of a reactor, according to one embodiment of the present invention.
FIG. 2 illustrates a comparison between three temperature control schemes: the Prior Art hot spot scheme, an Ideal scheme, and a scheme according to an embodiment of the present invention.
FIG. 3 illustrates another comparison between the Prior Art hot spot scheme and a scheme according to an embodiment of the present invention.
DETAILED DESCRIPTION
FIG. 1 is a cross-section of a reactor 1 , according to one embodiment of the present invention. The reactor 1 may include a tubular shell 3 , vertically oriented tubes 5 , a lower head 7 having a gas inlet 9 , and an upper head 11 having a gas outlet 13 . Tubes 5 of the reactor 1 may be fixed in lower 15 and upper 17 tube sheets and may be made from a thermally conductive material so that the reactor functions as a shell and tube heat exchanger. The tubes 5 may be packed with catalyst 19 only or catalyst with a temperature sensor 20 . The catalyst 19 may be solid particles, such as beads or pellets, and may be made from a material selected to facilitate a chemical reaction, such as vanadium-phosphorous-oxide (VPO). The columns of catalyst may be collectively referred to as a catalyst bed of the reactor 1 . A gas reactant stream HC+O 2 may be injected into the reactor 1 via the inlet 9 . The reactant stream HC+O 2 may include a first reactant, such as hydrogen or a hydrocarbon, such as a hydrocarbon having at least four carbon atoms in a straight chain, such as n-butane or benzene, and a second reactant, such as a gas having a substantial oxygen concentration, such as air.
As the reactant stream flows through the catalyst bed, an exothermic reaction may occur, thereby producing a gas product stream. The product stream may include a desired product, such as maleic anhydride and byproducts, such as inert gases, water, acetic acid, acrylic acid, carbon monoxide and carbon dioxide. The product stream may exit the reactor via the outlet 13 and may be further processed to separate the desired product from the byproducts. Alternatively, the reactant/product stream flow may be reversed. Alternatively, the desired product may be phthalic anhydride (PA), acrolein, methyl mercaptan, acrylic acid, butanediol, methanol, ethylene oxide, ethylene glycol, formaldehyde, hydrogenated vegetable oil or fat, or vinyl chloride monomer.
To remove heat energy from the exothermic reaction, a coolant may be injected into an inlet 21 formed through the shell. The coolant may circulate along outer surfaces of the tubes 5 , thereby removing heat energy. The coolant may discharge from the reactor at an outlet 23 where it may be cooled in an external heat exchanger 26 which is equipped with a flow control valve 27 , and recirculated via an external pump. Alternatively, coolant flow may be reversed. The coolant may be a liquid, such as molten salt or molten inorganic salt. The average or inlet temperature of the coolant may be controlled at a predetermined set temperature to maintain a stable average catalyst bed temperature.
To monitor the catalyst bed temperature, a plurality of temperature sensors 20 a, b may be disposed through respective openings formed in one of the heads 7 , 11 . The temperature sensors 20 a, b may be thermocouples, resistance temperature detectors (RTDs), thermistors, or optical fibers. The temperature sensors 20 a, b may extend into respective selective tubes 5 to sense temperatures in the tubes at various longitudinal heights. The temperature sensors may also be radially and tangentially dispersed throughout the reactor 1 . Commercial reactors may be sizable and have a multitude of tubes 5 , such as one thousand, ten thousand, twenty thousand, thirty thousand, or more tubes. To remain economically feasible, a number of temperature sensors that is a ratio to the number of tubes may be deployed, such as one temperature sensor for every one hundred, two hundred, three hundred, four hundred, or five hundred tubes. A single temperature sensor may contain several elements, such that more than one depth can be monitored within a single tube. The temperature sensors may be asymmetrically concentrated at various longitudinal heights. For example, in a maleic anhydride reactor, a majority of the reaction may occur at lower heights in the reactor and a correspondingly greater concentration of temperature sensors may extend to these heights.
Each of the temperature sensors 20 a, b may be in electrical or optical communication with a controller 25 . The controller 25 may be a microprocessor based computer and may be located in a control room (not shown). The controller may include a video screen for displaying temperature measurements to a human operator.
As discussed above, the prior art control scheme dictates remedial action if any one of the thermocouples, such as the “hot spot”, detects a temperature exceeding a predetermined maximum temperature limit. Due to the high variability associated with the “hot spot” temperature, there are times when reactant feed rate (and production) is curtailed when there has been no actual shift in the bed temperature distribution. Conversely, there are other times when the bed temperature distribution has shifted, causing a higher fraction of the bed to be above the maximum limit, and the maximum temperature does not detect this shift. The maximum bed temperature is a fairly unreliable indication of the true bed temperature distribution and the true fraction of the bed above a specified upper limit.
To overcome these shortcomings, the controller 25 may analyze the temperature measurements (T c ) from the temperature sensors 20 a, b , using a probability distribution as opposed to simply determining the maximum, thereby more accurately estimating a temperature profile of the catalyst bed. The probability distribution may be based on the theory that differences (ΔT) between each of the catalyst bed temperatures in the reaction zone (T c ) and the catalyst bed temperature (θ) adjacent the inlet may be distributed lognormally. This theory has been verified by statistical analysis of a maleic anhydride reactor. An additional temperature sensor may be used to obtain the catalyst bed temperature (θ) adjacent the inlet or the control temperature of the coolant may be used as a convenient approximation thereof. Let N(T c >T mx ) represent the number of thermocouples which exceed the maximum temperature limit (T mx ) and N(T c ) represent the total number of thermocouples. The controller may calculate a fraction
( F ( Bed > T mx ) = N ( T C > T mx ) N ( T C ) )
of the reactor bed greater than a maximum temperature limit (T mx ) using the lognormal probability distribution (LNPDF) of the temperature differences (ΔT). The calculated fraction of the reactor bed may then be compared to a predetermined maximum fraction to more accurately assess whether the reactor is operating within acceptable limits. If not, then the remedial action may be taken.
For example, the controller may be programmed to perform an operation. The operation may include inputting temperature measurements (T c ) from each temperature sensor 20 a, b within the catalyst bed. The operation may further include subtracting the coolant control temperature (as an approximation of θ) from each temperature measurement (T c ) to obtain a temperature difference (ΔT=T c −θ) and from the maximum temperature limit (T mx ) to obtain a maximum temperature limit difference (ΔT mx =T mx −θ). The operation may further include calculating the natural logarithm of each temperature difference (In(ΔT)). The operation may further include calculating the average (μ(In(ΔT))) and standard deviation (σ(In(ΔT))) of the natural logarithm of each temperature difference (In(ΔT)). The operation may further include generating a lognormal probability density function (LNPDF) using the calculated average and standard deviation of the natural logarithm of each temperature difference. The operation may further include estimating an integral (i.e., using an iterative numerical approximation) of the lognormal probability density function. The integral may be integrated from a first limit, such as the maximum temperature limit difference, to a second limit, such as infinity, to obtain the fraction of the catalyst best greater than the maximum temperature limit:
F
(
Bed
>
T
mx
)
=
∫
Δ
T
mx
∞
LNPDF
(
Δ
T
,
μ
,
σ
)
ⅆ
Δ
t
=
∫
Δ
T
mx
∞
1
σ
2
π
ⅇ
-
(
ln
(
Δ
T
)
-
μ
)
2
2
σ
2
ⅆ
Δ
t
The controller may then compare the fraction of the bed which exceeds the specified temperature maximum to a predetermined maximum fraction. If the calculated fraction is greater than the maximum fraction, the controller may automatically take remedial action, such as reducing the flow rate of the reactant stream. Alternatively, the controller may take remedial action if the calculated fraction is proximate to or equal to the maximum fraction. Alternatively, the controller may provide indication, such as an audio and/or visual alarm, to a human operator who may then take remedial action. If the calculated fraction is less than the maximum fraction, then the process may continue unabated or the reactant stream flow rate may even be increased, especially if the calculated fraction is substantially less than the maximum fraction. The controller may repeat the operation every interval of time, such as every five seconds, one second, one-half second, one-tenth second, one-hundredth or one-thousandth second. Alternatively, the PDF may be a logarithm of any base greater than zero and not one, such as ten.
The maximum temperature limit may depend on the specific reactants and/or catalyst used in the reactor. For example, a maximum temperature limit for a maleic anhydride reactor may be from about 300 to about 550 degrees Celsius or to about 500 degrees Celsius. The maximum fraction may also depend on the specific reactants, catalyst used in the reactor, and/or the age of the catalyst. For example, in a maleic anhydride reactor using a catalyst having a lifespan of three to four years, the maximum fraction of the catalyst bed which is at or above the maximum temperature limit may range from zero to three percent during a first half of the lifespan and then be increased to three to four percent for a second half of the lifespan.
FIG. 2 illustrates a comparison between three temperature control schemes: the Prior Art hot spot scheme, an Ideal scheme, and a scheme 200 according to an embodiment of the present invention. These curves were created by a Monte Carlo simulation of a maleic anhydride reactor having 31,000 to 35,000 tubes and 108 thermocouples in the catalyst bed and having a maximum temperature limit of 500 degrees Celsius and a maximum fraction of one percent.
In the Ideal control scheme, there is no inaccuracy, such that when the true percentage of the bed greater than 500 degrees Celsius is less than one percent, the control scheme detects the acceptable condition with absolute certainty. Conversely, when the true percentage of the bed greater than 500 degrees Celsius is greater than one percent, the Ideal control scheme detects the unacceptable condition with absolute certainty. Thus the Ideal Control scheme is a step function.
Referring now to the Prior Art scheme and the Embodiment 200 , the Embodiment 200 is generally closer to the Ideal scheme than the Prior Art scheme. For example, when the true percentage of the bed greater than 500 degrees Celsius is one-half percent, the probability that the Prior Art scheme will falsely indicate that the maximum fraction has been exceeded is about 45%, as compared to 10% for the Embodiment 200 . The exception in the one to one and one-half percent range where the Prior Art scheme enjoys an advantage in accuracy as compared to the Embodiment 200 is not significant due to generosity in safety factors. The Embodiment 200 significantly reduces risk of production and sales loss which occurs when the true fraction of the bed is less than the maximum fraction but the Prior Art scheme falsely indicates otherwise. Conversely, the Embodiment 200 provides greater protection against unknowingly operating the reactor with an excessive fraction of the bed above the upper temperature limit. FIG. 2 assumes 108 thermocouples are present. As the number of thermocouples increases, the Embodiment 200 will be closer to the Ideal scheme.
FIG. 3 illustrates another comparison between the Prior Art hot spot scheme and a scheme 200 according to an embodiment of the present invention. As with FIG. 2 , these curves were created by a Monte Carlo simulation of a maleic anhydride reactor having 31,000 to 35,000 tubes and 108 thermocouples in the catalyst bed and having a maximum temperature limit of 500 degrees Celsius and a maximum fraction of one percent. The actual fraction of the catalyst bed at a temperature greater than 500 degrees Celsius was set at one-tenth percent. Each control scheme was repeated for 1,000 observations (or intervals of time). The Prior Art scheme falsely detected an unacceptable condition a total of 93 times, as compared to 2 or 3 times for the Embodiment 200 . The false detections translate to a reduction in production and sales during 9.3% of the operating time for the Prior Art scheme, as compared to two-tenths of a percent for the Embodiment 200 .
Additional advantages may be realized from one or more embodiments of the present invention. The mean or average of the lognormal distribution is a measure of the heat transfer coefficient in the reactor and may be useful in comparing heat removal performance between reactors, thereby identifying the causes of poor reactor heat transfer. The standard deviation of the lognormal distribution is a measure of tube to tube variability in a given reactor and may be useful in identifying differences between reactors with respect to tube to tube variation in reactant stream composition and flow rate. For example, one maleic reactor having an increased ratio of thermocouples required a reduction in reactant stream flow rate. The initial diagnosis of the reactor was a problem with the reactor. However, upon implementing an embodiment of the present invention, the problem was identified as an increase in false alarms due to the Prior Art scheme used with the increased ratio of thermocouples and not the reactor itself.
While the foregoing is directed to embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow. | Embodiments of the present invention generally relate to temperature control of a reactor using probability distribution of temperature measurements. In one embodiment, a method of controlling a temperature of a chemical reaction includes injecting a reactant stream into a reactor and through a catalyst bed of the reactor. The reactant stream includes a hydrocarbon and oxygen. Injection of the reactant stream into the catalyst bed causes an exothermic chemical reaction. The method further includes circulating a coolant through the reactor, thereby removing heat from the catalyst bed. The method further includes measuring temperature at a plurality of locations in the catalyst bed. The method further includes calculating a fraction of the catalyst bed greater than a predetermined maximum temperature limit using a probability distribution generated using the temperature measurements. | 1 |
REFERENCE TO RELATED APPLICATIONS
This is a continuation-in-part application claiming priority from U.S. Pat. No. 8,490,803 which issued on Jul. 23, 3013 from application Ser. No. 13/134,369 filed on Jun. 6, 2011 which is incorporated by reference in its entirety.
TECHNICAL FIELD
The present invention relates to the field of baby bottles and in particular to baby bottles including separable compartments for storage of a dry powder(powdered formula) and a liquid (water) prior to use and means releasing, combining and for mixing same.
BACKGROUND OF THE INVENTION
Powdered baby formula is mixed with water to produce a liquid formula milk replacement for consumption by infants. The dry powdered formula may be stored for long periods of time without refrigeration. However, once the powdered formula is mixed with water, the liquid formula must either be used or refrigerated within a short period of time. Otherwise the liquid formula spoils.
Powdered baby formula and water are typically mixed by combining predetermined amounts of powdered formula and water in the bottle, attaching the nipple and lid, and shaking the baby bottle to thoroughly mix the powder with the water. This mixing process may be safely and accurately performed with the aid of suitable measuring devices and substantially sterile surroundings. In addition, the mixed liquid formula and bottle may be stored and refrigerated for later use.
However, where refrigeration is unavailable, it is necessary to perform the mixing process just before use. If proper measuring devices and substantially sterile surroundings are unavailable, the process becomes problematic because contamination, spillage and the production of incorrectly mixed formula can occur. When traveling, it is inconvenient to carry formula and water separately and to measure out and mix the ingredients every time formula is needed for a baby.
DESCRIPTION OF THE RELATED ART
U.S. Pat. No. 5,275,298 by Holley, Jr. teaches a multi-component bottle with a mixing valve including a ball valve body which is rotated to align two sets of apertures to release the powdered formula into the lower water compartment for mixing. Holley stores the powdered formula within the hollow ball portion of the ball valve. Holley requires the alignment of two pairs of apertures and uses a complex ball valve with a cam arrangement for opening and closing the valve, unlike the present invention which only requires alignment of an aperture of a rotatable disk and a fixed disk.
U.S. Pat. No. 5,794,802 by Caola teaches a multi-component bottle with a push rod under the nipple which is used to force open a valve member. Caola's valve doesn't involve the alignment of two apertures or the same type of sliding element for opening as is used in the present invention.
U.S. Pat. No. 6,045,254 by Inbar et al teaches a movable plug in a necked down portion of the bottle to separate the powder from the water. Turning a top portion of the bottle raises the plug and allows the powder to fall into the liquid
U.S. Pat. No. 5,419,445 by Kaesemeyer has a sealing member between upper and lower compartments which is dislodged by twisting a lid portion on the top of the bottle. The sealing member falls to the bottom of the container. A user can't easily see when the sealing member is dislodged.
SUMMARY OF THE INVENTION
The present invention provides a baby bottle including a nipple and separable compartments for holding powdered formula and water. By sliding or rotating a knob to a pre-selected mix position, apertures in the separable compartments are aligned thereby allowing mixture of the powdered formula from an upper compartment into a lower compartment containing the water. The bottle is shaken to thoroughly mix the formula and the water, after which, the bottle and formula mix are ready to use.
More particularly, with the present invention, there is provided a combination baby bottle and powdered formula and water storage device comprising a lid with a nipple, a two part mixing valve and a water compartment. The lid is a cylindrically shaped lid including a top wall, a first sidewall, and a nipple. The first sidewall contains first female threads. The top wall has a circular aperture formed therein sized to receive the nipple and the bottom surface of the top wall abuts a top surface of the outer marginal portion of the nipple. The first part of the two part valve is a cylindrically shaped stationary valve member includes a second sidewall with first male threads at a top edge. The first male threads are capable of being threaded into the first female threads to connect the lid to the stationary valve member. The stationary valve member includes a first circular bottom wall having a first aperture formed therein. The first aperture is sized to fit within a one third circular sector of the first bottom wall and is located so as not to include the center point of the first bottom wall. The second sidewall extends below the first bottom wall and includes second female threads. The second sidewall has a slot formed therein, the slot is above and parallel to the second bottom wall and extends around one third of the circumference of the second sidewall. The second part of the two part valve is a cylindrically shaped movable valve member having a third sidewall and a second bottom wall. The third sidewall has a first circumferential groove formed within the outside surface thereof which is located near a top edge. The third sidewall has a second circumferential groove formed within the outside surface and is located near the bottom edge. The first and the second grooves each have an polymeric or elastomeric sealing means such as an O-ring, washer, or disc disposed therein. The movable valve member is capable of being inserted within the stationary valve member whereupon the first bottom wall abuts the second bottom wall and the O-rings form a leak-proof seal between the second sidewall and the third sidewall. The slot is therefore situated between the O-rings and is sealed from leaking. The third sidewall has a rectangular window formed therein and located between the first groove and the second groove. The window contains a vertical axle with a lever pivoting thereon. The back side of the window is sealed off with a box which is integral with the third sidewall. The lever is capable of being fully contained within the window and the box and is capable of being pivoted out through the slot to a position where a user can push the lever to spin the movable valve member within the stationary valve member. The second circular bottom wall has a second aperture which is sized to fit within a one third circular sector of the second bottom wall. The second aperture is the same size as the first aperture and is located so as not to include the center point of the second bottom wall. The first aperture and the second aperture are totally mis-aligned when the lever is at a first end of the slot, thus keeping the formula powder separate from the water. The first aperture and the second aperture are totally aligned when the lever is at a second end of the slot. The cylindrically shaped water compartment includes a bottom wall and a fourth sidewall with second male threads at a top edge which are capable of being threaded into the second female threads to connect the stationary valve member to the water compartment.
More particularly, the baby bottle mixing device for mixing a liquid and powder, comprises, essentially of and/or consists of a cylindrically shaped lid including a top wall, a first sidewall, a first sidewall containing a first set of threads. The top wall has a circular aperture formed therein sized to receive said nipple. A cylindrical stationary valve member including a second sidewall with a first set of threads at a top edge, said first set of threads cooperatively engaging a second set of threads connecting said lid to said stationary valve member, a first circular bottom wall having a first aperture formed therein, said first aperture being sized to fit within a one third circular sector of said first bottom wall, said first aperture disposed between a side edge and a center point of said first bottom wall, said second sidewall extending below said first bottom wall and including third set of threads, said second sidewall having a slot formed therein, said slot disposed above and parallel to said second bottom wall, said slot extending around one third of a circumference of said second sidewall. A cylindrical shaped movable valve member includes a third sidewall and a second bottom wall, said third sidewall having a first circumferential groove formed within an outside surface thereof and located near a top edge thereof, said third sidewall having a second circumferential groove formed within an outside surface thereof and located near a bottom edge thereof, said first and said second grooves each including sealing means disposed therein, said movable valve member insertable within said stationary valve member whereupon said first bottom wall abuts said second bottom wall and said sealing means forming a leak-proof seal between said second sidewall and said third sidewall, said slot being situated between said grooves. The third sidewall has a rectangular window formed therein and located between said first groove and said second groove, said window containing a vertical axle with a lever pivoting thereon and said box and capable of being pivoted out through said slot to a position where a user can push said lever to spin said movable valve member within said stationary valve member, said second circular bottom wall having a second aperture formed therein, said second aperture sized to fit within a one third circular sector of said second bottom wall, said second aperture is of the same size as said first aperture, said second aperture extending from a side edge and a center point of said second bottom wall. The first aperture and said second aperture being misaligned when said lever is at a first end of said slot in an open position and said first aperture and said second aperture being aligned when said lever is at a second end of said slot in a closed position.
It is an object of the present invention to provide a pair of apertures contained in a rotatable disk and a fixed disk alignable whereby visible movement and positioning of same is clearly visible upon movement of an adjustment means such as a tab or knob located on the outside of the container.
It is an object of this invention to provide a baby bottle and storage device which separately stores dry formula and water for subsequent mixing and feeding.
It is an object of this invention to provide a baby bottle and storage device which provides any easy to use formula and water mixing valve.
It is an object of the baby bottle mixing device to include sealing means selected from the group consisting of an o-ring, a circumferential band, an elastomeric strip and combinations thereof.
It is an object of this invention to provide a baby bottle and storage device which provides a convenient and easily recognizable indication as to whether the mixing valve is open or closed.
It is an object of this invention to provide a baby bottle and storage device which is easily disassembled for cleaning.
An alternate embodiment of the present invention comprises, consists essentially of and/or consists of a baby bottle mixing device having the baby bottle with the mixing device threadably connecting thereto with a cylindrically shaped lid threadably engaging threads on top of the mixing device removably holding an elastomeric nipple onto the mixing device, and showing an optional nipple cover comprising a plastic dome secured to the lid by friction fit. The mixing device includes a cylindrical stationary valve member cap having a threaded cylindrical top for engaging a lid and an o-ring disposed therebetween, a tab or lever for rotating the movable valve member having an aperture therein of a selected size and shape inserted within the cap with an o-ring therebetween, a base member including an aperture of selected size and shape formed in a flat plate or panel in rotational sealable communication with the movable valve member including an o-ring therebetween, and an o-ring for insertion between the bottom surface of the base member and the top edge of a bottle.
Other objects, features, and advantages of the invention will be apparent with the following detailed description taken in conjunction with the accompanying drawings showing a preferred embodiment of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
A better understanding of the present invention will be had upon reference to the following description in conjunction with the accompanying drawings in which like numerals refer to like parts throughout the views wherein:
FIG. 1 is a front perspective view of the baby bottle.
FIG. 2 is a perspective view of a lid with a nipple installed.
FIG. 3 is a perspective view of the movable portion of the mixing valve.
FIG. 4 is a perspective view of the stationary portion of the mixing valve.
FIG. 5 is a perspective view of the water compartment.
FIG. 6 is a top view of the stationary portion of the mixing valve.
FIG. 7 is a top view of the movable portion of the mixing valve.
FIG. 8 is a perspective view of the stationary portion of the mixing valve showing the opening lever extended and ready for use.
FIG. 9 is a close up view of the opening lever on the movable portion of the mixing valve shown in FIG. 3 .
FIG. 10 is a top view of movable valve member 14 inside stationary valve member 24 with the apertures 36 and 37 mis-aligned.
FIG. 11 is a top view of movable valve member 14 inside stationary valve member 24 with the apertures 36 and 37 almost completely aligned.
FIG. 12 is a perspective view of an alternate embodiment of the baby bottle mixing device showing the baby bottle with the mixing device threadably connecting thereto with a cylindrically shaped lid threadably engaging threads on top of the mixing device removably holding an elastomeric nipple onto the mixing device, and showing an optional nipple cover comprising a plastic dome secured to the lid by friction fit.
FIG. 13 is a perspective view of the mixing device of FIG. 12 which is threadably connected to a conventional baby bottle.
FIG. 14 is an exploded view of the mixing device of FIGS. 13 showing the cylindrical stationary valve member cap having a threaded cylindrical top for engaging a lid and an o-ring disposed therebetween, a tab or lever for rotating the movable valve member having an aperture therein of a selected size and shape inserted within the cap with an o-ring therebetween, a base member including an aperture of selected size and shape formed in a flat plate or panel in rotational sealable communication with the movable valve member including an o-ring therebetween, and an o-ring for insertion between the bottom surface of the base member and the top edge of a bottle.
FIG. 15 is a sectional view of the mixing device of FIG. 14 showing placement of the o-rings, and positioning of the lever and movable valve member therein.
FIG. 16 is a bottom perspective view of the mixing device showing the lever and movable valve member rotated with respect to the base member showing the opening formed by the offset apertures.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIG. 1 shows a baby bottle 8 including a lid 10 with a nipple 12 , a stationary mixing valve member 24 with a slot 26 and a mixing lever 15 , and a water compartment 35 . FIGS. 2-5 show the individual components. Lid 10 , stationary mixing valve member 24 and water compartment 35 are cylindrical in shape.
FIG. 3 shows the movable mixing valve member 14 which is inserted into the top opening 21 of stationary mixing valve member 24 in preparation for use. Movable valve member 14 has an outer diameter which is slightly less than the inner diameter of opening 21 of stationary valve member 24 and includes sealing means comprising circumferential bands or most preferably O-rings 16 and 20 trapped within circular grooves surrounding the outside of the sidewall of movable valve member 14 . O-rings 16 and 20 provide a seal as movable valve member 14 is pressed down into stationary valve member 24 . As shown in FIG. 9 , lever 15 pivots on axle 17 in the side wall of movable mixing valve member 14 . Leak proof storage housing or box 13 is an integral part of the sidewall of movable valve member 14 and contains lever 15 and axle 17 so that powder stored within movable valve member 14 or liquid which is released into movable valve member 14 will not escape through window 19 in the outer sidewall of movable valve member 14 . Lever 15 must be able to rotate out of the way into the storage position as shown in FIG. 9 while inserting movable valve member 14 into stationary valve member 24
When inserting movable valve member 14 into stationary valve member 24 , bottom wall 11 of movable mixing valve member 14 is pressed down and seated against the bottom wall 23 of stationary valve member 24 . Bottom wall 23 has a crescent shaped aperture 36 . FIG. 8 shows bottom wall 23 and crescent aperture 36 in phantom lines. Bottom wall 11 of movable valve member 14 has a crescent shaped aperture 37 . Once movable valve member 14 is placed inside stationary valve member 24 , lever 15 may be swung out to a usable position as shown in FIG. 1 .
Lower portion 25 of stationary valve member 24 extends below bottom wall 23 and contains internal female threads (not shown) which are threaded onto male threads 32 to connect stationary valve member 24 to water compartment member 35 .
Lid 10 includes female threads (not shown) which are threaded onto male threads 22 of stationary mixing valve member 24 , shown in FIG. 4 . Lid 10 also includes a top wall 9 containing an aperture through which is inserted a nipple 12 . The outer marginal edge of nipple 12 is compressed securely between top wall 9 of lid 10 and the upper edge of stationary valve member 24 to form a leak proof fit. Water compartment member 35 includes sidewall 34 , male threads 32 and a bottom wall (not shown). It is understood that when the baby bottle is fully assembled, the threads connecting lid 10 , stationary valve member 24 and water compartment 35 form a water tight seal so that baby bottle 8 does not leak during use.
To use the bottle, a user first puts lever 15 in the storage position as shown in FIG. 9 . Then the user puts inserts valve member 14 down into stationary valve member 24 so that bottom wall 11 of movable mixing valve member 14 is pressed down and seated against the bottom wall 23 of stationary valve member 24 . Once movable valve member 14 is placed inside stationary valve member 24 , lever 15 is swung out to a usable position as shown in FIG. 1 . (With lever 15 in this position, apertures 36 and 37 are totally mis-aligned so that the powdered formula is prevented from dropping into water compartment 35 .) Next the user puts a selected amount of water in water compartment 35 . Then the user threads stationary valve member 24 onto water compartment 35 tightly. Then a selected amount of powdered formula is put into the stationary valve member 24 . Finally, lid member 10 (including nipple 12 ) is threaded tightly onto male threads 22 of stationary valve member 24 .
In the travel or storage mode, as shown in FIG. 10 , movable valve member 14 is positioned within stationary valve member 24 such that the apertures 36 and 37 are totally mis-aligned. FIG. 11 shows lever 15 and movable valve member 14 have been moved almost all the way to a position where apertures 36 and 37 are aligned and there is just a small part 38 of aperture 37 which is still covered. When a user wants to mix the water and powdered formula, lever 15 is moved all the way to the left end of slot 26 . This causes apertures 36 and 37 to become aligned and the formula will fall into the water. However, it can be seen that even if the apertures are only partially aligned, mixing of the water and powdered formula will still occur. Now the baby bottle is shaken and is ready to use. It is understood that apertures of other shapes such as round, square, triangular can be used instead of crescent and the selected shape is a matter of choice. In one preferred embodiment, the apertures in the valve members are sized to fit within a one third circular sector, that is, a circular sector of 120°, or less so that the movable valve must not be moved an excessive amount to align the apertures. Further, slot 26 would only extend one third of the way around the stationary valve member 24 .
Another preferred embodiment of the present invention is shown in FIGS. 12-16 .
The baby bottle mixing device is threadably connecting to the top of a baby bottle with a cylindrically shaped lid threadably engaging threads on top of the mixing device removably holding an elastomeric nipple having a flat lid onto the mixing device between the underside surface of the lid and the top edge of the mixing cap.
The cylindrical stationary valve member cap is generally conical in shape and includes a threaded cylindrical top side wall and smooth top edge for engaging the bottom surface of the lid and threadably engaging the interior threads of the lid to form a liquid tight seal therebetween. An o-ring may be disposed therebetween however the lid and/or top of the mixing chamber may be composed of a soft flexible material such as silicon so that a liquid tight seal may be obtained without the o-ring, or have an o-ring integrally formed therein. A tab or lever for rotating the movable valve member having an aperture therein of a selected size and shape is inserted within a rectangular opening formed in the cap for limited sideways motion. The lever cooperatively engages the cylindrical stationary valve member which is attached to the interior of the cap via a friction fit or threadable arrangement to form a liquid seal therewith. As shown in FIG. 15 , an o-ring is used to provide a seal; however the lid and/or top of the mixing chamber may be composed of a soft flexible material such as silicon so that a liquid tight seal may be obtained without the o-ring, or have an o-ring integrally formed therein.
The top of a base member including an aperture of selected size and shape comprises a flat plate or panel which abuts the cylindrical stationary valve member in rotational sealable communication with the movable valve member. An o-ring is disposed thereinbetween to provide a fluid tight seal. The cylindrical stationary valve member are sealed with o-ring for insertion between the bottom surface of the base member and the top edge of a bottle. In lieu of the o-ring, all of or a portion of the base member and/or stationary valve member may be composed of a soft flexible material such as silicon and formed so that a liquid tight seal may be obtained without the o-ring, or have an o-ring integrally formed therein. As shown in FIG. 15 , the cylindrical stationary valve member is held in the interior portion of the cap which includes threads on the interior bottom sidewall for cooperatively engaging threads formed on the top portion of the base member to secure the cylindrical stationary valve member in between and form a liquid tight seal. The entire unit can then be threadably connected to the top of a bottle.
The foregoing detailed description is given primarily for clearness of understanding and no unnecessary limitations are to be understood therefrom, for modification will become obvious to those skilled in the art upon reading this disclosure and may be made upon departing from the spirit of the invention and scope of the appended claims. Accordingly, this invention is not intended to be limited by the specific exemplification presented herein above. Rather, what is intended to be covered is within the spirit and scope of the appended claims. | A baby bottle including a nipple and separable compartments for holding powdered formula and water. By sliding or rotating a knob to a pre-selected mix position, apertures in the separable compartments are aligned thereby allowing mixture of the powdered formula from an upper compartment into a lower compartment containing the water. The bottle is shaken to thoroughly mix the formula and the water, after which, the bottle and formula mix are ready to use. | 0 |
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a national stage filing under 35 U.S.C. 371 of PCT/US2007/068573, filed May 9, 2007, which claims priority to Japanese Patent Application No. 2006-131247, filed May 10, 2006, the disclosure of which is incorporated by reference in its/their entirety herein.
FIELD OF THE INVENTION
The present invention relates to a method and a device for replicating structure, and more particularly to a method and a device for continuously replicating structure.
BACKGROUND
Three dimensional structures are widely used as constitutional elements for structured coated abrasive materials, retro-reflective materials, Fresnel lenses, mechanical fasteners, and the like. Three dimensional structures having fine cube-corners, trigonals, pyramids, stripes sequentially formed on a plane surface, are the examples thereof. Industrially, such structures are formed by casting a resin into a mold with a reversed shape of a three dimensional structure to replicate it.
Japanese Patent Kohyo Publication No. H8-505572, Japanese Patent Kohyo Publication No. H9-502665 and Japanese Patent Kokai Publication No. 2003-236434 and the like describe methods and devices for continuously replicating a three dimensional structure by using a film-form production tool with a reversed shape of the structure which is an object to be replicated, on a surface. According to these methods, basically, a composition comprising a solidifiable resin is coated on a reversed shape of structure on a film-form production tool while it is being sent, a substrate is laminated thereon, the composition is solidified, and then the film-form production tool is removed from the cured resin.
The conventional methods for replicating structure are effective when compositions, objects to be molded, have a relatively low viscosity. When a high viscosity resin or composition is simply coated on a surface of a shape on a film-form production tool, however, it can be difficult for the resin or composition to penetrate into the inside of the shape, and moreover, air inclusion occurs, whereby it is hard to replicate the structure accurately.
On the other hand, decompression die coaters have hitherto been known. For example, Japanese Patent Kokai Publication No. 2003-236434 describes that in order to prevent coating unevenness, a coating film is formed on a substrate by using decompression die coater part. FIG. 1 of the publication 3 shows an embodiment wherein a coating film 14 b is formed on a web 12 by using a slot die 13 with an discharge outlet 16 a for a coating liquid 14. FIG. 1 does not clearly depict, but a blank space under the slot die 13 shows a decompression chamber.
According to this coating embodiment, the web 12, which is an article to be coated, is wound around a backup roll 11. This structure does not allow the web 12 to move toward the backup roll 11, thereby necessarily forming a space between the surface to be coated of the web 12 and the discharge outlet, by the thickness of the coating film. In other words, the surface to be coated of the web does not contact to a surface 18 a of the discharge outlet of the slot die 13. Consequently, the conventional decompression die coater part must have such structure that coating liquid flows back toward the decompression chamber.
As a result, the conventional decompression die coater part cannot sufficiently enhance decompression degree of the decompression chamber, and it can be difficult to effectively impregnate high viscosity resin compositions into the inside of structure in a production tooling, even if they are used as coating means.
SUMMARY OF THE INVENTION
The present invention intends to solve the above-mentioned disadvantages, and the object thereof is to provide a method and device for accurately replicating structure.
Means for Solving the Problems
In one embodiment, the present invention provides a method for replicating structure comprising the steps of:
providing a film-form production tool having a front surface and a back surface, with a reversed shape of structure which is an object to be replicated, on the front surface;
applying decompression to the front surface of the film-form production tool;
sealing the reversed shape to keep decompression degree applied;
filling a composition which is an object to be molded, with applying sufficient fluid pressure, in the reversed shape; and
solidifying the object composition and transferring it on a substrate.
In another embodiment, the present invention provides a device for replicating structure comprising:
a decompression die coater part having a decompression opening, a plane face for supporting a film-form production tool, an outlet for discharging a composition which is an object to be molded, and a die coating surface, in sequential manner;
a film-form production tool having a front surface and a back surface, with a reversed shape of structure which is an object to be replicated, on the front surface, and placed so that the front surface faces the die coater part, wherein the front surface,
covers the decompression opening,
substantially contacts the face for supporting a film-form production tool,
covers the discharge outlet and the die coating surface, and keeps approximately certain distance over the die coating surface;
means for supporting the back surface of the film-form production tool at the position corresponding to the discharge outlet or the die coating surface;
means for moving the film-form production tool in the direction of from the decompression opening to the discharge outlet of the decompression die coater part; and
means for solidifying the composition which is the object to be molded, filled in the reversed shape, and transferring it on a substrate.
According to the method and device of the present invention, a high decompression degree is kept until inside of a reversed shape of structure on a film-form production tool is filled with a composition which is an object to be molded. A liquid pressure of a composition which is an object to be molded, is also sufficiently applied to the reversed shape of the structure. As a result, the composition which is the object to be molded, can completely penetrate into inside of the structure of the reversed shape in every corner, thus resulting in the accurate replication of the structure.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a cross-sectional view showing schematically structure of a device for replicating structure which was one embodiment of the present invention.
FIG. 2 is a plane view showing a positional relationship between a film-form production tool 2 and decompression die coater part 1 when they contact each other so as to keep a sealing state of a reversed shape.
FIG. 3 is an enlarged partial view showing illustratively an appearance of the structure replicated by using the method and the device of the present invention.
DETAILED DESCRIPTION
FIG. 1 is a cross-sectional view showing schematically structure of a device for replicating structure which is one embodiment of the present invention. The device comprises a decompression die coater part 1 , a film-form production tool 2 , and a backup roll 3 . The decompression die coater part 1 comprises a decompression opening 4 , a face for supporting a film-form production tool 5 , outlet for discharging a composition which is an object to be molded 6 , and a die coating surface 9 , in sequential manner. The wording “in sequential manner” used herein means that the face for supporting a film-form production tool 5 exists between the decompression opening 4 and the discharge outlet 6 , and the discharge outlet 6 exists between the film-form production tool 5 and the die coating surface 9 .
The film-form production tool 2 is a film with a reversed shape of structure which is an object to be replicated on its front surface. The structure, the object to be replicated, for example microstructure preferably is constituted of separated plural projections. The projections may have the base-face shape of dot form or rod form. The projections typically have the side-face shape with a top part that is not wider than its bottom part, because when the top part of the shape is wider than the bottom part, it can be difficult to remove the molding. Examples of the shape with a top part not wider than the bottom part are cubes, cylinders, rectangular columns, circular cones, circular truncated cones, triangular pyramids, quadrangular pyramids, pyramids, pyramids such as cube corners, truncated pyramids, and the like.
In the structure, the shape of the projections may be the same as or different from each other. The projections may also be arranged regularly or irregularly.
The projection with such a geometric shape has a diameter or a length of the base face of about 5 to 50000 μm, preferably 10 to 10000 μm, more preferably 20 to 5000 μm. The height of the projections is about 2 to μm, preferably 5 to 5000 μm, more preferably 10 to 2000 μm. The density of the projections is about 0.04 to ten million projections per cm 2 , preferably 1 to two million projections per cm 2 , more preferably 4 to five hundred thousand projections per cm 2 .
The film-form production tool may be prepared from thermoplastic resins, thermosetting resins, or photocurable resins. Examples of the thermoplastic resin from which the film-form production tool is prepared include polyesters, polycarbonates, poly(ethersulfones), poly(methyl methacrylate), polyurethanes, polyvinyl chloride, polyolefins, polystyrene, and the mixtures thereof. These materials may substantially be transparent to UV rays and visible light.
The thermoplastic resin is embossed with a tool with a basic pattern to form a structure with a reversed shape, which is an object to be replicated. Embossing is performed while the thermoplastic resin has flowability. After the embossing is finished, the thermoplastic resin is cooled to solidify. The tool with a pattern for use in embossing is made of a metal such as nickel, and the same structure as that of the object to be replicated is previously formed on its surface.
Examples of the thermosetting resin from which the film-form production tool is prepared include silicone resins, fluorocarbon resins, and the like. Examples of the photocurable resin from which the film-form production tool is prepared include acrylate urethane oligomers, and the like.
When the film-form production tool is prepared from the thermosetting resin, first, a thermosetting resin, which is not cured yet, is coated on a tool with a basic pattern. Then, the resin is solidified by curing or polymerizing with heat so as to have a reversed shape to the basic pattern of the tool. Finally, the cured resin is removed from the tool with the basic pattern. When the film-form production tool is prepared from the photocurable resin, it is prepared in the same manner as in the preparation of the production tooling from the thermosetting resin except that the resin is cured by radiating radial rays such as UV rays. Commercially available production film-form production tools may be used.
Furthermore, the structure with the reversed shape of the production tooling may have a releasing coating film on its surface, whereby the film-form production tool can be easily released from the molded article. Examples of the releasing coating film include films prepared from silicones and fluorochemicals.
The reversed shape formed on the film-form production tool preferably comprises a plurality of separated depressions or cavities. An opening of the depression has a regular or irregular shape such as rectangle, semicircle, circle, triangle, square, hexagon and octagon. A wall of the depression may be straight or chamfered. The configuration of the depressions may be regular or irregular. The edge around the depression may have contact with an adjacent edge. The depressions may be long gutter form.
The film-form production tool 2 is placed so that the front surface with the reversed shape of the structure which is the object to be replicated, faces decompression die coater part. The film-form production tool 2 is also placed so that said surface covers the decompression opening 4 , substantially contacts the face for supporting the film-form production tool 5 , and covers the discharge outlet for the composition which is the object to be molded 6 and the die coating surface 9 .
The surface of the film-form production tool 2 substantially contacts the face for supporting the film-form production tool 5 ″ means that the reversed shape of the structure on the surface of the film-form production tool 2 , such as each depression, can keep decompression degree applied from a decompression opening 4 until it reaches the discharge outlet 6 . For example, as shown in FIG. 1 , if the surfaces of the face for supporting a film-form production tool 5 and the film-form production tool 2 mate as plains, then the area around the opening of the depression contact the face for supporting a film-form production tool 5 without any space between them when they contact each other. As a result, the depression is sealed, whereby decompression degree applied from a decompression opening 4 is able to be kept until it reaches the discharge outlet 6 .
The die coating surface 9 is a continuous surface extended from the discharge outlet toward the direction opposite to the face for supporting a film-form production tool 5 . The die coating surface 9 may be flat or curved. The front surface of the film-form production tool keeps approximately certain distance over the die coating surface through the composition which is the object to be molded. That is the film-form production tool is placed so that the front surface wraps the die coating surface 9 .
A backup roll 3 is provided at the position corresponding to the die coating surface 9 of the decompression die coater part, in order to support the film-form production tool from the back surface. The position of the backup roll 3 may be at the vicinity of the discharge outlet 6 or at some distance from the discharge outlet 6 . The surface of the backup roll 3 is preferably made of a material having rubber elasticity. The backup roll preferably has a rubber hardness of 60 to 90 degrees.
By placing the film-form production tool so that the front surface wraps the die coating surface 9 , and by pressing the backup roll 3 to the position at which the die coating surface 9 , the composition which is the object to be molded 8 and the front surface of the film-form production tool 2 coexist, a composition which is an object to be molded is filled with sufficient liquid pressure into the reversed shape of the structure which is the object to be replicated.
FIG. 2 is a plane view showing a positional relationship between the film-form production tool 2 and the decompression die coater part 1 when they contact each other so as to keep the sealing state of the reversed shape (The backup roll 3 is not shown.). The width of a decompression opening 4 is narrower than that of the film-form production tool 2 , and the width of the discharge outlet 6 for the composition which is the object to be molded, is also narrower than that of the film-form production tool 2 . As a result, both a decompression opening 4 and the discharge outlet 6 are covered with the film-form production tool 2 .
If necessary for ensuring a route for the film-form production tool 2 , guide rolls 7 and 7 ′, and the like, may be used. Also, as means for moving the film-form production tool 2 in the direction of the discharge outlet from a decompression opening, and means for solidifying the composition which is the object to be molded, filled in the reversed shape of the structure on a substrate and transferring it, conventionally known methods may be used.
According to the method for replicating structure of the present invention, while the film-form production tool 2 is moved in the direction of the discharge outlet 6 from a decompression opening 4 , decompression is applied to the surface of the film-form production tool 2 from a decompression opening 4 , and the composition which is the object to be molded 8 , is extruded from the discharge outlet 6 .
A moving velocity of the film-form production tool 2 is not particularly limited, and it is usually 0.1 to 100 m/min, preferably 0.5 to 50 m/min. The moving velocity less than 0.1 m/min of the film-form production tool may cause a problem in production efficiency, and that of more than 100 m/min makes it difficult to keep decompression degree.
Decompression degree applied from a decompression opening 4 is suitably decided in the light of the size of the structure, the viscosity of the composition which is the object to be molded, and the ambient temperature, and the like. Decompression degree is usually not less than 100 mmHg, preferably not less than 300 mmHg, more preferably 500 mmHg. The decompression degree of less than 100 mmHg applied from a decompression opening 4 makes it difficult to remove the air entered into the structure.
The reversed shape of the structure on the film-form production tool 2 , which is applied decompression from a decompression opening 4 , runs to the area of the face for supporting a film-form production tool 5 , and the area around the opening contacts the face for supporting a film-form production tool 5 without any space. Then, the reversed shape runs on the face for supporting a film-form production tool 5 until it reaches the discharge outlet 6 , while the reversed shape is kept to be sealed. As a result, decompression degree applied from a decompression opening 4 to the reversed shape of the film-form production tool 2 can be kept until the shape reaches the discharge outlet 6 .
When the reversed shape on the film-form production tool 2 reaches the discharge outlet 6 , the composition which is the object to be molded 8 , is filled into the inside of the reversed shape. The composition which is the object to be molded 8 , is not particularly limited so long as it has flowability and is capable of solidifying. Such a substance usually includes composition containing resins capable of solidifying. The resins capable of solidifying may include thermoplastic resins, thermosetting resins and photocurable resins. The resins are solidified with a method of drying and removing solvents, a method of curing the resins with heat or light reaction, a method of setting the molten resins with cooling, or the like.
Examples of the composition which is the object to be molded, include abrasive slurry, which is a raw material for structured coated abrasive materials, resin compositions, which are raw materials for retro-reflective materials, Fresnel lenses, mechanical fasteners, and the like.
The composition which is the object to be molded, may have a high viscosity. For example, if the composition which is the object to be molded, has a viscosity of up to about hundred thousands cps at a coating temperature, structures can be replicated by the method and the device of the present invention. In other words, the method and the device of the present invention, is able to mold finely a wide variety of resins of from 1 cps to 100,000 cps, and is able to mold resins having a higher viscosity than those used in the conventional methods. Increasing the molecular weight of a resin to be molded is effective for preventing shrinkage or deformation of molded articles.
The extrusion velocity of the composition which is the object to be molded 8 , is suitably controlled so that the reversed shape on film-form production tool 2 is at least filled with the composition.
Then, the above-mentioned composition filled in the reversed shape on the film-form production tool 2 is solidified and transferred on a substrate. As means for solidifying and transferring the composition which is the object to be molded, any conventional methods such as described in Japanese Patent Kohyo Publication No. H8-505572 and Japanese Patent Kohyo Publication No. H9-502665 may be used.
For example, a substrate is laminated on the above-mentioned composition filled in the reversed shape on the film-form production tool 2 , and the composition is solidified by cooling, heating or light-radiating the obtained laminate, and then the film-form production tool 2 is removed from the solidified, molded article. Sheets may usually be used as the substrate, and it may be suitably decided depending on the use.
The present invention will be described in more detail by means of non-limiting Examples. In Examples, all parts, percentages and ratios are by weight unless otherwise noted.
EXAMPLES
Example 1
A resin composition capable of solidifying was prepared by mixing components shown in Table 1.
TABLE 1
Amount
Component
(%)
Tris(acryloxyethyl) isocyanurate (“ARONIX M-315” made by
38.31
Toa Gosei K.K.)
Trimethylolpropane triacrylate (“KS-TMPTA” made by Nippon
57.47
Kayaku K.K.)
Photopolymerization initiator (“Irgacure 369” made by Ciba
0.96
Specialty Chemicals Corp.)
Silane coupling agent (“KBM 503” made by Shin-etsu Kagaku
3.26
Kogyo K.K.)
Total
100
A composition which was an object to be molded, was prepared by mixing components shown in Table 2. The viscosity of the composition was determined, and was found about 50,000 cps at the ambient temperature.
TABLE 2
Component
Amount (part)
Talc (“SG-200” made by Nippon Talc K.K.)
50
The resin composition capable of solidifying
100
Total
150
Various kinds of polypropylene film-form production tool (made by 3M Company) was provided. The reversed shape on the film-form production tool was constituted with separated pyramid-shaped depressions. The depressions were regularly arranged so that the edge around the opening (square) of the depression contacted the adjacent one. One side of the opening was 150 to 700 μm, and the depth of the depression was 360 μm.
The composition which was the object to be molded, was coated on the film-form production tool by using a device having structure shown in FIG. 1 . Decompression degree of the device was adjusted to 720 mmHg when the coating was performed. An easily adhesion-treated polyester film of a thickness 125 μm was laminated on the composition. A UV ray was irradiated to the laminate to cure the composition, and then the film-form production tool was removed.
FIG. 3 is an enlarged partial view showing illustratively an appearance of the structure replicated by using the method and the device of the present invention. A plurality of pyramidal shaped composite materials 12 is formed on the upper surface of polyester film 11 . The composite materials 12 have a plurality of talc particles 13 dispersed in the binder 14 .
The process or the device of the present invention brought not less than 95% of packing in depressions of the film-form production tool even when the composition which was an object to be molded had relatively high viscosity. As a result, the microstructure to be replicated, even when it was pyramidal shape, was precisely reproduced up to its apex.
Comparative Example
Components shown in Table 3 were mixed to give a resin composition capable of solidifying.
TABLE 3
Amount
Component
(%)
Tris(acryloxyethyl) isocyanurate (“ARONIX M-315” made by
29.71
Toa Gosei K.K.)
Trimethylolpropane triacrylate (“KS-TMPTA” made by Nippon
169.31
Kayaku K.K.)
Photopolymerization initiator (“Irgacure 369” made by Ciba
0.96
Specialty Chemicals Corp.)
Total
100
Components shown in Table 4 were mixed to prepare a composition, an object to be molded. The viscosity of the composition was determined, and was found about 30,000 cps at the ambient temperature.
TABLE 4
Component
Amount (part)
Aluminium oxide (“WA 4000” made by Fujimi Inc.)
100
The resin composition capable of solidifying
62.2
Total
162.2
The same film-form production tool as used in Example 1 was wound around a backup roll so that the reversed shape side of the film was set outwardly. The composition which was the object to be molded, was coated on the film-form production tool by using decompression die coater part in accordance with the conventional embodiment shown in FIG. 1 of Japanese Patent Kokai Publication No. 2003-236434. Decompression degree of the device was adjusted to 711 mmHg when coating was performed. An easily adhesion treated polyester film of a thickness 125 μm was laminated on the composition. A UV ray was irradiated to the laminate to cure the composition, and then the film-form production tool was removed.
A conventional process or device brought about 70% of packing in depressions of the film-form production tool when the composition which was an object to be molded had relatively high viscosity. So when the microstructure to be replicated was, for example, pyramidal shape, air easily was taken in at the apex parts of the pyramid, and some pyramidal shapes had not been precisely reproduced at their apex parts. | To provide a method and a device for replicating structure which was capable of accurately replicating structure, even if a composition which was an object to be molded, has a relatively high viscosity. [Means for Solving] A method for replicating structure comprising the steps of: providing a film-form production tool having a front surface and a back surface, with a reversed shape of structure which is an object to be replicated, on the front surface; applying decompression to the front surface of the film-form production tool; sealing the reversed shape to keep decompression degree applied; filling a composition which is an object to be molded, with applying sufficient fluid pressure, in the reversed shape; and solidifying the object composition and transferring it on a substrate. | 1 |
FIELD OF THE INVENTION
The present invention relates to amino acid (statine) analogs that display selective inhibitory activity against plasmepsin and cathepsin D.
BACKGROUND OF THE INVENTION
Resistance to known antimalarial therapies is becoming an increasing problem and new therapies are therefore desperately needed. Upon infecting a host, the malaria parasite avidly consumes the host hemoglobin as its source of nutrients. Plasmepsin I and II are proteases from Plasmodium falciparum that are necessary during the initial stages of hemoglobin hydrolysis and digestion, which primarily occurs in the α-chain, between Phe 33 and Leu 34, although other sites may serve as substrates for hydrolysis as well. It has been shown in cultures inhibition of plasmepsin by a peptidomimetic inhibitor is effective in preventing malarial hemoglobin degradation and in killing the parasite (Francis, S. E., Gluzman, I. Y. Oksman, A., Knickerbocker, A., Mueller, Bryant, M. L., Sherman, D. R., Russell, D. G., and Goldberg, D. E. (1994) EMBO J, 13, 306-317). Thus, persons of skill in the art expect that plasmepsin inhibitors will provide effective antimalarial therapy.
Cathepsin D is a human protease in the endosomal-lysosomal pathway, involved in lysosomal biogenesis and protein targeting, and may also be involved in antigen processing and presentation of peptide fragments. The protease therefore displays broad substrate specificity but prefers hydrophobic residues on either side of the scissile bond.
Cathepsin D has been implicated in a variety of diseases, including corrective tissue disease, muscular dystrophy, and breast cancer. Most recently, cathepsin D is believed to be γ-secretase, the protease which processes the β-amyloid precursor protein to generate the C-terminus of β-amyloid (Dreyer, R. N., Bausch, K. M., Fracasso, P., Hammond, L. J., Wunderlich, D., Wirak, D. O., Davis, G., Brini, C. M., Bucholz, T. M., Konig, G., Kamark, M. E., and Tamburini, P. P. (1994) Eur. J. Biochem., 224, 265-271 and Ladror, U. S., Synder, S. W., Wang, G. T., Holzman, and Krafft, G. A. (1994) J. Biol. Chem., 269, 18422-18428), which is the major component of plaque in the brains of Alzheimer's patients. Consequently, persons of skill in the art expect that inhibitors of cathepsin D will be useful in treating Alzheimer's disease.
The present invention relates to amino acid (statine) analogs and their inhibitory action against aspartyl proteases, and more particularly, the invention relates to the identification of amino acid analogs that display selective inhibitory activity against plasmepsin and cathepsin D. Although statine-containing peptides are known which inhibit aspartyl proteases (Shewale, J. G.; Takahashi, R.; Tang, J., Aspartic Proteinases and Their Inhibitors, Kostka, V., Ed. Wlater de Gruyter: Berlin (1986) pp 101-116), there are only a few selective inhibitors for cathepsin D (Lin, T. Y.; Williams, H. R., Inhibition of Cathepsin D by Synthetic Oligopeptides, J. Biol. Chem. (1979), 254, 11875-11883; Rich, D. H.; Agarwal, N. S., Inhibition of Cathepsin D by Substrate Analogues Containing Statine and by Analogues of Pepstatin, J. Med. Chem. (1986) 29 (2519-2524), and for plasmepsin (Silva, A. M. et al., Structure and Inhibition of Plasmepsin II, A Hemoglobin-Degrading Enzyme From Plasmodium falciparum, Proceed Natl Acad Sci, 1996, 93, 10034-10039). The present invention also relates to the solid phase synthesis of such amino acid analogs.
SUMMARY OF THE INVENTION
I. Preferred Embodiments
The compounds of the present invention are represented by Formula I: ##STR2## wherein: R 1 and R 3 are independently chosen from the group consisting of alky, alkoxyalkyl and arylalkyl;
R 2 is H or S--C(O)--L--
wherein:
s is a solid support; and
--L-- is a linker; and
Y is --Aa--C(O)R 4 or --C(O)R 5 ;
wherein
Aa is an amino acid attached via its carboxyl to the amine nitrogen of structure I;
R 4 is chosen from the group consisting of alkyl, aryl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl; and
R 5 is ##STR3## wherein x is 0 or 1;
R 6 and R 7 are independently chosen from the group consisting of substituted alkyl, alkylcarbonyl and substituted alkylcarbonyl; and
R 8 is alkyl.
Preferred compounds of Formula I are those wherein --L-- is of Formula (a) ##STR4## wherein the left-hand bond is the point of attachment to --C(O)-- and the right hand bond is the point of attachment to the amide nitrogen of structure I.
A preferred embodiment of the invention are compounds of Formula I
wherein:
R 1 is chosen from the group consisting of butyl, 3-phenylpropyl and 3-methoxypropyl;
Y is --Aa--C(O)R 4 ;
Aa is chosen from the group consisting of valine, leucine, phenylalanine, isoleucine β-2-thienylalanine, t-butylglycine, cysteine and phenylglycine; and
R 4 is chosen from the group consisting of ##STR5## Another preferred embodiment of the invention are compounds of Formula I wherein:
R 1 is chosen from the group consisting of methyl, benzyl, butyl, 3-phenylpropyl, 3-methoxypropyl, 2-pyridinylmethyl and 3-pyridinylmethyl;
Y is --C(O)R 5 ;
R 6 is chosen from the group consisting of 3-pyridinylmethyl, phenylethoxyethyl, 3,4,5-trimethoxybenzyl, 4-acetamidobenzyl, 4-phenylbutyl, 3,4-dichlorobenzyl, 4-phenylbenzyl, 3-phenylpropyl, 3,5-bis(trifluoromethyl)benzyl, 3-phenylpropionyl, isobutyl, propionyl and 3,5-di (trifluoromethyl)phenylacetyl; and
R 7 is chosen from the group consisting of 4-isopropoxybenzoyl, nicotinoyl, 3,4,5-trimethoxybenzoyl, 3-phenoxybenzoyl, 3-(2-methoxyphenyl)propyl, 3,4,5-trimethoxyphenylpropionyl, 3,3-diphenylpropionyl, phenylacetyl, 3,4-dichlorophenylacetyl and ethyl adipoyl.
A preferred subset of the foregoing embodiment of the invention are compounds of the Formula I wherein:
R 1 is chosen from the group consisting of methyl, benzyl, butyl, 3-phenylpropyl and 3-methoxypropyl;
Y is --C(O)R 5 ;
R 5 is ##STR6## R 6 is chosen from the group consisting of 3-pyridinylmethyl, phenylethoxyethyl, 3,4,5-trimethoxybenzyl, 4-acetamidobenzyl, 4-phenylbutyl, 3,4-dichlorobenzyl, 4-phenylbenzyl, 3,5-bis(trifluoromethyl)benzyl, 3-phenylpropionyl and 3-phenylpropyl; and
R 7 is chosen from the group consisting of 4-isopropoxybenzoyl, nicotinoyl, 3,4,5-trimethoxybenzoyl, 3-phenoxybenzoyl, 3-(2-methoxyphenyl)propyl, 3,4,5-trimethoxyphenylpropionyl, 3,3-diphenylpropionyl, 3,4-dichlorophenylacetyl and ethyl adipoyl.
A second subset of the second preferred embodiment of the invention are compounds of Formula I wherein
R 1 is chosen from the group consisting of butyl, 2-pyridinylmethyl and 3-pyridinylmethyl;
R 5 is ##STR7## R 6 is chosen from the group consisting of 4-phenylbenzyl, isobutyl, propionyl and 3,5-di(trifluoromethyl)phenylacetyl;
R 7 is chosen from the group consisting of phenylacetyl, 3-phenoxybenzoyl and 3,3-diphenylpropionyl; and
R 8 is ethyl.
Another aspect of the invention is the use of divinylbenzene-cross-linked, polyethyleneglycol-grafted polystyrene beads optionally functionalized with amino groups (e.g., TentaGel™ S NH 2 , Rapp Polymere) as the solid supports for constructing compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
II. Abbreviations and Definitions
The following abbreviations and terms have the indicated meaning throughout:
Alloc=allyloxy carbonyl
Bn=benzyl
BNB=4-bromomethyl-3-nitrobenzoic acid
BOC=t-butyloxy carbonyl
Bu=butyl
c-=cyclo
DCM=Dichloromethane=methylene chloride=CH 2 Cl 2
DIC=diisopropylcarbodiimide
DIEA=diisopropylethyl amine
DMAP=4-N,N-dimethylaminopyridine
DMF=N,N-dimethylformamide
DVB=1,4-divinylbenzene
Et=ethyl
Fmoc=9-fluorenylmethoxycarbonyl
HATU=O-(7-Azabenzotriazol-1-yl)1,1,3,3-tetramethyluroniumhexafluorophosphate
HOAc=acetic acid
HOBt=hydroxybenzotriazole
m-=meta
Me=methyl
N 3 =azido
NaBH 3 CN=sodium cyanoborohydride=SCB
PEG=polyethylene glycol
Ph=phenyl
s-=secondary
t-=tertiary
TFA=trifluoroacetic acid
THF=tetrahydrofuran
"Alkyl" is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. "Lower alkyl" means alkyl groups of from 1 to 8 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t-butyl, pentyl hexyl, octyl, cyclopropylenthyl, bornyl and the like. Preferred alkyl groups are those of C 20 or below. "Cycloalkyl" is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of lower cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl and the like.
"Alkenyl" includes C 2 -C 8 unsaturated hydrocarbons of a linear, branched, or cyclic (C 5 -C 6 ) configuration and combinations thereof. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, c-hexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl and the like.
"Alkynyl" includes C 2 -C 8 hydrocarbons of a linear or branched configuration and combinations thereof containing at least one carbon-carbon triple bond. Examples of alkynyl groups include ethane, propyne, butyne, pentyne, 3-methyl-1-butyne, 3,3-dimethyl-1-butyne and the like.
"Alkoxy" refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.
"Acylamino" refers to acylamino groups of from 1 to 8 carbon atoms of a straight, branched or cyclic configuration and combinations thereof. Examples include acetylamino, butylamino, cyclohexylamino and the like.
"Halogen" includes F, Cl, Br, and I.
"Aryl" and "heteroaryl" mean a 5- or 6-membered aromatic or heteroaromatic ring containing 0-3 heteroatoms selected form O, N, and S; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, and S; or a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, and S; each of which rings is optionally substituted with 1-3 lower alkyl, substituted alkyl, substituted alkynyl, ═O, --NO 2 , halogen, hydroxy, alkoxy, OCH(COOH) 2 , cyano, NR 10 R 10 , acylamino, phenyl, benzyl, phenoxy, benzyloxy, heteroaryl, and heteroaryl or heteroaryloxy; each of said phenyl, benzyl, phenoxy, benzyloxy, heteroaryl, and heteroaryloxy is optionally substituted with 1-3 substituents selected from lower alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, cyano, phenyl, benzyl, benzyloxy, carboxamido, heteroaryl, heteroaryloxy, NO 2 , and NR 10 R 10 ;
R 10 is independently let, lower alkyl or cycloalkyl, and --R 10 R 10 may be fused to form a cyclic ring with nitrogen.
The aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole, and pyrazole.
"Arylalkyl" means an alkyl residue attached to an aryl ring. Examples include, e.g., benzyl, phenethyl and the like.
"Heteroarylalkyl" means an alkyl residue attached to a heteroaryl ring. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like.
"teterocycloalkyl" means a cycloalkyl where one to two of the methylene (CH 2 ) groups is replaced by a heteroatom such as O, NR' (wherein R' is H or alkyl), S or the like; with the proviso that when two heteroatoms are present, they must be separated by at least two carbon atoms. Examples of heterocycloalkyls include tetrahydrofuranyl, piperidine, dioxanyl and the like.
"Carboxyalkyl" means --C(O)R", wherein R" is alkyl.
"Substituted" alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl means alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl wherein up to three H atoms on each C atom therein are replaced with halogen, hydroxy, loweralkoxy, carboxy, carboalkoxy, carboxamido, cyano, carbonyl, NO 2 , NR 9 R 9 (wherein R 9 is H, alkyl or arylalkyl), alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, heteroaryloxy, and substituted phenyl, benzyl, heteroaryl, phenoxy, benzyloxy or heteroaryloxy.
Aa represents an amino acid and is intended to include the racemates and all optical isomers thereof. The amino acid side chains of Aa include, e.g., methyl (alanine), hydroxymethyl (serine), phenylmethyl (phenylalanine), thiomethyl (cysteine), carboxyethyl (glutamic acid), etc. Primary and secondary amino acids are intended to include alanine, asparagine, N-β-trityl-asparagine, aspartic acid, aspartic acid-β-t-butyl ester, arginine, N g -Mtr-arginine, cysteine, S-trityl-cysteine, glutamic acid, glutamic acid-γ-t-butyl ester, glutamine, N-γ-trityl-glutamine, glycine, histidine, N im -trityl-histidine, isoleucine, leucine, lysine, N.sup.ε -Boc-lysine, methionine, phenylalanine, proline, serine, O-t-butyl-serine, threonine, tryptophan, N in -Boc-tryptophan, tyrosine, valine, sarcosine, L-alanine, chloro-L-alanine, 2-aminoisobutyric acid, 2-(methylamino)isobutyric acid, D, L-3-aminoisobutyric acid, (R)-(-)-2 aminoisobutyric acid, (S)-(+)-2-aminoisobutyric acid, 2-thienyalanine, D-norvaline, L-norvaline, L-2-amino-4-pentenoic acid, D-isoleucine, L-isoleucine, D-norleucine, 2,3-diaminopropionic acid, L-norleucine, D,L-2-aminocaprylic acid β-alanine, D,L-3-aminobutyric acid, 4-aminobutyric acid, 4-(methylamino)butyric acid, 5-aminovaleric acid, 5-aminocaproic acid, 7-aminoheptanoic acid, 8-aminocaprylic acid, 11-aminodecanoic acid, 12-aminododecanoic acid, carboxymethoxylamine, D-serine, D-homoserine, L-homoserine, D-allothreonine, L-allothreonine, D-threonine, L-threonine, D,L-4-amino-3-hydroxybutyric acid, D,L-3-hyroxynorvaline, (3S,4S)-(-)-statine, 5-hydroxy-D,L-lysine, 1-amino-1-cyclopropanecarboxylic acid, 1-amino-1-cyclopentanecarboxylic acid, 1-amino-1-cyclohexanecarboxylic acid, 5-amino-1,3-cyclohexadiene-1-carboxylic acid, 2-amino-2-norbornanecarboxylic acid, (S)-(-)-2-azetidinecarboxylic acid, cis-4-hydroxy-D-proline, cis-4-hydroxy-L-proline, trans-4-hydroxy-L-proline, 3-4-dehydro-D,L-proline, 3,4-dehydro-L-proline, pipecolic acid, pipecolinic acid, nipecotic acid, isonipecotic acid, mimosine, citrulline, 2,3-diaminopropionic acid, D,L-2,4-diaminobutyric acid, (S)-(+)-diaminobutyric acid, ornithine, 2-methylornithine, N-ε-methyl-L-lysine, N-methyl-D-aspartic acid, D,L-2-methylglutamic, D,L-2-aminoadipic acid, D-2-aminoadipic acid, naphthylalanine, L-2-aminoadipic acid, (+/-)-3-aminoadipic acid, D-cysteine, D-penicillamine, L -penicillamine, D,L-homocysteine, S-methyl-L-cysteine, L-methionine, D-ethionine, L-ethionine, S-carboxymethyl-L-cysteine, (S)-(+)-2-phenylglycine, (R)-(-)-2-phenylglycine, N-phenylglycine, N-(4-hydroxyphenyl)glycine, D-phenylalanine, (S)-(-)indoline-2-carboxylic acid, α-methyl,D,L-phenylalanine, β-methyl-D,L-phenylalanine, D-homophenylalanine, L-homophenylalanine, D,L-2-fluorophenylglycine, D,L-2-fluorophenylalanine, D,L-3-fluorophenylalanine, D,L-4-fluorophenylalanine, D,L-4-chlorophenylalanine, L-4-chlorophenylalanine, 4-bromo-D,L-phenylalanine, 4-iodo-D-phenylalanine, 3,3', 5-triiodo-L-thyronine, (+)-3,3', 5-triiodo-L-thyronine sodium salt, D-thyronine, L-thyronine, D,L-m-tyrosine, D-4-hydroxyphenylglycine, D-tyrosine, L-tyrosine, o-methyl-L-tyrosine, 3-fluoro-D,L-tyrosine, 3-iodo-L-tyrosine, 3-nitro-L-tyrosine, 3,5-diiodo-L-tyrosine, D,L-dopa, L-dopa, 2,4,5-trihydroxyphenyl-D,L-alanine, 3-amino-L-tyrosine, 4-amino-D-phenylalanine, 4-amino-L-phenylalanine, 4-amino-D,L-phenylalanine, 4-nitro-L-phenylalanine, 4-nitro-D,L-phenylalanine, 3,5-dinitro-L-tyrosine, D,L-α-methyltyrosine, L-α-methyltyrosine, (-)-3-(3,4-dihydroxyphenyl)-2-methyl-L-alanine, D,L-threo-3-phenylserine, trans-4-(aminomethyl)cyclohexane carboxylic acid, 4-(aminomethyl) benzoic acid, D,L-3-aminobutyric acid, 3- aminocyclohexane carboxylic acid, cis-2-amino-1-cyclohexane carboxylic acid, γ-amino-β-(p-chlorophenyl) butyric acid (Baclofen), D,L-3-aminophenylpropionic acid, 3-amino-3-(4-chlorophenyl) propionic acid, 3-amino-3-(2-nitrophenyl)propionic acid, cyclohexylalanine, t-butylglycine, pyridylalanine and 3-amino-4,4,4-trifluorobutyric acid.
The statine residues used in this invention were prepared by the method of Rich (Rich et al., J. Org. Chem., 43, 3624 (1978)).
The material upon which the combinatorial syntheses of the invention are performed are referred to as solid supports, beads or resins. These terms are intended to include beads, pellets, disks, fibers, gels, or particles such as cellulose beads, poreglass beads, silica gels, polystyrene beads optionally cross-linked with divinylbenzene and optionally grafted with polyethylene glycol and optionally functionalized with amino, hydroxy, carboxy, or halo groups, grafted co-poly beads, poly-acrylamide beads, latex beads, dimethylacrylamide beads optionally cross-linked with N,N'-bis-acryloyl ethylene diamine, glass particles coated with hydrophobic polymer, etc., i.e., material having a rigid or semi-rigid surface; and soluble supports such as low molecular weight non-cross-linked polystyrene.
III. Optical Isomers-Diastereomers-Geometric Isomers
Some of the compounds described herein contain one of more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisometric forms which may be defined in terms of absolute stereochemistry as (R)- or (S)- , or as (D)- or (L)- for amino acids. The present invention is meant to include all such possible diastereomers, as well as their racemic and optically pure forms. Optically active (R)- and (S), or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included.
IV. Assays for Determining Biological Activity
1. Method for Plasmepsin II
The assay mix contained 50 mM sodium acetate (pH 5.0), 1 mg/ml BSA, 0.01% Tween 20, 12.5% glycerol, 18 % DMSO and 12 μM plasmepsin substrate. Twenty five μL of the assay mix was added to each well of a 96-well microtiter plate containing dried down bead eluate or empty control wells. The plates were then sonicated and mixed. 25 μL of 8 nM plasmepsin II, in 50 mM sodium acetate (pH 5.0), 1 mg/ml BSA, 0.01% Tween 20, and 12.5% glycerol, was added to the assay mix. The final concentrations were 4 nM plasmepsin II, 6 μM plasmepsin substrate, 9% DMSO, 50 mM sodium acetate (pH 5.0), 1 mg/ml BSA, 0.01% Tween 20, and 12.5% glycerol. The reaction was incubated for 10 minutes at 25° C. and then quenched by the addition of 25 μL of 1M Tris (pH 8.5) and 50 % DMSO to achieve a final concentration of 0.33M Tris and 23% DMSO. The EDANS fluorescence was measured using a Tecan, SLT FluoStar fluorescence plate reader with an excitation filter of 350 nm and an emission filter 510 nm. The background was determined by 25 μL of 50 mM sodium acetate (pH 5.0), 1 mg/ml BSA, 0.01% Tween 20, and 12.5% glycerol without enzyme.
2. Method for Cathepsin D
The assay mix contained 25 mM sodium formate (pH 3.5), 1 mg/ml BSA, 12% DMSO and 12 μM cathepsin D substrate. Twenty five μL of the assay mix were added to each well of a 96-well microliter plate containing dried down bead eluate or empty control wells. The plates were then sonicated and mixed. 25 μL of 1.6 nM cathepsin D, in 25 mM sodium formate (pH 3.5), and 1 mg/ml BSA, was added to the assay mix. The final concentrations were 0.8 nM cathepsin D, 6 μM cathepsin D substrate, 6% DMSO, 25 mM sodium formate (pH 3.5), and 1 mg/ml BSA. The reaction was incubated for 10 minutes at 25° C. and then quenched by the addition of 25 μL of 1M Tris (pH 8.5) and 50% DMSO to achieve a final concentration of 0.33 M Tris and 21% DMSO. The EDANS fluorescence was measured as stated herein above. The background was determined by 25 μL of 50 mM sodium formate (pH 3.5), and 1 mg/ml BSA without enzyme.
V. Methods of Synthesis
The compounds of the present invention may be prepared according to the following methods. In carrying out the syntheses, one typically begins with a quantity of solid support that will provide enough compound after cleavage from the solid support for biological testing in the herein described assays. In the case where the solid support is TentaGel™, it is recommended that approximately 0.5 g of beads of about 180 microns in diameter, with a loading capacity of about 300 picoM per bead, be used. As the chemical yield of compounds after photolysis typically ranges from approximately 20% up to 60%, this quantity will provide a yield (approximately>10 mg) sufficient for biological testing in the given protease assays. For actual synthesis, the appropriate reagents and reaction conditions are applied to a reaction vessel containing the specified quantity of beads. During the syntheses, the beads may be washed free of any excess reagents or by-products before proceeding to the next reaction. At the end of a given reaction sequence, the beads are suspended in a suitable solvent such as methanol and exposed to UV light (365 nm) for 3 hours at room temperature. This protocol releases the compounds of Formula I (wherein R 2 is H) for purification and biological testing.
A. Scheme 1: Derivatizing resin with bis-Boc lysine
A batch of amino-functionalized PEG-grafted polystyrene beads 3, e.g., TentaGel™ 3 amine may be modified with bis-Boc lysine 2 to increase the available reaction sites for ligand attachment. Bis-Boc lysine 2 is coupled to the amino-functionalized beads 3 by amide bond formation. Coupling is achieved by reacting a suspension of beads in DCM and adding 2, HOBt and DIC. The suspension is shaken overnight, drained or filtered, and then washed in succession with DMF, MeOH and DCM, yielding derivatized resin 1 which is then dried overnight under vacuum.
B. Scheme 2
The various amine choices (see Tables 1 and 2) are added to the reaction vessel containing resin 1. The amines are attached to resin 1 through the photo-labile linker, 4-bromomethyl-3-nitrobenzoic acid. This attachment is accomplished in two steps.
Step 1. The Boc protecting group on resin 1 is removed and the BNB is attached by the following method. A suspension of resin 1 in 1:1 TFA/DCM is shaken for about 1 hour, then washed with DCM, MeOH, 4:1 MeOH/Et 3 N, MeOH, DMF and then DCM. The resultant bis-amine resin 4 is suspended in DCM, and treated with a solution of BNB, HOBt and DIC in DCM. The suspension is shaken for about 3 hours, then drained and washed with DCM. The BNB resin 6 is dried overnight under vacuum.
Step 2. The BNB resin 6 from step 1 are reacted with a unique primary amine (see Tables 1 and 2) to generate compound 7. The coupling of the amine to resin 6 occurs through displacement of the linker bromide and formation of a new carbon-nitrogen bond. As a quality control for the reaction in this step, a small portion of each batch of resin may be removed and titrated with picric acid to determine the extent of amine loading.
C. Scheme 3
Amine 7 is then treated with one of the hydroxy-amino acid reagents (statines) 8 (see Tables 1 and 2). Each hydroxy-amino acid 8 is coupled to amine resin 7 by amide bond formation to produce compound 9.
Compounds 9 may be directed through either the chemistry of Schemes 4 and 5, yielding compounds as in Example 1 and found in Table 1, or in the alternative, through the chemistry of Schemes 6, 7 and 8, yielding compounds as in Example 2 and Table 2.
D. Scheme 4 (With Scheme 5, yields compounds as in Example 1)
Resin 9 is treated with TFA/DCM to remove the Boc protecting group, thus exposing the terminal amino group and forming compounds 10. Each reaction vessel is then treated with one amino acid 11 (see Table 1), for separate coupling of each amino acid to compound 10 by amide bond formation to produce compounds 12. The amino acids are introduced with the base-labile Fmoc on the alpha-nitrogen atom.
E. Scheme 5
Compounds 12 are treated with piperidine/DMF to deprotect the amino group by removing the Fmoc protecting group, thus giving rise to compounds 13, which in turn are treated with one carboxylic acid (see Table 1), which couples with compound 13 to generate compounds 14. Resin 14 may be cleaved by exposing it to UV light (ca. 360 nm) for 15-180 minutes at 25°-50° C. in a suitable solvent such as methanol to produce amides of Formula I (wherein R 2 is H), as in Example 1 and Table 1.
Scheme 6 (With Schemes 7 and 8, yields compounds as in Example 2)
Resin 9 (from Scheme 3) is treated with TFA/DCM to remove the Boc protecting group, thus exposing the terminal amino group and forming compounds 10. The compound is then treated with one diamino acid 17 (Table 2), for separate coupling of each diamino acid 17 to compounds 10 by amide bond formation, using HATU and DIEA, to produce compounds 18.
G. Scheme 7
Resin 18 is treated with TFA/DCM to selectively remove the Boc protecting group on the diamino acid ligand to produce amines 19. The resin is then treated with one carboxylic acid reagent or one carboxyaldehyde (see Table 2) for either separate coupling of each carboxylic acid to compound 19 by amide bond formation or separate reductive amination of each carboxyaldehyde to compound 19 with sodium cyanoborohydride in methanol to produce resin 20.
H. Scheme 8
Compounds 20 are then treated with palladium tetrakistriphenylphosphine, tributyltin hydride in acetic acid and DCM to selectively remove the Alloc protecting group on the diamino acid ligand to produce amines 21. Each vessel is then treated with one carboxylic acid reagent (see Table 2) for separate coupling of the carboxylic acid to compounds 21 by amide bond formation to produce resin 22. Resin 22 may be cleaved by exposing the resin to UV light (ca. 360 nm) for 15-180 minutes at 25°-50° C. in a suitable solvent such as methanol to produce amides Formula I (wherein R 2 is H), as in Example 2 and Table 2.
I. Scheme 9
Diamino acid intermediate 23, one of the diamine ligands (Table 2), is prepared from hydroxy proline 24 by first treating it with alloxychloroformate, in a solvent such as water, in the presence of a base, e.g., potassium carbonate to yield Alloc protected compound 25. Compound 25 is esterified with either acid in methanol or diazomethane in diethyl ether, producing ester 26, which is then converted to bromide compound 27 using a brominating reagent such as triphenylphosphine and carbon tetrabromide. The bromide substituent is in turn displaced with azide using either sodium or potassium azide in DMF. Resultant azide compound 28 is then reductively alkylated with acetaldehyde, by first treating it with triphenylphosphine to generate an imine which is in turn reduced to an N-ethyl amino group in compound 29. Amine 29 is treated with Boc anhydride in acetonitrile to produce compound 30 which in turn is hydrolyzed to carboxylic acid compound 23 by the action of lithium hydroxide in water.
EXAMPLE 1
Entry 11, Table 1 ##STR8## Step 1--Sequential Attachment of bis-Boc Lysine, Photo-labile Linker and an Amine
1a. Attachment of bis-Boc Lysine to TentaGel™
TentaGel™ resin (S-NH 2 , 1.0 g, 0.029 mmol/g, 0.29 mmol, 180-220 um) was suspended in a solution of bis-Boc lysine (0.87 mmol, 0.5 g), and HOBt (0.87 mmol, 0.12 g), then treated with DIC (01.7 mmol, 0.27 mL). The suspension was shaken overnight, then drained and washed with 15 mL each DMF (3×), MeOH (3×) and DCM (3×).
1b. Removal of Boc Protecting Group and Attachment of Photo-labile Linker
A suspension of resin 1 (1.0 g) in 1:1 TFA/DCM was shaken for 1 hour, then washed with 50 mL each DCM (3×), MeOH (3×), 4:1 MeOH/Et 3 N (1×), MeOH (3×), DMF (3×), then DCM (3×). This resin was then suspended in 25 mL DCM, then treated with a pre-incubated (45 min) solution of 4-bromomethyl-3-nitro benzoic acid (1.5 mmol, 0.40 g), HOBt (1.5 mmol, 0.23 g), DIC (3.2 mmol, 0.5 mL) in DCM (25 mL). The suspension was shaken for 3 hours, then drained and washed with three 50 mL portions of DCM.
1c. Addition of Amine
One gram of the step 1b resin was suspended in THF (50 mL) and then treated with butylamine (5.4 mmol) and shaken overnight. The resin was then drained and washed with 50 mL each DMF (3×), MeOH (3×), 10:1 MeOH/TFA (1×), MeOH (3×), DMF (3×), then DCM (3×).
Step 2--Addition of Phenylalanine-Derived Statine.
A suspension of the step 1c resin (1.0 g) in DMF (15 mL) was treated with the phenylalanine-derived Boc-protected statine (1.3 mmol), DIEA (2.6 mmol, 0.44 mL), then HATU (1.3 mmol, 0.5 g). This suspension was shaken for 6 hours, drained and washed with 15 mL portions of DMF (3×), MeOH (3×), DMF (3×), and DCM (3×). The dried resin 9 was divided into two portions.
Step 3--Deprotection and Attachment of Fmoc Valine
A suspension of resin 9 (0.5 g) in 40% TFA/DCM was shaken for 1 hour, then drained and washed with 50 mL each DCM (3×), MeHt (3×), 10% Et 3 N/MeOH (1×), MeOH (3×), and DMF (3×). The product (0.5 g; 0.33 mmol) was suspended in 10 mL of DMF, containing Fmoc-valine (0.48 mmol) and HATU (0.48 mmol). The suspension was shaken at room temperature for 10 minutes and then DIEA (0.99 mmol) was added. The resulting mixture was shaken for 2 hours, continuously monitoring the resin from the vessel with the Kaiser test to determine the absence of amine functionality. Once the coupling was complete (Kaiser test negative), the resin was filtered and washed with 10 mL portions of DMF (3×), MeOH (3×) and DCM (3×).
Step 4--Fmoc-Deprotection.
The resin (0.5 g) was suspended in 30% piperidine in DMF (15 mL) and shaken for 1 hour at room temperature. The resin was filtered, washed with 15 mL portions of DMF (2×), DCM (3×), MeOH (3×) and DCM (5×), then dried under vacuum.
Step 5--Attachment of 2,4-dimethoxybenzoic acid
The resin in a reaction vessel was combined with 2,4-dimethoxybenzoic acid (0.6 mmol), HATU (0.72 mmol) and DIEA (1.8 mmol) in DMF (15 mL). The resulting suspension of resin was shaken for approximately one hour at room temperature, at which time the Kaiser test was negative. The resin was filtered and washed with 10 mL each DMF (2×), MeOH (3×) and DCM (5×). The resin was filtered and subjected to a wash cycle consisting of 10 mL portions each TFA/water (1:1) (2×), DMF (2×), MeOH (4×), DMF (2×) and DCM (5×), then dried in vacuum.
Step 6--Cleavage by light
The resin was suspended in MeOH (20 mL) and the compound cleaved from the resin at 50° C., then light (365 nm) was shone on them for 3 to 4 hours. The suspension was filtered, the MeOH removed to give the title compound as confirmed by mass spectroscopy (mass spectrum (fab): m/z=528 (MH + )).
EXAMPLE 2
Entry 16, Table 2 ##STR9## Step 1--Deprotection and Attachment of Diamino Acid
A suspension of resin 9 (0.5 g) in 40% TFA/DCM, prepared as in Example 1, with the exception that 3-methoxypropylamine was used in place of butylamine, was shaken for 1 hour, then drained and washed with 50 mL portions of DCM (3×), MeOH (3×), 10% Et 3 N/MeOH (1×), MeOH (3×) and DMF (3×). A suspension of this resin in DMF (50 mL) was treated with the corresponding diamino carboxylic acid (entry 16, Table 2; 1.6 mmol), DIEA (3.3 mmol), then HATU (1.7 mmol). The suspension was shaken for 6 hours, then drained and washed with 50 mL portions of DMF (3×), MeOH (3×), DMF (3×), then DCM (3×) and filtered. The resin was dried in vacuo.
Step 2--Deprotection and Attachment of a Carboxyaldehyde
A suspension of resin batch one (0.5 g) in 40% TFA/DCM (10 mL) was shaken for 1 hour, then drained and washed with 10 mL portions of DCM (3×), MeOH (3×), 10% Et 3 N/MeOH (1×), MeOH (3×), and DMF (3×). This resin, suspended in 2% HOAc/DMF (10 mL), was treated with 3-phenylpropionyl (8.8 mmol), followed by the addition of NaBH 3 CN (4.4 mmol, 0.28 g). The resin was shaken overnight, then drained and washed with 10 mL portions of DMF (3×), MeOH (3×), then DMF (3×), DCM (3×). The resin was dried in vacuo.
Step 3--Deprotection and Attachment of 3-(2,3,4-Trimethoxyphenyl)Propionoic Acid
A suspension of resin (0.5 g) in DCM (10 mL) was treated with HOAc (4.8 mmol, 0.27 mL), Pd(PPh 3 ) 4 (0.072 mmol, 83 mg), then Bu 3 SnH (2.4 mmol, 0.64 mL). This suspension was shaken for 1 hour, then drained and washed with 10 mL portions of DCM (3×), pyridine (3×), DCM (3×), then DMF (3×). The resin in DMF (10 mL) was then treated with 3-(2,3,4-trimethoxyphenyl)propionoic acid (0.36 mmol), followed by DIEA (0.72 mmol, 0.13 mL), and HATU (0.36 mmol, 0.14 g). This suspension was shaken for 6 hours, then drained and washed with 10 mL portions of DMF (3×), MeOH (3×), then DMF (3×) and DCM (3×).
Step 4--Cleavage by Light
The resin was suspended in MeOH (20 mL) and the compound cleaved from the resin at 50° C., then light (365 nm) was shone on them for 3 to 4 hours. The suspension was filtered, the MeOH removed to give the title compound as confirmed by mass spectroscopy (mass spectrum (fab): m/z=719 (MH + )).
Using these methods, compounds in Tables 1 and 2 were prepared. The compounds in Tables 1 and 2 typically show greater than 2-fold selectivity for either plasmepsin or cathepsin D at an inhibitory activity (IC50) less than 10 micromolar.
TABLE 1__________________________________________________________________________R Groups for Compounds of Formula I where Y is an amino acid ##STR10##Entry R.sup.1 R.sup.3 R.sup.9 R.sup.4__________________________________________________________________________ 1 butyl CH.sub.2 Ph CH(Me)CH.sub.2 Me ##STR11## 2 butyl CH.sub.2 Ph CH(Me)CH.sub.2 Me ##STR12## 3 3-phenylpropyl CH.sub.2 Ph CH(Me)CH.sub.2 Me ##STR13## 4 butyl CH.sub.2 CH(Me).sub.2 CH(Me).sub.2 octyl 5 3-phenylpropyl CH.sub.2 CH(Me).sub.2 CH(Me)CH.sub.2 Me ##STR14## 6 3-phenylpropyl CH.sub.2 CH(Me).sub.2 CH(Me)CH.sub.2 Me ##STR15## 7 butyl CH.sub.2 Ph CH(Me).sub.2 ##STR16## 8 3-phenylpropyl CH.sub.2 Ph CH(Me).sub.2 ##STR17## 9 3-phenylpropyl CH.sub.2 Ph CH(Me)CH.sub.2 Me ##STR18##10 3-phenylpropyl CH.sub.2 Ph CH(Me)CH.sub.2 Me ##STR19##11 butyl CH.sub.2 Ph CH(Me).sub.2 ##STR20##12 butyl CH.sub.2 CH(Me).sub.2 Ph ##STR21##13 3-methoxypropyl CH.sub.2 CH(Me).sub.2 CH.sub.2 SH ##STR22##14 butyl CH.sub.2 CH(Me).sub.2 CH.sub.2 CH(Me).sub.2 ##STR23##15 butyl CH.sub.2 CH(Me).sub.2 CH.sub.2 Ph ##STR24##16 butyl CH.sub.2 CH(Me).sub.2 CH.sub.2 (2-thienyl) ##STR25##17 butyl CH.sub.2 Ph Ph ##STR26##18 butyl CH.sub.2 CH(Me).sub.2 C(Me).sub.3 (CH.sub.2).sub.3O(2,4-di-Cl)Ph19 3-methoxypropyl CH.sub.2 Ph Ph (CH.sub.2).sub.3O(2,4-di-Cl)Ph20 butyl CH.sub.2 Ph Ph ##STR27##21 butyl CH.sub.2 Ph Ph (2,4-di-OMe)phenyl__________________________________________________________________________
TABLE 2__________________________________________________________________________R Groups for Compounds of Formula I where Y is the diamino acid ##STR28##Entry R.sup.1 R.sup.3 n R.sup.6 R.sup.7__________________________________________________________________________ 1 benzyl Me 0 3-pyridinylmethyl 4-isopropoxybenzoyl 2 butyl CH.sub.2 Ph 0 Ph(CH.sub.2).sub.2 O(CH.sub.2).sub.2- (3,4,5-tri-OMe)benzoyl 3 butyl CH.sub.2 Ph 0 4-phenylbenzyl (3,4,5-tri-OMe)benzoyl 4 butyl CH.sub.2 Ph 1 (3,4,5-tri-OMe)benzyl 4-isopropoxybenzoyl 5 butyl CH.sub.2 Ph 1 (4-MeC(O)NH)PhCH.sub.2 3-phenoxybenzoyl 6 3-phenylpropyl CH.sub.2 Ph 0 4-phenylbutyl (3,4,5-tri-OMe)benzoyl 7 butyl CH.sub.2 Ph 0 (4-MeC(O)NH)PhCH.sub.2 (3,4,5-tri-OMe)benzoyl 8 butyl CH.sub.2 Ph 0 3,4-di-Cl-benzyl (3,4,5-tri-OMe)benzoyl 9 butyl CH.sub.2 Ph 0 4-phenylbenzyl (3,4,5-tri-OMe)benzoyl10 butyl CH.sub.2 Ph 1 (3,4,5-tri-OMe)benzyl 3-phenoxybenzoyl11 methyl CH.sub.2 Ph 0 4-phenylbenzyl 3-phenoxybenzoyl12 3-methoxypropyl CH.sub.2 Ph 1 3,5-bis-trifluoromethylbenzyl 4-isopropoxybenzoyl13 butyl CH.sub.2 Ph 0 3-phenylpropyl (3,4,5-tri-OMe)benzoyl14 methyl CH.sub.2 Ph 0 4-phenylbenzyl 3-(2-OMe-phenyl)propyl15 methyl CH.sub.2 Ph 0 3,4-di-Cl-benzyl nicotinoyl16 3-phenylpropyl CH.sub.2 Ph 0 3-phenylpropyl (3,4,5-tri-OMe-phenyl)propionyl17 butyl CH.sub.2 CH(Me).sub.2 0 3-phenylpropionyl 3,3-diphenylpropionyl18 3-methoxypropyl CH.sub.2 Ph 0 4-phenylbenzyl 3,3-diphenylpropionyl19 butyl CH.sub.2 Ph 1 4-phenylbenzyl 3,4-di-Cl-phenylacetyl20 butyl CH.sub.2 Ph 0 (3,4,5-tri-OMe)benzyl (3,4,5-tri-OMe-phenyl)propionyl21 methyl CH.sub.2 Ph 0 3,4-di-Cl-benzyl EtOC(O)(CH.sub.2).sub.4 C(O)22 butyl CH.sub.2 Ph 0 EtOC(O)(CH.sub.2).sub.4 C(O) 3,4,5-tri-OMe)benzoyl__________________________________________________________________________ ##STR29##Entry R.sup.1 R.sup.3 R.sup.6 R.sup.7__________________________________________________________________________23 butyl CH.sub.2 Ph 4-phenylbenzyl phenylacetyl24 2-pyridinylmethyl CH.sub.2 Ph Me.sub.2 CHCH.sub.2 3-phenoxybenzoyl25 3-pyridinylmethyl CH.sub.2 CH(Me).sub.2 propionyl 3,3-diphenylpropionyl26 3-pyridinylmethyl CH.sub.2 Ph 3,5-di-CF.sub.3 -phenylacetyl 3,3-diphenylpropionyl__________________________________________________________________________ ##STR30## | Compounds of Formula I ##STR1## are disclosed as inhibitors of plasmepsin and cathepsin D. The compounds are therefore useful to treat diseases such as malaria. In preferred compounds of formula I, Y is the residue of an N-acylated amino acid, a substituted 4-aminoproline or a substituted piperazinealkanoic acid. Intermediates in the solid phase synthesis of compounds of formula I, in which the compounds are attached to a solid support, are also disclosed. | 2 |
REFERENCE TO PENDING PRIOR PATENT APPLICATIONS
This patent application is a divisional of U.S. patent application Ser. No. 12/392,804, filed Feb. 25, 2009, for HELICOIL INTERFERENCE FIXATION SYSTEM FOR ATTACHING A GRAFT LIGAMENT TO A BONE. U.S. patent application Ser. No. 12/392,804 is a continuation-in-part of U.S. patent application Ser. No. 11/893,440, filed Aug. 16, 2007, for COMPOSITE INTERFERENCE SCREW FOR ATTACHING A GRAFT LIGAMENT TO A BONE, AND OTHER APPARATUS FOR MAKING ATTACHMENTS TO BONE and claims the benefit of U.S. Provisional Patent Application Ser. No. 61/200,285, filed Nov. 26, 2008, for HELICOIL FIXATION DEVICE. Each of the above-referenced applications is herein incorporated by reference in their entirety for all purposes.
FIELD OF THE INVENTION
This invention relates to medical apparatus and procedures in general, and more particularly to medical apparatus and procedures for reconstructing a ligament.
BACKGROUND OF THE INVENTION
Ligaments are tough bands of tissue which serve to connect the articular extremities of bones, and/or to support and/or retain organs in place within the body. Ligaments are typically made up of coarse bundles of dense fibrous tissue which are disposed in a parallel or closely interlaced manner, with the fibrous tissue being pliant and flexible but not significantly extensible.
In many cases, ligaments are torn or ruptured as the result of an accident. Accordingly, various procedures have been developed to repair or replace such damaged ligaments.
For example, in the human knee, the anterior and posterior cruciate ligaments (i.e., the “ACL” and “PCL”) extend between the top end of the tibia and the bottom end of the femur. The ACL and PCL serve, together with other ligaments and soft tissue, to provide both static and dynamic stability to the knee. Often, the anterior cruciate ligament (i.e., the ACL) is ruptured or torn as the result of, for example, a sports-related injury. Consequently, various surgical procedures have been developed for reconstructing the ACL so as to restore substantially normal function to the knee.
In many instances, the ACL may be reconstructed by replacing the ruptured ACL with a graft ligament. More particularly, in such a procedure, bone tunnels are generally formed in both the top of the tibia and the bottom of the femur, with one end of the graft ligament being positioned in the femoral tunnel and the other end of the graft ligament being positioned in the tibial tunnel, and with the intermediate portion of the graft ligament spanning the distance between the bottom of the femur and the top of the tibia. The two ends of the graft ligament are anchored in their respective bone tunnels in various ways well known in the art so that the graft ligament extends between the bottom end of the femur and the top end of the tibia in substantially the same way, and with substantially the same function, as the original ACL. This graft ligament then cooperates with the surrounding anatomical structures so as to restore substantially normal function to the knee.
In some circumstances, the graft ligament may be a ligament or tendon which is harvested from elsewhere within the patient's body, e.g., a patella tendon with or without bone blocks attached, a semitendinosus tendon and/or a gracilis tendon. In other circumstances, the graft ligament may be harvested from a cadaver. In still other circumstances, the graft ligament may be a synthetic device. For the purposes of the present invention, all of the foregoing may be collectively referred to herein as a “graft ligament”.
As noted above, various approaches are well known in the art for anchoring the two ends of the graft ligament in the femoral and tibial bone tunnels.
In one well-known procedure, which may be applied to femoral fixation, tibial fixation, or both, the end of the graft ligament is placed in the bone tunnel, and then the graft ligament is fixed in place using a headless orthopedic screw, generally known in the art as an “interference” screw. More particularly, with this approach, the end of the graft ligament is placed in the bone tunnel and then the interference screw is advanced into the bone tunnel so that the interference screw extends parallel to the bone tunnel and simultaneously engages both the graft ligament and the side wall of the bone tunnel. In this arrangement, the interference screw essentially drives the graft ligament laterally, into engagement with the opposing side wall of the bone tunnel, whereby to secure the graft ligament to the host bone with a so-called “interference fit”. Thereafter, over time (e.g., several months), the graft ligament and the host bone grow together at their points of contact so as to provide a strong, natural joinder between the ligament and the bone.
Interference screws have proven to be an effective means for securing a graft ligament in a bone tunnel. However, the interference screw itself generally takes up a substantial amount of space within the bone tunnel, which can limit the surface area contact established between the graft ligament and the side wall of the bone tunnel. This in turn limits the region of bone-to-ligament in-growth, and hence can affect the strength of the joinder. By way of example but not limitation, it has been estimated that the typical interference screw obstructs about 50% of the potential bone-to-ligament integration region.
For this reason, substantial efforts have been made to provide interference screws fabricated from absorbable materials, so that the interference screw can eventually disappear over time and bone-to-ligament in-growth can take place about the entire perimeter of the bone tunnel. To this end, various absorbable interference screws have been developed which are made from biocompatible, bioabsorbable polymers, e.g., polylactic acid (PLA), polyglycolic acid (PGA), etc. These polymers generally provide the substantial mechanical strength needed to advance the interference screw into position, and to thereafter hold the graft ligament in position while bone-to-ligament in-growth occurs, without remaining in position on a permanent basis.
In general, interference screws made from such biocompatible, bioabsorbable polymers have proven clinically successful. However, these absorbable interference screws still suffer from several disadvantages. First, clinical evidence suggests that the quality of the bone-to-ligament in-growth is somewhat different than natural bone-to-ligament in-growth, in the sense that the aforementioned bioabsorbable polymers tend to be replaced by a fibrous mass rather than a well-ordered tissue matrix. Second, clinical evidence suggests that absorption generally takes a substantial period of time, e.g., on the order of three years or so. Thus, during this absorption time, the bone-to-ligament in-growth is still significantly limited by the presence of the interference screw. Third, clinical evidence suggests that, for many patients, absorption is never complete, leaving a substantial foreign mass remaining within the body. This problem is exacerbated somewhat by the fact that absorbable interference screws generally tend to be fairly large in order to provide them with adequate strength, e.g., it is common for an interference screw to have a diameter (i.e., an outer diameter) of 8-12 mm and a length of 20-25 mm.
Thus, there is a need for a new and improved interference fixation system which (i) has the strength needed to hold the graft ligament in position while bone-to-ligament in-growth occurs, and (ii) promotes superior bone-to-ligament in-growth.
SUMMARY OF THE INVENTION
These and other objects are addressed by the provision and use of a novel heliCoil interference fixation system for attaching a graft ligament to a bone.
In one preferred form of the invention, there is provided a novel helicoil interference fixation system comprising:
a helicoil comprising a helical body comprising a plurality of turns separated by spaces therebetween, the helical body terminating in a proximal end and a distal end, and at least one internal strut extending between at least two turns of the helical body; and
an inserter for turning the helicoil, the inserter comprising at least one groove for receiving the at least one strut;
the helicoil being mounted on the inserter such that the at least one strut of the helical is mounted in the at least one groove of the inserter, such that rotation of the inserter causes rotation of the helicoil.
In another preferred form of the invention, there is provided a novel method for attaching a graft ligament to a bone, the method comprising:
providing a helicoil interference fixation system comprising:
a helicoil comprising a helical body comprising a plurality of turns separated by spaces therebetween, the helical body terminating in a proximal end and a distal end, and at least one internal strut extending between at least two turns of the helical body; and an inserter for turning the helicoil, the inserter comprising at least one groove for receiving the at least one strut; the helicon being mounted on the inserter such that the at least one strut of the helicoil is mounted in the at least one groove of the inserter, such that rotation of the inserter causes rotation of the helicoil;
forming a bone tunnel in the bone, and providing a graft ligament;
inserting the graft ligament into the bone tunnel; and
using the inserter to turn the helicon into the bone tunnel so as to secure the graft ligament to the bone using an interference fit.
In another preferred form of the invention, there is provided a novel helicoil comprising a helical body comprising a plurality of turns separated by spaces therebetween, the helical body terminating in a proximal end and a distal end, and at least one internal strut extending between at least two turns of the helical body, wherein the at least one internal strut comprises a helical construction.
BRIEF DESCRIPTION OF THE DRAWINGS
These and other objects and features of the present invention will be more fully disclosed or rendered obvious by the following detailed description of the preferred embodiments of the invention, which is to be considered together with the accompanying drawings wherein like numbers refer to like parts, and further wherein:
FIGS. 1-7 are schematic views showing a first helicoil interference fixation system formed in accordance with the present invention;
FIGS. 8-13 are schematic views showing a second helicoil interference fixation system formed in accordance with the present invention;
FIGS. 14-20 are schematic views showing a femoral fixation using the second helicoil interference fixation system of FIGS. 8-13 ;
FIGS. 21-25 are schematic views showing a full ACL reconstruction using the second helicoil interference fixation system of FIGS. 8-13 ;
FIGS. 26-28 are schematic views showing a soft tissue ACL fixation using the second helicoil interference fixation system of FIGS. 8-13 ;
FIGS. 29-31 are schematic views showing a third helicoil interference fixation system formed in accordance with the present invention;
FIG. 32 is schematic view showing a fourth helicoil interference fixation system formed in accordance with the present invention;
FIG. 33 is a schematic view showing a fifth helicoil interference fixation system formed in accordance with the present invention;
FIGS. 34-36 are schematic views showing a sixth helicoil interference fixation system formed in accordance with the present invention;
FIG. 37 is a schematic view showing a seventh helicoil interference fixation system formed in accordance with the present invention;
FIG. 38 is a schematic view showing an eighth helicoil interference fixation system formed in accordance with the present invention; and
FIG. 39 is a schematic view showing a ninth helicoil interference fixation system formed in accordance with the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention comprises the provision and use of a novel helicoil interference fixation system for attaching a graft ligament to a bone or other tissue.
For convenience, the present invention will hereinafter be discussed in the context of its use for an ACL tibial and/or femoral fixation; however, it should be appreciated that the present invention may also be used for the fixation of other graft ligaments to the tibia and/or the femur; and/or the fixation of other graft ligaments to other bones or to other tissue such as organs.
Looking first at FIGS. 1-7 , there is shown a novel helicoil interference fixation system 5 for securing a graft ligament to a bone. Helicoil interference fixation system 5 generally comprises a helicoil 10 for disposition in a bone tunnel so as to hold the graft ligament in position while bone-to-ligament in-growth occurs. Helicoil interference fixation system 5 also comprises an inserter 15 for deploying helicoil 10 in the bone tunnel. More particularly, and looking now at FIGS. 1-6 , and particularly at FIG. 5 , helicoil 10 generally comprises a helical body 20 terminating in a distal end 25 and a proximal end 30 . Helical body 20 is constructed so that there are substantial spaces or gaps 35 between the turns 40 of the helical body. Spaces or gaps 35 facilitate bone-to-ligament in-growth, i.e., by providing large openings through the helical body. These large openings facilitate the flow of cell- and nutrient-bearing fluids through the helicoil, and permit the in-growth of tissue across the helicoil, so as to enhance bone-to-ligament in-growth.
One or more struts 45 are disposed within the interior of helical body 20 , with the one or more struts 45 being secured to the interior surfaces 50 of helical body 20 . The one or more struts 45 provide a means for turning helicoil 10 during deployment within the body, as will hereinafter be discussed in further detail. In addition, the one or more struts 45 can provide structural support for the turns 40 of helical body 20 . The one or more struts 45 may be formed integral with helical body 20 (e.g., by a molding process), or they may be formed separately from helical body 20 and then attached to helical body 20 in a separate manufacturing process (e.g., by welding). Where the one or more struts 45 are formed integral with helical body 20 , the one or more struts 45 can be used to help flow melt into position.
In one preferred form of the invention, the one or more struts 45 comprise helical structures. And in one particularly preferred form of the invention, the one or more struts 45 comprise helical structures which spiral in the opposite direction from the spiral of helical body 20 , and the one or more struts 45 have a pitch which is substantially greater than the pitch of helical body 20 . See FIG. 5 .
Preferably, the number of struts 45 , and their size, are selected so as to close off an insignificant portion of the spaces or gaps 35 between the turns 40 of helical body 20 , whereby to substantially not impede the passage of fluids and tissue through the helicoil. At the same time, however, the number of struts 45 , their size, and composition, are selected so as to provide an adequate means for turning helicoil 10 during deployment, and to provide any necessary support for the turns 40 of helical body 20 .
In one preferred form of the present invention, one strut 45 is provided.
In another preferred form of the present invention, a plurality of struts 45 (e.g., two, three, four or more struts) are provided.
And in one preferred form of the present invention, the struts 45 collectively close off less than fifty percent (50%) of the spaces or gaps 35 between the turns 40 of helical body 20 .
And in one particularly preferred form of the present invention, the struts 45 collectively close off less than twenty percent (20%) of the spaces or gaps 35 between the turns 40 of helical body 20 .
Helicoil 10 is formed out of one or more biocompatible materials. These biocompatible materials may be non-absorbable (e.g., stainless steel or plastic) or absorbable (e.g., a bioabsorbable polymer). In one preferred form of the present invention, helicoil 10 preferably comprises a bioabsorbable polymer such as polylactic acid (PLA), polyglycolic acid (PGA), etc. In any case, however, helicoil 10 comprises a material which is capable of providing the strength needed to set the fixation device into position and to hold the graft ligament in position while bone-to-ligament in-growth occurs. Inserter 15 is shown in FIGS. 1-4 and 7 .
Inserter 15 generally comprises a shaft 55 having a distal end 60 and a proximal end 65 . One or more grooves 70 are formed on the distal end of shaft 55 . Grooves 70 receive the one or more struts 45 of helicoil 10 , in order that helicoil 10 may be mounted on the distal end of shaft 55 and rotated by rotation of shaft 55 . A tapered seat-forming thread 75 (e.g., a tapered cutting thread, a tapered opening or dilating thread, etc.) is formed in shaft 55 distal to grooves 70 . Tapered seat-forming thread 75 serves to precede helicoil 10 into the space between the graft ligament and the wall of the bone tunnel, and then to form a lead-in or opening in the graft ligament and the wall of the bone tunnel for receiving the turns 40 of helical body 20 , in much the same manner as a tap that creates the thread form, as will hereinafter be discussed in further detail. A handle 80 is mounted on the proximal end of shaft 55 in order to facilitate rotation of shaft 55 by the surgeon.
It should be appreciated that tapered seat-forming thread 75 is matched to helicoil 10 so that when helicoil 10 is mounted on inserter 15 , tapered seat-forming thread 75 provides the proper lead-in for helicoil 10 .
Preferably, interior surfaces 50 of helical body 20 and distal end 60 of inserter 15 are tapered, expanding outwardly in the proximal direction, so that helicoil 10 and inserter 15 form a positive seat such that the interior surface of the helicoil is in direct contact with the tapered body diameter of the inserter.
Thus it will be seen that, when helicoil 10 is mounted on the distal end of shaft 55 , inserter 15 may be used to advance the helicoil to a surgical site and, via rotation of handle 80 , turn helicoil 10 into the gap between a graft ligament and the wall of a bone tunnel, whereby to create an interference fixation of the graft ligament in the bone tunnel. Significantly, inasmuch as inserter 15 has a tapered seat-forming thread 75 formed on its distal end in advance of helicoil 10 , the tapered seat-forming thread can form a seat into the tissue in advance of helicoil 10 , whereby to permit the helicoil to advance easily into the tissue and create the desired interference fixation. Accordingly, helicoil 10 does not need to have any penetrating point on its distal end in order to penetrate the tissue.
If desired, inserter 15 may be cannulated so that the inserter and helicoil 10 may be deployed over a guidewire, as will hereinafter be discussed.
FIGS. 8-13 show another helicoil interference fixation system 5 , wherein helicoil 10 comprises two struts 45 and inserter 15 comprises two grooves 70 . The use of two struts 45 , rather than one strut 45 , may be advantageous since it may distribute the load imposed during rotation over a larger surface area. This may be important where helicoil 10 is formed out of a bioabsorbable polymer.
Helicoil interference fixation system 5 may be utilized in a manner generally similar to that of a conventional interference screw system in order to attach a graft ligament to a bone.
More particularly, and looking now at FIGS. 14-25 , there are shown various aspects of an ACL reconstruction effected using helicoil interference fixation system 5 .
FIG. 14 shows a typical knee joint 205 , with the joint having been prepared for an ACL reconstruction, i.e., with the natural ACL having been removed, and with a tibial bone tunnel 210 having been formed in tibia 215 , and with a femoral bone tunnel 220 having been formed in femur 225 .
FIG. 15 is a view similar to that of FIG. 14 , except that a graft ligament 230 has been positioned in femoral bone tunnel 220 and tibial bone tunnel 210 in accordance with ways well known in the art. By way of example, graft ligament 230 may be “towed” up through tibial bone tunnel 210 and into femoral bone tunnel 220 using a tow suture 235 .
FIGS. 16 and 17 show graft ligament 230 being made fast in femoral tunnel 220 using helicoil interference fixation system 5 . More particularly, in accordance with the present invention, helicoil 10 is mounted on the distal end of inserter 15 by fitting the struts 45 of helicoil 10 into the grooves 70 of the inserter. Then the inserter is used to advance helicoil 10 through tibial tunnel 210 , across the interior of knee joint 205 , and up into the femoral tunnel 220 . If desired, inserter 15 may be cannulated, so that the inserter and helicoil are advanced over a guidewire of the sort well known in the art. As the distal tip of the inserter is advanced, the tapered seat-forming thread 75 first finds its way into the space between the graft ligament 230 and the side wall of femoral bone tunnel 220 . Then, as the inserter is turned, tapered seat-forming thread 75 forms a seat into the tissue in advance of helicoil 10 , and helicoil 10 is advanced into the tissue so that the turns of helical body 20 seat themselves in the seat formed by seat-forming thread 75 . As this occurs, the graft ligament is driven laterally, into engagement with the opposing side wall of the bone tunnel. This action sets helicoil 10 between the side wall of femoral bone tunnel 220 and graft ligament 230 , thereby securing the interference fit between graft ligament 230 and the side wall of the bone tunnel, whereby to secure graft ligament 230 to the bone.
Thereafter, and looking now at FIGS. 18 and 19 , inserter 15 is withdrawn, leaving helicon 10 lodged in position between the graft ligament and the side wall of the bone tunnel. As seen in FIG. 20 , helicoil 10 maintains the interference fit established between graft ligament 220 and the side wall of the bone tunnel, thereby securing the graft ligament to the bone.
If desired, helicoil interference fixation system 5 can then be used in a similar manner to form a tibial fixation. See FIGS. 21-25 .
Significantly, forming the fixation device in the form of an open helical coil has proven particularly advantageous, inasmuch as the open helical coil provides the strength needed to set the fixation device into position, and hold the graft ligament in position while bone-to-ligament in-growth occurs, while still providing extraordinary access through the body of the fixation device. Thus, cell- and nutrient-bearing fluids can move substantially unimpeded through the body of helicoil 10 , and tissue in-growth can occur across the body of helicoil 10 .
Furthermore, it has been found that when the graft ligament thereafter imposes axial loads on the interference fit, struts 45 help maintain the structural integrity of turns 40 of helical body 20 , whereby to ensure the integrity of the interference fit.
In FIGS. 16-24 , graft ligament 230 is shown to include bone blocks at the ends of the ligament, e.g., graft ligament 10 may be a patella tendon with bone blocks attached. However, as seen in FIGS. 26-28 , graft ligament 230 can also constitute only soft tissue, e.g., graft ligament 230 may comprise a semitendinosus tendon and/or a gracilis tendon, and/or a synthetic device.
In FIGS. 5 and 11 , the one or more struts 45 are shown as having a helical structure. However, the one or more struts 45 may also be formed with a straight configuration. See, for example, FIGS. 29-30 , which show a helicoil 10 with a single straight strut 45 , and FIG. 31 which shows a helicoil 10 with multiple straight struts 45 .
Furthermore, as seen in FIG. 32 , the one or more struts 45 may be interrupted between turns 40 or, as seen in FIG. 33 , the one or more struts 45 may be selectively interrupted between turns 40 .
It should also be appreciated that an interference fit may be formed using a plurality of helicoils 10 . Thus, as seen in FIGS. 34-36 , a plurality of helicoils 10 may be loaded on an inserter 15 and used for a collective interference fit.
If desired, and looking now at FIG. 37 , the one or more struts 45 may be replaced with recesses 45 A. In this case, grooves 70 on inserter 15 are replaced by corresponding ribs (not shown), whereby to permit inserter 15 to rotatably drive helicoil 10 .
As seen in FIG. 38 , the period of turns 40 may change along the length of helicoil 10 .
Additionally, if desired, helicoil 10 can be tapered between its distal end 25 and its proximal end 30 .
Modifications
It will be appreciated that still further embodiments of the present invention will be apparent to those skilled in the art in view of the present disclosure. It is to be understood that the present invention is by no means limited to the particular constructions and method steps herein disclosed and/or shown in the drawings, but also comprises any modifications or equivalents within the scope of the invention. | A helicoil interference fixation system comprising:
a helicoil comprising a helical body comprising a plurality of turns separated by spaces therebetween, the helical body terminating in a proximal end and a distal end, and at least one internal strut extending between at least two turns of the helical body; and an inserter for turning the helicoil, the inserter comprising at least one groove for receiving the at least one strut; the helicoil being mounted on the inserter such that the at least one strut of the helicoil is mounted in the at least one groove of the inserter, such that rotation of the inserter causes rotation of the helicoil. | 0 |
The invention disclosed and claimed herein deals primarily with the use of magnetic separators for treating silicon-containing materials from a fluid bed reactor to remove magnetically influenced components in the silicon-containing materials. The removal of such components allows for enhanced reactivity of the silicon-containing materials in processes wherein the silicon-containing materials are raw materials for the production of silicon based compounds, such as, for example, basic alkylhalosilanes such as dimethyldichlorosilane, methylhydrogendichlorosilane, and other chlorosilanes such as trichlorosilane, which chlorosilanes are useful in the preparation of valuable silicon-containing products.
BACKGROUND OF THE INVENTION AND PRIOR ART
As indicated Supra, certain valuable halosilanes, that is, the halosilanes that form essentially the basis for the entire silicone products industry, are produced from the reaction between elemental silicon and an alkylhalide at elevated temperatures in the presence of a copper-based catalyst and various promoters. Other similar reactions are carried out to produce other silanes, for example, the preparation of trichlorosilane, which is a basic building block for the production of silicon metal.
There are literally hundreds of patents and publications directed to the basic reaction to produce the alkylhalosilanes, known in the industry as the Direct Process, the most fundamental and earliest being U.S. Pat. No. 2,380,995, that issued August 1945 to Rochow, directed to the chemical process and U.S. Pat. No. 2,389,931, that issued in November, 1945 to Reed, et al., directed to the fluidized bed reactors in the Direct Process.
The main purpose of the Direct Process is to make dimethyldichlorosilane, however, other silanes are produced such as methyltrichlorosilane, trimethylchlorosilane, tetramethylsilane and methyldichlorosilane, and other chlorosilanes and various methylchlorodisilanes, which find limited commercial use, along with direct process residue which is a combination of numerous compounds which are present in minor amounts and are not essentially commercially useful wherein the residues are high boiling having normal boiling points greater than about 71° C. These residual materials are well described in the literature.
There is a constant effort in the industry to enhance the Direct Process so that it is more selective in terms of producing the main component, dimethyldichlorosilane, and is more efficient to provide higher yields at a faster rate. In addition, intimate control of the process is desired such that when compounds other than dimethyldichlorosilane are desired, such as methyldichlorosilane, the process can be controlled to generate these compounds in higher yields.
Unfortunately, the commercial process as currently operated results in less control of the reaction as it proceeds, and this is thought to be due to the accumulation of impurities in the fluid bed reactors as the reaction within the fluid bed reactors progresses. In fact, the process is initially very active and highly selective to products of interest. Over time, performance degrades, allegedly due to the impurity buildup, and thus, the process has to be shut down periodically and the fluid bed contents purged, regenerated or refurbished in order to return the process to an acceptable yield level and rate of reaction, and more importantly, the selective formation of dimethyldichlorosilane. Metallurgical grade silicon typically contains 0.4% weight Fe, 0.15% weight Al, 0.08% weight Ca and 0.03% weight Ti (see U.S. Pat. No. 5,334,738 to Pachaly). The non-silicon metals form a range of intermetallic species such as FeSi 2 , CaSi 2 , FeSi 2 Ti, Al 2 CaSi 2 , Al 8 Fe 5 Si 7 , Al 3 FeSi 2 , Al 6 CaFe 4 Si 8 , FeSi 2.4 Al, and the like, which are also described in the open literature.
The selectivity of the formation of the chlorosilanes has been defined by Dotson, in U.S. Pat. No. 3,133,109, that issued May 12, 1964, as the ratio of organotrichlorosilane (T) to diorganodichlorosilane (D) (the T/D ratio), and it is generally desired to have this ratio below about 0.35 The modern objective is to minimize this ratio. Whenever used herein, the term “desired ratio” means the desired T/D ratio.
A further publication regarding the various factors affecting the degree of usage of the silicon in the Direct Process can be found in M. G. R. T. de Cooker, et. al., “The Influence of Oxygen on the Direct Synthesis of Methylchlorosilanes”, Journal of Organometallic Chemistry, 84, (1975), pp. 305 to 316, in which de Cooker discloses that during the Direct Process synthesis, a gradual deactivation of the contact mixture surface occurs. He speculates that this deactivation may be caused by a number of factors. For example, the deposition of carbon and carbonaceous products may block part of the surface. Furthermore, the activity can be decreased by decreasing the content of the promoters on the contact mixture surface per se, for example, as caused by the evaporation of ZnCl 2 , by the accumulation in the reactor of elements present as contaminants in the silicon, for example, iron, by the increase of free copper on the surface causing enhanced cracking, or by the blocking of the reactive sites by reaction of the contact mixture with traces of oxygen, yielding silicon and copper oxides. Silicon used in the experiments as disclosed in that article was technical silicon, as opposed to metallurgical silicon, wherein the main impurities of the technical silicon were described as being 0.4% weight Fe, 0.1% weight Al and 0.3% weight of each of Ca and Mg, and before use, the silicon was washed with water, dried, and treated with a magnet to remove part of the iron present in the silicon.
Thus, there is a need to overcome the impurity buildup and allow the reaction to run longer, with greater efficiency and increased yields, with better control over the products that are produced. Several references discuss impurities and their removal by withdrawing a stream from the reactor, separating an impurities-lean portion and returning it to the reactor. The term “content ratio” as used herein is calculated as the ratio of the weight percent of a given element in an impurities-rich fraction divided by the weight percent in an impurities-lean fraction. A content ratio of 1.0 indicates that there are equal concentrations of the given element in rich and lean fractions and thus no separation occurred for that element.
One solution for the removal of the impurities from the fluid bed reactants during the course of the reaction and thus decrease the impurity buildup in the reactors is disclosed in U.S. Pat. No. 4,307,242 that issued to Shah et al. on Dec. 22, 1981 in which a size classification method, e.g., aerodynamic centrifugal classifier, is used.
U.S. Pat. No. 4,281,149, that issued Jul. 28, 1981 to Shade describes a means of abrading a portion of the silicon particles in the reactor so surface poisoning is overcome and fresh reaction surfaces are exposed. Whenever used herein, the term “abraded” or “abrasion” means the processes set forth in Shade, which disclosure is incorporated herein by reference for what it teaches about the abrasion of solid particles from reactors.
The inventors herein are aware of other disclosures in the prior art that deal with the separation of metals from divided solid materials using magnetic separation technologies. There are two such disclosures from the refinery industry, neither of which deal with the magnetic separation of components from silicon-containing materials. One such piece of prior art is U.S. Pat. No. 5,147,527, that issued Sep. 15, 1992 to Hettinger, which discloses the magnetic separation of high metals-containing catalysts into low, intermediate and high metals, and active catalyst. Thus, the patent describes an improved process for converting carbo-metallic oils into lighter products using catalysts, the enhancement being a process of passing a portion of the catalyst particulates through a high strength magnetic field of at least one kilogauss and field gradients of at least 10 kilogauss/inch while conveying them on an electrostatic conducting belt and recycling the more active catalyst back to the process in which it was initially used.
A second disclosure can be found in U.S. Pat. No. 6,194,337, that issued on Feb. 27, 2001 to Goolsby, et al., in which the magnetic susceptibility of impure particles is enhanced to improve magnetic separation of undesirable contaminants in a catalyst.
Various references describe the application of magnetic forces to remove ferromagnetic and paramagnetic particulate impurities from mine ores and slurries. Svoboda, Jan., “Magnetic Methods for the Treatment of Minerals”, Developments in Mineral Processing -8”, ISBNO-44-42811-9, Elsevier, New York, 1987, reviews the state of magnetic separation technology. Other general references include “Magnetic Separation”, Perry's Chemical Engineers' Handbook , McGraw-Hill, New York, 7 th Edition, 1998, pp. 19-49 and Oberteuffer, John, Wechsler, lonel, “Magnetic Separation”, Kirk - Othmer Encyclopedia of Chemical Technology , 3 rd Edition, 1978, John Wiley & Sons, New York, Volume 15, pp.708-732. These references describe the technology of the induced magnetic roll separator, the permanent magnetic roll separator, the high gradient magnetic separator (HGMS), and open gradient magnetic separator, all of which are useful in the instant invention.
Some applications of magnetic separation have been demonstrated in silicon related chemistry. Wang, et al., in Magnetic and Electrical Separation , “Purification of Fine Powders by a Superconducting HGMS with Vibration Assistance, Vol. 10 (2000), pp. 161-178 demonstrate the ability of an HGMS to remove Fe 2 O 3 from quartz. Seider, et al., in U.S. Pat. No. 4,810,368, that issued on Mar. 7, 1989 shows the beneficial separation of magnetic impurities from silicon carbide. Barraclough, et al., in U.S. Pat. No. 5,349,921, that issued Sep. 27, 1994, improved the impurity distribution in semiconductor grade silicon with the application of a 500 gauss magnetic field during crystal growth. Wiesner, in U.S. Pat. No. 6,264,843, that issued on Jul. 24, 2001, teaches how to remove impurities from the machining of semiconductor material wherein particles from saw blades or lapping plates can be magnetically separated from the cutting fluid used during the machining process for silicon.
Various authors have reported on magnetic susceptibility of silicon-containing materials. U. Birkholz, et al., report in Physica Status Solidi, 1969, No.34, pp. K181-K184 the magnetic susceptibility of α-FeSi 2 in the temperature range of 0° C. to 1000° C. The α-FeSi 2 has low magnetic susceptibility with a flat response in the temperature range of 0° C. to 400° C. Small amounts of excess silicon added make the magnetic susceptibility negative, that is, diamagnetic. D. Mandrus, et al., in Physical Review B, Vol. 51. No. 8, February 1995, pp. 4763-4767, report the magnetic susceptibility of FeSi in the temperature range of 50 K to 700 K. The FeSi shows a peak magnetic susceptibility at approximately 225° C. However, from the FeSi phase diagram from O. Kubaschewski, Iron- Binary Phase Diagrams, Springer-Verlag, 1982, pp. 136 to 139, and from reported intermetallic phases of commercial grade silicon, FeSi is not expected to be present in the feed silicon for the Direct Process.
None of the above-described references teach, show, or describe the magnetic separation of magnetic influenced species from silicon materials from fluid bed reactors to benefit the production of silanes. Also, none of the above-described references teach, show or describe an optimum temperature for magnetically separating the impurities expected to be present in the silicon.
The processes disclosed and claimed herein control impurity buildup in the fluid bed of the reactor and enhance the reaction therein to provide a more efficient process, better selectivity, better process control and longer run times for the reaction.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic drawing of one embodiment of the process.
FIG. 2 is a graph of the results of the experiment set forth in Example 7.
THE INVENTION
What is disclosed as the invention herein is the use of magnetic separators for treating silicon-containing materials from fluid bed reactors to remove magnetically influenced components in the silicon-containing materials, the essentially purified silicon-containing materials per se obtained thereby, the use of the purified silicon-containing materials in the production of alkylhalosilanes, the processes therefor, along with modifications of fluid bed reactants (silicon-containing materials) in conjunction with the magnetic separation of impurities therefrom, the purified silicon-containing materials that are obtained from comminuting treatments, modified in conjunction with the magnetic separator, the aerodynamic classification treatments, modified in conjunction with the magnetic separator, the materials that are obtained from abrading treatments in conjunction with the magnetic separator, and the combination of the comminuting-modification and aerodynamic classification-modification in conjunction with the magnetic separator application.
Thus, in addition, it is contemplated within the scope of this invention to combine the teachings of Shade to enhance the reactivity of the fluid bed reactants in conjunction with the magnetic separator aspect of the invention disclosed and claimed herein.
Further, it is contemplated within the scope of this invention to combine the teachings of Shah from the '242 patent to reduce the impurities of the fluid bed solids in conjunction with the magnetic separator aspect of the invention disclosed and claimed herein, and finally, it is contemplated within the scope of this invention to combine both the Shade and Shah teachings in combination and in conjunction with the magnetic separator aspect of this invention to obtain enhanced results in the use of fluid bed reactors to produce chlorosilanes.
And further, it is contemplated within the scope of this invention to combine the teachings of Shade from the '149 patent to reduce the impurities of the fluid bed solids in conjunction with the magnetic separator aspect of the invention disclosed and claimed herein.
As used herein, “magnetically influenced components” means those materials contained in the silicon-containing materials from a fluid bed reactor that are separable from the silicon-containing materials by the use of a magnetic field, and include, for example, those that are ferromagnetic, paramagnetic, or diamagnetic in nature, and including those materials that by their physical nature, or by their association with such ferro-, para-, or diamagnetic materials, are carried along with the ferro-, para-, or diamagnetic materials, and are thus capable of being removed from the fluid bed silicon-containing materials. Magnetically influenced components include those mixtures enriched in species preferentially attracted in the magnetic fraction and those depleted of species preferentially repulsed in the non-magnetic fraction. Magnetically influenced compounds might also include ferrimagnetic and antiferromagnetic species. Examples of the fluid bed silicon containing materials have been set forth Supra with regard to the discussion in the paragraph surrounding U.S. Pat. No. 5,334,738.
A first embodiment of this invention is a process of treating silicon-containing solid material used in a reactor for producing chlorosilanes, the process comprising subjecting the silicon-containing solid material that has been used in said reactor, to a magnetic separator apparatus to separate constituents in the silicon-containing solid material into a magnetic portion and a non-magnetic portion.
A second embodiment of this invention is a process where the silicon-containing solid material from the fluid bed of a fluid bed reactor is removed from the reactor wherein the process comprises removing the silicon-containing solid material from a fluid bed of a fluid bed reactor, subjecting the silicon-containing solid material to a magnetic separator apparatus to separate constituents in the silicon-containing solid material into a magnetic portion and a non-magnetic portion and then returning the non-magnetic portion of the silicon-containing solid material to a fluid bed of a fluid bed reactor. Note that this embodiment contemplates that the treated silicon-containing solid material may be returned to the reactor that it was removed from or may be returned and used in a different fluid bed reactor.
Another embodiment of this invention is the use of the above-described process in a process for the production of alkylhalosilanes and more specifically, in the Direct Process for the production of alkylhalosilanes and in a process for the production of trichlorosilane.
Yet another embodiment of this invention is the silicon-containing materials per se that are produced by subjecting them to magnetic separation in which the silicon-containing materials are reduced in impurities.
Still another embodiment of this invention is a process for the preparation of chlorosilanes wherein the process comprises providing a fluid bed reactor and charging the fluid bed reactor with comminuted silicon, at least one catalyst for a Direct Process reaction, and at least one promoter for the Direct Process reaction. Thereafter, providing an alkyl chloride to the fluid bed reactor to form a fluid bed in the reactor and allowing the comminuted silicon, catalyst, promoter, and alkyl chloride to interact and react to produce alkylchlorosilanes at a desired ratio and at a desired reaction rate. Thereafter, upon a certain increase in the desired ratio or a reduction in the desired rate of the reaction, subject the contents of the fluid bed to a process comprising treating the fluid bed contents by subjecting the fluid bed contents to a magnetic separator apparatus to separate constituents in the fluid bed contents into a magnetic portion and a non-magnetic portion. Thereafter, removing the magnetic portion of the fluid bed contents from the fluid bed of the fluid bed reactor and continuing the Direct Process.
A further embodiment is a process for the preparation of chlorosilanes. The process comprises providing a fluid bed reactor and charging the fluid bed reactor with comminuted silicon, at least one catalyst for a Direct Process reaction and, at least one promoter for the Direct Process reaction. Thereafter, providing an alkyl chloride to the fluid bed reactor to form a fluid bed in the reactor and allowing the comminuted silicon, catalyst, promoter, and alkyl chloride to interact and react to produce alkylchlorosilanes at a desired ratio and at a desired reaction rate. Thereafter, upon a certain increase in the desired ratio or a decrease in the desired reaction rate, subject the contents of the fluid bed to a process comprising treating the fluid bed contents by comminuting the fluid bed contents to abrade the solids or to reduce the average particle size of the solids therein and then subjecting the comminuted fluid bed contents to a magnetic separator apparatus to separate constituents in the fluid bed contents into a magnetic portion and a non-magnetic portion. The magnetic portion of the fluid bed contents are removed from the fluid bed of the fluid bed reactor and the Direct Process is continued.
Going to yet another embodiment of this invention, there is a process for the preparation of chlorosilanes, the process comprising providing a fluid bed reactor and charging the fluid bed reactor with comminuted silicon, at least one catalyst for a Direct Process reaction, and at least one promoter for the Direct Process reaction. Thereafter, providing an alkyl chloride to the fluid bed reactor to form a fluid bed in the reactor and allowing the comminuted silicon, catalyst, promoter, and alkyl chloride to interact and react to produce alkylchlorosilanes at a desired ratio and at a desired rate. Thereafter, upon a certain increase in the desired ratio or a decrease in the desired reaction rate, subject the contents of the fluid bed to a process comprising treating the fluid bed contents by reducing and removing impurities from the solids portion of the fluid bed contents by subjecting the fluid bed contents to a size classification method using an aerodynamic centrifugal classifier process and then subjecting the purified fluid bed contents to a magnetic separator apparatus to separate constituents in the fluid bed contents into a magnetic portion and a non-magnetic portion. Thereafter, removing the magnetic portion of the fluid bed contents from the fluid bed of the fluid bed reactor and continuing the Direct Process.
Still, there is provided another embodiment of this invention which is a process for the preparation of chlorosilanes, the process comprising providing a fluid bed reactor and charging the fluid bed reactor with comminuted silicon, at least one catalyst for a Direct Process reaction, and at least one promoter for the Direct Process reaction and thereafter, providing an alkyl chloride to the fluid bed reactor to form a fluid bed in the reactor. Thereafter, allowing the comminuted silicon, catalyst, promoter and alkyl chloride to interact and react to produce alkylchlorosilanes at a desired ratio and at a desired reaction rate and upon a certain increase in the desired ratio or a reduction in the desired reaction rate, subject the contents of the fluid bed to a process comprising treating the fluid bed contents by comminuting the fluid bed contents to abrade the solids or to reduce the average particle size of the solids therein and thereafter, reducing and removing impurities from the milled solids portion of the fluid bed contents by subjecting the fluid bed contents to a size classification method using an aerodynamic centrifugal classifier process. The purified fluid bed contents are then subjected to a magnetic separator apparatus to separate constituents in the fluid bed contents into a magnetic portion and a non-magnetic portion and thereafter removing the magnetic portion of the fluid bed contents from the fluid bed of the fluid bed reactor and continuing the Direct Process.
Going to yet another embodiment of this invention, there is a process for the preparation of chlorosilanes, the process comprising providing a fluid bed reactor and charging the fluid bed reactor with comminuted silicon, at least one catalyst for a Direct Process reaction, and at least one promoter for the Direct Process reaction. Thereafter, providing an alkyl chloride to the fluid bed reactor to form a fluid bed in the reactor and allowing the comminuted silicon, catalyst, promoter, and alkyl chloride to interact and react to produce alkylchlorosilanes at a desired ratio and at a desired rate, Thereafter, upon a certain increase in the desired ratio or a decrease in the desired reaction rate, subject the contents of the fluid bed to a process comprising treating the fluid bed contents by reducing and removing impurities from the solids portion of the fluid bed contents by treating the fluid bed contents by abrading the fluid bed contents to remove impurities form the surface of the fluid bed contents particles and thereafter subjecting the purified fluid bed contents to a magnetic separator apparatus to separate constituents in the fluid bed contents into a magnetic portion and a non-magnetic portion. Thereafter, removing the magnetic portion of the fluid bed contents from the process and continuing the Direct Process.
DETAILED DESCRIPTION OF THE INVENTION
As set forth Supra, there is disclosed herein a process for the use of magnetic separators for treating silicon-containing fluid bed materials to remove magnetically influenced components in the silicon-containing materials.
Turning to FIG. 1, there is shown therein a schematic diagram of the process and apparatus 1 for the magnetic separation of magnetically influenced components 2 in silicon-containing materials 3 wherein a portion of the reaction mass (silicon-containing solid materials 3 ) are removed from the fluidized bed reactor 4 , subjected to the magnetic separator 5 and then returned to the fluidized bed reactor 4 .
As shown by way of example, metallurgical grade silicon 6 , methyl chloride 7 , catalysts and promoters 8 are fed to a fluidized bed reactor 4 . A magnetic separator 5 processes a portion of the reaction mass 3 . The silicon-containing solid materials 3 may optionally be diverted from the fluidized bed reactor 3 to be processed by the magnetic separator 5 , or alternatively, processed in-situ within the fluidized bed reactor 4 or treated by a process (not shown) to reduce the impurities before being moved to the magnetic separator 5 . The silicon-containing solid materials 3 as the feed material can be removed continuously, intermittently, or according to a batch schedule. The non-magnetic fraction 9 can be returned to the original reactor 4 or a separate secondary reactor (not shown) for further reaction of the treated silicon-containing materials 3 . The magnetic fraction 10 is removed from the original reactor 4 in order to control the impurities accumulation over time. The objective of this process is to improve the performance of the fluidized bed reactor and to improve the crude chlorosilane product 11 selectivity. The details of the actual use of the magnetic separator in this manner are set forth in the examples set forth infra.
As far as is known by the inventors herein, any magnetic separator devices that are effective for separating the magnetically influenced material are useful in the process of this invention. There are several commercial separators, some of which are described in Perry's Handbook and Kirk-Othmer Encyclopedia identified supra.
It should be understood by those skilled in the art that the metallurgical silicon that is used in reactors for the preparation of chlorosilanes can be treated with magnetic separators to remove magnetically influenced components prior to its use in such reactors, and it is contemplated within the scope of this invention to use such a treatment in conjunction with the processes disclosed and claimed herein, and especially when it is desired to remove “tramp” magnetically influenced components, especially iron, from such silicon. “Tramp” components are those components that are added to the metallurgical silicon through comminution processes that are applied to the silicon to reduce the size of the particles prior to its use in the reactors.
EXAMPLES
Example 1
A Carpco Model MIH(13) 111-5 high intensity induced roll magnetic separator manufactured by Outokumpu Technology Incorporated, Carpco Division, Jacksonville, Fla. was used to separate a sample of metallurgical grade silicon. The silicon was partially reacted with methyl chloride in a fluidized bed reactor before application in this example. The magnetic separator was set to process the sample at 180 rpm roll speed, 3 amp coil current, and 76% vibrator speed. The knife position was set at 87 degrees. The feed was separated into a magnetic fraction, a middle (intermediate) fraction, and a non-magnetic fraction. The elemental analysis is shown in Table 1 below. Iron shows a high content ratio of 14.65. Removal of iron and other non-silicon elements such as Al, Ca, Cr, etc. enhances the process and improves performance.
The relatively lower content ratio for copper is a desirable benefit. This indicates that separation of iron from an operating commercial fluidized bed reactor will remove relatively less of the copper catalyst present in the system. Copper (as elemental copper, a salt, or an oxide) is an expensive additive required to catalyze the reaction. Preferential removal of non-silicon, non-copper particles is a desirable feature of an impurities separation system.
Example 2
An Eriez model 50-4 dry vibrating magnetic filter (DVMF) was used to separate a sample of partially reacted silicon removed from a commercial fluidized bed reactor. The unit operated at 5000 gauss field strength. The cylinder was loaded with a ¼ inch expanded metal matrix that was vibrated vertically at 1200 rpm at an amplitude of 0.090 inches. The starting metallurgical grade silicon was comminuted in a ball mill and partially reacted with catalyst, promoters and methyl chloride. The feed to the DVMF was separated into a magnetic and non-magnetic fraction. The elemental analysis for this material is shown in Table 2 infra.
As shown in Table 2, the iron content ratio is high. The copper content ratio is relatively low. The carbon content ratio indicates that in addition to metallic impurities, carbonaceous deposits are also unexpectedly preferentially removed by magnetic separation. Other non-silicon, non-copper elements are also preferentially removed which enhances the process.
Example 3
The magnetic and non-magnetic fractions from Example 2 were analyzed using scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS). This analysis was performed to determine if magnetically susceptible metals were uniformly distributed within the silicon samples and if particles of certain known intermetallic impurities were more prevalent in the magnetic fraction when compared to the non-magnetic fraction. The samples were adhered to carbon tape on a graphite SEM stub. For this analysis, a thin layer of carbon was deposited onto the samples to make them conductive for the SEM/EDS analysis. Thirty particles in each sample were randomly chosen and analyzed to determine their atomic composition.
After the random analysis was completed, a “backscatter” analysis mode was employed. This mode showed particles with atomic weights higher than pure silicon. These areas were further explored to determine the composition of high atomic weight particles.
Most of the particles in the magnetic and non-magnetic fractions were highly pure silicon with greater than 90% weight silicon. In the magnetic fraction, thirteen of thirty particles contained greater than 0.1% weight iron. In the non-magnetic fraction, only one of thirty particles contained greater than 0.1% weight iron. In the randomly sampled magnetic fraction, two particles were observed with greater than 49% weight iron. With the machine in a backscatter mode, one further particle was identified with greater than 91% weight iron. No similar particles with greater than 30% weight iron were observed in the non-magnetic fraction. The elemental content of these high iron particles is consistent with the composition of grinding balls used in the ball mill used to comminute the lump silicon for use in this example. The grinder balls are gradually worn down, and the iron is thereby added to the powdered silicon. These three high iron particles are believed to be grinding ball fragments.
Several particles observed contained atomic compositions consistent with those previously reported in the open literature and attributed to intermetallic impurities commonly found in metallurgical grade silicon. For example, discrete particles of Si 8 Al 6 Fe 4 Ca can be observed in the magnetic fraction. In the random analysis of the magnetic fraction, two of the thirty particles are Si 8 Al 6 Fe 4 Ca. A third Si 8 Al 6 Fe 4 Ca particle was located in the magnetic fraction when analyzed in the backscatter mode (non-random sampling). The atomic compositions of these particles are shown in Table 3 infra with a reference composition for the Si 8 Al 6 Fe 4 Ca phase from Margaria, T., Anglezio, J. C., Servant, C., “Intermetallic Compounds in Metallurgical Silicon, INFACON 6, Proceedings of the 6 th International Ferroalloys Congress , Cape Town. Volume 1, Johannesburg, SAIMM, 1992, pp. 209 to 214. No Si 8 Al 6 Fe 4 Ca particles were found in the non-magnetic fraction.
Other non-silicon particles were observed with compositions substantially consistent with the reported compositions of the phases FeSi 2.4 Al, Si 2 FeTi, and CaSi 2 (with CaCl 2 ). The non-silicon metals particles observed were more prevalent in the magnetic fraction than in the non-magnetic fraction.
Example 4
The following demonstrates the benefit of partially reacting the silicon to improve magnetic separation. Metallurgical grade silicon was comminuted in a commercial ring roller mill and fed to a High Gradient Magnetic Separator (HGMS) capable of 20,000 gauss magnetic field. In this sample, the field strength was limited to 3000 gauss. The results can be found in Table 4, Infra.
There is virtually no concentration of non-silicon metals in this experiment. At the same field strength of 3000 gauss, a sample of silicon, partially reacted in a fluid bed reactor was processed. The results are presented in Table 5, infra.
Example 5
To demonstrate the harmful effect of iron on the direct process, iron powder was intentionally added to a sample of silicon and reacted in a laboratory direct process reactor. Numerous reactions with commercial metallurgical grade silicon were made to establish that the reactor system was in a state of statistical process control. A standard copper based catalyst and promoters were added to a batch of silicon and reacted with methyl chloride for 44 hours in a temperature-controlled oven at 320° C. To the test samples, iron powder was added to double the iron content. The iron used was Alpha Products catalog number 00170, 325 mesh (44 micron), 99.9+% purity on a metals basis. The results are shown on Table 6 infra. As shown from the Table, the elemental iron significantly harmed the T/D ratio.
Example 6
A portion of the magnetic fraction from Example 2 was tested to demonstrate the effect of temperature on the magnetic susceptibility of the material. The powdered silicon was placed in a 3 mm diameter quartz tube. The tube was evacuated and sealed with a torch. The magnetic susceptibility was tested with a Hartshorn mutual inductance bridge constructed according to the description by Maxwell, E., “Mutual Inductance Bridge for AC Susceptibility Measurements at Low Frequencies”, Review of Scientific Instruments, Volume 36, 1965, pp. 553-554. The test coils consisted of a primary coil with a winding density of 3150 turns/meter and two secondary coils wound in opposition with 120 turns each. The mutual inductance between one of the secondary coils and the primary coil was measured. Measurements were made of the empty coils and the sample of the magnetic fraction from Example 2. The measurements were calibrated, and the empty coil data was subtracted from the sample measurements and then normalized to units of nanohenries. A graph of results is shown in FIG. 2 with a drawn curve of best fit. As can be observed from FIG. 2, a peak magnetic susceptibility was observed at approximately 217° C.
Comparative Example 1
The various separation methods are compared to show the utility of the preferred magnetic processes compared to other magnetic and prior art non-magnetic separation methods. For comparison to a non-magnetic separation method, size classification, for example, separation of cyclone fines, as described by Shah et al. in U.S. Pat. No. 4,307,242 is included. The feed material is separated into two fractions. Fraction 1 is the iron-rich fraction that is the magnetic fraction of the examples in this invention or the fine fraction of the Shah examples. Fraction 2 is the purified fraction that is the non-magnetic fraction of the examples in this invention or the coarse fractions in the Shah examples. Example numbers for the Shah patent refer to those descriptions designated in the patent. The magnetic fraction designations are identified above. The comparison is set forth in Table 7, infra.
TABLE 1
Magnetic Separation With an Induced Roll Magnet
Total
Weight
Weight
Fraction
Al
Ca
Cu
Fe
in grams
%
wt. %
wt. %
wt. %
wt. %
Feed
207.48
100%
0.202
0.106
4.3
1.04
Magnetic
21.00
10.4
0.811
0.23
5.73
6.11
fraction
Middle
71.53
35.5
0.119
0.079
4.51
0.38
fraction
Non-magnetic
108.96
54.1
0.130
0.081
3.46
0.417
fraction
Content ratio
6.24
2.84
1.66
14.65
Note:
Additional metals were concentrated in the magnetic fraction. These include Cr, K, Mg, Mn, Na, Ni, P, Sn, Ti, V and Zn that had content ratios from 1.30 to 15.36.
TABLE 2
Magnetic Separation with a DVMF
Total
Weight
Weight
Fraction
Al
C
Ca
Cu
Fe
Grams
%
wt. %
wt. %
wt. %
wt. %
wt. %
Feed
4641.6
100%
0.24
0.34
0.15
4.6
1.0
Magnetic
132.6
2.9
2.40
1.40
0.85
6.1
15.0
fraction
Non-magnetic
4509.0
97.1
0.17
0.32
0.15
4.6
0.58
fraction
Content ratio
14.20
4.38
5.67
1.33
25.86
Note:
Additional elements including Mg, Mn, P, Sn, Ti, and Zn had content ratios from 1.84 to 24.76.
TABLE 3
Separation of Intermetallic Impurities
Si
Al
Fe
Ca
Mn
Particle type
wt. %
wt. %
wt. %
wt. %
wt. %
Si 8 Al 6 Fe 4 Ca.
43.3
29.8
20.9
5.6
0.4
as reported by
Margaria et al.
Magnetic fraction
40.1
24.3
18.9
4.0
0.6
particle number
1-5
Magnetic fraction
41.4
26.4
16.5
5.8
0.6
particle number
2-5
Magnetic fraction
42.9
26.1
17.0
4.5
0.7
particle number
1BS-4
TABLE 4
Poor Separation of Unreacted Comminuted Silicon
Weight
fraction
Al
Ca
Fe
Ni
%
wt. %
wt. %
wt. %
wt. %
Magnetic
4.3
0.17
0.12
0.32
0.006
fraction
Non-magnetic
95.7
0.15
0.13
0.31
0.005
fraction
Content Ratio
1.13
0.92
1.03
1.20
TABLE 5
Superior Separation of Partially Reacted Silicon
Weight
fraction
Al
Ca
Fe
Ni
%
wt. %
wt. %
wt. %
wt. %
Magnetic
13.3
1.02
0.58
5.6
0.05
fraction
Non-magnetic
86.7
0.39
0.32
0.9
0.012
fraction
Content ratio
2.62
1.81
6.22
4.17
TABLE 6
Damaging Effect of Iron on Direct Process Selectivity
Feed
Fe
T/D
% wt.
ratio
Standard Metallurgical Grade Silicon
0.34
0.072
Standard Silicon Plus Iron Powder
0.64
0.103
TABLE 7
Comparison of Separation Methods
Fe in
Fe in
Fe in
feed
fraction 1
fraction 2
Content
Separation Method
% wt.
% wt.
% wt.
Ratio
Shah Example 2H
3.6
4.6
2.8
1.64
Shah Example 4
2.5
4.9
1.9
2.58
High Grad. Magnetic Separator
1.53
5.6
0.9
6.22
Ex. 4
Induced roll Magnet Example 1
1.04
6.11
0.417
14.65
Dry Vibrating Magnetic Filter
1.0
15.0
0.58
25.86
Ex. 2 | Magnetic separators are used for treating silicon-containing materials from chlorosilane reactors to remove magnetically influenced components in the silicon-containing materials. The removal of such impurities allows for enhanced reactivity of the silicon-containing materials in processes wherein the silicon-containing materials are raw materials for the production of silicon based compounds, such as, for example, basic alkylhalosilanes such as dimethyldichlorosilane, methyldichlorosilane, and other chlorosilanes such as trichlorosilane, which chlorosilanes are useful in the preparation of valuable silicon-containing products. | 2 |
INTRODUCTION AND BACKGROUND
The present invention relates to the use of N-alkanoyl compounds as activators for hydrogen peroxide and for inorganic peroxo compounds which are sources of hydrogen peroxide and capable of releasing it in aqueous phase, wherein the activation consists in the formation of an organic percarboxylic acid. In a further aspect, the present invention relates to these new activators and their use in washing, bleaching and cleaning agents as well as disinfectant compositions containing inorganic peroxo compounds.
Inorganic peroxygen compounds are used as oxidizing agents in bleaching, washing and cleaning agents and disinfectants in order to improve the action of such agents. Hydrogen peroxide and such substances as release hydrogen peroxide in aqueous solution, such as perborates and percarbonates, in particular are used as peroxygen compounds. The action of the inorganic peroxygen compounds depends on the pH value and considerably on the temperature. While at temperatures above about 80° C. a good effect is achieved, it is known that at lower temperatures, especially at or below about 60° C. or at or below about 40° C., the co-utilization of so-called activators is required with the named inorganic peroxygen compounds. The activators are principally N-acyl or O-acyl compounds. In aqueous phase percarboxylic acids, which display a good washing, cleaning, bleaching and disinfecting action in the low-temperature range also, are formed out of H 2 O 2 or H 2 O 2 -releasing inorganic peroxygen compounds and the activators.
Among the N-acyl compounds, numerous classes of substances have been proposed in the past as activators, including N,N,N',N'-tetraacetylethylenediamine (TAED), N,N,N',N'-tetraacetylglycoluril (TAGU), N-(C 1 to C 4 )- or N-(C 6 to C 10 )-alkanoylhydantoins (DE-C 19 49 561 and U.S. Pat. No. 4,412,934 respectively), N,N'-(C 1 to C 8 )-alkanoyl-2,5-diketopiperazines (DE-A 20 38 106) and N-(C 1 to C 4 )-alkanoylsuccinimide (DE-C 19 49 561 and GB-B 855735). Despite this variety of proposed activators, of the N-acyl compounds previously disclosed essentially only TAED has been successful on the market.
From U.S. Pat. No. 4,412,934 bleaching agent compositions are known that contain as the activator, substances of the formula R--CO--L, wherein R is an alkyl group with 5 to 18 C atoms, whose longest chain R--CO has 6 to 10 carbon atoms, and the conjugate acid of the leaving group L has a pK a value of 6 to 13. Among the leaving groups, many groups linked to R--CO via oxygen but also a few via amide nitrogen are disclosed, including the N-hydantoinyl group, but not the N-succinyl group. Preferred leaving groups are phenol derivatives; the group R preferably represents linear (C 5 to C 9 )-alkyl chains; the activator nonanoyloxybenzenesulphonate (NOBS) is particularly preferred. NOBS is a very active activator, contained in conventional commercial bleaching agent compositions, whose bleaching effect exceeds that of TAED.
In view of the growing demand for washing, bleaching and cleaning agents and disinfectants for the low-temperature range, there is an interest in further activators based on N-acyl compounds, which come up to or exceed the property characteristics of NOBS. The activators should as far as possible be accessible from easily available raw materials and be readily biodegradable.
SUMMARY OF THE INVENTION
An object of the invention is to improve the low temperature performance of washing, bleaching and cleaning agents and disinfectants.
Another object of the invention is to devise formulations for the above purpose that are convenient to manufacture and do not adversely impact the environment. In achieving the above and other objects, one feature of the invention resides in the use of N-alkanoyl compounds of the formula (I), ##STR2## wherein R 1 represents a C 6 to C 10 alkyl group, and
R 2 represents hydrogen, an HOOC-- or HO 3 S-- group or a salt thereof, a C 1 to C 4 alkyl group or a hydroxyl group,
as activator for hydrogen peroxide and inorganic peroxo compounds that are sources of hydrogen peroxide and capable of releasing it in aqueous bleaching, washing, cleaning and disinfecting liquids.
In carrying out the present invention, in the aqueous bleaching, washing, cleaning and disinfecting liquids, the pH value is adjusted to greater than 4 up to 13, preferably to 8 to 11 and, a percarboxylic acid with 7 to 11 C atoms, active in bleaching and disinfection, is formed by perhydrolysis of the activator of formula (I). Peroxo-n-nonanoic acid is particularly active, so that the use of activators of formula (I) with R 1 equal to n-octyl is preferred. Activators with R 2 equal to hydrogen are also preferred because of their easy manufacture from readily available materials.
DETAILED DESCRIPTION OF THE INVENTION
The method according to the present invention relates to the activation of H 2 O 2 and such inorganic peroxygen compounds that release hydrogen peroxide in the aqueous phase especially perborates, in particular sodium perborate monohydrate and sodium perborate tetrahydrate, superoxidized sodium perborate and sodium percarbonate (2Na 2 CO 3 ·3H 2 O 2 ). Perphosphates, persilicates and persulphates can also be used. Several inorganic peroxo compounds can also be present during the activation. These compounds are well known in the art.
0.05 to 1 moles, preferably 0.1 to 0.5 moles, of activator of formula (I) are used for activation per equivalent of active oxygen of the hydrogen peroxide present and releasable from the inorganic peroxo compounds.
The activators to be used according to the invention can be used for activation in pure form or with auxiliary substances, such as granulating auxiliaries, stabilizers, and pH-regulating substances; suitable forms of addition are powders, pastes, tablets, granules or coated granules.
Activators to be used according to the invention are obtainable by conventional acylation of succinimide which is represented by the structural formula: ##STR3## Alternatively, they may be obtained by acylation of succinimide monosubstituted according to formula (I), such as malimide, 2-methylsuccinimide, 2-carboxysuccinimide or 2-sulphosuccinimide, with the required alkanoyl halide with 7 to 11 C atoms, such as nonanoyl chloride. While N-alkanoylsuccinimides with 1 to 5 as well as 12 and 18 C atoms in the alkanoyl groups have been described, the activators according to the invention, such as the particularly preferred nonanoylsuccinimide, are new substances.
The activators and peroxygen compounds can be used according to the invention both in purely aqueous phase and in aqueous-organic phase. A purely aqueous phase is present in the conventional washing, bleaching and cleaning liquors. An aqueous-organic medium can be suitable in disinfectant applications as well as for industrial oxidation processes. The pH value of the reaction medium can range from about 4 and 13, but processes are preferably operated in the alkaline range, usually at pH 8 to 11, since in this range not only the in-situ formation of the organic peracid proceed well but also the stability of the peroxo compounds is satisfactory.
A further provision of the invention is directed to bleaching, washing and cleaning agents and disinfectants that contain an inorganic peroxo compound and an activator selected from the group consisting of N-acylated succinimides and N-acylated monosubstituted succinimides of the previously mentioned formula I that are usable according to the invention. N-n-nonanoylsuccinimide is preferred as activator in these agents. The agents again contain the substances mentioned previously, in particular sodium perborates and sodium percarbonate, as inorganic peroxo compound. The agents contains 0.05 to 1 moles, preferably 0.1 to 0.5 moles, of activator of formula (I) per equivalent of active oxygen from the inorganic peroxo compound or compounds.
The agents can contain one or more inorganic peroxygen compounds as well as one or more activators, including at least one according to the invention and also conventional commercial or other previously known activators as required.
Activators to be used according to the invention and inorganic peroxygen compounds can be combined with all conventional ingredients of washing and bleaching agents in order to obtain washing and bleaching agents which are suitable for textile treatment in the low- and medium-temperature ranges, but also for washing at the boil.
The main constituents of such washing and bleaching agents, aside from the peroxo compounds and activators mentioned, are builders and surfactants. Among the builders, in particular sodium aluminum silicates (zeolites), phyllosilicates, condensed phosphates, alkali metal silicates, alkali metal carbonates, complexing aminocarboxylic acids, polyphosphonic acids, multivalent hydroxycarboxylic acids as well as polycarboxylic acids and salts of the acids have to be mentioned. To be mentioned, especially among the surfactants are nonionic surfactants, such as polyethylene glycol ethers of fatty alcohols and of alkylphenols as well as long-chain alkylglycosides, and anionic surfactants, such as alkylbenzenesulphonates and sulphates of fatty alcohols and polyethyleneglycol monoethers. Other substances in the washing and bleaching agents are electrolytes, pH-regulating substances, stabilizers, foam regulators, anti-redeposition agents, optical brighteners, enzymes and finishing agents. The substances and amounts to be used in such agents are known to the expert - H. G. Hauthal provides a review together with literature in "Chemie in unserer Zeit" 26 (1992) Nr. 6, 293-303).
Washing and bleaching agents according to the invention generally have the following composition:
______________________________________5 to 30 wt %, preferably 10 to 25 wt %, anionic and/or nonionic surfactants,5 to 60 wt %, preferably 20 to 40 wt %, builders selected from the group consisting of sodium aluminum silicates, condensed phosphates, alkali metal silicates, alkali metal carbonates and mixtures thereof,0 to 20 wt %, preferably 1 to 8 wt %, builders selected from the group consisting of complexing aminocarboxylic acids, polyphosphonic acids, polycarboxylic acids or their salts as well as mixtures thereof,2 to 35 wt %, preferably 10 to 25 wt %, inorganic peroxo compounds selected from the group consisting of sodium perborates and sodium percarbonate,0.3 to 20 wt %, preferably 1 to 10 wt %, of N-alkanoylsuccinimide compounds of formula (I) to be used according to the invention as activators to 100 wt % conventional auxiliary substances and water.______________________________________
Pure bleaching agents, such as can be used as additives for washing agents free of bleaching agents, generally have the following composition:
______________________________________5 to 50 wt %, in particular 15 to 35 wt %, inorganic peroxygen compounds, in particular sodium borate monohydrate or tetrahydrate or/and sodium percarbonate,2 to 50 wt %, in particular 5 to 25 wt %, N-alkanoylsuccinimide compounds of formula (I) to be used according to the invention as activators,0 to 5 wt % peroxide stabilizers, such as water glass and complexing agents,0 to 40 wt % pH-regulating agents,to 100 wt % other conventional auxiliary substances.______________________________________
Cleaning agents according to the invention usually contain surfactants, builders, peroxidated compounds and activators to be used according to the invention; scouring agents contain in addition constituents with abrasive action.
Disinfectants according to the invention are based in general on a combination of inorganic peroxo compounds and activators to be used according to the invention as well as auxiliary substances selected from the group consisting of stabilizers, surfactants, pH-regulating substances and, optionally, organic solvents and microbiocidal substances other than the percarboxylic acids formed from the activators and peroxo compounds.
It has been established that the activator effect of the activators, based on N-acyl compounds, to be used according to the invention sharply exceeds that of previously known N-acyl compounds, such as the TAED put on the market. Unexpectedly, the activator effect also does not merely approach that of the previously most effective activator NOBS, but surpasses it. The outstanding effect of the activators of formula (I) and of N-n-nonanoylsuccinimide in particular was surprising since N-alkanoylsuccinimides with few C atoms in the alkanoyl group have already been described as activators in the prior art. Measured by delta diffuse reflection increase (%) after washing in the Launder-o-meter under US washing conditions at 30° C. and equal dosages by weight of the activators, the effect of N-n-nonanoylsuccinimide is higher by a factor of about 2.3 than that of N-acetylsuccinimide, which is not according to the invention. The effectiveness as activators of TAED and NOBS is furthermore evident from the following table. The washing agent compositions used for the test and the concentrations of use thereof are to be taken from example 2.
TABLE 1______________________________________Delta diffuse reflection increase (%)*Activator Mean value** Ketchup______________________________________N-n- 1.7 2.3nonanoylsuccinimideN-acetylsuccinimide 0.7 -0.3TAED 0.4 -1.5NOBS 1.4 1.0without activator 0.0 0.0______________________________________ *Delta diffuse reflection increase (%) is obtained by subtracting the diffuse reflection increase for washing agents free from activator and bleaching agent from the diffuse reflection increase for washing agents containing activator and bleaching agent. **Mean value from 9 test strains in each case with coffee, tea, red wine, paprika, ketchup and curry.
The unusual effect of the activator according to the invention compared with NOBS in the bleaching of tomato ketchup stains also is evident from the preceding table.
The peracid release from activators according to the invention and sodium perborate is retarded compared with N-acetylsuccinimide and compared with NOBS, which can be advantageous with regard to the preservation of the activity of the enzymes which the washing agent possibly contains.
EXAMPLE 1
N-Nonanoylsuccinimide
20 g succinimide were suspended in 100 ml pyridine, 0.5 g N,N-dimethylaminopyridine added, and 39.2 g nonanoic acid chloride added dropwise at ice-bath temperature. Subsequently the mixture was stirred for 1 h at room temperature and 500 ml of 2N HCl solution were added with cooling. The aqueous phase was extracted with ethyl acetate and the organic phase washed with 2N HCl solution and dried (Na 2 SO 4 ). After removing the solvent, the residue was twice recrystallized from n-hexane. 31.6 g (65%) N-nonanoylsuccinimide were obtained as a colourless solid. Melting point: 59 to 60° C. (n-hexane). The 1 H-NMR spectroscopic data are in agreement with the structure.
EXAMPLE 2
Investigation of the activator effect of nonanoylsuccinimide by comparison with the activators not according to the invention, N-acetylsuccinimide, TAED and NOBS,
______________________________________Washing appliance: Launder-o-meterWashing temperature: 30° C.Water hardness: 5° dWashing programme: 500 ml washing tank 200 ml washing liquor 15 min washing time 3 × 30 sec rinsing timeLiquor ratio: 1:20Dosing: 1.35 g/l, equal to 0.27 g/wash cycle, of a washing agent, commercially available in the USA and free of bleaching agent and activator (containing anionic surfactants, zeolite A, sodium citrate, sodium sulphate, sodium silicate, soda and enzymes) 0.015 g each of sodium perborate monohydrate and activator per wash cycle.Test fabric: cottonTest stains: coffee, wfk 10K; tea wfk CFT BC-1; paprika wfk 10 N; curry wfk CFT BC-4; red wine EMPA 114; tomato ketchup wfk 10 T.______________________________________
After the washing of the test fabric, the diffuse reflection increase is measured in each case and compared with the diffuse reflection increase obtained by means of washing agent free of activator and bleaching agent (=delta remission). The values on which the diffuse reflection increase is based are mean values from nine of the same soilings.
The results follow from Table 1, which has already been described previously.
EXAMPLE 3
Peracid release by n-nonanoylsuccinimide in comparison with that by N-acetylsuccinimide.
8 g/l of washing agent free from bleaching agent and activator, 1.5 g/l sodium perborate monohydrate and 0.5 g/l activator were weighed into water at 30° C. and the formation of pernonanoic acid or peracetic acid determined as a function of time.
The following table shows the peracid equivalent after time t based on 1 mole of activator.
TABLE 2______________________________________ Equivalents period N-Time (min) N-nonanoylsuccinimide acetylsuccinimide______________________________________ 2 0.54 1.0 6 0.81 1.010 0.87 1.015 0.89 0.9920 0.90 0.9830 0.92 0.95______________________________________
EXAMPLE 4
Activator effect of N-n-Nonanoylsuccinimide and NOBS at 30° C. in the presence of sodium perborate and an enzyme-containing washing agent.
Cotton test fabric with blood staining (wfk CFT CS1) was washed. Washing appliance, washing temperature, wash programme and liquor ratio according to Example 2; water hardness 14° d.
Dosage:
Compact washing agent: 3.8 g/l=0.76 g/wash cycle
Washing agent recipe in g/l liquor:
______________________________________Washing agent constituents in g/l liquor______________________________________Alkylbenzenesulphonates 0.52Fatty alcohol ethoxylates 0.35Soap 0.10Zeolite A 1.52Polycarboxylates 0.18Soda 0.76Na and Mg silicates 0.24CMC 0.06Auxiliary substances (total) 0.07 3.8 g/l______________________________________
Enzymes: 0.085 g/l=0.0171 g/wash cycle protease (Savinase of the Novo company).
Bleaching agent: 0.144 g/wash cycle sodium borate monohydrate (SPM).
Activator:
a) 0.125 g/wash cycle N-n-Nonanoylsuccinimide
b) 0.144 g/wash cycle NOBS
The dosage of the activators was equal to that of the peracids:
O a from H 2 O 2 , 76 mg/l in each case; O a from peracid (calculated) each 33 mg/l.
After the wash, the diffuse reflection increase was measured:
TABLE 3______________________________________ Diffuse reflection increase (%)______________________________________a) N-n Nonanoylsuccinimide + 8.9SPMb) NOBS + SPM 8.1______________________________________
Comparison shows that the activator according to the invention surpasses the previously known activator.
Further modifications and variations of the foregoing will be apparent to those skilled in the art and are intended to be encompassed by the claims appended hereto.
German priority application P 44 30 071.9 is relied on and incorporated herein by reference. | A and N-acyl compounds are used for the activation of inorganic peroxo compounds in washing, bleaching and cleaning agents and disinfectants. Compounds of formula (I) ##STR1## wherein R 1 represents a C 6 to C l0 alkyl group; and R 2 represents hydrogen or selected substituents, are highly effective activators for aqueous bleaching, washing, cleaning and disinfecting liquors. A particularly preferred activator is N-n-nonanoylsuccinimide. | 2 |
BACKGROUND OF THE INVENTION
1. Field of Invention
This invention relates to a paddle support for a vessel to allow a rower to rest a paddle while rowing the vessel or while at rest. More particularly, the paddle support includes an elastic portion that allows extension of the support to accommodate reach or extension of the paddle position while also allowing return to a predetermined height.
2. Description of Related Art
The use of paddle supports and/or locks to assist in rowing a vessel is well known in the prior art. Typically, these devices provide support for an oar or a paddle and may also provide leverage to the rower during operation. These devices may be attached to the outer hull of the vessel, or they may be mounted on the floor of the vessel with a post that extends upward to engage a paddle or an oar at a height which facilitates the individual rower.
SUMMARY OF THE INVENTION
Paddle supports can be removably or permanently attached to a vessel during operation. This requires the paddle to be fixed in a position prior to operation. While this may provide the rower with both leverage and support, it also restricts the rower's range of motion when manipulating the paddle. If a rower accidentally removes the paddle from the support, he must then direct his time and attention to returning the paddle to the operating position within the support. Thus, these devices require the rower to make a conscious effort to return the paddle to the support before rowing may continue.
In addition, these devices do not allow the rower to reposition the support laterally without either removing and reattaching the support or making some other type of adjustment. Further, a rower may find it necessary from time to time to push the vessel away from fixed objects, such as rocks or peers, or to push debris away from the vessel itself In these situations, the necessity to remove and replace the paddle in the support may become problematic. This may be especially so when the vessel is moving rapidly through areas with many fixed objects, i.e., areas of rivers and streams containing rapids. Further, in other situations it may be necessary for the rower to shift his weight or move within the vessel in order to maneuver the vessel. For example, a rower maneuvering through an area of heavy surf in the ocean may need to lean forward or backward within the kayak to negotiate a wave. Likewise, the rower may also need to lean forward or backward when negotiating areas of rivers and streams containing rapids. In these situations, the ability of the rower to quickly and freely manipulate the paddle and adjust the reach of the paddle may be crucial in preventing injury to the rower as well as damage to the vessel. This is particularly true when the vessel is a kayak.
This invention provides an apparatus and method for supporting a paddle during operation of a vessel. The paddle support of this invention utilizes freestanding support sections that are telescopically attached to one another and removably attached to the paddle. The paddle support need not be attached to the vessel. This allows the rower to manipulate the paddle freely with the support attached. The paddle support is made up of a retainer at the top portion for retaining the paddle, an upright support section made up of telescopically connected support sections that may be adjusted or set to a proper height to facilitate the rower, and a base section that rests freely on the floor of the vessel. Further, in one exemplary embodiment, an elastic member can be located in a center of the separate support sections. The elastic member allows the rower to extend the paddle support beyond its overall length in various directions when the paddle support is attached to the vessel. This arrangement allows the paddle support to be manipulated either forward or laterally to facilitate the comfort of the rower, and to allow the rower to maneuver the paddle as necessary during operation. This is especially advantageous in situations involving fast moving water, such as rapids, or surf, and that the rower can quickly manipulate the paddle to push off of rocks and obstructions, or negotiate surf, returning just as quickly to rowing the vessel.
The paddle support of this invention may be adjusted in height to facilitate the comfort of the individual rower. This aids in reducing arm fatigue, by allowing the rower to operate the paddle in a range of motion which is most comfortable. It also allows the rower to rest the weight of the paddle in the rower's arms on the support during periods when the vessel is not being actively rowed.
In vessels such as canoes and kayaks, a rower may use a skirt to prevent water from entering the vessel. Typically, the skirt would cover the area between the rower's body and the edge of the inside of the vessel; for example, the exposed cockpit area of the kayak. Paddle support in the prior art are not particularly conducive for use with a skirt, because the support must either be attached a considerable distance from the rower's body, or must penetrate the skirt itself, creating a point where water may enter the vessel. In addition, because the supports of the prior art are in a fixed position and attached to the vessel itself, there is greater possibility of injury to the rower when operating in rough water conditions.
One exemplary embodiment of the current invention alleviates this condition, allowing for use of the paddle support with a skirt. In this embodiment, clamps may be removably attached to the rim of the cockpit area of a kayak. The clamps not only can support the paddle support but also can couple the paddle support and paddle to the vessel via elongated members. The clamps can be connected to a bottom portion of the paddle support via the elongated members. In addition, the clamps may allow for a quick release from the vessel when a predetermined force is applied. An example of this may be when the rower desires a quick exit from the vessel. On the other hand, when use of the clamps are not desired, the clamps can attach to the paddle support itself. This arrangement allows for compact storage of the paddle support.
The elongated members may be suspended across the cockpit area of a kayak or canoe when a skirt is utilized. The upright support portion of the paddle support may be located at the center portion of the vessel opening. When used in this manner, the clamps attach to the coaming or the edge of the vessel opening so as to provide tension across the elongated members with the base portion resting on the skirt. The elongated members may further be maintained in tension over the opening by a downward force exerted by the rower's arms, paddle, and paddle support all bearing down on the elongated members. In this way the support may be maintained close to the rower's body without interfering with a water tight skirt.
At least one of the elongated members may be provided with an extended portion to attach to the vessel. The extended portion acts as a back up leash in the event the clamps release from the vessel so that both the paddle support and paddle remain coupled to the vessel.
When the skirt is not used, the paddle support may alternatively rest on the bottom interior of the vessel or be suspended in tension across an opening above the base of the vessel via the elongated members and clamps.
Moreover, the base portion of the paddle support may also have a contact area of a material with a friction coefficient sufficient to reduce slippage. The contact area assists in providing a stable environment for using the paddle support, for example when the paddle support is placed on the bottom interior of the vessel.
In addition, an elastic member can be located within the central portion of the paddle support. The elastic member allows the rower to freely move the paddle such that he may extend the paddle past the overall length of the paddle support in an extended position and allowing the paddle to quickly return to the retracted rest position. The elastic member maintains the integrity of the paddle support by maintaining a connection between the retainer and the rest of the paddle support. In a preferred embodiment, the elastic member is located within the upper and lower support sections of the paddle support. One end of the elastic member is affixed to a lower portion of the lower support section while the opposing end is attached to the retainer at the upper portion of the upper support section. The arrangement and number of elastic members may vary. For example, the elastic member may be attached to an upper portion of the upper support section instead of the lower support section so as to allow greater mobility without having the upper and lower support sections from coming apart. Alternatively, the elastic member may also be non-elastic as long as the paddle is allowed to move past the set height when greater mobility is desired. However, this may not result in the ability to automatically return to the predetermined height. Thus, a greater freedom of movement may be achieved by virtue of the elastic member contained on the paddle support.
The height of the support may be varied by adjusting the overall length of the elongated member suspended over the opening and or adjusting the height of the paddle support itself. In various exemplary embodiments, the upper support section has holes for adjusting the height of the paddle support. The upper support section slidably fits within the lower support section. In a preferred embodiment, the upper support section has a plurality of predetermined spaced apart holes for height adjustment. A flexible plug is inserted into a hole for the desired height. Then, with the weight of the rower's arms and paddle bearing down on the paddle support, the upper section is pushed down within the lower section. When this occurs, the flexible plug is wedged between the upper and lower support sections so as to lock the paddle support from moving in a vertical direction and rotating about the longitudinal axis of the upper and lower support sections.
In another preferred embodiment for setting the height of the paddle support, a rigid plug member is provided. The plug member fits into the holes of the upper support section to allow the rower to adjust the overall height of the paddle support based on the location of the plug in the particular hole in the upper support section. The plug member in this embodiment prevents the upper support section from sliding further downward within the lower support section, while allowing the upper support section to rotate about the longitudinal axis of the upper support section. In this arrangement, the plug member provides the rower greater mobility by allowing the upper support section to move in an upward vertical direction when desired and to return to the set height via the elastic member.
Furthermore, the paddle support may be manufactured from any material that is lightweight to allow the paddle support to float in the water. In addition, the paddle support may be of any color that will allow for easy detection in the water.
Lastly, the apparatus and method of this invention allows for easy removal and storage of the paddle support. This in turn, facilitates the easy handling and transporting of the vessel, and that the entire paddle support apparatus is removed from the vessel leaving no outward projections which could hinder mounting and transporting on a vehicle.
These and other features and advantages of this invention are described in, or are apparent from, the following Detailed Description of Preferred Embodiments.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be described with reference to the accompanying drawings in which like elements are labeled with like numbers, and in which;
FIG. 1 shows an exemplary embodiment of a typical vessel with rower, paddle, skirt and paddle support according to this invention;
FIG. 2 is another exemplary embodiment of a vessel paddle and paddle support of this invention;
FIG. 3 is an exemplary embodiment of the paddle support of this invention suspended over the opening of a vessel by an elongated member;
FIG. 4 is an exemplary embodiment of the paddle support of this invention having an elongated member attached at the basis of the support for suspending the device over the opening of a vessel;
FIG. 5 is a cross-sectional view of an exemplary embodiment of a telescoping paddle support according to this invention;
FIG. 6 is an exemplary embodiment of the paddle support shown in an extended position;
FIG. 7 is an exemplary embodiment of this invention showing the clamps attached to the paddle support;
FIG. 8 is an exemplary embodiment of the paddle support showing an embodiment of the locking mechanism;
FIG. 9 is another embodiment of the locking mechanism;
FIG. 10 is an exemplary embodiment of a retainer and bushing for maintaining a paddle on a paddle support;
FIG. 11 is an exemplary embodiment of the paddle support on a canoe; and
FIG. 12 is an exemplary embodiment of the paddle support attached to a kayak.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
FIG. 1 shows an exemplary embodiment of the paddle support 100 . The paddle 20 is mounted to the top of the paddle support 100 by a retainer 50 at the upper portion of the paddle support 100 . The lower portion of the paddle support 100 is placed on top of skirt 35 while clamps 220 attach to both the skirt 35 and the coaming or rim 15 of the vessel 10 . With this arrangement water is prevented from entering the vessel 10 and also allowing the rower 30 to manipulate the paddle 20 in a full range of operational motion. The weight of the paddle 20 and the rower's arm on the paddle support 100 is ultimately distributed to the vessel 10 .
FIG. 2 is another exemplary embodiment of a vessel, paddle and paddle support of this invention. A longitudinal view of a typical vessel 10 is shown with the paddle support 100 shown in place resting on the interior bottom or base 60 of the vessel 10 . In this embodiment, the paddle support 100 is made up of a lower section 40 and an upper section 45 . However, it should be appreciated that in various exemplary embodiments, the paddle support 100 of this invention may be made up of an individual section or several sections without departing from the scope of the invention. The paddle support 100 has a lower ball section 100 connected to a base section 120 that rests on the bottom of the vessel 60 . According to one exemplary embodiment of the paddle support 100 of this invention, the base section 120 may be a suction cup. In other exemplary embodiments, the base section 120 may be a flat or rounded member that allows the paddle support to simply rest freely on the bottom of the vessel 60 . In this embodiment, the paddle support 100 is not attached to the vessel in anyway. This allows the rower to freely manipulate the paddle 20 with the paddle support 40 connected in anyway necessary without the encumbrance of having the paddle 20 physically attached to the vessel 10 . The vessel 10 has a rim 125 that may be used to connect the paddle support 100 to the vessel 10 . Those skilled in the art should recognize that the paddle support 100 may be used with a wide variety of vessels, and is not limited to the exemplary vessels shown.
FIG. 3 is an exemplary embodiment of the paddle support of this invention suspended over the opening of a vessel by an elongate member. As illustrated, paddle 20 is attached to the upper portion of paddle support 100 . In this embodiment, the paddle support 100 is suspended above seat portion 5 and over opening 25 of vessel 10 by the elongated members 200 which are attached to the rim 15 via clamps 220 . By adjusting the upper section 45 relative to the lower section 40 , the paddle support 100 may be placed in a desired position by the rower 30 . This also allows room for the rower's legs to fit below the elongated members 200 . In this manner, the weight of the paddle 20 and paddle support 100 may be supported by the rim 15 of the vessel 10 . The elongated members 200 may be of a flexible material that allows the paddle support 100 to rotate freely from the point of connection at the lower ball section 110 .
FIG. 4 is an exemplary embodiment of a paddle support according to this invention. As illustrated, paddle support 100 comprises a lower section 40 and upper section 45 that are telescopically connected. The upper section 45 has a plurality of spaced a part holes 130 for positioning the upper section 45 relative to the lower section 40 in order to adjust the paddle support 100 to the proper height for the rower 30 . Upper ball section 115 is connected to the top of the upper section 45 . Upper ball section 115 may also accommodate elastic member 125 (not shown). Attached to the upper ball section 115 is the retainer 50 for holding a paddle 20 (now shown). The retainer 50 is fastened to the upper ball section by fastener 55 as shown in FIG. 5 . The fastener 55 may be in the form of a screw or any other suitable type connecting means, such as a pin, bolt, nut, rod, hook and loop type fastener etc. In the embodiment of FIG. 4, a compass 75 is mounted to the top of the retainer 50 . However, in other exemplary embodiments, a clock, light or other such device may be mounted in lieu of a compass 75 . In addition, the compass 75 may be mounted at other portions of the paddle support 100 without departing from the scope of the invention.
The lower section 40 is connected to lower ball section 110 . Lower ball section 110 has a flexible portion that allows the paddle support 100 to pivot about lower ball 110 . Also lower ball 110 has ball opening 115 that accommodates elongated members 200 . The elongated members 200 pass through ball opening 115 and have at opposing ends clamps 220 . As mentioned above clamps 220 may be fastened to the rim or coaming 125 of vessel 10 . When a sufficient amount of tension is supplied to the elongated members 200 , paddle support 100 may suspend over opening 25 of vessel 10 as shown in FIG. 3 . Clamps 220 remain fixed to rim 125 but when a predetermined amount of force is applied, for example when rower 30 desires a quick exit, at least one of clamps 220 may easily release from the rim 125 . Lower section 40 has base 120 that is connected to lower ball section 110 is also connected to base 120 . Base 120 may be a flat or rounded member for resting the paddle support 100 on base 60 of vessel 10 as depicted in FIG. 2 or on skirt 35 as shown in FIG. 1 . Base 120 may alternatively be in the form of a suction cup for temporarily attaching the paddle support 100 to base 60 or skirt 35 . The elongated members 200 may be in the form of ropes, or can be manufactured from any suitable material such as plastic or elastic material. In addition, the clamps 220 may be flexible to facilitate attachment to the rim of the vessel, or they may be of a rigid material and tightened into place by adjusting the elongated members 200 . The elongated members may also be adjusted in length by the rower 30 to facilitate a desired placement of the paddle support 100 within the vessel 10 .
FIG. 5 is a cross-sectional view showing the telescoping connection of upper and lower support sections of a paddle support according to this invention. As illustrated, upper section 45 and lower section 40 are telescopically connected such that upper section 45 freely moves within lower section 40 . The plurality of holes 130 located in upper section 45 accommodate plug 135 so as to allow the rower 30 to adjust upper section 45 to a desired height. An elastic member 125 has opposing ends that each respectively attach to upper section 45 and lower section 40 . This arrangement allows the elastic member 125 to provide tension to urge the upper section 45 towards the lower section 40 . In this way the elastic member 125 allows a rower 30 to extend the paddle support 100 as depicted in FIG. 6 and then return to the set height position. The rower may also set the desired tension by adjusting elastic member 125 between upper section 45 and lower section 40 . Elastic member 125 allows a greater range of motion for rower 30 to manipulate a paddle 20 during use.
Alternatively, the elastic member 125 need not be attached to the lower support section 40 . The elastic member 125 may instead be attached to the upper support section 40 at one end and the other end attached to retainer 50 . In this way the rower 30 will still be allowed a desired range of motion by allowing paddle 20 to be lifted off of the paddle support 100 . In this arrangement upper support section 45 and lower support section 40 need not separate as shown in FIG. 6 .
FIG. 6 also shows leash 210 extending from clamp 220 . Leash 210 may be an extension of elongate member 200 and tethered to vessel 20 . If vessel 20 is capsized paddle support 100 and paddle 20 are prevented from drifting away from the vessel 20 . Alternatively, leash 210 may be used to retain the paddle support 100 in place when clamps 220 are fixed to rim 125 . To accomplish this, leash 210 may be wrapped around the rim 125 of vessel 10 so as to go around and behind rower 30 and tethered to the opposing clamp 220 . This additionally prevents clamps 220 from sliding along the rim 125 .
FIG. 7 shows the embodiment of the paddle support of FIG. 4 . In this view clamps 220 are retained on the lower support section 40 . This allows the paddle support 100 to be more compact for storage and also allows the rower 30 the option of not utilizing clamps 220 when using the paddle support 100 in the manner shown in FIG. 2 .
FIG. 8 shows an exemplary embodiment of a locking mechanism for the paddle support. In this view an extra length of elastic member 125 or any other elastic member extends from the upper area of paddle support 100 . The extra length of elastic member 125 is then fed into one of the plurality of holes 130 depending on the desired height for the paddle support 100 . A force is then applied to the paddle support 100 so that the upper support section 40 slides to the desired height. The extra length of elastic member 125 is then wedged or pinched between upper and lower sections 40 and 45 . The extended portion of elastic member 125 locks or sets the paddle support to the desired height. Also, the wedging of the extended portion 125 prevents upper support section 45 from rotating within lower support section 40 . However, when a predetermined upward force is applied, the upper support section 45 telescopingly extends to allow for a greater range of motion. When the rower 30 desires to return the paddle 20 to the set height the elastic member 125 provides a sufficient amount of tension to return the upper support section 45 within lower support section 40 to the predetermined set height.
Instead of using the extended portion of elastic member 125 to set the height of the paddle support 100 , a plug 135 may be inserted into hole 130 in order to set the upper section 45 at the proper height relative to the lower section 40 as shown in FIG. 9 . Plug 135 may be kept in place with an elastic band 136 that wraps around the upper section 45 , or may be maintained in the hole via an interference fit. Elastic band 136 allows the plug 135 to be retained on either the upper support section 45 or lower support section 40 . In this embodiment, upper section 45 is allowed to rotate about lower section 40 .
FIG. 10 is an exemplary embodiment of an elastic strap 80 and bushing 70 in place on a detachable paddle 20 . As illustrated, bushing 70 are located on opposite sides of retainer 50 . Bushings 70 are circular “C” shaped rings. The “C” shape allows bushings 70 to deflect to accommodate various paddle shaft diameters and attach around the shaft of paddle 20 . The bushings may also be made be of any material that will deflect to the shape of the various paddle diameters. Elastic straps 80 are then placed over the bushings 70 in order to maintain the bushings 70 in place on either side of the retainer 50 . This arrangement allows the rower 30 to position the paddle 20 in a desired location on top of the paddle support 100 and prevents the paddle 20 from sliding in either direction relative to the retainer 50 during rowing.
For use with a non-detachable paddle 20 retainer 50 is un-strapped from paddle support 100 and then strapped around the desired area along the shaft of paddle 20 . As mentioned above bushing 70 are positioned on opposite sides of the retainer 50 along the paddle shaft to retain the paddle 20 in the desired position and to prevent the paddle 20 from sliding out of the retainer 50 . Further, any means may be used to prevent bushing 70 from sliding out the shaft of paddle 20 . For example, an elastic strap or adhesive tape may be used to retain bushing 70 to a desired position.
FIGS. 11 and 12 show the versatility of the paddle support 100 . FIG. 11 shows two paddle supports 100 being used with a canoe. FIG. 12 shows a single paddle support 100 being used with a kayak.
While this invention has been described in conjunction with specific embodiments outlined above, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, the preferred embodiments of the invention as set forth above, are intended to be illustrative, not limiting. Various changes may be made without departing from the spirit and scope of the invention. | A paddle support for a vessel, such as a kayak or canoe. The paddle support includes an upright support member of adjustable length and a retainer at the top portion of the upright support member for retaining a paddle. The upright support member has an elastic cord that allows the paddle to extend past a predetermined set height to allow a rower a greater range of operation motion, while allowing return to the predetermined set height upon release of an external force. | 1 |
FIELD OF THE INVENTION
The present invention relates to a bearing plate for a safety binding securing the front end of a ski boot to a ski, this binding being equipped with a member for retaining the boot via a part of the sole which protrudes from the front end of the boot and is clamped between the retaining member and the bearing plate interposed between the ski and the boot, said bearing plate being compressible so as to adapt to the variations in thickness of the part of the sole clamped between the bearing plate and the retaining member.
Because of manufacturing tolerances, the thickness of the sole may vary by about plus or minus one millimeter. If the distance between the bearing plate and the retaining member of the binding is fixed, the force with which the sole is clamped varies with the thickness of this sole. An excessive clamping force has the effect of increasing the release values of the safety binding and therefore compromises the skier's safety. This is also the case when a binding which was initially adjusted for a child's sole is used by an adult.
PRIOR ART
Patent FR 2 655868 discloses a bearing plate consisting of a support plate which is integral with a base plate and is connected to this base plate by a bent part forming an elastic hinge. After repeated flexions, a hinge of this type presents risks of breaking due to fatigue of the material. Further, a bearing plate of this type presents a substantially constant resistance throughout its flexion travel. Now, it would be expedient for the force with which the sole is clamped by the binding to be higher for an adult than for a child. This is because a child is substantially less heavy than an adult, so that the adaptation of the level of the bearing plate to the variations in the thickness of the sole which are due to manufacturing tolerances would need to take place more easily than for an adult. It would therefore be desirable for the resistance of the bearing plate to pressure to increase with pressure. Take-up of the thickness tolerances of soles by an elastic means is also provided by document DE-A-32 30186.
In document WO 91/08808, it is proposed to interpose a layer of damping material between a bearing plate and the ski, it being possible for this damping material to have a progressive stiffness as a function of its compression, because of its shape or the material which forms it. The sole purpose of this material is to damp shocks and vibrations, but a bearing plate of this type will also have a tendency to adapt, in certain cases, to a variation in the thickness of the sole.
SUMMARY OF THE INVENTION
The object of the invention is to produce a bearing plate which adapts systematically to the variations in the thickness of the sole, in particular both to the soles of a child's boot and to the soles of an adult's boot, while presenting greater resistance to an adult's weight than to a child's weight and also being capable of withstanding repeated deformations without fatigue.
The bearing plate according to the invention is one which comprises an elastic body which is precompressed between a rigid mobile element intended to support the sole and a base connected to the ski, and means for limiting the deformation of the elastic body, these means consisting of at least one rigid face which opposes the free deformation of the elastic body, in at least one direction, beyond a certain deformation of this elastic body, so as to form a nonlinear system whose resistance to pressure is relatively small in a first range of deformation and is substantially higher in a second range of deformation.
According to one embodiment, the elastic body is in the form of a sleeve surrounding a rigid base, this base having at least approximately the form of a truncated pyramid or cone opposing the deformation of the sleeve beyond a certain degree of deformation.
The rigid element resting on the elastic body is advantageously surrounded and retained vertically by a retaining body fixed to the ski.
The bearing plate according to the invention makes it possible to obtain relatively low resistance to pressure in a first range of deformation, for example two millimeters, and a substantially higher resistance to pressure for a deformation exceeding two millimeters, for example between 2 millimeters and 3.5 millimeters, which values correspond to the maximum thickness of the sole of a boot for an adult. The level of the bearing plate, and with it the force by which the sole is clamped, will therefore adapt more easily to the variations in thickness of the sole of a boot for children.
BRIEF DESCRIPTION OF THE DRAWINGS
The appended drawing represents, by way of example, two embodiments of the bearing plate according to the invention.
FIG. 1 is a perspective view, without the binding, of the first embodiment.
FIG. 2 represents a view in vertical longitudinal section thereof, along the plane of symmetry, with the binding represented and the front of a child's boot engaged in the binding, these being represented by thin lines.
FIG. 3 is a similar view to FIG. 2, with an adult's boot engaged in the binding.
FIG. 4 represents the ideal deformation curve of the bearing plate as a function of the force exerted on this bearing plate.
FIG. 5 represents some alternatives for the cross section of the elastic body.
FIG. 6 is a view in longitudinal section of a second embodiment with a child's sole.
FIG. 7 is a similar view to FIG. 5 with an adult's sole.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIG. 1 shows a rigid element 1 which is surrounded and retained vertically by a retaining body 2, extended to the front by a part 3 in the form of a plate by which the body 2 can be fixed on a ski using two screws passing through holes 4 and 5. Once fitted, the binding will cover the part 3.
FIGS. 2 and 3 illustrate an example of applying the first method.
FIG. 2 represents the bearing plate fixed on a ski 6 with a binding body 7 including a retaining member 8 which, in known fashion, retains a boot 9 via its sole 10 which protrudes from the front end of the boot. The central part of the bearing plate is occupied by a base 11 in the form of a truncated pyramid with four faces. A sleeve 12 of elastic material is arranged around this base, the height of which sleeve is greater than the height of the base 11. Via its bottom, the base 11 positions the sleeve 12 transversely, while its inclined faces allow the sleeve to deform in the direction of its axis.
The rigid element 1 is retained in the retaining body 2, on the one hand, by a hook 13 and, on the other hand, by a lug 14 which catches under an engaging surface 15 of the retaining body 2.
The sleeve 12 is made of elastic material, for example SBS (Styrene Butadene Styrene), SEBS (Styrene Ethylene-Butadene Styrene, PDM (Polydimethylsiloxane), EPM (Ethylene Propylene Monomer), TPU (Thermoplastic Urethane) or natural or synthetic rubber. This material can also be a material which yields and thus is relatively inelastic.
In order to fit the rigid element 1, it is necessary for the sleeve 12 to be compressed to a certain degree. In the position represented in FIG. 2, the sleeve 12 is therefore slightly precompressed, so that the bearing plate already presents some resistance to compression. In the same figure, the thickness of the sole 10 of the child's boot which is represented is minimal, and the precompression of the sleeve 12 presents sufficient resistance to prevent the rigid part 1 from moving downward. If the sole 10 is slightly thicker, this variation in thickness will be taken up by the sleeve 12, the compression of the sleeve resulting merely in a slight increase in the force by which the sole is clamped, an increase which will have no effect on the ability of the binding to release.
It should be recalled here that the sole of the boot is inserted obliquely under the retaining member 8 of the binding, which constitutes the fulcrum of a lever consisting of the boot that compresses the bearing plate, on the one hand, under the effect of the skier's weight and, on the other hand, under the effect of the rear binding element which holds the heel of the boot against the ski.
When the child's boot 9 is replaced by an adult's boot 9', provided with a sole 10' which is thicker than the sole 10 of the child's boot, the bearing plate, that is to say the sleeve 12, is subjected to a relatively high pressure. The sleeve 12 deforms transversely both inward and outward, and the sides of the base 11 soon oppose the inward deformation, so that the resistance of the sleeve 12 to the deformation increases rapidly. When the pressure is sufficient, the rigid element 1 abuts against the base 11, this maximum lowering of the bearing plate corresponding to a maximum thickness of the sole 10'.
FIG. 4 represents the shape of the variation of the force F exerted on the bearing plate, which force is given in daN, as a function of the crushing of the bearing plate. Starting from the origin, the curve which is represented has a first part, of shallow slope, extending approximately up to two millimeters of crushing. This region of the curve corresponds to a child's boot sole. The two millimeter crushing is already obtained for a force of about 5 daN. Beyond two millimeters of crushing, the slope of the curve increases rapidly. This region corresponds to crushing by an adult's boot. It extends over a range of from about 5 to 20 daN. The maximum crushing in question is 3.5 millimeters, corresponding to the position represented in FIG. 3.
The cross section of the sleeve could have a form other than the rectangular one which is represented. A few examples are represented in FIG. 5.
The nonlinearity of the pressure/deformation relationship is generally obtained by means for limiting the deformation of an elastic body, these means consisting of at least one rigid face which opposes the free deformation of the homogeneous elastic body, in at least one direction beyond a certain deformation, that is to say a certain degree of deformation.
According to the second embodiment, represented in FIGS. 6 and 7, the elastic body 16, in the form of a stud, consists of two superimposed materials 16a and 16b with different hardnesses. In the example in question, the upper layer 16a has a substantially lower hardness than the layer 16b. The elastic body 16b is mounted in a hollow of a base 17 fixed to the ski 6, and is precompressed by a rigid element 18 mounted and retained in the base 17 like the element 1 in the first embodiment. The bottom of the base 17 in which the elastic element 16 rests forms an obliquely walled dish 19. The size of this dish 19 is such that, when the relatively hard layer 16b deforms, the dish opposes the transverse expansion of the elastic body.
In FIG. 6, the boot 9 is again a child's boot, while in FIG. 7, the boot 9' is an adult's boot. The thickness of the sole 10 in FIG. 6 is a minimum thickness. The precompressed elastic body 16 is substantially undeformed by the engagement of a boot. If the thickness of the sole 10 is slightly greater than represented, the upper layer 16a of the elastic body 16 deforms so as to take up this difference in thickness.
The sole 10' represented in FIG. 7 has a maximum thickness. The bearing element 18 is at its lowermost level, bearing on the base 17, and the elastic body 16 is greatly deformed. | A bearing plate for a front binding, equipped with a member (8) for retaining the boot via a part of the sole (10) resting on the bearing plate (1), this bearing plate being compressible so as to adapt to the variations in thickness of the sole. The bearing plate forms a nonlinear system comprising an elastic body (12) which is precompressed on a rigid base (11) and opposes the deformation of the elastic body beyond a certain degree of deformation, so as to form a nonlinear system. | 0 |
TECHNICAL FIELD
The invention relates to a gas bag module for a vehicle occupant restraint device, comprising a gas bag and a discharge arrangement to expose and/or alter a discharge opening through which gas can escape from the gas bag.
BACKGROUND OF THE INVENTION
Such a gas bag module in which a discharge region can be opened in the gas bag wall when a reduction to the internal pressure of the gas bag is required, is known for example from WO-A-2004/045919. A pyrotechnic charge in the form of a fuse is arranged directly on the discharge region such that the discharge region burns through or is torn open mechanically after the fuse has been ignited.
In the gas bag module shown in WO-A-03/097407 a blast pin is provided in order to expose a tubular discharge region of the gas bag.
In EP-A-1 279 574 a gas bag module is shown in which, in order to expose discharge openings, a slider is moved in a holding piece such that bores formed therein are in alignment with the discharge openings. The hot gas flowing into the gas bag melts the region of the gas bag which is situated between the bores of the slider and the discharge openings in the holding piece, such that a portion of the gas emerges from the gas bag during filling.
A gas bag module is known from U.S. Pat. No. 6,547,274 B in which the opening cross-section of a discharge opening in a carrier plate can be exposed by means of piezoelectrically controlled flaps. The current supply of the piezoelectric elements is controlled for example depending on the posture or physique of the vehicle occupant or on the speed of the vehicle.
SUMMARY OF THE INVENTION
The invention provides a gas bag module which makes it possible to control the discharge behaviour safely for the vehicle occupant without increasing the structural space.
According to the invention, a gas bag module for a vehicle occupant restraint device comprises a gas bag and a discharge arrangement in fluid connection with the gas bag. The discharge arrangement includes a discharge opening through which gas can escape from the gas bag, and has at least one element made of an electrically activatable polymer actuator to expose and/or alter the discharge opening upon activation of said polymer actuatuor.
Electro-chemo-mechanical actuators which contain an active layer of polymers which change their volume as a function of an electrical field or electrochemical potential, are designated as polymer actuators. In addition to this active layer, the polymer actuators essentially comprise a passive carrier layer which forms a sandwich-like composite with the active layer, such that when the voltage changes, the composite bends in a similar manner to a bimetal strip with a variation in temperature. A metal layer which is in direct connection with the active layer can serve as the electrode for initiating the electrochemical processes in the active layer leading to the change in volume.
The invention makes use of the fact that the polymer actuators can already be operated at voltage changes of a few volts and can achieve large deflections. It is therefore possible to influence the discharge behaviour of a gas bag module in a specific manner with the polymer actuators. More precisely, the element provided according to the invention with the polymer actuator is used to control the effective cross-section of the discharge opening, i.e. the element provides for the creation of a discharge opening and/or a change to the discharge cross-section. Through the use of such an element, costly and large opening mechanisms can be dispensed with. The discharge arrangement according to the invention has the additional advantage that neither explosive substances or the like, nor a melting of gas bag fabric are necessary to expose a discharge opening, i.e. a separation of particles is ruled out.
Basically, the discharge opening which is controlled by means of the discharge arrangement according to the invention, can be provided on a fixed component of the gas bag module or on the gas bag.
The polymer actuator is preferably integrated into the gas bag wall, in particular woven into the fabric of the gas bag wall or connected with the gas bag fabric by being sewn or glued on. Particularly preferably, the electrochemically inert fabric material may serve as the carrier layer for the active layer of the polymer actuator. When a voltage is applied to the polymer actuator, a deformation of the gas bag fabric is then brought about, whereby a discharge region in the gas bag wall can be produced, enlarged or reduced.
In particular, a predetermined breaking point can be provided in the discharge opening, for example through the existence of tear edges or by a change to the structure or thickness of the gas bag fabric on which the polymer actuator acts.
Alternatively, the polymer actuator can also be part of a covering which is arranged over a discharge opening formed in the gas bag wall.
With an arrangement of the polymer actuator on a pivotable flap, a hinge mechanism can be produced for controlling the flap.
Finally, the polymer actuator can act together with a silicone membrane, which is integrated in either the gas bag fabric or the covering, and which bursts through activation of the polymer actuator and exposes the discharge opening.
Advantageous developments of the invention are indicated in the sub-claims.
Further features and advantages of the invention will be apparent from the following description of preferred embodiments of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a diagrammatic illustration of the gas bag module according to the invention in a case of load; and
FIG. 2 shows an embodiment of the discharge arrangement.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
In FIG. 1 a vehicle occupant 10 is illustrated, plunging into an inflated gas bag 12 of a vehicle occupant restraint system. The gas bag 12 , which has unfolded out of the housing of a gas bag module 14 , has a gas bag wall 16 on which an electrically controllable discharge arrangement 18 is arranged. The discharge arrangement 18 serves to selectively provide a discharge opening through which gas can escape from the gas bag 12 , i.e. the discharge arrangement 18 provides for a discharge opening and/or a change in the discharge cross-section to be produced. The discharge arrangement 18 comprises a polymer actuator (not illustrated) which is connected directly or indirectly with an electronic control arrangement 20 , i.e. the polymer actuator is able to be activated by the electronic control arrangement 20 .
The polymer actuator preferably comprises a passive carrier layer and also an active layer of a polymer which changes its volume upon application of an electrical field or electrochemical potential, usually in the voltage range of −3V to +3V. A metal layer which can be vapour deposited onto the active layer or the carrier layer serves for contacting or as an electrode. Through the volume change in the active layer as a result of voltage variation, the sandwich-like composite of the active layer and the passive carrier layer bends in a similar manner to a bimetal strip with a variation in temperature. The polymer of the active layer may be selected in particular from the group of piezoelectric polymers, electrostrictive polymers, polymer gels, carbon nano-capillaries, conductive conjugate polymers and ion-conducting polymers. Ion-conducting polymers or polymer gels which serve as a solid electrolyte at the same time and can therefore be used under ambient conditions without further structural measures, are preferred.
In a particularly preferred embodiment, a portion of the gas bag wall in the region of the discharge arrangement 18 serves as a passive carrier layer of the polymer actuator, i.e. the polymer actuator is integrated into the gas bag wall or the gas bag fabric. In this case, a particularly compact type of construction of the discharge arrangement is possible.
In the case of load, when a discharge of gas from the gas bag 12 of the vehicle occupant restraint system is desired, the polymer actuator of the discharge arrangement 18 can be deformed mechanically by the application of an electric voltage. This mechanical deformation of the polymer actuator causes the gas bag fabric to tear in the region of the discharge arrangement 18 and therefore causes a discharge opening to be exposed. The electrical signal which is applied to the polymer actuator may be a pure control signal here, which only brings about the exposure of the discharge opening for example after a particular period of time has elapsed since the gas bag module was activated. However, it may also be a regulating signal, when the discharge opening is only to be exposed in particular cases of load. The electronic control arrangement 20 can therefore also evaluate the data of particular sensors which measure for example the internal pressure in the airbag or determine the weight of the vehicle occupant, and then decide, as a function of the respective case of load, whether the discharge opening is exposed.
In FIG. 2 a preferred embodiment of the discharge arrangement 18 is shown, which can be opened by means of polymer actuators 22 . The fabric of the gas bag 12 is already previously impaired by two intersecting tear edges 24 perpendicular to each other, acting as a predetermined breaking point, in order to facilitate the formation of the discharge opening. In each of the four sectors formed by the tear edges 24 , a polymer actuator 22 is situated respectively on the outer side of the gas bag fabric, the passive layer of the polymer actuator 22 being connected with the gas bag fabric, for example glued on, and the active layer of the polymer actuator 22 lying over it. When the gas bag is activated, the polymer actuators 22 may, if required, also be activated by means of the electronic control arrangement (not shown). In so doing, the active layer reduces its volume and the polymer actuator 22 exerts a force onto the fabric of the gas bag 12 which leads to the fabric tearing open at the sites which have been previously impaired. The fabric then flaps outwards, with the increased internal pressure in the gas bag assisting the formation of the discharge opening. Instead of the gas bag fabric, a silicone membrane can be present in the area of the discharge arrangement 18 , which is connected to the polymer actuator 22 and which tears open through an activation of the polymer actuator.
In addition, the polymer actuator may be arranged on a pivotable flap associated with the discharge opening, the flap being able to be formed on the gas bag. Alternatively, the actuator may be arranged on a flap formed on the housing of the gas bag module 14 , illustrated schematically at 18′ in FIG. 1 .
Finally, by means of the polymer actuators according to the present invention, it is possible to open, close or only change the discharge cross-section of a discharge opening already present for example in the housing 14 of the gas bag module, depending on the respective case of load. | A gas bag module for a vehicle occupant restraint device comprises a gas bag and a discharge arrangement in fluid connection with said gas bag. The discharge arrangement has a discharge opening, through which gas can escape from the gas bag, and at least one element made of an electrically activatable polymer actuator to expose and/or alter the discharge opening upon activation of said polymer actuator. | 1 |
PRIORITY
This application claims priority to German application no. 103 23 402.0 filed May 23, 2003.
TECHNICAL FIELD OF THE INVENTION
The present invention relates to an access authorization and right of use system of a motor vehicle that is designed for an access authorization request both with and without the use of a transponder.
BACKGROUND OF THE INVENTION
In the simplest case, such an access authorization and right of use system consists of one or several locks and appropriate keys. This simple access authorization and right of use system can open the doors of the motor vehicle or start the engine by means of the corresponding access authorization request (or the right of use request). An access authorization request follows as a result of the fact that the key fitting the relevant lock is actuated. Typically, these access authorization systems also have an anti-theft protection or an immobilizer that is implemented in the control device and processes and evaluates the access authorization request.
In addition to this simplest form of an access authorization system, an access authorization can also be implemented e.g. by means of a remote control in modem motor vehicles. Modem access authorization systems in motor vehicles use electronic protection systems, for example, by using the transponder method. In the case of such electronic systems, data is communicated between a transceiver fitted in the motor vehicle and a transponder fitted for example in a key or on a key fob of the user of the motor vehicle. Before the motor vehicle is opened or put into operation, coded data that ensures a proper access authorization for example by the owner of the motor vehicle is first of all exchanged.
Which one of these access authorization systems is fitted in a motor vehicle, very often depends on the corresponding requirements of the respective country for which the relevant motor vehicles are determined. Whereas in many countries, in addition to mechanical access authorization, electronic access authorization systems had already been solely prescribed for insurance reasons, such specifications do not exist in many countries. There the simplest mechanical access authorization systems are often quite sufficient so that the cost-intensive transponder method can be abandoned there.
The problem with the above is the fact that the relevant manufacturers must distinguish which motor vehicles are designed for which countries and which access authorization systems must subsequently be allocated to this motor vehicle. This distinction of the access authorization systems in each case requires different system architectures of the different access authorization systems that in each case vary to a lesser or greater extent for the different countries. This is very costly for the manufacturer of the motor vehicle or for the supplier of such access authorization systems because he has to design his production for the different access authorization systems. In order to minimize this additional cost and particularly also for manufacturing and flexibility reasons there is the need to possibly provide a single system architecture for all the access authorization systems that is particularly the same for such access authorization systems both with and without a transponder.
SUMMARY OF THE INVENTION
Therefore, the object of this invention is to provide a uniform system architecture for different access authorization systems used in a motor vehicle.
This object of the invention can be achieved by an access and right of use system, particularly a motor vehicle that is designed for an access authorization request both with and without the use of a transponder, comprising a mechanical key to initiate an access authorization request that has a key bit for a mechanical access authorization request and a housing that is designed to hold a transponder for a wireless access authorization request, a key acceptance unit that has a mechanical lock for holding the appropriate key bit and is designed to hold an immobilizer coil for receiving the wireless access authorization request, and a control device that has a diagnostic and evaluation circuit for processing and evaluating the access authorization request and which is designed to process and evaluate both an evaluation of a signal derived from the mechanical access authorization request via the key bit and an inductively connected signal in the case of the wireless access authorization request via the immobilizer coil.
The control device may have a first controllable switch that is connected to the key acceptance unit via a connecting line and can be supplied with energy via the key acceptance unit. The control device may have a modulating/demodulating unit that via a connecting line is at least connected to the key acceptance unit that is connected to the diagnostic and evaluation unit and via which an inductively connected access authorization request can be demodulated. The diagnostic and evaluation circuit may have a program-controlled unit, particularly a microcontroller or a microprocessor. The key acceptance unit may have a second switch connected in series with its load line connected to the control device via at least one connecting line. A key fob can be provided that has a remote control means for transmitting an access authorization request via remote control and that the key acceptance unit and/or the control unit is designed to hold a receiver for receiving the access authorization request via remote control. The housing of the key can be designed to hold remote control means for transmitting an access authorization request via remote control and the key acceptance unit and/or the control device can be designed to hold a receiver for receiving the access authorization request via remote control. A start/stop device can be provided that at least has a third switch and is connected to the control device. The start/stop device may form part of the key acceptance unit. A brake switch unit can be provided that at least has a fourth switch and is connected to the control device. An energy supply unit can be provided that is connected to a control device and which at least supplies the control device with a supply potential. A lock-in device can be provided for the steering column that is connected to the control device and the energy supply unit.
The idea of this invention is based on the fact that a uniform access authorization system must be provided that is embodied in such a way that it in each case has the same system architecture for the access authorization or the right of use for the different vehicle platforms and motor vehicle variants. Therefore, for the different vehicle platforms or country requirements, the system architecture for the access authorization system need not be changed according to the invention. Here, when changing a vehicle variant to another variant only slight changes to the individual components of the access authorization system are required which can be carried out very easily by the vehicle manufacturers themselves. As a result, this system can be provided very cost-effectively.
The invention particularly provides a common architecture for an access authorization system which is designed both for using with and without a transponder. Should a transponder be used, only a corresponding transponder must be fitted in the key that can interact with an immobilizer coil specially provided for this in a receiving unit of the motor vehicle. In this case, the corresponding system requirements have also already been taken into consideration in the system architecture. Should there be an access authorization system without a transponder method, the corresponding requirements are also taken into consideration.
Advantageous developments and further developments can be taken from the description with reference to the drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
Further features and advantages of the invention will emerge from the description which follows of the embodiments and from the accompanying drawings. They are as follows:
FIG. 1 —a first exemplary embodiment of an access authorization system according to the invention;
FIG. 2 —a second exemplary embodiment of an access authorization system according to the invention; and
FIG. 3 —a third exemplary embodiment of an access authorization system according to the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In all the drawings the same elements or functionally similar elements have been provided the same reference symbol, unless specified otherwise.
According to the invention, FIGS. 1 and 2 are wiring diagrams of the access authorization systems of a motor vehicle using the same system architecture.
In FIGS. 1 and 2 the reference symbol 1 in each case designates the access authorization system. The access authorization system has a key 2 , a key acceptance unit 3 as well as a control device 4 .
Key 2 can be embodied as a mechanical key 2 that functions with the well-known key-lock principle or as a credit card or chip card in a conventional way. Key 2 has a mechanical bow 20 that can be inserted in a lock (not shown) contained in the key acceptance unit 3 to actuate it. Therefore, the key acceptance unit 3 contains the corresponding mechanical system for the key bit 20 for opening a door lock or the steering column lock.
The control device 4 is connected to the key acceptance unit 3 via feeder lines 5 . When actuating the key 2 , an access authorization system request (or right of use request) is initiated that is processed and evaluated by the control device 4 . In order to process and evaluate this access authorization request, the control device 4 has a diagnostic and evaluation circuit 6 . This diagnostic and evaluation circuit 6 can be embodied for example as a program-controlled unit, for example as a microprocessor, a microcontroller or the like. The control device 4 or the diagnostic and evaluation circuit 6 checks whether or not a used key 2 is authorized and releases the corresponding control function when the doors are opened or the engine is started should key 2 be authorized.
A start/stop device 7 can also be provided. The start/stop device 7 contains one or several switches 8 that, on the one hand, their load lines are connected to a first connection 15 for a first supply potential GND and, on the other hand, to a microcontroller 6 via a feeder line. The number of switches 8 used depends on the needs and requirements of the respective motor vehicle manufacturer. By means of the start/stop device 7 , an active start of the engine is initiated or the engine is switched off. Alternatively, the start/stop device 7 can also be connected to other components (for example the interior lighting) in such a way that after the engine has started, the interior lighting is switched off or after the engine has been switched off the interior lighting is automatically switched on again.
The function of the start/stop device 7 can also be implemented in the housing of the key acceptance unit 3 .
A brake switch unit 9 can also be provided for example for the brake light. In this embodiment, the brake switch unit 9 has a switch 10 particularly a high-side switch 10 that with a first load line connection is connected to a second connection 16 for a second supply potential VBB and the second load line connection to a microcontroller 6 via a feeder line. When the brakes are actuated this switch 10 is switched on.
A steering wheel locking unit 11 is also provided. For example, the steering wheel locking unit 11 can be embodied as a purely mechanical steering wheel locking unit or in addition or alternatively also have an electrical or electronic steering wheel unit. The steering wheel locking unit 11 is connected to the control device 4 via a single communication line.
A power switch unit 12 is also provided. The power switch unit 12 is connected to the steering wheel locking unit 11 . The power switch unit 12 supply energy to the steering wheel locking unit 11 . For this purpose, one or several preferably intelligent power switches for example relays or MOSFETs are provided. In order to supply the steering wheel locking unit 11 , the energy supply and the control unit 12 are connected to it via connecting lines. Via these connecting lines, the power switch unit 12 controls the unlocking and locking of the steering wheel locking unit 11 .
The power switch unit 12 is also connected to the control device 4 via one or several data lines 13 . The power switch unit 12 can be embodied “intelligently” for control purposes and contains a processor or a controller. In this case, the data line 13 can be embodied as the CAN bus (CAN=controller area network). Should no intelligent control unit be provided, several control lines 13 are required.
The power switch unit 12 also supplies the different units of the access authorization system 1 and the engine control system with energy. This task can equally be undertaken by means of power switches such as for example relays or intelligent MOSFETs. Of importance here is the fact that these supply lines via which the corresponding units are supplied with energy are monitored and evaluated.
An engine control system 14 which is connected to the control device 4 via connecting lines can also be provided for controlling the engine output and the engine function.
The above-mentioned embodiments show that the architectures of the access authorization systems in FIGS. 1 and 2 are the same. These are only distinguished in individual exchangeable components without there being any deviations from the common system architecture. The only difference between the access authorization systems in FIGS. 1 and 2 is that the access authorization request is purely mechanical in the embodiment of FIG. 1 whereas, in the case of the embodiment in FIG. 2 , the electronic access authorization request can in addition or alternately also be made by using a transponder. In detail:
Key:
In the embodiment in FIG. 1 , the key 2 is embodied purely mechanically, i.e. it only shows a mechanical key bit 20 for the access authorization request. Here, a transponder is not provided.
In the embodiment in FIG. 2 , the key 2 also has a transponder 21 in addition to the mechanical key bit 20 that is provided in a location 21 ′ in the bow 22 of key 2 specially provided for this purpose. This location 21 ′ in housing 22 of the key specially provided for the transponder 21 already exists for the key in embodiment 1 (shown by a dotted line), but key 2 has no transponder 21 . However, the key 2 could very easily be supplemented there with a transponder 21 .
Key Acceptance Unit:
In the case of the embodiment in FIG. 1 , the key acceptance unit 3 has a release switch 23 . Here, the release switch 23 is embodied as a high-side switch 23 . The release switch 23 with its load line is connected in series to a load resistor 24 between the first connection 15 with the reference potential GND and a supply connection 17 for connecting a supply potential VBB. The release switch 23 is typically, but not necessarily, supplied with energy via the control device 4 and evaluated by the control device 4 . For this purpose, the control device 4 is connected to the center tap 18 between the release switch 23 and the resistor 24 via a connecting line 5 . The switch 23 is switched on if the key 2 is inserted and engages in the lock of the key acceptance unit 3 . However, the switch 23 only switches on if the key 2 also fits in the corresponding lock. Opening and closing the switch 23 is controlled by inserting and/or turning the key 2 .
In the case of the embodiment in FIG. 2 , the key acceptance unit 3 also in addition or alternatively has an immobilizer coil 25 that is connected to the control device 4 via connecting lines 5 . The immobilizer coil 25 virtually forms a transceiver via which data is communicated with the transponder 21 . According to FIG. 1 , a corresponding switch 23 and a resistor 24 that are required and are present for a mechanical access authorization, are not shown in FIG. 2 for reasons of improved clarity.
According to the invention, the key acceptance unit 3 is developed in such a way that it, on the one hand, already provides the corresponding elements 23 , 24 that are required for a mechanical access authorization request via the key bit 20 and it is also designed to hold a corresponding immobilizer coil 25 there even if this is not required by the specific requirement. However, if the corresponding requirement requires the presence of a transponder 21 or an immobilizer coil 25 this could very easily be implemented in places in the key 2 or the key acceptance unit 3 specially provided for this. This can also be carried out very advantageously by the manufacturer of the vehicle. The corresponding connections and feeder lines or the corresponding development of the key acceptance unit 3 are at least partially present.
Control Device:
In the case of the embodiment in FIG. 1 , the control device 4 has a switch 26 that can be controlled by the microcontroller 6 . Here, the controllable switch 26 with its load line between the connection of an energy supply not shown in the figures, for example a battery, is connected to the supply connection 17 of the key acceptance unit 3 . A supply potential VBB can be applied to the key acceptance unit 3 via this switch 26 that can be controlled by the microcontroller 6 .
In the case of embodiment 2, the control device 4 has a modulating unit/demodulating unit 27 —frequently also designated as a base station. Typically, the modulating unit/demodulating unit 27 is connected to four feeder lines 5 with the immobilizer coil 25 . Therefore, the immobilizer coil 25 can modulate or demodulate transmitted or received data via the modulating unit/demodulating unit 27 . In order to control the modulating/demodulating unit 27 , it is connected to the microcontroller 6 .
According to the invention, the control device 4 is developed in such a way that it at least partially already has the corresponding connections and feeder lines so that it can be designed and expanded very easily both for an application according to the embodiment 1 and an application according to the embodiment 2. The control device 4 must only be supplemented here with the corresponding components.
The modulating unit/demodulating unit 27 can also be provided in the key acceptance unit 3 or alternatively also embodied as an independent device.
FIG. 3 is a wiring diagram of a third access authorization system with the same system architecture according to the invention. The switching developments of the elements 2 , 3 , 4 , 7 , 10 are not shown here for reasons of improved clarity. However, it is understood that they can conform to the developments of FIGS. 1 and 2 .
Unlike the embodiments in FIGS. 1 and 2 , a key fob 30 is also provided in the embodiment of FIG. 3 . The key fob 30 contains a remote control function (RKE=remote keyless entry) for opening the door lock(s) with the remote control. Here, the key acceptance unit 3 and/or the control device 4 has a receiver that is not shown for receiving the access authorization request via remote control. Naturally, the receiver can also be fitted at any other place. However, typically but not necessarily the remote operation is carried out at frequencies in the range of approximately 447 MHz. However, the functionality of a remote operation need not necessarily be contained in a special key fob 30 , but can rather also be implemented in the housing 22 of the key 2 . The remote operation can have several switch settings to distinguish, for example, whether or not only the driver's door, all the doors, the boot lid, etc. should be opened or whether or not these doors should be locked.
The access authorization system 1 in FIG. 3 also has a so-called control unit 31 that comprises different comfort functions of the motor vehicle. The control unit 31 controls passive access and right of use processes. The control unit 31 is also connected to the control device 4 via the CAN lines 13 .
Although this invention was described above on the basis of preferred embodiments, it is not limited to these, but can be modified in many ways.
For example, according to the invention, the system architecture for an access authorization system 1 must not necessarily have all the units such as the start/stop device 7 , the brake switch unit 9 , the steering wheel locking unit 11 , the key fob 30 and the control unit 31 specified in FIGS. 1-3 . According to the invention, for a common system architecture of the access authorization system 1 , several or all of these units can be abandoned.
Naturally the switching embodiments specified in the figures have only been given as examples and the invention should not be limited to these. For example, in the case of the key acceptance unit 3 or the start/stop device 7 , the switches there need not necessarily be embodied as high-side switches, but can be embodied in any other way for example as low-side switches or as bridge circuits.
The control device 4 also need not necessarily have a controllable switch 26 for supplying the key acceptance unit 3 that can be controlled.
The invention was also described above on the basis of an access authorization system. However, the invention is not limited to this. In addition, an access authorization system rather expressly means (in addition or alternatively) a right of use system and an access authorization request is then a right of use request.
To summarize, it can be determined that in the case of the system architecture according to the invention for providing an access authorization system of the key both the key acceptance unit and the control device can be designed in a very simple way by simply varying or expanding simple system components for different system requirements. Here, the entire system architecture or the access authorization system must not be changed specially for the new requirement, but here the access authorization system must rather be supplemented or varied only with the corresponding components. This is also possible in a very simple way because the corresponding requirements, i.e. the corresponding feeder lines, connections and places must at least partially be present, but it must at least still be possible to subsequently supplement them without having to change the design of the entire access authorization system. Here, the special advantage is the fact that these variations or expansions can also still be carried out afterwards so that the manufacturer of the motor vehicle can develop the access authorization system according to his requests cost-effectively. | The system has a uniform system architecture that is designed for an access authorization request both with and without the use of a transponder. Should a transponder be used, only a corresponding transponder must be fitted in the key that can interact with an immobilizer coil specially provided for this in a receiving unit of the motor vehicle. In this case, the corresponding system requirements have also already been taken into consideration in the system architecture. As a result, the different system requirements for access and right of use systems to a great extent provide flexibility. | 1 |
BACKGROUND OF THE INVENTION
[0001] The invention relates to the use of sorbic acid as growth-stabilizing addition to feedstuffs preferably in concentrations of from >0 to <1.2% by weight (based on the feedstuff).
[0002] Antibiotics are frequently used to improve performance in the animal feed sector. The use of antibiotics in this sector is suspected of being responsible for the dangers derived from resistant bacteria, which may also endanger human health in the long term. It is therefore necessary to look for products about which there are fewer health doubts for this purpose of use. Thus, in other sectors too there is increasing replacement of substances about which there are physiological and epidemiological health doubts or else which are harmful for the environment, such as, for example, antibiotics, formaldehyde-emitting materials, halogenated substances and many others by materials about which there are fewer doubts, for example in human foods, feedstuffs, domestic animal feed, silages, pomace or other waste material from the food industry. The purpose of these materials is, on the one hand, aimed at maintaining the value of the actual product. However, on the other hand, it is also intended to improve the hygienic condition thereof and achieve a longer shelf life.
[0003] It is known that sorbic acid can be employed for preserving feedstuffs. Sorbic acid (trans,trans-2,4-hexadienoic acid) is a colorless solid compound which dissolves only slightly in cold water and is used around the world as preservative. The principle of action is determined by sorbic acid in undissociated form. Sorbic acid therefore displays its best effect in the acidic pH range. Sorbic acid and its salts have a very good microbiostatic, antimycotic action. At the same time, as unsaturated fatty acid, sorbic acid is virtually nontoxic, which is proven by very extensive data and by the decades of use of this acid in the human food sector, in animal feeds inter alia.
[0004] Feeding trials have been previously been carried out in particular with piglets, which demonstrated that various organic acids such as citric acid, fumaric acid or formic acid are able to have a beneficial effect on animal performance if they are mixed in optimal dosage with the piglet feed (Zbl. Hyg. 191, 265-276, Kirchgessner and Roth, 1991; Journal of Animal and Feed Sciences, 7, 1998, 25-33, Roth and Kirchgessner). However, these acids have corrosive effects and, because of their volatility, in some cases cause an odor nuisance and require special care in handling if the risk of intake by inhalation, which is undesirable from the health and safety viewpoint, is to be avoided.
[0005] It has also very recently been possible to show that sorbic acid in high concentrations (1.2-2.4% sorbic acid based on the feedstuff) has nutritional activity for rearing piglets (J. Anim. Physiol. a. Anim. Nutr. 74 (1995), 235-242, Kirchgessner et al.). At the 6th Pig and Poultry Nutrition Meeting (meeting proceedings, p. 60, 61, J. Rühle et al., ‘Zur Wirkung von Ameisen-, Milch- und Sorbinsäure auf einige Leistungs- und Stoffwechselkenndaten beim Absetzferkel’) the effect inter alia of sorbic acid for improving performance in piglet rearing was reported. Compared with formic and lactic acids, the best growth-promoting effect was achieved with sorbic acid. The concentration of sorbic acid per kg of feedstuff in these investigations was 0.185 mol/kg (about 2.1% by weight). In Kraftfutter/Feed Magazine February 1999, pp. 49ff (M. Freitag et al.), sorbic acid is described as performance-improving addition to the feed stuff ‘in the medium concentration range’; concentration ranges from 1.2 to 2.4% by weight in the feedstuff are known (see, for example, J. Anim. Physiol. a. Anim. Nutr. 74 (1995), 235 - 242, Kirchgessner et al.).
[0006] WO 00/36928 describes performance-improving additions to feedstuffs which contain C 6 -C 10 carboxylic acids or carboxylic acid salts. The additions are present in the feedstuff in amounts of 10-30% by weight. Unsaturated or even polyunsaturated carboxylic acids are not described therein, above all no sorbic acid.
[0007] As aliphatic unsaturated carboxylic acid, sorbic acid shows remarkably high storage stability and scarcely attacks metals and, in practical applications, causes scarcely any odor nuisance so that sorbic acid has advantageous physicochemical properties for processing in the stated range. This is additionally associated with good handling properties. Sorbic acid is therefore an ideal additive to feedstuffs. However, it is still a disadvantage that the use of sorbic acid—especially in the light of the high concentrations—is not economic. There has been a continuing need for a low-cost feedstuff with growth-stabilizing additions without the disadvantages of the materials normally used at present.
[0008] It has been found, surprisingly, that a marked and particularly economic improvement in growth in terms of growth rate and feed conversion can be achieved through the addition of smaller amounts of sorbic acid than generally assumed to date in agricultural livestock rearing especially piglet rearing. This emerges even with additions of from >0 to <1.2% by weight, based on the feed, in particular 0.5-1.0% by weight, preferably 0.625-0.875% by weight.
BRIEF DESCRIPTION OF THE INVENTION
[0009] The invention accordingly relates to the method of using sorbic acid as growth-stabilizing addition to feedstuffs, in particular in concentrations of from >0 to <1.2% by weight (based on the feedstuff). The invention further relates to a feedstuff for achieving a growth-stabilizing effect which comprises sorbic acid preferably in a concentration of from >0 to <1.2% (based on the feedstuff), and to sorbic acid-containing products for producing feedstuffs.
DETAILED DESCRIPTION OF THE INVENTION
[0010] Examples of suitable animal feedstuffs are green fodder, silages, dried green fodder, roots, tubers, fleshy fruits, grains and seeds, brewer's grains, pomace, brewer's yeast, distillation residues, milling byproducts, byproducts of the production of sugar and starch and oil production and various food wastes. Feedstuffs of these types may be mixed with certain feedstuff additives (e.g. antioxidants) or mixtures of various substances (e.g. mineral mixes, vitamin mixes) for improvement. Specific feedstuffs are also adapted for particular species and their stage of development. This is the case, for example, in piglet rearing. Prestarter and starter feeds are used here. Feedstuffs having the addition according to the invention of sorbic acid are moreover suitable as milk replacers for the early weaning of lambs or calves.
[0011] Sorbic acid can be added directly to the animal feedstuff, individual components thereof or other added substances such as feedstuff additives or else via premixes of various components to the actual feedstuff. These include inter alia mineral mixes, acid mixes and vitamin mixes, flavoring products, supplementary feedstuffs, mixtures thereof and mixtures of such products with components of the feedstuffs. They can be admixed with the feedstuffs, individual components thereof or dry with the feed, be added before further processing (e.g. extrusion) or be mixed in and dispersed in the mixture. If ascorbic acid is added via individual components of the feedstuff or premixes, the dosages are chosen so that they result in the contents according to the invention in the feedstuff.
[0012] Sorbic acid exists in solid form. It can be incorporated without difficulty into solid and pasty feedstuffs. Since the solubility limit is exceeded in feedstuffs which contain water and are only slightly acidic, it is expedient to employ sorbic acid of small particle size, in which case at least 80% by weight should be in the range below 555 μm, preferably even below 355 μm, in order to achieve distribution which is as uniform as possible.
[0013] The invention is illustrated below by means of examples.
EXAMPLE 1
[0014] In order to investigate the growth-stabilizing activity of sorbic acid in the concentration range according to the invention, feeding trials were carried out with groups of 48 weaners each housed singly. The feed in the four trial groups had an isoenergetic composition and was provided to the animals ad libitum. In this trial, the activity of sorbic acid in the low dose range was tested on piglets. For this purpose, 0 (no addition); 0.1; 0.55 and 1% by weight sorbic acid were added to the feed. The results of this trial are summarized in table 1. Addition of sorbic acid to the feed had a marked effect on the stock. In particular, the sorbic acid levels of 0.55 and 1% increased the growth rates starting from 491 g/day by 7% and 16% respectively (P<0.05). At the same time, the stock consumed 7% and 14%, respectively, more feed because of the addition of sorbic acid.
TABLE I Live weights, daily gains, feed consumption and feed conversion of rearing piglets on addition of sorbic acid to the feed Addition calculated as % by weight sorbic acid based on the total feed; day 0-41 - 0.1 0.55 1 Initial weight, kg 7.60 ± 7.60 ± 7.60 ± 7.60 ± 0.82 0.98 1.04 0.94 Final weight, kg 27.72 ab ± 26.69 b ± 29.16 ab ± 30.96 a ± 3.04 3.00 3.48 3.35 relative 100 96.3 105.2 111.7 Growth rate, g/d 491 b ± 466 b ± 526 ab ± 570 a ± 72 65 65 73 relative 100 94.5 107.1 116.1 Feed consumption, g/d 678 ab ± 640 b ± 729 ab ± 775 a ± 102 96 102 93 relative 100 94.4 107.5 114.3 Feed conversion 1.38 ± 1.38 ± 1.38 ± 1.36 ± (g feed/g gained) 0.04 0.08 0.06 0.08 relative 100 100 100 98.5
[0015] Comparison of the results of trials of identical design surprisingly reveals in addition that there is no linear dependence in the growth rates and feed conversion of the stock in particular on addition of sorbic acid to piglet feed (prestarter); the relative gains in the literature (J. Anim. Physiol. a. Anim. Nutr. 74 (1995), 235-242, Kirchgessner et al.: ‘Zur nutritiven Wirkung von Sorbinsäure in der Ferkelaufzucht’) on supplementation of feed with sorbic acid are shown in parentheses for use concentrations of 1.2 (109%), 1.8 (117%) and 2.4% (123%). By contrast, on use of sorbic acid in the concentrations according to the invention, considerably higher growth rates are achieved as shown in parentheses on addition of 0.55 (115%) and 1.0% (128%) sorbic acid.
[0016] In addition, on use of sorbic acid in the concentrations according to the invention, the feed conversion by the stock—compared with higher concentration ranges—is remarkably better. | The present invention relates to a method using sorbic acid, preferably in a concentration of >0 to <1.2% by weight (based on the feedstuff), with a growth-stabilizing effect. The feedstuff can be employed for improving performance in agricultural livestock rearing. | 0 |
BACKGROUND OF THE INVENTION
A search revealed a number of prior art patents concerned with holding wheelchairs in fixed positions for various reasons and in various environments. These patents are listed below and a copy of each is enclosed.
______________________________________Barclay 1,835,840 12/31Barclay 2,101,210 12/37Schiowitz 3,955,847 5/76Leon et al 4,019,752 4/77Moorman, Jr. 4,027,747 6/77Williams 4,060,271 11/77Hart 4,076,268 2/78Tulloch 4,083,594 4/78Nelson 4,093,303 6/78Arnholt et al 4,103,934 8/78Seay et al 4,246,984 1/81Korsgaard 4,265,478 5/81Guthrie 4,325,576 4/82Harder, Jr. 4,369,995 1/83Tenniswood 4,389,056 6/83Hinze 4,407,616 10/83______________________________________
None of these patents is specifically conerned with the disclosure herein.
SUMMARY OF THE INVENTION
For firmly and releasably holding a wheelchair in a predetermined position on a floor; say, the floor of a bus, longitudinally extending transversely spaced plates on the wheelchair are, at their rearward ends, abutted against a transverse backstop upstanding from the floor of the bus. At their forward ends the plates are engaged by a transverse bail rod controlled to swing upwardly and rearwardly from a position near the floor and away from the backstop into a position to engage notches in the forward ends of the plates. The bail rod engages the notches with a force sufficient to prevent any substantial motion of the wheelchair on the floor.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
FIG. 1 is a cross-section on a vertical longitudinal plane through a device as disclosed herein, the wheelchair being shown in broken lines and with a near wheel removed. The remaining part of the structure is shown partly in cross-section.
FIG. 2 is a cross-section of some of the structure shown in FIG. 1, the plane of section being indicated by the line 2--2 of FIG. 1.
FIG. 3 is an enlarged view of the interengaging portions of the wheelchair plates and of the restraining device.
FIG. 4 is a detailed elevation of the structure shown in FIG. 3.
FIG. 5 is a diagram showing the power structure and its control circuitry.
DETAILED DESCRIPTION
The problem addressed by the present disclosure is well and safely to secure a wheelchair of a relatively standard nature inside a vehicle such as a bus. While wheelchairs vary in construction, in general they all involve some sort of a frame, usually a tubular frame, and include a backrest portion, a seat portion, and a footrest portion all supported on an axle engaged by a pair of relatively large wheels preceded by a pair of relatively small wheels.
In the present instance and utilized primarily as an example, there is a wheelchair frame 6 inclusive of a number of tubular members, particularly a pair of longitudinally extending bottom tubes 7 and 8 disposed longitudinally and parallel to each other in a transversely spaced-apart orientation. Joined to such tubes 7 and 8 are pairs of upright members 9 toward the rear and upright members 11 toward the front. The members 9 are spanned by an axle 12 journalling a pair of large, ground-engaging wheels 13 and 14 at its opposite ends. The forward frame receives a pair of swivel wheels 16. There is a seat 18, preferably of a fabric nature, suspended between the side tubes of the wheelchair. There may be other accoutrements such as armrests, a back support and a foot rest and the like in accordance with the variations in normal wheelchair design. The wheelchair itself is not part of the present structure except as it is modified.
Part of the modification to a standard wheelchair is the provision of a pair of plates 21 and 22 extending generally in a vertical plate and longitudinally with respect to the chair. The plates themselves are approximately planar for the most part, but are incurved along the top to be appropriately situated with respect to the bottom frame tubes 7 and 8. The plates are preferably secured to the lower tubes by clamps 23 and 24, preferably made in two parts, and secured together by fasteners such as bolts 25 and nuts 26. The plates are thus disposed in the desired fore and aft location along the tubes 7 and 8 in a generally parallel condition.
Upstanding from the clamps 23 and 24 is a pair of rear braces 27 at one end secured by the fastenings 25 and at the other end connected by fastenings 28 to a horizontal pair of clamps 29 on upright frame tubes. To serve as additional bracing there are upstanding struts 31 at the lower end secured by fasteners for the clamps 24 and at the upper end secured by appropriate clamp fastenings 32 on the wheelchair frame. In the struts 31 there are apertures 33 designed to receive clips 34 at the ends of a seat belt 35 which extends over the seat 18.
It is especially to be noted that any upward force components imposed on the seat belt are directly resisted by the vertical struts 31, clamps 24, and plates 21 and 22, which are, in turn secured by the safety retainer of the invention.
In addition, there are diagonal reenforcing struts 36 at the lower end connected to an adjacent one of the fastening bolts 25, with the upper end connected by a fastening and clamp bolt 37 to a clamp 38 surrounding the adjacent tube of the wheelchair 6. This structure assures that the plates 21 and 22 are held very firmly with respect to the main frame of the wheelchair and against any dislodgement by even extreme forces which might ever be expected to be imposed thereupon.
Each of the plates 21 and 22 at its rear edge is terminated in a vertical margin 41. At its forward edge each plate 21 and 22 has a partial vertical margin 42, but also has a reentrant slot 43. This slot has generally horizontal margins, the lower one curving forwardly and downwardly to an inclined boundary 46 of the slot.
The main wheels 13 and 14 of the wheelchair are designed to rest on the floor 51 of a bus or comparable vehicle, for example. The floor is of considerable strength and is able firmly to support a transversely extending, upright backstop 53 permanently braced and secured to the floor and extending vertically to a predetermined height approximately the same as the vertical height of the plates 21 and 22. The transverse extent of the backstop is sufficient so that it can be abutted by both of the plates 21 and 22 at once, yet terminates well within the tread of the wheels 13 and 14.
Particularly in accordance with the invention, the floor 51 has mountings 56 serving as journals to receive a cross shaft 57 forming part of a bail 58. This is inclusive of a couple of upright levers 59 and 60 at the opposite ends of the shaft 57. The bail 58 is adapted to rotate through approximately ninety degrees from a position indicated by the broken line in FIG. 1 below the floor 51 and through a multiple slot 61 cut in the floor. The bail can assume an upper position with a cross rod 63 of the bail lying within the slots 43.
In addition to the end levers, there is preferably provided a central lever 66 extending from and secured to the cross shaft 57 and engaged by a pin to a yoke 67 at the forward end of a piston rod 68. The piston rod 68 joins a piston 69 reciprocable within a cylinder 71 having a pivot connection 72 to a housing 73 secured to the bottom of the floor 51.
Preferably the piston is maneuvered in the cylinder by means of compressed air, the air being derived from any suitable source, conveniently the supply of compressed air normally available on the bus. For that reason, the ends of the cylinder are connected by flexible conduits 81 and 82 to a standard control valve 83 connected to exhaust at 84 and to the supply 85 of air under pressure. The valve itself is controlled by energizing solenoids 86 and 87 in a circuit having conductors 88 and 89 going to a battery 91, preferably the bus battery. There is a driver's control switch 92 having a lead 93 going to the solenoid 86 used for securing the wheelchair in position and having a lead 94 going to the solenoid 87 for releasing the wheelchair. The switch 92 also has a conductor 96 going to a user's switch 97 so that by placing the switch 92 in central position, the driver may give control to the user. The user's control switch 97 is situated near the wheelchair. In one position, this switch 97 is joined to the lead 94 for release and in another position is joined to the lead 93 for securing the wheelchair.
With this arrangement and with the standard wheelchair adapted and augmented as shown, the wheelchair is moved from some remote position over the floor 51 of the bus into a location approximately as shown in FIG. 1. The wheelchair is backed so that the near ends of both of the side plates 21 and 22 come into or close to abutment with the backstop 53. When this position has been attained or approximately attained, the bus driver or wheelchair user operates either the control switch 92 or the control switch 97 and so operates the solenoid 86 to supply compressed air to the left-hand end of the cylinder 71. This expels the piston 69 and rocks the shaft 57 in a counterclockwise direction, in FIG. 1, thus moving the bail 58 from a position beneath the bus floor and out of the way of movement of the wheelchair into an upper position with the bail rod 63 entering into and in effect nearly or actually wedging itself into the slot 43.
In the final part of this movement of the bail, the force is such, if necessary, as to move the wheelchair rearwardly to cause the plates to be in firm end abutment with the backstop 53 or barrier. The bail rod 63 may cam against the curved bottom of the slot 43 and produce a downward force on the wheelchair. The piston rod extends almost completely to the right under the resilient pressure of the comprssed air in the cylinder. That presses the wheelchair firmly in position against any fore and aft or longitudinal movement. Since the bail is well within the slots, any vertical movement is prevented, as well. In addition, the levers 59 and 60 are close to or substantially against the sides of the plates 21 and 22 so that transverse displacement is likewise restricted.
With the parts in this position the wheelchair is firmly clamped or held or secured in its predetermined position on the bus floor and against dislodgement in longitudinal, transverse and vertical directions.
When the wheelchair is to be released, the control switch 92 or the switch 97 is moved into the proper extreme position. This energized the solenoid 87 while deenergizing the solenoid 86, reverses the valve 83 and causes compressed air to be released from the left end of the cylinder, as seen in FIG. 1, and compressed air to be introduced into the right end of the cylinder. The bail is thus rotated positively in a clockwise direction, as seen in FIG. 1, removing the bail rod 63 from the two slots 43 and removing the levers 59 and 60 from the sides of the plates 21 and 22. The bail 58 is rotated far enough so that it passes through the slot 61 and is below the floor of the bus. Under these conditions, the wheelchair can be manually moved forward from its blocked position and is ready for general use.
In the event that the bus were to become involved in an accident which resulted in the rupture of the hose from the air supply 85, any forward inertia possessed by the wheelchair and its occupant tends to urge the cross-rod 63 and associated levers 59 and 60 forwardly and downwardly in the path of the arcuate broken line shown in FIG. 3. However, owing to the shape and extent of the inclined boundary 46 forming the lower, forwardly and downwardly curving margin of the slot 43, the cross-rod 63 continues to be underlain by the boundary 46 until the cross-rod reaches the position indicated by the broken line circle second to the right of the cross-section 63 shown in FIG. 3. At this juncture, the forward portion of the curved boundary 46 comes into upwardly camming engagement with the bottom of the cross-rod 63. Thus, the cross-rod 63 can no longer swing downwardly and forwardly in the arc defined by the length of the levers 59 and 60 and further forward motion of the wheelchair is halted.
It can therefore be seen that even in the event of an interrupted air supply (in case of an accident, for example) the wheelchair and its seat-belted occupant are safely restrained and prevented from being thrust against a forwardly located object or person. Yet, release of the wheelchair can readily be effected thereafter by backing the wheelchair until the forward portion of the boundary wall 46 is clear of the cross-rod 63, at which juncture the bail can manually be swung forwardly and downwardly out of the way so that the wheelchair is ready for general use. | A device for holding a wheelchair stationary on a floor has a pair of notched plates at their rearward ends adapted to abut a transverse barrier upstanding from the floor and to be releasably engaged at their forward ends by a bail fastened to and swinging from the floor to engage the forward ends of the notched plates with sufficient resilient force to lock the wheelchair in position. | 0 |
FIELD OF THE INVENTION
The present invention relates generally to emergency eyewash stations and, more particularly, relates to a method and kit for retrofitting a plumbed eyewash station. The method and kit converts the plumbed station to a self-contained station that dispenses eyewash fluid emanating from a portable container instead of from a facility's plumbing system.
BACKGROUND OF THE INVENTION
There are a significant number of industrial eyewash sinks connected to a facility's portable water supply. Such eyewash sinks are commonly referred to as plumbed eyewash stations. A vast majority of these eyewash stations are only plumbed into the cold water supply. A new release by the American National Standards Institute (ANSI) for emergency eyewash equipment (ANSI Standard Z358.1-1998), however, recommends that the flushing solution be "tepid," which generally means having a temperature between about 65° F. and 95° F. This temperature range is not achievable with most municipal water supplies. Therefore, a hot water supply line and an appropriate mixing valve must be added to a plumbed station to produce tepid water. In addition, the plumbed stations are prone to the accumulation of harmful bacteria and can become clogged due to rust and scale in the plumbing pipes.
SUMMARY OF THE INVENTION
Accordingly, an object of the present invention is to provide a kit and method for retrofitting existing plumbed eyewash stations so that the retrofitted stations can dispense purified tepid eyewash fluid emanating from a portable container instead of from a facility's plumbing system. Such a retrofitting kit is generally less costly to produce than an entire self-contained eyewash station.
These and other objects are realized by providing a kit for retrofitting a plumbed eyewash station. The plumbed eyewash station includes a basin and an outlet pipe mounted within the basin. Prior to retrofitting the plumbed station, the outlet pipe is used to dispense water delivered thereto by a facility's plumbing system. The retrofitting kit includes a nozzle support and a self-contained eyewash fluid delivery system. The eyewash fluid delivery system includes a portable container and a nozzle in fluid communication with the container. The portable container contains eyewash fluid. To retrofit the plumbed station, the nozzle support is mounted to the outlet pipe; the portable container is placed on a support surface above the nozzle support; and the nozzle is mounted to the nozzle support. The nozzle is switchable from an initial sealed condition in which outlet apertures in the nozzle are blocked to an open condition in which the outlet apertures are exposed. The kit preferably includes an activation door and an actuation strap. The activation door is rotatably mounted to the nozzle support, and the actuation strap extends from the nozzle. During the retrofitting process, the activation door is closed to cover the nozzle, and the actuation strap is fastened to the closed activation door. The retrofitted eyewash station dispenses eyewash fluid emanating from the portable container instead of from the facility's plumbing system.
The above summary of the present invention is not intended to represent each embodiment, or every aspect of the present invention. This is the purpose of the figures and detailed description which follow.
BRIEF DESCRIPTION OF THE DRAWINGS
Other objects and advantages of the invention will become apparent upon reading the following detailed description and upon reference to the drawings in which:
FIG. 1 is a perspective view of a kit for retrofitting a plumbed eyewash station in accordance with the present invention;
FIG. 2 is a perspective view of a plumbed eyewash station prior to being retrofitted with the kit;
FIG. 3 is a perspective view of the eyewash station prepared to accept the kit;
FIG. 4 is a perspective view of the eyewash station retrofitted to include a nozzle support and activation door from the kit;
FIG. 5 is a perspective view of the eyewash station further retrofitted to be connected to a self-contained eyewash fluid delivery system;
FIG. 6 is similar to FIG. 5 but enlarged to show the connection between the nozzle support and the nozzles of the self-contained eyewash fluid delivery system;
FIG. 7 is a perspective view of the retrofitted eyewash station with the activation door in a closed position so that the eyewash station is ready for activation; and
FIG. 8 is a perspective view of the retrofitted eyewash station with the activation door in an open position following activation.
While the invention is susceptible to various modifications and alternative forms, a specific embodiment thereof has been shown by way of example in the drawings and will herein be described in detail. It should be understood, however, that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the appended claims.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Turning now to the drawings, FIG. 1 depicts a kit 10 for retrofitting a plumbed eyewash station. The kit 10 includes a nozzle support 12, an activation door 14, and a self-contained eyewash fluid delivery system 16. The nozzle support 12 includes a mounting bracket 18 and a nozzle plate 20 fixedly mounted to a flat upper portion of the bracket 18 by fasteners such as screws, bolts, rivets, or the like. The mounting bracket 18 includes a pair of spaced tabs 22 (one visible in FIG. 1), and the activation door 14 is rotatably mounted to the tabs 22 by fasteners, such as rivets, which allow the door 14 to rotate relative to the tabs 22.
The eyewash fluid delivery system 16 includes a pair of identical delivery arrangements. Each delivery arrangement includes a box 26, a flexible container 28 within the box 26, a nozzle 30, and a flexible hose 32 connecting the nozzle 30 to the flexible container 28. The flexible container 28 is substantially filled with eyewash fluid. The eyewash fluid is preferably a purified fluid such as a buffered isotonic saline solution, although it could be as simple as purified water. An exemplary solution is Eyesaline® solution manufactured by Fendall Company of Arlington Heights, Ill. Alternatively, the purified eyewash fluid may have a special composition directed toward certain types of hazards. The flexible container 28 is preferably a metallized MYLAR™ bag including a layer of polyethylene. The box 26 is preferably composed of corrugated plastic or thick-walled corrugated paperboard. If the box 26 is composed of corrugated paperboard, the paperboard is preferably wax-coated to protect the box 26 against such environmental conditions as humidity. The box 26 includes opposing front and back walls, opposing side walls, and opposing top and bottom walls. In FIG. 1, a portion of the box 26 is cut away to reveal the internal container 28.
The lower portion of the front wall of the box 26 forms a hole sized to accommodate an outlet fitment 34. One end of the flexible hose 32 is firmly connected to this outlet fitment 34. The other end of the flexible hose 32 is firmly connected to an inlet fitment 36 on the nozzle 30. In the preferred embodiment, the hose 32 has an inner diameter of approximately 0.38 inches (0.95 cm).
Each nozzle 30 includes an upper pressure plate 38 and a lower nozzle body 40. The lower nozzle body 40 includes the inlet 36 and an elongated array of apertures 42 (FIG. 8). Eyewash fluid entering the inlet 36 is distributed to the apertures via a distribution manifold. The array of apertures in the lower nozzle body 40 preferably includes approximately fourteen apertures arranged in two rows of seven apertures per row (FIG. 8). To permit the nozzles 30 to be slidably mounted to respective elongated slots 44 formed in the nozzle plate 20, opposing sides of each lower nozzle body 40 are grooved. The slots 44 cooperate with the grooved sides formed in each nozzle 30 to slidably engage the nozzles 30 in the respective slots 44 (FIG. 6). This sliding engagement of the nozzles 30 in the respective slots 44 positively locates the nozzles 30 with respect to the nozzle support 12. The width of each slot 44 is approximately the same as the width of each nozzle 30 in the region where they are grooved to create a fairly snug fit therebetween.
As best shown in FIG. 6, the upper pressure plate 38 is hingedly connected to the lower nozzle body 40. In particular, the upper pressure plate 38 forms a retaining tab 46 that is releasably held in a slot formed in the lower nozzle body 40. A seal element, such as a plastic shrink band 48, is used to firmly secure the upper pressure plate 38 to the lower nozzle body 40 such that the upper pressure plate 38 blocks the outlet apertures formed in the lower nozzle body 40. The shrink band 48 tightly circumscribes the nozzle 30 at an opposite end of the nozzle 30 relative to the hinged connection of the pressure plate 38 and nozzle body 40. To hermetically seal the nozzle apertures prior to activation of a retrofitted eyewash station, the upper pressure plate 38 forms an elongated internal pocket that accommodates a rubber gasket. The gasket presses against the apertures to prevent air flow into the apertures and to prevent any possible leakage of the eyewash fluid therefrom.
To permit separation of the upper pressure plate 38 from the lower nozzle body 40, a flexible actuation strap 50, composed of a flexible polymeric material, woven fabric, or the like, is fixedly adhered or mechanically fastened to the upper pressure plate 38. The strap 50 passes beneath the shrink band 48 between the upper surface of the pressure plate 38 and the inner surface of the shrink band 48. The strap 50 is not adhered to the upper surface of the pressure plate 38 in the region beneath the shrink band 48. The manner in which the strap 50 is used to separate the upper pressure plate 38 from the lower nozzle body 40, and thereby permit eyewash fluid to be dispensed from the lower nozzle body 40 via its apertures, is described in detail below.
Until a retrofitted eyewash station is activated, the eyewash fluid delivery system 16 is a hermetically sealed system extending from the flexible containers 28, through the respective hoses 32, to the nozzles 30. This sealed delivery system prevents any contamination of the eyewash fluid passageway formed by the containers 28, the hoses 32, and the nozzles 30. The eyewash fluid in the sealed delivery system is not exposed to the environment. Moreover, the sealed delivery system maintains the stability of the eyewash fluid contained in that fluid passageway for a time period as long as approximately two years. Such long-term stability of the eyewash fluid is advantageous because if the retrofitted eyewash station goes unused, its unused delivery system need not be replaced with a new delivery system for about two years. As a result, the maintenance required by the retrofitted eyewash station during long-term periods of nonuse is minimal.
Further information concerning the eyewash fluid delivery system 16 and its activation by the actuation straps 50 and activation door 14 may be obtained from U.S. Pat. No. 5,566,406 to Demeny et al., which is incorporated herein by reference in its entirety.
Referring to FIG. 2, there is shown a typical plumbed eyewash station 52 to be retrofitted with the kit in FIG. 1. The plumbed eyewash station 52 includes a basin or sink 54, a pair of outlet pipes 56, an external pipe 58, a valve 60, and a push handle 62 for opening and closing the valve 60. The outlet pipes 56 are mounted within the basin 54 and are typically fitted with respective nozzles 57. When the valve 60 is open, the external pipe 58 conveys water from a facility's plumbing system to the outlet pipes 56.
Referring to FIG. 3, to retrofit the plumbed station, a service technician first detaches the handle 62 from the closed valve 60. Detaching the handle 62 insures that a user of the eyewash station does not inadvertently activate the flow of water from the facility's plumbing system. The eyewash fluid of the retrofitted eyewash station should emanate from the eyewash fluid delivery system 16 (FIG. 1), not the facility's plumbing system. If the nozzles 57 would interfere with any components of the retrofit kit, the service technician also removes the nozzles 57 terminating the respective pipes 56 and optionally replaces the nozzles with plastic caps.
Referring to FIG. 4, the bracket 18 is clamped to the outlet pipes 56. As shown in FIG. 1, the bracket 18 is pre-assembled to carry the nozzle plate 20 and the activation door 14. The bracket 18 includes a pair of clamping members 64. The clamping members 64 are positioned on opposite sides of the pipes 56, snappingly engaged to each other beneath the pipes 56 at spaced locations 65 and 67, and then secured to each other (with the pipes 56 therebetween) using fasteners disposed immediately above the respective pipes 56. The fasteners are tightened until the clamping members 64 apply sufficient inward pressure to the pipes 56 that the bracket 18 is firmly held in place. The clamping members 64 preferably contain extra fastener holes to allow the bracket 18 to be clamped to different pipe configurations, where some holes are better positioned than other holes.
Referring to FIG. 5, the boxes 26 of the fluid delivery system 16 are placed on a shelf or support 68 mounted to a wall behind the eyewash station. The eyewash fluid in the flexible containers 28 in the respective boxes 26 is fed to the respective nozzles 30 by the force of gravity. Therefore, to meet the ANSI standard recommending that portable eyewash fountains deliver no less than 0.4 gallons per minute (1.5 liters per minute) of eyewash fluid for a time period of 15 minutes, the shelf 68 is positioned such that the bottoms of the boxes 26 are approximately twelve inches above the nozzles 30.
Referring to FIGS. 5 and 6, the nozzles 30 are slidably mounted to the nozzle plate 20. To engage the nozzles 30 in the respective slots 44 of the nozzle plate 20, the nozzles 30 are first positioned adjacent the outermost edges of the respective slots 44 (i.e., left edge of the left slot and right edge of the right slot). Next, with the opposing grooved sides of each nozzle 30 aligned with the opposing elongated edges of each respective slot 44, the nozzles 30 are slid inwardly through the respective slots 44 with the opposing grooved sides of each nozzle 30 slidably receiving the opposing elongated edges of each respective slot 44.
Referring to FIG. 7, after mounting the nozzles 30 to the nozzle plate 20, the activation door 14 is rotated to a closed position. Then, the actuation straps 50 are wrapped around and fastened to the activation door 14 by button-type fasteners 70. The opposing sides of the activation door 14 form notches 72 for locating the respective straps 50. In one embodiment, the fasteners 70 snap into respective holes formed in the activation door 14 slightly inward from the respective locating notches 72. The length of the straps 50 is selected such that the straps 50 are sufficiently slack to avoid placing undue stress on the shrink bands 48 (FIG. 6), and yet are sufficiently taut to fit within the notches 72 formed in the opposing sides of the door 14 so that slippage is not a problem when the eyewash station is activated. The eyewash station is now ready for operation in the event of an emergency requiring a user to flush his or her eyes.
Referring to FIG. 8, in response to an emergency requiring immediate eye flushing, the user opens the activation door 14 by grasping onto its integrally-formed handle 74 and pulling the activation door 14 via the handle 74 to its open position. Opening the activation door 14 activates the flow of the eyewash fluid from the nozzles 30 by pulling the straps 50 relative to the respective nozzles 30. More specifically, opening the activation door 14 pulls each strap 50 in a direction countering the force applied by the associated shrink band 48 (FIG. 6) to the nozzle 30. Pulling the actuation strap 50 first breaks the shrink band 48, and continued pulling of the strap 50 rotates the pressure plate 38 upward about the hinged connection between the pressure plate 38 and the nozzle body 40. As the activation door 14 reaches its open position, the pressure plate 38 is completely separated from the nozzle body 40. When the activation door 14 is in its open position, the pressure plates 38 hang from the activation door 14 by virtue of their attachment to the straps 50 which, in turn, are fastened to the activation door 14. The lower nozzle bodies 40 of the respective nozzles 30 remain mounted to the nozzle plate 20.
With the pressure plates 38 separated from their respective lower nozzle bodies 40, the eyewash fluid from the flexible containers 28 (FIG. 5) is dispensed from the lower nozzle bodies 40 via their apertures. The user flushes his or her eyes by bending over and positioning his or her eyes over the dispensed streams of eyewash fluid. The left eye is flushed with the streams emitted from the left nozzle body, while the right eye is flushed with the streams emitted from the right nozzle body. To prevent the emitted streams from falling back on the apertures in the nozzle bodies 40, the streams are emitted from the lower nozzle bodies 40 at a slight forward angle relative to the vertical direction.
The eyewash fluid dispensed from the nozzles 30 is captured by a drain 76 (FIG. 7) which, in turn, directs the captured eyewash fluid to either a floor or tank beneath the drain 76. The flexible containers 28 (FIG. 5) contain a sufficient volume of the eyewash fluid and are positioned at such a height above the nozzles 30 that the nozzles 30 deliver no less than 0.4 gallons per minute (1.5 liters per minute) of eyewash fluid for a time period of 15 minutes. As stated above, the eyewash fluid is gravity-fed from the containers 28 (FIG. 5) to the nozzles 30.
To prepare the eyewash station for another potential emergency, service personnel clean up and discard any waste fluid, discard the used eyewash fluid delivery system 16, and install a fresh delivery system. Because the procedure for installing the fresh delivery system is described above, it will not be repeated in detail herein. It suffices to state that new boxes 26 holding new flexible containers 28 containing fresh eyewash fluid are placed on the shelf above the eyewash station, and new nozzles 30 are slidably mounted to the nozzle plate 20. Next, the activation door 14 is closed, and new straps 50 extending from the new nozzles 30 are fastened to the activation door 14. The eye wash station is now ready for emergency use.
While the present invention has been described with reference to one or more particular embodiments, those skilled in the art will recognize that many changes may be made thereto without departing from the spirit and scope of the present invention. Each of these embodiments and obvious variations thereof is contemplated as falling within the spirit and scope of the claimed invention, which is set forth in the following claims. | A kit for retrofitting a plumbed eyewash station is provided. The plumbed eyewash station includes a basin and an outlet pipe mounted within the basin. Prior to retrofitting the plumbed station, the outlet pipe is used to dispense water delivered thereto by a facility's plumbing system. The retrofitting kit includes a nozzle support and a self-contained eyewash fluid delivery system. The fluid delivery system includes a portable container and a nozzle in fluid communication with the container. The portable container contains eyewash fluid. To retrofit the plumbed station, the nozzle support is mounted to the outlet pipe; the portable container is placed on a support surface above the nozzle support; and the nozzle is mounted to the nozzle support. The kit preferably includes an activation door and an actuation strap. The activation door is rotatably mounted to the nozzle support, and the actuation strap extends from the nozzle. During the retrofitting process, the activation door is closed to cover the nozzle, and the actuation strap is fastened to the closed activation door. The retrofitted eyewash station dispenses the eyewash fluid emanating from the portable container instead of from the facility's plumbing system. | 0 |
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention is directed to an X-ray apparatus of the type having a radiation source, an interchangeable radiation filter and an area dose measuring device with a measurement chamber and an allocated evaluation device for determining the area dose product on the basis of the measured signals provided by the measurement chamber, with the measurement chamber arranged preceding the filter in the beam path with reference to the radiation propagation direction.
[0003] 2. Description of the Prior Art
[0004] Measurement of the area dose product allows determination of the amount of X-radiation applied to the examination subject, for example a patient. This measurement is conventionally undertaken with an area dose-measuring device having a measurement chamber that is arranged in the beam path. This measurement chamber usually is an ionization chamber through which the X-rays pass and at which an output signal dependent on the amount of radiation can be obtained. The applied, surface area-dependent dose can be determined from this signal, usually in μGym 2 units.
[0005] Radiation filters are often employed in known X-ray apparatuses in order to attenuate or entirely blank the X-rays in certain filter-specific ranges. A large variety of interchangeable and employable filters are known, for example shoulder filters, foot filters, pelvis filters or skull filters. These filters, that are usually fashioned in the form of essentially rectangular plates, are inserted into the beam path. These insertion guides usually are arranged outside the housing containing the measurement device and further parts of the area dose-measuring device, such as, the evaluation device. The measurement chamber lies in front of the filter with reference to the radiation propagation direction. The measurement chamber often is integrated into a diaphragm device that follows the radiation source in the propagation direction, particularly in the depth diaphragm, and which has an outer housing section at which the insertion guides for the plate-like radiation filters are located.
[0006] Due to this arrangement wherein the radiation filters follow the measurement chamber, the problem arises that the filter effect does not enter into the determination of the area dose product. The filter performance that attenuates the X-rays that are actually applied to the subject is not taken into consideration since the measurement occurs preceding the radiation filter. Ultimately, thus, the applied dose is lower than that indicated by the “unfiltered” measured result.
SUMMARY OF THE INVENTION
[0007] An object of the present invention is to provide an X-ray apparatus that eliminates the aforementioned disadvantage associated with known X-ray apparatus in the determination of the area dose.
[0008] This object is achieved in accordance with the invention in an X-ray apparatus of the type initially described having a detector for recognizing a filter characteristic of the filter currently in use, such as the nature and/or the type of filter, and an evaluation fashioned for correcting the calculated surface dose product on the basis of at least one filter-specific correction value dependent on the identification of the filter in use.
[0009] In the inventive X-ray apparatus, the detector makes it possible to determine what filter type or what kind of filter is inserted into the beam path following the measurement chamber. On the basis of this knowledge, which is forwarded to the evaluation device, the evaluation device is able to suitably correct the area dose product that is calculated in the evaluation device based on the signal acquired by the measurement chamber preceding the radiation filter. This correction is undertaken using at least one filter-specific correction value, i.e. a correction value that takes the filter properties of the recognized filter into consideration. As a result, it is possible to calculate the filter effect of the following radiation filter and to include this in the calculated area dose product. This product thus indicates the actually applied X-rays as accurately as possible, rather than the unattenuated amount of radiation.
[0010] In order to recognize the nature or type of filter, it is necessary to be able to identify each inserted or insertable filter so that its filter-specific features or characteristics can be likewise identified. In a first embodiment of the invention, the detector for recognizing the nature and/or type of filter can be a transponder arranged at the filter and an acquisition device that picks up the transponder signal. This acquisition device, which can also be the corresponding excitation device, activates the transponder to emit the transponder signal. The acquisition device can be external to the surface dose-measuring device or the evaluation device itself can be fashioned for this purpose. Each radiation filter has its own filter-specific transponder, so that a simple acquisition and discrimination are possible.
[0011] As an alternative, the detector for recognizing the nature and/or type of filter can include at least one identification specifying the nature and/or type of filter and an acquisition device that acquires the identification. Expediently, the identification is a coding. (According to a first alternative of the invention, this can be an electronic coding that can be interrogated via the acquisition device. For example, the evaluation device itself also can be employed as the acquisition device. Each radiation filter can have a small integrated chip associated therewith that, for example, is automatically contacted by a corresponding connector plug upon insertion of the filter, the connection to the acquisition device being closed through the chip/plug connection.
[0012] As an alternative, the identification can be acquired by an optical reader device. For example, a label or an imprint can be used, particularly a bar code or the like. Further, specific reflection patterns at the filter can be employed as the identification, these being acquired via the optical reader device. Another alternative is to provide the identification as a structure applied to the radiation filter, particularly in the form of notches or the like. This structure likewise can be acquired by the optical reader device.
[0013] A further alternative for fashioning the identification in accordance with the invention is to provide projections or depressions, for example in the form of notches, at the radiation filter which activate switch or sensor elements when the radiation filter is introduced. The projections or depressions are specifically fashioned for each radiation filter, so that a specific switch or sensor element actuation occurs for each radiation filter. The respective filter type or kind of filter can then be recognized from the combination of actuated switch or sensor elements.
[0014] Magnetic identifications also can be used that, for example, can be acquired via Hall sensors that detect the generated magnetic field. For example, a number of magnetic identifications can be filter-specifically arranged here along a side of the filter, the positioning or the magnetic fields of these identifications in turn representing a coding for the filter type and/or kind of filter. Dependent on the output signals of the Hall sensor or sensors, the kind of filter or the filter type can be identified.
[0015] As already described, it is expedient to integrate the surface dose measuring device in a diaphragm device that follows the radiation source, particularly in the depth diaphragm, so that an overall closed system is achieved. The evaluation device also can be integrated; however, it is also possible to externally position the evaluation device.
[0016] Although a specific correction value can be allocated to each radiation filter which always is utilized for correction given employment of that radiation filter, it is expedient for the correction value employed for correction to be dependent on at least one parameter representing a criterion for the generated X-rays. The applied X-rays are variable within broad ranges by means of a corresponding setting of the operating parameters, i.e., for example, the operating voltage or the operating current. In order to be able to design the correction of the area dose product even more exactly, it is expedient to employ a correction value that is adapted to the employed parameters that influence the X-rays. For example, a number of correction values can be stored in the evaluation device that are allocated or dependent on specific parameters that influence the X-rays such as, for example, the tube voltage or the tube current. Dependent on which operating parameters are set by the physician or the radiology technician, the evaluation device that has the corresponding operating parameter information available to it then selects the appropriate correction value from the stored, filter-specific family of correction values. The resulting thus takes the actual operating conditions into consideration.
DESCRIPTION OF THE DRAWINGS
[0017] [0017]FIG. 1 is a schematic illustration of an inventive X-ray apparatus as well as a releasably introducible radiation filter.
[0018] [0018]FIG. 2 is a schematic illustration of the relevant parts of the inventive surface dose measuring device.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0019] [0019]FIG. 1 shows an inventive X-ray apparatus 1 , with only the radiation source 2 being shown, this being arranged at a telescoping arm 3 of a ceiling-mounted stand (not shown in detail). A diaphragm device 4 , for example a depth diaphragm, is provided under the radiation source 2 in the illustrated example; the shape of the beam in the x-direction and y-direction, or in the plane defined by those directions, can be shaped by this diaphragm device 4 , which shall be discussed in brief below.
[0020] At its housing, the depth diaphragm 4 has receptacles 5 for the acceptance of one or more radiation filters 6 . In the illustrated example, the receptacles are fashioned as lateral insertion channels 7 into which an essentially rectangular, plate-shaped radiation filter 6 is inserted. As shown in FIG. 2, the inserted filter 6 is then located in the beam path of the X-rays generated by the radiation source 2 , which is not shown in detail in FIG. 2. Only the focus 8 of the radiation source 2 is shown, the X-ray beam 9 expanding as it proceeds from said focus 8 . The shape of the X-ray beam is defined by x and y diaphragms 10 , 11 . The X-ray beam 9 likewise passes through the radiation filter 6 , so it is attenuated in the regions wherein the radiation filter 6 includes an X-ray filter medium 12 .
[0021] In order to determine the area dose product, an area dose measuring device 13 is provided that has a measurement chamber 14 , such as an ionization chamber, that is arranged in the beam path and precedes the radiation filter 6 , and also has an evaluation device 15 that is external therefrom in the illustrated example. The X-rays penetrate into the ionization chamber 14 , which leads to a particle ionization dependent on the radiation dose and ultimately leads to an output signal that is dependent on the degree of ionization. The functioning of such an ionization chamber as well as the calculation of the area dose product dependent on the output signal are well-known. The calculation ensues in the evaluation device 15 that receives the output signal of the ionization chamber 14 . A suitable calculating unit 16 is provided for the calculation. As warranted, a partial system control can ensue via the evaluation device 15 or the calculating unit 16 when an adequate area dose product is reached, but this shall not be discussed in detail. This is also well-known and need not be presented herein.
[0022] The evaluation device 16 also has a memory device 17 available to it wherein a number of filter-specific correction value families K F1 . . . K Fn are stored. A filter-specific correction value for the area dose product exists for each radiation filter 6 that is employed (a large variety of radiation filters can be employed) and the correction of this area dose product is necessary because the measurement chamber 14 is situated in front of the radiation filter 6 and the output signal at the side of the ionization chamber consequently is not influenced by the filter effect, and thus the beam attenuation produced by the radiation filter would not otherwise be taken into consideration.
[0023] In order to be able to select the right correction value from the stored correction values, it is necessary to be able to identify the inserted radiation filter 6 in terms of its nature or its type. Suitable means for recognizing the nature or type are provided for this purpose. First, a unique identification of each radiation filter 6 is required. The radiation filter 6 shown in FIG. 1 shows some identification versions. A transponder 18 can be used, with each radiation filter having its own specific transponder 18 . For example, a suitable drive device 19 can be provided in the evaluation device 15 , for driving the transponder 18 such that it transmits its transponder signal, which is in turn received and interpreted by the drive device 19 and the corresponding filter can be recognized in this way. Each filter has its own transponder that emits a filter-specific transponder signal, so that a definitive discrimination and recognition is possible.
[0024] A further, alternative identification version is a number of specifically shaped indentations 20 at the edge of the radiation filter 6 that, for example, can be acquired via an optical device 21 that is integrated in the diaphragm device 4 . The identification and coding of the respective filter type ensues by means of the shape of the employed indentations 20 and their arrangement and positioning relative to one another. Arbitrary codings are possible in this version.
[0025] Alternatively, reflection fields can be applied to the filter 6 that are acquired via the optical read device 21 .
[0026] Another possibility shown in FIG. 1 is the employment of an electronic identification 22 , for example in the form of a small microchip, that is automatically coupled via its terminal pins 23 to a suitable acquisition device 24 in the diaphragm, that then emits a corresponding output signal that is forwarded to the evaluation device 15 . Only one identification version need be provided at a radiation filter 6 ; the employment of the three different identification possibilities in FIG. 2 is only for explaining a number of exemplary alternatives. The same is true of the employment of the detector for the recognition of the identification. Only one of the drive device 19 , the optical reader device 21 or the electronic reader device 24 is to be provided.
[0027] In any case, the evaluation device 15 receives an information signal that describes the filter type or the kind of filter. In addition, the evaluation device 15 is provided with information data about the operating parameters of tube voltage U and tube current I that have been set for generating the X-rays. In addition to the information about the filter being utilized, these serve the purpose of selecting the correct filter-specific correction for the inserted filter value from the family of correction values.
[0028] Two correction value families for two specific radiation filters, namely the filters F 1 and Fn, are shown as an example in the memory area 17 in FIG. 2. The respective correction values in the two families are a 1 , b 1 . . . f 1 ,and b n . . . f n , whereby the index 1 indicates the correction value family for the filter F 1 and the index n indicates the correction value family for the filter Fn.
[0029] Further, respective operating parameters U/I are indicated, namely U 1 /I 1 , U 2 /I 2 , . . . , U 6 /I 6 .
[0030] The respective correction value family K F1 . . . K Fn is selected on the basis of the pending information signal about the introduced filter. Let it be assumed that the radiation filter F 1 is introduced, so that one of the correction values a 1 , . . . f 1 will thus be employed for the correction.
[0031] The exact determination of the correction value to be employed ensues on the basis of the pending voltage and current signals. Let it be assumed that the voltage and the current lie in respective value ranges around U 3 and I 3 . In this case, thus, the correction value c 1 would be utilized for the correction of the originally calculated area dose product without taking the filter attenuation into consideration. For example, the correction value c1 can be a defined value, for example in a μGym 2 unit, that is subtracted from the calculated area dose product. Alternatively, it can be a suitable percentage by which the calculated area dose product is to be reduced, etc. Different forms of correction values are employed as appropriate. When the pending voltage and current values do not lie in a prescribed interval range, i.e. when, for example, they are not to be allocated to U 4 and I 4 but, for example, to U 2 and I 5 , it is also possible to make a defined selection for determining the specific correction value, so that, for example, c 1 is selected given such a combination. Alternatively, there is the possibility of calculating, for example, an average value from b 1 and e 1 (with respect to U 2 or I 5 ). Different approaches are also possible.
[0032] The area dose product calculated in this way is then, for example, either output by the calculating device 16 and displayed at a monitor, or is forwarded to a central control device, which takes the area dose product into consideration in the framework of the higher-ranking control of the calculating device 16 .
[0033] Although modifications and changes may be suggested by those skilled in the art, it is the intention of the inventor to embody within the patent warranted hereon all changes and modifications as reasonably and properly come within the scope of his contribution to the art. | An X-ray apparatus has a radiation source, an interchangeable radiation filter and an area dose measuring device having a measurement chamber with an allocated evaluation device for determining the area dose product on the basis of a measured signal provided by the measurement chamber. The measurement chamber is arranged preceding the filter in the beam path with reference to the radiation propagation direction. A detector recognizes the nature and/or the type of radiation filter that is currently inserted in the beam path. The evaluation device corrects the area dose product that is calculated from the measured signal from the measurement chamber on the basis of at least one filter-specific correction value that is selected as a result of the detection of the filter nature and/or type. | 0 |
This application is a continuation-in-part of U.S. application Ser. Nos. 08/568,576, filed on Dec. 7, 1995 and 08/572,966, filed on Dec. 15, 1995. This application is also a continuation-in-part of international application PCT/IE96/00084, filed on Dec. 9, 1996.
TECHNICAL FIELD
The present invention relates to pyrimidine derivatives and guanine derivatives, and their use in treating tumour cells. In particular, it relates to 6-hetarylalkyloxy pyrimidine derivatives, O 6 -substituted guanine derivatives and S 6 -substituted thioguanine derivatives, these compounds exhibiting the ability to deplete O 6 -alkylguanine-DNA alkyltransferase (ATase) activity in tumour cells.
BACKGROUND ART
It has been suggested to use O 6 -alkyl guanine derivatives possessing O 6 -alkylguanine-DNA alkyltransferase depleting activity in order to enhance the effectiveness of chemotherapeutic alkylating agents, principally those that methylate or chloroethylate DNA, used for killing tumour cells. There is increasing evidence that in mammalian cells the toxic and mutagenic effects of alkylating agents are to a large extent a consequence of alkylation at the O 6 -position of guanine in DNA. The repair of O 6 -alkylguanine is mediated by ATase, a repair protein that acts on the O 6 -alkylated guanine residues by stoichiometric transfer of the alkyl group to a cysteine residue at the active site of the repair protein in an autoinactivating process. The importance of ATase in protecting cells against the biological effects of alkylating agents has been most clearly demonstrated by the transfer and expression of cloned ATase genes or cDNAs into ATase deficient cells: this confers resistance to a variety of agents, principally those that methylate or chloroethylate DNA. Whilst details of the mechanism of cell killing by O 6 -methylguanine in ATase deficient cells is not yet clear, killing by O 6 -chloroethylguanine occurs through DNA interstand crosslink formation to a cytosine residue on the opposite strand via a cyclic enthanoguanine intermediate, a process that is prevented by ATase-mediated chloroethyl group removal or complex formation.
The use of O 6 -methylguanine and O 6 -n-butylguanine for depleting ATase activity has been investigated (Dolan et al., Cancer Res., (1986) 46, pp. 4500; Dolan et al., Cancer Chemother. Pharmacol., (1989) 25, pp 103. O 6 -benzylguanine derivatives have been proposed for depleting ATase activity in order to render ATase expressing cells more susceptible to the cytotoxic effects of chloroethylating agents (Moschel et al., J. Med. Chem., 1992, 35, 4486). U.S. Pat. No. 5,091,430 and International Patent Application No. WO 91/13898 Moschel et al. disclose a method for depleting levels of O 6 -alkylguanine-DNA alkyl-transferase in tumour cells in a host which comprises administering to the host an effective amount of a composition containing O 6 -benzylated guanine derivatives of the following formula: ##STR2## wherein Z is hydrogen, or ##STR3## and R a is a benzyl group or a substituted benzyl group. A benzyl group may be substituted at the ortho, meta or para position with a substituent group such as halogen, nitro, aryl such as phenyl or substituted phenyl, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, alkenyl of up to 4 carbon atoms, alkynyl of up to 4 carbon atoms, amino, monoalkylamino, dialkylamino, trifluoromethyl, hydroxy, hydroxymethyl, and SO n R b wherein n is 0, 1, 2 or 3 and R b is hydrogen, alkyl of 1-4 carbon atoms or aryl. Chae et al., J. Med. Chem., 1994, 37, 342-347 describes tests on O 6 -benzylguanine analogs bearing increasingly bulky substituent groups on the benzene ring or at position 9. Chae et. al., J. Med. Chem. 1995, 38, 359-365 describe several 8-substituted O 6 -benzylguanines, 2- and/or 8-substituted 6-(benzyloxy)purines, substituted 6(4)-(benzyloxy)pyrimidines, and a 6-(benzyloxy)-s-triazine which were tested for their ability to inactivate ATase. Two types of compounds were identified as being significantly more effective than O 6 -benzylguanine at inactivating ATase in human HT29 colon tumour cell extracts. These were 8-substituted O 6 -benzylguanines bearing electron-withdrawing groups at the 8-position (e.g. 8-aza-O 6 -benzylguanine and O 6 -benzyl-8-bromoguanine) and 5-substituted 2,4-diamino-6-(benzyloxy)pyrimidines bearing electron withdrawing groups at the 5-position (e.g. 2,4-diamino-6-(benzyloxy)-5-nitroso- and 2,4-diamino-6-(benzyloxy)-5-nitropyrimidine). The latter derivatives were also more effective than O 6 -benzylguanine at inactivating ATase in intact HT29 colon tumour cells. WO 96/04280 published after the priority dates of this application concerns similar substituted O 6 -benzylguanines and 6(4)-benzyloxypyrimidines.
The present Applicants are also Applicants in International Patent Application PCT/IE94/00031 which was published under No. WO 94/29312. U.S. patent application Ser. No. 08/568,576, filed Dec. 7, 1995, is the corresponding application in the United States (the contents of which are incorporated herein by reference in their entirety) described O 6 -substituted guanine derivatives of formula I: ##STR4## wherein Y is H, ribosyl, deoxyribosyl, or ##STR5## wherein X is O or S, R" and R'" are alkyl, or substituted derivatives thereof;
R' is H, alkyl or hydroxyalkyl;
R is (i) a cyclic group having at least one 5- or 6-membered heterocyclic ring, optionally with a carbocyclic or heterocyclic ring fused thereto, the or each heterocyclic ring having at least one hetero atom chosen from O, N, or S, or a substituted derivative thereof; or
(ii) naphthyl or a substituted derivative thereof;
and pharmaceutically acceptable salts thereof.
In order to be useful for depleting ATase activity and thus enhance the effects of the above-mentioned chemotherapeutic agents, compounds should have combination of characteristics assessed by reference to:
1) In vitro inactivation of recombinant ATase.
2) Stability.
3) Solubility.
4) Inactivation of ATase in mammalian cells and/or tumour xenografts.
5) Sensitization of mammalian cells and/or tumour xenografts to the killing or growth inhibitory effects of the said chemotherapeutic agents.
The behaviour of novel compounds in this combination of tests is unpredictable. Molecular interactions including steric factors in the unpredictability of ATase inactivation may be related to the nature of the environment of the cysteine acceptor site in the ATase molecule.
The structure of the ATase protein derived from E. coli (Ada gene) has been elucidated by X-ray crystallographic techniques (M. H. Moore et. al., EMBO Journal, 1994, 13, 1495.). While the amino acid sequence of human ATase differs somewhat from that of bacterial origin, all known ATases (human, rodent, yeast, bacterial) contain the cysteine (Cys) acceptor site in a common fragment, Pro-Cys-His-Arg. A homology model of human ATase generated by computer from the crystal structure of the Ada protein (J. E. A. Wibley et. al., Anti-Cancer Drug Design, 1995, 10, 75.) resembles it in having the Cys acceptor buried in a pocket deep in the protein. Considerable distortion of the structure is necessary to bring either an O 6 -alkylated guanine residue in intact DNA, or even free guanine alkylated by a relatively large group like benzyl, close to the Cys acceptor. These configurational changes are initiated by a characteristic binding of duplex DNA to the protein (K. Goodtzova et. al. Biochemistry, 1994, 33, 8385).
Since the amino acid components and dimensions of the ATase active site "pocket" are still unknown as are the details of the mechanism involved, it is impossible to predict the activity of a particular O 6 -alkylated guanine or analogous ring system.
Published work in this field relates predominantly to the use of O 6 -alkyl guanine derivatives having a nucleus identical to that of guanine in DNA. Chae et. al., J. Med. Chem. 1995, 38, 359-365 have described tests on a limited number of compounds in which the guanine ring was modified. However these compounds all had benzyl substitution at the O 6 -position of the modified guanine ring or 6(4)-benzyloxy substitution on the pyrimidine ring. The observation that subtle changes in the substituents on the guanine ring or in the purine skeleton can generate agents that are very ineffective ATase inactivators, in comparison with their "parent" structure, suggests that more substantial modifications might also disrupt the ATase inactivating function.
There is a need for additional novel compounds useful for depleting ATase activity in order to enhance the effects of chemotherapeutic agents such as chloroethylating or methylating anti-tumour agents. It is a further object to provide compounds having better ATase inactivating characteristics than O 6 -benzylguanine and having different solubility patterns.
Another object of the invention is to provide pharmaceutical compositions containing compounds which are useful for depleting ATase activity. A further object of the present invention is to provide a method for depleting ATase activity in tumour cells. A still further object of the invention is to provide a method for treating tumour cells in a host in such a way that they become more sensitive to the above-mentioned alkylating agents.
The present invention provide 6-hetarylalkyloxy pyrimidine derivatives of formula II: ##STR6## wherein R is (i) a cyclic group having at least one 5- 6-membered heterocyclic ring, optionally with a carbocyclic or heterocyclic ring fused thereto, the or each heterocyclic ring having at least one hetero atom chosen from O, N or S, or a substituted derivative thereof; or
(ii) phenyl or a substituted derivative thereof,
R 2 is selected from H, C 1 -C 5 alkyl, halogen or NH 2 ,
R 4 and R 5 which are the same or different are selected from H, NH--Y' or NO n wherein Y' is H, ribosyl, deoxyribosyl, arabinosyl, R"XCHR"' wherein X is O or S and R" is alkyl and R"' is H or alkyl, or substituted derivatives thereof,
n=1 or 2,
or R 4 and R 5 together with the pyrimidine ring form a 5- or 6-membered ring structure containing one or more hetero atoms,
and pharmaceutically acceptable salts thereof,
with the proviso that R 2 is not NH 2 if R 4 and R 5 form a ring structure IX ##STR7## wherein Y is H, ribosyl, deoxyribosyl, or ##STR8## wherein X is O or S, R" and R"' are alkyl, or substituted derivatives thereof,
and with the proviso that R is not phenyl in the following circumstances a) to h):
a) if R 2 and R 5 are NH 2 and R 4 is NO or NO 2
b) if R 2 is NH 2 and R 4 and R 5 form a ring structure X ##STR9## c) if R 2 is NH 2 and R 4 and R 5 form a ring structure XI ##STR10## d) if R 2 is NH 2 , and R 4 is NO 2 and R 5 is H or CH 3
e) if R 2 , R 4 and R 5 are NH 2 ,
f) if R 2 and R 5 are NH 2 and R 4 is H,
g) if R 2 is H, and R 4 is NO 2 and R 5 is NH 2 , or
h) if R 2 is F or OH, and R 4 and R 5 form a ring structure XII ##STR11##
Certain O 6 -substituted guanine derivatives within the scope of the general formula in WO 94/29312 but not published therein have been found to have a surprisingly advantageous combination of properties which justifies the selection of such derivatives from among the class defined in WO 94/29312.
In another aspect, the present invention provides guanine derivatives of formula XIII: ##STR12## wherein E is O or S,
Y' is as defined for formula II above,
R 6 is a cyclic group having at least one 5- or 6-membered heterocyclic ring, optionally with a carbocyclic or heterocyclic ring fused thereto, the or each heterocyclic ring having at least one hetero atom chosen from O, N or S, or a substituted derivative thereof,
and pharmaceutically acceptable salts thereof, with the proviso that compounds published in WO 94/29312 are disclaimed.
In particular, the present invention selects advantageous compounds of formula XIV: ##STR13## wherein R 10 is bromo, chloro or cyano, and
Y' is as defined for formula II.
Most preferably, R 10 is bromo. A particularly preferred and selected compound is O 6 -(4-bromothenyl)guanine having the formula XV: ##STR14##
This compound has an advantageous combination of properties including potential for oral administration.
R or R 6 may suitably be a 5- or 6-membered heterocyclic ring or a benzo derivative thereof, in which latter case the pyrimidine moiety may be attached to R or R 6 at either the heterocyclic or the benzene ring.
In preferred embodiments, R or R 6 is a 5-membered ring containing S or O, with or without a second ring fused thereto.
Preferably, R or R 6 is a heterocyclic ring having at least one S atom; more preferably, R or R 6 is a 5-membered heterocyclic ring having at least one S atom; and most preferably, R or R 6 is a thiophene ring or a substituted derivative thereof. Alternatively, R or R 6 may be a heterocyclic ring having at least one O atom, particularly, a 5-membered heterocyclic ring having at least one O atom and more particularly R or R 6 may be a furan ring or a substituted derivative thereof. As another alternative, R or R 6 may be a heterocyclic ring having at least one N atom, particularly R or R 6 may be a 6-membered heterocyclic ring having at least one N atom and in particular, R or R 6 may be a pyridine ring.
The carbocyclic or heterocyclic ring fused to the heterocyclic ring in R or R 6 may itself be bicyclic e.g. naphthalene.
In general the term "substituted derivative" as used in relation to any of the compounds of the invention means any substituted derivative whose presence in the compound is consistent with the compound having ATase depleting activity.
In the definition of Y or Y', the term "substituted derivative" includes further substitution by one or more of the following groups: hydroxy, halo, alkoxy, amino, alkylamino, amido or ureido. In a particularly preferred group of compounds, R" is hydroxy-substituted alkyl and R"' is H, so that Y' is hydroxyalkoxymethyl, preferably having 1 to 10 carbon atoms in the alkoxy group.
In the definition of R or R 6 , the term "substituted derivative" includes substitution of the heterocyclic ring(s) and/or carbocyclic ring(s) by one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, aryl, halo, haloalkyl, nitro, cyano, azido, hydroxyalkyl, SO n R 7 where R 7 is alkyl and n=0, 1 or 2, or a carboxyl or ester group of the formula --COOR 8 wherein R 8 is H or alkyl. Halo, haloalkyl, cyano, alkylenedioxy, SO n R 7 (as defined above) and --COOR 8 wherein R 8 is alkyl are preferred substituents.
An alkyl, alkoxy, alkenyl, or alkynyl group preferably contains from 1 to 20, more preferably from 1 to 10 and most preferably from 1 to 5 carbon atoms. Halo includes iodo, bromo, chloro or fluoro. An aryl group preferably contains from 1 to 20, more preferably from 1 to 10 carbon atoms, particularly 5 or 6 carbon atoms.
One embodiment of the invention provides a pharmaceutical composition containing compounds of formula II or formula XIII, as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Optionally the composition may also contain an alkylating agent such as a chloroethylating or methylating agent.
In a further embodiment, the present invention provides a method for depleting ATase activity in a host comprising administering to the host an effective amount of a composition containing a compound of formula II or formula XIII as defined above, or a pharmaceutically acceptable salt thereof, more particularly a pharmaceutical composition as defined above. This method may alternatively be defined as a method of depleting ATase mediated DNA repair activity in a host.
The invention further provides a method for treating tumour cells in a host comprising administering to the host an effective amount of a composition containing a compound of formula II or formula XIII as defined above or a pharmaceutically acceptable salt thereof, more particularly a pharmaceutical composition as defined above and administering to the host an effective amount of a composition containing an alkylating agent. The method may be used for treatment of neoplasms including those which are known to be sensitive to the action of alkylating agents e.g. melanoma and glioma and others whose resistance to treatment with alkylating agents alone may be overcome by the use of an inactivator according to the invention.
The term "pharmaceutically acceptable salts" as used in this description and the claims means salts of the kind known in the pharmaceutical industry including salts with inorganic acids such as sulfuric, hydrobromic, nitric, phosphoric or hydrochloric acid and salts with organic acids such as acetic, citric, maleic, fumaric, benzoic, succinic, tartaric, propionic, hexamoic, heptanoic, cyclopentanepropionic, glycolic, pyruvic, lactic, malonic, malic, o-(4-hydroxy-benzoyl)benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, 1,2-ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-chlorobenzenesulfonic 2-naphthalenesulfonic, p-toluenesulfonic, camphorsulfonic, 4-methyl-bicyclo[2.2.2]oct-2-ene-1-carboxylic, glucoheptonic, 4,4'-methylenebis(3-hydroxy-2-naphthoic), 3-phenylpropionic, trimethyl-acetic, tertiary butylacetic, lauryl sulfuric, gluconic, glutamic, hydroxynaphthoic, salicyclic, stearic, or muconic, and the like.
Subject to the provisos above the preferred compounds of the invention are those of:
Type 1
Formula III ##STR15## wherein: R is as defined for formula II, particularly furyl or thienyl unsubstituted or substituted, preferably with a halogen such as chlorine, bromine or fluorine, or with cyano
Y' is as defined for formula XIII, preferably Y' is H or HOCH 2 CH 2 OCH 2 --;
R 2 is H, NH 2 , C 1 -C 5 alkyl, preferably methyl, or halogen, preferably fluorine;
R 3 is H or OH:
Type 2
Formula IV ##STR16## wherein: R is as defined for formula II, particularly phenyl, thienyl or furyl unsubstituted or substituted preferably with a halogen such as chlorine, bromine or fluorine, or with cyano, or phenyl having a methylenedioxy ring structure fused thereto;
Y' is as defined for formula XIII;
X is CH or N;
A is CH or N; and preferably when X═N, A═CH
Formula V ##STR17## wherein: R is as defined for formula II
X is CH or N
A is CH or N;
Type 3
Formula VI ##STR18## wherein: R is as defined for formula II, particularly, thienyl or furyl unsubstituted or substituted preferably with a halogen such as chlorine or bromine;
Z is O or S or CH═CH
A particularly preferred group of compounds of this type are O 6 -(4-halothenyl)-8-thiaguanines, particularly O 6 -(4-bromothenyl)-8-thiaguanine.
Formula VII ##STR19## wherein: R is as defined for formula II;
U is CH or N;
V is CH or N;
W is CH or N;
provided that U, V and W are not all CH.
Type 4
Formula VIII ##STR20## wherein: R is as defined for formula II, particularly thenyl or furyl optionally substituted with halogen preferably one or more of chlorine, bromine or fluorine;
T is H, NH 2 or NO n where n=1 or 2;
Q is H, NH 2 or NO n where N=1 or 2;
Type 5
Formula XVI ##STR21## wherein R is as defined for formula XIII
Y' is as defined for formula II
BRIEF DESCRIPTION OF DRAWINGS
The invention will be described in greater detail with reference to the accompanying drawings, in which:
FIGS. 1 to 4 are graphs showing the effect of pretreatment with compound B.4316 on Raji cell sensitization to different chemotherapeutic agents. Each graph plots percentage growth against the concentration (μg/ml) of the chemotherapeutic agent in the presence and absence of B.4316.
FIG. 1 shows the effect of 1 uM B.4316 pretreatment of Raji cell sensitization to temozolomide.
FIG. 2 shows the effect of 10 μm B.4316 pretreatment on Raji cell sensitization to BCNU.
FIG. 3 shows the effect of 10 μM B.4316 pretreatment on Raji cell sensitization to fotemustine.
FIG. 4 shows the effect of 10 μM B4316 pretreatment on Raji cell sensitization to melphalan and cisplatin.
FIG. 5 is a histogram showing the effect of 10 μM B4316 pretreatment on Raji cell sensitization to different chemotherapeutic agents, measured as sensitization factor (SF, defined below) based on D 50 except for fotemustine where SF is based on D 80 .
FIG. 6 is a similar histogram showing the effect of 10 μM B4349 pretreatment on Raji cell sensitization to different chemotherapeutic agents, with SF as for FIG. 5.
FIG. 7 is a series of histograms showing the inactivation of ATase in A375M tumours and murine host tissues two hours after interperitoneal (i.p.) administration of various inactivator compounds at 5 mg/kg. Inactivation was calculated as % of control ATase activity, measured as fm/mg protein.
FIG. 8 is a graph showing the kinetics of ATase depletion and recovery in A375M tumours and murine host tissues after administration of B.4363 (20 mg/kg i.p.). The graph plots % of control ATase activity against time (hours).
FIG. 9 is a graph of percentage residual activity of pure recombinant human ATase following incubation with increasing concentrations of inactivators O 6 -benzylguanine (BeG), O 6 -thenylguanine (B.4205) and O 6 -(4-bromothenyl)guanine (B.4280). The line at 50% residual activity is used for calculating I 50 values i.e. the concentration of inactivator required to produce a 50% reduction in ATase activity. The I 50 values shown are extrapolated from the curves. Preincubation was for 1 hour after which [ 3 H]-methylated substrate was added to determine residual activity of ATase.
FIG. 10A is three graphs of percentage cell growth against temozolomide concentration (μg/ml) showing the effect of pretreatment with BeG, B.4205 and B.4280 (0.5 μM final concentration) on the sensitivity of Raji cells to the growth inhibitory effects of temozolomide. Inactivator or vehicle was given 2 hours prior to temozolomide.
FIG. 10B is a histogram for the inactivators of FIG. 10A showing the sensitization factor based on D 50 of Raji cells to growth inhibition by temozolomide.
FIG. 11 is a histogram of ATase activity (fm/mg) against time (hours) showing the effect of ATase inactivators BeG, B. 4205 and B.4280 on ATase activity in human melanoma xenografts grown in nude mice. Animals were given a single dose of the inactivators intraperitoneally (i.p.) at 30 mg/kg or 50 mg/kg and sacrificed after the times shown.
FIG. 12 is a histogram showing the effect of ATase inactivators on ATase activity (fm/mg) inhuman melanoma xenografts grown in nude mice. Animals were given B.4205 or temozolomide alone or B.4205 or B.4280 in combination with temozolomide (50 mg/kg) i.p. at the does shown on three consecutive days (except where indicated) and sacrificed 24 hours after the final dose. The vehicles were corn oil for the inactivators and PBS (20% DMSO) for temozolomide.
FIG. 13 is a histogram showing the effect of ATase inactivators on ATase activity in livers of nude mice. Animals were given the B.4205 or temozolomide alone or B.4205 or B.4280 in combination with temozolomide (50 mg/kg, i.p.) at the doses shown on three consecutive days (except where indicated) and sacrificed 24 hours after the final dose.
FIG. 14A is a graph of % tumor growth against time (days) showing the effect of B.4205 on the sensitivity of human melanoma xenografts to growth inhibition by temozolomide. Animals were untreated, given temozolomide alone (100 mg/kg, i.p.) or B.4205 (5, 10 or 20 mg/kg i.p.) followed 1 hour later by temozolomide (100 mg/kg, i.p.) on five consecutive days. Tumour growth was monitored as described. The data from a number of separate studies are presented.
FIG. 14B is a graph of number of surviving mice against time (days) showing survival of animals (tumour-bearing nude mice) used in the study shown in FIG. 14A. Groups of animals in which the xenografts had reached the maximum size were terminated.
FIG. 15A is a graph showing the effect of B.4280 on the sensitivity of human melanoma xenografts to growth inhibition by temozolomide. Animals were untreated, given temozolomide alone (100 mg/kg. i.p.) or B.4280 alone (20 mg/kg, i.p.) or B.4280 (1, 5, 10 or 20 mg/kg, i.p.) followed 1 hour later by temozolomide (100 mg/kg, i.p.) on five consecutive days. Tumour growth was monitored as described. The data from a number of separate studies are presented.
FIG. 15B is a graph showing the survival of the animals (tumour-bearing nude mice) used in the study shown in FIG. 15A. Groups of animals in which the xenografts had reached the maximum size were terminated.
FIG. 15A is a graph of % tumour growth against time (days) showing the comparison of the effect of B.4280 given i.p. and orally (p.o.) on the sensitivity of human melanoma xenografts to growth inhibition by temozolomide. Animals were untreated, given temozolomide alone (100 mg/kg) or B.4280 alone (20 mg/kg, i.p.) or B.4280 (20 mg/kg, i.p.) or B.4280 (30 mg/kg, p.o.) followed 1 hour later by temozolomide (100 mg/kg, i.p.) on five consecutive days. Tumour growth was monitored as described. The data from a number of separate studies are presented.
FIG. 16B is a graph showing the survival of the animals used in the study shown in FIG. 16A. Groups of animals in which the xenografts had reached the maximum size were terminated.
FIG. 17 is a graph showing the survival of animals in a comparative test of the effects of BeG, B.4205 and B.4280 in combination with temozolomide (TZ) in non-tumour-bearing DBA 2 mice. Animals were given temozolomide alone (100 mg/kg i.p) or BeG (10 or 20 mg/kg, i.p.), B.4205 (10 or 20 mg/kg i.p.) or B.4280 (10 or 20 mg/kg i.p.) followed one hour later by temozolomide (100 mg/kg i.p.) on five consecutive days.
FIGS. 18 to 21 consist of pairs of graphs showing the kinetics of ATase depletion and recovery in various tumours and murine host tissues after administration of B.4280 at the doses indicated. The graphs plot ATase activity (fm/mg protein) and % of control ATase activity against time (hours):
FIG. 18 relates to B.4280 (20 mg/kg, i.p.) in A375M tumours and other tissues.
FIG. 19 relates to B.4280 (30 mg/kg, p.o.) in A375M tumours and other tissues.
FIG. 20 relates to B.4280 (30 mg/kg i.p.) in MCF-7 tumours and other tissues.
FIG. 21 relates to B.4280 (20 mg/kg i.p.) in DU-145 tumours and other tissues.
FIG. 22 is a graph of % tumour growth against time (days) showing the effect of B.4280 on the sensitivity of MCF-7 tumours to growth inhibition by temozolomide. Animals were untreated, were given temozolomide alone (100 mg/kg, i.p.) or B.4280 (PaTrin-2) (20 mg/kg i.p.) alone, or B.4280 (20 mg/kg i.p.) followed 1 hour later by temozolomide (100 mg/kg i.p.) on five consecutive days.
FIG. 23 consists of graphs of % tumor growth, number of surviving mice and mean weight (g) against time (days) showing the effect of a single dose of B.4280 (PaTrin-2) on the sensitivity of melanoma tumours to growth inhibition by a single dose of fotemustine. Animals were given fotemustine (20 mg/kg i.p.) alone, or B.4280 (30 mg/kg p.o) followed 1 hour later by fotemustine (20 mg/kg i.p.).
FIG. 24 consists of graphs of % tumour growth and number of surviving mice against time (days) for sensitization of A375M tumours with B.4205 (PaTrin-1) and B.4280 20 mg/kg pretreatment followed by 150 mg/kg temozolomide using a 5 day schedule as for FIG. 22.
FIG. 25 consists of graphs of % tumour growth, number of surviving mice and mean weight (g) against time showing sensitization of A375M tumours to temozolomide (100 mg/kg i.p.) following administration of 20 mg/kg B.4349 or B.4351 (i.p.).
FIG. 26 is a figure showing ATase activities in A375M tumours and murine host tissues at 2 hours and 24 hours following i.p. administration of 90 mg/kg B.4335.
In the specification the abbreviations "1 h" or "2 h" etc. mean "1 hour", "2 hours" etc. In the drawings the abbreviations "Temo" and "Tz" refer to temozolomide.
FIG. 27 consists of graphs of % tumour growth and weight (% of day 1 value) against time (days) showing tumour DU-145 prostate xenograft growth after temozolomide (100 mg/kg/day) and/or B.4280 (PaTrin-2) (20 mg/kg/day) days 1-5. Points are the means of values from at least 4 mice. Growth delays in each group were (p value): PaTrin-2 alone 0.1 days (>0.05); temozolomide alone 7.8 (>0.05). Both agents 15.3 (0238).
FIG. 28 is a reaction scheme for synthesis of O 6 -[ 3 H]-(4-bromothenyl)guanine.
FIG. 29 shows co-chromatography of authentic B.4280 and readioactivity in the product of O 6 -[ 3 H]-(4-bromothenyl)guanine synthesis. Shading indicates counts recovered (LH axis) and the line OD at 254 nm (RH axis).
FIG. 30 shows transfer of radioactivity from O 6 -[ 3 H]-(4-bromothenyl)guanine to rhATase after one hour incubation at 37° C.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Examples of compounds of the invention are shown in Tables 1a and 1b. They were synthesized by the procedures presented below, adapted as appropriate.
Type 1
A. O 6 -Substituted hypoxanthines were made by the action of alkoxide RCH 2 ONa on the quaternary salt N,N,N-trimethyl-1H-purin-6aminium chloride. 1
B. O 6 -Substituted 2-methylhypoxanthines were made similarly, from the quaternary salt from diazabicyclooctane (DABCO) and 6-chloro-2-methylpurine. 2
C. O 6 -Substituted 2-fluorohypoxanthines were made by diazotisation of the corresponding guanines using sodium nitrite and concentrated fluoboric acid at -25° C. 3
D. O 6 -Substituted 9-(2-hydroxyethoxymethyl)guanines were made by condensing the corresponding guanines after silylation with 2-acetoxyethoxymethyl bromide in the presence of mercuric cyanide followed by saponification of the O-acetyl group. 4
E. O 6 -Substituted 8-hydroxyguanines were made from 6-hetarylmethyl-2,4,5-triaminopyrimidines and 1, 1-carbonyldiimidazole in DMF. 5 Reaction of 6-chloro-2,4-diaminopyrimidine with alkoxide in DMSO, followed by nitrosation with sodium nitrite in aqueous acetic acid and reduction using sodium hydrosulphite in aqueous DMF, gave the 2, 4, 5-triamines.
Type 2
A. O 6 -Substituted 8-azaguanines were made from the above triamines and sodium nitrite in aqueous acetic acid. 6
B. O 6 -Substituted 8-aza-7-deazaguanines were made from the alkoxide RCH 2 ONa and 2-amino-6-chloro-8-aza-7deazapurine 7 in sulfolane or from the DABCO quaternary salt (in DMSO solvent) derived from it.
Type 3
A. O 6 -Substituted 8-oxaguanines were made by lead tetraacetate oxidation 8 of 6-hetarylmethyl-2,4-diamino-5-nitrosopyrimidines obtained as under Type IE.
B. O 6 -Substituted 8-thiaguanines were made from the triamine intermedites under Type IE and N-tosylthionylimine in pyridine. 9
C. O 4 -Substituted pterins were made from these triamines and glyoxal with sodium metabisulphite. 10
Type 4
A and B.
These pyrimidines were obtained as under Type IE.
C. O 6 -Substituted 2,4-diamino-5-nitropyrimidines were made by the action of alkoxide RCH 2 ONa in DMSO on 6-chloro-2,4-diamino-5-nitropyrimidine. 11
Type 5
S 6 -Substituted 6-thioguanines were prepared from the thiolate RCH 2 SNa and the quaternary salt 2-amino-N,N,N-trimethyl-1H-purin-6-aminium chloride (WO 94/29312).
O 6 -Substituted guanines as listed in Tables 6a and 6b were made by the standard preparation as described in WO 94/29312, usually with 3 mmol alcohol RCH 2 OH per mmol quaternary salt.
The alcohols were made as described in U.S. patent application Ser. No. 08/568,576, filed Dec. 7, 1995 by sodium borohydride reduction of the corresponding aldehydes, with two exceptions. For 4-bromothenyl alcohol 12 required for B.4280 the aldehyde is commercially available. 5-Chlorothiophen-2-aldehyde 13 and 5-methylthiothiophen-2-aldehyde 14 were prepared by Vilsmeier reaction on 2-chlorothiophen and 2-methylthiothiophen respectively. Sodium borohydride reduction of the methylthioaldehyde followed by sodium periodate oxidation 15 of the resulting methylthioalcohol yielded the methylsulphinylalcohol required for B.4294. Reduction of the chloroaldehyde gave 5-chlorothenyl alcohol 16 for B.4281.
Several other aldehydes were obtained by halogenation of the appropriate thiophen aldehyde or furfural. Thus, direct bromination gave 5-bromofurfural 17 and thence the alcohol 18 for B.4336. Halogen in presence of aluminum chloride on thiophen-2-aldehyde yielded 4-chlorothiophen-2-aldehyde 19 (for the alcohol for B.4298), on thiophen-3-aldehyde yielded 2-bromothiophen-4-aldehyde 20 (and eventually B.4313), and on 5-chlorothiophen-2-aldehyde yielded 4,5-dichlorothiophen-2-aldehyde 21 (for the alcohol 22 for B. 4318).
Cyanoaldehydes were obtained from copper cyanide and the corresponding bromoaldehydes in refluxing dimethylformamide. 5-Cyanothiophen-2-aldehyde 23 and its 4-cyano isomer 24 then gave the 5-cyano and 4-cyano 25 alcohols, for B.4283 and B.4317 respectively.
4-Methoxythenyl alcohol 26 (for B.4300) was prepared as described from 2,3-dibromosuccinic acid and methyl thioglycollate, and ultimate reduction of the methyl ester (not aldehyde in this case) by lithium aluminium hydride and 2-chloro-4-picolyl alcohol 27 (for B.4321) by sodium borohydride reduction 28 of the corresponding acid chloride, made in turn from reaction 29 of phosphorus oxychloride/pentachloride on isonicotinic acid N-oxide.
For B.4282, 3-pyridinemethanol N-oxide is commercially available. 5-Methylsulphonylthenyl alcohol (for B.4309) was obtained by m-chloroperbenzoic acid (MCPBA) oxidation of the alcohol resulting from reduction of 5-methylthio-2-thiophenecarboxaldehyde 30 .
6-Chloro-3-pyridinemethanol (for B.4319) and 5-bromo-3-pyridinemethanol (for B.4320) were made by treatment of 6-chloro and 5-bromonicotinic acids respectively with phosphorus oxychloride/pentachloride and reduction of the resulting acid chlorides with sodium borohydride 28 . Isothiazole-4-methanol (for B.4354) was obtained by reduction of the corresponding methyl ester (A. Adams, and R. Slack, J. Chem. Soc. 1959, 3061) with lithium aluminium hydride (M. Hatanaka and T. Ishimaru, J. Med. Chem. 16, 1973, 978).
4-bromo-2-thiophenecarboxaldehyde was converted into the 4-lithio derivative (A. L. Johnson, J. Org. Chem. 41, 1976, 1320) of its ethylene acetal and reaction of this organometallic with dimethyl disulphide followed by acid hydrolysis gave 4-methylthio-2-thiophenecarboxaldehyde (R. Noto, L. Lamartina, C. Arnone and D. Spinelli, J. Chem. Soc., Perkin Trans. 2, 1987, 689). Sodium borohydride reduced this aldehyde to the 4-methylthio alcohol (for B.4356), which in turn with one of two equivalents of MCPBA yielded the 4-methylsulphinyl and 4-methylsulphonyl alcohols (for B.4377 and B.4361 respectively). reaction of the above organometallic with naphthalene-2-sulphonyl azide (A. B. Khare and C. E. McKenna, Synthesis, 1991, 405) and sodium pyrophosphate followed by hydrolysis by the method (P. Spagnolo and P. Zamirato, J. Org. Chem., 43, 1978, 3539) for the preparation of other azidothiophene aldehydes gave 4-azido-2-thiophenecarboxaldehyde leading to the alcohol for B.4373.
5-Iodo-3-thiophenemethanol (for B.4357) came from the aldehyde obtained by treatment of 3-thiophenecarboxaldehyde with iodine-iodic acid-sulphuric acid (R. Guilard, P. Fournari and M. Person, Bull. Soc. Chim. France, 1967, 4121).
2-Naphtho[2,1-b]thienylmethanol (for B.4366) was prepared by lithium aluminium hydride reduction of the corresponding carboxylic acid (M. L. Tedjamulia,, Y. Tominaga, R. N. Castle and M. L. Lee, J. Heterocycl. Chem., 20, 1983, 1143). 5-Phenylthenyl alcohol (m.p. 91.5° C. for B.4378) resulted from sodium borohydride reduction of the aldehyde (P. Demerseman, N. P. Buu-Hoi and R. Royer, J. Chem. Soc., 1954, 4193) obtained by Vilsmeier reaction of 2-phenylthiophene (from Gomberg-Bachmann reaction (N. P. Buu-Hoi and N. Hoan, Rec. trav. chim., 69, 1950, 1455) of benzenediazonium chloride and alkali with thiophene).
By way of specific example, the preparation of O 6 -(4-bromothenyl)guanine (B.4280) will now be described.
Preparation of O 6 -(4-bromothenyl)guanine
A solution of 4-bromothenyl alcohol 12 [ 4.63 g, 24 mmol; R f 0.38 in TLC (PhMe-MeOH, 4:1)] in DMSO (4 ml) was treated cautiously with sodium hydride (60% in oil; 0.64 g, 16 mmol). After 1 hour's stirring, 2-amino-N,N,N-trimethyl-1H-purin-6-aminium chloride (1.83 g, 8 mmol) was added. After 1 hour's further stirring, acetic acid (1.3 ml) followed by ether (240 ml) was added and the solid filtered off after 1-2 h. Removal of solvents and excess of alcohol (b.p. 85-90° C./0.4 mm) from the filtrate yielded a negligible second fraction (17 mg). The main crop was triturated with water (10 ml), affording substantially pure product (1.89 g, 73%) with R f 0.22 in TLC (PhMe-MeOH, 4:1). It was recrystallized by dissolving in hot methanol (100 ml) and then concentrating. Analytical data are given in Tables 6a and 6b, together with data for other compounds. Other typical synthetic procedures are described by way of example in a special section later in this text.
Compounds of formula II or XIII in which Y' is R"XCHR"' and R"' is alkyl (seco-nucleosides) may be prepared by an analogous preparation to the reaction of O 6 -benzylguanine with -chloro-ethers (MacCoss et al., Tetrahedron Lett.; European Patent Application No. 184,473, loc. cit.) or with alkyl bromides (e.g. Kjellberg, Liljenberg and Johansson, Tetrahedron Lett., 1986, 27, 877; Moschel, McDougall, Dolan, Stine, and Pegg, J. Med. Chem., 1992, 35, 4486).
Typical "sugar" components corresponding to R"XCHR"', leading to seco-nucleosides, are made by methods described in e.g. McCormick and McElhinney, J. Chem. Soc., Perkin Trans. 1, 1985, 93; Lucey, McCormick and McElhinney, J. Chem. Soc. Perkin Trans. 1, 1990, 795.
Compounds of formula II or XIII in which Y is ribosyl or deoxyribosyl (nucleosides) may be prepared by methods analogous to the syntheses of O 6 -benzylguanine riboside and 2-deoxyriboside (Moschel et al. 1992; cf. Gao, Fathi, Gaffney et al., J. Org. Chem., 1992, 57, 6954; Moschel, Hudgins and Dipple, J. Amer. Chem. Soc., 1981, 103, 5489) (see preparation of Ribosides above).
INDUSTRIAL APPLICABILITY
The amount of the compound of the present invention to be used varies according to the effective amount required for treating tumour cells. A suitable dosage is that which will result in a concentration of the compound of the invention in the tumor cells to be treated which results in the depletion of ATase activity, e.g. about 1-2000 mg/kg body weight, and preferably 1-800 mg/kg body weight, particularly 1-120 mg/kg body weight, prior to chemotherapy with an appropriate alkylating agent.
The pharmaceutical composition of the invention may be formulated in conventional forms with conventional excipients, as described for example in and U.S. Pat. Nos. 5,525,606 and 5,091,430 and 5,352,669, the contents of which are incorporated herein by reference in their entirety. The composition may contain the inactivator according to the invention together with an appropriate alkylating agent; or the composition may comprise two parts, one containing the inactivator and the other containing the alkylating agent. The method of administering the compounds of the invention to a host may also be a conventional method, as described in WO 91/13898 for example. For administration of an inactivator according to the invention to patients, the pharmaceutical composition may suitably contain the inactivator in a suitable vehicle such as 40% polyethyleneglycol 400 in saline solution, or in saline or 3% ethanol (in saline), for intravenous injection, or in a powder form in suitable capsules for oral administration.
Alkylating agents may be administered in accordance with known techniques and in conventional forms of administration, as described in WO 91/13898 for example or preferably as a single dose immediately after or up to 24 hours after but preferably around 2 hours after administration of the ATase inactivating agents and also at doses lower than those used in standard treatment regimen. A reduction in dose may be necessary because the inactivators would generally be anticipated to increase the toxicity of the alkylating agents. Examples of chloroethylating agents include 1,3 bis (2-chloroethyl)-1-nitrosourea (BCNU), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), fotemustine, mitozolomide and clomesone and those described in McCormick, McElhinney, McMurry and Maxwell J. Chem. Soc. Perkin Trans. 1, 1991, 877 and Bibby, Double, McCormick, McElhinney, Radacic, Pratesi and Dumont Anti-Cancer Drug Design, 1993, 8, 115. Examples of methylating agents include temozolomide and U.S. Pat. No. 5,260,291 the contents of which are incorporated herein in their entirety) and dacarbazine, procarbazine, and streptozocin.
METHODS
O 6 -alkylguanine-DNA-alkyltransferase assay
Varying amounts of recombinant ATase or cell/tissue extracts were incubated with [ 3 H]-methylnitrosourea-methylated calf thymus DNA (specific activity, 17 Ci/mmol) at 37° C. for 1 hour in a total volume of 300 μl buffer 1/[50 mM Tris/HCl (pH 8.3), 3 mM dithiothreitol (DTT), 1 mM EDTA] containing 1 mg/ml bovine serum albumin (IBSA) for recombinant ATases and tissue extracts, or 1.1 ml buffer 1 for cell extracts. After incubation, bovine serum albumin (100 μl of 10 mg/ml in buffer 1) and perchloric acid (100 μl of 4M perchloric acid for 300 μl volumes and 400 μl for 1.1 ml volumes) and 2 ml of 1M perchloric acid were added. Samples were then heated at 75° C. for 50 minutes to hydrolyze the DNA. Samples were then centrifuged at 3,000 rpm for 10 minutes and the precipitate washed once with 4 ml of 1M perchloric acid, before being resuspended in 300 μl of 0.01M sodium hydroxide and dissolved in 3 ml of aqueous scintillation fluid (Ecoscint A, National Diagnostics). Counting efficiency was approximately 30%. ATase specific activity was calculated from the region where the activity was proportional to the amount of extract added, since with higher amounts of extracts the reaction becomes substrate limiting. ATase activity is expressed as fmol methyl transferred to protein per mg of total protein in the extract.
Method of Purification of Recombinant ATases
The cDNA cloning and overexpression of the human ATase has been reported previously 30 . Purification of the recombinant proteins was achieved either by affinity chromatography through a DNA-cellulose column as described by Wilkinson et al., 31 , 32, or by DEAE-cellulose ion-exchange chromatography. For the latter, the ATase protein was partially purified by ammonium sulphate precipitation (30-60%) and dialyzed against 10 mM Tris-HCl pH 7.5, 1 mM DTT, 2 mM EDTA, 10% glycerol, before loading on a DEAE-cellulose column. The ATase was then eluted with a 0-0.1 M NaCl gradient. The purified human ATase protein retained activity for more than one year when stored at high concentration at -20° C. in buffer 1 [50 mM-Tris/HCl (pH 8.3)/3 mM-dithiothreitol/1mM-EDTA] and could be thawed and refrozen several times without substantial loss of activity.
Incubation with Inactivators and ATase Assay
Compounds to be tested were dissolved in DMSO to a final concentration of 10 mM and diluted just before use in buffer 1. Recombinant ATase was diluted in buffer 1 containing 1 mg/ml bovine serum albumin (IBSA) and tilrated as described above in order that the reaction be conducted under ATase, and not substrate, limiting conditions. In each assay, fixed amounts of ATase (60-75 fmol) were incubated with varying amounts of O 6 -benzylguanine, or test compound in a total volume of 200 μl of IBSA containing 10 μg of calf thymus DNA at 37° C. for 1 hour. The [ 3 H]-methylated-DNA substrate (100 μl) containing 4 μg of DNA and 100 fmol of O 6 -methylguanine) was then added and incubation continued at 37° C. for 1 hour, until the reaction was complete. Following acid hydrolysis of the DNA as described above the [ 3 H]-methylated protein was recovered and quantitated by liquid scintillation counting. I 50 is the concentration of inactivator required to produce a 50% reduction in ATase activity under the above conditions.
Cell Culture and Preparation of Extracts
Mammalian cells including Raji cells (a human lymphoblastoid cell line from a Burkitt's lymphoma), A375M cells (human melanoma cells), MCF-7 cells (human breast cancer cells) and PC3 and DU145 (both human prostrate cancer cells) were cultured under standard conditions. For example, Raji cells were grown in suspension culture in RPMI medium supplemented with 10% horse serum. Cell pellets were resuspended in cold (4° C.) buffer I containing 2 μg/ml leupeptin and sonicated for 10 seconds at 12 μm peak to peak distance. After cooling in ice, the cells were sonicated for a further 10 seconds at 18 μm. Immediately after sonification, 10 μl/ml of phenylmethanesulphonylfluoride (PMSF 8.7 mg/ml in 100% ethanol) was added and the sonicates centrifuged at 15000cpm for 10 minutes at 4° C. to pellet cell debris. The supernatant was transferred to a tube on ice and kept for determination of ATase activity (see above).
Stability of Inactivators at 37° C. by Spectrophotometry.
Inactivators (10mM in DMSO) were diluted to 0.1mM in prewarmed degassed PBS (pH 7-7.2). PBS (Phosphate buffered saline) is 0.8% NaCl, 0.02% KCl, 0.15% Na 2 H 2 PO 4 , 0.02% KH 2 PO 4 . Samples were immediately transferred to a CARY13 spectrophotometer (cuvette block held at 37° C.) and scanned at an appropriate wavelength (according to the spectral properties of the compound) at 5-10 minute intervals for up to 80 hours. The results were expressed as percentage absorbance change versus time and T1/2 values (half life) extrapolated from this. In the tables the results of these tests are identified by "in PBS" or "by Spec".
Stability of Inactivators of ATase Assay
Inactivators (10 μM in DMSO) were diluted to the appropriate concentration (I 90 calculated from previous I 50 determination data) in buffer I without DTT and incubated for varying times at 37° C. Samples were then taken for use in the competition assay to assess the compound's ability to inactivate human ATase. The results were expressed as reduction in activating activity versus time and T 1/2 values extrapolated from this.
Inactivation of ATase Activity in Raji Cells.
Raji cells were diluted to between 5×10 5 /ml and 10 6 /ml in medium containing either the appropriate concentration of inactivator or an equivalent volume of vehicle (DMSO). Following incubation at 37° C. for 2 hours the cells were harvested by centrifugation, washed twice with PBS and the resulting cell pellets (between 5×10 6 and 10 7 cells per pellet) stored at -20° C. ATase activity was determined as described above, in duplicate cell extracts and expressed as the percentage activity remaining, based on that present in the untreated controls (350-450 fm/mg depending on the assay). I 50 (i.e concentration of inactivator required to reduce ATase activity by 50%) values were extrapolated from this data.
Sensitization of Mammalian Cells to Cytotoxic Agents.
Sensitization of mammalian cells to the cytotoxic effects of BCNU, temozolomide and other cytotoxic agents following a 2 hour pretreatment with inactivator was analysed using an XTT-based growth inhibition assay 22 . Cells were plated in 96 well plates (for example in the case of Raji cells at 500 cells/well) and incubated at 37° C. for 30 minutes prior to the addition of medium containing either the appropriate concentration of inactivator or an equivalent volume of vehicle. Following a 2 hour incubation at 37° C., medium containing either increasing doses of cytotoxic agent or equivalent vehicle was added and the cells allowed to grow for 6 days. At this time XTT solution was added and the cells incubated for a further 4 hours at 37° C. The resulting red/orange formazan reaction product was quantified by measuring adsorption at 450 nm on a microtitre platereader.
From this data the percentage growth of cells relative to that in control wells was determined for a range of BCNU, temozolomide or other cytotoxic agent doses in both the presence and absence of inactivator. Sensitization factor (SF) based on D 50 (D 50 . C /D 50 . I ) was determined by dividing the D 50 (i.e. dose at which there was 50% growth versus the controls untreated with alkylating agent) calculated for the cytotoxic agent alone (D 50 . C ) by that for the cytotoxic agent plus inactivator (D 50 . I ). A value of one (1) thus indicates no sensitization by the inactivator. Comparable Sensitization factors were also determined in some cases based on D 60 and D 80 , i.e. the dose at which there was respectively 60% or 80% growth compared to the untreated controls. In Table 3 the Sensitization Factor D 50 . C /D 50 . I is shown as D 50 control/D 50 `B`, with the letter `B` referring to the inactivator compound.
Xenograft Studies
Animals
Swiss mouse derived athymic male mice (o/nu) weighing between 20-30 g were obtained from ZENECA Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4T6, England. Animals were housed 4-5/cage in filter top cages and had access to food and water ad libitum. All animals were maintained under a controlled 12h-light-12h-dark cycle. These animals were used for all tests except those which are shown in FIGS. 11 and 17 and Table 8, as mentioned below.
Cells
A375M (human melanoma) and DU145 (human prostrate cancer) cells were grown in DMEM containing 10% foetal bovine serum (FBS), MCF-7 (human breast cancer cells) were grown in DMEM containing 10% FBS supplemented with 100iu insulin.
Tumours
A375M, DU145 and MCF-7 cells (10 6 ) in 100 μl PBS were injected subcutaneously into the right-hand flank of 8-10 week old o/nu athymic mice. These cells were allowed to develop into a tumour for 3-4 weeks (A375M and DU145 cells) and 4-6 weeks (MCF-7 cells). Once established, tumours were maintained by subcutaneous implantation of 2 mm 3 blocks into the right-hand flank of athymic o/nu mice. MCF-7 tumours are oestrogen positive and require oestrogen for growth. This was supplied as a subcutaneous implant (see below) at the tail base simultaneously to the tumour implant and monthly thereafter.
Preparation of Oestrogen Pellets
468 mg β-oestradiol was added to 9.7 g silastic and mixed until evenly distributed. 1.1 g of curing agent was added and the whole mixture spread into 3 (26 mm×12 mm×1 mm) glass fomers. These were then incubated at 42° C. overnight before being cut into 2 mm×2 mm×1 mm cubes, so that each pellet contained 2 mg estradiol.
ATase Depletion Experiments
Tumours were implanted as previously described and left 3-6 weeks to establish depending on tumour type. An inactivator was homogenized in corn oil at 5 mg/ml before administration by interperitoneal injection (i.p.) or oral gavage (p.o.). Mice were sacrificed at various times up to 72 h and tumours and murine tissues taken for ATase assay. Samples were snap frozen and stored at -20° C. until analysis.
Tumour Sensitization Experiments
O/nu mice were treated with the appropriate dose of the inactivator as indicated (4 mg/ml in corn oil) or the appropriate vehicle as a control 1 hour prior to administration of the appropriate dose of the cytotoxic agent (e.g. temozolomide 6 mg/ml in PBS+20% DMSO) or fotemustine or BCNU (2 mg/ml in PBS+3% ethanol) using the doses and schedules indicated.
Tumour Measurements
Animals were weighed twice weekly and xenograft tumour measurements taken using digital calipers. Tumour volume was calculated using the formula (h×w×l)π/6. Measurements continued until the tumour reached the maximum allowable volume (i.e. 1 cm 3 ). Results were expressed as percentage tumour growth using day 1 tumour volumes as controls.
In the tests on the compounds shown in Table 6 and in FIGS. 9 to 17, the Methods used were as described in WO 94/29312. The following items a) to c) are also to be noted:
a)Standard ATase assay
ATase substrate DNA was prepared by incubation of purified calf thymus DNA with N--[ 3 H]-methyl-N-nitrosourea (18.7 Ci/mmole, Amersham International). Cell or tissue extracts were incubated with [ 3 H]-methylated-DNA substrated (100 μl containing 6.7 μg of DNA and 100fmol of O 6 -[ 3 H]methylguanine) at 37° C. for 60 mins. Following acid hydrolysis of the DNA as previously described 33 the [ 3 H]-methylated protein was recovered and quantitated by liquid scintillation counting.
b) Drug Treatment
Mice were treated with the inactivator as a suspension in corn oil by intraperitoneal injection (i.p.) or by oral gavage (p.o.) 60 mins prior to temozolomide (100 mg/kg in 20% DMSO in phosphate-buffered saline) which was always given in intraperitoneal injection: this schedule was repeated on days 1 to 5 inclusive. Controls received vehicle alone, inactivator alone or temozolomide alone.
c) Animals
The mice in the tests shown in FIG. 11 and Table 8 were BALB-C derived athymic male mice (nu/nu athymic) from the in-house breeding colony of the Paterson Institute for Cancer Research as described in WO 94/29312 (Animal Services-ASU Mice).
The mice in the tests shown in FIGS. 12-16 were Swiss mouse derived athymic male mice (o/nu athymic) as described above.
The mice in the tests shown in FIG. 17 were DBA 2 mice from the in-house breeding colony of the Paterson Institute for Cancer Research (Animal Services Unit), originally from the Jackson Laboratory in 1970.
Test Results
The results of the ATase depletion assay on the compounds of Table 1 are shown in Table 2 or Table 3. Many of the compounds tested were more efficient in inactivating ATase than O 6 -benzylguanine. In accordance with the results in WO 94/29312 the parent application, compounds in which R is a heterocyclic group were more efficient than the comparable compounds having benzyloxy side chains. In general the compounds in which RCH 2 is substituted or unsubstituted thenyl were the most efficient, the most preferred being halo-substituted thenyl having its halo substituent in a 1,3-relationship with the methyleneoxy group attached to the pyrimidine residue.
Tables 3, 4 and 5 summarize data for a number of parameters. Table 3 includes depletion assay results for recombinant ATase of the following types:
______________________________________ hAT = human mAT = mouse rAT = rat chAT = Chinese hamster ogt = E. Coli ogt gene ada = E. Coli ada gene______________________________________
The combinations of properties for the various inactivators can be seen in the tables. The following surprising points are noted in particular:
B.4316 is a compound of surprisingly high water solubility.
B.4335 is a compound that is unexpectedly much more effective in the inactivation of ATase in Raji cells than of pure recombinant protein: generally, the I 50 for inactivation of recombinant ATase in vitro is lower or similar to that in cultured cells.
B.4343 is a compound that has a very low I 50 for ATase in vitro but is not as capable as agents with higher I 50 s (e.g. B.4335) in the sensitization of Raji cells to the growth inhibitory effects of temozolomide. A similar example is B.4351 versus B.4349.
B.4316 was twice as effective as B.4280 but sensitization to temozolomide of Raji cells was almost identical. Thus different cell lines may respond surprisingly differently to these agents.
FIGS. 1 to 3 show that temozolomide, BCNU and fotemustine inhibit the growth of Raji cells in a dose-dependent manner but sensitivity is greatly increased by exposure to B.4316 at 0.1, 1.0 and 10 μM respectively. In contrast B.4316 had no measurable effect on growth inhibition of Raji cells by melphalan or cisplatin (FIG. 4). This indicates that the inactivators were specifically sensitizing cells to the O 6 -alkylating agents and not other classes of alkylating compound.
FIGS. 5 and 6 respectively show the B.4316 and B.4349 sensitization factors for the above therapeutic agents in Raji cells.
FIG. 7 shows that of the inactivators examined human melanoma xenograft ATase depletion was complete only after administration of B.4314 and B.4351 under the experimental conditions used. The former was more effective in ATase depletion in liver and kidney of host animals whilst the latter was more effective in the brain, suggesting its relative ease in passing the blood-brain barrier. Noteworthy is the fact that whilst B.4311 was one of the most effective agents in sensitizing Raji cells to the toxic effects of temozolomide, it was surprisingly one of the least effective agents in depleting mouse tissue or tumour xenograft ATase activity.
FIG. 8 shows that B.4363 depletes ATase more effectively in human melanoma xenografts than in murine host tissues under the conditions used: relatively little effect was seen in brain tissue, suggesting its poor ability to cross the blood brain barrier.
The test results for the compounds of Table 6 (and some in Table 1) are shown in Table 7 and FIGS. 9 to 27.
B.4280, which is O 6 -(4-bromothenyl)guanine and has its bromo substituent in a 1, 3-relationship with the methylene group attached to the guanine residue, was more efficient in inactivating ATase in vitro than its 5-bromo analogue B.4269, in which the bromo substituent is in a 1, 4-relationship with the methylene group. Both B.4280 and B.4269 were more efficient than the unsubstituted thenyl derivative B.4205 despite having considerably larger O 6 substituents.
Another preferred compound is B.4317 which is O 6 -(4-cyanothenyl)guanine. B.4317 is a more efficient inactivator in vitro than its 5-cyano analogue B.4283 or the unsubstituted thenyl derivative B.4205.
Typical ATase inactivation profiles for BeG and B.4205 and B.4280 are shown in FIG. 9.
The inactivation of ATase resulted in the sensitization of Raji cells to the growth inhibitory effects of temozolomide (FIG. 10). B.4280 was considerably more effective than either B.4205 or BeG in this respect.
ATase in human melanoma xenografts was inactivated by BeG, B.4205 and B.4280 (FIG. 11) with some indication that the rates of recovery of ATase activity were different between the agents. B.4280 was the most effective in vivo inactivator at the doses examined.
B.4280 was able to inactivate ATase in most tissues as shown in Table 8. Thus, activity in brain, testis and bone marrow was near to control levels by 24 hours whereas lung and spleen activity had not completely recovered by 48 hours. Tumour activity was very low at 24 hours but had recovered completely by 48 hours. Differential recovery rates might be an important factor in the toxicity of ATase inactivators when used in combination with CNU or temozolomide.
Combination of B.4205 or B.4280 and temozolomide given over three days were more effective in ATase inactivation in tumour xenografts than either agent alone (FIG. 12). Decreasing the dose of B.4205 had no major effect on the ability of the agent to inactivate ATase, 10 mg/kg being as effective as 60 mg/kg. B.4280 was more effective than B.4205 at equivalent doses. As before (FIG. 11) there was some indication that ATase recovery was less efficient in the tumour xenograft (FIG. 12) than in the liver (FIG. 13).
B.4205 (FIG. 14A) and B.4280 (FIG. 15A) were effective in sensitizing human melanoma xenografts to the growth inhibitory effects of temozolomide. A comparison of the two sets of data indicates that B.4280 was about twice as effective as B.4205 in this respect. At equi-effective doses for tumour growth inhibition, B.4280 seems to be less toxic than B.4205 (FIGS. 14B and 15B).
In experiments using DBA 2 mice in combination with BCNU, B.4280 was considerably less acutely toxic than B.4205 or BeG as shown in Table 9. Oral administration of B.4280 was shown to be almost as effective as i.p. administration in sensitizing human melanoma xenografts to the growth inhibitory effects of temozolomide (FIG. 16A). Furthermore the oral combination appeared to be marginally less toxic than the i.p. route (FIG. 16B).
At a dose of 20 mg/kg of inactivator in combination with temozolomide in DBA 2 mice, B.4205 and B.4280 were shown to be less acutely toxic than BeG, with B.4280 being less acutely toxic than B.4205 (FIG. 17).
FIGS. 18 and 19 show that B.4280 (PaTrin-2) (i.p. at 20 mg/kg and p.o. at 30 mg/kg respectively) depletes ATase in human melanoma xenografts more completely and for a more extensive period than it does in host tissues.
FIG. 20 show that despite the considerably higher initial level of ATase activity in the human breast tumour, B.4280 depletes ATase therein more completely and for a longer period of time than in murine host tissues. In this study using 30 mg/kg B.4280 i.p. extensive depletion was seen in brain tissue, indicating the ability to cross the blood-brain barrier.
FIG. 21 likewise shows that despite the considerably higher initial level of ATase activity in the human prostrate tumour, B.4280 depletes ATase therein more completely and for a longer period of time than in murine host tissues. In this study using 20 mg/kg B.4280 i.p. relatively little depletion was seen in brain tissue, indicating by reference to FIG. 20 that the ability of B.4280 to cross the blood-brain barrier may be dose-dependent.
FIG. 22 shows that B.4280 (20 mg/kg i.p.) considerably increased the sensitivity of the human breast tumour xenograft to the growth inhibitory effects of temozolomide using a 5 day dosing schedule. This sensitization occurred despite the very high level of ATase in this tumour.
FIG. 23 shows that a single dose of B.4280 (30 mg/kg p.o.) considerably increased the sensitivity of the human melanoma tumour xenograft to the growth inhibitory effects of a single dose of the chloroethylating agent, fotemustine, without any substantial effect on toxicity.
Synthesis of O 6 -(Methylene[ 3 H])-(4-Bromothenyl)Guanine
Bromothenylaldehyde (0.79 mg, 66.8 umoles was reacted with NaB[ 3 H) 4 (0.0167 mmoles, 60 Ci/mmole) in isopropanol (350 μl) for 1 h at room temperature. The resulting [ 3 H]-4-bromothenylalcohol was extracted into pentane, dried, weighed and reacted with NaH (5.44 mg), and the quaternary ammonium salt of guanine (15.55 mg) in DMSO (250 μl) for 1 hour at room temperature. The product was recovered by precipitation from acetic acid-ether (15 μl glacial acetic in 1.5 ml ether), washed with ether, dried and triturated with H 2 O. After washing with water, the final product was dried to constant weight. FIG. 28 shows the scheme for synthesis of the radio-labelled B.4280.
High Performance Liquid Chromatography Analysis
An aliquot of the product was dissolved in buffer A (10mM KH 2 PO 4 containing 7.5% acetonitrile) and subjected to high performance liquid chromatography on an ODS-5 column. Elution at 1 ml/min was with a linear gradient over 20 minutes from 100% A to 20% A:80% B (10mM KH 2 PO 4 containing 80% acetonitrile). The effluent was monitored for UV absorption at 254 nm and fractions (1 min) were collected and assayed for radioactivity after addiition of 10 ml of Ecoscint A. It was shown that 96% of the radio activity co-chromatographed with authentic B.4280 (FIG. 29).
Incubation of an aliquot of the product with known amounts of pure recombinant human ATase resulted in the transfer of radioactivity to the protein (FIG. 30), strongly suggesting that the mechanism of ATase inactivation involves the transfer of the thenyl group to the active site cysteine residue in the ATase molecule. Measurement of the amount of radioactivity transferred to protein indicated that the O 6 -([ 3 H]-4-bromothenyl)guanine had a radiochemical purity of >96% and a specific activity of 16 Ci/mmole.
O 6 -([ 3 H]-4-bromothenyl)guanine can be used as an alternative to the standard method, which presently uses [ 3 H]-labelled substrate DNA, to determine the amounts of ATase, for example, in cell or tissue extracts. It may also be used to locate active ATase molecules in tumour and other tissue sections by incubation with such sections on microscope slides followed by washing, autoradiography and histological staining. It may also be used to monitor the formation of the [ 3 H]-labelled products of breakdown or metabolism of the agent after administration to mammals. It may also be used to determine the distribution of the B.4280 or its breakdown products in animal tissues and tumours by means of whole body autoradiography.
Typical Synthetic Procedures
Type 1A.
O 6 -(4-Bromothenyl)hypoxanthine, B.4292
4-Bromothenyl alcohol (1.16 g, 6 mmol) was added to sodium hydride (60% in oil; 0.16 g, 2 mmol) and DMSO (1 ml). The solution was stirred for 30 min. The trimethylammonium salt (0.427 g, 2 mmol) was then added and stirring continued for 2.5 h at 20° C. The solution was cooled in an ice bath and poured into ether (60 ml) containing acetic acid (0.32 ml). A white precipitate was collected, triturated with water (4 ml) and collected again to give B.4292 (436 mg, 69%) recrystallised from methanol.
Type 1B.
O 6 -Thenyl-2-Methylhypoxanthine, B.4350
DABCO Salt from 6-Chloro-2 -Methylpurine:
6-chloro-2 -methylpurine (0.5 g, 3 mmol) was dissolved in a mixture of DMF (5 ml) and diglyme (25 ml). DABCO (0.66 g, 6 mmol) was then added. The mixture was stirred for 1 h and the precipitate collected to give the quaternary salt (700 mg, 82%). NMR (300 MHz, DMSO-d 6 ): shift in ppm 2.65 (s), 3.27 (t, J=7.5 Hz), 3.78 (s), 4.14 (t, J=7.5 Hz), 8.21 (s).
Thenyl alcohol (684 mg, 6 mmol) was added to sodium hybride (60% in oil; 80 mg, 2 mmol) and DMSO (0.5 ml). The solution was stirred for 30 min. The DABCO salt was then added and stirring continued for 5 h. The solution was then poured into ether (30 ml) containing acetic acid (0.15 ml). A precipitate was collected, triturated with water (4 ml) and collected again to give O 6 -Thenyl-2-methylhypoxanthine (96 mg, 35%) recrystallised from acetonitrile.
Type 1C.
O 6 -(4-Bromothenyl)-2-Fluorohypoxanthine, B.4353
To 3.6 ml of 40% fluoroboric acid precooled to -25° C. in a bath was added O 6 -(4-bromothenyl) guanine (326 mg, 1 mmol) with vigorous stirring. A solution of sodium nitrite (0.116 g, 1.7 mmol) in water (0.15 ml) was added dropwise over a period of 10 min. After 20 min, the solution was poured into ice. The mixture was then allowed to stand at 0° C. for 15 h, then collected and dried to afford almost pure (t.l.c.) B.4353 (180 mg, 55%). Flash chromatography (Hexane-Ethyl Acetate decreasing polarity little by little) afforded B.4353.
Typical Synthetic Procedures (Continued)
Type 3D
O 4 -Thenyl-5-Deazapterin, B.4376
a) N 2 -Pivaloyl-5-deazapterin
A mixture of 5-deazapterin 33 ,34 (2.0 g, 13.36 mmol), 4-dimethylaminopyridine (0.22 g, 1.8 mmol) and pivalic anhydride (12 ml) was heated to 165° C. Excess pivalic anhydride was distilled off and the residue dissolved in dichloromethane and applied to a pad of silica gel, and eluted with 2% methanol in dichloromethane. Evaporation and recrystallisation of the product from ethanol gave shiny cream coloured crystals (2.25 g, 74%) of the pivaloyl derivative, m.p. 258-259° C.; λ max (MeOH) 277 nm; NMR (300 MHz, DMSO-d 6 )δ1.28(s), 7.44(q), 8.43(dd), 8.88(dd), 11.4(s), 12.31(s).
b) N 2 -pivaloyl-O 4 -thenyl-5-deazapterin:
A suspension of N 2 -pivaloyl-5-deazapterin (0.492 g, 2 mmol) in tetrahydrofuran (8 ml) was stirred for 10 min, and tri-n-butylphosphine (0.606 g, 3 mmol), thenyl alcohol (0.432 g, 3 mmol) and diisopropylazodicarboxylate (0.606 g, 3 mmol) were added successively. The reaction was allowed to proceed for 2 h at room temperature and evaporation than gave an oil. Hexane was added to induce crystallisation. Filtration and recrystallisation from hexane gave bright yellow crystals of the thenyl derivative (0.32 g, 47%) m.p. 107-108° C.; λ max (MeOH) 272, 311 nm; NMR (300 MHz, DMSO-d 6 )δ1.28(s), 5.86(s), 6.98(q), 7.28(dd), 7.43(dd), 7.52(q), 8.46(dd), 8.89(dd).
c) B.4376
N 2 -pivaloyl-O 4 -thenyl-5-deazapterin (0.28 g, 0.82 mmol) was heated for 24 h under reflux with aqueous NaOH (3M, 2 ml) and ethanol (1 ml). The solvent was removed by evaporation and the residual solid dissolved in water. Acidification with acetic acid gave a white precipitate. Filtration and recrystallisation of the solid from ethanol gave white crystals of O 4 -thenyl-5-deazapterin (B.4376), (0.107 g, 51%).
Type 4D
O 6 -(4-Bromothenyl)-5-Nitrocytosine, B.4380
Sodium hydride (60% in oil; 80 mg, 2 mmol) was added to a stirred solution of 4-bromothenyl alcohol (290 mg, 1.5 mmol) in dry DMSO (1 ml). After 30 min, 4-amino-2-chloro-5-nitropyrimidine 35 (174 mg, 1 mmol) was added and the mixture heated at 50° C. for 2 h. The DMSO was removed in vacuo and the pH adjusted to 7 with aqueous acetic acid. After extraction into ethyl acetate, the product B.4380 was crystallised from methanol (51 mg, 15%).
Type 5
S 6 -(4-Bromothenyl)-6-Thioguanine, B.4352
Sodium hydride (60% in oil; 44 mg, 1.1 mmol) was added to a stirred solution of 4-bromothenyl mercaptan (418 mg, 2 mmol) in dry DMSO (0.5 ml). After 30 min, 2-amino-N,N,N-trimethyl-1H-purin-6-aminium chloride (228 mg, 1 mmol) was added and stirring continued for 1 h. Acetic acid (0.12 ml) and ether (30 ml) were added and after decantation and trituration with fresh ether, B.4352 (38 mg, 11%) was filtered off.
9-Substituted O 6 -(4-Bromothenyl)Guanines:
O 6 -(4-Bromothenyl)-9-(Ethoxymethyl)Guanine, B.4369
O 6 -(4-Bromothenyl)guanine (652 mg, 2 mmol) was dissolved in sodium ethoxide (1M, 2 ml, 2 mmol). After 10 min, the ethanol was removed and the residue was dissolved in dry DMF. Chloromethyl ethyl ether (189 mg, 2 mmol) was added dropwise to the stirred solution under an atmosphere of argon. After 45 min, the solvent was removed. The oily product was crystallised from ethanol giving B.4369 (158 mg) as needles. A further 118 mg was obtained by flash chromatography of the mother liquor on silica gel with 5% ethanol in CH 2 Cl 2 . Total yield, 39%.
O 6 -(4-Bromothenyl)-9-(2-Hydroxyethoxymethyl)Guanine, B.4335
A stirred mixture of O 6 -(4-bromothenyl)guanine (294 mg, 1 mmol), (NH 4 ) 2 SO 4 (47 mg) and hexamethyldisilazane (5 ml) was heated at reflux for 3 h. Volatile material was then evaporated under vacuum. The residue was stirred with benzene (15 ml) and Hg(CN) 2 (344 mg, 1.3 mmol) under reflux for 30 min. A solution of (2-acetoxyethoxy)methyl bromide {Ref 4 p33} (197 mg, 1 mmol) in benzene (10 ml) was added, reflux maintained for 2 h, and the cloudy diluted with chloroform (150 ml). The organic phase was washed with saturated aqueous NaHCO 3 (30 ml), followed by KI (1M; 30 ml), dried over MgSO 4 and evaporated to give an oil (313 mg). This oil was chromatographed on a silica gel column with CHCl 3 --MeOH (12:1) as eluant, yielding almost pure (t.l.c.) O-acetate (141 mg) of B.4335.
Methanol (60 ml) was saturated with dry ammonia and poured onto this O-acetate in a flash which was tightly stoppered. After dissolution, stirring was stopped and the flask left closed overnight. Evaporation of methanol gave B.4335 (135 mg, 46%), recrystallised from isopropanol.
O 6 -4-Bromothenyl-9-(β-D-Ribofuranosyl)Guanine, B.4363
A mixture of 2',3',5'-tri-(O-acetyl)guanosine 36 (409 mg, 1 mmol), tri-n-butylphosphine (303 mg, 1.5 mmol) and 4-bromothenyl alcohol (290 mg, 1.5 mmol) in dry tetrahydrofuran (16 ml) was stirred at room temperature for 45 min. Then diisopropyl azodicarboxylate (303 mg, 1.5 mmol) was added dropwise and the mixture stirred for 2 h. The solution was evaporated leaving an oil which was dissolved in THF/MeOH/25% aqueous ammonia (1:1:1; 5 ml) and kept for 48 h at 4° C.
Adsorption on silica gel and column chromatography with CHCl 3 /MeOH (15:1 to 10:1) gave the riboside B.4363 (205 mg, 44%).
O 6 -4-Bromothenyl-9-(β-D-2'-Deoxyribofuranosyl)Guanine, B.4379.
A mixture of 3',5'-di-(O-acetyl)-2'-deoxyguanosine 37 (554 mg, 1.5 mmol), tri-n-butylphosphine (666.6 mg, 3.3 mmol) and 4-bromothenyl alcohol (638 mg, 3.3 mmol) in dry tetrahydrofuran (40 ml) was stirred at 80° C. for 15 min. Then diisopropyl azodicarboxylate (666.6 mg, 3.3 mmol) was added dropwise and 15 min later, the reaction mixture was cooled and evaporated leaving an oil. This was dissolved in THF/MeOH/25% aqueous ammonia (1:1:1; 5 ml) and kept for 48 h at 4° C. Adsorption on silica gel and column chromatography with CHCl 3 /MeOH (20:1) gave the 2'-deoxyriboside B.4379 (338 mg, 51%).
9-(β-D-Arabinofuranosyl)-O 6 -(4-Bromothenyl)Guanine, B.4368.
An alkoxide solution was made from sodium hydride (60% in oil; 60 mg, 1.5 mmol) and 4-bromothenyl alcohol (344 mg, 1.8 mmol) in dry DMSO (0.5 ml) over 1 h. It was reacted with 2-amino-9-(β-D-arabinofuranosyl)-6-chloropurine 38 (151 mg, 0.5 mmol) and stirred for 5 min at room temperature, then 15 min at 60-65° C. Cooling and trituration with ether (50 ml) and filtration yielded a solid which was dissolved in water (5 ml), neutralised with acetic acid and treated with silica gel. Column chromatography with ethyl acetate/MeOH (19:1) gave the arabinoside B.4368 (87 mg, 38%), pure on t.l.c.
O 6 -Substituted Guanines
These were made by the standard procedure from the quaternary salt 2-amino-N,N,N-trimethyl-1H-purin-6-aminium chloride and the appropriate alkoxide derived from the alcohol and sodium hybride in DMSO (cf.pp.16d, 17, 18, 47 of Jul. 12, 1995).
TABLE 1A__________________________________________________________________________ M.p. Mole- O.sup.6 -Substituent Yield Solvent for (decomp.) cular AnalysisCompound, Test No. RCH.sub.3 % Recrystn. (° C.) Formula Weight C H N__________________________________________________________________________Type 1A.HypoxanthinesB. 4293 furfuryl 60 MeOH 154 C.sub.18 H.sub.8 N.sub.4 O.sub.2 216B. 4291 thenyl 66 MeOH 168 C.sub.10 H.sub.8 N.sub.4 OS 232 Found 51.85 3.40 24.12 Req. 51.71 3.47 24.12B. 4292 4-bromothenyl 69 MeOH 170 C.sub.10 H.sub.8 BrN.sub.4 OS 311 Found 38.33 2.18 17.66 Req 38.6 2.26 18.001B. 2-MethylhypoxanthinesB. 4347 benzyl 43 MeCN 191-193.sup.a C.sub.12 H.sub.11 N.sub.4 O 240 Found 65.05 4.91 23.30 Req 64.99 5.03 23.32B. 4350 thenyl 35 MeCN 176-178.sup.a C.sub.12 H.sub.11 N.sub.4 OS 325 Found 53.63 3.90 22.67 Req 53.64 4.09 22.751C. 2-FluorohypoxanthinesB. 4353 4-bromothenyl 55 Column 142 C.sub.10 H.sub.4 BrFN.sub.4 3291D. 9-(2-Hydroxyethoxy-methylguaninesB. 4334 benzyl 46 i-PrOH 150-152.sup.a C.sub.15 H.sub.12 N.sub.5 O.sub.4 315 Found 57.19 5.59 21.93 Req 57.13 5.43 22.21B. 4335 4-bromothenyl 42 i-PrOH 156-158.sup.a C.sub.13 H.sub.14 BrN.sub.3 O.sub.2 S 400 Found 39.16 3.68 17.20 Req 39.01 3.53 17.531E. 8-HydroxyguaninesB. 4349 4-bromothenyl 56 Aq. EtOH >230 C.sub.10 H.sub.8 BrN.sub.5 O.sub.2 S. 351 Found 34.53 2.48 19.50 1/2 H.sub.2 O Req. 34.20 2.58 19.94Type 2A.8-AzaguaninesB. 4270 4-fluorobenzyl 40 Aq. MeOH >280 C.sub.10 H.sub.9 FN.sub.4 O 260 Found 51.50 3.85 29.44 Req. 50.77 3.49 32.30B. 4314 4-chlorothenyl 26 Aq. MeOH >200 C.sub.2 H.sub.5 ClN.sub.4 OS 282.7 Found 28.86 2.61 28.61 38.24 2.50 29.73B. 4289 4-bromothenyl 12 MeCN >190 C.sub.8 H.sub.5 BrN.sub.6 OS 327 Found 35.91 2.78 24.60 Req. 33.04 2.16 25.692B. 8-Aza-7-deazaguaninesB. 4310 benzyl MeOH 160 C.sub.18 H.sub.11 N.sub.5 O.sub.1 H.sub.2 O 259 Found 55.53 4.9 26.41 Req. 55.59 5.01 27.02B. 4340 4-fluorobenzyl 65 EtOH 188 C.sub.12 H.sub.12 FN.sub.5 O. 263.7 Found 53.82 3.76 25.97 1/4H.sub.2 O Req. 54.6 4.0 26.55B. 4339 4-chlorobenzyl 92 EtOH 242-244* C.sub.12 H.sub.10 ClN.sub.5 296 Found 51.15 3.89 23.43 1/4H.sub.2 O 1/4EtOH Req. 50.7 4.25 23.64B. 4343 piperonyl 50 EtOH 186B. 4348 furfuryl EtOH 150.sup.c C.sub.13 H.sub.11 N.sub.5 C.sub.3 28.5 Found 54.52 3.82 24.50 Req. 54.7 3.88 24.55B. 4338 thenyl 68 EtOH 180 C.sub.10 H.sub.6 N.sub.5 O.sub.2 1/4.sub.2 O 236.7 Found 50.96 3.87 29.54 Req. 50.96 4.06 29.71B. 4337 4-bromothenyl 79 EtOH 180 C.sub.10 H.sub.6 N.sub.5 OS 247 Found 47.58 3.54 27.41 Req. 47.7 3.8 27.8 C.sub.10 H.sub.2 BrNiOS 326 Found 37.08 2.52 21.31 Req. 36.8 2.5 21.5Type 3A.8-OzaguaninesB. 4272 4-fluorobenzyl 41 Acetone 223-224 C.sub.11 H.sub.5 N.sub.5 O.sub.2 261 Found 50.39 3.08 26.65 Req. 50.58 3.09 26.81B. 4285 4-chlorobenzyl 63 Acetone 219-220 C.sub.11 H.sub.8 ClN.sub.5 O.sub.2 277.7 Found 47.59 2.88 25.25 Req. 47.58 2.90 25.22B. 4299 4-chlorothenyl 55 Acetone 164-165 C.sub.12 H.sub.4 ClN.sub.5 O.sub.2 S 283.7 Found 37.68 2.15 24.43 Req. 38.10 2.13 24.69B. 4287 4-bromothenyl 61 Acetone 170-172 C.sub.2 H.sub.6 BrN.sub.5 O.sub.2 328 Found 33.30 1.85 21.37 Req. 32.94 1.84 21.343B. 8-ThioguaninesB. 4296 benzyl 39 EtOH C.sub.11 H.sub.8 N.sub.5 OS 259B. 4286 4-fluorobenzyl 11 PLC 182-184 C.sub.11 H.sub.5 FN.sub.2 OS 277B. 4315 4-chlorothenyl 13 MeOH C.sub.5 H.sub.6 ClN.sub.5 OS.sub.2 299.8 Found 36.27 2.04 23.07 Req. 36.06 2.02 23.36B. 4351 4-bromothenyl 41 MeOH 156-160 C.sub.9 H.sub.6 BrN.sub.5 OS.sub.2 144 Found 31.49 1.60 20.11 Req. 31.41 1.76 20.353C. Pterins (O.sup.2 -substituent)B. 4290 4-fluorobenzyl 55 MeOH >110 C.sub.13 H.sub.12 FN.sub.5 O 271 Found 57.87 3.88 25.65 Req. 57.56 3.72 25.82B. 4316 4-chlorobenzyl 41 MeOH >170 C.sub.13 H.sub.8 ClN.sub.5 OS 293.7 Found 44.93 2.84 23.72 Req. 44.98 2.75 23.84B. 4288 4-bromothenyl 63 MeOH 178-179 C.sub.11 H.sub.8 BrN.sub.5 OS 338 Found 39.34 3.13 20.25 Req. 39.07 2.38 20.71Type 4A.2,4-diamino-6-hydroxypyrimidinesB. 4305 4-fluorobenzyl 98 C.sub.6 H.sub.5 /Petrol 133-134 C.sub.11 H.sub.10 FN.sub.5 O 234 Found 56.20 4.79 23.66 56.40 4.73 23.92B. 4304 4-chlorobenzyl 31 C.sub.6 H.sub.5 122-123 C.sub.12 H.sub.11 ClN.sub.4 250.7 Found 52.43 4.56 22.47 Req. 52.70 4.42 22.35B. 4303 piperonyl 79 MeCN 168-171 C.sub.17 H.sub.12 N.sub.6 O.sub.5 260 Found 55.31 4.64 21.38 Req. 55.38 4.65 21.52B. 4307 thenyl 97 MePh 100 C.sub.9 H.sub.10 N.sub.4 OS 222 Found 48.83 4.58 25.25 Req. 48.63 4.54 25.21B. 4302 4-chlorothenyl 45 MePh 129-130 C.sub.9 H.sub.9 ClN.sub.4 OS 256.7 Found 42.40 3.68 22.00 Req. 42.11 3.53 21.834B. 2,4-Diamino-6-hydroxy-5-autrosopyrimidinesB. 4301 4-fluorobenzyl 76 MeOH >250 CH.sub.10 FN.sub.5 O.sub.2 263 Found 49.60 3.90 26.29 Req. 50.19 3.83 26.61B. 4311 4-chlorothenyl 84 Acetone >190 C.sub.9 H.sub.8 ClN.sub.5 O.sub.2 285.7 Found 37.54 2.79 24.22 Req. 37.84 2.82 24.51B. 4312 4-bromothenyl 62 Acetone 200-201 C.sub.9 H.sub.8 BrN.sub.5 O.sub.2 330 Found 32.87 2.38 20.96 Req. 32.74 2.44 21.214C. 2,4-Diamino-6-hydroxy-5-nitropyrtnidinesB. 4308 piperonyl 67 DMF >175 C.sub.12 H.sub.11 N.sub.5 O.sub.5 305 Found 47.44 4.07 22.83 Req. 47.22 3.63 22.94B. 4306 thenyl 34 MeOH 159-160 C.sub.9 H.sub.5 N.sub.6 O.sub.3 267 Found 40.99 3.71 25.99 Req. 40.44 3.39 26.21Type 3D.5-Deazapterins(O.sup.4 -substituent)B. 4276 thenyl 51 EtOH 215-216 C.sub.12 N.sub.10 N.sub.4 OS 2584D. 5-Nitrocytosines(O.sup.2 -substituent)B. 4380 4-bromothenyl 15 MeOH 143-144 C.sub.9 H.sub.7 BrN.sub.4 O.sub.3 3315. 6-Thtoguanines(S.sup.6 -substituent)B. 4228 piperonyl 69 CH.sub.2 OH 204-212 C.sub.13 H.sub.11 N.sub.5 O.sub.2 301 Found 50.25 3.60 23.66 Req. 51.82 3.68 23.24B. 4352 4-bromothenyl 11 CH.sub.2 OH 180-184 C.sub.14 H.sub.8 BrN.sub.5 O.sub.1 342 Found 35.07 2.42 19.49 1/2CH.sub.2 OH 35.16 2.66 19.84__________________________________________________________________________ M.p. Molecular Analysis.sup.aCompound, Test No. 9-Substituent Yield % Solvent for Recrystn. (° C.) Formula Weight C H N__________________________________________________________________________B.4369 ethoxymethyl 39 EtOH 134-5 C.sub.13 H.sub.14 BrN.sub.5 O.sub.2 S 384 40.58 3.71 17.97 (40.64.sup. 3.67 .sup. 18.23)B. 4370 n-octyloxymethyl 39 EtOH 90 C.sub.10 H.sub.20 BrN.sub.5 O.sub.2 S 468 48.97 5.67 14.82 (48.72.sup. 5.60 .sup. 14.95)B. 4334.sup.b 2-hydroxy- 46 i-PrOH 150-2 C.sub.15 H.sub.27 N.sub.5 O.sub.3 315 57.19 5.59 21.93 ethoxymethyl (57.13.sup. 5.43 .sup. 22.21)B. 4335 2-hydroxy- 42 i-PrOH 156-8 C.sub.13 H.sub.14 BrN.sub.5 O.sub.3 S 400 39.16 3.68 17.20 ethoxymethyl (39.01.sup. 3.53 .sup. 17.50)B. 4363 β-D-ribo- 44 C.sub.15 H.sub.16 BrN.sub.5 O.sub.5 S 458 furanosylB. 4368 β-D-arabino- 38 C.sub.15 H.sub.16 BrN.sub.5 O.sub.5 S 458 furanosylB. 4379 β-D-2-deoxyribo- 51 C.sub.15 H.sub.16 BrN.sub.5 O.sub.4 S 442 furanosyl__________________________________________________________________________ .sup.a Found, with required values in parenthesis. .sup.b O.sup.6benzyl
TABLE 1B__________________________________________________________________________ O.sup.6 -Substituent .sub.max (MeOH)Compound Type, Test No. RCH.sub.2 (nm) δ.sub.H [ppm from TMS, (CD.sub.3).sub.2 SO.sub.1 ]/(Hz)__________________________________________________________________________Type 1A.HypoxanthinesB. 4293 furfuryl 252 5.60(s), 6.53(dd, 3.1, 1.9), 6.69(d, J), 7.76(dd, 19, 3.9) 8.39(s), 8.55(s)B. 4291 thenyl 240 5.83(s), 7.08(dd, 5.1, 3.4), 7.35(d, 3.4), 7.6(d, 5.1), 8.39(s), 8.51(s)B. 4292 4-bromothenyl 251 5.80(s), 7.38(d, 13), 7.73(d, 13), 8.42(s), 8.58(s)Type 1B.2-MethylhypoxanthinesB. 4347 benzyl 256 2.61(s), 5.60(s), 7.50(m), 8.32(s)B. 4350 thenyl 240 2.63(s), 5.77(s), 7.05(dd, 5.1, 2.6, 7.33(d), 2.4), 7.58(dd, 5.1, 1.0) 8.26(s), 13.22(s)Type 1C.2-PhorohypoxanthinesB. 4353 4-bromothenyl 233, 255 5.77(s), 7.4(d, 1.5), 7.77(d, 1.5), 8.45(s), 13.64(bs)Type 1D.9-(2-Hydroxyethoxymethyl)guaninesB. 4334 benzyl 247, 283 3.48(m), 4.70(s), 5.45(s), 6.59(s), 7.45(m), 8.03(s),B. 4335 4-bromothenyl 245, 284 3.49(m), 4.71(s), 5.45(s), 5.66(s), 6.65(s), 7.30(d, 1.5) 7.72(d, 1.5) 8.04(s)Type 1E.8-HydroxyguaninesB. 4349 4-bromothenyl 239, 293 5.54(s), 6.24(s), 7.33(d, 1.4) 7.70(d, 1.4), 10.49(s) 11.12(s)Type 2A.δ-AzaguaninesB. 4270 4-fluorobenzyl 288 5.57(s), 7.04(s), 7.28(m), 7.65(m), 15.38(s)B. 4314 4-chlorothenyl 288 5.71(s), 7.13(s), 7.41(d, 1.5), 7.66(d, 1.5), 15.42(s).B. 4289 4-bromothenyl 287 5.73(s), 7.12(s), 7.43(d, 1.5), 7.76(d, 1.5), 15.39(s).Type 2B.8-Aza-7-diazaguaninesB. 4310 benzyl 217 5.50(s), 6.68(s), 7.74(m), 7.82(s), 12.87(bs)B. 4340 4-fluorobenzyl 278 5.49 (s), 6.70(s), 7.20(m), 7.61(m), 7.83(s), 12.88(bs)B. 4339 4-chlorobenzyl 276 5.50(s), 6.69(s), 7.49(d, 8.4), 7.56(d, 8.4), 7.83(s), 12.90(s)B. 4343 piperonyl 282 5.39(s), 6.95(s), 6.69(s), 6.94(d, 7.3), 7.04(dd, 7.9, 1.5), 7.1(dd, 1.5), 7.50(s) 12.86(bs).B. 4348 furfuryl 277 5.46(s), 6.52(s), 0.70(s), 6.71(s), 7.73(s), 7.79(s), 12.85(bs).B. 4338 thenyl 278 5.69(s), 6.73(s), 7.07(d, 3.5), 7.35(s), 7.60(d, 1.1), 7.79(s), 12.90(bs)B. 4337 4-bromothenyl 278 5.65(s), 6.76(s), 7.38(s), 7.72(d, 1.3), 7.91(s), 2.91(bs)Type 3A.N-OxaguaninesB. 4272 4-chlorobenzyl 257, 341 5.62(s), 7.39(1, 9.1), 7.68(s), 7.91(s), 7.97(s).B. 4285 4-chlorobenzyl 256, 340 5.63(s), 7.53(d, 8.3), 7.65(d, 8.3), 7.90(s), 7.97(s)B. 4299 4-chlorobenzyl 252, 343 5.78(s), 7.46(d, 1.6), 7.72(d, 1.6), 7.95(s), 8.01(s).B. 4287 4-bromothenyl 253, 343 5.79(s), 7.49(d, 1.6), 7.8(d, 1.6), 7.95(s), 8.01(s)Type 3B.8-ThiaguaninesB. 4296 benzyl 227, 361B. 4286 4-fluorobenzyl 235, 362 5.59(s), 7.29(d, 8.9), 7.51(s), 7.67(m)B. 4315 4-chlorobenzyl 228, 360 5.75(s), 7.44(d, 1.6), 7.55(bs), 7.69(d, 1.6)B. 4351 4-bromothenyl 228, 361 5.78(s), 7.45(d, 1.6), 7.46(bs), 7.75(d, 1.6)Type 3C.Pterins (O.sup.6 -substituent)B. 4290 4-fluorobenzyl 232, 264(sb, 5.56(s), 7.29(1.6, s), 7.4(bs), 7.66(s), 8.45(d, 1.8), 8.82(d, 1.8) 162B. 4316 4-chlorothenyl 232, 364 5.71(s), 7.41(d, 1.6), 7.47(bs), 7.67(d, 1.6), 8.40(d, 2.0), 8.83(d, 2.0)B. 4288 4-bromothenyl 231, 364 5.73(s, 7.44(d, 1.6), 7.50(bs), 7.77(d, 1.6)8.46(d, 2), 8.83(d, 2)Type 4A.2,4-diamino-6-hydroxy-pyrimidinesB. 4305 4-fluorobenzyl 238, 267 5.18(s), 5.19(s), 5.96(s), 6.10(s), 7.19(t, 8.8), 7.44(dd, 8.8, 5.8)B. 4304 4-chlorobenzyl 238, 268 5.11(s), 5.22(s), 5.96(s), 6.10(s), 7.44(s)B. 4303 piperonyl 236, 267 5.09(s), 5.11(s), 5.97(s), 6.01(s), 6.07(s), 6.91(d, 1.1), 7.00(s).B. 4307 thenyl 235, 267 5.08(s), 5.40(s), 6.00(s), 6.10(s), 7.03(dd, 8.1, 3.5) 7.20(dd, 8.1, 1.1), 7.54 (dd, 3.5, 1.1)B. 4302 4-chlorothenyl 236, 265 5.08(s), 5.35(s), 6.03(s), 6.13(s), 7.19(s), 7.55(d, 1.6).Type 4B.2,4-Diamino-6-hydroxy-3-nitroxopyrimidinesB. 4301 4-fluorobenzyl 336 5.59(s), 7.26(m), 7.65(m), 7.80(bs), 7.85(bs), 8.00(bs), 10.05(bs).B. 4311 4-chlorothenyl 335 5.73(s), 7.40(d, 1.6), 7.66(d, 1.6), 7.94(s), 7.98(d, 2.7), 8.11(d, 4.2), 10.03 (d, 4.2).B. 4312 4-bromothenyl 335 5.75(s), 7.42(d, 1.4), 7.75(d, 1.4), 7.93(s), 7.98(s), 8.12(d, 4.0), 10.04 (d, 4.0)Type 4C.2,4-diamino-6-hydroxy-5-nitropyrimidinesB. 4308 piperonyl 288, 330 5.33(s), 6.05(s), 6.95(d, 8.0), 7.00(dd, 8.0, 1.4), 7.10(d, 1.4); 7.26(bs), 7.3 7.96(bs).B. 4306 thenyl 234, 329 5.59(s), 7.03(dd, 5.1, 3.5), 7.28(d, 3.5), 7.32(bs), 7.56(d, 5.1),__________________________________________________________________________ 7.94(bs) Substituent .sub.max (MeOH)Compound Type, Test No. RCH.sub.2 (nm) δ.sub.H [ppm from TMS, (CD.sub.3).sub.2 SO.sub.1 ]/(Hz)__________________________________________________________________________Type 3D 5-Deazapterins (O.sup.4 -substituent) B. 4376 thenyl 248, 309 5.54(s), 6.96(q), 7.716(dd), 7.38(dd), 7.41(q), 8.39(dd), 8.79(dd).Type 4D 5-Nitrocytosines (O.sup.2 -substituent) B. 4380 4-bromothenyl 255 sh, 334 5.19(s), 7.20(s), 7.56(d), 8.24(s), 8.70(s), 8.90(s).Type 5 6-Thioguanines (S.sup.6 -substituent) B. 4228 piperonyl 245, 311 4.56(s), 6.06(s), 6.55(s), 7.03(d), 7.06(d), 7.14(s), 8.08(s), 12.67(bs). B. 4352 4-bromothenyl 241, 314 4.77(s), 6.52(s), 7.18(d), 7.51(d), 7.93(s), 12.61(bs)__________________________________________________________________________ .sub.max (MeOH)Compound Type, Test No. 9-Substituent Yield % (nm) δ.sub.H [ppm from TMS, (CD.sub.3).sub.2 SO.sub.1 ]/(Hz)__________________________________________________________________________B. 4369 ethoxymethyl 245, 284 3.35(s), 5.41(s), 5.66(s), 6.66(s), 7.38(d), 7.73(d), 8.04(s).B. 4370 n-octyloxymethyl 245, 284 0.09(t), 1.17(m), 3.36(t), 5.41(s), 5.66(s), 6.66(s), 7.38(d), 7.72(d), 8.03(s).B. 4334.sup.a 2-hydroxy- 245, 283 3.48(m), 4.70(s), 5.45(s), 6.59(s), 7.45(s), 8.03(s). ethoxymethylB. 4335 2-hydroxy- 245, 284 3.49(m), 4.71(s), 5.45(s), 5.66(s), 6.65(s), 7.30(d, 1.5), ethoxymethyl 7.72(d, 1.5), 8.40(s).B. 4363 β-D-ribo- -- 3.54(m), 3.63(m), 3.91(dd), 4.12(dd), 4.48(ddd), 5.12(dd), furanosyl 5.18(d), 5.45(d), 5.66(s), 5.80(dd), 6.61(s), 7.38(d), 7.71(d), 8.15(s).B. 4368 β-D-arabino- 245, 284 3.64(m), 3.76(dd), 4.07(m), 5.09(dd), 5.51(d), 5.53(m), furanosyl 6.13(d), 6.60(d), 7.37(d), 7.71(d), 7.95(s)B. 4379 β-D-2-deoxyribo- 2.39(ddd), 2.72(ddd), 3.65(ddd), 3.98(dd), 4.40(dd), 5.11(s) furanosyl 5.41(d), 5.80(s), 6.38(dd), 6.67(s), 7.49(d), 7.83(d), 8.25(s).__________________________________________________________________________ .sup.a O.sup.6benzyl
TABLE 2______________________________________ I.sub.50 (μM) T 1/2 (h)INACTIVAT0R TYPE hAT in PBS______________________________________1AB.4291O.sup.6 -(thenyl)-hypoxanthine >201.9B.4293O.sup.6 -(furfuryl)-hypoxanthine >168B.4292O.sup.6 -(4-bromothenyl)-hypoxanthine >16O.sup.6 -(benzyl)-hypoxanthine.sup.b 851BB.4347O.sup.6 -(benzyl)-2-methylhypoxanthine 75B.4350O.sup.6 -(thenyl)-2-methylhypoxanthine 141CB.4353O.sup.6 -(4-bromothenyl)-2-fluorohypoxanthine 1.4O.sup.6 -(benzyl)-2-fluorohypoxanthine.sup.a 481DB.4334O.sup.6 -(benzyl)-9-(2-hydroxyethoxymethyl) 8 >20guanineB.4335O.sup.6 -(4-bromothenyl)-9-(2-hydroxy See Table 3ethoxymethyl)guanine1EB.4349O.sup.6 -(4-bromothenyl)-8-hydroxyguanine See Table 3O.sup.6 -(benzyl)-8-hydroxyguanine.sup.a 0.32AB.4270O.sup.6 -(4-fluorobenzyl)-8-azaguanine 0.08B.4314O.sup.6 -(4-chlorothenyl)-8-azaguanine See Table 3B.4289O.sup.6 -(4-bromothenyl)-8-azaguanine >10O.sup.6 -(benzyl)-8-azaguanine.sup.a 0.072BB.4310O.sup.6 -(benzyl)-7-deaza-8-azaguanine >16B.4340O.sup.6 -(4-fluorobenzyl)-8-aza-7-deazaguanine 0.018 >16B.4339O.sup.6 -(4-chlorobenzyl)-8-aza-7-deazaguanine 0.02 1.5B.4343O.sup.6 -(piperonyl)-8-aza-7-deazaguanine See Table 3B.4348O.sup.6 -(furfuryl)-8-aza-7-deazaguanine 0.27B.4338O.sup.6 -(thenyl)-8-aza-7-deazaguanine 0.01B.4337O.sup.6 -(4-bromothenyl)-8-aza-7-deazaguanine 0.007 >203AB.4272O.sup.6 -(4-fluorobenzyl)-8-oxaguanine See Table 3B.4285O.sup.6 -(4-chlorobenzyl)-8-oxaguanine 4.6B.4299O.sup.6 (4-chlorothenyl)-8-oxaguanine 9.23B.4287O.sup.6 -(-4-bromothenyl)-8-oxaguanine 2.6B.4232O.sup.6 -(benzyl)-8-oxaguanine 0.253BB.4296O.sup.6 -(benzyl)-8-thiaguanine >17 0.02B.4286O.sup.6 -(4-fluorobenzyl)-8-thiaguanine >17B.4315O.sup.6 -(4-chlorothenyl)-8-thiaguanine.sup.c 0.006B.4351O.sup.6 -(4-bromothenyl)-8-thiaguanine See Table 33CB.4290O.sup.4 -(4-fluorobenzyl)-pterin >10 0.088B.4316O.sup.4 -(4-chlorothenyl)-pterin See Table 3B.4288O.sup.4 -(4-bromothenyl)-pterin >10 0.0254AB.43052,4-diamino-6-(4-fluorobenzyloxy)pyrimidine 4.0 >16B.43042,4-diamino-6-(4-chlorobenzyloxy)pyrimidine 5.0 >16B.43032,4-diamino-6-(3,4-piperonyloxy)pyrimidine 0.8 12.5B.43072,4-diamino-6-(thenyloxy)pyrimidine 4.2B.43022,4-diamino-6-(4-chlorothenyloxy)pyrimidine 0.17 >162,4-diamino-6-(benzyloxy)pyrimidine.sup.a 154BB.43012,4-diamino-6-(4-fluorobenzyloxy)-5- 0.0175 >16nitrosopyrimidineB.43112,4-diamino-(4-chlorothenyloxy)-5- See Table 3nitrosopyrimidineB.43122,4-diamino-6-(4-bromothenyloxy)-5- 0.045 4nitrosopyrimidine2,4-diamino-6-(benzyloxy)-5- 0.06nitrosopyrimidine.sup.a4CB.43062,4-diamino-6-(thenyloxy)-5- 2.3 >16nitropyrimidineB.43082,4-diamino-6-piperonyloxy-5-nitropyrimidine 0.5 9.22,4-diamino-6-benzyloxy-5-nitropyrimidine.sup.a 0.064DB.4380O.sup.2 (4-bromothenyl)-5-nitrocytosine 50B.4228S.sup.6 -(piperonyl)-6-thioguanine 50B.4352S.sup.6 -(4-bromothenyl)-6-thioguanine 8ComparativeB.4376O.sup.6 -thenyl-5-deazapterin 1,600______________________________________ Results for some 9substituted O.sup.6 (4bromothenyl)guanines are included in Table 7. .sup.a Data taken from Chae et al, J. Med. Chem. 1995, 38, 359-365 .sup.b Data taken from Moschel et al., J. Med. Chem. 1992, 35, 4486-4491. .sup.c B.4315 Raji I.sub.50 (uM) 0.002 Blank Space = not done.
TABLE 3__________________________________________________________________________ Sol- ubili- T.sup.1/2 Raji cell sensitisation ty Raji cell (h) (D.sub.50 control/D.sub.50 Wa-) toxicity at I.sub.50 I.sub.50 I.sub.50 I.sub.50 I.sub.50 I.sub.50 I.sub.50 T.sup.1/2 by BCNU TEMOZOLOMIDE ter 10 μM `B`Mol hAT Raji mAT rAT chAT ogt ada (h) As- Inactivator concentration (mg/.M) aloneInactivatorWgt (μM) (μM) (μM) (μM) (μM) (μM) (μM) PBS say 10 10 1.0 0.5 0.1 ml) (%__________________________________________________________________________ Growth)B4272261 0.05 0.023 0.125 0.075 0.04 >1000 >1000 5.7 2.6 1.88 1.41 -- -- -- 0.002 111.21 + 23.3B4311286 0.009 0.009 0.008 0.016 0.02 1.8 >1000 10 12.5 8.0 73.3 8.25 -- 1.4 0 113.0 + 31.0B4314283 0.011 0.012 0.073 0.037 0.03 2 >1000 >19 >48 7.62 84 4.61 -- 3.46 Not 55.5 + 7.3 done (D.sub.50 16 μM)B4316294 0.025 0.011 0.068 0.03 0.04 3.8 >1000 >19 32 6.4 66 13.2 -- 1.4 0.3 85.5 + 20.0B4335400 0.33 0.07 15.63 6.5 1.8 156 >1000 >19 >48 5.33 38 3.5 -- 1.0 0.009 98.4 + 12.2B4343285 0.007 0.0085 0.31 0.045 0.02 30 >1000 7.5 3 3.81 9.5 2.12 -- 1.6 0.01 97.0 + 10.0B4349342 0.018 0.007 0.043 0.074 0.02 0.08 >1000 7.3 >48 4.8 50.8 33 -- 2.4 0.002 90.0 + 13.0B4351344 0.003 0.005 0.071 0.027 0.03 5.8 >1000 >16 12 4.8 18.1 1.32 -- 1.2 Not 117.5 + 29.1 doneBeG 241 0.04 0.1 0.2 0.076 0.01 17 >1000 >64 >75 4.33 27.5 1.89 -- 1.03 0.023 82.2 + 11.0PaTrin-2326 0.003 0.003 0.05 0.019 0.03 0.85 >1000 >16 >48 6.0 60 33 8 5.5 Not 69.8 + 10.3 doneB.4280 (D50 44__________________________________________________________________________ μM) -- = Not Done
TABLE 4______________________________________EFFECT OF INACTIVATOR PRETREATMENT ON SENSITISATIONOF VAROUS HUMAN CANCER CELL LINES TO TEMOZOLOMIDE SENSITISATION FACTOR (D.sub.50 control/L).sub.50 `B`) MCF-7 PC3 DU145** RAJI Inactivator dose Inactivator dose (μM)INACTIVATOR (10 μM) 10 1.0 0.5 0.1______________________________________B4311 -- 5.56 3.75 73.3 8.25 1.4B4314* 2.0 1.71 84.0 4.61 3.46--B4316 7.6 3.53 66 13.2 1.4 --B4349 3.6 4.0 50.8 33.0 2.4 --BcG 2.88.94 5.45 27.5 1.89 1.03--PaTrin-2 3.13 4.6 4.14 60 33.0 8.0 5.5______________________________________ *Toxic to Raji cells at 10 μM **Sensitisation factor = D.sub.60 control/D.sub.60 `B -- Not done
TABLE 5______________________________________EFFECT OF INACTIVATOR PRETREATMENT ON SENSITISATIONOF VARIOUS HUMAN CANCER CELL LINES TO BCNU SENSITISATION FACTOR (D.sub.50 control/D.sub.50 `B`) RAJIINACTIVATOR Inactivator dose (μM)(10 μM) MCF-7 PC3 DU145** 10 1.0 0.1______________________________________B4311 -- 1.47 1.56 8.0 -- --B4314* -- 1.25 7.62 7.6 3.45B4316 1.37 1.35 3.57 6.4 -- --B4349 1.85 1.63 2.78 4.8 -- --BcG 1.94 1.41 1.79 4.33 -- --PaTrin-2 1.61 2.11 2.08 6.0 -- --______________________________________ *Toxic to Raji cells at 10 μM **Sensitisation factor = D.sub.60 control/D.sub.60 `B -- Not done
TABLE 6A__________________________________________________________________________ Yield % (based Solvent for M.p. (decomp.) AnalysisTest No.O.sup.6 -Substiutent on solvate) recrystn. (° C.) Formula C H N__________________________________________________________________________B.42804-bromothenyl 73 MeOH 204-205 C.sub.10 H.sub.8 BrN.sub.5 OS Found 36.7 2.45 21.46 Req. 36.82 2.47 21.47B 42815-chlorothenyl.sup.a 39 MeCN 155-158 C.sub.10 H.sub.8 ClN.sub.5 OS Found 41.81 2.86 24.10 Req. 42.63 2.86 24.86B.42835-cyanothenyl.sup.b 10 MeOH 200 upwards C.sub.11 H.sub.8 N.sub.6 OS Found 47.01 2.94 28.24 0.5 H.sub.2 O Req. 46.97 3.23 29.88B.42945-methylsulph- 32 MeOH 200 upwards C.sub.11 H.sub.11 N.sub.5 O.sub.2 S.sub.2 Found 42.58 3.62 22.27inylthenyl Req 42.71 3.58 22.64B.42984-chlorothenyl 34 MeCN 194-198 C.sub.12 H.sub.8 ClN.sub.5 OS Found 42.70 2.94 24.84 Req 42.63 2.86 24.86B.43004-methoxythenyl 44 MeOH 189-190 C.sub.11 H.sub.11 N.sub.5 O.sub.2 Found 47.73 4.15 25.05 Req 47.64 4.00 25.26B.43135-bromo-3- 7.6 MeCN 190 upwards C.sub.10 H.sub.2 BrN.sub.5 OS Found 37.02 2.43 20.95thienylmethyl Req 36.82 2.47 21.47B.43174-cyanothenyl 32 MeOH 213-216 C.sub.11 H.sub.8 N.sub.6 OS Found 48.50 2.84 30.66 Req 48.52 2.96 30.87B.43184,5-dichlorothenyl 38 MeOH 210 upwards C.sub.10 H.sub.7 Cl.sub.2 N.sub.5 Found 35.94 2.67 20.96 1H.sub.2 O Req 35.94 2.71 20.96B.43212-chloro-4-picolyl 10 MeOH 234 upwards C.sub.11 H.sub.9 ClN.sub.6 O Found 47.15 3.52 29.32 Req 47.75 3.29 30.37B.43365-bromofurfuryl 39 MeOH 180 upwards C.sub.10 H.sub.8 BrN.sub.5 O.sub.2. Found 38.22 2.71 21.93 0.25 H.sub.2 O Req 38.18 2.72 22.26__________________________________________________________________________O.sup.6 -Substituted guanines M.p.Compound, Yield Solvent for (decomp) Molecular AnalysisTest No. O.sup.6 -Substituted RCH.sub.2 % Recrystn. (C.*) Formula Weight C H N__________________________________________________________________________B.4282 3-picolyl 54 MeOH 244-254 C.sub.11 H.sub.10 N.sub.6 O.sub.2 258 N-oxideB.4309 5-methylsulphonyl- 12 EtOH 206-209 C.sub.11 H.sub.11 N.sub.5 O.sub.3 S.sub.2. 348 Found 41.46 3.83 20.13 thenyl 1/2 C.sub.2 H.sub.5 OH Req. 41.37 4.05 20.10B.4319 6-chloro-3-picolyl 58 MeOH >215 C.sub.11 H.sub.9 ClN.sub.6 O. 285.7 Found 46.01 3.49 29.05 1/2 H.sub.2 O Req. 46.25 3.53 29.42B.4320 5-bromo-3-picolyl 56 MeOH >220 C.sub.11 H.sub.9 BrN.sub.6 O. 330 Found 40.02 3.05 25.28 1/2 H.sub.2 O Req. 39.87 3.01 25.28B.4354 4-isothiazolyl 28 MeOH >200 C.sub.9 H.sub.8 N.sub.6 OS. 261.8 Found 41.59 3.64 31.53 3/4 H.sub.2 O Req. 41.32 3.59 32.16B.4356 4-methylthiothenyl 30 MeOH C.sub.11 H.sub.11 N.sub.5 OS.sub.2 293.4B.4357 5-iodo-3-thienyl- 23 MeOH >200 C.sub.10 H.sub.8 lN.sub.5 OS 373 methylB.4361 4-methyl- 95 MeOH 170-172 C.sub.11 H.sub.11 N.sub.5 O.sub.3 S.sub.2 325 Found 40.2 3.39 21.01 sulphonylthenyl Req. 40.61 3.41 21.53B.4366 naphtho[2,1-b]- 81 MeOH >150 C.sub.18 H.sub.13 N.sub.5 OS 347 thiophen-2-yl- methylB.4373 4-azidothenyl 37 MeOH >195.sup.a C.sub.10 H.sub.8 N.sub.8 SO 288B.4377 4-methyl- 55 MeOH 204-206 C.sub.11 H.sub.11 N.sub.5 O.sub.2 S.sub.2 309 sulphinylthenylB.4378 5-phenylthenyl 54 CH.sub.3 CN >170 C.sub.16 H.sub.13 N.sub.5 OS 323__________________________________________________________________________ .sup.a 5 6 mmol alcohol per mmol quaternary salt used in synthesis. .sup.b Dimethylformamide reaction solvent.
TABLE 6B__________________________________________________________________________Test No. O.sup.c -Substituent .sub.max (nm)(MeOH) δ.sub.H [ppm from TMS; (CD.sub.3).sub.2 SO.sub.1 ]J__________________________________________________________________________ (Hz)B. 4280 4-bromothenyl 238, 284 5.65(s), 6.40(s), 7.37(d), 7.71(d), 7.85(s), 12.49(s). (RCH.sub.2 OH:233).B. 4281 5-chlorothenyl 247, 284 5.59(s), 6.40(s), 7.06(d), 7.22(d), 7.87(s), 12.47(bs). (RCH.sub.2 OH:245).B. 4283 5-cyanothenyl 247, 272 5.73(s), 6.46(s), 7.49(d), 7.87(s), 7.92(d), 12.54(bs).B. 4294 5-methylsulphinylthenyl 243, 284(sh) 2.93(s), 5.73(s), 6.41(s), 7.40(d), 7.52(d), 7.88(s), 12.52(bs). [RCH.sub.2 OH:240, 274(sh)].B. 4298 4-chlorothenyl 238, 284 5.64(s), 6.42(s), 7.34(d), 7.62(d), 7.86(s), 12.51(s) (RCH.sub.2 OH:240).B. 4300 4-methoxythenyl 245(sh), 282 3.75(s), 5.57(s), 6.37(s), 6.60(d), 7.01(d), 7.85(s), 12.48(s). (RCH.sub.2 OH:258).B. 4313 5-bromo-3-thienylmethyl 240, 284 5.42(s), 6.38(s), 7.40(d), 7.72(d), 7.85(s), 12.47(s). (RCH.sub.2 OH:236).B. 4317 4-cyanothenyl 244, 284 5.68(s), 6.44(s), 7.74(d), 7.86(s), 8.60(d), 12.50(s). (RCH.sub.2 OH:244).B. 4318 4,5-dichlorothenyl 243, 285 5.58(s), 6.45(s), 7.41(s), 7.87(s), 12.52(s) (RCH.sub.2 OH:243).B. 4321 2-chloro-4-picolyl 241, 272(sh), 285 5.58(s), 6.36(s), 7.51(bs), 7.61(bs), 7.91(bs), 8.44(bs), 12.56(bs). [RCH.sub.2 OH:262, 268(sh)].B. 4336 5-bromofurfuryl 220, 284 5.42(s), 6.39(s), 6.64(d), 6.78(d), 7.85(s), 12.49(s). (RCH.sub.2 OH: 223)__________________________________________________________________________O.sup.6 -Substituted guanines O.sup.6 -Substituent .sub.max (MeOH)Compound Type, Test No. RCH.sub.2 (nm) δ.sub.H [ppm from TMS, (CD.sub.3).sub.2 SO,]J__________________________________________________________________________ (Hz)B. 4282 3-picolyl N-oxide 271 5.48(s), 6.41(s), 7.47(m), 7.87(s), 8.22(m), 8.42(s), 12.52(s)B. 4309 5-methylsulphonyl- 242, 284 5.75(s), 6.43(s), 7.47(d), 7.74(d), 7.87(s), 12.52(s). thenylB. 4319 6-chloro-3-picolyl 242, 276 5.53(s), 6.38(s), 7.59(d), 7.87(s), 8.05(dd), 8.64(d), 12.48(s)B. 4320 5-bromo-3-picolyl 242, 281 5.53(s), 6.41(s), 7.86(s), 7.86(s), 8.26(dd), 8.73(d), 8.78(d), 12.50(s).B. 4354 4-isothiazolyl 244, 284 5.58(s), 6.41(s), 7.84(s), 8.81(s), 9.22(s), 12.47(s)B. 4356 4-methylthio-thenyl 236, 283 2.48(s), 5.62(s), 6.40(s), 7.26(m), 7.85(s), 12.48(s).B. 4357 5-iodo-3- 240, 283 5.43(s), 6.38(s), 7.48(d), 7.77(s), 7.84(s), 12.47(s). thienylmethylB. 4361 4-methylsulphonyl- 240, 285 3.26(s), 5.70(s), 6.40(s), 7.72(s), 7.85(s), 8.38(d), thenyl 12.49(s).B. 4366 naphtho[2,1-b]- 244, 286 sh 5.90(s), 6.47(s), 7.60(t), 7.69(t), 7.86(t), 8.04(dd), thiophen-2-ylmethyl 295, 306 sh 8.44(s), 8.51(d), 12.51(s).B. 4373 4-azidothenyl 227, 280 5.64(s), 6.36(s), 7.20(s), 7.28(s), 7.84(s), 12.47(s).B. 4377 4-methylsulphinyl- 241, 285 2.82(s), 5.68(s), 6.33(s), 7.60(s), 7.82(s), 8.01(s), thenyl 12.45(s).B. 4378 5-phenylthenyl 244 sh, 289 5.57(s), 6.32(s), 7.31(m), 7.41(m), 7.41(m), 7.63(d), 7.82(s), 12.43(s).__________________________________________________________________________
TABLE 7__________________________________________________________________________ I.sub.50 (μM) Raji I.sub.50 Stability T 1/2(h)INACTIVATOR hAT By SpecM)__________________________________________________________________________B.4280O.sup.6 -(4-bromothenyl)guanine 0.0034 326B.4281O.sup.6 -(5-chlorothenyl)guanine 0.004 281.7 >10B.4282O.sup.6 -(oxido-3-picolyl)guanine >20B.4283O.sup.6 -(5-cyanothenyl)guanine >20 2B.4294O.sup.6 -(5-methylsulphinylthenyl)guanine >10B.4298O.sup.6 -(4-chlorothenyl)guanine >16 282B.4300O.sup.6 -(4-methoxythenyl)guanine 0.83B.4309O.sup.6 -(5-methylsulphonylthenyl)guanine 0.072 325 >16B.4313O.sup.6 -(5-bromo-3-thienylmethyl)guanine 326 0.0065 0.035B.4317O.sup.6 -(4-cyanothenyl)guanine >19 72B.4318O.sup.6 -(4,5-dichlorothenyl)guanine 0.015 348 2.5B.4319O.sup.6 -(6-chloro-3-picolyl)guanine 0.2 >13B.4320O.sup.6 -(5-bromo-3-picolyl)guanine >13B.4321O.sup.6 -(2-chloro-4-picolyl)guanine >16B.4336O.sup.6 -(5-bromofurfuryl)guanine 0.32 0B.4354O.sup.6 -(4-isothiazolylmethyl)guanine 0.07 248B.4356O.sup.6 -(4-methylthiothenyl)guanine 0.0095 293B.4357O.sup.6 -(5-iodo-3-thienylmethyl)guanine 0.009 >16B.4361O.sup.6 -(4-methylsulphonylthenyl)guanine >16B.4366O.sup.6 -(naphtho[2,1-b]thiophen-2-ylmethyl)guanine 0.05 347B.43689-(B-D-arabinofuranosyl)-O.sup.6 -(4-bromothenyl)guanine 0.115B.4369O.sup.6 -(4-bromothenyl)-9-(ethoxymethyl)guanine 0.28 384B.4370O.sup.6 -(4-bromothenyl)-9(octyloxymethyl)guanine 1.2 468B.4373O.sup.6 -(4-azidothenyl)guanine 0.0063 288B.4377O.sup.6 -(4-methylsulphinylthenyl)guanine 0.15 309B.4378O.sup.6 (5-phenylthenyl)guanine 0.75 323B.4379O.sup.6 -(4-bromothenyl)-2-deoxyguanosine 0.095 442__________________________________________________________________________
TABLE 7B__________________________________________________________________________ Stability T 1/2 (h) In vitro I.sub.50 (μM) (μM)INACTIVATOR M.Wt hAT mAT rAT chAT agt Raji I.sub.50 By Spec By Assay__________________________________________________________________________B.4363O.sup.6 -(4-bromothenyl)guanosine 0.24 >4816__________________________________________________________________________ Blank space = not done
TABLE 8______________________________________ATASE ACTIVITY IN VARIOUS TISSUES OF NU/NU MICE AFTERTREATMENT WITH 10 mg/kg (IP) B.4280MEAN ACTIVITY (fm/mg)Tissue 24 h 48 h Control*______________________________________Tumour 36 ± 7.79 140 ± 43.87 125Liver 100.7 ± 8.73 .14 110**Lung 24 ± 2.83. 2.05 43Kidney 28.7 ± 4.11. 4.03 33Spleen 68.3 ± 9.53.35 81Brain 16.3 ± 1.25-. 2.05 14Testis 44 ± 1.418 45Bone Marrow (pooled) 42 30______________________________________ *control values taken from a separate experiment **mean of 2 control liver values Table 8. Effect of B.4280 on ATase activity in several tissues of nude mice. Animals were given a single dose of B.4280 (10 mg/kg i.p.) and sacrificed 24 or 48 hours later.
TABLE 9______________________________________TOXICITY OF INACTIVATORS IN COMBINATION WITHBCNU IN DBA.sub.2 MICE % SURVIVAL AFTER 14 DAYSINACTIVATOR 12 mg/kg(60 mg/kg) 20 mg/kg BCNU 16 mg/kg BCNU BCNU______________________________________O.sup.6 -benzylguanine 33 (2/6) 0 (0/6)* 50 (3/6)**B.4205 0 (0/6) 100 (6/6)**B.4280 93 (14/15) 100 (15/15)______________________________________ *15 mg/kg BCNU **10 mg/kg BCNU All agents were given as a single i.p. dose Table 9 Effect of ATase inactivators on the acute toxicity of bischloroethylnitrosourea (BCNU) in DBA.sub.2 mice.
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31. Wilkinson, M. D., Potter, P. M., Cawkwell, L., Georgiadis, P., Patel, D., Swann, P. F. and Margison, G. P. (1989) Nucleic Acids Res. 17, 8475-8484.
32. Wilkinson, M. C., Cooper, D. P., Southan, C., Potter, P. M. & Margison, G. P. (1990) Nucleic Acids Res., 18, 13-16.
33. R. Bernetti, F. Mancini and C. C. Price, J. Org. Chem. 27, 1962, 2863.
34. M. T. G. Ivery and J. E. Gready, J. Heterocycl. Chem., 31, 1994, 1385.
35. A. Albert, D. J. Brown and G. Cheesman, J. Chem. Soc., 1951, 474.
36. M. J. Robins and B. Uznanski, Can. J. Chem., 59, 1981, 2601.
37. B. Zajc, M. K. Lakshman, J. M. Sayer and D. M. Jerina, Tetrahedron Lett., 33, 1992, 3409.
38. N. B. Hanna, K. Ramasamy, R. K. Robsins and G. R. Revankar, J. Heterocycl. Chem., 25, 1988, 1899. | The present invention provides certain 6-hetarylalkyloxy pyrimidine derivatives of formula II ##STR1## wherein R is (i) a cyclic group having at least one 5- or 6-membered heterocyclic ring, optionally with a carbocyclic or heterocyclic ring fused thereto, the or each heterocyclic ring having at least one hetero atom chosen from O, N, or S, or a substituted derivative thereof; or (ii) phenyl or a substituted derivative thereof,
R 2 is selected from H, C 1 -C 5 alkyl, halogen or NH 2 ,
R 4 and R 5 which are the same or different are selected from H, NH 2 or NO n where n=1 or 2, or R 4 and R 5 together with the pyrimidine ring form a 5- or 6-membered ring structure containing one or more heterocyclic atoms, and pharmaceutically acceptable salts thereof, exhibit the ability to deplete O 6 -alkylguanine-DNA alkyltransferase (ATase) activity. | 2 |
BACKGROUND OF THE INVENTION
This invention is in the field of brick manufacture and is specifically directed to a method and apparatus for rapidly forming bricks of irregular configuration having an antique or handmade appearance.
The brick making industry is highly developed and employs a substantial amount of automation for extruding, cutting and forming conventional rectangular bricks and the like having a geometrically uniform rectangular parallelpiped configuration in which the sides of the brick are planar with adjacent sides being perpendicular to each other. Equipment for producing the geometrically uniform bricks of the foregoing type includes automatic brick handling means for removing bricks from conveyor means which handling means requires that the individual bricks be equidistantly spaced in a proper geometric array on the conveyor in order for the handling equipment to function properly. Used or antique brick have become extremely popular in recent years and those of skill in the art have been unable to provide satisfactory equipment for the automatic manufacture of bricks having irregular surfaces with one of the main problems being due to the fact that prior known equipment for providing brick with irregular surfaces has been incompatible with the automatic brick handling equipment so as to consequently entail substantial manual labor and resultant expense. For example, irregular shaped brick members have been formed by taking conventional rectangular green brick formed of wet clay and dropping the brick from a height of approximately 3 or 4 feet so that the bricks are bent and deformed. However, deformation of brick in the foregoing manner results in the brick being in random array which cannot be handled by downstream automatic handling equipment unless the brick are manually aligned on a conveyor at a substantial cost in time and labor. Moreover, the forming of irregular brick in the foregoing manner results in substantial breakage and waste which further adds to the overall expense of the process.
Another disadvantage of the tumbling or dropping process is that many of the brick are deformed on all surfaces so that they do not have any truly planar surfaces and are substantially more difficult to process and lay than are brick having at least one planar surface.
Other approaches have included the use of embossing rollers or the like engaging the surface of the brick members as they are conveyed past the roller. Unfortunately, devices of the foregoing type frequently knock the brick over and destroy any previously existing uniform geometric array of the brick on the conveyor so that substantial manual labor is required for repositioning the brick in the position necessary for the brick to be subsequently handled by the automatic handling equipment.
Therefore, it is the primary object of this invention to provide a new and improved method and apparatus for fabricating brick of irregular configuration.
A further object of the invention is the provision of a new and improved apparatus and method for fabricating brick having generally irregular configuration but having one true planar surface.
Yet another object of the invention is the provision of a new and improved apparatus and method for fabricating bricks having an antique appearance.
SUMMARY OF THE INVENTION
Achievement of the foregoing objects of the invention is enabled by the preferred embodiment of the invention in which a horizontal brick feed belt conveyor provides a supply of green moist clay bricks which have just been previously cut from an extruded column of wet clay in a conventional manner. The bricks are spaced and aligned on the moving conveyor and an elastic hold-down member is mounted above the brick conveyor with a lower flight of the hold-down belt extending substantially parallel to the brick feed belt and positioned to engage the upper surface of the brick members as they are moved along a horizontal feed path by the brick conveyor. The lower flight of the hold-down belt is driven in the same direction as the brick on the conveyor and a relatively large irregularly surfaced impression roller is mounted adjacent to and engaging the upper surface of the lower flight of the hold-down belt. The impression roller has a number of protrusions which deflect portions of the elastic hold-down belt downwardly into the green brick immediately beneath the hold-down belt so that the green bricks are distorted and deformed to provide an irregular configuration. The distorting action of the protrusions on the impression roller causes the mortar faces of the brick to bulge inwardly and outwardly as well as the end faces in many instances so that the brick has an irregular configuration on all faces with the exception of the lower face which rests on the brick conveyor. The hold-down belt prevents the brick members from being knocked over by the operation of the impression roller and insures that the brick members remain in their desired geometric position on the conveyor so that they can be removed from the conveyor at a location downstream of the deforming station by conventional automatic brick handling equipment.
In one embodiment of the invention, the hold-down belt is driven by an electric variable speed motor drive system which can be adjusted to insure that the hold-down belt is operated at exactly the same speed as the brick conveyor belt. In another manner of operation, when the brick members are of such configuration as to have a large base portion resting on the brick conveyor, it is not necessary for the hold-down belt to be driven since the frictional engagement of the upper surface of the brick members provides a sufficient force on the belt to provide the necessary belt movement.
A better understanding of the manner in which the preferred embodiment achieves the objects of the invention will be enabled when the following written description is considered in conjunction with the appended drawings in which like reference numerals are used for the same parts in the different figures as described hereinafter.
DESCRIPTION OF THE DRAWINGS
FIG. 1 is a side elevation view of the preferred embodiment for practice of the invention;
FIG. 2 is a top plan view of the preferred embodiment;
FIG. 3 is an end elevation of the preferred embodiment;
FIG. 4 is a sectional view taken along lines 4--4 of FIG. 1;
FIG. 5 is a perspective view of a green brick of the type used in the inventive method and apparatus in practice of the invention; and
FIG. 6 is a perspective view illustrating a typical irregularly surfaced finished brick produced by the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Attention is initially invited to FIG. 1 which illustrates the preferred embodiment for practice of the invention which is generally designated 10 and which includes a generally horizontal brick conveyor 12 moving from left to right in FIG. 1 at a constant speed on which spaced and aligned conventional green uncured bricks 14 of rectangular parallelpiped configuration are positioned. The green uncured bricks 14 are formed in a conventional manner from a mixture of clay and water extruded from conventional extrusion means in a solid column that is subsequently cut into the individual brick members which are then separated to provide an approximate equidistant spacing of the green brick on conveyor 12 as illustrated in FIG. 1. Since the production of the individual green brick members 14 is in a completely conventional manner, it is not illustrated.
A vertically extending fixed frame including upstream vertical corner post members 16, downstream vertical corner post members 17 and transverse top members 19 and 19' are positioned over conveyor belt 12 for providing support for an adjustable frame carrying brick engaging means which forcefully presses downwardly on the green brick 14 to distort the brick to provide an irregularly shaped brick 14' having an antique or handmade appearance. The adjustable frame includes front and rear pivot arms 20 pivotally connected by pivot means 21 to the upstream vertical corner post members 16 with other components of the adjustable frame including approximately vertical members 22 which are joined at their upper ends by a motor support plate 23 with diagonal braces 24 being welded between vertical members 22 to provide a rigid adjustable frame structure pivotally adjustable about the axis of pivot means 21.
A threaded adjustment rod 25 is carried by bracket means 26 on the adjustable frame and has its lower end engaging a plate 27 on transverse component 19' of the base frame so that manual rotary adjustment of rod 25 serves to effect an adjustment of the vertical position of the adjustable frame elements 20, 23, 24 etc. about pivot 21.
Shaft bearing means 28 best illustrated in FIG. 4 are mounted on the pivot arms 20 of the adjustable frame and provide rotary support for a shaft 29 of a relatively large cylindrical impression roller 30 which has a plurality of rounded protuberances 31 on its outer surface. A variable speed electric motor 32 is mounted on the motor support plate 23 and drives a step-down transmission 33 having an output sprocket 34 connected by a chain 35 to a sprocket 36 keyed to the end of impression roller shaft 29 so that operation of motor 32 serves to rotate impression roller 30 to rotate in the direction of arrow 30' in FIG. 1.
The upstream vertical corner post members 16 of the fixed frame provide support for bearing members 38 in which an upstream belt roller 40 is supported for rotation. Similarly, an adjustable downstream belt roller 42 is mounted on adjustable bearings 43 carried on support bracket means 44 attached to the downstream vertical corner post member 17. It will be seen that rotation of conventional adjustment cranks 45 will serve to move the bearings 43 and roller 42 in a horizontal plane in an obvious manner as shown in FIG. 1. A flexible belt loop 46 formed of elastomeric material such as rubber or the like is entrained about the upstream and downstream belt rollers 40 and 42 and about the upper surface of the impression roller 30. Belt loop 46 is maintained in tension by a floating idler roller 48 mounted in bearings attached to pivotal support frame members 50 which are mounted for pivotal movement about pivot means 52 on the upstream vertical corner post members 16 as shown in FIG. 1. The weight of floating idler roller 48 obviously serves to maintain the belt 46 in tension regardless of the position of adjustment of the downstream roller 42. Rollers 40 and 42 are of the same size and have their axes of rotation in a common horizontal plane so that a lower horizontal flight 46' of the elastomeric belt member 46 extends between the rollers 40 and 42 in parallel alignment with the conveyor belt 12.
It will be observed that the protuberances 31 of the impression roller 30 engage the flight 46' to deflect discrete portions of the flight downwardly toward the conveyor 12 as shown in FIG. 1 and FIG. 4. The deflected portions of the belt flight 46' press into the upper surfaces of the green moist brick members 14 which are being conveyed from left to right in FIG. 1 so as to distort both the upper edge of the bricks engaged by the belt flight 46' and frequently one or more of the other faces of the bricks with the exception of the lower edge resting on conveyor 12 so as to provide an irregular brick 14'. The distortion of all faces of the bricks with the exception of the face resting on conveyor 12 is effected by virtue of the fact that the substantial downward impression of the belt into the upper face of the brick results in an outward bulging of one or more of the other faces. Consequently, when the finished irregular shaped brick is used to form a wall, it presents an irregular mortar edge having the appearance of antique or handmade brick.
Not only does the horizontal belt flight 46' provide an impression into the brick, it also engages the brick both upstream and downstream of the impression roller for keeping the brick from falling over and destroying the geometric array of the brick on the conveyor member. Consequently, the downstream handling equipment of conventional design can function to remove brick from the conveyor 12 for further processing. Obviously, the motor 32 is adjusted to provide a rotational speed of the impression roller 30, which drives belt 46, so that the belt 46 is moving at the same speed as the brick conveyed by roller 12.
While the variable speed electric motor 32 is normally employed for fabricating bricks having relatively narrow edge portions resting on the conveyor 12, it is possible when fabricating other bricks having relatively large face areas resting on the conveyor to use an alternate construction by elimination or deactivation of the drive means 32 to permit the frictional engagement of the belt flight. In all other respects, the operation of the alternative embodiment in which use of the motor 32 is eliminated is identical to that of the first embodiment.
It should be understood that the size, shape and number of protuberances 31 on the roller 30 can be varied in accordance with the nature of the brick being formed. Additionally, the adjustment of the roller 30 vertically by means 25 etc. can also be varied for providing a variation in the final product. In any event, all of the brick formed by the process differ from each other due to the irregular facing of the protuberances 31 so that the brick each have an individual appearance and shape to provide a handmade or antique appearance.
Numerous modifications of the subject invention will undoubtedly occur to those of skill in the art. For example, it is not essential that a roller be used for distorting the lower flight 21 downwardly into the brick conveyance area since plungers or other similar means such as multiple rollers of smaller diameter could also be used for the same purpose. The essential ingredient of the invention is the use of means for deflecting the moving belt member downwardly to provide a brick distortion without destroying the orderly array of the bricks. Therefore, it should be understood that the spirit and scope of the invention is to be limited solely by the appended claims. | A horizontal brick feed conveyor continuously feeds green undried moist clay bricks along a path beneath a lower horizontal flight of an elastic hold-down belt member mounted above and moving in the same direction as the conveyor to engage the upper surface of the conveyed brick; a relatively large motor-driven irregularly spaced impression roller is adjustably mounted adjacent the upper surface of the horizontal flight of the hold-down belt to engage the horizontal flight so that a number of protrusions on the roller deflect portions of the elastic hold-down belt downwardly into the green brick immediately beneath the hold-down belt so that the bricks are distorted and misshaped to give an antique or handmade effect. | 1 |
This application is a divisional application of Ser. No. 08/238,314, filed May 5, 1994, now U.S. Pat. No. 5,505,686.
BACKGROUND OF THE INVENTION
Endoscopes are commonly used to view the interior passage of an object. Art endoscope typically includes an endoscope body and optical components carried by the endoscope body to enable viewing of the passage distally of the distal end of the endoscope body and within a field of view of the endoscope. The optical components may include, for example, illumination and visualization fibers in the endoscope body for conducting light distally and an image proximally, of the endoscope body.
Endoscopes have industrial applications wherein the endoscope can be used to view a passage within, for example, industrial equipment. Endoscopes also have medical applications wherein the endoscope is used to view a passage within the body of a patient.
Medical endoscopes used for angioscopy are commonly placed in the vascular system using a guidewire. For example, the guidewire may first be placed within a blood vessel and the endoscope may have a lumen receiving the guidewire such that the endoscope can be moved along the guidewire to a desired position. It is also known to provide an angioplasty catheter, as opposed to an endoscope, with a fixed guidewire which allows the operator to track and place the catheter at the desired location in the vascular system.
One problem with these procedures is that it may be difficult to view curved, collapsed or partially collapsed portions of the passage. In addition, material within the passage may tend to obstruct viewing through the endoscope within the field of view of the endoscope.
In an effort to solve this problem, it is known to use a resectoscope for removing or ablating unwanted tissue. It is also known to use a nozzle in an attempt to spray material off the distal lens of the endoscope as shown, for example in Auhll et al U.S. Pat. No. 5,207,213. However, these techniques do not address the visualization problems posed by a curved, collapsed or partially collapsed passage and resection increases the likelihood of injury and trauma to the patient. Similarly, the use of a technique as shown for example in Hiltebrandt U.S. Pat. No. 4,682,585 for radially spacing the distal objective of the endoscope is also not effective to address these problems.
Endoscopes have also been introduced through hollow sleeves with sharpened points for puncturing the abdomen in laparoscopic procedures such as shown in Hiltebrandt U.S. Pat. No. 4,345,589 and Yoon U.S. Pat. No. 4,254,762. However, the rigidity of the hollow sleeves and their sharp tips make them unsuited for many procedures where tissue penetration is to be avoided and for passages which are curved.
SUMMARY OF THE INVENTION
This invention solves these problems. This invention enhances the viewing of a passage in which the endoscope is placed by relatively displacing the distal end of the endoscope and material within or forming the passage. This relative displacement of the distal end of the endoscope and such material may open a collapsed or partially collapsed passage, displace the distal end of the endoscope body from the wall of the passage, displace material within the passage that would otherwise obstruct the view and/or elongate a curved portion of the passage. This can be accomplished for both industrial and medical endoscopes, and in the case of medical endoscopes, it can be accomplished without increasing the likelihood of tissue penetration. The features of this invention are applicable to those endoscopes having a working channel or lumen and to those which do not.
The invention may be embodied in an endoscope which includes an elongated endoscope body having a distal end with the endoscope body being sized and adapted for insertion into a passage of an object. The object may be the body of a patient or industrial equipment. The endoscope also includes optical components carried by the endoscope body to enable viewing of the passage distally of the distal end within a field of view of the endoscope when the endoscope is in the passage.
To accomplish the desired relative displacement, the endoscope includes an elongated member mounted on, and carried by, the endoscope body such that the endoscope body and the elongated member are a unitary assembly which can be inserted as a unit into the passage. In this context, the elongated member may be either fixed longitudinally with respect to the endoscope body or mounted on the endoscope body for generally longitudinal movement relative to the endoscope body. In either event, however, the endoscope body and the elongated member are a unitary assembly which can be inserted as a unit into the passage. This unitary assembly can be contrasted with a conventional guidewire system in which a guidewire is first placed within a blood vessel and subsequently an endoscope or catheter is run over the guidewire to a desired location in the vessel.
The elongated member extends beyond the distal end of the endoscope body and is capable of contacting material within or forming the passage. The elongated member can relatively displace the distal end of the endoscope body and such material within the field of view of the endoscope to enhance viewing of the passage with the endoscope.
For those applications in which penetration of the wall of the passage being examined would not cause a problem, the elongated member may be rigid, if desired. However, for the vast majority of medical applications and for certain industrial applications, penetration of the wall of the passage being examined is to be avoided. To greatly reduce the likelihood of penetration of the wall of the passage, the elongated member can be made resilient. The resilience of the resilient member allows it to be elastically deflected, and when the deflecting force is removed, its resilience, elasticity or memory will return it to its original unstressed position. The resilient member is flexible in the sense that it can be very easily elastically or resiliently deflected, but is not flexible in the sense of a length of string which has no memory for returning to its original position. Preferably, the resilient member is highly elastic so it can be very easily deflected. If the resilient member required substantial force to deflect, the risk of penetration of the wall of the passage would increase. Because of the large number of applications where penetration of the wall of the passage being examined is desirable, the elongated member is often referred to as a resilient member below in this specification.
For medical applications where tissue penetration is to be avoided or for any other application where penetration of the object being examined is to be avoided, the resilient member preferably terminates distally in an enlarged distal tip portion. The enlarged distal tip portion is also more capable than a smaller distal tip portion in providing a relatively wide area in radial cross section for viewing. For some medical applications, it is preferred that the distal tip portion have a maximum cross sectional area which is at least about as large as the cross sectional area of the distal end of the endoscope body. For medical applications in the fallopian tube, the maximum cross sectional dimension of the distal tip portion is preferably between about 0.15 millimeter and 1.2 millimeters. To further reduce the likelihood of tissue penetration in a medical endoscope, a region of the resilient member proximally of the distal tip portion may be made of increased flexibility and in some cases of progressively increasing flexibility as such region extends distally.
To further reduce the likelihood of tissue penetration, the resilient member is preferably very elastic such that it can be easily deflected, and when the deflecting force is removed, it will return to its normal, unrestrained position. Although various different materials can be employed, a nickel-titanium alloy is preferred because of its inherent elasticity.
The spacing between the distal tip portion and the distal end of the endoscope body can be selected depending upon the nature of the passage being examined. Further by way of example, for medical applications in the fallopian tube, the distal tip portion has a distal end which is between about 1 millimeter and 15 millimeters from the distal end of the endoscope body.
The endoscope may be either rigid or flexible depending upon the usage to which it is to be put. For medical applications, it is ordinarily preferably made flexible and sized to be received within the desired interior body region of a patient.
In one preferred embodiment, the resilient member is fixed longitudinally with respect to the endoscope body. In a preferred construction, the endoscope body has an endoscope lumen and the resilient member is received in the endoscope lumen. This has the advantage of reducing the likelihood that the resilient member will separate from the endoscope body and be left within the passage. Although the resilient member can be fixed longitudinally on the endoscope body in different ways, it is preferred to use bonding material for bonding the resilient member to the endoscope body within the endoscope lumen. Alternatively the resilient member can be fixed to the endoscope body by crimping, fasteners and/or other mechanical techniques.
In one preferred construction, the endoscope body has a proximal end and the endoscope lumen extends through the endoscope body from the proximal end to the distal end. The endoscope includes a hub coupled to the endoscope body adjacent the proximal end of the endoscope body and the resilient member extends through the endoscope lumen and into the hub. The bonding material for bonding the resilient member to the hub may be provided in the hub. If the endoscope includes illumination and visualization fibers, these fibers may extend through the endoscope body and into the hub.
Various other techniques can be employed to mount the resilient member on the endoscope body. For example, a clip-on assembly may be coupled to the resilient member for enabling the resilient member to clipped onto the exterior of the endoscope body. Similarly, the endoscope lumen may be a separate lumen near the periphery of the endoscope which does not extend for the full length of the endoscope body. In this event, longitudinal axes of the resilient member and the endoscope body are radially offset at the distal end of the endoscope body. To reduce the radial offset and bring the axes closer together, the resilient member may be deflected distally of the distal end of the endoscope body.
The resilient member may also be mounted on the endoscope body for generally longitudinal movement relative to the endoscope body. This mounting is different from the sliding of an endoscope over a prepositioned guidewire in that the resilient member and the endoscope body are, in effect, a unitary assembly which can be inserted as a unit into the passage to be viewed. In this form of the invention, the endoscope body has an endoscope lumen and the resilient member is slidably received in the endoscope lumen. The endoscope may also include a controller mounted on the endoscope body for moving the resilient member longitudinally in the endoscope lumen. The controller may include a control slide coupled to the resilient member and mounted for sliding movement on the endoscepe body. Alternatively, the controller may include gears, wheels, a pull wire or other mechanical means for operating the resilient member.
Another feature of this invention is that the resilient member may be made very easily deflectable for insertion into the passage and then made appropriately resilient for use in relatively displacing the distal end of the endoscepe body and the material within or forming the passage. This may be accomplished, for example, by constructing the elongated member of a material having a transition temperature and with the elongated member being more easily deflected below the transition temperature than above the transition temperature. The ease of deflection may be brought about, for example, by the elongated member being soft and malleable and therefore very easily permanently bent or deformed. Alternatively, the ease of deflection may be the result of the elongated member being more flexible below the transition temperature than above it. Certain known shape memory materials such as nickel-titanium alloys have this property of being soft, malleable and somewhat nonresilient in an austenitic state below the transition temperature and resilient in a martenistic state above the transition temperature.
The transition temperature can be at various levels depending upon the nature of the alloy selected for the elongated member. For medical applications, it may be desirable to have a transition temperature which is less than about the temperature of the interior of the human body. This enables the elongated member to be easily deflected during insertion into the body passage and thereafter more resilient when it rises above the transition temperature as a result of being within the desired region of the body passage. Of course, the transition temperature may be higher or lower and the elongated member may be heated to the transition temperature utilizing various heating devices, including direct electrical heating of the elongated member by current flowing through it, and/or by fluids or heating devices in proximity to the elongated member.
Although the endoscope of this invention can be put to many different uses, one important usage is for medical purposes in the viewing of a passage in the body of a patient. In this event, the endoscope can be advanced into the passage in the body of the patient with the resilient member extending beyond the distal end of the endoscope body when the endoscope is at a region of the passage. In those embodiments in which the resilient member is movable longitudinally relative to the endoscope body, it is only necessary that the resilient member extend beyond the distal end of the endoscope body when the endoscope body is at the desired region of the passage. The distal end of the endoscope body and the material within or forming the passage within the field of view of the endoscope are then relatively displaced utilizing the resilient member. The interior passage can then be viewed utilizing the endoscope while the distal end of the endoscope and the material are relatively displaced. At least some of the displacement of the material in the distal end of the endoscope is in a radial direction and the displacement is preferably carried out as a result of contacting the resilient member and the material. This contact may occur in whole or in part during the advancing of the endoscope into the passage. If the resilient member is movable longitudinally relative to the endoscope body, it may be moved to assist or accomplish the displacing of the material and the distal end of the endoscope. This method can be carried out in various passages of a patient, such as the vascular system, gastrointestinal tract, neural passages in the brain and epidural passages, and it is particularly adapted for viewing of the interior of a fallopian tube.
Another feature of the invention is that the resilient member can be used to at least assist in guiding the endoscope at least part way through a curve or curved portion of the passage. This is of importance when using the endoscope in a passage, such as a fallopian tube, which contains one or more curved portions.
The invention, together with additional features and advantages thereof may best be understood by reference to the following description taken in connection with the accompanying illustrative drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is side elevational view of an endoscope constructed in accordance with the teachings of this invention.
FIGS. 2 and 3 are fragmentary, elevational views partially in section comparing the use of a prior art endoscope and the endoscope of this invention adjacent a curved region of a passage.
FIG. 4 is an enlarged sectional view taken generally along lines 4--4 of FIG. 1.
FIG. 5 is a fragmentary, axial sectional view through the hub and proximal regions of the endoscope body.
FIG. 6 is a fragmentary longitudinal sectional view through a distal region of the endoscope.
FIGS. 7-9 are fragmentary elevational views of a distal region of three different resilient members.
FIG. 10 is a fragmentary elevational view partially in section of a second embodiment of the invention.
FIG. 11 is a perspective view of a distal region of the endoscope of a third embodiment of the invention. The endoscope body is shown in phantom lines.
FIG. 12 is an enlarged fragmentary axial sectional view of an embodiment of the endoscope in which the resilient member is longitudinally movable.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIG. 1 shows an endoscope 11 which generally includes an endoscope body 13 and a hub 15. The endoscope 13 also includes one or more illumination fibers 17 (four being illustrated in FIG. 4) and image or visualization fibers 19 (FIG. 6) and a GRIN lens 20 retained in a bushing 22.
The endoscope body 13 is flexible and has a proximal end 21 and a distal end 23. The proximal end 21 is received within an axial passage 25 of the hub 15 (FIG. 5). A strain relief tube 27 receives a region of the endoscope body 13 adjacent the proximal end 21 and the strain relief tube is also received within the passage 25. An adhesive 28 (FIG. 1), such as a urethane adhesive, joins the endoscope body 13 to the tube 27. The endoscope body 13 and the tube 27 are affixed to the hub 15 in any suitable manner, such as by a urethane adhesive 30.
The illumination fibers 17 extend from the distal end 23 through the full length of the endoscope body 13, into the passage 25 and through a leg 29 or illumination connector of the hub 15 which is adapted to be coupled to a light source (not shown). Similarly, the image fibers 19 extend from the distal end 23 through the full length of the endoscope body 13 into the passage 25 and into a leg 31 of the hub 15. A suitable adhesive, such as an epoxy adhesive 32 may be used to bond the ends of the fibers 17 and 19 to the legs 29 and 31, respectively. The leg 31 could be adapted for coupling to an eyepiece (not shown) to permit direct visualization or for coupling to a camera (not shown) to enable the image to be viewed on a monitor. The hub 15 may be constructed of any suitable rigid material with a polymeric material such as ABS being preferred.
The optical components of the endoscope 11 may be of any kind which will enable viewing of a passage such as an interior body region of a patient. In the embodiment illustrated in FIGS. 1-6, these optical components include the illumination fibers 17, the image fiber 19 and the GRIN lens 20 (FIG. 4) which serves as an objective lens.
As described thus far in the Description of the Preferred Embodiments, the endoscope 11 may be substantially similar to the endoscope shown and described in Bacich et al U.S. Pat. No. 5,279,280, which is incorporated by reference herein. The endoscope of this invention departs from the prior art in that it includes an elongated resilient member 35 which, in this embodiment is fixed longitudinally with respect to the endoscope body 13. The resilient member 35 extends axially or longitudinally beyond the distal end 23 of the endoscope body 13.
The endoscope body 13 has an endoscope lumen 37 (FIG. 4 and 6) and the resilient member 35 is received in the endoscope lumen. In this embodiment, the endoscope lumen 37 extends completely through the endoscope body 13 from the proximal end 21 to the distal end 23 and the resilient member extends through the endoscope lumen and into the leg 31 of the hub 15.
In this embodiment, the resilient member 35 is fixed longitudinally with respect to the endoscope body 13 by bonding material such as epoxy 39 adjacent the distal end 23 (FIG. 6) and by the epoxy 32 (FIG. 5). Although the epoxy 39 is located closely adjacent the distal end 31, the bonding of the resilient member 35 to the endoscope body 13 can occur virtually anywhere along the length of the resilient member.
The resilient member 35 terminates distally in an enlarged distal tip portion 41 (FIGS. 1 and 6). The enlarged distal tip portion 41 has a smoothly rounded peripheral surface 43 which is blunt or nonpenetrating both proximally and at a distal end 44 so as to minimize the likelihood of penetrating tissue when the endoscope 11 is advanced or retracted within a passage. For example, the distal tip portion 41 may spherical or generally egg-shaped and may be constructed of a polymeric material or a metal such as stainless steel or a nickel-titanium alloy.
The resilient member also includes an elongated highly elastic strand or wire 45 which makes up substantially the full length oft he resilient member. In this embodiment, where high elasticity is desired, the wire 45 is constructed of a nickel-titanium alloy. The elasticity of the wire 45 makes the resilient member 35 highly flexible and easily deflected, but it will also enable the deflected resilient member to return to its natural or unstressed shape when the deflecting force is removed. The wire 45 preferably, although not necessarily, has a lubricous exterior surface. The lubricous surface may be provided in various ways such as by impregnation of a lubricous material such as polytetrafluoroethylene or by a lubricous coating of polytetrafluoroethylene, silicone oil, silicone wax or other suitable lubricous materials. The distal tip portion 41 may be a member separate from the wire 45 and attached to the wire or it may be an integrally enlarged portion of the wire 45.
In this embodiment, the endoscope 11 is flexible and is sized to be received within an interior body region of a patient. More specifically, the endoscope 11 is adapted to be used in a fallopian tube, and as such, the distal tip portion 41 preferably has a maximum cross sectional area which is at least about as large as the cross sectional area of the distal end 23 of the endoscope body 13. In one preferred construction for fallopian tube use the distal tip portion 41 preferably has a maximum cross sectional dimension which is about 0.6 millimeter. In addition, in this preferred construction the distal end 44 of the distal tip portion 41 is about 6 millimeters from the distal end 23 of the endoscope body 13.
FIG. 2 shows the use of a conventional endoscope 47 being used to view the interior of a fallopian tube 49 having a curved portion 51. The conventional endoscope 47 is delivered to a location within the fallopian tube 49 by an everting catheter 53 which may be of the type shown and described in Lowery et al U.S. Pat. No. 5,300,023 which is incorporated by reference herein. As shown in FIG. 2, the endoscope 47 has a field of view 55 which is obstructed by a wall 57 of the curved portion 51.
FIG. 3 illustrates the endoscope 11 of this invention delivered via a transvaginal route to the same region of the fallopian tube 49 by the everting catheter 53. More specifically, the endoscope 11 is advanced into the fallopian tube 49 in the body of a patient with the elongated resilient member 35 extending beyond the distal end 23 of the endoscope body when the endoscope is at the desired region of the fallopian tube. In advancing to the position of FIG. 3, the distal tip portion 41 of the resilient member 35 contacts the wall 57 of the curved portion 51 and relatively displaces the distal end 23 of the endoscope and wall 57. Consequently, the field of view 55 is materially less obstructed by the wall 57 of the curved portion 51 than in the prior art form shown in FIG. 2. The fallopian tube 49 can then be viewed utilizing the endoscope 11 while the distal end 23 of the endoscope body and the wall 57 are relatively displaced. At least some of the displacement of the wall 57 relative to the distal end of the endoscope body is in a radial direction. The contact between the distal tip portion 41 and wall 57 may occur during advancing or retracting of the endoscope 11 and while the endoscope is stationary within the fallopian tube 49. Because of the enlarged and rounded nature of the peripheral surface 44, the distal tip portion is unlikely to penetrate or damage the tissue of the fallopian tube. FIG. 3, which is somewhat schematic in nature, may also be considered as illustrating the use of the endoscope 11 in other body passages such the gastrointestinal tract, a passage of the vascular system, a neural passage or an epidural passage. Also if it is desired to move the endoscope 11 through the curved portion 51, the resilient member 35 serves, in effect, as a fixed guidewire to guide the endoscope through the curved portion.
FIG. 7 shows a distal region of a resilient member 35a which may be identical to the resilient member 35 in all respects not shown or described herein. Portions of the resilient member 35a corresponding to portions of the resilient member 35 are designated by corresponding reference numerals followed by the letter "a". The only difference between the resilient members 35 and 35a is that the latter has a fillet 61 of epoxy or other suitable material between the wire 45a and the enlarged distal tip portion 41a. The fillet 61 tapers as it extends proximally, i.e. is of progressively reducing cross sectional area as it extends proximally so as to minimize trauma to body tissue as the endoscope of which the resilient member 35a forms a part is retracted.
FIGS. 8 and 9 show resilient members 35b and 35c, respectively, each having a region immediately proximal of the distal tip portion which is of greater flexibility than a zone of the resilient member immediately proximal to such region. In FIG. 8 such region is of progressively increasing flexibility as such region extends distally. In FIG. 8, this is accomplished by progressively reducing the diameter of a region 54 of the wire 45b as the wire extends distally toward the distal tip portion 41b. The region 54 is of smaller diameter than a zone 56 immediately proximal to such region, and such region terminates at the distal tip portion 41a. In FIG. 9, increased flexibility is accomplished by winding the wire 45c into a coil 55 which terminates at the enlarged distal tip portion 41c and which is contiguous an unwound zone 56c of the wire 45c. In all other respects, the resilient members 35b and 35c may be identical to the resilient member 35. The resilient members 35a, 35b and 35c of FIGS. 7-9 can be used with any of the endoscopes of FIGS. 1 and 10-12.
FIG. 10 shows an endoscope 11d which is identical to the endoscope 11 in all respects not shown or described herein. Portions of the endoscope 11d corresponding to portions of the endoscope 11 are designed by corresponding reference numerals followed by the letter "d". The endoscope 11d differs from the endoscope 11 in that the endoscope lumen 37d is formed outside of the tube forming the endoscope body 13d, and thus the axes of the resilient member and the endoscope body 13d are radially offset at the distal end 23d of the endoscope body more than at that location in the endoscope 11. Another difference is that the resilient member 35d has a bend portion 69 distally of the distal end 23d of the endoscope body 13d so as to deflect the resilient member to bring the longitudinal axes of the resilient member closer together and to bring the distal tip portion 41d more into alignment with the axis of the endoscope body. In this embodiment, this deflection is sufficient so as to make the distal tip portion 41d almost directly in front of the endoscope body 13d. Of course, the degree of bending at the bend portion 69 can be varied as desired.
FIG. 11 shows an endoscope 11e which may be identical to the endoscope 11 in all respects not shown or described herein. Portions of the endoscope 11e corresponding to portions of the endoscope 11 are designated by corresponding reference numerals followed by the letter "e". A primary difference between the endoscopes 11 and 11e is that the latter includes a clip-on assembly 73 in the form of two snap-on clamps 75 and 77 for enabling the resilient member 35e to be clipped onto, and unclipped from, the exterior of the endoscope body 13e. The clamps 75 and 77 are resilient and extend more than half way around the endoscope body 13e. The embodiment of FIG. 11 enables a conventional endoscope to be converted so as to embody the features of this invention. The clamps 75 and 77 fixedly attach the resilient member 35e to the endoscope body 13e.
FIG. 12 shows an endoscope 11f which is identical to the endoscope 11 in all respects not shown or described herein. Portions of the endoscope 11f corresponding to portions of endoscope 11 are designated corresponding reference numerals followed by the letter "f". The primary difference between the endoscopes 11 and 11f is that in the endoscope 11f, the resilient member 35f is mounted on the endoscope body 13f for generally longitudinal movement relative to the endoscope body. In this embodiment, the resilient member 35f is slidably received in the endoscope lumen 37f and the endoscope includes a controller in the form of a control slide 81 mounted on the endoscope body for moving the resilient member longitudinally in the endoscope lumen. The endoscope lumen 37f opens at the distal end 23f of the endoscope body 13f. The control slide 81 is mounted for sliding movement in a slot 83 in the endoscope body 13f. The proximal end portion of the resilient member 35f is bent to form a tab 85 which is received in, and attached to, the control slide 81. The resilient member 35f can be moved longitudinally relative to the endoscope body 13f by moving the control slide 81 back and forth in the slot 83.
All of the embodiments of the invention can be used in the same manner as described above in connection with FIG. 3 for the endoscope 11. In addition, with the endoscope 11f, the resilient member 35f can be moved longitudinally relative to the endoscope body 13f during longitudinal movement of the endoscope body 13f or while the endoscope body is stationary to bring about relative displacement between the resilient member and any material, such as the wall 57 (FIG. 3), which is to be engaged and moved relative to the end portion 23f of the endoscope body. For example, the endoscope body 13f could be allowed to remain stationary in the fallopian tube 49 while the resilient member 35f is moved back and forth until a desired view of the interior of the fallopian tube is obtained.
Although the invention has been described with reference to an endoscope for medical use and particularly an endoscope for viewing of the fallopian tube, the features of this invention are applicable to industrial uses such as the viewing of passages of machinery and equipment.
An optional feature of the invention which is applicable to all of the embodiments described above is to construct the elongated member 35 (FIG. 1) of a nickel-titanium alloy which has a transition temperature such that the resilient member is more easily deflected below the transition temperature than above the transition temperature. For example, below the transition temperature with the elongated member in an austenitic state, it would be soft, malleable and somewhat non-resilient. Above the transition temperature in the martenistic state, the resilient member 35 is resilient. The transition temperature may be slightly less than the temperature of the interior of the human body. Consequently, when the endoscope 11 is transvaginally introduced into the fallopian tube 49, the resilient member 35 is below the transition temperature as a result of being within the everting catheter 53 and therefore insulated from the patient's body. However, by advancing the endoscope, and in particular the resilient member 35 distally so as to place the resilient member in the fallopian tube outside of the everting catheter 53, it will be heated by the patient's body to above the transition temperature and assume its desired resilient state for use in viewing, and if desired movement through, the fallopian tube.
Although exemplary embodiments of the invention have been shown and described, many changes, modifications and substitutions may be made by one having ordinary skill in the art without necessarily departing from the spirit and scope of this invention. | An endoscope including an elongated endoscope body sized and adapted for insertion into a passage, such as a passage of the body of a patient. Optical components are carried by the endoscope body to enable viewing of the passage distally of the distal end of the endoscope body within a field of view of the endoscope. An elongated, resilient member is mounted on and carried by the endoscope body such that the endoscope body and the resilient member are a unitary assembly which can be inserted as a unit into the passage. The resilient member extends beyond the distal end of the endoscope body and is capable of contacting material within or forming the passage and relatively displacing the distal end of the endoscope body and such material within the field of view of the endoscope to enhance viewing of the passage with the endoscope. | 0 |
BACKGROUND
[0001] The present invention relates to a method for the determination of the CaCO 3 content of a scrubbing liquid, which has been separated from a scrubbing liquid circuit of a scrubbing column.
DISCUSSION
[0002] Scrubbing columns of the above mentioned type serve for flue gas purification, for example for purifying flue gases from a coal power station or the like. Normally they comprise a scrubbing column having scrubbing liquid nozzles, which are often arranged on several levels, a scrubbing liquid sump, in which scrubbing liquid is collected, and an absorption zone, which extends inside a cylindric receptacle of the scrubbing column from the scrubbing liquid sump towards the upper scrubbing liquid nozzle level. Flue gas is introduced into a lower section of the absorption zone in the scrubbing column, flows upwards from there and leaves the scrubbing column through an outlet provided above the scrubbing liquid nozzles. On its way through the scrubbing column, the flue gas gets into contact with scrubbing liquid emerging from the scrubbing liquid nozzles and is purified, which is described in the following.
[0003] The scrubbing liquid preferably contains, apart from water, alkaline earths, which react with the sulphur oxides present in the flue gas and the sulphur oxides generated in the scrubbing column. Lime in form of calcium oxide, calcium hydroxide, calcium carbonate or the like is in particular used.
[0004] The alkaline earths react with the sulphur oxides present in the flue gas essentially to calcium sulphite, which is bound in the scrubbing liquid. In this manner, the flue gas is purified from the undesirable sulphur oxides and flows out of the purification device afterwards. However, the scrubbing liquid containing the calcium sulphite particles, which are kept floating in this one, flows into the scrubbing liquid sump and is collected there.
[0005] Calcium sulphate, which is generated during the flue gas desulfurization, has similar positive properties as natural gypsum. It is thus a desired by-product of the flue gas purification process, which is won from the scrubbing liquid collected in the scrubbing liquid sump. The calcium sulphate particles are removed together with the scrubbing liquid from the scrubbing liquid sump and are then extracted from the scrubbing liquid in a subsequent process. The calcium sulphate can then be further processed to materials, in particular construction materials.
[0006] For winning calcium sulphate of good quality it has to be taken care that as few alkaline earths as possible are contained in the scrubbing liquid collected in the scrubbing liquid sump, when the scrubbing liquid is removed from the scrubbing liquid sump for winning calcium sulphate.
[0007] On the other hand, it has to be assured that enough alkaline earths are present in the scrubbing liquid, in order to provoke a sufficient reaction in the absorption zone of the scrubbing column.
[0008] For determining the exact concentration of alkaline earths in the scrubbing liquid, it is known to determine the CaCO 3 content of the scrubbing liquid.
[0009] DE-A-19733284 describes a method for measuring the CaCO 3 content of a scrubbing suspension, in particular from the absorber of a flue gas purification device, in which a predetermined constant measuring stream in the bypass is continuously supplied to a pH measuring device and the pH value of the suspension is measured. Herein, the measuring stream is inoculated with an acid at an inoculation point in front of the pH measuring device in temporal intervals and the change of the pH value, which results from the inoculation with the acid, is measured. The CaCO 3 content of the suspension is afterwards determined from the difference of the measured pH values by comparison with data from reference measurements, which have been made in consideration of the residence time of the suspension for the flowing distance between the inoculation point and the pH measuring device. Decisive for the precision of the method is the fact that a certain acid volume is added to the predetermined suspension volume at the inoculation point and both volumes are sufficiently mixed with each other on their way to the pH measuring device, such that a correct measurement of the pH value can be carried out at the pH measuring device. In particular the precise dosage of the suspension and acid volume requires a high effort and can easily lead to inaccuracies, which then also have an effect on the accuracy of the measured pH value. A supervision of a correct dosage is also difficult to realize with this method. As a result, the method has some sources of error, which can adversely affect the reliability thereof.
[0010] DE-A-3809379 describes a method for the determination of the carbonate content of a partially used lime stone suspension, which continuously circulates in a flue gas purification device, for regulating the addition of fresh lime stone powder. Herein, a constant subset of the lime stone suspension is respectively extracted from a branch piping, which subset is separated from the circuit for measuring purposes. Acid is then added to this subset. Finally, the volume of the generated CO 2 is measured at constant temperature and under constant pressure and the value is used for the addition of fresh lime stone powder. Strictly speaking, in this method the gas quantity from the increase of pressure in a gas tight measuring cell and of the temperature in the measuring cell is measured in consideration of the change of volume caused by the addition of acid, and based upon this gas quantity, the carbonate content of the lime stone suspension is determined. In comparison to DE-A-19733284, this is thus an alternative method for the determination of the carbonate content.
OBJECTS AND SUMMARY OF THE INVENTION
[0011] It is an object of the present invention to provide an improved or alternative method for the determination of the CaCO 3 content of a scrubbing liquid, which has been separated from a scrubbing liquid circuit of a scrubbing column as well as a corresponding device.
[0012] In the method according to the present invention, a predetermined test volume of scrubbing liquid is at first separated from a continuously available scrubbing liquid volume flow. The test volume is then supplied to a measuring cell, in the same way as a previously dosed, predetermined HCl volume. Both volumes are mixed with each other and react with each other afterwards within a predetermined reaction time. Finally, the pH value of the so produced mixture is measured and the CaCO 3 content is determined based upon the change of the pH value.
[0013] In comparison to DE-3809379, the method according to the invention is an alternative method for the determination of the CaCO 3 content, in which not the volume of the generated CO 2 is measured at constant temperature and under constant pressure, but the pH value of the mixture of scrubbing liquid and HCl, which is present in the measuring cell, is detected.
[0014] In contrast to DE-A-19733284, scrubbing liquid and acid are not mixed in a pipe and then the pH value is measured, but a predetermined test volume of scrubbing liquid is separated from a continuously available scrubbing liquid volume flow and supplied, together with a dosed, predetermined HCl volume, to a measuring cell, both volumes are mixed and finally, after a predetermined reaction time, the pH value is measured. In comparison to DE-A-19733284, the method according to the invention has the advantage that it can be assured that both the scrubbing liquid test volume and the HCl volume can be precisely dosed. A correct mixing of both volumes can also be assured. Accordingly, the pH value determined by means of the method according to the invention is more accurate. Furthermore, the scrubbing liquid volume flow, the test volume in the measuring cell and the dosed HCl volume can for example be supervised by simple means and thus the plausibility of the pH measurement, which has been carried out by means of the method, can be verified, if this is desired.
[0015] According to a preferred variant of the method according to the present invention, the separation of the predetermined scrubbing liquid test volume is carried out by means of a sampling trap, which can be realized by relatively simple means, and the determination of the CaCO 3 content is carried out by means of a pH probe.
[0016] The scrubbing liquid volume flow, from which the predetermined scrubbing liquid volume is separated, is preferably a separately produced scrubbing liquid volume flow. This means that a separate scrubbing liquid circuit and thus a separate scrubbing liquid volume flow is generated for example by means of a closed circular pipeline, which is exclusively used for the measurement of the pH value. This has the advantage that the operation of the closed circular pipeline is independent from foreign pre-pressures, such that a self-supporting, stable circuit can be achieved by the design of the closed circular pipeline and the pump provided in this one. Such an extraction from the absorber and the operation of the closed circular pipeline with a separate pump have proved successful in many installations for realizing pH and density/solids measurements due to their operational reliability. However, the disadvantage of these designs is the higher investment costs for the additional arrangement of these closed circular pipelines.
[0017] It is to be understood that the scrubbing liquid test volume can of course also be extracted from a pipe with pressure inside, e.g. from the pipe, which leads from the scrubbing liquid sump to the scrubbing liquid nozzles. However, an independent pipe for carrying out the CaCO 3 measurement is preferred.
[0018] According to another advantageous embodiment of the method according to the invention, the scrubbing liquid test volume and/or the dosed HCl volume can be modified.
[0019] Furthermore, it is advantageous if the measuring equipment, which is used for the measuring cell, is regularly calibrated, in order to be able to always assure the required accuracy of the CaCO 3 measurement. The calibration is advantageously carried out by wet analytical comparison measurements.
[0020] Furthermore, at least the measuring cell and the sampling trap as well as the associated pipes are cleaned in regular time intervals, in order to correspondingly prevent deposits of solid matters.
[0021] Finally it is preferred according to the method of the invention that the plausibility of the pH measurement is verified by means of supervision of the scrubbing liquid volume flow, the test volume in the measuring cell and the dosed HCl volume, in order to assure a correct functioning of the method.
[0022] The device according to the invention for the determination of the CaCO 3 content of a scrubbing liquid comprises a closed circular pipeline, a pump, which is actively connected to the closed circular pipeline, a sampling trap provided in said closed circular pipeline for separating a scrubbing liquid sample and a measuring cell, which is connected to the sampling trap and which has a measuring equipment for determining the pH value of a scrubbing liquid sample.
[0023] Herein, the measuring equipment advantageously comprises an HCl dosage device and a pH probe for the determination of the pH value.
[0024] Furthermore, a rinsing device and/or an aerating are preferably provided.
[0025] The sampling trap advantageously comprises a by-pass, via which the scrubbing liquid is by-passed by means of the sampling trap during the separation of the scrubbing liquid test volume, in order to not interrupt the scrubbing liquid volume flow in the closed circular pipeline, such that this one is continuously available.
BRIEF DESCRIPTION OF THE DRAWING
[0026] In the following, a preferred embodiment of the present invention is described in detail with reference to the annexed FIG. 1 which shows a schematic view of an embodiment of the device according to the invention for the determination of the CaCO 3 content of a scrubbing liquid.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0027] The represented device comprises a closed circular pipeline 10 , through which scrubbing liquid is pumped by means of a pump 12 from a scrubbing liquid sump 14 of a scrubbing column 16 , which is only partially represented in the drawing. Herein, the scrubbing liquid, which has been extracted from said scrubbing liquid sump 14 , is returned to said scrubbing liquid sump 14 after flowing through the closed circular pipeline 10 , as it is indicated by the arrows A and B. The closed circular pipeline 10 further comprises stop valves 18 and 20 , which alternatively allow or prevent a passage of scrubbing liquid.
[0028] Downstream of said pump 12 , a sampling trap 22 is arranged in the closed circular pipeline, which sampling trap permits to separate a predetermined scrubbing liquid test volume from said closed circular pipeline. The sampling trap 22 is connected via a pipe 24 to a measuring cell 26 , which can be supplied with a scrubbing liquid test volume separated in said sampling trap 22 . Furthermore, pipe 28 , which can be opened and closed by means of the stop valve 28 a , allows the introduction of an HCl volume into said measuring cell 26 , wherein the HCl acid is taken from an HCl store tank 30 and the HCl volume, which shall be supplied to said measuring cell, is dosed in a dosage device 32 . Said measuring cell 26 further comprises an agitator 36 driven by a motor 34 , by means of which the scrubbing liquid and HCl volumes supplied to said measuring cell 26 can be mixed. After mixing both volumes, the pH value of the mixture can be determined by means of a pH probe 38 . By opening a stop valve 42 provided in a pipe 40 , the mixture can be evacuated from the measuring cell after determination of the pH value thereof.
[0029] For by-passing the sampling trap 22 , said closed circular pipeline 10 comprises a by-pass 44 having a stop valve 46 .
[0030] For cleaning said closed circular pipeline 10 , a rinse water pipe 48 having a stop valve 50 is further provided. If said valve 50 is opened, the rinse water can enter in the direction of pump 12 into said closed circular pipeline 10 .
[0031] Finally, a connecting branch 52 is placed at the sampling point 22 , which connecting branch comprises three inlets with corresponding stop valves 52 a , 52 b and 52 c . By opening the corresponding stop valves 52 a or 52 b , rinse water can be introduced via pipe 54 or alternatively compressed air can be introduced via pipe 56 into said connecting branch 52 and with opened stop valve 22 b into said sampling trap 22 . By opening stop valve 52 c , an aerating can be realized via pipe 58 . A corresponding aeration pipe 60 having a stop valve 62 and a rinse water inlet pipe 64 having a stop valve 66 are connected to said measuring cell 26 .
[0032] The operation of the device represented in FIG. 1 will be described in detail in the following.
[0033] In the initial position, all valves 18 , 20 , 22 a through 22 d , 42 , 46 , 50 , 52 a through 52 c , 62 and 66 are closed. For starting the represented device, the sop valves 18 , 20 , 22 a and 22 c are opened and pump 12 is switched on. Then, scrubbing liquid is pumped by means of said pump 12 from said scrubbing liquid sump 14 of scrubbing column 16 into said closed circular pipeline 10 through said sampling trap 22 back into said scrubbing liquid sump 14 .
[0034] If a predetermined scrubbing liquid volume shall be evacuated from said closed circular pipeline 10 by means of said sampling trap 22 , stop valve 22 c of said sampling trap 22 is at first closed.
[0035] In this way, a predetermined scrubbing liquid volume is dammed up in said sampling trap 22 and is enclosed in this one by closing stop valve 22 a of sampling trap 22 . When stop valve 22 a of said sampling trap 22 is closed, stop valve 46 of by-pass 44 is simultaneously opened, such that the scrubbing liquid no longer flows through said sampling trap 22 , but through by-pass 44 back into said scrubbing liquid sump 14 . The predetermined scrubbing liquid volume, which is contained in said sampling trap 22 , is guided via pipe 24 into measuring cell 26 by opening said stop valve 22 d and 52 c of said sampling trap 22 . An HCl volume, which is adapted to the scrubbing liquid volume, which has been introduced into said measuring cell 26 , is dosed in the dosage device 32 and is guided via pipe 28 into said measuring cell 26 by opening stop valve 28 a . Agitator 36 , which is driven by means of motor 34 , mixes the scrubbing liquid volume with the HCl volume in said measuring cell 26 . After a predetermined reaction time, the pH value of the mixture, which is present in said measuring cell 26 , is determined by means of pH probe 38 . As soon as the pH value has been determined, the mixture can be evacuated via pipe 40 by opening stop valve 42 .
[0036] For taking the next sample by means of said sampling trap 22 , said stop valves 22 d and 46 have to be closed again and said stop valve 22 a has to be opened again, such that scrubbing liquid flows again into the sampling trap.
[0037] If said closed circular pipeline 10 and said by-pass 44 shall be cleaned, valves 22 a and 22 c of said sampling trap 22 have to be closed and valve 46 has to be opened. Then, rinse water can flow through rinse water pipe 48 through the corresponding components and afterwards through the opened stop valve 20 back into said scrubbing column 16 . It is also possible to rinse said sampling trap 22 and the connecting pipes thereof and said closed circular pipeline 10 with closed valves 46 , 22 b and 22 d as well as opened valves 50 , 22 a , 22 c and 20 .
[0038] For the individual cleaning of said sampling trap 22 , valves 22 a and 22 c thereof have to be closed and valves 22 b and 22 d thereof have to be open. By opening valve 52 a , rinse water can flow from pipe 54 through connecting branch 52 into said sampling trap 22 and rinse this one. Form there, it flows through pipe 24 into said measuring cell 26 , then it flows out via pipe 40 by opening stop valve 42 .
[0039] The measuring cell itself can be filled with rinse water via pipe 64 by opening valve 66 . After rinsing, the water also flows out via valve 42 and pipe 40 .
[0040] It is to be understood that the represented device according to the invention is only an example and other modifications and changes are possible without leaving the protected scope of the present invention, which is defined by the annexed claims. | The present invention relates to a method for the determination of the CaCO 3 , content of a scrubbing liquid, which has been separated from a scrubbing liquid circuit of a scrubbing column. | 1 |
BACKGROUND OF THE INENTION
[0001] Diabetes mellitus is a major cause of morbidity and mortality. Chronically elevated blood glucose leads to debilitating complications: nephropathy, often necessitating dialysis or renal transplant; peripheral neuropathy; retinopathy leading to blindness; ulceration of the legs and feet, leading to amputation; fatty liver disease, sometimes progressing to cirrhosis; and vulnerability to coronary artery disease and myocardial infarction.
[0002] There are two primary types of diabetes. Type I, or insulin-dependent diabetes mellitus (IDDM) is due to autoimmune destruction of insulin-producing beta cells in the pancreatic islets. The onset of this disease is usually in childhood or adolescence. Treatment consists primarily of multiple daily injections of insulin, combined with frequent testing of blood glucose levels to guide adjustment of insulin doses, because excess insulin can cause hypoglycemia and consequent impairment of brain and other functions. Type II, or noninsulin-dependent diabetes mellitus (NIDDM) typically develops in adulthood. NIDDM is associated with resistance of glucose-utilizing tissues like adipose tissue, muscle, and liver, to the actions of insulin. Initially, the pancreatic islet beta cells compensate by secreting excess insulin. Eventual islet failure results in decompensation and chronic hyperglycemia. Conversely, moderate islet insufficiency can precede or coincide with peripheral insulin resistance. There are several classes of drugs that are useful for treatment of NIDDM: 1) insulin releasers, which directly stimulate insulin release, carrying the risk of hypoglycemia; 2) prandial insulin releasers, which potentiate glucose-induced insulin secretion, and must be taken before each meal; 3) biguanides, including metformin, which attenuate hepatic gluconeogenesis (which is paradoxically elevated in diabetes); 4) insulin sensitizers, for example the thiazolidinedione derivatives rosiglitazone and pioglitazone, which improve peripheral responsiveness to insulin, but which have side effects like weight gain, edema, and occasional liver toxicity; 5) insulin injections, which are often necessary in the later stages of NIDDM when the islets have failed under chronic hyperstimulation. Insulin resistance can also occur without marked hyperglycemia, and is generally associated with atherosclerosis, obesity, hyperlipidemia, and essential hypertension. This cluster of abnormalities constitutes the “metabolic syndrome” or “insulin resistance syndrome”. Insulin resistance is also associated with fatty liver, which can progress to chronic inflammation (NASH; “nonalcoholic steatohepatitis”), fibrosis, and cirrhosis. Cumulatively, insulin resistance syndromes, including but not limited to diabetes, underlie many of the major causes of morbidity and death of people over age 40.
[0003] Despite the existence of such drugs, diabetes remains a major and growing public health problem. Late stage complications of diabetes consume a large proportion of national health care resources. There is a need for new orally active therapeutic agents which effectively address the primary defects of insulin resistance and islet failure with fewer or milder side effects than existing drugs.
[0004] Currently there are no safe and effective treatments for fatty liver disease. Therefore such a treatment would be of value in treating this condition.
[0005] WO 02/100341 (Wellstat Therapeutics Corp.) discloses 4-[3-(2,6-Dimethylbenzyloxy)phenyl)-3-butenoic acid. WO 02/100341 does not disclose any compounds within the scope of Formula I shown below, in which m is 2 or 3.
SUMMARY OF THE INVENTION
[0006] This invention provides a biologically active agent as described below. This invention provides the use of the biologically active agent described below in the manufacture of a medicament for the treatment of insulin resistance syndrome, diabetes, cachexia, hyperlipidemia, fatty liver disease, obesity, atherosclerosis or arteriosclerosis. This invention provides methods of treating a mammalian subject with insulin resistance syndrome, diabetes, cachexia, hyperlipidemia, fatty liver disease, obesity, atherosclerosis or arteriosclerosis comprising administering to the subject an effective amount of the biologically active agent described below. This invention provides a pharmaceutical composition comprising the biologically active agent described below and a pharmaceutically acceptable carrier.
[0007] The biologically active agent in accordance with this invention is a compound of Formula I:
wherein n is 1 or 2; m is 2 or 3; q is 0 or 1; t is 0 or 1; R 2 is alkyl having from 1 to 3 carbon atoms; R 3 is hydrogen, halo, alkyl having from 1 to 3 carbon atoms, or alkoxy having from 1 to 3 carbon atoms;
A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from: halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or cycloalkyl having from 3 to 6 ring carbon atoms wherein the cycloalkyl is unsubstituted or one or two ring carbons are independently mono-substituted by methyl or ethyl; or a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and O and the heteroaromatic ring is covalently bound to the remainder of the compound of formula I by a ring carbon; and R 1 is hydrogen or alkyl having 1 or 2 carbon atoms. Alternatively, when R 1 is hydrogen, the biologically active agent can be a pharmaceutically acceptable salt of the compound of Formula I.
[0008] The biologically active agents described above have activity in one or more of the biological activity assays described below, which are established animal models of human diabetes and insulin resistance syndrome. Therefore such agents would be useful in the treatment of diabetes and insulin resistance syndrome. All of the exemplified compounds that were tested demonstrated activity in at least one of the biological activity assays in which they were tested.
DETAILED DESCRIPTION OF THE INVENTION
[0000] Definitions
[0009] As used herein the term “alkyl” means a linear or branched-chain alkyl group. An alkyl group identified as having a certain number of carbon atoms means any alkyl group having the specified number of carbons. For example, an alkyl having three carbon atoms can be propyl or isopropyl; and alkyl having four carbon atoms can be n-butyl, 1-methylpropyl, 2-methylpropyl or t-butyl.
[0010] As used herein the term “halo” refers to one or more of fluoro, chloro, bromo, and iodo.
[0011] As used herein the term “perfluoro” as in perfluoromethyl or perfluoromethoxy, means that the group in question has fluorine atoms in place of all of the hydrogen atoms.
[0012] As used herein “Ac” refers to the group CH 3 C(O)—.
[0013] Certain chemical compounds are referred to herein by their chemical name or by the two-letter code shown below. Compounds CO and CP are included within the scope of Formula I shown above.
CO 5-[3-(2,6-Dimethylbenzyloxy)-phenyl]-pent-4-enoic acid ethyl ester CP 6-[3-(2,6-Dimethylbenzyloxy)-phenyl]-hex-5-enoic acid ethyl ester
[0016] As used herein the transitional term “comprising” is open-ended. A claim utilizing this term can contain elements in addition to those recited in such claim.
[0000] Compounds of the Invention
[0017] In an embodiment of the agent, use, method or pharmaceutical composition described above, n is 1; q is 0; t is 0; R 3 is hydrogen; and A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from: halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy. In a more specific embodiment, A is 2,6-dimethylphenyl. Examples of such compounds include Compounds CO and CP.
[0018] In a preferred embodiment of the biologically active agent of this invention, the agent is in substantially (at least 98%) pure form.
[0000] Reaction Schemes
[0019] The biologically active agents of the present invention can be made in accordance with the following reaction schemes.
[0020] The compound of formula I where m is 2 or 3, q is 0, t is 0 or 1, and n is 1 or 2, R 3 is hydrogen, halo, alkoxy having from 1 to 3 carbon atoms or alkyl having from 1 to 3 carbon atoms, and R 1 is hydrogen or alkyl having from 1 to 2 carbon atoms, i.e. compounds of formula:
wherein A is described as above, can be prepared via reaction of scheme 1.
[0021] In the reaction scheme of Scheme 1, A, t, n, and R 3 are as above. R 4 is alkyl group having from 1 to 2 carbon atoms, p is 3 or 4, and s is 2 or 3. Y is a halide or leaving group. The compound of formula II is converted to the compound of formula V via reaction of step (a) by Mitsunobu condensation of II with III using triphenylphosphine and diethyl azodicarboxylate or diisopropyl azodicarboxylate. The reaction is carried out in a suitable solvent for example tetrahydrofuran. Any of the conditions conventionally used in Mitsunobu reactions can be utilized to carry out the reaction of step (a).
[0022] The compound of formula V can also be prepared by etherifying or alkylating the compound of formula II with a compound of formula IV via the reaction of step (b) by using suitable base such as potassium carbonate, sodium hydride, triethylamine, pyridine and the like. In the compound of formula IV, Y, include but are not limited to mesyloxy, tosyloxy, chloro, bromo, iodo, and the like. Any conventional conditions to alkylate a hydroxyl group with a halide or leaving group can be utilized to carry out the reaction of step (b). The reaction of step (b) is preferred over step (a) if compound of formula IV is readily available.
[0023] The compound of formula V is converted to the compound of formula VII via reaction of step (c) using Wittig reaction by treating the compound of formula V with the compound of formula VI. Any conventional method of reacting an aldehyde with a triarylphosphine hydrohalide can be utilized to carry out the reaction of step (c). Any of the conditions conventional in Wittig reactions can be utilized to carry out the reaction of step (c). The product can be isolated and purified by techniques such as extraction, evaporation, chromatography, and recrystallization.
[0024] The compound of formula VII is the compound of formula I where R 1 is alkyl having from 1 to 2 carbon atoms.
[0025] The compound of formula VII can be converted to compound of formula VIII via reaction of step (d) by ester hydrolysis. Any conventional method of ester hydrolysis will produce the compound of formula I where R 1 is H.
[0026] The compound of formula I where m is 2 or 3, q is 1, t is 0 or 1, and n is 1 or 2, R 3 is hydrogen, halo, alkoxy having from 1 to 3 carbon atoms or alkyl having from 1 to 3 carbon atoms, and R 1 is hydrogen or alkyl having from 1 to 2 carbon atoms, i.e. compounds of formula:
wherein A is described as above, can be prepared via reaction of scheme 2.
[0027] In the reaction scheme of Scheme 2, A, t, n, R 3 and R 2 are as above. R 4 is alkyl group having from 1 to 2 carbon atoms, p is 3 or 4, s is 2 or 3 and Y is chloro or bromo.
[0028] The compound of formula IX can be mesylated to furnish the compound of formula X via reaction of step (e). Any conventional conditions to carry out the mesylation reaction of a hydroxyl group can be utilized to carry out the step (e). The compound of formula X is then heated with the compound of formula XI to produce the compound of formula XII. Any of the conditions conventional to produce amino alcohol can be utilized to carry out the reaction of step (f).
[0029] In the compound of formula XII, alcohol can be displaced by chloro or bromo by treating the compound of formula XII with thionyl chloride, bromine, phosphorus tribromide or the like to produce the compound of formula XIII. Any conventional method to displace alcohol with chloro or bromo can be utilized to carry out the reaction of step (g).
[0030] The compound of formula XIII can be reacted with the compound of formula II via reaction of step (h) in the presence of a suitable base such as potassium carbonate, sodium hydride, triethylamine and the like. The reaction is carried out in conventional solvents such as dimethylformamide, tetrahydrofuran and the like to produce the corresponding compound of formula XIV. Any conventional method of etherification of a hydroxyl group in the presence of base (preferred base being potassium carbonate) can be utilized to carry out the reaction of step (h).
[0031] The compound of formula XIV can be converted to the compound of formula XV via reaction of step (i) using Wittig reaction by treating the compound of formula XIV with the compound of formula VI. Any conventional method of reacting an aldehyde with triarylphosphine hydrohalide can be utilized to carry out the reaction of step (i). Any of the conditions conventional in Wittig reactions can be used to carry out the reaction of step (i). The product can be isolated and purified by techniques such as extraction, evaporation, chromatography, and recrystallization.
[0032] The compound of formula XV is the compound of formula I where R 1 is alkyl having from 1 to 2 carbon atoms.
[0033] The compound of formula XV can be converted to compound of formula XVI via reaction of step (j) by ester hydrolysis. Any conventional method of ester hydrolysis will produce the compound of formula I where R 1 is H.
[0034] The compound of formula II where R 3 is hydrogen, halo, alkoxy having from 1 to 3 carbon atoms or alkyl having from 1 to 3 carbon atoms, i.e. compounds of formula:
can be prepared via reaction of scheme 3.
[0035] In the reaction scheme of Scheme 3, R 4 is alkyl group having from 1 to 2 carbon atoms, and P is a protecting group.
[0036] The compound of formula XVII can be converted to the compound of formula XVIII via the reaction of step (k) by protecting the hydroxy group and then deprotecting the ester group by utilizing suitable protecting and deprotecting groups such as those described in Protecting Groups in Organic Synthesis by T. Greene.
[0037] The compound of formula XVIII can be converted to the compound of formula XIX via reaction of step (l) by reducing acid to alcohol. The reaction can be carried out utilizing a conventional reducing agent for example alkali metal hydride such as lithium aluminum hydride. The reaction can be carried out in a suitable solvent, such as tetrahydrofuran. Any of the conditions conventional in such reduction reactions can be utilized to carry out the reaction of step (l).
[0038] The compound of formula XIX can be converted to the compound of formula XX via reaction of step (m) by oxidation of alcohol to the aldehyde. The reaction can be carried out utilizing a suitable oxidizing agent for example pyridinium chlorochromate, dimethyl sulfoxide activated by 2,4,6-trichloro[1,3,5]-triazine (cyanuric chloride, TCT) under Swern oxidation conditions (J.O.C. 2001, 66, 7907-7909) and the like. Any of the conditions conventional in such oxidation reactions can be utilized to carry out the reaction of step (m). In the compound of formula XX, the hydroxy group can be deprotected via reaction of step (n) by utilizing suitable deprotecting reagents such as those described in Protecting Groups in Organic Synthesis by T. Greene to give the compound of formula II.
[0039] The compound of formula VI, where R 4 is alkyl group having from 1 to 2 carbon atoms and p is 3 or 4, i.e. compounds of formula:
Ph 3 P + —(CH 2 ) p CO 2 R 4 }Br −
can be prepared via reaction of scheme 4.
[0040] In the reaction scheme of Scheme 4, R 4 and p are as above.
[0041] The compound of formula XXI is reacted with the compound of formula XXII via the reaction of step (o) to give compound of formula VI. Any of the conditions conventionally used in reacting triphenylphosphine with hydrohalide can be utilized to carry out the reaction of step (o).
[0042] The compound of formula III where t is 0 or 1, n is 1 or 2, i.e. compounds of formula:
A(CH 2 ) t+n —OH
wherein A is described as above, can be prepared via reaction of scheme 5.
[0043] In the reaction of Scheme 5, A is described as above and Y is a leaving group.
[0044] The compound of formula XXIII can be reduced to the compound of formula XXIV via reaction of step (p). The reaction is carried out utilizing a conventional reducing agent for example alkali metal hydride such as lithium aluminum hydride. The reaction is carried out in a suitable solvent, such as tetrahydrofuran. Any of the conditions conventional in such reduction reactions can be utilized to carry out the reaction of step (p).
[0045] The compound of formula XXIV is the compound of formula III where t is 0 and n is 1.
[0046] The compound of formula XXIV can be converted to the compound of formula XXV by displacing hydroxyl group with a halogen group preferred halogen being bromo or chloro. Appropriate halogenating reagents include but are not limited to thionyl chloride, bromine, phosphorous tribromide, carbon tetrabromide and the like. Any conditions conventional in such halogenation reactions can be utilized to carry out the reaction of step (q).
[0047] The compound of formula XXV is the compound of formula IV where t is 0 and n is 1.
[0048] The compound of formula XXV can be converted to the compound of formula XXVI by reacting XXV with an alkali metal cyanide for example sodium or potassium cyanide. The reaction can be carried out in a suitable solvent, such as dimethyl sulfoxide. Any of the conditions conventionally used in the preparation of nitrites can be utilized to carry out the reaction of step (r).
[0049] The compound of formula XXVI can be converted to the compound of formula XXVII via reaction of step (s) by acid or base hydrolysis. In carrying out this reaction it is generally preferred to utilize basic hydrolysis, for example aqueous sodium hydroxide. Any of the conditions conventionally used in hydrolysis of nitrile can be utilized to carry out the reaction of step (s).
[0050] The compound of formula XXVII can be reduced to give the compound of formula XXVIII via reaction of step (t). This reaction can be carried out in the same manner as described hereinbefore in the reaction of step (p).
[0051] The compound of formula XXVIII is the compound of formula III where t is 1 and n is 1.
[0052] The compound of formula XXVIII can be converted to the compound of formula XXIX via reaction of step (u) in the same manner as described hereinbefore in connection with the reaction of step (q).
[0053] The compound of formula XXIX is the compound of formula IV where t is 1 and n is 1.
[0054] The compound of formula XXIX can be reacted with diethyl malonate utilizing a suitable base for example sodium hydride to give compound of formula XXX. The reaction is carried out in suitable solvents, such as dimethylformamide, tetrahydrofuran and the like. Any of the conditions conventional in such alkylation reactions can be utilized to carry out the reaction of step (v).
[0055] The compound of formula XXX can be hydrolyzed by acid or base to give compound of formula XXXI via reaction of step (w).
[0056] The compound of formula XXXI can be converted to the compound of formula XXXII via reaction of step (x) in the same manner as described hereinbefore in connection with the reaction of step (p).
[0057] The compound of formula XXXII is the compound of formula III where t is 1 and n is 2.
[0058] The compound of formula XXXII can be converted to the compound of formula XXXIII via reaction of step (y) in the same manner as described hereinbefore in connection with the reaction of step (q).
[0059] The compound of formula XXXIII is the compound of formula IV where t is 1 and n is 2.
[0060] The compound of formula XVII where R 4 is alkyl group having from 1 to 2 carbon atoms and R 3 is halo, alkoxy having from 1 to 3 carbon atoms or alkyl having from 1 to 3 carbon atoms, i.e. compounds of formula:
can be prepared via reaction of scheme 6.
[0061] In the reaction of Scheme 6, R 1 is H. R 3 and R 4 are as above.
[0062] The compound of formula XXXIV can be converted to the compound of formula XVII via reaction of step (z) by esterification of compound of formula XXXIV with methanol or ethanol. The reaction can be carried out either by using catalysts for example H 2 SO 4 , TsOH and the like or by using dehydrating agents for example dicyclohexylcarbodiimide and the like. Any of the conditions conventional in such esterification reactions can be utilized to carry out the reaction of step (z).
[0063] The compound of formula XXXIV where R 1 is H and R 3 is halo, i.e. compounds of formula:
are either commercially available or can be prepared according to the methods described in the literature as follows:
1. 3-Br or F-2-OHC 6 H 3 CO 2 H Canadian Journal of Chemistry (2001), 79(11) 1541-1545. 2. 4-Br-2-OHC 6 H 3 CO 2 H WO 9916747 or JP 04154773. 3. 2-Br-6-OHC 6 H 3 CO 2 H JP 47039101. 4. 2-Br-3-OHC 6 H 3 CO 2 H WO 9628423. 5. 4-Br-3-OHC 6 H 3 CO 2 H WO 2001002388. 6. 3-Br-5-OHC 6 H 3 CO 2 H Journal of labelled Compounds and Radiopharmaceuticals (1992), 31 (3), 175-82. 7. 2-Br-5-OHC 6 H 3 CO 2 H and 3-Cl-4-OHC 6 H 3 CO 2 H WO 9405153 and U.S. Pat. No. 5,519,133. 8. 2-Br-5-OHC 6 H 3 CO 2 H and 3-Br-4-OHC 6 H 3 CO 2 H WO 20022018323 9. 2-Cl-6-OHC 6 H 3 CO 2 H JP 06293700 10. 2-Cl-3-OHC 6 H 3 CO 2 H Proceedings of the Indiana Academy of Science (1983), Volume date 1982, 92, 145-51. 11. 3-Cl-5-OHC 6 H 3 CO 2 H WO 2002000633 and WO 2002044145. 12. 2-Cl-5-OHC 6 H 3 CO 2 H WO 9745400. 13. 5-I-2-OHC 6 H 3 CO 2 H and 3-I, 2-OHC 6 H 3 CO 2 H Z. Chem. (1976), 16(8), 319-320. 14. 4-I-2-OHC 6 H 3 CO 2 H Journal of Chemical Research, Synopses (1994), (11), 405. 15. 6-I-2-OHC 6 H 3 CO 2 H U.S. Pat. No. 4,932,999. 16. 2-I-3-OHC 6 H 3 CO 2 H and 4-I-3-OHC 6 H 3 CO 2 H WO 9912928. 17. 5-I-3-OHC 6 H 3 CO 2 H J. Med. Chem. (1973), 16(6), 684-7. 18. 2-I-4-OHC 6 H 3 CO 2 H Collection of Czechoslovak Chemical Communications, (1991), 56(2), 459-77. 19. 3-I-4-OHC 6 H 3 CO 2 , J.O.C. (1990), 55(18), 5287-91.
[0102] The compound of formula XXXIV, where R 1 is H and R 3 is alkoxy having from 1 to 3 carbon atoms, i.e. compounds of formula:
can be synthesized via the reaction of scheme 8.
[0103] In the reaction of Scheme 8, R 1 and R 3 are as above, and R 4 is alkyl group having from 1 to 2 carbon atoms.
[0104] The compound of formula XXXV can be converted to the compound of formula XXXVI by reducing the aldehyde to primary alcohol. In carrying out this reaction, it is preferred but not limited to use sodium borohydride as the reducing reagent. Any of the conditions suitable in such reduction reactions can be utilized to carry out the reaction of step (a′).
[0105] The compound of formula XXXVI can be converted to the compound of formula XXXVII via reaction of step (b′) by protecting 1-3 Diols by using 1,1,3,3-Tetraisopropyldisiloxane. The suitable conditions for this protecting group can be described in the Protecting Groups in Organic Synthesis by T. Greene.
[0106] The compound of formula XXXVII can be converted to the compound of formula XXXVIII via reaction of step (c′) by protecting the phenol group using benzyl bromide. The suitable conditions for this protecting group can be described in the Protecting Groups in Organic Synthesis by T. Greene.
[0107] The compound of formula XXXVIII can be converted to the compound of formula XXXIX by deprotection using tetrabutylammonium fluoride via reaction of step (d′). The suitable conditions for the deprotection can be described in the Protecting Groups in Organic Synthesis by T. Greene.
[0108] The compound of formula can be converted to compound of formula XL via reaction of step (e′) by oxidation. Any conventional oxidizing group that converts primary alcohol to an acid for example chromium oxide and the like can be utilized to carry out the reaction of step (e′).
[0109] The compound of formula XL can be converted to the compound of formula XLI by esterification of compound of formula XL with methanol or ethanol. The reaction can be carried out either by using catalysts for example H 2 SO 4 , TsOH and the like or by using dehydrating agents for example dicyclohexylcarbodiimide and the like. Any of the conditions conventional in such esterification reactions can be utilized to carry out the reaction of step (f′).
[0110] The compound of formula XLI can be converted to the compound of formula XLII by etherifying or alkylating the compound of formula XLI with methyl halide or ethyl halide or propyl halide by using suitable base for example potassium carbonate, sodium hydride and the like. The reaction is carried out in conventional solvents, such as tetrahydrofuran, dimethylformamide. The reaction is generally carried out at temperatures of from 0° C. to 40° C. Any of the conditions suitable in such alkylation reactions can be utilized to carry out the reaction of step (g′).
[0111] The compound of formula XLII can be converted to the compound of formula XLIII via reaction of step (h′) by deprotection of ester and benzyl groups. The suitable deprotecting reagents can be described in the Protecting Groups in Organic Synthesis by T. Greene.
[0112] The compound of formula XXXIV, where R 1 is H and R 3 is alkoxy having from 1 to 3 carbon atoms, i.e. compounds of formula:
are either commercially available or can be prepared according to the methods described in the literature as follows:
1. 2-OMe-4-OHC 6 H 3 CO 2 H US 2001034343 or WO 9725992. 2. 5-OMe-3-OHC 6 H 3 CO 2 H J.O.C (2001), 66(23), 7883-88. 3. 2-OMe-5-OHC 6 H 3 CO 2 H U.S. Pat. No. 6,194,406 (Page 96) and Journal of the American Chemical Society (1985), 107(8), 2571-3. 4. 3-OEt-5-OHC 6 H 3 CO 2 H Taiwan Kexue (1996), 49(1), 51-56. 5. 4-OEt-3-OHC 6 H 3 CO 2 H WO 9626176 6. 2-OEt-4-OHC 6 H 3 CO 2 H Takeda Kenkyusho Nempo (1965), 24,221-8. JP 07070025. 7. 3-OEt-4-OHC 6 H 3 CO 2 H WO 9626176. 8. 3-OPr-2-OHC 6 H 3 CO 2 H JP 07206658, DE 2749518. 9. 4-OPr-2-OHC 6 H 3 CO 2 H Parmacia (Bucharest) (1970), 18(8), 461-6. JP 08119959. 10. 2-OPr-5-OHC 6 H 3 CO 2 H and 2-OEt-5-OHC 6 H 3 CO 2 H Adapt synthesis from U.S. Pat. No. 6,194,406 (Page 96) by using propyl iodide and ethyl iodide. 11. 4-OPr-3-OHC 6 H 3 CO 2 H Adapt synthesis from WO 9626176 12. 2-OPr-4-OHC 6 H 3 CO 2 H Adapt synthesis from Takeda Kenkyusho Nempo (1965), 24,221-8 by using propyl halide. 13. 4-OEt-3-OHC 6 H 3 CO 2 H Biomedical Mass Spectrometry (1985), 12(4), 163-9. 14. 3-OPr-5-OHC 6 H 3 CO 2 H Adapt synthesis from Taiwan Kexue (1996), 49(1), 51-56 by using propyl halide.
[0143] The compound of formula XXXIV, where R 1 is H and R 3 is an alkyl having from 1 to 3 carbon atoms, i.e. compounds of formula:
are either commercially available or can be prepared according to the methods described in the literature as follows:
1. 5-Me-3-OHC 6 H 3 CO 2 H and 2-Me-5-OHC 6 H 3 CO 2 H WO 9619437. J.O.C. 2001, 66, 7883-88. 2. 2-Me-4-OHC 6 H 3 CO 2 H WO 8503701. 3. 3-Et-2-OHC 6 H 3 CO 2 H and 5-Et-2-OHC 6 H 3 CO 2 H J. Med. Chem. (1971), 14(3), 265. 4. 4-Et-2-OHC 6 H 3 CO 2 H Yaoxue Xuebao (1998), 33(1), 67-71. 5. 2-Et-6-OHC 6 H 3 CO 2 H and 2-n-Pr-6-OHC 6 H 3 CO 2 H J. Chem. Soc., Perkin Trans 1 (1979), (8), 2069-78. 6. 2-Et-3-OHC 6 H 3 CO 2 H JP 10087489 and WO 9628423. 7. 4-Et-3-OHC 6 H 3 CO 2 H J.O.C. 2001, 66, 7883-88. WO 9504046. 8. 2-Et-5-OHC 6 H 3 CO 2 H J.A.C.S (1974), 96(7), 2121-9. 9. 2-Et-4-OHC 6 H 3 CO 2 H and 3-Et-4-OHC 6 H 3 CO 2 H JP 04282345. 10. 3-n-Pr-2-OHC 6 H 3 CO 2 H J.O.C (1991), 56(14), 4525-29. 11. 4-n-Pr-2-OHC 6 H 3 CO 2 H EP 279630. 12. 5-n-Pr-2-OHC 6 H 3 CO 2 H J. Med. Chem (1981), 24(10), 1245-49. 13. 2-n-Pr-3-OHC 6 H 3 CO 2 H WO 9509843 and WO 9628423. 14. 4-n-Pr-3-OHC 6 H 3 CO 2 H WO 9504046. 15. 2-n-Pr-5-OHC 6 H 3 CO 2 H Synthesis can be adapted from J.A.C.S (1974), 96(7), 2121-9 by using ethyl alpha formylvalerate. 16. 3-n-Pr-4-OHC 6 H 3 CO 2 H Polymer (1991), 32(11) 2096-105. 17. 2-n-Pr-4-OHC 6 H 3 CO 2 H 3-Propylphenol can be methylated to 3-Propylanisole, which was then formylated to 4-Methoxy-3-benzaldehyde. The aldehyde can be oxidized by Jone's reagent to give corresponding acid and deprotection of methyl group by BBr 3 will give the title compound. 18. 1. 3-Et-5-OHC 6 H 3 CO 2 H and 3-Pr-n-5-OHC 6 H 3 CO 2 H Adapt synthesis from J.O.C. 2001, 66, 7883-88 by using 2-Ethylacrolein and 2-Propylacrolein.
Use in Methods of Treatment
[0182] This invention provides a method for treating a mammalian subject with a condition selected from the group consisting of insulin resistance syndrome and diabetes (both primary essential diabetes such as Type I Diabetes or Type II Diabetes and secondary nonessential diabetes), comprising administering to the subject an amount of a biologically active agent as described herein effective to treat the condition. In accordance with the method of this invention a symptom of diabetes or the chance of developing a symptom of diabetes, such as atherosclerosis, obesity, hypertension, hyperlipidemia, fatty liver disease, nephropathy, neuropathy, retinopathy, foot ulceration and cataracts, each such symptom being associated with diabetes, can be reduced. This invention also provides a method for treating hyperlipidemia comprising administering to the subject an amount of a biologically active agent as described herein effective to treat the condition. As shown in the Examples, compounds reduce serum triglycerides and free fatty acids in hyperlipidemic animals. This invention also provides a method for treating cachexia comprising administering to the subject an amount of a biologically active agent as described herein effective to treat the cachexia. This invention also provides a method for treating obesity comprising administering to the subject an amount of a biologically active agent as described herein effective to treat the condition. This invention also provides a method for treating a condition selected from atherosclerosis or arteriosclerosis comprising administering to the subject an amount of a biologically active agent as described herein effective to treat the condition. The active agents of this invention are effective to treat hyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosis or arteriosclerosis whether or not the subject has diabetes or insulin resistance syndrome. The agent can be administered by any conventional route of systemic administration. Preferably the agent is administered orally. Accordingly, it is preferred for the medicament to be formulated for oral administration. Other routes of administration that can be used in accordance with this invention include rectally, parenterally, by injection (e.g. intravenous, subcutaneous, intramuscular or intraperitioneal injection), or nasally.
[0183] Further embodiments of each of the uses and methods of treatment of this invention comprise administering any one of the embodiments of the biologically active agents described above. In the interest of avoiding unnecessary redundancy, each such agent and group of agents is not being repeated, but they are incorporated into this description of uses and methods of treatment as if they were repeated.
[0184] Many of the diseases or disorders that are addressed by the compounds of the invention fall into two broad categories: Insulin resistance syndromes and consequences of chronic hyperglycemia. Dysregulation of fuel metabolism, especially insulin resistance, which can occur in the absence of diabetes (persistent hyperglycemia) per se, is associated with a variety of symptoms, including hyperlipidemia, atherosclerosis, obesity, essential hypertension, fatty liver disease (NASH; nonalcoholic steatohepatitis), and, especially in the context of cancer or systemic inflammatory disease, cachexia. Cachexia can also occur in the context of Type I Diabetes or late-stage Type II Diabetes. By improving tissue fuel metabolism, active agents of the invention are useful for preventing or amelioriating diseases and symptoms associated with insulin resistance, as is demonstrated in animals in the Examples. While a cluster of signs and symptoms associated with insulin resistance may coexist in an individual patient, it many cases only one symptom may dominate, due to individual differences in vulnerability of the many physiological systems affected by insulin resistance. Nonetheless, since insulin resistance is a major contributor to many disease conditions, drugs which address this cellular and molecular defect are useful for prevention or amelioration of virtually any symptom in any organ system that may be due to, or exacerbated by, insulin resistance.
[0185] When insulin resistance and concurrent inadequate insulin production by pancreatic islets are sufficiently severe, chronic hyperglycemia occurs, defining the onset of Type II diabetes mellitus (NIDDM). In addition to the metabolic disorders related to insulin resistance indicated above, disease symptoms secondary to hyperglycemia also occur in patients with NIDDM. These include nephropathy, peripheral neuropathy, retinopathy, microvascular disease, ulceration of the extremities, and consequences of nonenzymatic glycosylation of proteins, e.g. damage to collagen and other connective tissues. Attenuation of hyperglycemia reduces the rate of onset and severity of these consequences of diabetes. Because, as is demonstrated in the Examples, active agents and compositions of the invention help to reduce hyperglycemia in diabetes, they are useful for prevention and amelioration of complications of chronic hyperglycemia.
[0186] Both human and non-human mammalian subjects can be treated in accordance with the treatment method of this invention. The optimal dose of a particular active agent of the invention for a particular subject can be determined in the clinical setting by a skilled clinician. In the case of oral administration to a human for treatment of disorders related to insulin resistance, diabetes, hyperlipidemia, fatty liver disease, cachexia or obesity the agent is generally administered in a daily dose of from 1 mg to 400 mg, administered once or twice per day. In the case of oral administration to a mouse the agent is generally administered in a daily dose from 1 to 300 mg of the agent per kilogram of body weight. Active agents of the invention are used as monotherapy in diabetes or insulin resistance syndrome, or in combination with one or more other drugs with utility in these types of diseases, e.g. insulin releasing agents, prandial insulin releasers, biguanides, or insulin itself. Such additional drugs are administered in accord with standard clinical practice. In some cases, agents of the invention will improve the efficacy of other classes of drugs, permitting lower (and therefore less toxic) doses of such agents to be administered to patients with satisfactory therapeutic results. Established safe and effective dose ranges in humans for representative compounds are: metformin 500 to 2550 mg/day; glyburide 1.25 to 20 mg/day; GLUCOVANCE (combined formulation of metformin and glyburide) 1.25 to 20 mg/day glyburide and 250 to 2000 mg/day metformin; atorvastatin 10 to 80 mg/day; lovastatin 10 to 80 mg/day; pravastatin 10 to 40 mg/day; and simvastatin 5-80 mg/day; clofibrate 2000 mg/day; gemfibrozil 1200 to 2400 mg/day, rosiglitazone 4 to 8 mg/day; pioglitazone 15 to 45 mg/day; acarbose 75-300 mg/day; repaglinide 0.5 to 16 mg/day.
[0187] Type I Diabetes Mellitus: A patient with Type I diabetes manages their disease primarily by self-administration of one to several doses of insulin per day, with frequent monitoring blood glucose to permit appropriate adjustment of the dose and timing of insulin administration. Chronic hyperglycemia leads to complications such as nephropathy, neuropathy, retinopathy, foot ulceration, and early mortality; hypoglycemia due to excessive insulin dosing can cause cognitive dysfunction or unconsciousness. A patient with Type I diabetes is treated with 1 to 400 mg/day of an active agent of this invention, in tablet or capsule form either as a single or a divided dose. The anticipated effect will be a reduction in the dose or frequency of administration of insulin required to maintain blood glucose in a satisfactory range, and a reduced incidence and severity of hypoglycemic episodes. Clinical outcome is monitored by measurement of blood glucose and glycosylated hemoglobin (an index of adequacy of glycemic control integrated over a period of several months), as well as by reduced incidence and severity of typical complications of diabetes. A biologically active agent of this invention can be administered in conjunction with islet transplantation to help maintain the anti-diabetic efficacy of the islet transplant.
[0188] Type II Diabetes Mellitus: A typical patient with Type II diabetes (NIDDM) manages their disease by programs of diet and exercise as well as by taking medications such as metformin, glyburide, repaglinide, rosiglitazone, or acarbose, all of which provide some improvement in glycemic control in some patients, but none of which are free of side effects or eventual treatment failure due to disease progression. Islet failure occurs over time in patients with NIDDM, necessitating insulin injections in a large fraction of patients. It is anticipated that daily treatment with an active agent of the invention (with or without additional classes of antidiabetic medication) will improve glycemic control, reduce the rate of islet failure, and reduce the incidence and severity of typical symptoms of diabetes. In addition, active agents of the invention will reduce elevated serum triglycerides and fatty acids, thereby reducing the risk of cardiovascular disease, a major cause of death of diabetic patients. As is the case for all other therapeutic agents for diabetes, dose optimization is done in individual patients according to need, clinical effect, and susceptibility to side effects.
[0189] Hyperlipidemia: Elevated triglyceride and free fatty acid levels in blood affect a substantial fraction of the population and are an important risk factor for atherosclerosis and myocardial infarction. Active agents of the invention are useful for reducing circulating triglycerides and free fatty acids in hyperlipidemic patients. Hyperlipidemic patients often also have elevated blood cholesterol levels, which also increase the risk of cardiovascular disease. Cholesterol-lowering drugs such as HMG-CoA reductase inhibitors (“statins”) can be administered to hyperlipidemic patients in addition to agents of the invention, optionally incorporated into the same pharmaceutical composition.
[0190] Fatty Liver Disease: A substantial fraction of the population is affected by fatty liver disease, also known as nonalcoholic steatohepatitis (NASH); NASH is often associated with obesity and diabetes. Hepatic steatosis, the presence of droplets of triglycerides with hepatocytes, predisposes the liver to chronic inflammation (detected in biopsy samples as infiltration of inflammatory leukocytes), which can lead to fibrosis and cirrhosis. Fatty liver disease is generally detected by observation of elevated serum levels of liver-specific enzymes such as the transaminases ALT and AST, which serve as indices of hepatocyte injury, as well as by presentation of symptoms which include fatigue and pain in the region of the liver, though definitive diagnosis often requires a biopsy. The anticipated benefit is a reduction in liver inflammation and fat content, resulting in attenuation, halting, or reversal of the progression of NASH toward fibrosis and cirrhosis.
[0000] Pharmaceutical Compositions
[0191] This invention provides a pharmaceutical composition comprising a biologically active agent as described herein and a pharmaceutically acceptable carrier. Further embodiments of the pharmaceutical composition of this invention comprise any one of the embodiments of the biologically active agents described above. In the interest of avoiding unnecessary redundancy, each such agent and group of agents is not being repeated, but they are incorporated into this description of pharmaceutical compositions as if they were repeated.
[0192] Preferably the composition is adapted for oral administration, e.g. in the form of a tablet, coated tablet, dragee, hard or soft gelatin capsule, solution, emulsion or suspension. In general the oral composition will comprise from 1 mg to 400 mg of such agent. It is convenient for the subject to swallow one or two tablets, coated tablets, dragees, or gelatin capsules per day. However the composition can also be adapted for administration by any other conventional means of systemic administration including rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions, or nasally.
[0193] The biologically active compounds can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical compositions. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active ingredient no carriers are, however, usually required in the case of soft gelatin capsules, other than the soft gelatin itself. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semil-liquid or liquid polyols and the like.
[0194] The pharmaceutical compositions can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain still other therapeutically valuable substances, particularly antidiabetic or hypolipidemic agents that act through mechanisms other than those underlying the effects of the compounds of the invention. Agents which can advantageously be combined with compounds of the invention in a single formulation include but are not limited to biguanides such as metformin, insulin releasing agents such as the sulfonylurea insulin releaser glyburide and other sulfonylurea insulin releasers, cholesterol-lowering drugs such as the “statin” HMG-CoA reductase inhibitors such as atrovastatin, lovastatin, pravastatin and simvastatin, PPAR-alpha agonists such as clofibrate and gemfibrozil, PPAR-gamma agonists such as thiazolidinediones (e.g. rosiglitazone and pioglitazone, alpha-glucosidase inhibitors such as acarbose (which inhibit starch digestion), and prandial insulin releasers such as repaglinide. The amounts of complementary agents combined with compounds of the invention in single formulations are in accord with the doses used in standard clinical practice. Established safe and effective dose ranges for certain representative compounds are set forth above.
[0195] The invention will be better understood by reference to the following examples which illustrate but do not limit the invention described herein.
CHEMICAL SYNTHESIS EXAMPLES
Example 1
5-[3-(2,6-Dimethylbenzyloxy)-phenyl]-pent-4-enoic acid ethyl ester
[0196]
Step A: Preparation of 5-[3-(2,6-Dimethylbenzyloxy)-phenyl]-pent-4-enoic acid ethyl ester
[0197] A mixture of triphenylethylbutyrate phosphonium bromide (10.06 g, 22 mmol) and sodium hydride (0.581 g, 24.2 mmol) in dimethyl sulfoxide (45 ml) was stirred for 30 minutes under nitrogen. The reaction mixture was heated to 26.7° C. and 3-(2,6-Dimethylbenzyloxy)benzaldehyde (3.89 g, 16.2 mmol) diluted in dimethyl sulfoxide (15 ml) was added dropwise over 3 minutes. The reaction mixture was stirred for 3 hours at 50° C. A mixture of triphenylethylbutyrate phosphonium bromide (3.20 g, 70 mmol) and sodium hydride (0.185 g) in dimethyl sulfoxide (10 ml) was stirred under nitrogen for 30 minutes. This mixture was added, in bolus to the above reaction mixture at room temperature. The reaction mixture was stirred for Z hours at 50° C., cooled to room temperature and poured over ice (50 g) and water (50 ml) mixture. The aqueous mixture was extracted with ethyl acetate (3×125 ml). The combined organic layer was dried over Na 2 SO 4 , filtered and concentrated to afford the 12.5 g of brown oil. The oil was dissolved in 30 ml of hexanes:ethyl acetate (95:5) and chromatographed on a Biotage 75S silica gel column to give 4.9 g of a yellow oil. The yellow oil was subjected to another silica gel column chromatography eluting with hexane:chloroform (1:1) to hexane:ethyl acetate (9:1) to afford 3.40 g (62%) of a faint yellow oil product which solidified upon standing.
[0198] 1 H NMR (CDCl 3 ): 1.2 (t, 3H); 2.4-2.7 (m, 10H); 4.1 (q, 2H); 5.1 (s, 2H); 5.6-6.2 (m, 1H); 6.5 (t, 1H); 6.8 (m, 7H).
Example 2
6-[3-(2,6-Dimethylbenzyloxy)-phenyl]-hex-5-enoic acid ethyl ester
[0199]
Step A: Preparation of Triphenylethylvalerate Phosphonium Bromide
[0200] In a 100 ml three necked flask equipped with a stir bar, thermocouple and a reflux condenser with a nitrogen inlet was dissolved triphenylphosphine (11.80 g, 45 mmol) in toluene (25 ml), ethyl-5-bromovalerate (12.54 g, 60 mmol) was added to the solution and the reaction mixture was refluxed for 2 hours and then cooled to room temperature. The toluene was decanted away from the oily solid and the residue was slurried in hexane (100 ml). The hexane (3×100 ml) was decanted away three times from the oily residue and oily residue was heated on a Kugelrohr apparatus at 40° C., 0.1 torr for 30 minutes to afford 19.0 g (89.6%) of the title compound.
Step B: 6-[3-(2,6-Dimethylbenzyloxy)-phenyl]-hex-5-enoic acid ethyl ester
[0201] A mixture of triphenylethylvalerate phosphonium bromide (Step A, 13.29 g, 28.2 mmol) and sodium hydride (0.745 g, 31.0 mmol) in dimethyl sulfoxide (40 ml) was stirred for 30 minutes under nitrogen. The reaction mixture was heated to 26.7° C. and 3-(2,6-Dimethylbenzyloxy)benzaldehyde (5.00 g, 20.8 mmol) diluted in dimethyl sulfoxide (20 ml) was added dropwise over 4 minutes. The reaction mixture was stirred for 3 hours at 50° C. A mixture of triphenylethylvalerate phosphonium bromide (Step A, 5.56 g, 118 mmol) and sodium hydride (0.312 g) in dimethyl sulfoxide (15 ml) was stirred under nitrogen for 30 minutes. This mixture was added, in bolus to the above reaction mixture at room temperature. The reaction mixture was stirred for 6 hours at 50° C., cooled to room temperature and poured over ice (60 g) and water (60 ml) mixture. The aqueous mixture was extracted with ethyl acetate (3×150 ml). The combined organic layer was dried over Na 2 SO 4 , filtered and concentrated to afford the 14.3 g of brown oil. The oil was dissolved in 30 ml of hexane:ethyl acetate (95:5) and chromatographed on a Biotage 75S silica gel column to give 5.8 g of a yellow oil. The yellow oil was subjected to another silica gel column chromatography eluting with hexane:chloroform (1:1) to hexane:ethyl acetate (9:1) to afford 3.74 g (51%) of a dark yellow oil.
[0202] 1 H NMR (CDCl 3 ): 1.2 (t, 3H); 1.8 (m, 2H); 2.2-2.4 (m, 10H); 4.2 (q, 2H); 5.1 (s, 2H); 5.6-6.2 (m, 1H); 6.4 (t, 1H); 6.9-7.3 (m, 7H).
BIOLOGICAL ACTIVITY EXAMPLES
[0203] For all of the biological activity examples that follow, Compounds CO and CP were produced in accordance with chemical synthesis examples 1 and 2, respectively.
Example 3
Antidiabetic Effects of Compounds of the Invention in db/db Mice
[0204] Db/db mice have a defect in leptin signaling, leading to hyperphagia, obesity and diabetes. Moreover, unlike ob/ob mice on a C57BL/6J background, db/db mice on a C57BLKS background undergo failure of their insulin-producing pancreatic islet cells, resulting in progression from hyperinsulinemia (associated with peripheral insulin resistance) to hypoinsulinemic diabetes.
[0205] Male obese (db/db homozygote) C57B/Ksola mice approximately 8 weeks of age, were obtained from Jackson Labs (Bar Harbor, Me.) and randomly assigned into groups of 5-7 animals such that the body weights (40-45 g) and serum glucose levels (≧300 mg/dl in fed state) were similar between groups; male lean (db/+heterozygote) mice served as cohort controls. A minimum of 7 days was allowed for adaptation after arrival. All animals were maintained under controlled temperature (23° C.), relative humidity (50±5%) and light (7:00-19:00), and allowed free access to standard chow (Formulab Diet 5008, Quality Lab Products, Elkridge, Md.) and water.
[0206] Treatment cohorts were given daily oral doses of vehicle, compound CO (100 mg/kg), or Compound CP (100 mg/kg) for 4 weeks. At the end of the treatment period 100 μl of venous blood was withdrawn in a heparinized capillary tube from the retro-orbital sinus for serum chemistry analysis.
[0207] After 4 weeks of daily oral dosing, both Compound CO and Compound CP elicited a significant reduction in blood glucose (Table I). Both compounds also reduced serum triglycerides and free fatty acids (Table II) versus vehicle-treated db/db mice.
TABLE I Effect of Compounds CO and CP on serum glucose in b/db mice: Treatment for 4 weeks Glucose ± SEM Groups mg/dL Lean Control 193 ± 11 Vehicle (db/db) 747 ± 19 Cpd. CO - 100 mg/kg 651 ± 36* Cpd. CP - 100 mg/kg 404 ± 101* *p < 0.05 significantly lower than in vehicle-treated mice
[0208]
TABLE II
Effect of Compounds CO and CP on serum triglycerides and
free fatty acids in db/db mice: Treatment for 4 weeks
Triglycerides ± SEM
Free Fatty Acids ± SEM
Group
mg/dL
μM
Lean
96.4 ± 6.4
1637 ± 105
Vehicle
621 ± 54
2415 ± 134
Cpd. CO
320 ± 30*
2689 ± 70
Cpd. CP
150 ± 34*
1765 ± 39*
*= p < .05 significantly lower than vehicle-treated values | Agents useful for the treatment of various metabolic disorders, such as insulin resistance syndrome, diabetes, hyper-lipidemia, fatty liver disease, cachexia, obesity, atherosclerosis and arteriosclerosis are disclosed. Formula (I) wherein n is 1 or 2; m is 2 or 3; q is 0 or 1; t is 0 or 1; R 2 is alkyl having from 1 to 3 carbon atoms; R 3 is hydrogen, halo, alkyl having from 1 to 3 carbon atoms, or alkoxy having from 1 to 3 carbon atoms; A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from: halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or cycloalkyl having from 3 to 6 ring carbon atoms wherein the cycloalkyl is unsubstituted or one or two ring carbons are independently mono-substituted by methyl or ethyl; or a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and O and the heteroaromatic ring is covalently bound to the remainder of the compound of formula I by a ring carbon; and R 1 is hydrogen or alkyl having 1 or 2 carbon atoms. Alternatively, when R 1 is hydrogen, the biologically active agent can be a pharmaceutically acceptable salt of the compound of Formula (I). | 0 |
This application is a continuation-in-part of application Ser. No. 383,012 field Jul. 21, 1989, issued as U.S. Pat. No. 5,025,877 on Jun. 25, 1991.
FIELD OF THE INVENTION
This invention relates to a vehicle suspension system for vehicle that is provided with an optionally deployable auxiliary axle. More specifically, it relates to trucks and trailers wherein it is desired to control automatically both the lowering of an auxiliary axle, and the amount of load carried by that auxiliary axle.
BACKGROUND TO THE INVENTION
There is a limit to the axis load that can be permitted for highway vehicles if damage to the highway surface is to be minimized. Damage to a highway as a function of axle weight rises rapidly, once a certain load point has been passed. Government authorities closely monitor, and fine heavily, trucks that exceed these axle load limits.
The concept of an auxiliary axle that may be raised or lowered has been introduced to provide transport vehicles with a means to reduce the axle load on other axles when the critical load limit is exceeded. A disadvantage of such auxiliary axles is that due to their centrally located position on the truck body, they greatly reduce steerability when deployed with an inappropriate axle load. This is particularly true when the centrally located auxiliary axle is heavily loaded.
The loading of truck axles will vary while a truck is in motion. This can arise from a variety of conditions including wind, the gradient of hill or radius of a turn, whether the vehicle is accelerating or braking and from the shifting of cargo being carried. Thus, while a certain axle weight may be registered at a roadside scale, the actual axle load may increase over that limit, once the vehicle is in motion. These factors have given rise to systems for actually varying the load carried by an auxiliary axle, while the vehicle is in motion.
In addition to these listed factors affecting axle load the unevenness of the road surface, in terms of bumps and pot holes, can produced major transient excursions in axle loads.
A further reason for providing an auxiliary axle, and for providing a means for varying the load carried by an auxiliary axle, is that load limits may change passing from one jurisdiction to another, or when changing from a primary to a secondary road.
A problem that exists with systems designed to control the deployment and loading of auxiliary axles is that they may be bypassed by unconscientious operators who wish to carry loads that exceed proper load limits without the auxiliary axle deployed. They may choose to do this in order to improve the driveability of their vehicle in slippier conditions, to improve the ride, or on the theory that it will save tire wear.
At the same time, there are circumstances where it it would be reasonable to raise an auxiliary axle even through the maximum axle load for the remaining axles is exceeded. These include the cases where it is desired to operate a vehicle in reverse, of where it is necessary to pass the vehicle at low speed through a very tight radius turn.
Thus any sophisticated control system for the deployment of an auxiliary axle should provide both for security against evasion of the system, and for exceptions when intervention of the control system may be suspended.
PRIOR ART
Systems have been described to provide transport vehicles with an auxiliary liftable axle that may be retracted or lower automatically, according to whether the vehicle requires supplementary load-carrying capacity: U.S. Pat. No. 4,700,968 to Cherry.
It has also been proposed to control the weight borne by an axle on a vehicle by increasing or decreasing the pressure in an air-spring associated with an auxiliary axle on the vehicle--U.S. Pat. No. 4,789,038 to Nguyen. It has further been proposed to sense the load condition on a principal axle and to automatically cause the auxiliary axle to be lifted or deployed in accordance with predetermined load criteria for the principal axle: U.S. Pat. No. 4,284,165 to Carstensen et al and U.S. Pat. No. 4,854,409 to Hillbrand.
In these patents, recognition is given to the consideration that the automatic deployment of the scheduled loading of an auxiliary axle should not be responsive to short-term transients. Such transients, as mentioned previously, are always present when a vehicle is in motion.
The range in variations in axle loading associated with such transients becomes more substantial at higher vehicle speeds. Unnecessary response to transient load variations can impose a heavy toll on valves and control components. Accordingly, the ability to discriminate between such transients and true persistent changes in axle loads is a critical requirement for any auxiliary axle control system.
This problem, in the case of controlling axle loading, was met in Nguyen by providing a response "dead-zone" for axle loading within which intervention by the control system is suspended. Such a non-response dead-zone necessarily requires that the vehicle be permitted to operate with less than optimal axle loading within the boundaries of the dead-zone. Nevertheless, extreme transient excursions outside the dead-zone, as caused by a major pot-hole on a road surface, will cause such a system to commence adjustments to the loading of the auxiliary axle in-appropriately. The result is the wasteful and wearing cycling of the control system in which the system initiates an unnecessary change to auxiliary axle loading.
The use of a broad dead-zone to avoid cycling imposes a serious penalty on the carried since it prevents the vehicle from being used to its maximum potential payload under governmental axle load limits.
The problem of cycling in the deployment of an axle may also be addressed by provision of a delay mechanism that requires an overload condition to persist, outside a predetermined threshold, for a predetermined period of time before the auxiliary axle is deployed. However, such a delay system inherently fails to deploy the auxiliary axle until the load on the principal axle persistently lies outside the threshold (for lowering the auxiliary axle) for more than the delay period. Such a system is blind to oscillating loads that dip below the threshold within the delay period. Accordingly, the system is blind to fundamental loading changes to the extent of the amplitude of the oscillations. This can result in the failure of the auxiliary axle to deploy even though a principal axle is overloaded. Alternately, the vehicle has to be operated below its maximum capacity to accommodate the defacto dead-zone that is created.
The present invention addresses these problems. The present invention also embodies as additional, optional features a series of control functions that both provide a driver with flexibility in the deployment of the auxiliary axle and protect against the illegitimate subversion of the control system.
SUMMARY OF THE INVENTION
According to the invention in its broadest aspect, the control system for deploying and loading an auxiliary axle, or for continuously adjusting the loading of an auxiliary axle, responds to a average of samples of the measured load on the principal axle, or axles, from which axle load is being sensed. Such a system is able to operate without the necessity of providing a broad, non-response "dead-zone" in order to avoid unnecessary responses and cycling.
In accordance with a further feature of the invention, measurements are obtained, based in multiple sets of samples, and then compared to stored values obtained from prior samples. The results found are then used to verify that suspension components are responding to signals from the control system, and fail-safe reactions are implemented where correct responses by the vehicle suspension are not verified.
By a further feature of the invention, where certain preset limits for axle load conditions are passed, the control system ceases to act on the standard time-averaging basis, and commences to take corrective action immediately.
By a further feature of the invention when measured axle loads, based on the averaging of readings, exceed certain preset conditions that are indicative of probable control system or suspension system failure, the operation of the auxiliary axle in a substantially loaded condition is suspended. Resumption of normal operation occurs either on a manual "reset" by the operator, or upon the return of measured axle loads within the present conditions.
By a further feature of the invention the vehicle operator can choose between two load allocation schedules to direct the control system to operate on either an axil loading regime in which the auxiliary axle carries only the necessary supplementary weight to prevent over-loading of the principal axle(s); or on a regime by which the auxiliary axle shares load equally or proportionally with the principal axle(s).
By a further feature of the invention the length and count in the sampling period used to determine the average of load on the principal axle(s) is varied in accordance with whether the vehicle is moving, has ceased motion for more than a pre-determined period, or has just commenced moving from a previously stationary condition.
By a further feature of the invention the load on a number of axles or vehicle suspension points is measured by detecting cyclically the air pressure of air springs associated with such axles or suspension points, interspersed with samplings of a standard or atmospheric pressure source which are used to recalibrate the pressure sensing transducer.
By a further feature of the invention, corrective adjustments to the load condition of the auxiliary axle are effected by discrete, metered changes to the load controlling components. More particularly, method quantities of air are introduced into or removed from the supporting air springs, in in accordance with amounts calculated to be sufficient to achieve the desired changes.
By a further feature of the invention, if power to the control system is disconnected for more than a predetermined period of time while the vehicle is moving, the system is disabled in order to prevent subversion of the control system.
By a further feature of the invention, the ability of an operator to over-load the control system due to special circumstances is subject to limits based on the speed or motion of the vehicle.
By further feature of the invention the deployment or non-deployment of the auxiliary axil may be effected by the vehicle on the basis of manually over-riding the control system, but subject to limitations that prevent the operator from subverting the general operation of the control system.
By a further feature of the invention, the auxiliary axle can be automatically lifted, (and/or self-steering features locked) so that control by the control system is suspended, when the vehicle is placed in "reverse". Additionally, the axle may be held in a lifted position for some period of time after reverse is disengaged so that in maneuvering in and out of reverse the axle deployment system does not cycle up and down. However, such features are subject to limitations that prevent the operator from subverting the control system when the vehicle is moving for more than a predetermined period of time.
By a further feature of the invention the operation of the control system may be suspended automatically when the carrying out of an auxiliary vehicle function is detected, such as garbage compaction or boom operation; but subject to limitations that apply (when the vehicle is moving) to prevent the operator from subverting the control system.
By a further feature of the invention, the control system suspends implementation of corrective responses (to charged conditions) for a limited period of time, when the brakes are applied. This saves valve wear due to the cycling that would occur from the short term transfer of weight that arises on braking.
These and further features of the invention will be better understood from the description of the preferred embodiments which now follow.
SUMMARY OF THE FIGURES
FIG. 1 is a profile view of a truck with a liftable auxiliary axle that is suited to incorporate the invention.
FIG. 2 is a graph of lateral acceleration measured over 20 seconds for a truck travelling at 92 km/hour on an asphalt surface.
FIG. 3 is a graph showing individual sample readings of air spring pressure, for varying applied loads.
FIG. 4 is a schematic of the air control system for the air springs on the truck of FIG. 1.
FIG. 5 is a graph showing both the response of a prior art load adjustment system which relies on a "dead-zone" to filter-out transient pressure variation, and the response of the principal and auxiliary axles of the present invention to transient and distinct variations in load.
FIG. 6 is a graph showing both the response of a load adjustment system, according to the invention, to a series of increasing loads, followed by a series of decreasing loads, and then by intermittent loads.
FIGS. 7a, 7b, and 7c are a flow chart showing the logic employed by the computer controller which is operating in accordance with the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In FIG. 1 a truck having front 1 and rear 3 wheels is depicted. The center wheel 2 is mounted on an auxiliary axle 4 supported by a trailing arm 21 and air spring 23. Brakes 25 are also depicted.
The front axle 7 carries a leaf spring 13 anchored at its front end by a front shackle 15 and at the other end by a rear shackle 19 and shackle arm 17. An air spring 2 between the shackle arm 17 and the frame 9 of the chassis provides support for the overall front axle suspension 11.
Carried on the vehicle is a computer based control system which utilizes a computerized controller 30 to operate the pneumatic circuits, constituting collectively a computerized pneumatic circuit 29.
Tests have been conducted on the forces experienced by a vehicle, such as that in FIG. 1, when travelling on a finished road surface. FIG. 2 shows a graph of lateral acceleration experienced by an accelerometer mounted in a truck travelling at 92 km/hr up to the 12 second point, and decreasing thereafter. The vertical axis shows lateral acceleration in units of "G"0 or standard gravity. The momentary elevation in the graph at the 4-5 seconds point represents a momentary veering to one side.
The use of an accelerometer allows high frequency spikes a rising from vibration to be detected. As well, the undulating trend of this graph shows lateral sway.
This graph is significant as showing the high degree of variability in loads experienced by a vehicle. While it represents lateral acceleration, it is typical of the load variations experienced by an axle, vertically.
In the preferred embodiment, axle load is determined by taking pressure readings off the air springs (20), (23).
FIG. 3 is a graph showing a series of sample instantaneous readings, based on air spring pressure, corresponding to measured load values on a vehicle moving at a constant speed. The "best-fit" line for increasing load is shown by the diagonal line 901. As is apparent from this graph, there is considerable variability or scatter in the measured values. This variability is due to the motion of the vehicle, other "noise" in the load measuring system, and friction inherent in the suspension systems.
It is because of this variability in load reading that the present invention adopts averaging over a set of sample readings in order to generate a value for the measured load.
The pneumatic circuit for controlling and measuring air pressure in the air spring control system is shown in FIG. 4. In FIG. 4, an air supply 300 supplies air through air line 308 to a primary control valve 306 and then to a bleed valve 307. From there, air is distributed through air lines 309 to the air springs for the auxiliary axle 310. Air pressures in front right and left air springs 311, 312 are adjusted by standard height-control valves (not shown). The function of the air spring valves 303, 304, is to allow the front air springs 311, 312 to be sampled by the pressure transducer 313 through the air lines 314. Valve 301 acts a bleed outlet.
Bleed valve 307 is held closed by current supplied from the control system. In the event of a control system failure to maintain activating current to bleed valve 307, the valve opens and exhausts all air in the system to atmosphere. This disables the auxiliary axle by placing it in an unloaded state, which is a fail-safe condition. By using a 3/2 style valve, the entry of further air from the air source is simultaneously blocked, When bleed valve 307 is found to be ineffective in bleeding air (detected by monitoring for a drop in system pressure when the current to valve 307 is off) then a further valve 306 is placed in a closed condition.
As a further fail-safe condition, valves 303 and 301 assume open state if valve 307 is found to be ineffective. This allows all the air in the auxiliary air spring system to escape to atmosphere by a route alternate to valve 307.
A pressure transducer 313, which may typically be a piezo electric device such as a Motorola MXP series pressure sensor transducer (e.g. model MXP200A), is coupled to the pressure lines 314. By controlling the position of valves 303, 304, 305 the transducer 313 can be sample the pressure at any one of the air springs, 310, 311, 312. The valve 301 allows the transducer 313 to sample atmospheric pressure.
Centralized Load Measurement
A variety of known methods exist for measuring axle load. One means to measure axle load directly is to place a load cell between the axle and its suspension. However, it is inconvenient to expose a load cell to the full shocks and pressure transmitted by the axle to the suspension. An alternate indirect means to measure load is to place a strain gauge on an axle between the wheel and the suspension point. A further means, preferred in the present invention, is to utilize air springs in the suspension, and measure the pressure of air within such springs. The use of air springs is not, however essential to the application of the invention, and the invention may be adapted to any known load measuring system.
When using air spring pressure to measure axle load, the spring should be first tested to determine its load-vs-pressure response curve. This curve, along with corrections for hill gradients, etc., may then be used to generate satisfactorily accurate values for the load on each air spring supported axle from which pressure readings are being taken.
The use of air spring pressure as the parameter for measuring axle load conveniently allows load at a number of axle points to be measured by a single pressure transducer. A simple piezo-electric transducer which produces an electrical voltage which is a function of applied pressure has been found convenient for this purpose. Alternately, devices based on a strain gauge may be used.
Air lines are run from each air springs to be sampled to the single pressure transducer. A valved manifold is used to permit the transducer to sample consecutively the pressure in each of the lines.
For security in ensuring that proper readings are being taken, it is useful to provide a port on the manifold by which the transducer may periodically sample a source of air at standard pressure, usually the atmosphere. This may be used to repeatedly recalibrate the transducer by providing an electrical output which corresponds to this standard value.
A further valuable procedure that may be employed to ensure the reliability of pressure readings is to vent the pressure transducer to the atmosphere between readings. This may be done only momentarily, but for a sufficient period of time to purge the air derived from the last reading. The effect, when the manifold sampling mechanism is operating properly, is to intersperse measured pressure readings from consecutive air springs with a "zero" value reading. By checking for the presence of this interspersed zero-value reading, the fact that air from prior samplings has been purged can be verified.
If this purging procedure is not followed, then the control system receiving an apparent pressure-equivalent signal from the pressure transducer will be blind to a failure by a manifold valve to open. Instead, the transducer will provide, erroneously, a pressure reading based on the air sample of the last prior reading.
The provision of a procedure by which measured pressure readings from consecutive air springs are interspersed with sample readings from a standard pressure source provides a valuable confirmation that the valves within the pressure measuring system are operating correctly. This is a function that may be employed whether or not the control system for the auxiliary axle operates on a sampling basis.
The computerized controller 30 operates the air valves to provide or bleed air into each of the air springs 310, in accordance with the loading requirements for such axles.
Load Distribution Regimes
For a given gross vehicle load, there are a number of criteria that may be applied to establish the preferred distribution or load allocation for individual axles. Such allocations may not usually be fully obtainable. But they may approximated. Further, critical limits that should not be exceeded may be established.
The principal axle (or axles) on a vehicle must have adequate load in order to generate a sufficient cornering force. This is particularly true when the front axle is used to turn a vehicle with multiple rear axles.
When an auxiliary axle is deployed, it is generally done so to ensure that other axles on the vehicle do not exceed their maximum load limits. When the auxiliary axle has a controlled capacity to carry varying degrees of load a choice arises as to the weight distribution regime that is to be adopted.
In one mode, the auxiliary axle may be controlled so that it carries only that amount of weight necessary to bring the known load, or loads, on the monitored axles within their legal limits. This "supplementary" load regime has the advantage of burdening the auxiliary axle with the minimum degree of wear. It also represents a minimal change in the driving response characteristics of the vehicle.
A further regime for allocating the axle weight is to set the auxiliary axle load on a "proportional basis", in proportion to the load on the principal axle, or axles.
Where the proportional ratio is chosen so as to equalize the weight on such axles, government regulations may qualify these axle sets as "tandem" or "tridem" axles etc. and permit higher axle load limits. This can be of major advantage to carriers.
An auxiliary axle may also be operated under a load that is at a proportion other than equality with respect to the principal axle. This may be preferred as when the auxiliary axle is self-steering and may preferably be operated at a ratio of, for example, 40:60.
It is useful, therefore, to allow a driver to choose from a schedule of alternate loading regimes the regime that he prefers.
Determining Suitable Lift And Drop Points
It is useful to project in advance the effect of deploying, or lifting, the auxiliary axle before executing that maneuver.
In determining whether to deploy an auxiliary axle (that is already in a lifted position), the load on the principal axle may be compared to a preselected "drop-point" load value. This value is selected on the basis of consideration of axle load limits, vehicle handling (steering) characteristics, and ride quality. If that drop-point is exceeded, the auxiliary axle should be lowered.
However, once the auxiliary axle is deployed, the load of the principal axle will be reduced by some factor corresponding to the load being borne by the auxiliary axle, taking into account its geometric location.
To prevent "cycling", a predetermined "lift-point" load for the principal axle can be selected such that, if the auxiliary axle were to be lifted, the load on the principal axle will not be returned to above its drop-point.
This is shown in FIG. 6 which is a graph of the loads on the principal and auxiliary axles as a function of a varying total load for the vehicle. This latter parameter is shown on the "axle" as test or reading numbers.
From reading 0 to 15 is the principal axle was loaded progressively. At reading 7 the principal axle has reached its predetermined drop point and the auxiliary axle is still not deployed. At reading 8 the auxiliary axle has become deployed and loaded to 2900 kg. (its minimum permitted load).
Due to deployment of the auxiliary axle, the load on the principal axle has dropped. Over the next two readings 9, 10 the auxiliary axle maintains its minimum permitted load. If it were lifted at this point the principal axle would be overloaded.
Beyond reading 10, the auxiliary axle absorbs the additional load necessary to maintain the principal axle at its maximum permitted load value. This weight condition for the principal axle is a precisely controlled (within small tolerance limits) using the weight measuring technique of the invention.
From reading 15 to reading 19, the total vehicle load is being reduced. From reading 20 to 24 the system was cycled between controlled and control-suspended states (by using reverse) in order to show the consistency of the control system.
In order to make the decision to either lift or lower the auxiliary axle, measurements of load must be taken off the principal axle; and the load on the auxiliary axle must be either measured or approximated by calculation from the measured load. In doing so, it is important that the fluctuations arising from road irregularities, vehicle vibrations and friction within the suspension be averaged out. By averaging out the random variations in measured axle load a more precise control over the deployment (logic) of the auxiliary axle may be obtained.
In the preferred embodiment, the decision to lift the auxiliary axle is made when the principle axle load is below a minimum lower limit or lift-point and the auxiliary axle is at (or below) that minimum, for two consecutive confirmatory readings; or immediately for a single "emergency" reading of 20% under the minimum. The decision to lower the auxiliary axle is made when the load on the principle axle is above its maximum upper limit or drop-point, based on two consecutive, confirmatory readings; or immediately on a single "emergency" reading of 20% or more over the maximum.
In either case it is necessary to obtain a load measurement from the principle axle. In the case where a supplemental loading regime is being applied, it is further necessary to obtain a measurement of the load on the auxiliary axle before making a decision to lift the auxiliary axle.
When using other than the supplemental regime, the load on the auxiliary axle can be approximated by use of known physical relationships. For example, in a tandem unit in which one of the axles is the principal axle, and one the auxiliary axle, the total load would be approximately equal to twice the load on the primary axle.
A lower limit is placed on the loading of the auxiliary axle to prevent wheel hop, excessive suspension and tire wear and inadequate braking. This is generally accepted practice in the field.
An upper limit may be set based on road wear considerations and government regulatory limits. Since the loading of the auxiliary axle is controllable, it is possible to ensure that this axle, at least, never exceeds an authorized limit. This prevents the auxiliary axle from being required to bear the entire excess load, and distributes such excess load over the remaining axles. Thus when the auxiliary axle is held at its maximum load limit, excess loads are distributed over a remaining number of axles, reducing the pavement damage below that which a single axle would create.
The upper limit for the loading of an auxiliary axle may also be based on drive ability considerations. A limit on the loading of the auxiliary axle may be set in order to provide adequate cornering forces. This limit will depend on vehicle geometry.
Accommodation of Variations in Measured Axle Loads
It is a principal feature of this invention that a system is provided which accommodates, in an improved manner, transients and variations that arise in measured axle loads in controlling the pressure in the air springs 310. This improved performance is achieved by controlling pressure in accordance with a series of samples of measured air pressure taken over time. The series of samples constitute a "sample set" and the time over which samples are taken is identified herein as the "sampling period".
It is important to appreciate that the prior art, by reason of use of direct load measurements, requires the use of a non-response or "dead zone" for determining when to respond to apparent load changes. A dead-zone is used in order to suppress unacceptable cycling of the auxiliary axle control system. This use of direct load measurements and "dead-zone" criteria by the prior art results in less efficient loading of the axles measurements. The present invention provides a continuous response system. The measurement averaging procedure of the invention eventually causes the axle loads on the vehicle to be adjusted closely to their preferred values. Reliance on an inefficient and load-capacity-wasting "dead-zone" is eliminated.
The benefits of the invention may be seen in FIG. 5.
In FIG. 5 a truck, with the front axles taken as the principal monitored axles, is shown passing along a roadway 35 which has an initial flat portion 36, a descending portion 37, a central flat portion 38, an ascending portion 39, and a terminal flat portion 40.
The upper, and lower graphs 41a, 41b are aligned vertically with the path of the roadway 35 to show corresponding axle loads at each stage. The upper graph 41a shows the response of a "dead-zone" load control system to highway variations; and the lower graph 41b shows the response of a system operating in accordance with the invention.
The upper traces 43a, 43b in graphs 41, 42 show respectively the load on the principle axle. The lower traces 44a, 44b show the load on the auxiliary axle. A hypothetical maximum allowable axle load limit line 45 set at 10,000 in dimensionless units, is indicated on each graph 41a, 41b. The prior art graph 41a shows additionally a lower line 46 at the 8,000 level. The space between this lower line 46 and the load limit 45 represents the dead-zone 47 by which the prior art operates.
For the initial flat portion 36 of the roadway, the prior art vehicle is operating with a principal axle load 43a which is within the dead-zone 47, approximately centered. The variations in loading for which the dead-zone 47 is required are shown in the load curve 43a as being within the dead-zone 47. Therefore, no response in the system occurs.
When the descending portion 37 of the road is reached, weight shifts to the front axle and the load curves 43a, 43b for the principal axles jumps in both cases. Because the measured value of the load on the principal axle is now above the upper load limit 45, both systems respond by increasing the load on the auxiliary axle 44a, 44b. In both cases, the principal axle curve 43a,b returns to the upper load limit 45. However, the prior art response is more gradual to prevent over shooting. The response of the system of the invention is prompt, once the time to produce an average value has passed.
The prior art curve 43a is progressively moved down further into the dead-zone 47 as load transients exceed the upper limit 45. This requires a series of on-off reactions by the air system control valves, causing wear on the valves.
The principal axle curve 43b for the invention returns directly to the maximum load limit 45 and remains there, with the average load precisely at the set-point limit 45.
The auxiliary axle load levels 44a,b, in both cases, rise to accommodate the additional load imposed by the descending roadway 37.
At bottom of the descending roadway 37 the vehicle 1 resumes a level configuration along the lower flat portion 38.
In the case of both the prior art and inventive system, the principle axle experiences a reduction in load. This is apparent in the curves 43a,b. The valves for auxiliary axles are caused by the computer controller 30, to bleed air from the air springs, reducing the load on the auxiliary axles. Again, this occurs over time. At the same time, the loads on the principle axles are increased, and the curves 43a,b for each rise correspondingly.
At this stage the responses of the two systems differ. The system operating according to the invention increases the load on the principal axle until the curve 43a arrives at its "set point", namely the load limit 45 at position 50 after the sampling period has passed.
The prior art system, however, initially restores the load on the principal axle only to the point at the load curve 43a is within the dead-zone 47. Initially, this may be in a region close to the lower limit 46 of the dead-zone 47. But as before, as random excursions in the measured load extend outside the dead-zone 47, over the lower limit 46, the load curve 43a for the auxiliary axle will be progressively displaced upwards. This will associate with a repeated cycling of valves.
Once the prior art system has stabilized, it is important to note that the average load that will be carried by the auxiliary axle will always be somewhere in the center position of the dead-zone 47. On the scale provided, this represents a value of about 8,500-9,500, or up to 15% below the maximum load limit 45 of 10,000.
When the dead-zone is used, as in the prior art, the vehicle must always be loaded beneath its maximum crying capacity. By contrast the system of the invention allows a vehicle to be loaded to its absolute capacity limit.
The balance of the curves 43a,b and 44a,b show the respective responses of the auxiliary and principal axles for each system, as the vehicle mounts the inclined.
One should notice that a large bump 51 has an effect on the prior art auxiliary axle load 44a at point 52. Conversely bump 51 has no effect on the system based on the invention as shown at point 53.
Sampling Systems
In the preferred embodiment sampling sets are taken in groups of 30 samples usually over two to eight seconds. The number of samples and the sampling period may, however, be varied.
The average value of the two most recent past sample sets is stored and then compared to the average value of the most immediate sample set obtained. Any change will show up as a trend.
The presence of a trend in the correct direction is used to verify that the system is responding correctly when changes are being effected. If an indication that an anticipated change is not occurring (confirmed over at a present number of samplings, e.g. 5) the system issues an "error" signal and goes into "Fail Safe" mode where the loading of the auxiliary axle is discontinued.
The criteria for initiating a response are based on a comparison of the stored average value with the most recent average value, averaged together. This value than replaces the earlier stored value.
When the vehicle is stationary a higher sampling, or shortened sample set, rate is adopted for an initial period, typically 3 minutes. This increases the response rate of the system when, for instance, the vehicle stops at a scale. After the initial period has passed, the sampling rate is slowed down by a factor of 5 or 6 to preserve valve life.
Metered Response System
In other systems to control the actual loading of an auxiliary axle, commands are issued to execute changes on the basis that the response of the system is continuously being monitored, and the commands adjusted accordingly. Thus, air may be forced into an air spring while pressure within the spring is being monitored. When the desired pressure condition is detected, the introduction of further air is terminated.
In the application of the present invention, a "metered response" strategy is adopted.
According, to this metered response strategy, when a changed condition required that the air pressure within air springs must be changed, a calculation is made of the amount of air that should be introduced into, or bled from, the system to achieve the desired state. The control valve governing the introduction or release of air is then opened, on a predetermined basis, only from the appropriate period to achieve this result. Alternately, where a pressure regulator valve is used, the pressure regulator valve is set to the estimated, desired pressure.
This system allows for the rapid, approximate adjustment of the pressure in the air springs. Where a continuous feed-back system in used, the rate of change of pressure must be limited to prevent over-shooting.
Used in conjunction with the sample averaging system, described herein, this metered response mechanism avoids responding unnecessarily to transients arising from road irregularities. It also quickly reaches its desired set point without overshooting and cycling, and allows a quick response time, especially for emergency conditions. This feature is not present in continuous response systems.
This arrangement avoids the need for continuous feed-back and allows the pressure monitoring system to be applied to other components while the compensatory adjustment to air pressure is being effected. This feature suits, on a complementary basis, the use of a single pressure transducer (which is an expensive component) in conjunction with an alternate sample system for monitory the pressure states in each air spring.
Thus, very small adjustments may be effected by short-period openings of the supply or bleed valve, (or pressure regulator adjustments) without the necessity of monitoring exclusively the pressure in the air bag that is being adjusted. If the period between pressure samplings exceeds the adjustment period, the air pressure in the air spring rests in at a static, first-adjusted level, until it is determined that a further adjustment is required. If the pressure measuring system were to fail, a dangerous over-pressure condition will not develop.
Choice of Principal Axle
Throughout, this disclosure the "principal axle" is used to mean the axle, or group of axles, which are monitored for load and are thereby used to govern the decisions taken with respect to the auxiliary axle. It is preferable to utilize all direct load information available, and to use a combination of axles as a "principal axle" where measurements are available from each axle in the combination.
By reason of geometry, the axles on the same side of the center of mass or gravity of the vehicle that the auxiliary axle is on will be most affected by the deployment of the auxiliary axle. Customarily the auxiliary axle is placed between the front and rear axles, at a position near the center of gravity, where its deployment will affect the load on both the front and rear axles. When the auxiliary axle is forward of the centre of gravity, which is typical, it will have a greater effect on the front or steering axles. When an auxiliary axle in this location is deployed, care must be taken not to decrease the axle weight on the principal axle below the minimum necessary for adequate cornering. This minimum value is also a function of the position, weight, type and tire characteristics of the principal axle.
It is on this basis that in the preferred embodiments the weight on the front steering axle is measured and used as a basic consideration in deciding on the weight to be carried by the auxiliary axle.
Projecting Axle Loads
With a fixed-bed vehicle carrying a load the center of gravity, which has been determined, it is possible to calculate the total loads on one axle, without measuring it directly, based on the measured weight obtained from all of the other axles. When the load on more than one axle is unknown, or where the center of gravity is unknown, it is not possible to calculate the absolute loads on the unknown axle.
However, when the auxiliary axle is loaded by a given incremental amount, using the known geometry of the positions of the auxiliary and other axles, the corresponding effects on such axles can be determined.
Suspension of Control System
The control system is automatically suspended and the auxiliary axle unloaded, if down, when the vehicle is put into reverse. Once put into reverse the system remains suspended for one minute after reverse is disengaged. This allows the vehicle to be rocked.
An auxiliary input is provided by which the axle will be unloaded and the control system suspended while external activities are occurring. These include, for example, the compaction of the garbage or operation of a boom.
System Interlocks
In order to ensure that the system is not being subverted by an operator the apparently automatic suspension of system operation, if the vehicle is moving and a "reverse" indication has been received by the control system for over 5 to 15 minutes, then suspension of the operation of the input is terminated.
Similarly, the auxiliary input must not remain "on" for more than 15 minutes while the vehicle is in motion. If this occurs the suspension of the operation of the input is terminated.
The control system's operation may be suspended manually by operating a switch in the vehicle cab. The switch must remain on for over 1/2 second to reject stray electrical surges. If the manual switch suspending operation is activated for over 15 seconds the control system is disabled until a "factory reset" is effected. This may be at the vehicle's terminal.
Emergency Responses
The control system performs a number of validation procedures, and carries-out emergency responses in certain circumstances.
The axle loads are checked regularly for a serious overload condition, i.e. over 30% overload. If this is detected, an error in the control system is presumed and the "fail-safe" mode is adopted. That is, if the axle is down, it is unloaded. Monitoring continues and if this exceptional state ceases, then control resumes.
The ratio between the measured loads on the left and right front air springs is compared. If this exceeds 2:1 (and air pressure is over a minimum level, e.g. 20 lb) then the computer suspends intervention.
If the axle loads are over 20% outside their set-point targets, as determined by the last average value from a sample set, then corrective action is taken immediately, without waiting for a second sampling set.
These procedures ensure that serious conditions are dealt with appropriately, when they arise.
Control System
The control system 30 used in the preferred embodiment is based on a Omron (Trade Mark) C-28K CDRA programmable controller. It is wired to provide electrical controls to the various valves and indicators in the operators cab.
This controller may be programmed by installing an EPROM, or by transferring the program to the RAM within the controller. One of the further inputs is the geometry, weight, etc. of the vehicle.
Then program installed follows the logic flow of FIG. 7 cyclically, operating on a real-time basis.
As well, the analogue signal from the pressure detector is digitized in the preferred embodiment by an Omeron (tm) ClK AD--analogue to digital converter.
Other
Axle loads can equivalently be determined based on knowing the precise weight of the vehicle, its cargo and the locations of those masses in respect to the wheels.
The pressure transducer described can be replaced by a pair of pressure switches capable of variable settings. By setting the pressure controls on the respective switches to the lift and drop points, and sampling the number of events by which the switches are activated, the average pressure can be determined with reference to either pressure switch. This can be done by comparing the number of events that are counted.
Conclusion
The foregoing constitutes a description of a series of embodiments of the invention. These are exemplary only. The invention in its broadest and more particular aspects is further described and defined in the claims which now follow. | A control system for a liftable auxiliary axle samples axle load measurements, and responds with adjustments based on an average value for axle load taken over a number of samples. Further features provide the system with verification and fail-safe procedures, as well as protection against operator subversion. | 1 |
BACKGROUND OF THE INVENTION
High stools have long been used for seating at jobs that require a higher than normal seating position or greater than normal flexibility or frequent standing up and sitting down, such as working at a drafting table.
A stool known in the prior art features a rigid frame comprising a forward upright and a rear brace resting on parallel runners extending from side to side, which runners curve upward slightly at the ends to facilitate the user's extending sideways with a rocking motion of the stool and a seat, vertically adjustable by means of a telescoping tube located in the middle of the frame. This stool, because of its construction and the sidewards bending strain to which it is subjected, demands that the members be rugged, a requirement that results in a rather heavy stool that is difficult to handle. In addition to the handling difficulty, the construction is bulky and unfavorable for storage.
SUMMARY OF THE INVENTION The invention relates to a work-stool featuring a substantially upright slanting seat member bearing a forward-projecting seat and a rearwardly extending floor brace, in which stool the seat member and the brace are formed from pairs of rigid members, in which stool stability is provided by widening the brace as it reaches the floor, and in which the brace may be folded flat against the seat member for storage.
Another feature of the invention is that the seat member and brace are formed from light tubes, resulting in decreased weight and easier handling compared with prior art stools.
Yet another feature of the invention is that the lower portions of the brace and the seat member are located away from the user's feet.
Yet another feature of the invention is the decrease in storage space afforded by the folding frame.
Yet another feature of the invention is the durability of the mechanism for positioning the brace at a predetermined position when the stool is in use.
Yet another feature of the invention is a hinge that is designed to facilitate mass production.
Yet another feature of the invention is the safety feature of having the rotating portion of the joint enclosed within a protective cover.
Still another feature of the invention is the comfort afforded the user by ventilation provided by texture molded into the top surface of the seat.
BRIEF DESCRIPTION OF THE DRAWING
Other features and advantages of the invention will become evident from a study of the detailed description of the drawings, in which:
FIG. 1 shows a perspective view of a work stool according to the invention;
FIG. 2 shows a side view of the connection between the frame and the seat;
FIG. 3 shows a side view of one of the hinges joining the brace and the seat member;
FIG. 4 is a section along line IV--IV in FIG. 3;
FIG. 5 shows a plan view of the seat;
FIG. 6 shows a section of the seat along line VI--VI in FIG. 5.
DETAILED DESCRIPTION
In FIG. 1 the main components of stool 1 are seat member 2, brace 3 disposed at the rear of seat member 3, and seat 4 projecting forward from seat member 2.
Seat member 2 illustratively comprises two parallel members 5 and 6, bent at the top to form headpiece 7 and supported at the bottom by slanting members 8 and 9, respectively, which slanting members connect with footpiece 10 to complete a symmetric frame. The frame may be formed from a single member or from several shorter pieces. The members, illustratively tubular, may have any convenient shape. Hinges 11 and 12, connecting brace 3 and members 5 and 6, are located between the middle of the frame and the connection between members 5 and 6 and members 8 and 9. Brace 3 comprises two members, 13 and 14, which extend away from the hinges to crosspiece 15, which connects their lower ends. Brace 3 is in the general shape of a trapezoid with the lower side resting on the floor and with the shorter parallel side open, having the same axis of symmetry as frame 2 and being composed of a single tubular member.
Hinges 11 and 12 position brace 3 at the correct angle and also swing to position brace 3 flat against frame 2. In the spread position shown in FIG. 1, the spread is limited by a stop, not shown, so that the stool may be set up with footpiece 10 on one side and crosspiece 15 on the other side. Brace 3 is positioned substantially at right angles to frame 2.
Seat 4 comprises seat body 16 and mounting 17. Mounting 17 passes behind members 5 and 6 on the same side as brace 3 and extends outward with forward projecting ears 18 on both sides of seat body 16, which seat body projects forward substantially horizontally when stool 1 is in its use position. Seat body 16 and projecting ears 18 are fastened together in the upper portion of the projecting ears 18 with two colinear rivets 19, which define a rotation axis about which seat body 16 may be rotated up against frame 2 as shown in FIG. 2. In the lowered position, that part of seat body 16 that is within mounting 17 rests against members 5 and 6 so that when the weight on seat body 16 is increased, the pressure on members 5 and 6 is also increased and the vertical position is maintained by the increased friction. On the other hand, by lifting the seat, the friction may be eliminated so that the vertical position of the seat may be changed.
A detailed elevation showing the adjustment and bracing of seat 4 against frame 2 is shown in FIG. 2 in which a portion of member 5, a portion of seat body 16 (the in-use position in solid lines; the folded position in broken lines), mount 17 and one of rivets 19 is displayed. In the use position the lower portion (21) of rear edge 20 of seat body 16 presses against members 5 and 6. Rear face 22 of the seat body is indicated in the raised position in FIG. 2. Face 22 increases the clamping effect on tubes 5 and 6 of mounting 17 on the one side and seat body 16 on the other. In the upper region, especially near rivets 19, rear edge 20 of seat body 16 is separated well enough from tubes 5 and 6 to permit the folding of seat body 16 and for the vertical adjustment of seat 4 in the folded position. It should be understood that fastening means of conventional type may be used in place of the mechanism described above.
FIGS. 3 and 4 are detail views of the hinge 12. The hinge between tube 6 and brace 14 is indicated as number 25, and is formed from two gripping members 26 and 27 and pivot 28. Gripping members 26 and 27 are mirror images of one another. One end 35 of gripping member 26 curves out of the plane of the paper in FIG. 3, for gripping frame-member 6. The other end has a horseshoe shape 29 in that the outline of the member is a half circle centered on pivot 28, having a flange (30, 31) projecting out of the plane of the paper in FIG. 3. Flanges 30, 31 are shown in broken lines in FIG. 4, which is a section looking upward along line IV--IV. in FIG. 3. Near member 6, flanges 30, 31 are parallel to each other and perpendicular to edge 32 of end 35. As can be seen in FIG. 4, flanges 30, 31 and 35 all project equally far from the plane of the paper in FIG. 3, which paper plane is the plane of the main portion 33 of member 26. The corresponding portion 34 of member 27 is substantially parallel to portion 33. The distance between portions 33 and 34 is set so that there is clearance for the rotation of member 14 through opening 40.
Member 6 is prevented from moving out of the plane of the paper in FIG. 3 by the pressure of curved portions 35 and 36. It is prevented from moving sideways in the plane of the paper by edge 32 of curved portion 35 and those edges of flanges 30 and 31 that are in proximity with member 6. Curved portions 35 and 36 are formed to mate closely with member 6. Flange 30 ends at edge 39, against which member 14 rests when the seat is in the use position. The extension of flanges 30 and 31 toward the other gripping member provides a safety feature in that the enclosure of the pivoting area thus effected eliminates the danger of pinching when the frame is set up.
Member 14 pivots about pivot 28 which passes through member 14 a certain distance from end 41. This distance is so chosen that in the use position end 41 of brace member 14 touches the outside of member 6. End 41 is shaped to contact member 6 over a large area and thus to avoid the high pressures and resulting deformations that would result from a small contact area. Pivot 28 comprises a hollow pivot 42 with inner threads and threaded pivots or screws 43 which fasten gripping members 26 and 27 to pivot 42. Pivot 42 spaces members 26 and 27 by a predetermined distance. Pivot 42 passes through member 14 and has a smooth cylindrical surface that facilitates the pivoting of member 14 about pivot 28.
This pivot mechanism is simple, inexpensive, easy to fabricate in mass production and safe. Further, the direct contact between the brace members and the first member forms a highly desirable and reliable stop. In addition, pressure of member 14 against edge 39 relieves the burden on pivot 28.
FIGS. 5 and 6 show the seat in more detail. The shape of the seat is wider and flatter than a saddle. Seat 16 is hollow, double-shelled and blown out of one piece of plastic. As the section in FIG. 6 shows, it has a top surface contoured to fit the body with a high back and side edge and a rather flat bottom surface 48, which bottom 48 includes a molded grip 49. At the back there is a mounting 50 with a hole 51 for a fastener, so that the seat can be pivoted up to lie against frame 2.
Surface 47 is textured with a plurality of nubs 52 and a pattern of interconnected grooves 53 that is open to several sides. This channel system facilitates the ventilation of surface 47 in use, since the openness of the grooves permits the rapid dissipation of moisture. With the smoothly rounded nubs there is less damage and abrasion to clothing. At the same time the channel system is shallow for easy cleaning. For better ventilation of the main part of seat body 16, there are additional ventilation holes 54 in the channel 15. In the area surrounding holes 54, the top and bottom surfaces are connected together so that a direct ventilation passage is provided through seat body 16.
Obviously, the seat described above may be produced in many similar equivalent shapes and from many equivalent materials, such as plywood.
Although the invention is illustrated and described with reference to one preferred embodiment thereof, it is to be expressly understood that it is in no way limited to the disclosure of such a preferred embodiment, but is capable of numerous modifications within the scope of the appended claims. | The invention relates to a work stool used for a higher than normal seating position as required when working at a drafting table or the like. Features of the invention include a light weight frame that folds for storage, a wide base that does not interfere with the user's feet, and a vertically adjustable seat having a textured surface for ventilation. | 0 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a damping force generating mechanism for generating a damping force by pressing an elastic body.
2. Description of the Background Art
A damping force generating mechanism is used for various portions required for absorbing vibration, for example, used for a so-called bottom link type suspension of a motorcycle in which a front wheel is suspended from lower end portions of a front fork through links. A general example of such a bottom link type suspension is shown in FIG. 16 (see Japanese Patent Laid-open No. Sho 62-187608).
Referring to FIG. 16, there is shown a scooter type motorcycle 01 . A steering shaft 03 is turnably fitted in a head pipe 02 . A pair of right and left front forked portions 04 are integrally mounted on the lower end of the steering shaft 03 . A front wheel 06 is suspended from the lower ends of the front forked portions 04 through rocking arms 05 as link members.
With respect to the rocking arm 05 , the base end thereof is pivotably supported on the lower end portion of the front forked portion 04 , and the free end portion thereof rotatably supports the front wheel 06 . A suspension spring 07 is interposed between the upper portion of the front forked portion 04 and an approximately central portion of the rocking arm 05 .
A shock load applied to the front wheel from irregularities on the ground is damped by the suspension springs 07 . However, when a shock load is applied with an abrupt shock load, the suspension springs are largely rebounded after being contracted once.
In an example described in Japanese Patent Publication No. Sho 57-49432, as shown in FIG. 17, a front end of a link 012 is pivotably supported on the lower end portion of a front forked portion 011 containing a hydraulic damping mechanism. A front wheel 013 is rotatably supported on a central portion of the link 012 . A subcushion unit 14 is interposed between the rear end of the link 012 and the central portion of the front forked portion 011 .
The subcushion unit 014 includes a cylindrical main body 015 pivotably mounted on the front forked portion 011 . A piston 016 is slidably inserted in the cylindrical main body 015 and is connected to a leading end of a rod 017 pivotably mounted on the link 012 . A cushion rubber 018 utilized as a damping member is inserted in the cylindrical main body 015 in such a manner as to be mounted on the upper surface of the piston 016 . A stopper rubber 019 utilized as a stopper member is inserted in the cylindrical main body 015 in such a manner as to be mounted on the lower surface of the piston 016 .
The subcushion unit 014 thus generates a compression side damping force by the cushion rubber 018 , and also generates a tensile side damping force by the stopper rubber 019 . Consequently, the subcushion unit 014 can suppress both the bound and rebound of the front wheel 013 .
The above subcushion unit 014 , however, has a disadvantage. Since the piston 016 is slid in the cylindrical main body 015 , and the cushion rubber 018 and the stopper rubber 019 are separately provided on the upper and lower surfaces of the piston 016 , the mechanism is complicated in structure, being heavy and expensive.
SUMMARY OF THE INVENTION
In view of the foregoing, an object of the present invention is to provide an inexpensive damping force generating mechanism capable of generating both a compression side damping force and a tensile side damping force with a simple, lightweight structure.
To achieve the above object, a damping force generating mechanism is provided including an elastic body which generates a damping force when being pressed, and an internal pressure generating member inserted in the elastic body which resists the pressing force.
With this configuration, the mechanism enables a large displacement due to bending deformation of the elastic body and thereby it enables absorption of a sufficient energy. The creep generated upon bending deformation of the elastic body can be reduced by repulsion of the internal pressure generating member inserted in the elastic body accompanied by compressed deformation of the internal pressure generating member. Accordingly, a damping force generating mechanism can be obtained which is capable of reducing the characteristic change due to permanent set. The restoring ability after release of a load is also excellent due to repulsion of the internal pressure generating member.
The internal pressure generating member may comprise a spring member. With this configuration, the creep of the elastic body is reduced by repulsion of the spring member accompanied by the compression thereof. Accordingly, it is possible to make the characteristic change due to permanent set smaller and to enhance the restoring ability.
The internal pressure generating member may comprise a partitioned chamber containing a compressive gas or liquid. With this configuration, the creep of the elastic member is reduced by repulsion of a compressive gas or liquid compressed and deformed together with the partitioned chamber. Accordingly, it is possible to make the characteristic change due to permanent set smaller and to enhance the restoring ability.
The internal pressure generating member may comprise an elastic organic material. The internal pressure generating member, which is made from the organic material, can be easily molded in a shape most suitable for the application. The organic material may have a hollow portion. With this configuration, when the organic material is compressed, a specific repulsive force can be obtained by the presence of the hollow portion. The organic material may be a polyester-urethane based material. With this configuration, it is possible to obtain a specific repulsive force by a large elasticity of a polyester-urethane based material.
To further achieve the object of the invention, a damping force generating mechanism is provided which includes an elastic body which generates a damping force when being pressed, and a restricting wall for suppressing expansion of the elastic body generated in the direction perpendicular to the pressing direction of the elastic body.
When the elastic body is pressed, the expansion of the elastic body in the direction perpendicular to the pressing direction is restricted by the restricting wall. As such, the force of the elastic body applied to the restricting wall becomes larger and the sliding resistance of the elastic body is increased. As a result, a desirable relationship of load to displacement can be easily obtained by the action of the sliding resistance of the elastic body in addition to the elastic characteristic of the elastic body.
The elastic body may be separated from the restricting wall with a gap therebetween at the beginning of pressing of the elastic body, and brought into contact with the restricting wall with progressive pressing of the elastic body.
At the beginning of the pressing, since the elastic body is not brought into contact with the restricting wall due to the gap therebetween, the load is gradually increased with an increase in displacement only by the elastic characteristic of the elastic body. However, as the elastic body is pressed to a state where the elastic body is in contact with the restricting wall, the load is rapidly increased with an increase in displacement by a combination of the sliding resistance of the elastic body and the elastic characteristics of the elastic body. As a result, a desirable relationship of the load to the displacement can be obtained.
The contact area of the elastic body with the restricting wall may be enlarged with further progress of pressing of the elastic body. With this configuration, after the pressed elastic body is brought into contact with the restricting wall, the contact area of the elastic body with the restricting wall is enlarged and thereby the sliding resistance of the elastic body is increased. As a result, a desirable smooth relationship of the increased load to the increased displacement can be obtained.
The elastic body may have a hollow portion opened to the restricting wall side, with an intermediate elastic body inserted in the hollow portion. Therefore, when the elastic body is pressed, the intermediate elastic body is compressed, being swelled out of the opening of the hollow portion, and is brought in presscontact with the restricting wall.
When the elastic body is pressed, sliding resistance is generated due to the contact of the elastic body with the restricting wall in addition to the elastic characteristics of the elastic body, and also the sliding resistance of the intermediate elastic body due to the pressing contact of the restricting wall with the intermediate elastic body compressed and swelled from the opening of the hollow portion. As a result, a desirable relationship of the load to the displacement of the elastic body can be easily obtained.
To further achieve the object of the invention, a damping force generating mechanism is provided which includes an elastic body which generates a damping force when being pressed, a hollow portion opened in the elastic body in the direction perpendicular to the pressing direction, an intermediate elastic body inserted in the hollow portion, and a restricting wall provided opposite to the opening of the hollow portion. Thus, when the elastic body is pressed, the intermediate elastic body is compressed, being swelled out of the opening of the hollow portion, and is brought into pressing contact with the restricting wall.
At the beginning of the pressing of the elastic body, elastic characteristics of the elastic body and the intermediate elastic body are generated. However, as the pressing of the elastic body proceeds, the intermediate elastic body is compressed, being swelled out of the hollow portion of the elastic body, and is brought into contact with the restricting wall. Thus, sliding resistance of the intermediate elastic body is generated. As a result, a desirable relationship of the load to the displacement of the elastic body can be easily obtained.
Further scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will become more fully understood from the detailed description given hereinbelow and the accompanying drawings which are given by way of illustration only, and thus are not limitive of the present invention, and wherein:
FIG. 1 is a side view of a scooter-type motorcycle including a wheel suspension to which a damping force generating mechanism according to a first embodiment is applied, with parts partially omitted;
FIG. 2 is a side view of a front forked portion and the vicinity thereof;
FIG. 3 is a sectional view of essential portions of the front fork portion;
FIG. 4 is a sectional view taken on line IV—IV of FIG. 3;
FIG. 5 is an exploded view in perspective of a case, lid member and locking piece;
FIG. 6 is a sectional view of an elastic rubber body;
FIG. 7 is a view seen in the direction shown by arrow VII of FIG. 6;
FIG. 8 is a view seen in the direction shown by arrow VIII of FIG. 6;
FIG. 9 is a view seen in the direction shown by arrow IX of FIG. 6;
FIG. 10 is a graph showing an elastic characteristic of the elastic rubber body;
FIG. 11 is a sectional view of essential portions of a front forked portion according to a modification of the first embodiment;
FIG. 12 is a view seen from in the direction shown by arrow XII of FIG. 11, showing a locking portion of a lever with an elastic rubber body;
FIG. 13 is a view showing another example of the locking portion of the lever with the elastic rubber body shown in FIG. 12;
FIG. 14 is a sectional view of essential portions of a front forked portion according to another modification of the first embodiment;
FIG. 15 is a view seen from in the direction shown by arrow XV of FIG. 14, showing a locking portion of a lever with an elastic rubber body;
FIG. 16 is a view showing a motorcycle including a prior art front wheel suspension;
FIG. 17 is a sectional view showing another prior art front wheel suspension;
FIG. 18 is a side view of an elastic body containing a spring member according to a second embodiment;
FIG. 19 is a top view of the elastic body shown in FIG. 18;
FIG. 20 is a sectional view showing a damping force generating mechanism of a wheel suspension;
FIG. 21 is a sectional view showing the damping force generating mechanism of FIG. 20, which is in a state different from that in FIG. 20;
FIG. 22 is a graph showing an elastic characteristic of the damping force generating mechanism shown in FIG. 20;
FIG. 23 is a graph showing a change in creep amount with an elapsed time for the damping force generating mechanism shown in FIG. 20;
FIG. 24 is a sectional view of essential portions of a wheel suspension using a damping force generating mechanism according a modification of the second embodiment;
FIG. 25 is a sectional view of the essential portions of the damping force generating mechanism of FIG. 24, which is in a state different from that shown in FIG. 24;
FIG. 26 is a view showing a damping force generating mechanism of a wheel suspension according to a third embodiment;
FIG. 27 is a sectional view taken on line XXXVII—XXXVII of FIG. 26;
FIG. 28 is a sectional view showing the damping force generating mechanism of the wheel suspension of FIG. 26, which is in a state different from that in FIG. 26;
FIG. 29 is a sectional view taken on line XXIX—XXIX of FIG. 28;
FIG. 30 is a graph showing an elastic characteristic of the damping force generating mechanism shown in FIG. 26;
FIG. 31 is a sectional view of essential portions of a wheel suspension using a damping force generating mechanism according to a modification of the third embodiment;
FIG. 32 is a transverse sectional view taken on line XXXII—XXXII of FIG. 31;
FIG. 33 is a sectional view of the damping force generating mechanism of FIG. 31, which is in a state different from that in FIG. 31;
FIG. 34 is a sectional view of essential portions of a wheel suspension using a damping force generating mechanism according to another modification of the third embodiment; and
FIG. 35 is a sectional view of the damping force generating mechanism of FIG. 34, which is in a state different from that in FIG. 34 .
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
A damping force generating mechanism according to a first embodiment is described with reference to FIGS. 1 to 10 . FIG. 1 is a side view of a scooter-type motorcycle 1 including a wheel suspension to which a damping force generating mechanism in the embodiment is applied, with parts partially omitted.
A low level floor 4 is formed between a front portion 2 and a rear portion 3 of the body. A down frame 6 extends downwardly from a head pipe 5 provided on the front portion 2 of the body, being curved rearwardly from the lower end portion, and is integrated with the floor 4 .
A steering shaft 7 is turnably fitted to the head pipe 5 . A pair of right and left front forked portions 8 are integrally mounted on the lower end of the steering shaft 7 , and they extend downwardly therefrom. A rocking arm 9 as a link member is pivotably supported at the lower end of each front forked portion 8 by means of a pivot arm bolt 11 . A front wheel 13 is rotatably supported by the free ends of the rocking arms 9 through a front axle 12 .
The front forked portion 8 is U-shaped in cross section with a front wall and both side walls. The right and left side walls at the lower end portion of the front forked portion 8 have bolt holes. A bush 14 provided in a base end pivot portion 9 a of the rocking arm 9 is fitted between both side walls of the front forked portion 8 at a position corresponding to the bolt holes. The bush 14 is rotatably supported by a pivot arm bolt 11 passing through the bush 14 and the bolt holes of the side walls of the front forked portion 8 . Each side of the base end pivot portion 9 a of the rocking arm 9 is formed in a cylindrical shape having an enlarged diameter. A plate-like lever 10 is integrated with the outer peripheral surface of the cylindrical side portion of the base end pivot portion 9 a and extends therefrom in the radial direction.
In a state in which the rocking arm 9 extends rearwardly from the base end pivot portion 9 a , the lever 10 extends obliquely, upward at an angle of about 60 degrees relative to the rocking arm 9 . That is, it extends between the front forked portion 8 and the rocking arm 9 .
A fan-shaped case 15 is fixedly inserted in the front fork portion 8 at a position adjacent to the upper portion of the base end pivot portion 9 a of the rocking arm 9 .
As shown in FIG. 5, the case 15 is formed into a box-like shape having a fan-shaped side wall 15 a , an outer peripheral wall 15 b , a front wall 15 c and a rear wall 15 d . A slot 15 e is formed in the side wall 15 a along the front edge, and three circular holes 15 f are formed in upper and lower ends of the front wall 15 c and in the upper end of the rear wall 15 d in such a manner as to pass therethrough in the right and left direction, that is, in the width direction.
As shown in FIG. 5, there is provided a plate-like lid member 16 opposed to the side wall 15 a for blocking the opening of the case 15 . The lid member 16 , which is formed into the same fan-shape as that of the side wall 15 a , has a slot 16 e corresponding to the slot 15 e , and three circular holes 16 f corresponding to the circular holes 15 f.
A locking piece 17 is locked in the slots 15 e and 16 e opposed to each other. In a state in which the lid member 16 is fitted to the ease 15 , only the lower side of the case 15 is opened.
An elastic rubber body 20 is contained in the case 15 covered with the lid member 16 . The elastic rubber body 20 is formed into a shape shown in FIGS. 6 to 9 . That is, the elastic rubber body 20 has a fan-shaped cross section similar to but smaller than that of the inner space of the case 15 , and also has a large projection 20 a projecting from the rear surface of the fan-shaped cross section. In addition, corners at upper and lower ends of the front side of the fan-shaped cross section are slightly cut off.
A circular hole 20 b and a large-sized irregular rectangular hole 20 c are formed fore and aft in the elastic rubber body 20 having the above contour in such a manner as to pass through the elastic rubber body 20 in the width direction. Slots 20 e and 20 f are also formed in the elastic rubber body 20 . The slot 20 e (corresponding to the slot 15 e of the above case 15 ) is disposed between the circular hole 20 b and the front surface of the elastic rubber body 20 in such a manner as to extend in parallel to the front surface. The slot 20 f passes through a base portion of the projection 20 a in parallel to the rear surface of the elastic rubber body 20 .
The elastic rubber body 20 exhibits a hysteresis characteristic of compression and tensile actions, and it has both elastic and damper functions.
The elastic rubber body 20 , case 15 , and the like are assembled as follows. The lever 10 integrated with the rocking arm 9 is made to pass through the slot 20 f formed in the base portion of the projection 20 a of the elastic rubber body 20 , to be thus mounted in the elastic rubber body 20 . The case 15 covers the elastic rubber body 20 from the left side, and the lid member 16 closes the case 15 from the right side. Thus, the lever 10 is in a state being inserted in the case 15 through the lower opening of the case 15 .
The locking piece 17 is made to pass through the slot 15 e of the case 15 , the slot 20 e of the elastic rubber body 20 , and the slot 16 e of the lid member 16 , and hence to be fitted in the slots 15 e , 20 e and 16 e . Then, a screw 25 is threaded into the circular hole 15 f formed in the upper end portion of the rear wall 15 d of the case 15 and in the circular hole 16 f of the lid member 16 corresponding to the circular hole 15 f , to thus integrally fix the case 15 to the lid member 16 .
The case 15 covered with the lid member 20 , which is mounted to the lever 10 through the elastic rubber body 20 , is inserted into the recess on the back side of the front forked portion 8 to the extent that the front wall 15 c of the case 15 is brought into contact with the bottom of the recess.
Each of the right and left side walls of the front fork portion 8 has circular holes at specific upper and lower positions along the bottom. The circular holes 15 f and 16 f of the case 15 and the lid member 16 are aligned with the above circular holes, and bolts 26 are made to pass through these circular holes and are attached to nuts. Accordingly, the case 15 and the lid member 16 are co-fastened to the front forked portion 8 with the bolts 26 , to be thus fixed thereto.
In the assembled state, the elastic rubber body 20 is disposed in the case 15 as shown in FIGS. 3 and 4. That is, with respect to the elastic rubber body 20 , the front end portion is positioned in a state being locked by the locking piece 17 , the rear portion is held by the lever 10 inserted in the slot 20 f , and the projection 20 a projecting rearward is allowed to be brought in contact with the rear wall 15 d of the case 15 .
In this way, the front wheel suspension in this embodiment has a very simple structure that the elastic rubber 20 is interposed between the front forked portion 8 and the lever 10 in a state in which the front portion thereof is locked by the locking piece 17 and the rear portion thereof is locked by the lever 10 .
When the front wheel 13 is applied with a shock generated by irregularities of the ground and the rocking arm 9 is rocked, the positional states of the rocking arm 9 and the lever 10 integrated with the rocking arm 9 are changed from states indicated by a solid line of FIG. 3 to states indicated by a two-dot chain line. As a result, the lever 10 compresses the elastic rubber body 20 in the forward direction, that is, on the front forked portion 8 side, and elastically deforms it, to thereby generates a compression side damping force.
In this case, the elastic rubber body 20 has a progressive elastic characteristic shown in FIG. 10 in which the increasing ratio of a load to a displacement is large in a large displacement region as compared with a small displacement region. Specifically, in a small displacement region that only the irregular rectangular hole 20 c of the elastic rubber body 20 is deformed, a compressive stress is moderately generated to the displacement, but in a large displacement region that not only the irregular rectangular hole 20 c but also the circular hole 20 b are deformed, the compressive stress is rapidly increased with the displacement.
On the other hand, when the rocking arm 9 and the lever 10 are reversely rocked, the main body of the elastic rubber body 20 generates a tensile damping force, and simultaneously the projection 20 a is pressed and compressed by the rear wall 15 d of the case 15 , thus acting as a rebound stopper.
Accordingly, while the front wheel suspension in this embodiment has the simple structure in which the elastic rubber body 20 is interposed between the front fork portion 8 and the lever 10 , it exhibits a desirable damping effect due to the function of the elastic rubber body 20 generating both a compression side damping force and a tensile side damping force thereby effectively absorbing shock applied from the ground to the front wheel 13 .
In this way, the front wheel suspension in this embodiment does not require a pivot for supporting the elastic rubber body 20 , and has no sliding portion for a piston or the like, so that it can obtain a stable damping characteristic without the occurrence of any sliding friction, thereby enhancing the durability with a simple, lightweight, and inexpensive structure.
It is to be noted that it becomes possible to obtain various other elastic characteristics of the elastic rubber body 20 by changing the shapes of the circular hole 20 b and the irregular rectangular hole 20 c of the elastic rubber body 20 , and hence to easily provide an elastic body most suitable for each kind of vehicle.
Next, the structure of a front wheel suspension disposed at the lower end portion of a front forked portion 40 according to a modification of the first embodiment will be described with reference to FIGS. 11 and 12. This modification has the same basic structure as that of the first embodiment, except for slightly changed shapes of the parts. A base end pivot portion 41 a of a rocking arm 41 is rockably supported, by means of a pivot arm bolt 42 , at the lower end of the front forked portion 40 . The rocking arm 41 has a plate-like lever 43 extending from the base end pivot arm portion 41 a in the radial direction. A fan-shaped case 44 adjacent to the upper side of the base end pivot portion 41 a of the rocking arm 41 is fixedly fitted in the front forked portion 40 .
An elastic rubber body 45 , which has throughholes 45 b and 45 c passing through the elastic rubber body 45 in the width direction, is fitted in the case 44 . A locking piece 46 passes through the front portion of the elastic rubber body 45 and locks it. A lever 43 is inserted in a slot 45 d formed in the rear portion of the elastic rubber body 45 , and a projection 45 a projecting rearwardly from the rear portion is allowed to be brought into contact with the rear wall of the case 44 .
The lever 43 has a swelled portion 43 b , a stepped portion 43 c , and a flange portion 43 d . As shown in FIG. 12, the swelled portion 43 b is swelled right and left, that is, in the width direction on the base end side from a locking portion 43 a to be locked with the elastic rubber body 45 , and the stepped portion 43 c is formed at the boundary between the locking portion 43 a and swelled portion 43 b . The flange portion 43 d projects upward from the leading end of the lever 43 , as shown in FIG. 11 .
The lever 43 passes through the slot 45 d of the elastic rubber body 45 , and the elastic rubber body 45 is locked with the locking piece 43 a . At the same time, the elastic rubber body 45 is held between the stepped portion 43 c and the flange portion 43 d of the lever 43 . The sliding motion of the elastic rubber body 45 relative to the lever 43 is thus restricted by the stepped portion 43 c and the flange portion 43 d of the lever 43 . This allows the elastic rubber body 45 to effectively generate a damping force.
FIG. 13 shows another example of the lever. A lever 50 has a fitting portion 50 c on the base end side of a locking portion 50 a at the boundary between the locking portion 50 a and a swelled portion 50 b , and also has on the leading end side a flange portion 50 d projecting in the right and left direction. An elastic rubber body 51 is held between the fitting portion 50 c and the flange portion 50 d of the lever 50 , so that the sliding motion of the elastic rubber body 45 relative to the lever 43 is restricted.
Next, another modification of the first embodiment will be described with reference to FIGS. 14 and 15. The modification, which also concerns a front wheel suspension provided on the lower end portion of a front forked portion 60 , is substantially similar to the above modification shown in FIGS. 11 and 12 in terms of shapes of a rocking arm 61 , a lever 63 , a case 64 , and an elastic rubber body 65 , but is different therefrom in terms of the structure of restricting the sliding motion of the elastic rubber body 65 relative to the lever 63 .
A circular hole 63 b is formed in a plate-like locking portion 63 a of the lever 63 , and a circular hole 65 e corresponding to the circular hole 63 b is formed in the elastic rubber body 65 . The circular hole 65 e is continuous to a slot 65 d formed in a rear projection 65 a , and further to a recess formed in the opposed portion, to the slot 65 d , of the rear portion of the elastic rubber body 65 . A knock pin 66 is inserted in the circular hole 63 b of the lever 63 and the circular hole 65 e of the elastic rubber body 65 .
Accordingly, the sliding motion of the elastic rubber body 65 relative to the lever 63 is restricted by the knock pin 66 , so that the elastic rubber body 65 is allowed to effectively generate a damping force. The lever 63 , which has no flange portion at the leading end thereof, is easily inserted in the slot 65 d of the elastic rubber body 65 upon assembly.
Although description has been made by example of the front wheel suspension for a motorcycle in the above first embodiment and modifications thereof, the present invention can be applied to a rear wheel suspension, and used as a damper mechanism for a power transmission of an engine and a damper mechanism for a cam chain tensioner.
Hereinafter, a second embodiment of the present invention will be described with reference to FIGS. 18 to 23 . In the second embodiment also concerning a front suspension mechanism as in the first embodiment, parts corresponding to those in the first embodiment are indicated by the same reference characters.
FIGS. 18 and 19 shows the second embodiment, in which four holes having different shapes and passing through an elastic rubber body 120 i in the width direction are formed in the elastic rubber body 120 . The four holes, an elliptic hole 120 b (corresponding to the slot 15 e of the case 15 in the previous embodiment), an irregularly elliptic hole 120 c , a developed fan-shaped hole 120 d , and a contracted fan-shaped hole 120 e are arranged from the front side in this order. Further, a through-slot 120 f is formed in the base portion of a projection 120 a along the rear surface of the elastic rubber body 120 .
A metal spring member 121 as an internal pressure generating member is inserted in the developed fan-shaped hole 120 d . The spring member 121 is composed of radially extending plate springs arranged in a fan-shape corresponding to the internal space of the developed fan-shaped hole 120 d . The spring member 121 is made repulsive against a compression side pressing force while generating an internal pressure.
The elastic rubber body 120 is contained in a case 15 in a state shown in FIG. 20 . That is, with respect to the elastic rubber body 120 , the front end portion is locked and positioned by a locking piece 17 passing through the front portion. A lever 10 is inserted in the slot 120 f , and a projection 120 a projecting rearwardly is brought into contact with a rear wall 15 d of the case 15 .
As described above, the front wheel suspension in this embodiment has a simple structure in which the elastic rubber body 120 containing the spring member 121 is interposed between a front forked portion 8 and the lever 10 in the state that the front portion of the elastic rubber body 120 is locked with the locking piece 17 and the rear portion of the elastic rubber body 120 is locked with the lever 10 .
When a front wheel 13 is applied with shock generated by irregularities of the ground or a load upon braking and thereby the rocking arm 9 is rocked, the rocking arm 9 and the lever 10 integrated with the rocking arm 9 are rocked from a state shown in FIG. 20 to a state shown in FIG. 21 . The lever 10 thus presses the elastic rubber body 120 forward onto the front forked portion 8 , and it elastically deforms the elastic rubber body 120 . As a result, the spring member 121 inserted in the elastic rubber body 120 is compressed and is made repulsive while generating an internal pressure.
In this case, the elastic rubber body 120 has an elastic characteristic shown in FIG. 22, in which the displacement of the elastic rubber body 120 is increased from the initial state having an initial strain to a sufficiently large value by increasing the applied load, and then the displacement is decreased along the hysteresis curve by decreasing the load and finally it becomes zero when the load reaches zero. Accordingly, the elastic rubber body 120 can ensure a large displacement and obtain sufficient energy absorption, and further it improves the initial strain.
The result of an experiment of examining the generation amount of creep of the elastic rubber body 120 containing the spring member 121 is shown in FIG. 23 . In FIG. 23, an example of using the prior art elastic body not containing the spring member is shown by a broken line, and the example using the elastic rubber body 120 containing the spring member 121 is shown by a solid line. As is apparent from this figure, the creep amount of the elastic rubber body 120 is significantly reduced as compared with the prior art elastic body.
The characteristic change of the elastic rubber body 120 due to fatigue is thus small. Further, the elastic rubber body 120 is excellent in restoring ability after release of a load. That is, while the prior art elastic body causes approximately 100% of the permanent strain, the elastic rubber body 120 only causes approximately 40% of the permanent strain.
A modification of the second embodiment will be described with reference to FIGS. 24 and 25. The modification is the same as the second embodiment, except for an elastic body 130 and an internal pressure generating member 131 inserted in the elastic body 130 . In this modification, parts corresponding to those in the second embodiment are indicated by the same characters.
The elastic body 130 is made from polyester elastomer and has an outer shape being substantially the same as that of the elastic body 120 in the second embodiment. Further, an elliptic hole 130 b , and an irregularly elliptic hole 130 c formed in the elastic body 130 , and a slot 130 f passing through the elastic body 130 along the base portion of a rear projection 130 a are formed in the same shapes as those of the corresponding ones in the second embodiment. In this modification, however, the developed fan-shaped hole 120 d and the contracted fan-shaped hole 120 e are omitted, and instead, an irregular circular hole 130 d is formed and an internal pressure generating member 131 is inserted in the irregular circular hole 130 d.
The internal pressure generating member 131 is made from polyester-urethane being softer and more elastic than the elastic body 130 and is formed in a cylindrical shape having a specific wall thickness. When the elastic body 130 is applied with a load and a rocking arm 9 is rocked, the rocking arm 9 and a lever 10 integrated with the rocking arm 9 are rocked from a state shown in FIG. 24 to a state shown in FIG. 25, so that the lever 10 presses the elastic body 130 forward to a front forked portion 8 and thereby it elastically deforms the elastic body 130 . In such a state, the internal pressure generating member 131 inserted in the elastic body 130 is compressed and is made repulsive while generating an internal pressure.
The elastic body 130 can ensure a large displacement and obtain a sufficient energy absorption, and it is significantly reduced in creep by the effect of the internal pressure generating member 131 and thereby it is small in characteristic change due to fatigue. Further, the elastic body 130 is excellent in restoring ability after release of a load.
In addition, the elastic body may be made from rubber in place of polyester-urethane. Also, with respect to the internal pressure generating member 131 made from polyester-urethane, the cylindrical hollow type may be replaced with a solid type. And, a different elastic substance may be inserted in the hollow portion of the elastic body.
The internal pressure generating member may be made from an organic material having a specific elasticity, in place of polyester-urethane. In this case, the organic material can be easily molded into a shape most effective to the application use of the elastic body.
Additionally, it may be considered to form an enclosed partition chamber containing a compressive gas or liquid in the elastic body. When the elastic body is pressed and deformed, the gas or liquid contained in the partition chamber is compressed to generate an internal pressure. Such an elastic body is allowed to be significantly reduced in creep and hence to be reduced in characteristic change, and also to enhance the restoring ability after release of a load.
A third embodiment of the present invention will be described with reference to FIGS. 26 to 30 . In the third embodiment also concerning a front wheel suspension as in the previous embodiments, parts corresponding to those in the previous embodiments are indicated by the same characters. FIG. 27 shows the third embodiment using an elastic body 220 made from polyester elastomer. The elastic body 220 is formed in a shape being substantially similar to but smaller than that of the inner space of the case 15 . The elastic body 220 has right and left side surfaces 220 R and 220 L which are substantially parallel to each other and are slightly curved in such a manner as to be gradually close to each other in the direction from the front side to the rear side, and it has a large projection 220 a projecting from the rear portion thereof.
Three holes of different shapes are formed in the elastic rubber body 220 having such a contour. These holes, an elliptic hole 220 b (corresponding to the elliptic hole 15 e of the case 15 in the previous embodiment), an irregular elliptic hole 220 c , and an irregular elliptic hole 220 d are arranged from the front side in this order. Further, a slot hole 220 e is formed which passes through the base portion of the projection 220 a along the rear surface of the elastic rubber body 220 .
As shown in FIG. 27, the right and left side surfaces 220 R and 220 L of the elastic body 220 contained in the case 15 are respectively brought into contact with a side wall 15 a of the case 15 and a lid member 16 on the front side of the elastic body 220 , that is, on the side locked with a locking piece 17 , and they are gradually separated from the side wall 15 a of the case 15 and the lid member 16 with the increased gap as nearing the rear side. In this way, the front wheel suspension in this embodiment has a simple structure in which the elastic body 220 is interposed between a front forked portion 8 and a lever 10 in such a manner that the front portion thereof is locked with the locking piece 17 and the rear portion thereof is locked with the lever 10 .
When a front wheel 13 is applied with a shock generated by irregularities on the ground or a load upon braking and thereby the rocking arm 9 is rocked, the rocking arm 9 and the lever 10 integrated with the rocking arm 9 are rocked as shown in FIGS. 28 and 29, so that the lever 10 presses the elastic body 220 forward to the front forked portion 8 and thereby it elastically deforms the elastic body 220 .
When being pressed, the elastic body 220 is expanded in the direction perpendicular to the pressing direction, that is, in the vertical direction and also in the right and left direction. The expansion of the elastic body 220 in the right and left direction causes the right and left side surfaces 220 R and 220 L to be swelled and to be respectively brought in contact with the side wall 15 a of the case 15 and the lid member 16 . Consequently, the expansion of the elastic body 220 is suppressed by the above contact, and as the pressing of the elastic body 220 proceeds, the contact area thereof is increased, so that the sliding resistance of the elastic body 220 at the contact surface of the right and left side surfaces 220 R and 220 L with the side wall 15 a of the case 15 and the lid member 16 is increased. Thus, as the displacement (stroke) of the elastic body 220 is increased, the sliding resistance as well as the elastic force of the elastic body 220 is progressively increased.
The stroke-load characteristic in this embodiment is shown by a solid line of FIG. 30 . The stroke-load characteristic forms a hysteresis curve. At the beginning of the motion of the elastic body 220 , that is, when the stroke is small, the sliding resistance of the elastic body 220 is small and thereby the gradient of the curve of the load to the stroke is moderate. When the stroke becomes relatively large, the sliding resistance is added to the elastic force, and thereby the gradient of the curve is increased. When the stroke becomes very large, the gradient is further increased by the action of the progressively increased sliding resistance. In this way, the front wheel suspension in this embodiment exhibits the desirable damping effect.
The action of the sliding resistance can be easily adjusted by changing the shapes of the right and left side surfaces 220 R and 220 L of the elastic body 220 , to thereby easily obtain a specific stroke-load characteristic.
A modification of the third embodiment will be described with reference to FIGS. 31 to 33 . In the modification also concerning a front wheel suspension as in the third embodiment, parts corresponding to those in the third embodiment are indicated by the same characters. An elastic body 230 is formed into the same shape as that of the elastic body 220 in the third embodiment. However, in the elastic body 230 , an intermediate elastic body 235 is inserted in an irregular elliptic hole 230 C as one of hollow portions. The intermediate elastic body 235 is made from a material smaller in elastic modulus than the elastic body 230 , that is, deformable easier than the elastic body 230 .
In a state before the rocking arm 9 is rocked (see FIGS. 31 and 32 ), as shown in FIG. 32, the intermediate elastic body 235 is fitted in the irregular elliptic hole 230 c , that is, not swelled from the right and left openings of the irregular elliptic hole 230 c.
When the front wheel 13 is applied to shock generated by irregularities on the ground and the rocking arm 9 is rocked, the elastic body 230 is pressed and elastically deformed, so that the irregular elliptic hole 230 c is also compressed in the pressing direction and it compresses the intermediate elastic body 235 contained in the hole 230 c . At this time, the intermediate elastic body 235 made from a soft material is easily deformed, being expanded in the direction perpendicular to the compression direction, and is swelled from the right and left openings of the irregular elliptic hole 230 c to be brought in contact with the side wall 15 a of the case 15 and the lid member 16 . The expansion of the intermediate elastic body 235 is thus suppressed by the above contact, and consequently the sliding resistance thereof at the contact surface is increased.
As described above, right and left side surfaces 230 R and 230 L of the elastic body 230 itself are brought in contact with the side wall 15 a of the case 15 and the lid member 16 respectively, so that the sliding resistance of the elastic body 230 is increased. As a result, the elastic forces of the elastic body 230 and the intermediate elastic body 235 and the sliding resistance of the elastic body 230 are further added with the sliding resistance of the intermediate elastic body 235 . The stroke-load characteristic of the front wheel suspension having the above configuration is shown by a broken line of FIG. 30 .
In the stroke-load characteristic of this modification, the gradient of the curve is rapidly raised in a early region with a small stroke, as compared with the characteristic of the third embodiment shown by the solid line. In this way, the front wheel suspension in this modification is allowed to change the stroke-load characteristic with a simple structure in which the intermediate elastic body 235 is inserted and hence to easily obtain a specific characteristic.
Another modification will be described with reference to FIGS. 34 and 35. This modification has the same basic structure as that of the previous modification shown in FIGS. 31 to 33 , except that the shape of an elastic body 240 is slightly different from that of the above-described elastic body 230 . In this modification, parts corresponding to those in the previous modification are indicated by the same characters.
The elastic body 240 having right and left side surfaces 240 R and 240 L parallel to each other is contained in the case 15 between the side wall 15 a and the lid member 16 with gaps therebetween. As shown in FIG. 35, even when the elastic body 240 is pressed, the right and left side surfaces 240 R and 240 L are not brought in contact with the side wall 15 a and the lid member 16 with gaps kept therebetween. Accordingly, upon pressing of the elastic body 240 , the expansion thereof is not restricted, differently from the elastic body 230 in the previous modification.
An intermediate elastic body 245 is inserted in an irregular elliptic hole 240 c of the elastic body 240 , and as shown in FIG. 34, before the elastic body 240 is pressed, the intermediate elastic body 245 is contained in the irregular elliptic hole 240 c . However, as shown in FIG. 35, when the elastic body 240 is pressed, the intermediate elastic body 245 is compressed and expanded in the direction perpendicular to the compression direction, being swelled from the right and left openings of the irregular elliptic hole 240 c , and is brought in contact with the side wall 15 a of the case 15 and the lid member 16 . The expansion of the intermediate elastic body 245 is thus suppressed by the above contact, and thereby the sliding resistance thereof at the contact surface is increased.
Accordingly, when the elastic body 240 is pressed, the elastic force of the elastic body 240 is added with the sliding resistance of the intermediate elastic body 245 , so that there can be obtained a stroke-load characteristic different from that in the previous modification.
The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims. | An inexpensive damping force generating mechanism capable of generating both a compression side damping force and a tensile side damping force has a simple, lightweight structure. The damping force generating mechanism provides an inexpensive axle suspension capable of simplifying the suspension structure, reducing the weight, and effectively utilizing space. The damping force generating mechanism includes an elastic body which generates a damping force when being pressed. An internal pressure generating member is inserted in the elastic body and resists the pressing force. | 1 |
CROSS REFERENCE TO RELATED PATENT APPLICATIONS
This is a national phase filing of International Application No. PCT/EP02/10552, which was filed with the Patent Corporation Treaty on Sep. 19, 2002, and is entitled to priority of European Patent Application No. 01203581.2 filed Sep. 21, 2001 and European Patent Application No. 02076553.3 filed Apr. 19, 2002.
FIELD OF THE INVENTION
The invention relates to a new method for the preparation of organosilylated carboxylate monomers. The invention further relates to said obtained organosilylated carboxylate monomers and in another aspect, the invention further relates to their use for the synthesis of hydrolysable polymers, such as binders for modern antifouling coatings.
BACKGROUND
Antifouling paints are used to prevent and delay the fouling of underwater structures (e.g. ships' bottom, docks, fishnets, and buoys) by various marine organisms such as shells, seaweed, and aquatic bacteria. When such marine organisms adhere and propagate on an underwater structure like the bottom of a ship, the surface roughness of the whole ship may be increased to induce decrease of velocity of the ship or increase of fuel consumption. Further, removal of such aquatic organisms from the ship's bottom needs much labour and a long period of working time. In addition, if these organisms adhere and propagate on an underwater structure such as a steel structure they deteriorate their anticorrosive coating films leading to a reducing of the lifetime of the underwater structure.
Underwater structures are therefore coated with antifouling paint employing polymers containing various hydrolysable groups and more specifically organosilyl groups.
EP 0297505 relates to an antifouling paint that contains a polymer having organosilyl groups and/or organopolysiloxane groups in side chains. Since the organopolysiloxane group is derived from dehydrating condensation or like means of silicon oil with methacrylic acid, this patent refers to a mixture of oligomers having different numbers of the recurrence of the organosiloxane group.
Another patent JP 10245451 A describes a mixture of organosilylated carboxylate oligomers having different numbers of the recurrence of the organosiloxane group in acrylic rubber composition.
WO 8402915 and JP 63215780 A describe an antifouling paint of the hydrolysable self-polishing type employing a methacrylic ester polymer having triorganosilyl group in side chains or a similar polymer. Other examples of patents and patent applications related to the use of organosilyl acrylate polymers in antifouling compositions are EP 131626, U.S. Pat. No. 4,593,055, 4,594,365, JP 63118381 A, EP 0775733, WO 9638508, JP 11116257 A, EP 802243, EP 0714957, JP 07018216 A, JP 01132668 A, JP 05077712 A, JP 01146969 A and U.S. Pat. No. 4,957,989 and hereby incorporated by reference.
Some of the polymers used in the above-described antifouling paints are based on silylated carboxylate monomers.
Several processes are known as conventional techniques for the synthesis of said silylated carboxylate monomers.
JP 5306290 A describes a process to obtain a methacrylic functional group-containing organosilicon compound. The process comprises reacting methacrylic acid with a halogenoalkylsilane (e.g. trialkylsilylchloride) in the presence of a tertiary amine compound having a cyclic structure. This process has disadvantages such as the reduced availability and storage stability of the silyl chloride. Moreover, the reaction yields as a by-product a hydrogen halide (which provokes the corrosion of the production equipment) or a halide salt (which has to be removed by filtration).
The synthesis of trimethylsilyl methacrylate from methacrylic acid and hexamethyldisilazane is described in A. Chapman & A. D. Jenkins J. Polym. Sci. Polym. Chem. Edn. vol 15, p. 3075 (1977).
JP 10195084 A discloses the reaction of unsaturated carboxylic acid such as acrylic acid or methacrylic acid with a trialkylsilylhydride compound in the presence of a copper catalyst. One of the disadvantages of this method is the risk of hydrogenation of the unsaturated carboxylic acid due to a side reaction of the produced H2 on the carbon-carbon double bond.
Trialkylsilylcarboxylates of aliphatic carboxylic acids can be obtained by transesterification. H. H. Anderson et al. describe in J. Org. Chem 1716 (1953) the reactions of triethyl silyl acetates with halogenated propionic acids and in J. Org. Chem. 1296 (1954) the reactions of trifluoro silyl acetates or propionates with chloroacetic acid; they distil the acetic or propionic acid under reduced pressure.
Russian chemists (Izv. Akad. Nauk. Ussr. Ser. Khim. 968 (1957)) run similar reactions at much higher temperatures (190–210° C.).
JP 95070152 A discloses reactions of trialkylsilylacetates with C6 to C30 carboxylic acids (e.g. palmitic, myristic, benzoic, . . . ); the acetic acid is distilled under reduced pressure or azeotropically with hexane.
S. Kozuka et al. in Bull. Chem. Soc. Jap. 52 (7) 1950 (1979) study the kinetics of acyloxy exchange reaction between acyloxysilanes and carboxylic acids. The rate of the reaction has been found to proceed faster with a stronger attacking acid and a more basic leaving acyloxy group.
An object of the present invention is to provide a novel process capable of readily preparing organosilylated carboxylate monomers in a high yield from easily available starting materials.
Another object of the present invention is to provide a more direct method for the synthesis of such organosilylated carboxylate monomers, with easy work-up procedures.
A further object of the present invention is to provide a novel process offering an improvement vis-à-vis of the disadvantages disclosed above.
The present invention is based on the use of unsaturated carboxylic acids with acyloxysilanes to synthesize organosilylated carboxylate monomers. The use of unsaturated carboxylic acids in this reaction was unexpected as it is well known by the man of the art that the unsaturated carboxylic acids are polymerisable and lead to very low rate of reaction.
The present inventor has surprisingly found that by reacting acyloxysilanes with unsaturated carboxylic acids weaker than the leaving acyloxy group, organosilylated carboxylate monomers could be synthesised.
SUMMARY OF THE INVENTION
The present invention relates to a new process for the preparation of organosilylated carboxylate monomers of general formula (I)
wherein
R 1 , R 2 , R 3 , R 4 , R 5 each independently represent an alkyl, an aryl group or a hydrogen atom, R 6 represents a hydrogen atom or a methyl group or —CH 2 —COO—(SiR 4 R 5 O)n-SiR 1 R 2 R 3 wherein R 1 , R 2 , R 3 , R 4 , R 5 are as already defined, R 7 represents a hydrogen atom, an alkyl group or —COOR 9 wherein R 9 represents an alkyl group, n represents a number of dihydrocarbylsiloxane units from 0 to 200,
which process comprises the steps of reacting:
an acyloxysilane of formula (II)
wherein
R 1 , R 2 , R 3 , R 4 and R 5 are as already defined above and, R 8 is a hydrogen atom, a C 1 –C 3 alkyl group, a partially or totally hydrogenated C 1 –C 3 alkyl group, n represents the same number of dihydrocarbylsiloxane units as those defined above in formula (I),
with an unsaturated carboxylic acid of formula (III),
wherein
R 6 is a hydrogen atom or a methyl group or CH 2 COOH and, R 7 has the same meaning as that defined above.
According to one preferred embodiment of the process of the invention, n in formulas (I) and (II) equals zero.
According to another preferred embodiment, n in formulas (I) and (II) represents a number of dihydrocarbylsiloxane units from 1 to 200.
In a preferred embodiment R 1 , R 2 , R 3 , R 4 , R 5 and R 9 each independently represent a linear, branched, cyclic alkyl, aryl or substituted aryl group, saturated or unsaturated, containing from 1 to 12 carbon atoms, preferably from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms, yet more preferably 4 carbon atoms. More preferably, R 1 , R 2 , R 3 , R 4 , R 5 each independently are chosen from the group of methyl, ethyl, propyl, isopropyl, i-butyl, n-butyl, sec-butyl, t-butyl. In a more preferred embodiment R 1 , R 2 , R 3 are n-butyl or isopropyl and n equals zero. In another more preferred embodiment R 1 to R 5 are methyl and n is not zero.
In another embodiment when R 7 is —COOR 9 , the organosilylated carboxylates of general formula (I) and the unsaturated carboxylic compound (III) can be of either cis (maleic) or trans (fumaric) configuration.
The process of the invention enables to obtain organosilylated carboxylate monomers with exactly the desired number of the dihydrocarbylsilyloxane units.
According to one preferred embodiment, the organosilylated carboxylates obtained by the process of the invention have a number of dihydrocarbylsiloxane units (n) equal to 0.
According to another preferred embodiment, the organosilylated carboxylates obtained by the process of the invention have a number of dihydrocarbylsiloxane units (n) from 1 to 200, preferably from 1 to 19, more preferably from 1 to 4.
In a more preferred embodiment the organosilylated carboxylates obtained by the process of the invention are organosilyl acrylates or organosilyl methacrylates.
In yet a more preferred embodiment, when organosilyl methacrylates with n equals 1 are obtained by the process of the invention, not all of R 1 to R 5 are methyl.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a new process for the synthesis of organosilylated carboxylates according to the general scheme:
Unsaturated carboxylic acids represented by the above formula (III) are mixed with acyloxysilane (II) with or without solvent. The reaction is preferably set up in such a way that each mole of acyloxysilane is treated with at least one mole of unsaturated carboxylic acid. Examples of solvent which can be used in the process according to the invention include hexane, toluene, xylene, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and mixtures thereof. A preference is given for a solvent that causes no distillation of any of the reactants. A much-preferred solvent is a solvent making a low boiling azeotrope with the distilled acid. The reaction may be conducted with or without added polymerisation inhibitor. The reaction progress may be monitored by any suitable analytical method as well as with the determination of the amount of acid distilled.
Examples of unsaturated carboxylic acids which can be used in the process according to the invention include acrylic acid, methacrylic acid, crotonic acid, angelic acid, tiglic acid, maleic acid, fumaric acid, itaconic acid (methylenesuccinic acid), acrylic acid and methacrylic acid, and the mono-esters of the diacids, such as e.g. mono-butyl maleate, mono-ethyl fumarate.
The acyloxysilanes of general formula R 8 —COO—(SiR 4 R 5 —O) n —SiR 1 R 2 R 3 which can be used in the process according to the invention are derived from carboxylic acids R 8 —COOH having a boiling point of maximum 162° C., preferably of maximum 140° C., more preferably of maximum 120° C. in order to facilitate the removal of the product after the transesterification. Examples of acids R 8 —COOH are formic acid, acetic acid, propionic acid, butyric acid; formic acid and acetic acid with respectively 100° C. and 118° C. as boiling point are preferred. Because of the wider availability of trialkylsilylacetates, these products are most preferred for the process of this invention.
In another embodiment of the invention the acyloxysilanes are derived from partially or totally halogenated acids as defined hereabove, preferably from fluorinated or chlorinated acids, more preferably from trifluoroacetic acid with 72° C. as boiling point
The acyloxysilanes (II) for use in the process of the invention are known (see table) or (for higher alkyl groups on the silicium) can be obtained by known methods. Some examples are given in the following table:
Acyloxysilane
CAS registry number
Trimethylsilylformiate
18243-21-5
Trimethylsilylacetate
2754-27-0
Triethylsilylacetate
5290-29-9
Trimethylsilyltrifluoroacetate
400-53-3
Tri-n-propylsilylacetate
17315-26-3
Tri-n-butylsilylacetate
22192-48-9
Triisopropylsilyl acetate
17315-27-4
Trimethylsilylpropionate
16844-98-7
Trimethysilyltrichloroacetate
25436-07-1
Tert-butyldimethylsilyacetate
37170-48-2
Pentamethyl-1-acetoxy-disiloxane
70693-47-9
Heptamethyl-1-acetoxy-trisiloxane
3292-96-4
Nonamethyl-1-acetoxy-tetrasiloxane
3453-81-4
Undecamethyl-1-acetoxy-pentasiloxane
3560-95-0
Tridecamethyl-1-acetoxy-hexasiloxane
144139-44-6
Examples of the organosilylated carboxylate monomers prepared by the process of the invention using (meth)acrylic acid include trimethylsilyl (meth)acrylate, triethylsilyl (meth)acrylate, tri-n-propylsilyl (meth)acrylate, triisopropylsilyl (meth)acrylate, tri-n-butylsilyl (meth)acrylate, triisobutylsilyl (meth)acrylate, tri-s-butylsilyl (meth)acrylate, tri-n-amylsilyl (meth)acrylate, tri-n-hexylsilyl (meth)acrylate, tri-n-octylsilyl (meth)acrylate, tri-n-dodecylsilyl (meth)acrylate, triphenylsilyl (meth)acrylate, tri-p-methylphenylsilyl (meth)acrylate, tribenzylsilyl (meth)acrylate, tri t-butylsilyl (meth)acrylate.
Other examples include ethyldimethylsilyl (meth)acrylate, n-butyldimethylsilyl (meth)acrylate, bis(trimethylsilyl)itaconate, t-butyl dimethylsilyl (meth)acrylate diisopropyl-n-butylsilyl (meth)acrylate, n-octyldi-n-butylsilyl (meth)acrylate, diisopropylstearylsilyl (meth)acrylate, dicyclohexylphenylsilyl (meth)acrylate, t-butyldiphenylsilyl (meth)acrylate, phenyldimethylsilyl (meth)acrylate, lauryldiphenylsilyl (meth)acrylate, pentamethyl-1-(meth)acryloyloxy-disiloxane, heptamethyl-1-(meth)acryloyloxy-trisiloxane, nonamethyl-1-(meth)acryloyloxy-tetrasiloxane, undecamethyl-1-(meth)acryloyloxy-pentasiloxane, tridecamethyl-1-(meth)acryloyloxy-hexasiloxane.
Examples of organosilylated carboxylate monomers of general formula (I) wherein R 7 is the ester of the above-described formula (III) include triisopropylsilyl methyl maleate, triisopropylsilyl amyl maleate, tri-n-butylsilyl n-butyl maleate, t-butyldiphenylsilyl methyl maleate, t-butyldiphenylsilyl n-butyl maleate, triisopropylsilyl methyl fumarate, triisopropylsilyl amyl fumarate, tri-n-butylsilyl n-butyl fumarate, t-butyldiphenylsilyl methyl fumarate, and t-butyldiphenylsilyl n-butyl fumarate.
The advantage of this invention is that the process uses reactants, which can be easily handled. Another advantage lies in the simplicity and safety of the procedure (no filtration of salt neither trapping of corrosive gaseous matter). Furthermore, another advantage is that the reaction may take place without any added catalyst and can be performed under reduced pressure. A further advantage is that the formed carboxylic acid may be removed under azeotropic distillation. Also there is no need to add polymerisation inhibitors and no degradation of the material occurs. Due to its shortness, its easy work-up procedure and its high yield the process of the present invention can be considered as a substantial improvement over the existing methods described above.
Still another advantage of the invention is that the organosilylated carboxylate monomers obtained by the process according to the invention have the exactly desired number of dihydrocarbylsilyloxy units, said number of dihydrocarbylsilyloxy units being those as defined in the acyloxysilane.
The organosilylated carboxylate monomers obtained by the process of the invention can be polymerised with various other monomers such as vinyl monomers including acrylic esters, methacrylic esters, styrene, vinyl esters (e.g., vinyl acetate, vinyl propionate, vinyl butyrate, vinyl benzoate), vinyltoluene, alpha-methylstyrene, crotonic esters, and itaconic esters.
The polymers and copolymers of said monomers are useful in coating or paint composition. More preferably they are used as comonomer unit in the binder of antifouling coating compositions. When used in an antifouling coating composition, they give a film which undergoes neither cracking nor peeling and shows moderate hydrolysability to dissolve into seawater constantly at an adequate rate and which therefore exhibits excellent antifouling property for long term.
The antifouling coating compositions prepared using the monomers obtained by the process of the invention are tin-free coatings and provide an alternative to the present self-polishing coating technology based on hydrolysable tributyl tin polymers (the use of which is due to be banned in antifouling paints by 2003). The organosilylated carboxylate monomers provided by the process of the invention compared to organotin compounds are less toxic, less polar, more hydrophobic and more stable.
EXAMPLES
In the following examples, NMR data have been determined In CDCl3 and are expressed as delta versus TMS.
Example 1
Preparation of Trimethylsilyl Methacrylate
20 ml of acetoxytrimethylsilane and 11.4 ml of commercial methacrylic acid (ATOFINA Norsocryl® MAA) in 100 ml of hexane are mixed and heated. Azeotropic distillation of acetic acid affords trimethylsilyl methacrylate.
Trimethysilyl methacrylate: 13C NMR: 167.7, 137.6, 127.1, 18.2, −0.257; 29 Si NMR: 24.3; IR (film): 2963, 1703, 1335, 1256, 1178, 874, 854 cm−1.
Example 2
Preparation of Tri-n-butylsilyl Methacrylate
4 g of acetoxytri-n-butylsilane and 1.33 g of commercial methacrylic acid (ATOFINA Norsocryl® MAA) are mixed at room temperature, acetic acid is then distilled under reduced pressure (45° C./13 hPa) to afford tri-n-butylsilyl methacrylate.
Tri-n-butylsilyl methacrylate: 13 C NMR: 167.8, 137.9, 126.0, 26.7, 25.5, 18.5, 13.5, 14.0; 29Si NMR: 23.1; IR (film): 2959, 2927, 1703, 1334, 1174, 886, 766 cm−1.
Example 3
Preparation of Nonamethyl-1-methacryloyloxy-tetrasiloxane
5 g of nonamethyl-1-acetoxy-tetrasiloxane prepared as described in reference example of EP-0839869 and 2.31 g of commercial methacrylic acid (ATOFINA Norsocryl® MAA) are mixed at room temperature. Acetic acid is then distilled under reduced pressure (45° C./13 hPa) to afford nonamethyl-1-methacryloyloxy-tetrasiloxane.
Nonamethyl-1-methacryloyloxy-tetrasiloxane: 13C NMR: 166.8, 126.3, 137.8, 18.1, 1.95, 1.24, 1.03, −0.13; 29Si NMR: 7.3, −8.8, −20.1, −21.6; IR (film): 2963, 1730, 1372, 1260, 1083, 1045, 841, 809 cm−1.
Example 4
Preparation of Triisopropylsilyl Acrylate
4 g of acetoxy-triisopropylsilane and 1.6 g of acrylic acid (ATOFINA Norsocryl AA®) in 100 ml of toluene and 1 mL of N,N-dimethylformamide are mixed and heated. Azeotropic distillation of acetic acid affords triisopropylsilyl acrylate.
Triisopropylsilyl acrylate: 13C NMR: 132.5, 130.4, 175.0, 12.3, 17.0; 29Si NMR: 21.84; IR (film): 2948, 2870, 1708, 1620, 1465, 1403, 1290, 1209, 1046, 884, 818, 746 cm−1. | Process for the preparation of organosilylated carboxylate monomers comprising the step of reacting an acyloxysilane with an unsaturated carboxylic acid, the monomers and their use as comonomer unit in the binder of antifouling coating compositions. | 2 |
BACKGROUND
[0001] The present invention relates to the production of electric machines such as induction motors or generators. Known induction motors use multiple windings of conductive wire within a magnetic case to form a stator section and apply alternating current to these windings to cause a rotor within the stator section to turn. Induction generators work in the opposite way, where the rotor is turned and induces current in the windings. In both induction motors and generators, a magnetizing current is supplied to the rotor by the stator. This comes about due to slip between the rotor coils, often a “squirrel cage” coil configuration, and the rotating field produced by the stator. If the rotor turns faster than the stator field, mechanical power from the rotor is converted to real electrical power in the stator, and vice versa.
SUMMARY
[0002] A method of laminating a stack of sheet material, wherein the sheet material is cut and unwanted portions are removed, and additive manufacturing devices are used to build up structures of conducting and insulating materials within slots manufactured in at least some of the sheet materials in the stack. Further, the invention includes a stack of laminated sheet materials with additively manufactured portions, where adjacent sheets include conductive portions which are in electrical contact with one another. In some embodiments, this stack of laminated sheet materials forms an induction machine.
BRIEF DESCRIPTION OF THE DRAWINGS
[0003] FIG. 1 is a perspective view of a machine used to create electrical machines such as induction machines.
[0004] FIG. 2A is a cross-sectional view of a laser engineered net shaping device using powder material.
[0005] FIG. 2B is a side view of an electron beam melting device using a metal wire.
[0006] FIG. 3 is a perspective view of a machine used to create induction machines, with several layers of the induction machine completed.
[0007] FIG. 4 is a perspective cutaway of a stator.
[0008] FIG. 5 is a cross-sectional view of an additively manufactured component, showing a pattern of additively manufactured conductive windings encased in additively manufactured insulator regions encased in sheet material.
[0009] FIG. 6 is an exploded view of multiple layers of a laminated stack, showing a simplified winding structure.
DETAILED DESCRIPTION
[0010] In general, the present invention allows for high efficiency induction machines to be constructed that have efficiency comparable to or greater than the efficiencies obtained by permanent magnet machines, without the use of rare earth materials. Induction machines, including induction motors and induction generators, convert electrical energy to or from mechanical energy by rotating a rotor slightly slower or faster, respectively, than a rotating magnetic field produced by alternating currents applied to stator windings. In the case of an induction motor, the rotating magnetic field generated by these windings causes the rotor to rotate and deliver useful mechanical power at a rotor angular speed slightly less than the angular speed of the stator field.
[0011] FIG. 1 is a perspective view of rapid manufacturing system 10 . FIG. 1 further shows sheet material supply and take-up rolls, and a portion of sheet material on the working surface. The sheet material is coated on both sides with an insulator, for example iron oxide or glass material that has a coefficient of thermal expansion similar to that of the sheet material. Rapid manufacturing system 10 includes movable support 14 , laser 16 , minor 18 , movable optical head 20 , heated roller 22 , guides 24 , laser additive manufacturing apparatus 26 , and electron beam melting apparatus 28 . Also shown are sheet material 30 , supply roll 32 , and take-up roll 34 .
[0012] Movable support 14 is any solid foundation capable of holding a stack of laminated layers (not shown). Movable support 14 may include a sacrificial, disposable or removable portion, such that objects which are laminated onto support may be removed from rapid manufacturing system 10 more easily. Movable support 14 is attached to an actuator (not shown) which may be used to set the desired vertical position of movable support 14 . After each sheet layer is cut to the required shape and the conductor material and insulator material are deposited, the movable support moves down by the thickness of the sheet, a new sheet is positioned over the movable support, and the process is repeated.
[0013] Laser 16 is any laser suitable for cutting and sintering operations. For example, in many embodiments, a carbon dioxide laser may be used. Mirror 18 is any minor which will direct laser radiation. Preferably, mirror 18 is adjustable, such that the radiation incident upon minor 18 may be selectively aimed. Movable optical head 20 is a device capable of directing incident radiation onto the surface of sheet material 30 . For example, movable optical head 20 may include a minor, a lens, or other optics for focusing a laser beam. Further, movable optical head 20 may move in the region above movable support 14 , for example using an x-y positioning stage. Multiple lasers may be used, for example, for separate cutting and sintering operations, with corresponding mirrors and movable optical heads. In addition, an electron beam head can be used instead of a movable laser head. The surrounding environment is dependent on the type of additive manufacturing energy source.
[0014] Heated roller 22 is heated and movable above movable support 14 . In the embodiment shown in FIG. 1 , heated roller 22 is a cylinder. In alternative embodiments, heated roller may be a heated arc or knife blade laminator. Guides 24 as shown in FIG. 1 are rollers, but in alternative embodiments may be any fixed or rotatable arcuate structures. Heated roller 22 may also be integrated with an ultrasonic device to increase the efficiency of joining the laminates with the insulator layers.
[0015] Laser additive manufacturing apparatus 26 may be any laser additive manufacturing (LAM) apparatus recognized by those skilled in the art. For example, laser additive manufacturing apparatus 26 may be a Laser Engineered Net Shaping (LENS) apparatus, Direct Metal Laser Sintering (DMLS) apparatus, Laser Powder Deposition (LPD) apparatus, or Selective Laser Sintering (SLS) apparatus for polymers or metals. Additive manufacturing apparatus 26 may either include its own laser for softening, melting or sintering pulverant material, or laser 16 may be used to soften, melt or sinter the pulverant material (not shown) deposited by laser additive manufacturing apparatus 26 . Electron beam melting apparatus 28 may be any electron beam melting apparatus recognized by those skilled in the art. For example, electron beam melting apparatus 28 may be an Electron Beam Melting (EBM) apparatus or Electron Beam Wire (EBW) apparatus.
[0016] Sheet material 30 is a flexible sheet of any material which is desirable for building into a three-dimensional structure. For example, sheet material 30 may be a sheet of high silicon steel alloy. Sheet material 30 may include a diffusion layer, such as a layer of glass, iron oxide, polyamide, silicone, phenolic or polyether ether ketone (PEEK). Supply roll 32 is a cylindrical core with sheet material 30 wrapped around the cylindrical core. Similarly, take-up roll 34 is a cylindrical core with sheet material 30 wrapped around the cylindrical core.
[0017] Movable support 14 is free to move towards or away from sheet material 30 between supply roll 32 and take-up roll 34 . Typically, movable support 14 has a range of motion that is at least as large as the height of the desired stack of laminated layers (not shown). In alternative embodiments, movable support 14 may stay in a fixed position while rollers 24 are moved relative to movable support 14 .
[0018] Radiation (a laser beam) from laser 16 radiates towards minor 18 , which directs the radiation towards movable optical head 20 . Minor 18 is not necessary in all embodiments, and persons of ordinary skill in the art will recognize that alternatives, such as fiber optics, may be substituted to transmit radiation from laser 16 to movable optical head 20 . Alternatively, movable optical head 20 may not be necessary in embodiments where minor 16 directs radiation towards its ultimate target. Movable optical head 20 is capable of moving into positions where it can direct radiation towards laser additive manufacturing apparatus 26 or sheet material 30 . Heated roller 22 is movable across sheet material 30 , and may be used to apply heat and pressure to layers of a laminated stack (not shown) to cause binding of layers by inter-diffusion of adjacent diffusion layers.
[0019] Additive manufacturing apparatus 26 is movable along the surface of sheet material 30 opposite from movable support 14 . Additive manufacturing apparatus 26 may selectively deposit pulverant material. Electron beam melting apparatus 28 may also be used to selectively deposit pulverant material. Electron beam melting apparatus 28 is also movable about the surface of sheet material 30 opposite movable support 14 . In alternative embodiments, additive manufacturing apparatus 26 and electron beam melting apparatus 28 may be substituted; for example, alternative embodiments may have two (or more) additive manufacturing apparatuses and/or two (or more) electron beam melting apparatuses.
[0020] Sheet material 30 is rolled into both supply roll 32 and take-up roll 34 . Sheet material 30 is guided by guides 24 , and passes above movable support 14 . Additionally, sheet material 30 passes under movable head 20 , additive manufacturing apparatus 26 , electron beam melting apparatus 28 , and heated roller 22 . Supply roll 32 and take-up roll 34 are rotatable to advance sheet material 30 across movable support 14 or the laminated stack (see FIG. 3 ). It will be understood by those skilled in the art that in alternative embodiments, sheet layers may be formed by stamping, laser deposition, electron beam deposition, or other additive or subtractive manufacturing methods. The alternative of generating the laminate by using the laser additive manufacturing process and depositing high silicon steel powder alloy will allow the fabrication of controlled grain-oriented silicon steel laminates for magnetic structures, which will lead to decreasing core loss especially for high frequency or high harmonic designs.
[0021] The embodiment shown in FIG. 1 is used to create layers of components such as induction machines. Sheet material 30 is advanced to at least partially cover movable support 14 . Laser 16 is used to cut an outer periphery of a layer. Radiation from laser 16 is reflected off of minor 18 in the direction of movable optical head 20 . Movable optical head 20 redirects the radiation towards a desired target. Laser additive manufacturing apparatus 26 is used to selectively deposit pulverant material by applying powder to selected regions, then using radiation from laser 16 to sinter or melt the pulverant material in desired locations. Electron beam melting apparatus 28 may also be used to selectively deposit material. Electron beam melting apparatus 28 melts metal wire stock or pulverant material in desired locations using an electron beam. Heated roller 22 is used to apply heat and pressure to a cut portion of sheet material 30 with deposited material from laser additive manufacturing apparatus 26 or electron beam melting apparatus 28 .
[0022] The combination of additive manufacturing processes such as laser additive manufacturing apparatus 26 or electron beam melting apparatus 28 with laser cutting of sheet material allows for rapid manufacturing of objects with multiple materials throughout the body of the object. By repeatedly cutting and building up layers using the processes shown in FIG. 1 , a component may be built which is very difficult or even impossible to create using traditional manufacturing processes.
[0023] FIG. 2A shows an example of a laser additive manufacturing apparatus 26 . Laser additive manufacturing apparatus 26 includes pulverant material reservoir 202 , two pulverant material dispensers 204 , and laser guide 206 . Pulverant material reservoir 202 is any container suitable for holding pulverant material 208 . Pulverant material dispensers 204 may be opened or closed to selectively restrict flow of material. Laser guide 206 is shown as a channel in pulverant material reservoir 202 . Pulverant material 208 may be any pulverant material suitable for use in additive manufacturing, such as fine powders of conductors or insulators. For example, pulverant material 208 may be copper powder, or green glass powder. Laser radiation path 210 is a line along which movable optical head 20 may direct laser radiation.
[0024] Pulverant material reservoir 202 is connected to pulverant material dispensers 204 , which selectively restrict or allow flow of pulverant material 208 . Laser radiation path 210 passes through laser guide 206 and intersects the path of pulverant material 208 which is dispensed from pulverant material dispenser 204 .
[0025] In use, laser additive manufacturing apparatus 26 as shown in FIG. 2A moves in tandem with movable optical head 20 . Typically, laser 16 (shown in FIG. 1 ) and movable optical head 20 are used for additional functions, such as cutting or in other additive manufacturing processes. Therefore, laser additive manufacturing apparatus 26 need only be positioned in tandem with movable optical head 20 while additive manufacturing is occurring. In alternative embodiments, pulverant material 208 may be deposited by laser additive manufacturing apparatus 26 before movable optical head 20 sinters or melts pulverant material 208 . In those embodiments, it is not necessary for laser additive manufacturing apparatus 26 to include laser guide 206 , nor is it necessary for laser additive manufacturing apparatus 26 to move in tandem with movable optical head 20 . In alternate embodiments, additional pulverant material reservoirs containing additional types of pulverant material may be used.
[0026] Laser additive manufacturing apparatus 26 is one type of apparatus which may be used to build up structures within each of the sheets in a laminated stack of sheets. After an outer periphery and interior apertures are lased and unwanted sheet material is removed, laser additive manufacturing apparatus 26 may be used to build up any type of meltable or sinterable structure, such as insulating coatings or sections of conductive windings.
[0027] FIG. 2B shows an example of electron beam melting apparatus 28 . Electron beam melting apparatus 28 as shown in FIG. 2B includes electron beam source 250 , electron beam 252 , spool 254 , and meltable material 256 . Electron beam source 250 is a device which is capable of producing high energy electrons and focusing them into electron beam 252 . For example, electron beam source 250 may be a wire filament carrying a current, a high voltage accelerating circuit, and a series of magnets directing excited electrons through a metal foil window.
[0028] Spool 254 is unwound such that an end of meltable material 256 transects electron beam 252 as it emanates from electron beam source 250 . Where electron beam 252 transects meltable material 256 , meltable material 256 melts. Electron beam melting apparatus 28 may be moved such that melted portions of meltable material 256 are deposited in desired locations. In alternative embodiments, meltable material 256 may be delivered in powder form to the desired location.
[0029] By moving electron beam melting apparatus 28 to deposit melted portions of meltable material 256 in desired locations, electron beam melting apparatus 28 may be used as another way to additively manufacture features in each layer of a stack of a laminated stack of sheet materials. For example, electron beam melting apparatus 28 may be used to deposit insulating coatings or sections of conducting windings.
[0030] FIG. 3 shows rapid manufacturing system 310 partway through building a component. Rapid manufacturing system 310 includes movable optical head 320 , heated roller 322 , guides 324 , first LAM apparatus 326 , and second LAM apparatus 328 . First LAM apparatus 326 and second LAM apparatus 328 , as shown in FIG. 3 , are both LENS type additive manufacturing devices. As shown in FIG. 3 , first LAM apparatus 326 is used in conjunction with laser radiation directed by movable optical head 320 to sinter insulating material. Likewise, as shown in FIG. 3 , second LAM apparatus 328 is used in conjunction with laser radiation directed by movable optical head 320 to sinter conductive material. Also shown are sheet material 330 , supply roll 332 , take-up roll 334 , and laminated stack 336 . Laminated stack 336 is a stack of layers, wherein each layer is made up of a combination of sheet material 330 , insulated deposited by first LAM apparatus 326 , and conductive material deposited by second LAM apparatus 328 . Also shown are hole outlines 312 . Each hole outline 312 is the laser cut outline of material which has been cut from sheet material 330 , including the layer, apertures, and waste material.
[0031] Movable optical head 320 receives laser radiation from a laser source (not shown) and directs it towards desired locations on sheet material 330 . Rapid manufacturing system 310 has cut hole outlines 312 into sheet material 330 . Sheet material 330 passes between movable support 314 and movable optical head 320 . Movable support 314 may also move away from sheet material 330 such that laminated stack 336 is directly beneath sheet material 330 and fills part of the space between movable support 314 and sheet material 330 . First LAM apparatus 326 and second LAM apparatus 328 are arranged on the same side of sheet material 330 as movable optical head 320 . Heated roller 322 is also arranged on the same side of sheet material 330 as movable optical head 320 . Guides 324 set the position of sheet material 330 .
[0032] As sheet material 330 is advanced from supply roll 332 to above movable support 314 to take-up roll 334 , movable optical head 320 directs laser radiation toward the hole outlines 312 in sheet material 330 . Within these lased outlines, movable optical head 320 may cut additional features, such as an outer periphery of a layer as well as apertures for desired features within the layer. Some portion of the material within each outline is removed and either discarded or recycled. Such removal is typically accomplished using pressurized inert gas. First LAM device 326 and second LAM device 328 are used to deposit sinterable or meltable materials in desired locations. For example, first LAM device 326 may be used to deposit a sinterable insulating material within apertures cut by laser radiation emanating from movable optical head 320 . The insulating material deposited by first LAM device 326 need not fill the entirety of apertures cut by laser radiation emanating from movable optical head 320 . Rather, it is sometimes desirable to additively manufacture additional features of a different material. For example, second LAM device 328 may deposit conductive material within the apertures cut by laser radiation emanating from movable optical head 320 .
[0033] Each time a layer of sheet material 330 is cut and additive manufacturing is complete, heated roller 322 laminates the layer to an underlying structure and movable support 314 moves away from sheet material 330 by the roughly the thickness of one layer. The thickness of each layer is set by the thickness of sheet material 330 . For example, many sheet materials will be between 0.10 and 0.25 mm thick. The amount of movement of movable support 314 may be different from the thickness of sheet material 330 , if lamination by heated roller 322 causes any change to the thickness of the layer. The layer becomes the topmost part of laminated stack 336 , and also the physical support for the next layer that is constructed. After lamination and movement of movable support 314 , supply roll 332 and take-up roll 334 rotate to advance a different portion of sheet material 330 over movable support 314 and laminated stack 336 .
[0034] FIG. 3 shows how a laminated stack can be constructed using multiple additive manufacturing devices in one apparatus. Using multiple additive manufacturing devices in one apparatus allows for construction of components which were previously difficult or impossible to construct.
[0035] FIG. 4 shows component 400 , which includes additively manufactured features 408 within sheet material 430 . Component 400 may be any component that is built using two or more additive manufacturing materials within apertures in a laser-cut structure. For example, component 400 may be an induction machine such as an induction motor or an induction generator, wherein the laser-cut structure is a magnetic material such as silicon steel, and two additive manufacturing materials are a PEEK insulator disposed along the border of laser-cut apertures in the silicon steel and copper disposed along the inside border of the PEEK. Additively manufactured features 408 are typically segments of additively manufactured conductive material insulated by additively manufactured insulating material.
[0036] Additively manufactured features 408 are typically arranged within apertures in sheet material 430 such that conductive additively manufactured features are aligned with conductive additively manufactured features in at least one adjacent layer of laminated stack 436 . Insulating additively manufactured features are typically arranged to prevent electrical contact between conductive additively manufactured features and sheet material 430 , either in the same layer of laminated stack 436 or in adjacent layers of laminated stack 436 .
[0037] In order to create an induction machine, windings are frequently used to generate magnetic fields when current is applied. By choosing appropriate arrangements of additively manufactured features 408 in each layer of laminated stack 436 , component 400 may include windings of conductive material which are insulated from sheet material 430 . Additionally, additively manufactured features 408 may have their topology optimized to reduce interference and eddy currents as a result of current flowing through such windings.
[0038] Additively manufactured components such as the one shown in FIG. 4 have numerous advantages over similar components made using alternative manufacturing techniques. Induction motor components may be additively manufactured which use materials more efficiently and optimize the position of windings within the induction machine more precisely. By optimizing the design of magnetic, insulating, and conductive materials, it is possible to eliminate the use of rare earth materials in the motor, while maintaining efficiencies greater than those presently achieved in devices which do include rare earth materials. Further, it is possible to make induction machines which are more lightweight and smaller than their counterparts that are not made using multiple additive manufacturing processes.
[0039] FIG. 5 shows the surface of one layer in a laminated stack. FIG. 5 includes additively manufactured features 508 , each of which includes conductive material 562 and insulating material 564 , within sheet material 566 . As in previously described embodiments, conductive material 562 is any conductive material, and preferably one with low resistivity such as copper. Insulating material 564 may be any insulating material which prevents electrical contact between conductive material 562 and sheet material 566 . For example, insulating material 564 may be a high-melting-temperature polymer, or an oxide.
[0040] Additively manufactured features 508 are arranged throughout apertures cut in sheet material 566 . Within each aperture is an insulating coating made of insulating material 564 , and within at least some of those insulating coatings are pockets within which conductive material 562 is disposed. In some embodiments, sheet material may be arranged between groups of additively manufactured features. In other embodiments, such as the one shown in FIG. 5 , it is not necessary for interstices 568 to be present. Further, the shape of insulating and conductive materials may vary. For example, a large aperture could be present in sheet material 566 , and insulating material 564 could be arranged within the aperture and include a honeycomb, grid, or other arrangement of pockets within which conductive material is disposed.
[0041] In some embodiments, the structure of additively manufactured features 508 may be selected such that, in combination with additively manufactured features in other layers (not shown), the conductive portions combine to form intertwined conductor paths similar to Litz wire or other alternating current (AC) resistivity-reducing topologies. In many embodiments, insulating material 564 is present between each conductive material 562 and sheet material 566 .
[0042] FIG. 5 demonstrates the high packing density which is possible using additive manufacturing. Traditionally, induction machine windings are created using wrappings of conductive wire which has been coated with an insulator. Such windings are much less dense than the windings that can be additively manufactured. Shaped and oriented individual windings may be included in additively manufactured components such as the one shown in FIG. 5 , such as Litz wire and end wrapping topologies.
[0043] FIG. 6 is an exploded view of a stack of laminated layers. Component 600 is made of several layers of sheet material 630 , some of which contain additively manufactured features 608 . Conductive material 662 fills pockets formed by insulating material 664 and the underlying layer.
[0044] The layers of conductive material 662 , insulating material 664 , and sheet material 630 are arranged such that conductive material 662 in each layer is electrically connected to conductive material 662 in at least one adjacent layer. Furthermore, insulating material 664 is arranged such that there is no electrical connection between conductive material 662 and sheet material 630 .
[0045] The exploded view in FIG. 6 shows a simplified set of windings. In the diagram shown, the windings are twisted loops, but in other embodiments the loops may not be twisted. By providing untwisted loops, and disposing large quantities of interconnected loops, an induction machine stator may be constructed.
[0046] Improved stators may be created using additive manufacturing by placing these windings closer together than was previously possible with wire windings, and by optimizing the topology of the windings and their dimensions. Further, the relative thickness of the sheet metal or magnetic material may be decreased and it can be manufactured at the same time as the windings. These improvements mean a thinner magnetic portion with less eddy currents, less material used, and higher efficiencies.
[0047] While the invention has been described with reference to an exemplary embodiment(s), it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment(s) disclosed, but that the invention will include all embodiments falling within the scope of the appended claims.
DISCUSSION OF POSSIBLE EMBODIMENTS
[0048] The following are non-exclusive descriptions of possible embodiments of the present invention.
[0049] A method including (a) producing a layer of a sheet material including an aperture over a movable support, wherein the layer has a thickness and an outer periphery; (b) depositing an insulating material in a first portion of the aperture, adjacent to the outline of the aperture, to form an insulating coating with one or more pockets; (c) depositing a conductive material in the one or more pockets; (d) applying heat and pressure to the layer; (e) lowering the movable support by the thickness of the layer; and (f) repeating steps (a)-(e) to form a laminated stack of layers that define a component.
[0050] The method of the preceding paragraph can optionally include, additionally and/or alternatively, any one or more of the following features, configurations and/or additional components:
[0051] producing the layer of the sheet material includes positioning the sheet material over the movable support, laser cutting the sheet material to define the outer periphery of the layer, removing the sheet material outside the outer periphery of the layer, laser cutting the outline of the aperture in the layer, and removing the sheet material within an outline of the aperture;
[0052] laser welding the outer periphery of the layer;
[0053] depositing all of the sheet material, the insulating material, and the conductive material necessary to form the component;
[0054] depositing the conductive material in the one or more pockets further includes depositing the conductive material such that the conductive material in the one or more pockets is electrically connected to the conductive material in a pocket of at least one adjacent layer of the laminated stack of layers, and is electrically insulated from the sheet material by the insulating coating;
[0055] the sheet material includes steel coated with a diffusion layer;
[0056] the diffusion layer includes at least one of: glass, iron oxide, PEEK, phenolic, polyamide, and silicone;
[0057] the conductive material is copper;
[0058] the insulating material is one of the group consisting of: ceramic insulators, polymeric insulators, and insulating oxides;
[0059] laminating includes melting the diffusion layers of adjacent pieces of the sheet material;
[0060] depositing the insulating material includes using laser additive manufacturing to sinter the insulating material;
[0061] depositing the conducting material includes using laser additive manufacturing to sinter the conducting material;
[0062] depositing the conducting material includes using electron beam melting to melt the conducting material; and
[0063] removing the sheet material is accomplished using pressurized gas.
[0064] An apparatus includes a stack of laminated layers, at least one of the layers including a sheet material including at least one aperture; an insulating material arranged in a first portion of the aperture, adjacent to the sheet material; and a conducting portion arranged in a second portion of the aperture, adjacent to the insulating material, wherein the conducting portion of each layer is arranged in electrical contact with the conducting portion of at least one adjacent layer.
[0065] The apparatus of the preceding paragraph can optionally include, additionally and/or alternatively, any one or more of the following features, configurations and/or additional components:
[0066] the conducting portions of the stack of laminated layers form conductive windings of an electric machine;
[0067] the apparatus does not contain any rare-earth materials; and
[0068] the topology of the conductive windings are optimized for use as an induction machine.
[0069] A method of forming a component of an induction machine includes forming a plurality of layers of steel sheet with apertures for conductive windings, forming by additive manufacturing an electrically conductive winding layer within the aperture surrounded by an electrically insulating layer so that the winding layer is electrically insulated from the steel sheet, and laminating a plurality of sheets with the apertures aligned to form a component body of laminated steel sheets having insulated conductive windings extending through the component body.
[0070] The method of the preceding paragraph can optionally include the feature that the induction machine is one of an induction motor or an induction generator. | An improvement in apparatus and methods of making electrical machines, utilizing a combination of additive manufacturing techniques to create, in particular, small, high efficiency stators, but also useful for making complex rotor structures. | 1 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention is directed to the field of drive mechanisms for hand operated tools and the like.
2. Description of the Prior Art
Various prior art tools for use, for example, in the electrical industry are well known in the art and include crimpers, cable cutters, or other similar devices which are provided with relatively long handles to permit the user to obtain the necessary leverage for accomplishing a particular operation. In many cases the user is required to operate the tool in restricted or cramped quarters where the limited space prevents the user from fully spreading the handles of the tool, thereby restricting the available jaw opening. It has also been found that a user may experience great difficulty in attempting to apply the necessary force to the handles of the tool at the initiation of the operative stroke when the handles are angularly disposed at an included angle virtually approaching 180 degrees. A prior art device for at least partially alleviating the above problems is disclosed in U.S. Pat. No. 3,958,442 issued to Walia et al. on May 25, 1976. Although this device is designed to provide an adjustable handle for reducing the angular position of the handles at any given point in the operative stroke, the structure by which this is accomplished requires a two part handle member which, upon resetting of such handle, significantly reduces the leverage available from the handle when the resetting mechanism is employed to accomplish its stated purpose. Furthermore, the device requires a rather complex manipulation of a movable sleeve on the breakaway handle to reset the handle.
SUMMARY OF THE INVENTION
The invention overcomes the limitations and difficulties noted above with respect to prior art devices by providing a mechanism for use in either single or multiple stroke crimping or cutting tools and the like which permits the selective resetting of the angular position of the handles or arms of a manually operated tool during the operative stroke of the tool without varying the position of the tool jaws in a simpler, more convenient, and more versatile manner than in such prior art devices. The resetting mechanism includes, in a preferred embodiment, a pawl and ratchet arrangement whereby the ratchet portion comprises an arcuate segment coupled to one of the jaws of the tool at its juncture with a corresponding handle member, and a pawl member coupled to such corresponding handle member and which is releasably biased into operative engagement with the arcuate segment at any preselected point along the toothed outer surface of the arcuate segment. Thus, the full length of the handle member is employed to apply leverage to the jaw members regardless of where the corresponding handle member has been reset in the operative stroke. Such resetting is accomplished without any variation of the relative position of the jaw members so that any previously applied compressive force between the jaw members is maintained during the resetting operation. Several embodiments for accomplishing the release or disengagement of the pawl member from the arcuate segment are shown and include a selectively rotatable handle member having means thereon for deflecting the pawl member, and modifications of a portion of the pawl member to permit its direct manipulation by the user. The resetting mechanism is shown as applicable to various types of tools which include those employing a four bar linkage system and others employing simply a pair of pivotable jaw members directly fastened to their associated handle members. In each case the pawl member is provided with suitable biasing means for urging the pawl member into engagement with the arcuate segment. The relative locations of the pivot upon which the pawl is mounted and the pivot upon which the arcuate segment is mounted are so designed as to insure maximum engagement between these two parts during the operative stroke. It is therefore an object of this invention to provide an improved handle resetting mechanism for hand tools and the like.
It is another object of this invention to permit the use of relatively long handled cutter and crimping tools in confined spaces.
It is a further object of this invention to permit the user of a relatively long handled tool to vary or reset the angular position between the handles of the tool at will without disturbing the relative position of the jaw members at any fixed point in the operative stroke of the tool.
It is still another object of this invention to permit the user of a relatively long handled tool to reset such handles to any comfortable or convenient angular position at any fixed point in the operative stroke of such tool.
It is yet a further object of this invention to increase the versatility of a four bar linkage mechanism in a hand operated tool or the like.
It is still a further object of this invention to provide a resettable handle mechanism in a hand operated tool without affecting the maximum leverage available from such tool.
It is yet another object of this invention to provide a handle adjusting mechanism for a hand operated tool which permits the user to maximize the moment of force applied to the handles at any given point in the operative stroke.
Other objects and features of the invention will be pointed out in the following description and claims and illustrated in the accompanying drawings which disclose, by way of example, the principle of the invention and the best mode contemplated for carrying it out.
BRIEF DESCRIPTION OF THE DRAWINGS
In the Drawings
FIG. 1 is a front elevational view, partly cut away and partly in section, of a tool including a handle resetting mechanism constructed in accordance with the concepts of the invention.
FIG. 2 is a fragmentary side elevational view, partly cut away and partly in section, of the device of FIG. 1.
FIG. 3 is a top plan view, partly in section, taken along the line 3--3 of FIG. 1.
FIG. 4 is a top plan view similar to FIG. 3 showing a pawl release mechanism in its release position.
FIG. 5 is a fragmentary front elevational view, partly in section, showing details of the release mechanism of the device of FIG. 1.
FIG. 6 is a fragmentary front elevational view, partly cut away and partly in section, of the device of FIG. 1 showing the various positions to which one handle member of the device may be reset.
FIG. 7 is a fragmentary view, partly cut away and partly in section, showing a further embodiment of a pawl release means for a resetting mechanism constructed in accordance with the concepts of the invention.
FIG. 8 is a fragmentary view, partly cut away and partly in section, of yet another embodiment of a pawl release means for a resetting mechanism constructed in accordance with the concepts of the invention.
FIG. 9 is a fragmentary view, partly cut away and partly in section, of still a further embodiment of a pawl release means for a resetting mechanism constructed in accordance with the concepts of the invention.
FIG. 10 is a fragmentary view, partly cut away and partly in section, showing a further detail of the device of FIG. 9.
FIG. 11 is a fragmentary view of yet another embodiment of a pawl release means for a resetting mechanism constructed in accordance with the concepts of the invention.
FIG. 12 is a fragmentary view, partly cut away and partly in section, taken along the line 12--12 of FIG. 11.
FIG. 13 is a fragmentary front elevational view, partly cut away and partly in section, of a further embodiment of a handle resetting mechanism for a cutting tool constructed in accordance with the concepts of the invention.
FIG. 14 is a bottom plan view taken along the line 14--14 of FIG. 13.
Similar elements are given similar reference characters in each of the respective drawings.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Turning now to FIGS. 1 through 6 there is shown a tool 20 constructed in accordance with the concepts of the invention, including first and second jaw members 22 and 24 having respective first and second end portions 26 and 28, and 30 and 32, and pivotable about a common point shown as a pivot pin 34. A transverse link member 36 is coupled to the jaw members 22 and 24 by pins 38 and 40 to keep the jaw members 22 and 24 in position against the pin 34. The second end portion 28 of the first jaw member 22 is pivotally coupled to a first handle member 42 by means of a pin 44, while the second end portion 32 of the second jaw member 24 is similarly coupled to a second handle member 46 by means of a pin 48. The handle members 42 and 46 each comprise respective first portions 50 and 52 adjacent the respective jaw members 22 and 24, and respective second portions 54 and 56 extending from the respective first portions 50 and 52. The second portion 56 of handle member 46 is preferably rigidly attached to the first portion 52 while, in the embodiment shown in FIG. 1, the second portion 54 of handle member 42 is rotatable within the first portion 50 through a predetermined arc about its longitudinal axis for purposes which will be described in greater detail hereafter. Coupled to the second end 28 of the first jaw member 22 by means of pin 44 is a first element shown preferably as an arcuate segment 58 having a series of teeth 60 selectively located along its convexedly curved exterior edge 64 for engagement with a second element shown as a pawl means 64 which is movably coupled by means of pin 66 to the first portion 50 of handle member 42. The pawl means 64 includes a body portion 68 from which extends a tooth 70 arranged to mate and engage with the teeth 60 of segment 58 and is biased into an engaging position by means of a spring 72 which is attached at one end to an extension 74 on the pawl means 64 and at its other end to the first portion 50 of the handle member 42 by means of a pin 76. In the embodiment illustrated in FIG. 1, the tooth 70 of pawl means 64 may be released from engagement with the teeth 60 of the segment 58 by rotating the second portion 54 of the handle member 42 from a first or lock position to a second or unlock position. These two positions are identified by suitable indicia indicated by similar words on the second portion 54 of the first handle member 42, as shown in FIG. 1, which are arranged to be aligned with a reference indicator 78 located on the first portion 50 of the first handle member 42. The first portion 50 of the handle member 42 is provided with a slotted opening 80 which serves as a guide for pin 82 which extends outwardly from the surface of the part 84 of the second portion 54 of the handle member 42 located within the first portion 50. As shown in the sectional view of FIG. 5, the part 84 of the second portion 54 of the handle member 42 comprises a relatively flat end surface 86 on which is located a resilient washer 88 which bears against the adjacent undersurface 90 of the first portion 50, thus biasing the second portion 54 downwardly, as viewed in FIG. 5, away from the first portion 50 to permit the pin 82 to be forcibly seated within an enlarged recess 92 (FIG. 1) located at one end of the slotted opening 80 when the second handle portion 54 is oriented to the "lock" position as shown in FIG. 1. In this position, a release pin 94 extending longitudinally outwardly from the end surface 86 of the second handle portion 54 and located to one side of the central axis thereof (See FIGS. 3 and 4) is spaced away from and out of contact with the extending portion 74 of the pawl means 64. To accommodate the movement of the pin 94, the first portion 50 of the first handle portion 42 is provided with a central opening 96 (FIG. 5) through which the pin 94 protrudes. To rotate the second handle portion 54 to the "unlock" position, a slight pressure is applied to the second handle portion 54 in an upward direction, as viewed in FIG. 1, to compress the resilient washer 88 and release the pin 82 from the recess 92. The handle portion 54 is then rotated in a clockwise direction, as indicated by the arrow 98 in FIG. 1, to cause the pin 82 to traverse the slotted opening 80 and come to rest at the right end of the slotted opening 80, as viewed in FIG. 1, at which position the word "unlock" is aligned with the indicator 78. The movement of the release pin 94 from the "lock" to the "unlock" position is shown respectively in FIGS. 3 and 4, the direction of movement being shown by the arrow 100 in FIG. 4, which corresponds to the movement of the handle portion 54 shown by the arrow 98 in FIG. 1. In the "unlock" position, the release pin 94 is caused to contact the extending portion 74 of the pawl means 64, as shown in the dotted outline in FIG. 6, thereby rotating the pawl means 64 in a counterclockwise direction, as viewed in FIG. 6, and causing the pawl means tooth 70 to be moved out of engagement with the teeth 60 on the arcuate segment 58. Th handle member 42 is accordingly unlocked from its previous position and may be reset or reoriented to a new angular position with respect to the other handle member 46, as shown by the dotted handle member outline in FIG. 6. It should be understood that the included angle between the handle member 42 and the other handle member 46 may be increased without moving the second handle portion 54 to the "unlock" position, but rather by employing the normal ratcheting action of the pawl means 64 on the reverse stroke whereby the pawl means tooth 70 is caused to "ride" along the teeth 60 on the arcuate segment 58. When the desired new angular position of handle member 42 is reached, the second handle portion 54 of the first handle member 42 is rotated back to its "lock" position, as previously described, thus causing the release pin 94 to return to the position shown in FIG. 1 whereby the tooth 70 of the pawl means 64, under the influence of the biasing spring 72, is urged back into engagement with the teeth 60 on the arcuate segment 58, permitting the user to once again move the jaw members 22 and 24 in correspondence with the reset handle positions. This procedure may be repeated as often as necessary or desirable to provide the most comfortable or convenient disposition of the handle members 42 and 46 before, during, and after the operative cycle. To insure that the jaw members 22 and 24 are returned to an open position when the pawl means 64 is in the released position out of contact with the segment 58 and the handle member 42 is moved away from the handle member 46, the segment 58 may be provided with a protrusion 102 which is arranged for contact with a portion 104 of the peripheral surface of the segment 58. Thus, as the handle member 42 is moved in a counterclockwise position about the pin 44, as viewed in FIG. 1, the segment 58 is caused to follow the handle member 42, thereby forcing the pins 44 and 48 towards one another through a coupling comprising a link 106 which is pivotally coupled at one end 108 to one end of the segment 58 by a pin 110, and at its other end 112 to the first portion 52 of the second handle member 46 by a pin 114, and through the first portion 52 of the second handle member 46 to the pin 48 connecting the second handle member 46 to the second jaw member 24. First and second adjusting means shown respectively as threaded screw members 115 and 117 include respective shank portions 119 and 121 which extend transversely through suitable threaded openings in the first portion 52 of the second handle member 46 and abut the link 106 on either side of the link pin 114 to regulate the closure of the jaw members 22 and 24 by fixing the position of the coupling pin 110 relative to the jaw member pins 44 and 48 throughout the operative stroke. It should be noted that, in the particular embodiment illustrated in FIG. 1, the axis of the tooth 70 of the pawl means 64 is offset to the left of an axis 116 bisecting the pivot pins 44 and 66. Thus, as the handle member 42 is rotated about the pin 44 in a driving or clockwise stroke, as viewed in FIG. 1, the tooth 70 is driven into locking relationship with a respective one of the teeth 60 so that a compressive force is exerted on the pawl means 64 which is counteracted by the pin 66 which is thus caused to bear a major portion of the driving force. This arrangement significantly minimizes any shear force which may be exerted against the tooth 70, thereby providing for a more efficient and reliable drive system. However, as a result of such relationship, the pawl means 64 is caused to "ride" along the teeth 60 of the segment 58 in the backward or release stroke, thereby necessitating the employment of means such as the protrusion 102 for engagement with the handle member 42 to reposition the jaw members 22 and 24 into an open state after completion of the compressive stroke. A means such as spring member 118 is coupled between the respective second ends 28 and 32 of jaw members 22 and 24 to apply a separating force to the second ends 28 and 32 and, consequently, an equivalent closure force to the respective first ends 26 and 30 of the jaw members 22 and 24 to assist in holding a workpiece such as a terminal, or the like (not shown), between the jaw members 22 and 24 while the first handle member 42 is operatively disengaged from its respective jaw member 22, that is, when the pawl means 64 is in the "unlock" position. It should be noted that the operating mechanism employed in the tool 20 comprises generally a modified form of a conventional four-bar linkage in which jaw members 22 and 24 define two of the linkages, link member 106 defines the third linkage, and segment 58 together with pawl means 64 defining the modified fourth linkage. The invention may, however, be incorporated in other tool arrangements such as shown, for example, in FIGS. 13 and 14. A scissor-like tool 120, shown in fragmentary view in FIG. 13, comprises a pair of arcuate jaw members 122 and 124 movable in a common plane towards and away from one another and coupled together at a common pivot by means of a pin 126. Each jaw member 122 and 124 is provided with a respective extending handle portion 128 and 130 for moving the jaw members 122 and 124. The jaw members 122 and 124 are each provided with a respective tapered arcuate inner cutting edge 135 and 133 for severing elongate objects such as copper, aluminum, or steel cables or the like which, in many cases, require relatively large cutting forces. In most manually operated tools this is accomplished by providing large lever advantages to suitably multiply the available manual force. Accordingly, as in the tool 20 described above, the handle portions 128 and 130 of tool 120 may often assume a length of one meter or more which may prevent the use of the tool in confined spaces while additionally presenting a highly inconvenient handle disposition at the initiation of the operative stroke. Thus, an arrangement similar to that provided in tool 20 may be employed in the tool 120 to reset or adjust the relative angular disposition of the handle portions 128 and 130 at any fixed point in the operative stroke. To accomplish this function, the handle portion 130 is coupled to its respective jaw member 124 through elements 132 and 134 which are essentially duplicative of elements 58 and 64 of tool 20 and operate in a similar manner. Element 132 comprises an arcuate segment having a series of teeth 136 which are selectively engageable with a tooth 138 located on the element 134 which defines a pawl means pivotable about a pin 140 and biased into engagement with the element 132 by means of a spring 142. The release mechanism comprising part 144 associated with a rotatable handle portion 146 is essentially similar to corresponding parts 94 and 54 of tool 20 and operate in a similar manner. Thus, by releasing the element 134 from engagement with the tooth element 132, the handle portion 130 is free to rotate about the pivot pin 126 without disturbing or changing the relative disposition of the jaw members 122 and 124. Accordingly, the user may unlock the mechanism comprising parts 132 and 134, reset the handle portion 130 at any desired angular disposition with respect to the other handle portion 128, and then relock the mechanism to initiate or continue the operative stroke at the new handle position.
FIGS. 7 through 12 illustrate further embodiments of a pawl release mechanism for an adjustable tool handle constructed in accordance with the concepts of the invention. In FIG. 7 a pawl means 144 similar to element 64 of tool 20 includes an exposed lever portion 146 which may be manually contacted by the user for rotating the pawl means in the direction indicated by the arrow 148 to move the pawl means tooth 150 out of engagement with the teeth 60 of the arcuate segment 58. In FIG. 8 a similar release is accomplished by providing a pawl means 152 with an exposed knurled portion 154 for engagement by the user. A further alternative embodiment of a release means constructed in accordance with the concepts of the invention is shown in FIGS. 9 and 10 and includes a strut member 156 connected between a pawl means 158 and a shank portion 160 of a release activator 162 having a manually operable head portion 164 connected to the shank portion 160 and extending through a slot 166 in the second portion 54 of the first handle member 42. To release the pawl means 158 from engagement with the arcuate segment 58, the head portion 164 of the activator 162 is manually moved from the LOCK position to the UNLOCK position causing the pawl means 158 to rotate in a counterclockwise direction, as viewed in FIG. 9, about its pivot pin 168, thereby releasing the pawl means tooth 170 from engagement with the segment teeth 60. In FIGS. 11 and 12, the release operation is accomplished by providing a pawl means 172 with a manually operable lever member 174 extending outwardly from a side surface 176 thereof and through an arcuate slot 178 in a first handle member a portion of which is indicated by the numeral 180. Movement of the lever member 174 from the lower left position shown in FIG. 11 to the upper right end of the slot 178 will cause a corresponding rotational movement of the pawl means 172 to disengage it from the segment 58.
It will, of course, be readily appreciated that the resetting mechanism comprising the elements 58 and 64, although shown as provided for resetting or adjusting only one of the two handle members of tools such as 20 and 120, may be provided for resetting or adjusting both of the handle members (not shown) where necessary or desirable. Furthermore, although the interengagement between the segment 58 and the pawl means 64 is shown as comprising a mating tooth arrangement, such interengagement may be accomplished by alternative means such as pin and groove arrangements (not shown) in which the tooth 70 of pawl means 64 is replaced by a pin means which is selectively received within suitably dimensioned recesses or transverse holes provided at selected locations in the segment 58. | A mechanism for use in crimping and cutting tools and the like includes a resettable drive system which permits the user to selectively increase or decrease the angular opening between the tool handles at any fixed point in the operative stroke of the tool. The handles of the tool may thus be disposed at any desired angular relationship with respect to one another for operation either in close quarters or for more comfortable operation without sacrificing the lever advantage originally designed into the tool. | 1 |
BACKGROUND OF INVENTION
Structural substrates for panels are generally formed of compression molded fibrous webs which are cut and molded into the shape required. Such substrates are used to back up interior paneling members, such as door panels and the like within automobiles and for other analogous uses. In the current methods of manufacturing the web material, which is later cut and compression molded, it is conventional to mix together fibers of wood and synthetic plastic which are distributed, by means of conveyor belts and suitable distribution rollers, and the like into non-woven fiber mats. A powdery, synthetic resin molding compound is applied to such mats. The mats are then heated to partially cure the molding compound. This gives the resulting web sufficient structural integrity so that it may be picked up, handled, moved about and positioned within mold cavities. Since the resinous material is only partially cured, a substantial portion of it remains uncured. That uncured portion is cured during the compression molding process by the application of heat and pressure to the material while it is contained within a cavity type of mold.
In the foregoing procedure, the partially cured resinous molding powder tends to form a skin-like crust on the surfaces of the web as well as relatively hard portions within the web so that the web resists easy flexing. Consequently, the web is more difficult to drape within the mold cavity around irregular mold areas, especially those areas which have relatively sharp corners or straight or undercut walls and the like. In addition, such materials are difficult to deep draw because of their relative stiffness and resistance to draping.
Moreover, in such prior procedure, since the resinous material used is partially cured before the molding process, in order to have sufficient molding material available during the compression molding, larger amounts of molding material are needed. Alternatively, the finished substrate has less cured molding material than is desirable.
Thus, there has been a need for a fiber web material which is more pliable and easily drapable within a mold so as to produce sharper corners and better undercut or straight wall areas and which carries a maximum amount, within desired limits, of uncured molding material. The invention herein is concerned with such a web and a method of forming it, which results in a more pliable, drapable, web that can be more deeply and easily drawn in a compression molding operation.
SUMMARY OF INVENTION
This invention relates to a web used in compression molding of structural substrates formed of non-woven randomly oriented blended fibers. The web contains uniformly dispersed dry, completely uncured, resinous molding powder. The fibers are mechanically interlocked to each other and to a non-woven fiber scrim sheet covering at least one face of the web.
The web is formed by successive fiber blending steps in which the fibers are successively spread out into mats which are taken apart and reblended until a final step where the fibrous web, now containing uniformly dispersed dry molding powder, is mechanically locked to a scrim sheet by needling. At that point, the finished web, containing uncured molding powder, has structural integrity, for easy handling, and good pliability or extensibility for easy draping within a compression mold cavity.
The fiber blend is made of a mixture of wood fibers and synthetic plastic fibers, such as nylon, polyester or polypropylene or the like. The percentages of each of the fibers within the blend may be varied depending upon the requirements, costs, etc. For certain applications, it is contemplated to utilize blends of only synthetic fibers, but preferably of different kinds of synthetic plastics.
An important object of this invention is to provide a compression moldable web which has sufficient structural integrity and pliability or flexibility to enable deep drawing of the web in the mold, good draping over irregular mold surfaces, particularly over relatively sharp corners and undercuts. Another important object is to produce a web without the necessity of partial curing of molding powder so that 100% of the molding powder is available for the compression molding. Significantly, the crust or other stiffened resinous areas resulting from pre-curing are eliminated.
Another object of this invention is to eliminate the pre-curing or partial curing of the resinous molding powder web so as to enhance the extensibility of the fiber web during the molding procedure. This produces a more uniform density finished molded substrate without weak points that have occurred in the past due to varying densities or thicknesses of a web stretched within a compression mold cavity.
These and other objects and advantages of this invention will become apparent upon reading the following description of which the attached drawings form a part.
DESCRIPTION OF DRAWINGS
FIG. 1A is a schematic elevational view of the beginning portion of the equipment, and
FIG. 1B is a schematic elevational view, continuing the line of equipment from FIG. 1A.
FIG. 2 is a perspective, fragmentary view, showing schematically a portion of the initial blending portion of the equipment.
FIG. 3 is an enlarged, fragmentary, cross-sectional view of the web before needling.
FIG. 4 is an enlarged, fragmentary view, similar to FIG. 3, showing the needling step, and
FIG. 5 is a view similar to FIGS. 3 and 4 schematically showing the mechanically interlocked fibers and scrim following needling.
FIG. 6 is a fragmentary cross-sectional view of the molded substrate within the mold cavity.
DETAILED DESCRIPTION
Referring to FIG. 1, a bale of wood fibers enters the line of equipment upon a conveyor 11. The wood fibers, for example, may form a bale which is approximately 12 inches×12 inches×36 inches, weighing about 60 lbs. and having a moisture content of up to about 20% by weight. The wood is preferably of what is called a soft-hardwood, for example, wood of the aspen family, including yellow poplar, and similar such woods which are commercially available in fiber form.
The bale 10 proceeds into a bale breaker and shredder 12 which is schematically shown. This breaks up and shreds the bale into loose fibers 13 which are deposited upon a removal conveyor 14.
The fibers 13 are deposited into a feed hopper 15 of a dryer 16. Although different commercially available dryers may be used, a preferred dryer is a commercially available, tubular, forced air dryer having a hot air blower 17 which blows air through a long tube. The tube may be over 100 feet in length. The flowing air picks up the fibers entering through the feed hopper and carries them to the discharge orifice 18 of the dryer. This type of dryer is rapid acting and may carry the fibers through, drying them sufficiently to provide optimum molding conditions, such as to 5%, and preferably, to about 3% moisture by weight, in less than a minute.
The fibers exiting from the discharge orifice 18 of the dryer are carried away upon a conveyor 19. This conveyor also receives synthetic plastic fiber which begins as a bale 20 entering into the equipment upon a conveyor 21. A conventional bale breaker and shredder 22, which is schematically shown, shreds the bale into fibers 23 which are deposited as a thin coating over the blanket of wood fibers 13 upon the conveyor 24. By way of example, the coating of synthetic fibers may be on the order of an eighth or a quarter of an inch upon a 2 inch thickness of wood fibers. However, the thicknesses of the fiber deposits may vary considerably, depending upon the nature of the fibers and the fiber ratio of the final specified blend. Preferably, the wood fibers predominate. Optionally, the synthetic fibers 23 may be deposited from conveyor 23 upon conveyor 14 and travel through the dryer 16 with the wood fibers.
The wood fiber and synthetic fiber mixture is carried to a feed conveyor 28 (see FIGS. 1B and 2) where it is raised and dropped into the upper end of a large blending chamber 29. The fiber is gravity dropped downwardly through the chamber, being spread apart and evenly disbursed by a V-shaped spreader 30 located within the chamber.
The dropping fibers accumulate upon blending rolls 31, pass through the nip of the rolls and then, drop down through the lower end 32 of the blending chamber. The blended mixture of fibers 33 land upon a substantially horizontal collection conveyor 34 which conveys the blended fibers to a sloping conveyor 35. Such sloping conveyor, which has a roughened surface that may have cleats or treads or the like for roughening, carries the fibers upwardly to a pair of spiked or rough surface transfer rolls 38 and 39. These rolls transfer the fibers, while further blending them, to a control valve 40 (shown schematically) which may be in the form of a simple movable louvre or plate. The fibers then drop down, in a controlled volume, into a volumetric control chamber 41.
In FIG. 1B, the chamber 41 is shown as having one solid wall 42 and an opposing wall 43 formed of a conveyor belt which simultaneously moves the fibers downwardly through the control chamber while containing them within the chamber.
The fibers pass from the bottom of the control chamber into a group of spiked or rough surface transfer rolls 44 which carries them to a picker roll 45. The transfer rolls and picker rolls are conventional in equipment used to form non-woven mats. A conventional transfer roll may have spikes in the form of nail-like projections extending radially outwardly from its surface. Likewise, the picker roll is formed with a rough surface, such as a sawtooth-like surface or spikes or the like.
The fibers are transferred to the surface of the picker roll by the transfer roll spikes, the rough surface of the picker roll and also by means of high velocity air which blows the relatively loose fibers upwardly against the lower surface of the picker roll. The high velocity air is applied by a means of a suitable blower air duct 46 which extends the length of the picker roll. High velocity air for the duct is supplied by a suitable compressor or blower 47 which is schematically shown.
When the fiber is blown and conveyed upon the picker roll, it is further blended and forms an initial web or blanket 48, which is relatively weak. This web or blanket passes between an upper condenser roller 49 and a lower condenser roller 50 which compress the web and directs it to a conveyor 51.
As the web moves with the conveyor 51, it passes beneath a resin hopper 54 which is loaded with a dry powdery, resinous molding material 55, such as a phenolic resin powder. An example of such a material is a phenolformaldehyde novolac type resin containing hexamethylenetetramine for cure purposes supplied in powder form by Polymer Applications, Inc. and identified as PA-60-706 resin.
The resin powder drops downwardly upon the web passing beneath it for dispersion through the web. The resin powder filled web next passes through a group of spiked transfer rollers 56 and is carried around to a second, rough surface picker roll 57, aided by compressed air from an air duct 58. The compressed air is supplied by an air blower 59 which is schematically shown.
A secondary, further blended, web 60 is formed by the second picker roller operation and passes through a duct 61, aided by the flow of compressed air from the air duct 58. This secondary web is passed between an upper condenser roller 62 and a lower condenser roller 63. Preferably, the upper condenser upper condenser roller has a solid or air impervious surface while the lower condenser roller has a perforated surface to permit the escape of the compressed air from the duct 61.
Next, the web is conveyed upon a transfer conveyor 64 to a point where scrim 65 is applied. The scrim may be arranged in a suitable roll and unwound to cover the moving web.
The scrim is made of a thin sheet of non-woven synthetic fiber material, such as nylon, rayon, polypropylene and the like. An example of a commercially available scrim material is spun bonded nylon supplied by Monsanto. The particular kind of scrim material selected depends upon availability, cost, product specifications, etc.
The scrim may be applied either upon the upper surface or the lower surface of the web or even upon both surfaces, if required for the particular finished product. The scrim shown in the drawing is applied to the lower surface of the web and the composite web-scrim material passes into a conventional needling machine 66. This machine has a head 67 and a base 68. Numerous needles 69 (see FIG. 4) are secured to the vertically reciprocating head 67 and enter into sockets 70 formed in the base 68.
The needling operation disrupts and intertwines the fibers that are contacted by and displaced by the needles. Thus, the fibers mechanically interlock with each other and also interlock with the scrim. Consequently, as schematically illustrated in FIG. 5, there appear to be lines of interlocked fibers and an interlocking between the fiber blanket and the scrim sheet which mechanically fastens the material together.
The web moving out of the needling machine 66 is grasped by take-out rolls 71 and passes into a conventional, side trim roller cutter 72 for trimming and straightening the side edges of the web. Then the web proceeds through a blade type cutter 73, or some such suitable conventional cutter, for chopping the web into required lengths. These are removed upon a removal conveyor 75.
As illustrated in FIG. 5, the finished composite fiber/scrim, mechanically interlocked web 78 has areas of interlocked fibers 79 which provide the composite web with structural integrity and sufficient strength for handling. The finished web comprises a thoroughly blended or intermixed fiber composition with the powdered resin thoroughly and evenly dispersed through the web. All of the molding powder is uncured and available for molding when the material is placed within a conventional compression mold for heat and pressure molding into a desired shape.
Although the fibers and the handling of the fibers may vary in accordance with the procedure described above, examples of useful web compositions are as follows:
______________________________________ Approximate Preferred Range Approximate % by Weight % by Weight______________________________________Example I - CompositionWood Fiber 50-80 69Synthetic Fiber 0.02-10 9Resin (thermoset) 10-18 16Wax 0-3 2Water less than 5 4 100Example II - CompositionWood Fiber 60-70 66Synthetic Fiber 0.02-10 8Resin (thermoset/ 15-25 20thermoplastic)Wax 0-3 2Water less than 5 4 100______________________________________ Examples of typical materials used in the composition are: Wood fiber: aspen, poplar, pine, etc. e.g., roughly 35-45% retained on 8 mesh screen, with 17% moisture content Synthetic fiber: nylon, polyester, etc. e.g., Nylon 6 or 66, 1/2"-11/2" length, 9-15 denier (thickness of fiber) Thermoset resin: phenolic, epoxy, urethane, etc. Thermoplastic resin: polyvinyl chloride, polypropylene, etc. Wax: hydrocarbon, etc., e.g., Fuller WW0089 Scrim: Monsanto, spun bonded nylon, 0.03 oz. per square yard
For certain requirements, the natural wood fibers may be replaced in whole or in part by other natural fibers. Examples of such compositions, using shoddy, i.e., cotton, wool, etc., as follows:
______________________________________ Approximate Preferred Range Approximate % by Weight % by Weight______________________________________Example III - CompositionShoddy (cotton, wool, etc.) 50-80 69Synthetic 0.02-10 9Resin (thermoset) 10-20 16Wax 0-3 2Water less than 5 4 100Example IV - CompositionShoddy 65-75 69Synthetic Fiber 0.02-10 9Resin (thermoset/thermo- 14-18 16plasticWax 0-3 2Water less than 5 4 100______________________________________ Ratio (thermoset/thermoplastic): 1/2-2/1
In compression molding, a mold release wax is frequently desirable. As set forth in the examples, the wax is in a powder form and in a range of up to about 3% and preferably in the range of roughly 2%.
To dry the wood fibers, which typically come with roughly 16 to 20% moisture content, referring to an aspen type wood such as aspen, yellow poplar and the like, the fibers can be blown through the dryer tube which in a commercially form may be about 180 feet long at a temperature of between about 175°-300° Fahrenheit in less than a minute. This drops the moisture content to between 2-5% and roughly to a preferred 3% moisture by weight.
As can be seen, the wood fibers are deposited, from the broken bales of wood fiber, into a blanket or mat to a depth of roughly 2-3 inches. The synthetic fibers are deposited upon the wood fiber mass to a depth of roughly 1/4 inch. As mentioned before, the depths vary depending upon the percentages of the different fibers in the finished blend. These fibers are mixed repeatedly in order to get the high quality desired. That is, the fibers are in the first instance thoroughly blended in the blending chamber 29. Then they are re-blended in passing through the transfer rolls and into the volume control chamber 41. Next, they are again thoroughly re-blended and reconstituted into a fiber web in going through the first transfer roll group 44 and picker roll 45. They are again re-blended, but now containing the powder resin, in the second picker roll 57 and transfer roll group 56. This results in a blend uniformity which in the later compression molding operation provides a uniform density, and molded thickness substrate, and eliminates weak areas in both the cloth-like web and the molded substrate.
The finished web is pliable or readily extensible and thus easily drapable within a relatively deep compression mold having sharp corners, undercut areas and the like. The molded part forms relatively stiff, board-like, structural substrates for use in panels, such as the interior of an automotive vehicle door panel which is covered with an outside plastic shell or skin.
As illustrated schematically in FIG. 6, the web is draped within the cavity of die half 81. When the opposite die half 82 is registered to close the cavity, the web is molded under heat and pressure to form the relative thin, stiff substrate 80. By way of a typical example, the molding may be in the temperature range of 350-450 degrees F., with pressure at about 350-600 psi and for 30-60 seconds to produce a 0.10 inch thick substrate from a roughly 1/2 inch thick web. | A fibrous web useful for compression molding stiff, board-like structural substrates for panels is formed of a thoroughly intermixed blend of wood fibers and synthetic plastic fibers with a dry, powdery, resinous molding material uniformly disbursed throughout the blend. The mass of intermixed fibers and resinous molding material is covered with a thin, randomly oriented, fibrous scrim material and the fibers are locked to each other and to the scrim mechanically by means of needling them together. The web is formed by drying wood fibers, spreading them into a mat, covering the mat with the synthetic fibers and thereafter, dispersing the fibers through a dispersion chamber and re-collecting and re-spreading them into a web by means of a picker roller, gravity dropping a powdery resinous molding material upon the web, redistributing and intermixing the fibers and the molding material with a second picker roller, applying the scrim and needling the combined scrim and fiber web for mechanically interlocking them. | 1 |
FIELD OF THE INVENTION
[0001] This invention relates generally to a patio bench. More specifically, the present invention relates to a snap-together patio bench constructed of molded structural plastic panels to be capable of packaging and shipment in a knocked-down state for assembly at a desired site.
BACKGROUND INFORMATION
[0002] Modular furniture is known in the art, for example, U.S. Pat. No. 3,811,728 to Redemske discloses plastic modular furniture. The invention utilizes a plurality of plastic base modules having grooves formed on one face thereof. The base modules cooperate with various shells for sitting, sleeping, storage, and table tops. Each shell includes a perimetal edge for engaging the grooves on one of the base modules.
[0003] U.S. Pat. No. 4,140,065 to Chacon discloses a number of wooden panels to cover the entire areas of a back, a seat, or an end of a sofa or chair. The panels have tabs or hooks which fit into slots. Wedge shaped pegs are then used to secure the furniture components together.
[0004] U.S. Pat. Nos. 3,874,729 4,523,787, 4,932,720, 4,919,485 and 5,069,506 disclose various other embodiments of modular furniture.
[0005] Modular benches are also known in the art. For example, U.S. Pat. No. 4,919,480 to Drew discloses a sectional bench. The bench includes two A-shaped support members, a seat section and a plurality of slats secured to the A-shaped support members.
[0006] U.S. Pat. No. 3,748,012 to Abelman discloses a joining pedestal for benches assembled in a line. The pedestal has a lower post with a wide top to seat meeting end portions of adjoining bench seats. The end portions have setbacks to receive the shank of an upper pedestal portion. The upper pedestal extends rearwardly for attachment of a back portion. Before assembly of the pedestal, bench seat and back portion the joining areas are coated with an adhesive.
[0007] U.S. Pat. No. 5,938,281 to Keils discloses a seating structure for a child. The seating structure includes a box constructed of blow molded panels. The panels are connected at the ends with a pin that slides through apertures oriented transversely with respect to the panels. A bench seat is positioned within the box.
[0008] U.S. Pat. No. 3,463,546 to Geibel discloses a knockdown paperboard chair with a storage space. The paperboard chair is constructed from two blanks. One blank incorporates the back section and the side panels. Seat flaps are cut out from the side panels in such a way that the assembled chair resembles a swing chair and bottom flaps are interfolded together to form a base structure. A second blank forms a front section, a seat cover and a bottom flap.
[0009] Other U.S. Patents that disclose seats having storage areas positioned below the seat include U.S. Pat. Nos. 5,458,395, 5,692,335, 5,727,844, 6,390,551, 6,664,523.
[0010] Such prior art systems, while working well, have not met all of the needs of manufacturers to provide a product that can be easily manufactured, packaged and shipped or the needs of consumers requiring structural integrity combined with modularity, aesthetic appearance and ease of assembly.
[0011] Paramount among such needs is a panel system which creates a patio bench which resists panel separation, buckling, racking and weather infiltration. Security is a further consideration, the storage box formed by the panels must tie into the side panels and base panel in such a way as to unify the entire enclosure.
[0012] Also, from a versatility standpoint, a seat panel should be present which can be easily installed after assembly of the side and bottom components and which provides dependable security and pivoting access to the contents of the storage box.
[0013] There are also commercial considerations that must be satisfied by any viable patio bench system or kit; considerations which are not entirely satisfied by state of the art products. The patio bench must be formed of relatively few component parts that are inexpensive to manufacture by conventional techniques. The patio bench must also be capable of being packaged and shipped in a knocked-down state. In addition, the system must be modular and facilitate the creation of a family of patio benches that vary in appearance and functionality but which share common, interchangeable components.
[0014] Finally, there are ergonomic needs that a patio bench system must satisfy in order to achieve acceptance by the end user. The system must be easily and quickly assembled using minimal hardware and requiring a minimal number of tools. Further, the system must not require excessive strength to assemble or include heavy component parts. Moreover, the system must assemble together in such a way so as not to detract from the internal storage volume of the resulting storage box or otherwise negatively affect the utility of the patio bench.
BRIEF DESCRIPTION OF THE INVENTION
[0015] The present invention provides a system, or kit, of injection molded panels having integrated connectors which combine to form a patio bench. The panels are formed of injection molded plastic to interlock with one another without the need for separate fasteners or I-beam connectors. The system incorporates a minimum number of components to construct a patio bench by integrally forming the connectors into the injection molded panels. This minimizes the need for separate extruded or molded connectors to assemble the patio bench and facilitates snap-together assembly of the bench. The integrated connection of the side wall, seat and bottom panel components also provides for a storage box beneath the pivoting bench seat. The storage box is fully enclosed with wall panels to provide dry storage for items kept therein. Injection molding allows the panels to be formed with integral cross-bracing, ribs and gussets for increased rigidity while maintaining a lightweight construction that can be easily assembled and moved. The extra rigidity substantially prevents the panels from bowing inwardly and/or outwardly to resist panel racking and separation over time to maintain an aesthetically pleasing water resistant enclosure. The same side wall and bottom panel components are used to create a variety of patio benches, and the assembly of the patio benches require minimal hardware and a minimum number of hand tools.
[0016] The front and rear wall panels of the storage box have a combination of outwardly projecting locking posts and inwardly extending sockets for interlocking cooperative engagement with sockets and locking posts formed into the adjacent panels for locking the panels together in a substantially perpendicular relationship. The left and right end panels include integrally formed arm rests. In addition, the left and right end panels are constructed with inwardly extending contoured sockets for interlocking cooperative engagement with outwardly projecting locking posts on the ends of the front, rear and base panels. The engagement between the locking posts and the sockets serve to rigidly connect the components together without the need for additional fasteners. The back portion of the patio bench arm rests are formed hollow to accept a structural block which cooperates with the seat back, end panels and seat panel to provide additional rigidity and weight capacity to the assembled bench structure. The system further includes a seat panel which slides into place after the front, rear, side and bottom panels have been fully assembled. The seat panel is pivotally mounted to allow the storage compartment to be easily accessed, further increasing the utility of the patio bench. Integral formation of the connectors, via injection molding, permits connection to panels formed by other means such as blow molding and/or vacuum forming without the need for separate connectors. In this manner, a low cost yet structurally robust snap together patio bench can be constructed. Prior art assemblies that utilize extruded panels require separate connectors to attach the panels together, increasing the number of components and connections required to assemble a bench, thereby increasing the complexity and cost of assembly.
[0017] Accordingly, it is an objective of the present invention to provide a patio bench construction system wherein the patio bench components include integrated connectors for creating various patio benches which snap together using common components.
[0018] A further objective is to provide a patio bench with storage wherein the panels used for construction include integrated connectors accommodated by the process of injection molding.
[0019] Yet a further objective is to provide a bench assembly which includes a storage box wherein the side walls, cover, and bottom panel of the storage box are integrally interlocked without separate connectors or fasteners.
[0020] Another objective is to provide a bench assembly constructed of modular components having a pivotally mounted bench seat which provides access to an integral storage box.
[0021] Yet another objective is to provide a kit for a bench that is capable of being packaged and shipped in a knocked-down state and snapped together into a robust bench assembly.
[0022] Still yet another objective is to provide a combination of injection molded panels wherein connectors are integrally formed onto the edges thereof for connection to injection molded, extruded and/or blow molded panels to construct a bench assembly.
[0023] Other objectives and advantages of this invention will become apparent from the following description taken in conjunction with the accompanying drawings wherein are set forth, by way of illustration and example, certain embodiments of this invention. The drawings constitute a part of this specification and include exemplary embodiments of the present invention and illustrate various objects and features thereof.
BRIEF DESCRIPTION OF THE FIGURES
[0024] FIG. 1 is a top perspective view of one embodiment of the instant invention;
[0025] FIG. 2 is a bottom perspective view of one embodiment of the instant invention;
[0026] FIG. 3 is an exploded perspective view of the snap-together bench embodiment shown in FIG. 1 ;
[0027] FIG. 4 is a front elevational view of one embodiment of the instant invention;
[0028] FIG. 5 is a rear elevational view of one embodiment of the instant invention;
[0029] FIG. 6 is a side elevational view of one embodiment of the instant invention;
[0030] FIG. 7 is a section view along lines 7 - 7 of the bench embodiment shown in FIG. 4 illustrating the overlapping interlocking engagement between the panels constructing the bench assembly;
[0031] FIG. 8 is a top elevational view of one embodiment of the instant invention;
[0032] FIG. 9 is a bottom elevational view of one embodiment of the instant invention;
[0033] FIG. 10 is a top perspective view of one embodiment of the instant invention illustrating the bench seat in an open position to provide access to the storage box.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0034] While the present invention is susceptible of embodiment in various forms, there is shown in the drawings and will hereinafter be described a presently preferred embodiment with the understanding that the present disclosure is to be considered an exemplification of the invention and is not intended to limit the invention to the specific embodiments illustrated.
[0035] FIGS. 1-10 which are now referenced illustrate perspective, exploded and sectioned views of the patio bench, generally referenced as 10 , according to a preferred embodiment of the present invention. The patio bench is made up of a base panel 100 , left side panel 200 , right side panel 300 , front panel 400 , rear panel 500 , backrest panel 550 , and bench seat panel 600 . In the preferred embodiment, the panels comprising the assembly are formed of, but not limited to, a suitable polymeric material such as plastic, through the process of injection molding. Injection molding offers significant versatility, strength and stability advantages over materials and processes as utilized in the prior art. The result is that the panels comprising the patio bench 10 are formed as single wall unitary panels with integral connectors, cross bracing, surface texture and the like. Strengthening ribs 202 and gussets 204 are formed within the inner surfaces of the panels in order to enhance rigidity of the panels while leaving the external surface in a generally smooth condition for aesthetic purposes. The ribs 202 and gussets 204 increase the structural integrity of the patio bench 10 by preventing the panels 200 , 300 , 400 , 500 and 550 from bowing or bending inwardly or outwardly, and thus, adversely affecting the appearance or operation of the patio bench 10 . In this manner the patio bench of the instant invention is capable of handling a significant amount of weight while providing a lightweight construction that can be shipped in a knocked down condition for snap-together assembly upon a desired site.
[0036] Referring to FIGS. 1-7 , the front and rear panels 400 and 500 are each configured having a first end 408 , 508 and a second end 412 , 512 , an upper end 414 , 514 and a lower end 416 , 516 . Both the first and second ends include an integrally formed attachment means illustrated herein as an elongated post 410 . The posts 410 are generally constructed and arranged to cooperate with the sockets 208 provided in either end of the left 200 and right panels 300 . The lower ends 416 , 516 of the front and rear panels include an integrally formed socket 115 constructed and arranged to cooperate with the base panel in an interlocking overlapping manner. Integrally formed spring clips 126 provide additional engagement between adjacent panels by snapping into an aperture or depression formed into the adjacent panel to prevent the panels from separating. The upper end 514 of the rear panel 500 is constructed and arranged to include a plurality of integrally formed posts 518 , each post including an integrally formed spring lock 126 for engaging an aperture formed into the socket(s) 560 ( FIG. 7 ) of the backrest panel 550 . Also included on the upper end of the back panel 500 is a drip rail 520 . The drip rail extends along the length of the rear panel and is preferably positioned below a lower surface of the bench seat panel 600 . In this manner, water or moisture from the bench seat 600 and backrest 550 panels is channeled away from the storage box 522 ( FIG. 10 ) formed by the assembled panels.
[0037] Still referring to FIGS. 1-7 , a backrest panel 550 is illustrated. The backrest panel includes a top end 552 , a bottom end 554 , a left end 556 and a right end 558 . Sockets 560 are integrally formed along the bottom end 554 for interlocking cooperation with posts 518 of the back panel. The top end 552 of the backrest panel includes a removable and replaceable backrest cover member 562 . The backrest cover member includes an integrally formed socket 564 constructed and arranged to cooperate with a top end 552 of the backrest 550 in a snap-together arrangement. The backrest cover socket includes integrally formed spring locks 126 which cooperate with apertures 118 in the top end of the backrest panel. The left and right ends 556 , 558 of the backrest panel include integrally formed posts 518 depending downwardly from the top end 552 for interlocking cooperation with the armrest portion 212 of the side panels 200 , 300 . In a most preferred embodiment, the locking posts include spring locks 126 to engage the side panel and/or structural blocks 250 , 350 positioned in the armrest portion of the left and right side panels.
[0038] Referring to FIGS. 1-10 , the patio bench includes a left side panel 200 and a right side panel 300 each having integrally formed legs 210 and armrests 212 . The rear portion of the armrests 214 are formed hollow to accept a structural block 250 , 350 . Each structural block includes at least one integrally formed socket 560 for snap-together interlocking engagement with a left end or a right end respectively of the backrest panel. The structural block further includes a hinge pin aperture 566 constructed and arranged to cooperate with a hinge pin 602 formed to each distal end 604 , 606 respectively of the bench seat panel. The hinge pin aperture 566 aligns with an aperture 260 formed into the inner wall of the armrest 212 .
[0039] The left and right side panels 200 , 300 include integrally formed sockets 208 for interlocking engagement with the front and the rear panels 400 , 500 in a substantially perpendicular arrangement. In a most preferred embodiment, the armrests 212 include removable and replaceable armrest cover members 262 . The armrest cover members are preferably formed hollow to include integrally formed connectors constructed and arranged to cooperate with an upper surface of each of the left and right armrest. The internal portion of the armrest covers include spring locks constructed and arranged to cooperate with apertures 118 for interlocking engagement between the armrest covers and the armrests.
[0040] Each of the left and right panels include a drip rail 264 secured along the length of an inner surface of each respective panel. The drip rails are positioned to be below a lower surface of the bench seat panel, whereby water contacting an upper surface of the bench seat panel is directed to at least one of the drip rails to be channeled away from an interior area of the storage box. The drip rails include integrally formed C-shaped spring locks 266 which are arranged to cooperate with elongated apertures 268 formed into the inner surface of the left and right side panels. For engagement the C-shaped spring locks are directed through the apertures 268 and thereafter the drip rail is slid rearwardly to engage the spring locks and interlock the drip rail to the respective side panel.
[0041] Referring to FIGS. 3 , 4 , 7 and 10 , a bench seat panel 600 is illustrated. The bench seat panel includes an upper surface 608 , a lower surface 610 , a left end 604 , a right end 606 , a front end 612 and a rear end 614 . A hinge pin 602 is integrally formed onto each of the left and right ends to allow the bench seat panel 600 to be pivotable about a central axis A of the hinge pins to enclose the top portion of the storage box and to provide ingress into and egress from the storage box 522 . The front portion of the bench seat panel 600 includes an integrally formed latch member illustrated herein as a spring-catch 616 for releasably securing the cover in a closed position that is relatively parallel with respect to the ground surface. The spring-catch is constructed and arranged to cooperate with a catch plate 618 integrally formed to the front panel for releasable engagement between the bench seat panel 600 and the front panel 400 , whereby the bench seat panel is releasable upon pulling upward on a front portion thereof. The lower surface includes integrally formed ribs 202 and gussets 204 to add rigidity and weight capacity to the seat panel.
[0042] Referring to FIGS. 3 and 7 , the base panel 100 has a top surface 104 , bottom surface 106 ( FIG. 2 ), like-constructed front and rear edges 108 and 110 , and like-constructed left and right edges 112 and 114 . Extending along the edges of the base panel are a plurality of posts 206 . The posts are constructed and arranged to enter and mateably engage with sockets 115 formed along the lower portion of the left, right, front and rear panels in an overlapping interlocking fashion securing the panels together in a substantially perpendicular arrangement. The base panel also includes apertures 118 or indentations (not shown) for interlocking cooperation with spring locks 126 integrally formed into the sockets 115 . It should be noted that while the base panel is preferably constructed through the process of injection molding, the base panel may be formed by other suitable methods which may include, but should not be limited to, blow molding, vacuum forming or compression molding without departing from the scope of the invention. The integrally formed connectors, e.g. the sockets, facilitate connecting the injection molded panels to panels formed by other methods without the need for separate connectors and/or fasteners.
[0043] It will be appreciated that the purpose of the posts 410 , 518 and 206 are to align two panels in a substantially perpendicular or axially alined relationship and to facilitate their mechanical connection. The perpendicular panels are brought into an overlapping relationship wherein the posts enter the corresponding sockets 208 , 560 , 115 . The result is a mechanically secure connection between the panels. The overlapping edges between the panels as described above provides a secure connection and offers several advantages. First, the design allows the panels to be connected without the need for separate connectors or fasteners. Second, the design creates a positive lock that prevents separation of the panels. Third, the design maintains alignment of the panels in the same plane and prevents bowing or bending of either panel relative to one another. The resultant patio bench created by the combination of the interlocking panels benefits from high structural integrity and reliable operation.
[0044] It should be noted that the positions of the posts and sockets on respective panels can be reversed without departing from the scope of the invention. It should also be noted that while the posts and sockets are illustrated as having a substantially rectangular shape, both the posts and sockets may be configured in any shape and/or combination of shapes suitable for interlocking engagement between the adjacent panels; such shapes may include, but should not be limited to, polygons, cylinders, ovals, D-shapes and the like.
[0045] Referring generally to the FIGS., the front and rear panels 400 , 500 are attached to the base panel 100 by sliding the locking posts 206 along the edges 108 , 110 into the corresponding sockets 115 . The sockets 115 in the bottom portion of the front and rear panels correspond in shape and size to that of the locking posts 206 , and spring tabs 126 integrally formed into the sockets 115 align with apertures 118 in the locking posts 206 to engage the front and rear panels 400 and 500 . The result is a positive mechanical connection between the front and rear panels 400 , 500 , and the base panel 100 .
[0046] The left and right side panels 200 , 300 are attached to the front, rear, and base panels 400 , 500 , 100 by inserting the posts 410 , 206 into contoured sockets 208 , 115 until the spring tabs 126 integrally formed into the sockets engage the apertures 118 in the posts. The result is a positive mechanical connection between the left and right panels 200 , 300 , and the front 400 , back 500 and base panel 100 .
[0047] The backrest panel 550 is secured to the left, right and back panels 200 , 300 , 500 by sliding the socket 560 over posts 518 while simultaneously inserting posts 518 into sockets 560 in the upper portion of the armrest until the spring locks 126 engage the apertures 118 . The result is a positive mechanical connection between the backrest panel 550 , the back panel 500 , the left panel 200 , the right panel 300 and the structural blocks 250 , 350 .
[0048] The bench seat panel 600 is secured to the left and right panels by placing one of the hinge pins 602 into a respective aperture 260 of an armrest to engage the structural block aperture 566 . Thereafter the opposite end of the bench seat panel is slid downwardly until the other hinge pin engages the apertures in the side panel and structural block at the other end of the bench.
[0049] All patents and publications mentioned in this specification are indicative of the levels of those skilled in the art to which the invention pertains. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.
[0050] It is to be understood that while a certain form of the invention is illustrated, it is not to be limited to the specific form or arrangement herein described and shown. It will be apparent to those skilled in the art that various changes may be made without departing from the scope of the invention and the invention is not to be considered limited to what is shown and described in the specification.
[0051] One skilled in the art will readily appreciate that the present invention is well adapted to carry out the objectives and obtain the ends and advantages mentioned, as well as those inherent therein. The embodiments, methods, procedures and techniques described herein are presently representative of the preferred embodiments, are intended to be exemplary and are not intended as limitations on the scope. Changes therein and other uses will occur to those skilled in the art which are encompassed within the spirit of the invention and are defined by the scope of the appended claims. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the art are intended to be within the scope of the following claims. | The present invention relates to kit for a patio bench utilizing injection molded plastic panels capable of being packaged and shipped in a knocked-down state and constructed into a secure patio bench. The patio bench may also include an integral storage box positioned beneath the bench seat. The panels utilized for assembling the patio bench are also constructed to allow a number of patio benches to be configured using common components. | 0 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a detachable transmission mechanism for a wheel chair and particularly to an electric transmission mechanism used in a wheel chair with which a used wheel chair can be attached by way of DIY (Do It Yourself) so as to become an electric wheel chair.
2. Description of Related Art
The wheel chair was specially developed for handicapped or slowly moved aged persons and while a user sits in the wheel chair and pushes both lateral large wheels with both hands actuating grip rings coaxially connecting with the large wheels, the movement of the wheel chair can be obtained purposely. A weak person or a hand-hindered person resulting from illness or wound usually is unable to exert a force to the large wheels so that it is necessary to ask some other persons for gripping the handles at rear side of the wheel chair before the wheel chair can be moved. Hence, the conventional wheel chair has to be assisted by the user himself or any other person in order to meet the basic requirement of movement.
Accordingly, the so called electric wheel chair has been developed and the feature of the electric wheel chair is a transmission mechanism is provided under a “h” shaped seat, that is, one of two rear wheels is designed as the driving wheel and the other one rear wheel is the follower wheel so as to constitute a basis of moving forward. Two front wheels are controlled by a stir stem located at the armrests being shifted to front, rear, left or right so that the wheel chair can move toward a direction desired by the user. Although the conventional wheel chair has a good and easily operated control device, there still are following deficiencies: 1) the transmission mechanism of the electric wheel chair has to be driven with the electric power and it becomes unmoved in case of the electric power is depleted and the basic function of manual drive has lost; 2) In order to obtain the effect of speed differential (that is, the inner side rear wheel has a less rotational speed than the outer side rear wheel) for the two rear wheels and to avoid turning over or a risk of being unable to turn during the wheel chair making a turn, a sophisticate speed change box has to be mounted between the two rear wheels so that it increases the complicity of the transmission mechanism of the wheel chair; and 3) due to both the body and the transmission mechanism of the conventional electric wheel chair being made with complication, the production cost thereof is pretty high so that the retail price thereof is much more expensive and is not possible to become prevalent among handicapped and motion hindered persons.
SUMMARY OF THE INVENTION
An object of the present invention is to provided a detachable transmission mechanism for a wheel chair. The detachable transmission mechanism includes a control unit, an engaging unit, a battery unit and a transmission device. The original front wheels of the wheel chair can be detached and the hub and the pivot part are mounted to both the upper and lower frames of the wheel chair. The battery unit can be fixed to the wheel chair under the seat thereof. When a control switch is turned on, the driving wheel can rotate in a forward or a reversed direction with the wheel chair being capable of moving forward or backward. By turning the handle, a follower wheel at the bottom of the wheel chair can be rotated to allow the wheel chair making a turn.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention can be more fully understood by reference to the following description and accompanying drawings, in which:
FIG. 1 is an exploded perspective view of a detachable transmission mechanism for a wheel chair according to the present invention;
FIG. 2 is an exploded perspective view of a manual control device and a driving device according to the present invention;
FIG. 3 is a perspective view illustrating the transmission mechanism of the present invention being ready to be assembled to a wheel chair; and
FIGS. 4A and 4B are assembled perspective view of the transmission mechanism and the wheel chair shown in FIG. 3 with two different projection angles.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to FIGS. 1 through 4A and 4 B, the detachable transmission mechanism for a wheel chair consists of a control unit 1 , an engaging unit 2 , a battery unit 3 and a transmission device 4 .
Wherein, the control unit 1 is mainly to provide the entire transmission device 4 the ability to move and turn with a vertical shaft 11 at the top thereof engaging with a handle 12 being held and operated by a user and at the bottom thereof being connected to the engaging unit 2 . The vertical shaft 11 passes through a fixed hub 13 on the frame of the wheel chair so that the vertical shaft is able to rotate. The hub 13 consists of a sleeve 131 contained inside a U-clip 132 and at least one screw 133 can pass through the U-clip 132 and tightened with a nut 134 so that the U-clip 132 can be associated with the screw 133 firmly. A pivot lever 135 is extended from the bottom of the U-clip 132 to be connected to the wheel chair frame. By using a screw 137 passing through a pressing piece 136 and then fixing onto the pivot lever 135 , the frame can be enclosed and held at one lateral side of the wheel chair.
Nevertheless, to accommodate body types of different users, the vertical shaft 11 has a function of being adjustably lifted or descended. A plurality of positioning holes 112 are lined up on an outer pipe 111 and the lower part of the outer pipe 111 fits with an inner pipe 113 , which has a button hole 114 at the opening thereof is disposed corresponding to the positioning holes 112 . And a V-shaped elastic strip 115 , inserted into the opening of the inner pipe, has an abrupt button 116 extends outward laterally from the button hole 114 and engages with one of the positioning holes 112 selectively so as to lift the outer pipe 111 . Moreover, a fastener 14 is provided at the joint between the outer pipe 111 and the handle 12 and also the joint between the outer pipe 111 and the inner pipe 113 respectively. By stirring an engaging stem 141 and relatively turning a nut 142 , a loose/tightness effect on a pipe clamp 143 and thus the handle 12 can be adjusted to a suitable angle and provides better comfort during operating the transmission mechanism. Furthermore, a tight fit between the outer pipe 111 and the inner pipe 113 can be obtained instead of becoming loose and disconnected from each other easily.
The engaging unit 2 consists of a connecting frame 21 and a fixing base 22 . The connecting frame 21 has a F shape and there are two limit plates 211 , 212 extending outward from a lateral side thereof with an axial hole 213 , 214 on each of the limit plates. An axial rod 117 extends downward from the bottom of the inner pipe 113 to pass through the axial holes 213 , 214 . Furthermore, a joining plate 118 extends laterally from the bottom of the inner pipe 113 and is attached to and fastened to the limit plate 211 with a screw and a nut such that the vertical shaft 11 is supported on top of the connecting frame and thus form a relative movement with the connecting frame. The bottom of the connecting frame 21 has an inversed U-shaped joining part 215 , which is connected to the output unit 42 of the transmission device 4 by a screw rod.
The fixing base 22 is disposed between the two limit plates 211 , 212 and provided with a fitting ring 221 corresponding to the two axial holes 213 , 214 . A central bore 222 of the fitting ring 221 receives a sleeve 23 and the sleeve 23 is attached with an engaging plate 231 such that the engaging plate and the ring plate 223 can be joined to each other firmly. The sleeve 23 at the upper and the lower end thereof is inserted with a bearing 232 respectively and the axial rod 117 can pass through the bearings 232 for being able to rotate with facility. The axial rod 117 further passes through a washer 233 , a spring 234 and the lower limit plate 212 and then fastened to a connecting piece 235 so as to form a shock absorption system and accommodate to the rugged and rough road surface. In order to join the fixing base 22 to the wheel chair firmly, it is possible to provide a pivotal part, for instance, a base lever 224 and a support 225 extending in a way of being perpendicular to each other but disposed in different levels such that the base lever 224 and the support 225 can be joined to two perpendicular frames underneath the wheel chair respectively. Furthermore, by making use of two urging plates 226 being passed through by a screw 227 and engaging with the base lever 224 and support 225 respectively, the frames can be clamp commonly and the fixing base 22 can be fixed to a lateral side of the wheel chair at the lower part thereof.
Further, in order to fix the battery unit 3 in position, please refer to FIG. 3 again. A battery 32 shown is received in a case 31 and the bottom of the case 31 is attached with a lever cap 33 for the support lever passing through. By pressing the knob 34 tightly onto the support lever 225 , this will make the battery unit 3 fixed under the seat of the wheel chair and the contact poles 35 thereof provide the power needed by the transmission device 4 .
The transmission device 4 consists of a motor 41 , an output unit 42 and a driving wheel 43 . Wherein, the output unit 42 can be a turbine reducer, a pulley or a gear in practice. Referring to FIG. 2 again, when the motor 41 starts to run, it will make the output shaft 421 , which extends from the output unit 42 laterally to turn in the forward or revered direction according to the operation of a user. Thus, the driving wheel 43 , which is connected to the output shaft, can move forward or backward. The characteristic of the present invention is that the driving wheel 43 is connected with a manual control device 44 , that is, a shaft hole 431 in the driving wheel 43 is inserted with a respective bearing 432 at both ends thereof and an outer flange surrounding the shaft hole 431 provides at least two engaging holes 433 . An engaging groove 422 is provided on the output shaft 421 and extends longitudinally to pass over the two bearings 432 and a follower plate 441 . The follower plate 441 is provided with an engaging bolt 442 and a through hole 443 corresponding to the engaging groove 422 and the engaging hole 433 so that the follower plate 441 can rotate synchronously with the driving wheel 43 . An engaging plate 444 is attached to the outer wall of the follower plate 441 . The engaging plate 444 is pierced with a relay pipe 446 and has an engaging projection 445 corresponding one of the engaging holes 433 so that the engaging projection 445 can pass though and fit with the engaging hole 433 and the engaging plate 444 can rotate with the driving wheel 43 . Furthermore, on the other side of the engaging plate 444 , a spring 447 and a washer 448 are placed one after another for a fixing bolt 449 passing through and being fastened to the output shaft 421 . When the battery 32 in the battery unit 3 is depleted, the driving wheel 43 will not be able to turn. At this moment, the only thing has to be done by the user is to hold and then pull the engaging plate 444 outward along the relay pipe 446 . Under this circumstance, the spring 447 is compressed and the engaging projection 445 is free from both the engaging hole 433 and through hole 443 so that the engaging plate 444 is unable to rotate with the driving wheel 43 and the driving wheel is therefore in a state of no traction. Hence, the user can push the grip ring of the wheel and make the two large wheels at the two lateral sides of the wheel chair to rotate and move forward and the driving wheel 43 is in a state of idling and acts as a driven wheel.
Referring to FIGS. 3, 4 A and 4 B again, the detachable transmission mechanism of this invention has been built up as a master structure and a power supply part by way of modularized design. Thus, in case of the detachable transmission mechanism of the present invention being assembled with an existing wheel chair, a small wheel at the front lateral side of the wheel chair has to be removed first and then the pivot lever 135 , base lever 224 and support lever 225 are respectively attached to the upper and lower frame of the wheel chair. Next, both the pressing piece 136 and the urging plate 226 is used for enclosing and holding the frame such that the master structure can be fixed to a lateral side of the wheel chair. After that, the battery unit 3 and the support lever 225 are joined to each other so as to locate the power supply part in position before the assembly job is completed. Hence, once the control switch on the handle 12 is operated, the driving wheel 43 can move forward or backward. In case of making a turn, the user just has to hold and rotate the handle 12 and the driving wheel 43 can turn to another direction extremely conveniently.
It is appreciated that the effectiveness of the present invention resides in the transmission mechanism can be associated with an existing wheel chair used in ordinary families, hospitals, nursing home or rehabilitation center and it is not necessary to acquire an expensive electric wheel chair. Moreover, when the power of the battery unit is consumed, adjusting the manual device with hands will make the driving wheel not able to be actuated by the engaging plate and become in a state of idling. The wheel chair is then changed to the manual control and can move by pushing with hands. Furthermore, the present invention does not need complicated design of speed change box and wheel chair frame so that the production cost can be greatly reduced and the goal for popularity and low cost can be reached advantageously and it is impossible for the conventional electrical wheel chair can achieve effectively. Furthermore, the vertical shaft and the handle can be adjusted to lift and turn to accommodate for the build types of different users so that the user can obtain utmost comfort due to human engineering consideration in the present invention.
While the invention has been described with reference to the a preferred embodiment thereof, it is to be understood that modifications or variations may be easily made without departing from the spirit of this invention, which is defined by the appended claims. | A detachable transmission mechanism for a wheel chair includes a control unit, an engaging unit, a battery unit and a transmission device. The original front wheels of the wheel chair can be detached and the hub and the pivot part are mounted to both the upper and lower frames of the wheel chair. The battery unit can be fixed to the wheel chair under the seat thereof. When a control switch is turned on, the driving wheel can rotate in a forward or a reversed direction with the wheel chair being capable of moving forward or backward. By turning the handle, a follower wheel at the bottom of the wheel chair can be rotated to allow the wheel chair making a turn. | 0 |
REFERENCE TO RELATED APPLICATION
This application is related to U.S. patent application Ser. No. 07/324,454, filed Mar. 16, 1989 and entitled Sensor For Measuring Pulse Rate and/or Oxygen Saturation of Blood and Process for Making Same, the subject matter of which is hereby incorporated by references.
FIELD OF THE INVENTION
The present invention relates to an optoelectronic sensor for producing electrical signals for measuring physiological values, especially the circulation parameters of a person.
BACKGROUND OF THE INVENTION
The fastening of transmitters and receivers of optoelectronic physiological sensors onto the skin surface is very problematical. Even the slightest movements of the parts of the sensor relative to the skin surface lead to numerous artifacts (structures in a fixed cell or tissue formed by manipulations or by the reagent), and thus, lead to signal fluctuations. To avoid these movements, both the transmitter and the receiver need to be tightly pressed onto the skin surface.
Tight pressing can disturb the circulation of the blood through the capillary bed, which disturbance can also lead to erroneous measurements and recordings. A slighter inclination to the formation of artifacts simultaneously with higher signal quality cannot be attained with flexible or resilient clamps on the skin, or by means of elastic strips and the like.
Because of this, it has been suggested (see, e.g., European Patent 0 127 947 A2) to affix a light-impermeable strip to the support layer for the transmitter and receiver. The strip, in the area of the light outlet surface of the transmitter and in the area of the light admission surface of the receiver, has an opening for each. This strip is affixed to a sheet of clear polyester, coated on both sides with an adhesive material. Also, a porous protective layer can be affixed to the reverse side of the light impermeable layer supporting the transmitter and receiver members. Despite this costly construction of the transmitter and of the adhesive connection between the transmitter and the skin surface, the signal quality is still inadequate.
SUMMARY OF THE INVENTION
A object of the present invention is to disclose an optoelectronic sensor for producing electrical signals representative of physiological values which appreciably avoids artifacts and has the capacity to deliver a high quality signal.
The foregoing object is obtained by an optoelectronic sensor for producing electrical signals representative of physiological values, especially human circulation parameters. The sensor comprises a radiation transmitter having a radiation outlet surface, and a radiation receiver sensitive to receiving radiation emitted by the transmitter and influenced by the physiological values. The receiver is coupled to the transmitter and has a radiation admission surface. A transparent adhesive layer covers the transmitter and the receiver on at least sides thereof facing an object to be measured. The adhesive layer directly engages the radiation outlet surface and the radiation admission surface.
In this manner, the transparent adhesive layer, at least on its side turned toward the target or object being measured, also directly engages the area of the radiation outlet surface of the transmitter and the radiation admission surface of the receiver. An optical path (or radiation path) lies between the skin surface on the one hand and the transmitter, as well as the receiver on the other hand. The optical path consists of material of approximately identical optical density.
With the known sensor, on the contrary, incorporation of air is unavoidable, such that the optical path is formed of materials with different optical densities, such optical path has considerable internal reflections causing leakage of the radiation.
In the present invention, an optimum optical coupling between the transmitter, the skin surface and the receiver is guaranteed. The optical path does not lead to formation of internal reflections. A greater portion of the radiation thus pervades the tissue, whereupon the portion of radiation reaching the receiver is also considerably greater, attaining an excellent quality signal.
The inclination to form artifacts can also be suppressed for the most part by virtue of the adhering layer. In one preferred embodiment, the transparent layer has a highly transparent gel of silicon base. This material provides good optical qualities and good adhesion, and thus, fulfills all the requirements. Such gel may be obtained from Wacker-Chemie GmbH, Munich, West Germany, under the name RTV-2 Silikonkautschuk VP 7612, as a two-component sealing compound.
The adhesiveness of the gel is preferably adjusted to the desired value corresponding to the purpose of its use. The adhesiveness is adjusted by varying the mixture ratios of the two components forming the gel.
The transparent layer directly engaging the radiation outlet surface of the transmitter and the radiation admission surface of the receiver can be provided on one side of a transparent support sheet. The other side of the support sheet is provided with a transparent layer consisting of the same material. Such support sheet can also provide additional electrical insulation. However, it is especially advantageous for such support sheet to be coated on both sides for the formation of adhesive laminae. The lamina dimensions can be coordinated with the dimensions of the transmitter and those of the receiver. The adhesive lamina can be applied on each or a common adhesive lamina can be applied to both of the transmitter and receiver. After measurement, the lamina can be removed and discarded for reasons of hygiene. Such adhesive laminae can also have an uncoated gripping strap to facilitate handling.
The sensor can be covered on all sides with the layer of gel at least in the area of application. Thus, the properties of the gel can be selected to electrically insulate the transmitter and the receiver from the skin as well as to seal the transmitter and receiver from water, moisture and perspiration.
Insofar as required, on the side of the sensor which is turned away form the target to be measured, the gel layer can be covered with a reflective layer.
Other objects, advantages and salient features of the present invention will become apparent from the following detailed description, which, taken in conjunction with the annexed drawings, discloses preferred embodiments of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
Referring to the drawings which form a part of this disclosure:
FIG. 1 is a perspective view of an optoelectronic sensor according to a first embodiment of the present invention with gel only in the transmitter and receiver areas;
FIG. 2 is a perspective view of an optoelectronic sensor according to a second embodiment of the present invention operated by reflection with a raised adhesive lamina;
FIG. 3 is a side elevational view in section of an optoelectronic sensor according to a third embodiment of the present invention for fastening to a nose;
FIG. 4 is a plan view of an optoelectronic sensor according to a fourth embodiment of the present invention; and
FIG. 5 is a side elevational view in section of the optoelectronic sensor of FIG. 4.
DETAILED DESCRIPTION OF THE INVENTION
An optoelectronic sensor produces electrical signals representative of physiological values. The sensor can be used, for instance, for oximetry (the measure of the degree of oxygen saturation of blood) and plethysmography (the measure of the changes in the size of a part of the body by measuring changes in the amount of blood in that part).
The optoelectronical sensor of the present invention has a strip-like, flexible base member 1 made of a flexible synthetic resin, for instance, silicon rubber. A radiation transmitter 2 and a radiation receiver 3 are embedded in this strip-like base member 1, at some distance from each other along its length. The transmitter light discharge surface and the receiver light admission surface are independent of each other and unconfined. Radiation transmitter 2 and radiation receiver 3 are soldered onto a not shown, flexible conductor plate. One end of the conductor plate is soldered to a connection cable 4. The distance between radiation transmitter 2 and radiation receiver 3 is selected so that radiation transmitter 2 and radiation receiver 3 can be arranged on opposite sides of the fingers of a person.
The radiation outlet surface of radiation transmitter 2 and the radiation admission surface of receiver 3, as well as border area of base member 1 surrounding the transmitter and receiver, are coated with a highly transparent, adhesive gel 5. For the first exemplary embodiment, gel 5 is of the type distributed by Wacker-Chemie GmbH, Munich, West Germany, under the name RTV-2 Silikonkautschuk VP 7612, which is a mixture of two components applied to the surfaces to be coated. The mixing ratio of the two components influences the adhesiveness. After a vulcanization period, dependent upon the vulcanization temperature, the properties of gel 5 no longer change.
For execution of the measurement, gel 5 covering radiation transmitter 2 makes contact with the measurement area of the skin surface, and produces a reliable adhesive connection, essentially suppressing the formation of artifacts. Correspondingly, radiation receiver 3 is affixed to the associated measurement surface. The radiation emanating from radiation transmitter 2 must penetrate gel 5 only until it reaches the skin surface, and then pervades or soaks into the skin. The radiation emanating from the body part, influenced by the physiological value being measured, must pervade only gel 5 again as it comes out of the body, before reaching the radiation admission surface of radiation receiver 3. Thus, an optimum optical coupling of radiation transmitter 2 and radiation receiver 3 with the target, the object to be measured, is obtained. Additionally, an excellent quality signal is obtained.
In the optoelectronic sensor shown in FIG. 2, the radiation transmitter 12 and the radiation receiver 13 are arranged at a relatively small distance from each other, one adjacent to the other on a not shown conductor plate which is probably quadratic. The conductor plate is soldered to a connection cable 14. The base member 11, in which the conductor plate, radiation transmitter 12 and radiation receiver 13 are embedded, with the exception of the radiation outlet surface and the radiation admission surface is silicon rubber, as in the first exemplary embodiment. However, the base member could also be of some other synthetic resin material, because in this embodiment the flexibility does not play an essential role. This exemplary embodiment actually works on a reflective basis. In other words, the radiation emanating from the radiation transmitter 12 is reflected by the object to be measured, so that only reflected radiation reaches radiation receiver 13.
An adhesive lamina, indicated in its entirety as 16, reliably connects the sensor and the object to the measured, i.e., the skin surface of a person. For an optimum optical coupling, adhesive lamina 16 has a highly transparent support sheet 17. The support sheet dimensions are coordinated approximately with the dimensions of the front surface of the sensor. This support sheet 17 has a gripping strap 17' on one side. Both sides of support sheet 17, with the exception of its gripping strap 17', are coated with a highly transparent, adhesive gel 15. The gel is composed of the same material as gel 5 of the first exemplary embodiment. The adherence between gel 15 and support sheet 17 is greater than between gel 15 and the front side of the sensor.
For a measurement, adhesive lamina 16 is applied on the front of the sensor. The side of adhesive lamina 16, not facing or remote from sensor front side, is then installed on the measurement surface of the object to be measured. Of course, it is also possible to first install the adhesive lamina 16 on the measuring point and thereafter to initiate the use of the sensor. Also, in this case, a good adhesive connection for the most part suppresses the formation of artifacts and provides an optimum optical coupling. Support sheet 17 has an optical density at least nearly identical to the optical density of gel 15, and can improve the electrical insulation of radiation transmitter 12 and radiation receiver 13 relative to the skin surface of the person being tested.
The exemplary embodiment shown in FIG. 3 is intended for installation on the nose of a person. One end of a four-polar connection cable 24 is subdivided in its middle and is spread apart in a Y shape. The one pair of conductors is soldered onto radiation transmitter 22, while the other pair is soldered onto radiation receiver 23. Radiation transmitter 22 and radiation receiver 23 are embedded in opposite end segments of a base member 21 of silicon rubber, while the radiation outlet surface and the radiation admission surface are left uncovered. The notably narrower, flexible middle segment of the base member has the shape of a curve segment. In all, the sensor has the inner and outer contour of a sector of a circle.
The sensor is coated with gel 25 in the entire application area, i.e., in the total area of base member 21 and the subdivided cable end. For this purpose, the entire sensor, inclusive of the separated end parts of the connection cable, is immersed in gel 25. This gel 25 is of the same material used for gel 5 of the first exemplary embodiment.
In the exemplary embodiment shown in FIGS. 4 and 5, the sensor has a four-polar flat cable 34. Two radiation transmitters 32 are directly soldered onto cable 34 adjacent to one other along the cable length. Also along the cable length, at considerable spacing from these transmitters, radiation receiver 33 is located. The end segment of flat cable 34 supporting these optical structural components is coated with a gel 35, applied by immersion. On the reverse side of the end segment of flat cable 34 coated with gel 35, a sheet of paper 38 coated with aluminum is applied, and is held tightly thereon by gel 35. The aluminum coating serves as reflector and as a shield. On the front side, opposite paper 38, transparent sheet 39 is applied and is coated with gel 35 on the side not adjacent to or remote from the flat cable. Sheet 39 serves as additional insulation for the skin surface. Since sheet 39 has the identical optical density as gel 35, no inner reflections originate therein.
While various embodiments have been chosen to illustrate the invention, it will be understood by those skilled in the art that various changes and modifications can be made therein without departing from the scope of the invention as defined in the appended claims. | An optoelectronic sensor produces electrical signals representative of measurements of physiological values, especially the circulation parameters of a person. The sensor has at least one radiation transmitter and at least one receiver for radiation influenced by the physiological values being measured. The transmitter and receiver are covered with a transparent adhesive layer on their sides turned toward the object to be measured. The layer is transparent and adhesive at least on its side turned toward to the object to be measured. This transparent layer engages directly on the radiation outlet surface of the radiation transmitter and the radiation admission surface of the radiation receiver. | 0 |
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of the filing dates of provisional application Ser. No. 60/605,663, filed Aug. 30, 2004, and Ser. No. 60/644,424, filed Jan. 14, 2005.
FIELD OF THE INVENTION
[0002] The present invention is directed to furniture intended for outdoor use, such as tables, chairs, benches, chaise lounges, gliders, ottomans, and the like. The framework or support structure for the furniture includes integral storage for a cushion (or cushions) that may be associated therewith, or for other items. The storage compartments are intended to easily receive the intended contents in order to protect them when not in use from detrimental environmental conditions.
BACKGROUND OF THE INVENTION
[0003] Furniture having cushions as a component thereof is becoming increasingly popular for outdoor use. As can be appreciated, cushions associated with the furniture are exposed to detrimental environmental conditions. Such conditions can include precipitation, wind, sunlight, windborne dirt, dust and debris, and exposure to contact by plants and animals. Each of these can be detrimental to both the appearance and the integrity of the fabrics and padding that comprise the cushions. Further, such environmental exposure can also render the use of the furniture unpleasant until the cushions have sufficiently dried out or otherwise been cleaned off.
[0004] One way protection of outdoor furniture from the elements has been provided is by a cover. See, e.g., Waters U.S. Pat. No. 6,155,637, which shows a slip cover arrangement for chairs, such as glider rockers. See also, Gengler et al. U.S. Pat. No. 6,709,055 and Blome et al. U.S. Pat. No. 6,626,491. While such covers are generally effective in protecting the furniture, some persons may consider them to be aesthetically unpleasing. In addition, there is a general need for convenient weather-proof storage of various outdoor accessories.
SUMMARY OF THE INVENTION
[0005] The present invention is directed to furniture intended for outdoor use. The framework of the furniture includes structure providing a permanent compartment, or compartments, for receipt of any cushions that may be associated therewith, or other outdoor accessories, when not in use. The compartment protects the contents from the elements and, because the storage compartment is incorporated into the framework of the furniture, it provides a more pleasing appearance than a cover.
[0006] In one aspect of the invention, a chair is provided with a compartment suitable for storing seat or back cushion. A compartment for a seat cushion is typically provided under the seat frame, while a compartment for a back cushion is provided on the back side of the backrest. In another aspect of the invention, storage compartments for tables are provided underneath the table top.
[0007] The compartments are made by adding framework to the existing support frame of the particular type of furniture. The additional framework is covered with a material, preferably waterproof or weather resistant, suited for outdoor use that may be complementary to or identical with material that covers the remaining framework. This results in the storage compartment(s) being less visually objectionable.
[0008] The interior of the storage compartment(s) may be lined with a waterproof or water-resistant material, and the opening of the compartment may include a closure, such as a hinged or sliding door, or a weighted flap, to further protect the contents stowed therein from adverse environmental exposure.
[0009] It is accordingly a general aspect or object of this invention to provide an improved article of outdoor furniture that facilitates protection of cushions that may be associated therewith, or other items, from detrimental environmental conditions when not in use.
[0010] Another aspect or object of the invention is to provide a support frame for such outdoor furniture that has integral storage compartments for storage of cushions or other items.
[0011] Another aspect or object of this invention is to provide a weather-protective storage compartment in an unobtrusive location, whereby a user can quickly and conveniently store in or remove from the compartment an associated cushion or other item.
[0012] Other aspects, objects and advantages of the present invention will be understood from the following description of the preferred embodiments of the present invention, specifically included stated and unstated combinations of the various features which are described herein, relevant information concerning which is shown in the accompanying drawings.
BRIEF DESCRIPTION OF THE PHOTOGRAPHS
[0013] FIG. 1 is a front perspective view of a cushioned chair of the type suitable for the present invention with the cushions in place;
[0014] FIG. 2 is a rear perspective view of a chair shown in FIG. 1 , showing the integral storage compartments; and
[0015] FIG. 3 is a rear perspective view similar to FIG. 2 , except that the cushions are stowed in the storage compartments.
[0016] FIGS. 4-6 show a table incorporating a weatherproof storage compartment in accordance with the present invention, with the opening of an associated closure door or panel shown in sequence.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0017] As required, detailed embodiments of the present invention are disclosed herein. However, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which may be embodied in various forms. Therefore, the specific details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention in virtually any appropriate manner.
[0018] Turning to the drawings, a chair generally designated 10 , is shown in FIG. 1 . While the preferred embodiment is in the form of a chair for storage of any cushions associated therewith, it will be appreciated that the invention is suitable for use in connection with other types of outdoor furniture. The illustrated chair 10 is an armchair intended for outdoor use that has a frame which may be made of, e.g., aluminum tubing, cast aluminum, wrought iron, wood, etc. The frame is covered with a material suitable for outdoor use, such as, e.g., a synthetic waterproof or water-resistant material, to provide for a more attractive finish. Preferably, the chair is covered in a synthetic wicker material. However, other materials can be used to cover the frame without departing from the invention.
[0019] The chair 10 includes a backrest 14 and a seat frame or support 16 , which support cushions 18 , 20 , respectively, to provide for enhanced seating comfort. Storage compartments, generally designated 22 and 24 (seen in FIGS. 2 and 3 ), are provided integrally with the frame of the chair 10 and are sized to receive the back cushion 18 and seat cushion 20 , respectively.
[0020] The back cushion storage compartment 22 has a size and shape adapted to receive the back cushion 18 and extends from the backrest 14 of the chair. The storage compartment 22 comprises frame member 26 , seen in dotted lines in FIG. 2 . As illustrated, the frame members 26 extend from the top of the backrest to the mid-section of the rear legs of the chair. The frame members 26 are joined by a sufficient number of cross-frame members 28 (also shown in dotted lines) to provide structural rigidity. The frame members 26 , 28 support a covering material 30 to define the storage compartment 22 .
[0021] The covering material 30 is preferably chosen to create an unobtrusive appearance when combined with the covering on the remainder of the chair frame. The covering material 30 may be different from the synthetic wicker material covering the remainder of the frame, or the covering material 30 can be made of a material identical to that covering the remainder of the frame to further disguise the storage compartment 22 . Additionally, the covering material is preferably a waterproof/water-resistant material, which is suitable for outdoor use and provides a barrier to the elements with respect to the interior of the compartment.
[0022] Alternatively, or additionally, the interior of the compartment 22 can be provided with a waterproof/water-resistant lining to further protect the cushion when stored therein. If a lining is employed, it is preferably made of a material having a low co-efficient of friction so as to facilitate easy insertion and removal of the seat cushion from the compartment. The low co-efficient of friction for the lining may permit the storage compartment to be made slightly undersized (and, therefore, less visually obtrusive), as the cushion can be slightly compressed when placed into the compartment.
[0023] The upper end of the compartment 22 is open to facilitate receipt of the back cushion 18 . The opening may be provided with a closure, such as a hinged lid 31 or weighted flap (not shown) in order to provide more complete protection for a cushion stored therein. The lid or flap is also preferably made of a material that would complement or match that covering the remainder of the chair frame and back cushion storage compartment.
[0024] Similarly, the seat cushion storage compartment 24 comprises frame members 32 , 34 (shown in dotted lines in FIG. 2 ) that extend between the legs of the chair underneath the seat frame 16 . These frame members 32 , 34 support a covering material (not shown) like cover material 30 to define a storage compartment sized to receive the seat cushion 20 . Similar to storage compartment 22 , the covering material is suited for outdoor use and provides a barrier to environmental elements entering the compartment 24 . In addition, a protective lining can be provided on the interior of the compartment 24 , as well as a closure lid 36 or flap (not shown), to provide fuller protection for a cushion stored therein.
[0025] As is appreciated, some outdoor chairs have only seat cushions, and not back cushions. In such circumstances, only a single storage compartment, preferably under the seat frame, is needed. Additionally, the furniture item having the integral storage compartment need not be the same furniture item for which the cushion is used.
[0026] Turning to the FIGS. 4-6 , there is seen a second embodiment of the present invention in the context of a table, generally designated 38 . As is typical, the table 38 includes a table top 40 and four legs 42 , although more or fewer (i.e., at least three) legs may be used. Supported between the legs 42 underneath the table top 40 is a shelf 44 for supporting cushions or other items. The shelf 44 is defined by four frame members that extend between the legs 42 and which, in the illustrated embodiment, are covered with a waterproof/water-resistant material, as described above. However, the shelf 44 may be made of, e.g., a solid panel or sheet, without departing from the invention. In addition, a storage compartment is defined by the shelf 44 , in combination with three of the four sides that bound the shelf 44 , and the table top 40 (or a partition or panel 46 supported between the legs beneath the table top). In the illustrated embodiment, the sides bounding the shelf are defined, in part, by the legs 42 , and are closed by, e.g. covering with waterproof/water-resistant material. The compartment, as thus described and illustrated, is closed on five of six sides. As noted above, the interior of the compartment can also be provided with a waterproof/water-resistant lining.
[0027] To close the open side of the storage compartment, the table 38 includes a door or closure panel 48 that slides and pivots with respect to a track (not shown) mounted to the table 38 adjacent to the table top 40 . The panel 48 preferably comprises a frame that supports waterproof/water-resistant material like that defining the remainder of the storage compartment, and also may include a waterproof/water-resistant lining on its interior side.
[0028] With reference to FIGS. 4-6 , to obtain access to the storage compartment, the door or closure panel 46 is pivoted upwardly and then slid along the track so that it underlies the table top 40 . Various contents may then be placed into the storage compartment, such as cushions 50 that may be associated with other furniture, or other items (such as dinnerware, table linens, etc.). To close the storage compartment, the closure panel 48 is simply slid along the track outwardly from the table 38 , and then pivoted downwardly once the end of the track is reached.
[0029] It will be understood that the embodiments of the present invention which have been described are illustrative of the application of the principles of the present invention. Numerous modifications may be made by those skilled in the art without departing from the true spirit and scope of the invention, including combinations of the features that are individually disclosed or claimed herein. | Furniture intended for outdoor, includes framework defining structure providing a storage compartment, or compartments, for receipt of, e.g. cushions or other items when not in use. The compartment protects the contents from the elements and, because it is incorporated into the framework of the furniture, provides an aesthetically pleasing appearance. | 0 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a continuous fermenter vessel for receiving an agitated suspension culture of cells.
2. Description of the Related Art
Recent advances in the commercialisation of products produced by the in vitro fermentation of cells have led to a growing interest in the design of improved fermenter vessels and fermentation processes.
Fermentation is usually carried out either in a batch process or in a continuous process. Continuous processes are advantageous since they enhance the productivity of a given fermenter and reduce the nonproductive downtime necessary for cleaning and sterilisation which is normally required in a batch fermenter.
In known continuous fermenter vessels, a suspension of cells in an appropriate culture medium is agitated and maintained at a suitable temperature for fermentation. Suspension culture is continuously withdrawn from the fermenter, balanced by a continuous supply of fresh culture medium. A significant disadvantage of such fermenters is the continual loss of cells caused by the removal of culture. Fermenters are known in which removed suspension culture is passed through a continuous centrifugal separation device which separates cells from the culture supernatant. The cells are then fed back into the suspension culture.
In another known fermenter, a rotating basket of a filter material is provided, partially submerged in the culture, such that the inside of the basket is separated from the suspension culture by the filter. Culture supernatant passes through the filter and may be withdrawn continuously, whilst cells remain in the suspension culture. The rotation of the basket in the suspension culture reduces clogging of the filter material.
These known devices for providing cell feedback in continuous suspension cultures are complicated mechanically, require energy for their operation and may cause detrimental effects, such as cell rupture, upon the suspension culture. These features combine to reduce the economic viability of fermentation processes based on such fermenters.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a continuous fermenter vessel which substantially overcomes these disadvantages.
According to the present invention there is provided a continuous fermenter vessel for receiving a suspension culture of cells, the vessel comprising; means for agitating a suspension culture received in a first portion of the vessel; a second portion of the vessel defining, in use, a static settling zone, at least part of the bottom of the second portion communicating with the first portion; an inlet means for the continuous supply of culture medium to the vessel; and an outlet for the continuous withdrawal of culture supernatant from the second portion of the vessel from a point spaced above the bottom of the second portion wherein, in use, cells settling in the second portion are returned to the agitated suspension culture, and culture supernatant having a lower concentration of cells than the suspension culture is withdrawn from the second portion.
According to the present invention there is thus provided a continuous fermentation device for receiving a suspension culture of cells, the device comprising: a fermentation vessel having inlet means to deliver suspension culture medium; baffle means defining, in combination with interior walls of said vessel, a downcomer and a riser; pump means for forcing a suspension culture to circulate in the riser and downcomer; a portion of said baffle means further defining a static settling zone disposed within said vessel, wherein said zone is surrounded by at least one of said riser and said downcomer, said zone having a bottom opening communicating with at least one of said riser and downcomer, and a top opening connected to outlet means to draw off culture supernatant, and wherein said zone provides for cells to settle out in its bottom so as to result in a cell concentration lower in the supernatant than in the suspension.
In the fermenter, i.e., the continuous fermentation device, of the invention, the cell separation and cell feedback steps are achieved by the provision of a static settling zone. Suspension culture entering the static settling zone (replacing culture supernatant removed from the static settling zone) moves from the agitated suspension culture into a zone of low turbulence. In this zone, the cells begin to settle downwardly under the influence of gravity and, at the bottom of the static settling zone, are returned to the agitated suspension culture. The settling results in a cell concentration gradient within the static settling zone allowing the removal of culture supernatant from a point spaced above the bottom of the static settling zone. The culture supernatant at this point has a substantially lower cell concentration than the agitated suspension culture. The cell separation and feedback components of the fermenter of the invention have no moving parts and require no additional energy input.
The static settling zone may be situated anywhere within the fermenter or may form an appendage to the portion of the vessel for retaining, in use, the agitated suspension culture. However, in order to minimise movement within the static settling zone, it is preferred that the static settling zone is located entirely within the portion of the fermenter for retaining, in use, the agitated suspension culture. This significantly reduces temperature gradients within the static zone which may give rise to undesirable convection currents.
The means for agitating the suspension culture may be any suitable means for ensuring mixing of the cells. A suitable means is, for example, a mechanical stirrer. However, in a preferred form of the invention, agitation is caused by the injection of a gas, suitably air, through a gas inlet. The fermenter may be, for example, a so called "air-lift" fermenter in which a gas such as air is injected into an upwardly extending part of the fermenter known in the art as a riser. The riser communicates at top and bottom with the top and bottom respectively of a further upwardly extending part of the fermenter known in the art as a downcomer. A known configuration of an air-lift fermenter comprises a central divider in the fermenter vessel separating the vessel into two parts (riser and downcomer). An alternative configuration of air-lift fermenter comprises a draught tube substantially concentric with a cylindrical fermenter vessel, dividing the fermenter into a riser (within the draught tube) and a downcomer (in the annular space between the draught tube and the side of the fermenter vessel). (The riser could equally be the annular space between the draught tube and the inside of the fermentervessel, and the downcomer could be within the draught tube). The injection of a gas, such as air, into a lower part of the riser causes a reduction in the bulk density within the riser resulting in an upward flow of liquid in the riser, thus displacing the contents of the downcomer which circulates back into the bottom of the riser. In this way a fluid flow is caused, mixing the culture and maintaining the cells in suspension. The advantages of such a fermenter are that no moving parts are necessary and oxygenation of the culture occurs. Typically the cross-sectional area of the riser is substantially the same as the cross-sectional area of the downcomer.
In a preferred aspect of the invention the continuous fermenter vessel is an air-lift fermenter and the static settling zone comprises a conduit formed in a divider between a downcomer and a riser. In this way unwanted convection currents are prevented by ensuring that the static settling is surrounded by the well mixed suspension culture having a homogenous temperature. In use the working liquid level in the fermenter preferably is such that the top of the settling zone is covered by from 0.25 to 1.0 times the diameter of fermenter.
The divider may be, for example, a substantially cylindrical draught tube positioned substantially concentrically in a substantially cylindrical fermenter vessel. The static settling zone may comprise an annular space formed between inner and outer walls of at least a portion of the draught tube. The static settling zone is preferably closed at the top and communicates at the bottom with the downcomer. In air-lift fermenters of small volume for example less than ten liters, the draught tube may be double-walled along its length, forming an annular settling zone closed at the top, and communicating at the bottom with the suspension culture. Alternatively, and in particular for larger fermenters the static settling zone may comprise an annular space between inner and outer walls of an upper part of the draught tube only. In large fermenters the static settling zone must have a sufficiently large cross-sectional area so that the velocity of the upward flowing liquid is less than the settling velocity of the cells, to achieve good cell separation. To accommodate the cross-sectional area required for the static settling zone and still provide sufficient area for circulation around the vessel, an upper section of the fermenter may have a greater diameter relative to a lower section of the fermenter. The cross-sectional areas of the riser and downcomer in the upper section are substantially identical and may have a cross-sectional area of between 0.5 and 1.0 times the cross-sectional area of the riser and the downcomer respectively in the bottom section of the fermenter. To achieve this, the internal diameter of the concentric draught tube in an upper portion may be reduced relative to a lower portion of the draught tube. The upper and lower sections of the fermenter may be connected with frustoconical section having an angle of between 0° and 60° to the general axis of the fermenter.
The divider may take the form of a draught plate comprising a substantially vertical plate mounted in the vessel. The static settling zone may comprise a conduit formed in the plate either in an upper portion of the plate or along its length.
The continuous fermenter may be operated in known fashion using a continuous supply of culture medium and withdrawing continuously culture supernatant. The continuous fermenter may be operated continuously at a dilution rate (i.e. ratio of flow rate to fermenter volume) of between 0.02 hr -1 and 0.08 hr -1 , preferably about 0.042 hr -1 .
The fermenter may be used for the culture of any cells, capable of in vitro growth in suspension liquid culture, (including microcarrier culture), but is especially useful for the culture of animal cells such as, for example, hybridoma cell lines.
It has been determined that animal cells will sediment under gravity at a rate of between 0.9×10 -5 ms -1 and 4.0×10 -5 ms -1 and usually about 1.8×10 -5 ms -1 . In order therefore to allow for a reasonable balance of high continuous throughput and small size of static settling zone, a static settling zone having a transverse cross-sectional area of from 0.1 to 1.5 m 2 per m 3 of fermenter volume is preferred. Usually a static settling zone having a transverse cross-sectional area of 0.65 m 2 per m 3 of fermenter volume is used.
Animal cells in culture can exhibit a range of particle sizes representing the difference between complete growing cells, whole dead cells and cell fragments and hence will settle at a range of rates. In order to increase the overall rate of settling within the settling zone it is possible to culture the cells in a state of flocculation, for instance, by the addition of between 0.01 and 0.3% (w/v) of a polygalacturonic acid to the culture medium. This treatment causes the cells and cell fragments to aggregate into flocs of a greater overall particle size than individual cellular particles, thus resulting in an increased rate of settling. This phenomenon enables the cross-sectional area of the settling zone to be reduced and hence enables the diameter of the upper section of the fermenter also to be reduced.
BRIEF DESCRIPTION OF THE DRAWING
The invention is now illustrated by the following description with reference to the accompanying schematic drawings in which
FIG. 1 is an axial cross-section of an air-lift fermenter of the invention including a central divider plate,
FIG. 2 is an axial cross-section of an air-lift fermenter of the invention including a draught tube concentric with the fermenter vessel and,
FIG. 3 is axial cross-section of an air-lift fermenter of the invention including a double-walled concentric draught tube.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIG. 1 shows a continuous fermentation device which is an air-lift fermenter incorporating a static settling zone for separating culture supernatant from suspension culture. The air-lift fermenter comprises an outer vessel, shown generally at 1. The outer vessel comprises a lower cylindrical portion 3 and an upper cylindrical portion 5, the upper cylindrical portion being of greater diameter and connected to the lower cylindrical portion 3 by a frustoconical portion 7. The lower cylindrical portion 3 is provided with a base 15 to complete the outer vessel 1. A divider plate, shown generally at 9, is supported within the outer vessel 1 to divide the interior of the vessel into a riser, shown generally at 11, and a downcomer, shown generally at 13. The base 15 carries an air inlet 17 directly below and approximately centrally within the riser 11 which functions as a punp to force suspension culture to circulate in the riser and downcomer. The divider plate, shown generally at 9, functions as a baffle and forms a static settling zone 19 in the upper cylindrical portion 5 and frustoconical portion 7 of the outer vessel. The static settling zone 19, which is rectangular in axial cross-section, is sealed from the riser 11 and downcomer 13 with the exception of a port or bottom opening 21 at the bottom of the static settling zone 19, which communicates with the downcomer 13 in the embodiment of FIG. 1. The top of the static settling zone 19 is provided with an outlet or top opening 23 for withdrawing culture supernatant. The fermenter is provided with an inlet 25 for supplying culture medium to the fermenter. Thermostatically controlled heating means may be provided either in or around the outer vessel 1. The outer vessel 1 may be double-walled to provide a jacket, for example filled with water.
In use, a suspension culture of cells, suitably animal cells, is introduced into the fermenter through inlet 25 such that the top of the divider plate 9, designated 9a is covered by a depth of suspension culture corresponding to from 0.25 to 1.0 times the diameter of the lower cylindrical portion 3 of the outer vessel 1. The suspension culture is maintained in a turbulent flow condition by forcing air through air inlet 17. The air rises within the riser 11, reducing the bulk density of the liquid suspension in the riser 11 and causing a gross movement of liquid in the direction indicated by the arrows in FIG. 1. At the top of the riser 11 air within the suspension culture is disengaged.
A continuous supply of culture medium is provided through inlet 25. The culture medium includes nutrients and other factors necessary for efficient culture of the cells, and may additionally include between 0.01 to 0.3% (w/v) of a polygalacturonic acid. The use of a polygalacturonic acid promotes flocculation of animal cell and animal cell debris which assists in the efficient separation of animal cells and debris from the product stream. Culture supernatant is continuously withdrawn through outlet 23 at substantially the same rate as culture medium is supplied through inlet 25. In removing culture supernatant from the static settling zone 19, suspension culture is moved from the turbulent environment in downcomer 13 through port 21. The static settling zone 19 is a non-turbulent area in which cells and cell debris, being of a greater density than the culture supernatant, settle downwardly under gravity. The rate of removal of culture supernatant is such that cells within the static settling zone 19 move downwardly and eventually are returned to the downcomer 13 via port 21.
Under steady state conditions a cell concentration gradient is established in the static settling zone 19 allowing removal of culture supernatant through outlet 23 with little or no removal of bulk culture from the suspension culture. The angle of the frustoconical section 7 to the axis of the outer fermenter vessel 1 is between 0° and 60° depending upon the size of static settling zone 19 required by particular operating conditions. Under certain circumstances, for example in fermenters of low volume the outer fermenter vessel 1 may be a single cylindrical vessel and the static zone an area defined by a double-walled divider plate. In the embodiment shown in FIG. 1, the static settling zone 19 is provided with a baffle plate 27 which acts to reduce turbulence within the static settling zone. The angle of the baffle plate to the axis of the fermenter is between 0° and 60° and is, in general, parallel with a corresponding frustoconical section 7. The baffle plate is optional, and if provided extends from a half to the complete vertical distance of the frustoconical section 7. The static settling zone 19 has a cross-sectional area which depends upon the cells cultured in the fermenter. When using mammalian cells the settling zone suitably has a cross-sectional area of between 0.1 and 2.5 m 2 per m 3 of fermenter volume. Preferably the static settling zone 19 has a cross-sectional area of 0.65 m 2 per m 3 of fermenter volume.
Referring to FIG. 2 there is shown a further embodiment of the invention. As is clear from the drawing, the air-lift fermenter shown in FIG. 2 has a number of features in common with the air-lift fermenter described in relation to FIG. 1. These features are not here described further. The difference lies in the use of a draught tube 29 located concentrically within the outer vessel of the fermenter. The inside of the draught tube 29, in use, acts as the riser and the annular space between the outside of the draught tube 29 and the inside of the fermenter vessel acts as the downcomer. In the embodiment shown, the draught tube 29 comprises a lower cylindrical portion 31 and an upper cylindrical portion 33, the two portions being connected by a frustoconical portion 35. The reduction in diameter of the riser towards the top enables a larger cross-sectional area to be used at the upper end of the fermenter for the static settling zone. The static settling zone 37 comprises an annular space formed between the upper end of the draught tube 29 and a surrounding skirt 38 integral therewith. In general the operation and components of the air-lift fermenter shown in FIG. 2 are as described in relation to that of FIG. 1. As with the embodiment of FIG. 1, a baffle plate 39 may be provided at the bottom of the static settling zone 37 to prevent eddy currents. In the embodiment of FIG. 2 the baffle plate 39 is frustoconical. The preferred dimensions mentioned in respect of FIG. 1 apply to the corresponding parts of the air-lift fermenter of FIG. 2.
Referring to FIG. 3, an air-lift fermenter is shown which has a configuration especially suitable for low volume use. The air-lift fermenter shown in FIG. 3 comprises a cylindrical outer vessel 41 and a cylindrical draught tube 43 located concentrically within the outer vessel 41. The draught tube 43 is double-walled, an annular space formed between the two walls forming an annular static settling zone 45. The operation and general dimensions of the fermenter of FIG. 3 are as described above with reference to FIG. 1.
The following Examples illustrate the use of a fermenter of the invention for continuous suspension culture of animal cells.
EXAMPLE 1
An existing 5.5 liter (total volume) airlift fermenter was modified so as to permit its use for the cultivation of a suspension of mammalian cells in continuous mode with biomass feedback.
TABLE 1__________________________________________________________________________5 liter airlift fermenter MEDIUM CELLS IN OUTFLOW FEED RATE CELL POPULATION IN × ANTIBODY ANTIBODYMODE OF FERMENTER CELL CULTURE × 10.sup.-6 /ml 10.sup.-6 /ml CONCENTRATION OUTPUTOPERATION VOLUMES/DAY VIABLE TOTAL VIABLE TOTAL mg/Liter mg/day__________________________________________________________________________WITHOUT 0.5 1.3 2.0 1.3 2.0 30.4 63CELLFEEDBACKWITH CELL 1.0 5.3 10.4 0.6 1.5 75.2 323FEEDBACK__________________________________________________________________________
The fermenter was modified by constructing a double-walled draught tube. The walls of the draught tube were parallel as shown in FIG. 3. The fermenter was fitted with two harvest lines. The first harvest line led from the main bulk of the culture to the outside of the fermenter so that the culture could be harvested continuously without feedback of biomass. The second harvest line led from the top of the draught tube to the outside of the fermenter (FIG. 3) so that the culture fluid could be harvested continuously but with feedback of biomass to the main bulk of the culture.
NB1 hybridoma cells, secreting an IgM antibody, were cultivated in the fermenter described above. Culture medium was Dulbecco's modification Eagle's medium supplemented with foetal calf serum. Dissolved oxygen tension, pH and temperature were monitored and controlled automatically. Cell counts were made using a modified Fuch's Rosenthal counting chamber and cell viability was assessed by exclusion of trypan blue dye. Antibody was assayed by an IgM specific enzyme-linked-immunosorbent assay.
Experimental conditions and results are summarised in Table 1. Without biomass feedback, the viable cell population density was 1.3×10 6 cells/ml and the antibody concentration was 30.4 mg/liter. With operation of biomass feedback 89% of viable cells were removed from the outflow resulting in a fourfold increase in viable biomass in the culture to 5.3×10 6 cells/ml. The overall output of antibody was 63 mg/liter during operation without biomass feedback and 323 mg/day during operation with biomass feedback.
EXAMPLE 2
In a second example a 30 liter (total volume) air-lift fermenter was modified for use in continuous mode with biomass feedback. Modifications were similar to those described in Example 1 for the 5 liter fermenter except that two different configurations of draught tube were tested. The first configuration consisted of a parallel-walled draught tube as shown in FIG. 3.
TABLE 2__________________________________________________________________________30 Liter Airlift Fermenter MEDIUM CELL POPULATION CELLS IN OUTFLOW FEED RATE × × ANTIBODY ANTIBODYMODE OF FERMENTER 10.sup.-6 /ml 10.sup.-6 ml CONCENTRATION OUTPUTOPERATION VOLUMES/DAY VIABLE TOTAL VIABLE TOTAL mg/Liter mg/day__________________________________________________________________________WITHOUT CELL 0.5 1.6 2.3 1.6 2.3 26 325FEEDBACKWITH CELL 0.7 6.0 8.0 1.0 2.5 30 630FEEDBACK(parallel-walleddraught tubeWith cell 0.7 3.5 5.0 1.0 1.6 not --feedback done(constricteddraught tube__________________________________________________________________________
In the second configuration, the draught tube was slightly constricted towards its lower aspect (as shown in FIG. 2) in order to reduce turbulence within the liquid column contained between the draught tube walls.
Cell line, medium and experimental procedures were as described in Example 1, and the results are summarised in Table 2.
Without biomass feedback a viable cell population density of 1.6×10 6 cells/ml was attained. Under conditions of biomass feedback, viable cell population densities were 6.0×10 6 cells/ml for the parallel-walled draught tube, and 3.5×10 6 cells/ml for the draught tube with constricted aperture. Antibody output was 325 mg/day during operation without biomass feedback and 630 mg/day during operation with feedback.
It will be understood that the present invention has been described above purely by way of example, and modifications of detail can be made within the scope and spirit of the invention. | A continuous fermentation device for receiving a suspension culture of cells includes a fermentation vessel having inlet means to deliver suspension culture medium; baffle means defining, in combination with interior walls of said vessel, a downcomer and a riser; pump means for forcing a suspension culture to circulate in the riser and downcomer; a portion of said baffle means further defining a static settling zone disposed within said vessel, wherein said zone is surrounded by at least one of said riser and said downcomer, said zone having a bottom opening communicating with at least one of said riser and downcomer, and a top opening connected to outlet means to draw off culture supernatant, and wherein said zone provides for cells to settle out in its bottom so as to result in a cell concentration lower in the supernatant than in the suspension. The device may be employed in a method for the suspension culture of cells by culturing cells therein. | 2 |
FIELD OF THE INVENTION
The present invention provides a novel process for preparation of 5-aminomethyl substituted oxazolidinones, key intermediates for oxazolidinone antibacterials.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 5,688,792 (U.S. Pat. No. 5,688,792) disclosed oxazine and thiazine oxazolidinone derivatives. The compounds are antimicrobial agents. Among them linezolid, chemically N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo -5-oxazolidinyl]methyl]acetamide is the most important antibacterial agent. Linezolid is represented by the following structure:
Processes for preparation of linezolid were described in U.S. Pat. No. 5,837,870, WO 99/24393, WO 95/07271, J. Med. Chem. 39(3), 673-679, 1996 and Tetrahedron Lett., 40(26), 4855, 1999.
According to prior art processes, the 5-hydroxymethyl substituted oxazolidinones are converted to the corresponding 5-aminomethyl substituted oxazolidinones, key intermediates in the production of oxazolidinone antibacterial pharmaceuticals.
The prior art processes for preparing 5-aminomethyl substituted oxazolidinones are associated with many drawbacks. For instant in the preparation of linezolid, WO 95/07271 uses butyl lithium at very low temperature (−78° C.) and WO 99/24393 uses phosgene gas. It is known that the handling of butyl lithium and phosgene gas are difficult and the person skilled in the art appreciate a process that produces the product in good yield avoiding the ‘difficult to handle’ reagents.
We have discovered a novel process for preparation of 5-aminomethyl substituted oxazolidinone key intermediates using novel intermediates. The novel process solve the drawbacks associated with the prior processes and so, commercially viable for preparing these and related compounds.
SUMMARY OF INVENTION
The present invention provides a novel process to prepare 5-aminomethyl substituted oxazolidinones of formula I:
wherein
X is O, S, SO or SO 2 ;
R 1 is H, CH 3 or CN;
R 2 is independently H, F or Cl;
R 3 is H or CH 3 ;
n is 0,1 or 2;
which comprises;
a) reacting a compound of formula II:
wherein R 1 , R 3 , X, R 2 and n are as defined in formula I;
with R-epichlorohydrin of formula III:
to produce a compound of formula IV:
wherein R 1 , R 3 , X, R 2 and n are as defined in formula I;
b) converting the product of step (a) to chloromethyl oxazolidinone compound of formula V:
wherein R 1 , R 3 , X, R 2 and n are as defined in formula I; and
c) converting the chloromethyl oxazolidinone compound of step (b) to aminomethyl oxazolidinone of formula I.
The compounds of formula IV are novel and provides another aspect of the present invention.
The compounds of the formula V with the exception of the compound of formula V wherein R 1 =R 3 is H; one R 2 is H and the other R 2 is F; X is O; and n is 1 are novel.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel process for preparing 5-aminomethyl substituted oxazolidinones of formula I:
wherein
X is O, S, SO or SO 2 ;
R 1 is H, CH 3 or CN;
R 2 is independently H, F or Cl;
R 3 is H or CH 3 ;
n is 0,1 or 2.
Step—a) Phenyl Amine Compound of Formula II:
wherein R 1 , R 3 , X, R 2 and n are as defined in formula I;
is reacted with R-epichlorohydrin of formula III:
to provide chlorohydrin compound of formula IV:
wherein R 1 , R 3 , X, R 2 and n are as defined in formula I.
The quantity of epichlorohydrin is not critical, but for better yield at least one molar equivalent is required per equivalent of phenyl amine of formula II.
The reaction may be carried out with or without using a solvent.
If the reaction is carried out in the absence of solvent, the compounds of formula II and the formula III are usually heated together for sufficient time to obtain the compound of formula IV. The reactants are heated preferably to about 40-150° C. and more preferably to about 40-120° C. The time required for the conversion is 30 minutes to 10 hours, preferably 2 to 6 hours.
Preferably, the reaction between the compounds of formula II and formula III is carried out in a solvent. Any solvent, which is neutral towards the reactants, may be used. Operable solvents include cyclic ethers such as tetrahydrofuran; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; acetonitrile; and alcohols such as methanol, ethanol, t-amyl alcohol, t-butyl alcohol and Isopropyl alcohol; and a mixture thereof. Preferable solvent is selected from methanol, isopropyl alcohol and N,N-dimethylformamide.
The reaction is performed at or below boiling temperature of the solvent used, more preferably between 10° C. and boiling temperature of the solvent used and even more preferably at boiling temperature of the solvent used.
Time required for completion of the reaction depends on factors such as solvent used and temperature at which the reaction is carried.
The product obtained may be used directly in the next step, or it can be isolated from the reaction mixture and used in the next step.
The compounds of formula IV are novel and provides another aspect of the present invention.
Step—b) The Chlorohydrin Compound of Formula IV Produced as above is Subjected to Carbonylation to Provide Chloromethyl Oxazolidinone Compound of Formula V:
wherein R 1 , R 3 , X, R 2 and n are as defined in formula I.
The carbonylation is performed using any carbonylating reagent commonly known for such purpose. Among them carbonyldiimidazole, phosgene, methyl chloroformate, benzyl chloroformate and phenylchloroformate are preferred; carbonyldiimidazole being more preferred.
The carbonylation reaction is preferably performed by contacting the chlorohydrin compound of formula IV with carbonylating agent in the presence of an aprotic solvent or a mixture thereof. More preferably the chlorohydrin compound of formula IV is reacted with at least one molar equivalent of the carbonylating agent in the presence of an aprotic solvent such as methylene dichloride, ethylenedichloride or chloroform.
The compound of formula V wherein R 1 =R 3 is H; X is O; one R 2 is H and the other R 2 is F; n is 1 ((5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone) is mentioned in the J. Pharmaceutical and biomedical analysis, 2002, 30 (3), 635-642 as an possible impurity in linezolid. We disclosed the use of this compound and related compounds in the preparation of the compounds of formula I.
The compounds of formula V, wherein X, R 1 , R 2 , R3 and n are as defined in formula I with the exception of the compound of formula V, wherein R 1 =R 3 is H; one R 2 is H and the other R 2 is F; X is O; and n is 1 are novel and provide another aspect of present invention.
Step—c) The Chloromethyl Oxazolidinone Compound of Formula V Produced as above is Converted to Aminomethyl Oxazolidinone Compound of Formula I.
Preferred 5-amino methyl substituted oxazolidinones are the compounds of formula I, wherein R 1 =R 3 is H; R 2 is independently H and F; X is O or S; and n is 1. More preferred 5-amino methyl substituted oxazolidinones are the compounds of formula I, wherein R 1 =R 3 is H; R 2 is independently H and F; X is O; and n is 1. Still more preferred 5-amino methyl substituted oxazolidinones are the compounds of formula I, wherein R 1 =R 3 is H; one R 2 is H and the other R 2 is F; X is O; and n is 1.
The conversion of the compound of formula V to the compound of formula I can be achieved by a method known for the conversion of aliphatic chloride to the corresponding amine.
Thus, for example, chlorine atom of the chloromethyl oxazolidinone compound is first replaced by azide using azide source such as sodium azide or potassium azide to provide azide compound of formula VI:
wherein R 1 , R 3 , X, R 2 and n are as defined in formula I.
The azide compound is known and can be converted to the aminomethyl oxazolidinone compound by known methods such as those described in U.S. Pat. No. 5,688,792. For example, the azide compound is hydrogenated using for example palladium/carbon catalyst to provide the aminomethyl oxazolidinone compound.
Alternatively, the chloromethyl oxazolidinone compound is reacted with potassium phthalimide to provide phthalimido compound of formula VII:
wherein R 1 , R 3 , X, R 2 and n are as defined in formula I.
The reaction is carried out by contacting the 5-chloromethyl oxazolidinones with potassium phthalimide in a solvent or mixture of solvents. Selection of solvent is not critical, but preferable solvents are those that dissolve both the chloromethyl oxazolidinones and potassium phthalimide to ensure maximum contact between the reactants resulting in faster reaction. However, the process is also operable with solvents that only partially dissolve the chloromethyl oxazolidinones or potassium phthalimide. The preferable solvent is dimethyl formamide or acetonitrile.
The reaction is performed preferably between about 10° C. and the boiling temperature of the solvent used, more preferably between 40° C. and 100° C. and most preferably at the boiling temperature of the solvent used.
Time required for completion of the reaction depends on factors such as solvent used and temperature at which the reaction is carried out. For example, if the reaction is carried out by contacting the 5-chloromethyl oxazolidinones with potassium phthalimide in dimethylformamide under reflux conditions, about 2 to 10 hours is required for the reaction completion.
The phthalimido compounds of formula are known and can be converted to the aminomethyl oxazolidinone compounds by using for example Hydrazine hydrate or aqueous methylamine. These methods are known and are described for example in U.S. Pat. No. 5,688,792.
The aminomethyl oxazolidinone compounds of formula I are acylated by known methods using acylating agents such as acyl halides or acyl anhydrides to form the corresponding 5-acylaminomethyloxazolidinone compounds of formula VIII.
wherein R 1 , R 3 , X, R 2 and n are as defined in formula I; R represents C 1 to C 8 straight or branched alkyl groups. The preferred alkyl group is CH 3 .
The acylation can be carried out by known methods such as those described in U.S. Pat. No. 5,688,792.
One compound of formula VIII can be converted to another compound of formula VIII . Thus for example compounds of formula VIII, wherein X is S can be converted to the compounds of formula VIII, wherein X is SO or SO 2 by the methods such as those disclosed in U.S. Pat. No. 5,688,792.
The 5-acyl amino methyl substituted oxazolidinone of formula VIII are known to be antibacterial pharmaceutical agents.
R-Epichlorohydrin has the right configuration to obtain the compounds of formula I and VIII. The configuration of epichlorohydrine is retained through out the sequence of reactions of the invention. However, it is readily apparent to one skilled in the art that one could easily perform the identical process steps with the opposite enantiomeric form or racemic form to obtain the corresponding stereo isomers.
Therefore, using the chemistry of the claimed process with any of the enantiomeric forms is considered equivalent to the claimed processes.
In particular most important compound of formula VIII is linezolid (VIII, R 1 and R 3 is H; X is O, one R 2 is H and the other R 2 is F; n is 1).
The most preferred process for preparing linezolid is described as under:
a) 3-fluoro-4-morpholinyl aniline (formula II, R 1 =R 3 is H; X is O; one R 2 is H and the other R 2 is F; and n is 1) is reacted with R-epichlorohydrin (formula III) to produce N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline (formula IV, R 1 =R 3 is H; X is O; one R 2 is H and the other R 2 is F; and n is 1);
The quantity of epichlorohydrin is not critical, but for better yield at least one molar equivalent is required per equivalent of 3-fluoro4-morpholinyl aniline.
Any solvent, which is neutral towards the reactants, may be used. Operable solvents include cyclic ethers such as tetrahydrofuran; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; acetonitrile; and alcohols such as methanol, ethanol, t-amyl alcohol, t-butyl alcohol and Isopropyl alcohol. Preferable solvent is selected from methanol, isopropyl alcohol and N,N-dimethylforrnamide.
The reaction is performed at or below boiling temperature of the solvent used, more preferably between 10° C. and boiling temperature of the solvent used and even more preferably at boiling temperature of the solvent used.
Time required for completion of the reaction depends on factors such as solvent used and temperature at which the reaction is carried. For example, if the reaction is carried out in isopropyl alcohol solvent at the boiling temperature of the solvent, about 15 hours is required for the reaction completion.
The product obtained can be used directly in the next step, or it can be isolated from the reaction mixture and used in the next step.
b) N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline produced as above is subjected to carbonylation to provide (5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone (Formula V, R 1 =R 3 is H; X is O; one R 2 is H and the other R 2 is F; and n is 1).
The carbonylation is performed using any carbonylating reagent commonly known for such purpose. Among them carbonyldiimidazole, phosgene, methyl chloroformate, benzyl chloroformate and phenylchloroformate are preferred; carbonyldiimidazole being more preferred.
The carbonylation reaction is preferably performed by contacting the N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline with carbonylating agent in the presence of an aprotic solvent or a mixture of aprotic solvents. More preferably the N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline is reacted with at least one molar equivalent of the carbonylating agent in the presence of an aprotic solvent such as methylene dichloride, ethylenedichloride or chloroform.
c) (5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone produced as above is reacted with potassium phthalimide to provide (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide (Formula VII, R 1 =R 3 is H; X is O; one R 2 is H and the other R 2 is F; and n is 1);
The reaction is carried out by contacting the (5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone with potassium phthalimide in a solvent or a mixture of solvents. Selection of solvent is not critical, but preferable solvents are those that dissolve both the chloromethyl oxazolidinones and potassium phthalimide to ensure maximum contact between the reactants resulting in faster reaction. However, the process is also operable with solvents that only partially dissolve the chloromethyl oxazolidinones or potassium phthalimide. The preferable solvent is dimethyl formamide or acetonitrile.
The reaction is performed preferably between about 10° C. and the boiling temperature of the solvent used, more preferably between 40° C. and 100° C. and most preferably at the boiling temperature of the solvent used.
Time required for completion of the reaction depends on factors such as solvent used and temperature at which the reaction is carried out. For example, if the reaction is carried out by contacting the 5-chloromethyl oxazolidinones with potassium phthalimide in dimethylformamide under reflux conditions, about 3 to 7 hours is required for the reaction completion.
d) (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide produced as above is reacted with hydrazine hydrate or aqueous methyl amine to produce S-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (Formula I, R 1 =R 3 is H; X is O; one R 2 is H and the other R 2 is F; and n is 1). These methods of deprotection are known and described for example in U.S. Pat. No. 5,688,792. e) S-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine is reacted with acetic anhydride to produce linezolid.
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitations on the scope and spirit of the invention.
EXAMPLES
Example 1
3-Fluoro-4-morpholinyl aniline (39 g) is mixed with R-epichlorohydrin (18.5 g), isopropyl alcohol (200 ml) is added and heated for 16 hours at reflux temperature. The solvent is distilled to give 57 gm of N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyaniline.
Example 2
N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline (57 g) is dissolved in methylene dichloride (600 ml), diimidazolyl carbonyl (32 g) is added at ambient temperature and the reaction mixture is stirred for 20 hours. Then washed with water and distilled methylene dichloride to give 48 gm of (5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone.
Example 3
The mixture of (5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone (60 g), potassium phthalimide (40 g) and Dimethyl formamide (400 ml) is heated for 5 hours at reflux temperature. The reaction mixture is cooled to ambient temperature, poured in to 2 L water and filtered the solid to give 50 gm (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide.
Example 4
Methanol (240 ml) and Hydrazine hydrate (26 g) are added to a flask containing the (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide (40 g), heated for 1 hour at reflux temperature and cooled to room temperature. Then water (500 ml) is added to the reaction mass and extracted with methylene dichloride (300 ml). The combined extractions were washed with water (100 ml) and the solvent distilled to give 20 gm of S-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine.
Example 5
S-N-[[3-[3-Fluoro4-[morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (20 gm) is dissolved in Ethyl acetate (200 ml), Acetic anhydride (20 gm) is added drop wise at ambient temperature and stirred for 1 hour. The reaction mixture is then cooled to 0-5° C., filtered the solid and re-crystallized from Isopropyl alcohol (400 ml) to give 16 gm of N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. | The present invention provides a novel process for preparation of 5-aminomethyl substituted oxazolidinones, key intermediates for oxazolidinone antibacterials including linezolid. Thus linezolid is prepared by a) reacting 3-fluoro-4-morpholinyl aniline with R-epichlorohydrin; b) subjecting N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline produced above to carbonylation; c) reacting (5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone produced above with potassium phthalinide; d) reacting (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide produced above with hydrazine hydrate; and e) reacting S-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazo-lidinyl]methyl]amine produced above with acetic anhydride to produce linezolid. | 2 |
CROSS-REFERENCE TO RELATED APPLICATIONS
This is a continuation of International Application No. PCT/EP2007/063013, filed Nov. 29, 2007, which is hereby incorporated by reference in its entirety.
TECHNICAL FIELD
The technical field relates to airplane assembly. In particular, the technical field relates to a method for mounting a wing of an aircraft to a fuselage of the aircraft, a mounting system, a computer-readable medium, a program element and a processor.
BACKGROUND
When, during aircraft assembly, a wing of the aircraft has to be mounted to the fuselage of the aircraft care has to be taken that both the angle of attack and the sweep are correct. Therefore, the wing is mounted to a moveable positioning unit which is adapted for moving the wing to the fuselage and for adjusting the position of the wing with respect to the fuselage. However, this adjustment procedure is a laborious and time consuming process.
It is therefore at least one object of the invention to provide for an improved wing adjustment. In addition, other objects, desirable features, and characteristics will become apparent from the subsequent summary and detailed description, and the appended claims, taken in conjunction with the accompanying drawings and this background.
SUMMARY
According to an exemplary embodiment of the present invention, a method is provided for mounting a wing of an aircraft to a fuselage of the aircraft, the method comprising the step of determining a difference between a first actual z-position of a first mounting point of the wing and a first target z-position of the first mounting point, wherein the determination of the first difference is performed on the basis of a first measurement device attached to the fuselage and a first positioning device attached to the wing.
Therefore, according to this exemplary embodiment of the present invention, by simply attaching a measurement device to the fuselage and a positioning device to the wing, a mis-adjustment of the wing can be determined during the mounting procedure. This may provide for a fast and effective wing adjustment.
According to another exemplary embodiment of the present invention, the method further comprises the step of determining a second difference between a second actual z-position of a second mounting point of the wing and a second target z-position of the second mounting point, wherein the determination of the second difference is performed on the basis of a second measurement device attached to the fuselage and a second positioning device attached to the wing.
Therefore, according to this exemplary embodiment of the present invention, a second measurement of a mis-adjustment of the wing is performed, for example, at a different location of a contact area between wing and fuselage. Thus, a two-dimensional wing adjustment may be possible.
According to another exemplary embodiment of the present invention, the method further comprises the step of adjusting the wing with respect to the fuselage on the basis of at least one of the first difference and the second difference.
For example, according to this exemplary embodiment of the present invention, after having determined the two differences, a wing adjustment may be performed, resulting in a reduction or minimisation of the differences.
According to another exemplary embodiment of the present invention, the method further comprises the steps of attaching the first measuring device to the fuselage, arranging the first positioning device at a defined position relative to the first measuring device, transferring a hole located at the first mounting point to the first positioning device, resulting in a hole in the first positioning device, and attaching the first positioning device to the wing, such that the position of the hole corresponds to a position of a wing mounting point.
Thus, for example, the exact position of the first mounting point with respect to the measuring device may be transferred to the positioning device, which is then attached to the wing. Therefore, after moving the wing to the fuselage, it may be determined, whether the measuring device and the positioning device are now in the defined position relative to each other or not. If they are not in the defined position relative to each other, a corresponding difference is determined on which basis a further adjustment may be performed.
According to another exemplary embodiment of the present invention, arranging of the first positioning device at the defined position relative to the first measuring device is performed by means of a spacer.
For example, the spacer may be adapted as a lock consisting of, for example, aluminium, titanium or any other metal or metal compound, or any other material, such as a synthetic material. However, the spacer may be of any other form.
According to another exemplary embodiment of the present invention, the method further comprises the step of adjusting the wing on the basis of a crown fitting.
Such a crown fitting may provide for a correct wing adjustment along the y-axis as shown in FIG. 1 .
According to another exemplary embodiment of the present invention, the method further comprises the step of adjusting the wing on the basis of a determination of a contact between a spar and the wing.
This may provide for an exact wing adjustment with respect to the x-axis as shown in FIG. 1 .
According to another exemplary embodiment of the present invention, the determination of the first difference is performed by means of an electronic determination device.
Furthermore, the determination of the second difference may be performed by means of the same or a different electronic determination device. This may provide for a fast and exact difference determination.
According to another exemplary embodiment of the present invention, a mounting system for mounting a wing of an aircraft to a fuselage of the aircraft is provided, the mounting system comprising a determination unit for determining a first difference between a first actual z-position of a first mounting point of the wing and a first target z-position of the first mounting point, wherein the determination of the first difference is performed on the basis of a first measurement device attached to the fuselage and a first positioning device attached to the wing.
According to another exemplary embodiment of the present invention, a computer-readable medium may be provided, in which a computer program of mounting a wing of an aircraft to a fuselage of the aircraft is stored which, when being executed by a processor, causes the processor to carry out the above-mentioned method steps.
Furthermore, according to another exemplary embodiment of the present invention, a program element of mounting a wing of an aircraft to a fuselage of the aircraft is provided which, when being executed by a processor, causes the processor to carry out the above-mentioned method steps.
Furthermore, according to another exemplary embodiment of the present invention, a processor for mounting a wing of an aircraft to a fuselage of the aircraft may be provided, the processor being adapted to carry out the above-mentioned method steps.
The mounting and adjustment process may be embodied as the computer program, i.e., by software, or may be embodied using one or more special electronic optimisation circuits, i.e. in hardware, or the method may be embodied in hybrid form, i.e., by means of software components and hardware components.
The program element, according to an exemplary embodiment of the invention, is preferably loaded into working memories of a data processor. The data processor may thus be equipped to carry out exemplary embodiments of the methods of the present invention. The computer program may be written in any suitable programming language, such as, for example, C++ and may be stored on a computer-readable medium, such as a CD-ROM. Also, the computer program may be available from a network, such as the World Wide Web, from which it may be downloaded into processors or any suitable computers.
These and other aspects of the present invention will become apparent from and elucidated with reference to the embodiments described hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will now be described, by way of example only, with reference to the accompanying drawings, in which:
FIG. 1 shows a schematic representation of a section of a fuselage of an airplane to which the wing is mounted;
FIG. 2 shows a schematic representation of the mounting section according to an exemplary embodiment of the present invention;
FIG. 3 shows a schematic representation of the mounting section after having transferred the holes to the positioning devices;
FIG. 4 shows a schematic representation of a wing at which the positioning devices are attached;
FIG. 5 shows a schematic representation of positioning devices arranged at a defined location with respect to mounting devices with the help of spacer units, according to an exemplary embodiment of the present invention;
FIG. 6 shows a mounting system for performing the method according to an exemplary embodiment of the present invention;
FIG. 7 shows a representation of the mounting section of FIG. 1 in a first assembly state according to an exemplary embodiment of the present invention;
FIG. 8 shows a representation of the mounting section of FIG. 1 in a second assembly state according to an exemplary embodiment of the present invention;
FIG. 9 shows a representation of the mounting section of FIG. 1 in a third assembly state according to an exemplary embodiment of the present invention;
FIG. 10 shows a representation of the wing of FIG. 4 in a fourth assembly state according to an exemplary embodiment of the present invention;
FIG. 11 shows a representation of the mounting section of FIG. 1 and the wing of FIG. 4 in a fifth assembly state according to an exemplary embodiment of the present invention;
The illustrations in the drawings are schematic. In different drawings, similar or identical elements are provided with the same reference numerals.
DETAILED DESCRIPTION
The following detailed description of the invention is merely exemplary in nature and is not intended to limit application and uses. Furthermore, there is no intention to be bound by any theory presented in the preceding background or summary or the following detailed description.
FIG. 1 shows a schematic representation of an airplane fuselage 101 with a mounting section 102 at which a wing can be mounted. The mounting section 102 comprises mounting holes 201 , 202 , 204 , 205 . The mounting holes 201 , 202 , 204 , 205 are adapted for positioning the wing with the respect to the fuselage 101 .
The mounting section 102 may further comprise a front spar and a back spar (not depicted in FIG. 1 ). The wing which has to be mounted to the mounting section 102 may comprise a corresponding front spar and a corresponding back spar.
Front spar and back spar each comprise two bore holes 201 , 202 and 204 , 205 . Furthermore, first and second positioning devices 105 , 106 may be attached to the mounting section 102 (and arranged at a defined position with respect to the four bore holes).
The coordinate system at the upper left of FIG. 1 defines the directions of the x, y and z-axes.
FIG. 2 shows a schematic representation of the mounting section 102 after installation of the mounting devices 103 , 104 and the positioning devices 105 , 106 .
At a first step, the first measuring device 103 is attached to the fuselage or mounting section 102 by means of, for example, attachment devices 207 , 208 . Furthermore, at the other side of the mounting section 102 , the measuring device 104 is attached to the mounting section 102 by means of attachment devices 209 , 210 .
Then, in a second step, the first positioning device 105 is arranged at a defined position relative to the first measuring device 103 . Such arrangement may be performed with the help of a spacer 301 (as depicted in FIG. 5 ). Furthermore, the second positioning device 106 is arranged at a defined position relative to the second measuring device 104 .
Then, the positioning holes 201 , 202 are transferred into the first positioning device 105 , resulting in a hole in the first positioning device 105 . Furthermore, holes 204 , 205 are transferred to the second positioning device 106 .
Then, in a next step, the first and second positioning devices 105 , 106 are attached to the wing.
Then, the wing is moved towards the fuselage and the differences between the actual z-positions of the first and second mounting points 211 , 213 of the wing 107 (see FIG. 4 ) means first and second target z-positions 201 , 204 , respectively, are determined.
After that, a wing adjustment may be performed on the basis of the determined differences.
FIG. 3 shows a schematic representation of the mounting section 102 at which the first measuring device 103 and the second measuring device 104 are attached.
FIG. 4 shows a schematic representation of the wing 107 , at which the first positioning device 105 and the second positioning device 106 are attached at the mounting points 211 , 212 and 213 , 214 , respectively.
The mounting points 211 , 212 and 213 , 214 thereby correspond to the target positions 201 , 202 and 204 , 205 which are located at the mounting section 102 of the fuselage 101 .
FIG. 5 shows a schematic representation of the measuring devices 103 , 104 and the positioning devices 105 , 106 , which are arranged with respect to the measuring devices 103 , 104 with the help of respective spacer units 301 , 302 .
The spacer units 301 , 302 may, for example, have a thickness Δz1, Δz2 of, for example, 20 mm. However, the thickness may be bigger or smaller.
After having attached the measuring devices 103 , 104 to the mounting section 102 of the fuselage 101 and after having attached the positioning devices 105 , 106 to the wing 107 , and after having moved the wing towards the fuselage, Δz1 and Δz2 may be measured. In case Δz1 and Δz2 differ from the target value (which is, for example, 20 mm), a further wing adjustment may be performed.
The measuring devices or the positioning devices may comprise grooves or trenches, such that an attachment position can be varied. Therefore, the spacer 301 may always fit in between.
FIG. 6 shows a mounting system for mounting a wing of an aircraft to a fuselage of the aircraft, according to an exemplary embodiment of the present invention. The mounting system depicted in FIG. 6 comprises an output unit 601 , for example a computer screen, and an input unit 602 , for example a keyboard. Furthermore, the system comprises a processor 604 and a storage unit 603 in which a computer program for mounting the wing to the fuselage is stored.
Furthermore, the mounting system comprises a determination unit 605 adapted for determining the differences Δz1 and Δz2. The determination unit 605 may further be adapted for determining, for example a contact between a spar and the wing or for determining a crown fitting.
Further determination units may be provided.
The mounting system further comprises a wing mounting unit 606 , which is adapted for moving and positioning the wing 107 with respect to the fuselage 101 .
The wing mounting and positioning may be performed in a fully automated manner or user guided in a semi-automated manner.
FIG. 7 shows a representation of the mounting section of FIG. 1 in a first assembly state according to an exemplary embodiment of the present invention. As may be seen from the figure, a positioning device 106 is attached to the mounting section 102 of the fuselage.
FIG. 8 shows a representation of the mounting section of FIG. 1 in a second assembly state according to an exemplary embodiment of the present invention. Here, a measurement device 104 is attached to the mounting section 102 of fuselage at a predetermined distance from the measurement device 104 (e.g. by transferring holes from the fuselage to the measurement device 104 ). The distance is determined by spacer 302 .
FIG. 9 shows a representation of the mounting section of FIG. 1 in a third assembly state, in which all three elements 102 , 104 and 104 are assembled at the mounting section.
FIG. 10 shows a representation of the wing of FIG. 4 in a fourth assembly state according to an exemplary embodiment of the present invention. Here, the positioning device 106 is attached to the wing 107 , for example by using the transferred holes.
FIG. 11 shows a representation of the mounting section of FIG. 1 and the wing of FIG. 4 in a fifth assembly state according to an exemplary embodiment of the present invention. As may be seen from the figure, the wing 107 is moved towards the fuselage section 102 for final mounting of the wing 107 . By determining the difference Δz between actual z-position of the positioning device 106 and the z-position of the measurement device 104 (which z-position corresponds to the target z-position minus the height of the spacer 302 ) an adjustment of the wing 107 with respect to the fuselage may be performed on the basis of the difference.
It should be noted that the term ‘comprising’ does not exclude other elements or steps and the ‘a’ or ‘an’ does not exclude a plurality. Also, elements described in association with different embodiments may be combined. Moreover, while at least one exemplary embodiment has been presented in the foregoing summary and detailed description, it should be appreciated that a vast number of variations exist. It should also be appreciated that the exemplary embodiment or exemplary embodiments are only examples, and are not intended to limit the scope, applicability, or configuration in any way. Rather, the foregoing summary and detailed description will provide those skilled in the art with a convenient road map for implementing an exemplary embodiment, it being understood that various changes may be made in the function and arrangement of elements described in an exemplary embodiment without departing from the scope as set forth in the appended claims and their legal equivalents. | A method is provided for mounting a wing of an aircraft to a fuselage of the aircraft, in which a difference between a vertical target position and a vertical actual position of a mounting point is determined. Then, on the basis of the determined difference, a readjustment of the wing is performed. | 1 |
This application is a continuation application under 37 C.F.R. §1.53(b) of prior application Ser. No. 08/771,808 filed Dec. 23, 1996, now U.S. Pat. No. 5,827,439. The disclosures of the specification, drawings and abstract of application Ser. No, 08/771,808 are incorporated herein by reference.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is directed to a liquid quenching method for manufacturing an amorphous metal wire or thin strip (hereinafter "thin strip") by quenching and solidifying a molten alloy on a moving cooling substrate. More particularly, the present invention relates to a method for supplying molten alloy from a ladle storing the molten alloy to a tundish.
2. Description of the Prior Art
Liquid quenching methods for producing thin strips include, for example, the single roll method which discharges a molten alloy on to a single cooling roll rotating at a high speed resulting in the manufacture of a thin strip. In the twin roll method, the molten alloy is discharged between a pair of cooling rolls rotating at a high speed resulting in the manufacture of a thin strip.
A liquid quenching method which uses a single roll cooling/solidification apparatus, as shown in FIG. 7, will be explained. Molten alloy 6 is poured into a tundish 5 so that the level of the molten metal becomes constant. Twyer bricks 9 are disposed on the bottom wall of this tundish 5. An intermediate nozzle 10 and a nozzle holder 11 are interconnected to a passage 13 bored in these twyer bricks 9 to provide a fluid path for the molten alloy. An expanded internal space 14 is located inside the nozzle holder 11. A nozzle chip 12 is fitted to the distal end of the nozzle holder 11, and a nozzle slit 15 is inserted inside this nozzle chip 12 for discharging molten alloy onto the chill roll 8. The expanded internal space 14 inside the nozzle holder 11, the nozzle chip 12 and the nozzle slit 15 are illustrated in FIG. 8. Here, the expanded internal space 14 represents an expanded portion of the molten metal passage 13 inside the nozzle holder 11 so as to obtain a thin strip having a large width. The nozzle slit 15 provides an opening for jetting the molten metal flowing through the nozzle chip 12.
When a tundish stopper 4 is moved up, the molten alloy 6 inside the tundish 5 is allowed to flow through the molten metal passage 13 and is jetted from the nozzle slit 15 onto the cooling roll 8. At this time, the flow rate of the molten alloy 6 flowing out from the nozzle slit 15 onto the cooling roll 8 is controlled in accordance with the static pressure of the molten metal inside the tundish 5. The molten alloy 6 jetting out from the nozzle slit 15 is rapidly cooled on the surface of the cooling roll 8 and is formed into the thin strip 7.
The cooling roll 8 is illustrated in a small scale compared with the large scale of the tundish 5 in FIG. 7 in order to make the entire apparatus more easily understood.
In order to obtain the thin strip by either of the liquid quenching methods described above, the cooling rate must be set to at least about 10 2 K/sec. Therefore, there is a limitation on the sheet thickness of the resulting thin strip. It is as small as less than about 0.1 mm. When the thin strips having a thickness of less than 0.1 mm are produced by the liquid quenching method, there are differences in the limiting conditions of the various production factors in comparison with ordinary ingot casting methods and continuous casting methods according to conventional solidification technologies. The most important limiting condition is the feed quantity of the molten alloy. In the case of the continuous casting methods for steels, etc, that have been ordinarily employed, the quantity of the molten alloy that can be provided to a casting mold is several tons per minute. A greater quantity of molten alloy can be provided in ordinary ingot casting methods.
In contrast, in the liquid quenching method which is the subject of the present invention, the feed quantity of the molten alloy must be reduced to a very small quantity of not greater than 100 kg/min. This is because of the limitation on the thickness of the thin strip. The maximum strip thickness that can be ordinarily obtained by the single roll method, for example, is about 0.1 mm. The peripheral speed of the cooling roll in this case is about 10 m/sec and the maximum width of the thin strip is about 200 mm. In the case of alloys containing iron as the principal component, the feed quantity of the molten alloy must be controlled to about 90 kg/min.
When the thin strip is produced by the liquid quenching method in an industrial practice, it is a very important to minimize the feed quantity of the molten alloy.
In the case of a conventional continuous casting method, for example, the molten alloy is supplied from a ladle to the casting mold through a tundish. In this instance, a system using a ladle stopper fitted to a long nozzle hole at the bottom of the ladle is employed as one of the methods of controlling the feed quantity of the molten alloy. In other words, the feed quantity of the molten alloy is controlled by moving the ladle stopper up and down, thereby controlling an opening area of the long nozzle. Since a conventional continuous casting method can supply a large quantity of the molten alloy such as several tons per minute as described above, the feed quantity can be easily controlled by such a stopper system.
In contrast, in the case of the liquid quenching method, which is the object of the present invention, the feed quantity of the molten metal must be limited to not greater than 100 kg/min. Therefore, it becomes difficult to employ, as such, the stopper system described above. Japanese Unexamined Patent Publication (Kokai) No. 1-34550, for example, proposes a method which uses the stopper system in the liquid quenching method. Though this method is not limited to the production of the amorphous alloy thin strip, it is devised so as to reduce the relative feed quantity of the molten alloy. It measures the weight of the molten alloy inside the tundish during charging and controls the up or down moving speed of the ladle stopper and the ladle stopper position on the basis of this measurement so as to control the feed quantity of the molten alloy. This method limits the lower limit of the moving distance of the ladle stopper to 2 mm and the upper limit to 6 mm. It can control the feed quantity of the molten alloy with a very high level of accuracy.
According to this method, however, the weight of the tundish must be measured during charging and hence, the control becomes complicated. Further, because a measuring instrument and a computer must be installed, the setup cost becomes high and thus the production cost becomes high. If the moving distance of the ladle stopper is limited to an excessively small value, the operation becomes more difficult because most installations are not free from vibrations no matter how precise they may be. Because of vibration problems, the moving distance of the ladle stopper must be at least about 5 mm.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a simple and economical method for supplying a molten alloy for producing a thin strip which solves the problems encountered in the feed control of the molten metal in the conventional liquid quenching method by specifying the correlation between a long nozzle and a stopper.
The gist of the present invention resides in the following points.
The present invention is directed to method for supplying molten alloy to a moving cooling substrate for producing an amorphous metal wire or an amorphous metal thin strip.
A ladle is provided for receiving the molten alloy, with the ladle having a bottom wall defining a bottom surface of the ladle. A long nozzle is provided having a length and having an interior passage therein extending the length of the long nozzle. The length of the interior passage extends in a perpendicular direction or inclined to the perpendicular direction. The long nozzle has one end connected to the bottom wall of the ladle placing the interior passage of the long nozzle in fluid communication with the molten alloy in the ladle. A ladle stopper is provided disposed within the ladle. The ladle stopper has an outer wall surface parallel to the perpendicular direction. A tundish is provided below the ladle and in fluid communication with the long nozzle for receiving molten alloy from a distal end of the interior passage of the long nozzle.
Molten alloy is supplied from the ladle to the tundish by feeding molten alloy via the interior passage of the long nozzle.
Molten alloy is supplied from the tundish to the moving cooling substrate.
The ladle stopper is provided with a distal end region having a length which is received by the interior passage of the long nozzle at the one end of the long nozzle.
A distance (y) is defined as an overlap distance of the length of the distal end region of the ladle stopper received by the interior passage of the long nozzle during flow of the molten alloy through the interior passage.
An opening area (Ao) is defined which is a sectional area for molten alloy flow provided by the opening area in the interior passage of the long nozzle resulting from receiving the distal end region of the ladle stopper.
A distance (Ln) is defined as the distance from the bottom surface of the ladle to the minimum cross-sectional area of the interior passage of the long nozzle.
A distance (Lm) is defined as the distance from the bottom surface of the ladle to a height of molten alloy in the ladle at start of feed of the molten alloy.
When (y) is less than 0.1 mm, Ao is set to be 1.2 cm 2 and a ratio (Ln)/(Lm) is set be at least 1.5. When (y) is 0.1 to 200 mm, Ao is set to be 0.5 to 10cm 2 .
In another embodiment of the present invention, feed of molten alloy is started from the ladle to the tundish by moving the ladle stopper upward a selected distance thereby placing the ladle stopper in a selected position. The ladle stopper is maintained in the selected position until feeding of the molten alloy is completed.
In a further embodiment of the present invention, the distal end region of the ladle stopper is a protrusion having a length of at least 5 mm and having an outer wall surface, with the outer wall surface of the protrusion being parallel to the perpendicular direction. The interior passage of the long nozzle has an inner wall surface. The outer wall surface of the protrusion does not contact the inner wall surface of the interior passage when the protrusion is received by the interior passage.
In still a further embodiment of the present invention, the distal end region of the ladle stopper is a protrusion having a length of at least 5 mm and having an outer wall surface, with the outer wall surface of the protrusion being parallel to the perpendicular direction. The interior passage of the long nozzle has an inner wall surface. A portion of the outer wall surface of the protrusion contacts the inner wall surface of the interior passage when the protrusion is received by the interior passage.
In yet another embodiment of the present invention, the interior passage of the long nozzle has an inner wall surface and at least one obstacle to molten alloy flow is disposed on the inner wall surface of the interior passage.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic view showing an apparatus used for practicing the method of the present invention.
FIGS. 2(a) to 2(c) are views showing an example of a ladle stopper equipped with a protrusion that is used in the method of the present invention.
FIG. 3 is a schematic view showing an example of a ladle stopper and a long nozzle used in the method of the present invention.
FIG. 4(a) is a schematic view and FIG. 4(b) is an enlarged schematic view showing an example of a ladle stopper equipped with a protrusion and a long nozzle used in the method of the present invention.
FIGS. 5(a), 5(c) and 5(d) are sectional views taken along a line I--I of FIG. 3 and a line II--II of FIG. 4(a) showing the relationship of an overlap portion between a ladle stopper and a long nozzle used in the method of the present invention, wherein (a) and (b) show a noncontact state and (c) and (d) show a contact state, respectively.
FIGS. 6(a), 6(b), 6(c), 6(d) and 6(e) are views showing an example where an obstacle is disposed inside a long nozzle used in the method of the present invention.
FIG. 7 is a schematic view useful for explaining a single roll quenching/solidification apparatus used to cast a thin strip.
FIG. 8 is an enlarged schematic view useful for explaining a casting state using a single roll quenching/solidification strip production apparatus.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention will be explained in detail with reference to the accompanying drawings.
FIG. 1 is a schematic view showing an apparatus for the production of thin strip amorphous metal used for practicing the method of the present invention. A molten alloy held inside a ladle 3 is supplied to a tundish 5 by raising a ladle stopper 1 through a long nozzle 2. Next, the molten alloy is ejected at a high speed from a nozzle 7 and impinged onto a cooling roll 8 rotating at a high speed so as to form an amorphous thin strip 7. The flow of molten alloy is controlled by an opening/closing operation of tundish stopper 4 disposed inside the tundish.
The inventors of the present invention conducted intensive studies on methods of uniformly and stably supplying a molten alloy at a rate below 100 kg/min. The present inventors discovered that the feed quantity of the molten alloy depends on the length of an overlap portion between the distal end of the ladle stopper and the long nozzle. The present inventors also discovered that the feed quantity of the molten alloy depended upon the shape of the distal end of the ladle stopper and upon the area of opening defined between the ladle stopper and the long nozzle.
The resistance at the time of passage of the molten alloy can be changed by using a stopper having a thin protrusion of a length of 5 mm at the distal end portion thereof as the ladle stopper. An overlap portion is provided in the horizontal direction between the distal end of the ladle stopper and the long nozzle and this overlap portion is changed. By this method, the feed quantity of the molten alloy can be controlled. If the protrusion at the distal end of the ladle stopper is elongated, the overlap portion can be set to a predetermined length even when the moving distance of the ladle stopper is large. As a consequence, even when the moving distance of the ladle stopper is increased to at least 5 mm, the feed quantity of the molten alloy can be stably reduced to a rate not greater than 100 kg/min by combining and controlling the overlap portion and the opening area (Ao) defined by this overlap portion.
When the length of this overlap portion is small, however, setting of the opening area (Ao) can be controlled in the following manner. In such a case, the set position of the opening area (Ao) may be shifted below the long nozzle. It is necessary in this case, however, to change the set position of the opening area (Ao) in such a manner as to correspond to the height of the molten metal surface inside the ladle at the start of the feed of the molten alloy.
The feed quantity of the molten alloy can be supplied stably and uniformly at a rate of not greater than 100 kg/min by conducting casting so that:
(1) The opening area (Ao) inside the long nozzle is not greater than 1.2 cm 2 and the ratio (Ln/Lm) of the distance (Ln) from the bottom surface of the ladle to the position of the minimum sectional area inside the long nozzle to the height (Lm) of the molten metal level inside the ladle from the bottom surface of the ladle at the start of the feed of the molten alloy is at least 1.5 when the distance (y) of the overlap portion between the distal end portion of the ladle stopper and long nozzle is less than 0.1 mm.
(2) The opening area (Ao) inside the long nozzle is 0.5 to 10 cm 2 when the distance (y) is from 0.1 to 200 mm.
The stopper 1 used in the present invention is equipped with the protrusion 1A at the distal end thereof. This protrusion 1A has a shape corresponding to the intended production condition thin strip. The protrusion may have a small elliptic shape or a rectangular shape as shown in FIGS. 2(a) to 2(c), by way of example. When the protrusion is rectangular, the outer wall surface of this protrusion is preferably in parallel to the perpendicular direction.
The example where the protrusion 1A is small and elliptic corresponds to case (1) described above. Since in this instance it is difficult to stably set the opening area (Ao) defined by the overlap portion between the distal end of the ladle stopper and the long nozzle to a predetermined value, the opening area (Ao) inside the long nozzle must be set to a value not greater than 1.2 cm 2 when the distance (y) of the overlap portion between the distal end of the ladle stopper and the long nozzle is less than 0.1 mm. The ratio (Ln/Lm) of the distance (Ln) from the ladle bottom surface to the minimum sectional area position inside the long nozzle to the height (Lm) of the molten metal level inside the ladle at the start of the feed of the molten metal must be set to at least 1.5.
On the other hand, when the protrusion 1A has a rectangular shape and when the distance (y) of the overlap portion between the distal end portion of the ladle stopper and the long nozzle is from 0.1 to 200 mm, the opening area (Ao) inside the long nozzle must be set to 0.5 cm 2 to 10 cm 2 .
The inventors of the present invention have carried out experiments and studies by using stoppers having the conventional shapes such as those shown in FIGS. 2(a) and 2(b) in order to clarify the relationship between the long nozzle opening area and the flow rate of the molten alloy in the conventional method which reduces the flow rate of the molten alloy by reducing the area of the nozzle opening portion at the distal end of this stopper. Fe--B--Si--C system amorphous alloys were primarily used for this experiment. As a result, it has been discovered that in order to set the flow rate of the molten alloy to a value not greater than 100 kg/min by the conventional method, it is necessary to set the opening area (Ao) of the long nozzle to not greater than 1.2 cm 2 , the distance (y) of the overlap portion between the distal end of the stopper and the long nozzle to less than 0.1 mm and the ratio (Ln/Lm) of the distance (Ln) from the ladle bottom surface to the minimum sectional area position inside the long nozzle to the height (Lm) of the molten metal level inside the ladle at the start of the feed of the molten alloy to at least 1.5, as shown in FIG. 3. It has been further discovered that once the ladle stopper 1 is elevated by a predetermined distance at the start of the feed of the molten alloy, the stopper 1 must be kept at that position until the feed of the molten alloy 6 is completed. It had been believed in the past that the molten metal generates so-called "nozzle clogging" at such a small sectional area. Therefore, the result described above is quite opposite to the common belief.
Here, the term "opening area inside the long nozzle" means the minimum value of the sectional area of the long nozzle inner surface in the horizontal direction. In the case of the long nozzle which is conical and whose sectional area in the horizontal direction decreases in the flowing direction of the molten metal 6 as shown in FIG. 3, for example, the term indicates the inner area (Ao in FIG. 3) of the lowermost portion of the long nozzle 2. The terms "distance (Ln) from the ladle bottom surface to the minimum sectional area position inside the long nozzle" and "height (Lm) of the molten metal level inside the ladle at the start of the feed of the molten alloy" will be explained. First, the term "distance (Ln) from the ladle bottom surface to the minimum sectional area position inside the long nozzle" means the distance (Ln in FIG. 3) in the vertical direction from the bottom portion of the ladle 3 to the lowermost portion of the long nozzle 2 representing the minimum sectional area inside the long nozzle. The term "height (Lm) of the molten metal level inside the ladle at the start of the feed of the molten alloy" means the initial height (Lm in FIG. 3) of the molten alloy 6 held in the ladle 3. The sectional area of the long nozzle shown in FIG. 3 in the horizontal direction progressively decreases in the lower direction. Therefore, the minimum sectional area inside the long nozzle exists at the lowermost portion of the long nozzle. When the distance (y) of the overlap portion between the long nozzle and the distal end portion of the stopper is less than 0.1 mm in the long nozzle used in the present invention, the position of the opening area may be at any position inside the long nozzle if the opening area inside the long nozzle is not greater than 1.2 cm 2 .
FIG. 3 shows two positions as the stop positions of the ladle stopper. That is, the position before the feed of the molten alloy 6 to the tundish is started and the position at which the molten alloy 6 is being fed. In other words, the solid line represents the former position and the dotted line, the latter position. In the present invention, the ladle stopper 1 is kept fixed at the position indicated by the dotted line while the molten alloy 6 is being fed from the ladle 3 to the tundish. The method of the present invention can keep the feed quantity of the molten alloy constant even when the ladle stopper position is fixed during the feed of the molten alloy. The reason why the feed quantity of the molten alloy can be kept constant even when the ladle stopper is fixed will be described later. Because the position of the ladle stopper can be thus fixed during the feed of the molten alloy, it is no longer necessary to measure the weight of the tundish and to control the feed quantity of the molten alloy by moving the ladle stopper position up and down as has been required in the prior art. Therefore, the molten alloy can be fed easily and economically. Incidentally, the moving distance of the ladle stopper (Ls in FIG. 3) at the start of the feed of the molten alloy is not particularly limited, but a small value is not preferred in consideration of the vibration of the apparatus. The moving distance is preferably from about 5 to about 50 mm.
The inventors of the present invention have also discovered that when the ratio (Ln/Lm) of the distance (Ln) from the ladle bottom surface to the minimum opening area position inside the long nozzle to the height (Lm) of the molten metal level inside the ladle at the start of the feed of the molten alloy is set to at least 1.5, thickness fluctuations in the resulting thin strip do not occur. In other words, when the feed quantity of the molten metal changes, the height of the molten metal level of the molten alloy in the tundish changes, and this change of the molten metal level in the tundish directly results in the fluctuation of the jet pressure of the molten alloy impinged onto the cooling roll. Eventually, the fluctuations occur in the sheet thickness of the resulting thin strip. Therefore, the feed quantity of the molten alloy supplied from the ladle must be made as uniform as possible. However, when the ratio (Ln/Lm) of the distance (Ln) from the ladle bottom surface to the minimum sectional area position inside the long nozzle to the height (Lm) of the molten metal level inside the ladle at the start of the feed of the molten alloy is set to at least 1.5, the fluctuations of the strip thickness, which becomes a problem in the resulting thin strip, cannot be observed. This is the reason why the present invention sets the ratio (Ln/Lm) of the distance (Ln) from the ladle bottom surface to the minimum sectional area position inside the long nozzle to the height (Lm) of the molten metal level inside the ladle at the start of the feed of the molten alloy to at least 1.5.
In other words, because the distance (Ln) from the ladle bottom surface to the minimum sectional area inside the long nozzle is set to be greater than the height (Lm) of the molten metal level inside the ladle, the influence of the height of the molten metal level inside the ladle, that affects the feed quantity of the molten alloy, becomes small. When the distance (Ln) from the ladle bottom surface to the minimum sectional area inside the long nozzle becomes at least 1.5 times the height (Lm) of the molten metal level inside the ladle, the influence of the height of the molten metal level inside the ladle that affects the feed quantity of the molten alloy presumably becomes zero. Therefore, in the present invention, no fluctuation occurs in the feed quantity of the molten alloy even when the feed quantity is not controlled by moving the ladle stopper up and down during the feeding operation of the molten alloy. In other words, the ladle stopper can be kept fixed from the start till the end of the feed of the molten alloy. The value of Ln/Lm is preferably somewhat greater that 1.5 provided that this is permitted by the installation space.
If the production of the long nozzle having a minimum sectional area of not greater than 1.2 cm 2 is difficult, a long nozzle having a large sectional area is produced in advance as shown in FIGS. 6(a) to 6(e). Then an obstacle 16 having a varying shape is fitted into this long nozzle so that the resulting long nozzle has a reduced sectional area. The shape of the obstacle 16 include several different types. Examples are: at least one concentric circle obstacle, a spiral like obstacle, several protruded obstacles or porous like bricks. The sectional shape inside the long nozzle is not particularly limited in the present invention. In other words, so long as the minimum sectional area inside the long nozzle is not greater than 1.2 cm 2 , the sectional shape inside the long nozzle may be round, elliptic, polygonal or flowershaped. Further, the sectional shape inside the long nozzle may change in the flow direction of the molten alloy 6.
According to the prior art, the moving distance of the stopper must be set to an extremely small value of not greater than 2 mm. The term "moving distance of the stopper" means the distance indicated by Ls in FIG. 3 and is the stroke distance (hereinafter called the "stopper stroke") at the time of opening of the stopper for feeding the molten alloy. Most setups are not free from vibration even though they may be of a precision type. In view of vibrations, it is extremely difficult to stably set the stopper stroke to not greater than 2 mm in practical operation. In view of vibrations, the stopper stroke is preferably at least about 5 mm.
Therefore, the inventors of the present invention have examined feeding methods for molten alloys for setting the flow rate of the molten alloy to not greater than 100 kg/min even at a stopper stroke of at least 5 mm. The inventors found that when the long nozzle has a shape such that the inner wall surface of the opening at its upper portion is parallel to the perpendicular direction and the stopper has the protrusion at the distal end thereof whose outer wall surface is in parallel with the perpendicular direction as already described, the long nozzle opening area can be kept constant even when the stopper stroke is increased. When the y value shown in FIG. 4(a) is increased to a certain extent, the feed quantity of the molten alloy can be kept below 100 kg/min even when the long nozzle opening area exceeds 1.2 cm 2 .
The stopper 1 has the protrusion 1A at the distal end thereof, according to the present invention, as shown in FIG. 2(c). The outer wall surface of this protrusion 1A is preferably parallel to the perpendicular direction. The distance (y), in FIG. 4(a), of the overlap portion between the long nozzle 2 and the stopper protrusion 1A, is set to 0.1 to 200 mm and the opening area of the long nozzle is set to 0.5 to 10 cm 2 . Moreover, the inner wall surface at the upper part of the long nozzle 2 is, or is not, brought into contact with the outer wall surface of the protrusion of the stopper so as to feed the molten alloy 6 from the ladle 3 to the tundish.
Here, the term "long nozzle upper portion" means the upper end side of the long nozzle. That is, the portion near the end portion of the long nozzle connected to the ladle. More concretely, the term represents the portion within the range of about 200 mm from the uppermost end of the long nozzle towards its lower portion end.
The long nozzle used for the method of the present invention is limited to those which have a shape such that the inner wall surface of this upper opening portion is parallel to the perpendicular direction. The term "inner wall surface of upper opening portion" refers to the inner wall surface of the opening indicated by reference numeral 2A in the sectional view of the long nozzle 2 in the perpendicular direction shown in FIG. 4(a). In the long nozzle 2 used for the method of the present invention the inner wall surface 2A of the upper opening portion is in parallel with the perpendicular direction means that the sectional shape of the opening portion of the long nozzle 2 in the horizontal direction has the same shape within the range of about 200 mm from the uppermost end of the long nozzle 2 towards its lower end.
An important feature of the method of the present invention resides in that it uses the stopper 1 having the protrusion 1A whose outer wall surface is in parallel with the perpendicular direction. The arrangement wherein the outer wall surface of the protrusion 1A is in parallel with the perpendicular direction means that the sectional shape of the protrusion 1A in the horizontal direction has the same shape throughout the full length.
FIGS. 4(a) and (b) show the best feeding method for practicing the method of the present invention. In FIG. 4(a), two positions are shown as the stop positions of the ladle stopper 1 used for the method of the present invention. That is, the position before the start of the feed of the molten alloy 6 to the tundish and the position during the feed of the molten alloy 6. In other words, the dotted line represents the former position and the solid line represents the latter position. FIG. 4(b) is an enlarged view showing the location near the fitting portion between the ladle stopper 1 and the long nozzle 2 when the ladle stopper 1 is at the position at which the molten alloy is flowing into the tundish. FIG. 5(a) is a sectional view taken along a line IV--IV in FIG. 4(b). FIG. 4(a) illustrates an example where the ladle stopper 1 has a circular cylindrical shape and the long nozzle 2 has a cylindrical shape as illustrated are in FIG. 5(a).
The "distance (y) of the overlap portion between the long nozzle 2 and the stopper protrusion 1A" and the "opening area (Ao) of the long nozzle" used in the present method will be explained with reference to FIG. 4(a). First, the term "distance (y) of the overlap portion between the long nozzle 2 and the stopper protrusion 1A" is the distance represented by symbol y in FIG. 4(b). It is the distance of the area where the protrusion 1A of the ladle stopper 1 overlaps with the long nozzle 2 in the horizontal direction during the feed of the molten alloy. The case where this y value is from 0.1 to 200 mm will be explained in detail.
The term "opening area (Ao) of the long nozzle" is the area represented by symbol Ao in FIG. 5(a) to FIG. 5(d). It is the sectional area of the space defined by the inner wall surface 2A of the opening at the upper part of the long nozzle and the outer wall surface of the protrusion 1A of the stopper 1. In the method of the present invention, the Ao value is limited to 0.5 to 10 cm 2 .
In the method of the present invention, the sectional shape of the long nozzle in the horizontal direction is the same as the sectional shape of the protrusion of the stopper in the horizontal direction within the range of the distance y. Therefore, the value of the opening area Ao of the long nozzle has a constant value within the range of the distance y.
The reasons why the distance (y) of the overlap portion between the long nozzle 2 and the stopper protrusion 1A is limited to 0.1 to 200 mm and why the opening area (Ao) of the long nozzle is limited to 0.5 to 10 cm 2 in the method of the present invention will be explained.
It has been discovered that even when the y and Ao values shown in FIGS. 3 and 4(a), (b) , and FIGS. 5(a) to (d) are limited to 0.1 to 200 mm and to 0.5 to 10 cm 2 , respectively, the feed quantity of the molten alloy is set to a rate not greater than 100 kg/min. This is why the distance (y) of the overlap portion between the long nozzle and the stopper protrusion is limited to 0. 1 to 200 mm and the opening area (Ao) of the long nozzle is limited to 0.5 to 10 cm 2 .
Preferred combinations of the distance (y) of the overlap portion between the long nozzle and the stopper protrusion with the opening area (Ao) of the long nozzle will be illustrated concretely in the later-appearing Examples. Fundamentally, however, when the Ao value is decreased within the range described above, the y value can be decreased within the range described above. Their values may be suitably selected in accordance with a predetermined feed quantity for the molten alloy. If the Ao value is less than 0.5 cm 2 , however, clogging of the nozzle is likely to occur even though the feed is the amorphous alloy. For this reason, the method of the present invention limits the Ao value to at least 0.5 cm 2 . On the other hand, the reason why the upper limit of the Ao value is set to 10 cm 2 is to place an upper limit on the y value. The reason why the upper limit is placed on the y value is that problems would occur in fitting the stopper or during its opening and closing operations if the y value is excessively large. For these reasons, the y value is limited to not greater than 200 mm. When the y value exceeds 200 mm, centering with the long nozzle becomes difficult and fitting of the stopper also becomes difficult. If centering of the stopper with the long nozzle becomes inferior, the opening and closing operations of the stopper cannot be carried out smoothly. When the y value is set to 200 mm, the Ao value can be increased up to 10 cm 2 . This is the reason why the upper limit of Ao value is set to 10 cm 2 .
The reason why the upper limit of y is 200 mm is described above. The reason why the lower limit of y is 0.1 mm is to stably set a predetermined Ao value.
The stopper of the present invention is the stopper for controlling the feed quantity of the molten alloy for producing the amorphous alloy thin strip which is characterized in that the stopper has a thin protrusion, with the length of this protrusion being at least 5 mm. The outer wall surface of the protrusion is in parallel with the perpendicular direction. Here, the term "thin protrusion" means that the protrusion is so thin that it can be fitted into the opening of the long nozzle at the fitting portion with the long nozzle. The length of the protrusion of the stopper is limited to at least 5 mm. The stopper stroke must be at least 5 mm as previously discussed and the y value must be at least 0.1 mm.
The discovery that "the feed quantity of the molten alloy can be set to a rate not greater than 100 kg/min even when the stopper stroke is greater than 5 mm by setting the y and Ao value to 0. 1 to 200 mm and to 0. 5 to 10 cm 2 , respectively" was made performing experiments using the Fe-B-Si-C system amorphous alloy. This phenomenon results from the fact that the viscosity of an amorphous alloy in the molten state is far smaller than that of ordinary crystalline alloys. Since this phenomenon does not only occur in the Fe-B-Si-C system amorphous alloy but is believed to occur in a broad range of alloys that can be converted to amorphous alloys, the present invention can be widely applied to a variety of amorphous alloys.
According to the method of the present invention, the molten alloy can be provided supplied at a constant feed rate of not greater than 100 kg/min even when the position of the ladle stopper is fixed once the ladle stopper is moved upward at the time of the start of the feed of the molten alloy. Since the method of the present invention does not require the position of the ladle stopper to be moved up and down so as to control the flow rate of the molten alloy as has been necessary in the prior art, the operation can be carried out easily. Since the present invention does not require a complicated apparatus, it can economically supply the molten alloy.
When the height of the molten metal level in the tundish fluctuates to some extent due to the effect of the decrease of the molten metal level inside the ladle in the present invention, it is advisable to eliminate the fluctuation of the molten metal level in the tundish by inserting a dummy volume, for example, into the tundish and moving up and down this dummy volume in accordance with the fluctuation of the molten metal level of the tundish. A change of the height of the molten metal level in the tundish can cause fluctuation of the jet pressure of the molten alloy impinging on the cooling roll. Eventually, this can cause a fluctuation in the sheet thickness of the resulting thin strip. Thin strips having a large thickness fluctuation generally cause problems when used as industrial materials. The method of inserting the dummy volume into the tundish and keeping constant the height of the molten metal level in the tundish is an economical method and does not significantly increase the production cost of the thin strip.
The present invention does not specifically limit the stopper stroke of the ladle stopper at the start of the feed of the molten alloy. In view of the vibration of the apparatus, it is not preferred to set the stroke to an excessively small value. Preferably, therefore, the range of the stopper stroke is from about 5 to about 50 mm.
FIGS. 4(a) and (b) show the case where a circular cylindrical long nozzle is used by way of example. However, the shape of the long nozzle used for the method of the present invention is not specifically limited to a circular cylindrical shape. The sectional shape of the long nozzle may be circular, elliptic, flower-like or polygonal. FIGS. 5(a) to (d) are sectional views taken along a line II--II of FIG. 4(a) and line IV--IV of FIG. 4(b). FIG. 5(b) shows the long nozzle 2 having different shapes on the outside and the inside, that is, a circular outer shape and a flower-like opening shape. Further, the shape of opening of the long nozzle can be different at its upper and lower portions.
The present invention does not particularly limit the sectional shape of the protrusion on the stopper. When the shape of the opening of the long nozzle 2 is flower-shaped as shown in FIG. 5(b), for example, the shape of the overlap portion between the stopper 1 and the long nozzle 2 also may be flower-shaped.
Needless to say, the sectional shape of the opening of the long nozzle 2 in the horizontal direction does not have to be similar to the sectional shape of the protrusion 1A of the stopper 1 in the horizontal direction as shown in FIGS. 5(c) and 5(d), for example. In other words, FIGS. 5(c) and (d) are sectional views taken along the line IV--IV in FIG. 4(b). As can be appreciated from FIG. 5(c), the sectional shape of the protrusion 1A may be different in the horizontal direction from the sectional shape of the opening of the long nozzle 2 such as in the combination of the stopper 1 having the protrusion 1A whose sectional shape is elliptic used with a circular cylindrical long nozzle 2.
The preferred thin strip production apparatus used by the present invention is the single roll apparatus or the twin roll apparatus for jetting the molten alloy through the nozzle to the cooling substrate and quenching and solidifying the molten alloy by the thermal contact. The single roll apparatus includes a centrifugal quenching apparatus using the inner wall of a drum, an apparatus using an endless type belt, and improvement types such as those equipped with an auxiliary roll, a roll surface temperature controller, or casting in an inert gas or in vacuum at a reduced pressure.
The casting conditions used for the method of the present invention and specific casting operations will be explained. The jet pressure of the molten metal is 0.01 to 3 kg/cm 2 . It is set primarily by using the height of the molten metal level inside the tundish. The rotating speed (surface speed) of the cooling roll is within the range of 5 to 60 m/sec. Optimum values are selected for these conditions in accordance with the type of the alloys used, the thickness of the intended strips and other production conditions.
According to one embodiment of the method of the present invention, at least one portion of the outer wall surface of the protrusion of the stopper is brought into contact with the inner wall surface of the opening at the upper portion of the long nozzle during supplying the molten alloy 6 from the ladle 3 into the tundish 5. Here, the term "outer wall surface of the protrusion of the stopper is brought into contact with the inner wall surface of the opening at the upper portion of the long nozzle" represents the state shown in FIGS. 5(c). These drawing figures show embodiments where two portions of the outer wall surface of the protrusion 1A of the stopper 1 are in contact with two portions of the inner wall surface 2A of the opening at the upper portion of the long nozzle 2. The term "outer wall surface of the protrusion of the stopper is brought into contact with the inner wall surface of the opening at the upper portion of the long nozzle" represents such a state. When the outer wall portion of the protrusion of the stopper is brought into contact with the inner wall surface of the opening at the upper portion of the long nozzle, centering of the long nozzle with the stopper becomes easier. Therefore working factors during the production of the thin strip can be improved, and the supply of the molten alloy becomes easier.
EXAMPLE 1
The production of a Fe-B 12 Si 6 .5 C 1 (at %) alloy thin strip was carried out by using a single roll thin strip production apparatus as shown in FIG. 1. The molten alloy was in a ladle equipped with a ladle stopper and with a long nozzle as shown in FIG. 3. The ladle stopper used was of an ordinary type having an elliptic distal end (to which a fine protrusion may be attached). The long nozzle was made of alumina graphite and its inner sectional shape was circular. It had an inner diameter of 30 mm at the uppermost portion, an inner diameter of 12 mm at the lowermost portion, and a length of 1 m. The distance (y) of the overlap portion between the distal end portion of the ladle stopper and the distal end portion of the long nozzle was adjusted to 0.08 mm. The opening area inside the nozzle was 1.13 cm 2 and the distance (Lm) from the ladle bottom surface to the minimum sectional area position inside the long nozzle was 1 m.
Melting of the alloy was effected by a radio frequency induction system. The height of the molten alloy level inside the ladle before the start of feeding the molten alloy to the tundish was 250 mm. In other words, the height (Ln) of the level of the molten metal inside the ladle at the start of feeding the molten metal was 250 mm and the Ln/Lm value was 4 in this experiment. The ladle stopper used was made of alumina graphite, the same as the long nozzle, and had a cylindrical shape, a length of 800 mm and an outer diameter of 60 mm. A radius of curvature (combination of R 120 mm and R 15 mm) was applied to only the portion having a length of 35 mm at the distal end.
The molten alloy was guided into the tundish by moving up the ladle stopper 20 mm. Immediately thereafter, the production of the thin strip was started by moving up the tundish stopper 20 mm. Both of the ladle stopper and the tundish stopper were kept at the 20 mm elevated positions until the production of the thin strip was completed.
Other thin strip production conditions were as follows.
Molten alloy temperature inside ladle at charging: 1,350° C.; nozzle opening shape: opening formed by aligning two rectangular slits having a size of 120 mm×0.7 mm with a 1.5 mm-gap; surface speed of cooling roll at casting: 20 m/sec; gap between nozzle and cooling roll: 0.3 mm.
As a result, a thin strip having a width of about 120 mm and good properties could be obtained. Samples each having a length of 20 m were collected from the resulting thin strip at five positions spaced apart equidistantly in the longitudinal direction. The weight of each sample was measured. The weight was found to be about 0.95 kg for all the samples. Since each 20 m-long sample was the quantity of the thin strip produced within one second, the quantity of the molten alloy supplied to the tundish was about 57 kg/min. The thickness of the resulting thin strip was about 55 μAm. Fluctuation of the thickness in the longitudinal direction of the thin strip hardly existed. The thin strip so obtained was excellent in both magnetic and mechanical properties.
It can be understood from the results described above that the feed quantity of the molten alloy by such a supplying method of the molten alloy was not greater than 100 kg/min and the molten alloy could be uniformly supplied during casting.
EXAMPLE 2
The production of a Fe-B 12 Si 6 .5 C 1 (at %) alloy thin strip was carried out by using a single roll thin strip production apparatus as shown in FIG. 1. The molten alloy was in a ladle equipped with a ladle stopper and a long nozzle as shown in FIG. 4(a). The long nozzle used was made of alumina graphite and had a cylindrical shape. It had an inner diameter of 40 mm at the uppermost portion, an inner diameter of 25 mm at the lowermost portion, and a length of 1 m. The inner diameter had a constant value at the portion of a length of 200 mm from the upper-most portion to the lower portion. The lower portion had a predetermined taper. The long nozzle had an outer diameter of 60 mm for the portion having a distance of 200 mm from the uppermost portion towards the lower portion, and the outer diameter was 40 mm at the lowermost portion. The ladle stopper was made of alumina graphite, had a circular cylindrical shape having a length of 860 mm and an outer diameter of 60 mm. It had a circular cylindrical protrusion having a length of 60 mm at the distal end thereof as shown in FIG. 4(b). Three kinds of ladle stoppers were used and the diameter of the protrusion at the distal end of each stopper was changed.
Here, the protrusion at the distal end of the stopper and the long nozzle were arranged in such a fashion that they did not come into contact with each other so as to secure the opening area Ao, as shown in FIG. 5(a), (b).
Melting of the alloy was effected by a radio frequency induction system. The height of the molten metal level inside the ladle before the start of feeding of the molten alloy to the tundish was 250 mm. The casting experiment was carried out with one charge for each of three kinds of ladle stoppers, that is, three charges in total. As the conditions for each casting experiment for each charge, the values of y and Ao shown in FIG. 4(a), (b) and FIG. 5(a), (b) and the value of the stopper stroke (Ls) of the ladle stopper were tabulated in Table 1. Other thin strip production conditions were as follows.
Molten alloy temperature inside ladle at charging: 1,350° C.; nozzle opening shape: opening formed by aligning two rectangular slits having a size of 120 mm×0.7 mm with a 1.5 mm gap; surface speed of cooling roll at casting: 24 m/sec; gap between nozzle and cooling roll: 0.25 mm.
As a result, a thin strip having a width of about 120 mm and having excellent properties was obtained. Samples, each having a length of 24 m, were collected from the resulting thin strips at five positions spaced apart equidistantly in the longitudinal direction, and the weight of each sample was measured. Since this weight represented the weight of the molten alloy supplied within one second, the feed quantity of the molten alloy at the time of casting was calculated from this data. The minimum and maximum values were tabulated in Table 1 as the results.
TABLE 1______________________________________ resultcasting condition feed q'ty of strip y A.sub.o L.sub.s molten alloy thicknessNo mm cm.sup.2 mm kg/min μm______________________________________1 18 1.8 42 69-71 53-552 28 2.4 32 65-69 49-523 43 3.5 17 85-88 60-63______________________________________
As can be understood from this table, the values of the molten alloy feed quantity from the charge were substantially constant for each charge. The strip thickness of each of the 24 m-long samples collected was measured. The minimum and maximum values of the strip thickness of each sample were also tabulated in Table 1. A great fluctuation in the thickness of the thin strip could not be observed in any charge. It can be understood from this data that no fluctuation which would become a problem from the molten alloy feed quantity occurred in all the charges. The resulting thin strips were excellent in both magnetic and mechanical properties.
It can be understood from the results given above that the supplying method of the molten alloy can supply the molten alloy at a feed quantity of not greater than 100 kg/min and furthermore, substantially uniform during casting.
EXAMPLE 3
Production experiments for thin strips were carried out by using the same thin strip production apparatus as in Example 2. The ladle stopper had a circular cylindrical shape having a length of 900 mm and an outer diameter of 60 mm. It had a circular cylindrical protrusion having a length of 100 mm at the distal end thereof as shown in FIG. 4(a), (b). Three kinds of ladle stoppers were used, and the diameter of the protrusion at the distal end of each ladle stopper was changed. The casting experiments were carried out by changing the values y and Ao shown in FIGS. 4(a), (b) and 5(a), (b). The values y and Ao used for the respective casting experiments were tabulated in Table 2. The surface speed of the cooling roll was set to 26 m/sec, and other casting conditions were the same as those of Example 2.
As a result, thin strips having a width of about 120 mm and good properties could be obtained in all the charges. Samples each having a length of 26 m were collected from the resulting thin strips in the same way as in Example 1. The feed quantity of the molten alloy and the thickness of the thin strips were examined. Table 2 shows the results in the same way as in Table 1. From the data of the feed quantity of the molten alloy and the thickness of the thin strips tabulated in Table 2, fluctuation of the feed quantity of the molten alloy could not be observed in any charge. Fluctuations which would become the problem in the thickness of the thin strips could not be observed.
TABLE 2______________________________________ resultcasting condition feed q'ty of strip y A.sub.o L.sub.s molten alloy thicknessNo mm cm.sup.2 mm kg/min μm______________________________________1 62 5.5 38 72-75 52-562 76 6.4 24 63-65 47-513 88 7.3 12 66-69 49-52______________________________________
It can be understood from the results given above that the supplying method of the molten alloy can supply the molten alloy at a feed quantity of not greater than 100 kg/min and furthermore, is substantially uniform during casting.
EXAMPLE 4
The production of a Fe-B 12 Si 6 .5 C 1 (at %) alloy thin strip was carried out by using a single roll thin strip production apparatus shown in FIG. 1. The molten was in a ladle equipped with a ladle stopper and with a long nozzle as shown in FIG. 4(a). The long nozzle used was made of alumina graphite and had a cylindrical shape as shown in FIG. 4(a), (b). It had an inner diameter of 40 mm at the uppermost portion, an inner diameter of 25 mm at the lowermost portion and a length of 1 m. The inner diameter had a constant value at the portion of a length of 200 mm from the uppermost portion. The lower portion had a predetermined taper. The long nozzle had an outer diameter of 60 mm for the portion having a distance of 200 mm from the uppermost portion towards the lower portion, and the outer diameter was 40 mm at the lowermost portion. The ladle stopper was made of alumina graphite, had a circular cylindrical shape having a length of 900 mm, an outer diameter of 100 mm, and had an elliptic protrusion having a length of 60 mm at the distal end thereof as shown in FIG. 5(c). The major diameter of this elliptic protrusion was 40 mm. The stopper was in slight contact with the inner wall surface of the opening at the upper portion of the long nozzle at two position at both ends of the major diameter. Three kinds of ladle stoppers were used. The minor diameter of the elliptic shape of the protrusion at the distal end of each stopper was changed.
Melting of the alloy was effected by a radio frequency induction system. The height of the molten metal level inside the ladle before the start of the feeding of the molten alloy to the tundish was 250 mm. The casting experiment was carried out in one charge for each of three kinds of the ladle stoppers, i.e., three charges in total. The values of y and Ao shown in FIG. 4(a), (b) and FIG. 5(c) and the value of the stopper stroke (Ls) of the ladle stopper, as the condition of each casting experiment, are tabulated in Table 3. Other thin strip production conditions were as follows.
Molten alloy temperature inside ladle at charging: 1,350° C.; nozzle opening shape: opening formed by aligning two rectangular slits having a size of 120 mm×0.7 mm with a 1.5 mm-gap surface; speed of cooling roll at casting: 24 m/sec; gap between nozzle and cooling roll: 0.25 mm.
As a result, thin strips having a width of about 120 mm and good properties could be obtained in all of the charges. Samples each having a length of 24 m were collected from the resulting thin strips at five positions spaced apart equidistantly in the longitudinal direction. The weight of each sample was measured. Since this weight represented the weight of the molten alloy supplied for 1 second, the feed quantity of the molten alloy at the time of casting was calculated from this data. The minimum and maximum values of the results were tabulated in Table 3. The feed quantity of the molten metal in the charge was substantially constant for each charge as can be understood from these values. The sheet thickness was measured for each of the 24 m-long samples so collected. The minimum and maximum values of the strip thickness so obtained were also tabulated in Table 3. A great fluctuations could not be observed in the thickness of the thin strip for each charge. It could be understood from this data that no fluctuation which would become a problem resulting from the molten alloy feed quantity occurred in any of the charges. The resulting thin strips were excellent in both magnetic and mechanical properties.
It can be understood from the results given above that the supplying method of the molten alloy can supply the molten alloy at a feed quantity of not greater than 100 kg/min and furthermore, substantially uniformly during casting.
TABLE 3______________________________________ resultcasting condition feed q'ty of strip y A.sub.o L.sub.s molten alloy thicknessNo mm cm.sup.2 mm kg/min μm______________________________________1 58 5.2 42 68-72 54-572 78 6.5 22 64-67 50-543 89 8.1 11 65-69 52-55______________________________________
EXAMPLE 5
Production experiments for thin strips were carried out by using the same thin strip production apparatus as in Example 4. A ladle stopper had a circular cylindrical shape, a length of 900 mm and an outer diameter of 60 mm. It had a flower-shaped protrusion having a length of 60 mm at the distal end thereof as shown in FIG. 5(d). The y and Ao values shown in FIGS. 4(a), (b) and 5(d) were 13 mm and 1.5 cm 2 , respectively. The other casting conditions were the same as those of Example 4.
As a result, thin strips having a width of about 120 mm and good properties could be obtained. Samples were collected from the resulting thin strips in the same way as in Example 1. The feed quantity of the molten alloy and the thickness of the thin strips were examined. As a result, it was found out that the feed quantity of the molten alloy was 62 to 64 kg/min and the thickness of the thin strips was 49 to 52 μm. Fluctuation of the feed quantity of the molten metal could not be observed from these data and fluctuations which would become a problem resulting from molten alloy feed quantity could not be observed.
It can be understood from the results given above that the supplying method of the molten alloy can supply the molten alloy at a feed quantity of not greater than 100 kg/min and, furthermore, substantially uniform during casting. | A method for supplying molten metal alloy for producing thin amorphous metal wire or thin amorphous metal strip by liquid quenching and solidification on a moving cooling substrate controls the flow of molten metal from a ladle into a tundish. The ladle has a long nozzle with an interior passage for providing flow of molten metal alloy into the tundish. The ladle stopper has a distal end region received by the interior passage of the long nozzle. Control of the overlap between the distal end region of the ladle stopper received in the long nozzle during molten alloy flow and control of the sectional flow area provided in the long nozzle interior passage controls the flow quantity of molten alloy from the ladle into the tundish. | 1 |
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a § 371 national stage filing based on PCT/AU97/00492, filed Aug. 1, 1997, which claims priority through provisional application No. 60/024,279, filed Aug. 21, 1996 and Australian application PO 1402, filed Aug. 2, 1996.
FIELD OF THE INVENTION
The present invention relates to nucleic acids which encode glycosyltransferase and are useful in producing cells and organs from one species which may be used for transplantation into a recipient of another species. Specifically the invention concerns production of nucleic acids which, when present in cells of a transplanted organ, result in reduced levels of antibody recognition of the transplanted organ.
BACKGROUND OF THE INVENTION
The transplantation of organs is now practicable, due to major advances in surgical and other techniques. However, availability of suitable human organs for transplantation is a significant problem. Demand outstrips supply. This has caused researchers to investigate the possibility of using non-human organs for transplantation.
Xenotransplantation is the transplantation of organs from one species to a recipient of a different species. Rejection of the transplant in such cases is a particular problem, especially where the donor species is more distantly related, such as donor organs from pigs and sheep to human recipients. Vascular organs present a special difficulty because of hyperacute rejection (HAR).
HAR occurs when the complement cascade in the recipient is initiated by binding of antibodies to donor endothelial cells.
Previous attempts to prevent HAR have focused on two strategies: modifying the immune system of the host by inhibition of systemic complement formation (1,2), and antibody depletion (3,4). Both strategies have been shown to prolong xenograft survival temporarily. However, these methodologies are therapeutically unattractive in that they are clinically impractical, and would require chronic immunosuppressive treatments. Therefore, recent efforts to inhibit HAR have focused on genetically modifying the donor xenograft. One such strategy has been to achieve high-level expression of species-restricted human complement inhibitory proteins in vascularized pig organs via transgenic engineering (5-7). This strategy has proven to be useful in that it has resulted in the prolonged survival of porcine tissues following antibody and serum challenge (5,6). Although increased survival of the transgenic tissues was observed, long-term graft survival was not achieved (6). As observed in these experiments and also with systemic complement depletion, organ failure appears to be related to an acute antibody-dependent vasculitis (1,5).
In addition to strategies aimed at blocking complement activation on the vascular endothelial cell surface of the xenograft, recent attention has focused on identification of the predominant xenogeneic epitope recognised by high-titre human natural antibodies. It is now accepted that the terminal galactosyl residue, Gal-α(1,3)-Gal, is the dominant xenogeneic epitope (8-15). This epitope is absent in Old World primates and humans because the α(1,3)-galactosyltransferase (gal-transferase or GT) is non-functional in these species. DNA sequence comparison of the human gene to α(1,3)-galactosyltransferase genes from the mouse (16,17), ox (18), and pig (12) revealed that the human gene contained two frameshift mutations, resulting in a nonfunctional pseudogene (20,21). Consequently, humans and Old World primates have pre-existing high-titre antibodies directed at this Gal-α(1,3)-Gal moiety as the dominant xenogeneic epitope.
One strategy developed was effective to stably reduce the expression of the predominant Gal-α(1,3)-Gal epitope. This strategy took advantage of an intracellular competition between the gal-transferase and α(1,2)-fucosyltransferase (H-transferase) for a common acceptor substrate. The gal-transferase catalyzes the transfer of a terminal galactose moiety to an N-acetyl lactosamine acceptor substrate, resulting in the formation of the terminal Gal-α(1,3)-Gal epitope. Conversely, H-transferase catalyzes the transfer of a fucosyl residue to the N-acetyl lactosamine acceptor substrate, and generates a fucosylated N-acetyl lactosamine (H-antigen, i.e., the O blood group antigen), a glycosidic structure that is universally tolerated. Although it was reported that expression of human H-transferase transfected cells resulted in high level expression of the non-antigenic H-epitope and significantly reduced the expression of the Gal-α(1,3)-Gal xenoepitope, there are still significant levels of Gal-α(1,3)-Gal epitope present on such cells.
SUMMARY OF THE INVENTION
In view of the foregoing, it is an object of the present invention to further reduce levels of undesirable epitopes in cells, tissues and organs which may be used in transplantation.
In work leading up to the invention the inventors surprisingly discovered that the activity of H transferase may be further increased by making a nucleic acid which encodes a H transferase catalytic domain but is anchored in the cell at a location where it is better able to compete for substrate with gal transferase. Although work by the inventors focused on a chimeric H transferase, other glycosyltransferase enzymes may also be produced in accordance with the invention.
Accordingly, in a first aspect the invention provides a nucleic acid encoding a chimeric enzyme, wherein said chimeric enzyme comprises a catalytic domain of a first glycosyltransferase and a localization signal of a second glycosyltransferase, whereby when said nucleic acid is expressed in a cell said chimeric enzyme is located in an area of the cell where it is able to compete for substrate with a second glycosyltransferase, resulting in reduced levels of a product from said second glycosyltransferase.
Preferably the nucleic acid is in an isolated form; that is the nucleic acid is at least partly purified from other nucleic acids or proteins.
Preferably the nucleic acid comprises the correct sequences for expression, more preferably for expression in a eukaryotic cell. The nucleic acid may be present on any suitable eukaryotic expression vector such as pcDNA (Invitrogen). The nucleic acid may also be present or other vehicles whether suitable for eukaryotes or not, such as plasmids, phages and the like.
Preferably the catalytic domain of the first glycosyltransferase is derived from H transferase, secretor sialyltransferase, a galactosyl sulphating enzyme or a phosphorylating enzyme.
The nucleic acid sequence encoding the catalytic domain may be derived from, or similar to a glycosyltransferase from an species. Preferably said species is a species such as human or other primate species, including Old World monkeys, or other mammals such as ungulates (for example pigs, sheep, goats, cows, horses, deer, camels) or dogs, mice, rats and rabbits. The term “similar to” means that the nucleic acid is at least partly homologous to the glycosyltransferase genes described above. The term also extends to fragments of and mutants, variants and derivatives of the catalytic domain whether naturally occurring or man made.
Preferably the localization signal is derived from a glycosyltransferase which produces glycosylation patterns which are recognised as foreign by a transplant recipient. More preferably the localization signal is derived from α(1,3) galactosyltransferase. The effect of this is to downregulate the level of Gal-α(1,3)-Gal produced in a cell when the nucleic acid is expressed by the cell.
The nucleic acid sequence encoding the localization signal may be derived from any species such as those described above. Preferably it is derived from the same species as the cell which the nucleic acid is intended to transform i.e., if pig cells are to be transformed, preferably the localization signal is derived from pig.
More preferably the nucleic acid comprises a nucleic acid sequence encoding the catalytic domain of H transferase and a nucleic acid sequence encoding a localization signal from Gal transferase. Still more preferably both nucleic acid sequences are derived from pigs. Even more preferably the nucleic acid encodes gtHT described herein.
The term “nucleic acid” refers to any nucleic acid comprising natural or synthetic purines and pyrimidines. The nucleic acid may be DNA or RNA, single or double stranded or covalently closed circular.
The term “catalytic domain” of the chimeric enzyme refers to the amino acid sequences necessary for the enzyme to function catalytically. This comprises one or more contiguous or non-contiguous amino acid sequences. Other non-catalytically active portions also may be included in the chimeric enzyme.
The term “glycosyltransferase” refers to a polypeptide with an ability to move carbohydrates from one molecule to another.
The term “derived from” means that the catalytic domain is based on, or is similar, to that of a native enzyme. The nucleic acid sequence encoding the catalytic domain is not necessarily directly derived from the native gene. The nucleic acid sequence may be made by polymerase chain reaction (PCR), constructed de novo or cloned.
The term “localization signal” refers to the amino acid sequence of a glycosyltransferase which is responsible for anchoring it in location within the cell. Generally localization signals comprise amino terminal “tails” of the enzyme. The localization signals are derived from a second glycosyltransferase, the activity of which it is desired to minimise. The localization of a catalytic domain of a first enzyme in the same area as the second glycosyltransferase means that the substrate reaching that area is likely to be acted or by the catalytic domain of the first enzyme, enabling the amount of substrate catalysed by the second enzyme to be reduced.
The term “area of the cell” refers to a region, compartment or organelle of the cell. Preferably the area of the cell is a secretory organelle such as the Golgi apparatus.
In another aspect the invention provides an isolated nucleic acid molecule encoding a localization signal of a glycosyltransferase. Preferably the signal encoded comprises an amino terminus of said molecule; more preferably it is the amino terminus of gal transferase. The gal transferase may be described from or based on a gal transferase from any mammalian species, such as those described above. Particularly preferred sequences are those derived from pig, mouse or cattle.
In another aspect the invention relates to a method of producing a nucleic acid encoding a chimeric enzyme said enzyme comprising a catalytic domain of a first glycosyltransferase and a localization signal of a second glycosyltransferase whereby when said nucleic acid is expressed in a cell said chimeric enzyme is located in an area of the cell where it is able to compete for substrate with a second glycosyltransferase said method comprising operably linking a nucleic acid sequence encoding a catalytic domain from a first glycosyltransferase to a nucleic acid sequence encoding a localization signal of a second glycosyltransferase.
The term “operably linking” means that the nucleic acid sequences are ligated such that a functional protein is able to be transcribed and translated.
Those skilled in the art will be aware of various techniques for producing the nucleic acid. Standard techniques such as those described in Sambrook et al may be employed.
Preferably the nucleic acid sequences are the preferred sequences described above.
In another aspect the invention provides a method of reducing the level of a carbohydrate exhibited on the surface of a cell, said method comprising causing a nucleic acid to be expressed in said cell wherein said nucleic acid encodes a chimeric enzyme which comprises a catalytic domain of a first glycosyltransferase and a localization signal of a second glycosyltransferase, whereby said chimeric enzyme is located in an area of the cell where it is able to compete for substrate with said second glycosyltransferase, and wherein said second glycosyltransferase is capable of producing said carbohydrate.
The term “reducing the level of a carbohydrate” refers to lowering, minimising, or in some cases, ablating the amount of carbohydrate displayed on the surface of the cell. Preferably said carbohydrate is capable of stimulating recognition of the cell as “non-self” by the immune system of an animal. The reduction of such a carbohydrate therefore renders the cell, or an organ composed of said cells, more acceptable to the immune system of a recipient animal in a transplant situation or gene therapy situation.
The term “causing a nucleic acid to be expressed” means that the nucleic acid is introduced into the cell (i.e. by transformation/transfection or other suitable means) and contains appropriate signals to allow expression in the cells.
The cell may be any suitable cell, preferably mammalian, such as that of a New World monkey, ungulate (pig, sheep, goat, cow, horse, deer, camel, etc.) or other species such as dogs.
In another aspect the invention provides a method of producing a cell from one species (the donor) which is immunologically acceptable to another species (the recipient) by reducing levels of carbohydrate on said cell which cause it to be recognised as non-self by the other species, said method comprising causing a nucleic acid to be expressed in said cell wherein and nucleic acid encodes a chimeric which comprises a catalytic domain of a first glycosyltransferase and a localization signal of a second glycosyltransferase, whereby said chimeric enzyme is located in an area of the cell where it is able to compete for substrate with said second glycosyltransferase, and wherein said second glycosyltransferase is capable of producing said carbohydrate.
The term “immunologically acceptable” refers to producing a cell, or an organ made up of numbers of the cell, which does not cause the same degree of immunological reaction in the recipient species as a native cell from the donor species. Thus the cell may cause a lessened immunological reaction, only requiring low levels of immunosuppressive therapy to maintain such a transplanted organ or no immunosuppression therapy.
The cell may be from any of the species mentioned above. Preferably the cell is from a New World primate or a pig. More preferably the cell is from a pig.
The invention extends to cells produced by the above method and also to organs comprising the cells.
The invention further extends to non-human transgenic animals harbouring the nucleic acid of the invention. Preferably the species is a human, ape or Old World monkey.
The invention also extends to the proteins produced by the nucleic acid. Preferably the proteins are in an isolated form.
In another aspect the invention provides an expression unit which expresses the nucleic acid of the invention, resulting in a cell which is immunologically acceptable to an animal having reduced levels of a carbohydrate on its surface, which carbohydrate is recognized as non-self by said species. In a preferred embodiment, the expression unit is a retroviral packaging cell, cassette, a retroviral construct or retroviral producer cell.
Preferably the species is a human, ape or Old World monkey.
The retroviral packaging cells or retroviral producer cells may be cells of any animal origin where it is desired to reduce the level of carbohydrates on its surface to make it more immunologically acceptable to a host. Such cells may be derived from mammals such as canine, rodent or ruminant species and the like.
The retroviral packaging and/or producer cells may be used in applications such as gene therapy. General methods involving use of such cells are described in PCT/US95/07554 and the references discussed therein.
The invention also extends to a method of producing a retroviral packaging cell or a retroviral producer cell having reduced levels of a carbohydrate on its surface wherein the carbohydrate is recognised as non-self by a species, comprising transforming/transfecting a retroviral packaging cell or a retroviral producer cell with the nucleic acid of the invention under conditions such that the chimeric enzyme is produced.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 Schematic diagram of normal and chimeric glycosyltransferases
The diagram shows normal glycosyltransferases porcine α(1,3)galactosyltransferase (GT) and human α(1,2)fucosyltransferase (HT), and chimeric transferases ht-GT in which the cytoplasmic domain of GT has been completely replaced by the cytoplasmic domain of HT, and gt-HT in which the cytoplasmic domain of HT has been entirely replaced by the cytoplasmic domain of GT. The protein domains depicted are cytoplasmic domain CYTO, transmembrane domain TM, stem region STEM, catalytic domain CATALYTIC. The numbers refer to the amino acid sequence of the corresponding normal transferase.
FIG. 2 Cell surface staining of COS cells transfected with normal and chimeric transferases
Cells were transfected with normal GT or HT or with chimeric transferases gt-HT or ht-GT and 48 h later were stained with FITC-labelled lectin IB4 or UEAI. Positive-staining cells were visualized and counted by fluorescence microscopy. Results are from at least three replicates and values are+/−SEM.
FIG. 3 . RNA analysis of transfected COS cells
Northern blots were performed on total RNA prepared from COS cells transfected: Mock, mock-transfected; GT, transfected with wild-type GT; GT1-6/HT, transfected with chimeric transferase gt-HT; GT1-6/HT+HT1-8/GT, co-transfected with both chimeric transferases gt-HT and ht-GT; HT1-8/GT, transfected with chimeric transferase ht-GT; HT, transfected with normal HT; GT+HT co-transfected with both normal transferases GT and HT. Blots were probed with a cDNA encoding GT (Top panel), HT (Middle panel) or g-actin (Bottom panel).
FIG. 4 . Enzyme kinetics of normal and chimeric glycosyltransferases
Lineweaver-Burk plots for α(1,3) galactosyltransferase (□) and α(1,2)fucosyltransferase (▪) to determine the apparent values for N-acetyl lactosamine. Experiments are performed in triplicate, plots shown are of mean values of enzyme activity of wild-type transferases, GT and HT, and chimeric proteins ht-GT and gt-HT in transfected COS cell extracts using phenyl-B-D Gal and N-acetyl lactosamine as acceptor substrates.
FIG. 5 . Staining of cells co-transfected with chimeric transferases
Cells were co-transfected with cDNAs encoding normal transferases GT+HT (panels A, B), with chimeric transferases gt-HT+ht-GT (panels C, D), with HT+ht-GT (panels E, F) or with GT+gt-HT (panels G, H) and 48 h later were stained with FITC-labelled lectin IB4 (panels A, C, E, G) or UEAI (panels B, D, F, H).
FIG. 6 (SEQ ID No. 1) is a representation of the nucleic acid sequence and corresponding amino acid sequence of pig secretor.
FIG. 7 (SEQ ID No. 3) is a representation of the nucleic acid sequence and corresponding amino acid sequence of pig H.
FIG. 8 Cell surface staining of pig endothelial cell line (PIEC) transfected with chimeric α(1,2)-fucosyltransferase. Cells were transfected and clones exhibiting stable integration were stained with UFEAI lectin and visualised by fluorescence microscopy.
FIG. 9 Screening of chimeric α(1,2)-fucosyltransferase transferase in mice. Mice were injected with chimeric α(1,2)-fucosyltransferase and the presence of the transferase was analysed by dot blots.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The nucleic acid sequences encoding the catalytic domain of a glycosyltransferase may be any nucleic acid sequence such as those described in PCT/US95/07554, which is herein incorporated by reference, provided that it encodes a functional catalytic domain with the desired glycosyltransferase activity.
Preferred catalytic domains from glycosyltransferase include H transferase and secretor. Preferably these are based on human or porcine sequences.
The nucleic acid sequences encoding the localization signal of a second transglycosylase may be any nucleic acid sequence encoding a signal sequence such as signal sequences disclosed in P A Gleeson, R D Teasdale & J Bourke, Targeting of proteins to the Golgi apparatus. Glyconjugate J. (1994) 11: 381-394. Preferably the localization sis is specific for the Golgi apparatus, more preferably for that of the true Golgi. Still more preferably the localization signal is based on that of Gal transferase. Even more preferably the localization signal is based on porcine, murine or bovine sequences. Even more preferably the nucleic acid encodes a signal sequence with following amino acid sequence (in single letter code): MNVKGR (porcine) (SEQ ID NO. 11), MNVKGK (mouse) (SEQ ID NO. 12) or MVVKGK (bovine) (SEQ ID NO. 13).
Vectors for expression of the chimeric enzyme may be any suitable rector, including those disclosed in PCT/US95/07554.
The nucleic acid of the invention can be used to produce cells and organs with the desired glycosylation pattern by standard techniques, such as those disclosed in PCT/US95/07554. For example, embryos may be transfected by standard techniques such as microinjection of the nucleic acid in a linear form into the embryo (22). The embryos are then used to produce live animals, the organs of which may be subsequently used as donor organs for implantation.
Cells, tissues and organs suitable for use in the invention will generally be mammalian cells. Examples of suitable cells and tissues such as endothelial cells, hepatic cells, pancreatic cells and the like are provided in PCT/US95/07554.
The invention will now be described with reference to the following non-limiting Examples.
Abbreviations
The abbreviations used are bp, base pair(s); FITC, fluorescein isothiocyanate; GT, galactosyltransferase; H substance, α(1,2)fucosyl lactosamine; HT, α(1,2)fucosyltransferase; PCR, polymerase chain reaction;
Example 1 Cytoplasmic domains of glycosyltransferases play a central role in the temporal action of enzymes
Experimental Procedures
EXAMPLE 1
Plasmids—The plasmids used were prepared using standard techniques (7); pGT encodes the cDNA for the porcine α(1,3)galactosyltransferase (23), pHT encodes the cDNA for the α(1,2)fucosyltransferase (human) (25). Chimeric glycosyltransferase cDNAs were generated by polymerase chain reaction as follows: an 1105 bp product ht-GT was generated using primers corresponding to the 5′ end of ht-GT (5′-GC GGATCC ATGTGGCTCCGGAGCC ATCGTCAGGTGGTTCTGTCAATGC TGCTTG-3′) (SEQ ID NO. 5) coding for nucleotides 1-24 of HT (25) followed immediately by nucleotides 68-89 of GT (8) and containing a BamH1 site (underlined) and a primer corresponding to the 3′ end of ht-GT (5′-GC TCTAGA GCGTCAGATGTTATT TCTAACCAAATTATAC-3′) (SEQ ID NO. 6) containing complementarity to nucleotides 1102-1127 of GT with an Xbal site downstream of the translational stop site (underlined); an 1110 bp product gt-HT was generated using primers corresponding to the 5′ end of gt-HT (5′-GC GGATCC ATGAATGTCAAAGGAAGACTCTGCCTGGCCT TCCTGC-3′) (SEQ ID NO. 7) coding for nucleotides 49-67 of GT followed immediately by fnucleotides 25-43 of HT and containing a BamH1 site (underlined) and a primer corresponding to the 3′ end of gt-HT (5′-GC TCTAGA GCCTCAAGGCTTAG CCAATGTCCAGAG-3′) (SEQ ID NO. 8) containing complementarity to nucleotides 1075-1099 of HT with a Xba1 site downstream of the translational stop site (underlined). PCR products were restricted BamH1/Xba1, gel-purified and ligated into a BamH1/Xba1 digested pcDNA1 expression vector (Invitrogen) and resulted in two plasmids pht-GT (encoding the chimeric glycosyltransferase ht-GT) and pgt-HT (encoding the chimeric glycosyltransferase gt-HT) which were characterized by restriction mapping, Southern blotting and DNA sequencing.
Transfection and Serology—COS cells were maintained in Dubecco's modified Eagles Medium (DMEM) (Trace Biosciences Pty. Ltd. , Castle Hill, NSW, Australia) and were transfected (1-10 μg DNA/5×105 cells) using DEAE-Dextrau (26); 48 h later cells were examined for cell surface expression of H substance or Gal-α(1,3)-Gal using FITC-conjugated lectins: IB4 lectin isolated from Griffonia simplicifolia (Sigma, St. Louis, Mo.) detects Gal-α(1,3)-Gal (27); UEAI lectin isolated from Ulex europaeus (Sigma, St. Louis, Mo.) detects H substance (28). H substance was also detected by indirect immunofluorescence using a monoclonal antibody (mAb) specific for the H substance (ASH-1952) developed at the Austin Research Institute, using FITC-conjugated goat anti-mouse IgG (Zymed Laboratories, San Francisco, Calif.) to detect mAb binding. Fluorescence was detected by microscopy.
RNA Analyses—Cytoplasmic RNA was prepared from transfected COS cells using RNAzol (Biotecx Laboratories, Houston, Tex.), and total RNA was electrophoresed in a 1% agarose gel containing formaldehyde, the gel blotted onto a nylon membrane and probed with random primed GT or HT cDNA.
Glycosyltransferase assays—Forty-eight hours after transfection, cells were washed twice with phosphate buffered saline and lysed in 1% Triton X-100/100 mM cacodylate pH 6.5/25 mM MnCl2, at 4° C. for 30 min; lysates were centrifuged and the supernatant collected and stored at −70° C. Protein concentration was determined by the Bradford method using bovine serum allumin as standard (29). Assays for HT activity (30) were performed in 25 μl containing 3 mM [GDP- 14 C]fucose (specific activity 287 mCi/mmol, Amersham International), 5 mM ATP, 50 mM MPS pH 6.5, 20 mM MnCl2, using 2-10 μl of cell extract (approximately 15-20μg of protein) and a range of concentrations (7.5-75 mM) of the acceptor phenyl-B-D-galactoside (Sigma). Samples were incubated for 2 h at 37° C. and reactions terminated by the addition of ethanol and water. The amount of 14 C-fucose incorporated was counted after separation from unincorporated label using Sep-Pak C18 cartridges (Waters-Millipore, Millford, Mass.). GT assays (31) were performed in a volume of 25 μl using 3 mM UDP[ 3 H]-Gal (specific activity 189 mCi/mmol, Amersham International), 5 mM ATP, 100 mM cacodylate pH 6.5, 20 mM MnCl 2 and various concentrations (1-10 mM) of the acceptor N-acetyl lactosamine (Sigma). Samples were incubated for 2 h at 37° C. and the reactions terminated by the addition of ethanol and water. 3 H-Gal incorporation was counted after separation from non-incorporated UDP[ 3 H]-Gal using Dowex I anion exchange columns (BDH Ltd., Poole, UK) or Sep-Pak Accell plus QMA anion exchange cartridges (Waters-Millipore, Millford, Mass.). All assays were performed in duplicate and additional reactions were performed in the absence of added acceptor molecules, to allow for the calculation of specific incorporation of radioactivity.
Results
Expression of chimeric α(1,3)galactasyltransferase and α(1,2)fucosultransferase cDNAs
We had previously shown that when cDNAs encoding α(1,3)galactosyltransferase (GT) and α(1,2)fucosyltransferase (HT) were transfected separately they could both function efficiently leading to expression of the appropriate carbohydrates: Gal-α(1,3)-Gal for GT and H substance for HT (32). However when the cDNAs for GT and HT were transfected together, the HT appeared to “dominate” over the GT in that H substance expression was normal, but Gal-α(1,3)-Gal was reduced. We excluded trivial reasons for this effect and considered that the localization of the enzymes may be the reason. Thus, if the HT localization signal placed the enzyme in an earlier temporal compartment than GT, it would have “first use” of the N-acetyl lactosamine substrate. However, such a “first use” if it occurred, was not sufficient to adequately reduce GT. Two chimeric glycosyltransferases were constructed using PCR wherein the cytoplasmic tails of GT and RT were switched. The two chimeras constructed are shown in FIG. 1 : ht-GT which consisted of the NH 2 terminal cytoplasmic tail of HT attached to the transmembrane, stem and catalytic domain of GT; and gt-HT which consisted of the NH 2 terminal cytoplasmic tail of GT attached to the transmembrane, stem and catalytic domains of HT. The chimeric cDNAs were subcloned into the eukaryotic expression vector pcDNAI and used in transfection experiments.
The chimeric cDNAs encoding ht-GT and gt-HT were initially evaluated for their ability to induce glycosyltransferase expression in COS cells, as measured by the surface expression of the appropriate sugar using lectins. Forty-eight hours after transfection COS cells were tested by immunofluorescence for their expression of Gal-α(1,3)-Gal or H substance (Table 1 & FIG. 2 ). The staining with IB4 (lectin specific for Gal-α(1,3)-Gal) in cells expressing the chimera ht-GT (30% of cells stained positive) was indistinguishable from that of the normal GT staining (30%) (Table 1 & FIG. 2 ). Similarly the intense cell surface fluorescence seen with UEAI staining (the lectin specific for H substance) in cells each expressing gt-HT (50%) was similar to that seen in cells expressing wild-type pHT (50%) (Table 1 & FIG. 2 ). Furthermore, similar levels of mRNA expression of the glycosyltransferases GT and HT and chimeric glycosyltransferases ht-GT and gt-HT were seen in Northern blots of total RNA isolated from transfected cells (FIG. 3 ). Thus both chimeric glycosyltransferases are efficiently expressed in COS cells and are functional indeed there was no detectable difference between the chimeric and normal glycosyltransferases.
Glycosyltransferase activity in cells transfected with chimeric cDNAs encoding ht-GT and gt-HT
To determine whether switching the cytoplasmic tails of GT and HT altered the kinetics of enzyme function, we compared the enzymatic activity of the chimeric glycosyltransferases with those of the normal enzymes in COS cells after transfection of the relevant cDNAs. By making extracts from transfected COS cells and performing GT or HT enzyme assays we found that N-acetyl lactosamine was galactosylated by both GT and the chimeric enzyme ht-GT (FIG. 4 . panel A) over a the 1-5 mM range of substrate concentrations. Lineweaver-Burk plots showed that both GT and ht-GT have a similar apparent Michealis-Menten constant of Km 2.6 mM for N-acetyl lactosamine (FIG. 4 . panel B). Further HT, and the chimeric enzyme gt-HT were both able to fucosylate phenyl-B-D-galactoside over a range of concentrations (7.5-25 mM) ( FIG. 4 panel C) with a similar Km of 2.3 mM ( FIG. 4 panel D), in agreement with the reported Km of 2.4 mM for HT (25). Therefore the chimeric glycosyltransferases ht-GT and gt-HT are able to utilize N-acetyl lactosamine (ht-GT) and phenyl-B-D-galactoside (gt-HT) in the same way as the normal glycosyltransferases, thus switching the cytoplasmic domains of GT and HT does not alter the function of these glycosyltransferases and if indeed the cytoplasmic tail is the localization signal then both enzymes function as well with the GT signal as with the HT signal.
Switching Cytoplasmic Domains of GT and HT Results in a Reversal of the “Dominance” of the Glycosyltransferases
The cDNAs encoding the chimeric transferases or normal transferases were simultaneously co-transfected into COS cells and after 48 h the cells were stained with either IB4 or UEA1 lectin to detect Gal-α(1,3)-Gal and H substance respectively on the cell surface (Table 1 & FIG. 5 ). COS cells co-transfected with cDNAs for ht-GT+gt-HT ( FIG. 5 panel C) showed 30% cells staining positive with IB4 (Table 1) but no staining on cells co-transfected with cDNAs for GT+HT (3%) ( FIG. 5 panel A). Furthermore staining for H substance on the surface of ht-GT+gt-H co-transfectants gave very few cells staining positive (5%) ( FIG. 5 panel D) compared to the staining seen in cells co-transfected with cDNAs for the normal transferases GT+HT (50%) ( FIG. 5 panel B), ie. the expression of Gal-α(1,3)-Gal now dominates over that of H. Clearly, switching the cytoplasmic tails of GT and HT led to a complete reversal in the glycosylation pattern seen with the normal transferases i.e. the cytoplasmic tail sequences dictate the pattern of carbohydrate expression observed.
That exchanging the cytoplasmic tails of GT and HT reverses the dominance of the carbohydrate epitopes points to the glycosyltransferases being relocalized within the Golgi. To address this question, experiments were performed with cDNAs encoding glycosyltransferases with the same cytoplasmic tail: COS cells transfecterases with cDNAs encoding HT+ht-GT stained strongly with both UEAI (50%) and IB4 (30%) (Table 1 & FIG. 5 panels E, F) the difference in staining reflecting differences in transfection efficiency of the cDNAs. Similarly cells transfected with cDNAs encoding GT+gt-HT also stained positive with UEAI (50%) and IB4 (30%) (Table 1 & FIG. 5 panel G, H). Thus, glycosyltransferases with the same cytoplasmic tail leads to equal cell surface expression of the carbohydrate epitopes, with no “dominance” of one glycosyltransferase over the other observed, and presumably the glycosyltransferases localized at the same site appear to compete equally for the substrate.
In COS cells the levels of transcription of the cDNAs of chimeric and normal glycosyltransferases were essentially the same ( FIG. 3 ) and the immunofluorescence pattern of COS cells expressing the chimeric glycosyltransferases: ht-GT and gt-HT showed the typical staining pattern of the cell space Gal-α(1,3)-Gal and H substance respectively (Table 1 & FIG. 2 ), the pattern being indistinguishable from that of COS cells expressing normal GT and HT. Our studies showed that the Km of ht-GT for N-acetyl lactosamine was identical to the Km of GT for this substrate, similarly the Km of gt-HT for phenylBDgalactoside was approximately the same as the Km of HT for phenylbDgalactoside (FIG. 3 ). These findings indicate that the chimeric enzymes are functioning in a cytoplasmic tail-independent manner, such that the catalytic domains are entirely functional, and are in agreement with those of Henion et al (23), who showed that an NH 2 terminal truncated marmoset GT (including truncation of the cytoplasmic and transmembrane domains) maintained catalytic activity and confirmed that GT activity is indeed independent of the cytoplasmic domain sequence.
If the Golgi localization signal for GT and HT is contained entirely within the cytoplasmic domains of the enzymes, then switching the cytoplasmic tails between the two transferases should allow a reversal of the order of glycosylation. Co-transfection of COS cells with cDNA encoding the chimeric glycosyltransferases ht-GT and gt-HT caused a reversal of staining observed with the wild type glycosyltransferases (FIG. 5 ), demonstrating that the order of glycosylation has been altered by exchanging the cytoplasmic tails. Furthermore, co-transfection with CDNA encoding glycosyltransferases with the same cytoplasmic tails (i.e. HT+ht-GT and GT+gt-HT) gave rise to equal expression of both Gal-α(1,3)-Gal and H substance (FIG. 5 ). The results imply that the cytoplasmic tails of GT and HT are sufficient for the localization and retention of these two enzymes within the Golgi.
To date only twenty or so of at least one hundred predicted glycosyltransferases have been cloned and few of these have been studied with respect to their Golgi localization and retention signals (34). Studies using the elongation transferase N-acetylglucosaminyltransferase (33-37), the terminal transferases α(2,6)sialyltransferase (24-26) and β(1,4)galactosyltransferase (38-40) point to residues contained within the cytoplasmic tail, transmembrane and flanking stem regions as being critical for Golgi localization and retention. There are several examples of localization signals existing within cytoplasmic tail domains of proteins including the KDEL (SEQ ID NO: 15) and KKXX (SEQ ID NO: 16) motifs in proteins resident within the endoplasmic reticulum (41,42) the latter motif also having been identified in the cis Golgi resident protein ERGIC-53 (43) and a di-leucine containing peptide motif in the mamlose-6- phosphate receptor which directs the receptor from the trans-Golgi network to endosomes (44). These motifs are not present within the cytoplasmic tail sequences of HT or GT or in any other reported glycosyltransferase. To date a localization signal in Golgi resident glycosyltransferases has not been identified and while there is consensus that transmembrane domains are important in Golgi localization, it is apparent that this domain is not essential for the localization of all glycosyltransferases, as shown by the study of Munro (45) where replacement of the transmembrane domain of α(2,6)sialyltransferase in a hybrid protein with a poly-leucine tract resulted in normal Golgi retention. Dahdal and Colley (46) also showed that sequences in the transmembrane domain were not essential to Golgi retention. This study is the first to identify sequence requirements for the localization of α(1,2) fucosyltransferase and α(1,3) galactosyltransferase within the Golgi. It is anticipated that other glycosyltransferases will have similar localization mechanisms.
EXAMPLE 2
Use of Secretor in Construction of a Chimeric Enzyme
A construct is made using PCR and subcloning as described in Example 1, such that amino acids #1 to #6 of the pig α(1,3)-galactosyltransferase (MNVKGR) (SEQ ID NO: 14) replace amino acids #1 to #5 of the pig secretor (FIG. 6 ). Constructs are tested as described in Example 1.
EXAMPLE 3
Use of Pig H Transferase in Construction of a Chimeric Enzyme
A construct is made using PCR and subcloning as described in Example 1, such that amino acids #1 to #6 of the pig α(1,3)-galactosyltransferase (MNVKGR) (SEQ ID NO. 14) replace amino acids #1 to 8 of the pig H transferase (FIG. 7 ). Constructs are tested as described in Example 1.
EXAMPLE 4
Generation of Pig Endothelial Cells Expressing Chimeric α(1,2)Fucosyltransferase
The pig endothelial cell line PIEC expressing the chimeric α1,2fucosyltransferase was produced by lipofectamine transfection of pgtHT plasmid DNA (20 μg) and pSV2NEO (2 μg) and selecting for stable integration by growing the transfected PIEC in media containing G418 (500 μg/ml; Gibco-BRL, Gaithersburg, Md.). Fourteen independant clones were examined for cell surface expression of H substance by staining with UEA-1 lectin. >95% of cells of each of these clones were found to be positive. FIG. 8 shows a typical FACS profile obtained for these clones.
EXAMPLE 5
Production of Transgenic Mice Expressing Chimeric α(1,2)Fucosyltransferase
A NruI/NotI DNA fragment, encoding the full length chimeric α1,2fucosyltransferase, was generated utilizing the Polymerase Chain Reaction and the phHT plasmid using the primers:
5′ primer homologous to the 5′ UTR: 5′-T TCGCGA ATGAATGTCAAAGGAAGACTCTG, (SEQ ID NO. 9) in which the underlined sequence contains a unique NruI site; 3′ primer homologous to the 3′ UTR: 5′-G GCGGCCGC TCAGATGTTATTTCTAACCAAAT the underlined sequence contains a NotI site
The DNA was purified on gels, electroeluted and subcloned into a NruI/NotI cut genomic H-2Kb containing vector resulting in the plasmid clone (pH-2Kb-gtHT) encoding thee chimeric α(1,2)-fucosyltransferase gene directionally cloned into exon 1 of the murine H-2Kb gene, resulting in a transcript that commences at the H-2Kb transcriptional start site, continuing through the gtHT cDNA insert. The construct was engineered such that translation would begin at the initiation condon (ATG) of the hHT cDNA and terminate at the in-phase stop codon (TGA).
DNA was prepared for microinjection by digesting pH-2Kb-hHT with XhoI And purification of the H-2Kb-hRT DNA from vector by electrophoretic separation in agarose gels, followed by extraction with chloroform, and precipitation in ethanol to decontaminate the DNA. Injections were performed into the pronuclear membrane of (C57BL/6xSJL)F1 zygotes at concentrations between 2-5 ng/ml, and the zygotes transferred to pseudopregnant (C57BL/6xSJL)F1 females.
The presence of the transgene in the live offspring was detected by dot blotting. 5 mg of genomic DNA was transferred to nylon filters and hybridized with the insert from gtHT, using a final wash at 68° C. in 0.1xSSC/1% SDS. FIG. 9 thaws the results of testing 12 live offspring, with two mice having the transgenic construct integrated into the genome. Expression of transgenic protein is examined by estimating the amount of UEAI lectin (specific for H substance) or anti-H mAb required to haemagglutinate red blood cells from transgenic mice. Hemagglutination in this assay demonstrates transgene expression.
It will be apparent to the person skilled in the art that while the invention has been described in some detail for the purposes of clarity and understanding, various modifications and alterations to the embodiments and methods described herein may be made without departing from the scope of the inventive concept disclosed in this specification.
References cited herein are listed on the following pages, and are incorporated herein by this reference.
TABLE 1 EXPRESSION OF GAL-α(1,3)GAL AND H SUBSTANCE BY COS CELLS TRANSFECTED WITH cDNAs ENCODING NORMAL AND CHIMERIC GLYCOSYLTRANSFERASES COS cells transfected % IB4 positive % UEAI positive with cDNA encoding: cells cells GT 30 0 HT 0 50 ht − GT 30 0 gt − HT 3 50 GT + HT 3 50 ht − GT + gt − HT 33 5 GT + gt − HT 30 30 GT + ht − GT 30 0 HT + ht − GT 30 30 HT + gt − HT 0 50 Mock 0 0
Transfected COS cells were stained with FITC-labelled IB4 (lectin specific for Gal-α(1,3)Gal or UEAI (lectin specific for H substance) and positive staining cells were visualized and counted by fluorescence microscopy. Results are from at least three replicates.
References
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Chem. 268, 26310-26319 | The invention relates to nucleic acids which encode glycosyltransferase and are useful in producing cells and organs from one species which may be used for transplantation into a recipient of another species. It also relates to the production of nucleic acids which, when present in cells of a transplanted organ, result in reduced levels of antibody recognition of the transplanted organ. | 0 |
BACKGROUND OF THE INVENTION
This invention relates to a method of preparing feed grain compositions for livestock. More specifically, it relates to a process involving the fermentation of a mixture of animal wastes and grain.
Animal production based on confinement of animals in large groups means that animal wastes also are confined. This waste can be considered a raw material whose on-site concentration allows continuous collection and processing. For example, animal wastes contain sufficient nitrogen in the form of protein (ca. 20% of total N) and in forms readily convertible by microorganisms to protein (urea and ammonia nitrogen constitute ca. 30% of total N) to be potentially useful as a nutrient source for feeds.
Animal wastes have been collected and refed without further treatment to the same or different species, generally as a nitrogen source. These studies have been discussed by Anthony (J. Anim. Sci. 32: 4, 799-802, 1971) and extensively reviewed in detail by Smith ("Recycling Animal Wastes as a Protein Source," Symposium on Alternate Sources of Protein for Animal Production, Amer. Soc. Anim. Sci. and Committee on Animal Nutrition, Nat. Res., 1972; and "Nutritive Evaluations of Animal Manures," pages 55-74, In: G. E. Inglett, ed., Symposium: Processing Agricultural and Municipal Wastes, Avi Publishing Company, Westport, Connecticut).
In his report, Anthony stated that "it is detrimental to feed quality if manure is even partially decomposed by ubiquitous aerobic microorganisms."
In contrast to direct refeeding, feedlot manure has been ensiled (an anaerobic fermentation) with roughage (57 manure:43 hay, w/w; ca. 20% manure, dry basis) and termed Wastelage (Anthony, Proc., Conf. on Animal Waste Mangement, Cornell University, Ithaca, New York, pages 105-113, 1969; and Livestock Waste Management and Pollution Abatement, Proc. Int. Symposium on Livestock Wastes, Amer. Soc. Agri. Engineers, St. Joseph, Michigan, pages 293-296). The ensiled mixture fed at 40% of a corn ration afforded satisfactory gains, although feed:gain ratios are somewhat higher than with control rations. An anaerobic lactic fermentation of whole manure neutralized with anhydrous ammonia also has been reported (Moore and Anthony, J. Anim. Sci. 30: 2, 324, 1970), and acid treatment of the cellulosic fraction of manure to provide a substrate for yeast production has been proposed (Singh and Anthony, J. Anim. Sci. 27: 4, 1136, 1968).
We have found a method of preparing animal feed compositions comprising the steps
P1 a. mixing from 2 to 15 parts, dry weight basis (dwb) of animal feedlot waste (FDW) with 100 parts dwb of fragmented grain (FG) and an amount of water such that the resulting mixture contains from 35% to 45% moisture; and
b. aerobically fermenting the mixture resulting from step (a) while submitting the mixture to a tumbling action for a time sufficient to obtain a pH in the mixture of from 4 to 5.
A major advantage of the above method is the simplicity of operation. Each step can be accomplished on the feedlot site in easily obtainable and relatively inexpensive equipment. Daily production of waste can be used up quickly so that the problems of waste accumulation are eliminated. The product, when dried to ordinary corn storage conditions, can be stored in the same manner as corn.
Another major advantage is that the fermentation is aerobic and does not require the controls necessary to anaerobic fermentations. No pH control is necessary.
Microorganism growth is selective to lactobacilli while coliform and other organisms found in feedlot waste are eliminated. Within a short time after fermentation begins, fecal odor disappears and is replaced by a more pleasant silage-like odor. Possible health and pollution hazards inherent in the waste are reduced in the early stages of fermentation. Most of the nitrogen contained in the waste is conserved while the waste is converted to a feed having more more desirable amino acid compositions.
DETAILED DESCRIPTION OF THE INVENTION
The process is simple and is adaptable to both small and large animal units. It depends upon the fact that all livestock contain enteric bacteria including lactobacilli. Fresh wastes from the livestock inherently contain lactobacilli, usually about 1% of the total bacteria. All livestocks wastes are therefore useful as starting materials in the method of the invention. However, the discussion will be limited to feedlot wastes (FLW) which are easily collected. If economical methods of collecting other livestock wastes are discovered, they will also be suitable for use in the invention.
It is preferred that FLW used as starting materials be fresh. Weathered FLW do not yield optimum fermentations unless inocculated with lactobacilli.
The term FLW is defined herein to include the wastes from any feedlot animal such as hogs and cattle and FLW fractions such as feedlot waste liquids (FLWL) unless otherwise specified.
Hog FLW is relatively free from fibrous solids and is used directly without separation. Cattle FLW, which contains fibrous solids equaling up to 40% of total solids, also is utilized directly without separation, but it is preferable to remove the fibrous solids before mixing with the fragmented grain. Cattle FLW diluted with water to a solids content of from 3% to 20% is easily separated into a fibrous solid fraction and a liquid fraction (FLWL) containing from 2% to 15% solids.
Liquids obtained by hand squeezing the diluted waste through layers of cheesecloth or by gravity separation on a 30 -mesh screen contain from 20% to 40% of total raw waste solids. Approximately 90% of readily soluble and finely dispersed solids are partitioned into the liquid upon initial separation.
Any livestock feed grain is suitable for use in accordance with the invention including corn, wheat, and milo. Since microorganisms grow on the porous starch and not the hull of the feed grain, the grain kernels must be fractured or fragmented to expose the inner starchy parts to the fermentation media. Suitable means of accomplishing this include cracking, flaking, grinding, roller milling, and hammer milling. It is preferred that the particles resulting from the fragmentation be relatively coarse.
Grain and FLW are mixed together in quantities such that there are 2 to 15 parts dry weight basis (dwb) FLW solids per 100 parts dwb fragmented grain (FG,) and that the final moisture content of the FG-FLW mixture is from 35% to 45%. Since it is desirable to utilize as much FLW as possible, a mixture containing less than 2 parts FLW per 100 parts FG would be impractical. Mixtures with more than 15 parts FLW per 100 parts FG result in poor fermentations and retention of the fecal odor.
Moisture levels significantly less than 35% are insufficient to promote fermentation while those over 45% result in agglomeration of the grain particles and reduction of the tumbling action. There is no free liquid present in the mixtures at these moisture levels. The mixtures appear dry. The preferred moisture levels are from 38% to 42%.
Diluting raw cattle FLW to from 3% to 20% solids, separating the fibrous fraction by the methods described above, and mixing the FLWL with corn in suitable ratios of FLW solids:FG dwb resulted in a moisture level of about 40%. With raw wastes it is usually necessary to add water to achieve the proper moisture content.
Incubation is carried out in a container having a configuration and motion that provides a tumbling action to the FG-FLW particles. This was accomplished in containers of various shapes which were nearly horizontal and which were rotated at a speed that carried the particles up the side of the container until they fell back, tumbling over the particles below.
Flasks mounted perpendicularly to a nearly vertical rotating board, cylindrical containers rotating about nearly horizontal axes, and the like are suitable for incubation. The containers must be open to the air so that sufficient oxygen will be provided to support the aerobic fermentation which is enhanced by the tumbling action. Cement mixers are particularly suitable. No temperature control is necessary when the fermentation is conducted at the preferred ambient temperatures of from 18° to 38° C., thereby making the method ideal for on-site use.
Control of pH is also unnecessary.
The FG-FLW mixtures have initial pH's of from about 5.5 to 7.5. During fermentation pH of the mixture decreases to a minimum of from 4 to 5 at which time (usually 24 to 36 hours) growth of lactobacilli is essentially complete. Incubation is terminated when the pH of the mixture reaches 4 to 5, preferably 4 to 4.5. The product is fed directly to the feedlot animals, or it is dried, preferably at ambient temperatures, to a 12% or less moisture content for storage.
The following examples are intended to further illustrate the invention and are not to be construed as limiting the scope of the invention which is defined by the claims, infra.
All parts and percentages disclosed herein are by weight unless otherwise specified.
EXAMPLE 1
Fresh manure was collected by hand shovel from paved areas of a commercial beef cattle feedlot where the animals were fed a typical high-energy ration based on corn (Rhodes et al., Appl. Microbiol. 24: 3, 369-377, 1972). Collected waste (about 100 kg. per collection) was stored overnight at 4° C.
Raw waste (34.5% solids) was mixed with water to provide a mixture containing 22.1% solids which was stirred to a homogenous slurry. The FLW slurry was processed on a reciprocating screen as follows: A copper screen of 30 mesh (0.33 mm. wire, 0.59 mm. openings) was fastened over a rectangular wooden frame; an open three-sided wood frame was fastened on top of the screen frame to contain the slurry. The screen assembly was held tightly over a stainless steel tray which has separated openings at the lower end to discharge liquid and solids. The entire tray-screen assembly was held at 11° from horizontal and moves with a reciprocating motion through a 2-cm. displacement at ca. 300 strokes/minute when loaded. The screen was driven through a gear box and belt by a 1/4 h.p. electric motor. FLW ladled onto the high end of the screen traversed the length of the screen in about 1 minute under impetus of the screen motion. Liquid which separated from the waste through the screen drained from the receiving tray into a receiving vessel; fibrous solids migrated off the open lower end of the screen into a separate container. The FLW liquid (FLWL) containing 17.8% solids was stored at 4° C. in plastic containers until used. Fibrous solids were discarded.
Thirty-nine pounds of the FLWL was mixed with 50 pounds coarsely cracked corn having 10% moisture in a standard cement mixer having a 130-liter bowl (70 liter capacity). The mixer was belt driven through a reduction gear on a 1/4 h.p. electric motor so that the chamber rotated at 0.5 r.p.m. The interior of the mixer bowl (including mixing baffles) was sand blasted and painted with a two-component epoxy paint before use to eliminate rust formation from the acid fermentation. The bowl was held at 40° from horizontal. The mixer operated at ambient temperatures (18°-38° C.). The fermentation mixture was consistently 4° to 5° C. over ambient.
Fermentation was terminated after 36 hours, and the fermented product was dried in situ by blowing 60° C. air into the opening of the bowl while it continued to rotate. The fermented grain dried to a moisture content of 12% or less in 12-14 hours. Dried product dumped freely and was bagged and held for animal tests.
Analytical results were calculated to dry weight of fermented product. Moisture was determined by drying a weighed sample at 100° C. for 24 hours. Total nitrogen determined by micro-Kjeldahl was 2.68% for FLW and 1.33% for the corn (i.e., 17% and 8% crude protein, respectively). pH of fermented product was measured on a 5-g. sample triturated in distilled water for 10 minutes.
Microbial counts were done on material prepared by blending a 5-g. sample (wet weight) for 30 seconds in 20 ml. of cold 0.1 M phosphate buffer at pH 7 and then filtering and rinsing to volume through a loose fiberglass plug in a funnel. The turbid filtrate then was serially diluted in sterile distilled water. Counts were made by spread plating 0.3 ml. of appropriate dilutions in triplicate. Eugon agar was used for total counts and EMB for coliforms (both BBL, Bioquest Division of Becton, Dickinson Co.). Eugon plates were counted after 48-hour incubation at 28° C. and coliform counts were made after 24 hours at 37° C.
Ammonia determinations were performed on filtrates prepared with distilled water. Ammonia was measured with an ion-specific electrode (Orion Co., Cambridge, Massachusetts) on the supernatant of a blended sample centrifuged at 10,000 r.p.m. for 1 hour under refrigeration and reported as NH 3 -N, mg./g. dwb.
Results of the analysis of the above fermentation are tabulated in Table 1.
Table 1__________________________________________________________________________ Fermentation time, hoursAnalysis 0 12 24 36__________________________________________________________________________Moisture, % 42 42 41 41pH 6.31 4.63 4.37 4.21Ambient temperature, °C. 29 28 25.5 30Crude protein, % 10.3 10.2 10.2 10.1NH.sub.3 -N, mg./g., dwb 0.682 0.880 0.913 1.066Microbial pattern, counts/g., dwb Total 2.64 × 10.sup.9 2.30 × 10.sup.9 8.47 × 10.sup.8 1.39 × 10.sup.9 Coliform 1.70 × 10.sup.6 5.30 × 10.sup.6 3.10 × 10.sup.7 2.70 × 10.sup.7 Lactobacilli 1.47 × 10.sup.8 7.15 × 10.sup.9 3.97 × 10.sup.9 2.93 × 10.sup.9__________________________________________________________________________
EXAMPLE 2
Fresh cattle FLW having 42% solids was diluted with water to 24% solids and screened as described in Example 1. Thirteen pounds of FLWL (20% solids) and 13 pounds water were mixed with 50 pounds cracked corn (10% moisture, 8.0% crude protein) and fermented as described in Example 1.
Fermentation products were analyzed as described in Example 1 (Table 2).
EXAMPLE 3
Fresh cattle FLW having 34.5% solids was diluted with water to 22.1% solids and screened as described in Example 1. Thirty-six pounds of the FLWL (17.8% solids) were mixed with 50 pounds cracked corn (10% moisture) and fermented as described in Example 1. A fermentation typical of Example 1 resulted which had an initial pH of 6.1 and a final (30 hours) pH of 4.22.
EXAMPLE 4
Fresh cattle FLW having 26.0% solids was diluted with water to 18.6% solids and screened as described in Example 1. Seventeen and one-half pounds of the FLWL (16.5% solids) and 8 pounds water were mixed with 50 pounds cracked corn (10% moisture) and fermented as described in Example 1. A fermentation typical of Example 1 resulted which had an initial pH of 6.37 and a final (42 hours) pH of 4.28.
Table 2__________________________________________________________________________ Fermentation time, hoursAnalysis 0 6 12 24 36__________________________________________________________________________Moisture, % 38.7 38.7 39.0 39.3 37.0pH 5.39 5.20 4.67 4.01 4.01Crude protein, % 8.6 9.0 8.9 9.0 8.6NH.sub.3 -N, mg./g., dwb 0.168 0.159 0.164 0.189 0.208Microbial pattern, counts/g., dwb Total 2.78 × 10.sup.8 1.26 × 10.sup.8 1.97 × 10.sup.9 1.63 × 10.sup.9 8.65 × 10.sup.8Coliform 5.06 × 10.sup.6 6.53 × 10.sup.6 1.22 × 10.sup.6 1.24 × 10.sup.5 3.25 × 10.sup.5__________________________________________________________________________
EXAMPLE 5
Cracked corn (350 g., 10% moisture) and 175 g. fresh cattle FLWL prepared as described in Example 1 to contain 28% solids were mixed in 2-liter Erlenmeyer flasks. The flasks were held at 9° from horizontal on a board rotating at 0.6 r.p.m. Incubation was at 28° C. Two 5-g. samples were taken at 1, 6, 12, 24, 48, 72, and 144 hours. One sample was triturated in 10 ml. distilled water for 10 minutes and the pH measured before drying at 100° C. for 24 hours to give the dry weight. The second sample was blended with 20 ml. cold 0.1 M phosphate buffer (pH 7.0) for 30 seconds in a Waring Blendor, filtered through a loose glass-wool plug, and serially diluted (1:10) in 0.1% tryptone. Counts were made by spread plating 0.3 ml. of selected dilutions in triplicate.
The following media were used for counts: Eugon agar for total count, L and LBS agars for lactobacilli, Streptosel for total streptococci, KF Streptococcal with triphenyl tetrazolium chloride for fecal streptococci, Staphylococcus 110 for staphylococci, Eosin Methylene Blue (EMB) for coliforms, and Mycophil with added dihydrostreptomycin sulfate (0.2 mg./ml.), and penicillin G (330 units/ml.) for yeasts and molds. All media were BBL products (BBL, Division of Bioquest, Cockeysville, Maryland). EMB plates were incubated at 37° C. for 18 to 24 hours before counting; all other plates were counted after incubation at 28° C. for 2 days.
Apparent coliform colonies of the 24-hour sample were transferred from EMB plates to lactose broth and were examined microscopically. Colonies of lactobacilli from LBS and yeasts from Mycophil were transferred respectively to Micro Assay Culture Agar (BBL) and YM agar (Difco Laboratories, Detroit, Michigan). Isolates were incubated for 2 to 3 days at 28° C. before storing at 4° C. for subsequent examination. At each sample time, one to three plates of either the countable dilution or the next higher dilution were picked in entirety from LBS and from Mycophil (30 to 70 isolates per sample time).
A typical lactobacilli dominated fermentation resulted, Table 3.
EXAMPLE 6
Fresh cattle FLW was treated as described in Example 1 to produce a FLWL having 10% solids. The FLWL (225 g.) was mixed with 390 g. of cracked milo and fermented as described in Example 5. A typical fermentation resulted which had an initial pH of 5.35 and a final (72 hours) pH of 4.4
EXAMPLES 7-16
Fresh hog FLW collected from the Wayne Peugh farm, Dunlap, Illinois, was used in the fermentation without previous treatment. Suitable amounts of FLW, water, and cracked corn were mixed in a cement mixer and fermented as described in Example 1. Fermentation
Table 3__________________________________________________________________________ Fermentation time, hoursAnalysis 1 6 12 24 48 72 144__________________________________________________________________________pH 5.5 5.2 4.9 4.4 4.3 5.1 4.2Microbial pattern,counts/g., dwb Coliforms 7.2 × 10.sup.6 6.4 × 10.sup.6 5.9 × 10.sup.6 0 0 0 0 Lactobacilli 9.5 × 10.sup.6 2.6 × 10.sup.6 2.8 × 10.sup.8 2.6 × 10.sup.9 7.0 × 10.sup.8 2.1 × 10.sup.9 3.6 × 10.sup.9 Fecal streptococci 1.1 × 10.sup.5 1.8 × 10.sup.5 4.3 × 10.sup.5 2.7 × 10.sup.5 10.sup.3 10.sup.3 10.sup.2 Yeast 10.sup.4 10.sup.5 10.sup.6 2.1 × 10.sup.6 5.5 × 10.sup.6 9.5 × 10.sup.7 2.6 ×__________________________________________________________________________ 10.sup.7
conditions are listed in Table 4. Time of harvest was 36 hours, and the ambient temperature ranged from 18° to 38° C. Fermentation temperature was consistently from 3° to 5° C. higher than ambient. The initial fecal odor was always replaced by a silage-like odor soon after fermentation began.
Example 11 was sampled periodically during the fermentation, and the samples were analyzed for their microbial contents as described in Example 1. The microbial pattern is shown in Table 5.
EXAMPLE 17
Fresh hog FLW (200 g., 27% solids) was mixed with 125 ml. of water and 450 g. cracked corn (9.2% moisture) in a 2-liter flask and fermented and analyzed as described in Example 5. The unfermented corn contained 9.2% crude protein and the fermentation product contained 10.2% crude protein. Results of the analysis are shown in Table 6.
EXAMPLE 18
Products collected from several fermentations conducted as described in Example 5 were blended and offered to white Swiss mice in comparison to unfermented corn and a commercial pelleted diet. The fermented product and the unfermented corn were coarsely ground, cooked briefly in minimal amount of water to partially gelatinize the starch, and then formed into pellets. Each of the three diets was fed ad libitum for 21/2 months to six mice
Table 4__________________________________________________________________________Starting materialsFLW Corn Water pHExample Moisture, addedNo. Wt., lb. Solids, % Wt., lb. % Wt., lb. Initial At harvest__________________________________________________________________________7 10.0 29.1 50.0 12.9 24.0 6.4 4.58 15.0 29.9 50.0 12.9 15.0 5.8 4.69 20.0 29.9 50.0 12.9 13.5 5.3 4.610 19.5 24.5 50.0 8.8 15.1 6.0 4.711 25.0 21.8 50.0 13.1 7.1 7.2 5.112 25.5 19.0 50.0 9.0 8.5 6.2 --13 25.6 21.1 49.6 8.7 8.5 6.2 4.214 25.5 20.2 47.0 9.0 8.3 -- --15 28.0 22.2 50.0 13.1 4.9 -- 5.016 29.8 25.3 50.0 8.8 7.7 -- 4.6__________________________________________________________________________
Table 5__________________________________________________________________________Microbial patterncounts/g.,dwb Fermentation time, hours 0 6 12 24 30 36__________________________________________________________________________Total 3.2 × 10.sup.9 -- 1.1 × 10.sup.9 2.3 × 10.sup.9 -- 3.6 × 10.sup.9Coliform 0.9 × 10.sup.6 -- 1.9 × 10.sup.6 -- -- 1.4 × 10.sup.6Lactobacilli 1.6 × 10.sup.7 -- 2.9 × 10.sup.7 3.3 × 10.sup.9 -- 2.2 × 10.sup.9Yeasts 2.1 × 10.sup.5 -- 1.8 × 10.sup.3 1.5 × 10.sup.5 -- 3.9 × 10.sup.5__________________________________________________________________________
Table 6__________________________________________________________________________ Fermentation time, hoursAnalysis 0 12 24 36 48__________________________________________________________________________Moisture, % 38.9 38.0 40.2 39.6 40.2pH 5.95 4.88 4.61 4.50 4.50Crude protein, % 10.2 10.1 10.4 10.4 10.2NH.sub.3 -N, mg./g., dwb 0.144 0.177 0.160 0.169 0.202Microbial pattern, counts/g., dwb Total 1.4 × 10.sup.9 6.9 × 10.sup.8 1.2 × 10.sup.9 7.4 × 10.sup.8 3.2 × 10.sup.8 Coliform 7.0 × 10.sup.6 3.2 × 10.sup.5 5.0 × 10.sup.5 2.8 × 10.sup.6 3.9 × 10.sup.6 Lactobacilli 4.0 × 10.sup.7 6.0 × 10.sup.8 9.2 × 10.sup.8 6.5 × 10.sup.8 6.0 × 10.sup.8 Yeasts 2.8 × 10.sup.5 2.4 × 10.sup.5 4.7 × 10.sup.3 6.5 × 10.sup.3 4.0 × 10.sup.6__________________________________________________________________________
separated in cages of three segregated by sex. Mice were weighed every 3 or 4 days; weight data are shown in Table 7. The fermented product exhibited no overt toxicity to mice and consumption afforded equal growth rates compared to corn.
Table 7______________________________________ Days on diet, avg. weight in gramsDiet 1 10 21 42 74______________________________________Unfermentedcorn 14.7 15.6 17.6 20.0 23.3Fermentedcorn-FLWL 14.8 15.1 15.7 20.2 21.9Commercial feed 13.0 22.1 28.0 33.2 34.9______________________________________
EXAMPLE 18
Products (FG-FLW) from Examples 7 through 16 were combined and mixed in a twin shell blendor, mixed with hay, and fed to sheep in an acceptance-palatability test. Control sheep were fed a hay-cracked corn mixture. Acceptance and palatability were determined by measuring the total amount of feed unconsumed (weigh back) over a 10-day period (Table 8).
Table 8______________________________________ Hay, Cracked WeighControl g. corn, g. back, g.______________________________________2,841 3,000 8,800 1,4052,856 3,000 10,800 --2,868 3,000 10,400 3077,295 3,000 10,600 694Mean 3,000 10,150 602______________________________________ Hay, WeighExperimental g. FG-FLW, g. back, g.______________________________________2,848 3,000 10,800 52,854 3,000 10,800 --2,859 3,000 10,800 --7,294 3,000 10,800 61Mean 3,000 10,800 17______________________________________
EXAMPLE 19
The combined FG-FLW described in Example 18 was used to replace corn in a standard hen (control) diet (Table 9).
Table 9______________________________________Corn 63.15Alfalfa meal 5.00Soybean meal (44% C.P.) 19.00Meat and bone meal (49% C.P.) 2.00Solulac-500 (500 mcg.riboflavin/g.) 0.50Limestone 7.00Dicalcium phosphate 2.50Salt, plain 0.50DL-methionine (95% feedgrade) 0.10Vitamin-trace mineral premix(1552) 0.25______________________________________
Nineteen hens were fed the diet containing the FG-FLW mixture and 20 hens were fed the control diet. The feeding period was 21 days and feed consumption and egg production were measured during this time. The results are summarized in Table 10.
Table 10______________________________________ Feed consumed, Production, g./hen/day %______________________________________Control 116.4 31.2Experimental (Diet No. 2152 with 63.15% swine manure- corn replacing corn) 106.9 34.6______________________________________ | Feed grain compositions are prepared from grain and feedlot wastes by fermentation procedures which are carried out in simple equipment suitable for use on the feedlot site. The procedures are also suitable for industrial scale operations. Fecal odor of the waste is quickly eliminated and replaced by one that resembles the odor of silage. The fermented product has significantly more crude protein than corn, and it is palatable to livestock. | 0 |
BACKGROUND OF THE NEW VARIETY
The present invention refers to a new variety of peach tree which will hereinafter be denominated as the ‘2343 Jay Day peach tree which produces clingstone fruit which are mature for commercial harvesting and shipment approximately October 15-31 in a normal growing year in the San Joaquin Valley of Central California as a late fresh market peach with a good red blush coloration.
In the development of new commercial varieties of fruit specific characteristics places a premium on those varieties, which are early or late maturing, in the growing season. However, many such varieties have small size, lack of flavor, or coloration. In some instances there are other undesirable characteristics that decrease the commercial success. In order for a fruit to be a commercial success it must possess those characteristics of good size, good color, and good flavor. At the same time the date of maturity must be separate or different than other similar fruit. This new invention meets all of the aforementioned criteria and therefore is of commercial appeal to the consumer.
ORIGIN AND ASEXUAL REPRODUCTION OF THE NEW VARIETY
The present variety of peach tree was discovered by the inventor growing next to a swine pen adjacent to his orchard of ‘Calara’ peach trees (U.S. Plant Pat. No. 15,496) which is located near Sanger, Calif. The inventor discovered it as a seedling in 2012 and observed it for three years. The parentage is unknown. The new variety was asexually reproduced by the inventor in 2015 by bud grafting of trees onto ‘Nemaguard’ (unpatented) rootstock in the adjacent orchard of origin. The inventor has carefully examined the asexually reproduced trees which appear to be highly similar to the ‘Calara’, but which are not expected to first bear fruit until October 2016.
SUMMARY OF THE NEW VARIETY
The subject ‘2343 Jay Day’ tree is characterized by producing a large clingstone fruit which has good red blush coloration and is ripe for commercial harvesting and shipment approximately October 15-October 31 in the San Joaquin Valley of Central California. The new variety is similar to ‘Calara’ peach tree (U.S. Plant Pat. No. 15,496), but from which is distinguishable in that the fruit is similar and size and appearance but ripens many weeks later than the fruit of ‘Calara’ peach tree. The fruit of this new variety possesses a very good flavor as well as aroma which is greatly acceptable for a late ripening variety.
BRIEF DESCRIPTION OF THE DRAWING
The accompanying drawings are color photographs showing fruit and foliage of the new variety.
FIG. 1 shows branches, leaves and fruit of a tree of the new variety in situ.
FIG. 2 shows a close up of leaves and branches of the new variety.
FIG. 3 shows whole uncut fruit of the new variety.
FIG. 4 shows cut fruit of the new variety showing the pit, stone and flesh.
FIG. 5 shows branches of the new variety with flowers and buds.
DETAILED DESCRIPTION
Referring more specifically to the pomological description of this new and distinct variety of peach tree, the following has been observed under the ecological conditions prevailing in the location of origin which is near Sanger, Calif. in the San Joaquin Valley of Central California. All major color code designations are by reference to the Dictionary of Color by Maerz & Paul, First Edition 1930. Common color names are also occasionally employed.
TREE
Size: Tree is similar in size and growth habit to ‘Calara’ U.S. Plant Pat. No. 15,496. 10 ft×10 ft—medium size for peaches.
Vigor: Moderate at 4 th year of growth.
Figure (form): Upright and spreading with open vase system of training. Productivity is very good for tree in fourth year of growth. Regularity of bearing appears to be regular (i.e., every year, not in alternate years).
Trunk size: Medium (diameter 9″, 10″ above soil level)—moderately rough.
Color .—Olive drab, 15-J-1 to 15-J-12. Lenticels .—Oval form, medium. Length: from 2-10 mm. Color: tan, 11-G-4. Number: many.
Branches:
Size .—Medium. Surface texture .—Slightly rough. a. Mature — Slightly Rough. b. Immature — Smooth. Color code ( one year or older ).—Bronze-umber, 15-J-11. Color code ( immature ).—Light green, 18-G-6. Three to four scaffold with lateral branches, at this stage of growth, being develop fruit wood and allow maximum sunlight for fruit colors. Diameter of scaffold branches taken at about two feet above soil level is 3-4 inches in circumference.
LEAVES
Size: Medium to large.
Length: 57-174 mm.
Width: 30-45 mm.
Shape: Lanceolate, leaf tip acuminate.
Texture: Smooth.
Color code:
Upwardly disposed surface ( upper side ).—Light green, 25-A-10. Downwardly disposed surface ( underside ).—Pale green, 18-H-6.
Marginal form: Crenate, slightly undulate in larger leaves.
Leaf vein:
Color code .—Very pale green, 18-H-4. Thickness.— 0.5-1.5 mm.
Glandular characteristics: Reniform—alternate.
Color .—Cocoa turtle apache +, sahara −, 7-E-12. Size.— 2 mm. Number.— 2-4.
Petiole:
Size .—Medium. Length .—From 7-10 mm. Diameter .—From 1.5-2 mm. Color code .—Pale yellow-green, 18-L-4.
Leaf bud burst occurs during the third to fourth week in February in a normal year. The stipule length at approximately one week after bud burst averaged 0.9 cm in length (0.8-1 cm) on the most mature leaves.
FLOWERS
Flower buds: Hardy under typical central San Joaquin Valley climate condition.
Size .—Dormant buds of average size. Length .—From 8-16 mm. Form .—Ellipsoidal and slightly appressed to the bearing wood.
Bud scales:
Color .—Chianti Antique Ruby+ (6-L-6) and pubescent on surface.
Generally: Showy type.
Date of bloom: 100% bloom as of March 1, later than parent ‘Calara’.
Size: Generally medium to large.
Diameter: When fully expanded 25-30 mm (0.98 in-1.18 in).
Bloom quality: Abundant.
Fragrance: Slight—typical peach.
Petals:
Size .—Medium to large. Length: 15 mm (0.59 inch) to 18 mm (0.71 inch). Width: 10 mm (0.39 inch) to 13 mm (0.51 inch). Form .—Broadly ovate. Number .—Five. Color .—Pink (41-K-1) to very very light pink (41-B-1) at apex. Petal claws .—Broadly truncate. Width: 1 mm (0.039 inch). Length: 1.5 mm (0.059 inch). Petal margins .—Moderately undulated with somewhat rounded margins. Flower pedicel .—Very short 3-4 mm (0.12 inch-0.16 inch). Color: green (21-H-11). Surface: glabrous. Diameter: 1-2 mm (0.039 inch-0.079 inch).
Sepals:
Surface .—Pubescent. Size .—Medium to large. Form .—Broadly ovate. Color .—Maroon (55-H-7) to green (21-K-9) with same color maroon spots/flecks. Number .—Five.
Calyx:
Color .—Bronze (15-E-10) at base and maroon (55-H-7) near base of sepals.
Anthers:
Size .—Average. Color .—Azalea (4-J-3). Position of stigma .—Level in relation to the anthers.
Stamen: 8-15 mm (0.31 inch-0.59 inch).
Number.— 25-30. Position .—Level in relation to the petals.
Pollen is present: Color: narcissus (10-K-4).
Filament: Color: white (17-A-1) to light pink (51-F-1).
Pistil:
Length .—Average 20 mm (0.79 inch). Number .—One. Color .—Light green (17-J-7). Surface .—Pubescent. Pubescence present in ovaries .—Ovary densely covered with unbranched, multicellular trichomes, from 0.5 to 2 mm in length.
FRUIT
Date of maturity: October 15-31 in a normal year.
Size:
Diameter axial plane .—From 61-78 mm. Transverse in suture plane .—From 58-79 mm. Transverse at rt. angle to suture plane .—From 58-80 mm.
Form: Uniform.
Symmetrical or asymmetrical .—Shape of fruit is slightly asymmetrical.
Suture: Shallow but with distinct pumpkin orange (10-H-11) coloration from base to apex.
Ventral surface: Uneven.
Stem cavity:
Width .—From 6-8 mm. Depth .—From 12-19 mm. Length .—From 9-13 mm. Shape .—Oval.
Stem: Short.
Diameter .—From 2-3 mm.
Apex: Slightly Rounded.
Pistil point: Oblique.
Skin: Thickness normal for peach, light pubescence.
Sweetness: Medium/high.
Acidity: Medium.
Texture: Firm.
Tendency: None observed.
Color code:
Blush color .—Deep pinkish orange, 9-H-9 to 9-H-12. Ground color .—Varies over 50% at axis, from yellow to orange, 9-J-1 to 9-J-8. Flesh color .—Bright yellow, 9-L-1. Color at surface of pit cavity .—Sungod streaks, 2-H-12. Color of pit well .—Orange with reddish streaks, 2-A-11 to 3-L-11.
Juice production: Moderate.
Flavor: Very good to excellent.
Aroma: Good.
Fibers:
Number .—Few. Texture .—Firm.
Ripening: Even.
Eating quality: Very good to excellent.
Stone:
Attachment .—Clingstone. Fibers .—Numerous, Short, slightly thick. Size .—Medium. Length: from 33-38 mm. Width: from 22-25 mm. Diameter: from 16-18 mm.
Form: Ovate.
Apex: Sharply acute.
Color code, when dry: Light orange-tan to dark reddish brown, 3-B-11 and 8-C-6.
Base: Slightly rounded.
Sides: Unequal.
Texture: Pitted.
Ridges: On both sides of stone with ventral edge relatively narrow.
Tendency to split: None evident externally.
Use: Fresh Market; shipping variety for out-of-hand consumption by consumer from retail purchase.
Shipping and quality: Very Good.
Like most peach trees, the new variety has winter hardiness, and is not susceptible to damage during the dormant season. The fruit and foliage of the new variety do not evidence any particular susceptibility to heat.
The above description of this new variety of peach tree is based on the growing conditions prevailing near Sanger, Calif. in the Central San Joaquin Valley of California, variations of the usual magnitude and characteristics may occur due to change in cultural factors, including irrigation, fertilization, primary climatic changes, etc. | A new and distinct variety of peach tree which it is distinguished by producing late ripening fruit which are mature approximately October 15-31 in a normal year. | 0 |
BACKGROUND OF THE INVENTION
[0001] This invention relates to methods and apparatus for identifying and tracking units of raw materials based on unique natural characteristics.
[0002] As the complexity of raw material processing increases, and with the advancements in internal and external scanning methods, it becomes impractical, or expensive, to perform an exhaustive analysis of a piece at the point of processing. It is often far better to examine the unit earlier, where there is more time and space. To be useful, this information must be stored, and later correlate back to the specific unit. Currently, this requires a bar code, or other marking system, that places a physical mark, or tag, on the piece. This mark, or tag, may be difficult and expensive to apply, cosmetically undesirable, lost, become unreadable, interfere with the processing, or contaminate the by products and waste material.
[0003] In the example of processing of logs, the mass of information being evaluated in creating the most valuable solution for sawing the log can require more time than is practically acceptable in a production oriented setting. As a result the individual log/lumber may be pre-scanned or pre-evaluated with a system that is not in the critical time path. By scanning and evaluating the lumber or log prior to the processing procedure the predetermined solution can be ready for immediate implementation during the processing procedure. In order to accomplish this, the predetermined solution must be somehow linked to the corresponding log/lumber that was pre-evaluated.
[0004] The linking of a log/lumber with the appropriate predetermined solution has been accomplished in the past by means of queuing (e.g. once scanned, the logs are placed in order and supplied to be sawn in the known order, so the sawing solution is employed based on the position in line that the current log had) or by attaching an identification “tag” to the log/lumber. Since identification “tags” must be easily attached, be inexpensive, and be quickly read with great accuracy, bar coding has been the only practical method of identification.
SUMMARY OF THE INVENTION
[0005] In accordance with the invention, by measuring, classifying, and assigning the unit an identifier based on its naturally occurring physical anomalies, nature's bar code if you will, the piece may be later identified without the tribulations of a separate physical identifier.
[0006] Accordingly, it is an object of the present invention to provide an improved system for identifying and tracking units of raw materials based on natural characteristics of the material.
[0007] It is a further object of the present invention to provide an improved system to process logs and lumber.
[0008] It is yet another object of the present invention to provide an improved system and method for processing materials.
[0009] The subject matter of the present invention is particularly pointed out and distinctly claimed in the concluding portion of this specification. However, both the organization and method of operation, together with further advantages and objects thereof, may best be understood by reference to the following description taken in connection with accompanying drawings wherein like reference characters refer to like elements.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 is an end view of a grain pattern of a log indicating factors that can be considered to identify a log;
[0011] FIG. 2 is a flow chart of the steps of scanning a log;
[0012] FIG. 3 is a flow chart of the steps of later recognizing a previously scanned log;
[0013] FIG. 4 is a block diagram of an input processing side of a system according to the invention; and
[0014] FIG. 5 is a block diagram of a further processing side of a system according to the invention.
DETAILED DESCRIPTION
[0015] The system according to a preferred embodiment of the present invention comprises methods and apparatus to examine a log or other materials and use the material's naturally occurring features to uniquely identify the material for later recognition in another part of a process.
[0016] In a particular embodiment, end grain patterns of logs or lumber are used for identification.
[0017] A unit of raw, or in process, material is scanned using conventional electronic methods to identify unique, naturally occurring characteristics. These characteristics are classified and recorded, then become the unique identifiers or “finger print” for the material. Further conventional scanning and computation may occur to determine other aspect such as: size, weight, color, content, defects, shape, and the optimum method of processing. At some subsequent stage, the material is re-scanned to recognize the naturally occurring characteristics as before. This later scan is compared to the library of previously recorded “finger prints” to match the unit to previous stored data.
[0018] The result is that material can be scanned, and data stored, at an early stage where it is easier and more cost effective. The data is stored with the assigned “natural finger print” much like a conventional bar code but without the need to ever physically mark or tag the unit. The material may then be scanned later for its “natural finger print” and matched to the detailed information from earlier, more exhaustive scanning and computation.
[0019] A unit of raw, or in process, material may comprise biological materials such as whole tree stems, wood logs, wood pieces, other biological materials such as fruits or vegetables, or animals, or units of materials such as granite blocks, rocks, stones, and such.
[0020] The scanning may be accomplished using conventional methods to identify unique, naturally occurring characteristics. These methods may comprise examining on one, or more, surfaces or internally using conventional methods such as visual imaging, Infrared, Ultraviolet, X Ray, Ultrasonic, spectral, or other systems that may derive geometric, physical, chemical, or other unique external, or internal, characteristics.
[0021] The characteristics may comprise natural or created defects such as knots, grain, splits, colors, shape, density, wane, dimensions, and defects of wood units, fissures, aggregate content, color, internal structure, geometric shape, and defects of mineral units, color, weight, content, shape, internal characteristics of animals or parts of animals such as poultry, swine, cattle, and such, or fruits and vegetables to be processed, tracked, sorted, and so on.
[0022] These characteristics are classified, classification being based on a combination of characteristics such as color, contrast, density, composition, size, and shape, and their relative locations or patterns, and recorded through conventional electronic means such as a computer or control system, and then become the unique identifier or “finger print” for the material. Further conventional scanning and computation may occur to acquire other characteristics such as overall size and shape, or internal features to be used to determine the optimum utilization (other aspects may include weight, color, content, defects, shape, as well as the optimum method of processing. The material may then be sorted and routed or stored without the need to further mark the material. At some subsequent stage, the material is rescanned to recognize the naturally occurring characteristics as before and this is compared to the library of previously recorded “finger prints” to match the unit to previous computational data. The previous data is matched to the “finger print” to control further routing, or processing. For example, tree stems may be cut to length and sorted based on a decision made some time ago. Logs may be rotated, positioned, and sawn without rescanning. Wood pieces can be edged, trimmed, or sorted without requiring that they remain in strict sequence.
[0023] The butt ends of trees length stems, or pre cut logs, can be scanned in the woods, either by a person or harvester machine mounted system and stored with the tract information, truck and driver, size and weight, scale, grade, etc. When the stem arrives at the mill site, the butt ends are scanned and correlated back to the previous information. When the stem or log enters the mill for processing, the butt end is scanned again for inventory control and further information, such as the bucking cut pattern, may be added to the previous information. When the stem is cut into logs, the end of each log is scanned and each log gets an identifier. The log may also be scanned for optimized cutting patterns, grade, or desired orientation. Once the log reaches the carriage, or other primary breakdown machine, the end is scanned again the previous solution data is retrieved. The log may then be tracked, oriented, loaded, and processed based on some previous scanning and computation perhaps from the bucking scanning and optimization system. This log grade and yield can then be tracked back to the very stem and land tract to confirm timber cruising expectations.
[0024] The ends of the logs may be scanned to identify desired routes or sorted far down stream from the initial scanning system without the need to track each log.
[0025] The ends of the logs may be scanned to identify them after they have been placed in bulk storage or accumulated on transfers without the fear of getting out of sequence.
[0026] Stems may be scanned lineally far up stream for identification and optimization, accumulated on decks. Then, as the system approaches the cut up saw system, the butt end is rescanned and the solution it retrieved for processing. This eliminates the need to scan directly in front of the sawing system, or to keep strict separations of the stems after scanning to prevent getting stems out of sequence.
[0027] Ends of cants (two of four sided logs) can be scanned to recognize the grain and defect patterns, and correlated back to a previous optimized solution from the log processing machine, or even earlier at the log cut up system.
[0028] Ends of lumber are scanned for their “finger print” and matched up to previously determined edger, trimmer, or sort solutions.
[0029] A unique benefit of this system is that a company may invest in a single geometric or internal defect scanning system machine, with localized scanning and optimization and create a complete solution for the material. This more complex scanning and computational system can then process the data off line, maximizing the available processing time to achieve the absolute optimum solution. The system is insensitive to the orientation, and because the “finger print” is not dependent on any one given characteristic, it is able to ignore minor changes such as color fading.
[0030] FIG. 1 illustrates an example end of a log, for example, where ridge ending, spurs, bifurcation, dots, lakes, short ridges and crossovers may be employed as identifying factors.
[0031] FIG. 2 is a flow chart of steps in scanning a log, for example, wherein in step 100 , the log is scanned, and the data thereby generated is stored for future use (step 102 ). The scanned log may then be conveyed to storage, for example, to await further processing (step 104 ). Next, an optional step 106 , which may be employed in a particular embodiment, analyzes some or all of the data for determination of future processing of the log. This may comprise determination of optimal sawing configuration for maximum yield, whether in terms of maximum usable lumber or maximum profit, for example. The analysis step can be accomplished at any time after the log has been scanned, and may involve as noted herein, substantial computational analysis to determine optimal use or further processing of the log. The analysis data may then be suitably stored for retrieval later in connection with later processing of this log (step 108 ).
[0032] FIG. 3 is a flow chart of steps when retrieving a log, wherein in step 110 , the retrieved log is scanned for identifying characteristics, and the identifying characteristics are determined (step 112 ). The stored information about this particular log is then retrieved, since the log has been identified (step 114 ) and the log is then appropriately sent to further processing in accordance with interpretation of the analysis (step 116 ).
[0033] FIG. 4 is a block diagram of an input side of the system, wherein the incoming material, such as log 120 is passed through scanning position, wherein scanner 122 will scan the log under control of computer 124 , whereupon the log data is stored in a database 126 for future reference. The log is then suitably sent to storage 128 , to be held until some future time when the log is picked up for further processing.
[0034] Some of the scan data, for example, in the case of a log, the end grain pattern information portion of the scan, is employed to develop and identification key for the log which is then employed to link this log with its scan data in the future. The scan data in the database can include further information beyond the end grain patter, for example, and overall configuration scan to represent the shape of the log, or, other scanner information. The scan data may be provided to other computational equipment which can perform analysis of the scan data for future reference, such as optimal cutting information, defect detection, etc. This data can then be used in future processing of this log.
[0035] Referring to FIG. 5 , a block diagram of a later processing phase when the log is retrieved from storage, the log 120 ′ is conveyed from storage and again scanned by scanner 130 (typically at a different scanning location, although the same scanner as before can be employed if the system is so implemented) wherein scanner 130 suitably will be looking to scan only the identification portions of the log (e.g., the end grain patterns). Computer 124 ′ receives the scanner data, and, uses the scanned data to determine the identification of the log so as to retrieve the log's data from database 126 . This data will typically include information that computer 124 ′ uses to determine what further processing is to be made upon this particular log, and the computer will direct the conveying system to transfer to log to the appropriate further processing station or system. Further processing could include specific sawing operations (where the sawing instructions could be transmitted to the sawing system), defect removal station (wherein a portion of the log is removed or processed to eliminate defects), or other suitable processing.
[0036] Some applications of the system are:
[0037] Pre scanning for positioning a log on a sawmill primary breakdown system such as Double Length Infeed or a carriage, etc.
[0038] Lineal planer graders to keep boards in sequence.
[0039] Tracking boards for return to a sawmill resaw.
[0040] Fingerprint, face, palm print, etc. recognition technology may suitably be employed to analyze and match the material items.
[0041] The preferred embodiment is to employ the system and methods in log and lumber production. Since each log/lumber has a unique combination of growth rings and/or face grain, and these natural characteristics of wood are as unique as a human fingerprint. Accordingly a high resolution vision system and a high speed computer can identify each log or piece of lumber without the necessity of attaching a “tag” or keeping the log/lumber in queue.
[0042] Thus, in accordance with the invention, each log may be scanned and the appropriate solution for sawing stored together with identification data based on the vision system recognizing the “fingerprint” of the log, whether it be on the overall shape characteristics or the growth ring and/or face grain of the individual log.
[0043] Then, later, as a log arrives to a sawing station, another vision scan is made and the scan information is employed to recognize that log to enable retrieval of the sawing solution information particular to that individual log.
[0044] This system removes the need for queuing the logs or processing them or storing them in any particular order or location, and removes need for the attachment of labels or other physical id tags to the log.
[0045] While a preferred embodiment of the present invention has been shown and described, it will be apparent to those skilled in the art that many changes and modifications may be made without departing from the invention in its broader aspects. The appended claims are therefore intended to cover all such changes and modifications as fall within the true spirit and scope of the invention. | Systems and methods provide for identifying, tracking, and coordinating the processing of natural materials in a process. The unit material is scanned to determine natural physical characteristics. At least portions of these scanned characteristics are quantified and classified, then recorded as the unique identifier for the unit. The material may then be stored, shipped, or transferred to a further process, where the material is once again scanned for natural characteristics, compared to a library of previously recorded units and their characteristics, then processed, inventoried, tracked, or invoiced based on previous data associated with this specific unit, thereby eliminating the need for bar coding or other physical marking methods. | 1 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a folded disposable diaper, which can be packed in a package while being folded compactly. More specifically, the present invention relates to a folded disposable diaper, which can be packed in a small package and is therefore very convenient for shipment and handy for consumers.
2. Description of the Prior Art
A disposable diaper is composed of a back sheet and a top sheet, along with an absorption core interposed between the two sheets. The back sheet faces outwardly when the diaper is worn by a wearer and comprises a resin sheet which is liquid non-permeable and air permeable. The top sheet faces toward the wearer's skin and is in contact with the wearer's skin when the diaper is worn by the wearer and comprises a non-woven fabric or a porous resin sheet which is liquid permeable. The absorption core comprises a crushed pulp or a mixture of crushed pulp and super absorbent polymers as a raw material to absorb urine passing through the top sheet.
This absorption core is prepared by pressing the raw material to have a uniform thickness and thereafter cutting the raw material into a given shape such as sandglass-like form. The resulting absorption core is then interposed between the top sheet and the back sheet and sealed therebetween. The back sheet and the top sheet are of shapes almost similar to the shape of the absorption core, but with a larger outline than the outline of the absorption core. The two sheets are bonded together at a portion where the absorption core does not exist, for example, by means of a hot-melt adhesive coated on the back sheet and the top sheet.
This disposable diaper comprises a front waist region to be applied to the abdominal area of the wearer, a crotch region to be applied to the crotch thereof, and a back waist region to be applied to the dorsal area (back area) thereof. The back sheet and the top sheet protrude at both the right and left ends of each of the front waist region and the back waist region in the width direction of the diapers, where front flaps and back flaps are formed.
Retaining fasteners consisting of attaching members and retaining members are provided to the diaper. For example, the attaching members are fixed on the ends of the back flaps in the width direction, and retaining members are fixed on the surface of the back sheet in the front waist region.
When this diaper is worn, the back flaps are wound around the wearer from the dorsal area (back area) to the abdominal area along the body outline of the wearer, to be overlaid with the front waist region. Then, the attaching members and the retaining members are attached together.
After being manufactured at a plant, the diaper is folded and packed in a package for shipping as finished goods.
In such case, the diaper is folded in such a manner that both sides of the diaper in the width direction including the front and back flaps are folded inwardly, i.e. toward the top sheet, and then the front waist region and the back waist region are overlaid onto the crotch region.
However, both sides of the diaper to be folded inwardly generally include the absorption core therein. Hence, the absorption core is overlaid to have five layers in the resulting folded state. Thus, the thickness of the diaper in the resulting folded state is disadvantageously increased and the size of a package containing a plurality of the diapers in the resulting folded state is also increased.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a folded disposable diaper which is more compact in a folded state.
It is another object of the present invention to provide a folded disposable diaper which can be folded compactly while preventing deterioration of absorbency thereof.
The present invention provides a folded disposable diaper which is packed in a package after being folded inwardly about two first folding lines extending in a longitudinal direction of the diaper and then folded inwardly about two second folding lines extending in a transverse direction thereof perpendicular to the longitudinal direction. The diaper further includes a liquid permeable top sheet, a back sheet, and an absorption core interposed between the top sheet and back sheet. The absorption core has a front waist part, a crotch part and a back waist part which in use respectively face an abdominal area, a crotch and a dorsal area of a wearer. The absorption core has an unfolded shape wherein the front waist part and the back waist part are of larger transverse dimension than the crotch part as a result of having protrusions extending in the transverse direction on transverse sides of the front waist part and the back waist part. The two first folding lines are positioned adjacent to transverse side edges of the crotch part. The absorption core has four thin areas and one thick area, and the total thickness of the thin area, the top sheet and the back sheet is equal to or less than one half of the total thickness of the thick area, the top sheet and the back sheet. Each of the thin areas includes only one of the protrusions and is separate from the other areas. The thick area includes the crotch part and extends therefrom into the front waist part and into the back waist part over the entire longitudinal dimension of the absorption core. The thin areas and the thick area each can have such boundaries that when the protrusions are folded inwardly about the two first folding lines, each of the protrusions is received against the thin area corresponding thereto and within the boundary thereof. Also, the thick area is of larger transverse dimension in the crotch part than in the front waist part and the back waist part.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1(A) is a plane view of an unfolded state of the folded disposable diaper of the present invention, which is viewed from the side to be applied to a wearer;
FIG. 1(B) is a plane view showing a first folded state of the diaper of FIG. 1(A), which is folded inwardly along the lines L--L;
FIG. 1(C) is a perspective view showing a second folded state of the diaper, where the diaper at the first folded state shown in FIG. 1(B) is further folded inwardly along the lines M--M;
FIG. 2(A) is a cross sectional view of the diaper of FIG. 1(A) along the line IIA--IIA;
FIG. 2(B) is a cross sectional view of the diaper of FIG. 1(B) along the line IIB--IIB;
FIG. 2(C) is a cross sectional view of the diaper of FIG. 1(C) along the line IIC--IIC; and
FIG. 3 is a front view of the diaper at a state when the diaper is actually worn.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention will now be described with reference to the drawings.
A diaper 11 has a laminated structure where an absorption core 14 is interposed between a back sheet 12 and a top sheet 13. The back sheet 12 is faced outwardly when the diaper 11 is worn, and comprises a resin sheet, which is liquid non-permeable and air permeable, to prevent liquid, such as urine, from oozing out of the diaper 11. The top sheet 13 to be applied to the wearer's skin and in contact with the wearer's skin in use comprises a non-woven fabric or a porous resin sheet which is liquid permeable, so that excreted urine can permeate into the absorption core 14. Further, the absorption core 14 absorbs urine permeating through the top sheet 13, and comprises a highly absorbent crushed pulp, or a mixture of a crushed pulp and a super absorbent polymer.
As shown in FIG. 1(A), the diaper 11 is formed in a sandglass-like form. The narrow middle region of the sandglass-like form is a crotch region 19, while the wide top end regions and the wide bottom end regions thereof are a front waist region 18 and a back waist region 20, respectively.
The absorption core 14 in the sandglass-like form is arranged from the crotch region 19 to the front waist region 18 and to the back waist region 20. In the front waist region 18 and the back waist region 20, the absorption core 14 is prepared, in the regions surrounded with an alternate long and short dash line in both the left and right regions of the diaper, as thin thickness part 14b of a thickness thinner than the thickness of the absorption core in the remaining region. In the present example, the thickness of the absorption core 14 is uniform in the region excluding the thin thickness part 14b, and so as to discriminate the region from the thin thickness part 14b, the region is designated as a thick thickness part 14a. So as to enhance the absorbency in the crotch region 19, however, the absorption core 14 positioned in the crotch region 19 may satisfactorily be thicker than the thick thickness part in the central part of the front waist region 18 and the back waist region 20.
As shown in the cross sectional view of FIG. 2(A), the thickness of the diaper 11 at the thin areas 14b is equal to or less than one half of H1, which is the thickness of the diaper at the thick area 14a.
The back sheet 12 and the top sheet 13 are in a sandglass-like form, nearly similar to the form of the absorption core 14 but larger than the absorption core 14. The absorption core 14 is put in the center and interposed between the back sheet 12 and the top sheet 13. At parts where the absorption core 14 is not present between the back sheet 12 and the top sheet 13, namely at the margins in the width direction and the longitudinal direction, a hot-melt adhesive or the like is coated on the margins where the back sheet 12 and the top sheet 13 face to each other, to bond the back sheet 12 and the top sheet 13 together. In such manner, the absorption core 14 is sealed in between the back sheet 12 and the top sheet 13. The back sheet 12 and the top sheet 13 protrude in the front waist region 18 and the back waist region 20 of the diaper 11 in the width direction of the diaper 11, to form front flaps 18a and back flaps 20a.
At the end parts of the crotch region 19 in the width direction of the diaper 11 are arranged elastic members 17 elongating in the longitudinal direction of the diaper. At an elongated state between the back sheet 12 and the top sheet 13, the elastic members 17 comprising for example flat elastic braid are bonded to the back sheet 12 and the top sheet 13 by means of a hot-melt adhesive. The elastic members 17 form gatherings. When the diaper 11 is worn, the gatherings facing the thigh part of a wearer elastically press the thigh part.
Herein, the back waist region 20 of the diaper 11 is formed wider than the front waist region 18, and protrusions 20b are formed on both ends of the back waist region 20 in the width direction. Retaining fasteners 16 are fixed on the protrusions 20b, and the protrusions 20b are generally at a state folded inwardly onto the top sheet 13 of the diaper 11. When the diaper 11 is worn, the back waist region 20 is applied to the dorsal area of the wearer while the crotch region 19 is applied to the crotch thereof. Then, the diaper is folded at the crotch region 19 and the front waist region 18 is applied to the abdominal area of the wearer as shown in FIG. 3. Subsequently, the back flaps 20a are drawn forward along the body outline of the wearer toward the abdominal area. Thereafter, the retaining fasteners 16 of the protrusions 20b are fastened to another retaining fastener 15 fixed on the back sheet 12 in the front waist region 18.
Alternatively, instead of the retaining fastener 15, a film may be fixed on the surface of the back sheet 12 in the front waist region 18. Also, instead of the retaining fastener 16, an adhesive tape may be fixed on the surface of the top sheet 13 in the back waist region 20. In this case, the adhesive tape in the back waist region 20 adheres to the film in the front waist region 18 to attach the front waist region 18 and the back waist region 20 together.
After the production of the disposable diaper 11, the front flaps 18a on both the right and left sides in the front waist region 18 as well as the back flaps 20a on both the right and left sides in the back waist region 20 are folded along the lines L--L parallel to the longitudinal direction in the direction of arrow β. As a result, the diaper 11 is folded as shown in FIG. 1(B). Furthermore, the front waist region 18 and the back waist region 20 are folded along the lines M--M parallel to the width direction of the diaper in the direction of arrow γ to be overlaid on the crotch region 19 and the diaper is folded as shown in FIG. 1(C). The diaper folded at the state shown in FIG. 1(C) is packed in a package.
So as to make the thickness of the folded diaper 11 as thin as possible, the lines L--L should be present in a region where the absorption core 14 is not present in the crotch region 19. Furthermore, each of the lines L--L should be present outside of the center of the thin area 14b in the width direction. More specifically, when the thin area 14b is divided along the line L--L as shown in FIG. 1(A) and FIG. 2(A), the width dimension (I) of the thin area 14b is equal to or less than the width dimension (ii) of the thin area 14b. Accordingly, when the diaper 11 is folded along the lines L--L as shown in FIG. 2(B), each of the thin areas 14b is folded on itself.
Because the thickness of the diaper 11 at the thin area 14b is equal to or less than one half of the thickness H1 of the diaper 11 at the thick area 14a, the total thickness H2 of the diaper 11 where the thin area 14b is folded on itself is equal to or less than the thickness H1.
When the diaper 11 is further folded as shown in FIG. 1(C), the front waist region 18 and the back waist region 20, both folded along the lines M--M as shown in FIG. 1(B), are overlaid on the crotch region 19 as shown in the cross sectional view of FIG. 2(C). Because the total thickness H2 is equal to or less than the thickness H1 as described above, the total thickness H3 of the diaper 11 in a folded state as shown in FIG. 1(C) is the thickness of the sum of the crotch region 19, the front waist region 18 and the back waist region 20, namely 3 X H1, and the total thickness of the top sheets 13 and the back sheets 12 sandwiched therebetween.
In accordance with the present invention, therefore, the thickness of the folded diaper 11 can be suppressed to about 3-times the thickness of the diaper 11 in the unfolded state. The thickness of conventional diapers at their folded state is about 5-times the thickness of the conventional diapers in their unfolded state. When the thickness of the thick area 14a of the diaper 11 is the same thickness of a conventional diaper, the diaper of the present invention can be folded to about 3/5-times the thickness of a conventional diaper in its folded state. When the folded diaper of the present invention is packed in a package for shipment as a product, accordingly, the bulkiness of the product can be made less and the product can be made compact. Hence, a large number of such products can be shipped at one time, compared with conventional diapers, and the product is also handy for consumers.
Further, because the thickness of the absorption core in the crotch region is not reduced, the absorbency of the diaper is effectively maintained. Furthermore, the thickness of the absorption core in the crotch region can be more than the thickness of a conventional diaper and still the diaper of the present invention can be folded compactly compared with a conventional diaper.
The present invention has been described insofar in one example as the open-type disposable diaper. However, the present invention is not limited to the example. In accordance with the present invention, a brief-type diaper product can be made compact, by forming such thin thickness parts in the front waist region and the back waist region, whereby the thickness of the folded diaper can be made thin.
In accordance with the present invention, as has been described hereinabove, the thin thickness parts are formed in the front waist region and the back waist region of a disposable diaper to make the thickness of the folded diaper thin with no reduction of the thickness of the absorption core in the crotch region or with no loss of the absorption potency of the diaper. Thus, the diaper can be made thinner.
When the diaper of the present invention is folded and packed in a package for shipment as a product, the product can be made more compact. Compared with conventional diapers, a greater number of such products can be shipped at one time, which can contribute to the reduction of shipment cost. Because the product is not bulky, additionally, the product is handy for purchasers and consumers.
When the diaper is to be folded inwardly along a line parallel to the longitudinal direction of the diaper, furthermore, the line should be formed on each of the marginal sides in the width direction of the diaper, from the line parallel to the longitudinal line of the diaper, the parallel line dividing the thin thickness parts individually formed in the front waist region and the back waist region in halves on right and left sides, so that the area of the thin thickness parts in the inner region of the diaper, on which the end parts of the front waist region and the back waist region are overlaid, can be made larger than the area of the thin thickness parts in the front waist region and the back waist region to be folded inwardly. Hence, the thick parts of the diaper are never overlaid together to make the thickness of the folded diaper thinner. | A folded disposable diaper to be packed in a package while being folded inwardly about two first folding lines extending in a longitudinal direction of the diaper and then folded inwardly about two second folding lines extending in a transverse direction thereof perpendicular to the longitudinal direction. The diaper includes an absorption core having four thin areas and one thick area. The thickness of the diaper at the thin area is equal to or less than one half of the thickness of the diaper at the thick area. The first folding line is positioned outside of the center of the thin area in the transverse direction. Therefore, when the diaper is folded about the first folding lines, each of the thin areas is folded on itself to prevent an increase in the thickness of the folded diaper, while maintaining the absorbency of the absorption core. | 0 |
FIELD
[0001] The present invention relates generally to devices, systems and methods for making and using a multiple use temperature monitor adapter.
BACKGROUND
[0002] Temperature sensors are utilized in many different forms and in countless situations. While in some circumstances the results generated by the temperature sensor need not be highly accurate, in many applications a relatively high degree of precision is desirable or even essential. Furthermore, while in some applications the positioning of the temperature sensor is a simple matter, in situations involving limitations such as confined or obstructed spaces, positioning a temperature sensor in a desirable location may prove difficult. Thus, for certain situations, relatively accurate temperature sensors may be required that may be positioned with a relatively high degree of precision in order to provide acceptably accurate results without obstructing other activities surrounding the temperature sensor.
[0003] One such situation pertains to heart-lung machines. In medical situations where a patient's natural circulatory system is either inoperative or must be bypassed, a heart-lung machine, also referred to as a cardiopulmonary bypass circuit, may oxygenate and circulate the patient's blood in the place of the patient's heart and lungs. In addition to oxygenating the blood, such a machine may maintain circulation to help prevent the formation of blood clots and heat and/or cool the blood by use of a heat exchanger.
[0004] As such, it may be important to have an accurate measure of the temperature of the blood both entering and leaving the heat exchanger and/or circuit. At the same time, it may be important to carefully control the position of a temperature sensor probe within the blood flow, as the position of the probe in relation to the blood flow may create regions of reduced flow, which may lead to the formation of blood clots. Temperature sensor probes have been developed that have an adequately accurate temperature sensor for use in heart-lung machines.
[0005] But, as noted, temperature sensor probes may be needed both before and after the heat exchanger of the heart-lung machine. This dual location requirement may create issues with engaging the probe with the heart-lung machine. For instance, different manufacturers of components of the heart-lung machine may utilize different engagement mechanisms. Or, in certain circumstances, it may be required to have a relatively more secure fit between the temperature probe and the engagement mechanism, such as in circumstances where the blood is under relatively higher pressure. In addition, the optimal positioning of the temperature sensor may vary among different situations. Moreover, it may be desirable to physically separate a temperature probe from the patient's blood, as the probe may be relatively expensive and non-sterilizable. As such, multiple adapters have been developed for particular situations involving the use of a temperature probe with heart-lung machines. The different adapters allow for one temperature probe to be utilized with different components and different machines, while physically separating the temperature probe from the patient's blood and positioning the probe properly for accurate and safe temperature readings.
SUMMARY
[0006] The use of multiple adapters creates various issues with supply and availability. If a particular adapter is not available at a time in which it is needed, the heart-lung machine may not be useable at all, to the potentially fatal detriment of the patient. Furthermore, it may be more expensive to supply multiple different adapters compared against a single model adapter, as increased adapters may mean greater design efforts and a lack of efficiency of scale.
[0007] A multiple-use temperature monitoring adapter has been developed that may interface with multiple different ports or engagement mechanisms. The multiple-use adapter may be utilized in particular with heart-lung machines. By providing a single adapter for the temperature probe which may be used with many different engagement mechanisms on the heart-lung machine the availability of adapters may be enhanced while the cost may be reduced.
[0008] In an embodiment, the present invention provides a probe assembly for use with an elongated fluid conduit having a lateral fluid port, the fluid port having a longitudinal axis and a first end proximal the fluid conduit and a second end opposite the first end and having a tapered interior surface at a port taper angle, the port taper angle being acute with respect to the longitudinal axis of the lateral fluid port, the tapered interior surface forming a port lumen, the port lumen being narrower at the first end than at the second end. The assembly includes an adaptor slip having a longitudinal axis, a proximal end, a slip lumen and an exterior wall, at least a portion of the exterior wall nearest the proximal end of the adaptor slip being tapered at an adaptor taper angle, the adaptor taper angle is acute with respect to the longitudinal axis of the adaptor slip, the exterior wall is narrower at the proximal end of the adapter slip than away from the proximal end of the adaptor slip. The adaptor taper angle of the exterior wall of the adaptor slip is less than the port taper angle of the interior surface of the lateral fluid port. The adaptor slip is sized relative to the fluid port such that the exterior wall of the adaptor slip provides an interference fit with at least a portion of the interior surface of the fluid port at the proximal end of the adaptor slip when the proximal end of the adaptor slip is inserted into the fluid port. The adaptor slip has an external shoulder, the external shoulder abutting the second end of the fluid port when the proximal end of the adaptor slip is inserted into the fluid port, wherein, when the external shoulder abuts the second end of the fluid port. The adaptor slip has a sleeve having a closed proximal end, the closed proximal end of the sleeve having a known predetermined position with respect to the proximal end of the adapter slip. A probe is configured to be seated in the slip lumen with a proximate end of the probe being proximate to the closed proximal end of the sleeve.
[0009] In another embodiment, the present invention provides a probe assembly for use with an elongated fluid conduit having a lateral fluid port the fluid port having a longitudinal axis and a first end proximal the fluid conduit and a second end opposite the first end and having a tapered interior surface at a port taper angle, the port taper angle being acute with respect to the longitudinal axis of the lateral fluid port, the tapered interior surface forming a port lumen, the port lumen being narrower at the first end than at the second end. The assembly includes an adaptor slip having a longitudinal axis, a proximal end, a slip lumen and an exterior wall, at least a portion of the exterior wall nearest the proximal end of the adaptor slip is tapered at an adaptor taper angle, the adaptor taper angle is acute with respect to the longitudinal axis of the adaptor slip, the exterior wall is narrower at the proximal end of the adapter slip than away from the proximal end of the adaptor slip. The adaptor taper angle of the exterior wall of the adaptor slip is less than the port taper angle of the interior surface of the lateral fluid port. The adaptor slip is sized relative to the fluid port such that the exterior wall of the adaptor slip provides an interference fit with at least a portion of the interior surface of the fluid port at the proximal end of the adaptor slip when the proximal end of the adaptor slip is inserted into the fluid port. An external shoulder of the adapter slip abuts the second end of the fluid port when the proximal end of the adaptor slip is inserted into the fluid port, wherein, when the external shoulder abuts the second end of the fluid port, a location of the proximal end of the adaptor slip relative to the first end of the fluid port is determined by a length of the adaptor slip from the external shoulder to the proximal end of the adaptor slip. A probe is configured to be seated in the slip lumen and project a first predetermined distance beyond proximal end of the adaptor slip, the probe having a sensor positioned on a first end of the probe, wherein the sensor projects a second predetermined distance into the fluid conduit, the second predetermined distance is limited by the location of the proximal end of the adaptor slip and the first predetermined distance.
[0010] The present invention further provides an adapter slip having a longitudinal axis and a proximal end for seating in a lateral fluid port of an elongated fluid conduit, the fluid port having a longitudinal axis and a first end proximal the fluid conduit and a second end opposite the first end and having a tapered interior surface at a port taper angle, the port taper angle being acute with respect to the longitudinal axis of the lateral fluid port, the tapered interior surface forming a port lumen, the port lumen being narrower at the first end than at the second end. The adapter slip includes an interior wall that forms a slip lumen. At least a portion of an exterior wall nearest the proximal end of the adaptor slip is tapered at an adaptor taper angle, the adaptor taper angle being acute with respect to the longitudinal axis of the adaptor slip, the exterior wall being narrower at the proximal end of the adapter slip than away from the proximal end of the adaptor slip, the adaptor taper angle of the exterior wall of the adaptor slip being less than the port taper angle of the interior surface of the lateral fluid port. An external shoulder abuts the second end of the fluid port when the proximal end of the adaptor slip is inserted into the fluid port. A closed proximal end of an adapter sleeve is mated with the adapter slip and has a known predetermined position with respect to the proximal end of the adapter slip. The adaptor slip is sized relative to the fluid port such that the exterior wall of the adaptor slip provides an interference fit with at least a portion of the interior surface of the fluid port at the proximal end of the adaptor slip when the proximal end of the adaptor slip is inserted into the fluid port. In one embodiment, the sleeve is seated in said slip lumen. In another, the adaptor slip is molded around said sleeve. In one embodiment, the adapter slip further includes a collar coupled to the adaptor slip, the collar circumscribing the adaptor slip distal to said external shoulder, the collar being configured to engage an exterior surface of said lateral fluid port. In another embodiment, the adapter slip further includes a rib relative to said exterior wall of said adaptor slip, wherein said rib provides at least partial interference with at least a portion of said interior surface of said lateral fluid port when said proximal end of said adaptor slip is inserted into said fluid port; for example, the rib can form a seal with the interior surface of the lateral fluid port when the proximal end of the adaptor slip is inserted into the fluid port. In one example, the slip adapter, is affixed to the lateral fluid port using an adhesive, e.g., positioned distal of the rib, when the proximal end of the adaptor slip is inserted into the fluid port. In another embodiment of the adapter slip, the interference between the interior surface of the lateral fluid port and the external surface of the adaptor slip forms a seal when the proximal end of the adaptor slip is inserted into the fluid port. In one embodiment, the interference occurs only between a portion of the adaptor slip and lateral fluid port when the proximal end of the adaptor slip is inserted into the fluid port.
[0011] The present invention further provides an adapter slip having a longitudinal axis and a proximal end for seating in a lateral fluid port of an elongated fluid conduit, the fluid port having a longitudinal axis and a first end proximal the fluid conduit and a second end opposite the first end and having a tapered interior surface at a port taper angle, the port taper angle being acute with respect to the longitudinal axis of the lateral fluid port, the tapered interior surface forming a port lumen, the port lumen being narrower at the first end than at the second end. The adapter slip includes an interior wall that forms a slip lumen. At least a portion of an exterior wall nearest the proximal end of the adaptor slip is tapered at an adaptor taper angle, the adaptor taper angle being acute with respect to the longitudinal axis of the adaptor slip, the exterior wall being narrower at the proximal end of the adapter slip than away from the proximal end of the adaptor slip, the adaptor taper angle of the exterior wall of the adaptor slip being less than the port taper angle of the interior surface of the lateral fluid port. An external shoulder abuts the second end of the fluid port when the proximal end of the adaptor slip is inserted into the fluid port with a location of the proximal end of the adaptor slip relative to the first end of the fluid port being determined by a length of the adaptor slip from the external shoulder to the proximal end of the adaptor slip. The adaptor slip is sized relative to the fluid port such that the exterior wall of the adaptor slip provides an interference fit with at least a portion of the interior surface of the fluid port at the proximal end of the adaptor slip when the proximal end of the adaptor slip is inserted into the fluid port. In one embodiment, a collar is coupled to the adaptor slip, which circumscribes the adaptor slip distal to the external shoulder, the collar being configured to engage an exterior surface of the lateral fluid port. In another embodiment, a rib relative to the exterior wall of the adaptor slip provides at least partial interference with at least a portion of the interior surface of the lateral fluid port when the proximal end of the adaptor slip is inserted into the fluid port. For example, in one embodiment, the rib forms a seal with the interior surface of the lateral fluid port when the proximal end of the adaptor slip is inserted into the fluid port. The slip adapter, in one embodiment, is affixed to the lateral fluid port using an adhesive when the proximal end of the adaptor slip is inserted into the fluid port. In another embodiment, the adhesive is positioned distal of the rib. In addition, in another embodiment, the interference between the interior surface of the lateral fluid port and the external surface of the adaptor slip forms a seal when the proximal end of the adaptor slip is inserted into the fluid port. In another embodiment, the interference occurs only between a portion of the adaptor slip and lateral fluid port when the proximal end of the adaptor slip is inserted into the fluid port.
[0012] The present invention further provides an adapter slip having a longitudinal axis and a proximal end for seating in a lateral fluid port of an elongated fluid conduit, the fluid port having a longitudinal axis and a first end proximal the fluid conduit and a second end opposite the first end and having a tapered interior surface at a port taper angle, the port taper angle being acute with respect to the longitudinal axis of the lateral fluid port, the tapered interior surface forming a port lumen, the port lumen being narrower at the first end than at the second end. An interior wall forms a slip lumen. At least a portion of the exterior wall nearest the proximal end of the adaptor slip is tapered at an adaptor taper angle, the adaptor taper angle being acute with respect to the longitudinal axis of the adaptor slip, the exterior wall being narrower at the proximal end of the adapter slip than away from the proximal end of the adaptor slip, the adaptor taper angle of the exterior wall of the adaptor slip being less than the port taper angle of the interior surface of the lateral fluid port. An abuts the second end of the fluid port when the proximal end of the adaptor slip is inserted into the fluid port, wherein with the closed proximal end of a sleeve having a known predetermined position with respect to the proximal end of the adapter slip. The adaptor slip is sized relative to the fluid port such that the exterior wall of the adaptor slip provides an interference fit with at least a portion of the interior surface of the fluid port at the proximal end of the adaptor slip when the proximal end of the adaptor slip is inserted into the fluid port. A rib relative to the exterior wall of the adaptor slip provides at least partial interference with at least a portion of the interior surface of the lateral fluid port when the proximal end of the adaptor slip is inserted into the fluid port. A collar is coupled to the adaptor slip, which circumscribes the adaptor slip distal to the external shoulder, configured to engage an exterior surface of a first particular one of the lateral fluid port. The slip adapter is adapted to be affixed to a second particular one of the lateral fluid port using an adhesive when the proximal end of the adaptor slip is inserted into the fluid port. The interference between the interior surface of the lateral fluid port and the external surface of the adaptor slip is adapted to form a seal when the proximal end of the adaptor slip is inserted into a third particular one of the fluid port. For example, in one embodiment the sleeve is seated in the slip lumen. In another embodiment, the adaptor slip is molded around the sleeve. In another embodiment, the rib of the adapter slip forms a seal with the interior surface of the lateral fluid port when the proximal end of the adaptor slip is inserted into the fluid port. For example, adhesive is positioned distal of the rib. In another embodiment, the interference occurs only between a portion of the adaptor slip and lateral fluid port when the proximal end of the adaptor slip is inserted into the fluid port.
[0013] The present invention further provides an adapter slip having a longitudinal axis and a proximal end for seating in a lateral fluid port of an elongated fluid conduit, the fluid port having a longitudinal axis and a first end proximal the fluid conduit and a second end opposite the first end and having a tapered interior surface at a port taper angle, the port taper angle being acute with respect to the longitudinal axis of the lateral fluid port, the tapered interior surface forming a port lumen, the port lumen being narrower at the first end than at the second end. The adapter slip has a slip lumen and an exterior wall with at least a portion of the exterior wall nearest the proximal end of the adaptor slip being tapered at an adaptor taper angle, the adaptor taper angle being acute with respect to the longitudinal axis of the adaptor slip, the exterior wall being narrower at the proximal end of the adapter slip than away from the proximal end of the adaptor slip, the adaptor taper angle of the exterior wall of the adaptor slip being less than the port taper angle of the interior surface of the lateral fluid port. An external shoulder abuts the second end of the fluid port when the proximal end of the adaptor slip is inserted into the fluid port, wherein with a location of the proximal end of the adaptor slip relative to the first end of the fluid port being determined by a length of the adaptor slip from the external shoulder to the proximal end of the adaptor slip. The adaptor slip is sized relative to the fluid port such that the exterior wall of the adaptor slip provides an interference fit with at least a portion of the interior surface of the fluid port at the proximal end of the adaptor slip when the proximal end of the adaptor slip is inserted into the fluid port. A rib relative to the exterior wall of the adaptor slip provides at least partial interference with at least a portion of the interior surface of the lateral fluid port when the proximal end of the adaptor slip is inserted into the fluid port. A collar coupled to the adaptor slip, which circumscribes the adaptor slip distal to the external shoulder, the collar being configured to engage an exterior surface of a first particular one of the lateral fluid port. The slip adapter is adapted to be affixed to a second particular one of the lateral fluid port using an adhesive when the proximal end of the adaptor slip is inserted into the fluid port. The interference between the interior surface of the lateral fluid port and the external surface of the adaptor slip is adapted to form a seal when the proximal end of the adaptor slip is inserted into a third particular one of the fluid port.
[0014] In an embodiment, the rib forms a seal with the interior surface of the lateral fluid port when the proximal end of the adaptor slip is inserted into the fluid port.
[0015] In an embodiment, the adhesive is positioned distal of the rib.
[0016] In an embodiment, the interference occurs only between a portion of the adaptor slip and lateral fluid port when the proximal end of the adaptor slip is inserted into the fluid port.
DRAWINGS
[0017] FIG. 1 is an illustration of a patient being aided by a heart-lung machine;
[0018] FIG. 2 is an illustration of a temperature probe intended for use with the heart-lung-machine of FIG. 1 ;
[0019] FIG. 3 illustrates a multiple-use adapter slip intended for use with the heart-lung machine of FIG. 1 ;
[0020] FIG. 4 is a cut-away drawing of the adapter slip of FIG. 3 ;
[0021] FIG. 5 a and FIG. 5 b are illustrations of the adapter slip of FIG. 3 with a collar attached;
[0022] FIG. 6 a is a cutaway illustration of the adaptor slip of FIG. 3 with a temperature probe and collar positioned in an inlet port;
[0023] FIG. 6 b is an illustration of the adaptor slip of FIG. 3 with a temperature probe without a collar;
[0024] FIG. 7 is an exaggerated illustration of the adaptor slip of FIG. 3 with the inlet port of FIG. 6 ; and
[0025] FIG. 8 is a flowchart of a method for the making of an adaptor slip.
DESCRIPTION
[0026] It is often advantageous to know and regulate the temperature of the blood that is being oxygenated and circulated by a heart-lung machine. In many heart-lung machines multiple ports are provided into which temperature probes may be inserted to monitor the temperature of the blood. However, the ports on any given heart-lung machine, or among different heart-lung machines, may not be common, i.e., such ports may have differing configurations. In addition, it may be desirable to physically insulate, i.e., separate, the probe from the patient's blood should the probe be non-sterilizeable or, perhaps, be too expensive to be reasonably disposable.
[0027] In order to allow a single temperature probe to be used with different ports or engagement mechanisms on a single heart-lung machine or between and among different heart-lung machines, a multiple-use temperature monitor adapter has been developed. In an embodiment, the adapter may be configured to allow the temperature probe to generate accurate measurements in two or more different temperature ports in heart-lung machines. The adapter may also physically separate the temperature probe from the blood of the patient to allow the temperature probe to be reused in a different adapter without having to sterilize the probe.
[0028] FIG. 1 depicts a patient 5 being aided by heart-lung machine. Briefly, the machine generally draws blood of a patient 5 during a cardiovascular procedure through a venous line 11 , oxygenates the blood, and returns the oxygenated blood to the patient 5 through an arterial line 15 . Venous blood drawn from the patient through line 11 is discharged into a venous reservoir 2 . Cardiotomy blood and surgical field debris are aspirated by a suction device 16 and pumped by pump 18 into a cardiotomy reservoir 3 . Once defoamed and defiltered, the cardiotomy blood is also discharged into venous reservoir 2 . Alternatively, the function of the cardiotomy reservoir 3 may be integrated into the venous reservoir 2 . In the venous reservoir 2 , air entrapped in the venous blood rises to the surface of the blood and is vented to the atmosphere through a purge line 4 . Blood from patient 5 is directed to flow through inlet fluid port 20 and into venous reservoir 2 , then to heat exchanger 15 that maintains the temperature of the blood, then to oxygenator 16 that oxygenates the blood, and then through outlet fluid port 22 . Oxygenated and temperature-controlled blood is collected after moving out of the oxygenator 16 and preferably flows to an arterial filter 30 and then into the arterial line 15 . The arterial filter 30 preferably traps air bubbles in the blood that are larger than about 20-40 micrometers where the bubbles can be removed through a purge line 32 . In order to help control the temperature of the blood, inlet fluid port 20 and outlet fluid port 22 allow for the introduction of temperature probe 24 into the blood flow. In an embodiment, inlet fluid port 20 is a female luer lock consistent with the ISO 594/1-1986 standard. In another embodiment, outlet fluid port 22 is configured to engage temperature probe 24 or an adapter for temperature probe 24 with an adhesive seal. In an alternative embodiment, outlet fluid port 22 is configured with a screw-fit engagement mechanism. Other affixation methods for outlet fluid port 22 are contemplated. The circuit shown in FIG. 1 is exemplary, and it should be understood that the temperature probe 24 may be incorporated into any suitable position along the cardiopulmonary bypass circuit or other suitable extracorporeal system. For example, temperature probe 24 may be used to monitor the temperature at the inlet to the venous reservoir and/or outlet of the oxygenator, as shown, or with alternative components in the circuit, or any combination thereof.
[0029] FIG. 2 depicts temperature probe 24 that may be used in conjunction with a fluid port, such as inlet fluid port 20 and/or outlet fluid port 22 of the heart-lung machine shown in FIG. 1 . Temperature sensor 26 is positioned at the end of extender 28 to allow temperature sensor 26 to be positioned into relatively narrow conduits and ports. Locking mechanism 30 allows temperature probe 24 to be securely engaged with an adapter or port. Wire 32 is coupled to sensor 26 and transmits data from sensor 26 to a destination for ultimate use. In some embodiments, temperature probe 24 can be sterilized.
[0030] FIG. 3 shows a multiple-use adapter slip 40 configured to receive temperature probe 24 and itself be seated in inlet fluid port 20 and/or outlet fluid port 22 . Proximal end 42 of adapter slip 40 has exterior wall 44 , a portion of which is tapered portion 46 . Tapered portion 46 is tapered at an acute angle with respect to longitudinal axis 47 of adapter slip 40 in a manner which may be consistent with a female member of a luer lock. Shoulder 48 may provide an engagement stop with a distal end of inlet fluid port 20 and outlet fluid port 22 , controlling, at least in part, the depth of penetration of adapter slip within inlet fluid port 20 and outlet fluid port 22 , as well as within venous line 11 and arterial line 15 . Ring stop 49 may provide engagement with collar 60 (illustrated in FIGS. 5 a and 5 b ). Sleeve 50 may be seated within adapter slip 40 . Locking port 51 may be configured to engage with locking mechanism 30 of temperature probe 24 . When locking mechanism 30 is engaged with locking port 51 , temperature probe 24 and adapter slip 40 may be adequately securely coupled for medical applications.
[0031] In an embodiment, proximal end 42 is made from a thermoplastic, such as acrylonitrile butadiene styrene. In alternative embodiments, materials that are relatively rigid and non-porous are utilized. In further embodiments, the material of proximal end 42 is utilized everywhere on adapter slip 40 except for sleeve 50 . In various embodiments, proximal end 42 may be formed so that no seam exists in proximal end 42 . In alternative embodiments, a seam may be present, in some such embodiments the seam may be reduced in size by an abrasive or similar treatment.
[0032] In an embodiment, sleeve 50 is metallic, for example, brass plated with nickle. In an alternative embodiment, sleeve 50 is made from brass plated with nickel plated with gold. In such an embodiment, the brass is 260 brass, the nickel is electroless nickel per the AMS-2404AS standard and is 0.00005 to 0.0001 inches thick, and the gold is plated over the nickel per the SAE AMS 2422D and SATM B488 01, Type II, Grade C standard, and is 0.00001 to 0.00002 inches thick
[0033] FIG. 4 shows a cut-away drawing of adapter slip 40 . The interior of adapter slip 40 is hollow slip lumen 52 in which sleeve 50 is seated. As illustrated, sleeve 50 has sleeve lumen 54 which is configured with a sufficiently wide diameter to allow sensor 26 and extender 28 of temperature probe 24 to be seated in sleeve lumen 54 . In alternative embodiments, sleeve 50 does not extend back to shoulder 48 . In such embodiments, sleeve lumen 54 may be relatively shorter than illustrated, or not exist at all. In such an embodiment, temperature probe 24 may be seated in slip lumen 52 and contact sleeve 50 with sensor 26 and no other portion of temperature probe 24 .
[0034] In the illustrated embodiment, sleeve 50 is seated in lumen 52 , with base 56 of sleeve 50 proximate the material making up shoulder 48 . In the illustrated embodiment, a thermoplastic portion of adapter slip 40 is injection molded around sleeve 50 . The material of the adapter slip 40 may shrink as it cools, which may secure sleeve 50 in the plastic and provide a watertight seal. The watertight seal may prevent blood and other biological material from coming into contact with temperature probe 24 .
[0035] FIGS. 5 a and 5 b illustrate adapter slip 40 with collar 60 attached. As shown in the cutaway of FIG. 5 b , collar 60 may engage with adaptor slip 40 by snap-fit engagement distal of shoulder 48 and proximate ring stop 49 . Alternative engagement methods are also envisioned, including adhesive engagement and screw-fit engagement. Helical grooves 62 of collar provide a screw-fit receptor for inlet port 20 or outlet port 22 , which may be configured with a male screw-fit port. By screwing adapter slip 40 with collar 60 attached into engagement with inlet port 20 or outlet port 22 , a fluid-tight lock may be attained that may be relatively more secure against dislodgement from pressure internal to portions of a heart lung machine than a luer lock. As such, it may be advantageous to utilize collar 60 when internal pressure is relatively high and a luer lock when internal pressure is relatively low.
[0036] FIG. 6 is a cutaway illustration of adaptor slip 40 with temperature probe 24 and collar 60 positioned in inlet port 20 . As illustrated, inlet port 20 is not configured with screw-fit grooves to mate with grooves 62 of collar 60 . However, in alternative embodiments, such grooves may be available.
[0037] As illustrated, shoulder 48 engages with end 70 of inlet port 20 and may combine with the luer fit of adaptor slip 40 with inlet port 20 to establish the distance into venous line 11 which sleeve 50 extends. To create the luer fit between adaptor slip 40 and inlet port 20 , in an embodiment, the taper angle 90 ( FIG. 7 ) of tapered portion 46 of adapter slip 40 may be consistent with the ISO 594/1-1986 standard. In various embodiments the taper angle may exceed the specification for a luer taper consistent with the ISO 594/1-1986 standard. Collar 48 and the luer fit created by taper portion 46 and interior surface 72 of inlet port 20 may, alone or in combination, establish the distance sleeve 50 extends into venous line 11 .
[0038] As illustrated, an adhesive may be applied such that the adhesive forms a bond between proximal end 42 of adaptor slip 40 and inlet port 20 between shoulder 48 and tapered portion 46 . In alternative embodiments, adhesive may be in tapered portion 46 as well, in both tapered portion 46 and the space between tapered portion 46 and shoulder 48 , and in alternative portions of exterior wall 44 . The adhesive may provide affixing qualities, securing adaptor slip 40 to inlet port 20 more firmly than may be possible with a luer lock by itself. The adhesive may also provide fluid isolation, preventing, at least in part, fluid from seeping around adaptor slip 40 . Such fluid isolation provided by adhesive may be unnecessary in many embodiments, with the luer lock between adaptor slip 40 and inlet port 20 providing adequate fluid isolation.
[0039] Adaptor slip 40 may further incorporate circumferential rib 80 on or proximate tapered portion 46 . Rib 80 may prevent or reduce the amount of applied adhesive penetrating into inlet port 20 when the adhesive is applied between rib 80 and shoulder 48 . In addition, rib 80 may increase the security of the luer lock and the fluid isolation without incorporating adhesive, thereby potentially obviating a need for adhesive.
[0040] FIG. 7 shows an exemplary relationship between tapered portion 46 of adapter slip 40 and interior surface 72 of inlet port 20 , the relationships and angles exaggerated for illustrative purposes. Tapered portion 46 forms taper angle 90 with respect to longitudinal axis 47 . Interior surface 72 forms port taper angle 92 with respect to longitudinal axis 47 . As noted in the discussion of FIG. 6 , taper angle 90 may be consistent with, or exceed, the specification of the ISO 594/1-1986 standard. In an embodiment, port taper angle 92 may be consistent with the ISO 594/1-1986 standard. In alternative embodiments, taper angle 90 and port taper angle 92 may be varied as appropriate to alter a sealing qualify of the luer lock created between tapered portion 46 and interior surface 72 , to modify engagement of shoulder 48 with end 70 , or for other purposes as conditions may warrant.
[0041] FIG. 8 is a flowchart for the making of adaptor slip 40 . Sleeve 50 is formed ( 800 ). In an embodiment, the formation of sleeve 50 includes forming ( 802 ) a brass core, then plating ( 804 ) the brass core with nickel and plating ( 806 ) the nickel with gold. Proximal end 42 may be formed ( 808 ) around sleeve 50 such that no seam is present in proximal end, and plastic portions of adaptor slip may be formed ( 810 ) distal of proximal end 42 and around sleeve 50 . As proximal end 42 and the rest of adaptor slip 40 cool ( 812 ) the material may shrink, creating ( 814 ) a seal between the metal of sleeve 50 and the plastic portions.
[0042] In an embodiment, a seamless proximal end 42 may be formed by creating a generally cylindrical mold for proximal end 42 , and by creating half-cylinder molds for portions distal of proximal end 42 . When joined to create adapter slip 40 , the cylindrical mold of proximal end 42 may prevent any seams in proximal end 42 , with the seams occurring in the junction between proximal end 42 and the rest of adapter slip 40 , along with seams running longitudinally up opposite sides of the rest of adapter slip 40 . In alternative embodiments, molds incorporating only one or two pieces may be utilized.
[0043] Thus, embodiments of the devices, system and methods of a multiple use temperature monitor adapter are disclosed. One skilled in the art will appreciate that the present invention can be practiced with embodiments other than those disclosed. The disclosed embodiments are presented for purposes of illustration and not limitation, and the present invention is limited only by the claims that follow. | Device for adapting a temperature probe for a use in a port in a heart-lung machine. An adaptor slip is tapered at an adaptor taper angle less than a port taper angle. The adaptor slip is sized such that the exterior wall of the adaptor slip provides an interference fit with at least a portion of the fluid port. The adaptor slip has an external shoulder abutting the end of the fluid port. The adaptor slip additionally has a sleeve having a closed end having a position with respect to the end of the adapter slip. A probe is configured to be seated in a lumen of the adaptor slip with a proximate end of the probe being proximate to the closed end of said sleeve. | 0 |
CROSS REFERENCE TO RELATED APPLICATIONS
This application relates to the subject matter disclosed in the following United States patent and copending U.S. applications:
U.S. Pat. No. 4,926,197 to Childers, entitled "Plastic Substrate for Thermal Ink Jet Printer;"
U.S. application Ser. No. 07/864,889 filed herewith, entitled "Laser Ablated Nozzle Member For Inkjet Printhead;"
U.S. application Ser. No. 07/862,669 filed herewith, entitled "Nozzle Member Including Ink Flow Channels;"
U.S. application Ser. No. 07/864,822 filed herewith, entitled "Improved Inkjet Printhead;"
U.S. application Ser. No. 07/862,086 filed herewith, entitled "Improved Ink Delivery System for an Inkjet Printhead;"
U.S. application Ser. No. 07/864,930 filed herewith, entitled "Structure and Method for Aligning a Substrate With Respect to Orifices in an Inkjet Printhead;"
U.S. application Ser. No. 07/864,896 filed herewith, entitled "Adhesive Seal for an Inkjet Printhead;"
U.S. application Ser. No. 07/862,668 filed herewith, entitled "Integrated Nozzle Member and TAB Circuit for Inkjet Printhead;"
U.S. application Ser. No. 07/864,890 filed herewith, entitled "Wide Inkjet Printhead."
The above patent and copending applications are signed to the present assignee and are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention generally relates to inkjet printers and, more particularly, to nozzle or orifice members and other components for the print cartridges used in inkjet printers.
BACKGROUND OF THE INVENTION
Thermal inkjet print cartridges operate by rapidly heating a small volume of ink, causing the ink to vaporize and be ejected through an orifice to strike a recording medium, such as a sheet of paper. When a number of orifices are arranged in a pattern, the properly sequenced ejection of ink from each orifice causes characters or other images to be printed upon the paper as the printhead is moved relative to the paper. The paper is typically shifted each time the printhead has moved across the paper. The thermal inkjet printer is fast and quiet, as only the ink strikes the paper. These printers produce high quality printing and can be made both compact and portable.
In one design, the printhead includes: 1) an ink reservoir and ink channels to supply the ink to the point of vaporization proximate to an orifice; 2) a nozzle member in which the individual orifices are formed in the required pattern; and 3) a series of thin film heaters, one below each orifice, formed on a substrate which forms one wall of the ink channels. Each heater includes a thin film resistor and appropriate current leads. To print a single dot of ink, an electrical current from an external power supply is passed through a selected heater. The heater is ohmically heated, in turn superheating a thin layer of the adjacent ink, resulting in explosive vaporization and, consequently, causing a droplet of ink to be ejected through an associated orifice onto the paper.
One prior print cartridge is disclosed in U.S. Pat. No. 4,500,895 to Buck et al., entitled "Disposable Inkjet Head," issued Feb. 19, 1985 and assigned to the present assignee.
In these printers, print quality depends upon the physical characteristics of the orifices in a printhead incorporated on a print cartridge. For example, the geometry of the orifices in a printhead affects the size, trajectory, and speed of ink drop ejection. In addition, the geometry of the orifices in a printhead can affect the flow of ink supplied to vaporization chambers and, in some instances, can affect the manner in which ink is ejected from adjacent orifices. Nozzle members for inkjet printheads often are formed of nickel and are fabricated by lithographic electroforming processes. One example of a suitable lithographic electroforming process is described in U.S. Pat. No. 4,773,971, entitled "Thin Film Mandrel" and issued to Lam et al. on Sep. 27, 1988. In such processes, the orifices in an nozzle member are formed by overplating nickel around dielectric discs.
Such electroforming processes for forming nozzle members for inkjet printheads have several shortcomings. One shortcoming is that the processes require delicate balancing of parameters such as stress and plating thicknesses, disc diameters, and overplating ratios. Another shortcoming is that such electroforming processes inherently limit design choices for nozzle shapes and sizes.
When using electroformed nozzle members and other components in printheads for inkjet printers, corrosion by the ink can be a problem. Generally speaking, corrosion resistance of such nozzle members depends upon two parameters: inkjet chemistry and the formation of a hydrated oxide layer on the electroplated nickel surface of an nozzle member. Without a hydrated oxide layer, nickel may corrode in the presence of inks, particularly water-based inks such as are commonly used in inkjet printers. Although corrosion of nozzle members can be minimized by coating the plates with gold, such plating is costly.
Yet another shortcoming of electroformed nozzle members for inkjet printheads is that the completed printheads have a tendency to delaminate during use. Usually, delamination begins with the formation of small gaps between an nozzle member and its substrate, often caused by differences in thermal expansion coefficients of an nozzle member and its substrate. Delamination can be exacerbated by ink interaction with printhead materials. For instance, the materials in an inkjet printhead may swell after prolonged exposure to water-based inks, thereby changing the shape of the printhead internal structure.
Even partial delamination of an nozzle member can result in distorted printing. For example, partial delamination of an nozzle member usually causes decreased or highly irregular ink drop ejection velocities. Also, partial delamination can create accumulation sites for air bubbles that interfere with ink drop ejection.
Further, in prior art printheads for inkjet printers, it has been shown to be difficult to connect electrodes on the substrate which contains the thin film heaters to conductors on the printhead which are, in turn, connected to an external power supply for energizing the thin film heaters.
Thus, what is needed is a printhead having an improved nozzle member which does not suffer from the drawbacks of electroformed nozzle members and having an improved conductor configuration for connecting electrodes on the substrate to the conductors on the printhead for connection to an external power supply.
SUMMARY OF THE INVENTION
A novel, nozzle member for an inkjet print cartridge and method of forming the nozzle member are disclosed. In this method, the nozzles or orifices are formed in a flexible polymer tape by Excimer laser ablation. In one embodiment, a substrate containing heating elements is mounted on the back of the nozzle member. External conductors are located inside the flexible polymer tape and run between each of the nozzles. The conductors end at a via overlying an associated electrode on the substrate. The via electrically connects the conductors to the associated electrode.
In other aspects of the invention, vaporization chambers as well as ink channels, enabling ink to flow proximate to the orifices, are also formed by Excimer laser ablation.
The polymer material preferably is plastic such as teflon, polyamide, polymethylmethacrylate, polyethyleneterephthalate or mixtures and combinations thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention can be further understood by reference to the following description and attached drawings which illustrate the preferred embodiments.
Other features and advantages will be apparent from the following detailed description of the preferred embodiments, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the principles the invention.
FIG. 1 is a perspective view of an inkjet print cartridge according to the present invention.
FIG. 2 is a perspective view of the front surface of the nozzle member and electrical contact points on the printhead shown in FIG. 1.
FIG. 3 is a perspective view of the back of the tape of FIG. 2, revealing vaporization chambers, ink channels, and conductive vias for connection to electrodes on a silicon die which is to be mounted on the top surface of the tape of FIG. 3.
FIG. 4 is an enlarged perspective view, in cross-section and partially cut away, of the vaporization chambers, ink channels, and conductive vias shown in FIG. 3, taken along the line A--A in FIG. 3.
FIG. 5 is a view of the front of the nozzle member of FIG. 2, partially cut away, revealing the front surface of the nozzle member, a middle portion of the nozzle member, and a silicon die mounted on a back surface of the nozzle member.
FIG. 6 is an enlarged view, partially cut away, of the circled portion B--B in FIG. 5.
FIG. 7 is a cross-section taken along line C--C in FIG. 5 showing the connection of the conductors within the nozzle member to the electrodes on the silicon die.
FIG. 8 is a perspective view of a cross-section, partially cut away, taken along line D--D in FIG. 5 illustrating the conductors formed therein running between the vaporization chambers.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring to FIG. 1, reference numeral 10 generally indicates an inkjet print cartridge according to one embodiment of the present invention. The inkjet print cartridge 10 includes an ink reservoir 12 and a printhead 14. The printhead 14 has a nozzle member 16 having two parallel columns of holes or orifices 17 formed in a flexible polymer tape 18 by laser ablation. The tape 18 may be purchased commercially as Kapton™, Upilex™, or their equivalent, available from 3M Corporation.
FIG. 2 shows a front surface, in perspective, of the nozzle member 16 of FIG. 1 removed from the print cartridge 10. Behind the nozzle member 16 is a silicon substrate containing a plurality of individually energizable thin film resistors. Each resistor is associated with a single orifice 17 in the nozzle member 16 and acts as an ohmic heater when selectively energized by a pulse applied to one of the associated contact pads 20. The contact pads 20 connect to conductive traces formed internal to the tape 18, as will be described in detail later.
FIG. 3 is a perspective view of the back of the tape 18 of FIG. 2 prior to a silicon die being mounted thereon. Shown in FIG. 3 are ink channels 22, which are in fluid communication with an ink supply, wherein ink is fed around the edges of the silicon die to the ink channels 22 after the silicon die is mounted on the surface of the tape of FIG. 3. Each ink channel 22 is also in fluid communication with an associated vaporization chamber 24. When the silicon die is mounted to the tape 18 in FIG. 3, each of the heating elements on the silicon die aligns with an associated vaporization chamber 24 and, when the associated heating element is energized, the ink within the vaporization chamber 24 is vaporized and expelled as a droplet of ink through an associated orifice approximately centrally formed through vaporization chamber 24.
Also shown in FIG. 3 are openings 26 which expose conductive traces running internal to the tape 18. The internal conductors may be formed in a variety of ways, including forming conductive traces on the back of a nozzle member and then encapsulating the conductive traces using a lamination process. The traces may be formed using a conventional photolithographic process. The trace portions revealed through the openings 26 connect to the contact pads 20 shown on the front surface of the tape 18 in FIG. 2. The exposed traces through openings 26 are connected to electrodes on the silicon die when the silicon die is mounted on the surface of the tape 18 of FIG. 3. The openings 26 may be formed by laser ablation.
shown in FIG. 4 is an enlarged view of a portion of the surface of the tape 18 of FIG. 3, taken along line A-A in FIG. 3, showing in more detail the vaporization chambers 24, ink channels 22, orifices 17, and a portion of a conductive trace 28 leading to the trace portions 27 exposed through the opening 26. The dashed lines 29 illustrate the trace 28 running inside the tape 18.
FIG. 5 is a view of the front surface of the tape 18 of FIG. 2 cut away to reveal a middle portion of the tape 18 and the substrate 32 containing thin film resistors 34, which are energized by applying a voltage, such as ground potential, to a common electrode 36 and applying a pulse to any of the electrodes 38 to energize an associated resistor 34.
Overlying each of the resistors 34 is a vaporization chamber 24, shown in detail in FIG. 4, and an orifice 17, wherein energization of a resistor 34 causes ink in the vaporization chamber 24 to be expelled through the associated orifice 17. Ink is fed from the back of the silicon die 32 so as to enter the ink channels 22 from around the edges of the silicon die 32 so as to provide ink to the various vaporization chambers 24.
The conductive traces 28 are shown within the tape 18 running between each of the orifices 17 to overlie an associated thin film resistor electrode 38. The other ends of the conductive traces 28 are terminated by the contact pads 20.
FIG. 6 is an enlarged view of the tape 18 of FIG. 5 within the circle B--B of FIG. 5. Shown in detail in FIG. 6 are the common electrode 36, thin film resistors 34, electrodes 38 uniquely associated with each of the thin film resistors 34, ink channels 22, vaporization chambers 24, conductive traces 28, and orifice 17. Also shown is the ink feed source 40 which enables ink to flow around the edges 41 of the substrate 36 and to each of the ink channels 22.
In FIG. 6, the end portion of the conductor 28, shown as end portion 28a, is connected to an associated underlying electrode 38a by a via extending through the tape 18.
FIG. 7 shows this connection made through the via, wherein the end of the conductor 28, shown as 28a, is connected to an electrode 42 on the silicon substrate 32 using a conductively filled polymer 44 (or any suitable material) to short the end 28a to the electrode 42 through the via. other bonding means, such as ultrasonic welding, may also be used with suitable conducting bumps, or reflow soldering may be used without bumps.
FIG. 8 shows a cross-section of the tape 18, partially cut away, taken along the line D--D in FIG. 5, generally in line with a row of orifices 17 overlying each of the vaporization chambers 24 in FIG. 5. The numerals in FIG. 8 indicate the same elements as previously described.
FIG. 8 illustrates how the conductors 28 run between the vaporization chambers 24 and orifices 17. The conductors 28 may be formed on the bottom surface of the nozzle member 16 using a photolithographic process prior to the orifices 17 being formed. A liquid layer of, for example, phenolic butyryl modified epoxy may then be flowed over the conductors to encapsulate the conductors 28 in a flexible layer 46. Such a material may be obtained from Rogers Corporation in Chandler, Ariz. The resulting nozzle member 16 and laminated layer 46 are then laser ablated in a step-and-repeat process using an Excimer laser to form the orifices 17, vaporization chambers 24, and any other patterns. Such a laser ablation process is described in copending application Ser. No. 07/864,822, entitled "Improved Inkjet Printhead," assigned to the present assignees.
Also illustrated in FIG. 8 is the path 48 liquid ink takes from an ink source below the substrate 32 to enter the vaporization chambers 24.
As indicated in FIG. 8, the angled electrodes 38 leading from the thin film resistors 34 directly underlie an associated conductor 28 at a point obscured by the nozzle member 16 and layer 46. At the point where the conductor 28 and electrode 38 overlap, a via is formed as shown in FIG. 7 to connect the conductor 28 to the electrode 38.
The above-described concept of enclosing conductors in the nozzle member itself and connecting the conductors to electrodes on a substrate using a via may be applied to a variety of types of printhead structures. For example, instead of an edge ink-feed type printhead design, the concepts described herein can be applied to a center feed type printhead where ink is supplied to the orifices through a hole in the substrate. Further, the conductors do not have to run between the orifices to make contact with substrate electrodes, but may run in any pattern in order to overlie substrate electrodes so that an electrical connection may be made between the conductors and the electrodes with a suitable via. Further, the electrodes on the substrate do not have to connect to resistors on the substrate, but may connect to inputs of a demultiplexer or other decoder on the substrate which, in turn, provides the pulses to the resistors.
The foregoing has described the principles, preferred embodiments, and modes of operation of the present invention. However the invention should not be construed as being limited to the particular embodiments discussed. As an example, the above-described inventions can be used in conjunction with printers that are not of the thermal type, as well as printers that are of the thermal type, such as inkjet and thermal transfer printers. Thus, the above-described embodiments should be regarded as illustrative rather than restrictive, and it should be appreciated that variations may be made in those embodiments by workers skilled in the art without departing from the scope of the present invention as it is defined by the following claims. | A novel, nozzle member for an inkjet print cartridge and method of forming the nozzle member are disclosed. In this method, the nozzles or orifices are formed in a flexible polymer tape by Excimer laser ablation. In one embodiment, a substrate containing heating elements is mounted on the back of the nozzle member. Conductors for providing electrical signals to the substrate are located inside the flexible polymer tape and end at a via overlying an associated electrode on the substrate. The via electrically connects the conductors to the associated electrode. | 1 |
[0001] This U.S. Non-Provisional Patent Application claims the benefit of priority from U.S. Provisional Application No. 62/326,517, filed Apr. 22, 2016, the entire disclosure of which is hereby incorporated by reference.
FIELD
[0002] The present disclosure generally relates to implantable and retrievable medical devices. More specifically, embodiments of the present disclosure relate to devices that may be implanted in and extracted from a patient, and wherein the device is adapted to be accepted by a patient, promote vascularization and deliver donor cells to the patient.
BACKGROUND
[0003] Implantation of donor cells or other foreign bodies into an affected patient have successfully accomplished treatment of various conditions and diseases. For example, pancreatic islet beta-cells are known to sense blood sugar levels and secrete insulin to maintain homeostasis. In patients with diabetes, however, islet beta-cells are either lacking or ineffective. Diabetes is a disease of the pancreatic islet cells wherein those affected lack adequate levels of insulin and have difficulty controlling their blood sugar. One alternative to self-administration of medicine and insulin is islet transplantation. The procedure involves an infusion of isolated donor islets into the patient. If the donor cells are accepted, these islets will function to regulate blood glucose levels through the production of insulin. Islet transplantation is therefore a treatment strategy that allows diabetics to reduce or eliminate the need for insulin injections to control their disease.
[0004] U.S. Pat. No. 5,984,890 to Gast et al., which is hereby incorporated by reference in its entirety, discloses a medical device for the implantation of solids within an animal. Gast et al. do not provide or describe a specific implant, but disclose various methods and devices for implanting devices as well as various needs and applications for doing so.
[0005] U.S. Pat. No. 5,391,164 to Giampapa, which is hereby incorporated by reference in its entirety, discloses an implantable multiple-agent biologic delivery system including a pod for subcutaneous implantation. Various features of Giampapa are contemplated for use in embodiments of the present disclosure. Giampapa fails to disclose, however, devices, methods and systems as described herein.
[0006] U.S. Pat. No. 5,484,403 to Yoakum et al., which is hereby incorporated by reference in its entirety, provides a hypodermic syringe for implanting solid objects. The devices and methods provided by Yoakum et al. are contemplated for use with embodiments of the present disclosure. Specifically, Yoakum et al. provides a device for injecting implantable solid objects which may be used to insert one or more implants of the present disclosure within an animal.
SUMMARY
[0007] A long-felt and unmet need exists for a device and method that enables transplantation and subsequent retrieval or extraction of human islets and associated donor cells. Implantation and transplantation devices and methods of the present disclosure are not limited to those adapted for treating diabetes or any other specific condition. In various embodiments, devices and methods are described that are suitable for treatment of diabetes by islet transplantation. It will be expressly recognized, however, that the present disclosure is not limited to such methods, devices, or intended uses. Indeed, various applications and treatments are contemplated.
[0008] Although various embodiments contemplate the provision of donor islet cells and other cells within an implant and wherein the cells are ultimately provided to a patient, the present disclosure is not limited to implants comprising cells. It is contemplated that the devices and implants of the present disclosure may comprise various agents and materials including, but not limited to, cells, drugs, and various compounds that may be desirable to inject, insert or otherwise administer to a patient.
[0009] In various embodiments, an implant is provided, the implant generally comprising an islet transplantation device. The implant generally comprises a device for insertion within a patient, the device comprising a retrievable device adapted for treatment strategies including, but not limited to, islet transplantation.
[0010] In various embodiments, an implant comprising a hollow-core is provided. The implant comprises a shell enclosed in a soft alginate outer layer to provide immunoprotection and limit fibrosis. An outer coating of alginate and a vascularization inducer is provided to promote the growth of new blood vessels to the implant. In preferred embodiments, the implant comprises an islet transplantation device of generally cylindrical or pill-shaped construction that is approximately 2 mm in diameter and/or width and approximately 12 mm long. The implant is preferably rotationally symmetrical about a longitudinal axis, but may comprise other shapes. In alternative embodiments, the implant comprises a diameter or width of between approximately 0.50 mm and approximately 10 mm, and a length of between approximately 3 mm and approximately 50 mm. As one of skill in the art will recognize, the device is preferably sized so as to be accepted within an animal and such that it may be implanted and extracted using known technologies and devices. However, as the present disclosure provides devices, methods and systems that are not limited to specific animals (e.g. humans) or specific treatments, the device may comprise various dimensions.
[0011] Preferably, implants of the present disclosure are smaller than an ALZET™ osmotic pump and comprise a hollow core surrounded by at least two layers. In certain embodiments, a first layer comprises an alginate-polyacrylamide hybrid gel network, and a second layer comprises a soft, immunoprotective alginate outer layer. The first layer comprises a relatively stiff, tough hybrid gel to provide structural stability for subcutaneous implant insertion and removal. In various embodiments, devices and methods of the present disclosure provide implants that can be inserted into an intended location in approximately one to three minutes using standard procedures.
[0012] In various embodiments, a high level of islet function is promoted through at least one of several strategies. In certain embodiments, ultra-pure high-G alginate comprising the alginate-polyacrylamide matrix is covalently modified with ECM protein-specific peptides (RGD) to stimulate adhesion of islet cells. This alginate does not elicit an immune response. Vascularization is aided by recombinant VEGF-C that is distributed on the surface of the implant. As slow biodegradation of the outer alginate occurs, more VEGF-C is released, promoting extensive vascularization within a few days. During that time frame, oxygen is supplied through the gradual breakdown of calcium peroxide in the alginate-polyacrylamide matrix, as well as in the core matrix if oxygenation material is introduced by syringe along with the cells. After a certain period of time (e.g. 80 days), half the alginate mass of the implant may be lost, but structural stability is maintained by the alginate-polyacrylamide network, allowing the implant the associated cells or donor materials.
[0013] Alginates are polysaccharides that form an immunoisolating network, able to protect biofilm bacteria against phagocytosis in humans. Alginate is provided in various portions of implants of the present disclosure at least in part due to its immunoprotective properties.
[0014] In various embodiments, implants are provided with a hollow core adapted to be filled with cells suspended in partially polymerized high-G alginate and RGD for adhesion. An Alginate-Polyacrylamide (A-P) layer surrounds the hollow core, the A-P layer provided to increase stiffness, durability and oxygenation. An outer high-G alginate layer is provided around the A-P layer to enhance immunoprotection. An outermost layer is provided comprising high-G alginate and VEGF-C for vascularization induction and promotion of vascularization. In various embodiments, cells are inserted into the hollow core of the implant prior to completion of the outer high-G alginate layer and coating. Cell implantation is preferably accomplished by injection from a syringe needle or cannula.
[0015] Alginate use is known in tissue engineering, including clinical products using alginates and Phase II clinical trials involving alginate microcapsules supporting islet cells. The use of such alginates is contemplated in applications, methods and devices of the present disclosure.
[0016] Alginates with a G-content of 50% or above are recognized as not eliciting an immune response. In contrast, high-M alginates (70-80%) have been shown to stimulate immune cells in mice. This may be due to the presence of polycations in these studies involving high-M alginates, which by themselves stimulate the complement cascade and provoke an inflammatory reaction. It has been shown that beads made of different alginates, including high-M and high-G alginates with high molecular weight, performed similarly with a low degree of fibrosis when implanted subcutaneously in Wistar rats. High-M alginates may be preferred for implantation of pancreatic islets due to observed increased angiogenesis. However, this increased angiogenesis may be due to the smaller pore size of the high-M alginate creating an immune barrier to large molecules such as IgG (150 kDa), allowing more angiogenesis to proceed undisturbed. In various embodiments of the present disclosure, the use of high-G alginates is provided to reduce the immune response. High-G alginates have the additional advantage of not complexing as well with polycations compared to high-M alginates, reducing the chance of immune response by that route.
[0017] In various embodiments, a multilayer structure is provided to encapsulate the islet cells and offer greater structural strength to the implant as well as to isolate it from the immune system. Certain alginate encapsulation systems do not prevent protrusion of cells from the capsule, which leads to immunorejection, fibrosis, and eventually necrosis of the cells contained. An examination of the structural strength of a typical alginate gel offers insight into why protrusion is so common. The Young's modulus of an alginate gel can vary from 242+/−16 Pa to 1337+/−27 Pa. Soft tissues in general can range from a few kPa to a few hundred kPa, as exemplified by gelatin gels with similar Young's moduli. Thus, typical alginate gels have a stiffness no greater than that of the softest tissues. Rupture readily occurs when an alginate gel is stretched to about 1.2 times its original length, as might occur during implant extraction. However, a hybrid alginate-polyacrylamide gel strongly resists rupture, having a rigidity on the order of cartilage. The provision of such gels in implants of the present disclosure provides a device that is much easier to insert and remove. An extremely stretchable and tough hydrogel can be created by mixing two types of crosslinked polymer—ionically crosslinked alginate and covalently crosslinked polyacrylamide. The stress at rupture is known to be approximately 156 kPa for the hybrid gel, compared to only 3.7 kPa for the alginate gel alone and 11 kPa for the polyacrylamide gel alone. This is stiffer than soft tissue, but it is possible to make an even stiffer implant for sturdier implantation and extraction. Alginate-polyacrylamide hydrogels contemplated for use with embodiments of the present disclosure comprise both high stiffness and toughness, with elastic moduli on the order of 1 MPa.
[0018] According to the present invention, an effective administration protocol (i.e., administering a therapeutic composition in an effective manner) comprises suitable dose parameters and modes of administration that result in elicitation of an appropriate response in an animal that has a disease or condition, or that is at risk of contracting a disease or condition, preferably so that the animal is protected from the disease. A beneficial effect can easily be assessed by one of ordinary skill in the art and/or by a trained clinician who is treating the patient. Effective dose parameters can be determined using methods standard in the art for a particular disease. Such methods include, for example, determination of survival rates, side effects (i.e., toxicity) and progression or regression of disease.
[0019] In various embodiments, islets of the present disclosure comprise a diameter of between approximately 100-200 μm, and preferably of about 150 μm. The volume of 2000 islet equivalents (“IEQs”) is 3.53 cubic mm. The volume of a 2 mm×12 mm implant (of which approximately 25% of the total volume is available for cells) is approximately 9.42 cubic mm. The ratio of cell-containing volume to implant volume in certain embodiments of the present disclosure is thus approximately 0.375. Such embodiments provide room for both cell packing and subsequent growth. A person of ordinary skill in the art will appreciate that variations on the above concentrations, diameters, and volumes can be used to effectuate therapeutic dosages of islet cells in various animals. For example, the volume of 2,000 IEQs is effective in mice and 300,000-500,000 IEQs is effective in humans.
[0020] In certain embodiments, an outer alginate shell is provided with an implant. This shell is provided at least in part because alginate-polyacrylamide has been shown to create mild fibrosis compared to high-G alginate alone. As an example, it is known that a hybrid alginate-polyacrylamide gel was implanted in dorsal subcutaneous pockets in male Lewis rats for 8 weeks to assess inflammation, vascularization, and fibrosis. After eight weeks, the hybrid gel had been encapsulated with a fibrotic collagen encapsulation and showed new vasculature, but with the absence of macrophages or lymphocytic infiltrations that suggested a limited inflammatory response. Vascularization is desirable, but fibrosis should be kept to a minimum. Accordingly, embodiments of the present disclosure provide for an outer alginate shell and other features to limit fibrosis while still accomplishing objectives of the present disclosure.
[0021] Out of twenty five endogenous pro-angiogenic factors, vascular endothelial growth factor (VEGF) is the most studied regulator of vascular development. It shares 42% amino acid sequence identity with placental growth factor, and the placenta is an organ known for its rapid growth and vascularization. However, VEGF-C is a more potent promoter of angiogenesis than VEGF, and is thus contemplated for use as a means for promoting vascularization in implants of the present disclosure. To demonstrate the potency of VEGF-C, micropellets (0.35×0.35 mm) of sucrose aluminum sulfate have been known to be coated with hydron polymer type NCC to make them release their contents of either 160 ng of recombinant VEGF-C or VEGF slowly. These micropellets were implanted in the corneas of mice for five days and induced intensive neovascularization. Additionally, in vivo tests were performed on chicken embryos using methylcellulose disks containing 2.5 μg of VEGF-C or VEGF. The number of new vessel branches induced by VEGF-C in a 4-5 day incubation period was significantly greater than that induced by VEGF.
[0022] The MONOJECT™ AVID Injector is a syringe with a removable 12-gauge needle assembly. This device is known to be useful for injecting microchips into animals at both intramuscular as well as subcutaneous locations. In various embodiments, it is contemplated that this syringe, and/or various similar devices are useful for or provided as an implantation tool for implants of the present disclosure.
[0023] Cellular adhesion is important to cell survival, and how well cells adhere to and grow inside an implant depends on both the physical and chemical properties of the implant, particularly the surface of the implant. Islet cells in particular show greater survival when they are cultured in extracellular matrix proteins—fibronectin, collagen IV, or laminin. Collagen IV is an abundant material, but may not be suitable for use with certain embodiments of the present disclosure because it diminishes glucose-induced insulin responses. Alginate is therefore contemplated for use with embodiments of the disclosure. In certain embodiments, alginate is grafted with bioactive peptides such as the RGD sequence (Arg-Gly-Asp) found in ECM proteins, and cell adhesion is thereby promoted. Such embodiments preferably comprise a hollow core to facilitate insertion of a number of desired cell types. The cell suspension is perferrably mixed with partially polymerized alginate+RGD before introduction by syringe into the hollow core.
[0024] In various embodiments, a stiff alginate-polyacrylamide shell contains a chemical mechanism to diffuse oxygen to the cells in the hollow core. It is also contemplated that a partially polymerized alginate+RGD is mixed with the cells, which also contains the same oxygenation mechanism, thus allowing oxygen to be supplied directly next to the cells and ensuring a higher concentration than from the alginate-polyacrylamide shell alone. The oxygenation mechanism involves the following reaction:
[0000] 2CaO 2 +2H 2 O→O 2 +2Ca(OH) 2
[0025] To mitigate the expected production of H 2 O 2 from a competing reaction that takes place at physiological pH, catalase, which generates O 2 from H 2 O 2 , accompanies the oxygenation mechanism in both the alginate-polyacrylamide shell as well as when added with cells in the hollow core. CaO 2 maintains its oxygen-releasing capacity over a period of days to weeks due to its low solubility, but generation of insoluble products of CaO 2 and increasing alkalinity of the surrounding solution have been problematic for cell survival. To neutralize the resulting alkalinity, the alginate is crosslinked with Al 3+ , the most optimal known crosslinking ion in terms of allowing high oxygen-releasing efficiency, slow release kinetics, and good pH buffer capacity. The H 3 O+ generation through the hydrolysis of the released trivalent cations effectively neutralizes the pH increase caused by the oxygen-releasing process, yielding a neutral species (a hydrated metal hydroxide). The target quantity of CaO 2 necessary to ensure adequate initial oxygenation (up to 1 week) for islet cells is estimated at 5% (w/v) with the following rationale. It has been shown that rapid decomposition of a 0.2% (w/v) slurry of CaO 2 at pH 7; at this pH, H 2 O 2 was produced more rapidly and at higher quantities than 02. A 2% (w/v) mixture has been shown to yield adequate oxygenation duration within alginate beads, at least in the absence of cells. For example, up to 10 days of O 2 release has been demonstrated from 1, 5, and 10% concentrations of CaO 2 for 3T3 fibroblasts. The greatest cell growth occurred with the 5 wt % concentration.
[0026] VEGF-C is a more potent promoter of angiogenesis than VEGF, which is the most studied regulator of vascular development. Various embodiments of the present disclosure therefore provide VEGF-C as a means for promoting vascularization to an implant. A coating of VEGF-C is applied to the outside of the soft alginate outer layer, promoting vascularization on the surface of the implant. However, despite the external coating, it is possible due to the softness of this outer alginate layer that capillaries may grow into the implant. This breach of the outermost immunoprotective layer may result in some fibrosis due to contact with the polyacrylamide component of the alginate-polyacrylamide layer. However, the pore size of the alginate-polyacrylamide layer is such that antibodies cannot penetrate the layer, and its stiffness makes it unlikely that capillaries will quickly breach this layer. This should hold true until significant biodegradation occurs.
[0027] In one embodiment, an implantable cell delivery device is provided. The device is adapted to be inserted into the tissue of an animal and comprises a shell comprising a core operable to receive and store cells and a first layer provided to enhance immunoprotection and limit fibrosis. A second layer is provided, the second layer comprising an alginate polyacrylamide layer and having a stiffness. A third layer is provided comprising a vascularization inducer to promote the growth of new blood vessels to the device.
[0028] In further embodiments, implants are provided in a device as small as 4×4×1.5 cm or larger that can be implanted under the skin of an animal. The device as small as 4×4×1.5 cm can be comprised of up to 150 or fewer of the inner two layers of the implant design as disclosed herein and arranged in flat bundles of six implants. In an embodiment of a device larger than 4×4×1.5 cm, more than 150 of the inner two layers of the implants may be provided.
[0029] In further embodiments, the flat bundles of six implants can be layered in a device with or without the provision of an inner gap within the layered bundles of implants.
[0030] The Summary is neither intended nor should it be construed as being representative of the full extent and scope of the present disclosure. The present disclosure is set forth in various levels of detail in the Summary as well as in the attached drawings and the Detailed Description and no limitation as to the scope of the present disclosure is intended by either the inclusion or non-inclusion of elements, components, etc. in this Summary. Additional aspects of the present disclosure will become more readily apparent from the Detailed Description, particularly when taken together with the drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate embodiments of the disclosure and together with the general description of the disclosure given above and the detailed description of the drawings given below, serve to explain the principles of the embodiments.
[0032] FIG. 1 is a perspective view of an implant according to one embodiment of the present disclosure, with various features shown in phantom for illustrative purposes.
[0033] FIG. 2 is an illustration of a method of implanting an implant according to various embodiments of the present disclosure.
[0034] FIG. 3 is a side view of a syringe for implanting solid objects according to various embodiments of the present disclosure.
[0035] FIGS. 4A-4C are views of designs for implantation of multiple implants according to embodiments of the present disclosure.
[0036] FIG. 4A is a plan view of an arrangement of multiple implants according to one embodiment of the present disclosure.
[0037] FIG. 4B is a detailed perspective view of an implant for use with the embodiment of FIG. 4A .
[0038] FIG. 4C is a plan view of an arrangement of multiple implants according to one embodiment of the present disclosure.
[0039] FIG. 4D is a detailed perspective view of an implant for use with the embodiment of FIG. 4C .
[0040] FIG. 4E is an exploded perspective view of the arrangement of the embodiment of FIG. 4C .
[0041] FIG. 4F is a plan view of an arrangement of multiple implants according to one embodiment of the present disclosure.
[0042] FIG. 4G is a detailed perspective view of an implant for use with the embodiment of FIG. 4F .
[0043] FIG. 4H is an exploded perspective view of the arrangement of the embodiment of FIG. 4F .
[0044] It should be understood that the drawings are not necessarily to scale. In certain instances, details that are not necessary for an understanding of the disclosure or that render other details difficult to perceive may have been omitted. It should be understood, of course, that the disclosure is not necessarily limited to the particular embodiments illustrated herein.
DETAILED DESCRIPTION
[0045] FIG. 1 is a perspective view of an implant according to one embodiment of the present disclosure, with various features shown in phantom for illustrative purposes. As shown in FIG. 1 , the implant 2 comprises a substantially cylindrical shape. The embodiment of FIG. 1 provides a device with an outer surface or shape that comprises a rotationally symmetrical cylinder. It will be recognized, however, that implants 2 of the present disclosure may comprise various shapes, including pill shapes (i.e. cylinders with rounded ends), ovoid shapes, circular shapes, rectilinear shapes, etc. Accordingly, no limitation is provided herewith respect to the outer shape and dimensions of the insert(s). Preferably, the insert 2 comprises outer dimensions including a length L and a width W. In certain embodiments, the length L comprises a distance of between approximately 10.0 millimeters and 15.0 millimeters, and preferably of approximately 12.0 millimeters. In certain embodiments, the width W or diameter of the insert 2 comprises a distance of between approximately 1.0 and 5.0 millimeters, and preferably of approximately 2.0 millimeters. Thus, in preferred embodiments, inserts are provided comprising a length L of approximately 12.0 millimeters and a width W of approximately 2.0 mm. Although various alternative sizes and proportions are contemplated, inserts of preferred embodiments of the disclosure have been determined to provide a suitable interior volume while also being of the appropriate size and dimensions to be accommodated by various insertion and extraction devices.
[0046] The implant 2 of the embodiment of FIG. 1 comprises a hollow core 4 . The hollow core 4 is operable to be filled with donor cells that are ultimately to be implanted into a patient. In preferred embodiments, the cells are suspended in partially polymerized high-G alginate and RGD for adhesion. The hollow core 4 is surrounded by a first layer 6 , wherein the first layer 6 comprises alginate-polyacrylamide for stiffness, durability, and to promote oxygenation. The first layer 6 is further surrounded by a second layer 8 , wherein the second layer 8 comprises a high-G alginate layer for immunoprotection. Additionally, and as shown in the embodiment of FIG. 1 , the insert 2 comprises a third layer 10 . The third layer 10 comprises a coating of high-G alginate and VEGF-C for vascularization induction and the promotion of a host vascular system receiving and accepting the implant.
[0047] As shown in FIG. 1 , an implant 2 is provided comprising a multi-layer construction. The multilayer implant 2 provides greater structural strength to the implant, and provides isolation of at least certain portions of the implant from the immune system. The third layer 10 comprises an alginate shell to reduce the risk of fibrosis, while also promoting vascularization and vascular growth from the host into the implant 2 to facilitate acceptance of donor cells.
[0048] A syringe tip 12 is provided to insert cells into the hollow core 4 . Insertion of cells via the syringe 12 occurs at least prior to completion and formation of the third layer 10 , and preferably occurs prior to completion of the second and third layers 8 , 10 .
[0049] FIG. 2 is a perspective view of a method of removal of implants 2 according to various embodiments of the present disclosure. As shown, a plurality of implants 2 is provided within a patient 20 . Although five separate implants 2 are provided within the patent 20 in FIG. 2 , it will be recognized that removal techniques as shown and described herein may be performed with as few as one implant. The implants 2 are provided subcutaneously in the patient 20 , but may be provided as implants in various regions or portions of a patient's anatomy. It is contemplated that implants 2 of the present disclosure may be removed from a patient in approximately one to three minutes. One method of implant removal contemplated by the present disclosure comprises cleansing and/or disinfecting the incision site 14 , administering subcutaneous anesthesia, and making an incision that is preferably parallel to the longitudinal axis of an implant 2 . The implant is then palpated by a finger 18 , and at least a portion of the implant is forced through the incision. A tool 16 (e.g. forceps) is then used to grasp and extract the implant(s) 2 . It is contemplated that due to the use and presence of VEGF-C in implants 2 of the present disclosure, extensive vascularization will be present in and around the implantation site. Accordingly, removal methods in accordance with embodiments of the present disclosure contemplate a further step of cutting and/or removing this vasculature before or after implant removal. An anesthetic with epinephrine is preferably provided to promote vasoconstriction and thus reduce bleeding during this method.
[0050] FIG. 3 is a side view of a syringe for implanting solid objects according to various embodiments of the present disclosure. As shown, the syringe 30 comprises a plunger rod 32 within a barrel 34 . A synthetic rubber gasket 36 provides a user with the feel of a conventional fluid-injecting hypodermic syringe. The purpose of the gasket 36 is to provide a frictional force that resists the movement of the plunger 32 . Since there is no need for a leak-proof seal for a solid-object-implanting syringe, the gasket can 36 be made of a porous material or air channels can be incorporated in the gasket 36 to allow air to pass freely through the gasket, thereby avoiding air pressure build-up in the barrel that might force air through the cannula 38 and the incision in the body during the implantation procedure. An implant 2 in accordance with embodiments of the present disclosure is provided in the cannula 38 and is ready for implantation in the illustration of FIG. 3 . Application of force to the plunger rod 32 displaces a push rod 40 which forces the implant 2 out of the syringe 30 .
[0051] FIGS. 4A-4C are views of designs for implantation of multiple implants according to embodiments of the present disclosure. In one embodiment, and as shown in FIG. 4A , a plurality of implants 2 are provided on a sheet 50 . The sheet 50 comprises twenty-five flat bundles 52 of implants 2 disposed on a flat surface. In the depicted embodiment, the flat surface of the sheet 50 comprises alginate-polyacrylamide providing structural stiffness to hold the implants 2 within the sheet 50 . In the depicted embodiment, each bundle 52 comprises six implants. Thus, as depicted in FIGS. 4A-4B , the device comprises 150 of the inner two layers 4 , 6 of the implant design as disclosed herein and arranged in flat orientation. These flat bundles of implants 52 are contemplated as being bonded together with alginate-polyacrylamide (for example) for adequate structural stiffness for removing the implant as a whole, while allowing enough flexibility to rest under the skin.
[0052] In further embodiments, and as shown and described herein, multiple layers of flat bundles of implants can be provided. The device may comprise a single layer, two layers, three layers, or more. FIG. 4A depicts the flat bundles of implants 52 oriented in a single layer 50 .
[0053] FIG. 4C depicts a plurality of implants provided in a two-layer arrangement, wherein a first sheet 54 and a second sheet 56 are provided. Each of the sheets 54 , 56 comprises a plurality of bundles 52 of implants 2 , an example of which is shown in the detailed perspective view of FIG. 4D . The first sheet 54 comprises a plurality of spaced-apart gaps or voids 58 a , 58 b . The second sheet 56 comprises a single void 60 that is operable to and intended to at least partially align with the voids 58 a , 58 b of the first sheet when the first sheet 54 and the second sheet 56 are stacked or aligned. The voids 58 a , 58 b , 60 comprise apertures that are devoid of material and allow for transmission of materials including, for example, vasculature and tissue that is to grow in and around the device subsequent to implantation.
[0054] FIG. 4E is a perspective view of the first and second sheets 54 , 56 , which are intended to be stacked or layered. As shown, the voids 58 a , 58 b , 60 are positioned such that they at least partially align upon layering the sheets. The larger aperture 60 of the second sheet 56 provides for at least one bundle 62 to be exposed on both sides of the bundle, and the voids generally serve to allow for in-growth of tissue and vasculature subsequent to implantation of the sheet(s). In various embodiments, stacked or layered sheets comprise an alginate-based gel outer coating including vascular endothelial growth factor C (VEGF-C). This outer coating may be used to limit fibrosis and stimulate vascularization.
[0055] FIG. 4F is a top plan view of a plurality of implants provided on sheets. Specifically, a first 64 , second 66 and third sheet 68 are provided. Each of the sheets 64 , 66 , 68 are provided with a plurality of bundles of implants 52 , and the sheets are operable to be stacked or layered. At least some of the sheets comprise apertures or void spaces. Specifically, and as shown in the embodiment of FIG. 4F , the second and third sheets 66 , 68 comprise first and second apertures 70 , 72 . The apertures generally comprise areas that are devoid of material and allow for transmission of fluids and tissue. FIG. 4G is a detailed view of an implant 2 that is provided within a bundle 52 . The bundles of the depicted embodiment comprise six implants, which comprise implant structure(s) as shown and described herein.
[0056] FIG. 4H is an exploded perspective view of the first, second and third sheets 64 , 66 , 68 of FIG. 4F . The sheets comprise the same or similar length and width dimensions and are operable to be layered or stacked. The apertures 70 , 72 provided in the second and third sheets 66 , 68 provide that at least some of the implants of the first sheet 64 are exposed on both sides, even when the sheets are stacked in a three-layer orientation. Although FIG. 4H provides the first, second and third layers in a specific orientation, alternative embodiments are contemplated. For example, the second layer 66 and the first layer 64 may be transposed, such that layers with apertures are provided on the top and bottom and a middle layer is devoid of an aperture. Similar to the embodiment shown in FIG. 4E , this embodiment of stacked or layered first, second and third sheets 64 , 66 , 68 comprises an alginate-based gel outer coating including vascular endothelial growth factor C (VEGF-C). This outer coating may be used to limit fibrosis and stimulate vascularization.
[0057] In the instance of multiple layers of implant bundles, a gap or void is provided to allow for ingrowth of vasculature. Further, the inner gap can be surrounded as a group by the third layer which is the soft alginate shell containing VEGF-C. Such embodiments provide for a retrievable implant made possible, for example, through a 2 cm incision. In these embodiments of layered implant bundles, the implant bundles in layers are implanted under the animal's skin and subsequently unrolled so that the top layer of implant bundles rests flat under the skin. Removal of the implants can be done through an outpatient procedure.
[0058] In various embodiments, sheets or layers or implants are provided for insertion. No limitation with respect to the number of implants to be inserted within a patient is provided herein. However, in some embodiments, methods and devices are contemplated wherein between approximately 40 and approximately 200 implants as shown and described herein are provided for implantation within a patient.
[0059] While various embodiments of the present disclosure have been described in detail, it is apparent that modifications and alterations of those embodiments will occur to those skilled in the art. It is to be expressly understood that such modifications and alterations are within the scope and spirit of the present disclosure. Further, it is to be understood that the phraseology and terminology used herein is for the purposes of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having” and variations thereof herein are meant to encompass the items listed thereafter and equivalents thereof, as well as, additional items. | An implantable and retrievable medical device is provided. The device may be implanted in and extracted from a patient and the device is adapted to house and deliver donor cells or other drugs. The device comprises a hollow core having a volume for receiving cells and a plurality of layers surrounding the core. The layers comprise various materials suitable for enhancing immunoprotection and for promoting vascular growth into the device. | 0 |
BACKGROUND OF THE INVENTION
Under present practices beef cattle which are to be slaughtered for human consumption are usually kept in a feedlot for some time prior to slaughter in order to improve the quality of the meat to be finally sold to the public. In the feedlot the cattle are fed a carefully controlled diet including corn, dried alfalfa, and alfalfa and molasses mixture, vitamins, and often antibiotics. As large numbers of cattle are to be fed, it is common to introduce the feed into a feed wagon which then moves about the feedlot distributing the feed into feed bins available to the cattle. Feed wagons usable for this purpose are shown in my early U.S. Pat. Nos. 3,345,042 and 3,688,827. As disclosed in those patents, the feed is normally dumped into the containers in sequence, viz, alfalfa, followed by corn, followed by alfalfa and molasses mixture, etc., and thus it is initially in layers in the feed container. It is of course necessary that the ingredients of the feed be carefully and thoroughly mixed before being dispensed for consumption by the cattle, and thus means are normally provided in such feed wagons or containers to effect such mixing.
In many cases, the mixers utilized to thoroughly mix the feed in a feed wagon container require substantial power for operation and thus they must be connected to a power takeoff of a tractor of substantial horsepower in order properly to operate. With the mixing devices of the present invention, it has been found that the horsepower requirements can be substantially reduced while still producing a thorough and in some cases improved mixture of the feed ingredients.
SUMMARY OF THE INVENTION
The present invention contemplates the use of a generally rectangular container mounted on wheels and adapted to be pulled by a tractor. Within the container is a plurality of horizontally extending augers and a plurality of inclined augers spaced just above the inclined bottom of the container. A drive system is provided which is adapted to be connected to the power takeoff of the tractor for operating the augers, the operation of which results in the thorough mixing of the feed in the container. A controllable gate is provided and may be opened when the mixing has been accomplished to discharge the mixed feed when desired.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a top elevational view of a wheel-mounted container embodying the invention;
FIG. 2 is a rear end view of the apparatus shown in FIG. 1;
FIG. 3 is a vertical sectional view along line 3--3 of FIG. 2;
FIG. 4 is a view partially in vertical section illustrating the construction along each side of the container; and
FIG. 5 is a sectional view along line 5--5 of FIG. 3.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to the drawings, there is shown the cattle feed mixing and discharging apparatus 10 of the present invention, the apparatus including a generally rectangular open-top container 11 having a front wall 12 and side walls 13 and 14 together with a rear wall 15. Each of the side walls has a concave upwardly facing area 16 and 17 extending from the front wall 12 toward but terminating short of the rear wall 15.
Means are provided for thoroughly mixing the feed introduced into the container, the means being in the form of a plurality of augers including a first auger 20 extending horizontally from the front wall to the rear wall and having flights 21 extending from the front wall toward but terminating short of the rear wall. A pair of augers 22 and 23 extend parallel to each other and to the first auger and are located in a horizontal plane below the first auger. The second and third augers have flights 24 and 25 with the flights being located in the concave upwardly facing areas 16 and 17 respectively, with the flights 24 and 25 extending from the front wall of the container toward the rear wall but terminating short thereof.
The container has a bottom wall 26 having two scalloped or arcuate recesses 27 and 28 extending upwardly along the bottom from the rear wall to the front wall. A pair of inclined augers 30 and 31 extend parallel to each other with each having one end mounted in the front wall and extending downwardly from the front wall to the rear wall. The augers 30 and 31 have flights 32 and 33 thereon which extend from end to end of the augers with the flights being positioned to be received in said recesses 27 and 28 respectively.
A discharge chute 34 is located at the upper end of said recesses with the chute being controlled by a movable gate 35 mounted on the outside of the bottom wall and slidably carried by S-clamps 36. A piston and cylinder device 37 is secured to the bottom wall and to the gate for operating the latter. A discharge conveyor 38 is located beneath the chute 34 and includes an endless belt 39 carried by rollers 40. The discharge conveyor extends in a direction parallel to the front wall of the container and has a discharge trough 41 which extends beyond the container as shown in FIG. 1.
Means are provided for driving the various augers so far described from the power takeoff of a tractor or any other source of power. The drive means includes a drive shaft 42 rotatably mounted on frame member 43 and connected to a drive connector 44 adapted to be secured to the power takeoff of a tractor. The opposite end of the drive shaft 42 is connected by a U-joint 45 to a rotatable shaft 46 extending through the rear wall. A sprocket 47 is mounted on the shaft 46 and drives a chain 48 passing over a large sprocket 49 fixed to shaft 50 rotatably carried by the rear wall. The shaft 50 extends from the exterior of the rear wall to the interior thereof and carries a propeller-agitator 51 in the container to assist in the mixing action.
A pair of small sprockets 52 are mounted on the shaft 50 each of which carries a chain 53 and 54 led over a pair of larger sprockets 55 and 56 secured to the auger shafts 30 and 31 to drive the same. Drive shaft 42 also carries a sprocket 60 near its forward end over which a chain 61 passes to another sprocket 62 mounted on shaft 63. Another sprocket 64 is mounted on the outer end of shaft 63 and carries a chain 65 to a sprocket 66 on the end of auger shaft 20. The opposite end of auger shaft 20 which is rotatably mounted in the rear wall carries a pair of sprockets 67 and 68, drive chains 69 and 70 passing over sprockets 71 and 72 mounted on the outer end of the shafts of augers 23 and 22 respectively.
To drive the discharge conveyor, shaft 63 carries a sprocket 73 driving a chain 74 around drive sprocket 75 mounted on shaft 76 secured to rollers 40 with the chain 74 passing over an idler sprocket 77 and a second idler sprocket 78, each freely rotatable so that the shaft 76 rotates in a direction opposite to the direction of rotation of shaft 63.
The frame 43 which may be of any suitable construction sufficient to carry the container 11 and attendant apparatus is mounted for ground traversing movement on wheels 80 so that it may be easily towed by a tractor. | The invention relates to a cattle feeding device in the form of a movable container provided with a plurality of augers, some extending horizontally and some inclined in order to effect proper mixing of feed introduced into the container together with means for discharging the thoroughly mixed feed for consumption by cattle. | 1 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the general art of kitchen utensils, and to the particular field of tools and implements used for eating.
2. Discussion of the Related Art
When eating shellfish, such as crablegs, oysters, lobsters, shrimp or the like, a person is often required to open a portion of the shellfish, such as the legs or the like. This often occurs at a dinner table. Many people struggle with this, and some people avoid eating such foods because of the struggle required to open the food. Some people try to use forks, knives or other table utensils to accomplish the task of opening such food. This can be cumbersome and messy.
Therefore, there is a need for a shellfish opening tool that is easy to use.
Opening shellfish may be especially difficult for a handicapped person or an elderly person or someone who may have arthritis in their hands. These people may be deprived of the enjoyment of eating shellfish unless someone opens the food for them.
Therefore, there is a need for a shellfish opening tool that is easy to use, even for someone who may have limited dexterity in their hands.
One of the problems associated with opening shellfish for eating is the removal of the shell from the meat. This may take more hand dexterity than a person possesses. The meat must be held in place while the shell is removed, all while not creating a large mess.
Therefore, there is a need for a shellfish opening tool that is easy to use and can be used to remove the shell from the meat.
Some eating utensils include a plurality of interconnected parts. These interconnected parts may separate during heavy use such as may occur during the shelling of shellfish. This may create a mess and may even break a plate if the eating utensil is heavy as may be required to open shellfish.
Therefore, there is a need for a shellfish opening tool that is stable and secure.
PRINCIPAL OBJECTS OF THE INVENTION
It is a main object of the present invention to provide a shellfish opening tool that is easy to use.
It is another object of the present invention to provide a shellfish opening tool that is easy to use, even for someone who may have limited dexterity in their hands.
It is another object of the present invention to provide a shellfish opening tool that is easy to use and can be used to remove the shell from the meat.
It is another object of the present invention to provide a shellfish opening tool that is stable and secure.
SUMMARY OF THE INVENTION
These, and other, objects are achieved by a shellfish opening tool that comprises a handle section which includes a first handle, a second handle and a pivot connection pivotally connecting the first handle to the second handle; a rip element that is one piece with the first handle of the handle section, the rip element including a pointed end that is spaced apart from the first handle; and a pad which is one piece with the first handle, the pad having a first surface, a plurality of serrations on the first surface of the pad, the first surface of the pad being oriented to face the pointed end of the rip element.
The shellfish opening tool embodying the present invention is easy to use, even if the user has impaired hand dexterity and can be used to remove the shell from the meat. The tool can be used both at home and in a restaurant. The tool is formed of several elements that are one-piece construction and thus the tool will be stable and secure during use. The shellfish is easily trapped between the rip element and the pad and will be held on the pad in a stable manner while the rip element is used to remove the shell from the meat. The shell can be cracked open using arcuate portions on the handles in the manner of a vise.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
FIG. 1 is a perspective view of the shellfish opening tool embodying the present invention.
FIG. 2 is an elevational view taken along line 2 — 2 of FIG. 1 .
FIG. 3 is a front end elevational view of the shellfish opening tool shown in FIG. 1 .
FIG. 4 shows one end of the shellfish opening tool embodying the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Other objects, features and advantages of the invention will become apparent from a consideration of the following detailed description and the accompanying drawings.
Referring to the figures, it can be understood that the present invention is embodied in a shellfish opening tool 10 . Shellfish tool 10 comprises a handle section 12 which is operated to hold the shellfish and to remove the shell from the meat for eating.
Handle section 12 includes a first handle 14 which is an upper handle in a use orientation shown in FIG. 1 . The first handle 14 is one piece and includes side faces 16 and 18 , a first face 20 which is a top face in the use orientation, and a second face 22 which is a bottom face in the use orientation. The first face 20 includes an arcuate portion 24 which is sized and shaped to securely engage a shell of a shellfish in the manner of pliers or the like. Each of the side faces 16 , 18 of the first handle 14 includes a groove, grooves 26 and 28 . The first handle 14 further includes a first end 30 , a second end 32 , and a longitudinal axis 34 which extends between the first end 30 of the first handle 14 and the second end 32 of the first handle 14 . The first handle 14 further includes a projection 40 on the second face 22 of the first handle 14 and an arcuate portion 42 on the second face 22 of the first handle 14 adjacent to the projection 40 on the first handle 14 . A plurality of teeth, such as tooth 44 , are located on the second face 22 of the first handle 14 adjacent to the arcuate portion 42 . A projection 46 is located on the first face 20 of the first handle 14 .
A rip element 50 is positioned between the shell and the meat of a shellfish and is used to remove the shell from the meat. Rip element 50 is located on the first face 20 of the first handle 14 adjacent to the first end 30 of the first handle 14 . Rip element 50 includes a proximal end 52 which is one piece with the first handle 14 for stability and security, a distal end 54 , and a longitudinal axis 56 which extends between the proximal end 52 of the rip element 50 and the distal end 54 of the rip element 50 . The longitudinal axis 56 of the rip element 50 extends in the direction of the longitudinal axis 34 of the first handle 14 but at an angle thereto. The rip element 50 further includes a body 60 and the distal end 54 of the rip element 50 is pointed to form pointed tip 62 which is sized and shaped to be easily inserted between the shell and the meat of a shellfish. The body 60 of the rip element 50 tapers from the proximal end 52 to the distal end 54 so that insertion of the rip element 50 between the shell and the meat of the shellfish will push the rip element 50 between the shell and the meat in a manner that separates the shell from the meat. The body 60 of the rip element 50 extends at an angle with respect to the longitudinal axis 34 of the first handle 14 . The distal end 54 of the rip element 50 is spaced apart from the first end 30 of the first handle 14 .
Handle section 12 further includes a second handle 70 which is a lower handle in the use orientation. Second handle 70 is one piece and includes side faces 72 and 74 , a first face 76 which is a top face in the use orientation, and a second face 78 which is a bottom face in the use orientation. The first face 76 of the second handle 70 includes an arcuate portion 80 and each of the side faces 72 , 74 of the second handle 70 includes a groove, 82 and 84 . The second handle 70 further includes a first end 90 , a second end 92 and a longitudinal axis 94 which extends between the first end 90 of the second handle 70 and the second end 92 of the second handle 70 . The second handle 70 further includes a projection 96 on the first face 76 of the second handle 70 adjacent to arcuate portion 80 . A plurality of teeth, such as tooth 102 , are located on the first face 76 of the second handle 70 adjacent to the arcuate portion 80 of the second handle 70 .
A pivot connection 110 pivotally connects the first end 30 of the first handle 14 to the first end 90 of the second handle 70 so the handles 14 , 70 can be moved in the manner of pliers or the like.
Tool 10 further includes a pad 120 which is one piece with the first handle 14 of the handle section 12 . The pad 120 is used to support the shellfish during the removal of the shell from the meat. The pad 120 includes a first surface 122 which is a top surface in the use orientation and a second surface 124 which is a bottom surface in the use orientation. The first surface 122 of pad 120 has a plurality of serrations, such as serration 126 , thereon for ensuring that the shell and the meat do not slip relative to the tool. The pad 120 further includes a proximal end 130 and a distal end 132 . First surface 122 of the pad 120 is oriented to face the distal end 54 of the rip element 50 so the shell and the meat will be separated while the shellfish is securely held in place.
Use of tool 10 will be understood by one skilled in the art from the foregoing. Therefore, the use of tool 10 will only briefly be discussed. A shell of a shellfish is separated from the meat of the shellfish by first holding the shellfish between arcuate surfaces 42 and 80 and operating the handle section 12 in the manner of pliers to crack the shell. Rip element 50 is then inserted between the shell and the meat and the tool is forced forward to insert the rip element 50 further between the shell and the meat. The shell will be separated from the meat, and the shellfish is held in a stable orientation with respect to the tool 10 by the serrations on pad 120 during the process. Tool 10 can be formed of stainless steel or other such material for long life and easy cleaning.
It is understood that while certain forms of the present invention have been illustrated and described herein, it is not to be limited to the specific forms or arrangements of parts described and shown. | A tool is used to remove a shell from the meat of a shellfish and includes a handle section having a rip element on one handle and a serrated pad on the same handle. The tool further includes arcuate sections having teeth so the shell can be cracked using the tool in the manner of pliers. Once the shell is cracked, the rip element is inserted between the shell and meat and forced forward to separate the shell from the meat. The shellfish is held in a stable manner on the tool by the serrated pad. | 0 |
TECHNICAL FIELD AND BACKGROUND OF THE INVENTION
The invention relates to a device for discharging compact itemized or flowable media. In the case of pasty media the flowability may materialize only under overpressure, whilst in the case of gaseous, liquid and powdery media it may also materialize solely by gravitation. The invention relates also to a method for producing a discharge device for media.
Such discharge devices comprise a single or several wall bodies, each of which is integral, whereby wall bodies ajoining each other may be configured integral with one another. Such wall bodies may be configured plate or disk shaped, e.g. as a face end wall, and/or sleeve shaped. They may also form part of a housing, such as an outermost main housing, a plunger unit, an outlet port for the medium, an outlet and/or inlet port for the medium or the like. Each wall zone or each wall region of the wall body defines at right angles to the associated outer or surface material thicknesses facing away from each other, whereby the wall may pass through between these surfaces in one piece or with full cross-sections. These cross-sections may be defined in two section planes at right angles to each other, of which one lies e.g. parallel to a longitudinal axis of the wall body and the other transversely thereto.
Substantially all components of such a discharge device and especially of the wall bodies in each case may be produced by approximately the same shaping procedure, e.g. by injection molding or extrusion in a negative mold, from a material which relative to the material volume assumes differing expansions by a few percent under differing temperatures, especially shrinking in the solidified condition as ready for use at room temperature of e.g. 20° C. to an extent as compared to the condition in which it is heated e.g. in fabrication in excess of 100° to 200° C. In this fabrication the material, e.g. a thermoplast solidifies whilst still at the elevated temperature into a production shape and then shrinks e.g. on demolding during cooling by the cited amount until it has attained its useful shape.
Geometrically simple shapes such as planar, linear elongated, axial-symmetrical, circular or similar shapes are easier to produce than non-planar, curved, non-axially symmetrical, non-circular or similar shapes, particularly because the shaping means used in production are easier to fabricate. If for reasons of functioning of the discharge device a less simpler shape of the wall body is needed, there is the requirement to produce it in a shape which is simpler as compared thereto and then directly following and/or in the course of this production to translate the simpler production shape into the less simple useful shape.
OBJECTS OF THE INVENTION
An object of the invention is to provide a dispenser in which drawbacks of known configurations are avoided or advantages of the kind as described are achieved and which in particular comprises wall bodies which are translated from a simpler production shape into a less simple operational shape.
SUMMARY OF THE INVENTION
In accordance with the invention mutual excursion of adjacent wall zones of the wall body in each case in the useful shape as compared to the production shape is achieved in that they are subjected to a thermally promoted reshaping procedure. Although it is feasible to expose the wall body after solidification in the production shape and following demolding to a repeat localized heating to thus reshape it, however, it is expedient for reshaping to make use of the shrinkage behaviour of the material on cooling so that adjacent or juxtaposed wall zones are cooled at differing rates, a temperature gradient then existing between these wall zones, until they have achieved their final, dimensionally stable and rigid useful shape. In the useful shape especially the cross-sections oriented transversely to the longitudinal axis of the wall body are substantially more dimensionally stable or rigid than in the production state when still heated, whilst a pliant excursion or flexibility along the longitudinal axis under the conditions of use may still exist. Thick wall zones shrink more than thin wall zones so that when such wall zones of differing thickness are suitably arranged a significant change in shape results which e.g. as compared to the longitudinal axis does not materialize symmetrically and thus leads to a change in the longitudinal profile and/or the basic shape of the cross-section. For instance, a rod-shaped wall body may be subjected by shrinkage to a rod curvature and/or a cross-section of the rod may be translated into a flatter, for instance, elliptical shape.
The embodiment according to the invention is particularly suitable for sleeve-type or elongated tubular bodies, the inner and/or outer cross-sections of which are produced in an axially symmetrical shape or in a shape having circular cross-sections each oriented in a separate axis. When the longitudinal axes of these cross-sections are located eccentrically and/or in a common axial plane inclined to each other at an angle of few degrees, the sleeve features in this axial plane a minimum wall thickness on one side of the longitudinal axes and on the other side thereof a maximum wall thickness, these wall thicknesses continually or smoothly translating into each other. On removal of the wall body from the casting mold the thicker wall region shrinks quicker than the thinner and the tubular body is thereby translated from the linear elongated production shape into a curved useful shape in which the center lines of its two ends are located interrelated at an obtuse angle of e.g. more than 150°.
As a result of this the tubular body is particularly suitable as an intake, suction or uptake tube, via the free end of which the discharge device draws medium from the bottom region of a container into a pressure or pump chamber from which this drawn-in medium is then discharged through a discharge orifice. The uptake tube may be configured integral with the walls defining the discharge or pressure space, particularly with the shell thereof and adjoin the wall face of this space. As viewed axially the free end of the tube in the relaxed or unloaded condition assumes a precise location with respect to the walls of the space to the extent that it is located in the peripheral direction about the longitudinal axis at a predetermined position.
The corresponding wall zone may have parallel to the longitudinal axis over the full length of the wall body the maximum or minimum material thickness or an approximately constant wall thickness, however, it is also feasible to provide this corresponding thickness along an ascending spiral so that the wall body on shrinkage is curved in two planes at right angles to each other. Advantageously the wall thickness diminishes towards the free end of the wall body by a few angular degrees of e.g. less than 5° to permit simple removal from the casting mold by extracting the wall body in its longitudinal direction, the thicker wall region diminishing to advantage, relative to its wall thickness, less in percentage than the thin wall region.
A method according to the invention for producing a discharge device in which a wall body, such as a shell body, the shaping of which is done in a casting mold and then extracted from the casting mold in the production shape thus attained, as well as translating it into a final or useful shape by cooling and shrinkage is characterized according to the invention in that adjacent wall zones of the wall body following removal from the casting mold experience a mutual excursion by differing temperature exposure and are thus translated into the useful shape. Expediently, after material solidification and prior to removal from the casting mold or then at the latest, the wall zones are set to roughly the same temperature, they then cooling following or respectively at commencement of removal from the casting mold to a common temperature and thereby experience a mutual excursion. For this purpose, on cooling, the wall zones may be thermally exposed to heat reservoirs having differing reservoir capacities which may be formed directly by the wall zones so that an inherent thermal coupling materializes. On cooling the wall zones are exposed to differing degrees of shrinkage per unit of length and thus experience a mutual excursion.
These and further features are evident not only from the claims but also from the description and the drawings, each of the individual features being achieved by themselves or severally in the form of subcombinations in one embodiment of the invention and in other fields and may represent advantageous aspects as well as being patentable in their own right, for which protection is sought in the present.
BRIEF DESCRIPTION OF THE DRAWINGS
An example embodiment of the invention is explained in more detail in the following and illustrated in the drawings in which:
FIG. 1 shows a discharge device according to the invention as viewed transversely FIG. 2 shows a section of the illustration greatly magnified in FIG. 1, and FIG. 3 shows a cross-sections through the wall body according to FIG. 2
DETAILED DESCRIPTION
The discharge device 1 comprises two units 2, 3 which are require manually moving against each other, e.g. linearly shifted against each other for actuation or activation of the media discharge. Each of the units 2, 3 contains a housing 4 and 5 respectively forming its exposed outer side in use which is produced together with all other wall bodies formed integrally therewith by injection molding from plastics material. The main housing 4 of the unit 2 is to be connected fixedly located or integral with a media reservoir, such as the neck of a small bottle, by a fastener 6 which may be formed by a cap-shaped housing section or integrally with the housing 4. With radial spacing and within the fastener 6 the housing 4 forms a pressure housing 7 which surrounds a pressure space 8 at the outer periphery. The pressure space 8 could be formed by a media reservoir to be filled with a propellant, in this case, however, it is a pumping space of variable volume through the restriction of which the medium existing therein is forced out of the discharge device. This pressure space could also form the sole media reservoir of the discharge device.
The unit 3 contains a plunger unit 9 which is shiftable with respect to the base body or housing 4 along the longitudinal or central axis 10 to eject medium from the pressure space 8 and on its return stroke to suck medium back into the pressure space 8. The plunger unit 9 comprises a displacement member or plunger 11 which substantially closes off one face end of the pressure space 8 and is arranged on a piston rod 12 passing through the housing 4 or protruding from the outer end thereof. The plunger unit 9 carries an outlet valve 13 which by abutment at the end of the pump stroke and/or due to fluid pressure in the pressure space 8 opens and on a drop in pressure automatically recloses.
The extension of the piston rod 12 translates at its end facing away from the plunger 11 into an outlet port 14 at the free end of which the outlet orifice 15, e.g. an atomizing nozzle, for discharging the medium to the atmosphere is provided. On opening of the valve 13 the medium flows from the pressure space along the inner periphery of the hollow plunger 11 within the piston rod 12 and the discharge port 14 up to the media outlet 14. The outlet passage may be defined between valve 13 and the outlet orifice 15 by the inner peripheries of the bodies 12, 14 and a rod-shaped inner body inserted in the latter which forms the valve seat of the valve 13 and may serve to support a return spring located in the pressure space 8 for the plunger unit 9. The arrangements 1 to 15 are expediently located on a common central axis 10 or in longitudinal axes offset transversely to each other but in parallel.
For filling the pressure space 8 with medium a wall body 16, namely a tube which is dimensionally rigid under the assembly forces occurring or tubing which is flexible when exposed to such loads, is provided. This wall body 16 is translated from the linear production shape according to the invention as illustrated in FIG. 1 or indicated dot-dashed in FIG. 2 into the curved useful shape illustrated in FIG. 2 in which it has the stated dimensional rigidities. Each of the bodies 2 to 7, 9 and 11 to 14 could form, contain or be formed by such a wall body.
The innermost free end of the uptake tube 16 facing away from the outlet 15 forms an intake opening 17 passing through the end surface for the medium. The other end integrally adjoins the outermost wall face 18 of the housing 7 which may also form the valve seat of an inlet valve 19 for the pressure space 8. This inlet valve 19 may comprise a plate-shaped valve housing as shown in FIG. 1, a ball-shaped valve plate as shown in FIG. 2 or the like which may be opened only by the fluid pressure and, where necessary, may be urged into the closing position by a spring located within the pressure space 8. The housing 7 comprises in the region of the connection to the tube 16 opposite thereto a larger outer width and the outer width of the wall body in each case is expediently less than 50, 20, 10 or 5 mm. The tube 16 has preferably a maximum outer width of less than 4 mm and a maximum inner width of less than 3 mm or a maximum wall thickness of less than 3 or 2 mm. The wall thicknesses of the tube 16 are adapted in effect to their material properties, particularly to their shrinkage properties in producing the shape so that shrinkage means 20 are formed. Due to these the tube 16 shrinks from its straight shape into the excursion or curved shape, and at the end of this shrinkage it achieves the finished shape or final condition durably hardened and inherently stable.
Between its two ends 21, 22 the tube 16 has a length which is greater than four, six or ten times its maximum outer width. Except for a demolding conicity of 6 or 3 angular degrees at the most the outer width or inner width of the tube 16 is substantially constant over this length. Its wall thickness continually diminishes towards the free end roughly corresponding to this conicity and also continuously varies in each longitudinal section around the periphery between a maximum value and a minimum value. The inner periphery 23 like the oc 24 is circular in cross-sections over the full length. The inner periphery 23 is flared towards the free end and the outer periphery 24 is diminished to permit extraction and removal at the end 22 of a molding core for molding the inner periphery 23 and a molding sleeve for molding the outer periphery 24 on demolding. The two peripheries 23, 24 and their center lines 25, 26 respectively are located in both conditions as illustrated in FIGS. 1 and 2 to a degree eccentrically to each other which is substantially smaller than the mean width of the inner periphery 23 or the half thereof. In addition, the center lines 25, 26 are located in both conditions and over the full length of the tube 16 in a common axial plane 37 or in two axial planes 38, 39 offset from each other by this degree of eccentricity and at right angles to the latter axial plane. The axes 25, 26 approach each other at the end 22 at one of the angles cited and intersect at a spacing outside of the end 22 so that their maximum distance lies at the end 21.
The end 21 integrally translates into a housing section 27 forming the wall face 18 which as shown in FIG. 1 may have a constant outer width over its length which is greater than that of the end 21 and smaller than that of the housing 7. This section 27 having a dish-shaped cross-section forms together with the dished bottom the wall face 18. As shown in FIG. 2 the housing section 25 has the shape of a truncated cone. Its tapered end translates into the end 21 having the same outer width. Its flared end translates correspondingly into the sleeve of the housing 7. The end surface 22 comprises expediently sections axially offset with respect to each other, e.g. as viewed from the side at right angles to the plane 37 a concave shape so that the medium is also able to flow radially to the intake opening 17 when the end surface 22 in the region of diametrally opposed points ajoins the inner surface of the media reservoir.
Due to the configuration as described, in the longitudinal direction of the tube 16 adjacent or adjoining wall zones 28, 29 are formed, each of which extends over the full tubular circumference and, on shrinkage, experience a mutual excursion, thereby forming a curvature 30 of the tube 16. As a result of this an excursion of the end 22 occurs with respect to the axis 10 into a precisely defined radial direction sideways into its useful shape in which it may roughly adjoin the envelope surface about the outer side of the housing 7. In the cross-section as shown in FIG. 3 the sleeve of the tube 16 forms on one side of the planes 38, 39 and in region of the plane 37 a wall region 31 of maximum thickness. On the other side of the planes 38, 39 the sleeve forms in the region of the plane 37 a wall portion 32 of minimum thickness. Both wall regions 31, 32 intertranslate via wall regions 33 opposing each other on both sides of the plane 37, each of which is curved approximately by 180° and consistently diminish in thickness from region 31 to region 32. The wall regions 31 to 33 are defined solely by the peripheries 23, 24.
On shrinking and curving the tube 16 or its axis 25, 26 thus remains over its full length in the plane 37 and the excursion occurs exclusively transversely or at right angles to the planes 38, 39. The end surface 22 may be provided with respect to the axis 25 or 26 inclined to such an extent that it lies in the excursion condition roughly at right angles to the axis 10 or parallel to the bottom of the media reservoir so that also the last remainders of the medium can be drawn off therefrom. Due to the integral connection of the tube 16 to the housing 7 the associated longitudinal section of the tube 16 is able to remain free of curvature so that the curvature does not begin until spaced away from the end 21 which corresponds to at least a quarter, a third or the half of the length of the tube 16. In the region of the curvature the cross-sections 23, 24 may distort or shrink in the direction of an elliptical useful shape. The center line 261/2 of the end 22 in excursion is located at an acute angle to the axis 10 which is greater than the angle of conicity and amounts to a maximum of 40°, 30° or 20°.
In accordance with the invention an uptake tube 16 of defined precurvature and inherently rigid is formed. The thicknesses of the wall regions 31 to 33 continually diminish towards the end 22 or parallel to the axis 25, 26. The curvature 30 forms in the wall region 31 at the outer periphery 24 a curvature inner surface 34 and in the wall region 32 at the outer periphery 24 a curvature outer surface 35. Correspondingly inverse are the curvature relationships of the inner periphery 23 in the portions 31, 32. The inner periphery 23 adjoins at the end 21 the end of greater or equal width of an eccentric funnel-like tapered passage section, the narrower end of which adjoins a through-passage 36 in the face end wall 18 for the medium. The cylindrical through-passage 36 is substantially narrower than the inner periphery which in the wall region 32 parallel to the axis 25 or 26 and steplessly linearly adjoins the inner periphery 23. As a result of this the funnel section as well as the through-passage 36 may be simply produced by the same molding core as the inner periphery 23. The through-passage 26 directly adjoins the valve seat of the valve 19 on the side facing away from the funnel section.
The discharge device 1 is to be manually driven or actuated by an actuator 40 to force the medium from the orifice 15 in an amount metered by the pressure space 8. For this purpose a handle 41 protruding from the outer peripheries of the bodies 12, 14 is pressed by the fingers of one hand so that the unit 3 is pushed in the direction of the tube 16. One finger, particularly the thumb of the hand may thereby support the bottom of the media reservoir. The end 22 may thereby lie in the corner forced inwardly between the bottom surface and the inner periphery of the media reservoir and supported, urged where necessary, by one or both of these surfaces. On release of the actuator 40 the units 2, 3 automatically return to their starting position, as a result of which medium is drawn through the tube 16 into the increasing pressure space 8 for the next discharge.
The stated properties, dimensions, relative positions and the like may be provided precisely or merely roughly or substantially as explained and, where necessary, may depart greatly therefrom. | A fluid media dispenser is disclosed having an uptake tube or wall body configured with differing wall thicknesses so that, due to material shrinkage, a lateral curve is formed in the uptake tube or wall body which facilitates removal of the formed dispenser from a mold. A simplified injection mold/extrusion nozzle method for producing this dispenser is also disclosed. | 1 |
FIELD
[0001] This application relates to games, specifically to chess game variants.
BACKGROUND
[0002] Chess is a strategy game that is believed to have been known since at least the 6 th century. The game underwent revisions in 13 th century Europe, and the most popular modern form of the game is believed to have evolved in the 15 th century. Today, standard internationally accepted rules for chess are governed by the World Chess Federation (Federation Internationale des Echecs, FIDE) and published as “The Laws of Chess” at http://www.fide.com/fide/handbook.html?id=124&view=article, the contents of the entirety of which are herein incorporated by this reference.
[0003] The standard game of chess, while challenging, may lose the interest of players over time. Therefore, there remains a need for chess variants having unique and interesting variations to provide further challenges for the players.
SUMMARY
[0004] There is provided a chess game comprising an apparatus for displaying at least two sets of chess pieces and a playing area delineated into an array of 100 spaces which the pieces occupy or move through, each set of pieces comprising ten pawns and eleven officers, the officers including a king, wherein two of the officers are non-standard pieces that start play on the playing area, the two non-standard pieces both having a movement ability permitting movement of three spaces along a rank or file or two spaces along a diagonal in any one move and permitting jumping over intervening pieces, and wherein one of the officers is a wildcard piece that starts play off the playing area and may be introduced on to the playing area in a space adjacent the king by a player upon occurrence of a pre-defined condition, the wildcard piece having a randomly determined movement ability.
[0005] There is further provided a chess game comprising an apparatus for displaying at least two sets of chess pieces and a playing area delineated into an array of spaces which the pieces occupy or move through, each set of pieces comprising a plurality of pawns and a plurality of officers, the officers including a king, wherein at least one of the pieces in each set is a wildcard piece that starts play off the playing area and may be introduced on to the playing area in a space adjacent the king by a player upon occurrence of a pre-defined condition, the wildcard piece having a randomly determined movement ability.
[0006] There is further provided a method of playing a chess game comprising: arranging at least two sets of chess pieces on a playing area delineated into an array of spaces which the pieces occupy or move through, each set of pieces comprising a plurality of pawns and a plurality of officers, the officers including a king; providing at least one wildcard piece that starts play off the playing area; introducing the wildcard piece on to the playing area in a space adjacent the king by a player upon occurrence of a pre-defined condition; and, randomly determining a movement ability of the wildcard piece.
[0007] There is provided a chess game comprising an apparatus for displaying at least two sets of chess pieces and a playing area delineated into an array of spaces which the pieces occupy or move through, each set of pieces comprising a plurality of pawns and a plurality of officers, wherein at least one of the officers in each set is a non-standard piece that starts play on the playing area, the non-standard piece having a movement ability permitting movement along a rank or file up to a maximum of three spaces or along a diagonal up to a maximum of two spaces and permitting jumping over intervening pieces.
[0008] A method of playing a chess game comprising arranging at least two sets of chess pieces on a playing area delineated into an array of spaces which the pieces occupy or move through, each set of pieces comprising a plurality of pawns and a plurality of officers, wherein at least one of the officers in each set is a non-standard piece that starts play on the playing area, the non-standard piece having a movement ability permitting movement along a rank or file up to a maximum of three spaces or along a diagonal up to a maximum of two spaces and permitting jumping over intervening pieces.
[0009] The game comprises a playing area delineated into an array of spaces which the pieces occupy or move through. The array may be of any suitable size depending on the number of pieces in the game. Preferably the playing area comprises a number of spaces and a number of starting pieces on the playing area such that there are at least twice as many spaces as starting pieces. In a preferred embodiment, the playing area comprises 100 spaces. The array may comprise any suitable arrangement of spaces. Preferably, the array is set up as a grid whereby edge spaces define edges of the playing area surrounding interior spaces. The playing area may be of any shape, for example irregular, polygonal (e.g. square, rectangular, pentagonal, hexagonal), ellispsoidal or circular. A square or rectangular playing area is preferred. The spaces may be of any shape, for example irregular, polygonal (e.g. square, rectangular, pentagonal, hexagonal), ellispsoidal or circular. Square or rectangular spaces are preferred. In a preferred embodiment, the spaces are square or rectangular and the playing area is square or rectangular. In one embodiment, the playing area is delineated into a square or rectangular 8×8 array of square or rectangular spaces to provide 64 spaces in the playing area (e.g. a standard chess board), which is especially useful if only the wildcard piece is used. In another embodiment, the playing area is delineated into a square or rectangular 10×10 array of square or rectangular spaces to provide 100 spaces in the playing area, which is especially useful if two non-standard pieces are used.
[0010] The game comprises at least two sets of chess pieces. Each set is played by a separate player, either really or notionally, and each set is preferably distinguishable from the other set or sets, for example by color, shape, an associated signifier or some combination thereof. In some embodiments, there may be more than two sets of pieces, for example three, four or five sets of pieces, so that more than two players may play in the same game. Preferably, the game comprises two sets of pieces. Each set of pieces preferably comprises a same number and type of pieces, although in some variants, one set of pieces may comprise more or fewer pieces or pieces of different types to disadvantage one player over another. Each set of pieces comprises a king or equivalent piece. The king has the same properties as the king in standard chess. Each set of pieces preferably comprises other standard chess pieces (e.g. pawns, rooks, knights, bishops, and a queen) or equivalents thereof having the same properties as those in standard chess. Preferably, each set comprises a king, a queen, two bishops, two knights, two rooks and at least eight pawns. The king, queen, bishops, knights and rooks are termed “officers”. The starting pieces comprise all of the pawns and the king, queen, bishops, knights and rooks. Preferably, each set of pieces comprises at least sixteen starting pieces and the at least one wildcard piece that starts off the playing area.
[0011] Each set of pieces may comprise at least one wildcard piece, preferably one wildcard piece. The wildcard piece is also considered to be an officer. The wildcard piece starts play off the playing area and may be introduced to the playing area in a space adjacent the king by a player upon occurrence of a pre-defined condition. The pre-defined condition may be, for example, when an officer other than the king is captured for a first time or any other gameplay-related event. For clarity, the king adjacent to which the wildcard piece may be introduced is a player's own king and not a king of another player. Adjacent spaces include spaces that are horizontal, vertical or diagonal to the king, i.e. spaces that touch the space occupied by the king. The player may bring the wildcard piece on to the playing area at any time after the pre-defined condition occurs, or the player may have a pre-determined number of moves in which to introduce the wildcard piece. Preferably, the player may introduce the wildcard piece on to the playing area at any time after the pre-defined condition occurs.
[0012] Preferably the wildcard piece may be introduced only once and may not be re-introduced after having been captured, although some variants may permit re-introducing a captured wildcard piece multiple times. In the event that reintroduction of the wildcard piece is permitted, such reintroduction may occur upon re-occurrence of the pre-defined condition, for example after another of the player's officers other than the king is captured, or some other pre-defined condition. In one embodiment, players may have an unlimited number of opportunities to reintroduce their wildcard pieces provided the pre-defined condition is met, whereas in another embodiment the wildcard pieces may only be introduced until all of the possible randomly determined movement abilities have been used up.
[0013] Introducing the wildcard piece to the playing area is preferably a move ending the player's turn, although some variants may permit the introduction of the wildcard piece and permit a separate move in the same turn. If another player's piece is on a space adjacent to the king, the wildcard piece may be introduced into that space thereby capturing the other player's piece. In one embodiment, introducing the wildcard piece on to the playing area may not be done to capture another player's piece that has the king in “check” or to block a “check” of the king by another player's piece remote from the king. In another embodiment, introducing the wildcard piece on to the playing area may be done to capture another player's piece that has the king in “check” or to block a “check” of the king by another player's piece remote from the king. In another embodiment, capturing another player's piece upon introduction of the wildcard requires revealing the randomly determined movement ability of the wildcard piece.
[0014] When introduced on to the playing area, the wildcard piece receives a randomly determined movement ability. The movement ability may be randomly selected from any pre-determined list of choices and does not change for the remainder of the game. The list of choices may include, for example, two or more of the standard movement abilities of the king, queen, rook, bishop, knight, pawn and any one or more other non-standard movement abilities. Preferably, the wildcard cannot have the standard movement ability of the king. In one embodiment, the list of choices includes at least one non-standard movement ability. The non-standard movement ability may be any movement ability, for example a movement ability of a hybrid piece as described below or even an inability to move at all. If the wildcard piece is unable to move, the wildcard piece may also possess immunity to being captured, thereby becoming an effective blocker. In another embodiment, the list of choices comprises the standard movement abilities of the rook and bishop and at least one non-standard movement ability. In another embodiment, the list of choices comprises the standard movement abilities of the rook, bishop and knight and at least one non-standard movement ability. In another embodiment, the list of choices comprises the standard movement abilities of the queen, rook, bishop, knight and pawn and at least one non-standard movement ability.
[0015] In one embodiment, once the movement ability is randomly selected for a player's wildcard piece, that movement ability is no longer available to any other player's wildcard piece. In another embodiment, selection of the movement ability for one player's wildcard piece does not preclude selection of the same movement ability for another player's wildcard piece.
[0016] In a preferred embodiment, only the player introducing the wildcard piece on to the playing area is initially privy to the wildcard piece's movement ability. However, such initial privacy may not apply should the introduction of the wildcard piece result in the immediate capture of another player's piece adjacent to the king, in which case, the movement ability of the wildcard piece is revealed immediately. Further, the movement ability of the wildcard piece is revealed if the wildcard piece is used to capture another player's piece or should the player announce a “checkmate” involving use of the wildcard piece. The wildcard piece can be captured just like any other piece and, in one embodiment, upon capture, the movement ability of the wildcard piece is revealed to all players.
[0017] It may be advantageous to a player to keep the movement ability of the wildcard piece a secret for as long as possible. In one embodiment, if the wildcard piece places another player's king in “check” while the movement ability of the wildcard piece remains unrevealed, “check” does not have to be called and the other players king is unknowingly in “check”, whereupon if the other players next move does not take the king out of “check”, the wildcard piece can then capture the other players king ending the game for the other player. If a player unknowingly places his/her own king in “check” by another player's wildcard piece, the player's king may then be captured by the other players wildcard piece on the other players next turn thereby ending the game for the player.
[0018] Any suitable method of randomly determining the movement ability of the wildcard piece may be used, for example a die roll, a random generator on a computer, blindly selecting a token and the like. Any suitable name may be given to the wildcard piece, for example the Merlin™.
[0019] Each set of pieces may comprise one or more non-standard pieces instead of or in addition to the wildcard piece. If two or more non-standard pieces are used, the non-standard pieces may be the same or different. In a particularly preferred embodiment, each set of pieces may comprise one or more, preferably two, hybrid pieces having a non-standard movement ability that is a hybrid of the movement abilities of two or more standard chess pieces. In one embodiment, the movement ability of the hybrid piece is a hybrid of the queen and the knight by which the hybrid piece may move in any direction (horizontally, vertically or diagonally) up to a maximum of three spaces and may jump over intervening pieces. More preferably, movement of the hybrid piece along a rank or file is limited to no more than three spaces and movement along a diagonal is limited to no more than two spaces. Even more preferably, movement of the hybrid piece along a rank or file must be three spaces (not one or two) and along a diagonal must be two spaces (not one), thereby only emulating movement of a knight but in a straight line. As is usual in standard chess, movement of the hybrid piece cannot terminate on a space that is already occupied by a piece of the same player. The hybrid piece is an officer and is preferably a starting piece. Any suitable name may be given to the hybrid piece, for example the Longbow™.
[0020] When wildcard pieces are used, capture of a player's hybrid piece also triggers the ability of the player to introduce the wildcard piece on to the playing area. Further, the movement ability of the hybrid piece may be included in the list of choices for the movement ability of the wildcard piece. Because the hybrid piece may have a movement ability that can emulate other pieces, e.g. the queen, rook, bishop, knight or pawn, the exact nature of the wildcard piece can be kept a secret for an extended period of time because it may not be clear to the other player or players whether the wildcard piece has the movement ability of the standard piece or the hybrid piece.
[0021] In a particularly preferred embodiment, the chess game has at least two sets of pieces, each set comprising all of the standard chess pieces plus two extra pawns, two hybrid pieces and one wildcard piece for a total of 21 pieces. In an even more preferred embodiment, the chess game has two sets of pieces and the playing area comprises a 10×10 array of spaces for a total of 100 spaces in 10 ranks and 10 files. An initial configuration of the pieces on the playing area may comprise a row of 10 pawns on a player's second rank and a row of officers on the first rank. The officers may be positioned as in standard chess except that the hybrid pieces are between two other officers, preferably one between a first bishop and the king and the other between a second bishop and the queen. As previously indicated, the wildcard piece starts the game off the playing area so each player starts with 20 pieces on the playing area, 10 officers and 10 pawns.
[0022] “Check-mate” may be attained in the standard manner or as described above in connection with the wildcard piece. “Stale-mate” may be attained in the standard manner, or optionally if a player is only left with the king and can avoid “check-mate” for twenty moves. Further, “stale-mate” may arise from a unique situation where the player's only move may expose the player's king to a threat from an opponent's wildcard piece. This unique situation arises when the player has introduced the player's wildcard piece on to the playing area and it is possible to deduce the identity of the opponent's wildcard piece. In such a situation, when it is the player's turn to play and the player's king is not in “check”, but it is impossible for the player to make any move without placing the player's king in “check” from the opponent's wildcard piece or other of the opponent's pieces, then the player may reveal the identity of the player's own wildcard piece and declare a “stale-mate”. However, if the opponent challenges the declaration of “stale-mate”, the player must explicate the line of reasoning that allowed the player to deduce the identity of the opponent's wildcard piece, and if the player incorrectly deduced the identity of the opponent's wildcard piece, the player automatically loses the game.
[0023] Some examples of lines of reasoning for deducing the identity of a wildcard piece may be as follows. In one example, if the player has introduced the player's wildcard piece on to the playing area, the player may know what the identity of the opponent's wildcard piece cannot be. If the opponent has moved the opponent's wildcard piece the player has gained knowledge of what the opponent's wildcard piece may be. Based on the identity of the player's wildcard piece and the known movement ability of the opponent's wildcard piece, a process of elimination may reveal that the opponent's wildcard piece may have only one possible identity out of all the possibilities. In a second example, if the opponent has moved the opponent's wildcard piece in such a way such that the opponent's wildcard piece must be only one of the possible pieces, then the identity of the opponent's wildcard piece can be deduced. By deducing the identity of a wildcard piece, the wildcard piece is considered to have been revealed. Once the identity of the wildcard piece has been revealed, the unrevealed “checkmate” no longer applies and the player can declare a “stale-mate”.
[0024] Optionally, a winner may be resolved from a “stale-mate” by adding the value of all remaining pieces for each player with the player having the most value in pieces being declared the winner. The pieces may be valued as follows: pawn=1; knight=3, bishop=3, rook=5, hybrid piece=4, wildcard piece=7, queen=9. In the event that two players have the same highest piece value, a winner may be resolved randomly, for example by a coin toss.
[0025] Optionally, other rules variants may be introduced for interest or to accommodate the number of pieces and the size of the playing area. For example, pawns may be permitted to move one, two or three spaces forward in their first move rather than just one or two in order to be able to cover the distance across a larger playing area more quickly, if desired. En passant may or may not apply in the game as desired. Where en passant applies, an attacking pawn may execute the en passant maneuver if a defending pawn has moved two or three spaces forward during the defending pawn's first move. The attacking pawn must execute en passant in the turn immediately following the turn in which the defending pawn moved the two or three spaces.
[0026] Castling may involve any one or combination of a number of different variations. For example, castling may not be permitted at all. Castling may be permitted and involve any permutation of a rook and the king translating directly towards each other and the rook hopping over the king or the king hopping over the rook. For example, a rook may translate all the way to the king and the king hops over the rook or the king may translate all the way to a rook and the rook hops over the king. Castling may only be permitted if both the rook and king have not previously moved or may be permitted if one or both the rook and the king have previously moved as long as the rook and king are collinear (i.e. on the same rank or file). Castling along a file may be permitted in addition to or instead of castling along a rank.
[0027] The spaces of the playing area may be delineated by color or shading and playing area set up so that a darker space is at a bottom right corner of the playing area. The pieces may be distinguished by the standard black and white, but the player playing black pieces may be permitted to start play. Where light and dark spaces and light and dark pieces are used, the light queen may start on a light space and the dark queen on a dark space. Other than the variations described herein, the chess game follows standard chess rules, or any other compatible rule variants if desired.
[0028] The chess game comprises an apparatus for displaying the pieces and the playing area. In one embodiment, the apparatus may comprise physical chess pieces and a game surface comprising the array of spaces. The game surface may be a board, a table, a floor, a wall or any other surface that may support the pieces. In another embodiment, the apparatus may comprise a computer, an output device and an input device, the computer comprising a microprocessor for controlling operations and a non-transient electronic storage medium for storing information about the pieces and the playing area, and/or for storing computer executable code for carrying out instructions for implementing the method. The computer may further comprise a transient memory (e.g. random access memory (RAM)) accessible to the microprocessor while executing the code. A plurality of computer-based apparatuses may be connected to one another over a computer network system and geographically distributed. One or more of the computer-based apparatuses in the computer network system may comprise a microprocessor for controlling operations and a non-transient electronic storage medium for storing information about the pieces and the playing area, and/or for storing computer executable code for carrying out instructions for implementing the method, and the computer-based apparatuses in the network may interact so that the chess game may be played from remote locations. The output device may be a monitor, a printer, a device that interfaces with a remote output device or the like. The input device may be a keyboard, a mouse, a microphone, a device that interfaces with a remote input device or the like. With a computer, the pieces and playing area may be a graphical representation displayed in the output device. The input and/or output device may comprise physical chess pieces and/or a physical game surface comprising the array of spaces. The pieces may be movable manually in order to provide an electronic indication to the computer or in accordance with an electronic indication provided from the computer. In all embodiments, the pieces may be provided with any suitably distinguishing shape, color or other feature to distinguish each type of piece. There is also provided a computer readable non-transient storage medium having computer readable code stored thereon for executing computer executable instructions for carrying out the method.
[0029] Further features will be described or will become apparent in the course of the following detailed description. It should be understood that each feature described herein may be utilized in any combination with any one or more of the other described features, and that each feature does not necessarily rely on the presence of another feature except where evident to one of skill in the art.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] For clearer understanding, preferred embodiments will now be described in detail by way of example, with reference to the accompanying drawings, in which:
[0031] FIG. 1 depicts a chess board comprising a 10×10 square array of squares with chess pieces arranged in a starting position;
[0032] FIG. 2 depicts a 10×10 chess board showing a range of movement for a hybrid chess piece (L) and eight possible squares around a king (K) into which a wildcard piece (M) may be introduced;
[0033] FIG. 3 depicts a 10×10 chess board illustrating castling king side, castling queen side and initial pawn movements; and,
[0034] FIG. 4 depicts a 10×10 chess board illustrating en passant maneuvers.
DETAILED DESCRIPTION
[0035] As used herein, the term “standard” when used in the context of chess games and their components refers to the standard internationally accepted rules for chess governed by the World Chess Federation (Federation Internationale des Echecs, FIDE) and published as the FIDE Laws of Chess.
[0036] When describing the features of pieces of one color herein, the same description is applicable to pieces of another color.
[0037] Referring to FIG. 1 , one embodiment of a chess game is illustrated in which a chess board 100 comprises a square 10×10 array of square spaces arranged in a grid. The chess board 100 has ten ranks labelled 1-10 and ten files labelled a-j. Two sets of chess pieces are shown in their starting positions, where R=rook, Kn=knight, B=bishop, L=Longbow™, K=king, Q=queen, P=pawn and M=Merlin™. “Black” pieces are at the top of FIG. 1 and are shown in italicized letters. “White” pieces are at the bottom of FIG. 1 and are shown in non-italicized letters. The rooks, knights, bishop, queens, kings and pawns are all standard chess pieces with standard properties including movement. The standard pieces start in standard positions except that the ten files a-j permit the positioning of two extra pieces on black's back rank 10 and two extra pieces on white's back rank 1 . These extra pieces are the Longbow™, two of which (one of each color) are positioned between the kings and the bishops and two of which (one of each color) are positioned between the queens and the bishops. At the beginning of the game, the Merlin™ is positioned off the chess board 100 . The game proceeds in the standard manner except that black moves first and a pawn may be moved forward by 1, 2 or 3 squares in its file on the pawn's first move. A pawn that has already moved may subsequently only move one square in a given turn.
[0038] As the game proceeds, a player may have occasion to move a Longbow™ Referring to FIG. 2 , all possible movements of the white Longbow™ L from an interior square are shown. The white Longbow™ L attacks eight possible squares. The white Longbow™ L as shown in square d 7 may move 3 squares vertically in file d in either direction terminating at x in square d 10 or d 4 . Thus, the white Longbow™ L can attack two different squares in file d. The white Longbow™ L may alternatively move 3 squares horizontally in rank 7 in either direction terminating at x in square a 7 or g 7 . Thus, the white Longbow™ L can attack two different squares in rank 7 . Alternatively, the white Longbow™ L can move 2 squares along either diagonal in either direction terminating at x in square b 9 , b 5 , f 5 or f 9 . Thus, the white Longbow™ L can attack four different squares along the diagonals. The white Longbow™ L is not impeded by intervening pieces, whether of the same color or not, as the white Longbow™ L is permitted to jump over pieces in its path. However, the white Longbow™ L cannot terminate its movement in a square occupied by a piece of the same color. If the white Longbow™ L terminates its movement in a square occupied by a piece of the opposing color, that piece of the opposing color is captured.
[0039] As the game proceeds, a player, for example the player playing white, may lose his/her first officer. The officer captured may be a rook R, a knight Kn, a bishop B, a Longbow™ L or the queen Q, which are all starting pieces starting in the back rank as shown in FIG. 1 . As a move at any of the player's moves after losing the first officer, the player playing the white pieces may introduce the white Merlin™ M on to the board 100 . Referring to FIG. 2 , the white Merlin™ M may be first introduced on to the board 100 potentially in any of the eight squares h 4 , i 4 , j 4 , j 3 , j 2 , i 2 , h 2 or h 3 adjacent to the white king K in square i 3 . However, the white Merlin™ M cannot be introduced into a square occupied by a piece of the same color. Therefore, because the white pawn P occupies the square i 4 adjacent to the white king K, the white Merlin™ M cannot be introduced into square i 4 . The white Merlin™ M can be introduced into a square occupied by a piece of the opposing color, for example the black knight Kn in square h 4 , thereby capturing the piece of the opposing color. However, if a piece of the opposing color in a square adjacent to the white king K has the white king K in “check”, for example the black bishop B in square j 4 , the white Merlin™ M cannot be introduced into square j 4 . Further, if the white king K is in “check” from a piece of opposing color remote from the white king K, for example the black rook R in square f 3 , the white Merlin™ M cannot be introduced in square h 3 to block the “check”. In fact, as long as the white king K is in “check”, the white Merlin™ M cannot be introduced at all since the player has the obligation to counter the “check” before introducing the white Merlin™ M on to the board 100 . Thus, the white Merlin™ M can only be introduced on to the board 100 if it is white's turn to play, white has had at least one of its officers captured, white's king K is not in check and white's king K is not completely surrounded in adjacent squares by white pieces. As long as these requirements are met, the white Merlin™ M can be introduced at any time. In an alternate embodiment, the prohibition of introducing the Merlin™ M while the king is in check may be waived, in which case the Merlin™ M could be, for example, introduced in square h 3 to block the “check” from the black rook R in square f 3 or introduced in square j 4 to capture black bishop B in square j 4 .
[0040] When the Merlin™ is introduced on to the board, the player randomly chooses the movement ability of the Merlin™. The movement ability is selected from the standard movement abilities of the rook, knight or bishop or the movement ability of the Longbow™. Once the movement ability of the Merlin™ has been identified, the ability remains the same throughout the game. Selection can be conveniently made by drawing one of four tokens from a bag, each token having imprinted thereon a signifier of the type of piece the Merlin™ is to emulate. This token is kept secret by the player unless the player captures any opposing piece with the Merlin™ at any time after the Merlin™ is introduced on the board 100 or until the player uses the Merlin™ to make a “check-mate”. The token is not returned to the bag after the player's Merlin™ is captured.
[0041] As the game proceeds, a player may have occasion to castle, unless the rule variant does not permit castling. Castling is a special move involving a player's king and either of the players original rooks. It is the only move in chess in which a player may move two pieces in the same move turn. Referring to FIG. 3 , one embodiment where castling is permitted, castling king side and queen side is illustrated for a 10×10 chess board 100 . For example, when white castles king side, the white rook R in square j 1 moves three squares horizontally to the left along rank 1 to square g 1 and white king K in square f 1 then jumps over the rook to land in square h 1 . In castling queen side, the white rook R in square a 1 is moved four squares horizontally to the right along rank 1 to square e 1 and the white king K in square f 1 then jumps over the rook to land in square d 1 . Castling is only permitted if neither the king nor the castling rook has previously been moved, the squares between the king and the castling rook are not occupied by any pieces and the king is not in “check” prior to castling, does not move through “check” nor land on his destination square in which he would be in “check”. More specifically, a player cannot castle out of, through, or into “check”. It may be desirable for the player to move the king first to indicate to the opponent that the player is performing a castling maneuver. If the king castles through a square potentially attackable by an opponent's unrevealed Merlin™ and the opponent's unrevealed Merlin™ is a piece that could capture the king during the castling maneuver, the king is “checkmated” and the game is over once the opponent reveals the identity of the Merlin™.
[0042] As the game proceeds, a player invariably must move a pawn. Pawns are permitted to only move forward. Except when capturing another piece with a diagonal move, pawns may not move backward, horizontally or diagonally. Pawns normally move only one square; however, if a pawn has never moved, the pawn's first move may be one or more squares. For example, if a pawn has never moved, the pawn's first move may be one, two or three squares on the 10×10 chess board 100 illustrated in FIG. 3 for the black pawn P on square a 9 . From square a 9 the black pawn P may move one square to a 8 , two squares to a 7 or three squares to a 6 on the pawn's first move. After the first move, the pawn is limited to moving one square.
[0043] In games where en passant is permitted, one embodiment of how en passant may function for the 10×10 chess board 100 shown in FIG. 3 is illustrated in FIG. 4 . Because a pawn may move two or three squares on the pawn's first move, en passant may occur in two different situations. For example, if black pawn P at square e 9 was to move three squares to square e 6 , white pawn P at square f 6 would be able capture the black pawn P on white's very next move by moving to square e 7 in an en passant maneuver. Note that if black pawn P at square e 9 was to move two squares to square e 7 , white pawn P at square f 6 would still be able to capture the black pawn P using a normal capture maneuver. Referring to the white pawn P at square e 2 , if the white pawn P at square e 2 were to move two squares to square e 4 , black pawn P at square d 4 would be able to capture the white pawn now at square e 4 by moving to square e 3 in an en passant maneuver. Note that if white pawn P at square e 2 were to move three squares to square e 5 , black pawn P at square d 4 would still be able to capture the white pawn now at square e 5 by moving to square e 3 in an en passant maneuver. Thus, whenever the initial move of a first payer's pawn takes the pawn past or horizontally next to a pawn of a second player, the pawn of the second player may on the second player's very next move capture the pawn of the first player.
[0044] The novel features will become apparent to those of skill in the art upon examination of the description. It should be understood, however, that the scope of the claims should not be limited by the embodiments, but should be given the broadest interpretation consistent with the wording of the claims and the specification as a whole. | A chess game variant includes a wildcard piece that starts play off the playing area and that may be introduced on to the playing area in a space adjacent the king upon occurrence of a pre-defined condition, for example after an officer other than the king is captured for a first time. The movement ability of the wildcard piece may be randomly determined from the movement abilities of other officers, including any non-standard pieces used in the game. A non-standard piece may also be included in the chess game, for example a hybrid piece having a movement ability that is a hybrid of a queen and a knight where the hybrid piece can move in any direction and jump over other pieces but whose movement is restricted to no more than three spaces. | 0 |
BACKGROUND OF THE INVENTION
[0001] This application is based on provisional patent application Ser. No. 60/725,050 filed on Oct. 7, 2005.
[0002] 1. Field of the Invention
[0003] This invention relates to an anti-inflammatory composition for application to the nasal mucosa to control the inflammatory response in the nasal tissues often caused by inhalation of various pollutants and allergens and includes a combination of essential oils.
[0004] 2. Discussion of the Related Art
[0005] Allergies and chronic rhinitis are generally characterized by the excess proliferation of immune responder cells in the bloodstream and nasal fluids. The influx of responder cells to the airways and nasal passages produces the congestion, fluid outpouring and swelling that many allergy sufferers find so debilitating. While many antihistamines lessen some of these symptoms by preventing the release of histamine from mast cells or blocking histamine receptor sites, they do nothing to prevent the excess activation or proliferation of immune responder cells. The effects of pollution (ground level ozone, smog, sulfur dioxide, nitrogen oxide, and suspended particulates) in the air is believed to be responsible for a multitude of respiratory, as well as, cardiovascular ailments.
[0006] Allergic rhinitis, commonly referred to as “hay fever”, is believed to be a response to allergens such as pollens and molds and might be exacerbated by the exposure to pollution (ozone, NO, SO 2 , particulates). Primary sources for outdoor allergens include vascular plants (pollen, fern spores, soy dust), and fungi (spores, hyphae) with nonvascular plants, algae, and arthropods contributing smaller numbers of allergen-bearing particles.
[0007] Respiratory allergic diseases include seasonal allergic rhinitis or hay fever, perennial allergic rhinitis and allergic asthma. While the prevalence of allergies and associated conditions is difficult to accurately assess, recent estimates show that between 20% to 25% of the U.S population is afflicted with allergic rhinitis. It is believed that allergic rhinitis is currently the most common of all chronic diseases in children. Unfortunately, untreated allergic rhinitis not only detrimentally affects children's physical and psychosocial well-being, quality of life, and capacity to function and learn, but it is also associated with, and may contribute to, potentially serious conditions, including asthma and sinusitis.
[0008] In recent years, scientists have shown that air pollution from cars, factories and power plants is a major cause of chronic rhinitis, asthma and allergy attacks. More than 159 million Americans—over half the nation's population—live in areas with polluted air. A research study published in 2002 estimated that 30 percent of childhood asthma and allergic episodes are due to environmental exposures, costing the US more than $2 billion per year. Studies also suggest that air pollution may contribute to the development of asthma and allergic rhinitis in previously healthy people.
[0009] The following sources of air pollutants can trigger asthma and allergic rhinitis:
Ground Level Ozone: A toxic component of smog, ozone triggers asthma attacks and makes existing asthma worse. It may also lead to the development of asthma in children. Ozone is produced at ground level when tailpipe pollution from cars and trucks reacts with oxygen and sunlight. Ground level ozone is a big problem in cities with lots of traffic, such as Los Angeles, Houston and New York City. In 2004, according to the American Lung Association, 136 million people lived in areas that violated ozone air quality standards. Sulfur Dioxide (SO 2 ): A respiratory irritant associated with the onset of asthma and allergy attacks, sulfur dioxide is produced when coal and crude oil are burned. Coal-fired power plants, particularly older plants that burn coal without SO 2 pollution controls, are the worst SO 2 polluters. One in five Americans lives within 10 miles of a coal-fired power plant. Oil refineries and diesel engines that burn high-sulfur fuel also release large amounts of SO 2 into the air. Particulate Matter: This term refers to a wide range of pollutant such as dust, soot, fly ash, diesel exhaust particles, wood smoke and sulfate aerosols which are suspended as tiny particles in the air. Some of these fine particles can become lodged in the lungs and often trigger allergy and asthma attacks. Studies have shown that the number of hospitalizations for asthma increases when levels of particulate matter in the air rise. Coal-fired power plants, factories and diesel vehicles are major sources of particulate pollution. Around 81 million people live in areas that fail to meet national air quality standards for particulate matter in the United States alone.
[0013] Nitrogen Oxide (NOx): A gas emitted from tailpipes and power plants, nitrogen oxide contributes to the formation of ground-level ozone and smog. It also reacts with other air pollutants to form small particles that can cause breathing difficulties, especially in people with asthma and allergic rhinitis.
SUMMARY OF THE INVENTION
[0014] The present invention is directed to a composition comprising a combination of several essential oils for controlling inhalation of pollutants and allergens. Preferred embodiments of the composition include Jojoba oil, rosemary oil, any of a variety of citrus oils, sesame oil, soy oil, thyme oil, oregano oil, chamomile oil, peppermint oil, cardiospermum halicacabum, galphima glauca, luffa operculata , bee's milk, bee's wax, and aloe vera in various combinations and sub-combinations. The composition may further include lauric acid, d-limonene and luteolin. When the composition is applied to the nasal mucosa, these oils provide a physical barrier that acts as a target for oxidizing and chemically-active pollution components, reducing these effects on the epithelial cells that line the nasal mucosal surfaces. Anti-inflammatory benefits may also be provided by the composition through its capacity to up-regulate anti-oxidant and anti-inflammatory gene pathways, including, but not limited to, those of Nrf2, Heme Oxygenase-1, Catalase, the Glutathione redox system, Superoxide Dismutase, Quinone Reductase, Thioredoxin, and Toll-like Receptor-4. The composition may also provide protection by down-regulating gene pathways and their enzyme products that are pro-inflammatory and pro-oxidant. Examples include, but are not limited to, Nuclear Factor kappa B, Activator Protein-1, and inducible Nitric Oxide Synthase pathways. In addition, Rosmarinic acid, a plant polyphenol derived from rosemary leaf and present in rosemary oil, has been shown to provide effective, temporary relief of allergy symptoms. Rosmarinic acid, along with the other oils mentioned above, have significant antioxidant, anti-inflammatory and even some antimicrobial activities. The antioxidant activity of rosmarinic acid is known to be stronger than that of vitamin E. Rosmarinic acid, as well as other of the aforementioned oils, helps to prevent cell damage caused by free radicals and also provides anti-inflammatory properties. And, unlike antihistamines, these oils help to prevent the activation of immune responder cells, which cause swelling and fluid formation. Scientists have demonstrated that perilla leaf enriched with rosmarinic acid provided significant relief from seasonal allergies by inhibiting polymorphonuclear leukocyte infiltration into the nostrils. Unlike antihistamines, the composition of the present invention prevents the activation of immune responder cells by trapping many allergens and pollutants that seek to enter the body through the nose. The composition also protects the cells from the harmful effects of oxidizing agents such as those mentioned supra (i.e., ozone, nitrogen oxide, sulfur dioxide, and particulate matter.)
[0015] The composition of the present invention helps to alleviate the body's immunologic response to many allergens including, but not limited to, dust mites, pollen, hay fever, animal dander, dust, particulate pollution, ozone, sulfur dioxide, and nitrogen oxide. In particular, the composition is effective in trapping these allergens and alleviating the body's response to their presence. In the case of ozone, SO 2 and NOx, the composition acts as a barrier in the nose and lessens the IGA response in the body. It is also believed that the composition works to lessen the Interleukin expression in the nose, especially IL8, which is commonly responsible for the inflammatory response in the nasal cavity. A particularly effective formulation includes one or more of the following ingredients: jojoba oil, peppermint oil, rosemary oil, citrus oils, sesame oil, soy oil, thyme oil, coconut oil, oregano oil and chamomile oil. The composition may further include lauric acid, d-limonene, and aloe vera. In addition, the composition may include luteolin, another plant flavonoid that has been shown to maintain normal respiratory function and healthy fluid balance.
[0000] Objects and Advantages
[0016] Considering the foregoing, it is a primary object of the present invention to provide a composition for application to the nasal mucosa for controlling the respiratory effects of inhaled pollutants and allergens.
[0017] It is a further object of the present invention to provide a composition comprising a combination of essential oils for application to the nasal mucosa, wherein the composition is effective in trapping allergens and alleviating the body's response to their presence.
[0018] It is a further object of the present invention to provide a composition comprising a combination of essential oils for controlling inhalation of pollutants and allergens, and wherein the composition possesses anti-inflammatory and anti-oxidant properties.
[0019] It is a further object of the present invention to provide a composition comprising a combination of essential oils, wherein the composition interferes with the release or effectiveness of agents produced by bacterial, fungal or other biological contaminants that enter the nasal passages along with allergens and particulate matter.
[0020] It is a further object of the present invention to provide a composition comprising a combination of essential oils, wherein the composition masks or reduces the irritating or objectionable odors associated with exposure to airborne pollutants in indoor and outdoor environments.
[0021] It is a further object of the present invention to provide a composition comprising a combination of essential oils, wherein the composition interferes with the release and downstream pathway effects of chemicals released by cells involved with the immune/allergic response.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0022] The present invention is directed to a long lasting anti-inflamatory composition for application to the nasal mucosa. The anti-inflammatory composition of the present invention incorporates the use of one or more essential oils. Other oils and agents are contemplated for use in the composition as the anti-inflammatory solution, either alone or as a combination.
[0023] One or more primary ingredients of the composition are present according to the following percentages by weight of the composition:
Amount Ingredients (% by Weight of the Composition) Peppermint oil between 0.1% and 5% Jojoba oil between 5% and 70% Soy oil between 0.5% and 56% Cocos Nucifera (coconut oil) between 1% and 30% Citrus oil between 0.5% and 15% Rosemary oil between 0.5% and 20%
[0024] The anti-inflammatory composition of the present invention may include the following additional ingredients, alone or in combination: lauric acid; d-limonene; sesame oil; chamomile oil; cardiospermum halicacabum; galphimia glauca, luffa operculata ; bees milk; and a preservative such as benzylkonium chloride or BHT or sodium benzoate. Other additional ingredients of the composition may be present according to the following percentages by weight of the composition:
Amount Additional Ingredients (% by Weight of the Composition) Bee's Milk between .2% and 50% Bee's Wax between .5% and 10% Cardiospermum halicacabum between .2% and 5% Galphimia glauca between .2% and 5% Luffa operculata between .2% and 5% Chamomile oil between 1% and 10%
[0025] A further embodiment of the composition has been proven to help alleviate the body's immunologic response to many allergens and pollutants. The following ingredients have been found to be effective in the composition when present according to the following percentages by weight of the composition:
Amount Ingredients (% by Weight of the Composition) Bee's Wax between 0.01% and 30% Bee's Milk between 0.01% and 30% Fruit Wax between 0.1% and 5%
[0026] The following examples demonstrate various combinations of ingredients, including the essential ingredients, which have been observed to yield:
[0027] In one series of experiments using the test combination of ingredients according to the several examples of the composition listed below, epithelial cells of the human respiratory tract were utilized to test the protective effects of the preparation against oxidant damage caused by exposure to the environmental air pollutant, ozone. The cells were grown in culture at the air-liquid interface to allow them to undergo mucociliary differentiation to the cellular anatomy normally seen in vivo. Cells thus cultured grow on porous filters with medium below and their apical surfaces exposed to the air above. In one set of experiments, the apical surfaces of the cells were treated for 5 minutes with the test composition or with culture medium (control), which was immediately removed. The cultures were then transferred to environmentally controlled chambers for exposure to air, or air containing 0.20 ppm ozone, for 3 hours. The release of Tumor Necrosis Factor alpha (TNFα) was used as a marker of oxidant stress in the cells following ozone exposure. TNFα release was reduced by 89.7% post exposure in test composition-treated cells compared to those treated with culture medium. These results support the claim that application of the test composition provides immediate protection against the toxic effects of oxidant pollutants, such as ozone. In another set of experiments, cells were similarly pretreated with the test composition or medium control, but were held for three hours prior to exposure to ozone following the above protocol. In these experiments, TNFαrelease was completely abolished in test composition-treated cells compared to those treated with culture medium. These results support the claim that the test composition activates time-dependent changes within the cells, likely through anti-oxidant and anti-inflammatory pathways, that afford protection from exposure to agents that activate or cause damage to cells through oxidant pathways.
[0028] Examples of the test composition are as follows:
EXAMPLE 1
[0029]
Amount
Ingredient
(% by Weight of the Composition)
Peppermint oil
.5%
Aloe Vera oil
4.5%
Soy oil
70%
Cocos Nucifera
20%
Citrus Oil
4.9%
Benzalkonium chloride
.1%
EXAMPLE 2
[0030]
Amount
Ingredient
(% by Weight of the Composition)
Peppermint oil
.5%
Cocos Nucifera
20%
Citrus Sinensis
9.4%
Glycine Soja
70%
Benzylkonium Chloride
0.1%
(preservative)
EXAMPLE 3
[0031]
Amount
Ingredient
(% by Weight of the Composition)
Jojoba oil
34.8%
Cocos Nucifera
3%
Citrus Sinensis
2%
Aloe Vera
2.85%
Peppermint oil
.25%
Glycine Soja
57%
BHT
0.1%
EXAMPLE 4
[0032]
Amount
Ingredient
(% by Weight of the Composition)
Glycine Soja
35%
Citrus Sinensis
30%
Cocos Nucifera
30%
Bees Milk
4.9%
Preservative
0.1%
EXAMPLE 5
[0033]
Amount
Ingredient
(% by Weight of the Composition)
Bees Milk
50%
Lecithin
10%
Citrus Sinensis
20%
Glycine Soja
19.9%
Preservative
0.1%
[0034] In one of its applications, the anti-inflammatory and anti-oxidant composition is typically administered to the nasal mucosa with the use of a metered nasal spray applicator according to the following procedure:
[0035] 1. The bottle containing the composition is shaken well to ensure complete mixing of the ingredients.
[0036] 2. The tip of the applicator nozzle is inserted into one nostril.
[0037] 3. While breathing in gently through the nose, the applicator is activated to release a fine spray, in a volume from 10 to 200 microliters, into the nasal cavity.
[0038] 4. Step 3 is repeated for the second nostril.
[0039] In another of its applications, the composition is applied to the vestibule of each nostril using a cotton swab applicator according to the following procedure:
[0040] 1). Shake the bottle (containing the composition) well to insure complete mixture of the ingredients.
[0041] 2) Apply approximately 4 drops of the composition to the cotton tip of a cotton swab so that the cotton tip is fully saturated with the composition.
[0042] 3). Place the thumb and index finger on the swab stem directly below the wetted cotton tip of the swab. Prepare to apply the composition to the rim of each nostril just past the nasal opening.
[0043] 4). Place only the cotton tip of the swab just inside of the nostril opening. Using a gentle motion, make 3 or 4 circles to fully apply the composition to the rim of the nostril. Repeat this step for the other nostril.
[0044] 5). Discard the swab. Gently squeeze the nostrils together to ensure even distribution of the solution about the rim surrounding each nostril opening.
[0045] In order to evaluate the anti-inflammatory efficacy of one sample of the composition when applied to the nasal mucosa of human volunteers by spray application, a study was conducted at the National Institute of Health in Manila, Philippines. Modifications to standard methods for several procedures required for the study, such as nasal lavage, cytologic preparation of lavaged cells for differential analysis and the isolation of lavage fluid for quantification of markers of inflammation by enzyme-linked immunosorbent assay (ELISA), were validated in laboratories at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Md. The details of the Manila study are set forth below.
[0000] Purpose:
[0046] The study was designed to evaluate the effectiveness of the test composition, when applied by spray aerosol, in reducing measures of the inflammatory and irritating effects of ambient air pollution on the upper respiratory system. Study endpoints included both quantitative and qualitative measures of this effectiveness.
[0000] Scope and Design:
[0047] Following a double-blinded, randomized cross-over design, the study recruited and enrolled 45 subjects who worked as traffic enforcers for the Metropolitan Manila Development Authority. This group of subjects represents a cohort of individuals who are very highly exposed to primarily vehicular diesel exhaust and related street-level airborne gaseous and particulate pollutants on a daily basis. After screening to exclude smokers and those with acute or chronic respiratory diseases or specific allergies, informed consent was obtained and the subjects were randomly assigned to two groups, to start in either the test composition arm or the placebo arm. Both preparations were applied by metered spray in a volume of 50 microliters to each nostril. The study encompassed a three week period, comprising one week of three-times daily application of the test composition or placebo (Arm 1), one week of wash-out, and a final week of three-times daily application of the second of the two preparations (Arm 2). Subjects completed daily symptom questionnaires during each of the treatment arms and, at the beginning and end of each arm, subjects were interviewed and underwent nasal lavage to allow measurement of the levels of cellular inflammation and the release of inflammatory mediators. Interviews and internal controls were used to verify compliance with the treatment protocol. No reportable Adverse Events were observed during or following completion of the study.
[0048] While the composition of the present invention has been described and exemplified according to several preferred embodiments thereof, it is recognized that departures from the instant disclosure are fully contemplated within the spirit and scope of the invention which is not to be limited except as defined in the following claims as interpreted under the Doctrine of Equivalents. | An anti-inflammatory composition for application to the nasal mucosa includes a combination of essential oils. The composition is intended to help prevent and/or alleviate the effects of exposure caused by the inhalation of pollutants and allergens. Preferred embodiments of the composition include jojoba oil, rosemary oil, any of a variety of citrus oils, coconut oil, sesame oil, soy oil, thyme oil, oregano oil, chamomile oil, peppermint oil, cardiospermum halicacabum, galphimia glauca, luffa operculata , bee's milk, bee's wax, and aloe vera in various combinations and sub-combinations. The composition may further include lauric acid, d-limonene and luteolin. | 0 |
This application claims priority from provisional application Ser. No. 60/283,262, filed Apr. 12, 2001, the entire disclosure of which is hereby incorportated by reference.
This invention concerns novel tricyclic pyridyl carboxamides which act as oxytocin receptor antagonists, as well as methods of their manufacture, methods of treatment and pharmaceutical compositions utilizing these compounds. The compounds of the present invention are useful therapeutic agents in mammals, particularly in humans. More specifically, they can be used in the prevention and/or suppression of preterm labor, for the suppression of labor at term prior to caesarean delivery, to facilitate antinatal transport to a medical facility, and for the treatment of dysmenorrhea. These compounds also useful in enhancing fertility rates, enhancing survival rates and synchronizing estrus in farm animals; and may be useful in the prevention and treatment of disfunctions of the oxytocin system in the central nervous system including obsessive compulsive disorder (OCD) and neuropsychiatric disorders.
BACKGROUND OF THE INVENTION
Premature labor remains the leading cause of perinatal mortality and morbidity. Infant mortality dramatically decreases with increased gestational age. The survival rate of prematurely born infants increases from 20% at 24 weeks to 94% at 30 weeks. Moreover the cost associated with the care of an infant born prematurely is very high. While many agents have been developed for the treatment of premature labor in the last 40 years, the incidence of pre-term births and low birth weight infants has remained relatively unchanged. Therefore there remains an unmet need for the development of a safe and effective treatment of preterm labor.
Tocolytic (uterine relaxing) agents currently in use include β 2 adrenergic receptor agonists such as Ritodrine which is moderately effective in suppressing preterm labor, but it is associated with maternal hypotension, tachycardia, and metabolic side effects. Several other agents have been used to suppress premature labor, including other β 2 adrenergic agonists (terbutaline, albuterol), magnesium sulfate, NSAIDs (indomethacin), and calcium channel blockers. The consensus is that none of these agents is very effective; there is no clinical evidence showing that these compounds can prolong gestation for more than 7 days (Johnson, Drugs, 45, 684–692 (1993)). Furthermore, their safety profile is not ideal. Adverse effects include respiratory depression and cardiac arrest (magnesium sulfate), hemodynamic effects (calcium channel blockers), premature closure of the ductus arteriosus and oligohydramnios (NSAIDS; prostaglandin synthase inhibitors). Therefore there is an unmet need for safer and more efficacious agents for the treatment of preterm labor with better patient tolerability. Specific requirements with regard to safety include a product with no or low rates of tachycardia, limited anxiety, improved fetal safety, and few, if any, adverse cardiovascular effects.
One target of interest is the oxytocin receptor in the uterus, and a selective oxytocin receptor antagonist has been proposed as an ideal tocolytic agent. While the exact role of oxytocin (OT) in parturition has not been clearly defined, there is evidence strongly suggesting that it may play a critical role in the initiation and progression of labor in humans (Fuchs et al. Science 215, 1396–1398 (1982); Maggi et al. J. Clin. Endocrinol. Metab. 70, 1142–1154 (1990); Åkerlund, Reg. Pept 45, 187–191 (1993); Åkerlund, Int. Congr. Symp. Semin. Ser., Progress in Endocrinology 3, 657–660 (1993); Åkerlund et al., in Oxytocin , Ed. R. Ivell and J. Russel, Plenum Press, New York, pp 595–600 (1995)). Preliminary clinical trials with oxytocin receptor antagonists support the concept that a blockade of OT receptors reduces uterine myometrial activity and delays the onset of labor (Åkerlund et al., Br. J. Obst. Gynaecol. 94, 1040–1044, (1987); Andersen et al., Am. J. Perinatol. 6, 196–199 (1989); Melin, Reg. Pept. 45, 285–288 (1993)). Thus, a selective oxytocin antagonist is expected to block the major effects of oxytocin exerted mainly on the uterus at term, and to be more efficacious than current therapies for the treatment of preterm labor. By virtue of its direct action on the receptors in the uterus an oxytocin antagonist is also expected to have fewer side effects and an improved safety profile.
The following references describe peptidic oxytocin antagonists: Hruby et al., Structure-Activity Relationships of Neurohypophyseal Peptides, in The Peptides: Analysis, Synthesis and Biology ; Udenfriend and Meienhofer Eds., Academic Press, New York, Vol. 8, 77–207 (1987); Pettibone et al., Endocrinology, 125, 217 (1989); Manning et al., Synthesis and Some Uses of Receptor-Specific Agonists and Antagonists of Vasopressin and Oxytocin, J. Recept. Res., 13, 195–214 (1993); Goodwin et al., Dose Ranging Study of the Oxytocin Antagonist Atosiban in the Treatment of Preterm Labor, Obstet. Gynecol., 88, 331–336 (1996). Peptidic oxytocin antagonists suffer from a lack of oral activity and many of these peptides are non-selective antagonists since they also exhibit vasopressin antagonist activity. Bock et al. [ J. Med. Chem. 33, 2321 (1990)], Pettibone et al. [ J. Pharm. Exp. Ther. 256, 304 (1991)], and Williams et al. [ J. Med. Chem., 35, 3905 (1992)] have reported on potent hexapeptide oxytocin antagonists which also exhibit weak vasopressin antagonistic activity in binding to V 1 and V 2 receptors.
Various non-peptidic oxytocin antagonists and/or oxytocin/vasopressin (AVP) antagonists have recently been reported by Pettibone et al., Endocrinology, 125, 217 (1989); Yamamura et al., Science, 252, 572–574 (1991); Evans et al., J. Med. Chem., 35, 3919–3927 (1992); Pettibone et al., J. Pharmacol. Exp. Ther, 264, 308–314 (1992); Ohnishi et al., J. Clin. Pharmacol. 33, 230–238, (1993); Evans et al., J. Med. Chem. 36, 3993–4006 (1993); Pettibone et al., Drug Dev. Res. 30, 129–142 (1993); Freidinger et al., General Strategies in Peptidomimetic Design: Applications to Oxytocin Antagonists, in Perspect. Med. Chem. 179–193 (1993), Ed. B. Testa, Verlag, Basel, Switzerland; Serradeil-LeGal, J. Clin. Invest., 92, 224–231 (1993); Williams et al., J. Med. Chem. 37, 565–571 (1994); Williams et al., Bioorg. Med. Chem. 2, 971–985 (1994); Yamamura et al., Br. J. Pharmacol., 105, 546–551 (1995); Pettibone et al., Advances in Experimental Medicine and Biology 395, 601–612 (1995); Williams et al., J. Med. Chem. 38, 4634–4636 (1995); Hobbs et al., Biorg. Med. Chem. Lett. 5, 119 (1995); Williams et al., Curr. Pharm. Des. 2, 41–58 (1996); Freidinger et al., Medicinal Research Reviews, 17, 1–16 (1997); Pettibone et al., Biochem. Soc. Trans. 25 (3), 1051–1057 (1997); Bell et al., J. Med. Chem. 41, 2146–2163 (1998); Kuo et al., Bioorg. Med. Chem. Lett. 8, 3081–3086 (1998); Williams et al., Biorg. Med. Chem. Lett. 9, 1311–1316 (1999).
Certain carbostyril derivatives and bicyclic azepines are disclosed as oxytocin and vasopressin antagonists by Ogawa et al. in WO 94/01113 (1994); benzoxazinones are disclosed as oxytocin and vasopressin receptor antagonists by Sparks et al. in WO 97/25992 (1997); Williams et al. disclose piperidine oxytocin and vasopressin receptor antagonists in WO 96/22775 (1996); Bock et al. disclose benzoxazinone and benzopyrimidinone piperidines useful as oxytocin and vasopressin receptor antagonists in U.S. Pat. No. 5,665,719 (1997); piperazines and spiropiperidines useful as oxytocin and vasopressin receptor antagonists are disclosed by Evans et al. in U.S. Pat. No. 5,670,509 (1997) and by Bock et al. in U.S. Pat. No. 5,756,504 (1998); Bell et al. disclose piperazine oxytocin receptor antagonists in UK Patent Application, GB 2 326 639 A (1998); Bell et al. disclose benzoxazinone and quinolinone oxytocin and vasopressin receptor antagonists in UK Patent Application GB 2 326 410 A (1998); Bell et al. disclose benzoxazinone oxytocin and vasopressin receptor antagonists in U.S. Pat. No. 5,756,497 (1998); Matsuhisa et al. disclose difluoro tetrahydrobenzazepine derivatives as oxytocin antagonists in WO 98/39325 (1998); Ogawa et al. disclose heterocyclic bisamides with vasopressin and oxytocin antagonist activity in U.S. Pat. No. 5,753,644 (1998); and Ogawa et al. disclose benzazepine derivatives with anti-vasopressin activity, oxytocin antagonistic activity and vasopressin agonist activity, useful as vasopressin antagonists, vasopressin agonists and oxytocin antagonists in WO 97/22591 (1997) and U.S. Pat. No. 6,096,736 (2000).
Trybulski et al. disclose 3-carboxamide derivatives of pyrrolobenzodiazepine bisamides with vasopressin antagonist activity in U.S. Pat. No. 5,880,122 (1999); bicyclic thienoazepines with vasopressin and oxytocin receptor antagonist activity are disclosed by Albright et al. in WO 96/22294 (1996) and U.S. Pat. No. 5,654,297 (1997); and tricyclic benzazepines with vasopressin and oxytocin receptor antagonist activity are disclosed by Albright et al. in WO 96/22282 (1996) and U.S. Pat. No. 5,849,735 (1998).
Albright et al. broadly disclose tricyclic benzazepine compounds which possess antagonistic activity at the V 1 and/or V 2 receptors and exhibit in vivo vasopressin antagonistic activity, as well as antagonistic activity at the oxytocin receptors.
Venkatesan et al. broadly disclose tricyclic benzazepines with vasopressin and oxytocin antagonist activity in U.S. Pat. No. 5,521,173 (1996), WO 96/22292 (1996), and in U.S. Pat. No. 5,780,471 (1998).
Oxytocin antagonists can be useful for the treatment and/or prevention and/or suppression of preterm labor, for the suppression of term labor prior to a caesarian delivery, and to facilitate antinatal transport to a medical facility. They also can produce contraception in mammals given that oxytocin antagonists have been shown to inhibit the release of oxytocin-stimulated luteneizing hormone (LH) from pituitary cells (Rettori et al., Proc. Nat. Acad. Sci. U.S.A. 94, 2741–2744 (1997); Evans et al., J. Endocrinol., 122, 107–116 (1989); Robinson et al., J. Endocrinol. 125, 425–432 (1990)).
Oxytocin antagonists also have the ability to relax uterine contractions induced by oxytocin in mammals and thus can be also useful for the treatment of dysmenorrhea, a condition characterized by pain during menstruation (Åkerlund, Int. Congr. Symp. Semin. Ser., Progress in Endocrinology 3, 657–660 (1993); Åkerlund, Reg. Pept. 45, 187–191 (1993); Melin, Reg. Pept. 45, 285–288 (1993)). Primary dysmenorrhea is associated with ovulatory cycles, and it is the most common complaint of gynecologic patients. Myometrial hypercontractility and decreased blood flow to the uterus are thought to be causative factors for the symptoms of primary dysmenorrhea (Åkerlund, Acta Obstet. Gynecol. Scand. 66, 459–461 (1987). In particular, vasoconstriction of small uterine arteries by vasopressin and oxytocin is thought to produce tissue ischemia and pain (Jovanovic et al., Br. J. Pharmacol. 12, 1468–1474 (91997); Chen et al., Eur. J. Pharmacol. 376, 25–51 (1999)).
The administration of oxytocin receptor antagonists to farm animals after fertilization has been found to enhance fertility rates by blocking oxytocin induced luteolysis leading to embryonic loss (Hickey et al., WO 96/09824 A1 (1996), Sparks et al., WO 97/25992 A1 (1997); Sparks et al., U.S. Pat. No. 5,726,172 A (1998)). Thus, oxytocin receptor antagonists can be useful in farm animal husbandry to control timing of parturition and delivery of newborns resulting in enhanced survival rates. They can also be useful for the synchronization of estrus by preventing oxytocin induced corpus luteum re.g.ression and by delaying estrus (Okano, J. Reprod. Dev. 42 (Suppl.), 67–70 (1996)). Furthermore oxytocin receptor antagonists have been found to have a powerful effect in inhibiting oxytocin-induced milk ejection in dairy cows (Wellnitz et al., Journal of Dairy Research 66, 1–8 (1999)).
Oxytocin is also synthesized in the brain and released in the central nervous system. Recent studies have established the importance of central oxytocin in cognitive, affiliative, sexual and reproductive behavior, and in regulating feeding, grooming and response to stress in animals. Oxytocin may also influence normal behavior in humans. Modulators of oxytocin binding to its receptors in the central nervous system may be useful in the prevention and treatment of disfunctions of the oxytocin system, including obsessive compulsive disorder (OCD) and other neuropsychiatric disorders (Kovacs et al., Psychoneuroendocrinology 23, 945–962 (1998); McCarthy et al., U.K. Mol. Med. Today 3, 269–275 (1997); Bohus, Peptidergic Neuron, [Int Symp. Neurosecretion], 12 th (1996), 267–277, Publ. Birkhauser, Basel, Switz.; Leckman et al., Psychoneuroendocrinology 19, 723–749 (1994)).
Compounds which act as competitive inhibitors against vasopressin binding to its receptors are useful in the treatment or prevention of state diseases involving vasopressin disorders in mammals, which include vasodilation and aquaresis (free-water diuresis), treating hypertension and inhibiting platelet aggregation. They are useful in the treatment of congestive heart failure, cirrhosis with ascites, and in the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Furthermore, vasopressin receptor antagonists have been found to be useful in treating disturbances or illnesses of the inner ear, particularly those related to Meniere's disease (Zenner et al., WO 99/24051-A2 (1999)); and for the prevention and treatment of ocular circulatory disorders, particularly intraocular hypertension or glaucoma and vision disorders such as shortsightedness (Ogawa et al., WO 99/38533-A1 (1999)).
SUMMARY OF THE INVENTION
This invention relates to novel compounds selected from those of Formula (I):
wherein:
R 1 and R 2 are, independently, selected from hydrogen, (C 1 –C 6 )lower alkyl, halogen, cyano, trifluoromethyl, hydroxy, amino, (C 1 –C 6 ) lower alkylamino, (C 1 –C 6 ) lower alkoxy, —OCF 3 , (C 1 –C 6 ) lower alkoxy carbonyl, —NHCO[(C 1 –C 6 )lower alkyl], carboxy, —CONH 2 , —CONH[(C 1 –C 6 ) lower alkyl], or —CON[(C 1 –C 6 ) lower alkyl] 2 ;
R 3 is a substituent selected from hydrogen, (C 1 –C 6 ) lower alkyl, (C 1 –C 6 ) lower alkoxy, hydroxy, amino, (C 1 –C 6 ) lower alkylamino, CO lower alkyl (C 1 –C 6 ), or halogen;
R 4 is the moiety B–C; wherein:
B is selected from the group of:
and C is selected from the group of:
wherein:
A is CH or N; R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are, independently, selected from hydrogen, (C 1 –C 6 ) lower alkyl, (C 1 –C 6 ) lower alkoxy, (C 1 –C 6 ) lower alkylcarbonyl, (C 3 –C 6 ) lower alkenyl, (C 3 –C 6 ) lower alkynyl, (C 3 –C 8 ) cycloalkyl, formyl, cycloalkylcarbonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryl alkyloxycarbonyl, carbamoyl, —O—CH 2 —CH═CH 2 , halogen, halo lower alkyl, trifluoromethyl, OCF 3 , S(lower alkyl), —OC(O)N[lower alkyl] 2 , —CONH[lower alkyl], —CON[lower alkyl] 2 , lower alkylamino, di-lower alkylamino, lower alkyl di-lower alkylamino, hydroxy, cyano, trifluoromethylthio, nitro, amino, lower alkylsulfonyl, aminosulfonyl, lower alkylaminosulfonyl,
phenyl or naphthyl;
R 11 and R 12 are, independently, selected from the group of hydrogen, (C 1 –C 6 ) lower alkyl, (C 1 –C 6 ) lower alkenyl, (C 3 –C 6 ) lower alkynyl, hydroxy (C 1 –C 6 ) lower alkyl, alkoxy (C 1 –C 6 ) lower alkyl, acyloxy (C 1 –C 6 ) lower alkyl, cyclo lower alkyl, or aryl, optionally substituted by hydroxy, (C 1 –C 6 ) lower alkoxy, halogen, cyano, —SO 2 [(C 1 –C 6 ) lower alkyl, or —S[(C 1 –C 6 ) lower alkyl];
and R is selected from any of the following groups:
wherein:
R 13 is selected from hydrogen, (C 1 –C 6 ) lower alkyl, cyanoethyl or
R 14 is selected from hydrogen or (C 1 –C 6 ) lower alkyl;
R 15 is one or two substituents selected from the group of hydrogen, (C 1 –C 6 ) lower alkyl, halogen, trifluoromethyl, (C 1 –C 6 ) lower alkoxy, (C 1 –C 6 ) lower alkoxycarbonyl, or
R 16 represents one to two substituents selected from hydrogen, or (C 1 –C 6 ) lower alkyl;
m is an integer from 0 to 2;
n is an integer from 1 to 2;
and p is an integer from 0 to 1;
and the pharmaceutically acceptable salts, or pro-drug forms thereof.
Among the more preferred compounds of this invention are those of the formula:
wherein:
R 1 and R 2 are, independently, selected from hydrogen, (C 1 –C 6 )lower alkyl, halogen, cyano, trifluoromethyl, hydroxy, amino, (C 1 –C 6 ) lower alkylamino, (C 1 –C 6 ) lower alkoxy, —OCF 3 , (C 1 –C 6 ) lower alkoxycarbonyl, —NHCO[(C 1 –C 6 )lower alkyl], carboxy, —CONH 2 , —CONH (C 1 –C 6 ) lower alkyl, or —CON[(C 1 –C 6 ) lower alkyl] 2 ;
R 3 is a substituent selected from hydrogen, (C 1 –C 6 ) lower alkyl, (C 1 –C 6 ) lower alkoxy, hydroxy, amino, (C 1 –C 6 ) lower alkylamino, —CO lower alkyl (C 1 –C 6 ), or halogen;
R 4 is the moiety B–C; wherein:
B is selected from the group of:
and C is selected from the group of:
R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently, selected from H, (C 1 –C 6 ) lower alkyl, (C 1 –C 6 ) lower alkoxy, hydroxy (C 1 –C 6 ) lower alkyl, alkoxy (C 1 –C 6 ) lower alkyl, acyloxy (C 1 –C 6 ) lower alkyl, (C 1 –C 6 ) lower alkylcarbonyl, (C 3 –C 6 ) lower alkenyl, (C 3 –C 6 ) lower alkynyl, (C 3 –C 8 ) cycloalkyl, formyl, cycloalkylcarbonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, carbamoyl, —O—CH 2 —CH═CH 2 , halogen, halo lower alkyl, trifluoromethyl, —OCF 3 , —S(lower alkyl), —OC(O)N[lower alkyl] 2 , —CONH(lower alkyl), —CON[lower alkyl] 2 , lower alkylamino, di-lower alkylamino, lower alkyl di-lower alkylamino, hydroxy, cyano, trifluoromethylthio, nitro, amino, lower alkylsulfonyl, aminosulfonyl, or lower alkylaminosulfonyl;
R 11 and R 12 are, independently, selected from the group of hydrogen, (C 1 –C 6 ) lower alkyl, (C 1 –C 6 ) lower alkenyl, (C 3 –C 6 ) lower alkynyl, hydroxy (C 1 –C 6 ) lower alkyl, alkoxy (C 1 –C 6 ) lower alkyl, acyloxy (C 1 –C 6 ) lower alkyl, cyclo lower alkyl, or aryl, optionally substituted by hydroxy, (C 1 –C 6 ) lower alkoxy, halogen, cyano;
R is selected from any of the following groups:
wherein:
R 13 is selected from the group of hydrogen, (C 1 –C 6 ) lower alkyl, or cyanoethyl; R 14 is selected from hydrogen or (C 1 –C 6 ) lower alkyl; R 15 is one or two substituents selected, independently, from the group of hydrogen, (C 1 –C 6 ) lower alkyl, halogen, trifluoromethyl, (C 1 –C 6 ) lower alkoxy, (C 1 –C 6 ) lower alkoxycarbonyl; R 16 and R 16′ are selected independently from H, or (C 1 –C 6 ) lower alkyl; m is an integer from 0 to 2; n is an integer from 1 to 2; and p is an integer from 0 to 1; or a pharmaceutically acceptable salt or pro-drug form thereof.
As used herein the term “lower” in relation to alkoxy or alkyl is understood to refer to those groups having from 1 to 6 carbon atoms. Halogen refers to fluorine, chlorine, bromine or iodine.
It is understood by those practicing the art that some of the compounds of this invention depending on the definition of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 may contain one or more asymmetric centers and may thus give rise to enantiomers and diastereomers. The present invention includes all stereoisomers including individual diastereomers and resolved, enantiomerically pure R and S stereoisomers, as well as racemates, and all other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof, which possess the indicated activity. Optical isomers may be obtained in pure form by standard procedures known to those skilled in the art. It is also understood that this invention encompasses all possible regioisomers, E-Z isomers, endo-exo isomers, and mixtures thereof which possess the indicated activity. Such isomers may be obtained in pure form by standard separation procedures known to those skilled in the art. It is understood also by those practicing the art that some of the compounds of this invention depending on the definition of R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , R 11 and R 12 may be chiral due to hindered rotation, and give rise to atropisomers which can be resolved and obtained in pure form by standard procedures known to those skilled in the art. Also included in the present invention are all polymorphs and hydrates of the compounds of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention comprises the compounds described above, as well as pharmaceutical compositions containing the compounds of this invention in combination or association with one or more pharmaceutically acceptable carrier or excipient. In particular, the present invention provides a pharmaceutical composition which comprises a therapeutically effective amount of one or more compounds of this invention in a pharmaceutically acceptable carrier or excipient.
This invention also comprises methods for treating conditions in a mammal, preferably a human, which are remedied or alleviated by oxytocin antagonist activity including, but not limited to, treatment or prevention of preterm labor, dysmenorrhea and suppressing labor prior to caesarian delivery whenever desirable in a mammal, preferably in a human. The methods comprise administering to a mammal in need thereof a therapeutically effective but non-toxic amount of one or more of the compounds of this invention.
The present invention also comprises combinations of the compounds of the present invention with one or more agents useful in the treatment of disorders such as preterm labor, dysmenorrhea, and stopping labor prior to caesarian delivery. More specifically, the compounds of the present invention may be effectively administered in combination with effective amounts of other tocolytic agents used in the treatment or prevention of preterm labor, dysmenorrhea or suppressing labor prior to caesarean delivery including β-adrenergic agonists, calcium channel blockers, prostaglandin synthesis inhibitors, other oxytocin antagonists (e.g. atosiban), magnesium sulfate, ethanol, and other agents useful in the treatment of said disorders. The present invention is to be understood as embracing all simultaneous or alternating treatments of any combination of the compounds of the present invention with other tocolytic agents with any pharmaceutical composition useful for the treatment of preterm labor, dysmenorrhea, and suppressing labor prior to caesarean delivery in mammals.
The compositions are preferably adapted for intravenous (both bolus and infusion) and oral administration. However, they may be adapted for other modes of administration including subcutaneous, intraperitoneal, or intramuscular administration to a human or a farm animal in need of a tocolytic agent.
The compounds of the present invention can be used in the form of salts derived from non toxic pharmaceutically acceptable acids or bases. These salts include, but are not limited to, the following: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, citric acid, tartaric acid, succinic acid, maleic acid, benzoic acid, benzene sulfonic acid, fumaric acid, malic acid, methane sulfonic acid, pamoic acid, and para-toluene sulfonic acid . Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium, or with organic bases including quaternary ammonium salts. The compounds can also be used in the form of esters, carbamates and other conventional prodrug forms, which in general, will be functional derivatives of the compounds of this invention which are readily converted to the active moiety in vivo. This is meant to include the treatment of the various conditions described hereinbefore with a compound of this invention or with a compound which is not specifically disclosed but which converts to a compound of this invention in vivo upon administration. Also included are metabolites of the compounds of the present invention defined as active species produced upon introduction of these compounds into a biological system.
When the compounds of this invention are employed for the above utilities, they may be combined with one or more pharmaceutically acceptable excipients or carriers, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules (including time release and sustained release formulations), pills, dispersible powders, granules, or suspensions containing, for example, from 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs and the like, or parenterally in the form of sterile injectable solutions, suspensions or emulsions containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
The effective dosage of active ingredients employed may vary depending on the particular compound or salt employed, the mode of administration, age, weight, sex and medical condition of the patient, and the severity of the condition being treated. An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the agent required to prevent, counter or arrest the progress of the condition. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dose of from about 0.5 to about 500 mg/Kg of mammal body weight, preferably given in divided doses two to four times a day, or in a sustained release form. For most large mammals the total daily dosage is from about 0.5 to 100 mg, preferably from 0.5 to 80 mg/Kg. Dosage forms suitable for internal use comprise from about 0.05 to 500 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
These active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, glycerol, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example vitamin E, ascorbic acid, BHT and BHA.
These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy injectability exists. It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol (e.g. glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.
Furthermore, active compounds of the present invention can be administered intranasally using vehicles suitable for intranasal delivery, or transdermally using transdermal skin patches known to those ordinarily skilled in the art. When using a transdermal delivery system, the dosage administration will be continuous rather than in a single or divided daily doses. The compounds of the present invention can also be administered in the form of liposome delivery system wherein the liposomal lipid bilayers are formed from a variety of phospholipids.
Compounds of the present invention may also be delivered by the use of carriers such as monoclonal antibodies to which the active compounds are coupled. The compounds of the present invention may also be coupled to soluble polymers as drug carriers or to biodegradable polymers useful in achieving controlled release of the active agent.
Also according to the present invention there are provided processes for producing the compounds of the present invention.
Process of the Invention
The compounds of the present invention may be prepared according to one of the general processes outlined below.
The compounds of general formula (I) wherein R 4 consists of the moiety B–C, where B is selected from the group (a) or (b) and C is selected from the group of (c), (d), (e) and (f) defined hereinbefore, can be conveniently prepared as shown in Scheme I.
According to the above preferred process, a tricyclic azepine of formula (1) wherein
R 3 and R 4 are defined hereinbefore, is reacted with perhaloalkanoyl halide preferable trichloroacetyl chloride in the presence of an organic base such as N,N-diisopropylethyl amine (Hünig's base) in an aprotic organic solvent such as dichloromethane at temperatures ranging from −10° C. to ambient, to provide the desired trichloroacetyl intermediate of formula (2). Subsequent hydrolysis of (2) with aqueous base such as sodium hydroxide, in an organic solvent such as tetrahydrofuran or acetone at temperatures ranging from −10° C. to ambient, yields the intermediate acid of formula (3). The required activation of the carboxylic acid (3) for the subsequent coupling with a primary or secondary amine of formula (5) can be accomplished in several ways. Thus, (3) can be converted to an acyl halide preferable a chloride or bromide of formula (4, J=COCl or COBr) by reaction with thionyl chloride(bromide) or oxalyl chloride (bromide) or similar reagents known in the art, either neat or in the presence of an inorganic base such as potassium carbonate, or in the presence of an organic base such as pyridine, 4-(dimethylamino)pyridine, or a tertiary amine such as triethylamine in an aprotic solvent such as dichloromethane, N,N-dimethylformamide or tetrahydrofuran at temperatures ranging from −5° C. to 50° C. to yield the intermediate acylated derivative (4). Subsequent coupling of the acyl chloride(bromide) (4, J=COCl or COBr) with an appropriately substituted primary or secondary amine of formula (5) in the presence of a stoichiometric amount of Hünig's base, in an aprotic solvent such as dichloromethane, N,N-dimethylformamide or tetrahydrofuran, at temperatures ranging from ambient to the reflux temperature of the solvent, provides the desired compounds of formula (I) wherein
R, R 3 and R 4 are as defined hereinbefore.
Alternatively, the acylating species can be a mixed anhydride of the corresponding carboxylic acid, such as that prepared by treating said acid of formula (3) with 2,4,6-trichlorobenzoyl chloride in an aprotic organic solvent such as dichloromethane according to the procedure of Inanaga et al., Bull. Chem. Soc. Jpn. 52, 1989 (1979). Treatment of said mixed anhydride of formula (4) with an appropriately substituted primary or secondary amine of formula (5) in an aprotic solvent such as dichloromethane at temperatures ranging from ambient to the reflux temperature of the solvent, provides the desired compounds of formula (I) wherein
R, R 3 and R 4 are as defined hereinbefore.
Alternatively, amidation of the carboxylic acids of formula (3) can be effectively carried out by treatment of said acid with triphosgene in an aprotic solvent such as dichloromethane, followed by reaction of the activated intermediate with an appropriately substituted primary or secondary amine of formula (5) in the presence of an organic base such as Hünig's base at temperatures ranging from −10° C. to ambient.
Another preferred process for the preparation of the compounds of the present invention of formula (I) wherein
R, R 3 and R 4 are as defined hereinbefore, consists of treating the acid of formula (3) with an activating reagent such as N,N-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride in the presence of 1-hydroxybenzotriazole, followed by reaction of the activated intermediate with an appropriately substituted primary or secondary amine of formula (5), preferably in the presence of an organic base such as Hünig's base and a catalytic amount of 4-(dimethylamino)pyridine in an aprotic solvent such as dichloromethane, N,N-dimethylformamide or tetrahydrofuran at temperatures ranging from −10° C. to ambient.
In another preferred process, said acid (3) can be activated by treatment with other activating agents such as N,N′-carbonyldiimidazole in an aprotic solvent such as dichloromethane or tetrahydrofuran, at temperatures ranging from −10° C. to the reflux temperature of the solvent. Subsequent reaction of the intermediate activated imidazolide with an appropriately substituted primary or secondary amine of formula (5) provides the desired compounds of formula (I) wherein
R, R 3 and R 4 are as defined hereinbefore.
Alternatively, the coupling of the appropriately substituted primary or secondary amine of formula (5) with said acid of formula (3) can be effectively carried out by using hydroxybenzotriazole tetramethyluronium hexafluorophosphate as the coupling reagent in the presence of an organic base such as Hünig's base and in a solvent such as N,N-dimethylformamide at temperatures ranging from −10° C. to ambient, to provide in good isolated yield and purity the desired compounds of formula (I) wherein
R, R 3 and R 4 are as defined hereinbefore.
Related coupling reagents such as diphenylphosphoryl azide, diethyl cyano phosphonate, benzotriazol-1-yl-oxy-tris-(dimethylamino) phosphonium hexafluorophosphate and all other known in the literature that have been used in the formation of amide bonds in peptide synthesis can also be used for the preparation of compounds of formula (I) wherein
R, R 3 and R 4 are as defined hereinbefore.
As an alternative, reaction of the intermediate 3-trihalomethylketone of formula (2) directly with an appropriately substituted primary or secondary amine of formula (5) also provides the desired compounds of formula (I) wherein
R, R 3 and R 4 are as defined hereinbefore.
The method of choice for the preparation of compounds of formula (I) from the intermediate carboxylic acid (3) is ultimately chosen on the basis of its compatibility with the R, R 3 and R 4 groups, and its reactivity with the tricyclic diazepine of formula (1).
Another preferred process for the preparation of (I) of Scheme I is shown in Scheme II. A tricyclic diazepine of formula (1) is reacted with diphosgene in an aprotic solvent such as dichloromethane, preferably in the presence of an organic base such as triethylamine, followed by reaction of the resulting acylated intermediate with an appropriately substituted primary or secondary amine of formula (5), to provide the desired compounds of formula (I) wherein
R, R 3 and R 4 are as defined hereinbefore.
The tricyclic diazepines of formula (1) of Scheme I wherein R 4 is defined hereinbefore, can be conveniently prepared as shown in Scheme III.
Thus, a tricyclic diazepine of formula (6) is treated with an appropriately substituted acylating agent such as a haloaroyl halide, preferably an appropriately substituted acyl chloride(bromide) of formula (7, J=COCl or COBr) wherein R 4 is ultimately chosen on the basis of its compatibility with the present reaction scheme, in the presence of an inorganic base such as potassium carbonate, or in the presence of an organic base such as pyridine, 4-(dimethylamino)pyridine, or a tertiary amine such as triethylamine or N,N-diisopropylethyl amine, in an aprotic solvent such as dichloromethane, N,N-dimethylformamide or tetrahydrofuran, at temperatures ranging from −5° C. to 50° C. to provide intermediates of general formula (1) wherein R 4 is defined hereinbefore.
Alternatively, the acylating species of formula (7) can be a mixed anhydride of the corresponding carboxylic acid, such as that prepared by treating said acid with 2,4,6-trichlorobenzoyl chloride in an aprotic organic solvent such as dichloromethane according to the procedure of Inanaga et al., Bull. Chem. Soc. Jpn., 52, 1989 (1979). Treatment of said mixed anhydride of general formula (7) with a tricyclic diazepine of formula (6) in a solvent such as dichloromethane, and in the presence of an organic base such as 4-(dimethylaminopyridine), at temperatures ranging from 0° C. to the reflux temperature of the solvent, yields the intermediate acylated derivative (1) of Scheme III.
The acylating intermediate of formula (7) is ultimately chosen on the basis of its compatibility with the R 4 groups, and its reactivity with the tricyclic diazepine of formula (6).
The desired intermediates of formula (7) of Scheme III wherein R 4 consists of the moiety B–C wherein B is (a) and C is (c) can be conveniently prepared by a process shown in Scheme IV. Thus, an appropriately substituted aryl(heteroaryl) iodide (bromide, chloride, or trifluoromethane sulfonate) of formula (8, wherein P is a carboxylic acid protecting group, preferably P=alkyl or benzyl, M=I, Br, Cl, OTf)), and A, R 5 , R 6 and R 7 are defined hereinbefore, is reacted with an aryl(heteroaryl) tri(alkyl)tin(IV) derivative of formula (9, W=Sn(trialkyl) 3 , preferably Sn(n-Bu) 3 ) wherein A, R 8 , R 9 and R 10 are defined hereinbefore, in the presence of a Pd(0) catalyst, in the presence or absence of inorganic salts (e.g. LiCl), to provide the intermediate ester (10). Subsequent unmasking of the carboxylic function by hydrolysis, hydrogenolysis or similar methods known in the art, followed by activation of the intermediate acid (11) provides the desired compounds of formula (19) wherein A, R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are hereinbefore defined, suitable for coupling with the tricyclic diazepine of formula (6).
The desired intermediates of formula (7) of Scheme III wherein R 4 consists of the moiety B–C where B is (a) and C is (d), (e) or (f), or B is (b) and C is either (c), (d), (e) or (f), can be prepared by a process analogous to that exemplified in Scheme IV by replacing intermediates of formula (8 and 9) with appropriately substituted naphthyl, quinolyl, pyrimidinyl or pyrazinyl intermediates.
Alternatively, the desired intermediates of formula (10) of Scheme IV wherein R 4 consists of the moiety B–C where B is (a) and C is (c), can be prepared by coupling of the iodide(bromide, chloride, trifluoromethane sulfonate) (8, M=I, Br, Cl or OTf) and an appropriately substituted aryl(heteroaryl)boron derivative of formula (9, preferably W=B(OH) 2 ) in the presence of a palladium catalyst such as palladium(II) acetate or tetrakis(triphenylphosphine)palladium(0) and an organic base such as triethylamine or an inorganic base such as sodium(potassium or cesium) carbonate with or without added tetrabutylammonium bromide(iodide), in a mixture of solvents such as toluene-ethanol-water, acetone-water, water or water-acetonitrile, at temperatures ranging from ambient to the reflux temperature of the solvent (Suzuki, Pure & Appl. Chem. 66, 213–222 (1994), Badone et al., J. Org. Chem. 62, 7170–7173 (1997), Wolfe et al. J. Am. Chem. Soc. 121, 9559 (1999), Shen, Tetr. Letters 38, 5575 (1997)). The exact conditions for the Suzuki coupling of the halide and the boronic acid intermediates are chosen on the basis of the nature of the substrate and the substituents. Alternatively, the coupling of (8, M=I or Br) with (9, A=N) can be carried out by using a dialkylborane, preferably a diethylpyridoborane in the presence of an inorganic base such as potassium hydroxide and tetrabutylammonium bromide(iodide), in an aprotic solvent such as tetrahydrofuran, according to the method of Ishikura et al., Synthesis 936–938 (1984). The desired intermediates of formula (10) of Scheme IV can be similarly prepared from the bromide (8, M=Br) and the boronic acid (9) in a solvent such as dioxane in the presence of potassium phosphate and a Pd(0) catalyst.
Alternatively, a cross-coupling reaction of an iodide (bromide, or trifluoromethane sulfonate) of formula (9, W=Br, I or OTF) with a bis(pinacolato)diboron [boronic acid, or trialkyltin(IV)] derivative of formula (8, M=
B(OH) 2 , or SnBu 3 ) yields the desired intermediate of formula (10) which is converted to (I) in the manner of Scheme IV.
The desired intermediates of formula (10) of Scheme IV wherein R 4 consists of the moiety B–C wherein B is (a) and C is (d), (e) or (f), or B is (b) and C is either (c), (d), (e) or (f), can be prepared in analogous fashion by replacing intermediates of formulas (8 and 9) with appropriately substituted naphthyl, quinolyl, pyrimidinyl or pyrazinyl intermediates.
The required appropriately substituted aryl(heteroaryl) halides of formula (8, M=Br or I) of Scheme IV are either available commercially, or are known in the art, or can be readily accessed in quantitative yields and high purity by diazotization of the corresponding substituted anilines (8, P=H, alkyl or benzyl, M=NH 2 ) followed by reaction of the intermediate diazonium salt with iodine and potassium iodide in aqueous acidic medium essentially according to the procedures of Street et al,. J. Med. Chem. 36, 1529 (1993) and Coffen et al., J. Org. Chem. 49, 296 (1984) or with copper(I) bromide, respectively (March, Advanced Organic Chemistry, 3 rd Edn., p.647–648, John Wiley & Sons, New York (1985)).
Alternatively, the desired intermediates of formula (11, A=CH) of Scheme IV wherein R 4 consists of the moiety B–C wherein B is (a, A=CH) and C is (c, A=CH) can be conveniently prepared as shown in Scheme V by cross-coupling reaction of an appropriately substituted pinacolato borane of formula (13, A=CH) wherein R 8 , R 9 and R 10 are hereinbefore defined, with an aryl triflate of formula (14, Y=OTf) or an aryl halide (14, Y=Br, I) wherein R 5 , R 6 and R 7 are defined hereinbefore, according to the general procedures of Ishiyama et al., Tetr. Lett. 38, 3447–3450 (1997) and Giroux et al. Tetr. Lett. 38, 3841–3844 (1997), followed by basic or acidic hydrolysis of the intermediate nitrile of formula (15) (cf. March, Advanced Organic Chemistry, 3 rd Edn., John Wiley & Sons, New York, p. 788 (1985)).
Alternatively, reaction of an iodide (bromide, or trifluoromethane sulfonate) of formula (12, X=Br, I, or OTf) with a bis(pinacolato)diboron [boronic acid or trialkyl tin(IV)] derivative of formula (14, Y=
B(OH) 2 , or SnBu 3 ) yields the desired intermediate of formula (15) which is converted to (6) in the manner of Scheme V.
The desired intermediates of formula (11) of Scheme IV can be prepared in analogous fashion by replacing intermediates of formulas (13 and 14) with appropriately substituted naphthyl intermediates.
The desired phenyl boronic esters of formula (13) of Scheme V can be conveniently prepared by the palladium-catalyzed cross-coupling reaction of the pinacol ester of diboronic acid (16) with an appropriately substituted aryl halide preferably a bromide or iodide (12, X=Br, I) or aryl triflate (12, X=OTf) according to the described procedures of Ishiyama et al., J. Org. Chem. 60, 7508–7510 (1995) and Giroux et al., Tetr. Lett. 38, 3841–3844 (1997).
The desired compounds of formula (1) of Scheme IV wherein R 4 consists of the moiety B–C wherein B is (a) and C is (c) can be alternatively prepared by a process shown in Scheme VI.
Thus, a tricyclic diazepine of formula (6) is treated with an appropriately substituted acylating agent such as a halo aroyl(heteroaroyl)halide, preferably an iodo(bromo)aroyl(heteroaroyl)chloride(bromide) of formula (17, J=COCl or COBr; X=I, Br) wherein R 5 , R 6 and R 7 are hereinbefore defined, using any of the procedures hereinbefore described, to provide the acylated intermediate of general formula (18) of Scheme VI.
Alternatively, the acylating species of formula (17) can be a mixed anhydride of the corresponding carboxylic acid. Treatment of said mixed anhydride of general formula (17) with a tricyclic diazepine of formula (6) according to the procedure described hereinbefore yields the intermediate acylated derivative (18).
The acylating intermediate of formula (17) is ultimately chosen on the basis of its compatibility with A and the R 5 , R 6 and R 7 groups, and its reactivity with the tricyclic diazepine of formula (6).
A Stille coupling reaction of (18, X=I) with an appropriately substituted organotin reagent such as a trialkyltin(IV) derivative, preferably a tri-n-butyltin(IV) derivative of formula (9, W=SnBu 3 ) where A, R 8 , R 9 and R 10 are hereinbefore defined, in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium(0), in an aprotic organic solvent such as toluene and N,N-dimethylformamide, at temperatures ranging from ambient to 150° C. (cf. Farina et al., J. Org. Chem, 59, 5905 (1994) and references cited therein, affords the desired compounds of formula (1) wherein
A, R 3 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined hereinbefore.
Alternatively, reaction of a compound of formula (18, X=Cl, Br or I) with an appropriately substituted aryl(heteroaryl)boronic acid of formula (9, W=B(OH) 2 ) wherein A, R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are hereinbefore defined, in a mixture of solvents such as toluene-ethanol-water, and in the presence of a Pd(0) catalyst and a base such as sodium carbonate, at temperatures ranging from ambient to the reflux temperature of the solvent, yields the desired compounds of formula (1) wherein
A, R 3 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined hereinbefore.
The preferred substituted aroyl(heteroaroyl) chlorides(bromides) of formula (17) of Scheme VI (X=I, Br; J=COCl or COBr) wherein A, R 5 , R 6 and R 7 are as defined hereinbefore, are either available commercially, or are known in the art, or can be readily prepared by procedures analogous to those in the literature for the known compounds.
The intermediates of formula (9, W=Sn(alkyl) 3 , alkyl=n-butyl) of Scheme VI are either commercially available, or can be conveniently prepared as shown in Scheme VII from the corresponding bromo starting materials of formula (20) wherein A, R 8 , R 9 , and R 10 are hereinbefore defined, by first reacting them with n-butyl lithium followed by reaction of the intermediate lithiated species with a trialkyl (preferably trimethyl or tri-n-butyl)tin(IV) chloride.
The preferred substituted aryl(heteroaryl)boronic acids of formula (9, W=B(OH) 2 ) are either available commercially, or are known in the art, or can be readily prepared by procedures analogous to those in the literature for the known compounds.
The desired compounds of formula (1) of Scheme VI wherein R 4 consists of the moiety B–C wherein B is (a) and C is (d), (e) or (f), or B is (b) and C is either (c), (d), (e) or (f) can be prepared in analogous fashion by replacing intermediates of formulas (17 and 9) with appropriately substituted naphthyl, quinolyl, pyrimidinyl or pyrazinyl intermediates.
Alternatively, as shown in Scheme VIII, the appropriately substituted aroyl(heteroaroyl) halides, preferably aroyl(heteroaroyl)chlorides of formula (21, J=COCl) where A, R 5 , R 6 and R 7 are hereinbefore defined, are reacted with a tricyclic diazepine of formula (6) to provide the intermediate bromides of formula (22). Subsequent reaction of (22) with an hexa alkyl-di-tin (preferably hexa-n-butyl-di-tin(IV)) in the presence of a Pd(0) catalyst such as tetrakis(tri-phenylphosphine)palladium(0) and lithium chloride, provides the stannane intermediate of formula (23). Further reaction of the tri-n-butyl tin(IV) derivative (23) with the appropriately substituted aryl(heteroaryl) halide of formula (24, M=bromo or iodo) wherein A, R 8 , R 9 , and R 10 are hereinbefore defined, in the presence of a Pd(0) catalyst such as tetrakis(triphenylphosphine) palladium(0), yields the desired compounds of formula (1) wherein R 4 consists of the moiety B–C wherein B is (a) and C is (c), and
A, R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are defined hereinbefore.
The desired compounds of formula (1) of Scheme VIII wherein R 4 consists of the moiety B–C wherein B is (a) or (b) and C is (d), (e) or (f) can be prepared in analogous fashion by replacing intermediates of formulas (21 and 24) with appropriately substituted naphthyl, quinolyl, pyrimidinyl or pyrazinyl intermediates.
Alternatively, the desired compounds of formula (1) of Scheme VIII wherein R 4 consists of the moiety B–C wherein B is (a, A=CH), and C is (c, A=CH) can be prepared as shown in Scheme IX.
Thus, an appropriately substituted biphenyl of formula (43) wherein R 5 , R 6 , and R 7 are defined hereinbefore, is treated with carbon monoxide in the presence of a tricyclic diazepine of formula (6), a palladium(0) catalyst preferably PdBr 2 (Ph 3 P) 2 and a tertiary amine preferably n-tributylamine, in a solvent such as anisole or dioxane, at temperatures ranging from ambient to the reflux temperature of the solvent (cf. Schoenberg et al. J. Org. Chem. 39, 3327 (1974)) to provide the desired compounds of formula (1) wherein A is CH, and
R 3 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are defined hereinbefore.
In analogous fashion one can prepare compounds of formula (1) of Scheme IX wherein R 4 consists of the moiety B–C wherein B is (b) and C is (c, A=CH) or (d, A=CH) provided that the intermediates of formula (43) are replaced by the appropriately substituted phenyl or naphthyl intermediates.
A preferred process for the preparation of the compounds of formula (1) of Scheme I wherein
A, R 3 , R 5 , R 6 and R 7 are defined hereinbefore, and R 4 consists of the moiety B–C wherein B is (a) and C is (g) defined hereinbefore, is shown in Scheme X.
Thus, an appropriately substituted aroyl(heteroaroyl)halide preferably an aroyl(heteroaroyl)chloride of formula (25, J=COCl) is reacted with a tricyclic diazepine of formula (6) in the presence of a base such as pyridine, or a tertiary amine such as triethylamine or N,N-diisopropylethyl amine, in an aprotic organic solvent such as dichloromethane or tetrahydrofuran, at temperatures from −40° C. to 50° C. to provide the acylated intermediate of formula (26). Alternatively, the acylating species can be a mixed anhydride under the reaction conditions described hereinbefore. Subsequent reduction of (26) is preferably effected under conditions of catalytic reduction (i.e. hydrogen, Pd on charcoal), transfer hydrogenation (i.e. hydrazine/ethanol/Pd on charcoal) or under chemical reduction conditions (i.e. with tin(II)chloride dihydrate in a protic organic solvent such as ethanol, zinc in acetic acid) or related reduction conditions known in the art, to yield the desired aniline of formula (27). The exact conditions for the conversion of the nitro to amino group are chosen on the basis of compatibility with the preservation of other functional groups in the molecule. Condensation of (27) with a 1,4-diketone of formula (28) in an aprotic organic solvent such as benzene or toluene, in the presence of acetic acid or a catalytic amount of p-toluenesulfonic acid with concomitant removal of water, at temperatures ranging from ambient to reflux temperature of the solvent according to the general procedure of Bruekelman et al., J. Chem. Soc. Perkin Trans. I, 2801–2807 (1984) provides the desired compounds of formula (1) wherein R 4 consists of the moiety B–C wherein B is (a) and C is (g), and
A, R 3 , R 5 , R 6 , R 7 , R 11 and R 12 are defined hereinbefore.
The desired compounds of formula (1) of Scheme X wherein R 4 consists of the moiety B–C wherein B is (b) and C is (g) can be prepared in analogous fashion by replacing the intermediate of formula (25) with an appropriately substituted naphthyl.
Alternatively, the desired compounds of formula (1) of Scheme X can be prepared as shown in Scheme XI.
According to this process an aryl(heteroaryl)nitrile of formula (29) is condensed with a 1,4-diketone of formula (28) in an aprotic organic solvent such as benzene or toluene, in the presence of acetic acid or a catalytic amount of p-toluene sulfonic acid with concomitant removal of water, at temperatures ranging from ambient to reflux temperature of the solvent according to the general procedure of Bruekelman et al., J. Chem. Soc. Perkin Trans. I, 2801–2807 (1984) to yield the intermediate pyrrole of formula (30). Subsequent hydrolysis of the nitrile (30) to the carboxylic acid of formula (31) is efficiently accomplished by treatment of (30) with aqueous base (cf. March, Advanced Organic Chemistry, 3 rd Edn., John Wiley & Sons, New York, p. 788 (1985)). Subsequent conversion of the acid (31) into an acylating species, preferably an acid chloride(bromide) of formula (32, J=COCl or COBr) or a mixed anhydride is accomplished by procedures analogous to those described hereinbefore. The acylating agent (32) is used to acylate a tricyclic diazepine of formula (6) to provide the desired compounds of formula (1) wherein
A and R 3 are defined hereinbefore, and R 4 consists of the moiety B–C wherein B is (a) and C is the moiety (g) defined hereinbefore.
The compounds of formula (1) of Scheme XI wherein R 4 consists of the moiety B–C wherein B is (b) and C is (g) defined hereinbefore can be prepared in analogous fashion by replacing the intermediates of formula (29) with an appropriately substituted naphthyl.
A preferred process for the preparation of the desired compounds of general formula (I) of Scheme I wherein R 4 consists of the moiety B–C, where B is selected from the group (a) and C is selected from the group (g) defined hereinbefore is shown in Scheme XII.
Thus, a tricyclic diazepine of formula (33) wherein
and R 3 are defined hereinbefore, carrying a protecting group such a fluorenylalkoxycarbonyl group, preferably a fluorenylmethyloxycarbonyl (P=Fmoc) group, or an alkoxycarbonyl protecting group preferably a tert-butyloxycarbonyl (P=Boc) group is reacted with a perhaloalkanoyl halide preferably trichloroacetyl chloride, in the presence of an organic base such as N,N-diisopropylethyl amine (Hünig's base) or a tertiary amine such as triethylamine, optionally in the presence of catalytic amounts of 4-(dimethylamino)pyridine, in an aprotic organic solvent such as dichloromethane, at temperatures ranging from −10° C. to ambient to provide the desired trichloroacetyl intermediate of formula (34). Subsequent hydrolysis of the trichloroacetyl group with aqueous base such as sodium hydroxide in an organic solvent such as acetone, at temperatures ranging from −10° C. to ambient, is accompanied by simultaneous removal of the protecting group and yields the intermediate acid of formula (35). The required amidation of the carboxylic acid (35) can be effectively accomplished by treating (35) with an activating reagent such as N,N-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride in the presence of 1-hydroxybenzotriazole, followed by reaction of the activated intermediate with an appropriately substituted primary or secondary amine of formula (5) preferably in the presence of Hünig's base or a catalytic amount of 4-(dimethylamino)pyridine, in an aprotic solvent such as dichloromethane, N,N-dimethylformamide or tetrahydrofuran, at temperatures ranging from −10° C. to ambient.
Other coupling reagents known in the literature that have been used in the formation of amide bonds in peptide synthesis can also be used for the preparation of compounds of formula (36) wherein
R and R 3 are as defined hereinbefore. The method of choice for the preparation of compounds of formula (36) from the intermediate carboxylic acid (35) is ultimately chosen on the basis of its compatibility with the
and R 3 groups, and its reactivity with the tricyclic diazepine of formula (6). Subsequent reaction of a tricyclic diazepine amide (36) with an acylating agent of formula (32) of Scheme XI provides the desired compounds of formula (I) wherein
A and R 3 are defined hereinbefore, R 4 consists of the moiety B–C wherein B is (a) and C is the moiety (g) defined hereinbefore.
The preferred compounds of formula (I) of Scheme I wherein R 4 consists of the moiety B–C wherein B is (b) and C is the moiety (g) defined hereinbefore, can be prepared in analogous fashion by replacing the intermediate of formula (32) of Scheme XII with an appropriately substituted naphthyl intermediate.
Preferred processes for the preparation of compounds of formula (I) of Scheme I wherein R 4 consists of the moiety B–C wherein B is (a) or (b) and C is (d), (e) or (f) and
A, R, R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are defined hereinbefore, also utilize acylation of the amide intermediate (36) of Scheme XII with an acylating agent of formula (19) of Scheme IV.
An alternate preferred process for the preparation of the compounds of formula (I) of Scheme I wherein R 4 consists of the moiety B–C wherein B is (a) and C is (g) defined hereinbefore, is shown in Scheme XIII.
According to the above process a substituted tricyclic diazepine of formula (37) wherein
A, R 3 , R 5 , R 6 and R 7 are defined hereinbefore, carrying a protecting group such a fluorenylalkoxycarbonyl group, preferably a fluorenylmethyloxycarbonyl (P=Fmoc) group is reacted with a perhaloalkanoyl halide preferably trichloroacetyl chloride in the presence of an organic base such as N,N-diisopropylethyl amine (Hünig's base) or a tertiary amine such as triethylamine, in an aprotic organic solvent such as dichloromethane, at temperatures ranging from −10° C. to ambient, to provide the desired trichloroacetyl intermediate of formula (38). Subsequent deprotection of (38) is carried out by treatment with a solution of an organic base preferably piperidine, in an organic solvent such as N,N-dimethylformamide, at ambient temperature to provide the desired aniline (44). Condensation of (44) with a 1,4-diketone of formula (28) either neat or in an aprotic organic solvent such as benzene or toluene, in the presence of a catalytic amount of a carboxylic acid preferably p-toluene sulfonic acid or acetic acid with concomitant removal of water, at temperatures ranging from ambient to 100° C. or to the reflux temperature of the solvent according to the general procedure of Bruekelman et al., J. Chem. Soc. Perkin Trans. I, 2801–2807 (1984), provides the desired intermediate of formula (45). Subsequent hydrolysis of the trichloroacetyl group with aqueous base such as sodium hydroxide, in an organic solvent such as acetone or tetrahydrofuran, at temperatures ranging from −10° C. to the reflux temperature of the solvent, yields the intermediate carboxylic acid of formula (46). Subsequent amidation provides the desired compounds of formula (I) wherein R 4 consists of the moiety B–C wherein B is (a) and C is (g), and
A, R 3 , R 5 , R 6 , R 7 , R 11 and R 12 are defined hereinbefore,
The required amidation of (46) can be effectively accomplished by treating said carboxylic acid with an activating reagent such as N,N-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride in the presence of 1-hydroxybenzotriazole, followed by reaction of the activated intermediate with an appropriately substituted primary or secondary amine of formula (5), preferably in the presence of Hünig's base or a catalytic amount of 4-(dimethylamino)pyridine, in an aprotic solvent such as dichloromethane, N,N-dimethylformamide or tetrahydrofuran, at temperatures ranging from −10° C. to ambient. Other coupling reagents known in the literature that have been used in the formation of amide bonds in peptide synthesis can also be used for the preparation of compounds of formula (I) wherein R 4 consists of the moiety B–C wherein B is (a) and C is (g), and
A, R 3 , R 5 , R 6 , R 7 , R 11 and R 12 are defined hereinbefore. The method of choice for the preparation of compounds of formula (I) from the intermediate carboxylic acid (46) is ultimately chosen on the basis of its compatibility with the
and R 3 groups, and its reactivity with the tricyclic diazepine of formula (6).
The desired compounds of formula (I) of Scheme XIII wherein R 4 consists of the moiety B–C wherein B is (b) and C is (g) can be prepared in analogous fashion by replacing the intermediate of formula (27) with an appropriately substituted naphthyl intermediate.
Alternatively, the intermediate acids of formula (35) of Scheme XII wherein
and R 3 are defined hereinbefore, can be obtained by reacting a tricyclic diazepine of formula (6) with an excess of acylating agent preferably trifluoroacetic anhydride or trichloroacetyl chloride in the presence of an inorganic base such as potassium carbonate or an organic base such as N,N-diisopropylethylamine, in an aprotic solvent such as N,N-dimethylformamide, followed by basic hydrolysis of the intermediate bis-trifluoroacetyl(trichloroacetyl) intermediate of formula (39 X=F or Cl) preferably with aqueous sodium hydroxide in a protic organic solvent such as ethano, at temperatures ranging from ambient to the reflux temperature of the solvent as exemplified in Scheme XIV.
Preferred processes for the preparation of compounds of formula (I) of Scheme I wherein R 4 consists of the moiety B–C wherein B is (a) or (b) and C is (d), (e) or (f) and
A, R, R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are defined hereinbefore, also utilize acylation of the amide intermediate (36) of Scheme XII with an acylating agent of formula (17) of Scheme IV, as shown in Scheme XV.
Alternatively, the preferred compounds of formula (I) of Scheme I wherein R 4 consists of the moiety B–C wherein B is (a) and C is (c) and
A, R, R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are defined hereinbefore, can be prepared by acylation of the amide intermediate (36) of Scheme XII with an acylating agent of formula (21) of Scheme VIII, as shown in Scheme XVI.
Alternatively, the preferred compounds of formula (I) of Scheme (I) wherein R 4 consists of the moiety B–C wherein B is (a) and C is (c) and
A, R, R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are defined hereinbefore, can be prepared by acylation of the amide intermediate (36) of Scheme XII with an acylating agent of formula (19) of Scheme IV, wherein J is hereinbefore defined, as shown in Scheme XVII.
The subject compounds of the present invention were tested for biological activity according to the following procedures.
Vasopressin Binding in Chinese Hamster Ovary Cell Membranes Expressing Human Vasopressin V 1a Subtype Receptors
Receptor Source:
Chinese hamster ovary cells (CHO cells) stably transfected with the human vasopressin V 1a subtype receptors were either obtained from BioSignal Inc., 1744 rue Williams, Montreal, Quebec, Canada or obtained from M. Thibonnier, Case Western Reserve University School of Medicine, Cleveland, Ohio.
A. Passaging and Amplification of Cells:
CHO cells transfected with the human vasopressin V 1a subtype receptors obtained from M. Thibonnier (pZeoSV vector) are allowed to grow to confluency (approx. >90%) in T-150 flasks under sterile conditions, in a cell culture medium of F-12 Nutrient Mixture (HAM) with L-glutamine (Gibco Cat. # 11765-054) containing 15 mM HEPES (Gibco Cat. # 15630-080), 1% antibiotic/antimycotic (add 5 mL 100×, Gibco Cat. # 15240-062 per 500 mL F-12), 250 μg/mL Zeocin (add 1.25 mL of 100 mg/mL Invitrogen R-250-01 per 500 mL F-12) and 10% Fetal Bovine Serum (Qualified, heat inactivated, Gibco Cat. # 16140-063). The medium is removed by aspiration and the cells are washed with 10 mL of Hank's Balanced Salt solution (Gibco Cat. # 14175-095). The salt solution is removed by aspiration and the cells are trypsinized with 5 mL of trypsin-EDTA (0.05% trypsin, 0.53 mM EDTA-4Na, Gibco Cat. # 25300-070) for 1 min. The trypsin is removed by aspiration and the cells dislodged by tapping. Cell Culture medium (e.g. 30 mL for 1:30 split) is immediately added and mixed well to inactivate trypsin. 1 mL of detached cells is added to new culture flasks containing fresh cell culture medium (e.g., into 25 mL per T-150 flask), and mixed gently. The cells are incubated at 37° C. in 5% CO 2 . The medium is changed at 3 to 4 days interval (or as appropriate). The cells grow to confluency (approx. >75%–95%) within 7–8 days. All steps are done under sterile conditions.
B. Membrane Preparation:
The cells are washed twice gently with Hank's Balanced Salt solution (e.g,. use 10 mL per T-150 flask). The excess is removed and the cells are bathed for 15–30 min. in an enzyme-free Cell Dissociation Buffer (e.g. use 8 mL Hank's Based, Gibco Cat. # 13150-016 per T-150 flask) until the cells are loosened. The contents are transferred to centrifuge tubes (50 mL) kept in an ice bath. All subsequent steps are done at 4° C. The tubes are centrifuged at 300×g for 15 min (1380 rpm on SORVAL, Model RT6000D, using the rotor for 50 mL tubes). The supernatant is discarded and the cells suspended in homogenizing buffer(10 mM Tris-HCl containing 0.25 M sucrose and 1 mM EDTA, pH 7.4) ensuring that the volume of the buffer is about ten times the volume of the cell pellet. The cells are pooled into a centrifuge tube (50 mL) and homogenized with Polytron at setting 6 for 10 sec. The homogenate is transferred into a Potter-Elvjehm homogenizer and homogenized with 3 strokes. The homogenate is centrifuged at 1500×g for 10 min at 4° C. (3100 rpm using SORVAL, model RT6000D, using the rotor for 50 mL tubes). The pellet is discarded. The supernatant is centrifuged at 100,000×g for 60 min. at 4° C. (Beckman L8-80M ultracentrifuge; spin at 37,500 rpm with rotor type 70 Ti for 50 mL tubes; 38,000 rpm with type 80Ti for 15 mL tubes; or 35,800 rpm with rotor type 45Ti). The supernantant is discarded and the pellet suspended in 3 to 4 mL of Tris buffer (50 mM TRIS-HCl, pH 7.4). The protein content is estimated by the Bradford or Lowry method. The volume of the membrane suspension is adjusted with the membrane buffer (50 mM Tris-HCl containing 0.1% BSA and 0.1 mM PMSF) to give 3.0 mg/mL (or as appropriate) of protein. The membranes are aliquoted and stored at −70° C.
C. Radioligand Binding Assay:
In wells of a 96-well format microtiter plate, is added 90, 110 or 130 μL (to make up a final volume of 200 μL) of assay buffer containing 50 mM of Tris-HCl (pH 7.4), BSA (heat inactivated, protease-free), 0.1% of 5 mM MgCl 2 , 1 mg % aprotinin, 1 mg % leupeptin, 2 mg % 1,10-phenanthroline, 10 mg % trypsin inhibitor, and 0.1 mM PMSF. The inhibitors are added on the day of the experiment. The components are mixed at room temperature, and then kept in ice bath following adjustment of the pH to 7.4. To each well is added 20 μL of unlabeled Manning ligand (to give a final concentration of 0.1 to 10 nM for standard curve and 1000 nM for non specific binding) or test compounds in 50% DMSO (e.g. for final concentrations of 0.1 to 1000 nM or as appropriate) or 50% DMSO as vehicle control. 20 μL of 50% DMSO is added for Manning and other peptide ligands and the assay buffer volume is adjusted accordingly. To each well is added 50 μL of frozen membrane suspension thawed immediately prior to use and diluted in the assay buffer to the required concentration (equivalent to 25 to 50 μg of protein/well as needed). 20 μL of 8 nM [ 3 H]Manning ligand in the assay buffer, prepared just before use, is added, and incubated at room temperature for 60 min. shaking the plate on a mechanical shaker for the first 15 min. The incubation is stopped by rapid filtration of the the plate contents followed by wash with ice-cold buffer (50 mM Tris-HCl, pH 7.4) using a cell harvester (Tomtek and Printed filtermat-B filter paper). The filter paper is thoroughly dried (7–12 min. in a microwave oven) and impregnated with MeltiLex B/H melt-on scintillation wax sheets and the radioactivity counted in a betaplate scintillation counter.
Vasopressin Binding in Chinese Hamster Ovary Cell Membranes Expressing Human Vasopressin V 2 Subtype Receptors
Receptor Source:
Chinese Hamster Ovary (CHO) cells stably transfected with the human V 2 subtype receptors were obtained from M. Thibonnier, Case Western Reserve University School of Medicine, Cleveland, Ohio.
A. Passaging and Amplification of Cells:
CHO cells transfected with the human vasopressin V 2 subtype receptors obtained from M. Thibonnier (pZeoSV vector) are allowed to grow to confluency (approx. >90%) in T-150 flasks under sterile conditions, in a cell culture medium of F-12 Nutrient Mixture (HAM) with L-glutamine (Gibco Cat. # 11765-054) containing 15 mM HEPES (Gibco Cat. # 15630-080), 1% antibiotic/antimycotic (add 5 mL 100×, Gibco Cat. # 15240-062 per 500 mL F-12), 250 μg/mL Zeocin (add 1.25 mL of 100 mg/mL Invitrogen R-250-01 per 500 mL F-12) and 10% Fetal Bovine Serum (Qualified, heat inactivated, Gibco Cat. # 16140-063). The medium is removed by aspiration and the cells washed with 10 mL of Hank's Balanced Salt solution (Gibco Cat. # 14175-095). The salt solution is removed by aspiration and the cells trypsinized with 5 mL of trypsin-EDTA (0.05% trypsin, 0.53 mM EDTA-4Na, Gibco Cat. # 25300-070) for 1 min. The trypsin is removed by aspiration and the cells dislodged by tapping. Cell Culture medium (e.g. 30 mL for 1:30 split) is immediately added and mixed well to inactivate trypsin. 1 mL of detached cells is added to new culture flasks containing fresh Cell Culture medium (e.g. into 25 mL per T-150 flask), and mixed gently. The cells are incubated at 37° C. in 5% CO 2 . The medium is changed at 3 to 4 day interval (or as appropriate). The cells grow to confluency (approx. >75%–95%) within 7–8 days. All steps are done under sterile conditions.
B. Membrane Preparation:
The cells are washed twice gently with Hank's Balanced Salt solution (e.g. use 10 mL per T-150 flask). The excess solution is removed and the cells bathed for 15–30 min. in an enzyme-free Cell Dissociation Buffer (e.g. use 8 mL Hank's Based, Gibco Cat. # 13150-016 per T-150 flask) until cells are loosened. The contents are transferred to centrifuge tubes (50 mL) kept in ice bath. All subsequent steps are done at 4° C. The tubes are centrifuged at 300×g for 15 min (1380 rpm on SORVAL, Model RT6000D, using the rotor for 50 mL tubes). The supernatant is discarded and the cells suspended in homogenizing buffer(10 mM Tris-HCl containing 0.25 M sucrose and 1 mM EDTA, pH 7.4) ensuring that the volume of the buffer is about ten times the volume of the cell pellet. The cells are pooled into a centrifuge tube (50 mL) and homogenized with Polytron at setting 6 for 10 sec. The homogenate is transferred into a Potter-Elvjehm homogenizer and homogenized with 3 strokes. The homogenate is centrifuged at 1500×g for 60 min at 4° C. (3100 rpm using SORVAL, model RT6000D, using the rotor for 50 mL tubes). The pellet is discarded. The supernatant is centrifuged at 100,000×g for 60 min. at 4° C. (Beckman L8-80M ultracentrifuge; spin at 37,500 rpm with rotor type 70 Ti for 50 mL tubes; 38,000 rpm with type 80Ti for 15 mL tubes; or 35,800 rpm with rotor type 45Ti). The supernantant is discarded and the pellet suspended in 3 to 4 mL of Tris buffer (50 mM TRIS-HCl, pH 7.4). The protein content is estimated by the Bradford or Lowry method. The volume of the membrane suspension is adjusted with the membrane buffer (50 mM Tris-HCl containing 0.1% BSA and 0.1 mM PMSF) to give 3.0 mg/mL (or as appropriate) of protein. The membranes are aliquoted and stored at −70° C.
C. Radioligand Binding Assay:
In wells of a 96-well format microtiter plate, is added 90, 110 or 130 μL (to make up a final volume of 200 μL) of assay buffer containing 50 mM of Tris-HCl (pH 7.4), BSA (heat inactivated, protease-free), 5 mM of 0.1% MgCl 2 , 1 mg % aprotinin, 1 mg % leupeptin, 2 mg % 1,10-phenanthroline, 10 mg % trypsin inhibitor, and 0.1 mM PMSF. The inhibitors are added on the day of the experiment. The components are mixed at room temperature, and then kept in ice bath following adjustment of the pH to 7.4. To each well is added 20 μL of unlabeled arginine vasopressin (AVP) (to give a final concentration of 0.1 to 10 nM for standard curve and 1000 nM for non specific binding) or test compounds in 50% DMSO (e.g. for final concentrations of 0.1 to 1000 nM or as appropriate) or 50% DMSO as vehicle control. For vasopressin and other peptide ligands 20 μL of 50% DMSO is added and the assay buffer volume is adjusted accordingly. To each well is added 50 μL of frozen membrane suspension thawed immediately prior to use and diluted in assay buffer to the required concentration (equivalent to 25 to 50 μg of protein/well as needed). 20 μL of 8 nM [ 3 H]arginine vasopressin ligand in the assay buffer, prepared just before use is added and incubated at room temperature for 60 min. shaking the plate on a mechanical shaker for the first 15 min. The incubation is stopped by rapid filtration of the plate contents followed by wash with ice-cold buffer (50 mM Tris-HCl, pH 7.4) using a cell harvester (Tomtek and Printed filtermat-B filter paper). The filter paper is thoroughly dried (7–12 min. in a microwave oven) and impregnated with MeltiLex B/H melt-on scintillation wax sheets and the radioactivity counted in a betaplate scintillation counter.
Oxytocin Binding in Chinese Hamster Ovary Cell Membranes Expressing Human Oxytocin Receptors
Receptor Source:
Chinese Hamster Ovary (CHO) cells stably transfected with the human oxytocin receptor (cf. Tanizawa et al., U.S. Pat. No. 5,466,584 (1995) to Rohto Pharmaceutical Co. Ltd., Osaka, Japan) were obtained from M. Thibonnier, Case Western Reserve University School of Medicine, Cleveland, Ohio.
A. Passaging and Amplification of Cells:
CHO cells transfected with the human oxytocin receptors obtained from M. Thibonnier (pcDNA3.1 vector) are allowed to grow to confluency (approx. >90%) in T-150 flasks under sterile conditions, in a cell culture medium of F-12 Nutrient Mixture (HAM) with L-glutamine (Gibco Cat. # 11765-054) containing 15 mM HEPES (Gibco Cat. # 15630-080), 1% antibiotic/antimycotic (add 5 mL 100×, Gibco Cat. # 15240-062 per 500 mL F-12), 400 μg/mL of Geneticin (add 4 mL of 50 mg/mL per 500 mL F-12) and 10% Fetal Bovine Serum (Qualified, heat inactivated, Gibco Cat. # 16140-063). The medium is removed by aspiration and the cells are washed with 10 mL of Hank's Balanced Salt solution (Gibco Cat. # 14175-095). The salt solution is removed by aspiration and the cells trypsinized with 5 mL of trypsin-EDTA (0.05% trypsin, 0.53 mM EDTA-4Na, Gibco Cat. # 25300-070) for 1 min The trypsin is removed by aspiration and the cells dislodged by tapping. Cell Culture medium (e.g. 30 mL for 1:30 split) is immediately added and mixed well to inactivate trypsin. 1 mL of detached cells is added to new culture flasks containing fresh Cell Culture medium (e.g. into 25 mL per T-150 flask), and mixed gently. The cells are incubated at 37° C. in 5% CO 2 . The medium is changed at 3 to 4 days interval (or as appropriate). The cells grow to confluency (approx. >75%–95%) within 7–8 days. All steps are done under sterile conditions.
B. Membrane Preparation:
The cells are washed twice gently with Hank's Balanced Salt solution (e.g., use 10 mL per T-150 flask). The excess solution is removed and the cells bathed for 15–30 min. in an enzyme-free Cell Dissociation Buffer (e.g., use 8 mL Hank's Based, Gibco Cat. # 13150-016 per T-1 50 flask) until cells are loosened. The contents are transferred to centrifuge tubes (50 mL size) kept in ice bath. All subsequent steps are done at 4° C. The tubes are centrifuged at 300×g for 15 min (1380 rpm on SORVAL, Model RT6000D, using rotor for 50 mL tubes). The supernatant is discarded and the cells suspended in homogenizing buffer (10 mM Tris-HCl containing 0.25 M sucrose and 1 mM EDTA, pH 7.4) ensuring that the volume of the buffer is about ten times the volume of the cell pellet. The cells are pooled into a centrifuge tube (50 mL) and homogenized with a Polytron at setting 6 for 10 sec. The homogenate is transferred into a Potter-Elvjehm homogenizer and homogenized with 3 strokes. The homogenate is centrifuged at 1500×g for 10 min at 4° C. (3100 rpm using SORVAL, model RT6000D, using a rotor for 50 mL tubes). The pellet is discarded. The supernatant is centrifuged at 100,000×g for 60 min. at 4° C. (Beckman L8-80M ultracentrifuge; spin at 37,500 rpm with rotor type 70 Ti for 50 mL tubes; 38,000 rpm with rotor type 8OTi for 15 mL tubes; or 35,800 rpm with rotor type 45Ti). The supernantant is discarded and the pellet suspended in 3 to 4 mL of Tris buffer (50 mM TRIS-HCl, pH 7.4). The protein content is estimated by the Bradford or Lowry method. The volume of the membrane suspension is adjusted with the membrane buffer (50 mM Tris-HCl containing 0.1% BSA and 0.1 mM PMSF) to give 3.0 mg/mL (or as appropriate) of protein. The membranes are aliquoted and stored at −70° C.
C. Radioligand Binding Assay:
In wells of a 96-well format microtiter plate, is added 90, 110 or 130 μL (to make up a final volume of 200 μL) of assay buffer containing 50 mM of Tris-HCl (pH 7.4), BSA (heat inactivated, protease-free), 5 mM of 0.1% MgCl 2 , 1 mg % aprotinin, 1 mg % leupeptin, 2 mg % 1,10-phenanthroline, 10 mg % trypsin inhibitor, and 0.1 mM PMSF. The inhibitors are added on the day of the experiment. The components are mixed at room temperature, and then kept in ice bath following adjustment of the pH to 7.4. To each well is added 20 μL of unlabeled oxytocin (to give a final concentration of 0.1 to 10 nM for standard curve and 1000 nM for non specific binding) or test compounds in 50% DMSO (e.g. for final concentrations of 0.1 to 1000 nM or as appropriate) or 50% DMSO as vehicle control. For oxytocin and other peptide ligands, 20 μL of 50% DMSO is added and the assay buffer volume is adjusted accordingly. To each well is added 50 μL of frozen membrane suspension thawed immediately prior to use and diluted in assay buffer to the required concentration (equivalent to 25 to 50 μg of protein/well as needed). 20 μL of 8 nM [ 3 H]oxytocin in the assay buffer, prepared just before use is added and incubated at room temperature for 60 min. shaking the plate on a mechanical shaker for the first 15 min. The incubation is stopped by rapid filtration of the plate contents followed by washing with ice-cold buffer (50 mM Tris-HCl, pH 7.4) using a cell harvester (Tomtek and Printed filtermat-B filter paper). The filter paper is thoroughly dried (7–12 min. in a microwave oven) and impregnated with MeltiLex B/H melt-on scintillation wax sheets and the radioactivity counted in a betaplate scintillation counter.
Binding data is either reported as percent inhibition at a certain concentration or if an IC 50 was calculated, as a nanomolar concentration. The results of these tests on representative compounds of this invention are shown in Table I.
TABLE 1 Binding to membranes of Chinese Hamster Ovary (CHO) cell line stably transfected with human vasopressin V 1a receptor subtype, human vasopressin V 2 receptor subtype and human oxytocin receptor V 2 OT V 1a % inhibition % inhibition @ 100 % inhibition @ 100 (IC 50 , nM)*n @ Example nM (IC 50 , nM)* nM (IC 50 , nM)* 100 nM 1 (11.2) 9 18 2 (16.8) (3180) (1418) 3 (45) (>3000) (>3000) 4 (2.44) (791.78) (463.73) 5 (10.2) (>3000) (433) 6 (7.51) (927.96) (308.77) 7 (3.34) (803) (407) 8 (4.65) (801) (237) 24 50 7 26 25 50 21 33 26 47 17 23 27 22 20 16 28 50 28 20 29 42 0 12 30 25 −7 14 31 18 6 31 32 47 13 21 33 42 23 21 34 5 5 5 35 27 4 14 36 46 −3 24 37 60 12 7 38 26 0 21 39 35 10 11 40 17 15 11 41 41 20 16 42 33 −11 8 43 18 −6 7 44 22 11 31 45 37 5 19 46 31 7 8 47 1 −1 6 48 15 0 9 49 58 1 26 50 67 26 17 51 31 2 16 52 51 16 8 53 6 11 13 54 55 30 18 55 50 −7 5 56 31 −11 11 57 32 2 33 58 37 9 22 59 40 12 4 60 11 4 15 61 26 6 14 62 (10.68) (177) (1491) 63 (5.08) (273.45) (714.49) 64 91 21 13 65 95 25 16 66 92 58 24 67 91 40 24 68 93 81 13 69 94 72 15 70 77 8 10 71 81 20 24 72 89 54 11 73 32 6 16 74 91 63 1 75 62 −1 9 76 62 11 21 77 21 5 10 78 59 6 8 79 49 18 10 80 50 6 8 81 50 −6 5 82 27 −1 8 83 30 9 22 84 46 3 14 85 32 −5 5 86 21 1 11 87 52 1 4 88 44 8 13 89 67 29 15 90 44 14 11 91 44 11 10 92 30 21 0 93 69 50 27 94 37 0 5 95 7 1 −1 96 28 7 22 97 36 4 16 98 39 24 10 99 13 −7 12 100 24 10 0 101 (2.23) (355) (270) 102 (4.14) (275) (534) 103 (6.25) (448.88) (318.40) 104 99 32 23 205 −9 0 6 106 98 68 −10 107 92 12 30 108 83 4 24 109 70 7 0 110 94 49 32 111 36 4 23 112 (3.87) (1597) (1126) 113 (10.77) (365) (545) 114 94 56 18 115 66 22 8 116 101 77 63 117 13 1 4 118 83 62 −10 119 83 9 17 120 67 6 16 121 57 17 −4 122 61 9 −10 123 95 71 30 124 24 11 18 125 94 17 −10 126 93 38 5 127 102 66 15 128 88 31 10 129 98 54 28 130 0 5 12 131 99 83 −5 132 99 26 25 133 87 19 15 134 88 30 1 135 96 68 35 136 44 7 19 137 95 −1 11 138 97 8 42 139 96 21 34 140 95 −3 29 141 96 9 40 142 93 −5 16 144 57 11 2 145 22 −1 2 146 38 11 15 147 64 15 21 *Binding in Chinese Hamster Ovary cell membranes expressing human vasopressin V 1a and V 2 subtype receptors and human oxytocin receptors
The following examples are presented to illustrate rather than limit the scope of this invention.
EXAMPLE 1
[10-(2-Methyl-2′-trifluoromethyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-(4-pyridin-4-yl)-piperazin-1-yl)-methanone
Step A. 4-Bromo-3-methylbenzoic acid methyl ester
To a suspension of 4-bromo-3-methylbenzoic acid (10.0 g, 46.5 mmol) in methanol (125 mL) was added concentrated sulfuric acid (1 mL). The reaction was heated at reflux overnight with a homogeneous solution obtained after several minutes of heating. After cooling, the methanol was removed in vacuo and the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 10.2 g of title compound as a brown solid, m.p. 41–43° C.
1 H NMR (DMSO-d 6 , 400 MHz): δ 2.39 (s, 3H), 3.85 (s, 3H), 7.64–7.72 (m, 2H), 7.88–7.89 (m, 1H).
MS [EI, m/z]: 228 [M] + .
Anal. Calcd. for C 9 H 9 BrO 2 : C, 47.19, H, 3.90. Found: C, 47.22, H, 3.80.
Step B. (2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-carboxylic acid methyl ester
A mixture of 4-bromo-3-methylbenzoic acid methyl ester of Step A (2.0 g, 8.7 mmol), 2-trifluoromethyl-phenyl boronic acid (1.65 g, 8.7 mmol) and sodium carbonate (4.1 g, 38.7 mmol) in toluene:ethanol:water (50 mL:25 mL: 25 mL) was purged with nitrogen for 1 hour. After addition of the tetrakis(triphenylphosphine) palladium(0) catalyst (0.50 g, 0.43 mmol) the reaction was heated at 100° C. overnight. The cooled reaction mixture was filtered through Celite and the cake washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification by flash chromatography with a solvent gradient of 25% to 50% dichloromethane in hexane provided 2.0 g of the title compound as a colorless oil.
1 H NMR (DMSO-d 6 , 400 MHz): δ 2.03 (s, 3H), 3.88 (s, 3H), 7.26 (d, 1H), 7.34 (d, 1H), 7.66 (t, 1H), 7.75 (t, 1H), 7.81–7.83 (m, 1H), 7.86–7.88 (m, 1H), 7.90–7.91 (m, 1H)
MS [ESI, m/z]: 312 [M+NH 4 ] + .
Anal. Calcd. for C 16 H 13 F 3 O 2 : C, 65.31, H, 4.45. Found: C, 64.92, H, 4.54.
Step C. (2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-carboxylic acid
To a solution of (2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-carboxylic acid methyl ester of Step B (1.9 g, 6.5 mmol) in tetrahydrofuran (30 mL) was added 1 N sodium hydroxide (13 mL, 13 mmol). The reaction mixture was heated at reflux overnight, then cooled and acidified with 2 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.65 g of the title compound as a white solid, m.p. 171–174° C.
1 H NMR (DMSO-d 6 , 400 MHz): δ 2.02 (s, 3H), 7.23 (d, 1H), 7.34 (d, 1H), 7.65 (t, 1H), 7.75 (t, 1H), 7.79–7.81 (m, 1H), 7.86–7.89 (m, 2H), 13.00 (br, 1H).
MS [(−)ESI, m/z]: 279 [M−H] − .
Anal. Calcd. for C 15 H 11 F 3 O 2 : C, 64.29, H, 3.96. Found: C, 64.26, H, 3.80.
Step D. (10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]methanone
A suspension of (2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-carboxylic acid of Step C (0.50 g, 1.78 mmol) in thionyl chloride (3 mL) was heated at reflux for 90 minutes. After cooling, the thionyl chloride was removed in vacuo and the residue dissolved in toluene. The solution was concentrated in vacuo to yield the crude acid chloride as a brown oil. The acid chloride was dissolved in dichloromethane (5 mL) and slowly added to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.49 g, 2.66 mmol) and N,N-diisopropylethyl amine (0.68 mL, 3.90 mmol) in dichloromethane (15 mL). After stirring for 2 hours, the reaction was quenched with water. The organic layer was sequentially washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography using a solvent gradient of 15 to 25% ethyl acetate in hexane gave a white foam which was crystallized by sonication from ethanol/hexane to provide the title compound (0.55 g) as a white solid, m.p. 127–130° C.
1 H NMR (DMSO-d 6 , 400 MHz): δ 1.86 (s, 3H), 4.80–5.40 (br, 4H), 5.93–5.98 (m, 2H), 6.85 (t, 1H), 6.91–6.96 (m, 2H), 7.03–7.05 (m, 1H), 7.10–7.14 (m, 1H), 7.19–7.24 (m, 2H), 7.29 (s, 1H), 7.47–7.49 (m, 1H), 7.61 (t, 1H), 7.70 (t, 1H), 7.81 (d, 1H).
MS [EI, m/z]: 446 [M] + .
Anal. Calcd. for C 27 H 21 F 3 N 2 O: C, 72.64, H, 4.74, N, 6.27. Found: C, 72.48, H, 4.57, N, 6.16.
Step E. 2,2,2-Trichloro-1-(10-{[2-methyl-2′-trifluoromethyl-[1–1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)ethanone
To a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]methanone of Step D (1.87 g, 4.19 mmol) in dichloromethane (20 mL) was added N,N-diisopropylethyl amine (1.46 mL, 8.38 mmol) followed by the slow addition of trichloroacetyl chloride (1.45 mL, 13.0 mmol). The reaction mixture was stirred overnight at room temperature, and then quenched with water. The organic phase was washed with 0.1 N hydrochloric acid followed by water, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a green oil. Purification by flash chromatography using a solvent system of 20% ethyl acetate in hexane provided 2.2 g of title product as a pale, yellow foam.
1 H NMR (DMSO-d 6 , 400 MHz): δ 1.84 (s, 3H), 5.25 (br, 2H), 5.97 (br, 2H), 6.37 (d, 1H), 6.89–6.92 (m, 2H), 7.02–7.04 (m, 1H), 7.06–7.10 (m, 1H), 7.15–7.22 (m, 2H), 7.28 (s, 1H), 7.41–7.46 (m, 2H), 7.58 (t, 1H), 7.67 (t, 1H), 7.79 (d, 1H).
MS [(+)APCI, m/z]: 591 [M+H] + .
Anal. Calcd. for C 29 H 20 Cl 3 F 3 N 2 O 2 +0.20 C 4 H 8 O 2 +0.80 H 2 O: C, 57.37, H, 3.75, N, 4.49. Found: C, 57.06, H, 3.39, N, 4.50.
Step F. 10-(2-Methyl-2′-trifluoromethyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid
To a solution of 2,2,2-trichloro-1-(10-{[2-methyl-2′-(trifluoromethyl)[1-1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)ethanone of Step E (2.3 g, 3.9 mmol) in acetone (20 mL) was added 2.5 N sodium hydroxide (3.1 mL, 7.8 mmol). After stirring overnight, the reaction mixture was acidified with 2 N hydrochloric acid (4.3 mL, 8.6 mmol) and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown solid. Trituration with diethyl ether/hexane provided the title compound (1.32 g) as a white solid, m.p. 233–235° C.
1 H NMR (DMSO-d 6 , 400 MHz): δ 1.84 (s, 3H), 5.17 (br, 2H), 5.94 (br, 2H), 6.10–6.11 (m, 1H), 6.76 (d, 1H), 6.85–6.91 (m, 2H), 7.00–7.06 (m, 2H), 7.12–7.16 (m, 1H), 7.21 (d, 1H), 7.25 (s, 1H), 7.32–7.34 (m, 1H), 7.59 (t, 1H), 7.68 (t, 1H), 7.79 (d, 1H), 12.33 (br, 1H).
MS [ESI, m/z]: 491 [M+H] + .
Anal. Calcd. for C 28 H 21 F 3 N 2 O 3 : C, 68.57, H, 4.32, N, 5.71. Found: C, 68.39; H, 4.25, N, 5.64.
Step G. [10-(2-Methyl-2′-trifluoromethyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-(4-pyridin-4-yl-piperazin-1-yl)-methanone
To a solution of 10-(2-methyl-2′-trifluoromethyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step F (0.50 g, 1.02 mmol), 1-(4-pyridinyl)-piperazine (0.20 g, 1.23 mmol) and 1-hydroxybenzotriazole monohydrate (0.15 g, 1.11 mmol) in N,N-dimethylformamide (4 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.22 g, 1.15 mmol) followed by N,N-diisopropylethyl amine (0.27 mL, 1.55 mmol). The reaction mixture was stirred overnight, diluted with ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. Purification by flash chromatography using a solvent system of 10% methanol in chloroform provided 0.39 g of the title product which was dissolved in dichloromethane and concentrated in vacuo to a white foam.
1 H NMR (DMSO-d 6 , 400 MHz): δ 1.83 (s, 3H), 3.40–3.43 (m, 4H), 3.74–3.76 (m, 4H), 5.15 (broad s, 2H), 5.44 (s, 2H), 6.09 (d, 1H), 6.32 (d, 1H), 6.82–6.90 (m, 4H), 6.99–7.06 (m, 2H), 7.13 (t, 1H), 7.22 (d, 1H), 7.26 (s, 1H), 7.40–7.42 (m, 1H), 7.58 (t, 1H), 7.67 (t, 1H), 7.79 (d, 1H), 8.17–8.19 (m, 2H).
MS [(+)APCI, m/z]: 636 [M+H] + .
Anal. Calcd. for C 37 H 32 F 3 N 5 O 2 +0.14 CH 2 Cl 2 +0.04 C 3 H 7 NO: C, 68.80, H, 5.05, N, 10.85. Found: C, 66.63, H, 4.97, N, 10.41.
EXAMPLE 2
10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-3-({4-[(1-oxidopyridin-3-yl)methyl]piperazin-1-yl}carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine
Step A. 3-Chloromethyl-pyridine-1-oxide
To a solution of 3-hydroxymethyl-pyridine N-oxide (1.0 g, 8.0 mmol) in dichloromethane (40 mL) was added thionyl chloride (10 mL, 137 mmol). After stirring for 2 hours, the reaction mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer was repeatedly extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.60 g of the title product as a white solid, m.p. 133–137° C.
1 H NMR (DMSO-d 6 , 400 MHz): δ 4.74 (s, 2H), 7.40–7.45 (m, 2H), 8.17–8.20 (m, 1H), 8.35 (s, 1H).
MS [(+)APCI, m/z]: 144 [M+H] + .
Anal. Calcd. for C 6 H 6 ClNO: C, 50.19, H, 4.21, N, 9.76. Found: C, 49.56, H, 4.21, N, 9.58.
Step B. 4-[[10,11-Dihydro-10-[[2-methyl-2-trifluoromethyl-[1,1-biphenyl]-4-yl]carbonyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]carbonyl]-1-piperazinecarboxylic acid, tert-butyl ester
10-(2-Methyl-2-trifluoromethyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step F (1.0 g, 2.04 mmol), 1-(tert-butoxycarbonyl)piperazine (0.46 g, 2.47 mmol) and 1-hydroxybenzotriazole monohydrate (0.30 g, 2.22 mmol) were dissolved in N,N-dimethylformamide (8 mL). 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.43 g, 2.24 mmol) was then added followed by N,N-diisopropylethyl amine (0.55 mL, 3.09 mmol). The reaction mixture was stirred overnight, diluted with ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification by flash chromatography using a solvent gradient from 30% to 50% of ethyl acetate in hexane provided 1.1 g of the desired title compound as a white foam, m.p. 104–121° C. This material was redissolved in dichloromethane and concentrated in vacuo to a white foam.
1 H NMR (DMSO-d 6 , 400 MHz): δ 1.41 (s, 9H), 1.83 (s, 3H), 3.38 (br, 4H), 3.59–3.61 (m, 4H), 5.15 (br, 2H), 5.41 (s, 2H), 6.07 (d, 1H), 6.28 (d, 1H), 6.85–6.90 (m, 2H), 6.99–7.06 (m, 2H), 7.12–7.16 (m, 1H), 7.21 (d, 1H), 7.25 (s, 1H), 7.40–7.42 (m, 1H), 7.58 (t, 1H), 7.67 (t, 1H), 7.79 (d, 1H).
MS [(+)APCI, m/z]: 659 [M+H] + .
Anal. Calcd. for C 37 H 37 F 3 N 4 O 4 +0.09 CH 2 Cl 2 +0.18 C 4 H 8 O 2 C, 66.56, H, 5.71, N, 8.21. Found: C, 66.27, H, 5.40, N, 8.00.
Step C. 10,11-Dihydro-10-[[2-methyl-2-(trifluoromethyl)[1,1-biphenyl]-4-yl]carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine hydrochloride salt
The 4-[[10,11-dihydro-10-[[2-methyl-2-(trifluoromethyl)[1,1-biphenyl]-4-yl]carbonyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]carbonyl]-1-piperazinecarboxylic acid, tert-butyl ester of Step B (0.85 g, 1.29 mmol) was then added in one portion to stirred ethyl acetate (10 mL) saturated with hydrogen chloride gas at 0° C. The reaction mixture was stirred for 90 minutes under anhydrous conditions. A precipitate formed after several minutes. The reaction was then warmed to room temperature and diluted with diethyl ether. The precipitated product was collected by filtration and dried under high vacuum to provide 0.65 g of the desired title compound hydrochloride salt as an off-white foam.
1 H NMR (DMSO-d 6 , 400 MHz): δ 1.84 (s, 3H), 3.16 (br, 4H), 3.83–3.85 (m, 4H), 5.15 (br, 2H), 5.43 (s, 2H), 6.09 (d, 1H), 6.38 (d, 1H), 6.87–6.91 (m, 2H), 6.99–7.01 (m, 1H), 7.06 (t, 1H), 7.13–7.17 (m, 1H), 7.21 (d, 1H), 7.26 (s, 1H), 7.44–7.46 (m, 1H), 7.59 (t, 1H), 7.68 (t, 1H), 7.79 (d, 1H), 9.28 (br, 2H).
MS [(+)APCI, m/z]: 559 [M+H] + .
Anal. Calcd. for C 32 H 29 F 3 N 4 O 2 +1.0 HCl+1.00 H 2 O+0.06 C 4 H 10 O: C, 62.70, H, 5.32, N, 9.07. Found: C, 62.42, H, 5.22, N, 8.94.
Step D. 10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-3-({4-[(1-oxidopyridin-3-yl)methyl]piperazin-1-yl}carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine
A mixture of the 10,11-dihydro-10-[[2-methyl-2-(trifluoromethyl)[1,1-biphenyl]-4-yl]carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine hydrochloride salt of Step C (0.50 g, 0.84 mmol), 3-chloromethyl-pyridine-1-oxide of Step A (0.11 g, 0.77 mmol) and N,N-diisopropylethyl amine (0.30 mL, 1.70 mmol) in N,N-dimethylformamide (10 mL) was heated at 50° C. The reaction was then cooled, quenched with saturated aqueous sodium bicarbonate and extracted with chloroform. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. Purification by flash chromatography using a solvent system of 5% methanol in dichloromethane provided 0.47 g of the title compound as a yellow foam.
1 H NMR (DMSO-d 6 , 400 MHz): δ 1.84 (s, 3H), 2.42 (br, 4H), 3.52 (m, 2H), 3.64 (br, 4H), 5.15 (br, 2H), 5.40 (s, 2H), 6.06 (d, 1H), 6.24 (d, 1H), 6.84–6.90 (m, 2H), 6.99–7.06 (m, 2H), 7.15 (t, 1H), 7.21 (d, 1H), 7.25 (s, 1H), 7.29 (d, 1H), 7.35–7.42 (m, 2H), 7.58 (t, 1H), 7.68 (t, 1H), 7.79 (d, 1H), 8.11 (d, 1H), 8.17 (s, 1H).
MS [(+)APCI, m/z]: 666 [M+H] + .
Anal. Calcd. for C 38 H 34 F 3 N 5 O 3 +1.00 H 2 O+0.11 CH 2 Cl 2 : C, 66.04, H, 5.27, N, 10. Found: C, 65.88, H, 5.03, N, 10.03.
EXAMPLE 3
3-({4-[(2-Methyl-1-oxidopyridin-3-yl)methyl]piperazin-1-yl}carbonyl)-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine
Step A. 3-Hydroxymethyl-2-methyl-pyridine
Prepared according to a slightly modified procedure of I. M. Bell et al., J. Med. Chem . 41, 2146–2163 (1998). To a stirred solution of ethyl 2-methylnicotinate (2.0 g, 12.1 mmol) in tetrahydrofuran (40 mL) cooled to 0° C. was slowly added a 1 M solution of diisobutyl aluminum hydride in tetrahydrofuran (30 mL, 30 mmol). After 5 minutes, the reaction was quenched with saturated aqueous sodium bicarbonate and saturated aqueous sodium potassium tartrate. The aqueous phase was repeatedly extracted with chloroform. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2.5 g of the crude title compound as a yellow oil. The crude material was used as such in the next step.
1 H NMR (DMSO-d 6 , 400 MHz): δ 2.40 (s, 3H), 4.49 (d, 2H), 5.23 (t, 1H), 7.16–7.19 (m, 1H), 7.67–7.69 (m, 1H), 8.28–8.31 (m, 1H).
MS [(+)APCI, m/z]: 124 [M+H] + .
Step B. 3-Chloromethyl-2-methyl-pyridine
Prepared essentially according to the procedure of I. M. Bell et al., J. Med. Chem . 41, 2146–2163 (1998). To a stirred solution of the 3-hydroxymethyl-2-methyl-pyridine of Step A (2.5 g, 20.3 mmol) in dichloromethane (100 mL) was added thionyl chloride (15 mL, 206 mmol). After stirring for 2 hours, the reaction mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer was repeatedly extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.35 g of the title compound as an orange oil which was immediately used in the next step.
1 H NMR (DMSO-d 6 , 400 MHz): δ 2.54 (s, 3H), 4.82 (s, 2H), 7.21–7.24 (m, 1H), 7.75–7.78 (m, 1H), 8.39–8.41 (m, 1H).
MS [(+)APCI, m/z]: 142 [M+H] + .
Step C. 3-Chloromethyl-2-methyl-pyridine 1-oxide
Prepared essentially according to the procedure of I. M. Bell et al., J. Med. Chem . 41, 2146–2163 (1998). To a stirred solution of the crude 3-hydroxymethyl-2-methyl-pyridine of Step B (1.35 g, 9.53 mmol) in chloroform (50 mL) was added 90% m-chloroperbenzoic acid (2.0 g, 10.4 mmol). After stirring overnight at room temperature, an additional quantity of 90% m-chloroperbenzoic acid (1.0 g, 5.2 mmol) was added. The reaction mixture was stirred for an additional 3 hours and then quenched with saturated aqueous sodium bicarbonate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow solid. Purification by flash chromatography using a solvent system of 3% methanol in chloroform provided 0.85 g of the title compound as a brown-orange amorphous solid.
1 H NMR (DMSO-d 6 , 400 MHz): δ 2.41 (s, 3H), 4.84 (s, 2H), 7.26–7.29 (m, 1H), 7.38–7.40 (m, 1H), 8.25–8.27 (m, 1H).
MS [(+)APCI, m/z]: 158 [M+H] + .
Anal. Calcd. for C 7 H 8 ClNO: C, 53.35, H, 5.12, N, 8.89. Found: C, 52.69, H, 4.64, N, 8.06.
Step D. 3-({4-[(2-Methyl-1-oxidopyridin-3-yl)methyl]piperazin-1-yl}carbonyl)-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine
A stirred mixture of the 10,11-dihydro-10-[[2-methyl-2-(trifluoromethyl)[1,1-biphenyl]-4-yl]carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine hydrochloride salt of Example 2, Step C (0.50 g, 0.84 mmol), 3-chloromethyl-2-methyl-pyridine 1-oxide of Step B (0.13 g, 0.82 mmol) and N,N-diisopropylethyl amine (0.30 mL, 1.70 mmol) in N,N-dimethylformamide (10 mL) was heated at 50° C. overnight. The reaction mixture was then cooled, quenched with saturated aqueous sodium bicarbonate and extracted with chloroform. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. Purification by flash chromatography using a solvent system of 5% methanol in dichloromethane provided 0.41 g of the title product as a white foam.
1 H NMR (DMSO-d 6 , 400 MHz): δ 1.84 (s, 3H), 2.40 (s, 3H), 2.43 (br, 4H), 3.53 (s, 2H), 3.62 (br, 4H), 5.15 (br, 2H), 5.41 (s, 2H), 6.06 (d, 1H), 6.23 (d, 1H), 6.85–6.90 (m, 2H), 6.99–7.06 (m, 2H), 7.13–7.17 (m, 1H), 7.20–7.26 (m, 4H), 7.38–7.40 (m, 1H), 7.58 (t, 1H), 7.68 (t, 1H), 7.79 (d, 1H), 8.19–8.20 (m, 1H).
MS [ESI, m/z]: 680 [M+H] + .
Anal. Calcd. for C 39 H 36 F 3 N 5 O 3 +0.50 H 2 O+0.40 CH 2 Cl 2 : C, 65.48; H, 5.27, N, 9.69. Found: C, 65.08, H, 5.04, N, 9.62.
EXAMPLE 4
N-Methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-[(1-oxidopyridin-3-yl)methyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
Step A. tert-Butyl methyl(pyridin-3-ylmethyl)carbamate
To a stirred solution of 3-(methylaminomethyl) pyridine (1.0 g, 8.2 mmol) in dichloromethane (20 mL) was added di-tert-butyl dicarbonate (1.8 g, 8.2 mmol). After 10 minutes, the reaction was quenched with water. The organic layer was washed with 5% aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.8 g of crude product as a pale yellow oil, which was used as such in the next step.
1 H NMR (DMSO-d 6 , 400 MHz): δ 1.10 (s, 9H), 2.77 (s, 3H), 4.38 (s, 2H), 7.35–7.38 (m, 1H), 7.60–7.62 (d, 1H), 8.44–8.48 (m, 2H).
MS [ESI, m/z]: 223 [M+H] + .
Step B. tert-Butyl methyl[(1-oxidopyridin-3-yl)methyl]carbamate
To a stirred solution of tert-butyl methyl(pyridin-3-ylmethyl)carbamate of Step A (0.50 g, 2.25 mmol) in dichloromethane (15 mL) was added 90% m-chloroperbenzoic acid (1.3 g, 6.8 mmol). After stirring overnight, the reaction was quenched with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.38 g of product as a colorless oil.
1 H NMR (DMSO-d 6 , 400 MHz): δ 1.40 (br, 9H), 2.80 (s, 3H), 4.32 (s, 2H), 7.16 (d, 1H), 7.39 (t, 1H), 8.07 (s, 1H), 8.12 (d, 1H).
MS [ESI, m/z]: 239 [M+H] + .
Step C. Methyl-(1-oxy-pyridin-3-ylmethyl)-amine dihydrochloride
Hydrogen chloride gas was bubbled for 15 minutes into a solution of tert-butyl methyl[(1-oxidopyridin-3-yl)methyl]carbamate of Step B (0.38 g, 1.60 mmol) in ethyl acetate (10 mL) kept at 0° C. A drying tube was attached, and the reaction warmed to room temperature while stirring for 1 hour. The reaction was then concentrated in vacuo to give 0.31 g of the title product as an amorphous white solid, which is used as such in the nest step.
1 H NMR (DMSO-d 6 , 400 MHz): δ 2.52 (t, 3H), 4.16 (t, 2H), 7.64–7.67 (m, 1H), 7.86(d, 1H), 8.46–8.48 (m, 1H), 8.60 (br, 1H), 8.68 (s, 1H), 9.75 (br, 2H).
MS [(+)APCI, m/z]: 139 [M+H] + .
Anal. Calcd. for C 7 H 10 N 2 O+2 HCl: C, 39.83, H, 5.73, N, 13.27. Found: 40.01, H, 5.77, N, 13.19.
Step D. N-methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-[(1-oxidopyridin-3-yl)methyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
To a stirred solution of the 10-(2-methyl-2′-trifluoromethyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step F (0.50 g, 1.02 mmol), methyl-(1-oxy-pyridin-3-ylmethyl)-amine dihydrochloride of Step C (0.26 g, 1.23 mmol) and 1-hydroxybenzotriazole (0.16 g, 1.18 mmol) in N,N-dimethylformamide (4 mL) was added 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.21 g, 1.10 mmol) followed by N,N-diisopropylethyl amine (0.73 mL, 4.10 mmol). The reaction mixture was stirred overnight, diluted with ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography eluting with 2% methanol in chloroform provided 0.52 g of the title compound, which was redissolved in dichloromethane and concentrated in vacuo to give a white foam.
1 H NMR (DMSO-d 6 , 400 MHz): δ 1.84 (s, 3H), 3.07 (s, 3H), 4.67 (s, 2H), 5.15 (br, 2H), 5.49 (s, 2H), 6.08 (d, 1H), 6.40 (br, 1H), 6.86–6.91 (m, 2H), 7.00–7.07 (m, 2H), 7.13–7.17 (m, 1H), 7.22 (d, 1H), 7.26–7.29 (m, 2H), 7.39–7.45 (m, 2H), 7.59 (t, 1H), 7.68 (t, 1H), 7.80 (d, 1H), 8.15–8.19 (m, 2H).
MS [ESI, m/z]: 611 [M+H] + .
Anal. Calcd. for C 35 H 29 F 3 N 4 O 3 +0.14 CH 2 Cl 2 +0.14 CHCl 3 : C, 66.29, H, 4.64, N, 8.76. Found: C, 64.26, H, 3.98, N, 8.39.
EXAMPLE 5
10-{[6-Chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
Step A. 4-Iodo-5-chloro-2-methoxy benzoic acid
A stirred solution of 4-amino-5-chloro-2-methoxy benzoic acid (12.25 g , 60.8 mmol) in water (136 mL) and concentrated sulfuric acid (34 mL) was cooled to 0° C. in a flask fitted with an overhead stirrer. A solution of sodium nitrite (4.62 g , 66.9 mmol) in water (26 mL) was added dropwise while keeping the internal temperature around 0° C. Potassium iodide (11.11 g, 66.9 mmol) and iodine (4.24g, 33.5 mmol) were dissolved in water (130 mL) and added dropwise to the stirred reaction mixture. After 2 hours the reaction was extracted with ethyl acetate. The organic extracts were then washed with 10% sodium thiosulfate and brine, then dried over magnesium sulfate, filtered and evaporated to dryness to yield 11.32 g of the title compound, m.p. 150–151° C. This material was used without further purification.
1 H NMR (DMSO-d 6 , 400 MHz): δ 13.03 (br, 1H), 7.70 (s, 1H), 7.63 (s, 1H), 3.82 (s, 3H).
MS [(−)-APCI, m/z]: 311 [M−H] −
Anal. Calcd. for C 8 H 6 ClIO 3 : C, 30.75, H, 1.94. Found: C, 31.28, H, 1.78.
Step B. 2-Chloro-2′-trifluoromethyl-5-methoxy-[1,1′-biphenyl]-4-carboxylic acid
To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acid of Step A (3.12 g, 10 mmol) in N,N-dimethylformamide(100 mL) was added 2-trifluoromethyl phenyl boronic acid (5.70 g, 30 mmol) and potassium carbonate (12.73 g, 92 mmol). This mixture was purged with nitrogen and then treated with a catalytic amount of tetrakis(triphenylphosphine) palladium(0) (0.58 g, 0.5 mmol). The reaction was heated to reflux overnight, cooled, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to provide a nearly quantitative amount of the title acid which was used in the next step without further purification.
Step C. 10-{[6-Chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine
A stirred solution of the 2-chloro-2′-trifluoromethyl-5-methoxy-[1,1′-biphenyl]-4-carboxylic acid of Step B (3.46 g, 10.46 mmol) in tetrahydrofuran (20 mL) containing a catalytic amount of N,N-dimethylformamide was treated dropwise with thionyl chloride (1.36 g, 11.51 mmol). The reaction mixture was stirred for 2 hours, and then added dropwise to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.92 g 10.46 mmol) in tetrahydrofuran (20 mL) containing triethylamine (2.32 g, 23 mmol). The reaction mixture was stirred for 2 hours, diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. Trituration of the residue with acetone gave 3.14 g of the title compound. Recrystallization from acetone/hexane provided white crystals, m.p. 208–210° C.;
1 H NMR (DMSO-d 6 , 400 MHz) δ 3.46 (s, 3H), 5.16–5.20 (br, d, 3H), 5.89 (t, 1H), 5.97 (s, 1H), 6.70 (s, 1H), 6.80 (t, 1H), 7.80–7.00 (m, 10H).
MS [(+) ESI, m/z]: 497 [M+H] + .
Anal. Calcd. for C 27 H 20 ClF 3 N 2 O 2 +0.5 H 2 O: C, 64.10, H, 4.18, N, 5.54. Found: C, 64.40, H, 3.97, N, 5.54.
Step D. 10-{[6-Chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid
A solution of the 10-{[6-chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step C (2.29 g, 4.6 mmol) in dichloromethane (30 mL) was treated with N,N-diisopropylethylamine (0.62 g, 4.84 mmol) and stirred for 10 minutes. Trichloroacetylchloride (0.92 g, 5.07 mmol) was then added dropwise. The reaction mixture was stirred overnight, diluted with dichloromethane, washed with 0.1N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to yield the crude trichloroketone intermediate which without further purification, was dissolved in acetone and treated with an excess of 1N sodium hydroxide The mixture was stirred overnight, and then diluted with isopropyl acetate and acidified with 1 N hydrochloric acid. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The solid residue was triturated with methanol to provide the title compound (1.23 g ) as a white solid, m.p. 220–222° C. (dec).
1 H NMR (DMSO-d 6 , 400 MHz) δ 3.40 (s, 3H), 6.12 (d, 1H), 6.68 (s, 1H), 6.72 (d, 1H), 6.94 (s, 2H), 7.07 (t, 1H), 7.25 (d, 2H), 7.62 (t, 2H), 7.70 (t, 1H), 7.78 (d, 1H), 12.31 (br, 1H).
MS [(+)APCI, m/z]: 541 [M+H] + .
Anal. Calcd. for C 28 H 20 ClF 3 N 2 O 4 +0.25 H 2 O: C, 61.66, H, 3.79, N, 5.14. Found: C, 61.47, H, 3.64, N, 5.06.
Step E. 10-{[6-Chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
To a stirred solution of the 10-{[6-chloro-3-methoxy-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step D (0.250 g, 0.46 mmol) in N,N-dimethylformamide (2 mL) was added 3-(methylaminomethyl)pyridine (0.068 g, 0.55 mmol), 1-hydroxybenzotriazole (0.069 g, 0.51 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.087 g, 0.51 mmol), and N,N-diisopropylethyl amine (0.090 g, 0.69 mmol). After stirring overnight, the reaction mixture was taken up in chloroform, washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and evaporated to yield the title compound (0.153 g) as a solid which was recrystallized from ethyl acetate, m.p. 124–126° C. The sample was shown to be 93% pure by analytical HPLC [Primesphere C-18 column (2.0×150 mm); mobile phase: 45/55 acetonitrile/water containing 0.1% phosphoric acid].
1 H NMR (DMSO-d 6 , 400 MHz) δ 3.02 (s, 3H), 3.41 (br, 3H), 4.74 (s, 2H), 5.36 (br, 1H), 5.40 (br, 1H), 6.08 (d, 1H), 6.33 (s, 1H), 6.68 (s, 1H), 6.95 (s, 2H), 7.09 (t, 1H), 7.25–7.90 (m, 8H), 8.51 (t, 2H).
MS [(+)APCI, m/z]: 645 [M+H] + .
Anal. Calcd. for C 35 H 28 ClF 3 N 4 O 3 : C, 65.17, H, 4.38, N, 8.69. Found: C, 63.84, H, 4.47, N, 9.00.
EXAMPLE 6
10-[(2′,6-Dichloro-3-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
Step A. 2-Chloro-2′-chloro-5-methoxy-[1,1′-biphenyl]-4-carboxylic acid
To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acid of Example 5, Step A (3.38 g, 10.8 mmol) in N,N-dimethylformamide (80 mL) was added 2-chloro phenyl boronic acid (5.07 g, 32.4 mmol) and potassium carbonate (3.44 g, 32.4 mmol). This mixture was purged with nitrogen and then treated with tetrakis(triphenylphosphine) palladium(0) (0.625 g, 0.54 mmol). The reaction was heated to reflux overnight, cooled, acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to provide 2.4 g of the title acid which was used in the next step without further purification.
Step B. 10-{[2′,6-Dichloro-3-methoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine
A stirred solution of the 2-chloro-2′-chloro-5-methoxy-[1,1′-biphenyl]-4-carboxylic acid of Step A (2.29 g, 7.71 mmol) in tetrahydrofuran (20 mL) containing a catalytic amount of N,N-dimethylformamide was treated dropwise with thionyl chloride (1.00 g, 8.48 mmol). The reaction mixture was stirred for 2 hours, and then added dropwise to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.42 g, 7.71 mmol) in tetrahydrofuran (20 mL) containing triethylamine (1.72 g, 16.96 mmol). The reaction mixture was stirred for 2 hours, diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. Trituration of the residue with ethyl acetate provided 1.93 g of the title compound which was recrystallized from ethyl acetate/hexanes as white crystals, m.p. 209–211° C.
1 H NMR (DMSO-d 6 , 400 MHz) δ 3.55 (s, 3H), 5.16–5.20 (br, m, 3H), 5.89 (t, 1H), 5.97 (s, 1H), 6.71 (s, 1H), 6.80 (s, 1H), 7.04–7.60 (m, 10H).
MS [(+)APCI, m/z]: 463 [M+H] + .
Anal. Calcd. for C 26 H 20 Cl 2 N 2 O 2 +0.25 C 4 H 8 O 2 : C, 66.81, H, 4.57, N, 5.77. Found: C, 66.76, H, 4.24, N, 5.93.
Step C. 10-[(2′,6-Dichloro-3-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid.
A solution of the 10-[(2′,6-dichloro-3-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step B (1.36 g, 2.94 mmol) in dichloromethane (25 mL) was treated with N,N-diisopropylethyl amine (0.398 g, 3.08 mmol) and stirred for 10 minutes. Trichloroacetylchloride (0.587 g, 3.23 mmol) was then added dropwise. The reaction mixture was stirred overnight, diluted with dichloromethane, washed with 0.1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to yield the crude trichloroketone intermediate which without further purification, was dissolved in acetone and treated with an excess of 1 N sodium hydroxide. The mixture was stirred overnight, and then diluted with isopropyl acetate and acidified with 1 N hydrochloric acid. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The solid residue was triturated with methanol to provide the title compound (1.02 g) as a white powder which was used as such in the next step.
Step D. 10-[(2′,6-Dichloro-3-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
To a stirred solution of the 10-[(2′,6-dichloro-3-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine carboxylic acid of Step C (0.250 g, 0.49 mmol) in N,N-dimethylformamide (2 mL) was added 3-(methylaminomethyl) pyridine (0,073 g, 0.59 mmol), 1-hydroxybenzotriazole (0.074 g, 0.54 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.093 g, 0.54 mmol), and N,N-diisopropylethyl amine (0.096 g, 0.74 mmol). After stirring overnight, the reaction mixture was taken up in chloroform, washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and evaporated to dryness. Trituration of the residue with ethyl acetate provided the title compound (0.225 g) as a white solid, m.p. 196–198° C., found to be 93.88% pure by analytical HPLC [Primesphere C-18 column (2.0×150 mm); mobile phase: 45/55 acetonitrile/water containing 0.1% phosphoric acid].
1 H NMR (DMSO-d 6 , 400 MHz) δ 3.02 (s, 3H), 3.46 (br, s, 3H), 4.74 (s, 2H), 5.38 (s, 2H), 6.08 (d, 1H), 6.33 (s, 1H), 6.69 (s, 1H), 6.98–7.72 (m, 12H), 8.49–8.53 (m, 2H).
MS [(+)APCI, m/z]: 611 [M+H] + .
Anal. Calcd. for C 34 H 28 Cl 2 N 4 O 3 : C, 66.78, H, 4.62, N, 9.16. Found: C, 64.98, H, 4.63, N, 9.45.
EXAMPLE 7
10-{[2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
Step A. Trifluoromethanesulfonic acid 4-formyl-2-methoxy-phenyl ester
To a solution of vanillin (6.08 g, 40.0 mmol) and triethylamine (6.70 mL, 48.0 mmol) in dichloromethane (300 mL) was added dropwise a solution of trifluoromethanesulfonic anhydride (12.4 g, 44.0 mmol) in dichloromethane (100 mL) at 0° C. After stirring for 2 hours, the solution was concentrated, and the residue washed with water and extracted twice with ethyl acetate. Upon drying and concentrating, the residual dark oil was subjected to flash chromatography on silica gel eluting with 20% ethyl acetate in hexane providing the title product (8.91 g) as a light yellow oil, which was used in the next step without further purification.
Step B. 2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxaldehyde
A stirred solution of trifluoromethanesulfonic acid 4-formyl-2-methoxy-phenyl ester of Step A (6.9 g, 22.1 mmol), 2-trifluoromethyl phenyl boronic acid (5.4 g, 28.6 mmol) and potassium phosphate (13.2 g, 62.2 mmol) in N,N-dimethylformamide (120 mL) was degassed with nitrogen, whereupon a catalytic amount (0.285 g) of [1,4-bis-(diphenylphosphine)butane]palladium (II) dichloride was added. The solution was heated to 120° C. for 5 hours, poured into water and extracted with ethyl acetate. The combined extracts were washed with water, dried over anhydrous magnesium sulfate and filtered through a plug of silica gel. Removal of the solvent provided the crude title compound (4.54 g) as an oil, which was used as such in the next step.
1 H NMR (200 MHz, CDCl 3 ): δ 10.03 (s, 1H), 8.14 (d, 1H), 7.31–7.56 (m, 6H), 3.91 (s, 3H).
Step C. 2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylic acid
The 2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxaldehyde of Step B (0.95 g, 3.41 mmol) and sulfamic acid (0.43 g, 4.43 mmol) were dissolved in a mixture of tetrahydrofuran and water (1:1, v/v, 30 mL). Sodium chlorite (0.31 g, 4.43 mmol) was added under stirring, and the solution turned yellow. After 30 minutes, additional sodium chlorite (0.1 g) and sulfamic acid were added, and the solution stirred an additional hour. The solution was then concentrated, and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was dried and concentrated to yield an oil, which solidified upon trituration with hexane to provide the title compound (0.84 g) as a yellow solid, which was used in the next step.
Step D. (10,11-Dihydro-5H-pyrrolo[2,1-c][1,4] benzodiazepin-10-yl)-(2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-methanone
The 2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylic acid of Step C (1.6 g, 5.40 mmol) was added to a flask containing toluene (30 mL), thionyl chloride (1.4 mL) and one drop of N,N-dimethylformamide. The solution was stirred at 70° C. for 1 hour and then concentrated in vacuo. The residue was diluted with dichloromethane (40 mL) and to this solution was added 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.94 g, 5.16 mmol). After the solution became homogeneous, N,N-diisopropylethyl amine (1.07 mL, 6.19 mmol) was added in one portion at 0° C. After 30 minutes the solution was concentrated, and the residue partitioned between water and ethyl acetate. The ethyl acetate was dried and concentrated to give a crude oil, which was chromatographed on silica gel eluting with 30% ethyl acetate in hexane to yield 1.2 g of product. The solid was recrystallized from ethyl acetate/hexane to provide the desired title product (0.87 g) as colorless crystals, m.p. 146–148° C.
1 H NMR (400 MHz, DMSO-d 6 ) δ 7.72 (d, 1H), 7.62 (t, 1H ), 7.53 (t, 1H), 7.46 (d, 1H), 7.19 (m, 2H), 7.11 (t, 1H), 6.92–7.01 (m, 4H), 6.83 (s, 1H), 5.95 (br, 1H), 5.91 (s, 1H), 5.31 (br, 4H), 3.45 (s, 3H).
MS [(+)ESI, m/z]: 463 [M+H] + .
Anal. Calcd. for C 27 H 21 F 3 N 2 O 2 : C, 70.12, H, 4.58, N, 6.06. Found: C, 70.53; 4 H, 4.72, N, 5.89.
Step E. 10-{[2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid
To a stirred solution of the (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-methanone of Step D (2.34 g, 5.0 mmol) and N,N-diisopropylethyl amine (1.04 mL, 6.0 mmol) in dichloromethane (100 mL) was added dropwise a solution of trichloroacetyl chloride (1.09 g, 6.0 mmol) in dichloromethane (20 mL) kept at 0° C. After the addition was complete, the solution was stirred overnight at room temperature, then washed with 10% aqueous potassium carbonate. The organic phase was dried and concentrated to yield a black residue. The residue was purified by filtration through a plug of silica gel, eluting with 20% ethyl acetate in hexane. The resulting tan colored product was dissolved in acetone and 1 N NaOH (2:1, v/v) and the mixture was stirred for 30 minutes. The solution was then concentrated and extracted with ethyl acetate. The combined organic phases were dried and concentrated to yield a yellow oil. The oil was triturated with hexane, and the resulting solid was removed by filtration to yield the title compound (1.86 g) as an off white solid, which was used without further purification.
Step F. 10-{[2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
To a stirred solution of the 10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step E (0.17 g, 0.37 mmol) in N,N-dimethylformamide (15 mL), was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.092 g, 0.48 mmol) and 1-hydroxybenzotriazole monohydrate (0.065 g, 0.48 mmol). After the solution became homogeneous 3-(methylaminomethyl) pyridine (0.045 g, 0.37 mmol) was added, and the solution was stirred at room temperature overnight. The solution was then poured into water and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried and concentrated to dryness. The residue was subjected to silica chromatography eluting with 10% methanol in chloroform. The pure fractions were concentrated and the residue azeotroped and triturated several times with hexane to provide the title product (0.150 g) as an amorphous white solid, 150–153° C. (dec.)
1 H NMR (400 MHz, DMSO-d 6 ): δ 3.14 (s, 3H), 3.46 (s, 3H), 4.82(s, 2H), 5.52 (br, 2H), 6.06 (s, 1H), 6.43 (s, 1H), 6.85–6.97 (m, 4H), 7.04 (t, 1H), 7.18 (t, 1H), 7.21 (d, 1H), 7.42 (d, 1H), 7.56 (t, 1H), 7.62 (t, 1H), 7.74 (d, 1H), 7.86 (t, 1H), 8.29(m, 1H), 8.89 (m, 2H).
MS [EI, m/z]: 610 [M] + .
Anal. Calcd. for C 35 H 29 F 3 N 4 O 3 : C, 64.96, H, 4.67, N, 8.66. Found: C, 63.28, H, 4.85, N, 8.22.
EXAMPLE 8
10-{[2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-N-(1-oxo-pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
The title compound [white solid, 0.112 g, m.p. 165–170° C. (dec.)] was prepared from 10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo.[2,1-c][1,4].benzodiazepine-3-carboxylic acid of Example 7, Step E (0.225 g, 0.48 mmol) and methyl-(1-oxy-pyridin-3-ylmethyl)-amine dihydrochloride of Example 4, Step C (0.140 g, 0.70 mmol) in the manner of Example 4, Step D.
1 H NMR (400 MHz, DMSO-d 6 ): δ 3.14 (s, 3H), 3.46(s, 3H), 4.62(s, 2H), 5.52 (br, 2H), 6.06 (s, 1H), 6.41 (s, 1H), 6.85–6.973 (m, 4H), 7.04 (t, 1H), 7.18 (t, 1H), 7.20(d, 1H), 7.23 (d, 1H), 7.42 (m, 2H), 7.56 (t, 1H), 7.62 (t, 1H ), 7.74 (d, 1H), 8.18(m, 2H).
MS [EI, m/z]: 626 [M] +
Anal. Calcd. for C 35 H 29 F 3 N 4 O 4 : C, 67.09, H, 4.66, N, 8.94. Found: C, 65.28, H, 4.49, N, 8.00.
EXAMPLE 9
10-[4-(Naphthalen-1-yl)-benzoyl]-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxamide
Step A. 4-Naphthalen-1-yl-benzoic acid methyl ester
Methyl 4-bromobenzoate (0.96 g, 4.46 mmol) was added to a mixture of 1-naphthaleneboronic acid (0.73 g, 4.25 mmol) and sodium carbonate (0.075 g, 7.08 mmol) in toluene (30 mL), ethanol (6 mL) and water (12 mL). The resultant solution was purged with nitrogen for 10 minutes before tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.09 mmol) was added. The reaction mixture was heated to reflux for 65 hours. The solution was cooled to ambient temperature, then filtered through a pad of Celite, which was subsequently rinsed with ethyl acetate. The combined filtrate was diluted to 100 mL with water/ethyl acetate (1:1). The aqueous layer was extracted with ethyl acetate, and the combined extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to yield the title compound as a gold oil (1.09 g). This material was used without further purification in the next step.
1 H NMR (300 MHz, DMSO-d 6 ) δ 8.10 (d, 2H), 8.02 (t, 2H), 7.75 (d, 1H), 7.57 (m, 6H), 3.92 (s, 3H).
Step B. 4-Naphthalen-1-yl-benzoic acid
To a stirred solution of the 4-naphthalen-1-yl-benzoic acid methyl ester of Step A (1.09 g, 4.15 mmol), in methanol (18 mL) and water (6 mL), cooled to 5° C., was added lithium hydroxide monohydrate (0.42 g, 10.0 mmol). The solution was allowed to warm to ambient temperature as stirring was continued for 20 hours. The reaction mixture was poured into water, acidified to pH 4 with acetic acid, and the resultant precipitate was isolated by vacuum filtration to afford the title compound as an off-white solid (0.92 g), m.p. 221–224° C.
1 H NMR (400 MHz, DMSO-d 6 ): δ 6.40–7.60 (m, 7H), 7.56 (d, 1H), 7.98 (d, 1H), 8.01 (d, 1H), 8.07 (d, 2H).
MS [EI, m/z]: 248 [M] + .
Anal. Calc'd. for C 17 H 12 O 2 : C, 82.24, H, 4.87. Found: C, 81.90, H, 4.63.
Step C. [4-(Naphthalen-1-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4] benzodiazepin-10-yl]methanone
N,N-Dimethylformamide (2 drops) was added to a solution of the 4-naphthalen-1-yl-benzoic acid of Step B (0.60 g, 2.40 mmol) in anhydrous tetrahydrofuran (15 mL). Oxalyl chloride (0.34 g, 2.64 mmol) was added and the mixture was warmed to reflux. The resultant solution was cooled to ambient temperature before being evaporated to dryness to give the crude acid chloride as a golden solid, which was used without further purification. To a mixture of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.37 g, 2.00 mmol) and triethylamine (0.24 g, 2.40 mmol) in dichloromethane (5 mL), cooled in an ice bath, was added dropwise a solution of the crude acid chloride in dichloromethane (5 mL). The cooling bath was removed and after stirring for 48 hours, the reaction mixture was washed sequentially with water, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride and 1 N sodium hydroxide. The dichloromethane solution was dried with anhydrous magnesium sulfate, filtered, then evaporated to dryness to yield a brown foam. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (4:1) resulted in a white foam (0.47 g). Treatment of the white foam with diethyl ether and sonication resulted in a white solid (0.37g), m.p. 169.5–171° C.
1 H NMR (400 MHz, DMSO-d 6 ): δ 5.32 (br, 4H), 5.93 (m, 1H), 5.97 (s, 1H), 6.83 (m, 1H), 7.01 (d, 1H), 7.18 (m, 2H), 7.32, (t, 2H), 7.41, (d, 1H), 6.45–7.60 (m, 5H), 7.93 (d, 1H), 7.97 (d, 1H)
MS [EI, m/z]: 414 [M] + .
Anal. Calcd. for C 17 H 12 O 2 +0.4H 2 O: C, 82.60, H, 5.45, N, 6.64. Found: C, 82.71, H, 5.44, N, 6.54.
Step D. 10-[(4-Naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid
The title compound was prepared by treatment of [4-(naphthalen-1-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone of Step C with trichloroacetyl chloride, followed by basic hydrolysis of the intermediate trichloroacetate ester in the manner of Example 7, Step E.
Step E. 10-[4-(Naphthalen-1-yl)-benzoyl]-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
The title compound was prepared by the coupling the 10-[4-(naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step D, with 3-(methylaminomethyl)pyridine (1.25 equiv) in the manner of Example 7.
EXAMPLE 10
10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-(pyridin-4-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-carboxamide
Step A. (4-Bromo-2-chloro-benzoyl)-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4] benzodiazepine
N,N-Dimethylformamide (1 drop) was added to a solution of 4-bromo-2-chlorobenzoic acid (2.20 g, 9.35 mmol) in anhydrous tetrahydrofuran (20 mL). Oxalyl chloride (1.46 g, 11.46 mmol) was added and the mixture was warmed to reflux. The resultant solution was cooled to ambient temperature before being evaporated to dryness to give the crude acid chloride as a gold viscous liquid, which was used without further purification. To a mixture of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.44 g, 7.79 mmol) and triethylamine (0.95 g, 9.35 mmol) in methylene chloride (40 mL), cooled in an ice bath, was added dropwise a solution of the acid chloride in dichloromethane (20 mL). The cooling bath was removed and after stirring for 22 hours, the reaction mixture was washed sequentially with water, saturated aqueous sodium bicarbonate, 0.5 N hydrochloric acid and water. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered, then evaporated to dryness to yield an off-white foam. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (2:1) resulted in a white foam (3.02 g), m.p. 77–80° C. This material was used as is in the next step.
1 H NMR (400 MHz, DMSO-d 6 ): δ 5.45 (br, 4H), 7.02 (t, 1H), 7.07 (td, 1H), 7.14 (td), 7.32 (br, 1H), 7.38 (d, 2H), 7.60 (br, 1H).
MS [EI, m/z]: 400 [M] + .
Step B. (2-Chloro-4-naphthalen-1-yl-phenyl)-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4] benzodiazepin-10-yl)-methanone
1-Naphthaleneboronic acid (0.52 g, 3.00 mmol) was added to a mixture of (4-bromo-2-chlorophenyl)-(5H, 11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone of Step A (1.27 g, 3.15 mmol) and sodium carbonate (0.53 g, 4.98 mmol) in toluene (22.5 mL), ethanol (4.5 mL) and water (9 mL). The resultant solution was purged with nitrogen for 10 minutes, then tetrakis(triphenylphosphine)palladium (0.18 g, 0.06 mmol) was added. The reaction mixture was heated to reflux for 76 hours. The solution was cooled to ambient temperature, then filtered through a pad of Celite, which was subsequently rinsed with ethyl acetate. The combined filtrate was diluted to 100 mL water/ethyl acetate (1:1). The aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to yield a brown oil. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (5:1) resulted in a white solid which was dried under vacuum (0.62 g), m.p. 115–117.5° C.
1 H NMR (400 MHz, DMSO-d 6 ): δ 5.91 (t, 1H), 6.02 (br, 1H), 6.84 (br, 1H), 7.14 (m, 2H), 7.24 (d, 1H), 7.34, (d, 1H), 7.95 (d, 1H), 7.98 (d, 1H).
MS [(+)ESI, m/z]: 449 [M+H] + .
Anal. Calcd. for C 29 H 21 ClN 2 O+0.25 H 2 O: C, 76.72, H, 4.79, N, 6.17. Found C, 76.72, H, 4.53, N, 5.95.
Step C. 10-{[2-Chloro-4-(naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid
Prepared by treatment of [2-chloro-4-(naphthalen-1-yl)-phenyl]-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone of Step B with trichloroacetyl chloride, followed by basic hydrolysis of the intermediate trichloroacetate ester in the manner of Example 5, Step D.
Step D. 10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-(pyridin-4-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-carboxamide
The title compound was prepared by the coupling the 10-[2-chloro-4-(naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step C, with 4-(aminomethyl)pyridine (1.25 equiv) in the manner of Example 1, Step G.
EXAMPLE 11
{[10-(4-Methyl-napthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(pyridin-4-yl)-1-piperazinyl]methanone
Step A. 4-(4-Methyl)-napthalen-1-yl-benzoic acid
To a mixture of 1-bromo-4-methyl napthalene (1.11 g, 5.00 mmol) and 4-carboxyphenyl boronic acid (1.00 g, 6.00 mmol) in ethylene glycol dimethyl ether (20 mL) was added a solution of sodium carbonate (2.37 g, 22.38 mmol) in water (18.75 mL). The resultant mixture was purged with nitrogen for 20 minutes before tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.02 mmol) was added. The reaction mixture was heated to reflux for 68 hours. After the solution cooled to ambient temperature, the solvent was removed in vacuo and the residue was acidified with 5 N hydrochloric acid to produce an orange-brown solid that was isolated by vacuum filtration. This material was used without further purification in the next step.
1 H NMR (300 MHz, DMSO-d 6 ): δ 2.70 (s, 3H), 7.57 (d, 2H), 8.07 (d, 2H).
Step B. [4-(4-Methyl-naphthalen-1-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone
N,N-Dimethylformamide (2 drops) was added to a solution of 4-(4-methyl)-napthalen-1-yl-benzoic acid of Step A (0.90 g, 3.43 mmol), in anhydrous tetrahydrofuran (10 mL). Oxalyl chloride (0.52 g, 4.12 mmol) was added and the mixture was warmed to reflux. The resultant solution was cooled to ambient temperature before being evaporated to dryness to give the crude acid chloride as a brown residue, which was used without further purification. To a mixture of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.53 g, 2.86 mmol) and triethylamine (0.35 g, 3.43 mmol) in dichloromethane (10 mL), cooled in an ice bath, was added dropwise a solution of the crude acid chloride in dichloromethane (10 mL). The cooling bath was removed and after stirring for 137 hours, the reaction mixture was washed sequentially with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The dichloromethane solution was dried over anhydrous magnesium sulfate, filtered, then evaporated to dryness to yield an amber oil. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (4:1) resulted in a tan foam (0.49 g). Treatment of this material with diethyl ether and sonication resulted in an off-white solid (0.37 g), m.p. 160–162° C.
1 H NMR (400 MHz, DMSO-d 6 ): δ 2.66 (s, 3H), 5.32 (br, 4H), 5.93 (t, 1H), 5.97 (br, 1H), 6.83 (t, 1H), 7.01 (d, 1H), 7.22 (d, 2H), 7.28 (d, 2H), 7.39 (t, 3H), 7.45 (m, 2H), 7.57 (m, 2H), 8.06 (d, 1H).
MS [(+)ESI, m/z]: 429 [M+H] + .
Anal. Calcd. for C 30 H 24 N 2 O+0.13 H 2 O: C, 83.63, H, 5.67, N, 6.50. Found: C, 83.63, H, 5.64, N, 6.43.
Step C. 10-{[4-(4-Methyl-naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid
Prepared from [4-(4-methyl-naphthalen-1-yl)-phenyl]-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl]methanone of Step B by treatment with trichloroacetyl chloride, followed by basic hydrolysis of the intermediate trichloroacetate ester in the manner of Example 1, Steps E and F.
Step D. {[10-(4-Methyl-napthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(pyridin-4-yl)-1-piperazinyl]methanone
Prepared by the coupling of 10-{[4-(4-methyl-naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step C, with 1-(4-pyridinyl)-piperazine (1.2 equiv.) in the manner of Example 1.
EXAMPLE 12
10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)-carbonyl]-N-methyl-N-[2-(pyridin-4-yl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
Step A. (2-Methyl-2′-methoxy-[1,1′-biphenyl]-4-yl)carboxylic acid methyl ester
A mixture of 3-methyl-4-bromobenzoic acid methyl ester (2.0 g, 8.7 mmol), 2-methoxyphenyl boronic acid (1.32 g, 8.7 mmol) and sodium carbonate (4.1 g, 38.7 mmol) in toluene:ethanol:water (50 mL:25 mL: 25 mL), was purged with nitrogen for 1 hour. After addition of the tetrakis(triphenylphosphine) palladium(0) catalyst (0.50 g, 0.43 mmol), the reaction mixture was heated at 100° C. overnight. After cooling, the reaction was filtered through Celite and the cake washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification by flash chromatography on silica gel with a solvent gradient from 20% to 50% dichloromethane in hexane gave 2.0 g of product as a colorless oil.
1 H NMR (DMSO-d 6 , 400 MHz): δ 2.09 (s, 3H), 3.70 (s, 3H), 3.85 (s, 3H), 7.00–7.04 (m, 1H), 7.08–7.11 (m, 2H), 7.23 (d, 1H), 7.37–7.41 (m, 1H), 7.77–7.79 (m, 1H), 7.83–7.84 (m, 1H).
MS [(+)APCI, m/z]: 257 [M+H] + .
Anal. Calcd. for C 16 H 16 O 3 : C, 74.98, H, 6.29. Found: C, 74.06, H, 6.17.
Step B. (2-Methyl-2′-methoxy-[1,1′-biphenyl]-4-yl)carboxylic acid
The (2-methyl-2′-methoxy-[1,1′-biphenyl]-4yl)carboxylic acid methyl ester of Step A (1.9 g, 7.4 mmol) was dissolved in tetrahydrofuran (30 mL) and 1 N sodium hydroxide (15 mL, 15 mmol) was added. The reaction mixture was heated at reflux overnight, then cooled and acidified with 2 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.6 g of product as a white solid, m.p. 160–162° C.
1 H NMR (DMSO-d 6 , 400 MHz): δ 2.09 (s, 3H), 3.70 (s, 3H), 7.00–7.03 (m, 1H), 7.08–7.10 (m, 2H), 7.20 (d, 1H), 7.36–7.40 (m, 1H), 7.75–7.78 (m, 1H), 7.82 (s, 1H), 12.85 (br, 1H).
MS [(−)APCI, m/z]: 241 [M−H] − .
Anal. Calcd. for C 15 H 14 O 3 : C, 74.36, H, 5.82. Found: C, 73.93, H, 5.71.
Step C. (10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)-methanone
The (2-methyl-2′-methoxy-[1,1′-biphenyl]-4-yl)carboxylic acid of Step B (0.50 g, 2.06 mmol) was suspended in thionyl chloride (3 mL) and the mixture heated at reflux for 30 minutes. After cooling, the thionyl chloride was removed in vacuo. The residue was dissolved in toluene and concentrated in vacuo to give the crude acid chloride as a brown oil. The acid chloride was then dissolved in dichloromethane (5 mL) and slowly added to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.57 g, 3.10 mmol) and N,N-diisopropylethyl amine (0.79 mL, 4.53 mmol) in dichloromethane (15 mL). After stirring for 1 hour, the reaction was quenched with water. The organic layer was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography using a solvent gradient of 5 to 15% ethyl acetate in hexane yielded a white foam which crystallized upon sonication in ethanol/hexane to give 0.42 g of the desired title product as a white solid, m.p. 133–135° C.
1 H NMR (DMSO-d 6 , 400 MHz): δ 1.93 (s, 3H), 3.65 (s, 3H), 4.80–5.40 (br, 4H), 5.92–5.96 (m, 2H), 6.81–6.82 (m, 1H), 6.89–6.91 (m, 1H), 6.95–7.05 (m, 5H), 7.16–7.25 (m, 3H), 7.31–7.35 (m, 1H), 7.47–7.49 (m, 1H).
MS [(+)ESI, m/z]: 409 [M+H] + .
Anal. Calcd. for C 27 H 24 N 2 O 2 : C, 79.39, H, 5.92, N, 6.86. Found: C, 79.16, H, 5.87, N, 6.90.
Step D. 2,2,2-Trichloro-1-{10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone
To a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)-methanone of Step C (1.5 g, 3.67 mmol) in dichloromethane (20 mL) was added N,N-diisopropylethyl amine (1.28 mL, 7.35 mmol) followed by slow addition of trichloroacetyl chloride (1.23 mL, 11.0 mmol). The reaction mixture was stirred overnight at room temperature then quenched with water. The organic phase was washed with 0.1 N hydrochloric acid followed by water, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a green oil. Purification by flash chromatography on silica gel using a solvent system of 20% ethyl acetate in hexane provided 2.1 g of title compound. The material was redissolved in dichloromethane and evaporated to dryness to provide a yellow foam, which was used in the next step.
1 H NMR (DMSO-d 6 , 400 MHz): δ 1.94 (s, 3H), 3.65 (s, 3H), 5.25 (br, 2H), 5.97 (br, 2H), 6.36–6.37 (m, 1H), 6.90–6.92 (m, 1H), 6.96–7.06 (m, 5H), 7.15–7.23 (m, 2H), 7.26 (s, 1H), 7.32–7.36 (m, 1H), 7.44–7.47 (m, 2H).
MS [(+)APCI, m/z]: 553 [M+H] + .
Anal. Calcd. for C 29 H 23 Cl 3 N 2 O 3 +0.13 C 4 H 8 O 2 +0.13 CH 2 Cl 2 : C, 61.79, H, 4.25, N, 4.86. Found: C, 60.43, H, 4.50, N, 4.80.
Step E. 10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid
To a solution of 2,2,2-trichloro-1-{10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step D (2.0 g, 3.6 mmol) in acetone (20 mL) was added 2.5 N sodium hydroxide (2.9 mL, 7.25 mmol). After stirring overnight, the reaction mixture was acidified with 2 N hydrochloric acid (4.0 mL, 8.0 mmol) then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown solid. Trituration with diethyl ether-hexane provided 1.4 g of the desired product as a white solid, m.p.174–184° C.
1 H NMR (DMSO-d 6 , 400 MHz): δ 1.93 (s, 3H), 3.65 (s, 3H), 5.17 (br, 2H), 5.94 (br, 2H), 6.09–6.10 (m, 1H), 6.77 (d, 1H), 6.89–7.06 (m, 6H), 7.10–7.19 (m, 2H), 7.23 (s, 1H), 7.31–7.38 (m, 2H), 12.31 (br, 1H).
MS [(−)APCI, m/z]: 451 [M−H] − .
Anal. Calcd. for C 28 H 24 N 2 O 4 +0.10 C 4 H 10 O: C, 74.17, H, 5.48, N, 6.09. Found: C, 73.63, H, 5.68, N, 5.94.
Step F. 10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)-carbonyl]-N-methyl-N-[2-(pyridin-4-yl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
Prepared by treatment of 10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step E, with 4-(2-methylaminoethyl)pyridine (1.2 equiv.) in the manner of Example 5, Step E.
EXAMPLE 13
N-Methyl-10-[(3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)-carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxamide
Step A. 4-Iodo-2-methoxybenzoic acid methyl ester
4-Amino-2-methoxybenzoic acid methyl ester (3.0 g, 16.6 mmol) was suspended in water (40 mL) and concentrated sulfuric acid (10 mL). The suspension was cooled in an ice/salt water bath, and an aqueous solution (10 mL) of sodium nitrite (1.26 g, 18.3 mmol) was added dropwise so that the temperature remained close to 0° C. After the addition, a homogeneous, yellow-green solution was obtained. An aqueous solution (60 mL) of potassium iodide (3.02 g, 18.2 mmol) and iodine (2.31 g, 9.1 mmol) was then added dropwise, and the reaction stirred for an additional 1 hour. The reaction mixture was then extracted with ethyl acetate, the organic extracts were combined and washed with 1 N sodium thiosulfate, 1 N sodium hydroxide and brine. After drying over anhydrous sodium sulfate the solution was filtered and concentrated in vacuo to give 2.7 g of the title product as an orange oil which was used in the next step.
1 H NMR (DMSO-d 6, 400 MHz): δ 2.76 (s, 3H), 3.82 (s, 3H), 7.39 (s, 2H), 7.48 (s, 1H).
MS [EI, m/z]: 292 [M] + .
Step B. 4-Iodo-2-methoxybenzoic acid
The 4-iodo-2-methoxybenzoic acid methyl ester of Step A (2.7 g, 9.24 mmol) was dissolved in tetrahydrofuran (40 mL) and 1 N sodium hydroxide (20 mL, 20 mmol) was added. The reaction mixture was heated at reflux for 3 hours, then cooled and concentrated in vacuo to give an orange oil that was partitioned between ethyl acetate and 2 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2.5 g of title product as a yellow-orange solid, m.p. 144–146° C.
1 H NMR (DMSO-d 6 , 400 MHz): δ 3.81 (s, 3H), 7.37 (s, 2H), 7.44 (s, 1H), 12.72 (br, 1H).
MS [EI, m/z]: 278 [M] + .
Anal. Calcd. for C 8 H 7 IO 3 +0.10 C 4 H 8 O 2 : C, 35.17, H, 2.74. Found: C, 35.37, H, 2.49.
Step C. 10-(4-Iodo-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4] benzodiazepine
A suspension of 4-iodo-2-methoxybenzoic acid of Step B (2.5 g, 9.0 mmol) in thionyl chloride (10 mL) was heated at reflux for 1 hour. After cooling, the thionyl chloride was removed in vacuo. The residue was dissolved in toluene and concentrated in vacuo to give the crude acid chloride as a brown solid. The acid chloride was then dissolved in dichloromethane (10 mL) and slowly added to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.75 g, 9.5 mmol) and N,N-diisopropylethyl amine (3.4 mL, 19.5 mmol) in dichloromethane (20 mL). After stirring for 2 hours, the reaction was quenched with water. The organic layer was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography on silica gel using a solvent gradient of 15 to 25% ethyl acetate in hexane provided 3.6 g of title product as a white foam, which was redissolved in dichloromethane and evaporated to dryness prior to use in the next step.
1 H NMR (DMSO-d 6 , 400 MHz): δ 3.55 (br, 3H), 4.80–5.32 (br, 4H), 5.88–5.90 (m, 1H), 5.94 (s, 1H), 6.79 (s, 1H), 6.94 (s, 1H), 7.03 (t, 1H), 7.09–7.13 (m, 3H), 7.20–7.22 (m, 1H), 7.36–7.38 (m, 1H).
MS [(+)ESI, m/z]: 445 [M+H] + .
Anal. Calcd. for C 20 H 17 IN 2 O 2 +0.10 C 4 H 8 O 2 +0.13 CH 2 Cl 2 : C, 53.13, H, 3.92, N, 6.04. Found: C, 53.03, H, 3.65, N, 6.03.
Step D. (10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl]-methanone
A mixture of 10-(4-iodo-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step C (1.8 g, 4.1 mmol), 2-methylphenyl boronic acid (0.55 g, 4.1 mmol) and sodium carbonate (1.9 g, 17.9 mmol) in toluene:ethanol: water (20 mL:10 mL:10 mL) was purged with nitrogen for 1 hour. After addition of the tetrakis(triphenylphosphine) palladium(0) catalyst (0.24 g, 0.21 mmol), the reaction mixture was heated at 100° C. overnight. After cooling, the reaction was filtered through Celite and the cake washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification by flash chromatography on silica gel using a solvent system of 20% ethyl acetate in hexane provided 1.5 g of title product as a white foam, which was redissolved in dichloromethane and evaporated to dryness in vacuo prior to use in the next step.
1 H NMR (DMSO-d 6 , 400 MHz): δ 2.08 (s, 3H), 3.54 (s, 3H), 4.80–5.30 (br, 4H), 5.89–5.91 (m, 1H), 5.97 (s, 1H), 6.66 (s, 1H), 6.77–6.80 (m, 2H), 6.93–7.01 (m, 2H), 7.09–7.10 (m, 2H), 7.19–7.24 (m, 3H), 7.36–7.38 (m, 2H).
MS [(+)ESI, m/z]: 409 [M+H] + .
Anal. Calcd. for C 27 H 24 N 2 O 2 +0.10 CH 2 Cl 2 : C, 78.05, H, 5.84, N, 6.72. Found: C, 78.12, H, 5.13, N, 6.69.
Step E. 2,2,2-Trichloro-1-{10-[(3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone
To a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl]-methanone of Step D (1.36 g, 3.33 mmol) in dichloromethane (15 mL) was added N,N-diisopropylethyl amine (1.2 mL, 6.89 mmol) followed by slow addition of trichloroacetyl chloride (1.1 mL, 9.85 mmol). The reaction mixture was stirred overnight at room temperature then was quenched with water. The organic phase was washed with 0.1 N hydrochloric acid followed by water, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a green oil. Purification by flash chromatography on silica gel using a solvent system of 20% ethyl acetate in hexane gave 1.7 g of title product as a yellow foam.
1 H NMR (DMSO-d 6 , 400 MHz): δ 2.09 (s, 3H), 3.50 (s, 3H), 5.30 (br, 2H), 5.87 (br, 2H), 6.37–6.38 (m, 1H), 6.64 (s, 1H), 6.82–6.83 (m, 1H), 6.90–6.92 (m, 1H), 6.97–6.99 (m, 1H), 7.10–7.12 (m, 2H), 7.20–7.25 (m, 4H), 7.35–7.37 (m, 1H), 7.44–7.46 (m, 1H).
MS [(+)APCI, m/z]: 553 [M+H] + .
Anal. Calcd. for C 29 H 23 Cl 3 N 2 O 3 +0.20 C 4 H 8 O 2 +0.40 H 2 O: C, 61.85, H, 4.42, N, 4.84. Found: C, 61.50, H, 4.07, N, 4.72.
Step F. 10-[(3-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2, 1-c][1,4]benzodiazepine-3-carboxylic acid
To a solution of 2,2,2-trichloro-1-{10-[(3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step E (1.6 g, 2.9 mmol) in acetone (20 mL) was added 2.5 N sodium hydroxide (2.3 mL, 5.8 mmol). After stirring overnight, the reaction was acidified with 2 N hydrochloric acid (3.2 mL, 6.4 mmol) then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown solid. Trituration with diethyl ether/hexane provided 1.2 g of desired product as an off-white solid, m.p. 201–204° C.
1 H NMR (DMSO-d 6 , 400 MHz): δ 2.09 (s, 3H), 3.48 (s, 3H), 5.20 (br, 2H), 5.85 (br, 2H), 6.12 (s, 1H), 6.62 (s, 1H), 6.73 (d, 1H), 6.79–6.87 (m, 2H), 6.91–6.95 (m, 1H), 6.99–7.03 (m, 1H), 7.06–7.12 (m, 1H), 7.18–7.25 (m, 4H), 7.39 (br, 1H), 12.31 (br, 1H).
MS [(+) ESI, m/z]: 453 [M+Na] + .
Anal. Calcd. for C 28 H 24 N 2 O 4 +0.10 C 4 H 10 O+0.15 C 4 H 8 O 2 : C, 73.61, H, 5.58, N, 5.92. Found: C, 73.23, H, 5.49, N, 6.06.
Step G N-Methyl-10-[(3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)-carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxamide
Prepared from the 10-[(3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step F and methyl-pyridin-3ylmethyl-amine (1.1 equiv.) in the manner of Example 5.
EXAMPLE 14
7,8-Dimethoxy-{10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepin-3-yl}[4-(pyridin-2-yl)-1-piperazinyl]methanone
Step A. 1-[(4,5-Dimethoxy-2-nitrophenyl)methyl]-1H-pyrrole-2-carboxaldehyde
To a suspension of sodium hydride (0.724 g, 60% suspension in oil) in N,N-dimethyl formamide (50 mL) was added pyrrole 2-carboxaldehyde (1.7 g, 18.1 mmol) and the reaction mixture was stirred for 30 minutes. It was then cooled to 0° C. and 4,5-dimethoxy-2-nitrobenzyl bromide (5.0 g, 1 equiv) was added dropwise over 20 minutes. After the addition, the reaction mixture was stirred at room temperature for 3 hours. It was then diluted with ethyl acetate (450 mL), washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product was triturated with water, filtered and washed with water. This material was dried over anhydrous potassium carbonate in vacuo to provide the title compound as a yellow crystalline solid (4.97 g), m.p. 109–112° C., which was used in the next step.
Step B. 7,8-Dimethoxy 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine
A mixture of the 1-[(4,5-dimethoxy-2-nitrophenyl)methyl]-1H-pyrrole-2-carboxaldehyde of Step A (4.97 g), acetic acid (0.5 mL), magnesium sulfate (0.5 g) and 10% palladium on charcoal (0.5 g) in ethyl acetate (50 mL) was hydrogenated overnight at atmospheric pressure. The reaction was then filtered through Celite and the solvent removed in vacuo to give the crude title compound as an amber foam (3.2 g) which was used in the next step without further purification.
Step C. 7,8-Dimethoxy-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(4-bromo-3-methyl-phenyl)-methanone
To a solution of 7,8-dimethoxy-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step B (3.20 g) in dichloromethane (20 mL) was added 3-methylbenzoyl chloride (3.4 g, 1.1 equiv) and triethylamine (2.0 g, 1.5 equiv) and the mixture was stirred at room temperature overnight. The solvent was then removed in vacuo and the residue chromatographed on silica gel eluting with a solvent gradient from 5 to 50% of ethyl acetate in petroleum ether to provide the title compounds as a yellow crystalline solid (3.5 g), m.p. 165–168° C.
1 H NMR (CDCl 3 , 200 MHz): δ 2.30 (s, 3H), 3.55 (br, 3H), 3.85 (s, 3H), 5.1 (br, 4H), 6.05 (br, 1H), 6.1 (t, 1H), 6.3 (br, 1H), 6.65 (t, 1H), 6.8 (s, 2H), 7.3 (s, 2H).
MS [(+)ESI, m/z]: 442 [M +H] + .
Step D. 7,8-Dimethoxy-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]-[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]methanone
The 7,8-dimethoxy-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(4-bromo-3-methyl-phenyl)-methanone of Step C (1.0 g) was reacted with 2-trifluoromethylphenyl boronic acid (0.645 g, 1.5 equiv.), potassium phosphate (0.964 g, 2.0 equiv.) and a catalytic amount (0.050 g) of tetrakis(triphenylphosphine) palladium(0) in refluxing dioxane (10 mL) under nitrogen for 24 hours. The reaction was then cooled to room temperature, filtered through Celite, and the solvent removed in vacuo. The residue was dissolved in dichloromethane and the solution was washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product so obtained was purified by chromatography on silica gel eluting with 5% ethyl acetate/dichloromethane to provide the title product (1.0 g) as a white crystalline solid, m.p. 187–188° C.
1 H NMR (DMSO-d 6 , 400 MHz): δ 1.85 (s, 3H), 3.40 (s, 3H), 3.70 (s, 3H), 6.20 (br, 4H), 5.92 (t, 1H), 5.96 (s, 1H), 6.56 (s, 1H), 6.77 (t, 1H), 6.90 (m, 1H), 7.05 (m, 2H), 7.20 (d, 1H), 7.30 (s, 1H), 7.58 (t, 1H), 7.68 (t, 1H), 7.80 (d, 1H).
MS [(+)APCI, m/z]: 507 [M+H] + .
Anal. Calcd. for C 29 H 25 F 3 N 2 O 3 : C, 68.77, H, 4.97, N, 5.53. Found: C, 68.85, H, 5.05, N, 5.43.
Step E. 7,8-Dimethoxy-{10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepin-3-yl}[4-(pyridin-2-yl)-1-piperazinyl]methanone dihydrochloride salt
A solution of 7,8-dimethoxy-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl][2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]methanone of Step D (0.31 mmol), diphosgene (1.1 equiv.) and triethylamine (1.5 equiv.) in dichloromethane (5 mL) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (5 mL). To the solution was added triethylamine (1.5 equiv.) and 1-(2-pyridinyl)piperazine (1.5 equiv.) The reaction mixture was washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was first chromatographed on silica gel eluting with a solvent gradient of methanol in ethyl acetate to provide the title compound as a foam.
Treatment of a solution of the free base in ethanol with anhydrous hydrogen chloride in dioxane followed by removal of the solvent provided the dihydrochloride salt.
EXAMPLE 15
10-[(6-Chloro-3-methoxy-2′-ethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(pyridin-2-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
Step A. 2-Chloro-2′-ethoxy-5-methoxy-[1,1′-biphenyl]-4-carboxylic acid
To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acid of Example 15, Step A (0.500 g, 1.6 mmol) in N,N-dimethylformamide (30 mL) was added 2-ethoxy phenyl boronic acid (0.8 g, 4.8 mmol) and potassium carbonate (2.04 g, 14.7 mmol). This mixture was purged with nitrogen and then treated with a catalytic amount of tetrakis(triphenylphosphine) palladium(0) (0.093 g, 0.08 mmol). The reaction was heated to reflux overnight, cooled, acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to yield the title acid which was used in the next step without further purification.
Step B. 10-{[6-Chloro-3-methoxy-2′-ethoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine
To a stirred solution of the 2-chloro-2′-ethoxy-5-methoxy [1,1′-biphenyl]-4-carboxylic acid of Step A (0.491 g) in tetrahydrofuran (5 mL) containing a catalytic amount of N,N-dimethyl formamide was added dropwise thionyl chloride (0.210 g, 1.76 mmol). The reaction mixture was stirred for 2 hours, and then added dropwise to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.294 g, 1.60 mmol) in tetrahydrofuran (5 mL) containing triethylamine (0.357 g, 3.52 mmol). The reaction mixture was stirred for 2 hours, diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. Trituration of the residue with methanol provided the title compound as an off-white solid, 99.24% pure by analytical HPLC [Primesphere C-18 column (2.0×150 mm); mobile phase 70/30 acetonitrile/water containing 0.1% phosphoric acid], m.p. 213–215° C.
1 H NMR (DMSO-d 6 , 400 MHz): δ 1.11, (t, 3H), 3.51 (s, 3H), 3.92 (q, 2H), 5.17–5.20 (br, m, 3H), 5.89 (t, 1H), 5.97 (s, 1H), 6.67–7.55 (m, 10H).
MS [(+)APCI, m/z]: 473 [M+H] + .
Anal. Calcd. for C 28 H 25 ClN 2 O 3 : C, 71.11, H, 5.33, N, 5.92. Found: C, 70.31, H, 5.27, N, 5.79.
Step C. 10-{[6-Chloro-3-methoxy-2′-ethoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid
Prepared by treatment of 10-{[6-chloro-3-methoxy-2′-ethoxy-1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step B with trichloroacetyl chloride, followed by basic hydrolysis of the intermediate trichloroacetate ester in the manner of Example 1, Steps E and F.
Step D. 10-[(6-Chloro-3-methoxy-2′-ethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(pyridin-2-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
Prepared by coupling the 10-{[6-chloro-3-methoxy-2′-ethoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step C with 2-(aminomethyl)pyridine (1.25 equiv.) in the manner of Example 1.
EXAMPLE 16
10-[(6-Chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-yl)carbonyl]-N-methyl-N-[2-(pyridin-2-yl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
Step A. 2-Chloro-2′-fluoro-5-methoxy-[1,1′-biphenyl]-4-carboxylic acid
To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acid of Example 15, Step A (3.72 g, 19.1 mmol) in N,N-dimethylformamide (20 mL) was added 2-fluorophenyl boronic acid (5.0 g, 35.7 mmol) and potassium carbonate (14.8 g, 107 mmol). This mixture was purged with nitrogen and then treated with a catalytic amount of tetrakis(triphenylphosphine) palladium(0) (0.688 g, 0.59 mmol). The reaction was heated to reflux overnight, cooled, acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was flash chromatographed on acid washed silica using a 10 to 50% gradient of diethyl ether in hexane to provide the desired title compound (3.8 g) as a white solid.
1 H NMR (DMSO-d 6 , 400 MHz) δ 3.83 (s, 3H), 7.15 (s, 1H), 7.30–7.35 (m, 2H), 7.42 (m, 1H), 7.48–7.54 (m, 1H), 7.74 (s, 1H).
MS [(+)ESI, m/z]: 298 [M+NH 4 ] + .
Anal. Calcd. for C 14 H 10 ClFO 3 : C, 59.91, H, 3.59. Found: C, 59.79, H, 3.35.
Step B. 10-{[6-Chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine
To a stirred solution of 2-chloro-2′-fluoro-5-methoxy-[1,1′-biphenyl]-4-carboxylic acid of Step A (3.80 g, 13.5 mmol) in tetrahydrofuran (20 mL) containing a catalytic amount of N,N-dimethylformamide was added dropwise thionyl chloride (1.77 g, 14.9 mmol). The reaction mixture was stirred for 2 hours, and then added dropwise to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (2.49 g, 13.5 mmol) in tetrahydrofuran (20 mL) containing triethylamine (3.0 g, 29.8 mmol). The reaction mixture was stirred for 2 hours, diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. Recrystallization of the residue from ethyl acetate/heptane provided the title compound as a pale yellow solid, m.p. 192–194° C., found to be 99.99% pure by analytical HPLC [Primesphere C-18 column (2.0×150 mm); mobile phase: gradient from 10 to 100% of acetonitrile/water containing 0.1% phosphoric acid, 7 minute gradient].
1 H NMR (DMSO-d 6 , 400 MHz): δ 3.55 (s, 3H), 5.19 (br m, 2H), 5.90 (t, 1H), 5.96 (s, 1H), 6.80 (s, 2H), 7.07–7.63 (m, 10H).
MS [(+)ESI, m/z]: 447 [M+H] + .
Anal. Calcd. for C 26 H 20 ClFN 2 O 2 +H 2 O: C, 69.60, H, 4.54, N, 6.24. Found: C, 69.39, H, 4.41, N, 6.20.
Step C. 10-{[6-Chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid
A solution of the 10-{[6-chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step B (3.02 g, 6.76 mmol) in dichloromethane (35 mL) was treated with N,N-diisopropylethyl amine (0.960 g, 7.43 mmol) and stirred for 10 minutes. Trichloroacetyl chloride (1.47 g, 8.10 mmol) was then added dropwise. The reaction mixture was stirred overnight, diluted with dichloromethane, washed with 0.1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to yield the crude trichloroketone intermediate which without further purification, was dissolved in acetone and treated with an excess of 1 N sodium hydroxide The mixture was stirred overnight, and then diluted with isopropyl acetate and acidified with 1 N hydrochloric acid. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The solid residue was triturated with methanol to provide the title compound (2.95 g) as a beige solid, m.p. 207–208° C.
1 H NMR (DMSO-d 6 , 400 MHz): δ 3.49 (br, 3H), 6.12 (d, 1H), 6.72 (d, 1H), 6.77 (s, 1H), 7.01 (d, 2H), 7.09 (m, 1H), 7.26 (m, 4H), 7.45 (m, 2H), 7.61 (br, 1H), 12.35 (br, 1H).
MS [(+)APCI, m/z]: 491 [M+H] + .
Anal. Calcd for C 27 H 20 ClFN 2 O 4 : C, 66.06, H, 4.11, N, 5.71. Found: C, 65.68, H, 4.24, N, 5.48.
Step D. 10-[(6-Chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-yl)carbonyl]-N-methyl-N-[2-(pyridi-2-yl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
Prepared by the coupling of the [(6-chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step C with methyl-(2-pyridin-2-yl-ethyl)-amine (1.25 equiv.), in the manner of Example 1.
EXAMPLE 17
10-{[6-(Naphthalen-1-yl)-pyridin-3-yl]carbonyl}-N-(pyridin-4-ylmethyl)-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxamide
Step A. (6-Chloro-pyridin-3-yl)-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone
A solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (100 mmol) and N,N′-diisopropylethyl amine (130 mmol) in dichloromethane (500 mL) was cooled to 0° C. 6-Chloronicotinoyl chloride (130 mmol) was added dropwise under nitrogen. The solution was stirred for one hour as it returned to room temperature. The reaction mixture was filtered through a sica gel pad, washed with 0.5 N sodium hydroxide and water, dried over anhydrous magnesium sulfate. The solution was again filtered through a silica gel pad and evaporated to dryness in vacuo. The residual oil crystallized from diethyl ether to provide the title compound as a colorless crystalline solid, m.p. 165–167° C.
1 HNMR 9400 Mhz, DMSO-d 6 ): δ 5.35 (br, 4H), 5.91 (t, 1H), 5.97 (s, 1H), 6.83 (t, 1H), 7.0 (br d, 1H), 7.18 (t, 1H), 7.19 (t, 1H), 7.39 (d, 1H), 7.46 (dd, 1H), 7.71 (d, 1H), 8.26 (s, 1H).
MS [EI, m/z]: 323 [M] + .
Anal. Calcd. for C 18 H 14 ClN 3 O: C, 66.77, H, 4.36, N, 12.98. Found: C, 65.91, H, 4.18, N, 12.69.
Step B. [6-(Naphthalen-1-yl)-pyridin-3-y]-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone
A suspension of (6-chloro-pyridin-3-yl)-[10,11-dihydro-5H-pyrrolo{2,1-c][1,4]benzodiazepin-10-yl]methanone of Step A (0.645 g, 1.9 mmol) and naphthalene boronic acid (0.372 g, 2.1 mmol) in a mixture of toluene (1.2 mL), ethanol (2 mL) and 1M aqueous sodium carbonate (0.4 mL) was sparged with nitrogen for 10 minutes. To this was added palladium(I) acetate (0.026 g, 0.1 mmol). The mixture was heated at reflux under a static pressure of nitrogen for 48 hrs. The reaction was diluted with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium bicarbonate then water. The sample was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a brown oil. Flash chromatography of the residue on silica gel eluting with 20–50% ethyl acetate in hexane, yielded 0.180 g of a solid which was recrystallized from chloroform to provide the title compound as off white crystals, m.p. 155–158° C.
1 H NMR (400 MHz, DMSO-d 6 ): δ 5.40 (br, 4H), 5.93(m, 1H), 5.99 (s, 1H), 6.84 (s, 1H), 7.08(br d, 1H), 7.16 (t, 1H), 7.23 (t, 1H), 7.52 (m, 6H), 7.84(d, 2H), 7.98 (dd, 2H), 8.55 (s, 1H).
MS [(+)ESI, m/z]: 416 [M+H] + .
Anal. Calcd. for C 28 H 21 N 3 O+0.5 H 2 O: C, 79.22, H, 5.23, N, 9.90. Found: C, 79.08, H, 4.94, N, 9.73.
Step C. 10-{[6-(Naphthalen-1-yl)-pyridin-3-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[1,2-c][1.4]benzodiazepine-3-carboxylic acid
Prepared from [6-(naphthalen-1-yl)-pyridin-3-yl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone of Step B by treatment with trichloroacetyl chloride, followed by basic hydrolysis of the intermediate trichloroacetate ester in the manner of Example 1, Steps E and F.
Step D. 10-{[6-(Naphthalen-1-yl)-pyridin-3-yl]carbonyl}-N-(pyridin-4-ylmethyl)-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxamide
Prepared by the coupling of 10-{[6-(naphthalen-1-yl)-pyridin-3-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[1,2-c][1.4]benzodiazepine-3-carboxylic acid of Step C, and 4-(aminomethyl)pyridine (1.25 equiv) in the manner of Example 1.
EXAMPLE 18
10-[(6-Phenyl-pyridin-3-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
Step A. 10-(Methoxycarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid
A solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (5 mmol) and N,N-diisopropylethyl amine (12 mmol) in dichloromethane (100 mL) was cooled to 0° C. and treated dropwise with trichloroacetylchloride (12 mmol) in dichloromethane (20 mL). The solution was maintained at 0° C. for two hours and then allowed to warm to room temperature overnight. The solution was then treated with methanol (25 mL) and stirring was continued for 2 hours. The solution was washed with 0.1N hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to yield the title compound as a white solid, m.p. 153–154° C. (dec.).
Anal. Calcd. for C 15 H 14 N 2 O 4 +0.06 C 4 H 8 O 2 +0.07 C 3 H 6 O: C, 62.77, H, 5.08, N, 9.48. Found: C, 62.26, H, 5.22, N, 9.37.
Step B. 10-(Methoxycarbonyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
The title compound was prepared by coupling the 10-(methoxycarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step A with 3-(aminomethyl)pyridine (1.2 equiv.), in the manner of Example 1, Step G.
Step C. N-(3-Pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
A solution of 10-(methoxycarbonyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide (5 mmol) of Step B in methanol (50 mL) was treated with potassium carbonate and stirred at room temperature overnight. Water was then added to the solution and the pH adjusted to 6 with 6N hydrochloric acid. The solution was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate, and evaporated to dryness. The residual oil was triturated with ethyl acetate and hexane to yield the title compound as a powder.
Step D. 10-[(6-Phenyl-pyridin-3-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
A solution of 6-phenyl-nicotinyl chloride (6 mmol) [prepared by the method of Ogawa (Ogawa et al WO 9534540)] in dichloromethane (20 mL) was added dropwise to a cold (0° C.) solution of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Step C (5 mmol) and N,N-diisopropylethyl amine (6 mmol) in dichloromethane (100 mL). The solution was stirred at 0° C. for 2 hours and then allowed to warm to room temperature overnight. The solution was washed with pH 6 buffer, and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel using 5% methanol in chloroform containing 0.5% ammonium hydroxide, to provide the title compound.
EXAMPLE 19
[3-Methyl-4-(pyridin-4-yl)-phenyl]-{3-[4-(pyridin-2-yl)-piperazin-1-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl-methanone
Step A. (4-Bromo-3-methylphenyl)-[10,11-dihydro-5H-pyrrolo[2,1 c][1,4]benzodiazepin-10-yl]methanone
A solution of 4-bromo-3-methyl benzoic acid (4.3 g, 2 mmol) in dry tetrahydrofuran (100 mL) was cooled to 0° C. under nitrogen. To this was added N,N-dimethylformamide (50 μL) followed by oxalyl chloride (2.2 mL, 25 mmol) dropwise to control the gas evolution. When the gas evolution ceased, the mixture was warmed to reflux for 5 minutes then cooled to room temperature and concentrated in vacuo. The sample was treated with tetrahydrofuran and evaporated to dryness (twice) to yield the crude acid chloride as an orange oil. A solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (3.60 g, 20 mmol) and Hünig's base (4.35 mL, 25 mmol) in dichloromethane was cooled to 0° C., and a solution of the crude acid chloride in dichloromethane (25 mL) was added dropwise. The mixture was stirred overnight at room temperature, washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate and brine. The solution was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to yield a solid (8.01 g) which was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane to provide the title compound (6.03 g) as a white solid.
1 H NMR (300 MHz, CDCl 3 ): δ 2.30 (s, 3H), 5.20 (br, 4H), 6.05 (d, 2H), 6.70 (s, 1H), 6.85 (br, 2H), 7.17 (m, 2H), 7.30 (m, 2H), 7.37 (d, 1H).
Step B. [3-Methyl-4-(pyridin-4-yl)phenyl]-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone
A suspension of (4-bromo-3-methylphenyl)[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone of Step A (1.14 g, 2.9 mmol), pyridine-4-boronic acid (0.368 mg, 2.9 mmol) and sodium carbonate (0.760 g, 7.2 mmol) in a mixture of toluene (30 mL), water (10 mL), and ethanol (5 mL) was sparged with nitrogen for 15 minutes. To this was added tetrakis(triphenylphosphine)palladium(0) (0.027 g) and the mixture was heated to reflux under a static pressure of nitrogen. After 24 hours additional boronic acid (0.128 mg, 1 mmol) and sodium carbonate (0.116 g) were added and the heating was continued for 24 hours. Additional catalyst (0.012 g) was added and heating was continued for another 24 hours. The mixture was partitioned between ethyl acetate and hexane. The water layer was washed twice with ethyl acetate and the combined organic layers were dried over anhydrous magnesium sulfate and stripped to a solid. Flash chromatography of the residue on silica gel eluting with 30% ethyl acetate in hexane provided a solid which was recrystallized from ethyl acetate/hexane to provide the title compound (0.254 g) as tan plates m.p. 208–210° C.
1 H NMR (400 MHz, DMSO-d 6 ): δ 1.75 (s, 3H), 1.77 (s, 3H), 5.18 (br, 4H), 5.89 (s, 2H), 6.05 (br, 1H), 6.08 (t, 1H), 6.69 (t, 1H), 6.85 (br, 1H), 7.03 (br, 3H), 7.16 (t, 1H), 7.35 (d, 1H).
MS [EI, m/z]: 379 [M] + .
Anal. Calcd. for C 25 H 21 N 3 O+0.5 H 2 O: C, 77.30, H, 5.71, N, 10.82. Found: C, 77.01, H, 5.37, N, 10.68.
Step C. 10-[3-Methyl-4-(pyridin-4-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1 c][1,4]benzodiazepine-3-carboxylic acid
To a stirred solution of [3-methyl-4-(pyridin-4-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone of Step B (5 mmol) and N,N-diisopropylethyl amine (12 mmol) in dichloromethane (200 mL) cooled to 0° C. was added dropwise a solution of trichloroacetyl chloride (12 mmol) in dichloromethane. The temperature was maintained at 0° C. until the addition was complete. The reaction was stirred overnight as it warmed to room temperature. The solution was then washed with 10% aqueous sodium bicarbonate and the organic layer was dried, concentrated and filtered through a pad of silica gel with 1:1 ethyl acetate/hexane containing 0.1% acetic acid. The filtrate was concentrated in vacuo and the residue was dissolved in acetone and 1N sodium hydroxide (2:1,v/v) and stirred at room temperature for 1 hour and then the pH was adjusted to pH 4 with glacial acetic acid. The solution was concentrated to one half the volume in vacuo and the residue extracted with ethyl acetate. The combined organic layers were dried and evaporated to an oil which was triturated with hexane to yield a solid (0.98 g).
Step D. [3-Methyl-4-(pyridin-4-yl)-phenyl]-{3-[4-(pyridin-2-yl)-piperazin-1-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl-methanone
The title compound was obtained from the 10-[3-methyl-4-(pyridin-4-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1c][1,4]benzodiazepine-3-carboxylic acid of Step C and 1-(pyridin-2-yl)piperazine ((1.2 equiv.), in the manner of Example 1.
EXAMPLE 20
10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-8-[(piperidin-1-yl)carbonyl]-N-(pyridin-4-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
Step A. [4-(2-Formyl-1H-pyrrole-1-yl)methyl]-3-nitro]-benzoic acid methyl ester
To a suspension of sodium hydride (8.1 g, 60% suspension in oil) in N,N-dimethylformamide (25 mL) was added dropwise over 15 minutes a solution of pyrrole 2-carboxaldehyde (9.1 g, 1 equiv.) in N,N-dimethylformamide (25 mL). After the addition, the reaction mixture was stirred for 30 minutes and then cooled to 0° C. A solution of 4-bromomethyl-2-nitrobenzoic acid (25.0 g, 1 equiv.) in N,N-dimethylformamide (50 mL) was added dropwise over 20 minutes. After the addition, the reaction mixture was stirred at room temperature for 1 hour and then iodomethane (1.2 eq.) was added. The reaction mixture was stirred at room temperature overnight and diluted with water (200 mL). The solid was filtered, washed with water and dried over anhydrous potassium carbonate in vacuo at 50° C. to provide the crude title compound as a brown solid (26 g) which was used as such in the next step.
Step B. 10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylicacid methyl ester
To a stirred solution of tin(II) chloride dihydrate (23 g, 3.5 eq) in 2 N hydrochloric acid (106 mL) was added the [4-(2-formyl-1H-pyrrole-1-yl)methyl]-3-nitro]-benzoic acid methyl ester of Step A (8 g). Methanol (200 mL) was then added to this solution and the reaction mixture was stirred at 40° C. for 2 hours. The reaction was then cooled to room temperature, quenched by the addition of saturated aqueous sodium carbonate (20 mL) and filtered through Celite. The filter pad was washed with methanol and hot ethyl acetate. The filtrate and washings were combined, concentrated in vacuo to a volume of 300 mL and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a volume of 200 mL. Acetic acid (1 g) and 10% palladium on charcoal (1.5 g) were added and the mixture was hydrogenated overnight at atmospheric pressure. The reaction was then filtered through Celite and the solvent removed in vacuo to give a dark brown crystalline solid (16.4 g). This was dissolved in dichloromethane and filtered through a silica pad eluting with dichloromethane to provide the title compound as a yellow crystalline solid (11.7 g). Recrystallization from 1,2-dichloroethane yielded a yellow crystalline solid (5.7 g), m.p. 198–200° C.
1 H NMR(CDCl 3 , 200 MHz): δ 3.95 (s, 3H), 4.50 (s, 2H), 5.20 (s, 2H), 6.05 (t, 2H), 6.70 (t, 1H), 7.05 (d, 1H), 7.15 (s, 1H), 7.20 (d, 1H), 7.30 (s, 1H).
Step C. Methyl 10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1.4]benzodiazepine-8-carboxylate
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylic acid methyl ester of Step B (1.64 g) in 1,2-dichloroethane (25 mL) was added 4-(2-trifluoromethylphenyl)-3-methylbenzoyl chloride (2.0 g, 1.1 eq) prepared in the manner of Example 1, Step D and triethylamine (1.0 g) and the mixture was stirred at room temperature overnight. The solvent was then removed in vacuo and the residue chromatographed on silica gel eluting with 10% ethyl acetate in petroleum ether to provide the title compound as a white crystalline solid, m.p. 180–182° C.
1 H NMR (DMSO-d 6 , 400 MHz): δ 1.80 (s, 3H), 3.70 (s, 3H), 5.0–5.5 (br, 4H), 5.80 (t, 1H), 6.00 (s, 1H), 6.85 (t, 1H), 6.90 (s, 1H), 7.00 (br, 1H), 7.20 (d, 1H), 7.35 (s, 1H), 7.60 (t, 2H), 7.70 (t, 2H), 7.75 (d, 1H), 7.80 (d, 1H).
MS [(+)ESI, m/z]: 505 [M+H] + .
Anal. Calcd. for C 29 H 23 F 3 N 2 O 3 : C, 69.04; H, 4.60; N, 5.55. Found: C, 67.76; H, 4.30; N, 5.40.
Step D. 10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylic acid sodium salt
To a stirred solution of methyl 10-{[2-methyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1.4]benzodiazepine-8-carboxylate of Step C (0.200 g) in ethanol (5 mL) was added 2.5 N sodium hydroxide (4 mL). The reaction mixture was then stirred overnight at room temperature and the solvent removed in vacuo. The residue was acidified with 2 N hydrochloric acid and extracted with diethyl ether. The combined extracts were dried over anhydrous magnesium sulfate and filtered, and the the filtrate evaporated to dryness. The residue was dissolved in anhydrous ethanol and treated with 2.5 N sodium hydroxide (1.0 equiv.). After stirring for 30 minutes at room temperature, the solvent was removed in vacuo to provide the title compound sodium salt as a white solid, m.p. 210° C.
1 H NMR (DMSO-d 6 , 400 MHz): δ 1.85 (s, 3H), 5.20 (br, 3H), 5.90 (s, 2H), 6,80 (t, 1H), 6.90–7.80 (m, 11H).
MS [(+)APCI, m/z]: 491 [M+H] + .
Anal. Calcd. for C 28 H 21 F 3 N 2 O 3 Na+H 2 O: C, 63.27; H, 4.36; N, 5.27. Found: C, 63.04; H, 4.21; N, 4.99.
Step E. 8-[(Piperidin-1-yl)carbonyl]-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine
Prepared by coupling of 10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylic acid of Step D with piperidine, in the manner of Example 1, Step G.
Step F. 10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-8-[(piperidin-1-yl)carbonyl]-N-(pyridin-4-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
Prepared by treatment of 8-[(piperidin-1-yl)carbonyl]-{[2-methyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step E with diphosgene (1.1 equiv.) and triethylamine (1.5 equiv.) followed by 4-(aminomethyl)pyridine (1.5 equiv.) in the manner of Example 14, Step E.
EXAMPLE 21
10-[(3,6-Dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
Step A. 2,5-Dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylic acid
A suspension of 4-bromo-2,5-dimethoxybenzoic acid [prepared in the manner of Bortnik et al., Zh. Org. Khim . 8, 340 (1972)] (2.43 g, 9 mmol), 2-trifluoromethylphenyl boronic acid (5.3 g, 28 mmol), and potassium carbonate (6.21 g, 60 mmol) in dioxane (40 mL) was sparged with nitrogen and treated with tetrakis(triphenylphosphine)palladium(0) (0.328 g, 0.2 mmol). The mixture was heated to reflux for 48 hours, cooled, acidified with 1N hydrochloric acid and extracted with ethyl acetate The extracts were dried over anhydrous magnesium sulfate, filtered and stripped to a solid which was used as such in the next step.
1 H NMR (300 MHz, CDCl 3 ): δ 3.90 (s, 3H), 4.05 (s, 3H), 7.30 (d, 1H), 7.70 (s, 1H).
Step B. 10-{[3,6-Dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine
The title compound was prepared in the manner of Example 19, Step A using 2,5-dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylic acid of Step A (1.63 g, 5 mmol), oxalyl chloride (700 μL, 8 mmol), N,N-dimethylformamide (10 μL), 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.93 g, 5 mmol) and Hünig's base (1.78 ml, 10 mmol). Flash chromatography over silica gel using a solvent gradient from 30% ethyl acetate in hexane to 100% ethyl acetate provided the title compound (0.900 g) as a solid. Recrystallization from acetone/hexane yielded white needles, m.p. 210–213° C.
1 H NMR (400 MHz, DMSO-d 6 : δ3.41 (s, 3H), 3.56 (s, 3H), 5.21 (br, 4H), 5.90 (t, 1H), 5.96 (s, 1H), 6.50 (s, 1H), 6.80 (s, 1H), 7.00 (s, 2H), 7.07 (s, 1H), 7.10 (t, 1H), 7.18 (d, 1H), 7.37 (d, 1H), 7.53 (t, 1H), 7.62 (t, 1H), 7.73 (d, 1H).
MS [(+)ESI, m/z]: 493 [M+H] + .
Anal. Calcd. for C 28 H 23 F 3 N 2 O 3 : C, 68.29, H, 4.71; N, 5.69. Found: C, 67.98, H, 4.66, N, 5.61.
Step C. 10-{[3,6-Dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]-carbonyl}-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxylic acid
Prepared from 10-{[3,6-dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]-carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step B and trichloroacetyl chloride, followed by basic hydrolysis of the intermediate trichloroacetate ester, in the manner of Example 1, Steps E and F.
Step D. 10-[(3,6-Dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
Prepared from 10-{[(3,6-dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]-carbonyl}-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxylic acid of Step C and methyl-pyridin-3-ylmethyl-amine (1 equiv.) in the manner of Example 5, Step E.
EXAMPLE 22
10-[(2′-Chloro-2-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(pyridin-2-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-carboxamide
To a solution of 10-{[2-methoxy-2′-chloro[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid (0.230 g, 0.54 mmol) [prepared from trifluoromethanesulfonic acid 4-formyl-2-methoxy-phenyl ester of Example 7, Step A and 2-chlorophenyl boronic acid, in the manner of Example 7, Steps B–E], in N,N-dimethylformamide (15 mL) is added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.120 g, 0.625 mmol) and 1-hydroxybenzotriazole (0.625 mmol). To the homogeneous solution was added methyl-pyridin-2-ylmethyl-amine (0.625 mmol) and the stirring was continued at room temperature overnight. At the end of this time the solution was poured into water and extracted with ethyl acetate. The combined extracts were washed with water, dried and concentrated and the residue was chromatographed on silica gel, eluting with 95:5 chloroform:methanol. The pure fractions were concentrated, and the residue azeotroped and triturated several times with hexane to yield the title product.
EXAMPLE 23
{[[3-(Pyridin-2-ylmethyl)amino]carbonyl]-4H-10H-3a, 5,9-triaza-benzo[f]azulen-9-yl}-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-methanone
Step A. 2-Chloromethyl-pyridine-3-carboxylic acid methyl ester
A solution of methyl 2-methyinicotinate (20.0 g, 0.132 mol) and trichloroisocyanuric acid (46.0 g, 0.198 mol) in dichloromethane (100 mL) was stirred at room temperature overnight. The reaction mixture was then washed with saturated aqueous sodium carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated in vacuo to provide the title compound as a yellow liquid (11.2 g), which is used as such in the next step
Step B. 2-(2-Formyl-pyrrol-1-ylmethyl)-pyridine-3-carboxylic acid methyl ester
To a suspension of sodium hydride (5.8 g, 0.12 mol), was in dry N,N-dimethyl formamide (25 mL) was added slowly under nitrogen a solution of pyrrole 2-carboxaldehyde (10.5 g, 0.11 mol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was then cooled to 5° C. and 2-chloromethyl-pyridine-3-carboxylic acid methyl ester of Step A was added slowly, the temperature being maintained at or below 20° C. After the addition was complete, the reaction was stirred at room temperature for 30 minutes. The mixture was evaporated to dryness, and the residue was dissolved in ethyl acetate (250 mL). This solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was then removed in vacuo leaving a dark crystalline solid (23.4 g), which was purified by chromatography on silica gel eluting with a gradient of ethyl acetate/petroleum ether to provide the title compound as a tan crystalline solid (13.75 g), m.p. 91–93° C.
Step C. 1-(3-Phenylacetyl-pyridin-2-ylmethyl)-1H-pyrrole-2-carbaldehyde
To a stirred solution of 2-(2-formyl-pyrrol-1-ylmethyl)-pyridine-3-carboxylic acid methyl ester of Step B (13.65 g, 55.9 mmol) in methanol (50 mL) was added sodium hydroxide (2.2 g, 55.9 mmol.). The reaction mixture was refluxed under nitrogen for 2 hours, and then the solvent was removed in vacuo. A portion of the residual yellow solid.(5 g) was suspended in a mixture of benzyl alcohol (20 mL) and benzene (30 mL). Diphenylphosphoryl azide (6.54 g, 1.2 equiv.) was added, and the reaction was slowly heated to reflux. After refluxing for 1 hour, the mixture was cooled and washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to provide the title compound as a tan crystalline solid (4.4 g), m.p. 109–111° C.
Step D. 9,10-Dihydro-4H-3a,5,9-triaza-benzo[f]azulene
A stirred mixture of 1-(3-phenylacetyl-pyridin-2-ylmethyl0-1H-pyrrole-2-carbaldehyde of Step C (1.0 g), in ethyl acetate (10 mL) containing 10% palladium on charcoal (10 mg.), magnesium sulfate (0.010 g) and 5 drops of acetic acid was hydrogenated at atmospheric pressure until hydrogen uptake ceased. The reaction mixture was then filtered through Celite and the solvent removed in vacuo. The crude product (yellow crystalline solid, 0.530 g) was purified by chromatography on silica gel eluting with a gradient of ethyl acetate in petroleum ether to provide the title product as a yellow crystalline solid, m.p. 171–172° C.
Step E. (4-Bromo-3-methyl-phenyl)-(4H, 10H-3a, 5,9-triaza-benzo[f]azulen-9-yl)-methanone
To a stirred solution of the 9,10-dihydro-4H-3a,5,9-triaza-benzo[f]azulene of Step D (1.0 g) in dichloromethane (10 mL) was added 3-methyl-4-bromobenzoyl chloride (1.39 g) and triethylamine (1.1 mL). After stirring for 2.5 hours, the reaction mixture was washed with water, dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo to provide the title product as a tan crystalline solid (2.3 g), which was used without further purification.
Step F. (2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-(4H, 10H-3a, 5,9-triaza-benzo[f]azulen-9-yl)-methanone
A stirred mixture of (4-bromo-3-methyl-phenyl)-(4H, 10H-3a, 5,9-triaza-benzo[f]azulen-9-yl)-methanone of Step E (1.0 g), 2-trifluoromethyl-boronic acid (1.49 g, 3.0 equiv.), potassium phosphate (2.2 g) and a catalytic amount (0.050 g) of tetrakis(triphenylphosphine) palladium (0) in dioxane (10 mL) was refluxed for 2 hours. The solvent was then removed in vacuo and the residue dissolved in dichloromethane. The solution was then washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was then chromatographed on silica gel eluting with 5% ethyl acetate in dichloromethane to yield a colorless gum which crystallized upon addition of a little diethyl ether to provide the title compound as a cream-colored crystalline solid (0.500 g), m.p. 153–155° C.
1 H NMR (DMSO-d 6 , 400 MHz): δ 1.85 (s, 3H), 5.10 (s, 2H), 5.40 (s, 2H), 5.90 (t, 1H), 6.00 (s, 1H), 6.90 (t, 1H), 6.94 (d, 1H), 7.03 (d, 1H), 7.12 (dd, 1H), 7.23 (d, 1H), 7.28 (s, 1H), 7.37 (d, 1H), 7.58 (t, 1H), 7.68 (t, 1H), 7.80 (d, 1H), 8.27 (d, 1H)
MS [(+)ESI, m/z]: 448 [M+H] + .
Anal. Calcd. for C 26 H 20 F 3 N 3 O: C, 69.79, H, 4.51, N, 9.39. Found: C, 69.91, H, 4.30, N, 9.26).
Step G. 2,2,2-Trichloro-1-{[9-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-9,10-dihydro-4H-3a, 5,9-triaza-benzo[f]azulen-3-yl}-ethanone
To a solution of (2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-(4H, 10H-3a, 5,9-triaza-benzo[f]azulen-9-yl)-methanone in methylene chloride was added trichloroacetyl chloride (1.1 equiv.) and triethylamine (1.5 equiv,) After stirring overnight at room temperature, the reaction was washed with water, dried over anhydrous magnesium sulfate, and evaporated to dryness to provide the crude title compound which was used as such in the next step.
Step H. 9-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4yl)carbonyl]-9,10-dihydro-3a,5,9-triaza-benzo[f]azulen-3-carboxylic acid
To a solution of 2,2,2-trichloro-1-{[9-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-9,10-dihydro-4H-3a,5,9-triaza-benzo[f]azulen-3-yl}-ethanone of Step G in acetone was added 2.5 N sodium hydroxide (1.0 equiv.). After stirring overnight, the solvent was removed in vacuo leaving the crude sodium salt of the carboxylic acid. This was dissolved in anhydrous ethanol and treated with 2 N hydrochloric acid (1.0 equiv.). The solvent was removed in vacuo, the residue redissolved in anhydrous ethanol and the solvent again removed in vacuo. The crude title compound was then dried in vacuo over phosphorus pentoxide.
Step I. {[[3-(Pyridin-2-ylmethyl)amino]carbonyl]-4H-10H-3a,5,9-triaza-benzo[f]azulen-9-yl}-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-methanone
To a solution of the 9-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4yl)carbonyl]-9,10-dihydro-3a,5,9-triaza-benzo[f]azulen-3-carboxylic acid (3.38 mmol) of Step H in N,N-dimethylformamide (20 mL) was added 1-hydroxybenzotriazole (1.1 equiv.) and [3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.2 equiv.), followed by 2-(aminomethyl)pyridine (1.2 equiv.) and N,N-diisopropylethyl amine (1.5 equiv.). The reaction mixture was stirred overnight, then diluted with ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue was effected by chromatography on silica gel eluting with a gradient of methanol in ethyl acetate to provide the title compound as a white foam.
The compounds of following Examples 24–143 were prepared according to the General Procedures A–K described below.
General Procedure A
Step A. An appropriately substituted haloaryl carboxylic acid (1.1 mol) was converted to the acid chloride by using oxalyl chloride (1.5 mmol) and a catalytic amount of N,N-dimethylformamide in dichloromethane. Upon consumption of the acid as determined by HPLC analysis, all volatiles were removed in vacuo. The resulting residue was dissolved in dichloromethane and added dropwise to a stirred and cooled (0° C.) solution of an appropriately substituted 5H-pyrrolo[2,1-c][1,4]benzodiazepine (1 mmol) and N,N-diisopropylethyl amine (1.2 mmol) in dichloromethane. After 1–16 hours, the mixture was diluted with dichloromethane and washed with 10% aqueous sodium bicarbonate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated.
Step B. To the residue was added an appropriately substituted boronic acid (1.2 mmol), potassium carbonate (2.5 mmol), tetrabutylammonium bromide (1 mmol), palladium(II) acetate (3% mole) and water/acetonitrile (1:1, 2 mL). The contents were heated to 70° C. for 1.5 hours, then ethyl acetate was added and the organic phase washed with water. The solution was filtered through a small plug of Celite and concentrated to dryness.
Step C. The residue was dissolved in dichloromethane and N,N-diisopropylethyl amine (2 mmol) was added. The flask was purged with nitrogen and trichloroacetyl chloride was added dropwise to the stirred reaction mixture. After 16 hours, the reaction was quenched by adding aqueous potassium carbonate (100 g/300 mL) and the organic phase removed. The aqueous layer was extracted with additional dichloromethane and the combined extracts dried over anhydrous sodium sulfate, filtered and concentrated.
Step D. The crude product from Step C was dissolved in tetrahydrofuran (1 mL) and 2N sodium hydroxide (1.5 mL) was added. The mixture was heated (70° C.) for 1.5 hours, 2N hydrochloric acid was added and the product extracted with ethyl acetate. The organic phase was dried, filtered and concentrated. The residue was purified by column chromatography using a gradient of ethyl acetate in hexane contaning 1% glacial acetic acid as the eluant.
Step E. To a stirred solution of a carboxylic acid of Step D above (1.85 mmol) in anhydrous tetrahydrofuran (14 mL) was added 1,1′-carbonyl diimidazole in one portion. The mixture was stirred at room temperature (6–8 hours). The progress of the reaction was monitored by HPLC and when the starting carboxylic acid was consumed, the mixture was worked up to provide the intermediate imidazolide.
Step F. An aliquot of a tetrahydrofuran solution (400 μL, 0.05 mmole) containing the imidazolide of Step E (0.05 mmol) was treated with a 0.25 M solution of an appropriate amine (0.1 mmol). The mixture was heated at 60° C. and the progress of the reaction followed by HPLC. The solvent was removed and the residue dissolved in dichloromethane (1 mL). The organic phase was washed with brine-water (1:1, v/v, 1 mL) and the aqueous layer extracted with additional dichloromethane. The combined extracts were dried and evaporated to dryness and the residue purified by flash chromatography on silica gel. The column (prepacked in 2.5% methanol in dichloromethane contaning 1% triethylamine) was eluted with a solvent gradient from 2.5 to 5% methanol in dichloromethane, to provide the desired title compound. The desired title compounds were either obtained as crystalline solids by exposure to diethyl ether or were further converted into their salts by any of the following procedures.
Step G. Compounds prepared according to Step E that dissolved in diethyl ether were treated with a stoichiometric amount of 1N hydrochloric acid in diethyl ether whereby the hydrochloride salts precipitated out as white solids. Compounds that did not conform to the above category, were dissolved in the minimal amount of tetrahydrofuran, then diluted with diethyl ether. The hydrochloride salts were formed upon addition of 1N hydrochloric acid in diethyl ether with stirring. Compounds that did not immediately precipitate out of solution were stirred for 12–16 hours whereupon a white solid precipitated out.
General Procedure B
To a stirred solution of an appropriately substituted carboxylic acid of General Procedure A, Step D (2 mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide (0.229 g, 2.2 mmol) and a catalytic amount of 4-(dimethylamino)pyridine in dichloromethane (6 mL) was added the appropriately substituted amine (2.2 mmol) in dichloromethane (2 mL). The reaction was allowed to stir at room temperature for 16 hours, then diluted with dichloromethane. The organic layer was washed with water, saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel (prepacked in dichloromethane containing 2.5% methanol and 1% triethylamine and eluted with a solvent gradient of 2.5 to 5% methanol in dichloromethane) to provide the desired title compound.
General Procedure C
Triphosgene (742 mg, 2.5 mmol) was added to a stirred solution of a carboxylic acid of General Procedure A, Step D (5.0 mmol) in dichloromethane (10 mL). The clear solution was allowed to stir at room temperature (14 hours) after which time the solution turned red. To the reaction mixture was added a solution of the required amine (10.0 mmol) and N,N-diisopropylethyl amine (10.0 mmol) in dichloromethane (5 mL). The mixture was diluted with dichloromethane and washed with water and brine. The organic phase was dried, filtered and concentrated to afford a residue which was purified by flash chromatography on silica gel. The column (prepacked in 2.5% methanol in dichloromethane contaning 1% triethylamine) was eluted with a solvent gradient from 2.5 to 5% methanol in dichloromethane, to provide the title compound.
General Procedure D
A stirred solution of a carboxylic acid of General Procedure A, Step D (3.54 mmol) and the appropriately substituted amine (3.72 mmol) in N,N-dimethylformamide (10 mL) was cooled to 0° C. N,N-diisopropylethyl amine (3.89 mmol) was added and the mixture stirred for five minutes. O-(1-Benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (1.42 g, 3.72 mmol) was added to the mixture in one portion. HPLC analysis revealed that the reaction was complete within five minutes. The solvent was removed at reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined extracts were dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (prepacked in ethyl acetate containing 2% triethylamine and eluted with 100% ethyl acetate) to provide the title compound.
General Procedure E
To a 0.25 M solution of a carboxylic acid of General Procedure A, Step D (200 μL) in N,N-dimethylformamide was added sequentially a 0.5 M solution of N,N-diisopropylethyl amine (200 μL) in N,N-dimethylformamide and a 0.25 M solution of O-(7-aza-1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (210 μL) in N,N-dimethylformamide. The mixture was stirred vigorously at room temperature and then a 0.25 M solution of the appropriately substituted amine (200 μL) in N,N-dimethylformamide was added. Stirring was continued for 24 hours at room temperature, then the mixture was diluted with ethyl acetate, and washed with 1:1 water/brine. The organic layer was dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (prepacked in ethyl acetate containing 2% triethylamine and eluted with 100% ethyl acetate) to provide the title compound.
General Procedure F
Step A. To a solution of an appropriately substituted anilino carboxylic acid in methanol was added thionyl chloride. The mixture was heated for 16 hours. The volatiles were removed under reduced pressure and the hydrochloride salt of the carboxylic acid methyl ester was recovered after trituration with methanol/diethyl ether. The solid was dissolved in concentrated hydrochloric acid and cooled. An aqueous solution of sodium nitrite was added and the mixture was stirred at 0° C. for one hour. An aqueous solution of KI/I 2 was prepared and added to the cooled mixture so that the reaction temperature did not exceed 0° C. After 1–2 hours the reaction was complete as evidenced by TLC/HPLC analysis. The product was recovered by extraction with ethyl acetate. The combined extracts were dried, filtered and concentrated to afford the desired substituted aryl iodide which could be further purified by recrystallization.
Step B. To a solution of an appropriately substituted aryl halide methyl ester of Step A (2 mmol) and an appropriately substituted boronic acid (2 mmol) in 20% aqueous acetone was added cesium carbonate (3 mmol) followed by palladium(II) acetate (60 μmol). The mixture was heated (70° C.) with stirring for 8–16 hours. The reaction was concentrated to remove the acetone after TLC/HPLC analysis indicated the reaction was complete. The aqueous phase was extracted with ethyl acetate and the combined extracts were filtered through a pad of Celite. The filtrate was washed with 5% aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel.
Step C. The product from Step B was dissolved in tetrahydrofuran (1 mL) and 2N sodium hydroxide (1.5 mL) was added. The mixture was heated (70° C.) for 1.5 hours, 2N hydrochloric acid was added and the product extracted with ethyl acetate. The organic phase was dried, filtered and concentrated. The residue was purified by column chromatography using ethyl acetate in hexane contaning 1% glacial acetic acid as the eluant.
Step D. To a suspension of the carboxylic acid of Step C (60 μmol) in dichloromethane (100 μL) was added a 0.45 M solution of oxalyl chloride (200 μL) in dichloromethane followed by dichloromethane (100 μL) containing a catalytic amount of N,N-dimethylformamide. The mixture was allowed to sit at room temperature for 16 hours, then the volatiles were removed in vacuo to afford the crude acid chloride. A solution of the acid chloride in tetrahydrofuran (0.3 M, 200 μL), was utilized to acylate a solution (0.3 M, 200 μL) of an appropriately substituted 5H-pyrrolo[2,1-c][1,4]benzodiazepine in tetrahydrofuran according to the General Procedure A, Step A.
General Procedure G
A mixture of an appropriately substituted aryl bromide methyl ester (or an aryl iodide methyl ester of General Procedure F, Step A) (8.3 mmol), an appropriately substituted boronic acid (9.1 mmol), potassium carbonate (20.8 mmol), tetrabutylammonium bromide (or iodide) (8.3 mmol), palladium(II) acetate and water (8–9 mL) was stirred with heating (70° C.) for 1.5 hours, whereupon the reaction was deemed complete by HPLC analysis. The oily upper layer was extracted with ethyl acetate, the extracts washed with brine, dried and concentrated to dryness. The residue was filtered through a column of silica gel to provide the desired coupled product of General Procedure F, Step B.
General Procedure H
The coupling of an appropriately substituted aryl bromide methyl ester (or an aryl iodide methyl ester of General Procedure F, Step A) (8.3 mmol) to an appropriately substituted pyridyl borane was carried out using potassium hydroxide as the base, in the presence of tetrabutylammonium bromide (or iodide) and a tetrakis(triphenylphoshine) palladium (0) catalyst essentially according to the published procedure of M. Ishikura, Synthesis, 936–938 (1994), to provide the desired coupled product of General Procedure F, Step B.
General Procedure I
The coupling of an appropriately substituted aryl bromide methyl ester (or an aryl iodide methyl ester of General Procedure F, Step A) (8.3 mmol) to an appropriately substituted boronic acid was carried out essentially according to General Procedure F, Step B except that the solvent was acetonitrile.
General Procedure J
The desired substituted aryl iodide of General Procedure F, Step A was prepared by reaction of an appropriately substituted amino carboxylic acid in concentrated hydrochloric acid at 0° C. with an aqueous solution of sodium nitrite followed by the addition of an aqueous solution of KI/I 2 at 0° C., followed by esterification of the resulting iodo aryl carboxylic acid with methanolic hydrochloric acid.
General Procedure K
The acylation of an activated appropriately substituted arylpyridine carboxylic acid of Procedure H was carried out by dissolving the acid (0.06 mmol) in a solution of oxalyl chloride in dichloromethane (12 mg/200 μL) followed by a catalytic amount of N,N-dimethylformamide in dichloromethane (100 μL). After stirring at room temperature for 16 hours, the volatiles were removed and tetrahydrofuran added, followed by the addition of a solution of the appropriately substituted 5H-pyrrolo[2,1-c][1,4]benzodiazepine and N,N-diisopropylethyl amine (1:2 molar ratio) in tetrahydrofuran. After stirring for 20 hours, the reaction was worked up essentially as described in General Procedure A, Step A.
EXAMPLE 24
10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 543.23874. Calcd. for C 34 H 31 N 4 O 3 : 543.23907
EXAMPLE 25
10-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 543.23831. Calcd. for C 34 H 31 N 4 O 3 : 543.23907
EXAMPLE 26
10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 529.22343. Calcd. for C 33 H 29 N 4 O 3 : 529.22342
EXAMPLE 27
10-[(2′-Methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 513.22772. Calcd. for C 33 H 29 N 4 O 2 : 513.22851
EXAMPLE 28
10-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 543.23855. Calcd. for C 34 H 31 N 4 O 3 : 543.23907
EXAMPLE 29
10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 577.20052. Calcd. for C 34 H 30 ClN 4 O 3 : 577.20010
EXAMPLE 30
10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 593.19557. Calcd. for C 34 H 30 ClN 4 O 4 : 593.19501
EXAMPLE 31
10-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 579.23816. Calcd. for C 37 H 31 N 4 O 3 : 579.23907
EXAMPLE 32
10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 559.23363. Calcd. for C 34 H 31 N 4 O 4 : 559.23399
EXAMPLE 33
10-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 559.23423. Calcd. for C 34 H 31 N 4 O 4 : 559.23399
EXAMPLE 34
10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 583.18978. Calcd. for C 36 H 28 ClN 4 O 2 : 583.18953
EXAMPLE 35
10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 581.21516. Calcd. for C 34 H 28 F 3 N 4 O 2 : 581.21589
EXAMPLE 36
10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 543.23845. Calcd. for C 34 H 31 N 4 O 3 : 543.23907
EXAMPLE 37
10-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 527.24341. Calcd. for C 34 H 31 N 4 O 2 : 527.24416
EXAMPLE 38
10-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 543.23838. Calcd. for C 34 H 31 N 4 O 3 : 543.23907
EXAMPLE 39
10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 529.22338. Calcd. for C 33 H 29 N 4 O 3 : 529.22342
EXAMPLE 40
10-[(2′-Methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 513.22773. Calcd. for C 33 H 29 N 4 O 2 : 513.22851
EXAMPLE 41
10-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 543.23838. Calcd. for C 34 H 31 N 4 O 3 : 543.23907
EXAMPLE 42
10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 577.20054. Calcd. for C 34 H 30 ClN 4 O 3 : 577.20010
EXAMPLE 43
10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 593.19500. Calcd. for C 34 H 30 ClN 4 O 4 : 593.19501
EXAMPLE 44
10-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 579.24077. Calcd. for C 37 H 31 N 4 O 3 : 579.23907
EXAMPLE 45
10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 559.23341. Calcd. for C 34 H 31 N 4 O 4 : 559.23399
EXAMPLE 46
10-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 559.23373. Calcd. for C 34 H 31 N 4 O 4 : 559.23399
EXAMPLE 47
10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 583.18952. Calcd. for C 36 H 28 ClN 4 O 2 : 583.18953
EXAMPLE 48
10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 581.21409. Calcd. for C 34 H 28 F 3 N 4 O 2 : 581.21589
EXAMPLE 49
10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 557.25366. Calcd. for C 35 H 33 N 4 O 3 : 557.25472
EXAMPLE 50
10-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 541.25935. Calcd. for C 35 H 33 N 4 O 2 : 541.25981
EXAMPLE 51
10-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 557.25363. Calcd. for C 35 H 33 N 4 O 3 : 557.25472
EXAMPLE 52
10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 543.23801. Calcd. for C 34 H 31 N 4 O 3 : 543.23907
EXAMPLE 53
10-[(2′-Methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 527.24446. Calcd. for C 34 H 31 N 4 O 2 : 527.24416
EXAMPLE 54
10-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 557.25403. Calcd. for C 35 H 33 N 4 O 3 : 557.25472
EXAMPLE 55
10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 591.21606. Calcd. for C 35 H 32 ClN 4 O 3 : 591.21575
EXAMPLE 56
10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 607.21044. Calcd. for C 35 H 32 ClN 4 O 4 : 607.21066
EXAMPLE 57
10-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 593.25470. Calcd. for C 38 H 33 N 4 O 3 : 593.25472
EXAMPLE 58
10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 573.24957. Calcd. for C 35 H 33 N 4 O 4 : 573.24964
EXAMPLE 59
10-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 573.24949. Calcd. for C 35 H 33 N 4 O 4 : 573.24964
EXAMPLE 60
10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 597.20525. Calcd. for C 37 H 30 ClN 4 O 2 : 597.20518
EXAMPLE 61
10-{[2-Methyl-2′-trifluoromethyl=[1,1′-biphenyl]-4-yl]carbonyl}-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 595.22982. Calcd. for C 35 H 30 F 3 N 4 O 2 : 595.23154
EXAMPLE 62
10-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 571.27074. Calcd. for C 36 H 35 N 4 O 3 : 571.27037
EXAMPLE 63
10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 605.23088. Calcd. for C 36 H 34 ClN 4 O 3 : 605.23140
EXAMPLE 64
10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 587.26595. Calcd. for C 36 H 35 N 4 O 4 : 587.26529
EXAMPLE 65
10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 571.27090. Calcd. for C 36 H 35 N 4 O 3 : 571.27037
EXAMPLE 66
10-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 555.27479. Calcd. for C 36 H 35 N 4 O 2 : 555.27546
EXAMPLE 67
10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 557.25425. Calcd. for C 35 H 33 N 4 O 3 : 557.25472
EXAMPLE 68
N-Methyl-10-[(2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 541.25992. Calcd. for C 35 H 33 N 4 O 2 : 541.25981
EXAMPLE 69
10-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 571.27107. Calcd. for C 36 H 35 N 4 O 3 : 571.27037
EXAMPLE 70
10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 621.22598. Calcd. for C 36 H 34 ClN 4 O 4 : 621.22631
EXAMPLE 71
10-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 607.27097. Calcd. for C 39 H 35 N 4 O 3 : 607.27037
EXAMPLE 72
10-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 587.26443. Calcd. for C 36 H 35 N 4 O 4 : 587.26529
EXAMPLE 73
10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 611.22029. Calcd. for C 38 H 32 ClN 4 O 2 : 611.22083
EXAMPLE 74
N-Methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 609.24719. Calcd. for C 36 H 32 F 3 N 4 O 2 : 609.24719
EXAMPLE 75
{10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 598.28159. Calcd. for C 37 H 36 N 5 O 3 : 598.28127
EXAMPLE 76
{10-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 582.28589. Calcd. for C 37 H 36 N 5 O 2 : 582.28636
EXAMPLE 77
{10-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 598.28309. Calcd. for C 37 H 36 N 5 O 3 : 598.28127
EXAMPLE 78
{10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 584.26487. Calcd. for C 36 H 34 N 5 O 3 : 584.26562
EXAMPLE 79
{10-[(2′-Methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 568.27112. Calcd. for C 36 H 34 N 5 O 2 : 568.27071
EXAMPLE 80
{10-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 598.28310. Calcd. for C 37 H 36 N 5 O 3 : 598.28127
EXAMPLE 81
{10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 632.24224. Calcd. for C 37 H 35 ClN 5 O 3 : 632.24230
EXAMPLE 82
{10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 648.23671. Calcd. for C 37 H 35 ClN 5 O 4 : 648.23721
EXAMPLE 83
{10-[(3-Methoxy-4-(naphthalen-1-yl)-benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone
HRMS [(+) ESI, m/z]: 634.28252. Calcd. for C 40 H 36 N 5 O 3 : 634.28127
EXAMPLE 84
{10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 614.27683. Calcd. for C 37 H 36 N 5 O 4 : 614.27619
EXAMPLE 85
{10-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 614.27583. Calcd. for C 37 H 36 N 5 O 4 : 614.27619
EXAMPLE 86
{10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 638.23142. Calcd. for C 39 H 33 ClN 5 O 2 : 638.23173
EXAMPLE 87
(10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)[4-(2-pyridinyl)-1-piperazinyl]methanone
HRMS [(+) ESI, m/z]: 636.25827. Calcd. for C 37 H 33 F 3 N 5 O 2 : 636.25809
EXAMPLE 88
10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 543.23946. Calcd. for C 34 H 31 N 4 O 3 : 543.23907
EXAMPLE 89
10-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 527.24367. Calcd. for C 34 H 31 N 4 O 2 : 527.24416
EXAMPLE 90
10-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 543.23964. Calcd. for C 34 H 31 N 4 O 3 : 543.23907
EXAMPLE 91
10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 529.22290. Calcd. for C 33 H 29 N 4 O 3 : 529.22342
EXAMPLE 92
10-[(2′-Methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 513.22881. Calcd. for C 33 H 29 N 4 O 2 : 513.22851
EXAMPLE 93
10-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 543.23950. Calcd. for C 34 H 31 N 4 O 3 : 543.23907
EXAMPLE 94
10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 577.20008. Calcd. for C 34 H 30 ClN 4 O 3 : 577.20010
EXAMPLE 95
10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 593.19387. Calcd. for C 34 H 30 ClN 4 O 4 : 593.19501
EXAMPLE 96
10-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 579.23927. Calcd. for C 37 H 31 N 4 O 3 : 579.23907
EXAMPLE 97
10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 559.23401. Calcd. for C 34 H 31 N 4 O 4 : 559.23399
EXAMPLE 98
10-[(2,3′-Dimethoxy-[1,1′-biphenyl]4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 559.23341. Calcd. for C 34 H 31 N 4 O 4 : 559.23399
EXAMPLE 99
10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 583.18912. Calcd. for C 36 H 28 ClN 4 O 2 : 583.18953
EXAMPLE 100
10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 581.21569. Calcd. for C 34 H 28 F 3 N 4 O 2 : 581.21589
EXAMPLE 101
10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 557.25414. Calcd. for C 35 H 33 N 4 O 3 : 557.25472
EXAMPLE 102
10-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]4-yl)carbonyl]-N-methyl-N-(3-pyridinyImethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 557.25453. Calcd. for C 35 H 33 N 4 O 3 : 557.25472
EXAMPLE 103
10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 573.24906. Calcd. for C 35 H 33 N 4 O 4 : 573.24964
EXAMPLE 104
10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 543.23907. Calcd. for C 34 H 31 N 4 O 3 : 543.23907
EXAMPLE 105
N-Methyl-10-[(2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 527.24394. Calcd. for C 34 H 31 N 4 O 2 : 527.24416
EXAMPLE 106
10-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 557.25454. Calcd. for C 35 H 33 N 4 O 3 : 557.25472
EXAMPLE 107
10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 591.21599. Calcd. for C 35 H 32 N 4 O 3 : 591.21575
EXAMPLE 108
10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 607.21037. Calcd. for C 35 H 32 ClN 4 O 4 : 607.21066
EXAMPLE 109
10-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 593.25393. Calcd. for C 38 H 33 N 4 O 3 : 593.25472
EXAMPLE 110
10-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 573.24936. Calcd. for C 35 H 33 N 4 O 4 : 573.24964
EXAMPLE 111
10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 597.20513. Calcd. for C 37 H 30 ClN 4 O 2 : 597.20518
EXAMPLE 112
N-Methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 595.23096. Calcd. for C 35 H 30 F 3 N 4 O 2 : 595.23154
EXAMPLE 113
{10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 598.28145. Calcd. for C 37 H 36 N 5 O 3 : 598.28127
EXAMPLE 114
{10-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 582.28638. Calcd. for C 37 H 36 N 5 O 2 : 582.28636
EXAMPLE 115
{10-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 598.28161Calcd. for C 37 H 36 N 5 O 3 : 598.28127
EXAMPLE 116
{10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone
HRMS [(+) ESI, m/z]: 584.26455. Calcd. for C 36 H 34 N 5 O 3 : 584.26562
EXAMPLE 117
{10-[(2′-Methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 568.27184. Calcd. for C 36 H 34 N 5 O 2 : 568.27071
EXAMPLE 118
{10-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo]2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 598.28188. Calcd. for C 37 H 36 N 5 O 3 : 598.28127
EXAMPLE 119
{10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 632.24169. Calcd. for C 37 H 35 ClN 5 O 3 : 632.24230
EXAMPLE 120
{10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 648.23779. Calcd. for C 37 H 35 ClN 5 O 4 : 648.23721
EXAMPLE 121
{10-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 634.28198. Calcd. for C 40 H 36 N 5 O 3 : 634.28127
EXAMPLE 122
{10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone
HRMS [(+) ESI, m/z]: 614.27656. Calcd. for C 37 H 36 N 5 O 4 : 614.27619
EXAMPLE 123
{10-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]:. 614.27612. Calcd. for C 37 H 36 N 5 O 4 : 614.27619
EXAMPLE 124
{10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 638.23111. Calcd. for C 39 H 33 ClN 5 O 2 : 638.23173
EXAMPLE 125
10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 587.26570. Calcd. for C 36 H 35 N 4 O 4 : 587.26529
EXAMPLE 126
10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]:. 571.27020. Calcd. for C 36 H 35 N 4 O 3 : 571.27037
EXAMPLE 127
10-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 555.27738. Calcd. for C 36 H 35 N 4 O 2 : 555.27546
EXAMPLE 128
10-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 571.27053. Calcd. for C 36 H 35 N 4 O 3 : 571.27037
EXAMPLE 129
10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 557.25454. Calcd. for C 35 H 33 N 4 O 3 : 557.25472
EXAMPLE 130
N-Methyl-10-[(2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 541.25983. Calcd. for C 35 H 33 N 4 O 2 : 541.25981
EXAMPLE 131
10-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 571.27053. Calcd. for C 36 H 35 N 4 O 3 : 571.27037
EXAMPLE 132
10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 605.23199. Calcd. for C 36 H 34 ClN 4 O 3 : 605.23140
EXAMPLE 133
10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 621.22570. Calcd. for C 36 H 34 ClN 4 O 4 : 621.22631
EXAMPLE 134
10-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 607.27001. Calcd. for C 39 H 34 N 4 O 3 : 607.27037
EXAMPLE 135
10-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 587.26451. Calcd. for C 36 H 35 N 4 O 4 : 587.26529
EXAMPLE 136
10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 611.22112. Calcd. for C 38 H 32 ClN 4 O 2 : 611.22083
EXAMPLE 137
N-Methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 609.24693. Calcd. for C 36 H 32 F 3 N 4 O 2 : 609.24719
EXAMPLE 138
{10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[2-(3-pyridinyl)-1-piperidinyl]methanone
HRMS [(+)ESI, m/z]: 597.28526. Calcd. for C 38 H 37 N 4 O 3 : 597.28602
EXAMPLE 139
{10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[2-(3-pyridinyl)-1-piperidinyl]methanone
HRMS [(+)ESI, m/z]: 583.26953. Calcd. for C 37 H 35 N 4 O 3 : 583.27037
EXAMPLE 140
{10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[2-(3-pyridinyl)-1-piperidinyl]methanone
HRMS [(+)ESI, m/z]: 631.24693. Calcd. for C 38 H 36 ClN 4 O 3 : 631.24705
EXAMPLE 141
{10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[2-(3-pyridinyl)-1-piperidinyl]methanone
HRMS [(+)ESI, m/z]: 613.28118. Calcd. for C 38 H 37 N 4 O 4 : 613.28094
EXAMPLE 142
(10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)[2-(3-pyridinyl)-1-piperidinyl]methanone
HRMS [(+)ESI, m/z]: 635.26206. Calcd. for C 38 H 34 F 3 N 4 O 2 : 635.26284
EXAMPLE 143
[3-Methoxy4-(pyridin-3-yl)-phenyl]-{3-[4-(pyridin-4-yl)-piperazin-1-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl-methanone
MS [(+)ESI, m/z]: 585 [M+H] + . Calcd. for C 35 H 33 N 6 O 3 : 585.261
The compounds of following Examples 144–147 were prepared according to the general procedures described below.
General Procedure L
Step A. To a stirred cooled (0° C.) solution of an appropriately substituted 10-(4-amino)benzoyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (10 mmol) in dichloromethane (20 mL) was added N,N-diisopropylethyl amine (2.09 mL, 12 mmol) followed by the addition of 9-fluorenylmethyl chloroformate (2.85 g, 11 mmol) in one portion. The reaction was allowed to warm to room temperature. TLC analysis was used to monitor the progress of the reaction and after 8 hours, indicated that a single product was formed. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by flash column chromatography (Biotage Flash 40S, gradient elution from 10 to 20% ethyl acetate in hexanes) to provide the desired appropriately substituted 4-(fluorenylmethoxycarbonyl)-10,1-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine.
Step B. Trichloroacetyl chloride (3.35 mL, 30 mmol) was added to a solution of an appropriately substituted 4-(fluorenylmethoxycarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step A (10 mmol) and N,N-diisopropylethyl amine (3.48 mL, 20 mmol) in dichloromethane, and the solution was stirred at ambient temperature for 2 hours. An aqueous solution of sodium bicarbonate (0.5 M) was added to the mixture and the organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in a solution of piperidine in N,N-dimethyl formamide (20%, v/v) and stirred until the starting material was no longer observed by HPLC/TLC analysis. The mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The desired appropriately substituted 2,2,2-trichloro-1-[10-(4-aminobenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}-ethanone was isolated by flash chromatography (Biotage, Flash 40M, gradient elution from 20 to 30% ethyl acetate in hexanes).
Step C. An appropriately substituted 1,4-diketone (25 mmol) was added to a vial containing an appropriately substituted aniline of Step B (4.4 mmol) followed by the addition of acetic acid (1 mL). The contents of the vial were stirred and heated (80° C.) without the vial capped (to allow for the removal of water). After 1 hour the solution was diluted with ethyl acetate (20 mL). The organic phase was washed with water, aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by flash column chromatography to afford the desired appropriately substituted 2,2,2-trichloro-1-{10-{4-(1H-pyrrol-1-yl)-benzoyl]-10,11-dihydro[2,1-c][1,4]benzodiazepin-3-yl}-ethanone.
Step D. The material from Step C (3.85 mmol) was dissolved in tetrahydrofuran (10 mL) and treated with aqueous sodium hydroxide (2 N, 3 mL). The mixture was allowed to stir with heating (80° C.) overnight. After cooling to room temperature, aqueous hydrochloric acid (2 N, 3.2 mL) was added and product was recovered by extraction with ethyl acetate. The combined extracts were evaporated and the residue purified by flash column chromatography, eluting with a gradient of 20 to 50% ethyl acetate in hexanes to provide the desired appropriately substituted title compound.
EXAMPLE 144
10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-N-methyl-N-[2-(pyridin-2-yl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 574.28119. Calcd. for C 35 H 36 N 5 O 3 : 574.28127
EXAMPLE 145
{10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(pyridin-2-yl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 601.29180. Calcd. for C 36 H 37 N 6 O 3 : 601.29217
EXAMPLE 146
{10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(pyridin-4-yl)-1-piperazinyl]methanone
HRMS [(+)ESI, m/z]: 601.29177. Calcd. for C 36 H 37 N 6 O 3 : 601.29217
EXAMPLE 147
10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-N-methyl-N-[2-(pyridin-4-yl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide
HRMS [(+)ESI, m/z]: 574.28047. Calcd. for C 35 H 36 N 5 O 3 : 574.28127 | This invention provides novel substituted tricyclic pyridyl carboxamides which act as oxytocin receptor competitive antagonists, as well as methods of their manufacture, pharmaceutical compositions and methods of their use in treatment, inhibition, suppression or prevention of preterm labor, dysmenorrhea, endometritis, suppression of labor at term prior to caesarean delivery, and to facilitate antinatal transport to a medical facility. These compounds are also useful in enhancing fertility rates, enhancing survival rates and synchronizing estrus in farm animals; and may be useful in the prevention and treatment of disfunctions of the oxytocin system in the central nervous system including obsessive compulsive disorder (OCD) and neuropsychiatric disorders. | 2 |
CROSS-REFERENCE TO RELATED APPLICATION
This application is a National Stage entry of International Application No. PCT/EP2007/005623, filed Jun. 27, 2007, which in turn claims priority from U.S. Provisional Application No. 60/816,594 filed Jun. 27, 2006, the entire specification claims and drawings of which are incorporated herewith by reference.
The present invention provides extracts of the microalga Aphanizomenon Flos Aquae Aquae Ralfs ex Born. & Flah. Var. flos aquae (AFA Klamath) and the biologically active components thereof endowed with antioxidant, antinflammatory and antitumor properties. Furthermore the invention provides nutritional, cosmetic and pharmaceutical compositions containing effective amounts of the extract or the active components thereof, in particular AFA-phycocyanin, with its C-phycocyanin/phycoerythrocyanin complex, AFA-phytochrome and mycosporine-like aminoacids (MAAs), alone or in combination with cofactors contained in the algae, for use in the prophylaxis or treatment of diseases, disturbances or conditions involving acute or chronic inflammation and oxidative degeneration of body cells or tissues or uncontrolled cell proliferation.
BACKGROUND OF THE INVENTION
Aphanizomenon Flos Aquae (AFA), which is one of the many types of blue-green algae, is found in abundance in Upper Klamath Lake in southern Oregon. It is one of the few edible microalgae, and it differs from other microalgae grown in ponds, such as Spirulina and Chlorella , insofar as it grows wild in an optimal environment which allows it to develop a truly remarkable nutritional profile, including a wide range of vitamins and organic minerals, proteins and aminoacids, Omega 3 fatty acids. It is also known to contain a certain number of nutrients endowed with antioxidant properties, such as chlorophyll and carotenes. Various studies in the last few years have shown significant antioxidant and antinflammatory properties possessed by the phycocyanins of the blue-green microalga Spirulina; more recently, the in vitro antioxidant properties of a crude extract of AFA have been reported (Benedetti S., Scoglio S., Canestrari F., et al., Antioxidant properties of a novel phycocyanin extract from the blue-green alga Aphanizomenon Flos Aquae, in Life Sciences, 75 (2004): 2353-2362).
DISCLOSURE OF THE INVENTION
The invention provides extracts of Klamath microalgae ( Aphanizomenon Flos Aquae Aquae Ralfs ex Born. & Flah. Var. flos aquae ) which concentrate the active components of the alga, namely:
a) a specific phycobiliprotein complex, unique to AFA algae, which contains i) a phycobilisome comprising C-phycocyanin (C-PC) and phycoerythrocyanin (PEC)—hereafter indicated as “AFA-phycocyanins”—and including its specific chromophore phycoviolobilin; ii) an AFA-specific phytochrome (herein indicated as AFA-phytochrome”); b) MAAs (mycosporine-like aminoacids), chlorophyll and carotenes.
The extraction process makes use of centrifugation and size exclusion separation techniques which can be modulated to modify the concentration of the different components. To guarantee adequate concentration of different components, the first phase is preparing an aqueous extract (herein indicated as Basic Extract), according to the following steps:
a) freezing the freshly harvested AFA alga and thawing it, or, if the starting material is dried AFA powder, sonicating the water-diluted AFA powder, to disrupt the cells; b) centrifuging the product of step a) to separate the supernatant (retaining most of the cytoplasmatic fraction) from the precipitate (retaining most of the cell wall fraction); c) collecting the supernatant containing the water-soluble components (Basic Extract).
It is possible to further concentrate the water-soluble fractions by passing the supernatant through an ultra-filtration membrane. In particular, to prepare extracts concentrated in water-soluble components, the primary aqueous extract described above (Basic Extract) is subjected to size-exclusion ultrafiltration, preferably by using a membrane with a molecular weight cut-off of 30 kDa, whereby a retentate (indicated as Extract B) and a filtrate are obtained. Extract B contains a higher concentration of AFA-phycocyanins (C-PC+PEC) and of the AFA-phytochrome. Interestingly, even though MAAs have a molecular weight well below the cut-off size employed, the retentate also increases the concentration of MAAs. The filtrate, on the other hand, has a higher concentration of carotenes, chlorophyll and essential fatty acids.
The lipophilic components of the extract are mainly represented by carotenes, chlorophyll, and alpha-linolenic acid (18:3n-3), all of which are present in relatively high amounts in AFA algae. These components are in part retained in the supernatant (Basic Extract), but for the most part they are present in the precipitate resulting from centrifugation at step b) above. This precipitate can be then subjected to a further process of extraction directed at concentrating the above mentioned liposoluble substances. The concentration of the liposoluble substances is preferably obtained through an ethanol based extraction, according to the following steps:
a) suspending the dried precipitate in a solution of 100% ethanol, homogenizing and maintaining the homogenate under constant stirring for 24 h at room temperature in the dark; b) centrifuging the resulting suspension at 3000 rpm for 5′ at 4° C.; c) collecting the supernatant; d) optionally, subjecting the pellet to a second ethanol extraction according to steps a) through c); e) drying the supernatant to obtain a lipid-soluble concentrate (Extract C).
The thus obtained liposoluble component-enriched fraction can then be added to Basic Extract or to the filtrate from the ultrafiltration, to obtain the highest possible concentration of liposoluble substances that enhance the effects of the biologically-active substances already present in the extracts.
The extracts according to the invention can be provided in the form of nutritional supplements, pharmaceutical and/or cosmetic products. The Basic Extract is generally preferred as it retains very significant antioxidant and anti-inflammatory properties.
The components that retain or enhance the antioxidant properties of the extract have been isolated and physico-chemically characterized. The specific type of AFA-phycocyanin (C-PC/PEC); the chromophore phycoviolobilin (PVB); the specific AFA-phytochrome; the mycosporine-like amino acids (MAAs) porphyra and shinorine, resulted the most active, singularly or in various combinations, and their antioxidant activity was further increased by other components such as chlorophyll, beta-carotene, pro-vitamin A carotenoids, xantophyllic carotenes such as canthaxanthin, vitamins and minerals. In addition to their demonstrated antioxidant activity, both the Basic Extract and the purified AFA-phycocyanins were found to significantly inhibit the cycloxygenase-2 (COX-2) enzyme; this property was then confirmed for the Basic Extract which, by including both AFA-PC and other antinflammatory molecules, proved able to prevent and/or suppress inflammation in an in vivo animal model. Furthermore, tested on a tumor cell line, the AFA-phycocyanin showed to possess high antiproliferative activity.
Accordingly, the invention further includes a nutritional, cosmetic or pharmaceutical composition containing, as the active ingredient, an extract of Klamath microalgae or an isolated and purified active component thereof, in particular: a) the specific type of AFA-phycocyanins (C-PC/PEC), as present in AFA or in any other microalgae b) the PEC; c) the phycoviolobilin (PVB); d) the AFA-phytochrome; e) the mycosporine-like amino acids (MAAs) porphyra and shinorine, as present in AFA, or from any other algal source; optionally in combination with co-factors or coadjuvants selected from chlorophyll, beta-carotene, pro-vitamin A carotenoids, xantophyllic carotenes, canthaxanthin, vitamins and minerals, and optionally in combination with nutritionally, cosmetically or pharmaceutically acceptable vehicles or excipients. To prepare the compositions according to the invention, the different liquid extracts mentioned above can be either used as such or can be dried through methodologies such as freeze-drying, spray-drying, and others.
In a preferred embodiment, the nutritional compositions are dietary supplements in the form of tablets, capsules, beverages, which are useful for increasing or supporting the natural defenses against pathogens, for scavenging oxidant species produced by metabolic, inflammatory and aging processes. In another preferred embodiment, the cosmetic compositions are in the form of topical preparations, such as emulsions, gels, lotions, powders, eyewashes, particularly ointments or creams, for use in the prevention or treatment of dermatological or age-related affections, and as photo-protective agents to prevent skin aging and photo-oxidative degeneration of skin and hair.
In a yet further preferred embodiment, the pharmaceutical compositions are in the form of tablets, capsules, sachets, syrups, suppositories, vials and ointments and can be used for the prevention or treatment of free-radical mediated pathologies, inflammation or neoplasias.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a comparison of the components of the cellular lysate of AFA Klamath with the components of the cellular lysate of Synechocystis PCC 6803.
FIG. 2 shows the spectrophotometric graphic of the extract resulting from the purification of AFA-PC and its chromophore, PCB.
FIG. 3 shows a spectrophotometric scan of purified PCB indicating two peaks of absorption, 370 nm and 690 nm.
FIG. 4 shows the structures of mycosporine-like amino acids (MAAs).
FIG. 5 shows a spectrophotometric scan of partially purified MAAs. FIG. 6 shows a chromatogram of MAAs purified by HPLC.
FIG. 7 shows the UV spectra of purified MAAs indicating their absorption maximum at 334 nm.
FIG. 8 shows the reduction in malondialdehyde (MDA) levels in plasma samples oxidized by CuCl 2 and pre-incubated with an AFA Klamath extract and the SERUM BLUE™ extract.
FIG. 9A shows that AFA-PC and its chromophore, PCB, inhibited the lipid peroxidation in erythrocytes in a dose-dependent manner.
FIG. 9B shows that AFA-PC inhibits the AAPH-induced lysis of erythrocytes.
FIG. 10 shows the effects of AFA-PC on the kinetics of the loss of fluorescein's fluorescence after the addition of AAPH.
FIG. 11 shows the kinetics of quenching of fluorescein's fluorescence at different concentrations of PCB.
FIG. 12 shows the linear regression analysis of Trolox, GSH, AA, PC and PCB with respect to their ORAC value.
FIG. 13 shows a dose-dependent inhibition of intracellular fluorescence in Jurkat cells upon simultaneous addition of H 2 O 2 and phycocyanin (left panel) and H 2 O 2 and phycocyanobilin (right panel).
FIG. 14 shows a dose-dependent inhibition of intracellular fluorescence in Jurkat cells pre-incubated with phycocyanin (left panel) and phycocyanobilin (right panel) and then exposed to oxidative stress by the addition of H 2 O 2 .
FIG. 15 shows the approximate molecular weight of AFA-phytochrome. FIG. 16 shows the light-absorbing properties of AFA-phytochrome. FIG. 17 shows the reduction in MDA levels in plasma samples simultaneously incubated with CuCl 2 and increasing quantities of AFA-phytochrome.
FIG. 18 shows that MAAs cause a dose-dependent reduction in erythrocyte hemolysis.
FIG. 19 shows that MAAs cause a dose-dependent reduction in MDA levels.
FIG. 20 shows a comparison of the effect of Basic Extract and pure phycocyanin on MDA levels.
FIG. 21 shows the effect of Basic Extract and pure phycocyanin on the formation of conjugated dienes.
FIG. 22 shows a dose-dependent reduction in the formation of conjugated dienes caused by AFA Extract with increasing concentrations of phycocyanin.
FIG. 23 shows a dose-dependent decrease in MDA levels caused by AFA Extract with increasing concentrations of phycocyanin.
FIG. 24 shows the decay in fluorescence caused by AAPH in the absence (blank) and presence of hydrosoluble extract and liposoluble extract relative to the reference standard Trolox.
FIG. 25 shows the effect of supplementation with AFA algae and AFA extract on the plasma levels of MDA, GSH and retinol in healthy subjects.
FIG. 26 shows the effect of supplementation with an AFA and AFA extract-based product on the plasma levels of MDA, carbonyls, and AOPP in patients undergoing hyperbaric treatment.
FIG. 27 shows the effect of supplementation with an AFA and AFA extract-based product on the plasma levels of total thiols in patients undergoing hyperbaric treatment.
FIG. 28 shows the effect of supplementation with an AFA and AFA extract-based product on the plasma levels of TEAC in patients undergoing hyperbaric treatment.
FIG. 29 shows the effect of Liposoluble Extract, Hydrosoluble Extract, phycocyanin, and phycocyanobilin on the cyclooxygenase (COX) activity.
FIG. 30 shows that AFA extract inhibits the outflow of plasma in stomach and bladder of mice injected with 0.25 μmol/kg capsaicin.
FIG. 31 shows that AFA extract inhibits the outflow of plasma in stomach and duodenum of mice injected with 2 nmol/kg of SP.
FIG. 32 shows that AFA-PC shows a dose and time dependent anti-proliferative effect. FIG. 33 shows an in vivo analysis of skin surface upon application of a cream containing 8% Basic Extract of AFA Klamath.
FIG. 34 shows the improvement in skin elasticity obtained during the 30-day period of treatment with a cream containing 8% Basic Extract of AFA Klamath.
FIG. 35 shows the improvement in skin moisturization obtained during the 30-day period of treatment with a cream containing 8% Basic Extract of AFA Klamath.
FIG. 36 shows the improvement in volume of skin wrinkles during the 30-day period of treatment with a cream containing 8% Basic Extract of AFA Klamath.
FIG. 37 shows a reduction in the number and width of skin wrinkles obtained during the 30-day period of treatment with a cream containing 8% Basic Extract of AFA Klamath.
DETAILED DESCRIPTION OF THE INVENTION
Structural Determination and Specific Characteristics of the AFA Alga's Phycobilisomes (AFA-Phycocyanins)
In the intact cyanobacterial cell phycocyanins (PC) are present inside the phycobilisome in the functional form (..) 6 (1). Following the break-up of the cell, the protein can be found in different aggregation states (monomers, dimers, trimers, hexamers) according to the organism analyzed. In the case of Klamath AFA algae, the electrophoretic analysis of the PC, both as contained in the AFA extracts and as purified from the extract itself, has shown that the protein is found for the most part in its trimeric form (..) 3 , with a total molecular weight of 121000. A monomer .. weighs approximately 40000 (18500 subunit .+21900 subunit .). The majority of the studies on the purified PC from Spirulina indicate instead that the protein is found in Spirulina in the monomeric form .. with a molecular weight of approximately 37500, thus showing a different aggregation state relative to the purified PC from AFA.
The chromatographic analysis of the AFA's phycobilosomes has also shown that, as in other cyanobacterial species, the . subunit of PC binds a prosthetic group, while the . subunit binds two. The prosthetic group or chromophore is called phycocyanobilin (PCB) and is responsible both for the blue color of the protein and for its antioxidant power (2).
A fundamental difference between AFA and Spirulina rests on the different structure of the phycobilisome. As opposed to Spirulina , the phycobilisome of AFA Klamath does not contain the pigment allo-phycocyanin, but only the pigment c-phycocyanin bound to a structural component which is missing in Spirulina , namely phycoerythrocyanin (PEC). PEC is a photosynthetic pigment which has so far been identified only in a limited number of cyanobacterial species (3). PEC has a chemical structure very similar to that of PC, being composed by the two subunits . e . which associate to form monomers and trimers. Nevertheless, while every monomer of PC binds 3 molecules of PCB, PEC possesses the unique characteristic of binding two molecules of PCB to the subunit . and one molecule of phycoviolobilin (PVB) to the . subunit, which is responsible of the purple color of the pigment.
The phycobilisome of Klamath algae is peculiarly constituted by the union of c-phycocyanin and phycoerithrocyanin, and this different qualitative structure of the phycobilisome of AFA Klamath algae adds a further decisive factor distinguishing AFA from Spirulina and other blue-green algae.
FIG. 1 compares the components of the cellular lysate of AFA with those of another well known cyanobacterium, Synechocystis PCC 6803. In both cyanobacteria it is possible to see the blue band representing the phycobilisome, but in AFA algae the phycobilisome presents a lower molecular mass, confirming that, as opposed to common microalgae such as Spirulina , in the AFA phycobilisome only phycocyanins, but not allo-phycocyanins, are present. Furthermore, FIG. 1 shows that in AFA is also present a light purple band (shown by the arrow) which is typical of phycoerythrocyanins, thus proving their presence in the phycobilisome of Klamath algae.
Each blue band has been further analyzed through HPLC connected to mass spectrometer (RP-HPLC-ESI-MS). Thanks to the different retention times, the proteins of the phycobilisome have been separated and identified based on their molecular mass. The results obtained are shown in the following tables. First it can be observed that while in Synechocystis (Table 1) both phycocyanin (cpcA at 28.2 min and cpcB at 28.9 min) and allo-phycocyanin (apcA at 30.7 min and apcB at 31.2 min) are present, in AFA (Table 2) only phycocyanin (cpcA at 28.8 min and cpcB at 30.0 min) is present. Secondly, in AFA a protein with molecular mass of 19469 has been identified which is not present in Synechocystis and which corresponds to the beta subunit of the phycoerythrocyanin with two bilins attached (pecB at 25.0 min).
TABLE 1
proteins present in the phycobilisome of Synechocystis .
Reten-
tion
Measured
Expected
Protein
NCBI
time
molecular
molecular
[homologous
Number of
(min)
mass
mass
organism]
access
14.5
9322
9322
cpcD
gi|16329820
22.6
32505
32520
cpcC
gi|16329821
32388
30797
cpcC
gi|16329822
24.6
28770
27392
cpcG
gi|16329710
24.8
28885
28522
cpcG
gi|16332194
28.2
18173
17586
cpcA (sub.
gi|2493297
phycocyanin)
28.9
19313
18126
cpcB (sub.
gi|2493300
phycocyanin)
30.7
17866
17280
apcA (sub.
gi|266765
allophycocyanin)
31.2
17816
17215
apcB (sub.
gi|266766
allophycocyanin)
TABLE 2
proteins present in the phycobilisome of AFA Klamath algae
Reten-
tion
Measured
Expected
Protein
NCBI
time
molecular
molecular
[homologous
Number of
(min)
mass
mass
organism]
access
15.2
9031
8925
hypothetical protein
gi|45510540
Avar03000795
[ Anabaena variabilis
ATCC 29413]
8895
cpcD
gi|131740
[ Nostoc sp. PCC 7120]
25.0
19469
18284
pecB:
gi|548504
19308
phycoerythrocyanin
beta chain
[ Nostoc sp. PCC 7120]
18370
hypothetical protein
gi|45510532
Avar03000787 (pecB)
[ Anabaena variabilis
ATCC 29413]
26.4
31044
32078
cpcC
gi|20141679
[ Nostoc sp. PCC 7120]
32219
hypothetical protein
gi|45510539
Avar03000794 (rod
linker Mw 32000)
[ Anabaena variabilis
ATCC 29413]
31295
pecC
gi|464511
[ Nostoc sp. PCC 7120]
31304
hypothetical protein
gi|45510534
Avar03000789 (pecC)
[ Anabaena variabilis
ATCC 29413]
30124
29333
hypothetical protein
gi|46135436
Avar03000801 (cpcG4)
[ Anabaena variabilis
ATCC 29413]
26.8
26119
28637
hypothetical protein
gi|45510544
Avar03000799 (cpcG2)
[ Anabaena variabilis
ATCC 29413]
27.8
10994
10986
fdxH2: ferredoxin
gi|1169673
vegetative
[ Anabaena variabilis ]
28.8
17714
17457
cpcA
gi|9957319
[ Nostoc sp. PCC 7120]
30.0
19222
18332
cpcB
gi|38894
[ Nostoc sp. PCC 7120]
This unique structure is an important element to explain the stronger antioxidant and antinflammatory action of the AFA algae's extract concentrating its phycocyanins, and most of all it is essential to explain why the purified AFA-phycocyanin resulted more powerful than other PC such as the one from Spirulina (as shown by both antioxidant and antinflammatory tests, see below). The binding between C-PC and PEC in AFA phycobilisome is so strong that cannot be broken by known purification methodologies (see below). Hence, the purified AFA-PC should be intended as the purified AFA-phycobilisome, constituted by the complex C-PC/PEC. For sake of simplicity, though, this complex is indicated as “AFA-PC” or PC.
Purification Methodologies ( FIG. 2 )
AFA-PC and its chromophore PCB have been purified starting from the Basic Extract. PC was purified from the dried AFA extract as follows:
suspend 500 mg of extract in 50 ml of 100 mM Na-phosphate buffer pH 7.4; centrifuge at 2500 rpm for 10′ at 4° C.; collect the supernatant and add solid ammonium sulfate to a 50% saturation; precipitate the proteins for 60 min at 4° C. while keeping the sample in agitation; centrifuge at 10000 rpm for 30 min at 4° C.; discard the clear colorless supernatant and resuspend the blue precipitate in a small volume of 5mM Na-phosphate buffer pH 7.4; dialyze overnight at 4 .C against the same buffer; place the dialyzed PC in a 2.5×25 cm hydroxyapatite column (Bio-Rad Laboratories, CA, USA) balanced with 5 mM Na-phosphate buffer pH 7.4; elute the sample with Na-phosphate buffer pH 7.0 of increasing ionic strength (from 5 to 150 mM); collect the fractions and read the absorbance at 620 nm and 280 nm with the spectrophotometer; pool the fractions in which Abs 620 /Abs 280 >4 (index of pure PC); precipitate the PC with ammonium sulfate at 50% saturation for 1 hour at 4°; centrifuge at 10000 rpm for 30′ at 4° C.; discard the supernatant and suspend again the PC in a 150 mM of Na-phosphate buffer pH 7.4; dialyze against the same buffer at 4° C.; transfer the purified PC in a flask and store in darkness at +4° C. or −20° C.
FIG. 2 shows the spectrophotometric graphic of the extract resulting from the purification. It can be seen that the purified PC is indeed the whole phycobilisome containing the two subunits C-PC and PEC. In fact, it is known that the absorption maximum of C-PC is 620 nm, which in the spectrometry of FIG. 2 represents the top of the peak. It is also known that the absorption maximum of PEC is 566 nm for the .-subunit (phycoviolobilin) and respectively 593 nm and 639 nm for the two PCBs of the .-subunit. All three values are indeed included in the bell-shaped peak constituting the spectrophotometric pattern of purified PC. Considering the strong link between C-PC and PEC in AFA algae, i C-PC as well as PEC are necessarily present in the purified PC extract. This means that the PC from AFA is significantly different, both structurally and functionally, from the PCs of other cyanobacteria, including the one from Spirulina , on which most studies have been done. In particular this difference consists in that the AFA PC has one part, namely C-PC, in common with PCs from other sources and one portion, the PEC component, which is different, so that its properties, associated to the complex C-PC/PEC, are novel and exclusively attributable to AFA (and similar C-PC/PEC complexes from other microalgae).
Quantification of AFA-Phycocyanin
To measure the molar concentration of the pur PC we used the coefficient of molar extinction . at 620 nm, which for the trimeric form (..) 3 is equal to 770000 M −1 cm −1 . This means that a solution of 1 M of PC at 620 nm has an absorption value of 770000.
To measure the concentration of PC in the extracts we used the coefficient of specific extinction E 1% at 620 nm of 70 l g −1 cm −1 . This means that a solution containing 1% of PC (that is 1 g/100 ml) at 620 nm absorbs 70. Based on these calculations, the average content of PC in the Basic Extract is equal to 80-100 mg/g DW (8-10% DW); whereas the average content of PC in the Extract B is approximately 360 mg/g DW (36% DW).
Purification of the PCB Chromophore ( FIG. 3 )
Suspend 500 mg of extract in 50 ml of distilled H 2 O. Centrifuge at 2500 rpm for 10′ at 4° C. Decant the deep blue supernatant and precipitate the PC with trichloroacetic acid at 1%. Incubate for 1 h in the dark at 4° C., while agitating. Centrifuge at 10000 rpm for 30′ at 4° C. Gather the pellet containing PC and wash 3 times with methanol. Resuspend the pellet in 10 ml of methanol containing 1 mg/ml of HgCl 2 . Incubate for 20 h at 42° C. in darkness to release the PCB from PC. Centrifuge at 2500 rpm for 10′ to remove the proteins. Add to the supernatant containing PCB .-mercaptoethanol (1 μl/ml) to precipitate the HgCl 2 . Incubate at −20° C. for 24 h. Centrifuge at 10000 rpm for 30′ at 4° C. to remove the white precipitate. Add to the supernatant 10 ml of methylene chloride/butanol (2:1, v/v). Wash with 20 ml of distilled H 2 O and centrifuge at 3000 rpm for 10′. Remove the upper phase, collect the lower part containing PCB. Wash the PCB in 15 ml H 2 O 3 times. Dry under nitrogen and store at −20° C.
The resulting spectrophotometric scan shows that the PCB presents two peaks of absorption, at 370 and 690 nm.
Antioxidant Superiority of the Klamath Algae's Phycocyanins in Comparison with other Phycocyanins.
Phycocyanins (PC) are the blue pigments typical of all blue-green microalgae, but with different structural and functional characteristics in each specific microalga (22). As to sources of PC used as nutritional supplements and potential natural drugs, research has so far focused on Spirulina. Spirulina 's phycocyanins have shown to possess antioxidant (23) and antinflammatory (24,25,26) properties, with significant activity on different physiological areas such as liver (27), respiratory system (28), and brain (29,30). Given the lack of research on other phycocyanins such as those of Klamath algae, we have comparatively measured the antioxidant capacity of the aqueous extract from AFA (Klamath) algae in relation to the product Serum Bleu™, a liquid extract concentrating PC from microalga Spirulina platensis.
The reduction of MDA (malondialdehyde) levels in plasma samples oxidized by CuCl 2 and pre-incubated with the two extracts is shown in FIG. 8 , where it is possible to see that the extract at a PC concentration of 100 nM is by far more efficient in inhibiting the oxidation of plasma lipids, with the inhibition of the MDA formation reaching the level of 89% vs. an inhibition of 33% produced by Serum Bleu™ at the identical PC concentration of 100 nM. This shows that at the same PC concentration the AFA extract is significantly more powerful than the Spirulina 's extract. Such difference can be attributed to two distinct and complementary factors: a) a structural and thus functional diversity of the two types of PC; b) the presence in the extract of further antioxidant factors that are missing, as in the case of the phytochrome, or more scarcely present, such as MAAs, in other microalgae such as Spirulina. The higher antioxidant power of AFA PC in relation to C-PC (from Spirulina ) is however shown also through a comparison with the data available in the literature on lipoperoxidation.
Plasma and Erythrocytes Lipid-Peroxidation
When tested for its anti lipid-peroxidation properties on rat liver microsomes oxidized with AAPH, C-PC from Spirulina inhibited the production of TBARS (conjugated diens, MDA) with an IC50 of 11.35 μM (23, Bhat et al.). C-PC from Spirulina has also been tested by Romay & Gonzales (41) against human erythrocytes lysis induced by AAPH: the IC50 in this case was 35 μM.
We tested the same ability of both AFA-PC and its PCB to inhibit the formation of MDA on: a) human plasma oxidized by CuCl 2 ; b) on RBC (red blood cells or erythrocytes) oxidized by AAPH. We also tested the ability of AFA-PC and PCB to inhibit the AAPH-induced lysis of erythrocytes. In the former case, plasma samples were obtained after centrifugation of the heparinized blood from healthy volunteers at 1500 g for 10 min. The extent of lipid oxidation in plasma samples incubated for 2 h at 37° C. with PBS (control) or with 100 μM CuCl 2 in the presence of increasing concentrations of PC or PCB (range 0.1-1 μM) was assayed by measuring TBA-reactive substances at 535 nm (42). In relation to erythrocytes, heparinized blood samples were obtained from healthy volunteers via venapuncture after obtaining informed consent. Red blood cells (RBC) were isolated by centrifugation at 1500 g for 10 min, washed three times with PBS and finally re-suspended using the same buffer to an hematocrit level of 5%. RBC were incubated with PBS (control) or 50 mM AAPH for 4 hours at 37° C. in the presence of different concentrations of PC or PCB (range 0.1-1 μM). TBA-reactive substances, mainly malonyldialdehyde (MDA), as indicators of lipid peroxidation, were assayed as previously described (42). Briefly, a 1 ml reaction mixture was incubated at 95° C. for 1 h with 250 μl of TBA (0.67%) and 100 μl of H 3 PO 4 (0.44 M); then 150 μl of TCA (20%) were added. After centrifugation, the peroxide content in the supernatant was determined using the molar extinction coefficient (OD 535 ) of MDA.
As reported in FIG. 9A , PC and PCB inhibited in a dose-dependent manner (p<0.05 for each concentration tested) the extent of lipid peroxidation in RBC (erythrocytes) incubated for 2 hours at 37° C. with the peroxyl radical generator AAPH (panel A); at the same time, PC and PCB dose-dependently protected plasma lipids from metal-induced oxidation (p<0.05) in samples incubated for 2 hours at 37° C. with CuCl 2 (panel B). In both inhibition experiments, IC 50 values were approximately 0.140 μM and 0.160 μM for PC and PCB (vs. 11.35 μM of C-PC from Spirulina ).
We also tested the ability of AFA-PC to inhibit the AAPH-induced lysis of erythrocytes: as shown by FIG. 9B , AFA-PC has been able to constantly (that is from the 1st to the 6th hour) inhibit the lysis of erythrocytes more than 50% with just 250 nM of AFA-PC (vs. the IC50 of 37 μM for C-PC from Spirulina ).
Even taking in account some difference in the testing method or concentration, in both cases the superiority of AFA-PC over C-PC from Spirulina is truly remarkable, the difference in IC50 values being 75 to 150 times in favour of AFA-PC. An even greater indication of the difference in potency can be seen by the fact that, as reported in the same study by Bhat et al. (23) lipid-peroxidation is inhibited 95% with a Spirulina C-PC dosage of 200 μM. In FIG. 9A we can see that, to obtain a similar degree of inhibition only 1 μM of AFA-PC is required, that is 200 times less. This confirms that the significant difference between the C-PC on its own and the C-PC/PEC complex which characterizes AFA algae and its extracts is due precisely to PEC, the only element that differs, thus showing PEC to be a very powerful molecule on its own.
In addition, the IC50 of PC is slightly lower than that of PCB. This is somewhat surprising, given that the PCB, being considered its most active principle, once purified and thus more concentrated, should be significantly stronger than the whole molecule of which is the active component. The fact that it is actually slightly weaker, though still very powerful, means that in the whole PC there are other factors that may actually be even more potent than the PCB itself. We know that the whole PC contains PEC, besides C-PC and its PCB chromophore, which includes as its chromophores both PCB and PVB (phycoviolobilin). Therefore, we believe that the factor creating a significant difference in potency between the purified PCB and the whole PC is precisely the PEC component, particularly its PVB chromophore, which is considered a very strong antioxidant.
Evaluation of the Antioxidant Capacity (ORAC) of AFA-PC and its PCB
The ORAC (Oxygen Radical Absorbance Capacity) method is widely used to determine the total antioxidant capacity of pure and composed substances, measuring their activity in comparison to the Trolox (an hydrosoluble analog of vitamin E) as a reference molecule (31). However, up to now it has never been used to determine the antioxidant capacity of pure natural molecules from cyanobacteria such as PC and PCB.
The ORAC assay was carried out at 37° C. on a FLUOstar OPTIMA spectrofluorimeter (BGM LABTECH, Germany) at 485 nm excitation and 520 nm emission, using the method of Ou et al. (32) with minor modifications. Briefly, in the final assay mixture, fluorescein (FL) (0.05 μM) was used as a target of free radical attack, with AAPH (4 mM) as a peroxyl radical generator. Trolox (1 μM) was used as a control standard and phosphate buffer as a blank. The concentrations of tested compounds in the assay mixture ranged from 0.025 μM to 2 μM. All substances were dissolved and diluted with 75 mM Na-phosphate buffer pH 7; PCB solution was made by dissolving the compound first in ethanol and then bringing the solution to the desired concentration with the buffer. All samples were run in triplicate. Fluorescence was recorded every 5 min after AAPH was added. Final results (ORAC values) were calculated using the differences in the areas under the fluorescence decay curves (AUC) between the sample and blank and expressed as Trolox equivalents:
ORAC value=[(AUC sample −AUC blank )/(AUC trolox −AUC blank )]×(molarity trolox /molarity sample )
Linear regression analyses of ORAC values (y) versus AA, GSH, PC and PCB concentrations (x) adequately described the data as assessed by the correlation coefficient.
PC is a fluorescent water-soluble protein that upon excitation at 620 nm, emits at 647 nm this own fluorescence did not interfere with FL emission at 520 nm and no modifications of fluorescence intensity were evidenced after PC was added to the reaction mixture. The effects of PC on the kinetics of FL fluorescence loss after addition of AAPH are reported in FIG. 10 , clearly showing a linear correlation between PC concentrations (ranging from 0.025 to 0.150 μM) and the net area under the fluorescence decay curve (AUC) (r=0.998, p<0.0001).
The chromophore PCB is responsible for the brilliant blue color of PC and after release from the protein, presents two characteristic peaks of absorption at 370 and 690 nm that, as in the case of PC, did not affect FL fluorescence. FIG. 11 shows the kinetics of FL quenching with different bilin concentrations and the positive correlation (r=0.995, p<0.0005) of AUC versus PCB concentrations (range 0.025-0.150 μM).
Finally, the ability of pure PC and PCB to directly quench peroxyl radicals has been compared to those of well-known pure antioxidants molecules. FIG. 12 reports the linear regression analysis of Trolox, GSH, AA, PC and PCB with respect to their ORAC value. Based on these data, we found that PC and PCB had the highest ORAC values (20.33 and 22.18 Trolox equiv., respectively), whereas GSH and AA showed the lowest (0.57 and 0.75). The fact that also in the ORAC test the value of AFA-PC and PCB are quite similar confirms the very important role played by PEC in the AFA-PC.
No references on ORAC values are available for the natural compounds cited; however, to our knowledge, the ORAC value of PCB (whether expressed as μmol Trolox/μmol PCB or as μmol Trolox/mg PCB) is the highest found in literature as regards pure antioxidant molecules for which the ORAC activity has been evaluated using FL as fluorescent probe (ORAC FL ). As example, Ou et al. (Ou et al., 2001) determined the antioxidant capacity of different phenolic compounds by the ORAC FL method, and the highest values found were 7.28 and 6.76 μmol Trolox/μmol compound which, if the relative ORAC values are expressed as μmol Trolox/mg sample rather than μmol Trolox/μmol sample, becomes 24.0 and 23.3 μmol Trolox/mg compound, for flavonoids quercetin and (+)-catechin, respectively; while the ORAC for the PCB becomes 37.0 μmol Trolox/mg.
Protective Effect of AFA-Phycocyanin and its PCB on Cultured Cells.
Starting from the Basic extract, and following the methodology already described, we have purified the AFA-phycocyanin, with its C-PC/PEC complex, to test its antioxidant properties on live cultured cells. The Jurkat cells (immortalized line of leucemia T-lymphocytes) have been subjected to oxidative stress with 500 μM H2O2, together or without increasing dosages of AFA-PC and PCB. The fluorescence emitted by the intracellular probe (dichlorofluorescein), following oxydation from H2O2, has been recorded after 30 minutes of incubation with H2O2 through a fluorimeter (exc. at 492 nm and emission at 520 nm). By incubating cells with both AFA-PC (range 0.1-10 μM) and 500 μM H2O2 for 30 minutes we observe a dose-dependent protective effect with a reduction of intracellular fluorescence induced by H2O2, with an IC 50 of 0.5 μM, and a 100% inhibition (non-oxidized cells) at 10 μM ( FIG. 13 ).
The antioxidant properties of the whole PC, composed of C-PC and PEC, resides in its chromophores, which are phycocyanibilin (PCB) for C-PC and both PCB and PVB (phycoviolobilin) for PEC. We have purified the C-PC chromophore PCB, to test it on cultured cells oxidized with H2O2 (range FCB 0.1-40 μM). Also in this case we observe a dose-dependent antioxidant effect with an IC 50 of 0.5 μM, and a 100% inhibition (non-oxidized cells) at 40 μM ( FIG. 13 ).
At the concentrations that have been tested, both AFA-PC and the PCB incubated for 30 minutes with the cultured cells and without H2O2 do not have any oxidative effect, as shown by the fact that there is no increase of intracellular fluorescence.
Most importantly, to evaluate the cellular absorption of PC and PCB, both compounds have been pre-incubated for 2 hrs. with the cells; afterwards, the medium has been washed, to exclude any unabsorbed PC and PCB, and the cells have been oxidized for 30 min. with H2O2. As shown by the FIG. 14 , there is a dose-dependent inhibition of intracellular fluorescence. This means that the cell is able to retain both antioxidant molecules, either in the membrane or in the cytoplasm.
This is a very important finding, as it proves that the antioxidant activity of the two molecules are very likely effective in vivo for therapeutic purposes.
Whereas studies done on the purified Spirulina C-PC had already proven its ability to penetrate cellular cytosol (43), this is the first demonstration of the ability of the purified PCB to enter and being retained in the cell. Furthermore, this is the first time that the same ability is demonstrated for the specific AFA-PC (C-PC/PEC complex). At the concentrations tested, both PC and PCB incubated for 2 hrs. with the cells did not produce any oxidative effect, as shown by the fact that there is no increase in the intracellular fluorescence.
Whereas in FIG. 13 , where oxidative agent and antioxidants were added at the same time, we see that the degree of cell protection afforded by PC and PCB is equivalent; in the absorption test, as shown from FIG. 14 , PCB's antioxidant effect results to be slightly faster (IC50 1.9 μM for PCB vs. 4.2 μM for PC); and also slightly higher (more than 90% protection by PCB; less than 90% by PC). This means that the degree of absorption of the PCB, relative to the PC, is indeed slightly higher (as could be expected, given the more purified nature of the PCB). Nevertheless, the degree of absorption is truly remarkable for both compounds, given that in both cases is very close to the degree of protection afforded with the simultaneous addition of antioxidants and oxidative agent.
On the other hand, this live cells test confirms a previous consideration on the essential relevance of the PEC component for the antioxidant property of the whole PC. As shown by both FIGS. 13 and 14 , the fact that the whole purified PC has the same very high antioxidant potency as the purified PCB, the concentration of which is much higher after purification relative to its concentration as part of the whole PC, indicates that the PCB is not the only active agent of PC, and that in fact whatever other agent or agents (starting with PVB) are present in PC, they are very likely significantly more potent than PCB itself.
Novel Determination of Synergic Factors that Make the Extract More Effective than the AFA-Phycocyanins Contained in it.
We have seen that the AFA-PC, with its C-PC/PEC complex, is significantly more potent than the pure C-PC from other algae such as Spirulina , But there are in Klamath algae other factors which explain also the superiority of its extracts, starting with the Basic extract, relative to its main antioxidant and antinflammatory principle, the phycocyanins/phycoerithrocyanin complex.
The main factor that explains such difference is the second element that composes the wider phycobiliprotein complex constituting the light control system of AFA algae, namely its specific phytochrome, in absolute terms the most powerful antioxidant principle so far found in the algae. Further factors can be identified in the specific molecules typical of all algae called “mycosporine-like aminoacids” or MAAs, of which Klamath algae is particularly rich; and a series of nutritional molecules whose antioxidant and antinflammatory action is already known, such as chlorophyll, beta-carotene and carotenoids, plus various vitamins and minerals.
A) Identification of “AFA-Phytochrome”, a Unique Phytochrome Typical of Klamath Algae
Phytochromes are photoreceptors, pigments that plants use to detect light, and that are sensitive to light in the red and far-red region of the visible spectrum. They perform many different functions in plants, including the regulation of flowering (through circadian rhythms), germination and the synthesis of chlorophyll. The latter is particularly relevant in relation to AFA algae, because the presence of this unique type of phytochrome in AFA may be explained by its lack of the other phycobiliprotein commonly used by other cyanobacteria to complement C-phycocyanin in the process of photosynthesis, namely allo-phycocyanin. While, as we have seen, the place of allo-phycocyanin in Klamath algae is taken by PEC, it is likely that PEC alone is not sufficient, especially considering that Klamath alga lives in a non-tropical environment which needs a high light harvesting efficiency, and so AFA algae seems to integrate its higher needs with its own phytochrome.
While AFA phytochrome, which has been detected and is described here for the first time, has its own peculiar structure, it is still possible to define it as a representative of the general family of phytochromes. Over the years, different types of phytochromes have been found in plants, which not only have different phytochrome genes (3 in rice, but 6 in maize, for instance), but most of all the specific phytochrome of each plant, or at least of each plant family, has significantly different protein components and thus structure. Nevertheless, what makes them all phycochromes is that they all use the same biliprotein, called phytochromobilin, as a light-absorbing chromophore, This chromophore is similar to the phycocyanin's chromophore phycocyanobilin, and is characterized by being a single bilin molecule consisting of an open chain of four pyrrole rings (tetrapyrroles). Since the active principle of all phytochromes, in their different general structure, still remains this chromophore, even taking in account some variations among different species, it is possible to attribute the properties of each single phytochrome to other phytochromes. (44) More specifically, in its P r normal state this biliprotein absorbs light at a maximum of 650-670 nM; whereas when activated by red light it is transformed into P fr with an absorbance maximum of 730 nM.
AFA Phytochrome Description and Purification
AFA-phytochrome, while having a relatively unique structure, has a biliprotein as its chromophore that absorbs light in the red/far-red spectrum. To establish its structure and activities we have purified the phytochrome with the following protocol:
Suspend 1 g of extract in 10 ml of 1 K-phosphate buffer, pH 7.0. Vortex twice for 1 min with half their volume. Incubate cells for 35′ with 2% Triton X 100. Centrifuge at 28000 rpm for 16-18 h. Collect supernatant on a sucrose density step gradient. Spin the gradient using swing-out rotors at 150000 g for 12 h. Store at −20° C.
The phytochrome corresponds to the lysate band of an intense orange color, which is visible at approximately 1M of sucrose, while the phycobilisome stands at approximately 0.75M. This relation of the two bands also gives a reliable indication about the molecular weight of the phytochrome present in the algae, which is about 4 times that of the trimeric AFA-PC: the latter being 121Kd, we can preliminarily establish the MW of AFA-phytochrome at approximately 480Kd ( FIG. 15 )
Tested for its light-absorbing properties, the phytochrome shows to absorb light with two peaks at 672 nM and 694 nM, which corresponds respectively to P r (red-light absorbing) e P fr (far-red light absorbing) forms in a state of balance ( FIG. 16 ).
As to the quantity of phytochrome contained in AFA, our first evaluation gives the following preliminary result: 2 mg./gr. (or 0.2% DW). As to the extracts, the concentration increases to approximately 0.5% in the Basic Extract, and approx. 1% in the Extract B.
Antioxidant Activity
The purified AFA-phytochrome has shown to be a very powerful antioxidant. The incubation for 2 hrs. of human plasma samples with oxidative agent CuCl 2 at 100 μM generates increased levels of malondialdehyde (MDA), a late byproduct of lipid peroxidation which is measured through spectrophotometer at 535 nm after a reaction with thiobarbituric acid (TBA test). When plasma is incubated for 2 hrs at 37° C. with CuCl 2 100 μM together with increasing quantities of AFA-phytochrome (2-16 nM) extracted from AFA algae, it is possible to observe a very strong dose-dependent reduction of the MDA levels ( FIG. 17 ). In fact, we obtain an almost complete inhibition of lipoperoxidation, with MDA levels close to control, with just 16 nM of AFA phytochrome. It is remarked that the IC50 of 3.6 nM is 45 times less than the IC50 obtained for the PCB. There is no doubt that the phytochrome herein described is responsible for the higher antioxidant activity observed with the Basic Extract compared to the AFA-PC.
B) Identification of “Mycosporine-Like Aminoacids” (MAAs) of Klamath Algae
MAAs are water soluble compounds, characterized by a cyclohexenone or cyclohexenimine chromophore conjugated with a nitrogen atom substituting for an amino acid or its amino alcohol (as shown in FIG. 4 ).
They have an absorption maximum ranging from 310 to 360 nm and an average molecular weight of around 300 (4). MAAs are passive sunscreens, preferentially absorbing UV photons followed by a dissipation of the absorbed radiation energy in the form of harmless heat without generating photochemical reactions and thereby protecting, at least partially, photosynthesis and growth of phototropic organisms. Besides having a role in UV screening, it has been demonstrated that several MAAs also show antioxidant properties acting as scavengers of photodynamically generated reactive oxygen species in organisms (5).
We tested the presence of MAAs in the cyanophyta Aphanizomenon flos - aquae and its extract. Whereas most of the cyanobacteria reported to date contain shinorine as their primary MAAs; we found a rare occurrence of porphyra-334 as the primary MAA in Aphanizomenon flos - aquae in addition to a small amount of shinorine.
Extraction, Purification and Quantification of MAAs
MAAs were extracted as previously reported (6). Briefly, 20 mg of AFA powder or 20 mg of extract were extracted in 2 ml of 20% (v/v) aqueous methanol (HPLC grade) by incubating in a water bath at 45° C. for 2.5 h. After centrifugation (5000 g; GS-15R Centrifuge, Beckman, Palo Alto, USA), the supernatant was evaporated to dryness and re-dissolved in 2 ml 100% methanol, vortexed for 2-3 min and centrifuged at 10000 g for 10 min. The supernatant was evaporated and the extract re-dissolved in the same volume of 0.2% acetic acid for the analysis in HPLC or in 200 μl of phosphate buffer (PBS) for the evaluation of antioxidant properties. The samples were filtered through 0.2 μm pore-sized syringe filters (VWR International, Milan, Italy) before being subjected to HPLC analysis, or to the test of antioxidant properties (see below).
The MAAs of AFA and of its extracts, have an absorption maximum of 334 nm. Further purification of MAAs was done using a HPLC system (Jasco Corporation, Tokyo, Japan) equipped with a Alltima C18 column and guard (4.6×250 mm i.d., 5 μm packing, Alltech, Milan, Italy), according to the literature (7). The wavelength for detection was 330 nm; the mobile phase was 0.2% acetic acid at a flow-rate of 1.0 ml min −1 . Identification of MAAs was done by comparing the absorption spectra and retentions time with standards such as Porphyra and Pterocladia sp., mainly containing porphyra-334, shinorine and palythine, kindly provided by Dr Manfred Klisch, Friedrich-Alexander-Universitat, Erlangen, Germany. Absorption spectra of samples were measured from 200 to 800 nm in a single-beam spectrophotometer (DU 640, Beckman, Palo Alto, USA). The raw spectra were transferred to a computer and treated mathematically for the peak analyses of MAAs.
MAAs were partially purified from AFA sample and from the extract as described earlier. Extraction of samples with 20% methanol at 45° C. for 2.5 h resulted in a prominent peak at 334 nm (MAAs); even if small amounts of photosynthetic pigments (such as phycocyanin at 620 nm) were also extracted with this procedure (see the following figure, dashed line). MAA samples were further treated with 100% methanol in order to remove proteins and salts and finally with 0.2% acetic acid to remove non polar-photosynthetic pigments. The resultant partially purified MAAs had an absorption maximum at 334 nm ( FIG. 5 , solid line).
Further analysis and purification of MAAs was done by HPLC with a view to find whether the compounds absorbing at 334 nm was a single MAA or a mixture of more than one MAAs. The chromatogram of the sample ( FIG. 6 ) shows the presence of two MAAs with retention times of 4.2 (peak 1) and 7.6 min (peak 2) that were identified as shinorine and porphyra-334, respectively. Porphyra-334 seems to be the major MAA in AFA since shinorine was present only in small quantities (peak area ratio 1:15).
The UV spectra of the purified MAAs confirmed their absorption maximum at 334 nm ( FIG. 7 ). Taking into account that the molar extinction coefficients at 334 nm for shinorine and porphyra-334 are of 44700 and 42300 M −1 cm −1 , respectively, we calculated:
a) for Klamath algae, concentrations of 0.49 mg g −1 DW for shinorine and 7.09 mg g −1 DW for porphyra-334; the total MAA content being thus equal to 0.76% algal DW; b) for the extract, concentrations of 17-21 mg for MAAs (that is 1.7-2.1% DW).
These are significant data, as the whole algae AFA contains high constitutive level of MAAs (0.76% DW), close to the maximal concentration found under UV exposure, i.e. 0.84% (8). Also, we found that the extract has a much higher concentration than the whole algae, reaching levels that are much higher than the maximal potential concentration.
MAAs (shinorine and porphyra-334 in the extract) are structurally simple molecules, with a molecular weight of 300. This allows these water soluble molecules to easily cross the various barriers, from the intestinal membrane to the blood-brain barrier, confirming their ability to express their antioxidant activity anywhere is needed, from the gut to the brain.
Evaluation of the Antioxidant Effect of MAAs
To evaluate the antioxidant properties of the MAAs contained in the extract, samples of human erythrocytes have been incubated for 3 hrs at 37° C. with increasing quantities of MAAs (5-80 μM) together with 100 mM AAPH to induce the free radical chain formation with consequent oxidation of the membrane phospholipids with parallel increase of erythrocyte hemolysis, measured by dosing hemoglobin with the Drabkin's solution (33). The results are shown in FIG. 18 , where it is possible to observe how MAAs cause a dose-dependent reduction in erythrocyte hemolysis induced by AAPH, thus protecting the cell from oxidative damage.
In the same way, the incubation of the plasma samples with oxidative agent (CuCl 2 100 μM) generates increased levels of malondialdehyde (MDA), a late byproduct of lipid peroxidation which is measured through spectrophotometer at 535 nm after a reaction with thiobarbituric acid (TBA test). When plasma is incubated for 2 hrs at 37° C. with CuCl 2 100 μM together with increasing quantities of MAAs (5-80 μM) extracted from AFA Klamath, it is possible to observe a dose-dependent reduction of the MDA levels, as shown in FIG. 19 . With a concentration of MAAs equal to 80 μM MDA levels are obtained very similar to those of the non-oxidated plasma (control).
Both tests allows us to state that MAAs from AFA are true antioxidant molecules conferring to the extract more power as a scavenger of free radicals besides that deriving from its phycocyanins.
C) Determination of Further Synergic Factors that Make the Extract More Powerful than the Phycocyanins Contained in it.
AFA Klamath algae contain a wide matrix of nutrients endowed with different functional activities. In particular, Klamath algae and the extract contain important active principles such as chlorophyll; beta-carotene and other pro-vitamin A carotenoids; xantophyllic carotenes such as canthaxanthin; antioxidant vitamins and minerals.
Chlorophyll
In the last few years there has been a strong development in the research on a molecule, chlorophyllin (CHLN), which is a semi-synthetic analog of chlorophyll (CHL). Various studies have demonstrated significant antioxidant properties of CHLN, notably higher than the more common antioxidant (vitamins C and E, GSH, etc.), particularly in relation to essential organs such liver and brain (9). The antioxidant property is associated to a specific antinflammatory property, due to the ability of CHLN to selectively inhibit COX-2 (10). Chlorophyll's ability to selectively inhibit COX-2, together with the same ability by phycocyanins, makes the extract particularly powerful as a natural anti-inflammatory. This also helps explaining the fact, that the extract is a more powerful COX-2 inhibitor than the phycocyanins contained in it.
More generally, CHLN has shown anti-mutagenic (11). and anti-proliferative properties in relation to various types of tumor, such as those of the liver (12), breast (13) and colon (14). Since phycocyanins also have significant anti-proliferative properties, the simultaneous presence of both molecules makes the extract a potentially significant anti-tumor product.
Even though most studies have been done on the semi-synthetic CHLN, given the close similarity of the two molecules, the same properties can be attributed also to natural chlorophyll. In fact, when the anti-proliferative capacity of the two molecules has been compared, natural CHL has shown to be significantly more powerful than CHLN; and at much lower concentrations (15).
The antioxidant, anti-inflammatory and anti-proliferative synergy of phycocyanins and chlorophyll contributes to the significant superiority of the AFA Klamath extract, considering that in Klamath algae the concentration of chlorophyll is one of the highest in nature, with a minimum of 1% (as opposed to a maximum concentration of 0.3% for the vegetables richest in chlorophyll like wheatgrass and other grasses).
The method to quantify chlorophyll a in AFA algae is based on the extraction of the pigment in an organic solvent after breaking the algal cells, and the subsequent spectrophotometric determination, as discussed in the literature (16).After using different types of organic solvents, we found methanol to have the best extraction ability. The sample (100 mg of AFA REFRACTANCE WINDOW 2 MESH 122/071005) has been suspended in 10 ml of 100% methanol, homogenized through a mechanical potter for 3′ and left on a rotating plate for 24 h at room temperature in the dark.
The resulting extract has been then centrifuged at 3000 rpm for 5′ at 4° C.; the supernatant had been collected and dosed, while the pellet has been again resuspended in 10 ml 100% methanol for a second time extraction. After 24 h at room temperature, the extract has been centrifuged at 3000 rpm for 5′ at 4° C., the supernatant has been collected and dosed, while the pellet has been again resuspended in 10 ml 100% methanol for a third time extraction. The chlorophyll a concentration in the three methanol extracts has been calculated by means of the following Porra equation (17), with the pigment having a characteristic absorption peak at 664 nm.
Chlorophyll a (μg/ml)=16.29×Abs 664
With the first extraction, we obtained a chlorophyll a concentration of 96.11 μg/ml; with the second and third extractions, concentrations of 4.63 and 0.68 μg/ml. The total content of chlorophyll a in the AFA sample is therefore of 101.42 μg/ml, or 10.14 mg/g DW (1.014% DW).
By using the same methodology described above, we found that in the Basic Extract there is an approximate reduction of the chlorophyll content of 50%, thus with a concentration of around 0.5%.
Carotenes
Klamath algae has a high content of carotenes, expressed in beta-carotene. Moreover, it contains a wide spectrum of carotenes, both precursors and non-precursors of vitamin A. Among the non-precursors, Klamath algae has a particularly significant content of canthaxanthin:
Klamath algae Total carotenes as beta-carotene=1600 mg/Kg
Canthaxanthin=327 mg/Kg
Basic Extract Total carotenes as beta-carotene=420 mg/Kg
Canthaxanthin=41 mg/Kg
Extract B Total carotenes as beta-carotenes=2400 mg/Kg.
The above numbers are an average of different tests on different batches of product over the years. The concentration of carotenes in the Basic Extract is clearly reduced, although it remains significant. Most of all, the carotenes in the algae and its extract are highly assimilated by our organism, because they are from a natural food source which does not have any cellulose membrane nor other factors that in common vegetables partially inhibit assimilation. Plasma retinol is the active form of vitamin A, and it has shown to have important antioxidant properties, and to be able to protect various systems of our organism, from the eye to the liver, from the mouth to the nervous system (18).
Particularly interesting is the content of canthaxanthin, a carotenoid endowed with an antioxidant action higher than beta-carotene itself relative to ROS (19), and intermediate between beta-carotene and lycopene (maximum effect) and lutein and zeaxanthin (minimum effect) in relation to the singlet oxygen (20). Canthaxanthin possesses also strong anti-lipoperoxidation properties (21), synergic with the same properties of the phycocyanins and chlorophyll contained in the algae and its extract. This synergy helps explain the fact that the extract, in terms of antioxidant and anti inflammatory activity, is more powerful than the purified phycocyanins contained in it.
Testing the Basic Extract vs. AFA-Phycocyanins and PCB.
Basic Extract's Inhibition of TBARS Formation from Oxidative Damage by CuCl 2
The antioxidant power of the extract, with a standardized content of AFA's PC, has been compared also with that of the purified PC itself, as well as with that of the purified chromophore phycocyanobilin (PCB), the active prosthetic group of the PC. The tests on the malonyldialdehyde (MDA) formation generated by the oxidation of plasma with CuCl 2 show that the extract has a higher antioxidant power than the pure PC and its chromophore PCB, due to the presence in the whole extract of other active antioxidant molecules; while PC and PCB have a similar antioxidant capacity, with a degree of inhibition of MDA formation of 30-40% at a concentration of 100 nM, the Basic Extract, with a similar concentration of 100 nM of PC generates a degree of inhibition of up to 89% ( FIG. 20 ).
Also in the formation of conjugated dienes after oxidation of plasma with CuCl2 the Basic Extract at a concentration of 100 nM PC has an antioxidant capacity significantly higher than the pure PC at the same concentration of 100 nM. FIG. 21 shows indeed that, contrary to the pure PC, with the extract the formation of conjugated dienes is practically completely inhibited. Again, this shows how the Basic Extract is significantly more potent than the pure PC, clearly due to the presence in it of other active molecules, in particular the AFA-phytochrome.
Pre-Incubated Basic Extract's Inhibition of TBARS Formation from Oxidative Damage by CuCl2
When the AFA extract was pre-incubated with the samples of human plasma, the subsequent incubation of the same samples with the oxidative agent CuCl 2 at 100 μM, the oxidation of the lipoproteins, as measured by the production of the early by-products conjugated dienes through a spectrophotometer at 245 nm), was strongly reduced in a dose-dependent manner. The progressive diminution of the oxidation, oxidation which moreover develops after a first lag-phase in which the formation of dienes is inhibited by the extract, reaches a level of almost complete inhibition with a PC concentration of just 150 nM in the extract ( FIG. 22 ).
The oxidation of plasma lipids with CuCl 2 produces also, at a later stage, the formation of malonyldialdehyde or MDA. The pre-incubation of plasma with the AFA extract also generates a dose-dependent reduction of the MDA levels, so strong that with a PC concentration of just 100 nM we obtained MDA values wholly comparable with those of non-oxidated or control plasma (# p<0.05) ( FIG. 23 ).
ORAC Evaluation of the Basic Extract
To evaluate the antioxidant capacity of the extract in terms of the ORAC test, we used the same methodology we used to test the ORAC for PC and PCB. In order to test both the water soluble and the lipid soluble components of the AFA extract, we first prepared the two water and lipid soluble extracts, as follows.
Preparation of the Water Soluble Extract
Weigh 10 mg of extract in 1 ml of distilled water and homogenize for 1 min through a mechanical potter. Centrifuge at 2500 rpm for 10′ at 4° C. to remove cellular debris. Collect the supernatant and resuspend the pellet in 1 ml of water. Homogenize for 1 min with a mechanical potter. Centrifuge at 2500 rpm for 10′ at 4° C. Collect the supernatant and mix with that obtained from the first water extraction. Preserve the water extract (with a blue color for the presence of the PC) at +4 o-20° C.
Preparation of the Lipid Soluble Extract
Resuspend the pellet obtained from the previous extraction in 1 ml of acetone. Homogenize for 1 min with a mechanical potter. Centrifuge at 2500 rpm for 10′ at 4° C. Collect the supernatant and resuspend the pellet in 1 ml of acetone. Homogenize for 1 min with a mechanical potter. Centrifuge at 2500 rpm for 10′ at 4° C. Collect the supernatant and mix with that obtained from the first extraction with acetone. Preserve the lipophilic extract (with an orange color for the presence of carotenes) at +4°-20° C.
FIG. 24 shows the decay of the fluorescence caused by AAPH in the absence (blank) and presence of the two extracts relative to the reference standard Trolox. Based on the measurement of the areas under the curve, we obtained an ORAC for the water soluble extract of 828 μmol Trolox equiv/g dry weight; and for the lipid soluble extract of 468 μmol Trolox equiv/g dry weight. This means that the total ORAC capacity is of 1296 μmol Trolox equiv/g dry weight.
In Vivo Studies
Effect of the Supplementation with an AFA Algae and AFA Extract on the Plasma Levels of MDA, GSH and Retinol in Healthy Subjects.
The following study was done with a formula mostly based on AFA algae and an AFA alga extract. Even though it was also containing gastrointestinal factors such as lactobacillus acidophilus and proteolytic enzymes, the antioxidant activity is to be attributed mostly to the algal factors.
Eight relatively healthy subjects freely volunteered to participate in the study: 4 men and 4 women, age 23 to 63, whose clinical history did not show any serious previous pathology, gastrointestinal, glycemic or otherwise. None of the subjects was following any special dietary or caloric restrictions, none was vegetarian, and during the supplementation no food or lifestyle modification was suggested.
Before the study started, the participants underwent objective medical analysis and evaluation of their medical history, which for the most part showed only the presence of some of the ailments, presumably of a neurovegetative nature, commonly found in the population, such as episodes of dyspepsia, generic gastrointestinal irregularities, occasional headaches, sense of heaviness after a meal, occasional events of painful joints, some instances of premenstrual syndrome.
The nutritional formula used in the study was administered in “0” vegetable capsules, containing 500 mg of powder thus composed: AFA Klamath lake algae, 200 mg; AFA extract, 100 mg; Lactobacillus Acidophilus DDS-1 (10 bill. CFU/gr), 100 mg; fermented maltodextrines with proteolytic activity, 100 mg. Each participant, starting at day 0, has taken 9 capsules a day, 3 capsules with each meal.
The blood samples were taken in heparinized vacutainers at time 0, after 1 month, and after 3 months, and each sample was divided in two parts. One part was analyzed by the Analytical Laboratory of the Hospital of Urbino for the most common parameters: emocromocytometric exam with automatic system and COULTER principle (impedenziometric), proteic and lipidic assay with automatic system and Dry Chemistry, enzymatic test for the functioning of liver, heart and kidney, thyroid profile through automated instruments based on immunophelometric and chemiluminescence principles, lymphocytes immunophenotyping through flow citometry.
The other part of the blood sample was used to test the levels of lipoperoxidation through measurement of MDA and of the antioxidants reduced glutathione (GSH), vitamin E (.-tocopherol) and vitamin A (retinol). Blood samples have been processed through centrifugation at 3000 r.p.m. for 10 minutes at +4° C., and the plasma thus obtained has been stocked at −20° C. to be used as follows. Plasmatic MDA was measured through a spectrophotometer at 535 nm according to the TBARS (thiobarbituric acid-reactive substances) methodology (28). GSH dosage was based on the GSH ability to reduce the disulfide DTNB (5,5′-dithiobis 2-nitrobenzoic acid) (29). In its reduced form, DTNB (c.e.m. 13600 M −1 cm −1 ) develops an intense yellow color, which is measured at 412 nm. Plasma levels of α-tocopherol and retinol have been determined through HPLC (Jasco Corporation, Tokyo, Japan) as described in (30) by utilizing an Alltima C18 column (5 μm, 250 mm×4.6 mm i.d.; Alltech, Italia) preceded by an Alltech pre-column (7.5×4.6 mm i.d). The chromatographic profiles have been analyzed with the Borwin 1,5 software (Jasco Corporation, Tokyo, Japan).
The results obtained on the three parameters tested, concerning the oxidative/antioxidant status of the subjects, are shown in FIG. 25 .
It is important the fact that the very positive results on the antioxidant status and on lipoperoxidation generated by the supplementation with the product have been obtained without introducing any dietary or lifestyle modifications. AFA-phycocyanins, phytochrome and the MAAs present in the AFA algae, and further concentrated in the AFA extract, perform also a strong positive control as a free radical scavenger, and thanks to the high level of chlorophyll, carotenoids and other antioxidant vitamins and minerals present in the AFA algae and its extract, the product proposes itself as a powerful enhancer of the general antioxidant activity in the human body.
The results can be summarized as follows:
a) there is a very high average increase in plasma retinol, namely +60% after 3 months of supplementation; b) there is an impressive decrease in the plasma levels of MDA −35.5%), one of the most significant markers of lipoperoxidation. This result strongly confirms in vivo, the very impressive results in vitro shown above; c) The overall antioxidant protection afforded by the product helped also the body to generate a significant increase in endogenous GSH (+16.8%).
Effects of the Supplementation with an AFA and AFA Extract-Based Product on Patients Undergoing Hyperbaric Treatment.
The hyperbaric oxygen therapy is used successfully for the treatment of several clinical conditions, such as decompression derived illnesses, carbon monoxide intoxications, gaseous embolisms and tissue infections. The exposition to hyperbaric oxygen, indeed, generates a favorable increase of the oxygen dissolved in the blood. Yet, together with a beneficial action, there can also be an increase of the circulating ROS (reactive-oxygen species) which can damage cells and tissues, if not protected by sufficient antioxidant defenses (34). This is why patients undergoing hyperbaric therapy are generally supplemented with antioxidant vitamins.
To evaluate the effects of the AFA and AFA Klamath extract-based formula on the oxidative stress induced by hyperbaric therapy, 9 patients of the “Centro di Terapia Iperbarica” of Fano (Italy) have been enrolled in the study. Among the 9 patients there were 5 males and 4 females, between 16 and 73 years of age, and affected by different pathologies like aseptic osteonecrosis of the femur (n=5), rheumatic polymyalgia (n=1) and femoral and tibial ostheomyelitis (n=3).
These patients have been supplemented with the same product described above. Starting from the first hyperbaric session, the patients have started taking 6 capsules a day divided among the three main meals.
The collection of the blood samples from each patient has been performed immediately before and after the 1 st and the 15 th hyperbaric session. The samples have then been evaluated for their content of some oxidation markers, such as MDA, carbonyls, AOPP, as well as plasma thiols, liposoluble vitamins and the total antioxidant level of the plasma itself.
The results show that in the patients supplemented with the formula the hyperbaric treatment does not generate any increase in the oxidative markers even after 15 sessions ( FIG. 26 ) In fact, considering that there is usually a significant increase in those markers with progression of the therapy, here we actually see a 7.8% decrease, from the 1 st to the 15 th session, of the MDA levels (lipoperoxidation), with values moving from 1.54±0.17 μmol/l (1 st session) to 1.42±0.16 μmol/l (15 th session) (p<0.05); a 20.5% decrease of the AOPP (late byproducts of the oxidation of proteins), with values moving from 105.7±18.8 μmol/l (1 st session) to 84.0±15.5 μmol/l (15 th session) (p<0.05); while the protein carbonyls (early byproducts of the oxidation of proteins) remain unchanged ( FIG. 26 ).
The general antioxidant profile too is maintained during the hyperbaric treatment. The plasma levels of the total thiols (SH groups of glutathione and proteins) increase 8.3% (p=n.s.), with values that move from 254±18 μmol/l (1 st session) to 275±30 μmol/l (15 th session). At the same time we see a significant increase (p<0.05) of the total antioxidant status of the plasma, with values moving from 1.19±0.03 mmol/l Trolox equivalents (1 st session) to 2.04±0.03 mmol/l Trolox equivalents (15 th session), as shown in FIGS. 27 and 28 .
Given that the plasma levels of the most common antioxidants (tocopherols, carotenoids, retinol) remain unchanged, we can suppose that the increase in the total antioxidant status is due partly to the replenishment of the antioxidant consumed, such as carotenoids and retinol, by the same nutrients provided by the formula; and by the parallel accumulation in the circulatory system of specific algal antioxidants such as phycocyanins, phytochrome, MAAs and chlorophyll. Altogether, the AFA and AFA extract based formula greatly increases antioxidant defenses, efficiently protecting the patients undergoing hyperbaric therapy from the increase of free radicals produced by hyperbaric oxygen.
Antiinflammatory Activity
In vitro Studies.
Cyclooxygenase enzymes (COX) catalyze the first step in the synthesis of eicosanoids such as prostaglandins (PG), thromboxanes and prostacyclins. There are two different isoforms of this enzyme: COX-1 is involved in the normal regulation of homeostasis; whereas COX-2 is responsible for the production of PGs, which in turn promote acute inflammation.
Phycocyanins from blue-green algae have a powerful antinflammatory activity. It has been shown that phycocyanins from the microalga Spirulina Platensis are efficient selective inhibitors of COX-2 (35), and that they inhibit in a physiological and partial manner the cascade that from the fatty acids leads to the formation of inflammatory eicosanoids (36).
Given that the phycocyanins from Klamath AFA algae are different from the ones from Spirulina , ands that no test has ever been done on their effect on the COX enzymes, we decided to perform such test through the immunoenzymatic kit “COX Inhibitor Screening Assay” of the Cayman company. We thus evaluated the COX-1 and COX-2 inhibition by the AFA extract (both the water soluble part in water, and the lipid soluble in acetone; range 25-200 μg/ml); by the pure PC (0.03-3 μM) and PCB (0-15 μM). The results are shown in FIG. 29 , presenting the graphic of the percent activity of COX-1 and COX-2 at the different concentrations of AFA extract, PC and PCB.
The liposoluble fraction of the AFA Basic Extract selectively inhibits COX-2 with an IC 50 of 134 μg/ml, while the COX-1 increases. The water-soluble fraction too selectively inhibits COX-2 with an IC 50 of 84.5 μg/ml; whereas the COX-1 is only moderately inhibited (30% inhibition for 200 μg/ml of AFA extract).
The pure PC acts on both enzymes, but even in this case the inhibition is preferential for the COX-2 relative to the COX-1, being the activity on the COX-2 almost 10 times higher than that on the COX-1 (IC 50 0.15 vs. 1.1 μM). Finally, the chromophore PCB increases the COX-1 activity and is scarcely inhibitor of the COX-2.
We thus confirmed that also the phycocyanins of AFA Klamath algae are powerful antinflammatory molecules, capable of a significant selective inhibition of COX-2. It is also interesting to notice that the COX inhibition is produced not only by the water soluble extract, containing phycocyanins, but also by the lipid soluble extract, thus indicating that other molecules present in the AFA extract.
Here we can also propose some comparative considerations with the studies that have been performed on the phycocyanins from Spirulina . In the study by Reddy et al., the IC 50 for the phycocyanins from Spirulina Platensis is reported to be 0.18 μM, against the 0.15 μM of the phycocyanins from Klamath. Apart from this slight difference in favor of the Klamath PC, there is a further and more relevant difference to underline. At 1 μM the phycocyanins from Spirulina generate a COX-2 inhibition around 60%; while the phycocyanins from Klamath, at the same concentration of 1 μM, generate an inhibition of around 75%. This is a substantial difference, showing that AFA phycocyanins can generate faster and more profound antinflammatory effects.
Also, the percentage of inhibition produced by AFA phycocyanins is midway between the lower level of Spirulina 's PC and the higher level of drugs such as celecoxib and rofecoxib (37). This means that the degree of COX-2 inhibition produced by Klamath algae's PC is ideal: high enough to produce a fast and effective antinflammatory activity, yet still partial and thus physiological to avoid the typical cardiovascular side effects of the drugs.
Also very relevant is the COX-2 inhibition activity of the AFA extract. As shown by the figures, the liposoluble component has a significant degree of inhibition (IC 50 134 .g/ml), even though lower than that of the water soluble component, together an activity of promotion of the COX-1. This creates and interesting result, because if the inhibition of the COX-2 reduces the production of inflammatory eicosanoids, the stimulation of the COX-1 increases the endogenous production of the antinflammatory eicosanoids, thus doubling the total antinflammatory effect. This makes the liposoluble fraction of AFA Basic Extract a unique antinflammatory agent, endowed with important pharmacological properties. The present patent also protects the nutritional and pharmacological use of any liposoluble extract from Klamath algae.
If then we look at AFA Basic Extract as a whole, the combined activity of the water soluble and lipid soluble components generates a significant inhibition of the COX-2, given that both act as powerful COX-2 inhibitors; and a substantial maintenance of the same level of the COX-1, resulting from the reduction of the COX-1 produced by the water soluble component on the one hand (−30%), and the stimulation of the COX-1 produced by the liposoluble component (+45%). The IC 50 for the AFA extract as a whole is around 100 .g/ml (the average of the two components), while at the dosage of 200 .g/ml there is a COX-2 inhibition of approximately 75%. This is the level of per cent inhibition discussed above in relation to the pure PC, and the consideration presented there acquire a particular meaning in light of the fact that 200 .g/ml in vitro can plausibly correspond to an in vivo dosage of just 600-800 mg (38). Even while waiting for experimental confirmations, we can plausibly state that the AFA extract, at dosages easily reached with just 1-2 capsules/tablets a day, constitute a powerful antinflammatory agent, endowed of therapeutic properties, nutriceutical and pharmacologic, really unique. These properties have been confirmed by an in vivo animal study.
In vivo Study
In this study we investigated the antinflammatory properties of an algal extract containing PC (AFA extract) in male Swiss albino mice subjected to a pro-inflammatory stimulus with capsaicin 0.25 .mol/kg (the active principle of chili pepper) or with substance P 2 nmol/kg (acting with the receptors responsible for the inflammatory neurogenic response). The tissues inflammation levels have been measured through a spectrophotometric dosage of the coloring agent Evan's Blue accumulated in the inflammation sites as a consequence of the outflow of the plasma proteins in the tissues. As shown in FIG. 30 , the intravenous injection of capsaicin (0.25 .mol/kg) or SP (2 nmol/kg) induces and increase in the outflow of plasma in the examined tissues relative to that observed in the control mice not subjected to the inflammatory stimulus. The pre-treatment of the mice with the AFA extract (1600 mg/kg or 800 mg/kg) significantly inhibits the outflow of plasma, bringing it down to values equal to the control group.
Indeed, the injection of capsaicin induces an increase of plasma outflow both in the stomach (23.2±0.2 vs. 29.9±0.5 ng EB/g of tissue, p<0.05) and in the urinary bladder (33.2±5.2 vs. 39.9±1.8 ng EB/g of tissue, p<0.05). The pretreatment of the mice with 1600 mg/kg of AFA extract induces a significant decrease of plasma proteins outflow in both tissues, with values of 23.6±0.2 ng EB/g in the stomach and 30.6±2.3 ng EB/g in the urinary bladder.
In a similar way, the injection of SP induces a significant increase of plasma outflow in the stomach (13.5±1.1 vs. 22.1±1.8 ng EB/g of tissue, p<0.05) and in the duodenum (17.2±1.2 vs. 24.0±1.8 ng EB/g of tissue p<0.05). The pre-treatment of mice with 800 mg/kg of AFA extract decreases the plasma proteins outflow with values of 20.1±1.3 ng EB/g in the stomach (p=n.s.) and 16.7±1.9 ng EB/g in the urinary bladder (p<0.05) ( FIG. 31 ).
Antiproliferative Activity
In the literature it has been reported that the pure PC from the microalga Spirulina possesses in vitro a significant property to inhibit the growth of tumor cellular lines such as the leukemia cell lines (39) and the macrophagic cellular lines (40), through an apoptotic mechanism.
We then tested the antiproliferative activity of pure AFA-PC, with its C-PC/PEC complex, on the monocyte-macrophagic RAW 264.7 tumor cell line by incubating the cells with increasing dosages of PC (range 0-25 μM). The analysis of the vitality of the cells after 24, 48 and 72 hrs. of incubation has shown that AFA-PC has a very significant dose and time dependent antiproliferative effect, as results from FIG. 32 .
AFA Extract's Dermatological and Cosmetic Properties
Given the antioxidant and antinflammatory properties of the phycocyanins and other synergic molecules in AFA Klamath algae and its extracts, it is evident that, beside the oral administration for nutritional and pharmacological purposes, they can also be used topically on the skin, both for dermatological therapeutic uses and for cosmetic purposes.
Occlusive Patch Test (Irritation Test)
As a preliminary study, we tested Klamath AFA algae toxicologically, to establish that its dermatological use does not create any toxic or inflammatory reaction. The test has been performed at the “Centro di Cosmetologia” of the University of Ferrara, Italy. The “occlusive patch test” has been performed in order to evaluate the irritant effect of the cosmetic product when applied in a single dose to the intact human skin. The test has been run on 20 healthy volunteers of both sexes, which have given a written consent to the experimentation. The following subjects have been excluded from the test:
all subjects who participated in similar tests in the last two months;
all subjects affected by dermatitis;
all subjects with a history of allergic skin reaction;
all subjects under anti-inflammatory drug therapy (either steroidal or non-steroidal).
The test has been performed on the powder of AFA Klamath algae. To prepare the product for application, the powder has been mixed with distilled water and directly applied into a Finn chamber (Bracco) by using a syringe; then, it has been applied lo the skin of the forearm or the back of the participants protected by a self-sticking tape. The cosmetic product was left in contact with the skin surface for 48 hours, asking the participants not to wash the area where the product had been applied for the next 48 hours. Removal of the Finn chamber and cleaning of the skin area from residual cosmetic product was carried out by the experimenter. The evaluation of skin reactions was performed 15 min and 24 hours after the removal of the Finn chambers, according to the following scale:
Erythema: 0—Absent 1—Light 2—Clearly visible 3—Moderate 4—Serious Edema: 0—Absent 1—Light 2—Clearly visible 3—Moderate 4—Strong
The sum of erythema and edema score is defined “irritation index”. Irritation index values at 15 min. and 24 hours are recorded in the final report. The average irritation index of the 20 tests is calculated. The product was then classified according to the following parameters:
Average irritation
INDEX
CLASS
<0.5
non irritating
0.5-2.0
slightly irritating
2.0-5.0
moderately irritating
5.0-8.0
highly irritating
The results of the test on AFA Klamath algae, according to the methodology and parameters described above are:
“The tested product, applied diluted with distilled water (1:10) under occlusive conditions on the healthy skin of 20 volunteers resulted in a mean index of irritation of:
0.25 (zero. twenty five) 15 minutes after the removal of the Finn Chamber
0.15 (zero. fifteen) 24 hours after the removal of the Finn Chamber.
According to the evaluation scale used, the product Klamath Algae ( Aphanizomenon Flos Aquae ) can be classified as: not irritating”.
Efficacy Study
Once ascertained the non irritating and non toxic nature of the algae as a cosmetic and dermatological ingredient, we proceeded to prepare a cream containing 8% of the Klamath algae Basic Extract, to test its efficacy on cosmetic parameters such as skin elasticity, hydration and wrinkles. The test was conducted randomly on 15 individuals age 30 to 65. They were not chosen for specific dermatological or skin problems, and in fact on parameters such as volume of wrinkles the fact that most participants did not have serious wrinkles made the result statistically insignificant. Nevertheless, the results on wrinkles reduction, when wrinkles were actually present, was quite clear. The study, although not final on some parameters for lack of statistical significance, it is a preliminary report that strongly confirms the dermatological and cosmetic properties of the AFA extract, and which thus warrants further studies more clearly oriented to specific dermatological and skin problems. Here we present the methodology and main results of the study.
The test was performed comparing a product with 8% AFA extract with a placebo product constituted by the same vegetable base, but without the algae extract. We will call the two products:
a) Vegetable emulsion with AFA extract
b) Basic vegetable emulsion.
15 volunteers of female sex, with an age between 30 and 65 years old have been selected for the test, following the under mentioned inclusion criteria:
good state of general health; no dermatopathies; no pharmacological treatment in progress; promise not to change the usual daily routine; no atopy in the anamnesis.
The two products were applied by the participants themselves every day, one for each side of the face, as follows:
on the right side of the face (DX): vegetable emulsion with AFA extract; on the left side of the face (SX): basic vegetable emulsion.
The parameters that have been analyzed for this study were:
Skin elasticity Moisturization index Skin profilometry
The measurements of the parameters were done according the following scheme:
before product application (T0) after 15 (T15) and 30 (T30) days of products application.
Skin Elasticity
Skin elasticity was measured by means of CUTOMETER® SEM 575 (COURAGE+KHAZAKA electronic GmbH). The measurement of the elasticity has been done on a scale of 0 to 1, 1 representing the maximum elasticity possible.
Skin Moisturizing Index
The measurement of the skin moisture is based on the internationally recognized CORNEOMETER®. A healthy skin in normal room condition (20° C. and 40-60% air humidity) in the tested region should have a moisturizing index >50. moisturizing index in the range 35-50 reveals a dry skin, while inferior by 35 a very dry skin. These values are only indicative for the interpretation of the results.
Skin Profilometry
By means of VISIOSCAN VC 98 for the in vivo analysis of skin surface it is examined the reduction of the wrinkles ( FIG. 33 ). The parameters are:
SEr: roughness; SEsc: scaliness; SEsm: smoothness, is proportional to width and form of the wrinkles; Sew: wrinkles, is proportional to number and width of the wrinkles;
Volume: is proportional to the wrinkles depth, the deeper wrinkles are, the bigger is the volume parameter.
When the results on the various parameters were analyzed statistically through a multifactorial variance analysis (ANOVA) performed with the specific software Statgraphic plus (version 5.1), only for two parameters, namely skin elasticity and skin moisturization, statistically significant results were obtained. The conclusion that was reached by the researchers of the University of Pavia who performed the test under our instructions, was the following: “The use of the active product, applied on the right side of the face, caused a statistically significant increase of moisturization and elasticity, relative to the baseline values; whereas the treatment with placebo (left side), did not generate significant variations during the whole period of treatment.”
As for the above conclusion, there was no statistically significant result on the skin profilometry. However, this was due not to a failure of the product, but to the fact that most of the participants had starting conditions, at time 0, that made it impossible, given that their skin was already close to an optimal condition, any serious improvement. This has been the weak point of the study. However, when we made a selection of the participants who actually had a skin condition in need of improvement (without falling into a condition of dermatological pathology), and interpreted the results accordingly, we obtained the following results.
Skin Elasticity
Out of 15 participants, only 12 had elasticity conditions that were less than optimal. In fact, given an elasticity index of 0 to 1 (1 being the maximum possible), we had a range of values among the participants from 0.57 to 0.98. On the base of this range, we established 3 plausible categories:
0.9 to 1=optimal elasticity condition
0.75 to 0.9=medium elasticity condition
<0.75=low elasticity condition.
Taking into account a 30 days period of treatment, the graph of FIG. 34 reports the level of improvement as the passage of the participants from a lower to a higher level:
Of the 12 participants analyzed, at the beginning 4 had a low elasticity, and 8 a moderate or medium skin elasticity. After 30 days of treatment, there were no more participants with low elasticity; only 2 with medium elasticity, and the remaining 10 had moved up to high elasticity, with an impressive shift from 0 to 10 in this last category!
Skin Moisturization
A healthy skin in normal room condition (20° C. and 40-60% air humidity) in the tested region should have a moisturizing index >50. Moisturization values in the range 35-50 reveal a moderately dry skin, while the value <35 indicates a very dry skin. Taking these values as our interpretation standard, the graph of FIG. 35 reports the improvement realized in the 30 days period as the passage of the participants from a lower to a higher level:
Of the 15 participants, only 1 (blue color) had a very dry skin; 7 had a moderately dry skin; 7 had a normally moisturized skin. Even though only 8 out of 15 needed a real improvement, the final result shows that at the end of the period of treatment, there were no participants left with a very dry skin; the participants with moderately dry skin were reduced from 7 to 5; while the participants with a healthily moisturized skin moved from 7 to 10.
Skin Profilometry
As to the skin profilometry, some of the parameters tested were not usable because too many of the participants had initial or T0 values close to nothing. That is, when we looked at the Ser or akin roughness parameter, we saw that 12 out of 15 participants had an initial value of 0.0 or no skin roughness at all; and in relation to the parameter SEsc or skin scaliness, 10 out of 15 participants had a value of 0.0 or no scaliness at all. Therefore, we limited our evaluation to the two parameters of Sew, or number and width of wrinkles, and VOL, referring to the volume of the wrinkles measured in terms of the wrinkles' depth. Even here, since only 7 participants for the Sew and 9 for the VOL had initial values in need of correction, the remaining having values close to zero, we could not reach statistical significance. Nevertheless, the participants that had even slightly altered values had significant improvements, as shown by FIG. 36 .
Thus, in terms of reduction of the volume or depth of the wrinkles, we have a range of decrease in the 30 days period of treatment from −18% to −65%, a very significant level of achievement in terms of wrinkle's volume improvement.
In FIG. 37 , there is a reduction of the wrinkles number and width in the 30 days period of treatment that goes from −5% to −48%, again a significant result which justifies the claim of the potential efficacy of the AFA extract based cosmetic cream on wrinkles, and most of all that warrants the realization of more specific studies on wrinkles reduction, by selecting participants more specifically affected by this problem.
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44. Hughes J. Lamparter T., Prokaryotes and Phytochrome. The Connection to Chromophores and Signaling , in Plant Physiology , December 1999, Vol. 121, pp. 1059-1068. | The invention provides extracts of the microalga Aphanizomenon Flos Aquae Aquae Ralfs ex Born. & Flah. Var. flos aquae (AFA Klamath) and biologically active components thereof, in particular AFA-phycocyanins, determined as the complex c-phycopcyanin/phycoerythrocyanin (including the chromophore phycoviolobilin), AFA-phytochrome and mycosporine-like aminoacids (MAAs), nutritional, cosmetic and pharmaceutical compositions containing the same, for use in the prophylaxis or treatment of diseases, disturbances or conditions involving acute or chronic inflammation and oxidative degeneration of body cells or tissues or uncontrolled cell proliferation. | 0 |
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent application Ser. No. 14/238,695 filed Feb. 12, 2014, entitled “Device and Method to Accurately and Easily Assemble Glass Slides,” which claims priority to 35 USC §371 of PCT Application Serial No. PCT/US2012/51400, filed Aug. 17, 2012, entitled “Device and Method to Accurately and Easily Assemble Glass Slides,” which claims priority to U.S. Provisional Application No. 61/525,056, filed Aug. 18, 2011, entitled “Device and Method to Accurately and Easily Assemble Glass Slides,” which are each incorporated herein in their entirety by reference.
TECHNICAL FIELD
[0002] Embodiments of the present invention relate generally to laboratory devices and more specifically to systems and methods for the preparation and assembly of slide arrays for further experimentation.
SUMMARY OF THE EMBODIMENTS
[0003] According to some embodiments of the present invention, a device accepts a slide array that is to be assembled. A book-like hinged device can be constructed such that two surfaces with location points are exposed to facilitate the loading of two separate slides. One leaf of the book-like device is constructed such that it is a fixed mounting surface placed upon a bench top or other such piece of furniture. The other leaf of the book-like device is moveable from a fully open configuration to a full closed configuration, approximately 180 degrees of motion. Upon closing the hinge, the action brings two slides together in an accurate, repeatable, and easily managed manner. In the preferred configuration, a vacuum chuck on the moveable leaf of the book-like device holds a moveable slide firmly in place prior to its placement on top of a fixed slide. A spring loaded catch on the upper, moveable portion of the device can also maintain a hold on a slide during operation. The vacuum is applied on command of the operator. The closing of the book-like device brings the moving slide and the fixed slide into close but not intimate contact. Once the operator releases the vacuum upon command, the two slides are brought into final, resting position with a minimum of impact.
[0004] According to some embodiments of the present invention, the slide array is to be assembled inside of a separate carrier to allow further processing. The fixed slide is to be assembled inside of the carrier and then placed on a tooled spot on the fixed leaf of the book-like device. Further processing can include the application of an additional carrier on the top slide and the addition of a screw-type clamp to fixate the slide array.
[0005] According to some embodiments of the present invention, the slides described herein are composed of a transparent glass. The invention is not limited to the size of glass slide normally encountered in normal laboratory operations. The slides can be of a large variety of sizes and shapes. The slides need not be of identical sizes, smaller slides can be placed on a larger slide or vice versa. The slides need not be composed of transparent glass, other materials such as metals or plastics can be accurately assembled using the herein described device.
[0006] Various modifications and additions can be made to the exemplary embodiments discussed without departing from the scope of the present invention. For example, while the embodiments described above refer to particular features, the scope of this invention also included embodiments having different combination of features and embodiments that do not include all of the above described features.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1 illustrates an accurate slide assembly device 100 , according to the embodiments of the present invention.
[0008] FIG. 2 illustrates an accurate slide assembly device 100 , with a Hybridization chamber base installed in the loading position, according to the embodiments of the present invention.
[0009] FIG. 3 illustrates an accurate slide assembly device 100 , with a hybridization gasket slide loaded into the Hybridization chamber base, according to the embodiments of the present invention.
[0010] FIG. 4 illustrates an accurate slide assembly device 100 , with an experimental slide loaded into the vacuum chuck on the moveable arm, according to the embodiments of the present invention.
[0011] FIG. 5 illustrates an accurate slide assembly device 100 , with the vacuum producing cylinder depressed, according to the embodiments of the present invention.
[0012] FIG. 6 illustrates an accurate slide assembly device 100 , with the vacuum producing cylinder extended after release, producing a vacuum under the experimental slide, according to the embodiments of the present invention.
[0013] FIG. 7 illustrates an accurate slide assembly device 100 , with the moveable arm partly rotated into the slide dropping position, according to the embodiments of the present invention.
[0014] FIG. 8 illustrates an accurate slide assembly device 100 , with the moveable arm further deployed into the slide dropping position, according to the embodiments of the present invention.
[0015] FIG. 9 illustrates an accurate slide assembly device 100 , with the moveable arm in its final position prior to the release of the experimental slide, according to the embodiments of the present invention.
[0016] FIG. 10 illustrates a detailed view of an accurate slide assembly device 100 , with the experimental slide still held on the vacuum chuck slightly above the hybridization gasket slide just prior to final placement, according to the embodiments of the present invention.
[0017] FIG. 10 A is a close up view of the indicated portion of the accurate slide assembly device of FIG. 10 .
[0018] FIG. 11 illustrates an accurate slide assembly device 100 , with the experimental slide and the hybridization gasket slide in contact after the release of the vacuum in the vacuum chuck, according to the embodiments of the present invention.
[0019] FIG. 11 A is a close up view of the indicated portion of the accurate slide assembly device of FIG. 11 .
DETAILED DESCRIPTION
[0020] Unless otherwise indicated, all numbers expressing quantities of ingredients, dimensions reaction conditions and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.”
[0021] In this application and the claims, the use of the singular includes the plural unless specifically stated otherwise. In addition, use of “or” means “and/or” unless stated otherwise. Moreover, the use of the term “including,” as well as other forms, such as “includes” and “included,” is not limiting. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one unit unless specifically stated otherwise.
[0022] With reference to FIG. 1 , the Accurate Slide Assembly Device (ASAD) 100 consists of a base 101 whereby the static slide assembly tooling base 102 is solidly affixed in place, according to the embodiments of the present invention. Attached to the tooling base 102 is the moveable arm 103 via hinge 105 that keeps the respective tooling points, lower hybridization tooling area 108 and upper slide chuck 110 , in accurate registration or alignment with one another, according to the embodiments of the present invention.
[0023] With reference to FIGS. 1 , 2 , and 4 , Groove 107 (as shown in FIG. 1 ) allows the placement of a flexible seal 111 (as shown in FIG. 2 ), such as an o-ring, into the upper slide chuck 110 to provide a vacuum to be held in the vacuum space 106 once an experimental slide 113 (as shown in FIG. 4 ) has been placed in the upper slide chuck 110 , according to the embodiments of the present invention. With reference to FIG. 4 , hard tooling points 115 fix the experimental slide 113 in a tightly constrained location, according to the embodiments of the present invention.
[0024] With reference to FIG. 3 , lower slide receiver 112 is the part of the Hybridization chamber base fixture that receives the hybridization gasket slide 114 . Hybridization gasket slide 114 preferably includes several of chambers thereon in which material for processing may be added. Each chamber may be surrounded by a gasket or a flexible seal (similar to the flexible seal 111 above). Once the hybridization gasket slide 114 has been prepared by adding material to the surface, the operation of the ASAD 100 can commence, according to the embodiments of the present invention.
[0025] With reference again to FIG. 4 , the experimental slide 113 is held in place against the o-ring 111 (as shown in FIG. 2 ) after a vacuum is imposed in the open volume or vacuum space 106 (as shown in FIGS. 1 & 2 ). In the present configuration, as illustrated in FIGS. 4-6 , the vacuum is generated by manually pushing button 109 down on the spring return cylinder 104 and then releasing the button 109 to allow the spring to drive the piston inside of the cylinder 104 upwards. A flexible tube 117 connects the cylinder generated vacuum to the open volume or vacuum space 106 (as shown in FIGS. 1 & 2 ) in the moveable arm 103 , according to the embodiments of the present invention.
[0026] With reference to FIGS. 7-9 , once the experimental slide 113 is firmly seated against the o-ring 111 (as shown in FIG. 2 ) and sufficiently registered in the hard tooling points 115 , the moveable arm 103 can be articulated by rotation and the experimental slide 113 can be placed over the hybridization gasket slide 114 and inside of the lower slide receiver 112 , according to the embodiments of the present invention. The moveable slide (e.g., experimental slide 113 in this embodiment) is located in a controlled position so that as the slides (e.g., experimental slide 113 and hybridization gasket slide 114 in this embodiment) are brought into close proximity with each other, there will be no interference with the removable tooling (e.g., lower slide receiver 112 in this embodiment) or the stationary slide (e.g., hybridization gasket slide 114 in this embodiment). This location is provided in the present, preferred configuration by raised surfaces that are carefully designed to press against the periphery of the moveable slide, without interfering with the rest of the tooling or the fixed slide.
[0027] With reference to FIGS. 10 & 11 , the experimental slide 113 can then be released by depressing the button 109 (as shown in FIGS. 1-9 ) and allowing the cylinder spring to drive the cylinder 104 to its neutral state. This action causes the vacuum to be released to atmospheric pressure and the experimental slide 113 falls onto the hybridization gasket slide 114 under the force of gravity, according to the embodiments of the present invention.
[0028] With reference again to FIG. 10 , the small distance 118 between the experimental slide 113 and the hybridization gasket slide 114 allows the eventual placement of the experimental slide 113 and the hybridization gasket slide 114 (as illustrated in FIG. 11 ) to be gentle and non-disruptive event, according to the embodiments of the present invention. In this embodiment, the distance 118 is preferably, but not limited to, a distance on the order of about 1 millimeter or less.
[0029] With reference once more to FIG. 1 , the grooves 116 that are placed in static slide assembly tooling base 102 are present to allow a clamp (not shown) to be applied onto a stack of hybridization base, hybridization gasket slide, printed slide and the hybridization chamber top in order to fixate the two slides (as shown in FIG. 11 ) one on top of the other and held in place by the hybridization top in order to facilitate further processing, according to the embodiments of the present invention. Once gravity has brought the upper slide (i.e., experimental slide 113 ) into contact with the lower slide (i.e., hybridization gasket slide 114 ), it is possible to clamp the slides together without disturbing the orientation thereof. The device may now be used to repeatably fixate other pairs of slides.
[0030] The Accurate Slide Assembly Device (ASAD) 100 is intended to take a first prepared or otherwise unused slide (including, but not limited to, experimental slide 113 ) and place it in close proximity in a parallel attitude to a second prepared or otherwise unused slide (including, but not limited to, hybridization gasket slide 114 ). Prior to positioning in either upper slide chuck 110 or the lower slide receiver 112 , either of the first and second slides may be used or unused, prepared or unprepared, already processed or not yet processed.
[0031] In the above-described embodiment, vacuum was provided using the assembly—comprising the manually actuated button 109 and spring return cylinder 104 —that is connected to the o-ring-lined upper slide chuck 110 via flexible tube 117 . This, however, is not the only method of supplying a vacuum to the ASAD 100 . Other sources of vacuum include, but are not limited to, an external source that can be piped to the instrument, an on-board source that can be generated with a bulb commonly found in laboratories used for operating pipettes, and an air cylinder that is manually operated to provide a sufficient vacuum to pull the slide against an o-ring. The required vacuum pressure is on the order of inches of water (or about 2.5 to 25 mbar).
[0032] For the above-described embodiment, releasing the vacuum to atmospheric pressure may be accomplished via use of one of numerous valving options that are known to those skilled in the art.
[0033] In the above-described embodiment, the device is manually operated, but the device may be configured to operate robotically in ways known to those skilled in the art. In the above-described embodiment, a single hinge 105 is used, because it is the easiest configuration, but a combination of hinges and slides may also be built into the device to accomplish the same or similar task. Either slides, hinges, or both fit the task.
[0034] Although the above-described embodiment utilizes a hybridization chamber base, the device need not have a hybridization chamber base, but may simply be used to assemble the slides.
[0035] In some embodiments, the upper slide chuck 110 may be configured to be adjustably shifted along any direction within a plane that is parallel to the surface of the moveable arm 103 , in order to allow for ease of alignment between the experimental slide 113 and hybridization gasket slide 114 when the moveable is rotated to a position above the static tooling base.
[0036] Various embodiments of the disclosure could also include permutations of the various elements recited in the claims as if each dependent claim was a multiple dependent claim incorporating the limitations of each of the preceding dependent claims as well as the independent claims. Such permutations are expressly within the scope of this disclosure.
[0037] While the invention has been particularly shown and described with reference to a number of embodiments, it would be understood by those skilled in the art that changes in the form and details may be made to the various embodiments disclosed herein without departing from the spirit and scope of the invention and that the various embodiments disclosed herein are not intended to act as limitations on the scope of the claims. All references cited herein are incorporated in their entirety by reference. | Embodiments provide a slide assembly device having a static tooling base which is statically and solidly affixed to a base such as a table and a moveable tooling arm that is rotatable about a hinge connected to the static tooling base, so that moveable tooling arm rotates about the hinge in a manner similar to a book cover opening and closing. The embodiments further provide an upper slide chuck that is removably attachable to the moveable tooling arm and a lower slide receiver that is removably attachable to the static tooling base. The upper slide chuck is configured to hold an experimental slide via a vacuum mechanism to engagedly hold the experimental slide to the upper slide chuck while the moveable tooling arm is rotated about the hinge from an open-book position to a closed-book position. | 1 |
FIELD OF THE INVENTION
[0001] The object of the invention is an arrangement as defined in the preamble of claim 1 and a method for monitoring a safety circuit as defined in the preamble of claim 12 .
BACKGROUND OF THE INVENTION
[0002] In elevator systems and escalator systems, movement of the transport appliance is permitted only when the preconditions required to ensure the safety of passengers are fulfilled. For example, in elevator systems movement of the elevator car is permitted only when the doors of the elevator car and of the shaft are closed. In elevator systems and escalator systems safety is typically ensured with a safety circuit. The safety circuit can be implemented e.g. such that switches, which are connected to each other in series, are placed in the points that are essential from the standpoint of safety. The electricity supply of the motor of the transport appliance and in an elevator system the opening of the holding brakes are only permitted if all the switches of the safety circuit are closed.
[0003] Normally at least the coil of the main contactor and the coil of the machinery brake of the motor are in the same circuit with the switches. The circuit of the switches is arranged to open in a dangerous situation, in which case the main contactors open and the machinery brake energizes. The status of the safety circuit can also be monitored with the control system, e.g. by measuring the voltage across the circuit of the switches according to prior art.
[0004] In order to locate a dangerous situation, the status of individual switches in the elevator system or escalator system must be measured. For this purpose at least some of the switches of the safety circuit are conventionally wired separately to the control system for measuring the statuses of individual switches. The control system can be disposed in the machine room or e.g. on the landing floor of the elevator, and the switches can be situated at a distance from the control system, such as in the elevator shaft or in the elevator car. In this case wiring individual switches to the control system substantially increases the amount of wiring.
[0005] If individual switches are not monitored and their operation is not supervised either, there must otherwise be safeguards for the safe operation of the circuit formed by the switches. In this case the switch must be constructed as a duplicated switch that opens under forced control. This kind of switch of special construction is expensive.
[0006] Prior art technology is represented in publication elevator US-20040173410, which contains an arrangement for monitoring the door switches of an elevator system. Each door switch is monitored separately and the status data of the switches is transmitted to a serial interface bus. For adequate reliability to be achieved with this kind of solution, the measurements of the switches as well as the serial interface bus and the electronics participating in the serial interface communication must be duplicated. This increases the costs of the overall system. In addition, if it is desired to connect different actuators to the same system, also the controls of these actuators as well as their monitoring must be duplicated in order to achieve adequate reliability.
[0007] Publication JP 9-2764 A presents an arrangement for monitoring the safety circuit of an elevator. The arrangement comprises a control appliance, and the safety circuit comprises as serial circuit of switches. The arrangement comprises means for measuring the status of at least one switch, as well as means for conveying the status information of the switch to the control appliance.
PURPOSE OF THE INVENTION
[0008] The purpose of this invention is to disclose an arrangement and a method for monitoring individual safety circuit switches. The purpose of the arrangement and the method is to improve the dependability and operating reliability of the whole system.
ADVANTAGES OF THE INVENTION
[0009] With the invention at least one of the following advantages, among others, is achieved:
When the operation of the switches is monitored with two independent measurements, it is possible to achieve adequate operating reliability with switches that are simple in structure. If the monitoring electronics of a switch is disposed in a T-connector separate from the switch, the switch itself is small in size and it is easy to place e.g. in the landing door of the elevator. If the status data of the switches are sent to the control appliance as serial interface signals, individual switches do not need to be separately wired to the control appliance for monitoring purposes, in which case the wiring of the overall system is simplified. The data transfer channel used for monitoring the switches can also be used for transmitting different control commands of the elevator system, such as the control commands of actuators, as well as for transmitting monitoring and measuring information. Thus the wiring of the system is reduced and simplified. If the monitoring electronics of a switch is not integrated in a fixed manner into the switch, the switch can be changed without the need to change the monitoring electronics. Since a switch is a mechanical, wearing part, this reduces servicing costs. The control system can send to the servicing center an itemized defect notification specifying in which part of the safety circuit the defect is located. When the monitoring electronics of a switch is disposed inside a T-connector, in the manner proposed in the invention, it can be made moisture-proof and thus the reliability of the electrification of the elevator is improved. When the switches are arranged into a serial connection circuit, the status of serial connection circuit can be measured with the control system. When, in addition to this, the status of individual switches is measured and the status information is conveyed to the control system along the data transfer channel, duplicated measurement of the status of a switch is achieved. In this case a normal, single-channel unduplicated serial interface bus can be used as a data transfer channel while still achieving an adequate level of reliability.
SUMMARY OF THE INVENTION
[0018] The arrangement of the invention for monitoring a safety circuit is characterized by what is disclosed in the characterization part of claim 1 . The method according to the invention for monitoring a safety circuit is characterized by what is disclosed in the characterization part of claim 12 .
[0019] Other embodiments of the invention are characterized by what is disclosed in the other claims. Some inventive embodiments are also discussed in the descriptive section of the present application. The inventive content of the application can also be defined differently than in the claims presented below. The inventive content may also consist of several separate inventions, especially if the invention is considered in the light of expressions or implicit sub-tasks or from the point of view of advantages or categories of advantages achieved. In this case, some of the attributes contained in the claims below may be superfluous from the point of view of separate inventive concepts.
[0020] In the arrangement according to the invention for monitoring a safety circuit the safety circuit comprises at least one serial circuit of two or more switches. The arrangement also comprises a control appliance, first means for measuring the status of at least one switch, as well as means, in connection with the first means, for conveying the status information of the switch to the control appliance.
[0021] In one arrangement according to the invention at least one serial circuit of switches is fitted in connection with the brake control circuit and/or the power input circuit of the motor. In this case the brake and/or the power supply of the motor can be controlled on the basis of the status of the switch.
[0022] In one arrangement according to the invention at least one serial circuit of switches is in the brake control circuit and/or in the power supply circuit of the motor.
[0023] In the arrangement according to the invention safety circuit means two or more switches, which are connected in series for monitoring the safety of a transport system. The switches can be safety switches disposed in points in the system that are important from the standpoint of safety. These kinds of points are e.g. the landing doors of an elevator system, in which the switches can be disposed for monitoring the position of the door. Other important points in an elevator system from the standpoint of safety are e.g. the ends of the elevator shaft. Final limit switches can be disposed in these, which open when the elevator car moves to the switch. On the basis of the opening of the switches, further movement of the elevator car closer to the ends is prevented e.g. by controlling a prior-art stopping appliance of the elevator system.
[0024] One arrangement according to the invention comprises second means for measuring the status of the serial circuit of switches.
[0025] In one arrangement according to the invention first means are fitted in connection with a switch for measuring the voltage between the contacts of the switch.
[0026] In one arrangement according to the invention first means for measuring the current traveling in a switch are fitted in connection with the switch.
[0027] In one arrangement according to the invention second means for measuring the status of the serial circuit of switches are in the control appliance.
[0028] In one arrangement according to the invention the means for conveying the status information of a switch to the control appliance comprises a transmitter in connection with the switch, a receiver in connection with the control appliance, and a data transfer channel between the transmitter and the receiver.
[0029] One arrangement according to the invention comprises a T-connector. In this case the first means for measuring the status of a switch as well as the transmitter are fitted inside the T-connector.
[0030] In one arrangement according to the invention the safety circuit contains at least one actuator, and a transmitter is in connection with the actuator.
[0031] In one arrangement according to the invention a receiver, which is connected to a data transfer channel, is in connection with the actuator.
[0032] In one arrangement according to the invention a transmitter is fitted to send status information to the control appliance preferably as a serial interface message.
[0033] In one arrangement according to the invention the control appliance contains a receiver.
[0034] In the method according to the invention for monitoring a safety circuit the safety circuit comprises a serial circuit of two or more switches. In the method the status of at least one switch is measured with the first means, and the status information of the switch is sent to the control appliance using the first means for conveying the status information of the switch to the control appliance.
[0035] In one method according to the invention at least one serial circuit of switches is fitted in connection with the brake control circuit and/or with the power input circuit of the motor.
[0036] In one method according to the invention the status of at least one serial circuit of switches is measured with the second means for measuring the status of the serial circuit of switches.
[0037] One arrangement according to the invention comprises a data transfer channel, a T-connector, a detector of the status of a switch, and a transmitter. One method according to the invention in this case comprises the phases: means for measuring the status of at least one switch are fitted in connection with the switch; a transmitter is fitted in connection with the means; the means for measuring the status of at least one switch as well as a transmitter are fitted inside a T-connector; and the transmitter is connected to a data transfer channel such that the connection between the transmitter and the data transfer channel remain inside the T-connector.
[0038] The arrangement and the method according to the invention relate generally to safety circuits of various transport systems, such as an elevator system, an escalator system, a travelator, or a crane system or a drum drive elevator system.
[0039] On the basis of the status of the safety switch it is possible to control e.g. the machinery brake or a stopping appliance that grips the guide rail of the elevator car and thus prevent a situation that poses danger to the passengers of the elevator car. The serial circuit of switches can be a part of the control current circuit of a stopping appliance, in which case the current supply of the circuit disconnects when the switch opens, and the stopping appliance operates. On the basis of the status of the safety switches it is also possible to disconnect the power supply circuit of the elevator motor. Power supply circuit means a power input circuit formed of possible main contactors and the frequency converter of an elevator motor, the disconnection of which prevents power flowing from the power sources to the elevator motor. Disconnection can be effected e.g. by opening the main contactor or by preventing the connection of the switches of the frequency converter. The serial circuit of switches can be a part of the power supply circuit, in which case the opening of a switch disconnects the power supply circuit. On the basis of the status of the switches it is possible on the other hand to also control the elevator motor with the frequency converter such that the elevator car is stopped in a controlled way at the nearest exit floor under the control of the frequency converter. In this case the power supply circuit and the brake control circuit are not necessarily opened.
[0040] The arrangement according to the invention can comprise one serial connection circuit, in which all the switches are connected in series. The arrangement can also comprise a number of different serial connection circuits, each of which contains two or more switches.
[0041] In the arrangement according to the invention the status of the safety circuit can be measured by measuring separately the status of at least one serial connection circuit as well as the status of the separate switches of the serial connection circuit. The arrangement according to the invention comprises at least first means for measuring the status of at least one separate switch. In addition, the arrangement according to the invention can comprise second means for measuring the status of the serial circuit of switches.
[0042] The status of an individual switch can be measured with the first means e.g. by measuring the voltage between the contacts of the switches with some kind of prior-art voltage measurement method. This kind of method can be e.g. a resistor disposed in parallel with the switch and a serial circuit of an opto-isolator, in which case as the voltage over the switch grows on the primary side of the opto-isolator, and thus also on the secondary side, current begins to flow. In this kind of measuring system voltage must be supplied to the serial circuit of switches with some kind of prior-art AC or DC voltage source. When at least one of the switches of the serial connection circuit opens, it is possible to measure the voltage difference over the contacts of the switch.
[0043] Another method of measuring the status of an individual switch with the first means is measuring the current traveling through the switch. The current can be measured with some kind of prior-art current measuring appliance, such as with a Hall sensor or with a series resistor. When at least one of the switches of the serial connection circuit opens, the flow of current through the switch ceases. If in this case it is desired to specify the switch that opened, a parallel connection resistor must be in parallel with at least the opened switch, so that the passage of current through the other switches of the serial connection circuit does not disconnect and so that the closed switches can be identified on the basis of the passage of current.
[0044] In one preferred embodiment of the invention at least one serial connection circuit is disposed as a part of the power supply circuit of the motor. In this case the opening of the serial connection circuit disconnects the power supply circuit and the power supply to the elevator motor is cut.
[0045] In one embodiment of the invention a transmitter is in connection with the switch and the control appliance contains a receiver. The status information of the switch is transmitted with the transmitter to the data transfer channel and is received by the control appliance from the data transfer channel with the receiver. The status information can be conveyed e.g. with some prior-art serial interface signal, such as with a SPI, UART or DTMF signal. The status information can also be conveyed as e.g. an analog signal.
[0046] In one embodiment of the invention means for detecting the status of a switch as well as a transmitter are disposed inside a special T-connector. A T-connector means a connector, from which the conductor branches in three different directions. The connector in question can be used e.g. to connect a new wiring branch in connection with a main branch. The new wiring branch can be e.g. a measuring wire of a switch, and the main branch can be a data transfer channel.
[0047] Separate actuators can also be connected to the safety circuit according to the invention. On such actuator can be a stopping appliance, such as a guide rail brake, that grips the guide rail of the elevator car. The guide rail brake can be connected to the safety circuit e.g. such that at least one serial connection of switches is in the magnetizing circuit of the guide rail brake. When a switch opens the magnetizing current supply of the guide rail brake disconnects and the guide rail brake connects mechanically to the guide rail of the elevator car.
[0048] A receiver, which is connected to the data transfer channel, can be in connection with the actuator. Correspondingly, a transmitter can be in connection with the control appliance of the elevator system. A control appliance means here an appliance generally needed to control an elevator system, comprising all the higher level control systems, such as the control systems of the elevator system, of the elevator car and of the elevator motor as well as e.g. systems related to fault diagnostics. In one embodiment of the invention the control appliance sends actuator control signals to the data transfer channel with the transmitter, such as controls of the guide rail brake, and the actuator, e.g. the guide rail brake, receives control signals from the data transfer channel with its receiver. The guide rail brake connects to the guide rail according to the control signals. A transmitter can also be in connection with the actuator, with which the actuator sends information about its operating status to the control appliance. The control appliance can send a control command to the actuator and read the signal sent by the actuator after this, and thus monitor the operating condition of the actuator. The control electronics of the transmitter, the receiver and possibly of the actuator can be disposed inside the T-connector. The control electronics of the actuator means the control logic, means for measuring the status of the actuator and a possible amplifier circuit, with which the control signal of the actuator is amplified, e.g. for controlling the current of the magnetic circuit of the guide rail brake. The control signals can travel in the data transfer channel as prior-art serial interface signals.
[0049] The transmitter and the receiver can be integrated into the same microcircuit.
LIST OF FIGURES
[0050] In the following, the invention will be described in more detail by the aid of a few examples of its embodiments with reference to the attached drawings, wherein
[0051] FIG. 1 presents one arrangement according to the invention for monitoring the safety circuit of an elevator system
[0052] FIG. 2 presents the means incorporated in one arrangement according to the invention for measuring the voltage between the contacts of the switch
[0053] FIG. 3 presents the means incorporated in one arrangement according to the invention for measuring the current traveling in a switch
[0054] FIG. 4 presents a first T-connector fitted into an arrangement according to the invention
[0055] FIG. 5 presents a second T-connector fitted into an arrangement according to the invention
[0056] FIG. 6 presents monitoring electronics fitted in connection with a switch
[0057] FIG. 7 presents an actuator connected to an arrangement according to the invention
[0058] FIG. 8 presents an arrangement according to the invention for monitoring the safety circuit of an escalator system
DETAILED DESCRIPTION OF THE INVENTION
[0059] FIG. 1 presents an elevator system, in which the arrangement according to the invention is applied. In the elevator system according to FIG. 1 the power supply of the elevator motor occurs via the power supply circuit 24 . At least one stopping appliance of the elevator car is controlled with a brake control circuit ( 13 ). The switches 3 , 4 , 5 , 6 are disposed in points that are important from the standpoint of the safety of the elevator system. The switches 3 , 4 are disposed in connection with the landing doors and the switches 5 , 6 in connection with the end limits of the elevator. The brake control circuit 13 contains an input 26 for the serial circuit 2 of switches, as also the power supply circuit 24 of the motor contains an input 25 for the serial circuit of switches. When at least one of the switches of the serial connection circuit opens, the power control circuit of the motor and also the brake control circuit are disconnected, in which case the power supply to both the motor and to the brake are disconnected and the elevator system switches to drive prevented mode. The arrangement according to the invention comprises means 10 , 11 for measuring the status of a switch as well as a transmitter 14 in connection with these means, with which the status information of the switch is sent to the data transfer channel 8 . The control appliance 1 contains a receiver 15 connected to the data transfer channel, and the control appliance reads the status of the switches by means of this, in which case the status of an individual switch of the serial connection circuit 2 can be identified. In addition, the control appliance can contain an input for the serial circuit 2 of switches as well as means 23 for measuring the status of the serial circuit of switches. In this case the control appliance can compare with each other at least the measured status data of the switches 3 , 4 , 5 , 6 to the status information of the serial connection circuit separately measured with the means 23 and on the basis of the comparison can deduce the operating condition of the measurements of the serial connection circuit. If, for example, the status data of the switches read with the receiver 15 of the control appliance differ from the status data of the serial connection circuit 2 measured with the means 23 , it can be inferred that there is an error in at least one measurement. In this case the control appliance 1 prevents the next run with the elevator.
[0060] In a second arrangement according to the invention the serial connection circuit is not wired separately to the brake control circuit or to the power supply circuit, but only to the control appliance 1 . In this case the control appliance 1 only reads the status of the serial connection circuit 2 with the means 23 . In addition to this, the control appliance 1 reads the status of the individual switches 3 , 4 , 5 , 6 of the serial connection circuit 2 from the data transfer channel 8 with the receiver 15 . If the control appliance detects that the safety of the elevator system is jeopardized, such as the switch 3 , 4 of a landing door being open or an end limit switch 5 , 6 that has opened, the control appliance 1 prevents the next run by controlling open at least the brake control circuit 13 and possibly also the power supply circuit 24 . In addition to this the control appliance 1 compares the status of the serial connection circuit measured with the means 23 to the status data of the individual switches read with the receiver 15 and when it detects that these differ from each other it infers that at least one measurement ( 10 , 11 , 23 ) of the switches is defective. Also in this case the control appliance 1 prevents the next run. The control appliance 1 can also send defect information to the servicing center both when it detects that the safety of the elevator system is jeopardized and when it detects that a measurement is defective. Since the control appliance reads the operating status of individual switches it is possible to send to the servicing center information about which point important from the standpoint of the safety of the elevator system a malfunction occurs. This improves the diagnostics of the elevator system.
[0061] The means 23 for measuring the status of the serial connection circuit 2 of switches can comprise a voltage source, with which voltage is supplied to the serial connection circuit, as well as means for measuring the voltage from some other point of the serial connection circuit. The voltage measured depends on whether there are open switches in the serial connection circuit between the input point of the voltage and the measuring point.
[0062] FIG. 2 presents means incorporated in one arrangement according to the invention 10 for measuring the voltage between the contacts of a switch. The arrangement in this embodiment of the invention comprises a prior-art AC or DC voltage source, with which the serial connection circuit is supplied. If the switch opens, the voltage between the contacts of the switch grows. This voltage is measured by connecting a resistor in parallel with the switch in series with the primary side of the opto-isolator. As the voltage between the contacts of the switch grows, the current on the primary side, and thus also on the secondary side, of the opto-isolator grows, and this current is measured from the secondary side e.g. with a measuring resistor.
[0063] FIG. 3 presents means incorporated in one arrangement according to the invention 11 for measuring the current traveling through a switch. In this embodiment of the invention the arrangement comprises some prior-art AC or DC voltage source. The current is measured with some prior-art appliance 1 , such as with a series resistor or with a Hall sensor. When the switch 3 , 4 , 5 , 6 opens, the passage of current in the switch ceases. In order for the opened switch to be identified, the passage of current in the other switches of the serial connection circuit must continue. Owing to this, a current path, such as resistor, according to FIG. 3 must be added in parallel with at least the open switch.
[0064] FIG. 4 presents a T-connector 17 fitted into an arrangement according to the invention. The means 10 , 11 for measuring the status of a switch are fitted inside the T-connector, as is also the transmitter 14 . The data transfer channel 8 is in the main branch of the T-connector. By means of the connector control electronics 7 for measuring the status of the switch 3 , 4 , 5 , 6 is connected to the data transfer channel 8 . Measuring conductors 9 are on the poles of the switch, which are taken inside the T-connector to the means 10 , 11 for measuring the status of the switch. The measured status information is sent to the data transfer channel 8 with the transmitter 14 , which is connected to the data transfer channel in the connection point 18 inside the T-connector. The T-connector can be manufactured to be waterproof, in which case the electrical connection points are protected from dampness and the reliability of the electrical system of the elevator improves.
[0065] FIG. 5 presents a second T-connector 17 fitted into an arrangement according to the invention. The wiring of the T-connector varies from that of FIG. 4 in that both the conductor of the data transfer channel 8 and the conductor of the serial circuit 2 of switches run in the main branch of the T-connector, and the measuring conductors 9 are in series with the serial circuit 2 of switches. An advantage of this embodiment of the invention is that the conductors of both the serial circuit 2 and of the data transfer channel 8 can be led in the same wiring bundle from the main branch of the T-connector to the connector, in which case the wiring in connection with the T-connector is simplified.
[0066] FIG. 6 presents monitoring electronics 7 according to one embodiment of the invention fitted in connection with a switch. The monitoring electronics can comprise means 10 , 11 for measuring the status information of the switch, a transmitter 14 , and a receiver 15 for receiving control commands from the data transfer channel 8 . Correspondingly, the control appliance 1 can contain a transmitter for sending control commands to the data transfer channel. Control commands can be used e.g. to control an actuator fitted to the arrangement according to the invention.
[0067] FIG. 7 presents an actuator, with its control electronics, connected to an arrangement according to the invention. In this embodiment of the invention the actuator is a guide rail brake. FIG. 6 presents a part of the magnetic circuit 19 of the guide rail brake. The magnetic circuit is magnetized by supplying current to the magnetizing coil 20 , and when current flows the guide rail brake is open. In this case the elevator can move freely along the guide rail. When the current flowing in the coil 20 disconnects, the guide rail brake grips hold of the guide rail and movement of the elevator car is prevented. In this embodiment of the invention the serial circuit of the switches 3 , 4 , 5 , 6 is in the circuit of the magnetizing coil 20 . Disconnection of any switch causes disconnection of the circuit of the magnetizing coil. The status of at least one switch 3 , 4 , 5 , 6 in the circuit of the magnetizing coil 20 is measured with the measuring means 10 , 11 . The status information is sent to the data transfer channel 8 with the transmitter 14 . In addition, the arrangement contains a receiver 15 , with which the control commands of the guide rail brake are received from the data transfer channel 8 . The control commands are taken to the control logic 22 , which in turn controls the current of the magnetizing coil 20 with the switch 21 . In this arrangement according to the invention it is possible to test the condition of the control and monitoring appliance by sending a testing signal to the data transfer channel 8 with the control appliance 1 , with which the switch 21 is controlled on. The status of at least one switch 3 , 4 , 5 , 6 in the circuit of the magnetizing coil 20 is measured with the measuring means 10 , 11 and the status information is sent to the data transfer channel, from where it is read with the control appliance 1 . After this a new testing signal is sent with the control appliance 1 , with which the switch 21 is controlled off, the change in the status of the switch 3 , 4 , 5 , 6 is read from the data transfer channel and thus the condition of the control and monitoring appliance is deduced.
[0068] FIG. 8 presents how one arrangement according to the invention for monitoring a safety circuit is applied in an escalator system. The figure presents only some of the points important from the standpoint of the safety of the escalator system and some of the safety switches disposed in these points.
[0069] At the upper exit and the lower exit of an escalator system are comb plates ( 33 ), which are intermeshed with the step chain ( 34 ), closing the point of bending that occurs in the change of direction of the step belt. A step chain means a combination of steps and a fixing chain connecting them. The comb plate contains safety switches ( 27 , 32 ) which open if the comb plate for some reason moves along with the step chain. Moving can result e.g. if a passenger or an object has become entangled in the step chain. In addition, key start switches as well as manually-operated emergency stop switches 28 , 31 are in connection with the bottom exit and/or the top exit. In addition, in this embodiment of the invention the step chain contains a step-break detector 29 as well as a missing-step detector 30 . The serial circuit 2 of switches is taken to the control appliance 1 , which contains means 23 for measuring the status of the serial circuit. The serial circuit can be in the brake control circuit 13 as well as in the power supply circuit 24 of the escalator motor, which are not presented in this figure. When a switch opens the brake control circuit and the power supply circuit open, in which case the step chain stops. Control electronics 7 , which reads the status of an individual switch and sends the status information to the data transfer channel 8 , is in connection with the switches. The control appliance 1 contains a receiver 15 , by means of which the control appliance reads the status data of the switches, is connected to the data transfer channel. On the basis of the status information of the switches the control appliance identifies in which part of the escalator system the defect has occurred. Information about the defect as well as information about the location of the defect can be sent to the servicing center. By comparing the status information of the serial circuit of switches and the status data of individual switches it is also possible to deduce the operating condition of the measurements.
[0070] In one arrangement according to the invention both the power supply circuit 24 and the brake control circuit 13 are opened with a controllable switch, the control of which comes from the control appliance 1 . In this embodiment of the invention the switches are not directly in the brake control circuit or in the power supply circuit, in which case a short-term break of the serial circuit similar in nature to a malfunction does not cause a break in the brake control circuit or in the power supply circuit, and the step chain does not stop unnecessarily as a consequence of malfunctions. Since the control appliance reads the status information of the switches separately as status information of the serial circuit and as status information of the individual switches, adequate reliability of operation is achieved with duplicated measurement. Additionally, the controllable switch in this arrangement according to the invention must be reliable. Reliability can be increased according to prior art e.g. by duplicating the switch element and the control electronics of the switch.
[0071] The invention is not limited solely to the embodiments described above, but instead different variations are possible within the scope of the inventive concept defined by the claims below.
REFERENCES OF THE FIGURES
[0000]
1 control appliance
2 serial circuit of switches
3 door switch
4 door switch
5 top end limit switch
6 bottom end limit switch
7 monitoring electronics of switch
8 data transfer channel
9 switch state measuring wires
10 means for measuring voltage between the contacts of the switch
11 means for measuring current flowing in the switch
13 brake control circuit
14 transmitter
15 receiver
17 T-connector
18 connection point
19 part of magnetic circuit of guide rail brake
20 magnetic coil
21 control switch of guide rail brake
22 control logic
23 means for measuring the state of the serial circuit of switches
24 power-supply-circuit of the motor
25 input of serial circuit of switches in the power input circuit
26 input of serial circuit of switches in the brake control circuit
27 switch of comb plate of bottom exit of escalator
28 key start switch
29 step-break detector
30 missing-step detector
31 manually-operated emergency stop switch
32 switch of comb plate of top exit of escalator
33 comb plate
34 step chain of escalator | The present invention presents an arrangement and a method for monitoring a safety circuit. The system comprises a control appliance and the safety circuit comprises at least one serial circuit of two or more switches. The arrangement according to the invention comprises first means for measuring the status of at least one switch, as well as means, in connection with the first means, for conveying the status information of the switch to the control appliance. In the method according to the invention the status information of at least one switch is measured with the first means and the status information of the switch is sent to the control appliance using the first means for conveying the status information of the switch to the control appliance. | 1 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to writing or marking apparatus and more specifically to writing instruments and other apparatus for creating unique markings, or covert prints within an ink line marked with ink, or other marking substances, thereby providing means for verification of document authorship, origin and/or content authenticity.
2. Description of the Related Art
It can be appreciated that writing or marking apparatus and other instruments for marking substrates such as pens have been in use for centuries. Specifically, pens are used to write and/or sign documents such as contracts, currency, bonds, stocks, securities, travelers checks, bank checks, credit cards, credit cards receipts, passports, airline tickets, labels, green cards, prescription slips, tests and examinations, police or witness reports, affidavits, research documents, legal waivers and releases, and any other business, personal, legal and/or government documents in which identification of the creator or signatory is critical. Writing instruments may also be used in many unofficial applications, including but not limited to personal correspondence, journaling for posterity, archiving and scrap-booking, writing for publication, autographing, or a variety of other unofficial purposes.
Writing instruments known in the art are limited in that they do not provide means for identifying writing or their marks as unique to a particular writing instrument for the purposes of security or verification of authorship, origin and/or content authenticity. Reliance on writing analysis has been one of the sole bases for establishing authenticity. Thus, conventional writing instruments do not offer security features, and it is possible to forge or otherwise deceitfully obscure the origin, authorship and/or content authenticity of writings by simply mimicking the signature or writing of another individual or mechanism.
While conventional writing instruments and marking apparatus such as pens are suitable for writing and creating a mark, they often fail to provide means of verification of document authorship, origin and/or content authenticity on solely the basis of the instrument used. The marking apparatus of the present invention, including the writing instruments presented herein, substantially improve upon the designs of the prior art by providing a writing instrument and marking apparatus that create a unique marking or covert print within a printed or written ink line or marking, thereby providing means of verification of document authorship, origin and/or content authenticity.
SUMMARY OF THE INVENTION
In view of the foregoing disadvantages inherent in writing instruments of the prior art, the present invention provides a new covert-print writing apparatus construction wherein the same can be utilized for creating unique markings, or covert prints, within the written or printed ink line(s) to provide means of verification of document authorship, origin and/or content authenticity of all lines or markings created by the writing apparatus, including all content in addition to the signature, if present.
The general purpose of the present invention, which will be described subsequently in greater detail, is to provide a marking apparatus resulting in a new covert-print writing or marking apparatus with an inherent security function which is not anticipated, rendered obvious, suggested, or even implied by any of the prior art writing or marking instruments, either alone or in any combination thereof.
A primary object of the present invention is to provide a covert-print apparatus that will overcome the shortcomings of the prior art devices.
Another object of the present invention is to provide a writing apparatus for creating unique covert-print markings within the written ink line(s) or mark(s) to provide means of verification of document authorship, origin and/or content authenticity, including all content in addition to the signature.
Still another object is to provide a covert-print apparatus that provides a unique result that is unobtrusive and does not limit or interfere with normal use of the writing apparatus.
Yet another object is to provide a covert-print apparatus that provides a unique result that may not be noticed without the benefit or use of a reading device.
It is a further object to provide a covert-print apparatus that provides a unique result without any special effort or training of the creator or writer.
It is still a further object to provide a covert-print apparatus that provides a unique result that may not be copied or reproduced by conventional means.
It is yet a further object to provide a covert-print apparatus that may be utilized for various levels of security and in multiple circumstances.
It is an additional object to provide the option of a self-contained verification system in the form of an included magnifying device in the covert-print apparatus to enable examination of covert prints within the written line(s) and check code authenticity and/or clarity.
These objects are achieved by a writing or marking instrument for creating a unique marking having a casing, having a working end and a non-working end; an ink source situated in said casing; and a point having covert-printing means disposed on an outer surface thereof for depositing a line or character or mark having a covert-print embedded code formed by said covert-printing means, said point being disposed at the working end of the casing, said point being a movable member arranged to rotate when moved along a surface, and said point being in fluid flow communication with said ink source.
The objects are additionally achieved by a method of making a covert-printed line comprising the steps of: employing a marking apparatus comprising a casing having a working end and a non-working end; an ink source situated in the casing; and a point disposed at the working end of the casing and mounted for rotation when moved along a surface, said point having covert-printing means disposed thereon, wherein said point communicates with said ink source and a writing surface; moving said point of said marking apparatus across said writing surface such that said point rotates along said surface; and depositing a written line on said writing surface that incorporates covert-print embedded code formed by said covert-printing means.
The objects are further achieved by a method for authenticating a written ink line or mark as being unique to a particular marking apparatus, the method requiring the steps of assigning a writing instrument comprising a casing having a working end and a non-working end; an ink source situated in casing; and a point disposed at the working end of the casing, said point having a unique covert-printing means disposed thereon to a specific creator; having said creator employ said writing instrument for applying a coded marking on a surface such as by writing, thereby creating a writing having a covert-printed code formed therein; inspecting said writing for said covert-printed code formed on the surface; and ensuring that said covert-printed code formed by said code of the covert-printing means matches said covert-printing means of said assigned writing instrument.
Other objects and advantages of the present invention will become obvious to the reader and it is intended that these objects and advantages are within the scope of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
Various other objects, features and attendant advantages of the present invention will become fully appreciated as the same becomes better understood when considered in conjunction with the accompanying graphics, in which like reference characters designate the same or similar parts throughout the graphic, and wherein:
FIG. 1 is a perspective view of a first embodiment of the covert-print apparatus of the present invention.
FIG. 2 is a magnified perspective view of the tip of the covert-print apparatus shown in FIG. 1 .
FIG. 3 is a magnified view of the point of the covert-print apparatus shown in FIG. 1 .
FIG. 4 is a magnified perspective view of the point of the covert-print apparatus shown in FIG. 1 , shown in cross-section to illustrate depth.
FIG. 5 is a magnified perspective view of a layered point of the covert-print apparatus shown in FIG. 1 shown in cross-section to illustrate depth.
FIG. 6 is a perspective view of an alternate embodiment of the covert-print apparatus of the present invention having a non-spherical point.
FIG. 7 is a magnified perspective view of the point of the covert-print apparatus of the present invention having a non-spherical point shown in window A of FIG. 6 .
FIG. 8 is a magnified front view of the tip of the covert-print apparatus of the present invention shown in window A of FIG. 6 .
FIG. 9 is a cross-sectioned side view of the ink reservoir of the covert-print apparatus of the present invention shown in FIG. 1 .
FIG. 10 is a side view of the magnifying cap for any embodiment of the covert-print apparatus of the present invention.
FIG. 11 is a side perspective view illustrating the cap of the covert-print apparatus of the present invention illustrating the microprint feature within the written ink line or mark magnified using the magnification feature of the cap.
FIG. 12 is a side perspective view of the magnifying cap of the covert-print apparatus of the present invention in use with a doctor's prescription pad.
DETAILED DESCRIPTION OF THE INVENTION
A covert-print apparatus 300 is illustrated in FIGS. 1 to 12 , in which similar reference characters denote similar elements throughout. For purposes of this application and a description of the invention herein, “covert-print” means any coded markings, in the form of lines or other characters from which embedded codes are not visible and may not be noticed without the benefit or use of a reading device.
Covert-print apparatus 300 , as illustrated in FIG. 1 , has a casing 20 , a tip 30 , a stem 25 , and a point 70 . As illustrated in FIG. 2 , point 70 is housed within stem 25 . Stem 25 is housed within tip 30 . Stem 25 regulates the ink flow between the reservoir and the point. Casing 20 preferably has a reservoir or source of ink 100 , as illustrated in FIG. 9 . Tip 30 is removably coupled by any suitable means to the working end casing 20 . Point 70 allows appropriate access to ink reservoir or source 100 through stem 25 . As shown in FIG. 3 , point 70 is preferably spherical, having unique covert-print features 120 that are permanently formed on the surface of point 70 . Covert-print features 120 may be raised or recessed or both simultaneously. Point 70 is designed to deliver ink directly onto a writing surface. Casing 20 , tip 30 , stem 25 , and point 70 may vary considerably in color, size, shape, volume, weight, density, and material. Tip 30 and/or stem 25 may also be integrally formed with ink reservoir or source 100 . Covert-print apparatus 300 may further have a cap 130 for protecting tip 30 , as illustrated in FIG. 11 .
Referring again to FIG. 1 , casing 20 , is preferably thin and tubular, such that it may be easily gripped and manipulated for the purpose of creating controlled markings on a writing surface. Tip 30 is preferably conical in shape. Tip 30 houses the stem 25 that houses point 70 in such a way as to allow limited access to ink reservoir or source 100 , while also allowing point 70 to protrude appropriately to make direct contact with a writing surface. Tip 30 may be coupled to casing 20 by a variety of means, including but not limited to screwing onto threads cut into the working end of casing 20 , snapping into place, fitting into or onto casing 20 by means of friction or vacuum or suction pressure (whereby pressure inside the casing is significantly lower than atmospheric pressure outside the casing, allowing this acting force to hold parts of the casing together as one unit) or being fitted and secured by means of an adhesive, or otherwise fastened in such a way as to be secure for use while allowing necessary access, opening, detaching, or disassembling of components for the purposes of refilling, emptying, cleaning, or any other action needed for use or maintenance. It should be noted that tip 30 and casing 20 may comprise one integral piece, as in a disposable embodiment of the present invention.
Casing 20 has an opening for the insertion, removal, and replacement of ink reservoir or source 100 . Ink reservoir 100 preferably has openings, where necessary, to allow air to enter and, thus, ink to escape. Alternatively, ink reservoir 100 may be pressurized, thereby averting the need for an opening.
Ink reservoir or source 100 (if a separate reservoir or other component is employed) is inserted into casing 20 , by means of an opening located in one end of casing 20 , or alternately by means of separating a first half of casing 20 from a second half of casing 20 and reattaching the halves around ink reservoir or source 100 by any of a number of secure and removable means as described above. Tip 30 is coupled to the working end of casing 20 by any of a number of secure and removable means as described above. Ink reservoir 100 may alternately be inserted and attached by screwing means, if ink reservoir 100 and tip 30 are designed as separate components and may therefore be disengaged from one another without damaging or otherwise hindering the functioning of covert-print apparatus 300 . Alternatively, ink reservoir 100 , casing 20 , tip 30 , stem 25 and point 70 in any combination may also be formed as one integral unit such that any attempt to insert ink or replace ink reservoir 100 would render covert-print apparatus 300 inoperable, thus limiting the use of that specific covert-print apparatus 300 by rationing the initial load of ink to an amount suitable for a limited number of uses.
In an alternate embodiment, ink reservoir 100 is pressurized or specially designed to preclude the need for an air hole in casing 20 to allow delivery of ink. In an additional embodiment not shown, ink may be deposited directly into an opening in casing 20 . Covert-print apparatus 300 may employ additional alternate ink sources. Non-limiting examples of such ink sources include, but are not limited to a liquid reservoir, a sponge, and powdered or solid color sources. Casing 20 may also be designed to hold and dispense ink without need for a separate ink reservoir 100 . Covert-print apparatus 300 may additionally be designed to allow the insertion, attachment, or use of tip 30 , or wherein tip 30 and stem 25 is inextricably a part of ink reservoir or source 100 .
Covert-print apparatus 300 may have a spring loaded mechanism for the engagement and disengagement of stem 25 that selectively causes stem 25 to be moved between a retracted position wherein it is concealed within tip 30 and an extended position, as illustrated in FIG. 1 . Alternately, covert-print apparatus 300 may have a rotating tip mechanism for retracting stem 25 . Retracting and rotating tip mechanisms are well known in the art.
Covert-print apparatus 300 may be designed to allow for the use of a variety of covers or caps 130 , which may fit over the non-working end of casing 20 . Cap 130 may have features, including but not limited to a discerning or decoding means 150 for the examination of covert prints in a marking made using covert-print apparatus 300 . Discerning or decoding means 150 may be a magnifying means, UV means, or other means for revealing covert-print coding in a marking made using covert-print apparatus 300 .
Referring to FIGS. 3 through 5 , point 70 is preferably spherical. Covert-print features 120 are disposed on the surface of point 70 . Covert-print features 120 may be engraved into the surface of point 70 , as shown in FIG. 3 . Alternately, as shown in FIG. 5 , covert-print features 120 may be layered onto point 70 or raised above the surface of point 70 (not shown). Covert-print feature 120 may simply be in the form of a magnetic pattern with no other special qualities. The point may be manufactured as one solid unit of all the same material or a mixture of materials FIG. 3 , or may be comprised of multiple layers of different materials FIG. 5 or multiple layers of the same material FIG. 5 . Covert-print features 120 may be symbols, numbers, letters, or any other recognizable characters or images or microprint, and may utilize ultraviolet, magnetism, or physical indentation to create said markings. Point 70 is housed in the end of stem 25 in such a way as to enable appropriate access to ink reservoir or source 100 while also protruding appropriately from stem 25 in such a way as to remain secure while making contact with a writing surface. In use, point 70 is in direct contact with the document or writing surface. As point 70 is drawn along the surface, ink is drawn onto point 70 from ink reservoir 100 and is transferred onto a writing surface, leaving a written ink line or mark. Within the written ink line or mark, point 70 also leaves a negative or positive, microphotographic, spectroscopic, ultraviolet, physical, optical, atomic, molecular, or magnetic image of the symbols, numbers, letters, or any other recognizable characters, images or markings engraved into, protruding from, or magnetically or chemically printed on point 70 . The markings may appear in the form of magnetic differences in the ink pattern of the written line, which may include varying or alternating colored pigments. These markings may or may not be visible to the naked eye, ultraviolet or other light-dependent markings that may or may not be visible to the naked eye, or physical indentations that may or may not be visible to the naked eye. The markings may include a time-sensitive factor, such as but not limited to an encoded date or magnetized or chemically induced ink whose magnetic field or chemical composition weakens as time passes, thus limiting the period of time in which that particular covert-print apparatus' mark may be considered valid and providing additional security.
Point 70 may be a ball bearing, such as those found in conventional ballpoint pens, with the unique feature of being engraved with covert-print features 120 . Point 70 may also be a differently shaped piece that is mounted on one or more axes and is capable of smoothly rolling along a surface, allowing free rotation preferably 360 degrees, while delivering a controlled ink marking to a writing surface. Covert-print features 120 are preferably engraved into point 70 and may vary in depth, height, width, internal volume, size, shape, font, and other characteristics. Covert-print features 120 may wrap around the surface of point 70 , may appear more than once on point 70 , and/or may appear in more than one direction or orientation on point 70 . Point 70 may leave only an impression of covert-print features 120 and may otherwise leave a written ink line or mark that appears to be normal or typical to the naked eye.
Point 70 may be housed securely within stem 25 by means of fitting precisely into a portion of stem 25 molded and assembled for that purpose. Thus, point 70 may be attached by means of secure containment within stem 25 . Stem 25 should allow enough space for movement of point 70 , as well as the controlled flow of ink from ink reservoir 100 across point 70 and onto a writing surface. Stem 25 may have a spherical space comprised of curved parts, fitted together to enclose point 70 , while allowing access to ink reservoir or source 100 on one side and access to the writing surface on the other.
To apply ink from a writing instrument to a substrate, point 70 is rotated by applying pressure to the substrate with the tip of the covert-print apparatus 300 . As the working end of the covert-printing apparatus 300 is rolled across a substrate (or other writing surface), point 70 is rotated due to friction, and ink which clings to point 70 is drawn from ink reservoir 100 and transferred to the substrate. The invention dispenses covert-printed features 120 within the written ink line or mark as the point 70 rolls across the substrate (or other writing surface), applying ink in the conventional manner, with the following unique result: ink is not applied to areas of the substrate (or other writing surface) where point 70 has been engraved, leaving a negative image of the covert-printed features 120 engraved into point 70 of the instrument.
In an alternate embodiment of point 70 , a positive imprint of covert-print features 120 may be left if point 70 is not engraved but, rather, is molded or otherwise formed to have protruding markings within the engraving, or both methods may be utilized simultaneously on a single point. In addition, chemical, magnetic, or physical indentation methods may or may not also be utilized singly or in combination with the previously described methods.
Ink employed in the current invention may vary considerably in color, chemical composition, volume, density, viscosity, magnetism, and other physical properties. The inks disclosed in U.S. Pat. Nos. 6,613,815, 6,528,557 and 5,958,121 are incorporated by reference herein. The ink or color source may be designed to be deliverable from within ink reservoir 100 or across the point 70 and onto the substrate or writing surface effectively in the conventional manner to create normal written ink line(s) or mark(s). However, the ink or color source must be chosen to have additional special properties. The ink or color source must cling to point 70 without in any way obscuring the unique covert-print features 120 on point 70 . Additionally, upon being applied to a substrate or writing surface, the ink or color source must not spread or bleed such that the image left by covert-print features 120 on point 70 is in any way obscured, unless they are obscured intentionally. In general, the ink must support the unique result of leaving unique, legible or otherwise clear covert-print markings within the written ink line(s) or mark(s).
In an alternate embodiment, point 70 has covert-print features 120 that protrude from point 70 , rather than simply being engraved or cut out of point 70 . In this embodiment, ink must again be chosen for the properties cited above, namely, the ability to cling to point 70 without obscuring covert-print features 120 , and the ability to be applied to a substrate without obscuring covert-print features 120 . Ink may also be designed in such a way as to make covert-print features 120 appear either noticeably lighter or darker than the rest of the inked line(s), or be visually distinguishable only through the physical imprint of covert-print features 120 upon the paper. The ink or color source may only be visible under certain types of light, or by applying specially designed chemical agents, or by waiting a certain period of time for changes to occur in the ink or in a reaction of the ink with conventional or specially treated substrate which would then render the ink visible or detectable. The unique covert-print markings may be made by magnetically charged particles within specialized ink, drawn into a magnetized patterns, colors, symbols, numbers, letters or characters on the points' surface or into covert-print feature 120 by a precise magnetic charge in point 70 , and may thus be visible with the naked eye or using a magnetic reading device. The markings may have an option of enhanced clarity of the covert-print through magnetically charged ink and components, or a process through which residual ink is removed from the engraved covert print by means of physical or magnetic displacement.
In another alternate embodiment, point 70 may be a spherical or differently shaped piece, capable of smoothly rolling along a writing surface, as shown in FIGS. 6 and 8 . In this embodiment, differently shaped point 70 is mounted on one or more axes, allowing it to rotate freely, preferably 360 degrees, while delivering a controlled ink marking to a writing surface. According to this embodiment, point 70 may be a sphere, oval, or other piece capable of rolling and spinning about a central axis 75 running through a middle of point 70 . The central axis 75 of point 70 may be a small pin or similar means. The pin is attached to a ring shaped piece 35 which is securely contained by stem 25 , while leaving sufficient room for rotation of the ring, to allow maximum rotation of point 70 , preferably in 360 degrees.
The present invention also provides a method for authenticating a written document as being unique to a particular marking apparatus. Covert-print apparatus 300 provides an efficient and logical form of document security, assuring the recipient of a written document that the origin of a document is authentic. Covert-print features provide a means for a knowing recipient to verify the origin, authorship, and/or content of any text by verifying that it was written by the possessor of a particular instrument.
Writing may be verified as authentic based on several characteristics. Preferably, verification is not based solely on covert-printed code being discernable within every portion of a questionable written ink line or mark. For example, should a signature's authenticity require confirmation, the written ink line or mark will have a majority of the surface encoded with covert print in order to qualify as authentic. It must be taken into account that writing of different letters, characters, numbers and symbols have varying amounts of overlapping within a written line or single symbol or character. In these instances, the presence of covert-printed code within the area of the character or characters that typically overlaps will not be considered as critical part to the authentication process, because the overlapping areas will likely have less distinguishable covert print than an area of the line not overlapping. During the verification process an additional security step may be employed by analyzing the position and/or angle of covert-print features 120 of point 70 . A questionable covert-printed ink line may now be compared with expected values based on the position and/or angle layout of the authentic covert-print record.
Additionally, if several samples of the authorized owner's writing are taken (signatures, etc.) using the covert-print apparatus as the means of writing, then OCR software or a method by which the written ink line or mark is verified may be refined by giving the areas of the text that overlap in the sample(s) less emphasis than other areas not overlapping when comparing the questionable text with the sample text. Workers skilled in the art will recognize that changes may be made in form and detail of this process. Further, it is not desired to limit the invention to the exact process and method described, and accordingly, all suitable other methods and processes of the authentication process will become obvious to the reader and it is intended that these methods and processes are within the scope of the present invention.
The invention can best be manufactured by introducing an additional step or steps to the known processes for manufacturing a conventional ballpoint pen, wherein point 70 of covert-print apparatus 300 is engraved with unique covert-print features 120 . The engraving may be accomplished by means including, but not limited to, use of a laser, diamond-tipped or other highly dense cutting tools, or, alternatively, by molding point 70 with covert-print features 120 already embedded in the mold. Alternatively, precision magnetizing of point 70 may be used, or the point 70 may be created using already magnetized particulates that are then molded appropriately to form covert-print pattern 120 when point 70 is utilized or a smooth spherical point for use with non-engraved magnetization only verification. Point 70 may or may not be magnetically charged and may or may not have a physical engraving.
Covert-print apparatus 300 leaves unique markings within the written ink line or mark itself, thereby identifying the specific instrument used to compose the line or mark. If each covert-print apparatus 300 is manufactured with its own unique covert-print features 120 engraved or magnetized into point 70 , anything written with that specific covert-print apparatus 300 leaves covert-print features 120 within the written ink lines or marks. This allows a recipient to verify the authenticity of a document written with covert-print apparatus 300 . (This is contingent on the instrument being assigned to and in the possession of the authorized signatory at the time of use). Additionally, any written content contained in the document may be verified in the same manner, considerably limiting any possibility of fraud or deception.
In practice, point 70 of covert-print apparatus 300 rolls over a writing surface, leaving a written line. Within the written ink line or mark, point 70 leaves features 120 (in the standard variation, covert-print negatives of the engraving), which may or may not be too small to see or notice upon casual observation of the writing with the naked eye, identifying the specific instrument that was used to write. Features 120 can be seen by examining the writing with a magnifying glass, or possibly closely with a very healthy naked eye. However, features 120 may be designed such that they cannot be copied by conventional photocopiers, or by any other method, without the original covert-print apparatus 300 . These unique markings assure the recipient of a document that it was written by a particular covert-print apparatus 300 , and is not forged or reproduced.
Covert-print apparatus 300 provides a means for heightening document security. A creator may examine writing made using the covert-print apparatus 300 for the presence of unique covert-print features 120 . The features 120 may or may not be visible with close scrutiny by the healthy naked eye, or by means of a magnifying glass (which may or may not be attached to covert-print apparatus 300 ), or by means of electronic character recognition, or optical character recognition, or by means of a chemical test, or magnetic reading device, or any of these used singly or in any combination. Covert-print features 120 could be stored in a physical or electronic database that could be made available to consumers, corporations, organizations and/or governing bodies, or these entities may store their own databases, for the purposes of verifying a document's content containing individually assigned unique markings. This verification procedure may be used to authenticate the writing and signatures contained in official documents or contracts, including but not limited to currency, bonds, stocks, securities, travelers checks, bank checks, credit cards, credit cards receipts, passports, airline tickets, labels, green cards, prescription slips, tests and examinations, police or witness reports, affidavits, research documents, legal waivers and releases, and any other business, personal, legal and/or government document in which identification of the creator or signatory is critical. It may also be used in many unofficial applications, including but not limited to personal correspondence, journaling for posterity, archiving and scrap booking, writing for publication, autographing, or a variety of other unofficial purposes. In addition, the covert-print may be used to prove date of authorship in any case in which the time of writing is an important factor, including but not limited to patent applications, checks, affidavits, and any other legally binding or non-legally binding documents. Additionally, covert-print apparatus 300 may be used simply for entertainment of its novel features.
An example of use of the covert-print apparatus 300 as a security means is now described. A ballpoint-type covert-print apparatus 300 has a point 70 that is engraved “JOHNSMITH01”. This covert-print apparatus 300 is reserved for John Smith. No other person can then order a covert-print apparatus 300 that leaves the mark “JOHNSMITH01”. John Smith now brings his writing instrument to his local bank and signs a new signature card, and within the ink lines of his signature appears the unique negative image(s) of the characters “JOHNSMITH01” repeating several times in a random configuration. Now any forged checks can be rejected, even if the signature is very similar, because the bank clerk may now verify the security markings on the check left by the unique covert-print apparatus 300 . The bank clerk or optical character recognition and verification mechanism (O.C.R.), as described in U.S. Pat. No. 6,373,573 and incorporated herein by reference may simply view John Smith's signature card, or access the bank's electronic database; or a global covert-print apparatus signatory database, and then examine the questionable check or document for the matching “JOHNSMITH01” covert-print feature. Additionally, the amounts and other handwritten fields on the check can be verified in the same manner. Thus, the authenticity of the check's signature and/or other fields' content can by verified or disproved and a potential forgery or unauthorized check modifications can be averted.
A second example employing covert-print apparatus 300 as a security device is shown in FIG. 12 . In this example, a medical prescription written by a doctor could be verified by the pharmacy using that physician's covert-print signature card, or by accessing their own or a globally maintained physical or electronic database of physician signatures with covert-print 120 feature. This application could not only reduce costs associated with fraud, reduce illegal sale and distribution of prescription drugs, and save millions of people's wasted time and energy associated with calling in highly restricted prescriptions or revisiting physicians' offices, but it could also potentially save lives. By allowing quick and easy verification of prescriptions, dangerous delays in receiving vital drugs can be avoided for the millions of people who depend on prescriptions to live. In addition, potentially harmful self-medicating, recreational use, and other abuses of prescription drugs can be avoided by significantly reducing prescription fraud.
Although the present invention has been described with reference to preferred embodiments, workers skilled in the art will recognize that changes may be made in form and detail without departing from the spirit and scope of the invention.
With respect to the above description then, it is to be realized that the optimum dimensional relationships for the parts of the invention, to include variations in size, materials, shape, form, function and manner of operation, assembly and use, are deemed readily apparent and obvious to one skilled in the art, and all equivalent relationships to those illustrated in the graphic and described in the specification are intended to be encompassed by the present invention.
The present invention—in its written aspect or in the covert-print feature itself—may include, among other things, variations that are microphotographic, spectroscopic, optical, magnetic, atomic, molecular, or biological (as in the case of DNA), in any combination or used singularly, all of which may be used as verification means.
Therefore, the foregoing is considered as illustrative only of the principles of the invention. Further, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation shown and described, and accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the invention. | A covert-print marking apparatus creates a unique marking system and method of using a casing or housing with a working-end and a non-working-end, a source or ink or other marking substance situated in the casing and a point having a covert-printing element on a outer surface of the casing. Thus the covert-printing element deposits a covert-printed line or mark with an embedded code formed by the element. The point bearing the covert-printing element is located at the working end of the casing. The marking element is a movable member that is able to rotate when moved along a surface, and the point is in fluid flow communication with the source of ink or other marking substance, chemical or element. | 1 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method and apparatus of blow molding a preform which has been previously formed by injection molding or extruding. Particularly, the present invention concerns a blow molding technique which utilizes molds arranged in two rows. 2. Description of the Related Art
In order to improve throughput, it is customarily performed in the blow molding technique that a plurality of hollow containers are simultaneously formed through one cycle including a series of steps such as injection molding step, blow molding step, ejecting step and other steps. One of the prior art systems for performing such a cycle comprises two rows of supporting plates for neck molds and two rows of blowing molds as described in Japanese Patent Publication No. 18847/1989. FIG. 9 is a cross-sectional view showing such a blow molding system which comprises an injection molding stage 10 for forming a preform and a blow molding stage 12 for forming a final product 22 from the preform. The system also comprises two rows of supporting plates 16 at each stage, each row of which are arranged spaced away from one another by a pitch P. Each of the supporting plates 16 holds one or more than two neck molds 14. The preform injection molding stage 10 includes two rows of injection-cavity molds 18 arranged opposed to the corresponding row of supporting plates 16 and spaced away from one another by the pitch P while the blow molding stage 12 includes two rows of blow-cavity molds 20 arranged opposed to the corresponding row of supporting plates 16 and spaced away from one another by the same pitch.
However, the pitch P between each row of supporting plates 16 must be selected to be relatively wide. This causes the entire system to increase in dimension because the pitch P must be determined to be compatible with the opening motion in the blow molding stage 12. More particularly, each of the blow-cavity molds 20 comprises a pair of mold halves 20a which are opened when a hollow product is to be removed out of the mold. Therefore, the magnitude of the pitch P is required to be equal to the total thickness of two inside mold halves 20a plus the movement of the blow mold halves 20a on being opened. Simultaneously, each of the mold halves 20a must have a sufficient thickness to resist a given internal pressure (blowing pressure) without flexure. Thus, such a thickness in each mold half 20a will be added into the thickness of a backing plate (not shown) for supporting that mold half. This will cause the pitch P to increase.
For such a reason, the entire molding system cannot but increase in size and also occupy a larger space. Such a problem is exaggerated when it is wanted to form hollow containers having an increased diameter. Two rows of injection molds or temperature regulating sections can be arranged at most in alignment with the rows of blowing molds. In addition, this results in increase of conveying area.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide a blow molding method and apparatus which can reduce the entire size of the system while utilizing two rows of preform supporting plates so as to increase the throughput per one cycle.
To this end, the present invention provides a method of conveying preforms to a blow molding stage while supporting the preforms by two rows of supporting plates, placing each preform within the respective one blowing mold in two rows of blowing molds for two rows of supporting plates, closing each of the blowing molds to form a hollow product and opening the blowing mold to remove the hollow product, the improvement being characterized by the steps of providing two rows of supporting plates which are variable in row pitch; supporting the preforms by the respective supporting plates; and changing the row pitch from one to another in the blow molding stage.
The row pitch between two rows of supporting plates becomes the maximum value when the blowing molds are opened in the blow molding stage. If the row pitch can be changed from the maximum value to another smaller value, the row pitch between the supporting plates only in the blow molding stage may be increased when it is wanted to increase the row pitch for the opening. The row pitch between two rows of supporting plates may be decreased on conveying or in the other operating stage. This enables the entire system to reduce in size, in comparison with the prior art system which utilizes the fixed row pitch between two rows of supporting plates.
Where each of the blowing molds includes a pair of mold halves, the first mold halves in the blowing molds may be fixedly mounted on each other in a back-to-back manner, with each of the second mold halves being only moved. In such an arrangement, each of the first mold halves can have its thinned thickness sufficient to resist the blowing pressure. The center-to-center distance between two rows of blowing molds can be correspondingly reduced when the second mold halves are opened. Even though the value of the row pitch on opening is applied to the row pitch between two rows of supporting plates on conveyance or in the other operating stage, the entire system can be reduced in size. In such a case, the row pitch between two rows of supporting plates is preferably decreased to be equal to the row pitch between two rows of blowing molds since only the first mold half is moved toward the second mold half on blow molding to reduce the row pitch between the rows of blowing molds.
Where a pair of mold halves are to be moved away from each other about the row pitch line in two rows of blowing molds, the fixed row pitch between the rows of blowing molds becomes substantially larger. If the system is constructed to be variable in row pitch, the row pitch can be increased only in the blow molding stage while the row pitch can be decreased on conveyance or in the other operating stage. This also contributes to reduction of the entire size of the system.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1 and 2 are schematic views of one embodiment of a preform moving frame constructed in accordance with the present invention, with the pitch between each row of supporting plates being variable.
FIG. 3 is a schematically cross-sectional view of the blow molding system with the blowing molds being opened.
FIG. 4 is a schematically cross-sectional view of the blow molding system with the blow molds being closed.
FIG. 5 is an enlarged view illustrating the relationship between first and second neck-mold supporting plates.
FIGS. 6(A) and 6(B) are schematic views illustrating a modification of the mechanism for changing the row pitch between two rows of supporting plates.
FIGS. 7(A) and 7(B) are schematic views illustrating another embodiment which has a different timing for changing the row pitch.
FIGS. 8(A) and 8(B) are schematic views of a further embodiment of the present invention which is applied to a blow molding stage including first and second movable mold halves in each blowing mold.
FIG. 9 is a schematically cross-sectional view of a prior art blow molding apparatus.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention will be described in connection with a biaxial orientation type blow molding process.
Referring to FIGS. 1 and 2, there is shown a neck-mold moving frame 30 which is of a square-like configuration and includes two rows of first neck-mold supporting plates 32 mounted therein such that the row pitch between these rows is variable. The row pitch can be changed between a first smaller pitch P1 and a second larger pitch P2. The moving frame 30 also includes four stoppers 30a formed therein adjacent to its four corners and four positioning members 30b for centering the supporting plates in the second pitch P2.
The moving frame 30 further includes guide shafts 34 along which the two rows of supporting plates 32 are moved. Each of the guide shafts 34 extends through each of the supporting plates 32 at a through-hole 32a. Each through-hole 32a is stepped to form a shoulder. A coil-shaped compression spring 36 is located between the shoulders in the opposite through-holes 32a and slidably fitted around the corresponding one of the guide shafts 34 which extends through the through-holes 32a. Under the influence of each spring 36, the first neck-mold supporting plates 32 are biased to provide the second pitch P2. When the supporting plates 32 are set to have the second row pitch P2, the positioning members 30b engage into triangle-shaped grooves 32b formed in the respective first neck-mold supporting plates 32 at their end faces. When any external force is applied to the first neck-mold supporting plates 32 against the action of the spring 36, the supporting plates 32 may engage with each other at their opposed faces to realize the first pitch P1, for example. Alternatively, another stopper means may be provided for positioning the first neck-mold supporting plates 32 in the first pitch P1.
As shown in FIG. 5, the first neck-mold supporting plates 32 are mounted attheir bottom on a guide rail 32c. The guide rail 32c slidably supports second openable neck-mold supporting plates 38 (also see FIG. 3). By opening and closing the second neck-mold supporting plates 38, the neck molds 14 (e.g. two for each plate) are opened and closed.
FIGS. 3 and 4 illustrate a biaxial orientation type blow molding stage intowhich the aforementioned neck-mold moving frame 30 is incorporated. The neck-mold moving frame 30 is so arranged that it is horizontally moved andguided by any suitable actuating mechanism which may be one as disclosed inU.S. patent application Ser. No. 07/559,266 or European Patent Application No. 90114722.3. Alternatively, a rotary conveyance type mechanism as disclosed in Japanese Patent publication No. 18847/1989 may be used herein.
Two rows of blowing molds 40 are provided for two rows of first neck-mold supporting plates 32. Each of the blowing molds 40 comprises a first mold half 42 fixed to another first mold half 42 in the other blowing mold in aback-to-back manner and a second mold half 44 which is movable relative to the stationary mold half 42. Each of the second mold halves 44 is rigidly connected with a movable block 46 which also serves as a reinforcing member resisting the blowing pressure. Each of the movable blocks 46 is connected with a locking and driving mechanism 48.
Each of the movable blocks 46 fixedly supports, at its top, a pushing member 50 which is used to urge the corresponding one of the neck-mold supporting plates. Each of the pushing members 50 is connected with a damper spring 52 for absorbing an impact on actuation. The pushing members50 are located at the same height whereat the second neck-mold supporting plates 38 are positioned.
In such an arrangement, one blow molding cycle is as follows:
Preforms 24 are formed in an injection molding state (not shown) and then supported by the first neck-mold supporting plates 32. The preforms 24 arethen regulated in temperature in a temperature regulating state (not shown)and thereafter conveyed to the biaxial orientation type blow molding stage.On conveyance, the row pitch between the rows of first neck-mold supportingplates 32 is set at the second pitch P2.
As seen from FIG. 3, the second pitch P2 is selected to be equal to a center-to-center pitch between two rows of first and second mold halves 42, 44 when they are opened. In each blowing mold 40, the second mold half44 is movable while the first mold half 42 is stationary. Furthermore, the two first mold halves 42 in the adjacent blowing molds 40 are rigidly connected with each other in the back-to-back manner. Therefore, the firstmold halves 42 can resist a given blowing pressure even if they have a decreased thickness. As a result, the pressure embodiment may have the second pitch P2 reduced in size, in comparsion with the prior art blowing molds 20 having a center-to-center pitch P shown in FIG. 9.
In such a second pitch P2, the preforms may be conveyed and the injection molding cavity molds and temrperature regulating pots and the others may be arranged. Therefore, the entire system may be miniaturized correspondingly.
In the biaxial orientation type blow molding stage, the row pitch in the first neck-mold supporting plates 32 is set to be the second pitch P2 whenthe preforms are conveyed into the blowing molds 40.
As shown in FIG. 3, the locking and driving mechanisms 48 are actuated after each of the preforms 24 has been placed between the first and secondmold halves 42, 44 in one pair. As the movable blocks 44 are moved by the respective locking and driving mechanism 48, the second mold halves 44 aremoved into their closed position. At the same time, the pushing members 50 are moved against the respective second neck-mold supporting plates 38. After the pushing members 50 engage the respective plates 38, the pushing members 50 moves the second movable supporting plates 38 to reduce the rowpitch between the first and second supporting plates, against the action ofthe compression springs 36. After the locking has been completed as shown in FIG. 4, the first pitch P1 is set with the opposite ends of the first neck-mold supporting plates 32 being in contact with each other. Simultaneously, the first and second mold halves 42, 44 will be brought into intimate contact with each other in each blowing mold 40. This condition enables the biaxial orientation type blow molding process to be executed. Thus, each preforms 24 will be formed into a hollow container 22stretched in both the horizontal and vertical axes.
After the blow molding step, the locking and driving mechanisms 48 are again actuated in the opposite direction to move the second mold halves 44into their opened position and to release the pushing members 50. Thus, therows of first neck-mold supporting plates 32 are automatically returned to their original positions in the second pitch P2 under the action of the compression coil springs 36. As a result, hollow containers 22 may be removed out of the blowing molds 40 in the final or ejections step.
The opening and closing of the blowing molds 40 are preformed only by driving the second mold halves 44. Therefore, the opening and closing mechanism may be simplified inconstruction and reduced in size.
It is to be understood that the present invention is not limited to the aforementioned arrangement and may be applied in various modifications or changes within the scope of the invention.
FIG. 7 shows another embodiment of a blow molding apparatus according to the present invention, in which the row pitch can be changed at a different timing. Referring to FIG. 7, each of blowing molds 40 is vertical movable between a position shown in FIG. 7(A) and another position shown in FIG. 7(B). On the upward movement, the blowing mold 40 is opened such that a preform 24 can be placed therein. On the downward movement, the final product 22 can be moved from the blowing mold 40. Alternatively, supporting plates which holds preforms may be moved vertically.
First of all, the first pitch P1 is set. Under this condition, blowing molding operation are carried out. When it is wanted to open the blowing molds, the second pitch P2 is set. After the final products 22 have been removed out of the molds, the row pitch is again set at the first pitch P1. During the steps before and after the blowing molding stage, the conveying and molding of preforms 24 can be realized with the first pitch P1. Thus, the entire system can be reduced in size. In such a case, the rows of first neck-mold supporting plates 32 may be biased to set the second pitch P1 under the action of a coil-like tension spring 70. In order to set the second pitch P2, the first neck-mold supporting plates 32may be moved away from each other against the action of the tension spring 70 by the use of any suitable drive mechanism. If done so, any external force will not be required to provide the first pitch P1 in the conveying or other step.
The present invention may be applied also to a blow molding system including blowing molds 20 each of which comprises a pair of mold halves 20a movable into their open position as shown in FIG. 9. Such as embodiment is shown in FIG. 8. Referring to FIG. 8, two rows of blowing molds 20 has a row pitch equal to the second pitch P2. During one cycle including preform placement, blow molding and final product removal, firstneck-mold supporting plates 32 are set to have the same row pitch as that of the blowing mold rows, as shown in FIG. 8(A). In the conveying or othersteps, the row pitch is set to be smaller than the second pitch P2 (i.e. the first pitch P1), as shown in FIG. 8(B). As a result, the size of the blow molding stage is maintained invariable, but the conveying path and other stages may be reduced in size. Even in such a case, it is preferred that the first neck-mold supporting plates 32 are biased to provide the first or smaller pitch P1 therebetween at all times, under the action of the tension spring 70.
Although the present invention is preferably applied to a blow molding system operated in a cycle having all the steps from the initial injectionmolding step to the final ejection step, it may be similarly applied to a so-called cold preform system operated with only two steps of regulating the temperature of a preform and blow molding the preform at a proper blowing temperature. In the latter case, such neck-mold supporting plates as described above will not be utilized and the row pitch between supporting plates for supporting preforms at their neck portions may be variable.
The aforementioned embodiments are not intended to limit any mechanism for changing the pitch in the supporting plate rows. FIG. 6 shows another mechanism for changing the row pitch by the use of tapered surfaces which are moved relative to each other. As seen from FIG. 6(A), each of the first neck-mold supporting plates 32 includes a tapered face 32d formed therein at one side edge and functioning as a cam follower. A plate closing cylinder 60 is disposed above the first neck-mold supporting platerows 32. The cylinder 60 comprises a cylinder rod 62 which supports a slopecams 64 adapted to cooperate with the tapered faces 32d in the supporting plates 32. When the cylinder rod 62 is downwardly moved by the cylinder 60before the second mold halves 44 are moved to their closed positions or in synchronism with the mold closing operation, the slope cams 64 cooperate with the respective tapered faces 32d in a surface contact manner to move the first neck-mold supporting plates 32 toward each other so that the first pitch P1 will be provided, as shown in FIG. 6(B). | The present invention provides a blow molding apparatus which conveys preforms to a blow molding stage while holding the preform by two rows of supporting plates, places the preforms in two rows of blowing molds disposed corresponding to the supporting plates, blow molding the preform into hollow containers when the blowing molds are in their closed positions, thereafter opening the blowing molds to remove the molded containers therefrom. In this blow molding apparatus the row pitch between the supporting plates is changed between one when the blowing molds are opened and another when the blowing molds are in the other conditions. In this apparatus, the row pitch between the supporting plates is not required to maintain the maximum pitch when the blowing molds are opened. Thus, the blow molding system may be reduced in size and occupying area. | 1 |
This is a continuation-in-part of U.S. Ser. No. 07/944,949 filed Sep. 15, 1992, now abandoned.
FIELD OF THE INVENTION
This invention relates to a method and an apparatus for processing of materials such as organic waste material. In particular, this invention relates to an apparatus for compressing and extruding the material, with subsequent pelletization, if desired.
BACKGROUND TO THE INVENTION
The processing of material such as waste water residuals (sewage sludge), manure, yard waste, food processing wastes, etc., generally includes a stage in which the material is put into a form for subsequent use. Commonly, the material is pelletized for later use as fertilizer, for example.
Pellets are a desirable form because such wastes, even at the tail end of a processing stream have a large water component and relatively small pellets are more easily dried than non-pelletized material. In particular circumstances, such as the processing of sewage sludge into fertilizer, other materials are often mixed into the waste. Formation of the combined materials into evenly sized pellets results in a product in which the combined materials may be evenly distributed in use, such as during spreading onto a farmer's field. It has generally been found that it is necessary, or at least desirable to mix binding agents with the material of the processing stream prior to pelletization in order to ensure that the material have sufficient adhesion properties. Otherwise, the treated material might crumble apart, which is generally undesirable.
Several approaches to downstream pelletization of organic waste material and the like have been taken in the past. One pelletizer includes a large diameter disk having a shallow circumferential wall. The disk rotates about an axis perpendicular to the center of the disc and inclined to the horizontal. Moist material is fed onto the disk and sticks to the disk. As the disk rotates, pellets are formed.
Another approach involves a tilted cylindrical drum which rotates about the central axis of the drum. Material is fed into the raised end of the drum. Material is pelletized as the drum rotates. Interior drum walls having openings spaced radially inwardly of the drum periphery permit only the larger particles (which rise to the top of the rotating material) to flow towards the other end of the drum for eventual exit therefrom.
These two approaches produce the pellets desired in many situations, but suffer the disadvantage of being relatively slow. Pellet size and uniformity of size and shape of the pellets formed could be improved.
Yet another apparatus utilizes rollers which act against a cylindrical screen to force material through the screen web.
A known pelletizer utilizes a pair of horizontal rollers in abutting side-by-side contact with each other. The rollers rotate so that material may be fed downwardly into the crevice between the rollers. There are notches in each of the rollers which are aligned with each other so that material enters the notches, is compressed therein as the rollers rotate and expelled in pelletized form from the underside of the rollers.
In any event, to be effective, any pelletizer or pelletization process takes into account the fact that organic material being treated includes living matter, generally a bacterial component, the maintenance of which is generally desirable. For example, bacteria-containing sludge waste is desirable for use as fertilizer. Pelletization processes which kill or otherwise degrade the bacterial component to a degree sufficient to reduce the usefulness of the pelletized sludge as fertilizer are considered disadvantageous.
SUMMARY OF THE INVENTION
It has thus been found possible to compress and extrude such waste material according to the present invention. Extruded material may be cut into pellet-sized pieces as it is extruded from the apparatus if desired.
In a first broad aspect, an apparatus of the present invention includes a container for the material having an inlet end and an outlet end for the inflow and outflow of the material. There is a first plate located at the outlet end and rotatable with respect to the container about an axis extending between the inlet and outlet ends. There is a second plate located within the container and rotatable with respect to the container about the axis and axially spaced apart from the first plate. The second plate has a leading radial edge and a surface facing toward the outlet end angled from the leading edge toward the outlet end for forcing material in contact therewith axially toward the outlet end of the container so as to compress material between the first and second plates as the second plate rotates. The first plate has one or more apertures through it for extrusion of compressed material through the first plate as the first plate rotates.
According to a preferred aspect of the invention, described in greater detail below, the first plate rotates in a first rotational direction (either clockwise or counterclockwise) and the second plate rotates in the opposite direction as the material is processed through the apparatus. The plates are rotatable at independently selected speeds so as to select the degree of compression of material.
The apparatus can include means for conveying material from the inlet end to the leading edge of the second plate.
In the preferred apparatus the container is oriented with the inlet end above the outlet end so that material travels under the force of gravity from the inlet end to the second (i.e., upper) rotating plate. Further, the apparatus includes a first stator located above the second plate and having walls defining a plurality of compartments so as to retain material positioned within each compartment (i.e., that has fallen or otherwise entered into the compartment) such that, as the leading edge of the second plate passes under each compartment as the second plate rotates, material within the compartment is brought into contact with the leading edge. The leading edge thus grabs the material to entrain it below the second plate into the zone of the apparatus between the first and second plates.
The apparatus most preferrably includes another rotating member within the container vessel, rotatable about the axis and located above the first stator. The member has a pair of wings, generally coplanar with each other, having spaces therebetween to permit passage of material from the inlet end into the first stator. At least one of the wings, but preferrably both, has an underside angled downwardly of the wing's leading edge so as to force downwardly material in contact with the underside.
There can be a second stator located above the rotatable member and having walls defining a plurality of compartments so as to position material within each compartment such that as the member rotates to a position such that one of the spaces between the wings brings the compartment into communication with an underlying compartment of the first stator to permit material to fall under the force of gravity from the compartment into the underlying compartment of the first stator.
There can be a third stator located between the first and second plates and having walls defining a plurality of compartments so as to limit rotational movement of material within the compartments.
Preferrably, the apertures of the first plate are angled downwardly and away from the direction of rotation the first plate so as to facilitate flow of material thereinto as the first plate rotates. Further, the walls of the third stator can be angled downwardly and in the direction of rotation of the second plate so as to enchance flow of material in the direction of the apertures as the first and second plates rotate.
In a very specific embodiment, the apparatus includes a powered shaft rotatable about the axis having the second plate and rotatable member fixedly mounted thereto. The first plate is rotatably mounted on the same shaft but powered by a second a motor geared to rotate the first plate.
As previously mentioned, the apparatus may include cutting means for cutting material to a predetermined length as the material emerges from the apertures of the first plate.
In a second broad aspect, an apparatus of the present invention includes a container for material to be processed having inlet and outlet ends. There is a compression zone at the outlet end within the container including means for exerting compressive forces on material in the zone in an axial direction toward the outlet end so as to compress the material. There is slicing means within the container and located toward the outlet end for movement in a direction transverse to the axial direction for slicing off a portion of the compressed material. There is a surface associated with the slicing means having an axial component such that the surface is oriented to force the sliced portion toward the outlet end with movement of the slicing means. As with the first broad apparatus aspect, there is extrusion means at the outlet end having apertures located to accept therethrough material forced toward the outlet end by the surface whereby material is extruded from the outlet end of the container.
A preferred slicing means includes a rotatable plate having a side which is oriented toward the compression zone against which material is compressed by the means for exerting compressive forces. The means for exerting compressive forces can be a helical screw rotatable about an axis parallel to the axial direction.
The slicing means can further include a blade located to have a leading edge for slicing off a portion of the compressed material with rotational movement of the rotatable plate. The blade itself can have a surface oriented toward the outlet end shaped to guide the sliced off portion toward the apertures of the extrusion means. There can, of course be a number of blades and extrusion outlets.
In a first broad aspect of the method of the present invention, organic waste material or the like is processed by pressing the material into a cavity between first and second axially spaced apart parallel plates rotating about a common central axis in opposite rotational directions to each other. The method includes compressing the material between the plates by means of a surface on the first plate angled into the cavity and subsequently extruding the material through apertures in the second rotating plate.
More preferrably, the first plate is located axially above the second plate and the method includes the step of feeding material to be processed onto the top of the first plate for entry into the cavity through one or more openings in the first plate. The feeding step can include limiting rotation of material located between the first and second plates by means of a stator located above the second plate, the stator having upright walls defining compartments to retain material positioned in each compartment.
There can be a third plate located axially above the first plate and the feeding step can include the step of passing material to be processed under the force of gravity through openings between rotationally spaced apart wings of the third plate and compressing the material between the third and first plates by means of a surface on an underside of the third plate angled toward the first plate.
Compressing the material between the third and first plates can include the step of limiting rotation of material located between the third and first plates by means of a stator located therebetween, the stator having upright wall defining compartments to retain material positioned in each compartment.
The feeding step can include limiting rotation of material located above the third plate by means of a stator located above the third plate, the stator having upright walls defining compartments to retain material positioned in each compartment.
The extruding step can include directing the material through apertures angled downwardly and away from the direction of the rotation of the second plate.
In a second broad aspect of the method of the present invention, processing the material includes forcing the material against a moving plate having a planar motion by pressing the material in an axial direction perpendicular to the plane of motion. This is followed by slicing off a portion of the material being compressed by means of a blade moving parallel to the motion of the plate and extruding the sliced off portion through one or more apertures in the plate.
The method, of course can include a step of cutting the material to length as the material emerges from the apertures.
BRIEF DESCRIPTION OF THE DRAWINGS
Certain embodiments of the invention are described with reference being made to the accompanying drawings wherein:
FIG. 1 is a side elevation of a first embodiment of the present invention in partial section;
FIG. 2 is a detail in elevation of compacting and extruding portions of the FIG. 1 embodiment;
FIG. 3 is a top plan view of the uppermost stator of the FIG. 1 embodiment, this being the same as the middle stator;
FIG. 4 is a sectional view of the stator shown in FIG. 3 taken along 4--4 of FIG. 3;
FIG. 5 is a top plan view of the uppermost rotating member of the FIG. 1 embodiment;
FIG. 6 is a side elevation of an uppermost rotating member shown in FIG. 5;
FIG. 7 is a top plan view of the middle rotating member of the FIG. 1 embodiment;
FIG. 8 is a side elevation of the middle rotating member shown in FIG. 7;
FIG. 9 is a top plan view of a lower stator of the FIG. 1 embodiment;
FIG. 10 is a side elevation of the lower stator shown in FIG. 9;
FIG. 11 is a top plan view of a lowermost rotating member of the FIG. 1 embodiment;
FIG. 12 is a sectional view taken along 12--12 of FIG. 11;
FIG. 13 is a top plan view of an extruder die for use as part of the FIG. 1 embodiment;
FIG. 14 is a side elevation of the die of FIG. 13;
FIG. 15 is a side elevation of a second embodiment of the present invention in partial section;
FIG. 16 is a top view of a cutting-extruder member for use as part of the FIG. 15 embodiment;
FIG. 17 is a side elevation of a portion of the cutting-extruder member shown in FIG. 16 as seen from the right hand side of FIG. 16;
FIG. 18 is a top plan view of a rotary wheel of the FIG. 15 embodiment;
FIG. 19 is a sectional view taken along 19--19 of FIG. 18 showing an enlarged detail of extruder outlets; and
FIG. 20 is a bottom plan view of the rotary wheel shown in FIG. 18.
DETAILED DESCRIPTION OF THE INVENTION
Turning to the drawings, a first embodiment pelletizing apparatus 10 is shown generally in FIG. 1. Material to be pelletized is fed through an auger rotatingly housed in tube 12 into the upper end of drum 14. The material travels under the force of gravity toward the lower end of the drum where it is eventually entrained, compacted and extruded out of the bottom of the apparatus, the entrainment, compaction and extrusion portions of the appartus being described in greater detail below. Strands of extruded material are cut to length as desired by cutters well known in the art, and the newly formed pellets drop downwardly for collection.
A detailed view of the entrainment, compaction and extrusion portions of the apparatus is shown in FIG. 2. The uppermost member of this part of the appartus is stator 16, shown in even greater detail in FIGS. 3 and 4. Stator 16 is installed in a fixed position with respect to the drum. The stator includes inner collar 18, rim 20 connected to each other by dividers 22 so as to be divided into pie-shaped compartments 24. Each divider lies on a radius extending outwardly from the central axis of shaft 26 and is spaced by about 30° from its neighboring dividers.
Located in-line immediately below the uppermost stator is member 28 affixed to vertical rotary shaft 26, under rotational control of motor 30. Rotary member 28 is shown in greater detail in FIGS. 5 and 6. Collar 32 of member 28 is affixed to shaft 26 by a key received in a keyway and fixed in place by a set screw. Member 28 includes two essentially identical wings 34 affixed to its central collar, the wings being symmetrically located with respect to each other about a central vertical axis of the member. A first portion 36 of each wing descends downwardly from its leading edge 38 about 11/4 inches (about 3.2 cm) through an angle of about 90°. The remaining 30° portion 40 lies generally in a plane perpendicular to the vertical. Leading edge 38 and following edge 42 of each wing each lie generally on a radius extending horizontally outwardly from the central axis of shaft 26 and are spaced about 120° from each other. The leading edge portion of the wing is curved or otherwise bevelled downwardly in the rotational direction of the following edge of the wing.
Located in-line immediately below upper rotary member 28 is a second stator 44. Middle stator 44 is essentially identical in shape to uppermost stator 16, but it is rotationally offset from the first stator such that each divider 22 of the underlying stator bisects the pie-shaped compartment of the overlying stator when viewed from above. Stators 16, 44 are fixed with respect to rotary shaft 26 which passes through the central collars of the stators. The stators are each fixed in position with respect to drum 14 to which they are bolted. The vanes or dividers 22 of the stators act to limit rotation of material in stator compartments and in this way are considered to be oriented in an upright position.
Located in-line immediately below intermediate stator 44 is member 46 affixed to rotary shaft 26. Rotary member 46 is shown in greater detail in FIGS. 7 and 8. Rotary member 46 includes two essentially identical wings 48 rigidly affixed to central collar 50. As seen in plan view, each wing 48 is more or less semi-circular. The leading edge 52 of each wing 48 of the middle rotary member is spaced above the following edge 54 of the other wing. Each wing descends downwardly from its leading edge to its following edge about 3/4 of an inch (about 1.9 cm). Protruding from the underside of the trailing end of each wing 48 is deflector 56 which is rougly triangular in cross-section. Deflector 56 spans the full extent of following edge 54.
Located in-line immediately below rotary member 46 is lower stator 58. Stator 58, like the other stators, is installed in a fixed position with respect to the drum. Stator 58 includes inner collar 60, outer rim 62, and intermediate ring 64, the three annular elements being concentric with one another. Tilted vanes 66 extend radially outwardly from collar 60 to rim 62. Similarly angled vanes 68 extending radially outwardly from ring 64 to rim 62. There are eight of each of vanes 66, 68, respectively, the differently extending vanes alternating with each other and being evenly spaced from each other. There is thus an angle of 45° between neighboring vanes 66, each of which angle is bisected by one of vanes 68. All of the vanes are tilted in the same direction and to about the same extent, roughly 45° with respect to the vertical (which is greater than the extent of the tilt shown in the figures).
Located in-line immediately below the lower stator is lowermost rotary member 70. Member 70 is rotatably mounted with respect to shaft 26. Member 70 is under the rotational control of pinion 72, the member and pinion being operably connected by meshing teeth 74, the pinion being powered by motor 76.
Lowermost member 70 is fitted with die 78 containing a row of extruder apertures 80. As can be seen most readily in FIGS. 11 to 14, die 78 is held in place by screws on one side and supported by the lowermost member 70.
The arrangement is such that in operation, upper and middle rotary members 28, 46 rotate in the same direction and at the same speed as each other, these members being fixedly attached to rotary shaft 26 under the control of motor 30. Lowermost rotary member 70 is set to rotate in an opposite rotational direction to the other rotary members. Being under the control of separate motors, the rotational speed of the lower member 70 can thus be set independently of upper and middle rotary members 28 and 46. The relative rotational directions of shaft 26, rotating extruder disc 70 and pinion 72 are shown by arrows 82, 84, 86, respectively.
Material fed into the apparatus follows the path generally illustrated by arrow 88. The amount of inflow is controlled by the speed of an auger (not shown) located in inlet duct 12. The feeding auger is operated by a separately controlled motor, also not shown. Material drops into compartments 24 of the uppermost stator. Distribution of such material may be mechanically enhanced, as desired, by a vertical auger rotating above stator 16.
The divider walls of the uppermost stator limit rotation of material in the compartments in reaction to contact with the top surface of upper rotating member 28. As member 28 rotates in a counterclockwise direction, as viewed from above the apparatus, material can fall between the gap between the following edge of one rotating wing and the leading edge of the other wing. Such material is captured or entrained by the upper rotating member and pressed into compartments of the middle stator. The downwardly sloping underside of rotating member 28 forces entrained material downwardly into compartments of the middle stator.
Rotating immediately below the middle stator is middle rotating member 46. Material is drawn into compartments of the lower stator by rotating member 46. As member 46 rotates, material being forced downwardly through the compartments of the middle stator is captured under leading edge 52. The underside of each wing of member 46 is inclined to force material in contact therewith in a downward direction as the member rotates.
In full operation, once a steady-state flow of material is reached, compartments of the middle and lower stators are generally full of material. Material is continuously being captured by the upper rotating member and fed into compartments of the middle stator. In turn, material is constantly drawn and compressed into compartments of the lower stator by the middle rotating member.
Egress of the material out of compartments of the lower stator is through the holes 80 of extruder die 78. The plates or vanes of the lower stator are angled so as to force compressed material passing through the stator in a generally counterclockwise direction. Extruder apertures 80 are oriented so as to accept therethrough material as lowermost member 70 rotates in a clockwise direction. Exiting material is cut to the length desired by conventional cutters, illustrated below in connection with a second embodiment. It is possible that material would be extruded and formed to length, if at all, at some later time.
In operation, the speed of rotation of the rotating capturing and compressing members and the speed of rotation of the bottom rotating plate member are independently controlled. It is possible to select the pressure being exerted on the compressed material in the lower stator from a range of pressure by varying these relative speeds. The faster the lower plate rotates with respect to the upper two rotating members, the lower the pressure exerted on compressed material within the compartments of the lowermost stator. Lowering the relative rotational speed of the lowermost plate with respect to the upper rotating members will, of course, raise the pressure exerted on the compressed material, thereby increasing the degree of compaction of the material prior to extrusion.
Drum 14 of the illustrated apparatus has an inner diameter of about 30 inches (about 76 cm). The upper stator and the middle stator each have a height of about three inches (about 7.6 cm) while the lower stator has an overall height of about two inches (about 5.1 cm). The rotary shaft and the extruder plate are each driven by a 20 horsepower gear motor having a speed which can be varied thanks to an AC inverter control, and a specific output torque.
The apparatus shown is of mill steel. Rotating members 28, 46 are each fixedly connected to rotary shaft 26 by means of a key received in a key way and set screws.
It has been found possible, with the illustrated first embodiment apparatus, to process sewage sludge containing appropriate binding agents and a water content of about 40%, at a continuous throughput rate of about eight tons per hour. A single extuder die having twenty-eight 3/8-inch holes was used. An appropriate turning speed of the upper rotating members 28, 46 connected to the rotary shaft was found to be 26 r.p.m. A satisfactory turning speed of the lower rotating extruding member 70 was found to be 15 r.p.m. Suitably compacted sludge appropriate for use as fertilizer was thus obtained. Tests determined that the bacterial content of the processed sludge was satisfactory for the product to be used as fertilizer.
It is expected that the disclosed apparatus could well process a material having a moisture component selected from over a wide range. It should be possible to process a stock material having anywhere from about 5% to 60% water, or possibly higher with the single apparatus. An upper limit of the water component would be reached where it is no longer possible to obtain extruded material of the desired consistency. Obviously the parameters of operation, relative and absolute speeds of the various components, would have to be varied to obtain results desired in a particular situation. It might also be preferrable to alter the number of dies used, etc.
Die 78 of the first embodiment is installed so as to be interchangeable with other dies. In this way dies having extruder holes of various diameters may be intstalled as needed. It will further be appreciated that the extruder wheel may be fit with more than one die. It would generally be preferred, although not absolutely necessary, that dies be evenly angularly spaced from each other. A given die may have more than one row of extrusion outlets. Many variations are possible. Die sets having as few as one hole could be used, extruding holes could be drilled directly into rotating member 70, etc.
An apparatus of the present invention would often be used as part of a pre-existing sewage treatment process. As such, modifications to the apparatus might be necessary to adapt the invention for such use. For example, an apparatus having a larger throughput may be desired. The size of the components of the apparatus could be suitably chosen. It may be desirable, for whatever reason to have material fed into the lower end of the apparatus and extruded from the upper end. If the apparatus were inverted to accommodate such a requirement, a mechanism for conveying material from the apparatus inlet to the rotating entrainment plate would be necessary. An auger similar to that described below in connection with a second embodiment apparatus could provide such a suitable conveying means. It might be required, under particular circumstances, that material be expelled through a stationary, rather than a rotating extruder. It is the relative movement of the apparatus components that is important. Thus, in such case, the rotating parts of the illustrated embodiment could be fixed in place and the stationary parts, such as the drum and stators could be arranged so as to rotate, appropriate modifications to other portions of the appartus being made.
As part of a larger material processing operation, in which inflow of material into the apparatus varies from time to time, appropriate sensors could be installed to alter the speed of operation of the apparatus in response to such variations. This would be done to ensure that the stator compartments of the apparatus remain full, i.e., that the preferred steady-state flow of material is maintained so as to maintain a fairly constant degree of compaction of material.
The motors of the illustrated embodiment are under AC inverter control which are under computer control, circuitry being contained in panel 90. Parameters for operation of the various components can thus be pre-set, facilitating operation of the apparatus.
A second embodiment apparatus 92 is illustrated in FIGS. 15 to 20. Drum 94 is provided with feedstock material inlet 96 at its upper end. Rotary auger 98 is under the control of motor 100. Below compression zone 102 is provided rotary wheel 104, journaled about the central shaft 106 of rotary auger 98 so as to have the same axis of rotation as the auger. Rotary wheel 104 is powered by an arrangement similar to that shown for the lowermost extruder wheel of the first embodiment apparatus, described above.
Rotary wheel 104 is fitted with four cutting-extruder members 108. Member 108 provides blade 110. Aperture 112 below blade 110 curves downwardly and communicates with extruder channels 114. The position of the slicing blade can be adjusted by means of screw 116. Plate 118 defines extruder outlets 120, the plate being held in place by screws 122. Conventional cutters 124 are provided to cut material as it emerges from extruder outlets 120.
In operation, the auger is rotated in a direction to convey feedstock downwardly toward compression zone 102, in the case of the illustrated embodiment, in the clockwise direction as viewed from above. Rotary extruder wheel 104 is rotated in a direction such that leading edge 126 of blades 110 slice off material in the compression zone, in the case of the illustrated embodiment, in the clockwise direction as viewed from above. The rotational speeds of the auger and rotary wheel can be set independently of each other.
Material is thus fed into drum 94 through inlet 96 and generally follows the path of arrow 128. Eventually the compression zone becomes filled with material which then undergoes compaction due to compressive forces exerted by the auger and in-flow of additional material. Once a suitable pressure is reached within the compression zone, rotary wheel 104 is turned on and blades 110 slice off portions of the material as the wheel rotates. Material is forced downwardly by bearing surfaces 130 through apertures 112 and out of the drum through extruder outlets 120. Cutters 124 serve to cut the extruding strands of material into appropriate lengths.
As with the first embodiment, there are many variations available to a person skilled in the art to the second embodiment which lie within the scope of the invention as defined in the appended claims.
Both embodiments of the invention disclosed herein are for use in industrial-type settings and it will be appreciated that the invention can be used to process and pelletize material continuously. It will of course be understood that variations in the size of the apparatuses, materials of construction, the precise means for providing relative movement of the compaction and extrusion components, etc. can be varied and remain well within the scope of the invention. For example, the mill steel of the disclosed embodiment could be any suitable material, such as hard steel, stainless steel, plastic, particularly polyvinyl chloride, fiberglass, tool steel, etc. The scope of the invention is defined by the claims which follow. | Apparatus and method for processing of material such as organic waste material by compressing and extruding the material, with subsequent optional pelletization. In one embodiment, an apparatus includes a container having inlet and outlet ends. There is a first plate (70) at the outlet end and rotatable about an axis extending between the ends. There is a second plate (28, 46) axially spaced apart from the first plate having a leading radial edge and a surface facing toward the outlet end angled from the leading edge toward the outlet end for forcing material in contact therewith axially toward the outlet end so as to compress material between the first and second plates as the second plate rotates about the axis. The first plate has apertures for extrusion of material. A second embodiment apparatus includes a compression zone at the outlet end including means for exerting compressive forces on material in the zone in an axial direction toward the outlet end so as to compress the material. There is slicing means (108) for movement in a direction transverse to the axial direction for slicing off a portion of the compressed material and a surface associated with the slicing means oriented to force the sliced portion toward the outlet end. | 1 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] NONE
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Research and development of this invention and Application have not been federally sponsored, and no rights are given under any Federal program.
REFERENCE TO A MICROFICHE APPENDIX
[0003] NOT APPLICABLE
BACKGROUND OF THE INVENTION
[0004] 1. Field of the Invention
[0005] This invention relates to an interactive sports contest system which allows remotely located participants to compete with one another. More particularly, it relates to an interactive professional wrestling fantasy contest system in which team rosters and rating scores are utilized in determining winners and losers of a scheduled competition between the remote participants.
[0006] 2. Description of the Related Art
[0007] As is known and understood, interactive contest systems are known and have been developed for various sports team competitions commonly known as “fantasy baseball”, “fantasy football”, and “rotisserie league”. One such system is that set out in U.S. Pat. No. 5,263,723, described for use in interactive baseball, basketball, football, hockey, soccer, golf and other events, where individual player performances may be presented in the form of selected statistics, and wherein each participant in the contest is given a certain amount of imaginary dollars with which to purchase a subset of selected players.
[0008] Although such interactive contest system may perform its described operations, a reading of it quickly illustrates how complicated it is—including central controllers, data terminals and links, statistical and team roster databases, player scoring computers, etc.—all of which must interact precisely to determine the individual scores. In describing a fantasy basketball league, for example, computer formula are utilized to take into account minutes played, field goals made and missed, 3-point goals made and missed, free throws made and missed, rebounds, assists, technical fouls, personal fouls, and the number of games in which the selected player's team won or lost. Clearly, that becomes quite different for a participant in such contest competition to determine how he/she is doing at any instant of time. Formula for other types of fantasy sports competitions are also set out, noted as being usable for implementation with other athletic events, but similarly exhibit the same problems in not allowing a participant to keep up with the scoring as it goes along.
[0009] Obviously, if someone wished to compare his/her own skills of selection without actually participating in such competition, that cannot be done with contests of this type without joining in on the league, and paying its required participation fee. Equally obvious is that by being assigned a certain number of imaginary dollars with which to purchase players available—so that the participant with the highest return on investment is there declared to be the contest winner—the interactive contest system which results is simply not one readily and easily usable, except by a limited number of diehard participants.
SUMMARY OF THE INVENTION
[0010] As will become clear from the following description, an interactive contest system for use in a professional wrestling fantasy league according to the present invention can be easily implemented, and easily scored by its individual participants with pen and paper at the same time. As will be appreciated, this follows from the fact that televised professional wrestling competitions on network or cable are set by a promotion company having a “stable” or roster of wrestlers within its organization. Worldwide Wrestling Entertainment, Inc., for instance, has some 100 professional wrestlers under its control who regularly appear on one of its Monday, Thursday and Sunday wrestling programs, and sometimes on two or more of them each week. In accordance with the teachings of the invention, competition may be had among a plurality of remote participants in such a professional wrestling fantasy league by aggregating to each participant several of these professional wrestlers to form a team roster, and rating scores attributable to their performances during these television show appearances in accordance with a predetermined set of identified database criteria. In a one-month's series of televised appearances of these wrestlers, participant “winners” and “losers” can be determined depending upon what happens during these televised showings.
BRIEF DESCRIPTION OF THE DRAWING
[0011] These and other features of the invention will be more clearly understood from the following description, taken in connection with the accompanying drawing, in which:
[0012] FIG. 1 is a simplified block diagram helpful in an understanding in its operations.
DETAILED DESCRIPTION OF THE INVENTION
[0013] As will become clear from the description below, identified database criteria maintained by the system operator 20 assigns positive point values to a first predetermined set of televised professional wrestling performances, and/or assigns negative point values to a different set of televised professional wrestling performances. For example, points can be established for a “drafted” wrestler when he/she is the winner of a match, is the winner of a main-event match, or is the winner of a match through the use of a specialized move unique to that wrestler. At the same time, different sets of points can be established for one of the winning of a match by disqualification, winning an opening match of the televised show appearance, or being interviewed as part of the televised show itself. Correspondingly, negative points can be awarded according to the invention for one's losing a match, for being disqualified from a match, or by assaulting someone who is associated with the television show appearance other than the wrestling opponent—e.g., a referee, an announcer, a ringside official, etc.
[0014] As will be seen below, different ways exist for viewers to compete in contest with these various wrestling entertainments, and in a simple manner which allows him/her to “score” for their own “drafted” wrestlers, as well as for those which they may not have selected.
[0015] In accordance with the invention, three manners of participation in the contest system are available, with one of them preferably slated for a series of competitions along the lines of head-to-head contests similar to that in which competitions exist between seeded athletes and/or their teams, as #1 against #15, #2 against #14, #3 against #13, and so forth, hopefully resulting in a final competition between successful winners, #1 against #2. In accordance with a preferred point ascribing system as presently envisioned, points may be awarded (or subtracted) in the following manners, and in the amounts set forth, and for the indicated criteria assigned to such database.
NAME ABBREVIATION POINTS a. TV TIME TVT 2 b. TV MICROPHONE TVM 5 c. WRESTLING WRE 3 d. SPECIAL MATCH SPM 5 e. WINNING A MATCH WIM 3 f. WINNING A SPECIAL MATCH WSM 7 g. WINNING A FINISHING MOVE WFM 7 h. WINNING-DISQUALIFICATION WDQ 2 i. FINISHING MOVE FIN 4 j. OPENING OPN 8 k. OPENING SHOW W/MATCH OPM 4 l. MAIN EVENT MNE 10 m. STRIKING AN AUTHORITY STA 6 n. SHOW STOPPERS SST 10 o. LOSING A MATCH LOS 3 p. LOSING/DISQUALIFICATION LDQ 2
[0016] A description of these criteria according to the invention may be as following:
a. (TVT)—awarded anytime one of the “drafted” wrestlers is seen on camera; b. (TVM)—awarded anytime one of the “drafted” wrestlers speaks on a television microphone and is heard by the audience; c. (WRE)—awarded when participating in a regular singles or tag-team match; d. (SPM)—awarded anytime one of the “drafted” wrestlers appears in a Title Match, a Hard-Core Match, a Rumble or any other match deemed to be special; e. (WIM)—awarded anytime one of the “drafted” wrestlers wins any type of match; f. (WSM)—awarded anytime one of the “drafted” wrestlers wins a special match as identified in “d” above; g. (WFM)—awarded where one of the “drafted” wrestlers successfully employs one of his/her finishing moves to win a match; h. (WDQ)—awarded when winning a match because of disqualification; i. (FIN)—awarded when the “drafted” wrestler employs one of his/her finishing moves during the course of a match; j. (OPN)—awarded when the “drafted” wrestler opens the televised show with live action other than participating in a match; k. (OPM)—awarded when the “drafted” wrestler opens a televised show with any type of match; l. (MNE)—awarded when the “drafted” wrestler wrestles in a main event, or, for example, as the last match of a televised show; m. (STA)—awarded when the “drafted” wrestler strikes a person of authority as a referee, announcer, or promoter; n. (SST)—awarded when the “drafted” wrestler is involved with a special interview segment of a show; o. (LOS)—awarded when the “drafted” wrestler loses any type of match; and p. (LDQ)—awarded when the “drafted” wrestler loses a match because of disqualification.
[0033] In carrying out the invention, and illustrating how it might be utilized with a professional wrestling promoter having 100 or so professional wrestlers under contract, 10 remote participants may be joined into a league, with each one in turn selecting through its own data terminal 14 one of the 100 wrestlers in forming a team roster—the first selecting from the group of 100, the second selecting from the remaining 99, the third from the remaining 98, etc. Such list of wrestlers forming its own database storage means 10 , might include for the Worldwide Wrestling Entertainment, Inc. promotion, The Rock; Brock Lesnar; Kevin Nash; Steve Austin; Big Show; Kurt Angle; Undertaker, etc. Eight wrestlers selected by each participant would then form a “team”.
[0034] During preferably a one-month's worth of televised show appearances, each participating contestant could then watch each televised wrestling show on network or cable, entering the point awards scored (positive, or negative) not only for his/her “drafted” wrestler, but for all those contracted with the promoter while the show is being televised. At the end of each show, the participant would then be able to score his/her own team's performance, and compare it with that available with other groupings of selected wrestlers. At the end of the time period in question, an overall winner would be determined as such scoring is likewise being simultaneously maintained by the system operator in its own database 20 of match watching. (A second database storage means 12 listing the parts to be awarded, as well as each wrestler's finishing moves would be maintained as well, linked with the first database and updated as needed.) Depending upon the number of players participating in a competition, 15, 31 or 63 other winners of like 10-contestant leagues could be determined, to then be followed in a final tournament—as, by participating in a further one week competition between pairs of winners, with the individual winner of each such pair continuing to compete against one another until an ultimate winner is declared. In such competition, a fee could be charged for each participant—of some $19.95 for example—with the prize ultimately awarded being determined on the numbers of participants who choose to compete.
[0035] In a second manner of play, individuals can elect just to play for “fun”, without engaging in head-to-head competition in league format. There, a person could just sign up for one-month of play, selecting on the terminal Internet screen 16 his/her use name and password along with the names of the wrestlers “drafted”, for the system operator to maintain the scoring and reporting back with the outcome.
[0036] In a third manner of play, the Internet user could form their own league, with its own set of rules, abbreviations and points to be assigned to any televised criteria, for the system operator to maintain that as well, and to provide the results once the selected time period has run its course.
[0037] As will be understood, these manners of use of the present invention allow the professional wrestling fan to keep score whenever watching a televised network or cable wrestling show in comparing his/her selections against those of others. Of course, while a participant-by-participant individual draft of available wrestlers from the professional wrestler “List” as the numbers decrease, is one which leads to a fairer end result when judging a competition—as compared to each just selecting at the beginning of a one-month's competition just the most popular fan favorites—going ahead even in this manner increases viewer interest as the matches progress, rather than in only watching those matches involving the more prominent wrestling “superstars”. Watching a match between lesser known personalities would then promote enhanced viewer involvement as the points awardable would be the same where the lesser personality wins a match, employs a finishing move, or is disqualified, in equal numbers to that attributable with the name performers as Brock Lesnar or Steve Austin.
[0038] While there have been described what are considered to be preferred embodiments of the present invention, it will be readily appreciated by those skilled in the art that modifications can be made without departing from the scope of the teachings herein. Thus, whereas the foregoing description assigns predetermined “positive” and “negative” points of prescribed amounts for criteria associated with the happening of any wrestling match event, different criteria and/or points can be established—as winning or losing by pin fall, winning or losing by “giving up”, winning or losing by “being counted out”, or winning or losing a “championship”. For at least such reason, therefore, resort should be had to the claims appended hereto for a true understanding of the scope of the invention. | In an interactive contest system which permits competition among a plurality of remote participants as a professional wrestling fantasy league, a method employing a database storage means for storing a preferred wrestling team roster and rating scores attributable thereto in determining winners and losers of a scheduled competition in accordance with a predetermined set of identifying criteria and point values in a second database associated with performances of a wrestler before, during and after any arranged match. | 0 |
PRIORITY CLAIM
[0001] This application is a continuation and claims the benefit of priority under 35 U.S.C. §§120, 365, and 371 to Patent Cooperation Treaty Patent Application No. PCT/KR2009/005703, filed on Oct. 6, 2009. This application further claims the benefit of priority to Korean Application Nos. 10-2008-0105224 filed Oct. 27, 2008, 10-2008-0125800 filed Dec. 11, 2008, and 10-2009-0091728 filed Sep. 28, 2009. The disclosures of the above applications are incorporated herein by reference in their entireties.
TECHNICAL FIELD
[0002] The present invention relates to a moonpool and a drillship having the moonpool, more specifically to a moonpool and a drillship having the moonpool that has a modified moonpool structure to reduce vibrations and resistance caused by the flow of seawater inside the moonpool during the sailing of the drillship.
BACKGROUND
[0003] With the rapid industrial and manufacturing development in the global scale, use of fossil fuels, such as petroleum, has been increased, and international oil prices have been steadily soaring. Accordingly, stable production and supply of crude oil has become an increasingly important issue.
[0004] For this reason, petty deep sea oil fields, which have been neglected until recently for their technical difficulties of drilling and lack of economic feasibility, have begun to receive attention, and ships having drilling equipment fitted for oil field development have been developed in step with the development of resource development technologies.
[0005] For the conventional sea drilling equipment, a rig ship or a fixed-type platform have been commonly used, which can be moved by another tugboat and carries out its drilling operation while being fixed at a location in the sea by mooring equipment.
[0006] Developed and used more recently for deep sea drilling is a drillship, which is closer to an ordinary vessel with the state-of-the-art drilling equipment and can sail with its own locomotive power. Such drillship needs to be designed to have optimal sailing capacities as well as drilling capabilities because it needs to frequently move its location for the development of petty oil fields.
[0007] The drillship is installed with a large opening (referred to as “moonpool” hereinafter) for lowering a drilling pipe. Although this structure is indispensably essential for the use of the drillship, this structure is very disadvantageous in terms of the sailing speed.
[0008] In other words, due to periodic oscillation of the water surface inside the moonpool caused by the relative movement between the seawater flowed in and out of the moonpool and the seawater outside the hull, and the resulting movement of the hull, resistance is increased during the sailing of the drillship, resulting in the reduced speed and more fuel consumption. It has been observed that this resistance is increased by as much as 50%.
[0009] To date, designed and utilized for the purpose of reducing such increase of resistance have been affixture affixed inside the moonpool, affixture on the bottom of the ship around the moonpool, movable opening/closing devices inside the moonpool, etc. However, the affixture inside the moonpool has a complicated structure compared to its effect, and the movable opening/closing device is not widely used because its cost for installation and maintenance is very high.
[0010] Contrived to solve the above problems, the present invention provides a moonpool and a drillship having the moonpool that can reduce the resonance and resistance caused by the vertical movement of the seawater inside the moonpool while the drillship is sailing.
[0011] The present invention also provides a moonpool and a drillship having the moonpool that can reduce the amplitude of a sloshing movement and the resistance caused by the sloshing movement of the seawater inside the moonpool while the drillship is sailing.
SUMMARY
[0012] An aspect of the present invention features a moonpool formed in a drillship that includes: a first space formed by being penetrated from a bottom surface through an upper deck of the drillship so as to carry out a drilling operation; and a second space formed on a side of the first space in a lengthwise direction of the drillship, a bottom of the second space being open toward a lower side of the drillship.
[0013] A maximum length and a maximum width of a transverse section of the second space can be smaller than a maximum length and a maximum width of a transverse section of the first space.
[0014] The moonpool can include a partition wall, which is formed between the first space and the second space. An upper line of the partition wall can be formed at a predetermined height from a bottom surface of the drillship in such a way that the seawater flowed into the first space can flow into the second space.
[0015] The upper line of the partition wall can be formed between two meters below a water line of the drillship and two meters above the water line of the drillship.
[0016] Perforations can be formed in the partition wall.
[0017] The second space can be formed at least at one of a stern side and a bow side of the first space in a lengthwise direction of the drillship.
[0018] An upper surface of the second space can be open toward an upper side of the drillship.
[0019] A transverse section of the first space and the second space respectively can have the shape of a quadrangle that is extended in a lengthwise direction of the drillship.
[0020] A transverse width of the second space that is perpendicular to the lengthwise direction of the drillship can be formed to be smaller than a transverse width of the first space.
[0021] A length of the second space that is extended in the lengthwise direction of the drillship can be formed to be smaller than a length of the first space.
[0022] The length of the second space can be 10% to 50% of the length of the first space.
[0023] An opening opened toward a lower side of the first space can maintain a constant transverse width and then become narrower in a stern-side direction of the drillship.
[0024] A baseplate that is placed on a same plane as a bottom surface of the drillship can be installed on both corners of an end of the opening opened toward the lower side of the first space, wherein the both corners of the end are located in a stern-side direction of the drillship and the baseplate has the shape of a triangle.
[0025] A transverse section of the second space can have the shape of a semi-circle or a polygon.
[0026] Another aspect of the present invention features a drillship having the moonpool described above.
[0027] According to the present invention, a second space is formed on a side of a first space in the lengthwise direction of a drillship so that the overall length of a moonpool is increased. Therefore, vertical movements of the water surface inside the moonpool can be changed, and the amplitude of the water surface movement inside the moonpool and the resistance of the drillship can be reduced.
[0028] Moreover, by installing a partition wall having a particular upper line height between the first space and the second space, the amplitude of sloshing movements of the water surface inside the moonpool can be reduced, and the resistance caused by the sloshing movements can be reduced.
[0029] Furthermore, by forming an opening opened toward a lower side of the first space to maintain a constant transverse width and become narrower in a stern-side direction of the drillship, the amount of seawater flowed into the first space can be relatively reduced, and the resistance applied to the drillship can be reduced.
BRIEF DESCRIPTIONS OF THE DRAWINGS
[0030] FIG. 1 is a plan view of a moonpool in accordance with a first embodiment of the present invention.
[0031] FIG. 2 is a cross-sectional view of FIG. 1 seen along the II-II line.
[0032] FIG. 3 shows a modification example of a second space included in the moonpool in accordance with the first embodiment of the present invention.
[0033] FIG. 4 shows another modification example of a second space included in the moonpool in accordance with the first embodiment of the present invention
[0034] FIG. 5 shows yet another modification example of a second space included in the moonpool in accordance with the first embodiment of the present invention
[0035] FIG. 6 is a plan view of a moonpool in accordance with a second embodiment of the present invention.
[0036] FIG. 7 is a cross-sectional view of FIG. 6 seen along the VII-VII line.
[0037] FIG. 8 is a cross-sectional view of FIG. 6 seen along the VIII-VIII line.
[0038] FIG. 9 is a plan view of a moonpool in accordance with a third embodiment of the present invention.
[0039] FIG. 10 is a cross-sectional view of FIG. 9 seen along the X-X line.
[0040] FIG. 11 shows the result of a towing experiment of model ships in which moonpools in accordance with the embodiments of the present invention are formed.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0041] Hereinafter, certain embodiments of the present invention will be described with reference to the accompanying drawings.
[0042] FIG. 1 is a plan view of a moonpool in accordance with a first embodiment of the present invention, and FIG. 2 is a cross-sectional view of FIG. 1 seen along the II-II line.
[0043] Referring to FIGS. 1 and 2 , a moonpool 5 in accordance with a first embodiment of the present invention is formed between a bow and a stern of a drillship 1 , and includes a first space 10 for carrying out a drilling operation and a second space 20 formed adjacent to the first space 10 .
[0044] The first space 10 is formed by penetrating an upper deck 2 from a bottom surface 3 of the drillship 1 . In this case, the first space 10 can be vertically formed from the bottom surface 3 of the drillship 1 , and the first space 10 can be limited by inner walls 51 , 52 , 53 , 54 , 55 that are extended vertically in a hull 50 of the drillship 1 .
[0045] Referring to FIG. 1 , the transverse section of the first space 10 is shaped to be a quadrangle such as, for example, a rectangle that is extended in a lengthwise direction of the drillship. In this case, the transverse section of the first space 10 is symmetric about a center line from the bow to the stern of the drillship 1 . The first space 10 formed as described above can be used as a pathway to lower a drilling device (not shown), a drilling pipe (not shown), etc. to the seabed.
[0046] An opening 13 opened to a lower side of the first space 10 in accordance with the first embodiment of the present invention is shaped to be a quadrangle such as, for example, a rectangle that is extended in a lengthwise direction of the drill ship.
[0047] However, it shall be appreciated that the shape of the first space 10 in accordance with the first embodiment of the present invention is only an example, and a variety of shapes can be used as long as the first space 10 can be used as a pathway for carrying out a drilling operation.
[0048] A second space 20 is formed on a side of the first space 10 in the lengthwise direction of the drillship. In this case, referring to FIG. 2 , a bottom of the second space 20 is formed to be open toward a lower side of the drillship 1 , and the second space 20 can be limited by inner walls 56 , 57 , 58 extended vertically in the hull 50 of the drillship 1 .
[0049] Through the opening of the second space 20 formed as described above, the seawater can be flowed in and out of the second space 20 . In this case, an upper surface of the second space 20 can be opened toward an upper side of the drillship.
[0050] Referring to FIG. 1 , the transverse section of the second space 20 is shaped to be a quadrangle that is extended in a lengthwise direction of the drillship. In this case, the transverse section of the second space 20 is symmetric about a center line from the bow to the stern of the drillship 1 .
[0051] Moreover, the second space 20 is formed to be in contact with a rear side of the first space 10 (i.e., the stern side of the first space 10 in the drillship 1 ). Here, it is possible that the second space 20 is formed in contact with a front side of the first space 10 (i.e., the bow side of the first space 10 in the drillship 1 ), and it is also possible that the second space 20 is formed on both sides of the first space 10 in the lengthwise direction of the drillship, that is, the bow side and the stern side of the first space 10 .
[0052] Accordingly, compared to a moonpool having only the first space 10 formed therein (referred to as “conventional moonpool” hereinafter), the length of the moonpool 5 (the length in the bow-stern direction of the drillship 1 in FIG. 1 ) in accordance with the first embodiment of the present invention is increased.
[0053] This increase of length changes a movement pattern of the seawater occurring in the conventional moonpool. More specifically, in the moonpool 5 in accordance with the first embodiment of the present invention that is relatively longer, vertical movements of the seawater that predominantly occurred in the conventional moonpool are reduced, and instead sloshing movements predominantly occur.
[0054] Here, since the vertical movements of the water surface inside the moonpool cause greater resistance to the drillship than the sloshing movements do, the moonpool 5 in accordance with the first embodiment of the present invention can give less resistance to the drillship 1 than the conventional moonpool.
[0055] According to the first embodiment, a length L 2 of the second space 20 is formed to be smaller than a length L 1 of the first space 10 . In this case, it is preferable that the length L 2 of the second space 20 is between 10% and 50% of the length L 1 of the first space 10 .
[0056] If the length L 2 of the second space 20 becomes excessively great, the area of the opening of the moonpool 5 becomes excessively great, adversely increasing the resistance occurring while the drillship 1 is sailing. Therefore, it is preferable that the length of the second space 20 is small compared to the length of the first space 10 .
[0057] It is preferable that a width W 2 of the second space 20 is smaller than a width W 1 of the first space 10 . If the width W 2 of the second space 20 is greater than or equal to the width W 1 of the first space 10 , the area of the opening is excessively increased, adversely increasing the occurred resistance due to the seawater flowed into the moonpool of the drillship.
[0058] The second space 20 in accordance with the first embodiment of the present invention has a quadrangular sectional shape with a smaller length and width than the first space 10 . However, this is only an example, and the second space 20 can have a variety of shapes as long as the maximum sectional length and maximum sectional width of the second space 20 are smaller than the sectional length and sectional width of the first space 10 , respectively.
[0059] In this regard, FIG. 3 to FIG. 5 show modification examples of the second space included in the moonpool in accordance with the first embodiment of the present invention.
[0060] Referring to FIG. 3 , a transverse section of a second space 20 a can have the shape of a semi-circle. Here, the shape of a semi-circle can include the shape of a semi-ellipse. In this case, a maximum length L 2 a and a maximum width W 2 a of the transverse section of the second space 20 a are smaller than a maximum length L 1 and a maximum width W 1 of the transverse section of the first space 10 , respectively.
[0061] The transverse section of the second space can have the shape of a polygon. For example, as it can be seen in FIG. 4 , a transverse section of a second space 20 b can have the shape of a triangle. In this case, a maximum length L 2 b and a maximum width W 2 b of the transverse section of the second space 20 b are smaller than the maximum length L 1 and the maximum width W 1 of the transverse section of the first space 10 , respectively.
[0062] Alternatively, as it can be seen in FIG. 5 , a transverse section of a second space 20 c can have the shape of a trapezoid. In this case, a maximum length L 2 c and a maximum width W 2 c of the transverse section of the second space 20 c are smaller than the maximum length L 1 and the maximum width W 1 of the transverse section of the first space 10 , respectively.
[0063] FIG. 6 is a plan view of a moonpool in accordance with a second embodiment of the present invention. FIG. 7 is a cross-sectional view of FIG. 6 seen along the VII-VII line, and FIG. 8 is a cross-sectional view of FIG. 6 seen along the VIII-VIII line. Referring to FIG. 6 to FIG. 8 , a moonpool 65 in accordance with a second embodiment of the present invention is formed between a bow and a stern of a drillship 61 , and includes a first space 10 for carrying out a drilling operation, a second space 20 formed adjacent to the first space 10 and a partition wall 30 formed between the first space 10 and the second space 20 .
[0064] Here, any elements that are identical to those described with reference to the first embodiment will not be described, and unless described specifically, these elements will be considered to be identical to those of the first embodiment, and the description thereof will be substituted by the description provided with reference to the first embodiment. Hereinafter, the elements peculiar to the second embodiment of the present invention will be mainly described.
[0065] According to the second embodiment of the present invention, the partition wall 30 is installed between the second space 20 and the first space 10 . The partition wall 30 is installed in order to partition the entire length of the moonpool 65 into certain lengths.
[0066] Accordingly, sloshing movements with a big amplitude that occurs in a relatively long (i.e., L 1 +L 2 ) space can be changed to sloshing movements with a small amplitude in a relatively short (i.e., L 1 and L 2 , respectively) space due to the presence of the partition wall.
[0067] In this case, the partition wall 30 is formed in such a way that the seawater inside the first space 10 can flow to the second space 20 . To that end, according to the second embodiment, the partition wall 30 is formed in such a way that its upper line is placed at a predetermined_height from the bottom surface 3 of the drillship 61 .
[0068] With respect to the installation height of the partition wall with reference to FIGS. 7 and 8 , the partition wall 30 is formed in such a way that the upper line of the partition wall 30 is extended to a water line of the drillship 61 . In this case, the upper line of the partition wall 30 can be placed between two meters below the water line and two meters above the water line.
[0069] It shall be appreciated, however, that the shape of the partition wall 30 in accordance with the second embodiment of the present invention is an example only and that the partition wall can be modified in various ways as long as it can reduce the resistance occurred in the drillship pursuant to the seawater in the first space 10 flowing over the upper line of the partition wall 30 to the second space 20 .
[0070] Moreover, the partition wall 30 can be formed with perforations, through which the seawater in the first space 10 and the second space 20 can respectively flow in and out of the second space 20 and the first space 10 .
[0071] FIG. 9 is a plan view of a moonpool in accordance with a third embodiment of the present invention, and FIG. 10 is a cross-sectional view of FIG. 9 seen along the X-X line. Hereinafter, the elements peculiar to the third embodiment will be mainly described. Here, any elements that are identical to those described with reference to the first and second embodiments will not be described, and unless described specifically, these elements will be considered to be identical to those of the first and second embodiments, and the description thereof will be substituted by the description provided with reference to the first and second embodiments.
[0072] Referring to FIGS. 9 and 10 , the transverse section of a first space 10 in accordance with a third embodiment of the present invention is shaped to be a quadrangle, for example, a rectangle, that is extended in a lengthwise direction of a drillship 71 .
[0073] In this case, an opening 73 that is opened toward a lower side of the first space 10 is formed to keep a fixed transverse width and become narrower toward a stern of the drillship 71 . To that end, in the third embodiment of the present invention, a baseplate 40 that is placed on the same plane as a bottom surface 3 of the drillship 71 is installed on both corners of a rear-side end (i.e., an end part located in the stern-side direction of the drillship 71 ) of the opening 73 , which is opened toward the lower side of the first space 10 . Here, the baseplate 40 can have the shape of a triangle.
[0074] As such, by forming the opening 73 that is opened toward the lower side of the first space 10 to become gradually narrower along the moving direction of the seawater that moves from the bow to the stern of the drillship 71 when the drillship sails forward, the amount of the seawater that flows into the first space 10 becomes relatively reduced, thereby reducing the resistance applied to the drillship 71 .
[0075] The size and shape of the opening 73 opened toward the lower side of the first space 10 shall be determined in such a way that a drilling pipe, etc. that are descended toward the seabed are not interfered. The size of the baseplate 40 shall be also determined in the same respect.
[0076] FIG. 11 shows the result of a towing tank experiment of model ships in which moonpools in accordance with the embodiments of the present invention are formed. Illustrated in FIG. 11 are results on the relations between speed and effective horsepower by conducting an experiment in a towing tank with a model ship in which the conventional moonpool (having the first space only) is formed (referred to as the “first model ship” hereinafter), a model ship in which the moonpool in accordance with the first embodiment of the present invention (having the first space and the second space only) is formed (referred to as the “second model ship” hereinafter),_a model ship in which the moonpool in accordance with the second embodiment of the present invention (having the partition wall between the first space and the second space, the opening toward the lower side of the first space having a quadrangular shape) is formed (referred to as the “third model ship” hereinafter), and a model ship in which the moonpool in accordance with the third embodiment of the present invention (having the partition wall between the first space and the second space, the opening toward the lower side of the first space maintaining a fixed width and becoming narrower in the stern-side direction) is formed (referred to as the “fourth model ship” hereinafter). Here, the values indicated in the effective horsepower axis refer to relative values with an assumption that the effective horsepower required to tow the first model ship with 13 kts is 100 .
[0077] Describing the experiment results by referring to FIG. 11 , it can be seen that when the first model ship (with the conventional moonpool) and the second model ship (with the first embodiment) are compared, the second model ship has approximately 4% less resistance than the first model ship at the speed of 13 kts. This means that the second model ship can sail with less engine horsepower than the first model ship at the same sailing speed.
[0078] This trend is more prominent when the speed of the model ships is greater. For example, at the speed of 15 kts, the resistance is decreased by about 16%. This means that the second model ship can sail with a significantly less engine horse power than the first model ship at the sailing speed of 15 kts.
[0079] As such, the second model ship can sail with less engine horse power at a particular speed because the resistance occurred during the sailing is less than the first model ship.
[0080] Comparing the first model ship (with the conventional moonpool) with the third model ship (with the second embodiment) referring to FIG. 11 , it can be seen that the third model ship has approximately 10% less resistance than the first model ship at the speed of 13 kts. This means that the third model ship can sail with less engine horse power than the first model ship at the same sailing speed.
[0081] This trend is more prominent when the speed of the model ships is greater. For example, at the speed of 15 kts, the resistance is decreased by about 30%. This means that the third model ship can sail with a significantly less engine horse power than the first model ship at the sailing speed of 15 kts.
[0082] As such, the third model ship can sail with less engine horse power at a particular speed because the resistance occurred during the sailing is less than the first model ship.
[0083] Comparing the third model ship (with the second embodiment) with the fourth model ship (with the third embodiment) referring to FIG. 11 , it can be seen that the fourth model ship has approximately 3% less resistance than the third model ship in the entire range of sailing speeds. This means that the fourth model ship can sail with relatively less fuel than the third model ship at any particular sailing speed.
[0084] While some embodiments of the present invention have been described above, the technical ideas of the present invention are not restricted to the embodiments presented above, and it shall be appreciated that anyone skilled in the art to which the present invention pertains can present a variety of other embodiments by supplementing, modifying, deleting and adding the elements within the scope of the same technical ideas, but such varieties shall be considered to be included in the scope of technical ideas of the present invention. | The moonpool includes: a first space formed by being penetrated from a bottom surface through an upper deck of the drillship so as to carry out a drilling operation; and a second space formed on a side of the first space in a lengthwise direction of the drillship, a bottom of the second space being open toward a lower side of the drillship. The second space is formed on a side of the first space in the lengthwise direction of the drillship so that the overall length of the moonpool is increased. | 1 |
FIELD OF THE INVENTION
This invention relates to the field of cyclic fluid control valves with particular application being their use for control of pulsing gas pressures in supporting gas cushions of air cushion vehicles.
BACKGROUND OF THE INVENTION
This invention offers a simple reliable valve for, among other applications, reduction of pressure pulses in the supporting gas cushions of air cushion vehicles. It utilizes a low cost rugged design that is normally rotary in concept and that will operate for extended periods with little or not maintenance.
My Air Ride Boat Hull designs, as described in U.S. Pat. Nos. 4,392,445 and 4,739,719 among others, brought out the need for the instant invention. The Air Ride Boat Hull designs utilize a blower pressurized air cushion positioned in the underside of the hull where such pressurized air cushion supports approximately 85 percent of the weight of the boat. It is not uncommon, during normal operation in low sea states, to have an approximately two to six cycle per second (cps) pressure pulse or spike occur in the gas cushion since the cushion is in reality a large gas spring. These pressure pulses result in heave forces that act on the hull that are of significant magnitude to cause an uncomfortable ride.
As an example, the 368 passenger 109 by 34 foot "Metro Manhattan" Air Ride Surface Effect Ship (SES) Ferry built by Avondale Industries, New Orleans, that will go into operation in New York, experiences an approximate three cps pressure spiking when operating in one to two foot seas. The pressure spikes or pulses experienced can amount to approximately 40,000 pounds of force on the 340,000 pound hull during each pressure spike. This makes for an uncomfortable bouncy or what has been described as a "cobblestone" like ride for passengers. This "cobblestone" ride is characteristic of virtually all large air cushion craft, of which the Air Ride SES is a variant, when operating in small to moderate waves.
The U.S. Navy has funded work to resolve this ride problem in their SES's. The resulting solution is in the form of a Ride Control System (RCS) that is commercially manufactured in the United States. A similar system is now also manufactured in Sweden. These systems are very similar in that they sense air cushion pressures and other hull operating characteristics and feed such information into a microprocessor controller. The controller processes the input data and then outputs operating conditions to gas cushion vent valves and/or blower inlet flow control valves.
The gas cushion vent valves are operated in such manner so as to open and thereby vent pressure peaks as they occur in the air cushion. The blower inlet flow control valves accomplish essentually the same thing; however, they do so by restricting blower flow and pressure outputs in time with the pressure peaks. These on-the-market RCS's utilize valves that are made up of a series of Venetian blind type louvers that are set in a rectangular frame. The louvers can be closed to essentually shut off gas flow or operated at various degree of openess at frequencies that coincide with the pressure pulsing frequency in the air cushion.
Powered hydraulic actuators are used to operate the louvers at their required operating frequencies in both systems. Due to their inherent design characteristics, these 2 to 6 cps cycling hydraulically powered louver valves are expensive initially, largely due to the hydraulic systems, and require significant maintenance due to the two to six cps stop and start wear on joints, louvers, and hydraulic systems.
A main feature of the present invention overcomes the shortcomings of the just discussed start and stop cycling louver valves. The instant invention centers around an inherently simple and reliable cycling valve design that can be driven by low cost motors. This valve is intended to be applied mainly to control of air cushion vehicle cushion pressure pulses; however, it can be utilized wherever a need exists for a low cost reliable valve that is capable of rapid and continual cycling. The features and improvements offered by the instant invention are discussed in the following sections.
SUMMARY OF THE INVENTION
A major object of the present invention is to offer an inherently simple cycling valve design that is based, in its preferred embodiment, on a rotating valve element that can be driven by low cost motors such as synchronous electric motors. A second major object is to offer means to easily control the size of the gas flow aperture formed each time the valve cycles.
It is an object of the invention that the cycling periods of the valves can be either regular or irregular or combinations of regular and irregular as operating conditions require.
A further object of a preferred embodiment of the invention is to present a design that can be easily incorporated into a rectangular duct where rotating element drive motor(s) would preferably be positioned outside of the flow path(s) and therefore easy to service.
It is also intended as a object of the invention that any valve so described herein can have its elements positioned such that an essentually blocked flow or shutoff condition can be realized.
A further feature of the invention is the use of dynamic low leakage seals, such as non-contacting labyrinth seals, for sealing, wherever possible, to insure minimum friction losses, maximum reliability, and lowest cost.
It is also intended that any valves or portions thereof, such as drive motors, will be easy to get to for servicing.
An optional object of the invention is to offer a rotating valve that is substantially axially in line with inlet and/or outlet flow paths.
Another object is to offer a very simple valve that consists, at least partially, of simple rotatable discs with openings that align to form the fluid flow aperature during portions of their rotation.
Another major feature of the instant invention is to offer means to incorporate any of the invention's valves into a RCS for an Air Cushion Vehicle (ACV) such as an Air Ride Surface Effect Ship (SES) or Air Ride Boat Hull as it is sometimes called.
An object of the invention, in the case of installation in an ACV, is that multiple compartments can be incorporated into the ACV's gas cushion so that the different ACV supporting compartments can be equipped with the instant invention RCS thereby allowing control of pitch, roll, heave, and other characteristics of the ACV in a finely tuned way.
As a feature of the invention, it is intended that the operation of any of the invention's valves can be controlled by a microprocessor or other type controller where such controller receives inputs of such information as valve upstream and/or downstream fluid pressures, gas cushion pressures, vehicle g-forces, and vehicle orientation.
The invention will be better understood upon reference to the drawings and detailed description of the invention which follow in which:
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 presents a cross sectional view of a typical Air Cushion Vehicle (ACV), in this case an Air Ride Surface Effect Ship (SES), or Air Ride Boat Hull as it is sometimes called, to which the instant invention can be applied. Included in this view are a boat hull with supporting pressurized air cushion in its underside, a powered blower, flexible bow seals, blower inlet RCS valve, air cushion discharge RCS valve, and RCS control module or controller and its input source devices.
FIG. 2 is a cross sectional view, as taken through line 2--2 of FIG. 1, that shows the ACV blowers, blower inlet RCS valves, and forward flexible seals as are used in this instance.
FIG. 3 presents a cross sectional view, as taken through line 3--3 of FIG. 1 but also including an RCS control module and its input source devices, that also shows location of gas cushion vent ducts and RCS valves positioned therein.
FIG. 4 presents a typical plot of pressure oscillations that occur in an ACV supporting gas cushion. This shows a typical 3 cps regular cycling or pulsing that might occur during calm water operation with or without a RCS, high amplitude regular cycling or pulsing that might occur during high speed operation in seastate 2 with no RCS, and reduced amplitude pulses that might occur with a RCS on. It is to be noted that regular or consistant cycling or pulsing is shown for illustration purposes only and it is realized that irregular intervals of cycling or pulsing can occur in actual operation conditions.
FIG. 5 shows a preferred embodiment of the instant inventive valve in a cross sectional view as taken through line 5--5 of FIGS. 2 and 3. Shows are an inner rotary member drum valve portion, outer opening size controlling rotary member drum valve portion, and drive motors for each drum. Gas is shown flowing through openings in the two drums as they are lined up in this cross sectional view.
FIG. 6 is a cross sectional view as taken through line 6-6 of FIG. 5 that shows the inner and outer rotary drive member drive portions and the outer housing in which they are positioned. Note the flow direction arrows in this view which clearly show the resulting aperature when the openings in the two drum portions are partially, as in the case here, aligned.
FIG. 7 presents an exploded isometric arrangement of the valve shown in FIGS. 5 and 6. Shown are the movable or rotary portions of the valve including the drumlike rotors including their gas passage openings, rotor drive motors, and bearings.
FIG. 8 presents a cross sectional view of an optional valve concept, as taken through line 8--8 of FIGS. 2 and 3, that is basically axial in orientation to the main gas ducts. In this case, the two rotating elements are inside of a fixed cylindrical housing member. When openings in the two rotary elements and the fixed cylindrical housings are aligned, there is gas flow through the valve as is shown in this view.
FIG. 9 is a cross sectional view, as taken through line 9-9 of FIG. 8, that shows the fixed housing portion of the valve proximal the valve inlet. Also shown are a rotor support bearing.
FIG. 10 offers a cross sectional view, as taken through line 10--10 of FIG. 8, that shows the fixed housing and rotary members just aft of the valve inlet.
FIG. 11 is a cross sectional view, as taken through line 11--11 of FIG. 8, that presents workings of the valve when openings in the rotary members and the fixed housing are aligned and maximum gas flow is underway through the valve.
FIG. 12 presents another variation of the valve portion of the instant invention, as taken through line 12--12 of FIGS. 2 and 3, that is probably the simplest arrangement. This involves two simple rotary discs that are driven by simple, in this instance, electric motors. The discs have holes placed such that, when either fully or partially aligned, gas flows through the aperture thus formed in the valve.
FIG. 13 is a cross sectional view, as taken through line 13--13 of FIG. 12, that shows the fixed housing portion of the valve of FIG. 12 as it appears just aft of the valve inlet flange.
FIG. 14 shows a cross sectional view, as taken through line 14--14 of FIG. 12, that shows the fixed housing as it develops further downstream of the valve inlet flange than that shown in FIG. 13. Also shown in FIG. 14 is a rotor drive motor.
FIG. 15 presents a cross sectional view, taken through line 15--15 of FIG. 12, that shows a first rotary disc and its gas flow openings.
FIG. 16 is a cross sectional view, as taken through line 16--16 of FIG. 12, that shows a second rotary disc and openings for gas flow in such disc. Cycling or pulsing gas flow occurs when the openings are aligned.
DETAILED DESCRIPTION
With reference to each of the aforementioned Figures in turn, and using like numerals to designate similar parts throughout the several views, a preferred embodiment and several alternative embodiments will now be described.
FIG. 1 discloses a cross sectional view of an Air Cushion Vehicle (ACV) Hull 30, which in this instance is an Air Ride Boat Hull, with the instant invention installed. Shown are a blower inlet Ride Control System (RCS) valve 37, inlet duct 40, blower 31, blower drive engine 32, hull supporting gas cushion 39, gas flow arrows 36, flexible bow seal 33, gas cushion outlet RCS valve 38, outlet duct 41, sea surface waterline 34, and gas cushion waterline 35. Also shown are a controller 45, normally a microprocessor, that can receive inputs from a gas cushion pressure transducer 42, accelerometer 43, and/or inclinometer 44. The ouputs of the controller 45 are fed into the inlet RCS valve 37 and/or the gas cushion outlet RCS valve 38. The most important input to the controller 45 is the pressure readings from the gas cushion pressure transducer 42 as that supplies information on rate and magnitude of pressure pulses in the gas cushion 39. The controller 45 analyzes the input signals and then sends output signals to the RCS valves 37,38 to open and close them in proper cycles.
FIG. 2 is a cutaway view, as taken through line 2-2 of FIG. 1, that shows a front portion of an ACV hull 30, blowers 31, blower drive engine 32, blower inlet ducts 40, inlet RCS valves 37, gas flow arrows 36, flexible bow seals 33, and sea surface 34. In this particular arrangement with blowers 31 and inlet RCS valves 37 positioned both port and starboard, it is possible to control blower inlet openings or apertures differently on port and starboard sides of the gas cushion 39. The gas cushion 39 can be divided, in the case of the Air Ride boat hull, by the center divider 62 or other means such as additional rows of flexible seals, now shown, that would be positioned aft of the forward row of flexible seals 33 shown.
FIG. 3 presents a cutaway view, taken through line 3-3 of FIG. 1, that illustrates a hull 30 section taken through a midship portion of the gas cushion 39. Shown are sea surface waves 34 and wave surfaces 35 that make up the lower surface of the gas cushion 39. This view also shows gas cushion vent RCS valves 38 as they are positioned in ducts 41 that are used to vent pressure pulses from the gas cushion 39. For convenience, the controller 45, pressure transducers 43, accelerometer 43, and inclinometer 44 are also shown in this view although they are actually positioned further forward in FIG. 1. In this particular variation of the Air Ride boat hull invention, a center divider 62 is used to separate port and starboard side of the gas cushion 39. This division of the gas cushion 39 offers advantages in that each side of the gas cushion 39 can be controlled separately. It is also possible to incorporate one or more additional rows of flexible seals, not shown, such as the forward row of flexible seals 33 that would divide the ACV's main gas cushion 39 into a series of longitudinally disposed smaller gas cushion portions, not shown, where such smaller gas cushion portions would also be controlled separately by incorporation of the instant invention RCS system(s).
FIG. 4 presents an idealized but representative plot 46 of gas cushion pressure vs. time for several different operational conditions of a typical ACV. In each case the frequency of pressure oscillations is assumed to be three cps and at a constant rate for purposes of this illustration. It can be seen from the first second of operation in calm seas that little pressure variation occurs and a relatively constant pressure of about 100 Pounds per Square Foot (PSF) is realized. The second second shows operation in seal state 2 with the RCS off, or for an ACV with no RCS, with gas cushion pressures peaking at about 130 PSF during pressure pulses. The 30 PSF differential pressure can result in an impact force of about 60,000 pounds of force on a 300,000 pound 110 foot ACV so these pressure pulses cause noticeable impacts. The third second of operation shows the expected reduction of pressure pulse values due to having the RCS on and in operation with the ACV in sea state 2. Reductions in pressure peaks by eighty percent or move can be realized with the RCS on.
FIG. 5 presents a preferred embodiment of a valve 37,38 to the instant invention, as taken through line 5--5 of FIGS. 2, 3, and 6, where the gas flow arrows 36 are shown entering only, as would be for the FIG. 2 gas cushion RCS vent valve 37. This was done to simplify the drawings; however, it is to be understood for this and subsequent figures that the gas flow arrows 36 could flow in either direction to allow either inflow or outflow venting through either inlet or outlet valves 37,38. In this particular valve design 37,38 substantially rectangular inlet or outlet ducts 40,41 supply gas to rotary elements 48,51. The rotary elements 48,51 have openings 59,60 that are aligned in this instance thereby creating an aperture for gas flow as is shown by the gas flow arrows 36. Since the rotary elements 48,51 are independently controllable, it is possible to set a different aperture size at will. The rate of change of position of either or both rotary elements 48,51 can either be held constant for a constant cps rate and aperture size setting or can be varied to set an irregular cps rate and/or variable aperture size setting.
The inner rotary element 48 is driven by motor 47 which receives control signals and power through leads 54, and is supported by shaft bearings 49. The outer rotary element 51 is driven by motor 50 that receives control signals and power through leads 54, and is supported by shaft bearings 52. The motors 47,50 are attached to motor mount plates 63 by fasteners 53. Motors 47,50 can be of a variety of types including electric, hydraulic, pneumatic, and the like. Motors 47,50 normally include a shaft position indicator device 66 which in its preferred embodiment is an optical encoder. Outputs of the shaft position indicator device 66 wold normally be fed into the controller of FIGS. 1 and 3.
A very important aspect of this valve design is the preferred use of labyrinth seals 61 on various portions of rotary elements 48,51 and static housing member 57. Labyrinth seals 61 are low cost, reliable, dynamic seals that do not normally have rubbing contact which results in long life and little frictional related efficiency losses at the expense of some fluid leakage. A labyrinth seal is normally composed of one or more grooves that are oriented transversely to the leakage flow. As the leakage flow makes the torturous passage by the grooves and the ridges or lips of the labyrinth seal it becomes turbulent. This turbulence severely restricts flow passage and hence there is a reduction in the leakage flow rate.
The rotary elements 48,51, mounted transverse to the ducts 40,41 in this instance as indicated by rotary elements axial centerline 65, are normally cylindrical in shape to ease fabrication as well as to allow easy alignment with normally rectangular shaped inlet and outlet ducting 40,41. However, it is obvious that the rotary elements 48,51 may have other shapes than cylindrical with shapes such as a truncated conical shape, bowed drum shape which has a bigger diameter near the center than at each end, spherical, and other shapes are easily possible. Also, shapes other than rectangular are recognized as feasible for inlet and outlet ducting 40,41.
FIG. 6 shows a cutaway view, as taken through line 6--6 of FIG. 5, that illustrates typical rotary valves 37,38, their rotary elements 48,51 as they are positioned inside of housing 57, various labyrinth seals 61. The gas flow arrows 36 show passage through rotary element openings 59,60 that are shown partially in line and thus forming about a half of a full open valve aperture in this instance.
The rotary element rotation direction arrows 55 show rotation in either direction for either rotary element 48,51 in this example. In the preferred embodiment of the invention, a first rotary element, such as the rotary inner element 48, could be continuously rotating in one direction at a rotational speed equivalent to the pressure pulse spikes, about three cps, in an ACV gas cushion. The second rotary element, outer rotary element 51, could be rotated in either direction as required to set the overall valve aperture size realized during each valve cycle. The housing 57 actually forms a means to help in selection of the aperture size as it can accommodate any part of or all of the opening 60 in the outer rotary element 51.
It is most important to note in FIGS. 5 and 6 that only one of the rotary valve elements 48,51 is required for the valve to function. In such case, the housing 57 acts as a second and only other valve element and sets, in conjunction with the single rotary valve element 48 or 51, the valve fluid flow aperture seen during rotation of the single rotary valve element 48 or 51.
It is also to be noted that, while much of the thrust of the text of this application is directed toward control of gas pressure peaks in gas cushions ACV's, it is quite possible to use these valves 37,38 in all manner of applications. They can be used with all manner of fluids, such as water as well as air, and with granular solids such as sugar and the like.
FIG. 7 presents an exploded view of the valves shown in FIGS. 5 and 6 in isometric layout. Starting on the lower right, shown are a shaft position indicator 66, the inner rotary element drive motor 47, drive motor input/output leads 54, outer rotary element bearing 52, outer rotary element 51 including its opening 60, centerline 65, inner rotor element bearing 49, rotary element rotation direction arrows 55, inner rotary element 48 and its opening 59, inner rotary element bearing 49, end cap portion of outer rotary element 51, outer rotary element bearing 52, and outer rotary element drive motor 50. Seals, such as labyrinth seals, are now shown in this exploded view to simplify the drawing.
FIG. 8 presents an alternative, axially oriented as shown by rotary element axial centerline 65, rotary valve 37,38 configuration as shown in a view taken through line 8-8 of FIGS. 2 and 3. This axially oriented valve 37,38 utilizes and inner rotary element 48 and its opening 59, outer rotary element 51 and its opening 60, inner rotary element drive motor 50 and leads 54, outer rotary element drive motor 47 and leads 54, inner rotary element bearings 49, outer rotary element bearings 52, shaft position indicators 66, and fasteners 53. Also shown are gas flow arrows 36, inlet and outlet ducts 40,41, and valve housing 57.
The operation of the axially oriented valve 37,38 of FIG. 8 is similar to the transverse to the duct valve described in discussions of FIGS. 5, 6, and 7 previously. In this axial case, housing portions are positioned outward of the rotary elements 48,51 to help control gas flow, in the case of the inner housing portion, and to form part of the duct in the case of the outer housing. The use of the optional axially oriented valve 37,38 has advantage in certain situations where space outside of the ducts 40,41 is limited. The transverse to duct orientation valves described in FIGS. 5 and 6 offer the advantage of having motors positioned outside of the ducts which reduces maintenance requirements and also makes servicing easier. Further, it is possible to orient the inlet or discharge ducts 40,41 so that they are at other angles to the valves 37,38 in any of the valve concepts. Also, while the cylindrical rotor element 48,51 design is shown in this axial valve arrangement for simplicity, it is desirable to utilize a truncated cone rotor design with the large end of the cone forward to have maximum flow area forward in a preferred arrangement of an axial layout of the instant invention.
FIG. 9 presents a cutaway view, as taken through line 9-9 of FIG. 8, that shows the housing 57, including housing openings 58, just forward of the rotary elements. This view also includes the inner rotary element, shaft bearing 49.
FIG. 10 is a cutaway view, as taken through line 10-10 of FIG. 8, that shows inner rotary element 48, outer rotary element 51, rotary element rotation direction arrows 55, housing 57, and housing opening 58. This view shows openings 59 in the inner rotary element 48 that are positioned in its end.
FIG. 11 shows a cutaway view, as taken through line 11-11 of FIG. 8, that is located further downstream than the view taken in FIG. 10. This shows inner rotary element 48 opening 59, outer rotary element 51 opening 60, and housing openings 58 as they would be aligned for maximum aperture opening and therefore minimum flow restriction. Gas flow arrows 36 show the direction of gas flow in this instance. Also shown are labyrinth seals 61 and rotary element 48,51 rotation direction arrows 55.
FIG. 12 shows a cutaway view, as taken through line 12-12 of FIGS. 2 and 3, of a simpler version of the instant invention where rotary elements 90,92 are simple rotary plates or discs. It gives up something for this simplicity, compared to the drum rotor concept presented in FIGS. 5 and 6 for example, in that it presents a smaller aperture at maximum rotary element 90,92 opening alignment. It is possible to increase the size of the aperture by enlarging or bowing out the housing 57, as is shown in FIG. 12 to make the rotary elements 90,92 and therefore their openings 59,60 larger. Although not shown, a further variation of this simple rotary plate version of the instant invention that has little or no aperture area reduction will now be described. In such configuration, the axial centerline of much enlarged rotary elements 90,92 are located outside of ducts 40,41 and the openings 59,60 are at least approximately the same size as the ducts 90,92. In this alternative configuration, the ducts 40,41 are located to one side of the rotary element 48,51 centerline 65 such that they align with the rotary element openings 59,60 during each cycle of the rotary elements 48,51. A further advantage of this alternative configuration is that drive motors 47,50 can be positioned outside of housing 57 for easy servicing.
Other items shown in FIG. 12 are inlet and outlet ducts 40,41, which are normally round in this version of the invention, housings 57, gas flow arrows 36, fasteners 53, rotor drive motors 47,50, motor leads 54, shaft or rotor position indicators 66, labyrinth seals 61, and rotor bearings 49, 52. This version of the instant invention valve 36,38 is designed to be easily installed and removed through parallel flanges 64. As a further point of note, these simple configurations, as other versions of the instant invention, allow for shutting off of the aperture completely so that substantially a zero flow condition exists.
FIG. 13 is a cutaway view, as taken through line 13--13 of FIG. 12, shows the housing 57 and its gas flow openings 58 upstream of the rotors. In this case, the housing is going through a translation in shape from a rectangular shape at the inlet of the duct 40,41.
FIG. 14 presents a cutaway view, as taken through line 14-14 of FIG. 12, that shows the housing further downstream than the housing portion presented in FIG. 13. In such instance, the housing 57 and its openings 58 are tending toward a roundness. Also shown is a motor 50.
FIG. 15 shows a cutaway view, as taken through line 15--15 of FIG. 12, that illustrates the housing 57 with flange bolt holes 56, rotary valve element 92 and its openings 60, and rotor rotation direction arrow 55.
FIG. 16 illustrates a cutaway view, as taken through line 16-16 of FIG. 12, of rotor 90 that is positioned just aft of the rotor shown in FIG. 15. The openings 59 in rotor 90 can be seen to be only partially in line with the rotor 92 openings 60 of FIG. 15. This misalignment of rotor openings 59,60 provides a means to control aperture open timing; however, this simpler variation of the instant invention is not capable of actually varying the aperture size as are the variations that were presented in FIGS. 5 and 6 and FIG. 8. A housing portion that aligns with rotor openings during part of their rotation is normally utilized to provide an aid to aperture adjustment. Also shown in FIG. 16 are a housing 57, housing flange bolt holes 56, and rotor rotation direction arrow 55.
While the invention has been described in connection with a preferred and several alternative embodiments, it will be understood that there is no intention to thereby limit the invention. On the contrary, there is intended to be covered all alternatives, modifications and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims, which are the sole definition of the invention. | A simple, low cost, and reliable, normally cyclic, fluid control valve that in preferred configuration includes one or more rotary valve elements where such valve elements have openings that align with each other and/or with a flow passageway thus forming an aperture for fluid flow during valve cycles. Rotary valve elements may be oriented in different directions to connecting ducts and may have a variety of shapes with a preferred shape being cylindrical. Simple motors drive rotary valve elements such that a rate of valve cycling and/or amount of aperture can be easily controlled by a controller such as a microprocessor. Easy valve servicing and installation are other features. Dynamic sealing of the fluids is preferably accomplished by use of simple low cost labyrinth seals. A primary application of this cyclic fluid control valve is for control of pulsing gas pressures in supporting gas cushions of air cushion vehicles where it may be used to vent gas cushion pressure pulses and/or control inlet gas to a pressurizing blower that supplies a gas cushion. In its primary application, to an air cushion vehicle, valve operation is normally controlled by inputs from a controller that has received inputs of gas cushion pressures, gas pressures proximal a valve, vehicle g-forces, vehicle inclinometer, and/or the like. | 1 |
FIELD OF THE INVENTION
The present invention relates to a method for anisotropic etching of silicon.
BACKGROUND INFORMATION
It is known to etch defined features, for example trenches, combs, tongues, flexural beams, or the like, anisotropically with low to medium selectivity into silicon substrates that are preferably utilized with the semiconductor technique. The individual features to be etched in are usually defined by way of etching masks applied onto the silicon substrate, via so-called masking layers, for example a photoresist layer. In the anisotropic etching technique it is necessary to arrive at exactly laterally defined recess in the silicon. These recesses, penetrating in the depth direction, must possess lateral boundaries which are as accurately perpendicular as possible. The edges of the masking layers which cover those silicon substrate regions that are not to be etched must not be underetched, so as to maximize the lateral accuracy of the feature transfer from the mask into the silicon. This results in the need to have etching proceed only on the nature floor, and not on the previously created sidewalls of the features. It is proposed in German Patent 42 41 045 to perform the etching of profiles into silicon substrates using a method which alternatingly provides plasma polymer deposition and plasma etching steps. In this context, deposition and etching steps are performed in a chemical context based exclusively on fluorine compounds; during the inherently isotropic etching steps, forward advancement of the sidewall polymer film applied during the previous deposition steps already effectively passivates the freshly exposed portions of the silicon sidewall, so that the inherently isotropic etching step becomes locally highly anisotropic. This technique of local anisotropy by way of forward advancement of a sidewall film allows relatively wide etching steps at very high speed without etching into the sidewall, which consequently exhibits only minor roughness. In general, the performance of this plasma etching, when it is done with microwave excitation (propagation ion etching or PIE), does not create any appreciable wall roughess. This process does, however, create serious problems in a so-called inductively coupled system with high-frequency plasma excitation (ICP=inductively coupled plasma). With this, a pronounced recess becomes etched into the silicon directly beneath the edge of the photoresist mask. This recess is an effect of the inductive excitation, which is associated with magnetic and electric fields in the region of the substrate, for example a silicon wafer, and appears with greater or lesser severity on ICP systems of various designs. Inductively coupled plasma systems are playing an increasingly important role because of their robustness and versatility, and are inherently well suited for the process described above. A factor playing a major role in the formation of the etching recesses is the fact that the transition region between photoresist mask and silicon represents a discontinuity in conjunction with electric fields of the plasma source, and is exposed to a greater ion bombardment than the lower portion of the sidewall. In addition, the mechanism of the advancing sidewall film is not yet completely effective at the mask edge, and passivation of the sidewall there is thus weaker. This results in the so-called underetching, so that the etched-in silicon features no longer exhibit the necessary accuracy and critical dimensions.
SUMMARY OF THE INVENTION
The method according to the present invention for anisotropic etching in silicon avoids the problems of underetching in previously conventional ICP etching processes by the fact that the quantity of polymer deposited in the course of the polymer deposition steps which are accomplished alternatingly with the etching steps is initially too great, and then gradually decreases. The shortage of sidewall polymer at the beginning of the process is thus remedied by an excess of polymer, so that the sidewall remains sufficiently passivated. The greater ion bombardment at the discontinuity point now also no longer results in any etching of the critical region. It is thus an essential feature and a particular advantage of the process that it operates first with an excess of polymer, and that this excess then decreases in the course of the alternating polymer deposition and etching steps. The disadvantages of an excess deposition of polymer that have occurred hitherto include the occurrence of so-called positive-slope profiles, i.e. the sidewall of the etched trench is no longer perpendicular, but rather tapers with increasing etching depth, until a pointed tip occurs. A correction made, for example, only once to this profile by way of suitable process parameters results once again in the recess problem at the transitional discontinuity point. This also is eliminated by the gradual reduction in deposited polymer in the course of the polymer deposition steps. The so-called initially over-rich process with a positive profile begins with no recess formation, so that the process transitions gradually to one which generates perpendicular profiles with less polymer deposition, and the greater part of the etching operation is performed therewith.
Advantageous embodiments and developments of the method.
In a particularly advantageous embodiment of the method according to the present invention, adjustment of the polymer deposition steps is performed continuously from one process cycle to the next. It is advantageous to begin with a so-called “rich” (i.e. high-polymer) process parameter set, which would result in a positive profile but definitely prevents any recess formation beneath the mask edge. With each of the following cycles the polymer concentration in the process is then slightly scaled back, so that this continuous adjustment of various process parameters minimizes both discontinuities in the profile transitions and the risk of forming a recess. Advantageously, adjustment of the parameter set is accomplished over the first 20 μm of etching depth if, for example, etching is to occur to a depth of 100 μm into silicon.
In a further advantageous development of the method according to the invention, present the quantity of deposited polymer decreases in discrete steps. The process begins, for example, with a long deposition time for each step, and etching is performed for a while with that parameter set; the deposition time is then reduced, etching continues for a certain period with the new parameter set, and so on until a parameter set generating a vertical profile has been arrived at.
Advantageously, it is possible to control the decrease in polymer quantity by varying the duration of the etching steps or the polymer deposition steps, since no internal plasma properties change when the duration of the individual steps is changed. Varying the duration of the etching step or the polymer deposition step is simple, and the effects of modification are readily apparent.
A further preferred possibility is to control the polymer quantity by varying the substrate temperature, or to change the pressure during deposition. It is important to note in this context that a sudden transition from a parameter set generating a positive profile to a much less positive one also creates the risk of recess formation: when a transition is made to a perpendicular profile, if it occurs suddenly, the positive profile is very similar in shape to the profile of the resist mask edge (or of the SiO 2 mask edge, if a hard-material mask is being used), and the transition to a less-positive profile shape once again constitutes a definite and significant discontinuity in the sidewall, which once again can cause problems with recess formation in ICP systems. It is therefore advantageous not to perform this adjustment in very large steps, but to transition to a vertical parameter set in several steps. It is advantageous in particular if etching is first performed for a certain distance with the positive parameter set before transitioning to a less-positive or vertical one, since the sidewall already generated acts as a polymer deposit, and the more extensive that polymer deposit already is, the better the sidewall film transport mechanism functions. In practice, for example, it is possible to make this adjustment in three parameter steps each with an etching width of 10 μm, and then to continue etching with a vertical parameter set, for example if etching is to proceed to a total depth of 100 μm in silicon. It is also possible to etch nanofeatures on the silicon, i.e., make the adjustment in parameter steps each having an etching width in the order of nanometers.
In a further particularly advantageous embodiment of the method, all the parameters are continuously adjusted. Etching begins with a rich (i.e. high-polymer) process parameter set which would result in a positive profile but definitely prevents recess formation beneath the mask edge. With each of the following cycles, one of the influencing parameters, for example the polymer deposition time, duration of the etching steps, substrate temperature, or pressure, is changed accordingly. This continuous adjustment of the entire parameter set also minimizes both discontinuities in the profile transitions and thus the risk of forming recesses.
In practice, the overall result of each of the advantageous embodiments of the method according to the present invention is a vertical etching profile, even though the process begins with an initially positively sloped, tapering profile and transitions gradually to a vertical etching profile. The reason for this is that the positive profile portion in a vertically etching process is protected only by the sidewall polymer, and no longer by the mask, since the tapering positive profile projects beyond the mask edge into the trench, and the sloping sidewall is exposed to a more severe ion bombardment than an already vertical sidewall. The vertically etching process thus slowly removes the projecting portion of the overall profile, and this deviation from the vertical profile shape therefore corrects itself automatically. The only prerequisite for this is that after the transition to the vertical-etching process parameter set, whether in discrete steps or continuously in the manner described, etching is continued for a sufficiently long time for this profile correction to occur completely. The values indicated, namely 10 to 20 μm for the initialization steps and then approximately 80 μm over which etching takes place with the vertically etching process, represent a rough guideline for process design. Different etching depths greater than 100 μm can, of course, also be achieved with this strategy.
The method according to the present invention can be used, for example, to etch isolated vertical silicon webs only 1 μm wide by 40 μm deep, with no feature loss. It is possible with this technique to produce features which have an aspect ratio, i.e. the ratio of depth to feature width, of 100:1 to 200:1. The etching rate in this context reaches values of 5 μm/min and more, and mask selectivity attains values of 100:1 (photoresist) or 200:1 (SiO 2 ) . Features of this kind were hitherto possible to manufacture only with the LIGA technique (synchrotron illumination in PMMA), laboriously and at great expense.
DETAILED DESCRIPTION
In an etching chamber or in another suitable reaction vessel, a correspondingly prepared silicon substrate—i.e. a silicon substrate coated with an etching mask made, for example, of photoresist, the etching mask leaving exposed the region of the silicon substrate which is to be anisotropically etched into—is exposed to a first polymer deposition step in order to apply a polymer deposit onto the mask edges. There then follows a first etching step, which immediately “feeds” on the applied polymer deposit and thus etches almost purely anisotropically. It is essential for the method according to the present invention that the first step be a polymer deposition step, so that the sidewall protection mechanism functions during the subsequent etching step. Further polymer deposition and etching steps are then accomplished alternatingly. The method according to the present invention can of course also be performed with an analogous apparatus that accomplishes the individual process steps. A mixture of, for example, SF 6 and Ar, which exhibits a gas flow of between 0 and 200 standard cu3 /min and a process pressure of between 10 and 100 μbar, is used in this method. Plasma generation is accomplished in this connection preferably with microwave irradiation at power levels between 300 and 1200 W (2.45 GHz), or by high-frequency irradiation at power levels of 500 to 2000 W, in an ICP source which is especially preferred for the method according to the present invention. At the same time, a substrate bias voltage is applied to the substrate electrode to accelerate the ions. The substrate bias voltage is preferably between 35 and 70 V, and can be achieved with a high-frequency feed (13.56 megahertz) at power levels between 2 and 10 W.
The first polymer deposition step, and of course also those which cyclically follow it, is performed with a mixture of, for example, CHF 3 (trifluoromethane) and Ar. Advantageously, however, it is also possible to use other fluorine-containing gases instead of trifluoromethane, for example octafluorocyclobutane (Freon C 318), hexafluoropropene (HFP, Hoechst) or its dimers, or tetrafluoroethene (TFE). It is also possible to perform the process without argon. The mixture possesses a gas flow of preferably 0 to 200 standard cm 3 /min and a process pressure of between 10 and 100 μbar. In a preferred embodiment of the method according to the present invention, octafluorocyclobutane or hexafluoropropene is used, since these compounds exhibit particularly good polymerization properties under ICP excitation. During the polymer deposition step, the exposed surfaces, i.e. the etching floor and the side surfaces, are covered very uniformly with a polymer. This polymer layer on the edges and surfaces of the etching mask forms a highly effective temporary etch protectant. The polymer layer applied onto the etching floor during the polymerization step is rapidly broken through during the subsequent etching step, since the polymer is very quickly removed with ion assistance, and the chemical conversion of the reactive plasma species with the silicon on the etching floor can proceed. The sidewalls of the features being etched remain protected during the etching step by the sidewall polymer applied during the previous polymer deposition step or steps.
During the first etching step which then follows, chemically reactive species and electrically charged particles are generated in the mixture of SF 6 and Ar in the reactor with the aid of an electrical discharge. The positively charged cations generated in this fashion are accelerated toward the silicon substrate by the electrical bias voltage applied to the substrate electrode, and are incident approximately perpendicularly onto the substrate surface left exposed by the etching mask and promote chemical reaction of the reactive plasma species with the silicon. They also ensure polymer film transport in the depth direction of the etched trench; this is the consequence in particular of that portion of the ions which is not incident absolutely perpendicularly, and strikes the sidewalls. The etching step can be performed until the desired etching depth has been attained. This is then followed by another polymer deposition step, although this time less polymer is deposited than the first time. The etching steps and polymerization steps are repeated alternatingly, with appropriate adjustments in the process parameters, enough times for the quantity of deposited polymer gradually to decrease. These process parameters comprise the physical quantities listed below:
1. Elevation in ICP power level, for example to >1000 W, with simultaneous increase in the flow of passivation gas, for example C 4 F 8 , C 3 F 6 , (C 3 F 6 ) 2 , CHF 3 , to, for example, >200 sccm (sccm=standard cm 3 /min=cm 3 /min at 1 bar), which results in enhanced polymer deposition.
2. Increase in the duration of deposition steps, which also results in enhanced polymer deposition.
3. Decrease in the duration of the etching steps, which effectively increases passivation of the sidewalls.
4. Reduction in wafer temperature, which also increases polymer deposition.
5. Performing the deposition steps in the pressure region most favorable for polymer deposition in ICP systems, i.e. around 10 μbar; and
6. Elevating the pressure during the etching steps to 20 to 30 μbar in order to increase the etching radical concentration but decrease the concentration of ions which remove the polymer. | A method is proposed for anisotropic etching of micro- and nanofeatures in silicon substrates using independently controlled etching steps and polymer deposition steps which succeed one another alternatingly, the quantity of polymer deposited decreasing in the course of the polymer deposition steps, thus preventing any underetching of the micro- and nanofeatures. | 1 |
This is a division of application Ser. No. 07/672,499, filed Mar. 20, 1991.
FIELD OF THE INVENTION
The present invention relates to a foam flotation reactor for the separation of two products: one hydrophobic and the other hydrophilic.
BACKGROUND OF THE INVENTION
Flotation processes have been developing over a period of more than 100 years, and various designs are in existence. One such system is the conventional mechanical cell employing an impeller located within a tank. A gas is introduced and dispersed through the impeller in order to generate bubbles to which the hydrophobic particles to be concentrated will adhere (see C. C. Harris, 1976). These mechanical cells continue to be the machines most widely used at the present time.
However, recent years have seen the introduction into the ore industry of machines generically known a "pneumatics," which had already been used in chemical processes and for waste water treatment (see Clarke & Wilson, 1983). In these machines the mixing of the gas and slurry takes place by means of injection nozzles. The most common of these devices are those known as columns and those of the Flotaire type (see K. V. S. Sastry, 1988). These have not yet been used in the ore industry on a large scale, however, due to difficulties in controlling their operation.
Finally, another type of machine has been developed recently, the length of which is shorter than that of columns. In these machines, the slurry is injected under pressure (see G. J. Jameson, 1988).
SUMMARY OF THE INVENTION
The present invention provides, in a flotation system, a reactor for separating hydrophobic material in a continuous and mechanically and energetically efficient manner. The reactor, which has a chamber that is preferentially but not necessarily of circular cross section, is used to bring together a slurry containing the material to be separated, a foam of controlled bubbles produced by a generator, and water for washing the foam. A controlled and efficient mixing of the slurry and foam in a turbulent manner in the lower part of the reactor chamber is effected, so that the foam is dispersed homogeneously over the entire cross section of the reactor, and enters into intimate contact with the particles that are desired to be extracted.
The slurry and foam are mixed in free ascent in the middle part of the reactor chamber, so that the desired particles have time to adhere to the controlled bubbles, and the undesired particles entrained by the movement of the fluid are able to detach themselves from the bubbles and then descend.
Separation of the particles of sterile material entrained with the rich foam of the desired material is effected in the upper part of the reactor chamber by means of a decrease in the cross section of the reactor which causes the rich foam to be compacted and its discharge velocity increased, and by a plane and controlled stream of water applied in the upper part of the foam.
Situated outside the above-mentioned reactor is a system for the generation of foam consisting of very fine and controlled bubbles. The generator contacts a stream of gas introduced at relatively low pressure and relatively high flow volume with a stream of liquid which preferentially, but not necessarily, contains the dissolved froth-producing reagent. An effective and intimate contact is produced between gas and the liquid/frothing agent mixture by means of a device made of a material of controlled porosity and having a relatively large area of contact, which permits a high bubble-generating capacity. The cost of the bubble-generating device is relatively low; it is easy to replace mechanically and comprises no movable mechanical parts.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of the flotation reactor of the present invention;
FIG. 2 is a vertical cross-section of the flotation reactor of FIG. 1 taken along its vertical axis;
FIG. 3 is a perspective view of the foam-generating device of the present invention; and
FIG. 4 is a vertical cross-section of the foam-generating device of FIG. 3, taken along its vertical axis.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIGS. 1 and 2 show the reactor of the present invention which is used for the process of separation by flotation.
The slurry composed of an organic fluid such as water and the desired material to be recovered is fed by gravity or pump via a tube 2 into the reactor 1, which is preferably of circular cross section. Tube 2 is directed toward the axis of the reactor wherein a tube 3 (standpipe) is situated. Tube 3 is internally lined with an abrasion-resistant material, and carries the slurry to the impeller 4. The impeller is of the propeller type with a downward action; it is moved by a system consisting of the shaft 5, pulley 6 and motor 7, and generates considerable turbulence in the lower zone 8 of the reactor.
The slurry thus agitated meets a stream of small bubbles produced outside the reactor by the foam generator 9, which is described in greater detail below. The slurry enters into intimate contact with the stream of foam. The particles of desired material which are already hydrophobically activated on their surface preferentially adhere to the gas bubbles which they encounter.
The mix of slurry and bubbles rapidly ascends due to the currents generated by the agitation and the forces of flotation. The turbulence generated in the lower section is abated by a grid 10 arranged horizontally over the entire reactor cross section. Grid 10 is preferably of a strong material such as steel. The ascent of the bubbles enriched with the desired material continues at a slower rate in the middle zone 11, which permits undesired and mechanically entrained particles to be detached. This also creates a higher probability of contact with particles of the desired ore which had been ascendingly entrained by the flow lines and which may not have made contact with the bubbles.
The bubbles with the major part of the product to be separated form an upper foam zone 12 which is compacted, aided by the conical shape of the reactor 13 and of the upper part of the tube (standpipe) 14. The same conical shape in the upper part of the reactor aids in facilitating the discharge of the foam.
Immersed in the aforementioned foam zone 12 is a tube 15 fed with water and arranged in an annular fashion around the reactor and supported by a structure 16. From this tube, water is sprayed into the foam preferably by means of twelve sprays 17 of low flow rate, which washes the foam in order to detach the sterile or undesired material from the rich foam and increase the quality of the product.
The sterile or undesired material is transferred by gravity through a conduit 18 of preferably rectangular cross section arranged at one side of the reactor, preferably at 180° opposite the inlet of the slurry feedpipe 2. Conduit 18 has a system of variable discharge openings 19. The reactor also has a tube 20 extending from a level above the surface of the foam to a point preferably 100 mm above the bottom, which helps in impeding the settling of relatively large particles.
The body of the reactor contains four baffles 21 in a longitudinal position and disposed at 90° intervals along the cross section. These baffles prevent the formation of a vortex.
A generator used for the creation of the stream of bubbles is shown in FIGS. 3 and 4. The generator 9 consists of two opposite conical parts 22 united by means of flanges 23. The ratio of height to maximum diameter of the cone should be between 1 and 2, and preferably 1.5. Arranged between the two parts is a generating element 24 having a controlled pore size. Generating element 24 preferably consists of a synthetic fiber 25, although it can also be a porous ceramic or metallic material. Element 24 is supported at its lower part by a strong metallic grid 26 preferably made of stainless steel, and is protected at its upper part by another metallic grid 27, also preferably made of stainless steel and with openings between 6 and 70 mesh, and preferably between 10 and 30 mesh.
The ratio between the greatest and smallest diameter of the conical parts is between 9 and 17, and preferably between 11 and 14.
To produce the bubbles, a gas at a relatively low pressure, i.e. between 1 and 4 kg/cm 2 and preferably between 1.5 and 2.5 kg/cm 2 is introduced by known means, such as diaphragm flow meters or orifice plates, through the lower inlet 28. This may be any industrially available gas, such as air, nitrogen, oxygen, carbon dioxide or argon. The gas passes through interspaces between objects arranged in the zone 29. These objects should be inert to oxidation and be preferably of spherical shape. In certain cases these objects may even be absent.
The gas passes through the generating element 24 and meets a stream of liquid previously mixed with the frothing agent or other reagents and which is tangentially fed via a tube 30. The liquid/frothing agent is typically introduced to the upper conical chamber at a height of between 10 and 60 mm above the porous element, and preferably between 25 and 35 mm above the porous element. The liquid flow is administered and measured by known means. The preferred ratio between gas and liquid/frothing agent should be between 3 and 7 per cent. Upon contact of the gas and the liquid/frothing agent mixture, bubbles of controlled size will be generated, said size depending essentially on the pore size and the flow volumes of gas and liquid/frothing agent, and on the quality and type of frothing agent. The flow of bubbles should typically be between 0.15 and 0.40 m 3 /min per cubic meter of cell volume, and preferably between 0.20 and 0.30 m 3 /min.
The bubbles formed leave through the orifice 31 and can be introduced directly into the above-described flotation reactor. Alternatively, the bubbles could be combined with the slurry to be treated, and the combined bubbles and slurry introduced to the reactor chamber. This could be accomplished by simply joining a tube carrying bubbles to the slurry tube ahead of the reactor slurry inlet, as would be readily understood by one skilled in the art.
To check the performance of the porous element, the inlet and outlet pressures are measured by manometers 32 arranged at both ends of the bubble generator.
In contrast to flotation in conventional mechanical subaeration cells in which the bubbles are generated internally by impellers and whose energy consumptions range between 8.46 and 157 kW/m 3 h for small-size units and between 0.77 and 48.6 kW/m 3 h for large-size units--the latter being larger than 100 m 3 --the present reactor operates with bubbles generated externally and with an average energy consumption of 5.41 kW/m 3 h for a cell of 4.6 m 3 .
Moreover, in contrast to flotation in prior-art pneumatic columns, the height of the reactor of the present invention is considerably less than that of the aforementioned machines. As a result, the known problems of mechanical operation in controlling the height of the slurry and of the discharge of thick materials do not arise in this reactor, by virtue of the smaller load exerted by the slurry on the valves.
Furthermore, in contrast to the prior-art bubble generators used in ore flotation columns wherein a high air and/or water pressure is generally used, the generator forming part of the present invention uses gas at a relatively low pressure and a liquid/frothing agent at practically atmospheric pressure.
Also, unlike in the prior-art bubble generators for use in flotation columns in which the bubbles already formed are introduced into the column by means of dispensers immersed in the slurry, which are prone to problems with clogging, in the generator of the present invention the bubbles are introduced through the bottom of the reactor and directly toward the above-described impeller.
Finally, contrary to the relatively complex manufacture of the prior-art bubble generators for use in flotation columns, the generator of the present invention is simple to manufacture, and, above all, the porous element can be replaced with ease and at a relatively low cost.
Any of various desired materials can be collected by the present invention. For example, lead sulfide, zinc sulfide, copper sulfide, or a sulfide of any other base metal containing gold or silver can be collected. The desired material can be a non-metallic ore such as coal, kaolin, fluorite, barite, celestite, ilmenite, phosphorite or magnesite. The desired material could also be a metal cation or anion, such as cyanide, phosphate, arsenite, molybdate or fluoride, any of which might typically be contained in solutions. Ink or kaolin contained in paper pulp are also possible desired materials for collection by the present invention. A further desired material might be a colloid or surfactant used in the treatment of waste water, or any other organic agent to be separated from a solution. These examples are intended to be illustrative, and not exhaustive, of the materials that can be collected by the present invention. | A foam flotation reactor for the separation of hydrophobic and hydrophilic products is provided. The reactor combines a material to be beneficiated, collector reagents, and a stream of specifically generated gas bubbles, in order to collect the desired product in the foam in a more efficient manner. A narrowed upper part of the reactor and accompanying water sprays force separation of undesired particles. A foam generator efficiently supplies a bubbly liquid/frothing agent to the reactor. | 1 |
CROSS REFERENCES TO RELATED APPLICATIONS
[0001] The present application claims priority to U.S. Provisional Patent Application No. 61/382,430, filed on Sep. 13, 2010.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not Applicable
BACKGROUND OF THE INVENTION
[0003] 1. Field of the Invention
[0004] The present invention relates to a golf club head having a movable back weight configuration. More specifically, the present invention relates to a titanium driver with a lightweight receiving back cap designed to be loosened to allow access to an interior, repositionable weight.
[0005] 2. Description of the Related Art
[0006] Technical innovation in the configuration, material, construction and performance of golf clubs has resulted in a variety of new products. The advent of metals as a structural material has largely replaced natural wood for wood-type golf club heads, and is but one example of this technical innovation resulting in a major change in the golf industry.
[0007] Titanium drivers have been used by golfers for over a decade. They represent the vast majority of the drivers produced and used around the world. Callaway Golf Company's second and third generation titanium driver body styles (Hawkeye '99 and Hawkeye '01) each used a secondary metal for weighting, tungsten and bismuth respectively. The tungsten was externally visible, while the bismuth was not. Callaway has not used dissimilar metal for weighting purposes on its titanium bodied drivers for several years, but has welded titanium pieces or used thicker, as-cast, weighting regions or varying wall thicknesses to accomplish weight placement. While this type of weighting is useful for performance, it does not provide strong talking points or visual cues to describe or illustrate performance intentions.
[0008] Although the prior art discloses many variations of golf club heads, the prior art fails to provide a club head with a high-performance weighting configuration with visual cues to describe or illustrate performance intentions.
BRIEF SUMMARY OF THE INVENTION
[0009] The inventors have found that, by incorporating certain design features into a driver design, a golfer may have an improved driver that is better suited to his or her needs, abilities, and preferences to hit better shots and have a unique method of interfacing with a movable weight of the driver head.
[0010] One such design feature is a moveable weight used to affect the position of the club head's center of gravity to provide ball trajectories that are better suited to the golfer's swing. Another design feature is the omission of welding operations from the driver and, as a result, eliminating the cost associated with purchasing secondary parts (faceplates, crown plates, sole plates, etc.) and the secondary operations (fixturing, grinding, blending, etc.) used to finish the club head. A further design feature is a affixing a moveable weight to a golf club head by housing it into a removable or captive, yet movable, back cap. Yet another design feature is the use of a lightweight material for the back cap, such as magnesium, composite graphite, aluminum, or plastic to minimize the mass of the back cap to provide more available mass for the movable weight.
[0011] One aspect of the present invention is a club head comprising a body comprising a face component and an aft body, wherein the body is integrally cast from a metal material, and wherein the aft body has an opening, a gasket covering the opening, a back cap having an interior surface, wherein the back cap is slidably affixed to the gasket, and at least one removable weight positioned on the interior surface of the back cap. In a further embodiment, the body may have a volume of approximately 440 to 480 cubic centimeters and a weight of 180 to 210 grams. In another embodiment, the interior surface of the back cap may have a plurality of predefined weight receiving locations, such as on a heel side and a toe side of the back cap. In another embodiment, the golf club head further comprises a screw, wherein the at least one removable weight is semi-permanently fastened to the interior surface of the back cap with the screw. In yet another embodiment of the present invention, the golf club head further comprises a plurality of screws, wherein the gasket is permanently affixed to the aft body with an adhesive, and wherein the back cap is semi-permanently affixed to the gasket with the plurality of screws.
[0012] In another further embodiment, the gasket and the back cap are each composed of a lightweight material, which may be selected from the group consisting of composite and aluminum, and the at least one removable weight is composed of a heavy material, which may be selected from the group consisting of stainless steel, titanium alloy, and tungsten alloy, having a density greater than the density of the lightweight material. In yet another further embodiment, the body is integrally cast from titanium alloy. In another embodiment, the aft body comprises a crown portion and a sole portion, and the opening is located in the sole portion.
[0013] The golf club head of the present invention may further comprise a slider tee comprising an end portion and a head portion, wherein the gasket comprises an elongated slot, wherein the back cap comprises a socket, wherein the end portion of the slider tee is threaded through the slot and fixed in the socket, and wherein the head portion of the slider tee is sized to prevent the slider tee from disengaging from the slot. The slider tee may be composed of a lightweight material selected from the group consisting of composite, aluminum alloy, magnesium, and plastic, and may permit the back cap to slide along a length of the elongated slot. The back cap may slide on a linear, rotational, or curved path along the length of the elongated slot.
[0014] Another aspect of the present invention is a driver-type golf club head comprising a body having a rearwardly located opening, wherein the body is composed of a titanium material, and wherein the body has a volume of approximately 440 to 480 cubic centimeters and a weight of 180 to 210 grams, a movable assembly covering the opening, and at least one weight member removably secured within the movable assembly, wherein the at least one weight member is composed of a high density metal material, and wherein the golf club head has no welding in its construction. In a further embodiment of the present invention, the movable assembly comprises a gasket and a back cap, and may further comprise a slider tee, wherein the gasket is composed of an aluminum material, wherein the gasket is affixed to the body with adhesive, wherein the slider tee movably connects the back cap to the gasket, and wherein the back cap is composed of a composite material. The at least one weight member may be composed of a metal material selected from the group consisting of stainless steel, titanium alloy, and tungsten alloy, and the body of the driver-type golf club head may be integrally cast.
[0015] Yet another aspect of the present invention is a driver-type golf club head comprising a body comprising a crown portion composed of a composite material, a face portion composed of a titanium alloy, and a sole portion composed of a titanium alloy, wherein the sole portion comprises a rearwardly located opening, and wherein the face portion and the sole portion are integrally cast, a gasket covering the opening, wherein the gasket is permanently affixed to the body with an adhesive material, and wherein the gasket is composed of an aluminum alloy, a slider tee, a back cap having an interior surface, wherein the back cap is slidably affixed to the gasket with the slider tee, at least one screw, and at least one removable weight secured to the interior surface of the back cap with the screw, wherein the golf club head has no welding in its construction, and wherein the body has a volume of approximately 440 to 480 cubic centimeters and a weight of 180 to 210 grams.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0016] FIG. 1 is an exploded, rear, heel-side view of a golf club head according to an embodiment of the present invention.
[0017] FIG. 2 is an exploded, rear, toe-side view of the golf club head shown in FIG. 1 .
[0018] FIG. 3 is an exploded, toe-side view of the golf club head shown in FIG. 1 .
[0019] FIG. 4 is an interior, perspective view of the back cap and weight shown in FIG. 1 in an assembled configuration according to one embodiment of the present invention.
[0020] FIG. 5 is an interior, perspective view of a back cap and weight shown in FIG. 1 in an assembled configuration according to another embodiment of the present invention.
[0021] FIG. 6 is a front, perspective view of the gasket and the back cap shown in FIG. 1 in an assembled configuration.
[0022] FIG. 7 is a top, perspective view of the gasket and the back cap shown in FIG. 6 .
[0023] FIG. 8 is a rear, perspective view of the gasket and the back cap shown in FIG. 6 .
[0024] FIG. 9 is a top, plan view of the golf club head shown in FIG. 1 in a fully assembled configuration, with the back cap slid towards the toe to reveal a weight.
[0025] FIG. 10 is a bottom, perspective view of the assembled golf club head shown in FIG. 9 .
[0026] FIG. 11 is a top, plan view of the assembled golf club head according to another embodiment of the present invention, with the back cap slid towards the heel to reveal a weight.
[0027] FIG. 12 is a rear, perspective view of the assembled golf club head shown in FIG. 1 .
[0028] FIG. 13 is a heel, plan view of the golf club head shown in FIG. 12 .
[0029] FIG. 14 is a bottom, plan view of the assembled golf club head shown in FIG. 12 .
[0030] FIG. 15 is a rear, plan view of the golf club head shown in FIG. 12 .
[0031] FIG. 16 is a rear, perspective view of the golf club head shown in FIG. 12 .
DETAILED DESCRIPTION OF THE INVENTION
[0032] The present invention is generally directed to a golf club head with a novel, movable weight configuration that allows a golfer to affect the position of the center of gravity in the club head to provide ball trajectories that are better suited to the golfer's swing. The movable weight may be housed in a removable back cap or a captive but movable back cap. The present invention is also directed to a golf club head created without welding operations, which reduces or eliminates the cost associated with purchasing secondary parts (faceplates, crown plates, sole plates, etc.) and the secondary operations (fixturing, grinding, blending, etc.) used to finish the club head.
[0033] Exploded views of the preferred embodiment of the present invention are shown in FIGS. 1-3 . The golf club head 40 shown in FIGS. 1-3 has a hollow interior and is generally composed of a body 42 having a face 60 , an aft body 70 comprising a crown 62 and a sole 64 , and a hosel 50 , a back cap 80 , a gasket 90 , screws 100 , 101 , 102 , 103 , a movable weight 120 , and a slider tee 130 . The club head body 42 also may optionally have a ribbon, skirt, or side portion (not shown) disposed between the crown 62 and sole 64 portions. The golf club head body 42 is preferably partitioned into a heel section 66 nearest the hosel 50 , a toe section 68 opposite the heel section 66 , and a rear section 75 opposite the face component 60 . The embodiment of the golf club head 40 shown in FIGS. 1-16 has a volume of at 300 to 500 cubic centimeters, more preferably a volume of 440 to 480 cubic centimeters, and most preferably a volume of 450 to 470 cubic centimeters, a mass of 160 to 225 grams, and most preferably a mass of 180 to 215 grams, and a face 60 with a characteristic time that is close to, but does not exceed, 257 μs.
[0034] In the preferred embodiment shown in FIGS. 1-3 , the face 60 , aft body 70 , and hosel 50 are made of titanium. The surfaces of titanium investment castings are generally contaminated with oxygen due to a reaction with the oxide mold material, a ceramic shell system. This contamination creates a brittle surface layer called α-case, which must be removed or the titanium will be subject to cracking and failure during use. The shell system of the present invention retards the formation of α-case on the surface of the titanium. In particular, the golf club head body 42 of the present invention is designed as a one-piece casting that does not require any secondary operation(s) to affix the face 60 , sole 64 , or crown plate 62 to the body 42 . The club head body 42 of the present invention has all these portions integrally cast together in one complete unit.
[0035] An opening 110 in the aft portion 70 of the club head, shown in FIGS. 1 and 2 , is large enough to extract all the internal core pieces of the molding tool after casting. This opening is then covered by a gasket 90 , which fits between the titanium body 42 and a lightweight back cap 80 . The integral casting method allows for better sound, strength, and thickness control because it eliminates the seam created by a welding operation, which adds weld material that must then be ground away. Welding operations add cost due to the process, consumable materials, fixturing, and finishing. The preferred driver of the present invention is not subject to such secondary welding and finishing operations.
[0036] In other embodiments, the face 60 , aft body 70 , and hosel 50 may be made from cast, machined, or forged metals or from composite materials, and may be formed integrally or pieced together. In yet other embodiments, the face 60 , aft body 70 , and hosel 50 may each be composed of different materials. For example, the face 60 may be made of cast titanium alloy and the crown 62 may be made of a composite material. The golf club of the present invention may also have material compositions such as those disclosed in U.S. Pat. Nos. 6,244,976, 6,332,847, 6,386,990, 6,406,378, 6,440,008, 6,471,604, 6,491,592, 6,527,650, 6,565,452, 6,575,845, 6,478,692, 6,582,323, 6,508,978, 6,592,466, 6,602,149, 6,607,452, 6,612,398, 6,663,504, 6,669,578, 6,739,982, 6,758,763, 6,860,824, 6,994,637, 7,025,692, 7,070,517, 7,112,148, 7,118,493, 7,121,957, 7,125,344, 7,128,661, 7,163,470, 7,226,366, 7,252,600, 7,258,631, 7,314,418, 7,320,646, 7,387,577, 7,396,296, 7,402,112, 7,407,448, 7,413,520, 7,431,667, 7,438,647, 7,455,598, 7,476,161, 7,491,134, 7,497,787, 7,549,935, 7,578,751, 7,717,807, 7,749,096, and 7,749,097, the disclosure of each of which is hereby incorporated in its entirety herein.
[0037] In the preferred embodiment shown in FIGS. 1-3 , the back cap 80 is composed of a composite material. In another embodiment, the back cap 80 is composed of magnesium or magnesium alloy. In other embodiments, the back cap 80 of the present invention may be made from another, very lightweight material, such as aluminum or plastic, to minimize the mass of the back cap and provide more available mass for the movable weight 120 . The back cap 80 of the present invention may, in other embodiments, be made of a material with a density less than that of the remainder of the golf club head 40 , including the face 60 , aft body 70 , hosel 50 , and weight 120 .
[0038] As shown in more detail in FIGS. 4 and 5 , the back cap 80 holds a weight 120 having a weight of 1 to 50 grams, more preferably 1 to 30 grams, and most preferably a weight of approximately 5 to 20 grams in a desired location. The weight 120 is preferably composed of a material having a higher density than the material used to make the gasket 90 and the back cap 80 , including, but not limited to, stainless steel, titanium alloy, and tungsten alloy.
[0039] In the embodiment depicted in FIGS. 4 , 9 , and 10 , the weight 120 is attached to an interior surface 85 of the back cap 80 with a screw 100 on the side of the back cap 80 closest to the toe section 68 to result in a neutrally weighted club head 40 . In the embodiment depicted in FIGS. 5 , 11 , and 12 , the weight 120 is attached to an interior surface 85 of the back cap 80 with a screw 100 on the side of the back cap 80 closest to the heel section 66 to result in a draw weighted club head 40 . These two positions affect a different sidespin to the ball which for some golfers will improve the ball flight of the golf ball for greater distance and directional control. The weight 120 may be removably attached to the back cap 80 by means other than a screw 100 including, but not limited to, removable adhesive or snap-in features. The presence in the back cap 80 of a receptacle, or visually observable features, for receiving the weight 120 or a screw 100 for affixing the weight 120 to the back cap 80 constitutes a predefined weight-receiving location.
[0040] Table 1 shows mechanical properties and data related to a neutrally-weighted driver designed according to the present invention, while Table 2 shows mechanical properties and data related to a draw-weighted driver designed according to the present invention. These tables demonstrate that the location of the weight 120 within the back cap 80 can affect the center of gravity and inertia value of a golf club head 40 , among other things.
[0000]
TABLE 1
Impact Loft:
11.000
Design Loft:
11.000
Lie:
0.000
Bulge:
12.000
Roll:
10.004
Face Angle:
0.000
F1:
3.225
Total Mass:
198.038
Head Frame Mass Properties:
CGX, CGY, CGZ: 0.7483, 0.7982, 1.1275
IXX, IYY, IZZ: 2829.59, 2635.67, 4092.70
IXY, IXZ, IYZ: 393.50, −73.80, −109.64
Hosel Frame Mass Properties:
CGX, CGY, CGZ: 0.7483, 1.2922, −2.7366
IXX, IYY, IZZ: 2829.59, 3192.93, 3535.44
IXY, IXZ, IYZ: 284.95, −281.23, −716.54
Impact Frame Mass Properties:
CGX, CGY, CGZ: 1.3480, −0.0090, 0.1431
IXX, IYY, IZZ: 2847.93, 2635.67, 4074.36
IXY, IXZ, IYZ: 407.19, 168.15, −32.54
Impact Center X, Y, Z: −0.6023, 0.8072, 1.2443
Bulge Roll Apex X, Y, Z: −0.6023, 0.8072, 1.2443
Component Weight Breakdown:
Solid Name
Weight (g)
Density (g/in 3 )
Layer
1-
164.80
72.400
100
2-
13.13
29.500
91
3-
8.99
127.000
91
4-
6.35
23.100
92
5-
1.07
127.000
91
6-
1.07
127.000
91
7-
1.07
127.000
91
8-
1.07
127.000
91
9-
0.59
23.100
88
[0000]
TABLE 2
Impact Loft:
11.000
Design Loft:
11.000
Lie:
0.000
Bulge:
12.000
Roll:
10.004
Face Angle:
0.000
F1:
3.225
Total Mass:
198.039
Head Frame Mass Properties:
CGX, CGY, CGZ: 0.7483, 0.6696, 1.1274
IXX, IYY, IZZ: 2772.49, 2635.88, 4035.61
IXY, IXZ, IYZ: 127.37, −74.03, −61.12
Hosel Frame Mass Properties:
CGX, CGY, CGZ: 0.7483, 1.1856, −2.6648
IXX, IYY, IZZ: 2772.49, 3130.24, 3541.25
IXY, IXZ, IYZ: 64.19, −132.60, −671.80
Impact Frame Mass Properties:
CGX, CGY, CGZ: 1.3480, −0.1375, 0.1430
IXX, IYY, IZZ: 2790.74, 2635.88, 4017.35
IXY, IXZ, IYZ: 136.69, 167.94, −35.69
Impact Center X, Y, Z: −0.6023, 0.8072, 1.2443
Bulge Roll Apex X, Y, Z: −0.6023, 0.8072, 1.2443
Component Weight Breakdown:
Solid Name
Weight (g)
Density (g/in 3 )
Layer
1-
164.80
72.400
100
2-
13.13
29.500
91
3-
8.99
127.000
91
4-
6.35
23.100
92
5-
1.07
127.000
91
6-
1.07
127.000
91
7-
1.07
127.000
91
8-
1.07
127.000
91
9-
0.59
23.100
88
[0041] Though the preferred embodiment of the back cap 80 shown in FIGS. 4 and 5 provides only two locations for the weight 120 , the back cap 80 in other embodiments may have more than two different locations to which the weight 120 may be affixed or otherwise placed such that a golfer can move the center of gravity (CG) of the golf club head 40 upwards and downwards in addition to toe-wards and heel-wards. The golf club 40 of the present invention may also include more than one weight 120 .
[0042] As shown in more detail in FIGS. 6-8 , the gasket 90 is fixed to the back cap 80 with screws 101 , 102 , 103 . The gasket 90 of the preferred embodiment is made of aluminum. In other embodiments, the gasket 90 may be composed of another lightweight material, including, but not limited to, magnesium, magnesium alloy, plastic, or composite graphite. As shown in FIGS. 1-3 , the gasket 90 covers the opening 110 in the aft portion 70 of the club head. The gasket 90 is glued and/or mechanically fastened over the opening 110 , which allows the back cap 80 to be more precisely fastened to the club head 40 . In the preferred embodiment depicted in FIGS. 1-16 , the golf club head body 42 is hollow, and the gasket 90 prevents foreign objects from entering the hollow interior of the body 42 .
[0043] The gasket 90 also separates the golf club head 40 body from the material of the back cap 80 . This separation prevents an electrochemical process called galvanic corrosion, which occurs when reactive materials in the presence of an electrolyte (e.g., water) come into contact with one another. In the preferred embodiment, where the body 42 is made of titanium, the gasket 90 is made of aluminum, and the back cap 80 is made of a lightweight material, the separation between the body 42 and back cap 80 is desirable, particularly if the back cap 80 is made of a metal material. The body 42 , gasket 90 , and lightweight back cap 80 of the preferred embodiment of the present invention are also coated with a material to insulate them from inadvertent contact with reactive materials. In other embodiments, the body 42 , gasket 90 , and/or lightweight back cap 80 may or may not be coated.
[0044] In the preferred embodiment, a slider tee 130 mechanism allows the back cap 80 to move along the gasket 90 to give a golfer access to the repositionable weight 120 , which can be relocated into receptive areas within the interior of the back cap 80 . The slider tee 130 may be made from one or more lightweight materials, including, but not limited to, aluminum, aluminum alloy, magnesium, composite, and plastic. As shown in FIGS. 1-5 , the end portion 132 of the slider tee 130 , which in the preferred embodiment is made of aluminum, is threaded through a slot 140 in the gasket 90 and inserted into a socket 135 in the back cap 80 . The end portion 132 of the slider tee 130 may be permanently or removably secured within the socket 135 by any means, but preferably by an adhesive. The head portion 134 of the slider tee 130 , shown in FIGS. 1-7 , prevents the slider tee 130 from slipping through the slot 140 . The slot 140 permits the slider tee 130 , and thus the back cap 80 , to slide laterally along the gasket 90 . In other embodiments, the slot 140 may permit the back cap 80 to slide up and down in addition to, or instead of, side to side.
[0045] Removal of the screws 101 , 102 , 103 loosens the back cap 80 from the golf club head 40 and gasket 90 . FIGS. 9-10 show a neutrally-weighted embodiment of the present invention without the screws 101 , 102 , 103 . In this embodiment, the back cap 80 has been slid along the slot 140 of the gasket 90 in the direction of the toe section 68 to reveal the weight 120 . FIGS. 11-12 show a draw-weighted embodiment of the present invention without the screws 101 , 102 , 103 . In this embodiment, the back cap 80 has been slid along the slot 140 of the gasket 90 in the direction of the heel section 66 to reveal the weight 120 . In each of these embodiments, once the weight 120 has been relocated, the back cap 80 can be slid back into a closed position that is fully flush with the gasket 90 and the screws 101 , 102 , 103 can be replaced.
[0046] In the embodiments shown in FIGS. 1-16 , the screws 100 , 101 , 102 , 103 used to affix the weight 120 to the back cap 80 and the gasket 90 to the back cap 80 are composed of stainless steel. In other embodiments, the screws 100 , 101 , 102 , 103 may be composed of another material, including a metal, a composite, or a plastic. FIGS. 13-16 show the preferred embodiment of the invention in its fully assembled form.
[0047] In an alternative embodiment, the back cap 80 is not movably affixed to the golf club head 40 via a slider tee 130 attached to a gasket 90 , but instead is completely removable. In this embodiment, a golfer or fitting professional can detach the back cap 80 from the golf club head 40 by removing all of the screws 101 , 102 , 103 and alter the location of the weight 120 within the back cap 80 . After such modification is completed, the back cap 80 can be re-attached to the golf club head 40 .
[0048] The golf club head of the present invention may be constructed to take various shapes, including traditional, square, rectangular, or triangular. In some embodiments, the golf club head of the present invention takes shapes such as those disclosed in U.S. Pat. Nos. 7,163,468, 7,166,038, 7,169,060, 7,278,927, 7,291,075, 7,306,527, 7,311,613, 7,390,269, 7,407,448, 7,410,428, 7,413,520, 7,413,519, 7,419,440, 7,455,598, 7,476,161, 7,494,424, 7,578,751, 7,588,501, 7,591,737, and 7,749,096, the disclosure of each of which is hereby incorporated in its entirety herein.
[0049] The golf club head of the present invention may also have variable face thickness, such as the thickness patterns disclosed in U.S. Pat. Nos., 5,163,682, 5,318,300, 5,474,296, 5,830,084, 5,971,868, 6,007,432, 6,338,683, 6,354,962, 6,368,234, 6,398,666, 6,413,169, 6,428,426, 6,435,977, 6,623,377, 6,997,821, 7,014,570, 7,101,289, 7,137,907, 7,144,334, 7,258,626, 7,422,528, 7,448,960, 7,713,140, the disclosure of each of which is incorporated in its entirety herein. The golf club of the present invention may also have the variable face thickness patterns disclosed in U.S. Patent Application Publication No. 20100178997, the disclosure of which is incorporated in its entirety herein.
[0050] From the foregoing it is believed that those skilled in the pertinent art will recognize the meritorious advancement of this invention and will readily understand that while the present invention has been described in association with a preferred embodiment thereof, and other embodiments illustrated in the accompanying drawings, numerous changes, modifications and substitutions of equivalents may be made therein without departing from the spirit and scope of this invention which is intended to be unlimited by the foregoing except as may appear in the following appended claims. Therefore, the embodiments of the invention in which an exclusive property or privilege is claimed are defined in the following appended claims. | A titanium bodied driver that utilizes a lightweight receiving back cap, which is designed to be non-removable from the club head but can be loosened to allow its interior to be accessed to reposition one or more movable weights into alternative receiving locations, is disclosed herein. The back cap may also be designed to be completely removable from the driver body to gain access to the one or more weights that can be re-positioned in alternative receiving areas within the back cap's interior. | 0 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to refrigeration, and in a more particular sense has reference to those structures in the refrigeration category described commercially as refrigerated display cases. Such cases are of the type used in food markets, and within this general category the invention comes within the field of invention wherein the display case has an air passage through which air is circulated about the displayed food products, often flowing as an air curtain across an open front of the display case. In yet a more particular sense, the invention has reference to improvements in this type of display case, wherein a service opening is provided at the rear of the case, through which dairy product support carts may be rolled into and out of the case. The invention relates to a hollow structure normally closing the service opening through which the carts are moved, the structure being both a part of the air flue or conduit, and a foldable door for the service opening.
2. Description of the Prior Art
It has heretofore been proposed to provide, in refrigerated display cases of the type generally described above, service openings at the rear of the display cases, through which dairy product support carts can be rolled into and out of the case. It has been proposed that the carts be left within the case to provide convenient means for displaying the products without the necessity of unloading the same and transferring them to shelves such as are normally provided in refrigerated display cases.
It has further been suggested to provide, for the service openings of the cases, closures that serve as air passages communicating with other portions of the air conduit above and below the closures when the closure are in their normal, closed positions.
Usually, closures of this type when used in refrigerated display cases are of the sliding or hinged type. Such doors, unfortunately, present certain problems with respect to rolling carts into and out of the display case.
To appreciate the problems that have arisen, it should first be noted that cases of this type are often of great length, particularly when used in large supermarkets. In such installations, it is common to provide an array of identical display cases, end-to-end, that may extend to an overall length of perhaps 60 to 70 feet, typically.
In such installations, it is desirable that the maximum amount of the total, overall length be available for stocking the displayed food products, that is to say, there should be minimum spacing between the dairy carts, since open spaces between side-by-side carts represent completely wasted, refrigerated areas in the product display space of the display case. Additionally, such open spaces are visually unattractive and detract from the merchandising capability of the case as a means for promoting sales of the displayed products.
Typically, a dairy product support cart, of the type that is rolled into and out of the case to serve as shelving accessible to the customer, is approximately 36" in width. It follows that if the service opening is closed by a series of hinged doors, there would normally be one door for each cart location. That door would have to be of a width that would have a transverse dimension sufficiently greater than the cart width to permit clearance on both sides of the cart when it is moved through the service opening defined by opening of the door. Further, between adjacent doors mullions must be provided if the doors are hinged, of sufficient width and strength to support the doors when they are swung to open positions.
If follows that in such arrangements, substantial open spaces occur between adjacent carts when the carts are in position within the display cases.
The disadvantages of using hinged doors, whether or not they also provide air ducts when in their closed positions, can thus be readily noted when their use is contemplated for dairy cases into which product support carts are to be loaded.
The same problems arise with respect to sliding closures. Whether or not these are hollowly formed to define air ducts in their closed positions, they share with hinged doors the problem that they of necessity leave open spaces between adjacent carts within the display case, a highly undesirable feature which, as noted above, not only detracts from the merchandising ability of the equipment, but also reduces its overall, effective length as a product display area.
It has in fact been proposed to provide foldable flexible closures for the rear surface openings of display cases of the type described, as shown in U.S. Pat. No. 4,034,572, issued July 12, 1977 to the assignee of the present application. While to some extent these facilitate the positioning of carts directly side-by-side with minimum open areas between them, they at the same time take away from the available duct space at the rear of the case. It is desirable, in this connection, that the duct be continuous from end-to-end of the case, so as to provide for uniform refrigeration and an efficient air curtain across the front access opening of the display case.
SUMMARY OF THE INVENTION
The present invention aims to eliminate the deficiencies of the prior art, in the described type of refrigerated display case. To this end, there is provided a case which, over its entire length, has a service opening closed by a plurality of side-by-side, contacting combined duct-and-door sections. These, in the fully closed positions thereof, completely close the back of the case, but at the same time provide continuous ducting over the entire length of the case, disposed in full communication with the top and bottom duct portions conventionally provided therein. The sections are identically formed, each including flexible, accordion-pleated walls, transversely spaced apart and connected to define a duct means when the sections are in their extended, closed positions. The sections, when folded to open positions, expose any selected cart location, leaving ample clearance for movement of a cart into or out of the case, while at the same time being adapted to permit carts to be positioned a minimum distance apart, almost in contact with one another, thereby to make maximum use of the refrigerated product display space.
The accordion combination duct and door sections are all mounted rollably in upper and lower trackways, which themselves are ported to provide the desired communication between the ducts defined by the sections, and the adjacent air passages provided in the fixed upper and lower portions of the display case.
BRIEF DESCRIPTION OF THE DRAWINGS
While the invention is particularly pointed out and distinctly claimed in the concluding portions herein, a preferred embodiment is set forth in the following detailed description which may be best understood when read in connection with the accompanying drawings, in which:
FIG. 1 is a front perspective view of a display case according to the present invention, the accordion sections being in their extended, closed positions;
FIG. 2 is a greatly enlarged, fragmentary, transverse sectional view substantially on line 2--2 of FIG. 1;
FIG. 3 is a transverse sectional view substantially on line 3--3 of FIG. 1, a dairy product support cart being illustrated in chain-dotted outline as it appears immediately prior to being moved into the case;
FIG. 4 is a horizontal section substantially on line 4--4 of FIG. 1, with all of the combination duct-and-door sections being in fully extended, closed positions;
FIG. 5 is a view on the same cutting plane as FIG. 4, in which two of the sections have been folded to permit movement of a cart into one cart location within the case;
FIG. 6 is a horizontal section on the same cutting plane as FIG. 4, in which the sectional wall structure has been collapsed to permit movement of a cart into a second cart location;
FIG. 7 is a horizontal section on the same cutting plane as FIG. 4, in which the sectional wall has been partially collapsed or folded to permit movement of a cart into a third cart location;
FIG. 8 is a front perspective view, portions being broken away, showing a modified construction;
FIG. 9 is a sectional view, substantially on line 9--9 of FIG. 8;
FIG. 10 is a fragmentary perspective view of one of the accordion wall sections.
DESCRIPTION OF THE PREFERRED EMBODIMENT
In the form of the invention illustrated in FIGS. 1-7, the refrigerated display case 10 constituting the present invention includes (FIGS. 1 and 3) a flat base plate 12 flush with the store floor F, overlying a recess 14 formed in the floor to define therebetween a bottom duct portion 16 having near the front of the case an inlet grille 17. Case 10 includes a vertical, insulated back wall 18 rigid at its upper end with a forwardly projecting, insulated top wall 20. At the ends of the case (FIG. 1) upper end walls 22 serve to rigidify the structure and at the same time close the air ducting of the case at its end. Similarly, lower end walls 24 are provided at the ends of the case to discharge a similar purpose. Extending the full length of the case between walls 22 is a plenum wall 26 inclined upwardly from the rear to the front of the case to define, in cooperation with top wall 20, a plenum 28 in which is mounted evaporator coil 30 through which air is circulated by primary fan 32. The case may also be provided with an upper front panel 34 cooperating with a forwardly declining extension 35 of wall 20 to define an ambient air chamber in which is mounted ambient air circulation fan 36 adapted to provide a protective curtain of ambient air in front of the curtain of refrigerated air discharged through nozzle 27 provided at the front of the plenum.
A lower front panel 38 mounted forwardly of inlet 17 aids in channeling the refrigerated air into the inlet 17 after it passes downwardly across the customer access opening 39 located at the front of the case.
The construction so far described is conventional, in that the components so far described are similar in structure and function to corresponding components disclosed in the above mentioned U.S. Pat. No. 4,034,572.
In accordance with the invention, the back wall 18 is open for the full distance between the end walls of the case as shown at 40, fully from the floor to a height sufficient to permit a dairy product support cart C (see FIG. 3) to be moved into and out of the case over a sill 41 extending along the bottom edge of the open back 40, flush with floor F.
Normally closing the open back 40 over its full length and height is a foldable combination duct-and-door structure generally designated 42. In the illustrated example, this comprises three identically constructed, abutting, individually openable sections 44, 46, 48 respectively. Obviously, there can be any number of sections, according to the length of the particular case as ordered by the operators of the food market.
The several sections are mounted rollably in upper and lower trackways common to all of the sections. The upper trackway (see FIG. 2) includes a downwardly opening channeled, upper track member 50 extending the full length of the case. Fixedly secured to and depending from the track member 50, and co-extensive in length therewith, is an upper track element 52 also formed as a channel member and opening laterally to receive upper rollers 54 of the several sections 44, 46, 48.
The description of one of the sections will suffice for all. Each section, thus, includes a plurality of the upper rollers 54, mounted upon angular upper roller brackets 56 welded or otherwise fixedly secured to upper cross members 58. In a typical embodiment, the rollers could be provided as shown in FIG. 10, at the ends of their associated section, with the cross members 58 being disposed at the ends, and being fixedly secured to facing, channeled end walls 78 of the associated section.
Each section further includes transversely spaced flexible sidewalls 60 which may be formed of a rugged, heavy, flexible plastic material impervious to the passage of air therethrough and strengthened by a strong cloth backing, in a preferred embodiment.
At the lower end of each section, lower cross members 62 formed to the same width as the members 58, are fixedly secured to the respective end walls 78 of the section in the same manner as the cross members 58. The flexible walls 60, it may be noted, are secured to the respective end walls 78 by rivets 63 or equivalent fasteners, spaced uniformly apart over the full height of the wall structure (see FIG. 1).
Depending from the respective lower cross members 62 (FIG. 2) are lower roller support posts 64, each of which supports a pair of lower rollers 66, rollably engaged with confronting lower track elements 68 of right angular cross-section, welded or otherwise fixedly secured to the opposite sidewalls of an upwardly opening channel 70 integrally formed in and extending longitudinally and centrally of a lower track member 72. Over the full length of the channel 70, there are formed, both in the sidewalls and in the web of the channel, air inlet ports 74 communicating with the bottom duct portion 16, so that air flowing through said duct portion 16 in the direction of the arrows shown in FIGS. 2 and 3 will be directed upwardly through the rear duct portion 75 defined between the sidewalls 60 of each section.
In the web portion of the upper track member 50, there is formed a series of uniformly spaced outlet ports 76, these being spaced longitudinally of the upper track member so as to occur over the full length of the case. Air exiting from the upper end of the sectional, foldable, back wall 42 passes through the ports 76 into the plenum 28, to be recirculated through the display case.
As previously noted, each section is closed at its ends by end walls 78. The end walls 78 of each section are formed as confronting channels, with the flexible walls 60 of the section riveted to the sidewalls of the channels at 63. The channels are of a rigid metal material, to maintain the walls 60 in transversely spaced relation at the ends of each section.
Intermediate the ends of each section, there are provided, at selected intervals, flexible cross tapes 80, and secured thereto are thin but strong, relatively rigid, transversely extending brace plates 82, which maintain the walls in the desired transversely spaced relation at selected locations between the ends of each section. As a result, when each section is fully collapsed or folded, it will fold accordion fashion along crease lines 84 pre-formed in the flexible material from which the sidewalls 60 are made.
In FIGS. 8 and 9, there is illustrated a refrigerated display case which is identical to that of FIGS. 1-7 in all respects, except for the construction of the accordion wall and a resultant change in the pattern of the air flow when the combined duct and service door is in closed position.
In this form of the invention the flexible closure has been designated 42a, and includes sections 44a, 46a, 48a. The description of one section suffices for all. Each section includes a rear flexible wall identical to that in the first form of the invention. Each section includes, however, a forward flexible wall 60a which, at its lower end, has its air-impervious material cut away a few inches above the base plate 12 as at 86. The space between the lower extremity of the wall 60a and the point 86 at which the air-impervious material thereof terminates is occupied by a foraminous or net material secured to the lower extremity of the non-pervious flexible material of the forward wall, and providing a bottom portion 88 of wall 60a, which bottom portion in effect becomes a flexible inlet grille for the rear duct portion 75 when the several sections of the flexible closure are in their closed positions.
In some cases, this is desirable for the purpose of improving the air flow characteristics of the display case, by providing more air at the inlet end of the flexible rear wall, and thereby maintain sufficient volume within the rear duct portion 75. In the illustrated arrangement, the bottom duct portion 16 is still provided, so that there is air flow therethrough as well as across the well of the case above the base plate.
Obviously, the construction shown in FIGS. 8 and 9 can be advantageously used, in instances in which it is not desired to form a bottom recess 14 in the floor of the store. The modified construction permits installation of a case directly upon any flat floor surface wherein installation is desired. In these circumstances, there would be no bottom duct portion 16 or floor inlet grille 17. Rather, the base plate 12 would be closed across the entire bottom of the case. Air would enter the lower end of the flexible combined air duct and door through the mesh fabric flexible inlet 88 thereof only. In these circumstances, the lower track member 72 would be made without openings 74, or alternatively, could be made as shown in FIG. 2 with the openings 74 being simply left inoperative due to the omission of the bottom duct portion 16.
In use, and referring particularly to FIGS. 4-7, in all forms of the invention the flexible rear wall can be opened at any cart location desired. In FIG. 4 it is shown in fully closed position. In FIG. 5, it may be assumed that it is desired to roll a cart C into one end of the case. In this event, sections 44, 46 would be folded to whatever extent is necessary to provide clearance for the cart. As soon as the cart is in position, the flexible wall is again closed.
In FIG. 6, a cart C is being moved into the other end of the case. In this event, sections 48, 46 are folded to the extent necessary to provide clearance for the cart.
In FIG. 7, the cart is being moved into a center location. In this instance, sections 44, 46 are folded against one end of the case, to provide an intermediate opening for cart entry.
In every instance, it may be noted that the sections can be opened to whatever degree is necessary to accommodate passage of the cart. Further, the carts can be disposed within the case, in side-by-side relation with minimum clearance space between them, as distinguished from cases provided with sliding or hinged doors. At the same time, as shown in FIG. 4, when the sections are in their extended closed positions they provide a continuous back wall over the entire length of the case, and most importantly, a rear duct portion 75 that is also continuous over the full length of the case and that is of constant transverse and vertical dimensions over its entire area, thus assuring a smooth and uniform air pattern for the entire length of the product display area of the case.
While particular embodiments of this invention have been shown in the drawings and described above, it will be apparent, that many changes may be made in the form, arrangement and positioning of the various elements of the combination. In consideration thereof it should be understood that preferred embodiments of this invention disclosed herein are intended to be illustrative only and not intended to limit the scope of the invention. | A refrigerated display case, of the type in which air flows through a duct and is circulated about a product display space, has a service opening at the rear of the case. Disclosed is an accordion-pleated, hollow wall structure which is both an air duct and a door. The structure in its closed position communicates at top and bottom with adjacent portions of the conduit through which air is circulated during refrigeration or, in some instances, during defrost cycles of the case. In its open position, the hollow structure defines a service opening at the rear of the case through which dairy product support carts can be rolled into or out of the case. The hollow structure is sectionally formed in a manner to define the service opening at any selected cart location. | 0 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a device and a method for sharpening dental curettes.
Sharpening dental tools is problematic in that it must be able to be performed regularly by the operator or his assistants and must be precise and uniform.
2. Description of the Related Art
Manual sharpening devices for dental curettes are known, such as the Kramer sharpener or the device described in document CH 683 505, and motorised devices are known, such as the “Hawe PerioStar 3000” (trademark) from Kerr Hawe, the “LM Rondo Plus” from LM Dental Oy, or the “Sidekick” (trademark) from Hu-Friedy.
It often takes longer and is more complex to uniformly and precisely sharpen a cutting edge of a dental curette using manual devices. These devices require a great amount of dexterity and precision on the part of the operator in the placement and movements imparted to the curette. The motorised devices are easier to use but still require precise positioning of the curette with respect to the sharpening stone.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to a device and method for sharpening dental curettes which are simple, less costly, easy to implement by the operator or his assistants and which permit precise and simple positioning of a dental curette to be sharpened in order to achieve precise and uniform sharpening of the cutting edge(s) of said curette. The present invention also relates to a sharpening guide for implementing the sharpening method using said device.
The device and the method for sharpening dental curettes in accordance with the invention are characterised by the features listed in claim 1 and claim 16 respectively. The sharpening guide for implementing said sharpening method is for its part characterised by the features listed in claim 19 .
In particular, in one preferred embodiment of the invention, the device comprises a magnifying lens in line with the grinding wheel providing a magnification of the sharpening area and thus permitting precise and easy positioning of a dental curette to be sharpened by the operator.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings schematically illustrate, by way of a non-limiting example, several embodiments of the device for sharpening dental curettes in accordance with the invention for the implementation of the method for sharpening such curettes in accordance with the invention.
FIG. 1 is a side view of a first embodiment of the device in accordance with the invention.
FIGS. 2 and 3 are front and rear views respectively of a sharpening guide of the sharpening device illustrated in FIG. 1 .
FIG. 4 is a side view of a second embodiment of the device in accordance with the invention.
FIGS. 5 and 6 are front and rear views respectively of a sharpening guide of the sharpening device illustrated in FIG. 4 .
FIG. 7 is a view of the device illustrated in FIG. 1 during use thereof by a practitioner for sharpening a dental curette.
FIG. 8 illustrates a dental curette.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
A first embodiment of the device in accordance with the invention will now be described with reference to FIGS. 1 to 3 . The sharpening device 1 for dental curettes in accordance with the invention, shown in a first embodiment in FIG. 1 , has a base plate 2 on which there is articulated a frame 3 and at least one sharpening guide 4 .
Preferably, the inclination of the frame 3 with respect to the base plate 2 is adjustable using a first adjustment screw 5 for example.
The frame 2 supports a magnifying lens 6 , a sharpening guide support 7 as well as a motorised grinder 8 .
The magnifying lens 6 is fixed to the free end 3 a of the frame 3 . The axis of the magnifying lens 6 and the axis of the guide support 7 are preferably perpendicular to the axis of the frame 3 . Second adjustment screws 10 a , 10 b enable the height of the guide support 7 and of the magnifying lens 6 respectively to be adjusted with respect to the frame 3 .
The grinder 8 as illustrated in FIG. 1 comprises an electrical connecting cable 11 , a trigger 12 and a mandrel 13 intended to receive a grinding wheel 14 . Preferably, the grinding wheel 14 has a cylindrical flat form and the active surface of the grinding wheel 14 is parallel to the axis of the frame 3 .
Preferably, the mandrel 13 and the grinding wheel 14 are designed such that the grinding wheel 14 is press-fitted to the mandrel 13 and can be removed from said mandrel 13 using neither an unscrewing process nor another tool. It is thus easier to change the grinding wheel and it is very easy to simply turn over the grinding wheel 14 when one surface thereof is worn for example.
The grinding wheel 14 could be of a different size, shape or abrasive grain and the grinder 8 could further comprise a speed regulator or even be battery-operated.
The grinder 8 is placed on the frame 3 between the magnifying lens 6 and the guide support 7 and the axis of the grinding wheel 14 is preferably perpendicular to the axis of the frame 3 . Preferably, and as illustrated in FIG. 1 , the grinder 8 is fixedly attached to the frame 3 by locking screws 15 and a secondary frame 16 .
The sharpening device 1 in accordance with the invention is intended to be placed on a table or any other working surface. For ease of use, the base plate 2 preferably comprises feet 17 . Said feet 17 could be height-adjustable. For safe and suitable gripping of the device, the feet preferably comprise anti-slip pads 18 . This device could comprise any other suitable fixing means such as a clamp for example.
The sharpening guide support 7 is formed in this first embodiment by a rod 19 whose height can be adjusted with respect to the frame 3 . The rod 19 supports a rotating guide disk 4 fixed to said rod 19 using a screw 20 for example. The guide disk 4 is freely rotatable with respect to the rod 19 . Indexing means are provided to determine the different usage positions of the guide disk during rotation thereof. Preferably, these indexing means comprise a protrusion (not shown) provided on the rod 19 and co-operating with at least one but preferably six recesses 21 in the rear face 4 b of the guide disk as shown in FIGS. 2 and 3 .
The guide disk is divided into at least one but preferably six sectors on its front face 4 a shown in FIG. 2 . Each indexing position of the guide disk is determined by a recess 21 and corresponds to a sector. The recesses 21 and the sectors are designed such that the correct position for each sector with respect to the grinding wheel 14 is ensured when snap-fitting the protrusion of the guide support 7 into the recess 21 corresponding to said sector.
Each of the sectors of the guide disk 4 comprises an indicator formed preferably of four markings:
the first marking 22 is the letter R or L and indicates that said sector is intended to be used as a guide for a right-handed or left-handed operator respectively. the second marking 23 contains the name of the type of curette to which the sector corresponds. There are three types of dental curettes: universal curettes, scalers (sickles) and Gracey-type curettes. the third marking 24 designates the respective angles 10°, 20° and 30° corresponding to the different types of curette: 10° corresponding to the universal curettes, 20° to the scalers (sickles) and 30° to the Gracey-type curettes. the fourth marking 25 is an indicating line, the angle of which with the horizontal corresponding to the angle of the third marking (the angles and orientations of the markings are defined for each sector in its indexing position). It is this line which will be used as a guide for the operator during sharpening. As illustrated in FIG. 2 , the inclination of the indicating line also depends upon the laterality of the guide, i.e., upon the first marking 22 : if said sector is intended to be used as a guide for a right-handed operator, the indicating line rises from left to right from the point of view of the operator. If said sector is intended to be used as a guide for a left-handed operator, the indicating line then falls from left to right from the point of view of the operator.
Thus, a single guide disk 4 allows three different types of curette to be sharpened, whatever the laterality of the operator.
As a variation, the device could comprise two guide disks 4 , one for right-handed operators and one for left-handed operators. Each disk would then be divided into three sectors, one for each type of curette, each sector having an indicator formed of the second 23 , third 24 and fourth 25 markings described above. The rear face of such disks then comprises three recesses 21 , each corresponding to a sector and allowing the disk to be positioned by means of a snap-fitting arrangement with the protrusion of the guide support 7 .
Preferably, and as illustrated in FIG. 1 , the sharpening device in accordance with the invention further comprises an eyepiece 26 stored in a storage mount 27 provided for this purpose on the base plate 2 . The eyepiece 26 enables the result of the sharpening operation to be verified after it is completed.
Preferably, the device in accordance with the invention further comprises an illumination system 29 allowing the grinding wheel 14 and the sharpening area of the dental curette to be sharpened to be illuminated. In the embodiments described in the Figures, the illumination system 29 comprises a hinged arm 30 fixed to the frame 3 between the magnifying lens 6 and the grinder 8 using a fixing screw 31 and preferably having a light-emitting diode (LED) lamp 32 . The hinged arm 30 can be pivoted with respect to the frame in order to position the illumination system in a suitable manner depending upon whether the operator is right-handed or left-handed.
Preferably, the device in accordance with the invention further comprises a stabilising support 33 fixed to the secondary frame 16 , the lateral and height position of which on said frame being adjustable using a third adjustment screw 34 for example. Said stabilising support 33 is designed to provide a support platform for the hand of the operator when sharpening a dental curette. The hand of the operator is thus stabilised and possible shaking is minimised, ensuring an even greater degree of precision when sharpening the dental curette.
A second embodiment of a device for sharpening dental curettes in accordance with the invention will now be described with reference to FIGS. 4 to 6 . In this embodiment, the guide disk 4 is replaced by at least one but preferably six sharpening guides 40 . The sharpening guides 40 are in the form of a rectangular plate. The rear face 40 b of each of the sharpening guides 40 , which is shown in FIG. 6 , has a recess 41 whose position varies depending upon the guides. The role and said position of the recess 41 will be explained hereinafter. The front face 40 a of each of the guides, which is shown in FIG. 5 , has markings which will also be explained hereinafter.
In this embodiment, the base plate 2 has second storage mounts 43 which are each intended to receive a sharpening guide 40 in a vertical position. The presence of said storage mounts 43 thus facilitates the storage of the sharpening guides 40 as well as their accessibility for the operator.
The storage mounts 43 could be replaced by any other storage system, whether fixed to the base plate 2 or not. Thus, the sharpening device could comprise a housing used to store the sharpening guides 40 .
The frame 3 supports, as in the first embodiment, a magnifying lens 6 , a sharpening guide support 7 as well as a motorised grinder 8 .
In this embodiment, the sharpening guide support 7 has the shape of a rest 44 comprising a leg 45 and a tray 46 provided with a shoulder 47 intended to receive a sharpening guide 40 . The tray 46 has a protrusion 48 intended to co-operate with the recess 41 in each of the sharpening guides 40 . The correct positioning of a sharpening guide 40 on the tray 46 is ensured when snap-fitting the protrusion 48 into the recess 41 in said guide and by the shoulder 47 preventing the guide from pivoting. Of course, the sharpening guides 40 could conversely comprise a protrusion on their rear face which then co-operates with a recess in the tray of the rest.
The protrusion 48 , the recess 41 and the shoulder 47 of the rest 44 thus form positioning means for the sharpening guides 40 on the rest 44 . In general, these positioning means could be formed by any other suitable element and the rest 44 does not have to comprise a shoulder 47 .
There are four markings on the front face 40 a of each sharpening guide 40 shown in FIG. 5 , these markings being similar to those shown on each sector of the guide disk 4 described in the first embodiment of the invention:
the first marking 22 is the letter R or L and indicates that the guide is intended to be used by a right-handed or left-handed operator respectively. the second marking 23 contains the name of the type of curette to which the guide corresponds. the third marking 24 designates the respective angles 10°, 20° and 30° corresponding to the different types of curette: 10° corresponding to the universal curettes, 20° to the scalers (sickles) and 30° to the Gracey-type curettes. the fourth marking 25 is an indicating line, the angle of which with the horizontal corresponding to the angle of the third marking 24 . It is this line which will be used as a guide for the operator during sharpening. As illustrated in FIG. 5 , the inclination of the indicating line also depends upon the laterality of the guide, i.e., upon the first marking: if the guide is intended for a right-handed user, the indicating line rises from left to right from the point of view of the operator. If the guide is intended for a left-handed user, the indicating line falls from left to right from the point of view of the operator.
The position of the recess 41 on the rear face 40 b of each sharpening guide 40 also depends upon the type of dental curette to which the guide corresponds as well as the laterality of said guide.
The other components of the device in accordance with the second embodiment, such as the magnifying lens 6 , the illumination system 29 , the stabilising support 33 and the grinder 8 are similar to those described in the first embodiment in every respect.
The method of sharpening dental curettes in accordance with the invention implemented using a device for sharpening dental curettes in accordance with the first embodiment will now be described with reference to FIG. 7 and has the following steps:
1. The operator adjusts the inclination of the frame 3 with respect to the base plate 2 , the height of the guide support 7 and of the magnifying lens 6 as well as the position of the illumination system 29 and of the stabilising support 33 in accordance with his height, his laterality, the height of the chair and/or the table on which the device is placed. 2. The operator selects a sector of the guide disk 4 corresponding to the type of dental curette 50 to be sharpened, illustrated in FIG. 8 , and to the laterality of the operator and causes the guide disk 4 to pivot until said sector is suitably positioned. Said sector is correctly positioned when the protrusion of the guide support 7 co-operates with the recess 21 of the rear face 4 b of the disk 4 corresponding to the selected sector. 3. The curette to be sharpened is manually held by the operator who applies the edge 51 to be sharpened onto the grinding wheel 14 whilst aligning the last straight part x of the curette 50 on the line 25 marked on the sharpening guide. 4. The grinder 8 is started using the trigger 12 . Whilst keeping the straight part x of the curette 50 aligned with the line 25 of the guide and the edge 51 to be sharpened supported against the grinding wheel 14 , the operator simultaneously imparts a rotational movement to the handle of the curette 50 on an axis coinciding with said handle to follow the curve of the edge 51 to be sharpened. This operation is greatly facilitated owing to the magnification provided by the magnifying lens 6 thus permitting extremely precise positioning and sharpening. 5. The operator monitors the result of the sharpening using the eyepiece 26 placed on the base plate 2 of the device.
The method of sharpening dental curettes in accordance with the invention implemented using a device for sharpening dental curettes in accordance with the second embodiment is similar to the above-described method except that step 2 is replaced by the following step:
2′: The operator places a sharpening guide 40 corresponding to the type of dental curette 50 to be sharpened, illustrated in FIG. 8 , and to the laterality of the operator onto the rest 44 . The sharpening guide 40 is correctly positioned when the protrusion 48 of the tray 46 of the rest 44 co-operates with the recess 41 in the rear face 40 b of the guide 40 .
By providing a suitable mode of operation, this device may also be used to sharpen excavators, small operating scissors or other instruments which require sharpening.
The magnifying lens 6 enables the operator to easily and precisely position the dental curette to be sharpened with respect to the corresponding guide. The magnifying lens preferably has a diameter of 100 mm and thus also acts as a protective screen between the grinding wheel and the operator.
The described device is simple and is characterised by extremely safe usage, an extremely quick positioning of the tool, an extremely fine cutting surface state, precise sharpening and a working position which is comfortable and suitable for everyone. | A device for sharpening one or more cutting edges of a dental curette has a base support with a frame articulated thereon, and at least one sharpening guide. The frame supports a grinding wheel rotationally driven by a motor and a sharpening guide support intended to receive the sharpening guide(s). The guide includes at least one indicator in the form of a line marked on the guide, whose angle with the horizontal being between 10° and 50° but preferably equal to 10°, 20° or 30° and corresponding to the type of dental curette to be sharpened. The sharpening guide(s) can move with respect to the support, and the support and/or the guide include(s) indexing and positioning elements determining indexing positions of the guide on the support, each indexing position corresponding to a different indicator. A method of sharpening one or more cutting edges, and a sharpening guide are described. | 1 |
RELATED APPLICATIONS
[0001] The present application is a continuation in part of application Ser. No. 12/331,105, entitled “Descent Control Device”, filed on Dec. 9, 2008, and claiming priority from Canadian Patent Application No. 2,613,855 entitled “Egress Descent Control Device” which was filed on Dec. 10, 2007. Both of the aforementioned applications are incorporated by reference herein in their entirety.
FIELD
[0002] The present application relates to apparatus for controlling the descent rate of a structure along a cable, and more particularly to a descent control device for controlling the speed of descent of a cable-suspended apparatus for emergency escape from a platform on a rig.
BACKGROUND
[0003] Often it is necessary to have someone working on a rig platform (such as a derrick tubing board, for example). Sometimes, however, rig workers on such platforms are faced with a blowout or fire or some other kind of accident and need to escape quickly from the platform in order to avoid being seriously or fatally injured. Various t-bar or chair-based systems exist for providing a means for escaping from such platforms; however a difficulty encountered with known escape systems is that functionally impaired workers (e.g. workers who are in a state of shock as a result of the accident, or workers who have been burned, or disoriented by gases as a result of the accident) can have difficulties in accessing and operating them.
[0004] In Canadian Patent Application no. 2,539,883 filed Mar. 16, 2006 by Boscher et al and entitled APPARATUS FOR ESCAPING AREA OF ACCIDENT, which is incorporated by reference in its entirety herein, an apparatus is provided for emergency escape from a drilling rig platform along a path defined by at least one cable extending between the platform and a remote, terminal location. The apparatus includes a frame in which a top of the frame is located above a bottom of the frame when the frame is erect. The frame defines an interior space large enough to accommodate a worker. A locking system includes a locking mechanism and also a foot-actuated disengager that is located at least proximate to the bottom of the frame. The locking mechanism is adapted to interlock with a mating portion on the platform to prevent the frame from traveling away from the platform when the locking mechanism engages the mating portion. The disengager is connected to the locking mechanism and has a foot receiving surface region upon which force can be applied to displace the disengager between a first, engaged position and a second position to disengage the locking mechanism from the mating portion. The frame will travel away from the platform to the terminal location under gravity when the locking mechanism is disengaged.
[0005] The Boscher et al. device uses an automatic braking system attached at the bottom of the frame, beneath the disengager to permit quick descent along the path defined by the cable, but still sufficiently slowed down to prevent an excessively forceful impact when the frame arrives at the terminal location.
[0006] Conventional systems include braking systems that employ hand actuated levers (including overriding automatic brake settings). A preferred system disclosed in the Boscher et al device is the Rollgliss® Rescue Emergency Descent Device friction brake, model no. 3303001 manufactured by DBI/SALA & Protecta. This system employs a series of brake pads that expand into a brake drum during descent to slow descent to a rate of about 15 feet/second.
[0007] Because of the intangible factors that will affect braking power with such systems, the rate at which enclosures equipped with such systems will fail will invariably have considerable variability, which makes it difficult to ensure compliance with applicable safety standards, such as those mandated by the Canadian Association of Oilwell Drilling Contractors (CAODC). Such standards mandate, amongst other things, that the enclosure land with a speed no greater than 12 ft/s.
[0008] The release of the pod pulls on the spooled cable, causing the pads to be placed in frictional contact with a drum to slow the descent of the pod. The physical contact between the pads and the drum creates a potentially hazardous risk of overheating of the components and cable and causes wear on both items which must be taken into account in maintenance operations, especially given that the device is hopefully only sporadically used. Additionally, both the pads and the drum should be subjected to regular maintenance and/or inspections to ensure that corrosion does not build up on either surface which may deleteriously impact the gripping performance of the braking system. Indeed, such braking systems face re-certification inspections after use and on a semi-annual or annual basis.
[0009] Moreover, such braking systems have a latch mechanism that call for manual engagement of a spooled cable clasp when the enclosure was brought to the side of the derrick or structure. Such manual engagement necessarily incurs a risk of human error, which, in the frenetic occasions when the pod is to be used, could have catastrophic consequences.
SUMMARY
[0010] In accordance with an embodiment of the invention, a descent control device for controlling rotational motion of an object is disclosed. The device comprises at least one drive assembly configured for rotationally engaging the rotating object to be controlled, a first substantially planar ferromagnetic moving element in rotationally locked engagement with the at least one drive assembly, the first moving element comprising at least one recess formed in a surface thereof having at least one magnet fixedly disposed therein, a second substantially planar ferromagnetic moving element in rotationally locked engagement with the at least one drive assembly, the second moving element comprising at least one recess formed in a surface thereof having at least one magnet fixedly disposed therein, and at least one conducting plate disposed proximate to the first and second moving elements. A magnetic field may be induced by rotational movement of the first moving element or the second moving element relative to the at least one conducting plate in a direction to oppose acceleration of the at least one drive assembly as it rotationally engages the object to be controlled.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] The embodiments of the present application will now be described by reference to the following figures, in which identical reference numerals in different figures indicate identical elements and in which:
[0012] FIG. 1 is a perspective view of a platform with an enclosure attached by means of a cable between the platform and a terminal location;
[0013] FIG. 2 is a detailed side view inside of a braking assembly of an enclosure of FIG. 1 wherein the braking assembly includes a descent control device partially behind and partially extending through the mounting plate of the braking assembly;
[0014] FIG. 3 is a detailed cross-sectional view of the braking assembly and the descent control device of FIG. 2 taken along line A-A;
[0015] FIG. 4 is a plan view of a rotor for use in an example embodiment of the descent control device of FIG. 3 ;
[0016] FIG. 5 is a cross-sectional view of the rotor of FIG. 4 along the line B-B; and
[0017] FIG. 6 is a detailed cross-sectional view of an alternative embodiment if the descent control device.
DETAILED DESCRIPTION
[0018] The present application will now be described for the purposes of illustration only, in conjunction with certain embodiments shown in the enclosed drawings. While preferred embodiments are disclosed, this is not intended to be limiting. Rather, the general principles set forth herein are considered to be merely illustrative of the scope of the present application and it is to be further understood that numerous changes covering alternatives, modifications and equivalents may be made without straying from the scope of the present application, as defined by the appended claims.
[0019] In particular, all dimensions described herein are intended solely to be exemplary for purposes of illustrating certain embodiments and are not intended to limit the scope of the invention to any embodiments that may depart from such dimensions as may be specified.
[0020] Referring first to FIG. 1 , there is shown, an existing embodiment of an enclosure shown generally at 100 that is secured in position next to a platform 102 by a cable 104 and a locking mechanism 106 . The enclosure 100 is accessible from the platform 102 by an exit 108 . The enclosure 100 includes a braking assembly 110 affixed to a metal frame 112 of the enclosure 100 . The cable 104 is affixed, at one end, to the platform 102 by a platform anchor 114 , and at the other end, to a terminal anchor (not shown) at the terminal location (not shown). The cable 104 runs through the braking assembly 110 such that the cable 104 defines the path of descent of the enclosure 100 when the enclosure 100 is released from the platform 102 . As will be described in greater detail in FIG. 2 and FIG. 3 , the cable 104 is acted upon by the braking assembly 110 to slow the descent of the enclosure 100 .
[0021] Preferably, the cables 104 used are ½-inch diameter steel cables.
[0022] Preferably, the platform anchor 114 , connected to one end of cable 104 , is several feet above the exit 108 . The other end of cable 104 is connected to a terminal anchor (not shown) at the terminal location (not shown). The terminal location is located at a lower elevation and safely distant from the platform 102 . Preferably, the terminal location is horizontally distanced about 80 to 100 feet from the platform 102 . Preferably, each cable 104 is connected between the platform 102 and the terminal location by screwed in anchors that have been pull tested.
[0023] The platform 102 is generally of such design that an exit 108 is formed at the location where the enclosure 100 is releasably secured to the platform 102 such that a rig worker 116 can depart the platform 102 through exit 108 and enter enclosure 100 .
[0024] Preferably, the platform 102 is at an elevated location on a rig of the type used for drilling or servicing of wells, for example. Those skilled in the art will appreciate that at least some example embodiments of the enclosure with descent control device disclosed herein are suitable for use in conjunction with other types of platforms such as a racking board or monkey board, for example.
[0025] The enclosure 100 is a rigid structure designed for providing a vehicle for a rig worker 116 to depart the platform 102 in the case of an accident such as a blowout or the like. Preferably, the enclosure 100 comprises a metal frame 112 composed of a plurality of metal members that define an interior space of the enclosure 100 at least sufficiently large to accommodate one rig worker 116 . A rig worker 116 on the platform 102 can enter the enclosure 100 by departing the platform 102 through the exit 108 to enter the interior space of the enclosure 100 .
[0026] It will be understood that the enclosure 100 could be brought up from the terminal location to a position adjacent to the platform 102 by one of a number of different methods. In some embodiments, the weight of the enclosure 100 , including contents such as passengers or cargo may be, but is not limited to, approximately 700 lbs.
[0027] To releasably secure the enclosure 100 to the platform 102 , a locking mechanism 106 is employed between the enclosure 100 and platform 102 . The enclosure 100 remains secured to the platform 102 adjacent to the exit 108 when the locking mechanism 106 is engaged. The locking mechanism 106 is disengaged by a rig worker 116 entering the enclosure 100 .
[0028] Disengaging the locking mechanism 106 triggers the release of the enclosure 100 from the platform 102 commencing descent of the enclosure 100 from its location adjacent to platform 102 along the path defined by cable 104 to a terminal location (not shown).
[0029] To protect a rig worker 116 from an accidental fall off of a rig platform, it is typical for a number of safety lines 118 to be employed. Each safety line 118 connects the rig worker 116 to either the platform 102 or the enclosure 100 . Lanyards 120 connect each end of a safety line 118 to one of the rig worker 116 , platform 102 , or enclosure 100 .
[0030] Referring for instance to the example embodiment illustrated in FIG. 1 , the two safety lines 118 connect the rig worker 116 to the enclosure 100 rather than the platform 102 . The impact of this setup is that a rig worker 116 in an accident situation can save the time and effort of disconnecting lanyards 120 from the platform 102 and reconnecting them to the enclosure 100 before exiting the platform 102 .
[0031] When a rig worker 116 enters the enclosure 100 releasing the locking mechanism 106 , the enclosure 100 will automatically commence its descent from its initial location proximate to platform 102 to a terminal location at a decreased elevation and increased horizontal displacement from the platform 102 . The path of descent of the enclosure 100 is defined by the cable 104 which runs through the braking assembly 110 . The cable 104 is anchored to the platform 102 at one end by platform anchor 114 , and anchored at the other end to the terminal location (not shown) by a terminal anchor (not shown).
[0032] In FIG. 1 , a single cable 104 and a single braking assembly 110 are shown, however embodiments of an enclosure 100 with multiple braking assemblies 110 each operating upon a different cable 104 are also envisioned within the scope of the present invention. Preferably, two braking assemblies 110 are affixed on opposite sides of the enclosure 100 . Each braking assembly 110 operates upon one of two cables 104 , with those cables 104 appropriately anchored to define a path of descent of the enclosure 100 from a position adjacent to the platform 102 to a terminal location (not shown).
[0033] FIG. 2 shows a detailed side view inside of a braking assembly 110 of an enclosure 100 of the example embodiment in FIG. 1 . The braking assembly 110 includes at least one descent control device 200 partially visible in front of mounting plate 202 in FIG. 2 and extending behind the mounting plate 202 to which the braking assembly 110 is attached. Preferably, one or more descent control devices 200 are used to ensure that the enclosure 100 descends at a controlled rate and manner.
[0034] In the example embodiment, the braking assembly 110 includes two driven sheaves 204 between two idler sheaves 206 . All four sheaves are attached to the mounting plate 202 . Each sheave has a peripheral surface in contact with the cable 104 . In at least one example, the cable 104 runs through the braking assembly 110 passing under or over each of the four sheaves in such a manner that the cable 104 is in contact with a maximum of about ¼ of the diameter of any single sheave. At least one of the driven sheaves 204 is attached to, rotationally drives, and receives a rotational braking force from a descent control device 200 and thus acts as a drive assembly.
[0035] In the example embodiment, a drive gear 208 is attached to each descent control device 200 . The teeth of the drive gears 208 are mutually interlocked so as to synchronize the rate of rotation of each driven sheave 204 preventing them from slipping against the cable 104 and losing synchronization. This configuration also allows the two driven sheaves 204 to cooperatively grip the cable 104 without slipping during descent. It will be understood that alternative examples wherein a different number of driven sheaves and idler sheaves are employed may be possible. Furthermore, although in the illustrated example embodiment the cable 104 passes directly over the top of the sheave 204 and directly under the bottom of the sheave 206 , those skilled in the art will appreciate that other cable engagement configurations are possible.
[0036] During descent of the enclosure 100 from the platform 102 , the sheaves 204 , 206 rotate as the enclosure 100 travels down the path defined by cable 104 from a position proximate to the platform 102 to the terminal location. During rotation, the idler sheaves 206 bear no load and offer minimal resistance to the descent of the enclosure 100 . They primarily aid in maintaining the position of the cable 104 as it passes along the driven sheaves 204 . However, each driven sheave 204 drives a descent control device 200 which generates rotational braking force slowing the descent of the enclosure 100 . How this braking force is generated is best explained with reference to FIG. 3 .
[0037] FIG. 3 is an enlarged cross-sectional view along line A-A of a descent control device 200 mounted through the mounting plate 202 of FIG. 2 . Descent control device 200 includes an input shaft 300 affixed to a rotor 302 , a flange plate 304 connected to a back plate 306 which together form a conductor surrounding the rotor 302 , a spacer 308 affixed to the input shaft 300 and holding the rotor 302 in place between the back plate 306 and the flange plate 304 , a flange bushing or bearing 310 rotatably connecting the input shaft 300 to the flange plate 304 and a back bushing or bearing 312 rotatably connecting the input shaft 300 to the back plate 306 . The rotor 302 includes a plurality of recesses 314 which receive magnets 316 in such a configuration that forms several distinct regions of polarity on the rotor 302 . In the embodiment shown in FIG. 3 , the descent control device 200 is attached to the mounting plate 304 by fasteners 319 .
[0038] The input shaft 300 is preferably an elongate cylindrical member having a first end and a second end, through which the axis of rotation is defined, and a shoulder 301 about which the diameter of the input shaft 300 changes. The first end of the input shaft 300 is affixed to a driven sheave 204 . The second end of the input shaft rotationally engages the flange bearing 310 and back bearing 312 . The rotor 302 is mounted on the input shaft 300 at the shoulder 301 . The spacer 308 is mounted on the input shaft 300 on the other side of the rotor 302 such that the position of the rotor 302 relative to the input shaft 300 is fixed both rotationally and longitudinally. The input shaft 300 drives rotation of the rotor 302 when it is rotated with the rotation of a driven sheave 204 .
[0039] The rotor 302 is preferably a substantially planar ferromagnetic steel cylindrical disc which is centrally affixed to the input shaft 300 and held in place on the input shaft 300 between the shoulder 301 and the spacer 308 . A side view of an example rotor 302 is displayed in FIG. 4 and in cross-sectional view in FIG. 5 . The rotor 302 includes a plurality of recesses 314 . In one embodiment, recesses 314 are present on both sides of the rotor 302 . In an alternative embodiment (not shown) recesses 314 could pass completely through the rotor 302 . Each recess 314 receives a magnet 316 having axial magnetization. All magnets 316 are mounted in the same magnetic pole orientation such that the main flux exiting the rotor 302 is of the same polarity. The return flux goes back to the rotor 302 in the area adjacent to each magnet 316 .
[0040] In one embodiment, each recess 314 may be ¾″ in diameter and ⅛″ deep to receive a Neodymium rare earth or other fixed magnet 316 . In some example embodiments, two rings of recesses 314 contain 48 magnets 316 , on each side of the rotor 302 . In an alternative embodiment, the rotor 302 may itself be a magnet 316 , having a corresponding magnetic pole orientation, and obviating any use of recesses 314 .
[0041] The flange plate 304 is formed of a conductive metal in such a shape as to encircle the input shaft 300 and enclose one side of the rotor 302 . The flange plate 304 is connected to the flange bushing 310 which secures the axial position of the flange plate 304 relative to the input shaft 300 but permits rotational movement of the input shaft 300 relative to the flange plate 304 . In one embodiment, the flange plate 304 is attached to the mounting plate 202 by fasteners 319 to secure the descent control device 200 to the enclosure 100 and to prevent axial rotation of the flange plate 304 during rotation of the input shaft 300 . The flange plate 304 is connected to the back plate 306 at points radially distal from the rotor 302 such that the connected flange plate 304 and back plate 306 form a cavity inside of which the rotor 302 is proximate to both the flange plate 304 and the back plate 306 but may freely rotate relative thereto. The flange plate 304 forms part of the conductor in which eddy currents are induced.
[0042] The back plate 306 is formed of a conductive metal in a shape to enclose the second end of the input shaft 300 and the side of the rotor 302 not otherwise enclosed by the flange plate 304 . The back plate 306 is connected to the back bushing 312 , which secures the axial position of the back plate 306 relative to the input shaft 300 but permits rotational movement of the input shaft 300 relative to the back plate 306 . The back plate 306 is connected to the flange plate 304 at points radially distal from the rotor 302 by means of a plate fastener 318 such that the connected back plate 306 and flange plate 304 form a cavity inside of which the rotor 302 is proximate to both the back plate 306 and flange plate 304 but may freely rotate. The back plate 306 forms another part of the conductor in which eddy currents are induced.
[0043] Thus, the rotation of the rotor 302 creates a traveling wave of magnetic field relative to the conductor which induces eddy currents between the conductor and the rotor. As such, the descent control device 200 operates passively in that there is no applied power or control to operate it. As long as the magnets 316 remain magnetized and relative motion is developed between the magnets 316 and the conductor, a braking force is generated. During rotation, a traveling wave magnetic field is in motion relative to a conducting medium. The relative motion of this wave induces eddy currents in the conductive medium in a pattern which mirrors that of the driving field. The induced eddy currents interact with the field of the magnets 316 to develop a braking force. The braking force is a function of the relative strengths of the magnets 316 and induced currents and their relative phase offsets. The magnitude and phase offset of the induced current varies as a function of the relative wave velocity, magnetic field strengths, wavelength of the field and conductor resistivity.
[0044] The shoulder 301 surrounds and forms a portion of the input shaft 300 around which the diameter of the input shaft 300 changes. One side of the rotor 302 abuts the shoulder 301 so as to maintain a minimum spacing between the rotor 302 and the flange plate 304 .
[0045] The spacer 308 surrounds and abuts the input shaft 300 and abuts the other side of the rotor 302 opposite the shoulder 301 by contacting the inner race of back bearing 312 . The spacer 308 holds the rotor 302 securely in place against the shoulder 301 of the input shaft 300 to maintain a spacing between the backing plate 306 and the rotor 302 . The spacing between the rotor 302 and flange plate 306 and the spacing between the rotor 302 and the backing plate 306 prevent frictional contact between the rotor 302 and the flange plate 304 or back plate 306 and yet maintain a desired braking force of the descent control device 200 .
[0046] The flange bearing 310 surrounds the input shaft 300 to hold the flange plate 304 in place axially while permitting rotation of the input shaft 300 . The flange bearing 310 may be a ball bearing, bushing, spacer, sleeve, coupling or other such instrument which holds the flange plate 304 in place axially while permitting rotation of the input shaft 300 .
[0047] The back bearing 312 surrounds the input shaft 300 to hold the back plate 306 in place axially while permitting rotation of the input shaft 300 . The back bearing 312 may be a ball bearing, bushing, spacer, sleeve, coupling or other such instrument which holds the back plate 306 in place axially while permitting rotation of the input shaft 300 .
[0048] The strength of the braking force is also proportional to the distance between the rotor 302 and the conductors and thickness of the conductors. Those having ordinary skill in this art will appreciate that the braking force may be controlled by adding or removing magnets 316 ; changing the displacement between the flange plate 304 and rotor 302 ; changing the displacement between the back plate 306 and rotor 302 ; changing the diameter of back plate 306 , flange plate 304 or the rotor 302 ; changing the type or strength of the magnets 316 ; and changing the material from which the back plate 306 , flange plate 304 and the rotor 302 are composed. For example, the back plate 306 and flange plate 304 could be composed of steel, while the rotor 302 could be composed of aluminum, especially if the magnets 316 were housed in the conductor plates 304 and 306 . Alternatively, the rotor 302 could be composed of copper or laminated steel and copper or plastic.
[0049] Also visible in FIG. 3 , a sheave channel 320 preferably semicircular in shape is carved into the circumferential end surface of each driven sheave 204 and idler sheave 206 . The sheave channel 320 guides and increases traction of the cable 104 . In an example embodiment, each sheave channel 320 is slotted to a specific size and spacing to accept the cable 104 there around in a traction fit and also acts to displace any debris that may have built up on the cable 104 such as snow, ice, grease, dirt, wax or the like.
[0050] To further assist in the removal of snow, ice, grease, dirt, wax, or the like, and to increase heat dissipation when the cable moves through the sheave channel 320 , each driven sheave 204 or idler sheave 206 , may include a series of channel bores 322 bored parallel to the axis of rotation near the circumferential end surface of each sheave and partially through the sheave channel 320 .
[0051] Turning now to FIG. 4 and FIG. 5 , an example rotor 302 is further described. In FIG. 4 a rotor 302 shaped as a cylindrical disc includes three rings of recesses 314 each recess 314 adapted to accept a magnet 316 . At the center of the rotor 302 a key 400 is cut out of the rotor 302 to receive the shoulder 301 of the input shaft 300 in such a manner to affix the rotor 302 to the input shaft 300 for rotation together.
[0052] In FIG. 5 , a cross section of the rotor of FIG. 4 along the line B-B illustrates one embodiment where a plurality of recesses 314 exist on both sides of rotor 302 for receiving magnets 316 .
[0053] In a preferred example embodiment, the descent control device 200 consists of a steel rotor 302 , aluminum (6061-T6) flange plate 304 and aluminum (6061-T6) back plate 306 . The surface of the rotor 302 is spaced 0.040 inches from the flange plate 304 on one side and the same distance from the back plate 306 on the other. The flange bearing 310 and back bearing 312 are both ball bearings. The magnets 316 are NdFeB N42 0.750″ diameter, 0.125″ thick and 13,200 Gauss/3,240 surface field Gauss.
[0054] FIG. 6 is a cross-sectional view of an alternative embodiment of a descent control device 500 according to the present disclosure. The descent control device 500 includes an input shaft 600 on which a pair of rotors 602 are mounted. A flange plate 604 is rotatably mounted to the input shaft 600 via a flange bearing 601 , and a middle plate 605 is mounted to the flange plate 604 . Together, the flange plate 604 and middle plate 605 form a conductor substantially surrounding the first rotor 602 . A back plate 606 is rotatably mounted to the input shaft 600 via a back bearing 612 , and is affixed to the middle plate 605 at a point distant from the input shaft 600 . Together, the back plate 606 and the middle plate 605 form a conductor substantially surrounding the second rotor 602 .
[0055] The input shaft 600 is similar to the input shaft 300 , with the exception that is has two shoulders 601 a and 601 b about which the diameter of the input shaft 600 changes. The diameter of the input shaft 600 increases at a first shoulder 601 a, and decreases at a second shoulder 601 b, creating a raised portion of the input shaft 600 between the shoulders 601 a and 601 b.
[0056] A first end 620 of the input shaft 600 is affixed to a driven sheave 204 and a second end 622 of the input shaft 600 rotationally engages the flange plate 604 and the back plate 606 via a flange bearing 610 and a back bearing 612 , in substantially the same manner as the embodiment shown in FIG. 3 . Each of the flange plate 604 , the back plate 606 , the flange bearing 610 and the back bearing 612 are substantially similar to the flange plate 304 , back plate 306 , flange bearing 310 and back bearing 312 , respectively.
[0057] Each of the rotors 602 is similar to the rotor 302 . The rotors 602 have recesses 614 (similar to recesses 314 ) for receiving magnets 616 (similar to magnets 316 ). The rotors 602 are mounted on the input shaft 600 at the shoulders 601 a and 601 b. Spacers 608 (that are similar to spacers 308 ) are inserted between the rotors 602 and the flange plate 604 and back plate 606 in substantially the same manner as the embodiment shown in FIG. 3 , to fix the rotors 602 in position against the shoulders 601 a and 601 b, both rotationally and longitudinally, relative to the input shaft 600 .
[0058] The middle plate 605 is provided between the flange plate 604 and the back plate 606 . The middle plate 605 can be made from the same materials as the flange plate 604 and the back plate 606 , or from any other material that the flange plate 604 and back plate 606 could be made from. The middle plate 605 engages the flange plate 604 at a point away from the input shaft 600 . An “O”-ring 618 is provided at the interface between the flange plate 604 and the middle plate 605 to help prevent contaminants such as dirt from reaching the rotors 602 . The middle plate 605 extends in an “L” shape from the flange plate 604 along the axis of the input shaft 600 and then toward the input shaft 600 between the rotors 602 . The middle plate 605 does not contact either of the rotors 602 or the input shaft 600 . In this configuration, the middle plate 605 , in combination with the flange plate 604 forms a cavity in which the first rotor 602 can rotate freely proximate to the flange plate 604 and the middle plate 605 .
[0059] The back plate 606 engages the middle plate 605 at the “bend” in its “L” shape. An additional “O”-ring 618 is provided at the interface between the middle plate 605 and back plate 606 to help prevent contaminants such as dirt from reaching the rotors 602 . In this configuration, the middle plate 605 , in combination with the back plate 606 forms a cavity in which the second rotor 602 can rotate freely proximate to the middle plate 605 and the back plate 606 .
[0060] The flange plate 604 , middle plate 605 and back plate 606 are held together by bolts (not shown) extending through channels formed by aligned bolt holes (not shown) in each of the flange plate 604 , middle plate 605 and back plate 606 . The bolts extend from a proximal end proximate the back plate 606 to a distal end proximate the flange plate 604 . The distal ends of the bolts are threaded, and the threads engage corresponding threading provided on inner surfaces of the bolt holes in the flange plate 604 . It will be apparent to those of skill in the art that other suitable means of fastening the flange plate 604 , middle plate 605 and back plate 606 together are possible.
[0061] Rotation of the rotors 602 creates a traveling wave of magnetic field relative to the conductors surrounding the rotors 602 and induces eddy currents between the conductors and the rotors 602 , in substantially the same manner as the embodiment shown in FIG. 3 . It will be appreciated by those skilled in the art that descent control device 500 will create approximately twice the amount of braking force as descent control device 200 , since twice as many rotors and magnets are provided. Actual test results show that descent control device 500 generates a braking force of approximately 80 lbs when rotating at 800 rpm. This is approximately twice the braking force generated by descent control device 200 when rotating at 800 rpm, which testing has shown to be approximately 38-40 lbs.
[0062] In some implementations, the descent control device 500 can be interchangeable with the descent control device 200 . By connecting input shaft 600 to the driven sheave 204 in substantially the same manner that input shaft 300 can be connected to the driven sheave 204 , and mounting the descent control device 500 to the mounting plate 202 (again, in substantially the same manner in which descent control device 200 is mounted to the mounting plate 202 ), the descent control device 500 can be used to slow the descent of the enclosure 100 along its path of descent in the same manner as descent control device 200 . It should therefore be understood that references in this description to the descent control device 200 and its components shown in FIG. 3 can apply equally to the descent control device 500 and its components shown in FIG. 6 .
[0063] In operation, the enclosure 100 descends along the path defined by at least one cable 104 . Descent of the enclosure 100 along cable 104 causes rotation of at least one driven sheave 204 which causes rotation of the input shaft 300 of the descent control device 200 . Rotation of the input shaft 300 causes rotation of the rotor 302 and the magnets 316 contained in the recesses 314 of the rotor 302 . Rotation of the magnets 316 causes the magnetic field created by the axial polarity of the magnets 316 to rotate. The rotational movement of the magnetic field relative to the conductor (formed in one embodiment by the flange plate 304 and back plate 306 ) induces eddy currents in the conductor in a pattern which mirrors that of the magnetic field created by the magnets 316 . Because the eddy currents and the magnetic field mirror each other, they interact to oppose the rotation of the magnetic field. This opposition to rotation of the magnetic field translates to a braking force against the rotation of the magnets 316 in the rotor 302 , against the rotation of the input shaft 300 , against the rotation of the driven sheave 204 and against the enclosure 100 descending along the cable 104 . Consequently, the enclosure 100 descends along the path defined by the cable 104 at a rate controlled by the braking force of the descent control device 200 .
[0064] Because the strength of the eddy currents is proportional to the velocity of the rotor 302 relative to the stationary conductor, as the rate of descent of the enclosure 100 increases, the braking force increases. Similarly, decreasing the rate of descent of the enclosure 100 decreases the braking force. This proportionality produces a smoother deceleration and allows the enclosure 100 to descend in a controlled manner towards the terminal location (not shown), resulting in a gentle landing. Rates of descent of about 14 ft/s (peak at around 22 ft/s) have been experienced for descents from high elevations, while more moderate descent elevations result in rates of descent of about 7-8 ft/s and landing speeds as low as 2 ft/s.
[0065] In simulation testing, a first-order analysis assumed a single pure sinusoid traveling magnetic wave due to field rotation. The simulation assumed a pole gap field amplitude of 3240 Gauss, conductor resistivity of 4×10 −8 ohm-m (aluminum), approximate gap field wavelength of 25 mm, drive sheave diameter of 4.0″, effective rotor drag area (both sides) of 61 square inches, total weight of enclosure and contents of 600 lbs and descent by gravity at a 45 degree descent angle. This simulation of the magnetic drag (braking force) indicates that a pair of descent control devices applied to an enclosure is capable of producing a maximum of approximately 420 lbs of drag at a maximum descent speed of 28 ft/s, which is approximately equal to the gravity force of a 600 pound load descending at a 45° angle. The braking force decreases when descent speed exceeds 28 ft/s. At a descent speed of 12 ft/s, the drag force on the enclosure is approximately 180 lbs. However, this date should be treated as an estimate and approximate only.
[0066] In fact, the magnetic field is significantly more complex than a single pure sinusoid traveling magnetic wave, with higher order terms that will result in multiple traveling waves of different amplitudes and lengths. Each traveling wave will produce its own characteristic drag/speed curve. The total drag is the Fourier sum of the force contributed by each of these traveling waves. The higher order wave components due to edge effects tend to substantially increase the total braking force. As such, the total braking force may be in the range of 50% to 100% greater than that predicted by the single-wave analysis.
[0067] It will be apparent to those having ordinary skill in this art that various modifications and variations may be made to the embodiments disclosed herein, consistent with the present application, without departing from the spirit and scope of the present application.
[0068] For example, the magnets could be mounted in the back plate 306 and flange plate 304 and the conductor could be formed from the rotor 302 .
[0069] Similarly, a descent control device 200 can be mounted in a braking assembly 110 by rotationally connecting the input shaft 300 to the mounting plate 202 or by affixing the flange plate 304 to the mounting plate 202 .
[0070] In a further embodiment, the enclosure 100 includes a means for attachment to a trailer or fork lift to facilitate transportation when detached from cables 104 and/or the removable attachment of wheels to facilitate repositioning below the initial point.
[0071] In some implementations, the descent control device 200 (or the descent control device 500 ) can be used in many different applications to provide braking force, by rotationally connecting the input shaft 300 (or 600 ) to the moving component on which braking force is to be applied. By way of example, an enclosure such as enclosure 100 can be fixedly mounted to a loop of cable at a single point. The loop of cable can extend from a receiver sheave mounted to a raised platform from which a worker may need to escape to a terminal sheave located on the ground some distance away from the platform, defining a path of descent of the enclosure. The cable loop can move in a circular manner around the receiver sheave and terminal sheave when the enclosure descends along the path of descent. The terminal sheave can be rotationally connected to the input shaft 300 (or 600 ) of a descent control device 200 (or 500 ). In such a configuration, the rotation of the terminal sheave would drive the rotation of the rotor 302 (or 602 ), and the braking force generated by such rotation would in turn slow the rotation of the terminal sheave, thus slowing the descent of the enclosure.
[0072] Other embodiments consistent with the present application will become apparent from consideration of the specification and the practice of the application disclosed herein.
[0073] Accordingly, the specification and the embodiments disclosed therein are to be considered exemplary only, with a true scope and spirit of the invention being disclosed by the following claims. | A descent control device for controlling rotational motion of an object includes: at least one drive assembly for rotationally engaging the rotating object; a first substantially planar ferromagnetic moving element in rotationally locked engagement with at least one drive assembly and comprising at least one recess formed in a surface thereof having at least one magnet fixedly disposed therein; a second substantially planar ferromagnetic moving element in rotationally locked engagement with at least one drive assembly, and comprising at least one recess formed in a surface thereof having at least one magnet fixedly disposed therein; and at least one conducting plate disposed proximate the first and second moving elements. A magnetic field may be induced by rotational movement of the first or second moving element relative to at least one conducting plate in a direction to oppose acceleration of at least one drive assembly as it rotationally engages the object. | 1 |
CROSS REFERENCE TO OTHER APPLICATIONS
[0001] This application claims the benefit of and incorporates by reference U.S. Provisional Application No. 61/287,456 filed Dec. 17, 2009.
FIELD OF THE INVENTION
[0002] The invention relates in general to tire molds, and a pneumatic tire having grooves in the shoulder area oriented in the axial direction.
BACKGROUND OF THE INVENTION
[0003] Creation of internal grooves in the shoulder area of a tire that are oriented axially may have several advantages. First, the axial grooves may decrease the heat generation in the tire that is built up when the tire is rolling. Second, the grooves may evacuate the water by the tire side during operation on a vehicle, which may improve the visibility of drivers behind the vehicle. The grooves also provide tire flexibility in the shoulder area which may improve tire performance. The grooves may also be used to mount temperature sensing devices to monitor the shoulder temperature. The grooves may be also used to install retractable stud pins for enhanced winter driving.
DEFINITIONS
[0004] “Aspect Ratio” means the ratio of a tire's section height to its section width.
[0005] “Axial” and “axially” means the lines or directions that are parallel to the axis of rotation of the tire.
[0006] “Bead” or “Bead Core” means generally that part of the tire comprising an annular tensile member, the radially inner beads are associated with holding the tire to the rim being wrapped by ply cords and shaped, with or without other reinforcement elements such as flippers, chippers, apexes or fillers, toe guards and chafers.
[0007] “Belt Structure” or “Reinforcing Belts” means at least two annular layers or plies of parallel cords, woven or unwoven, underlying the tread, unanchored to the bead, and having both left and right cord angles in the range from 17° to 27° with respect to the equatorial plane of the tire.
[0008] “Bias Ply Tire” means that the reinforcing cords in the carcass ply extend diagonally across the tire from bead-to-bead at about 25-65° angle with respect to the equatorial plane of the tire, the ply cords running at opposite angles in alternate layers.
[0009] “Breakers” or “Tire Breakers” means the same as belt or belt structure or reinforcement belts.
[0010] “Carcass” means a laminate of tire ply material and other tire components cut to length suitable for splicing, or already spliced, into a cylindrical or toroidal shape. Additional components may be added to the carcass prior to its being vulcanized to create the molded tire.
[0011] “Circumferential” means lines or directions extending along the perimeter of the surface of the annular tread perpendicular to the axial direction; it can also refer to the direction of the sets of adjacent circular curves whose radii define the axial curvature of the tread as viewed in cross section.
[0012] “Cord” means one of the reinforcement strands, including fibers, which are used to reinforce the plies.
[0013] “Inner Liner” means the layer or layers of elastomer or other material that form the inside surface of a tubeless tire and that contain the inflating fluid within the tire.
[0014] “Inserts” means the reinforcement typically used to reinforce the sidewalls of runflat-type tires; it also refers to the elastomeric insert that underlies the tread.
[0015] “Ply” means a cord-reinforced layer of elastomer-coated, radially deployed or otherwise parallel cords.
[0016] “Radial” and “radially” mean directions radially toward or away from the axis of rotation of the tire.
[0017] “Radial Ply Structure” means the one or more carcass plies or which at least one ply has reinforcing cords oriented at an angle of between 65° and 90° with respect to the equatorial plane of the tire.
[0018] “Radial Ply Tire” means a belted or circumferentially-restricted pneumatic tire in which the ply cords which extend from bead to bead are laid at cord angles between 65° and 90° with respect to the equatorial plane of the tire.
[0019] “Sidewall” means a portion of a tire between the tread and the bead.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] The invention will be described by way of example and with reference to the accompanying drawings in which:
[0021] FIG. 1 is a simplified schematic of a tire mold showing part of a mold segment, tire carcass, sidewall plate and mold device, wherein the mold is in the open position;
[0022] FIG. 2 is a cross-sectional view of FIG. 1 in the direction 2 - 2 ;
[0023] FIG. 3 is an exploded perspective view of a second piston and sleeve;
[0024] FIG. 4A is a cross-sectional view of a first chamber, T shaped member, u shaped spring and plate;
[0025] FIG. 4B is a cross-sectional view of a first chamber, T shaped member, u shaped spring and plate wherein the u shaped spring is flattened;
[0026] FIG. 5 are cross-sectional views of the silicone skins of the first, second and third member;
[0027] FIG. 6 is a view of the third member in the normal and flexed position;
[0028] FIG. 7 is the apparatus of FIG. 1 shown in a partially closed position;
[0029] FIG. 8 is the apparatus of FIG. 1 shown in a fully closed position;
[0030] FIG. 9 is a cross-sectional view of FIG. 8 in the direction 9 - 9 ; and
[0031] FIG. 10 illustrates the apparatus of FIG. 1 with the blade extended and the first chamber being filled up with the working fluid;
[0032] FIG. 11 illustrates the apparatus of FIG. 1 with the blade beginning to retract as the first chamber is filled up with the working fluid;
[0033] FIG. 12 illustrates the apparatus of FIG. 1 with the blade fully retracted as the first chamber is filled with fluid and the wave spring is expanded;
[0034] FIG. 13 illustrates the apparatus of FIG. 1 when the mold is opened.
[0035] FIGS. 14A and 14B illustrate the time it takes a piston to travel a distance X, shown without a silicone skin ( FIG. 14A ) and with a silicone skin ( FIG. 14B ).
DETAILED DESCRIPTION OF THE INVENTION
[0036] Referring to the drawings, a first embodiment of a tire mold device 10 is shown. The tire mold device 10 is useful for molding lateral grooves in the side of a tire. The tire device 10 may be installed in a tire mold segment near the shoulder area of a tire. The tire mold typically comprises a plurality of tread molding segments 20 , wherein each tread molding segment has an inner face 21 which mates with a portion of a sidewall plate 22 . The tread segment further includes an inner surface 25 for molding the tire tread. The tire mold further comprises other components which have been removed for clarity, and are otherwise known to those skilled in the art. Located on the inner surface 25 of the segment is an optional plug 31 . The plug may be used to form a housing in the tire tread for a stud pin.
[0037] FIGS. 1 and 2 illustrate a cross-sectional view of a portion of a tread segment, and sidewall plate shown in the open or start position. A green unvulcanized carcass tread T is shown positioned within the mold. The mold blade apparatus 10 has a retractable blade 54 for forming a hole in a green tire, and is shown in the retracted position in FIGS. 1 and 2 . The retractable blade 54 is received within a cylindrical housing 51 which is contained within an axially oriented slot 13 formed in the shoulder area of the segment. The retractable blade 54 is biased into a retracted position by a compression spring 24 . The retractable blade 54 has a bottom portion 26 which is engaged by the compression spring 24 . The bottom portion 26 of the blade 54 is also in mating engagement with a first working member 28 . Preferably the first working member 28 is encased in a silicone skin 29 . The silicone skin 29 is elastic and acts like a spring to retract the retractable blade to its starting position in a faster time than without the skin as shown in FIG. 14 . As shown in FIG. 6 , the working member 28 fills up with a working material from a second chamber 60 . The working material preferably has a viscosity in the range of about 800 to about 1200 MPas. One example of a material suitable for use as a working material is an RTV type silicone, which is in the form of a jelly or paste at room temperature. An RTV type silicone suitable for use as a working fluid is sold under the trade name Silgel 612 by Wacker Chemie AG. The silicone skin 29 is solid and elastic at room and elevated mold temperatures and has an elongation at break greater than or equal to 450%. The skin material may be RTV-M 536 sold by Wacker Chemie AG.
[0038] The mold blade apparatus 10 further includes a first piston 30 which is positioned in a radial slot 11 for engagement with the sidewall plate 22 . The engagement of the first piston 30 with the sidewall plate 22 actuates the mold blade apparatus 10 when the mold segments are in the closed position as shown in FIG. 4 . The mold blade apparatus further includes a wave spring 12 positioned within the first piston 30 . A second piston 40 is received within the radial slot 11 and has a pin 42 received there through. The second piston 40 is received within a sleeve 44 and has an end cap 46 screwed thereon. As shown in FIG. 3 , the pin 42 of second piston 40 slides within slots 46 of sleeve 44 . The ends of pin 42 are connected to radially oriented pins 43 . Pins 43 are positioned to engage the sidewall plate 22 . Compression of pins 43 slides the second piston 40 radially outward, expanding a first chamber 50 . The first chamber 50 is formed within the slot 11 , between the second piston 40 and a plate 54 . The first chamber 50 is preferably encased with silicone skin cap 53 to form a leak proof barrier. A compression spring 48 is positioned within the sleeve 44 and biases the second piston 40 away from the end cap 46 in a radially downwards direction. A third piston 14 is positioned between the first piston 30 and the second piston 40 . Preferably, the first piston, second piston and third piston are aligned or coaxial.
[0039] As shown in FIGS. 4A and 4B , the plate 54 has a center T shaped member 56 which is seated in a T shaped passageway by U shaped spring 58 . The T shaped member 56 has an interior passageway 55 for passage of a working fluid from the first chamber 50 to a second chamber 60 . FIG. 4A illustrates when the U shaped spring holds the T shaped member against the T shaped passageway so that flow is prevented in the T shaped passageway by engagement of the member 45 with the sidewalls 47 . Flow is only permitted through center passageway 55 . When the U shaped spring force is overcome as shown in FIG. 4B , flow may occur through the T shaped passageway and into the interior passageway 55 , from the first chamber 50 to the second chamber 60 . Thus the T shaped member 56 acts as a flow restrictor that is designed to allow only a small amount of flow when the fluid flows in a first direction. When the flow reverses direction, a much larger flow rate q may pass through the restrictor due to the restrictor being unseated from the channel edges that block off the outer flow paths. The larger flow rate allows rapid charging of the first chamber and a return to the initial position for restarting of the mold sequence.
[0040] Positioned with the second chamber 60 is a second member 70 and a third member 72 . The second and third member 70 , 72 are preferably formed from a working material that has a viscosity in the range of about 800 to about 1200 MPas. One example of a material suitable for use as a working material is an RTV type silicone, which is in the form of a jelly or paste at room temperature. An RTV type silicone suitable for use as a working fluid is sold under the trade name Silgel 612 by Wacker Chemie AG. Preferably the second member 70 is contained within a silicone U shaped skin 71 , as shown in FIG. 5 . Preferably the third member 72 is also contained within a silicone skin 73 , as shown in FIG. 5 . The silicone skins 53 , 71 , 73 are solid and elastic and have an elongation at break greater than or equal to 450%. The silicone skin material may be RTV-M 536 sold by Wacker Chemie AG.
[0041] FIGS. 1 and 2 illustrate the molding device 10 in the start position wherein the blade 54 is retracted, and the first piston 30 is positioned for engagement with the sidewall plate 22 . FIG. 7 illustrates the tread segment in a partially closed position. The first piston 30 engages sidewall plate 22 . The two pins 43 on each side of the first piston 40 are in contact with the sidewall plate. The pins 43 push up the second piston 40 , overcoming the force of the compression spring 48 to enlarge the first chamber 50 . The first piston 30 and third piston 14 force the working material into the second chamber 60 and then into the skin 29 to move the retractable pin 52 . As shown in FIG. 7 , the retractable pin 52 is out of the tread segment at its maximum position, but the mold is not yet closed. A gap between the tread segment and the sidewall plate still exists.
[0042] FIG. 8 illustrates the mold in a closed position. The waved springs 12 are compressed (the waved springs must be still compressed to ensure the variation of the silicone expansion) The spring force of the waved springs 12 must be greater than the compression spring force 24 to maintain the retractable pin 52 at its maximum position. The force of the waved springs acts on the working material, moving from chamber 60 to chamber 50 by the smaller orifice 55 of the T shaped member 56 . The dimension of this orifice and the compression forces of the springs will be adjusted to respect the curing time.
[0043] FIG. 10 illustrates the mold still in the closed position and the blade still in its extended position. The volume of the working material in the first chamber 50 is increasing, which decreases the force exerted on the waved springs. When the wave spring force is the same as the compression spring 24 force+elastic force of the skin 29 , the retractable pin 52 is beginning its backwards movement. FIG. 14A illustrates the time T 2 needed for a piston to travel a distance X, shown without a silicone skin. FIG. 14B illustrates the time it takes a piston (with a silicone skin) to travel a distance X. The piston with a silicone skin travels the distance faster because of the spring effect.
[0044] FIG. 11 illustrates the blade 54 retracting from the tire tread. The force of the compression spring 24 forces the working material from the first member 29 into the chamber 50 . FIG. 12 illustrates that the pin 52 is fully retracted, which is timed with the end of the tire curing cycle. Chamber 50 is filled with the working material.
[0045] FIG. 13 illustrates the end of the tire curing cycle and the mold is opened to remove the cured tire. The two pins 43 on each side of the second piston 40 no longer exert a force on the second piston 40 . The compression spring 48 acts on the chamber 50 , forcing the working material out of the chamber and into the second chamber 60 . The U shaped spring 58 is compressed as shown in FIG. 4B , and the working fluid passes through passage 55 and through the T shaped passageway. The chamber 50 is emptied as the working fluid is returned to chamber 60 , filling members 70 , 72 .
[0046] Variations in the present invention are possible in light of the description of it provided herein. While certain representative embodiments and details have been shown for the purpose of illustrating the subject invention, it will be apparent to those skilled in this art that various changes and modifications can be made therein without departing from the scope of the subject invention. It is, therefore, to be understood that changes can be made in the particular embodiments described which will be within the full intended scope of the invention as defined by the following appended claims. | A mold device is described for use in a mold having a plurality of tread molding segments. Each tread molding segment has an end face for mating with an adjoining segment. The mold device includes a piston located on the segment and is actuated by the opening and closing of the mold. The piston is positioned within a first chamber and has a plunger end in communication with a working material and a spring. Each of the mold segments further includes a retractable blade assembly having a distal end in fluid communication with a second chamber. The first chamber is in fluid communication with the second chamber. Closing of the mold compresses the piston, forcing the working fluid to transfer from the first chamber to the second chamber, actuating the blade assembly. | 1 |
FIELD OF THE INVENTION
[0001] This disclosure relates generally to a method for non-invasively determining a patient's blood pressure.
BACKGROUND OF THE INVENTION
[0002] An accurate and reliable technique for continuously measuring blood pressure involves inserting a saline filled catheter through the patient's vascular system to the point at which it is desired to perform the measurements. The catheter is connected to a pressure sensor, which measures the pressure in the vessel. An alternative method uses a catheter with a pressure sensor at the tip that directly senses the blood pressure. Procedures such as these are commonly referred to as “invasive procedures” because they involve making an incision through the patient's skin and inserting the catheter into a blood vessel. A problem with invasive procedures is that they can cause patient discomfort and increase the risk of complications such as infection.
[0003] Non-invasive blood pressure (NIBP) algorithms typically inflate a pressure cuff above the patient's systolic pressure and measure oscillations under the cuff as the cuff is deflated either in steps or continuously. The resulting oscillometric envelope is used to determine the patients' blood pressure. The cuff pressure corresponding to the maximum oscillation amplitude is typically taken as the mean arterial pressure (MAP). Systolic and Diastolic pressures are computed using a fixed ratio of the maximum oscillation amplitude. Some NIBP monitors also use the shape of the oscillometric envelope to compute the Systolic and Diastolic pressures. The problem with conventional NIBP techniques is that they do not compensate for arterial compliance changes and are therefore imprecise.
BRIEF DESCRIPTION OF THE INVENTION
[0004] The above-mentioned shortcomings, disadvantages and problems are addressed herein which will be understood by reading and understanding the following specification.
[0005] In an embodiment, a method for estimating systolic blood pressure and diastolic blood pressure includes obtaining a predetermined type of blood pressure data from a patient, and providing previously acquired blood pressure data obtained from a plurality of different subjects. The previously acquired blood pressure data is adapted to convey the manner in which a systolic amplitude ratio and a diastolic amplitude ratio vary with respect to the predetermined type of blood pressure pulse data obtained from the patient. The method also includes implementing the previously acquired blood pressure data to select a systolic amplitude ratio and a diastolic amplitude ratio that most closely correlate with the predetermined type of blood pressure data obtained from the patient. The selected systolic amplitude ratio and diastolic amplitude ratio are adapted to compensate for the effects of arterial compliance. The method also includes implementing the selected systolic amplitude ratio and the selected diastolic amplitude ratio to generate a systolic blood pressure estimate and a diastolic blood pressure estimate.
[0006] In another embodiment, a method for estimating systolic blood pressure and diastolic blood pressure includes providing a non-invasive blood pressure monitor having a cuff configured to apply a selectable pressure level to a patient. The method also includes estimating a first pulse transit time at a first cuff pressure level, and a second pulse transit time at a second cuff pressure level. The method also includes calculating a pulse transit time ratio, which is defined as the first pulse transit time divided by the second pulse transit time. The method also includes providing blood pressure data adapted to correlate a plurality of pulse transit time ratios with a corresponding plurality of systolic amplitude ratios and diastolic amplitude ratios. The method also includes selecting one of the systolic amplitude ratios and one of the diastolic amplitude ratios that most closely correlate with the calculated pulse transit time ratio. The selected systolic and diastolic amplitude ratios are adapted to compensate for the effects of arterial compliance. The method also includes implementing the selected systolic and diastolic amplitude ratios to generate a systolic blood pressure estimate and a diastolic blood pressure estimate.
[0007] In yet another embodiment, a method for estimating systolic blood pressure and diastolic blood pressure includes estimating a pulse wave velocity of a blood pressure pulse being transmitted through a patient. The method also includes providing blood pressure data adapted to correlate a plurality of pulse wave velocity values with a plurality of systolic amplitude ratios and a plurality of diastolic amplitude ratios. The method also includes selecting one of the plurality of systolic amplitude ratios and one of the plurality of diastolic amplitude ratios that are most closely correlated with the estimated pulse wave velocity. The selected systolic and diastolic amplitude ratios are adapted to compensate for the effects of arterial compliance. The method also includes implementing the selected systolic and diastolic amplitude ratios to generate a systolic blood pressure estimate and a diastolic blood pressure estimate.
[0008] Various other features, objects, and advantages of the invention will be made apparent to those skilled in the art from the accompanying drawings and detailed description thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 is a schematic diagram of a patient monitoring system in accordance with an embodiment;
[0010] FIG. 2 is a graph of cuff pressure versus time illustrating a method for estimating blood pressure using a non-invasive blood pressure monitoring system;
[0011] FIG. 3 is a block diagram illustrating a method in accordance with an embodiment;
[0012] FIG. 4 is a block diagram illustrating a method in accordance with an embodiment;
[0013] FIG. 4 a is a graph of oscillation amplitude versus PTT ratio ;
[0014] FIG. 5 is a block diagram illustrating a method in accordance with an embodiment;
[0015] FIG. 5 a is a graph of PTT versus cuff pressure;
[0016] FIG. 5 b is a graph of oscillation amplitude versus PTT slope ; and
[0017] FIG. 6 is a block diagram illustrating a method in accordance with an embodiment.
DETAILED DESCRIPTION OF THE INVENTION
[0018] In the following detailed description, reference is made to the accompanying drawings that form a part hereof, and in which is shown by way of illustration specific embodiments that may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the embodiments, and it is to be understood that other embodiments may be utilized and that logical, mechanical, electrical and other changes may be made without departing from the scope of the embodiments. The following detailed description is, therefore, not to be taken as limiting the scope of the invention.
[0019] Referring to FIG. 1 , a patient monitoring system 10 is shown in accordance with an embodiment. The patient monitoring system 10 includes a pulse oximeter 12 and a non-invasive blood pressure (NIBP) monitor 14 . The pulse oximeter 12 is connected to a probe 16 that is attachable to a finger 18 of a patient 20 . The pulse oximeter 12 is operable to sense or identify volume pulses referred to hereinafter as SpO2 pulses at the patient's finger 18 , and to thereafter transmit data pertaining to the SpO2 pulses to a processor 22 .
[0020] The NIBP monitor 14 is connected to an inflatable cuff 24 via a flexible tube 26 . The NIBP monitor 14 includes a pump 28 adapted to inflate the cuff 24 , and one or more valves 30 adapted to deflate the cuff 24 . In the embodiment depicted, the inflatable cuff 24 is wrapped around the patient's upper arm 32 , however other locations (e.g., forearm) and other limbs could also be used. The NIBP monitor 14 includes a pressure transducer 34 operable to sense or identify pressure pulses referred to hereinafter as NIBP pulses at the portion of the patient's arm 32 to which the cuff 24 is attached. Thereafter, the NIBP monitor 14 can transmit data pertaining to the NIBP pulses to the processor 22 .
[0021] The NIBP monitor 14 is configured to measure mean arterial pressure (MAP), systolic blood pressure (SBP), and diastolic blood pressure (DBP) in a known manner. With reference to FIGS. 1 and 2 , a process of measuring MAP, SBP and DBP will be described for exemplary purposes in accordance with one embodiment.
[0022] The exemplary process of measuring MAP, SBP and/or DBP is performed by increasing and decreasing the pressure of the cuff 24 in the manner illustrated by the cuff pressure curve 36 of FIG. 2 , and generally simultaneously measuring a series of NIBP pulses 38 . This process is initiated by implementing the pump 28 to inflate the cuff 24 and thereby increase cuff 24 pressure to a supra-systolic pressure level. As is known in the art, at supra-systolic cuff pressure blood is completely occluded or obstructed from flowing through the artery under the cuff 24 , systolic pressure is the cuff pressure level at which blood just begins flowing through the artery under the cuff 24 , and diastolic pressure is the cuff pressure level at which blood flow through the artery under the cuff 24 is unobstructed. After cuff 24 pressure is increased to a supra-systolic pressure level, the cuff 24 is deflated (via valve 30 ) in a controlled manner adapted to produce a series of decreasing pressure level steps. It should be appreciated that while the exemplary embodiment has been described and depicted as including a stepwise cuff pressure reduction, other embodiments may alternatively implement a generally continuous cuff pressure reduction.
[0023] After the cuff 24 reaches systolic pressure, the pressure level measured by the pressure transducer 34 oscillates due to the force exerted on the cuff 24 by the entry of blood into the artery under the cuff 24 . The term “oscillation” refers to a measurable pressure level oscillation produced by this change in volume. Two consecutive oscillations are generally measured at each cuff pressure level step. As shown in FIG. 2 , MAP is identifiable as the cuff pressure level at which oscillation amplitude is maximum (OA max ). SBP is identifiable as the cuff pressure level at which oscillation amplitude is approximately equal to (0.5*(OA max )), and DBP is identifiable as the cuff pressure level at which oscillation amplitude is approximately equal to (0.625*(OA max )). A plurality of SpO2 pulses 40 are also shown in FIG. 2 to illustrate typical SpO2 data acquired during the previously described cuff inflation/deflation sequence.
[0024] The processor 22 is operable to calculate pulse transit time (PTT) in response to data from the pulse oximeter 12 and the NIBP monitor 14 . For purposes of this disclosure, PTT is defined as the time required for a given pressure pulse to travel from one reference point (e.g., the patient's arm 32 ) to another reference point (e.g., the patient's finger 18 ). It will be understood by those skilled in the art that a pressure pulse is accompanied by a volume pulse, which is what is measured by the NIBP cuff 24 and the probe 16 . As an example, if the probe 16 and cuff 24 are attached to the same limb, PTT can be calculated by measuring the time interval between a NIBP pulse and an immediately subsequent SpO2 pulse. PTT can be measured, for example, as the “foot-to-foot delay”, the “peak-to-peak delay”, or the delay between maximum slope points. The “foot-to-foot delay” refers to the time interval measured between the foot of a NIBP pulse and the foot of an immediately subsequent SpO2 pulse. Similarly, the “peak-to-peak delay” refers to the time interval measured between the peak of a NIBP pulse and the peak of an immediately subsequent SpO2 pulse.
[0025] FIG. 3 is flow chart illustrating a method 100 that is also referred to hereinafter as the algorithm 100 . The individual blocks of the flow chart represent steps that may be performed in accordance with the method 100 . Unless otherwise specified, the steps 102 - 110 need not be performed in the order shown.
[0026] Referring now to FIGS. 1 and 3 , at step 102 , cuff 24 pressure is increased to a supra-systolic pressure level. At step 104 , the cuff 24 pressure is reduced in a controlled manner which may include, for example, a stepwise pressure reduction or a generally continuous pressure reduction. Also at step 104 , while cuff 24 pressure is being reduced, the processor 22 measures PTT. As previously described, PTT can be measured by measuring the time interval between each NIBP pulse and the immediately subsequent SpO2 pulse.
[0027] At step 106 , the algorithm 100 determines whether the current cuff 24 pressure value is below diastolic pressure. This determination can be made by comparing a current cuff 24 pressure value measured by the pressure transducer 34 with the calculated DBP value. The DBP value can be calculated using a baseline amplitude ratio that is not adjusted for pulse transit time such as, for example, the previously described DPB amplitude ratio of 0.625, or can alternatively be calculated in any other known manner. If, at step 106 , the current cuff 24 pressure is not below diastolic pressure, the algorithm 100 returns to step 104 . If, at step 106 , the current cuff 24 pressure is below diastolic pressure, the algorithm 100 proceeds to step 108 .
[0028] At step 108 , cuff 24 pressure is reduced. If cuff 24 pressure is being reduced in a stepwise manner, the cuff 24 pressure is further reduced by one step. If cuff 24 pressure is being reduced in a generally continuous manner, the cuff 24 pressure is further reduced in a continuous manner by 10 mm Hg. At step 110 , the processor 22 measures PTT. The PTT measurement of step 110 is taken at a sub-diastolic pressure level.
[0029] Referring to FIG. 4 , a flow chart illustrates a method 200 adapted for use in combination with the method 100 (shown in FIG. 3 ) to precisely estimate SBP and DBP. The method 200 may also be referred to hereinafter as the algorithm 200 . The individual blocks of the flow chart represent steps that may be performed in accordance with the method 200 . Unless otherwise specified, the steps 202 - 208 need not be performed in the order shown.
[0030] At step 202 , PTT ratio is calculated according to the equation PTT ratio =(PTT MAP /PTT subdias ). The variable PTT MAP represents the pulse transit time measured at the mean arterial pressure level, and is acquired by the processor 22 (shown in FIG. 1 ) at step 104 of the algorithm 100 (shown in FIG. 3 ) in the manner previously described. The variable PTT subdias represents the pulse transit time measured at a sub-diastolic pressure level, and is acquired by the processor 22 at step 110 of the algorithm 100 in the manner previously described.
[0031] At step 204 , previously acquired blood pressure data is provided. The previously acquired blood pressure data generally represents multiple blood pressure measurements taken in a known manner (e.g., via intra-arterial, oscillometric and/or auscultatory procedures) from a plurality of different individuals. The previously acquired blood pressure data is preferably provided in a format adapted to correlate PTT ratio with systolic and diastolic amplitude ratios. As an example, the previously acquired blood pressure data may be provided in the form of a graph as depicted in FIG. 4 a , however it should be appreciated that the data may alternatively be provided in any known format including, for example, a look-up table, a spreadsheet or a database.
[0032] Referring to FIG. 4 a , a graph of oscillation amplitude versus PTT ratio is shown to illustrate a method for compiling previously acquired blood pressure data in accordance with step 204 of the algorithm 200 (shown in FIG. 4 ). PTT ratio may be calculated, for example, in accordance with the previously provided equation PTT ratio =(PTT MAP /PTT subdias ). The graph of FIG. 4 a can be generated by calculating SBP amplitude ratio, DBP amplitude ratio and PTT ratio values for each of the previously acquired blood pressure measurements. Thereafter, a SBP data point 210 having (X, Y) coordinate values of (PTT ratio , SBP amplitude ratio), and a DBP data point 212 having (X, Y) coordinate values of (PTT ratio , DBP amplitude ratio) are plotted for each previously acquired blood pressure measurement. An SBP best-fit line 214 is calculated for the SBP data points 210 and a DBP best-fit line 216 is calculated for the DBP data points 212 . The process of calculating a “best-fit line” is well known mathematical process and therefore will not be described in detail. While a linear fit is shown in FIG. 4 a , the data might also be fitted to a polynomial, exponential or other curvilinear function.
[0033] A non-limiting example will now be provided to better illustrate the previously described method for generating the graph of FIG. 4 a . For purposes of this example, assume that the previously acquired blood pressure of a single test subject was intra-arterially measured, and that this test subject was determined to have a PTT of 95 milliseconds at MAP, a PTT of 70 milliseconds at a sub-diastolic pressure level, a systolic oscillation amplitude ratio of 0.475, and a diastolic oscillation amplitude ratio of 0.610. The “systolic oscillation amplitude ratio” refers to the test subject's oscillation amplitude at SBP divided by their oscillation amplitude at MAP, and the “diastolic oscillation amplitude ratio” refers to the patient's oscillation amplitude at DBP divided by their oscillation amplitude at MAP. For the exemplary embodiment, PTT ratio is calculated as (PTT MAP /PTT subdias ) or (95/70)=1.35. Accordingly, the exemplary SBP data point 210 a having (X, Y) coordinate values of (1.35, 0.475), and the exemplary DBP data point 212 a having (X, Y) coordinate values of (1.35, 0.610) are plotted as shown in FIG. 4 a . After plotting SBP data points 210 and DBP data points 212 for each of a plurality of different test subjects in the manner previously described, the SBP best-fit line 214 is calculated for the SBP data points 210 and the DBP best-fit line 216 is calculated for the DBP data points 212 .
[0034] Referring to FIG. 4 , at step 206 the PTT ratio value calculated at step 202 is compared with previously acquired blood pressure data of step 204 in order to obtain optimal systolic and diastolic ratios. As a non-limiting example, assume that the PTT ratio calculated at step 202 is equal to 1.50, and that the previously acquired blood pressure data provided at step 204 is represented by the graph of FIG. 4 a . For purposes of this non-limiting example, the optimal systolic ratio is 0.480 which is the Y-axis value corresponding to the point of intersection between the X-axis PTT ratio value (i.e., 1.50) and the SBP best-fit line 214 . Similarly, the optimal diastolic ratio is 0.620 which is the Y-axis value corresponding to the point of intersection between the X-axis PTT ratio value (i.e., 1.50) and the DBP best-fit line 216 . It should be appreciated that, unlike conventional fixed systolic and diastolic amplitude ratios, the previously described optimal systolic and diastolic amplitude ratios are variable to compensate for the effects of arterial compliance.
[0035] Referring again to FIG. 4 , at step 208 the optimal systolic and diastolic ratios that were obtained at step 206 are used to recalculate SBP and DBP. The previously calculated optimal systolic amplitude ratio value 0.480 and optimal diastolic amplitude ratio value 0.620 will again be used for illustrative purposes. Referring to FIG. 2 and according to the illustrative embodiment, SBP can be recalculated as the cuff pressure level at which NIBP oscillation amplitude is approximately equal to (0.480*(OA max )), and DBP can be recalculated as the cuff pressure level value at which NIBP oscillation amplitude is approximately equal to (0.620*(OA max )). The recalculated SBP and DBP values are generally more accurate than conventional SBP/DBP estimates because the recalculated values are based on optimal systolic and diastolic amplitude ratios selected to compensate for the effects of arterial compliance.
[0036] Referring to FIG. 5 , a flow chart illustrates a method 300 adapted for use in combination with the method 100 (shown in FIG. 3 ) to precisely estimate SBP and DBP. The method 300 may also be referred to hereinafter as the algorithm 300 . The individual blocks of the flow chart represent steps that may be performed in accordance with the method 300 . Unless otherwise specified, the steps 302 - 312 need not be performed in the order shown.
[0037] At step 302 , PTT versus cuff pressure data points 314 are plotted as shown in FIG. 5 a . The data points 314 represent the pulse transit time measured during the process of reducing cuff pressure level, and are obtained from steps 104 and 110 of the algorithm 100 (shown in FIG. 3 ). At step 304 , a best-fit line 316 (shown in FIG. 5 a ) is calculated for the data points 314 . At step 306 , PTT slope is calculated as the slope of the best-fit line 316 .
[0038] At step 308 , previously acquired blood pressure data is provided. The previously acquired blood pressure data generally represents multiple blood pressure measurements taken in a known manner (e.g., via intra-arterial, oscillometric and/or auscultatory procedures) from a plurality of different individuals. The previously acquired blood pressure data is preferably provided in a format adapted to correlate PTT slope with systolic and diastolic amplitude ratios. As an example, the previously acquired blood pressure data may be provided in the form of a graph as depicted in FIG. 5 b , however it should be appreciated that the data may alternatively be provided in any known format including, for example, a look-up table, a spreadsheet or a database.
[0039] Referring to FIG. 5 b , a graph of oscillation amplitude versus PTT slope is shown to illustrate a method for compiling previously acquired blood pressure data in accordance with step 308 of the algorithm 300 (shown in FIG. 5 ). The graph of FIG. 5 b can be generated by calculating SBP amplitude ratio, DBP amplitude ratio and PTT slope values for each of the previously acquired blood pressure measurements. Thereafter, a SBP data point 318 having (X, Y) coordinate values of (PTT slope , SBP amplitude ratio), and a DBP data point 320 having (X, Y) coordinate values of (PTT slope , DBP amplitude ratio) are plotted for each previously acquired blood pressure measurement. An SBP best-fit line 322 is calculated for the SBP data points 318 and a DBP best-fit line 324 is calculated for the DBP data points 320 . While a linear fit is shown in FIG. 5 b , the data might also be fitted to a polynomial, exponential or other curvilinear function.
[0040] Referring to FIG. 5 , at step 310 the PTT slope value calculated at step 306 is compared with previously acquired blood pressure data of step 308 in order to obtain optimal systolic and diastolic ratios. According to the embodiment wherein the blood pressure data is complied in the form of a graph, the optimal systolic ratio is the Y-axis value corresponding to the point of intersection between the X-axis PTT slope value (obtained at step 306 ) and the SBP best-fit line 322 (shown in FIG. 5 b ). Similarly, the optimal diastolic ratio is the Y-axis value corresponding to the point of intersection between the X-axis PTT slope value (obtained at step 306 ) and the DBP best-fit line 324 (shown in FIG. 5 b ). At step 312 the optimal systolic and diastolic ratios are used to recalculate SBP and DBP in a manner similar to that previously described with respect to step 208 of the algorithm 200 (shown in FIG. 4 ). The recalculated SBP and DBP values are generally more accurate than conventional SBP/DBP estimates because the recalculated values are based on optimal systolic and diastolic amplitude ratios selected to compensate for the effects of arterial compliance.
[0041] Referring to FIG. 6 , a flow chart illustrates a method 400 adapted for use in combination with the method 100 (shown in FIG. 3 ) to precisely estimate SBP and DBP. The method 400 may also be referred to hereinafter as the algorithm 400 . The individual blocks of the flow chart represent steps that may be performed in accordance with the method 400 . Unless otherwise specified, the steps 402 - 410 need not be performed in the order shown.
[0042] At step 402 , the distance D (shown in FIG. 1 ) between the cuff 24 and the probe 16 is estimated. The distance D can be estimated in any known manner such as, for example, by physically measuring this distance along the arm 32 of the patient 20 (shown in FIG. 1 ). At step 404 , pulse wave velocity (PWV) is calculated according to, the equation PWV=D/PTT. PTT values for this calculation can be obtained at steps 104 and/or 108 of the algorithm 100 (shown in FIG. 3 ).
[0043] At step 406 , previously acquired blood pressure data is provided. The previously acquired blood pressure data generally represents multiple blood pressure measurements taken in a known manner (e.g., via intra-arterial, oscillometric and/or auscultatory procedures) from a plurality of different individuals. The previously acquired blood pressure data is preferably provided in a format adapted to correlate PWV with systolic and diastolic amplitude ratios. The form in which the blood pressure data is provided may include, for example, a look-up table, a spreadsheet, a graph or a database.
[0044] At step 408 , the PWV value calculated at step 404 is compared with previously acquired blood pressure data of step 406 in order to obtain optimal systolic and diastolic ratios. According to an illustrative embodiment wherein the blood pressure data is complied in the form of a look-up table (not shown), the optimal systolic and diastolic ratios are obtainable by indexing the previously acquired systolic and diastolic ratios that most closely corresponds to the PWV value calculated at step 404 . At step 410 the optimal systolic and diastolic ratios are used to recalculate SBP and DBP in a manner similar to that previously described with respect to step 208 of the algorithm 200 (shown in FIG. 4 ). The recalculated SBP and DBP values are generally more accurate than conventional SBP/DBP estimates because the recalculated values are based on optimal systolic and diastolic amplitude ratios selected to compensate for the effects of arterial compliance.
[0045] While the invention has been described with reference to preferred embodiments, those skilled in the art will appreciate that certain substitutions, alterations and omissions may be made to the embodiments without departing from the spirit of the invention. Accordingly, the foregoing description is meant to be exemplary only, and should not limit the scope of the invention as set forth in the following claims. | A method for estimating systolic and diastolic pressure is disclosed herein. The method includes obtaining a predetermined type of blood pressure data from a patient, and providing previously acquired blood pressure data obtained from a plurality of different subjects. The method also includes implementing the previously acquired blood pressure data to select systolic and diastolic amplitude ratios that most closely correlate with the predetermined type of blood pressure data obtained from the patient. The selected systolic and diastolic amplitude ratios are adapted to compensate for the effects of arterial compliance. The method also includes implementing the selected systolic and diastolic amplitude ratios to generate a systolic and diastolic blood pressure estimates. | 0 |
This is a divisional of application Ser. No. 08/174,535 filed on Dec. 28, 1993, U.S. Pat. No. 5,545,665.
FIELD OF THE INVENTION
The present invention provides 7-[5-hydroxy-2-(hydroxyhydrocarbyl or heteroatom-substituted hydroxyhydrocarbyl)-3-hydroxycyclopentyl(enyl)] heptanoic or heptenoic acids and amine, amide, ether, ester and alcohol derivatives of said acids, wherein one or more of said hydroxy groups are replaced by an ether group. The compounds of this invention are potent ocular hypotensives, and are particularly suitable for the management of glaucoma. Moreover, the compounds of this invention are smooth muscle relaxants with broad application in systemic hypertensive and pulmonary diseases; with additional application in gastrointestinal disease, reproduction, fertility, incontinence, shock, inflammation, immune regulation, disorders of bone metabolism, renal dysfunction, cancer and other hypoproliferative diseases.
BACKGROUND OF THE INVENTION
Ocular hypotensive agents are useful in the treatment of a number of various ocular hypertensive conditions, such as post-surgical and post-laser trabeculectomy ocular hypertensive episodes, glaucoma, and as presurgical adjuncts.
Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) may be either open-angle or acute or chronic angle-closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract.
The underlying causes of primary glaucoma are not yet known. The increased intraocular tension is due to the obstruction of aqueous humor outflow. In chronic open-angle glaucoma, the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impeded. In acute or chronic angle-closure glaucoma, the anterior chamber is shallow, the filtration angle is narrowed, and the iris may obstruct the trabecular meshwork at the entrance of the canal of Schlemm. Dilation of the pupil may push the root of the iris forward against the angle, and may produce pupillary block and thus precipitate an acute attack. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of various degrees of severity.
Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and subsequently, into the canal of Schlemm. Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior synechia in iris bombe and may plug the drainage channel with exudates. Other common causes are intraocular tumors, enlarged cataracts, central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.
Considering all types together, glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision. In cases where surgery is not indicated, topical β-adrenoreceptor antagonists have traditionally been the drugs of choice for treating glaucoma.
Prostaglandins were earlier regarded as potent ocular hypertensives; however, evidence accumulated in the last two decades shows that some prostaglandins are highly effective ocular hypotensive agents and are ideally suited for the long-term medical management of glaucoma. (See, for example, Starr, M. S. Exp. Eye Res. 1971, 11, pp. 170-177; Bito, L. Z. Biological Protection with Prostaglandins Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc., 1985, pp. 231-252; and Bito, L. Z., Applied Pharmacology in the Medical Treatment of Glaucomas Drance, S. M. and Neufeld, A. H. eds., New York, Grune & Stratton, 1984, pp. 477-505). Such prostaglandins include PGF 2 α, PGF 1 α, PGE 2 , and certain lipid-soluble esters, such as C 1 to C 5 alkyl esters, e.g. 1-isopropyl ester, of such compounds.
In the U.S. Pat. No. 4,599,353 certain prostaglandins, in particular PGE 2 and PGF 2 α and the C 1 to C 5 alkyl esters of the latter compound, were reported to possess ocular hypotensive activity and were recommended for use in glaucoma management.
Although the precise mechanism is not yet known, recent experimental results indicate that the prostaglandin-induced reduction in intraocular pressure results from increased uveoscleral outflow [Nilsson et al., Invest. Ophthalmol. Vis. Sci. 28 (suppl), 284 (1987)].
The isopropyl ester of PGF 2 α has been shown to have significantly greater hypotensive potency than the parent compound, which was attributed to its more effective penetration through the cornea. In 1987 this compound was described as "the most potent ocular hypotensive agent ever reported." [See, for example, Bito, L. Z., Arch. Ophthalmol.105, 1036 (1987), and Siebold et al., Prodrug5, 3 (1989)].
Whereas prostaglandins appear to be devoid of significant intraocular side effects, ocular surface (conjunctival) hyperemia and foreign-body sensation have been consistently associated with the topical ocular use of such compounds, in particular PGF 2 α and its prodrugs, e.g. its 1-isopropyl ester, in humans. The clinical potential of prostaglandins in the management of conditions associated with increased ocular pressure, e.g. glaucoma, is greatly limited by these side effects.
Certain phenyl and phenoxy mono, tri and tetra nor prostaglandins and their 1-esters are disclosed in European Patent Application 0,364,417 as useful in the treatment of glaucoma or ocular hypertension.
In a series of co-pending United States patent applications assigned to Allergan, Inc. prostaglandin esters with increased ocular hypotensive activity accompanied with no or substantially reduced side-effects are disclosed. The co-pending U.S. Ser. No. 386,835 (filed 27 Jul. 1989), relates to certain 11-acyl-prostaglandins, such as 11-pivaloyl, 11-acetyl, 11-isobutyryl, 11-valeryl, and 11-isovaleryl PGF 2 α. Intraocular pressure reducing 15-acyl prostaglandins are disclosed in the co-pending application U.S. Ser. No. 357,394 (filed 25 May 1989). Similarly, 11,15- 9,15- and 9,11-diesters of prostaglandins, for example 11,15-dipivaloyl PGF 2 α are known to have ocular hypotensive activity. See the co-pending patent applications U.S. Ser. No. 385,645 filed 27 Jul. 1990, now U.S. Pat. No. 4,494,274; 584,370 which is a continuation of U.S. Ser. No. 386,312, and 585,284, now U.S. Pat. No. 5,034,413 which is a continuation of U.S. Ser. No. 386,834, where the parent applications were filed on 27 Jul. 1989. The disclosures of these patent applications are hereby expressly incorporated by reference.
SUMMARY OF THE INVENTION
We have found that certain 7-[5-hydroxy-2-(hydroxyhydrocarbyl or heteroatom-substituted hydroxyhydrocarbyl)-3-hydroxycyclopentyl(enyl)] heptanoic or heptenoic acids and amine, amide, ether, ester and alcohol derivatives of said acids, wherein one or more of said hydroxy groups are replaced by an ether group are potent ocular hypotensive agents. We have further found that such compounds may be significantly more potent than their respective parent compounds and, in the case of glaucoma surprisingly, cause no or significantly lower ocular surface hyperemia than the parent compounds.
The present invention relates to methods of treating cardiovascular, pulmonary-respiratory, gastrointestinal, reproductive, allergic disease, shock and ocular hypertension which comprises administering an effective amount of a compound represented by the formula I ##STR1## wherein either the cyclopentane radical or the α or ω chain may be unsaturated; R is a hydrocarbyl radical or a heteroatom substituted hydrocarbyl radical comprising up to ten carbon atoms and one or more of the hydrogen or carbon radicals in said hydrocarbyl radical may be substituted with oxygen, sulfur, nitrogen, phosphorus or halogen, e.g. chloro and fluoro; R 1 , R 2 and R 3 are selected from the group consisting of hydroxy, hydrocarbyloxy and heteroatom substituted hydrocarbyloxy wherein said hydrocarbyl radical comprises up to 20, e.g. 10 carbon atoms; Y represents 2 hydrogen radicals or an oxo radical and X represents a hydroxyl, a hydrocarbylcarboxy, a hydrocarbyloxy, amino or mono or dialkyl amino radical; provided, however, at least one of R 1 , R 2 and R 3 is a hydrocarbyloxy or heteroatom substituted hydrocarbyloxy, i.e., an ether group and preferably only one of R 1 , R 2 and R 3 is an ether group, or a pharmaceutically-salt thereof.
Preferably R, R 1 , R 2 and R 3 are selected from the group consisting of alkyl, alkenyl or aryl radicals and heteroatom-substituted derivatives thereof wherein the heteroatoms are as defined above and said radicals have up to 10 carbon atoms. Said heteroatom-substituted derivatives may include halo, e.g. fluoro, chloro, etc., nitro, amino, thiol, hydroxy, alkyloxy, alkylcarboxyl radicals. Examples of suitable R, R 1 , R 2 , and R 3 radicals are methyl, ethyl, propyl, butyl, propenyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyridyl, etc.
Most preferably, R 1 , R 2 and R 3 are selected from the group consisting of hydroxy and alkyloxy or alkenyloxy radicals having up to 7 carbon atoms.
More preferably the method of the present invention comprises administering a compound represented by the formula II ##STR2## wherein y is 0 or 1 to 5, Z is a radical selected from the group consisting of halo, e.g. fluoro, chloro, etc., nitro, amino, thiol, hydroxy, alkyloxy, alkylcarboxy, etc. and n is 0 or an integer of from 1 to 3, x and z are 0 or 1, and when x is 0, z is 1 and when z is 0, x is 1 and the symbols R 1 , R 2 , R 3 , and Y are as defined above.
Preferably the compound used in the above method of treatment is a compound of formulas (III or IV). ##STR3## wherein R 1 , R 2 , R 3 , X and Y are as defined above and the hatched and triangular lines are defined below.
In a further aspect, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formulae (I), (II), (III), or (IV) wherein the symbols have the above meanings, or a pharmaceutically acceptable salt thereof in admixture with a non-toxic, pharmaceutically acceptable liquid vehicle.
In a still further aspect, the present invention relates to certain novel 7-[5-hydroxy-2-(hydroxyhydrocarbyl or hydroxyheteroatom-substituted hydrocarbyl)-3-hydroxycyclopentyl(enyl)] heptanoic or heptenoic acids and amine, amide, ether, ester and alcohol derivatives of said acids, wherein one or more of said hydroxy groups are replaced by an ether group or a pharmaceutically acceptable salt of such compounds.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
FIG. 1 is a schematic representation of the synthesis of the ethers of this invention, i.e., the 9; 11; 15; 9, 11; 9, 15; 11, 15 ethers, etc.
FIG. 2 is a schematic representation of the synthesis of various other compounds of the invention from said 9, 11 and/or 9, 15 ethers of FIG. 1.
FIG. 3 is a schematic representation of the synthesis of 15-acyl analogues of certain of the ethers of the invention.
FIG. 4 is a schematic representation of the synthesis of certain of the 5, 6 trans compounds of the invention.
DETAILED DESCRIPTION OF THE INVENTION
In all of the above formulae the dotted lines on bonds between carbons 5 and 6 (C-5) of the a chain, between carbons 13 and 14 (C-13) of the w chain, and between carbons 10 and 11 (C-11) of the cyclopentane ring, indicate a single or a double bond which can be in the cis or trans configuration (Of course, the C-10 and C-11 double bonds being part of the cyclopentane ring will exist only as cis double bonds). If two solid lines are used that indicates a specific configuration for that double bond. Hatched lines at positions C-8, C-9, C-11, C-12 and C-15 indicate the a configuration. If one were to draw the b configuration, a solid triangular line would be used.
In the compounds used in accordance with the present invention, compounds having the C-8, C-9, C-11, C-12 or C-15 substituents in the a or b configuration are contemplated.
For the purpose of this invention, unless further limited, the term "alkyl" refers to alkyl groups having from one to ten carbon atoms, the term "cycloalkyl" refers to cycloalkyl groups having from three to seven carbon atoms, the term "aryl" refers to aryl groups having from four to ten carbon atoms. The term "hydrocarbyl" means radicals having up to 20 carbon atoms and the remaining atoms comprising said hydrocarbyl radical are hydrogen. In the "heteroatom-substituted" radicals any of the carbon atoms or the hydrogen atoms may be replaced by one of the above defined heteroatoms. Such hydrocarbyl radicals include aryl, alkyl, alkenyl and alkynyl groups of appropriate lengths, and may be methyl, ethyl, propyl, butyl, pentyl, or hexyl, or an isomeric form thereof; ethenyl, propenyl, etc.; phenyl, etc.
In FIG. 1 PGF 2a or 17-phenyl (18, 19, 20 trinor) PGF 2a is reacted with diazomethane to convert such compounds to the corresponding 1-methyl ester. In this scheme R 4 is n-propyl or phenyl. Subsequently, as shown in Reaction 1b and further illustrated in Examples 1 and 3, the above 1-methyl esters are reacted with an organoiodide, represented by R 1 I, R 2 I or R 3 I, in the presence of Ag 2 O and dimethyl formamide, e.g. at 23° C.
In FIG. 2 the 1-methyl ester, prepared according to the reaction 1b of FIG. 1, is reacted to provide various compounds of this invention. As shown in Reaction 2d and Example 7, the 1-methyl ester may be hydrolyzed with 0.5N aqueous LiOH in tetrahydrofuran (THF) to yield the corresponding acid. Alternatively, the 1-methylester may be reduced with LiBH 4 in ethylether, in accordance with Reaction 2c and as illustrated in Example 6, to yield the corresponding alcohol. This alcohol may be subsequently converted into the 5-t-butyl dimethyl siloxy derivative and reacted, in accordance with Reaction 2e, with 2,6-di-t-butyl pyridine in CH 2 Cl 2 and subsequently reacted with methyl triflate (MeOTF) to form the 1-methoxy derivative. To provide other 1-hydrocarbyloxy esters the alternate Reaction 2e may be utilized whereby the 1-alcohol may be reacted with the hydrocarbyl chloride, R 7 Cl, wherein R 7 is a hydrocarbyl radical comprising up to 20 carbon atoms, e.g. a C1 to C4 alkyl chloride, in the presence 4-dimethylaminopyridine (DMAP) in triethylamine and CH 2 Cl 2 . Finally, the 1-methylester may be reacted, in accordance with Reaction 2a and as illustrated in Example 4, with an amine, R 5 R 6 NH, wherein R 5 and R 6 are selected from the group consisting of hydrogen and hydrocarbyl radicals, preferably hydrogen and C 1 to C 4 alkyl radicals, in CH 3 OH, for example at a temperature of 55° C., to yield the corresponding amides. Such amides may be subsequently reduced with LiAlH 4 in THF, in accordance with Reaction 2b and as illustrated by Example 5, to yield the corresponding amines.
In FIG. 3 the 1-methyl ester, prepared according to the reaction scheme of FIG. 1, is reacted in accordance with Reaction 3a of FIG. 3 and as illustrated by Example 17 to yield the 15-pivaloyl ester of said 1-methyl ester. The compound is subsequently reacted in accordance with Reaction 3b of FIG. 3 and illustrated by Example 17a to yield the 11-methoxy derivative. This compound may then be converted to the 1-acid in accordance with Reaction 3c, as illustrated by Example 17b, to yield the 11-methoxy, 15 pivaloyloxy acid of the invention.
In FIG. 4, the 1-methylester prepared in accordance with the reaction scheme of FIG. 1, is consecutively reacted according to Reactions 1a through 1c, as illustrated in Example 18 to yield the 5-trans compounds of this invention.
The following novel compounds may be used in the pharmaceutical compositions and the methods of treatment of the present invention.
Methyl 7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl]-5Z-heptenoate
7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl]-5Z-heptenoic acid
7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl]-5Z-hepten-1-ol
7-[5α-Hydroxy-2β-(3α-pivalyl-1E-octenyl)-3α-methoxy-cyclopentyl]-5Z-heptenoic acid
Methyl 7-[5α-Hydroxy-2β-(3α-pivalyl-1E-octenyl)-3α-methoxy-cyclopentyl]-5Z-heptenoate
7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl]-5Z-hepten-1-pivalate
Methyl 7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl]-5E-heptenoate
7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl]-5E-heptenoic acid
7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl]-5E-hepten-1-ol
Methyl 7-[3α-ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-heptenoate
7-[3α-Ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-heptenoic acid
7-[3α-Ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-hepten-1-ol
7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl]-5Z-heptenamide
N,N-Dimethyl-7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-methoxy-cyclopentyl]-5Z-heptenamide
Methyl 7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-(2-propenoxy)-cyclopentyl]-5Z-heptenoate
7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-(2-propenoxy)-cyclopentyl]-5Z-hepten-1-ol
7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-(2-propenoxy)-cyclopentyl]-5Z-heptenoic acid
Methyl 7-[3α,5α-dimethoxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-heptenoate
7-[3α,5α-dimethoxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-heptenoic acid
7-[3α,5α-dimethoxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-hepten-1-ol
Methyl 7-[3α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-5α-methoxy-cyclopentyl]-5Z-heptenoate
7-[3α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-5α-methoxy-cyclopentyl]-5Z-heptenoic acid
7-[3α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-5α-methoxy-cyclopentyl]-5Z-hepten-1-ol
N-Isopropyl-7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-methoxy-cyclopentyl]-5Z-heptenamide
N-Isopropyl-7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-methoxy-cyclopentyl]-5Z-heptenamine
N,N-Dimethyl-7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-methoxy-cyclopentyl]-5Z-heptenamine
7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-propoxy-cyclopentyl]-5Z-hepten-1-ol
7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-propoxy-cyclopentyl]-5Z-heptenoic acid
Methyl-7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3αpropoxy-cyclopentyl]-5Z-heptenoate
Methyl-7-[3α,5α-dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl]-5Z-heptenoate
7-[3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl]-5Z-heptenoic acid
7-[3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl]-5Z-hepten-1-ol
1-Acetoxy-7-[3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl]-5Z-heptene
7-[3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl]-1-methoxy-5Z-heptene
7-[3α-ethoxy-5α-hydroxy-2β(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-heptenamide
N-Isopropyl-7-[3α-ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-heptenamide
N-Isopropyl-7-[3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl]-5Z-heptenamide
Methyl-7-[3α,5α-Dihydroxy-2β-(3αethoxy-1E-octenyl)-cyclopentyl]-5Z-heptenoate
7-[3α,5α-Dihydroxy-2β-(3α-ethoxy-1E-octenyl)-cyclopentyl]-5Z-heptenoic acid
Methyl 7-[3α-Butoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-heptenoate
7-[3α-Butoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-hepten-1-ol
7-[3α-Butoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-heptenoic acid
N-Isopropyl-7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-propoxy-cyclopentyl]-5Z-heptenamide
7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-propoxy-cyclopentyl]-5Z-heptenamide
Isopropyl-7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-propoxy-cyclopentyl]-5Z-heptenoate
7-[3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl]-5Z-heptenamide
Isopropyl-7-[3α,5α-dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl]-5Z-heptenoate
Methyl-7-[3α,5α-Dihydroxy-2β-(3α-methoxy-5-phenyl-1E-pentenyl)-cyclopentyl]-5Z-heptenoate
7-[3α,5α-Dihydroxy-2β-(3α-methoxy-5-phenyl-1E-pentenyl)-cyclopentyl]-5Z-heptenoic acid
7-[3α,5α-Dihydroxy-2β-(3α-methoxy-5-phenyl-1E-pentenyl)-cyclopentyl]-5Z-heptenamide
A pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or undesirable effect on the subject to whom it is administered and in the context in which it is administered. Such salts are those formed with pharmaceutically acceptable cations, e.g., alkali metals, alkali earth metals, etc.
Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, or a pharmaceutically acceptable salt thereof, as an active ingredient, with conventional ophthalmically acceptable pharmaceutical excipients, and by preparation of unit dosage forms suitable for topical ocular use. The therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v), preferably about 0.001 to about 1.0% (w/v) in liquid formulations.
For ophthalmic application, preferably solutions are prepared using a physiological saline solution as a major vehicle. The pH of such ophthalmic solutions should preferably be maintained between 4.5 and 8.0 with an appropriate buffer system, a neutral pH being preferred but not essential. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. A preferred surfactant is, for example, Tween 80. Likewise, various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose cyclodextrin and purified water.
Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
In a similar vein, an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
Other excipient components which may be included in the ophthalmic preparations are chelating agents. The preferred chelating agent is edentate disodium, although other chelating agents may also be used in place of or in conjunction with it.
The ingredients are usually used in the following amounts:
______________________________________Ingredient Amount (% w/v)______________________________________active ingredient about 0.001-5preservative 0-0.10vehicle 0-40tonicity adjustor 0-10buffer 0.01-10pH adjustor q.s. pH 4.5-7.5antioxidant as neededsurfactant as neededpurified water as needed to make 100%______________________________________
The actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
The ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate application to the eye. Containers suitable for dropwise application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution. One package may contain one or more unit doses.
Especially preservative-free solutions are often formulated in non-resealable containers containing up to about ten, preferably up to about five units doses, where a typical unit dose is from one to about 8 drops, preferably one to about 3 drops. The volume of one drop usually is about 20-35 ml.
The invention is further illustrated by the following non-limiting Examples.
EXAMPLE 1
Methyl 7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl]-5Z-heptenoate
In accordance with Reaction 1b of Scheme 1,300 mg. (0.815 mmols) of the 1-methylester of PGF 2 α were dissolved in 1.0 mL of dimethylformamide (DMF). To this solution was added 150.5 mg. (0.649 mmol) of Ag 2 O and 173.6 mg. (1.22 mmol) of methyliodide (MeI) and the resulting solution was stirred at 23° C. to obtain (8% yield) of the named compound in admixture with the 9-mono (4% yield), 15-mono and 11, 15 bis (14% yield) methyl ethers of the 1-methylester of PGF 2 α. (The compounds obtained in admixture with the named compound may also be referred to as the 5α-methoxy, 2β-(3α-methoxy-1E-octenyl) and 2β-(3α-methoxy-1E-octenyl)-3α methoxy analogues of the named compound, respectively. The ethers were separated using high pressure liquid chromatography (HPLC) and eluting the admixture with a 1 to 1 mixture of hexane (hex) and ethylacetate (EtOAc) over a Whatman PARTISIL 10 PAK column.
EXAMPLE 1a
Methyl-7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3αpropoxycyclopentyl]-5Z-heptenoate.
The named compound may be prepared by substitution of n-propyliodide for methyl iodide in the procedure of Example 1.
EXAMPLE 1b
Methyl-7-[3α-ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-heptenoate.
The named compound may be prepared by substitution of ethyliodide for methyl iodide in the procedure of Example 1.
EXAMPLE 1c
Methyl-7-[3α-Butoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl]-cyclopentyl]-5Z-heptenoate.
The named compound may be prepared by substitution of n-butyliodide for methyl iodide in the procedure of Example 1.
EXAMPLE 1d
Methyl-7-[5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α(2-propenoxy)-cyclopentyl]-5Z-heptenoate.
The procedure of Example 1 is repeated using allyliodide in place of methyliodide to yield the named compound.
EXAMPLE 2
Isopropyl 7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl]-5Z-heptenoate
the procedure of Example 1 was repeated except that the 1-isopropylester of PGF 2 α was utilized as the reactant in place of the corresponding methyl ester to yield a reaction solution containing an admixture of mono and bis methyl ethers. The reaction solution was diluted with CH 2 Cl 2 and filtered through Celite. The filtrate was concentrated under vacuum, diluted with ethylether (Et 2 O) and washed twice with water. The organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under vacuum. The residue was purified by flash column chromatography (FCC) with an eluant of 1 to 1 hex/EtOAc to yield 120 mg. (59% yield) of the named compound and the 15-methyl ether analogue, thereof. 80% of the purified mixture was the named compound.
EXAMPLE 3
Isopropyl 7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-propoxy-cyclopentyl]-5Z-heptenoate
20 mg (0.050 mmol) of PGF 2 α was combined with 47 mg (0.252 mmol of O-isopropyl N,N'-diisopropyl isourea in 1.0 mL of benzene and heated at 85° C. for 20 hours. The reaction mixture was concentrated in vacuo and the residue was purified by FCC using a 3 to 1 mixture of hexane and EtOAc to yield 16.3 mg (74% yield) of the 11-isopropylester of PGF 2 α. The named compound may be prepared from said 11-isopropyl ester by substitution of propyliodide for methyliodide in the procedure of Example 2.
EXAMPLE 4
N-Isopropyl-7-(5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-methoxy-cyclopentyl]-5Z-heptenamide
In accordance with Reaction 2a of FIG. 2, 220 mg (0.5759 mmol) of the compound of Example 1 were mixed with 549 mg (5.759 mmol) of isopropylamine hydrochloride in 6.0 mL of isopropylamine and heated in a sealed tube for 72 hours at 75° C. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with water. The organic layer was treated as in Example 2 to yield 23.5 mg (10% yield) of the named compound.
EXAMPLE 4a
N,N-Dimethyl-7-(5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-methoxy-cyclopentyl]-5Z-heptenamide
The named compound is prepared in accordance with the procedure of Example 4 by using methylamine hydrochloride in methylamine.
EXAMPLE 4b
N-Isopropyl-7-(3α-ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-heptenamide
The named compound is prepared by substituting the compound of Example 1b in the process of Example 4.
EXAMPLE 4c
N-Isopropyl-7-(5α-hydroxy-2β-(3αhydroxy-1E-octenyl)-3.alpha.-propoxy-cyclopentyl]-5Z-heptenamide
The named compound is prepared by substituting the compound of Example 1a in the process of Example 4.
EXAMPLE 4d
N,N-Dimethyl-7-(5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-methoxy-cyclopentyl]-5Z-heptenamide
Dimethylamine (˜5 ml) was condensed in a tube containing 100 mg (0.1639 mmol) of the 5-t-butyldimethylsiloxy, 3-methoxy derivative of PGF 2 α, methylester dissolved in 6.0 mL of CH 3 OH. The resultant solution was stirred in a sealed glass tube for 48 hours and concentrated in vacuo. The residue diluted with THF (1.0 mL) and treated with Bu 4 NF (0.26 mL of a 1.0M solution, 0.262 mmol) at 23° C. After 16 hours, the reaction was diluted with Et 2 O and washed with H 2 O. The organic portion was dried (MgSO 4 ), filtered and concentrated in vacuo. FCC (100% EtOAc followed by 9:1 CH 2 Cl 2 /MeOH) gave 24.2 mg (39%) of the product.
EXAMPLE 5
N-Isopropyl-7-(5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-methoxy-cyclopentyl]-5Z-heptenamine
In accordance with Reaction 2b of FIG. 2, 75 mg of the compound of Example 4, dissolved in 2.0 mL of tetrahydrofuran (THF) were treated with 34.6 mg (0.9165 mmol) of lithium aluminumhydride (LAH) at 23° C. After 24 hours, the reaction mixture was quenched with 2.0 N NaOH and extracted with EtOAc. The organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under vacuum. The residue was purified with FCC using a 6:1:0.1 mixture of CH 2 Cl 2 /MeOH/NH4OH to yield 19.0 mg (26% yield) of the named compound.
EXAMPLE 5a
N,N-Dimethyl-7-(5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-3.alpha.-methoxy-cyclopentyl]-5Z-heptenamine
The named compound is prepared by substitution of the compound of Example 4a in the procedure of Example 5.
EXAMPLE 6
7-(5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl]-5Z-hepten-1-ol
In accordance with Reaction 2c of FIG. 2, 20.2 mg (0.0529 mmol) of the compound of Example 1 were dissolved in 1.5 mL of Et 2 O and treated with 2.3 mg (0.105 mmol) of LiBH 4 to yield a reaction mixture comprising the named product. The resulting product was purified by FCC with a 1 to 1 mixture of hex/EtOAc followed by 100% EtOAc to yield 16.3 mg (87%) of the named compound.
EXAMPLE 6a
7-[3α-Ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-hepten-1-ol
The named compound is prepared by substituting the compound of Example 1b in the process of Example 6.
EXAMPLE 6b
7-[3α-Butoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-hepten-1-ol
The named compound is prepared by substituting the compound of Example 1c in the process of Example 6.
EXAMPLE 6c
7-[3α-Propoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-hepten-1-ol
The named compound is prepared by substituting the compound of Example 1(a) in the process of Example 6.
EXAMPLE 6d
7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-(2-propenoxy)-cyclopentyl]-5Z-hepten-1-ol
The procedure of Example 6 is repeated using the compound of Example 1(d) as the starting material to yield the named compound.
EXAMPLE 7
7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl]-5Z-heptenoic acid
40 mg (0.1047 mmol) of the compound of Example 1 were dissolved in a mixture of 0.31 mL of 0.5N aqueous LiOH and 0.62 mL of THF in accordance with Reaction 2d of Scheme 2. After the reaction mixture was acidified with 10% aqueous citric acid and extracted with CH 2 Cl 2 . The organic portion was dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by FCC using a 95 to 5 mixture of EtOAc and MeOH to yield 28.6 mg (75% yield) of the named compound.
EXAMPLE 7a
7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-propoxy-cyclopentyl]-5Z-heptenoic acid
The named compound is prepared by substituting the compound of Example 1a in the procedure of Example 7.
EXAMPLE 7b
7-[3α-Ethoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-heptenoic acid
The named compound is prepared by substituting the compound of Example 1b in the procedure of Example 7.
EXAMPLE 7c
7-[3α-Butoxy-5α-hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-heptenoic acid
The named compound is prepared by substituting the compound of Example 1c in the procedure of Example 7.
EXAMPLE 7d
7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-(2-propenoxy)-cyclopentyl]-5Z-heptenoic acid
The named compound is prepared by substituting the compound of Example 1d in the procedure of Example 7.
EXAMPLE 8
7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl]-5Z-heptenamide
According to the procedures described for Example 4, the compound of Example 1 is reacted with NH 4 Cl dissolved in NH 3 to yield the named compound.
EXAMPLE 8a
7-[3α-Ethoxy-5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-heptenamide
In accordance with Example 8, 100 mg (0.252 mmol) of the compound of Example 1(b) is reacted with 135 mg (2.52 mmol) of NH 4 Cl dissolved in 5 mL of NH 3 to give the named compound in 69% yield.
EXAMPLE 8b
7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-propoxy-cyclopentyl]-5Z-heptenamide
In accordance with Example 8, 52 mg (0.127 mmol) of the compound of Example 1(a) is reacted with 68 mg (1.27 mmol) of NH 4 Cl dissolved in 4.5 mL of NH 3 to give the named compound in 86% yield.
EXAMPLE 9
7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl]-1-pivaloyloxy 5Z-heptene
The 1-t-butyldimethylsilyl ester of 3-methoxy PGF 2 α and 5.2 mg (0.239 mmol) of LiBH 4 was dissolved in 1.0 mL of ethylether and stirred for 16 hours at 23° C. The reaction mixture was quenched with 2.0N aqueous NaOH and extracted with CH 2 Cl 2 . The organic portion was dried over anhydrous Na 2 SO 4 , filtered and concentrated under vacuum. The residue was dissolved in 0.5 mL of pyridine and cooled to 0° C. 17.7 uL(0.143 mmol) of trimethylacetyl chloride were added and after 24 hours the reaction was diluted with EtOAc, washed with saturated aqueous NH 4 Cl and brine and dried over anhydrous MgSO 4 . The dried product was filtered and concentrated under vacuum before purifying by use of FCC and a 1 to 1 mixture of hexane and EtOAc to yield 15.9 mg (31% yield of the named compound).
EXAMPLE 10
7-[3α,5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl]-1-methoxy-5Z-heptene
In accordance with Reaction 2e of Scheme 2, a solution of the compound of Example 6 and 0.46 mL 2,6-di-t-butylpyridine (2.058 mmol) in 2.0 mL CH 2 Cl 2 was treated with methyl triflate (194 ul, 1.715 mmol) and stirred for 48 hours at 23° C. The reaction mixture was quenched with saturated aqueous NaHCO 3 and extracted with CH 2 Cl 2 . The combined organic portion was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was diluted with 2.0 mL of THF and 1.4 mL of a 1.0M solution of Bu 4 NF in THF. After 16 hours, the reaction was diluted with EtOAc and washed with H 2 O. The organic portion was dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. Treating by FCC with 1:1 hex/EtOAc gave 66.1 mg (53% yield) of the named compound.
EXAMPLE 11
1-Acetoxy-7-[3α-5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl]-5Z-heptene
1-Acetoxy-7-[3α,5α-t-butyldimethylsiloxy-2β-(3α-meth-oxy-1E-octenyl)-cyclopentyl]-5Z-heptene is reacted with Bu 4 NF in THF at room temperature to yield the named compound.
EXAMPLE 12
Methyl 7-[3α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-5α-methoxy-cyclopentyl]-5Z-heptenoate
The named compound is prepared in accordance with the procedure of Example 1.
EXAMPLE 12a
7-[3α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-5α-methoxy-cyclopentyl]-5Z-heptenoic acid
The named compound is prepared by reacting the compound of Example 12 in accordance with the process of Example 7.
EXAMPLE 12b
7-[3α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-5α-methoxy-cyclopentyl]-5Z-hepten-1-ol
The named compound is prepared by reacting the 1-t-butyl dimethylsiloxy ester of the compound of Example 12(a) in accordance with the process of Example 6.
EXAMPLE 13
7-[3α-5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl]-5Z-hepten-1-ol
The 15-monomethyl ether of Example 1 is reacted in accordance with the process of Example 6 to yield the named compound.
EXAMPLE 13a
7-[3α-5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl]-5Z-heptenoic acid
The 15-monomethyl ester of Example 1 is reacted in accordance with the process of Example 7 to yield the named compound.
EXAMPLE 13b
Isopropyl-7-[3α-5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl]-5Z-heptenamide
The 15-monomethyl ester of Example 1 is reacted in accordance with the process of Example 4 to yield the named compound.
EXAMPLE 13c
7-[3α-5α-Dihydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl]-5Z-heptenamide
The 15-monomethyl ester of Example 1 is reacted in accordance with the process of Example 8 to yield the named compound.
EXAMPLE 14
Methyl-7-[3α-5α-Dihydroxy-2β-(3α-ethoxy-1E-octenyl)-cyclopentyl]-5Z-heptenoate
The named compound is prepared in accordance with the process of Example 1 by replacing methyliodide with ethyl iodide.
EXAMPLE 14a
7-[3α-5α-Dihydroxy-2β-(3α-ethoxy-1E-octenyl)-cyclopentyl]-5Z-heptenoic acid
The named compound is prepared by reacting the compound of Example 14 in accordance with the process of Example 7.
EXAMPLE 14b
N-Isopropyl-7-[3α-5α-Dihydroxy-2β-(3α-ethoxy-1E-octenyl)-cyclopentyl]-5Z-heptenamide
The named compound is prepared by reacting the compound of Example 14 in accordance with the process of Example 4.
EXAMPLE 14c
7-[3α-5α-Dihydroxy-2β-(3α-ethoxy-1E-octenyl)-cyclopentyl]-5Z-heptenamide
The named compound is prepared by reacting the compound of Example 14 in accordance with the process of Example 8.
EXAMPLE 15
Methyl-7-[3α-5α-Dimethoxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-heptenoate
The named compound is isolated from the reaction product of Example 1.
EXAMPLE 15a
7-[3α-5α-Dimethoxy-2β-(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-heptenoic acid
The named compound is prepared by substituting the 3,5-dimethylether of Example 15 in the process of Example 7.
EXAMPLE 15b
7-[3α-5α-Dimethoxy-2β(3α-hydroxy-1E-octenyl)-cyclopentyl]-5Z-hepten-1-ol
The named compound is prepared by substituting the 3,5-dimethylether of Example 15 in the process of Example 6.
EXAMPLE 16
Methyl-7-[3α-5α-Dihydroxy-2β-(3α-methoxy-5-phenyl-1E-pentenyl)-cyclopentyl]-5Z-heptenoate
The named compound is prepared according to the process described in Example 1 by substituting the 1-methylester of 17-phenyl, 18, 19, 20-trinor PGF 2 α for the 1-methylester of PGF 2 α.
EXAMPLE 16a
7-[3α-5α-Dihydroxy-2β-(3α-methoxy-5-phenyl-1E-pentenyl)-cyclopentyl]-5Z-heptenoic acid
The named compound is prepared by substituting the compound of Example 16 in the process of Example 7.
EXAMPLE 16b
7-[3α-5α-Dihydroxy-2β-(3α-methoxy-5-phenyl-1E-pentenyl)-cyclopentyl]-5Z-heptenamide
The named compound is prepared by substituting the compound of Example 16 in the process of Example 8.
EXAMPLE 17
Methyl 7-[3α,5αDihydroxy-2β(3α-pivalyl-1E-octenyl)-cyclopentyl]-5Z-heptenoate
PGF 2 α (40.4 mg 0.114 mmol) was suspended in Et 2 O(1 mL) and cooled to 0°. A solution of CH 2 N 2 in Et 2 O was added dropwise to the above suspension until a yellow color persisted. The solution was warmed to 25° for 30 minutes before concentration to yield the PGF 2 α methyl ester as an oil. The crude ester was combined with 14 mg., (0.137 mmol) n-butyl boronic acid (BuB(OH) 2 ) in 0.25 mL of CH 2 Cl 2 and heated at reflux temperature for 30 minutes. The reaction mixture was concentrated and the residue dissolved in dry benzene. The benzene was evaporated under reduced pressure. The process was repeated twice to remove traces of water present from the reaction, leading to boronate ester, which was subsequently dissolved in 0.2 mL of dry pyridine and treated with pivalyl chloride (0.043 mL, 0.34 mmol) and 4-DMAP (about 1 mg). The reaction mixture was stirred at 25° for 14 h before being concentrated. The residue was dissolved in EtOAc(10 mL) and washed with 10% citric acid (7 mL). The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated. The residue was dissolved in MeOH (3 mL) and stirred at 25° for 2 h. The solvent was removed and replaced with fresh MeOH. This process was repeated once more. After removal of solvent, the residue was purified by chromatography (silica, 50-60% EtOAc/hexane) to yield the named product as an oil.
EXAMPLE 17a
Methyl-7-[5α-Hydroxy-2β-(3α-pivalyl-1E-octenyl)-3α-methoxy-cyclopentyl]-5Z-heptenoate
The named compound is prepared by substituting compound of Example 17 for the 1-methylester of PGF 2 α in the process of Example 1. (See Reaction 3b of FIG. 3.)
EXAMPLE 17b
7-[5α-Hydroxy-2β-(3α-pivalyl-1E-octenyl)-3α-methoxy-cyclopentyl]-5Z-heptenoic acid
The named compound is prepared by substituting the compound of Example 17a in the process of Example 7. (See Reaction 3c of FIG. 3.)
EXAMPLE 18
Methyl-7-[5α-Hydroxy-2β-(3α-hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl]-5E-heptenoate
987 mg (2.68 mmol) of the 1-methyl ester of PGF 2 α was mixed with 1.43 g (13.41 mmol) of 2,6-lutidine and 2.48 g (9.38 mmol) of t-butyldimethylsiloxytriflate [(TB)(CH 3 ) SiOSO 2 CF 3 ] in 13.4 mL of CH 2 Cl 2 and the solution was stirred for 16 h to yield the tri-(t-butyldimethylsiloxy) ester of the 1-methyl ester of PGF 2 α. (See Reaction 4a of FIG. 4.) The triester was purified by elution (using FCC techniques) with a 30 to 1 solution of hexane and EtOAc 312 mg (0.0088 mmol) of diphenylsulfide in 4.4 mL of benzene and the resulting solution was stirred under long wave UV light exposure for 12 hours. (See Reaction 4b of FIG. 4.) The resulting solution was concentrated under vacuum and purified by elution, as above, with a 20 to 1 solution of hexane and EtOAc to yield 296.1 mg (95% yield) of the 5-trans triester. 318 mg (0.447 mmol) of the 5-trans triester were combined with 2.7 mL of a 1.0M solution of Bu 4 NF in THF and 4.4 mL of THF. The solution was stirred overnight at 23° C., diluted with EtOAc, washed with H 2 O and brine and the organic portion was filtered, concentrated under vacuum and purified, using FCC techniques and 100% EtOAc. to yield 123.3 mg (75% yield) of the triol of the 5-trans 1-methyl ester of PGF 2 α.
The triol was substituted in the process of Example 1 to yield the named compound. (See Reaction 4c of FIG. 4.)
EXAMPLE 18a
7-[5α-Hydroxy-2β-(3α-Hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl]-5E-heptenoic acid
The named compound is prepared by substituting the compound of Example 18 in the process of Example 7.
EXAMPLE 18b
7-[5α-Hydroxy-2β-(3α-Hydroxy-1E-octenyl)-3α-methoxy-cyclopentyl]-5E-hepten-1-ol
The named compound is prepared by substituting the compound of Example 18 in the process of Example 6.
EXAMPLE 19
Methyl-7-[3α-methoxy-5α-hydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl]-5Z-heptenoate
The named compound is isolated from the reaction product of Example 1.
EXAMPLE 19a
7-[3α-methoxy-5α-hydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl]-5Z-heptenoic acid
The named compound is prepared by substituting the dimethylether of Example 19 in the process of Example 7.
EXAMPLE 19b
7-[3α-methoxy-5α-hydroxy-2β-(3α-methoxy-1E-octenyl)-cyclopentyl]-5Z-hepten-1-ol
The named compound is prepared by substituting the dimethylether of Example 19 in the process of Example 6.
EXAMPLE 20
EFFECTS ON INTRAOCULAR PRESSURE
The effects of certain of the above examples on intraocular pressure are provided in the following Table 1. The compounds were prepared at the said concentrations in a vehicle comprising 0.1% polysorbate 80 and 10 mM TRIS base. Dogs were treated by administering 25 ul to the ocular surface, the contralateral eye received vehicle as a control. Intraocular pressure was measured by application pneumatonometry. Dog intraocular pressure was measured immediately before drug administration and at 4 hours thereafter.
The examples which show excellent IOP-lowering effect include Examples 1, 1a, 1b, 6 and 6a wherein the 11 position is substituted with a lower alkyl ether, i.e. a C 1 to C 3 alkyl ether and the 1-position is a lower alkyl ester, e.g. a methyl ester, or an alcohol group. Furthermore, a comparison of Example 1 and 18 shows that the 5-trans or 5-cis isomers are substantially similar in their IOP-lowering effect. Finally, the 9 and 15-substituted lower alkyl ether derivatives wherein the 1-position is substituted with a lower alkyl ester group are also very effective in lowering IOP. (Compare Examples 12 and the 15-monoester of Example 1.) In contrast, various derivatives wherein the 11-position is substituted with a lower alkyl ether group and the 1-position is an acid or an amino group showing lower effect in lowering IOP at a concentration of 0.1%. (See Examples 4a, 4b, 4c, 5, 7d, 18a, 19a and 19b.) However, it is believed that higher concentrations would have greater effect in lowering IOP.
In Table 1, hyperemia is measured by visual estimation. Slight hyperemia would be given a value between 0 and 0.5; moderate hyperemia would be given a value from 0.5 to 1.0 and severe hyperemia would be given a value of greater than 1.0. Miosis would be evaluated as 0 (nothing), slight (slite) or pinpoint (pin), i.e., the pupil would be the size of a pinpoint.
TABLE 1______________________________________ HYPEREMIA/EXAMPLE DOG IOP MIOSIS______________________________________ 1 0.01/+3.0 0.03/0 0.1%/-6.2 0.50/pin 6 0.01/-1.6 0.08/0 0.1%/-5.7 0.75/pin17a 0.1%/-1.3 0.03/slite17 0.1%/-2.5 0.82/pin 9 0.1%/-2.5 0.17/slite18 0.01/0 0.08/slite 0.1%/-6.3 0.03/slite18a 0.1%/0.0 0/018b 0.1%/-3.0 0.03/slite 1b 0.1%/-5.2 0.44/pin 7b 0.1%/-3.9 0.75/pin 6a 0.1%/-6.5 0.03/pin 01%/0.0 8 0.1%/-3.3 0.56/pin 4a 0.1%/0.0 0.33/slite 1d 0.1%/-3.8 0.66/pin 6d 0.1%/-2.3 0.58/pin 7d 0.1%/0.0 0.31/pin19 0.1%/-2.4 0.75/pin19a 0.1%/0.0 0.04/019b 0.1%/0.0 0/slite12 0.01/-3.3 0/slite 0.1%/-7.8 0.53/pin12a 0.1%/-2.8 0.25/slite12b 0.1%/-4.2 0/slite 5 0.1%/0.0 0.08/0 6c 0.1%/-2.0 0.29/slite 7a 0.1%/-3.9 0.54/pin 0.01/0 0.62/slite 1a 0.1%/-7.6 0.83/pin 0.01/0 0.29/slite 1 0.1%/-7.8 0.89/pin(15-mono ester) 0.01/-2.0 0.83/pin 0.1%/-4.5 1.34/pin11 0.1%/-2.9 0.42/slite10 0.1%/-1.8 0/0 8a 0.1%/0 0.29/pin 0.1%/-2.9 0.21/pin 4b 0.1%/0 0.08/slite13b 0.1%/-3.9 0.5/pin14 0.1%/-4.5 0.50/pin 1c 0.1%/-4.4 1.17/pin 6b 7c 0.1%/-1.6 0.70/0 4c 0.1%/0 0/0 8b 0.1%/-3.8 0.79/pin 2a 0.1%/-1.8 0.47/pin13c 0.1%/-3.2 0.59/pin 0.01%/-4.0 0.44/pin14d 0.1%/-2.7 0.46/pin 0.1%/-5.1 0.81/pin 2 0.1%/-4.2 0.56/pin16a 0.1%/-3.8 ND/pin16b 0.1%/-4.4 0.47/pin______________________________________
The foregoing description details specific methods and compositions that can be employed to practice the present invention, and represents the best mode contemplated. However, it is apparent from one of ordinary skill in the art that further compounds with the desired pharmacological properties can be prepared in an analogous manner, and that the disclosed compounds can also be obtained from different starting compounds via different chemical reactions. Similarly, different pharmaceutical compositions may be prepared and used with substantially the same results. Thus, however detailed the foregoing may appear in text, it should not be construed as limiting the overall scope hereof; rather, the ambit of the present invention is to be governed only by the lawful construction of the appended claims. | The invention relates to 7-[5-hydroxy-2-(hydroxyhydrocarbyl or heteroatom-substituted hydroxy hydrocarbyl)-3-hydroxycyclopentyl(enyl)] heptanoic or heptenoic acids and derivatives of said acids, wherein one or more of said hydroxy groups are replaced by an ether group. The compounds of the present invention are potent ocular hypotensives, and are particularly suitable for the management of glaucoma. | 0 |
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a Continuation application of application Ser. No. 09/228,097 filed Jan. 11, 1999 now U.S. Pat. No. 6,254,609, the contents of which is hereby incorporated by reference.
FIELD OF THE INVENTION
This invention relates to a stent delivery catheter system, such as the kind used in percutaneous transluminal coronary angioplasty (PTCA) procedures. More particularly, it relates to a stent delivery catheter employing two retractable sheaths which may be retracted to release a self-expanding stent, a balloon assisted expandable stent or a balloon expandable stent.
BACKGROUND OF THE INVENTION
In typical PTCA procedures, a guiding catheter is percutaneously introduced into the cardiovascular system of a patient and advanced through the aorta until the distal end is in the ostium of the desired coronary artery. Using fluoroscopy, a guide wire is then advanced through the guiding catheter and across the site to be treated in the coronary artery. An over the wire (OTW) balloon catheter is advanced over the guide wire to the treatment site. The balloon is then expanded to reopen the artery. The OTW catheter may have a guide wire lumen which is as long as the catheter or it may be a rapid exchange catheter wherein the guide wire lumen is substantially shorter than the catheter. Alternatively, a fixed wire balloon catheter could be used. This device features a guide wire which is affixed to the catheter and cannot be removed.
To help prevent arterial closure, repair dissection, or prevent restenosis, a physician can implant an intravascular prosthesis, or a stent, for maintaining vascular patency inside the artery at the lesion. The stent may either be a self-expanding stent, a balloon assisted expandable stent or a balloon expandable stent. For the latter type, the stent is often delivered on a balloon and the balloon is used to the expand the stent. The self-expanding stents may be made of shape memory materials such as nitinol or constructed of regular metals but of a design which exhibits self expansion characteristics.
In certain known stent delivery catheters, a stent and an optional balloon are positioned at the distal end of the catheter, around a core lumen. The stent and balloon are held down and covered by a sheath or sleeve. When the distal portion is in its desired location of the targeted vessel the sheath or sleeve is retracted to expose the stent. After the sheath is removed, the stent is free to self-expand or be expanded with a balloon.
In a coronary stent deployment system which utilizes a retractable sheath one problem which is encountered is the interaction of the sheath and the stent upon retraction of the sheath. Typically, as the sheath slides off of the stent, the stent is subjected to potential marring by the sheath. While this problem can be minimized by making the sheath of soft materials, such materials are often unsuitable for use with a self-expanding stent where prolonged storage results in creep deformation of the inner sheath.
It is desirable to provide a medical device delivery system which provides a protective, non-marring inner sheath for the medical device and is capable of retaining the medical device for brief periods of time and which further has an additional outer sheath over the inner sheath which is capable of retaining the medical device for lengthy periods of time, thereby allowing the device to have a suitable shelf life.
SUMMARY OF THE INVENTION
The present invention provides a medical device delivery system in which two sheaths, an inner sheath and an outer sheath, cover a medical device mounted on the distal end of the medical device delivery system. In its various embodiments, the invention contemplates a delivery system in which the inner sheath is either a tear away sheath or a retractable sheath and the outer sheath is either a retractable sheath or a pull away sheath.
In accordance with the present invention, the outer sheath is desirably constructed to be more creep resistant than the inner sheath. The outer sheath may be made of a material having a higher hoop strength than the inner material. The inner material should be capable of retaining the medical device in place on the delivery system for at least a short period of time before it either is retracted or opens due to material failure. The outer sheath should be capable of retaining the medical device for longer periods of time so that the device may have a reasonable shelf life.
To this end, the invention provides a medical device delivery system comprising a manifold at the proximal end of the delivery system. Extending distally from the manifold is an inner tube. At the distal end of the inner tube is a medical device mounting region for concentrically mounting a medical device thereon. Covering the medical device mounting region, at least in part, is a distal inner sheath attached to the inner tube at the distal region of the inner tube. The distal inner sheath is concentrically disposed about the inner tube. The medical device delivery system also comprises a distal outer sheath, concentrically disposed about the inner tube. At least a portion of the distal outer sheath is disposed about at least a portion of inner sheath.
In one embodiment of the invention, the distal inner sheath is a tear away sheath and the distal outer sheath is retractable by means of an outer sheath retraction device. The outer sheath retraction device extends in a distal direction from the manifold. The distal outer sheath extends from the distal end of the retraction device.
In another embodiment of the invention, the distal inner sheath is retractable by means of an inner sheath retraction device. The inner sheath retraction device extends in a distal direction from the manifold. The distal inner sheath extends from the distal end of the inner sheath retraction device. Similarly, the outer sheath is retractable by means of an outer sheath retraction device. The outer sheath retraction device extends in a distal direction from the manifold. The distal outer sheath extends from the distal end of the outer sheath retraction device.
In another embodiment of the invention, the distal inner sheath is retractable by means of an inner sheath retraction device. The inner sheath retraction device extends in a distal direction from the manifold. The distal inner sheath extends from the distal end of the inner sheath retraction device. The distal outer sheath contacts the inner sheath, and extends proximally from the distal region of the inner tube. The distal outer sheath is removed prior to insertion of the device in the body.
In all of the embodiments, the delivery system may further comprise the medical device mounted on the medical device mounting region. Among the contemplated medical device for use with this system are stents and grafts. Desirably, the stent will be self-expanding or a balloon assisted expandable stent.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 shows a longitudinal cross-sectional view of an embodiment of the inventive medical device delivery system.
FIG. 2 shows a partial cut-away perspective view of the distal end of the embodiment of FIG. 1 .
FIG. 3 shows an enlarged view of region 3 of the medical device delivery system of FIG. 1 .
FIG. 4 shows a longitudinal cross-sectional view of an embodiment of the inventive medical device delivery system.
FIG. 5 shows a longitudinal cross-sectional view of an embodiment of the inventive medical device delivery system.
FIG. 6 shows a perspective view of a stent for use with the inventive medical device delivery system.
FIG. 7 shows a perspective view of a graft for use with the inventive medical device delivery system.
FIG. 8 shows a side elevational view of a vena cava filter for use with the inventive medical device delivery system.
DETAILED DESCRIPTION OF THE INVENTION
While this invention may be embodied in many different forms, there are described in detail herein specific preferred embodiments of the invention. This description is an exemplification of the principles of the invention and is not intended to limit the invention to the particular embodiments illustrated.
The present invention provides a medical device delivery system in which the medical device is contained and/or surrounded and/or protected by both an inner sheath and an outer sheath.
In several of the embodiments, the inner sheath is a tear away sheath. The presence of a tear away inner sheath protects the medical device from being marred upon the sliding removal of the outer sheath. After the outer sheath is removed, the inner tear away sheath, no longer contained by the outer sheath, opens as a result of the expanding force of the self-expanding, balloon assisted or balloon expandable medical device.
Turning to the figures, FIG. 1 shows one embodiment of the inventive medical device delivery system generally at 110 . The medical device delivery system 110 has a proximal end and a distal end and comprises a manifold 120 located at the proximal end of delivery system 110 . Extending in a distal direction from manifold 120 is an inner tube 124 having a distal region 128 and a proximal region 132 . At the distal region of inner tube 124 is a medical device mounting region 136 for concentrically mounting a medical device thereon. Delivery system 110 further comprises a distal inner sheath 140 attached to inner tube 124 at distal region 128 . Distal inner sheath 140 is concentrically disposed about inner tube 124 and covers at least a portion, desirably a substantial portion and more desirably the entirety of medical device mounting region 136 to retain a medical device about the medical device mounting region. Inner sheath 140 is fixedly attached to the medical device delivery system and desirably is mounted to the inner tube. As shown in FIG. 2, distal inner sheath 140 is a perforated 137 or scored tear away sheath. A distal outer sheath 144 is concentrically disposed about inner tube 124 and at least a portion of distal outer sheath 144 is disposed about at least a portion of distal inner sheath 140 . The device further comprises an outer sheath retraction device 148 which extends in a distal direction from manifold 120 . Distal outer sheath 144 is seen to extend from the distal end of outer sheath retraction device 148 .
Although there are a variety of outer sheath retraction devices that may be used in the practice of the invention, as shown in FIGS. 1 and 3, a preferred outer sheath retraction device 148 comprises a proximal outer tube 152 , a collapsible sheath 156 extending from the distal end of proximal outer tube 152 and a distal outer tube 160 . The proximal end of distal outer tube 160 extends from the distal end of the collapsible sheath 156 . A slidable pull wire 164 extends from manifold 120 to distal outer sheath 144 . In use, the distal end of retraction device 148 moves in a proximal direction upon sliding pull wire 164 proximally thereby retracting distal outer sheath 144 . Tear away inner sheath 140 may then open as a result of the force of the expansion of the expandable medical device. Because the tear away inner sheath is fixedly attached to the medical device delivery system, the tear away inner sheath is withdrawn from the body of the medical device delivery system is withdrawn.
The stent delivery system may, optionally, further comprise a medical device mounted on the medical device mounting region 136 . While a variety of medical devices are contemplated, in the embodiment shown in FIGS. 1 and 2, the medical device is a self-expanding stent 168 .
In another embodiment of the inventions, as shown in FIG. 4, the delivery system, shown generally at 210 , comprises a manifold 220 , an inner tube 224 having a distal region 228 , a proximal region 232 and a medical device mounting region 236 for concentrically mounting a medical device thereon as in the previous embodiment. Similarly, as in the previous embodiment, delivery system 210 further comprises a distal inner sheath 240 . Distal inner sheath 240 is concentrically disposed about inner tube 224 and covers at least a portion of medical device mounting region 236 . Unlike in the previous embodiment, delivery system 210 further comprises a inner sheath retraction device 241 having a distal end and a proximal end. Inner sheath retraction device 241 , consists of pull collar 243 mounted on proximal end of distal end of inner sheath 240 and a pull wire 245 extending distally from manifold 220 to pull collar 243 .
As in the previous embodiment, a distal outer sheath 244 is concentrically disposed about inner tube 224 . At least a portion of distal outer sheath 244 is disposed about at least a portion of distal inner sheath 240 . Also, the device comprises an outer sheath retraction device 248 comprising a proximal outer tube 252 , a collapsible sheath 256 and a distal outer tube 260 as described for the embodiment of FIGS. 1-3. The collapsible sheath section of the medical device delivery system is similar to that shown in FIG. 3, differing only in the presence of an additional wire, corresponding to a slidable pull-wire operably associated with the inner sheath. Slidable wire 264 extends from manifold 220 to distal outer sheath 244 and in use, the outer sheath retraction device works in a manner identical to that described for the outer sheath retraction device described above. Alternatively, although not shown in FIG. 4, inner sheath 240 may also be retracted via a collapsible retraction device similar to retraction device 248 used to retract outer sheath 244 .
Also shown is an optional medical device in the form of a self-expanding stent 268 mounted on the medical device mounting region 236 .
In another embodiment, the invention comprises a medical device delivery system shown generally at 310 in FIG. 5 . Medical device delivery system 310 , as in the previous embodiments, comprises a manifold 320 , an inner tube 324 having a distal region 328 , a proximal region 332 and a medical device mounting region 336 for concentrically mounting a medical device thereon. Delivery system 310 further comprises a distal inner sheath 340 . Distal inner sheath 340 is concentrically disposed about inner tube 324 and covers at least a portion of medical device mounting region 336 . As in the embodiment of FIG. 4, delivery system 310 further comprises a inner sheath retraction device 341 having a distal end and a proximal end. Inner sheath retraction device 341 , consists of pull collar 343 mounted on proximal end of distal end of inner sheath 340 and a pull wire 345 extending distally from manifold 320 to pull collar 343 .
As in the previous embodiments, a distal outer sheath 344 (in sock form) is concentrically disposed about inner tube 324 . At least a portion of distal outer sheath 344 is disposed concentrically about at least a portion of distal inner sheath 340 . Unlike in any of the previous embodiments, distal outer sheath 344 extends proximally from the distal end of the inner tube and is removable by sliding the distal outer sheath in a distal direction. Distal outer sheath 344 is in contact with distal inner sheath 340 . Mounted concentrically about the inner tube and carrying the pull wire is outer tube 360 . Although distal outer sheath 344 is depicted in FIG. 5 as being closed at the distal end, it may optionally be open at the distal end. In use, distal outer sheath 344 is removed prior to insertion of the medical device delivery system into the body. A removable sheath such as that disclosed in U.S. Pat. No. 5,800,517 to Anderson et al., incorporated herein in its entirety by reference, may be used.
Also shown is an optional medical device in the form of a self-expanding stent 368 mounted on the medical device mounting region 336 .
In another embodiment, not shown, the medical device delivery system is substantially similar to that shown in FIG. 5 differing only in that the retraction device for retracting the inner sheath is a collapsible sheath as shown in FIGS. 1 and 3.
In the various embodiments of the invention, suitable manifolds, as are known in the art, may be employed. In the embodiment containing two retractable sheaths, the manifold must be able to accommodate two retraction mechanism. In the other embodiments in which one retraction device is employed, the manifold must be able to accommodate one retraction device.
The inner tubes employed in the various embodiments may be made of suitable materials as are known in the art including. Preferably, the inner tubes are made of flexible, but incompressible construction such as a polymer encapsulated braid or coil. Such construction is known in the art. The braid/coil may be comprised of stainless steel encased in a polymer such as Polyimide with an inner layer of Teflon.
The pull collars attached to the retractable sheaths may suitably be ring-shaped members made of stainless steel affixed to the interior of the retractable sheaths by an appropriate adhesive such as Loctite 4011, a cyanoacrylate. Desirably, the pull collar will be made of a radio-opaque material such as gold.
The outer sheath, desirably will be made of a material which has sufficient strength to contain a self-expanding stent in the stent's unexpanded configuration. It is desirable that the outer sheath be constructed so as to be creep resistant. It is also highly desirable that the inner sheath be constructed to be less creep resistant than the outer sheath.
Some of the benefits of the present invention may also be realized in a system wherein the outer sheath is made of a thicker material than the inner sheath.
Suitable materials for the outer sheath include polyimide, Pebax, polyethylene, Nylon, and metal for the embodiments in which the outer sheath is retractable via a retraction device extending to the manifold. Suitable materials for the sock-like distal outer sheath include polyimide, Pebax, polyethylene, Nylon, and metal. As for the distal inner sheath, suitable materials include PTFE, Pebax, polyurethane, polyethylene, and polyimide for the tear away embodiments and for the retractable distal inner sheath embodiments.
The invention also contemplates the use of porous materials for the inner and outer sheaths thereby allowing for the inflow of bodily fluids into the medical device mounting region. This can be helpful in priming the medical device by forcing out any air in the region of the medical device. Suitable porous materials include Suitable porous materials include expanded polytetrafluoroethylene (ePTFE), polyester and silicone. Desirably, the materials will have a pore size ranging from 0.01 mm to 5.0 mm.
Although the tear away sheath has been described as being mechanically released by the force of the expanding medical device, the invention also contemplates the use of a tear away sheath which is hydrolytically released. The sheath may be ‘glued’ shut via a bio-compatible water soluble material. The sheath may then be opened by supplying water thereto so as to dissolved the ‘glue’. Optionally, the glue may be chosen such that it is stable in the presence of fluids at bodily temperatures by dissolves upon exposure to a fluid of slightly elevated temperature such as water at a temperature of 42° C. Alternatively, the sheath may be glued shut via a material which is releasable via actinic energy such as ultraviolet radiation or gamma radiation supplied thereto.
The distal inner and outer sheaths may be bonded to the inner tube and/or retraction devices by the use of suitable adhesives including Loctite 4011, a cyanoacrylate as well as methacrylate, or H. B. Fuller 3507, a urethane adhesive. Other suitable bonding methods include pressure welding, heat welding and laser welding.
The invention also contemplates the use of various lubricants on at least a portion of one or more of the inner and outer sheaths to facilitate the relative motion of the inner and outer sheaths upon retraction or removal of the outer sheath. As seen in FIG. 2, distal inner sheath 140 has an inner surface facing the inner tube and an outer surface 138 facing distal outer sheath 144 . Similarly, distal outer sheath 144 has an inner surface 146 facing distal inner sheath 140 and an outer surface facing outward. A lubricant may applied to at least a portion of at least one of outer surface 138 of inner sheath 140 or inner surface 146 of outer sheath 144 so as to reduce frictional forces between the two sheathes. The lubricant may be applied selectively to the surfaces or, alternatively, may be applied to the entirety of the surfaces.
Although the inner surface and outer surface to which lubricants may be applied have been highlighted in FIG. 2, it is understood that the invention provides for the similar use of such lubricants on the outer surface of the inner sheath and the inner surface of the outer sheath in the other embodiments as well.
In all of the above embodiments, a lubricant may, optionally, be applied to at least a portion of the inner wall and/or outer wall. Suitable lubricants include silicones, PVP (polyvinyl pyrrolidone), PPO (polypropylene oxide) and PEO. Additionally, BioSlide™ coating produced by SciMed made be used as well. BioSlide™ is a hydrophilic, lubricious coating comprising polyethylene oxide and neopentyl glycol diacrylate polymerized in a solution of water and isopropyl alcohol in the presence of a photoinitiator such as azobisisobutronitrile.
Additional details of the design of embodiments of the inventive medical device delivery system which employ collapsible sheaths, in particular the portion of the device proximal to the inner sheath may be found in the various embodiments disclosed in U.S. Pat. No. 5,534,007 to St. Germain and Olson, incorporated herein in its entirety by reference.
In addition to the use of a collapsible sheath retraction device for retracting the outer sheath, the invention also contemplates the use of other suitable retraction means as are known in the art including slidably sealed retractable sheaths and midshaft seals as described in co-pending commonly assigned U.S. patent application Ser. No. 08/722,834 filed Sep. 27, 1996, and a continuation-in-part application Ser. No. 09/071,484 filed May 1, 1998. The entire contents of both applications are hereby incorporated in their entirety by reference. Other contemplated retraction means include sheaths activated directly by pull-collars as described in U.S. patent application Ser. No. 09/071,484 filed May 27, 1998, and screw-like retraction devices as described in U.S. Pat. No. 5,201,757 to Heyn et al. all of which are incorporated herein in their entirety by reference.
Although the medical device shown in the figures have all been described as self-expanding stents, other mechanically expandable stents may be used as well, including balloon expandable stents. A perspective view of one suitable stent is shown in FIG. 6 at 668 . Other medical devices suitable for delivery with the present delivery system include implants such as grafts and vena cava filters. A suitable graft is shown in FIG. 7 at 768 while a suitable vena cava filter is shown in FIG. 8 at 868 .
As shown in the figures, the medical device delivery systems may further comprise other optional features, as are known in the art, such as bumpers 172 , 272 , 372 and 472 and markers 176 , 276 , 376 and 476 . Bumpers 172 - 472 may be made of polyethylene and are affixed to inner tube 124 by adhesive such as H. B. Fuller 3507. Marker bands 176 - 476 are preferably made of a radio-opaque material such as gold although other materials such as stainless steel may be used as well. The markers are included to aid in positioning and may be affixed to inner tube 124 by adhesive such as Loctite 4011.
While several specific embodiments of the present invention have been described, the invention is directed more generally toward the inclusion of two sheaths in any other suitable catheter design not specifically described herein including fixed wire, over-the-wire and rapid-exchange catheters.
In the case of the fixed-wire design, the guidewire is fixedly attached to the medical device delivery system. A fixed-wire delivery system is described in U.S. Pat. No. 5,702,364 to Euteneuer et al., incorporated herein in its entirety by reference, and may be suitably modified for use with the inventive medical device delivery system.
In an over-the-wire embodiment, the inner tube extends proximally to a manifold and a guide wire may be inserted into the inner tube from the proximal end, the guide wire extending to the distal end of the system. The medical device delivery system may then ride on the guidewire.
Similarly, a rapid exchange delivery system is described in U.S. Pat. No. 5,534,007 to St. Germain et al., incorporated herein in its entirety by reference, and may be suitably modified for use with the inventive medical device delivery system. Specifically, the rapid-exchange version may be realized by terminating the inner tube in a guide wire port in a location along the system distal to the proximal end of the system to allow for insertion of a guide wire therein. In the rapid-exchange embodiment, only a portion of the medical device delivery system rides on a guidewire. Typically, the usable length of the medical device delivery system is approximately 135 cm. For a rapid-exchange medical device delivery system, the distance from where the guide wire accesses the inner tube to the distal tip will be approximately 5 cm to 35 cm.
The above Examples and disclosure are intended to be illustrative and not exhaustive. These examples and description will suggest many variations and alternatives to one of ordinary skill in this art. All these alternatives and variations are intended to be included within the scope of the attached claims. Those familiar with the art may recognize other equivalents to the specific embodiments described herein which equivalents are also intended to be encompassed by the claims attached hereto. | A medical device delivery system is disclosed which has a distal inner sheath and a distal outer sheath covering a medical device mounting region and any medical device mounted thereon. The outer sheath is designed to retain the medical device for lengthy periods of time while the inner sheath is designed to retain the sheath for shorter periods of time. | 0 |
BACKGROUND OF THE INVENTION
This invention relates to medical devices used in minimally invasive surgery and more particularly to an improved dexterous tool for minimally invasive surgical procedures. The surgical manipulator will also be ideally suited for tele-surgery.
SUMMARY OF THE INVENTION
Minimally invasive surgery has been widely accepted as a safe and cost-effective procedure as millions of such procedures have been performed to date. A current limitation in minimally invasive surgical procedures, laparoscopic surgery for example, is the lack of an externally controllable articulated robotic manipulator which will be able to freely maneuver within the torso while supporting a surgical tool such as a pair of scissors, or an optical device such as a camera, or both. In the case of laparoscopic surgery, the surgical instrument commonly used is a single-purpose rigid link supporting either a surgical tool or a camera. The existing state-of-the-art in dexterous manipulators involve a rigid link with a short tip that can bend up to 90 degrees uni-directionally. This system provides better maneuvering capability than a completely rigid tool, but is far from providing the desired level of dexterity of manipulation that a surgeon would like to have. A surgeon may need to approach an internal organ within the torso with an arbitrary orientation, such as in the case of inserting a catheter inside the common bile duct for exploration and or removal of stones. Such procedures are quite difficult to perform in the absence of greater manipulator dexterity.
A dexterous minimally invasive surgical manipulator should meet the following requirements:
(a) It should be small enough to pass through a standard trocar sleeve 10 millimeter (mm) or less in diameter,
(b) it should be able to bend up to 180 degrees, bi-directionally,
(c) it should be able to apply sufficient forces as required to perform common minimally invasive surgical procedures, and
(d) it should be able to support a surgical tool or an optical device, or both a surgical tool and an optical device.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a Plan View of a 4-Link AMMIS
FIG. 2 is a Side View of a 4-Link AMMIS
FIG. 3 is a Side View of the AMMIS in an articulated configuration.
FIG. 4 is a conceptual diagram showing an AMMIS in various configurations during a minimally invasive surgical procedure.
FIG. 5 is a perspective view of a 4-Link AMMIS.
DESCRIPTION OF THE INVENTION
The design objective of the articulated manipulator for minimally invasive surgery (AMMIS) is to achieve dexterity with the minimum number of actuators. The use of fewer actuators enables the miniaturization of the articulated structure and provides additional space for the accommodation of peripheral devices that add functionalities to the manipulator.
The central idea behind the manipulator (AMMIS) design is to concatenate a series of linkages in which every link is both a driven-link and a driving-link. Using this idea, the power from a single actuator located at the base link can be transmitted to the end of the chain of linkages while providing articulation to each and every one of the linkages.
The conceptual manipulator discussed above can be realized by the mechanism illustrated in FIGS. 1 and 2. FIG. 1 depicts the plan view of a four-link articulated manipulator chain with a single actuator located on Link-O which serves as the base of the manipulator. FIG. 2 depicts the side view of the mechanism. Gear-1 is the actuator or the driving gear and can be connected to a servo-motor or can be driven manually. All gears in this particular design have the same pitch number and the same pitch diameter--this only simplifies our discussion and is not a limitation of our manipulator design.
We first notice that Gear-2 is rigidly connected to Link-1. As the driving gear, Gear-1, rotates β degrees clockwise, Gear-2 and Link-1 will simultaneously rotate β degrees in the counter-clockwise direction about the common axes of Gear-2 and Gear-3. Gear-4 is mounted on Link-1 and is meshed with Gear-3 which cannot rotate about its own axis. Therefore, as Link-1 rotates counter-clockwise, Gear-4 behaves as a planetary gear to Gear-3 and rotates counter-clockwise about its own axis. Gear-5 is meshed together with Gear-4 and Gear-6. Thus Gear-6 rotates β degrees counter-clockwise as Gear-4 rotates β degrees counter-clockwise. Gear-6 is rigidly connected to Link-2; this implies that Link-2 will rotate β degrees in the counterclockwise direction with respect to Link-1 about the common axes of Gear-6 and Gear-7 as viewed from the side illustrated in FIG. 2. As Gear-6 rotates β degrees counter-clockwise, Gear-8 behaves as a planetary gear to Gear-7 which cannot rotate about its own axis relative to Link-1.
Using the same reasoning as above, we can show that Link-3 will rotate β degrees counter-clockwise with respect to Link-2 about the common axes of Gear-10 and Gear-11, and Link-4 will also rotate β degrees counter-clockwise with respect to Link-3 about the axis of Gear-14. Therefore, we have a mechanism where each link rotates β degrees counter-clockwise with respect to the previous link as the driving gear rotates β degrees clockwise. In effect, we achieve a total of 4 β degrees counterclockwise rotation at the end of Link-4 of this four link AMMIS (articulated manipulator for minimally invasive surgery) with respect to the base link, Link-O, as shown in FIG. 3.
If a larger bend is required, one or more linkages can be added to the 4-link AMMIS to achieve more rotation at the end of the chain. Also, by rotating the driving gear clockwise and counter-clockwise, it is possible to achieve bi-directional articulation of the AMMIS. FIG. 3 shows the AMMIS in solid lines from the side when Gear-1 is rotated clockwise by an angle β and in broken lines when the links of the AMMIS are aligned with each other. A schematic of the AMMIS in various configurations during a minimally invasive surgical procedure is shown in FIG. 4. The dimensions shown in this embodiment are by way of example only.
The articulated manipulator for minimally invasive surgery (AMMIS) has the following advantages and new features:
(a) The compact and simple mechanical design of the AMMIS makes miniaturization possible such that it can pass through a, for example, 10 mm (0.39 inch) or smaller standard trocar sleeve during a minimally invasive surgical procedure. The mechanical design of the AMMIS is scaleable for further minimization so that it can pass through a trocar sleeve 5 mm in size while carrying a single end-effector.
(b) The AMMIS is capable of carrying a miniature camera, for example, 5 mm (0.20 inch) in diameter commercially available at present, along with an end-effector such as a pair of scissors or a gripper. Unlike the single-purpose instruments that are currently in use, the manipulator will prove to be a multi-purpose surgical tool.
(c) The AMMIS is capable of dexterous manipulation. It can be designed to follow a serpentine path of tight radii and make bends of 180 degrees or more bi-directionally, by using even and odd number of gears in successive links, or by using a plurality of actuators.
(d) The AMMIS has sufficient structural rigidity to generate forces that would be required during surgical procedures, such as cutting, sowing, etc.
(e) The AMMIS is close to a perfectly linear system since the angular motion of each link is proportional to the rotation of the actuator. Its simple and compact design simplifies the control of its articulated motion. The AMMIS provides quick response time to transmit motion from the actuator to the various links of the AMMIS.
(f) The compact nature of the design, the simplicity of control and the quick response time of the AMMIS makes it an ideal candidate for tele-surgery.
Currently, there are a number of articulated manipulators in the research stage. These are usually driven by Shape Memory Alloy (SMA) actuators or tendons. Our manipulator is superior to these articulated manipulators as it offers all the desired characteristics of a surgical manipulator, as mentioned above. Shape Memory Alloy wire actuated manipulators cannot make sharp bends though it can apply large forces. Manipulators employing Shape Memory Alloy springs can make sharp bends but cannot apply large forces. Moreover, Shape Memory Alloy actuators have a slow response. Articulated manipulators using tendon drives are inherently difficult to control. Moreover, tendon driven manipulators cannot be easily miniaturized.
Instead of using gears as the driving mechanism other mechanisms such as friction wheels, pulleys and tendons, sprockets and chains, wheels and connecting rods, etc. can be employed to achieve similar articulated motion of the surgical manipulator.
In the AMMIS design presented here, the magnitude of rotation between adjacent linkages were the same and were equal to the magnitude of rotation of the driving gear. This is due to the fact that the gear ratios between adjacent linkages were chosen to be unity. The magnitudes of rotation of adjacent linkages can be made to differ by choosing gears of varying pitch diameter. This can be used for achieving different shapes of articulation.
In the AMMIS design presented here, each linkage has two gears for the transmission of power from the previous link to the next. An addition of an even number of gears to any particular linkage will enable us to change the length of that link and hence the shape of articulation of the manipulator, while maintaining the uniformity in the direction of rotation of every linkage. If an odd number of gears are added to a link, the direction of rotation of the next link is reversed with respect to that particular link. In other words, an AMMIS can be designed to achieve various forms of articulation using different number of gears per link while using only a single driving mechanism.
Though the embodiment of the AMMIS, discussed above, can provide a substantial degree of articulation, it is essentially a single degree-of-freedom mechanism since the different links of the AMMIS cannot be moved independently relative to each other. An AMMIS can be designed with multiple driving mechanisms (actuators) controlling two connected, yet independently controllable portions of the AMMIS, thereby to achieve multiple degrees-of-freedom for more complex articulation. For example, a plurality of intermeshing gears could be provided on a first portion, extending from the proximal end of the first portion to its distal end, thereby to manipulate a second portion connected to the distal end of the first portion. In such an embodiment, the first and second portions together constitute a complex two-actuator AMMIS with two independent actuators.
Various modifications, changes and embodiments are shown and described herein; others will be obvious to those skilled in this art. Accordingly, it is intended that the foregoing be illustrative only and not limiting of the scope of the invention. | A mechanism is described to provide dexterity through articulation. The mechanism includes a plurality of concatenated segments for transferring angular rotational motion from a driving device located at its base to the distal end. Each segment in the mechanism acts as both a driven element and a driving element whereby each segment is articulated so that the total articulation of the mechanism is the sum of the articulation motions of each segment. | 1 |
CROSS REFERENCE TO RELATED APPLICATIONS
This is a continuation of U.S. patent application Ser. No. 09/398,332, filed Sep. 17, 1999, now U.S. Pat. No. 6,517,503, which claims the benefit under 35 U.S.C. §119 (e) of U.S. Provisional Application Serial No. 60/101,084, filed Sep. 18, 1998.
BACKGROUND OF THE INVENTION
This invention relates generally to orthoses for providing assistance in walking. More particularly, the present invention relates to an improved knee joint for such an orthosis.
An orthosis is a brace or other orthopedic device that is applied to a segment of a human body for the purpose of assisting in the restoration or improvement of its function. Orthoses can provide assistance in walking to persons having any of several types of walking disability. One known type of orthosis is a knee/ankle/foot orthosis which controls the motion and alignment of a knee and an ankle when a person attempts to walk. Such orthoses can be made of molded plastic materials or of metal and leather parts. Various knee and ankle joints can be added to achieve the desired function.
Typical reasons for wearing such an orthosis include stroke, brain injuries, spinal cord injury and post-polio treatment. A person who is not able to move his leg in a functional manner to ambulate, must wear a knee/ankle/foot orthosis to stabilize his leg and allow for ambulation. It has been found that for people with weak knee joints, a locking mechanism is necessary in order to lock a calf supporting orthosis to prevent movement in relation to a thigh supporting orthosis, thereby allowing the person to walk, albeit stiff legged.
There are many types of knee joints used on such orthoses. However, all the known joints which lock during ambulation are manual. In other words, when a patient is using the orthosis, he has a choice of walking with his leg locked in extension or in a free swing. If the patient chooses the locked position, he is forced to walk stiff legged. However, for some people, flexing at the knee during walking would result in a buckling of the person's leg. Therefore, walking stiff legged is much preferable to being not able to walk at all. Of course, a movement of the calf orthosis in relation to the thigh orthosis is necessary when the person decides to sit down.
As far as is known, there are no knee joints currently on the market which have the ability to automatically lock and unlock without direct manual patient intervention.
Accordingly, it has been considered desirable to develop a new and improved orthosis knee joint which would overcome the foregoing difficulties and others while providing better and more advantageous overall results.
BRIEF SUMMARY OF THE INVENTION
In accordance with the present invention, there is provided an orthosis for assistance in walking.
More particularly in accordance with this aspect of the invention, the orthosis includes an orthosis system which comprises a foot plate including at least one pressure sensor that senses the pressure exerted by a patient's foot on the foot plate, a circuit connected to at least one pressure sensor in the foot plate and a knee joint which is selectively locked and unlocked by the circuit. To this end, the knee joint is electrically operated.
More particularly mechanical orthotic joint of the selectively lockable orthotic joint invention includes an energizable electromagnetic coil, a spring washer deflectable in an axial direction when the electromagnetic coil is energized and an arrangement of first and second plates. The first plate has a face or an operative surface composed of a plurality of spaced teeth. The second plate also has a face or an operative surface having a plurality of spaced teeth that are complementary to the plurality of spaced teeth of the first plate. The second plate is mounted so that it is deflectable in an axial direction such that the plurality of spaced teeth of the second plate can engage the plurality of spaced teeth of the first plate when the electromagnetic coil is energized. The engagement of the first and second plates locks movement of the orthotic joint in at least one direction when the first and second plates are engaged.
More particularly, the mechanical orthotic joint of the selectively lockable orthotic joint invention includes an energizable electromagnetic coil, a spring washer is deflectable in an axial direction when the electromagnetic coil is energized and an arrangement of first and second plates. The first plate has a face or an operative surface composed of a plurality of spaced teeth. The second plate also has a face or an operative surface having a plurality of spaced teeth that are complementary to the plurality of spaced teeth of the first plate. The second plate is mounted so that it is deflectable in an axial direction such that the plurality of spaced teeth of the second plate can engage the plurality of spaced teeth of the first plate when the electromagnetic coil is energized. The engagement of the first and second plates locks movement of the orthotic joint in at least one direction when the first and second plates are engaged.
In accordance with one embodiment, the first and second plates are complementary and each comprise ratchet plates allowing the orthotic joint to move only in one direction when the joint is in a locked position. More specifically, in one embodiment, when unlocked the orthotic joint is movable in a flexion direction and an extension direction and when the orthotic joint is locked, it is movable only in the extension direction.
The first and second plates may comprise a low hysteresis magnetic material.
In accordance with another aspect of the present invention, a method for selectively locking and unlocking an orthotic joint is provided. One embodiment locks the orthotic joint to permit movement only in the extension direction.
In accordance with the method, an orthotic joint of the type previously described is utilized. Pressure is sensed by the pressure sensor and an electronic control signal is generated with the electronic circuit that is indicative of pressure sensed by the pressure sensor. In response to the electronic control signal, the orthotic joint locks through its locking mechanism.
One advantage of the present invention is the provision of a knee joint which allows patients, who are currently walking stiff legged with a locked knee joint in a knee/ankle/foot orthosis, to walk with a more normal gait.
Another advantage of the present invention is the provision of an orthosis which will make sitting and standing much safer and easier for any patient forced to manually unlock his knee joint.
Still another advantage of the present invention is the provision of an orthosis system which senses the pressure placed by a patient's foot on a foot plate of the orthosis and can automatically trigger a knee joint of the orthosis to lock and unlock. The knee joint will be locked when pressure is placed by the patient's foot on the foot plate. It will be unlocked when the patient's foot no longer exerts pressure on the foot plate.
In accordance with another aspect of the invention, a selectively lockable orthotic joint is provided. The selectively lockable orthotic joint includes an electronic circuit for providing at least one control signal indicative of a value. At least one mechanical orthotic joint is provided that includes a locking mechanism that is in communication with the circuit. The locking mechanism can be selectively locked and unlocked in response to the control signal. The control signal provided by the electronic circuit can originate from a variety of sources other than by sensing pressure or weight. For example, the control signal can originate from EMG signals in leg muscles, from EEG signals, from a sensor that detects distance between the ground and the bottom of a shoe or other article, such as a cane, for example. In addition, a controller could be provided for operation by the user, such as a joy stick or other type of switch in order to generate or otherwise provide the control signal for locking and/or unlocking the locking mechanism of the mechanical orthotic joint.
Still other benefits and advantages of the invention will become apparent to those of average skill in the art upon a reading and understanding of the following detailed specification.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention may take physical form in certain parts and arrangements of parts, a preferred embodiment of which will be described in detail in this specification and illustrated in the accompanying drawings which form a part hereof and wherein:
FIG. 1A is a side elevational view in cross section along line 1 A— 1 A of FIG. 13 of a knee joint according to the present invention in an unlocked condition;
FIG. 1B is a side elevational view in cross section of the knee joint of FIG. 1A in a locked condition;
FIG. 2A is a top plan view of the toroidally shaped housing of the joint of FIG. 1A;
FIG. 2B is a cross-sectional view taken along line 2 B— 2 B of FIG. 2A;
FIG. 3A is a top plan view of a bottom ratchet plate of the knee joint of FIG. 1A;
FIG. 3B is a side elevational view in cross section along line 3 B— 3 B of FIG. 3A;
FIG. 4A is a bottom plan view of a top ratchet plate of the knee joint of FIG. 1A;
FIG. 4B is a side elevational view in cross section along line 4 B— 4 B of FIG. 4A;
FIG. 5A is a top plan view of the top end portion of the knee joint of FIG. 1A;
FIG. 5B is a side elevational view in cross section taken along line 5 B— 5 B of FIG. 5A;
FIG. 6 is a top plan view of an inner retaining ring of the knee joint of FIG. 1A;
FIG. 6A is a cross-sectional view along lines 6 A— 6 A of FIG. 6;
FIG. 7 is a top plan view of the retaining cap of the knee joint of FIG. 1A;
FIG. 7A is a cross-sectional view along line 7 A— 7 A of FIG. 7;
FIG. 8 is a top plan view of an outer retaining ring of the joint of FIG. 1A;
FIG. 9 is a top plan view of a spring washer of the joint of FIG. 1A;
FIG. 10 is an exploded perspective view of components of the knee joint of FIG. 1A;
FIG. 11 is a circuit diagram of a circuit which is employed with the knee joint of FIG. 1 A and the force or pressure sensor of FIG. 12;
FIG. 12 is a perspective view of the force or pressure sensor employed with the joint of FIG. 1A;
FIG. 13 is a perspective view of an orthosis in accordance with the invention incorporating the joint of FIG. 1 A and the sensor of FIG. 12;
FIG. 14 is a fragmentary perspective exploded view of an alternate embodiment joint in accordance with the invention; and
FIG. 15 illustrates a cross-sectional schematic view of a portion of the alternate embodiment of FIG. 14 .
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to the drawings wherein the drawings are for purposes of illustrating a preferred embodiment of the invention only and not for purposes of limiting same, FIGS. 1A and 1B, 10 and 13 , for example, show a knee joint 10 which is used in an orthosis 10 ′ or orthopedic appliance, for example in FIG. 13 . It is evident that two such knee joints would need to be employed for the two legs of a patient, one joint for each leg of the patient. Perhaps, even four knee joints could be used, one on either side of the knee of each leg of the patient. It is to be understood that joint 10 could be used other than as a knee joint, for example.
Joint 10 includes a toroidally shaped housing 12 . Toroidally shaped housing 12 is depicted individually in FIGS. 2A and 2B. With reference now to FIGS. 2A and 2B, the toroidally shaped housing 12 has an inner wali 14 , a base wall 16 and an outer wall 18 which together define a cavity 20 . A plurality of spaced teeth 22 protrude upwardly from the inner wall 14 . Preferably, eight such teeth are provided, although any suitable number of teeth can be utilized. A continuous flange 24 extends upwardly from the outer wall 18 . A rib 26 extends radially inwardly from the inner wall 14 into a central opening 28 to form a toroidal ledge 26 ′ approximately half way up the height of the inner wall.
With reference again to FIGS. 1A and 1B and 10 , an electromagnetic coil 30 is located in cavity 20 . Electromagnetic coil 30 is formed around a plastic bobbin 32 . Positioned on either side of rib 26 are a first bearing 34 and a second bearing 36 . The bearings can be conventional roller bearings or other suitable bearings, as desired. A bottom ratchet plate 38 is also provided for the knee joint. Bottom ratchet plate 38 is depicted in greater detail FIGS. 3A and 3B. Bottom ratchet plate 38 includes a planar bottom surface 40 , as illustrated in FIG. 3B, and a top face 42 having a plurality of radially extending spaced teeth 44 protruding therefrom. As is evident from FIG. 3A, sixty such teeth 44 are preferably located on the top face 42 with each tooth being spaced from the adjacent teeth by slots, although any suitable number of teeth can be utilized. Preferably, the teeth 44 are cut in a saw tooth pattern radially at a 30 degree slope. A set of eight spaced slots 46 are cut into the bottom ratchet plate 38 . The slots extend radially outwardly from a central opening 48 of the plate 38 as is evident from FIG. 3 A.
The joint of FIGS. 1A and 1B is further provided with a top ratchet plate 50 , which is shown in more detail in FIGS. 4A and 4B. Top ratchet plate 50 is preferably constructed of a magnetically soft material, for example a low hysteresis, solenoid quality magnetic stainless steel. Bottom plate 38 may be constructed of similar material. With reference now to FIG. 4A, top ratchet plate 50 includes a top face 52 (FIG. 4B) and a bottom face 54 . A plurality of spaced teeth 56 are cut into the bottom face 54 . Preferably sixty such teeth are provided. As with the bottom plate 38 , the teeth 56 in the top plate are cut in a saw tooth pattern radially at a 30 degree slope such that a tip of each tooth is separated from a tip of each adjacent tooth by 6 degrees. The teeth 56 of the top ratchet plate are meant to be and should be of suitable design and number to engage and mesh with the teeth 44 of bottom ratchet plate 38 when the two ratchet plates are brought into contact with each other. Also provided on top ratchet plate 50 is a slot 58 which circumscribes the teeth 56 . A plurality of spaced apertures 60 ′ extend through top ratchet plate 50 . These apertures are positioned radially outwardly of slot 58 . As is evident from FIGS. 1B and 10, suitable fasteners 60 can extend into the top ratchet plate apertures.
With reference now to FIGS. 1A, 1 B and 10 , a shaft 62 is also provided. As shown in FIGS. 5A and 5B shaft 62 includes a stem portion 64 and an enlarged top end 66 having a set of spaced apertures 68 extending therethrough. Note that in FIGS. 5A and 5 B, the diameter of flange 66 is illustrated smaller than the diameter illustrated in the other figures. A bottom end of the stem portion 64 is provided with a centrally located aperture 70 . Each of these apertures accommodates suitable fasteners 60 and 61 . Referring to FIGS. 1A and 1B, also provided is an inner retaining ring 72 . As detailed in FIG. 6, inner retaining ring 72 has a central aperture 72 ′ for accommodating stem portion 64 and includes a set of apertures 74 extending therein. Each of apertures 74 is also meant to accommodate a suitable fastener 60 . A retaining cap 76 is also provided. As shown in FIGS. 7 and 7A, retaining cap 76 has a centrally extending aperture 78 for accommodating a suitable fastener 61 . Fasteners 60 and 61 can be threaded fasteners or any other suitable type of fastener, for example.
Joint 10 is also provided with an outer retaining ring 80 . As shown in FIG. 8 a set of apertures 82 extend through retaining ring 80 to accommodate suitable fasteners 60 . As shown in FIGS. 1A, 1 B, 9 and 10 , a spring washer 84 is further provided. Spring washer 84 is preferably comprised of a plurality of very thin pieces of metal which, when assembled, is very compliant in an axial direction while maintaining a high rigidity in torsion. For example, spring washer 84 may consist of approximately 60 pieces of 0.001 inch thick stainless steel disks. The axial compliance allows the spring washer to be deflected at relatively low electromagnetic forces allowing the upper ratchet plate to mesh with the lower ratchet plate. Spring washer 84 , further depicted in FIG. 9, has a set of outer apertures 86 for accommodating a suitable first set of fasteners 60 and a set of inner apertures 88 similarly for accommodating a suitable second set of fasteners 60 . Spring washer 84 also has a central opening 90 to accommodate stem portion 64 of shaft 62 .
Spring washer 84 is very compliant in the axial direction, permitting deflection of upper ratchet plate 50 even with relatively low electromagnetic attraction forces, typically deflecting about {fraction (1/16)} th of an inch in an axial direction with an electromagnetic force of several pounds. Thus, the significant axial deflection that is obtained with low electromagnetic forces permits operation of joint 10 at low power consumption levels which is important for battery-operated use. Spring washer 84 , however, is strong and stiff in torsion, providing the necessary reaction torque to support the moments required in an orthotic application. Any suitable washer that performs the function of spring washer 84 can be utilized in accordance with the invention.
As is evident from FIGS. 1A, 1 B and 10 , shaft 62 is located in central opening 28 of toroidally shaped housing 12 . Retaining cap 76 is fastened to shaft 62 by fastener 61 . In this way, two bearings 34 and 36 can be secured in place in central opening 28 of housing 12 . Bottom ratchet plate 38 is seated on inner wall 14 of housing 12 . To this end, several spaced slots 46 in bottom ratchet plate 38 accommodate several spaced teeth 22 in housing 12 . More particularly, eight slots 46 and eight teeth 22 are provided in housing 12 . It is apparent that no keying is necessary since bottom ratchet plate 38 can be rotated in relation to the housing to any desired extent so long as the slots 46 are aligned with teeth 22 .
Top ratchet plate 50 is positioned above bottom ratchet plate 38 . In the condition illustrated in FIG. 1A, top ratchet plate 50 is spaced from bottom ratchet plate 38 . This allows a movement of joint 10 in either rotational direction (flexion or extension). In the position illustrated in FIG. 1B, the teeth of top ratchet plate 50 engage the teeth of bottom ratchet plate 38 to prevent any further rotation of the joint. Preferably, the two ratchet plates are spaced from each other as indicated when in the unactuated state as shown in FIG. 1 A.
With reference again to FIG. 1A, spring washer 84 is fastened to flange 66 of shaft 62 via inner retaining ring 72 . Spring washer 84 is also fastened to top ratchet plate 50 and outer retaining ring 80 by fasteners 60 . In this way, top ratchet plate 50 is normally spring-biased away from bottom ratchet plate 38 . However, top ratchet plate 50 is pulled into contact with bottom ratchet plate 38 when electromagnetic current is flowing through electromagnetic coil 30 .
With reference now to FIG. 11, a circuit 100 which includes an integrated circuit 100 ′, which can be a Microchip Model No. PIC16C715, is employed to control the operation of joint 10 . The integrated circuit is preferably powered by a pair of 3 volt batteries 102 and 104 . Electromagnetic coil 30 is preferably powered by a pair of 1.5 volt batteries 106 and 108 .
With reference now to FIG. 12, an insole pressure or foot force sensor 110 is also used in connection with the joint 10 . More particularly, a set of output lines 112 lead from a set of sensors 114 in the insole to circuit 100 . Batteries 102 and 104 provide a reference signal for the sensors. A pair of output lines 116 ′ from circuit 100 extend to the electromagnetic coil 30 . The pair of 1.5 volt batteries 106 and 108 , which are of relatively higher power than the power of the 3 volt batteries, are meant to power the electromagnetic coil.
Insole pressure sensor 110 is preferably provided with five sensors which detect pressure by a voltage drop across very thin resistors, for example the foot force sensor provided by Cleveland Medical Devices, Inc. It should be apparent to one skilled in the art that more or less sensors may be used. The insole is slipped inside a patient's shoe. The signal from the insole is translated through wires 112 to circuit 100 . Integrated circuit 100 ′ also contains a programmable microprocessor. Any suitable microprocessor can be utilized. The processor determines a threshold level and sends a signal to the joint 10 attached to a knee joint as depicted in FIG. 13 . However, the joint need not be limited to a knee joint, but may also be an ankle, wrist or elbow joint. Any suitable pressure or force sensor can be used in accordance with the invention.
With the orthosis of the present invention, when a person puts his foot on the floor, the sensors 114 in insole sensor 110 sense a pressure and can trigger the joint 10 to lock by energizing electromagnetic coil 30 thereby bringing the top ratchet plate 50 down into contact with bottom ratchet plate 38 engaging respective teeth 56 and 44 . Preferably, this action prevents any further rotation of the joint in one rotational direction, however, this may lock the joint entirely from rotating. More particularly, top ratchet plate 50 and shaft 62 cannot rotate via bearings 34 and 36 in relation to bottom ratchet plate 38 and housing 12 toward a bent knee position. Preferably, when the teeth of the upper and lower ratchet plates are engaged, the joint allows incremental slip (ratcheting) in a joint extension. However, when no more pressure is sensed by sensors 114 of the insole sensor 110 , circuit 100 will unlock the knee joint by ceasing the flow of electric current in the electromagnetic coil.
Once this occurs, spring washer 84 will pull top ratchet plate 50 out of engagement with bottom ratchet plate 38 . This will allow a rotation of the knee joint in both directions. In particular, top ratchet plate 50 and shaft 62 are again capable of rotating in relation to bottom ratchet plate 38 and housing 12 . Thus, the joint is unlocked when pressure of the patient's foot is no longer exerted on the insole sensor 110 . This invention will allow a user who is currently wearing stiff legged knee/ankle/foot orthoses to walk with a more normal gait. In addition, it will make sitting and standing safer and easier for any user currently forced to manually unlock their knee joint.
When a threshold level is reached, a magnetic field is generated by electromagnetic coil 30 to pull top ratchet plate 50 into engagement with bottom ratchet plate 38 , no longer allowing the two ratchet plates to rotate freely in relation to each other. This locks the knee joint and prevents it from bending into flexion. However, the joint will still allow extension. As an example, if the patient is attempting to stand and gets stuck halfway up, the joint will block flexion and prevent the patient's knee from buckling. But, it will still ratchet into extension and allow the patient to continue moving vertically. Thus, a very important advantage of the present invention is the provision of a knee joint in which flexion is prevented when the top ratchet plate 50 meshes with bottom ratchet plate 38 but extension is still allowed. This is accomplished due to the orientation of the meshing teeth 44 and 56 of the bottom and top ratchet plates 38 and 50 .
As a second example, a user, when he takes a step, will have the insole read the floor contact and lock the knee for the user. The knee remains locked through the step and then unlocks when the user initiates swing through, i.e. takes the pressure off the first leg and puts the pressure on the second leg. The knee joint will then lock again at the next initial floor contact.
Sensors 114 could be wired in series or in parallel for the signal which is sent through wires 112 to circuit 100 . Preferably, the output of all of sensors 114 is summed together. If a set point is reached, electromagnetic coil 30 is triggered and the knee joint is locked. However, the logic of the chip on the integrated circuit could be programmed to differentiate between, e.g. a heel strike and a toe strike of the foot plate. The logic of the circuit may also provide that given patterns of pressure, for example placing pressure on only inner or outer pressure sensors, detected by the sensors could disengage the teeth in the joint permitting an individual to sit.
Joint 10 according to the present invention can be attached to any conventional knee/ankle/foot/elbow/wrist orthosis or any knee brace as long as the brace is fabricated to the joint size specification. A person skilled in the art should realize that the orthotic joint of the present invention supports passive locking arrangements wherein the joint is locked until the coil is magnetized which unlocks the joint as opposed to the active locking embodiment of the joint as described above.
FIGS. 14 and 15 illustrate an alternate embodiment of an electronically controlled orthotic joint according to the present invention. This embodiment as shown in FIGS. 14 and 15 provides an electromagnetic coil 118 located within a housing 120 . Actuating portion 122 is provided as well as opposing teeth inserts 124 and 126 . Engagement of the teeth inserts 124 and 126 is actuated by energizing coil 118 . The coil is energized under control of a microprocessor (not shown) as in the above embodiment. Energizing the coil produces an axial force on actuating portion 122 which forces teeth insert 124 into engagement with teeth insert 126 . In this embodiment, a passive spring (not shown) causes the teeth of teeth inserts 124 and 126 to disengage upon interruption of current through coil 118 . This embodiment can also provide for incremental slip in a single rotational direction as desired. Further, teeth inserts 124 and 126 are constructed of non-magnetic material so that they may be made of a more durable material, for example tool steel. This embodiment also provides a spline interface (not shown) between outer support ring 130 and actuating element 122 . This spline interface is on the internal surface of outer support ring 130 and the external surface of actuating element 122 . This spline interface permits axial translation of actuating element 122 while enabling large torques to be transmitted from outer support ring 130 to actuating element 122 . This arrangement permits application of large torques from outer support ring 130 to the opposite outer support ring 128 as follows. Torques are transmitted from element 130 to element 122 via the spline interface. Torques are thus transmitted from actuator element 122 to teeth insert 124 , which is fastened rigidly to element 122 . When engaged due to actuation (axial translation of element 122 ), teeth insert 124 meshes with teeth insert 126 enabling transmission of torques that oppose knee flexion. Teeth insert 126 , rigidly fastened to housing 120 , transmits torques to housing 120 via its fasteners. Finally, housing 120 , which is rigidly fastened to outer support ring 128 , transmits torque to outer support ring 128 via fasteners (not shown). In this manner, torques can be transmitted from support arm 132 of outer support ring 130 to support arm 134 of the opposite outer support ring 128 . Support arms 132 and 134 provide a convenient structure to mechanically interface the locking mechanism to orthotic bracing. One skilled in the art should recognize that an equal and opposite torque is transmitted to outer support ring 128 and support arm 134 in a similar manner.
FIG. 14 depicts how joint 117 is integrated into an orthotic device. Outer support rings 128 and 130 house joint 117 . As shown in FIG. 14, joint 117 is comprised of an electromagnetic coil 118 , housing 120 , actuating portion 122 , and teeth inserts 124 and 126 . The outer support rings are constructed of non-magnetic metallic material. Outer support ring 130 has an attached support arm 132 which attaches to a limb portion of a patient. Similarly, outer support ring 128 has a support arm 134 that attaches to the same limb portion of a patient as support arm 132 , but joint 117 is aligned with the patient's joint which is to be supported.
While the invention has been described with respect to certain preferred embodiments, as will be appreciated by those skilled in the art, it is to be understood that the invention is capable of numerous changes, modifications and alterations that are within the scope of the appended claims. | A selectively lockable orthotic joint is provided that in one embodiment includes at least one pressure sensor and an electronic circuit associated with the pressure sensor for generating or providing a control signal indicative of pressure, force or other value sensed by the sensor. A mechanical orthotic joint is provided that has a locking mechanism that can be selectively locked and unlocked in response to the control signal. | 0 |
BACKGROUND OF THE INVENTION
The present invention is related to an apparatus and method for storing an ice slurry of an aqueous liquid of a fruit such as orange juice, grapefruit juice, pineapple juice, grape juice, apple juice and the like for subsequent use or reconstitution.
It is often the case that aqueous beverages must be stored under stabilized conditions in large quantities after preparation and prior to distribution to consumers. For instance, fruit juices such as orange, grapefruit, pineapple, grape and apple juice are pasteurized in order to deactivate enzymes and kill microorganisms, and stored under refrigerated conditions in order to retard temperature induced flavor changes and to control the presence of microorganisms. Juices may also be deaerated in order to control oxidation and accompanying degradation.
At present, it is a common practice that aqueous beverages such as orange juice which must be kept cold or frozen in order to avoid rapid deterioration and/or growth of microorganisms are stored in drums (e.g., 55 gallons), bags or in frozen blocks following their preparation and prior to packaging for distribution to consumers. The juice stored in this manner requires labor intensive systems for filling, storing and retrieving the juice. Furthermore, the cost of packaging material can add significantly to the selling price of the juice. Exposure during the retrieval process may cause loss of juice or flavor qualities and provides opportunities for contamination or adulturation. Open block storage of juices can have the disadvantage of losing water vapor and may leak concentrate during storage.
Other systems for storing ice slurries are known for purposes other than the storage of beverages. For instance, ice slurries have been used for cooling purposes such as in air-conditioning systems of commercial buildings. Such systems may operate by feeding water through a heat exchanger to convert part of the water to ice, feeding the resulting ice slurry to a storage tank, removing cold aqueous liquid from the storage tank and feeding it through a heat exchanger in order to cool a second fluid which is to be used for cooling purposes The now warm aqueous liquid is returned to the storage tank and is cooled by contact with the ice that is stored therein.
U.S Pat. No. 4,584,843 (Pronger, Jr. et al.) relates to a method and apparatus for storing an ice slurry for cooling purposes such as in air-conditioning systems of commercial buildings, which is said to increase storage capacity. Aqueous liquid is removed from storage tank (preferably from the lower part of the tank) and fed through a heat exchanger to convert at least part of the aqueous liquid to ice crystals. The resulting slurry is then fed to a distribution conduit system located in the upper part of the storage tank, where it flows through a plurality of nozzles and descends uniformly. The ice crystals are evenly deposited as a bed of ice with a horizontal surface. Cold aqueous liquid is then removed from the lower part of the storage tank and fed through a heat exchanger in indirect heat exchange with a fluid to be cooled for cooling purposes. The now warm aqueous liquid is then returned to the storage tank, where it is cooled via downward trikling through the ice therein.
U.S. Pat. No. 4,509,344 (Ludwigsen et al.), U.S. Pat. No. 4,596,120 (Knodel et al.), and U.S. Pat. No. 4,254,635 (Simon et al.) relate to other cooling systems.
While such cooling systems are applicable to some commercial cooling applications, there has been no disclosure or suggestion that they would be applicable to the storage of fruit juice type beverages. Moreover, such processes would not be effective for the storage of fruit juice beverages which must be kept at low temperatures because they expose the stored liquid to warm temperatures. Aqueous beverages including fruit juices such as orange juice and the like cannot be warmed to any appreciable degree due to stability and contamination concerns.
Ice slurries have also been prepared for the purpose of producing an ice slush. For example, U.S. Pat. No. 4,750,336 (Margen) relates to an ice slush apparatus for producing ice slush which is said to prevent ice build-up. An aqueous liquid is passed through a conduit having cooled walls in which ice particles can form. In order to prevent ice build-up on the conduit walls, a helical path is provided which causes the aqueous liquid to contact the cooled walls. The ice particles are drawn to the center of the helical flow due to their lower density while the heavier liquid portion moves toward the walls due to gravitational forces generated. However, this system is not designed for storing large quantities of liquids.
U.S. Pat. No. 4,096,709 (Barthel) relates to a rupture-preventing air-releasing water-freezing reservoir. To prevent rupture caused by the expansion of water upon freezing and at the same time release the warmer air after producing the freezing of water into ice, the reservoir is surrounded by duplex wall structure of insulating material such as styrofoam in the form of slabs spaced inward from the tank wall by compression springs. The air escapes through the interstices between the styrofoam after expending its freezing effect upon the body of water inside the inner styrofoam wall. The water located between the slabs is prevented from freezing by the insulating effect of the styrofoam. This system is not practical for use in storing large quantities of aqueous liquids.
It is therefore an advantage of the present invention to provide a method and apparatus for storing an ice slurry of an aqueous fruit juice while substantially reducing the chances of rupturing the storage tank.
It is another advantage of the present invention to provide a method and apparatus for storing an ice slurry of an aqueous fruit juice such as orange, grapefruit, pineapple, grape, apple and the like which allows for the release of pressure build-up within the ice storage tank caused by expansion of the liquid during ice formation.
It is also an advantage of the present invention to provide a method and apparatus for the efficient storage of large quantities of an aqueous fruit juice in an ice slurry state.
It is a further advantage of the present invention to provide a method and apparatus for storing an ice slurry of a fruit juice type beverage in a manner which maintains a substantially stable environment.
It is yet another advantage of the present invention to provide a method and apparatus for storing a slurry of a heat labile fruit juice type beverage in large quantities under a commercially sterile or aseptic conditions while allowing for a melt down of the slurry substantially without leaving any ice while maintaining a temperature at which microorganism growth does not affect the stability of the beverage.
SUMMARY OF THE INVENTION
In accordance with the above-mentioned objectives and others, the present invention relates to an apparatus in the form of a storage tank for storing an aqueous liquid in an ice slurry state. Due to the lower density of ice as compared to liquid, the ice slurry is progressively more ice-free toward the bottom of the storage tank such that a layer of ice or ice slurry floats on a layer of liquid. A transferring means is provided for removing the liquid from the bottom of the storage tank to the top of the tank. A communicating means located within the tank has an opening above the layer of ice and receives the liquid from the transferring means and returns it to the ice slurry at a point below the ice cap without the liquid substantially contacting the layer of ice. Preferably, the communicating means is centrally located within the storage tank. It is preferred that the apparatus further comprise temperature controlling means for controlling the temperature of the transferring means such that ice does not begin to grow therein and thereby clog or plug the transferring means. Preferably, the temperature of the ice slurry flowing through the transferring means is maintained at or just above the freezing point of the aqueous liquid.
Excessive pressure build-up in the storage tank caused by the formation of ice under an ice cap is prevented by the circulation of the relatively ice-free liquid.
The present invention is also related to a method for storing an aqueous liquid in an ice slurry state which comprises introducing an ice slurry of an aqueous liquid into a storage tank and maintaining the temperature of the ice slurry such that a layer of ice floats on a layer of mother liquid, withdrawing liquid from the bottom of the storage tank and feeding it to the top of the tank at a rate faster than the rate of ice floatation within the communicating means, and transferring the liquid below the layer of ice substantially without the liquid contacting the layer of ice, thus keeping the ice particles well dispersed.
When it is desired to empty the storage tank, the ice slurry is substantially converted back to the liquid state. This is accomplished by a thawing step in which the transferring means and walls of the storage tank are warmed in order to raise the temperature of aqueous liquid. The thawing step preferably also comprises directing a portion of the warmed aqueous liquid from the transferring means onto the upper surface of the ice cap to increase the thawing rate.
After the ice slurry has been sufficiently warmed such that substantially all of the ice has melted and the aqueous liquid has been substantially returned to its original state, the aqueous liquid may be withdrawn from the storage tank. Thereafter, the aqueous liquid may undergo further processing and packaging.
In one embodiment of the present invention, the aqueous liquid is a fruit juice such as orange juice, grapefruit juice, pineapple juice, grape juice, apple juice, or the like. Preferably, the fruit juice which is to be stored includes orange juice, grapefruit juice, and the like. For practical purposes, it is preferred that the juice to be stored has previously been pasteurized and that the system be keep as near asepsis as possible. It is with this in mind that the present apparatus has been designed such that it is easy to clean.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a cross-sectional view of an apparatus in accordance with the present invention.
DETAILED DESCRIPTION
When an aqueous beverage is stored in an ice slurry state in a container, whether it be a drum, a storage tank, etc., a layer of ice (i.e., an ice cap) forms at the upper surface of the slurry. This is in part due to the fact that ice tends to float to the top of the slurry because it is less dense than the aqueous mother liquid. At the same time, the ice slurry in the lower part of the tank becomes relatively ice free. As this occurs, the freezing point of the mother liquid decreases. When the walls of the tank are cooled, the slurry along the walls is colder relative to the slurry in the center of the tank, and the portion of the ice cap which is in proximity to the side walls tends to be more solid relative to the center of the tank.
As the ice cap progressively becomes thicker and more rigid, it begins to resist further upward movement. Formation of additional ice below the ice cap exerts increasingly greater pressure against the liquid which is trapped below the ice cap and within the confines of the container walls. This in turn causes the liquid to exert greater pressure against the container. Eventually, the pressure builds up to such a level that the walls of an economically designed container become susceptible to deformation and possible rupture. By "economically designed" it is meant that the tank may be filled to capacity without providing for the hazards of ice formation.
The present invention is based in part on the known principle that by transferring ice slurry from the bottom of the container to the top of the container at a rate faster than the rate of ice floatation, the freezing of the slurry into a solid ice cap will not occur. Sufficient agitation or pumping of an entire tank would be expensive and virtually impossible at ice percentages needed for long term storage. The present invention takes advantage of this known principle without the penalty of stirring the entire tank.
The aqueous liquid which is to be stored may be introduced into the storage tank in an ice slurry state, or may be introduced as a liquid and cooled to an ice slurry state within the storage tank. The quantity of liquid which is pumped into the storage tank is monitored and controlled by a metering device, a gauge, or the like.
The capacity of the storage tank is dependent upon the percentage of ice desired in the ice slurry. Expansion of the ice slurry due to ice formation should be considered when making this determination. As a practical limit, the storage tank may be filled to about 80% capacity when an ice-free liquid juice is introduced and it is desired that 70% ice slurry is to be stored.
Preferably, the liquid is fed into the storage tank at a temperature in proximity to its freezing point. After a sufficient level of liquid is fed into the tank, some of the liquid is circulated through a heat exchanger until an ice slurry containing the desired percentage of ice is obtained. The heat exchanger used may be any device known in the art, such as a scraped surface heat exchanger. It is preferred that the ice slurry be made external to the storage tank because the slurry can be formed more rapidly. Another less efficient but acceptable manner to prepare an ice slurry would be to cool the walls of the storage tank to suitable a temperature below the freezing point of the liquid to be stored.
The storage tank has a top, a bottom and side walls. On the side walls one can define an upper part of the tank above the ice slurry level and a lower part of the tank below the ice cap. The storage tank is preferably maintained in a cold environment, at a temperature below the freezing point of the liquid to be stored. The cold environment may be accomplished by any means known in the art, such as by placing the storage tank in an enclosure or "cold room" which is kept at a predetermined temperature. It is also possible to accomplish this by maintaining the storage tank in a cold environment using a jacket or coil-wrapping the tank with a heat exchanger, or by providing internal coils for heat exchange purposes.
The circulation of liquid from the bottom of the tank to the top of the tank is accomplished via an opening located in the lower part of the storage tank through which the slurry flows into a transferring means, such as a pipe assembly. A pump is preferably used to draw the liquid from the bottom of the tank into the pipe assembly. The flow of the liquid is directed via the pipe assembly to the top of the tank. The opening for removing the liquid may be located anywhere below the ice cap, although it is preferable that the opening be located in the bottom of the storage tank. Likewise, the transferring means may return the liquid to the tank at any point above the ice cap. However, it is preferable that the transferring means return the liquid in proximity of the top of the storage tank so that a vent can always be provided above the ice cap.
The liquid is in turn transferred from the transferring means to a communicating means such as a tube without substantially contacting the layer of ice in the upper part of the tank. The communicating means returns the necessary quantity of liquid that is required to replace that which is withdrawn to the lower part of the storage tank. The upper portion of the communicating means acts as a vent so that any excess liquid is allowed to spill out through the vent onto the ice cap.
In order to control pressure build-up due to the formation of ice below the ice cap, the liquid in the lower part of the storage tank is pumped out of the opening vented in the top headspace and drained back to the lower part of the tank at a rate faster than the rate of ice floatation.
By continuously circulating the liquid through the communicating means (in a downward direction) at a rate faster than the rate of ice floatation, the freezing of the liquid within the communicating means and the plugging of the same is prevented. The rate at which the liquid is circulated is determined by the cross-sectional area of the communicating means and flow characteristics of the liquid being stored, and can be adjusted to suit the particular needs of the system at any given time.
If the rate of pumping is insufficient to relieve the pressure build-up in the lower part of the tank, or the pump fails altogether, the liquid may also flow upward through the communicating means and spill out through the vent onto the top of the ice cap, thereby relieving pressure.
In a preferred embodiment of the present invention, the liquid juice to be stored is single strength orange juice having a Brix from about 7° to about 15°, and most preferably from about 10° to about 13°. Single strength orange juice having such a Brix has a freezing point of about 28° F. In order to preserve the flavor and other qualities of the orange juice, the temperature of the juice should not be allowed to rise over about 35° F. It is preferred to store the juice in as stable and aseptic condition as possible. Therefore, it is preferred that the juice which is to be stored in the storage tank be pasteurized. Pasteurization temperatures should be high enough to deactivate enzymes such as pectinase and kill deleterious microorganisms. It is also preferred that the juice be deaerated in order to reduce oxidation of the juice.
Referring to FIG. 1, a storage tank 1 is shown containing an ice slurry A. The storage tank 1 has side walls comprising an upper part 1a and a lower part 1b. As ice builds up in the storage tank 1, an ice cap Aa is formed on the upper surface of the slurry A. If the ice cap Aa becomes too thick, it may cling to the sides of the tank and trap the ice forming liquid below which would exert increasing amounts of pressure against the same.
An opening 2 is located in the lower portion 1b, and preferably near the bottom 1d, of the storage tank 1. Pump 3 pulls liquid out through opening 2 in the bottom 1d of the storage tank 1. The liquid is directed to the upper portion 1a and preferably to the top of 1c of the storage tank 1 via a pipe assembly 7. Instead of being allowed to contact the ice cap Aa or ice slurry located in the upper part 1a of the storage tank, the liquid is directed into the upper opening 10a of a substantially vertically oriented communicating tube 10 which is located within the storage tank. Communicating tube 10 has openings which serve as a communication means between the upper and lower parts of the storage tank 1. The upper opening 10a of the communicating tube 10 is above the upper surface of the ice cap Aa, while the lower opening 10b of the communicating tube 10 is located below the ice cap in the lower portion 1b of the tank 1. The liquid which flows through vertical tube 10 thus returns to the lower portion 1b of the tank 1. The communicating tube 10 thus provides a vent in part as a vertical liquid column through the ice cap functioning as a means of relieving pressure at critical times such as when ice is being formed.
The temperature of the liquid being transported through the pipe assembly 7 is controlled in order to prevent freezing of the slurry within the same and in the communicating tube 10. At the same time, the temperature of the liquid being transported through the pipe assembly 7 should not be raised to such a level that the liquid is warmed to an undesirable level, e.g., such that the liquid within the storage tank is warmed to a significant degree. The temperature is controlled by any means known in the art. In FIG. 1, glycol tracer lines 12 having inlets 12a and outlets 12b and 12c are shown which run along the pipe assembly 7. The temperature of the glycol tracer lines 12 are supplied by a heat exchanger system (not shown).
In the preferred embodiment the liquid pumped through the scraped surface heat exchanger is exposed to a temperature substantially below the freezing point of the liquid. Thus an ice containing slurry is formed and returned to the tank where the ice crystals separate naturally. The circulation of the liquid in this manner is preferably continued until the percentage of ice in the stored liquid reaches a predetermined level. Once the desired ice percentage is achieved, the freezing system may be turned off.
Any excess pressure build-up in the system caused by ice formation is vented by the above-mentioned circulation of liquid through pump 3 or in case of pump failure through the communicating tube. Pressure build-up alone will force liquid to vent out through the vent at 10a. Accordingly, it may not be necessary to cause the circulation of liquid once an equilibrium is established.
The possibility of deformation of the tank and/or rupture is significantly decreased by the above-mentioned circulation of the liquid. As a result, higher percentage of ice can be stored in the storage tank with a substantially decreased risk of deformation and/or rupture.
The present invention also provides a means for thawing the ice slurry when it is desired to empty the tank. At such time, the temperature of the glycol tracer line 12 is raised to a predetermined level effective to melt ice particles and warm the liquid circulating through the pipe assembly 7. The predetermined temperature must be chosen with regard to the particular characteristics of the stored aqueous liquid. For example, when storing aqueous liquids such as citrus juices, the glycol tracer lines 12 are brought to a maximum usable temperature which is slightly above the freezing point of the particular citrus juice. This is done to preserve the stability and flavor of the juice. During thawing it is preferred that heat be applied to the side walls of the storage tank 1. This has the effect of releasing the attached ice cap Aa from the side walls of the storage tank 1. Only a small gap of liquid (approximately 1/16 inch) is needed between to separate the ice cap from the interior side walls of the tank before the ice cap is released.
Heat may be applied to the storage tank 1 by any method which will release the ice cap Aa from the side walls. In a preferred embodiment, this is accomplished by blowing warm air (via a fan) against the tank at a temperature slightly above the freezing point of the juice. For example, when the storage tank holds approximately 140,000 gallons, it is preferred that air slightly above the freezing point of the juice is blown against the walls of the tank at from about 800 to about 12000 cubic feet per minute (cpm), and most preferably at about 1000 cpm. By also applying heat to the outside of the tank, the ice cap will become free to float about the upper surface Aa of the slurry. In another embodiment, coils which are installed in the side walls of tank are used to supply heat.
Heating the side walls of the storage tank is advantageous because it prevents the ice cap from clinging to the side walls of the tank as when some of liquid below the ice cap is withdrawn. If the tank wall is not warmed and some of the liquid below the ice cap is removed, it is possible that a sudden increase in fluid pressure caused by the impact of the ice cap when it does release will damage and/or rupture the storage tank.
The thawing of the storage tank continues until the average temperature of the juice is approximately the same as it was prior to freezing. In practice, the thawing of the storage tank begins several days prior to removing the contents in the case of large commercial installations. In the case of a citrus juice, the temperature of the liquid preferably should not rise to more than about 1-2 degrees above the ice formation-equilibrium temperature of the stored juice, to minimize the possible growth of microorganisms and to preserve the juice flavor.
In a preferred embodiment, during thawing a substantial flow of juice through the pipe assembly 7a spills over the outer edge of the communicating tube 10 and onto the ice cap Aa. The desired flow is determined by the amount of juice to be thawed and temperature to which the product can be safely raised. By directing the relatively warmer liquid onto the ice cap, this thawing process is enhanced.
In one embodiment, the communicating tube 10 includes a vertical mixer 20 which shaves from the floating ice cap when it comes into contact with the vertical mixer blade. This permits even faster melting by the inclusion of the shavings in the warmed slurry.
The apparatus may also include agitation means located in proximity to the bottom of the storage tank for agitating the thawed liquid juice to achieve a uniform mixture prior to draining the storage tank. This is especially preferred when the juice has a significant amount of pulp or other suspended material, as in the case of orange juice.
Referring to FIG. 1, an agitator 9 is provided in the lower portion 1b of the storage tank 1. Once the stored slurry has been sufficiently thawed, agitator 9 is turned on in order to stir the now-liquid product into a uniform mixture. The agitation of the liquid juice will also serve to provide a more uniform temperature.
The storage tank 1 is then drained via outlet 17 to a receiving system where the juice undergoes further processing and packaging. It is preferred that pump 3 and vertical mixer 20 (if installed), run continually while emptying the storage tank, so that part of the flow of the liquid goes through the pipe system 7 until the tank is substantially empty.
The storage tank used in the present invention may be any size; however, it is envisioned that the present invention is suitable for tanks having a capacity from about 10,000 gallons to about 500,000 gallons or more.
For example, when an ice slurry of a single strength orange juice of about 12° Brix and having a freezing point of about 28° F. is to be stored, the storage tank 1 is preferably maintained at a temperature from about 5° F. to about 17° F. during storage of the orange juice. This may be accomplished by placing the storage tank 1 inside a cold room 23. At such a temperature, the orange juice will be stored at about a 70% ice slurry.
As previously explained, the temperature of the glycol tracer line 12 should be controlled in order to prevent the possibility of freeze-up of the juice within the pipe assembly 7. Accordingly, in the present example, the glycol tracer line 12 is adjusted to keep the temperature of the pipe assembly 7 from about 18° F. to about 30° F. and most preferably at about 18° F.±2° during storage. This is because the concentrated orange juice from the bottom of the storage tank 1 in the present example which is withdrawn and pumped through pipe assembly 7 will have a Brix of about 42° and a freezing point of about 18° F. It is also preferred that an enclosure 22 which is kept at about 28° F. surround the pump 3 and the base of the storage tank 1 in order to prevent freezing of the piping and pumps.
During the thawing of the single strength orange juice, it is preferred that the temperature of the glycol tracer line 12 be raised to about 29°-30° F. and that the side walls of the storage tank be warmed with air at a temperature of about 32° F. The interior of enclosure 22 should still be kept at about 28° F. The thawing step should continue until the temperature of the thawed single strength orange juice in the storage tank is from about 29° F. to about 30° F.
In another prepared embodiment of the present invention, the orange juice which is to be stored is concentrated. The temperatures related above with reference to single strength orange juice will be adjusted downward in reflection of the higher solids content and lower freezing point of the concentrate. The amount of temperature adjustment depends upon the particular concentration of the juice chosen, and is readily deducible to those skilled in the art. For example, orange juice concentrated to 42° Brix has an initial freezing point of about 18° F. Orange juice concentrated to 42° Brix should be stored in an ice storage tank kept in an environment at a temperature of about 10° F. When the tank is to be emptied, the temperature of the tank should be raised to about 18° F. The temperature of the glycol tracer line should once again be controlled to prevent the possibility of freeze-up in the pipe assembly 7.
The examples provided above are not meant to be exclusive. Such variations of the present invention as would be obvious to those skilled in the art are contemplated to be within the scope of the appended claims. | A method and apparatus for storing an ice slurry of a aqueous liquid is disclosed. A storage tank contains an ice slurry which is in the form of a layer of ice (i.e., an ice cap) floating on liquid. Liquid is pumped out from the lower part of the storage tank and fed to the top of the storage tank. The liquid which is fed to the top of the ice storage tank is returned to the lower part of the tank substantially without contacting the layer of ice contained therein via a vertically oriented tube. By pumping the liquid out of the lower part of the storage tank and recirculating it, pressure build-up due to the ice cap is controlled. In one embodiment, the liquid to be stored is a fruit juice such as orange juice, grapefruit juice, pineapple juice, grape juice, apple juice, or the like. | 1 |
FIELD OF THE INVENTION
[0001] The present invention relates to methods for producing neural cells that express tyrosine hydroxylase and compositions relating to the same.
BACKGROUND OF THE INVENTION
[0002] CNS disorders include, for example, disease states of the CNS, dysfunction of the CNS and acute injuries to the CNS. Alzheimer's disease, Parkinson's disease, depression, epilepsy, schizophrenia, and brain injury, for example, may all be termed CNS disorders. As may be appreciated, any improvement in the treatment of CNS disorders is highly desirable.
[0003] In that respect, developing dopaminergic neurons originating from aborted human embryos have previously been implanted in the brains of patients with Parkinson's disease and have successfully restored function (Bjorklund, Novartis Found Symp 2000; 231: 7-15). A method of treating CNS disorders with implanted neurons is, therefore, a promising approach to the treatment of CNS disorders. However, the logistical and ethical problems associated with preparing sufficient numbers of well-characterized fetal cells for the large number of individuals that need such treatment make this therapeutic approach unrealistic. This limitation of fetal cells might be circumvented, however, by the identification of a specific neural cell line capable of being expanded in vitro for cell banking. Such a cell line should be able to differentiate into cells with a neuronal phenotype similar to the nigral dopaminergic neurons. Furthermore, the cells should be able to survive, maintain their dopaminergic phenotype, and function following transplantation and integration into the striatum. With respect to grafting such cells into a mammal in need of such treatment, such techniques are well known to one of skill in the art (for example, U.S. Pat. Nos. 5,082,670 and 5,762,926, both hereby incorporated by reference).
[0004] Continuously dividing multipotent cultures of human neural progenitor cells derived from embryonic forebrain tissue remain viable in vitro for at least 35 passages or more than 350 days (Carpenter, Exp Neurol. 1999 August; 158(2): 265-78.). Under serum-free conditions in the presence of epidermal growth factor (EGF), basic fibroblast growth factor (bFGF) and leukaemia inhibitory factor (LIF), these cultures grow as non-adherent clusters (“neurospheres”). When plated on a substrate in medium without mitogens, the cells in the culture differentiate and have the ability to generate the major phenotypes in the CNS (i.e., neurons, astrocytes and oligodendrocytes). The majority of the neurons formed under these conditions, however, are immunoreactive for gamma-amino butyric acid (GABA). Only rarely are neuronal cells expressing tyrosine hydroxylase (TH) observed (Svendsen, Exp Neurol 1997 November; 148(1): 135-46, Carpenter, 1999). TH expression is important because TH catalyzes the rate-limiting step in the biosynthesis of dopamine. Specifically, TH utilizes tyrosine, molecular oxygen and tetrahydrobiopterin as co-substrates in the formation of 3,4-dihydroxyphenylalanine (DOPA). Aromatic amino acid decarboxylase (AADC) then converts DOPA to dopamine (DA). In noradrenergic cells, dopamine is converted to norepinephrine by the enzyme dopamine-β-hydroxylase (DBH). Thus, cells producing dopamine and norepinephrine are both characterized by the expression of TH (and AADC). In contrast, adrenergic cells specifically express DBH, which is not expressed in dopaminergic cells.
[0005] It is therefore of great interest to develop methods which not only allow the differentiation of neural progenitor cells in vitro, but do so in such a way that maximizes the percentage of neuronal cells which express TH. U.S. Pat. No. 5,851,832 (hereby incorporated by reference) describes the in vitro growth and proliferation of multipotent neural stem cells and their progeny. However, as compared with the techniques described herein, the methods described therein do not result in a population of neural cells wherein a significant percentage of the cells are TH expressing neurons. U.S. Pat. No. 5,980,885 (hereby incorporated by reference) describes the growth factor induced proliferation of neural precursor cells in vivo. However, the methods described therein are not directed towards the in vitro proliferation of neurons and, as compared with the techniques described herein, do not result in a population of neural cells wherein a significant percentage of the cells are TH expressing neurons. U.S. Pat. No. 5,981,165 (hereby incorporated by reference) describes the in vitro induction of dopaminergic cells. However, as compared with the techniques described herein, the methods described therein do not result in a population of neural cells wherein a significant percentage of the cells are TH expressing neurons. U.S. Pat. No. 5,968,829 and the related U.S. Pat. No. 6,103,530 (both hereby incorporated by reference) describe the use of Leukemia Inhibitory Factor in order to increase the rate of stem cell proliferation or neuronal differentiation. However, as compared with the techniques described herein, the methods described therein do not result in a population of neural cells wherein a significant percentage of the cells are TH expressing neurons. Similarly, U.S. Pat. Nos. 6,040,180, 6,251,669, and 6,277,820 (all incorporated by reference herein) describe methods and uses for neuronal progenitor cells or CNS stem cells. However, as compared with the techniques described herein, the methods described therein do not result in a population of neural cells wherein a significant percentage of the cells are TH expressing neurons. U.S. Pat. No. 6,312,949 describes cells comprising an exogenous nucleic acid Nurr1 that induces TH enzyme synthesis within a cell. However, the methods disclosed therein are directed to elevated TH expression within an individual cell and are distinguished from the methods described herein.
[0006] Thus, a need remains in the art for a solution to the known logistical and ethical problems of efficiently preparing sufficient numbers of well-characterized dopaminergic cells. A possible solution would be the identification of a method for producing a specific neural cell line expandable in vitro for cell banking. Such a cell line should be able to efficiently differentiate into cells with a neuronal phenotype similar to the nigral dopaminergic neurons. Furthermore, the cells should be able to survive, maintain their dopaminergic phenotype and function following transplantation and integration into the striatum.
SUMMARY OF THE INVENTION
[0007] The invention provides a method for the in vitro production of a population of neural cells wherein a significant percentage of those cells express tyrosine hydroxylase (TH). In that respect, the invention provides a method for the in vitro production of neural cells expressing TH. The method comprises expanding neural progenitor cells using growth factors and/or by immortalization, plating the cells on a substrate, introducing a defined culture medium containing one or more growth factors belonging to the FGF family, a molecule which gives rise to an increase in intracellular cyclic AMP (cAMP), and an agent stimulating or capable of activating protein kinase C (PKC). The method provides TH expressing cells in significant numbers, similar to that observed in fetal ventral mesencephalon cultures (5-20%). It also provides cells in which the expression of TH is stable after removal of the induction medium. The invention provides a means for generating large numbers of TH expressing neural cells for neurotransplantation into a host in the treatment of CNS disorders, for example, neurodegenerative disease, neurological trauma, stroke, other neurodegenerative diseases, neurological trauma, stroke, and other diseases of the nervous system involving loss of neural cells, particularly Parkinson's disease. Additionally, the TH expressing cells may be used for drug screening or gene expression analysis as would be apparent to one of skill in the art.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] [0008]FIG. 1 depicts cultures of human neural progenitors established from human fetal forebrain (10wFBr991013) plated on PLL/laminin coated coverslips in N2 medium containing aFGF (100 ng/ml), BDNF (50 ng/ml), forskolin (25 μM), TPA (100 nM), dbcAMP (100 μM), GDNF (20 ng/ml), IGFI (100 ng/ml), IL-1α (200 pg/ml). After 3 days incubation, cells were fixed and immunostained for TH. Representative fields using a 20× objective (upper picture) and a 40× objective (lower picture) are shown.
[0009] [0009]FIG. 2 depicts cultures of human neural progenitors established from human fetal forebrain (10wFBr991013) plated on PLL/laminin coated coverslips in N2 medium containing aFGF (100 ng/ml), forskolin (25 μM), TPA (100 nM) and dbcAMP (100 μM). After 3 days incubation, cells were fixed and immunostained for TH. A representative field using a 20× objective is shown.
[0010] [0010]FIG. 3 depicts cultures of human neural progenitors established from human fetal forebrain (10wFBr991013) plated on PLL/laminin coated coverslips in N2 medium containing aFGF (100 ng/ml), BDNF (50 ng/ml), forskolin (25 μM), TPA (100 nM), dbcAMP (100 μM), GDNF (20 ng/ml), IGFI (100 ng/ml), IL-1α (200 pg/ml). After 1,3 and 7 days incubations, cells were fixed and immunostained for TH and the percentage of TH positive cells were quantified
[0011] [0011]FIG. 4 depicts cultures of human neural progenitors established from human fetal forebrain (10wFBr991013) plated on PLL/laminin coated coverslips in N2 medium containing aFGF (100 ng/ml), BDNF (50 ng/ml), forskolin (25 μM), TPA (100 nM), dbcAMP (100 μM), GDNF (20 ng/ml), IGFI (100 ng/ml), IL-1α (200 pg/ml). After 3 days incubation, the medium was changed to N2 medium without any additions. After 3 additional days, cells were fixed and immunostained for TH. A representative field using a 40× objective is shown.
[0012] [0012]FIG. 5 depicts three electrophoreses. Panel A depicts electrophoresis of PCR products amplified using specific primers for TH (expected size 342 bp) and cDNA generated by reverse transcription of RNA extracted from human neural progenitor cells incubated in induction medium for 1 (T1), 3 (T3) or 7 (T7) days or in 1% FBS for 7 days (F7). Panel B depicts electrophoresis of PCR products amplified using specific primers for AADC (expected size 331 bp) and cDNA generated by reverse transcription of RNA extracted from human neural progenitor cells incubated in induction medium (TH) or 1% FBS (FBS) for 7 days. cDNA generated from adult human Substantia Nigra mRNA (SN) was included as a positive control in Panels A and B. Panel C depicts electrophoresis of PCR products amplified using specific primers for DBH (expected size 440 bp) and cDNA generated by reverse transcription of RNA extracted from human neural progenitor cells incubated in induction medium (TH) or 1% FBS (FBS) for 7 days. cDNA generated from adult human Adrenal Gland (AG) was included as a positive control in Panel C.
[0013] [0013]FIG. 6 depicts cultures of human neural progenitors established from human fetal forebrain (10wFBr991013) plated on PLL/laminin coated coverslips in N2 medium containing aFGF (100 ng/ml), BDNF (50 ng/ml), forskolin (25 μM), DA (10 μM), TPA (100 nM), dbcAMP (100 μM), GDNF (20 ng/ml), IGFI (100 ng/ml), IL-1α (200 pg/ml). After 7 days incubation, cells were fixed and immunostained for AADC. A representative field using a 20× objective is shown.
[0014] [0014]FIG. 7 depicts cultures of HNSC.100 cells (human neural progenitor cells immortalized with v-myc) stained for TH. The HNSC.100 cells were seeded on glass coverslips coated with. PLL and laminin in differentiation medium with the following additions: aFGF (100 ng/ml), BDNF (50 ng/ml), forskolin (25 μM), TPA (100 nM), dbcAMP (100 μM), GDNF (20 ng/ml), IGFI (100 ng/ml), IL-1α (200 pg/ml). After 1 day, cells were fixed and stained for TH as described in Example 1. A representative field using a 40× objective is shown.
DETAILED DESCRIPTION OF THE INVENTION
[0015] Although there are reports in the literature describing agents capable of affecting TH expression (as well as more generally affecting survival and differentiation in both non-catecholamine and catecholamine cells), the prior art does not provide methods or compositions for an efficient induction of TH expression in a growth factor-expanded neural culture under defined conditions.
[0016] For example, human CNS stem cells differentiate spontaneously upon removal of growth factors. However, the predominant neuronal phenotype generated is GABAergic (Vescovi, 1999). TH-expressing neurons have been generated in small numbers from embryonic forebrain multipotent stem cells by treatment with basic fibroblast growth factor (bFGF/FGF2) in combination with a glial cell conditioned medium (Daadi, J. Neurosci. 1999 June 1; 19(11): 4484-97). TH induction has been achieved in cultures of primary neurons using acidic fibroblast growth factor (aFGF/FGF1), along with various co-activators such as brain or muscle extracts (lacovitti, Neuroreport 1997 Apr. 14; 8(6): 1471-4). As can be seen, to the extent that these methods were able to produce TH expressing neuronal cells at all, the methods were not efficient.
[0017] Iacovitti (1997) was able to induce TH in neurons newly differentiated from NT2 cells derived from a human embryonal carcinoma by treating the cells with FGF1 and coactivators including dopamine (DA), 12-O-etradecanoylphorbol-13-acetate (TPA), 3-isobutyl-1-methylxanthine (IBMX) and forskolin. This was not successful in the undifferentiated precursors (NT2) derived from a teratocarcinoma. Furthermore, this approach did not induce TH when attempted with a number of murine and rodent cell lines, including an EGF-propagated neural stem/progenitor cell line grown as neurospheres. Carpenter (1999) reported generating a few TH-positive cells from human neurospheres with an induction protocol using a combination of IL-1b, IL11 and GDNF over a period of 20 days, however neither quantification nor characterization of these cells has been published. More recently Caldwell et al. (Nat Biotechnol. 2001 May;19(5):475-9) found that multiple factors did not generate TH-expressing cells from human neurospheres. In conclusion, the efficient and stable induction of TH in neural progenitor cells has not been achieved to date using a defined medium.
[0018] Methods that are successful for TH induction in primary or differentiated neurons have not transferred to neural progenitor cells. The use of cell conditioned media has met with some success in generating TH-expressing progenitor cells, however, the variable nature and unknown content of these media does not lead to readily reproducible results.
[0019] Finally, with respect to the NT2 and other tumorigenic cell lines, TH-expressing cells produced from growth factor expanded neural progenitor cells have advantages over TH expressing cells generated from NT2 cells. Cultures generated from NT2 cells are potentially tumorigenic, in addition they require a long TH induction protocol (6 weeks predifferentiation to neurons followed by 5 days exposure to the TH induction cocktail). The TH-expressing cells of the present invention are distinguished from NT2 cells by being normal, non-tumorigenic cells expanded either by growth factors or by well-defined genetic modification. In contrast, NT2 cells are spontaneously immortal, being derived from a metastatic tumor.
[0020] The present invention provides methods for producing a population of neural cells in vitro, wherein a proportion or percentage of the cells express tyrosine hydroxylase. In so doing, the invention provides methods that allow the generation of a significant number of TH immunoreactive cells displaying neuronal properties from neural progenitor cultures. According to the methods of the present invention, in vitro production of neural cells expressing tyrosine hydroxylase is achieved by expanding neural progenitor cells using growth factors and/or by immortalization, plating the cells on a substrate, and introducing a defined culture medium to which has been added: one or more growth factors belonging to the FGF family; a molecule which gives or results in an increase in intracellular cAMP; and an agent stimulating or activating PKC.
[0021] Neural progenitor cells may be obtained from the adult and developing mammalian CNS, preferably from embryonic brain tissue. They may also be generated from embryonic stem cells. Such techniques as may be required for obtaining neural progenitor cells or for generating neural progenitor cells from stem cells are well known to one of skill in the art. Cultures of neural progenitor cells may be maintained and expanded in the presence of one or more growth factors such as epidermal growth factor (EGF), leukaemia inhibitory factor (LIF) and FGF2 (Carpenter, 1999) or ciliary neurotrophic factor (CNTF). These cells are self-renewing, the cells proliferate for long periods in mitogen containing serum free media, and the cells, when differentiated, comprise a cell population of neurons, astrocytes and oligodendrocytes.
[0022] Neurosphere cultures generated from human embryonic forebrain have a significant expansion potential. When grown in the presence of EGF, bFGF and LIF, cell cultures preserve their multipotency, remain viable, and are capable of expansion for more than 30 passages (i.e., at least one year). This can result in a 10 7 fold increase in cell numbers. Theoretically, such cultures generated from one or only a few fetuses should be sufficient as supply for transplantation of all patients with Parkinson's disease.
[0023] Neural progenitor cells immortalized by genetic modification may be grown as adherent cultures or in suspension cultures as “neurospheres”. They may be generated by introduction of an oncogene such as vmyc, or by introduction of DNA sequences expressing a telomerase.
[0024] The neural progenitor cells described herein may be immortalized or conditionally immortalized using known techniques. Among the conditional immortalization techniques contemplated are Tet-conditional immortalization (see WO 96/31242, incorporated herein by reference), and Mx-1 conditional immortalization (see WO 96/02646, incorporated herein by reference). A number of immortalized cell lines with the characteristics of neural stem/progenitor cells are described in the literature. Examples include HNSC.100 (Villa et al., 2000; Exp. Neurol. 161; 67-84), H6 cells (Flax et al., 1998; Nat. Biotech. 16, 1033-1039) and RN33B cells (Whittemore and White, 1993; Brain Res. 615, 27-40).
[0025] In addition to human embryonic forebrain, neurosphere cultures can also be generated from other regions of the developing brain including the mesencephalon and spinal cord. Although data using rodent tissue indicate that some positional identity (reflected by expression of regional markers) is preserved in the primary neurospheres, subculturing seems to lead to the generation/selection of a more uniform type of neurosphere and loss of regional specificity (Santa-Olalla et al., 2000 Soc. Neurosci. abstract 23.3). Accordingly, the conditions for TH induction of this invention can be applied to neurosphere cultures generated from sources other than human embryonic forebrain. Such cultures could include those generated from the adult human or rodent CNS, or from embryonic stem cells. The cultures produced by the methods of the present invention may be trypsinized and reseeded without losing the TH expressing cells. This makes such cultures a potentially attractive alternative to the fetal transplants used for implantation in Parkinson's patients.
[0026] The term “neural stem cell” as used herein refers to an undifferentiated neural cell that can be induced to proliferate using the methods of the present invention. The neural stem cell is capable of self maintenance, meaning that, with each cell division, one daughter cell will also be a stem cell.
[0027] The term “neural cell” as used herein refers to neurons, including dopaminergic neurons as well as glial cells, including astrocytes, oligodendrocytes, and microglia.
[0028] The term “expanding” is used interchangeably with “proliferating” and as used herein it means cultivation of cells.
[0029] The term “progenitor cell” as used herein refers to any cell that can give rise to a distinct cell lineage through cell division. For example, a neural progenitor cell is a parent cell that can give rise to a daughter cell having characteristics similar to a neural cell. A neural progenitor cell may be the non-stem cell progeny of a neural stem cell.
[0030] The term “population” as used herein in the context of cells, refers to more than one cell, preferably, many cells. In a preferred usage, a population of cells results from the expansion of similar, or preferably identical cells.
[0031] The term “significant percentage”, when used herein to describe the percentage of cells expressing TH in a population of neural cells, refers to a percentage that is higher than that percentage resulting from the methods of the prior art.
[0032] The term “substantial percentage”, when used herein to describe the percentage of cells expressing TH in a population of neural cells, refers to a percentage that is higher than that percentage resulting from the methods of the prior art described herein.
[0033] The term “improved percentage”, when used herein to describe the percentage of cells expressing TH in a population of neural cells, refers to a percentage which exceeds that percentage of cells expressing TH in a population of neural cells resulting from the spontaneous differentiation of CNS cells upon removal of growth factors.
[0034] The term “base line percentage” when used herein, describes the percentage of cells expressing TH in a population of neural cells resulting from the spontaneous differentiation of CNS cells upon removal of growth factors. The term is preferably used with a numerical modifier, for example, “twice the base line percentage” or, in general, any multiplier that exceeds one (i.e., 1.1, 1.5, 2.0 etc.).
[0035] The term “catecholamine-related deficiency” as used herein is any physical or mental condition that is associated with or attributed to an abnormal level of a catecholamine such as dopamine. This abnormal level may be restricted to a particular region of the mammal's brain (i.e. midbrain) or adrenal gland. A catecholamine deficiency can be associated with disease states such as Parkinson's disease, manic depression, and schizophrenia. In addition, catecholamine-related deficiencies can be identified using clinical diagnostic procedures.
[0036] The term “tyrosine hydroxylase-related deficiency” as used herein is any physical or mental condition that either is associated with underproduction or abnormal production of tyrosine hydroxylase or could be managed or treated by tyrosine hydroxylase expression. TH deficiencies may be associated with disease states such as, for example, Parkinson's disease.
[0037] One embodiment of this invention is directed towards a method for producing a population of neural cells in vitro wherein a significant percentage of the cells in the population express tyrosine hydroxylase. This method comprises introducing a population of expanded and plated neural progenitor cells to a defined culture medium, wherein the culture medium comprises: (1) one or more growth factors belonging to the Fibroblast Growth Factor (FGF) family; (2) a molecule which results in the activation of cyclic AMP (cAMP) dependent protein kinase (PKA); and (3) an agent which activates Protein Kinase C (PKC).
[0038] Another embodiment of this invention is directed towards a method for producing a population of neural cells in vitro wherein a percentage of the cells of the population express tyrosine hydroxylase, the method comprising the following steps:
[0039] (a) expanding a population of neural progenitor cells;
[0040] (b) plating the population of neural progenitor cells on a substrate; and
[0041] (c) introducing the population of neural progenitor cells to a defined culture medium, said culture medium comprising:
[0042] (i) one or more growth factors belonging to the FGF family;
[0043] (ii) a molecule which gives an increase in intracellular cAMP; and
[0044] (iii) an agent that stimulates PKC.
[0045] In one embodiment of the method of this invention, a significant percentage of the cells in the population of produced neural cells express tyrosine hydroxylase.
[0046] In another embodiment of the method of this invention, a substantial percentage of the cells in the population of produced neural cells express tyrosine hydroxylase.
[0047] In another embodiment of the method of this invention, an improved percentage of the cells in the population of produced neural cells express tyrosine hydroxylase.
[0048] In another embodiment of the method of this invention, the percentage of the cells in the population of produced neural cells expressing tyrosine hydroxylase is equal to (n times the base line percentage) where n is greater than one and (n times the base line percentage) does not exceed 100. In a preferred embodiment n is between 2 and 5. In another preferred embodiment, n is between 5 and 10. In another preferred embodiment, n is between 10 and 25.
[0049] In another preferred embodiment, n is between 25 and 500. In another embodiment, n is greater than 500. The base line percentage is typically in the order of magnitude 0.1% or less.
[0050] In another embodiment of the method of this invention, the percentage of the cells in the population of produced neural cells expressing tyrosine hydroxylase is greater than zero when the baseline percentage is zero.
[0051] In a preferred embodiment, the neural progenitor cells are expanded by immortalization through genetic modification.
[0052] In a preferred embodiment, the growth factor is selected from the group consisting of EGF, bEGF/FGF2, LIF, and CNTF, or a combination thereof.
[0053] In a preferred embodiment, the substrate is selected from the group consisting of PLL, PDL, PON, laminin, fibronectin and collagen, or a combination thereof.
[0054] In a preferred embodiment, the substrate contains PLL and laminin or PLL and fibronectin.
[0055] In a preferred embodiment, the defined culture medium is DMEM-F12 supplemented with N2 or B27.
[0056] In a preferred embodiment, the growth factor belonging to the FGF family is selected from the group consisting of aFGF/FGF-1, bFGF/FGF2, FGF4, and FGF8, or combinations thereof, preferably aFGF/FGF-1 and bFGF/FGF2. Preferably, the concentration of the growth factor belonging to the FGF family in the culture medium is from 1 to 500 ng/ml, more preferably from 10 to 200 ng/ml. When more than one compound is used, each compound is used in the before mentioned concentration.
[0057] In a preferred embodiment, the molecule that gives an increase in intracellular cAMP is selected from the group consisting of dbcAMP, IBMX, forskolin, 8-BrcAMP, and CPT cAMP, or combinations thereof.
[0058] In a preferred embodiment, the molecule that gives an increase in intracellular cAMP is a combination of forskolin and dbcAMP. Preferably, the concentration of the molecule that gives an increase in intracellular camp in the culture medium is from 10 to 1000 μM, more preferably from 10 to 200 μM. When more than one compound is used, each compound is used in the before mentioned concentration.
[0059] In a preferred embodiment, the agent stimulating PKC is selected from the group consisting of TPA, DPT, DPP; bryostatin 1 and mezerein, or combinations thereof, preferably TPA. Preferably, the concentration of the agent stimulating PKC in the culture medium is from 50 to 200 μM, more preferably from 75 to 150 μM. When more than one compound is used, each compound is used in the before mentioned concentration.
[0060] In a preferred embodiment, the culture medium further comprises a factor which improves the survival or maturation of the TH expressing neurons.
[0061] In a preferred embodiment, the survival or maturation factor is selected from the group consisting of: GDNF Family (GDNF; NTN; ART/NBN); Neurotrophins (BDNF; NT4/5; NGF); Insulins (IGF-I, IGF-II, insulin); and Interleukins (IL-1á; IL-1â); or combinations thereof.
[0062] In a preferred embodiment, the percentage of tyrosine hydroxylase expressing cells is significantly increased by further addition of Shh.
[0063] In a preferred embodiment, the percentage of the produced cell population expressing tyrosine hydroxylase is greater than 1%, more preferably greater than 2%, more preferably greater than 3%, more preferably greater than 4%, more preferably greater than 5%, more preferably greater than 6%, more preferably greater than 7%, more preferably greater than 8%, more preferably greater than 9%, more preferably greater than 10%, more preferably greater than 11%, and most preferably greater than 12%.
[0064] In a preferred embodiment, TH expressing neurons are also immunoreactive for AADC.
[0065] In a preferred embodiment, the TH expressing neurons do not express DBH.
[0066] In a preferred embodiment, the neural progenitor cells are selected from the group consisting of adult human CNS cells; adult rodent CNS cells; human embryonic cells; human fetal cells; human embryonic or fetal forebrain cells; and embryonic stem cells.
[0067] In another embodiment, the invention is directed towards compositions produced according to the method described herein.
[0068] In a preferred embodiment, the composition is produced through trypsinization and seeding of the TH expressing cells.
[0069] In another embodiment, the invention is directed towards a method for treating a mammal with a tyrosine hydroxylase-related deficiency, such as a disease state of the central nervous system, e.g. Parkinson's disease, comprising administering the composition of this invention directly into the CNS of the mammal, e.g. by transplantation.
[0070] The present invention further relates to a culture medium comprising
[0071] (a) one or more growth factors belonging to the Fibroblast Growth Factor (FGF) family;
[0072] (b) a molecule which results in the activation of cyclic AMP (cAMP) dependent protein kinase (PKA); and
[0073] (c) an agent that activates Protein Kinase C (PKC).
[0074] The present invention further relates to the use of the composition according of the invention for drug screening. The drug may e.g. be screened for a desired effect on TH expressing cells, such as enhancement of cell survival, increase in TH expression, etc. The present invention further relates to the use of the composition according to the invention for gene expression analysis. Such analysis may e.g. have the purpose of investigating the gene expression profile during neural progenitor cell differentiation or the gene expression profile of the differentiated cell.
[0075] Furthermore, the present invention relates to the use of the composition according to the invention for producing antibodies against TH expressing cells. Such antibodies may e.g. be used for screening, identification, isolation and/or cell sorting of biological samples for TH expressing cells.
[0076] The invention further relates to the use of the composition according to the invention for investigating the biochemistry and molecular mechanisms of neural progenitor cell differentiation, for example for identifying compounds or genes involved in the induction of progenitor cell differentiation.
[0077] Also, the invention relates to a composition according to the invention for use as a pharmaceutical for treating a tyrosine hydroxylase-related deficiency.
[0078] Finally, the invention relates to the use of a composition according to the invention for the manufacture of a pharmaceutical for treating a disease state of the central nervous system.
[0079] Defined Culture Medium
[0080] A defined culture medium contains a variety of essential components required for cell viability, including inorganic salts, carbohydrates, hormones, essential amino acids, vitamins, and the like. Preferably, DMEM or F-12 are used as the standard culture medium, most preferably a 50/50 mixture of DMEM and F-12. Both media and a mixture are commercially available (DMEM-Gibco/LifeTechnologies 61965-026; F-12-Gibco/LifeTechnologies 31765-027; DMEM/F12 (1:1)-Gibco/LifeTechnologies 31331-028). A supplement supporting the survival of neural cells in serum-free medium is added to the medium, preferably N2 or B27 supplement. N2 supplement is commercially available (N2-Gibco/LifeTechnologies 17502-048) and contains insulin 5 μg/ml, transferrin 100 μg/ml, progesterone 6.3 ng/ml, putrescine 16.11 μg/ml and selenite 5.2 ng/ml. B27 supplement is commercially available (B27-Gibco/LifeTechnologies 17504-044) and is a proprietary modification of Brewer's B18 formulation (Brewer, 1989; Brain Res. 494:65). Preferably, the conditions for culturing should be as close to physiological as possible. The pH of the culture medium is typically between 6-8, preferably about 7, most preferably about 7.4. Cells are typically cultured between 30-40° C., preferably between 32-38° C., most preferably between 35-37° C. Cells are preferably grown in 5% CO 2 .
[0081] Substrates
[0082] Plating neurosphere cultures on a charged substrate like polyomithine (PON) allows a significant fraction (10-50%) of the cells to become neurons (Carpenter et al., 1999; Ostenfeld et al., Exp Neurol 2000 July; 164(1): 215-26). Signals derived from the extracellular matrix have significant influences on neuron differentiation and development. In the present invention, a mixture of poly-L-Lysine (PLL) and laminin is used as a substrate for the cells, as laminin is known to promote firm attachment and extensive neurite outgrowth in many neuronal cell cultures (Poltorak et al., Exp Neurol 1992 August; 117(2): 176-84; Ernsberger and Rohrer, Dev Biol 1988 April; 126(2): 420-32; Savettieri et al., Cell Mol Neurobiol 1998 August; 18(4): 369-78). Furthermore, cells are seeded as small spheres which are formed in proliferation medium 5-7 days after dissociation to single cells. When the cell suspension is seeded on suitable substrate and mitogens omitted from the medium, within 10 hours β-tubulin positive cells can be observed on top of cells with glial morphology of which some are migrating out from the core of the sphere. Likewise, TH-expressing cells are observed very early after plating for differentiation. In contrast, dissociation of the spheres to single cell suspension only result in no or very few TH positive neurons and only at high cell density. This suggests that preservation of cell-cell contact is important and is consistent with the observation of high numbers of TH immunoreactive cells in patches within the culture. The need for cell-cell interaction may be explained by the possibility that many of the effects of the inducing factors are mediated through the glial cells present in the culture. In addition to PON and PLL, poly-D-lysine (PDL) may be used as a charged substrate. PDL, by virtue of its stereoisomerism cannot be metabolized by the cells.
[0083] Laminin is an example of an extracellular matrix protein. Other examples include fibronectin, tenascin, janusin, and collagen. These have been associated with the maintenance and differentiation of neurons in vitro (Lochter, Eur J Neurosci 1994 Apr. 1; 6(4): 597-606) and could also be used in the differentiation of the cells of this invention.
[0084] Growth factors belonging to the Fibroblast growth factor (FGF) family have been found to be important in the development of dopaminergic neurons. These include aFGF/FGF-1, bFGF/FGF2, FGF4, FGF8.
[0085] Molecules which gives rise to an increase in intracellular cyclic AMP (cAMP) include 3-isobutyl-1-methylxanthine (IBMX), forskolin, and cAMP derivatives; 8-bromo-cAMP (8br-cAMP), 8-(4-chlorophenylthio)-cAMP (CPT-cAMP), N 6 , 2′-O-dibutyryl cAMP (dbt-cAMP). The effects of increasing intracellular cAMP have been attributed to activation of cAMP-dependent protein kinase (PKA) (Frodin, J Biol Chem 1994 Feb. 25; 269(8): 6207-14).
[0086] Activators of protein kinase C (PKC) include the phorbol esters; 12-O-tetradecanoylphorbol-13-acetate (TPA), 12-deoxyphorbol-13-tetradecanoate (DPT) 12-deoxyphorbol-13-phenylacetate (DPP); bryostatin 1 and mezerein (Huguet, Eur J Pharmacol 2000 Dec. 20; 410(1): 69-81).
[0087] Factors which improve the survival and maturation of the TH expressing neurons may also be added to the culture medium. These factors include members of the Glial cell-line Derived Neurotrophic Factor (GDNF) family; GDNF; Neurturin (NTN); Artemin/Neublastin (ART/NBN); Neurotrophins; Brain Derived Neurotrophic Factor (BDNF); Neurotrophic Factors (NT4/5); Nerve Growth Factor (NGF); Insulins (IGF-I, IGF-II, insulin); Interleukins (IL-1á; IL-1â).
[0088] Sonic hedgehog (Shh), a developmental signaling protein believed to be involved in the development and survival of dopaminergic cells. It has recently been reported that the expression of TH in the developing midbrain is mediated by the synergy of FGF8 and Shh (Ye, Cell. 1998 May 29; 93(5): 755-66). More recently attempts use this combination in vitro induced TH expression in fewer than 2% of NT2/hNT cells. (lacovitti, Exp Neurol 2001 May; 169(1): 36-43).
[0089] The neural cells of this invention have numerous uses, including for drug screening, diagnostics, genomics and transplantation. The cells of this invention may be transplanted “naked” into patients according to conventional techniques, into the CNS, as described for example, in U.S. Pat. Nos. 5,082,670 and 5,618,531, each incorporated herein by reference, or into any other suitable site in the body. In one embodiment of the present invention, the cultures containing TH-expressing cells are transplanted directly into the CNS. Parenchymal and intrathecal sites are contemplated. It will be appreciated that the exact location in the CNS will vary according to the disease state. The cells may also be encapsulated and used to deliver biologically active molecules, according to known encapsulation technologies (see, e.g., U.S. Pat. Nos. 4,352,883; 4,353,888; and 5,084,350, each incorporated herein by reference).
[0090] The following examples are provided for illustrative purposes only, and are not intended to limit the scope of the claims in any way.
EXAMPLES
Example 1
Induction of TH Immunoreactivity in Growth Factor Expanded Human Forebrain Cultures
[0091] Cultures of human neural progenitors established from human fetal forebrain expanded in N2 medium supplemented with EGF/bFGF/LIF or EGF/bFGF/CNTF as indicated were mechanically passaged and maintained in expansion medium for 5-7 days. The small spheres were then plated on glass coverslips coated with poly-L-lysine (PLL, 100 μg/ml) and laminin (50 μg/ml) at a cell density of 100.000 cells/cm 2 in N2 medium containing 1% FBS for “default differentiation” or in N2 medium supplemented with aFGF (100 ng/ml), BDNF (50 ng/ml), forskolin (25 μM), DA (10 μM), TPA (100 nM), dbcAMP (100 μM), GDNF (20 ng/ml), IGFI (100 ng/ml), IL-1α (200 pg/ml). N2 medium consists of DMEM:F12 (1:1) supplemented with N2 (insulin, transferrin, selenium, progesterone and putrescine), 0.6% glucose and 5 mM HEPES. After 3 days incubation, cells were fixed in 4% paraformaldehyde in PBS for 20 min at room temperature. The cells were washed three times with PBS, followed by overnight incubation with primary antibody (rabbit anti-TH, PelFreez 1:100 or Chemicon 1:800) diluted in PBS incubation buffer which contained 10% normal goat serum, 0.3% Triton X-100 (Sigma) and 1% BSA at 4° C. in a humidified chamber. The cells were washed with PBS, and incubated for 1 hr at room temperature in the dark with secondary antibody (anti-rabbit Cy3, (Chemicon 1:500) diluted in incubation buffer. After washing with PBS, nuclei were counterstained with DAPI or Hoechst 33342. Negative controls (omission of the primary antibody) were included in each experiment.
[0092] To quantify the percentage of TH cells, cells were counted in at least three fields from three to six independent coverslips randomly chosen using a 20× objective. The number of TH-immunoreactive cells in each field was counted. The total cell number was obtained by counting nuclei counterstained with DAPI or Hoechst 33342.
[0093] No TH positive cells could be detected in the “default differentiated” cultures. In contrast, approximately 4-10% of the cells became immunoreactive to TH after 3 days. As seen in Table I, passaging of the cultures had no significant effect on the efficiency of TH induction as the number of TH positive neurons generated in a culture after 28 passages was similar as in a culture only passaged for 2 times. Although, a much more efficient expansion of cultures was achieved in medium containing LIF or CNTF, the presence of these growth factors during expansion was dispensable for induction of TH positive cells. In a culture expanded in bFGF/EGF, 8.69±1.12% TH positive cells were observed as compared with a parallel culture established from the same case in bFGF/EGF/LIF 9.85±1.23%. Furthermore, the ability to induce TH expression seems to be a general phenomenon of human neural progenitor/stem cell cultures generated from different regions including cortex and subcortex and is not developmentally dependent as TH induction was observed in cultures generated from tissue of different gestational ages from 6 to 10 weeks (data not shown). Many of the TH positive cells showed the neuronal bipolar morphology seen in FIG. 1 (lower picture).
TABLE 1 Cell cultures TH-induced 3 days % TH 10FBr 990419 P2 EGF/bFGF/LIF 4.7 ± 0.2 9FBr 000126 P28 EGF/bFGF/LIF 4.2 ± 0.5 9FBr 000126 P11 EGF/bFGF/LIF 4.8 ± 0.1 10FBr 991013 P24 EGF/bFGF/CNTF 4.1 ± 0.5
Example 2
Importance of Substrate
[0094] Human neural progenitor cultures expanded in bFGF and CNTF (11.5 wCTX 001115 cells) or in EGF, bFGF and LIF (10wHFBr991013) were seeded after trituration or as small spheres on 12 mm coverslip coated with different substrates at a cell density of 200,000/well in N2 medium containing the TH inductive factors described in Example 1. The different substrate tested was: Poly-L-Ornithine (PLO, 100 μg/ml); PLL (100 μg/ml); PLL combined with lamimin (as above); and PLL (100 μg/ml) combined with fibronectin (50 μg/ml). After incubation for 3 days, cells were fixed in 4% PFA and immunostained for TH as described in Example 1.
[0095] TH positive cells were seen on all substrates, although cells (10 wHFBr991013 spheres) plated onto Poly-L-Ornithine (PLO) or PLL alone did not migrate well. No difference of TH induction was seen between the cells plated onto PLL/laminin and PLL/fibronectin. Likewise, quantification indicated that a similar number of TH positive cells were induced on PLL/fibronectin and PLL/laminin from the 11.5CTX001115 cells:
PLL/fibronectin 10.6822% PLL/laminin 10.6845%
Example 3
Importance of the Various Factors For TH Induction
[0096] Human neural progenitor cells expanded in EGF/bFGF/LIF (991013FBr) cells were seeded as small spheres (5 days after trituration to single cell suspension) on PLL/laminin coated 12 mm coverslips at a cell density of 100.000 cells/cm 2 in N2 medium containing different combinations of the factors described in Example 1. After incubation for 3 days, cells were fixed in 4% PFA and immunostained for TH as described in Example 1.
[0097] The results of these experiments indicated that:
[0098] 1) If Forskolin, dbcAMP or TPA are omitted from the cocktail described in Example 1, significantly fewer TH immunoreactive cells are observed Table 2);
[0099] 2) Same numbers of TH positive cells with a similar morphology as observed with the cocktail described in Example 1 can be induced with a cocktail consisting of aFGF (100 ng/ml), Forskolin (25 μM), dbcAMP (100 μM) and TPA (100 nM) (Table 2, FIG. 2);
[0100] 3) Omitting one of the following factors did not affect induction of TH positive cells: BDNF, IGF-I, GDNF, dopamine and IL-1α. FIG. 1 shows a culture induced to express TH in the absence of dopamine; and
[0101] 4) FGF-1/aFGF maybe replaced with FGF-2/bFGF in the same concentration (100 ng/ml) without any effect on numbers or morphology of TH immunoreactive cells
TABLE 2 Factors % TH Standard* 9.43 ± 0.39 Standard without Forskolin 5.18 ± 0.46 Standard without dbcAMP 5.30 ± 0.88 Standard without Forskolin/dbcAMP 3.86 ± 0.30 Standard without TPA 0.61 ± 0.21 aFGF, Forskolin, dbcAMP, TPA 8.69 ± 0.45
Example 4
Additional Factors may Further Increase the Number of TH Positive Cells
[0102] Human neural progenitor cells were seeded as small spheres (5 days after trituration to single cell suspension) on PLL/laminin coated 12 mm coverslips at a cell density of 100.000 cells/cm 2 in N2 medium containing aFGF (100 ng/ml), forskolin (25 μM), DA (10 μM), TPA (100 nM), dbcAMP (100 μM), GDNF (20 ng/ml), IGFII (100 ng/ml), IL-1α (200 pg/ml) (small cocktail) or aFGF (100 ng/ml), forskolin (25 μM), DA (10 μM), TPA (100 nM), dbcAMP (100 μM), GDNF (20 ng/ml), IGFI (100 ng/ml), IL-1α (200 pg/ml), FGF8b (100 ng/ml) and SHH (100 ng/ml) (big cocktail). After incubation for 3 days, cells were fixed in 4% PFA and immunostained for TH as described in Example 1.
[0103] A statistically significant increase (25%) in the number of TH positive neurons was observed after addition of SHH and FGF-8b to the small cocktail:
[0104] % TH positive cells in cultures treated with the small cocktail: 9.974±1.198
[0105] % TH positive cells in cultures treated with the big cocktail: 12.938±1.198.
Example 5
Time Course Of TH Induction
[0106] Human neural progenitor cells expanded in EGF/bFGF/LIF (991013FBr) cells were seeded as small spheres (5 days after trituration to single cell suspension) on PLL/laminin coated 12 mm coverslips at a cell density of 100.000 cells/cm 2 in N2 medium containing the factors described in Example 1 except that dopamine was omitted from the cocktail. Parallel cultures were incubated for 1-7 days. Half of the medium was changed every other day.
[0107] As seen in FIG. 3, maximal TH induction was achieved already after 1 day of exposure to the TH cocktail and sustained for at least 7 days. Although there were no increase in numbers, maturation of the TH positive cells towards a more differentiated neuronal phenotype with longer processes was observed after 3 and 7 days of TH induction.
Example 6
Stability of the TH Positive Phenotype
[0108] Human neural progenitor cells expanded in EGF/bFGF/LIF (991013FBr) cells were seeded as small spheres (5 days after trituration to single cell suspension) on PLL/laminin coated 12 mm coverslips at a cell density of 100.000 cells/cm 2 in N2 medium containing the factors described in Example 1 except that dopamine was omitted from the cocktail. After incubation for 3 days, the induction medium was removed and N2 medium supplemented with 1) GDNF, 2) GDNF+IGF-I, 3) 1% FBS+GDNF, 4) 1% FBS, 5) IGF-I, 6) no additions or 7) fresh TH-induction medium were added to parallel TH induced cultures. After additional three days of culturing, cells were fixed and stained for TH as described in Example 1.
[0109] It was possible to find TH-positive cells after changing to all the media described above. TH-positive cells displaying long, elaborate processes were even observed in serum free medium without any additions as seen in FIG. 4.
[0110] In another experiment, cells were seeded for TH induction in T 25 flasks at a cell density of 100.000 cells/cm 2 . After exposure to induction medium described in Example 1 but without dopamine for 3 days, the induction medium was removed and cells were washed with PBS (without Ca 2+ and Mg + ). Then Trypsin-EDTA (0.05% Trypsin, 0.53 mM EDTA Life Technologies 25300-054), and cells were incubated for 5 minutes at 37° C. The flask was tapped manually to loosen the cells from the surface. The trypsin was inactivated by adding N2-medium with 10% FBS and the cells collected by centrifugation for 5 minutes at 1500 rpm. Then the cells were replated onto PLL-lysine/laminin coated coverslips in N2 medium with or without different additives. After additional three days of culturing, cells were fixed and stained for TH. Cells exposed to induction medium without replating for 6 days were included as positive controls.
[0111] It was possible to find TH-positive cells in all the seven different media including N2 medium without additions. In one experiment, 3.6% TH-positive cells were observed after replating in induction medium, 3.0% TH-positive cells replated in medium with no additions, and 1.5% TH-positive cells replated in medium with 1% FBS.
[0112] Thus, the induction of TH is stable and the TH positive cells survive trypsinization and replating in medium without TH inductive factors.
Example 7
Further Characterization of TH-Induced Cells
[0113] Cultures of human neural progenitor cells expanded in bFGF/EGF/LIF (10wFBr991013) were seeded in 100-mm dishes coated with PLL/laminin as small spheres (5 days after trituration to single cell suspension) at a cell density of 100,000/cm 2 in N2 medium containing TH induction factors, as described in Example 1, except that dopamine was omitted from the cocktail. Half of the medium was changed every other day. After 7 days incubation in TH induction medium, total RNA was prepared using Trizol according to the manufacturers protocol (Gibco-BRL). After treatment with DNase, total RNA was reverse transcribed into cDNA with Superscript II RNase H using random hexamer primers (Amersham Pharmacia) according to the manufacturers instructions (Gibco-BRL). The PCR reactions were carried out in a 15-μl volume containing 0.5 unit of Taq polymerase (Amersham Pharmacia), 50 mM Tris-HCl, pH 7.5, 50 mM KCl, 1.5 mM MgCl 2 , 10 pmol of specific primer, 200 μM of each of the dNTPs, and RT product equivalent to 125 ng total RNA. The PCR was run for 25-35 cycles and the thermal profile used following a pre-denaturation step at 94° C. for 5 min were specific for the individual primer sets.
[0114] Primers:
[0115] TH: 5′ GCCCCCACCTGGAGTACTT3′ and 5′GCGTGGCGTATACCTCCTTC3′ (94° C. 30″; 57° C. 30″; 72° C. 30″) resulting in a product of 344 bp
[0116] AADC: 5′CGGCATTGGCAGATACCACT 3′ and
[0117] 5′ ATTCCACCGTGCGAGAACAG 3′ (94° C. 30″; 53° C. 30″; 72° C. 30″) resulting in a product of 331 bp
[0118] DBH: 5′CACGTACTGGTGCTACATTAAGGAGC 3′ and
[0119] 5′ AATGGCCATCACTGGCGTGTACACC 3′ (94° C. 30″; 68° C. 30″; 72° C. 30″) resulting in a product of 440 bp
[0120] The PCR products were separated on a 2% agarose gel and visualized by ethidium bromide.
[0121] As seen in FIG. 5 (Panels A-C), by using cDNA generated by reverse transcription of RNA extracted from cells that had been incubated for 7 days under conditions inducing TH immunoreactivity, PCR products of the expected sizes could be amplified with primers specific for TH and AADC but not DBH cDNA. These results are consistent with the presence of cells in the TH induced cultures expressing mRNA encoding dopaminergic rather than noradrenergic/adrenergic enzymatic marker proteins.
Example 8
Detection of AADC Immunoreactivity In TH-Induced Cultures
[0122] Human neural progenitor cells expanded in EGF/bFGF/LIF (991013FBr) cells were seeded as small spheres (5 days after trituration to single cell suspension) on PLL/laminin coated 12 mm coverslip at a cell density of 100,000/cm 2 in N2 medium containing the factors described in Example 1, except that dopamine was omitted from the cocktail. After incubation for 7 days, cells were fixed in 4% PFA and immunostained for AADC as described in Example 1, except that a rabbit anti-AADC antibody (Chemicon) diluted 1:2000 was used as primary antibody. As seen in FIG. 6, cells staining brightly for AADC were observed in the TH induced cultures supporting the expression data obtained in Example 7.
Example 9
Induction of TH Immunoreactivity in a Human Neural Progenitor Cell Line Immortalized with V-MYC
[0123] HNSC.100 cells were grown in DMEM:F12 medium supplemented N2, 1% BSA, 20 ng/ml EGF and 20 ng/ml bFGF as adherent cultures in PLL (10 μg/ml) coated TC flasks. For seeding on glass coverslips coated with PLL (50 μg/ml) and laminin (25 μg/ml), cells were trypsinized and plated at a cell density of 25,000 cells/cm 2 in differentiation medium (growth medium without EGF and bFGF) with or without the following additions: aFGF (100 ng/ml), BDNF (50 ng/ml), forskolin (25 μM), TPA (100 nM), dbcAMP (100 μM), GDNF (20 ng/ml), IGFI (100 ng/ml), IL-1α (200 pg/ml). After 1 day, cells were fixed and stained for TH as described in Example 1. The result of this experiment shown in FIG. 7 demonstrate that also a human neural progenitor cell line immortalized with v-myc can be induced to generate cells staining brightly for TH immunoreactivity, when exposed to the combination of growth factors and signaling molecules described in the example. In contrast, a control culture incubated without the factors added, no TH positive neurons could be found (data not shown).
[0124] Equivalents
[0125] From the foregoing detailed description of the specific embodiments of the invention, it should be apparent that unique methods and compositions have been described. Although particular embodiments have been disclosed herein in detail, this has been done by way of example for purposes of illustration only, and is not intended to be limiting with respect to the scope of the appended claims that follow. In particular, it is contemplated by the inventor that various substitutions, alterations, and modifications may be made to the invention without departing from the spirit and scope of the invention as defined by the claims. For instance, the choice of the particular cell, substrate, or the particular factors used is believed to be a matter of routine for a person of ordinary skill in the art with knowledge of the embodiments described herein.
1
6
1
19
DNA
Artificial
TH primer 1
1
gcccccacct ggagtactt 19
2
20
DNA
Artificial
TH primer 2
2
gcgtggcgta tacctccttc 20
3
20
DNA
Artificial
AADC primer 1
3
cggcattggc agataccact 20
4
20
DNA
Artificial
AADC primer 2
4
attccaccgt gcgagaacag 20
5
26
DNA
Artificial
DBH primer 1
5
cacgtactgg tgctacatta aggagc 26
6
25
DNA
Artificial
DBH primer 2
6
aatggccatc actggcgtgt acacc 25 | The invention provides a means for efficiently generating large numbers of TH expressing neural cells for neurotransplantation into a host to treat neurodegenerative disease, neurological trauma, stroke, or in other neurodegenerative disease, neurological trauma, stroke, or in other diseases of the nervous system involving loss of neural cells, particularly Parkinson's disease. | 2 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from Israel Patent Application No. 232133, filed Apr. 13, 2014, entitled “Self-Combusting Ignition Device”.
FIELD OF THE INVENTION
[0002] The invention relates to the field of ignition devices.
BACKGROUND
[0003] Outdoor cooking is an immensely popular activity enjoyed by many people. The burning of combustible fuel pieces from coal to charcoal to wood chips is well known. Common applications include burning charcoal in a backyard barbecue and burning coal lumps in a fireplace. Commonly, the actual combustible material is sold and stored in bulk containers.
[0004] For instance, a 10 or 20 lb bag of charcoal can be kept in a consumer's garage next to their barbecue grill. Chunks of coal or wood may also be shipped in heavy bag containers. In each case, a consumer dispenses a portion of the pieces of combustible material to be burned. For instance, the consumer may pour briquettes from a charcoal bag into a grill then arrange them into a solid pyramid.
[0005] It is often said that the combustion of these materials is not very efficient. The classic “pile” of charcoal briquettes in a grill burns slowly and inefficiently. This arrangement of charcoal typically requires some accelerant either applied onto or soaked into the briquette mixture. Also, airflow must usually be handled in order to achieve a quick and even burn.
[0006] The foregoing examples of the related art and limitations related therewith are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent to those of skill in the art upon a reading of the specification and a study of the figures.
SUMMARY
[0007] The following embodiments and aspects thereof are described and illustrated in conjunction with systems, tools and methods which are meant to be exemplary and illustrative, not limiting in scope.
[0008] One embodiment relates to a self-combusting ignition device comprising a hollow, funnel-shaped body made of a combustible material which is devoid of charcoal, said body having (a) a relatively narrow top opening and a relatively wide bottom opening, and (b) at least one ventilation conduit adjacent said relatively wide bottom opening.
[0009] Another embodiment relates to a method for igniting flammable elements, the method comprising: positioning a self-combusting ignition device inside a barbecue grill, said device comprising a hollow, funnel-shaped body made of a combustible material which is devoid of charcoal, said body having (a) a relatively narrow top opening and a relatively wide bottom opening, and (b) at least one ventilation conduit adjacent said relatively wide bottom opening; piling up the flammable elements over said device; and igniting said device, thereby causing at least some of the flammable elements to ignite and, upon said device being consumed by combustion, to settle inside the barbecue grill.
[0010] Optionally, said funnel-shaped body is concave.
[0011] Optionally, said at least one ventilation conduit is multiple ventilation conduits.
[0012] Optionally, said multiple ventilation conduits are each a half-cylindrical niche.
[0013] Optionally, said combustible material comprises paper.
[0014] Optionally, said combustible material comprises cardboard.
[0015] Optionally, said combustible material comprises corrugated cardboard.
[0016] Optionally, said body is soaked in liquid fuel.
[0017] Optionally, said relatively wide bottom opening is defined by an elevated bottom rim, configured to prevent charcoal pieces which are piled up over the device from slipping over.
[0018] Optionally, the piling up is over a majority of an outer surface of said device.
[0019] Optionally, the flammable elements comprise charcoal pieces.
[0020] Optionally, the igniting of said device is by throwing a burning piece of paper into said relatively narrow top opening.
[0021] In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the figures and by study of the following detailed description.
BRIEF DESCRIPTION OF THE FIGURES
[0022] Exemplary embodiments are illustrated in referenced figures. Dimensions of components and features shown in the figures are generally chosen for convenience and clarity of presentation and are not necessarily shown to scale. The figures are listed below.
[0023] FIG. 1 shows a perspective view of a self-combusting ignition device;
[0024] FIG. 2 shows a side view of the self-combusting ignition device of FIG. 1 ;
[0025] FIG. 3 shows a top view of the self-combusting ignition device of FIG. 1 ;
[0026] FIG. 4 shows a side view of the self-combusting ignition device of FIG. 1 , inside a barbecue grill; and
[0027] FIG. 5 shows a side view of the barbecue grill after the self-combusting ignition device has been consumed.
DETAILED DESCRIPTION
[0028] A self-combusting ignition device is disclosed herein. The device may be made, fully or partially, from a combustible material, and be used to ignite one or more other flammable elements, such as pieces of charcoal, wood, etc. For simplicity of discussion, these flammable elements are hereinafter referred to as “charcoal pieces”, although other types of flammable elements, such as pieces of wood or the like, are intended herein as well. The device may be manually ignited by a user, causing the device to self-combust and, in turn, ignite the charcoal pieces which are piled over it.
[0029] Reference is now made to FIGS. 1 , 2 and 3 , which show a perspective view, a side view and a top view of a self-combusting ignition device (hereinafter simply “device”) 100 , in accordance with an exemplary embodiment. It should be noted that device 100 may look essentially the same when looked at from the top and from the bottom. Hence, the top view of FIG. 3 may be similar to a bottom view of the device, and any differences may be only those derived from a thickness of the body of device 100 —which differences may be barely noticeable between bottom and top views.
[0030] Device 100 may have a body 102 generally shaped as a concave funnel, which may be positioned essentially upside-down when in use. Namely, the narrower opening of the funnel is at its top, while the wider opening of the funnel is at its bottom. In the figure, the narrower opening is defined by a top rim 104 , while the wider opening is defined by a bottom rim 108 .
[0031] In some embodiments (not shown), a body of a self-combusting ignition device, or at least a portion of the body, may be shaped differently than what FIGS. 1-3 show, for example as a convex funnel, a cone, a triangular pyramid, a rectangular pyramid—or any other hollow shape having a wider opening at its bottom and a narrower opening at its top.
[0032] A thickness of body 102 is optionally substantially uniform along the entirety of the body. For example, the thickness of body 102 may be between 1-2 millimeters, 2-3 millimeters, 3-4 millimeters, 4-5 millimeters, 5-6 millimeters, 6-7 millimeters, 7-8 millimeters, 8-9 millimeters, 9-10 millimeters, or more. Alternatively, the thickness of body 102 may be non-uniform, namely—some areas may be thicker than others.
[0033] Body 102 may be made of one or more solid, combustible materials, or of a combination of one or more solid combustible materials with one or more solid, non-combustible materials. The term “solid, non-combustible materials” refers to solid materials whose flash point is higher than temperatures typically reached to in barbecue grill fires. Solid, non-combustible materials may include, for example, various reinforcement structures which may be used within body 102 , such as metallic meshes, metallic threads, etc.
[0034] Examples of suitable solid, combustible materials for body 102 include various types of paper products (e.g. paper sheets, cardboard, corrugated cardboard, etc.), various fabrics (e.g. of animal sources, plant sources, etc.), various types of processed wood, and more. The one or more solid, combustible materials of body 102 may be characterized as being easily ignitable, such as by holding a burning match, a portable lighter and/or burning object next to them for a brief duration (e.g. up to a few seconds).
[0035] Additionally or alternatively, body 102 may be made combustible (or its degree of combustibility be enhanced) by soaking it in liquid fuel. This may be performed either during manufacturing or by the user, just prior to igniting device 100 . If body 102 is soaking in liquid fuel during manufacturing, it may be consecutively packed in a sealed package, such as a plastic wrap, such that the liquid fuel does not vaporize until device 100 is being used.
[0036] In some embodiments, body 102 is devoid of charcoal of any form and shape. In some embodiments, body 102 does not have any charcoal attached to it. Instead, charcoal may be piled up over body 102 when use of device 100 is desired; during this piling up, the charcoal does not become attached to body 102 but rather sits over it freely.
[0037] Body 102 may include one or more ventilation conduits adjacent its bottom opening, such as conduits 106 . Conduits 106 may be shaped as half-cylindrical niches in body 102 , which niches disrupt the generally circular circumference of bottom rim 108 . When device 100 is positioned on an essentially flat surface, bottom rim 108 may contact the surface (fully or partially), while conduits 106 provide pathways for air to flow into an inside void of body 102 .
[0038] The embodiment of FIGS. 1-3 shows eight conduits 106 (only three of which are referenced, for the sake of simplicity); however, other embodiments (not shown) may include a different number of conduits, such as 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12 or more.
[0039] In some embodiments (not shown), a body of a self-combusting ignition device may include, adjacent to its bottom rim, one or more ventilation conduits shaped differently than what FIGS. 1-3 show, as long as these ventilation conduits allow air to flow into an inside void of the body when the body is positioned on an essentially flat surface.
[0040] In some embodiments (not shown), a bottom rim of a self-combusting ignition device may be elevated, to essentially form a circumferential concave bowl around the lower part of the device. Namely, the elevated rim may prevent charcoal pieces which are piled up over the device from slipping over its lowermost edges. Those of the charcoal pieces which get supported by this bottom rim, may serve to support charcoal pieces which are positioned higher up over the device.
[0041] Reference is now made to FIG. 4 , which shows device 100 of FIGS. 1-3 , positioned inside a barbecue grill 110 , which is shown only schematically. Barbecue grill 110 may be shaped, for example, as a container open at its top (or being equipped with a removable cover at its top). Namely, barbecue grill 110 may have at least a bottom surface (which is optionally essentially flat) and side walls encircling the bottom surface. In this figure, parts of device 100 which are hidden behind charcoal pieces are shown with phantom lines.
[0042] Device 100 may be used, in some embodiments, according to the following method:
[0043] First, device 100 may be positioned in a suitable location for setting fire, such as inside barbecue grill 110 or even on bare ground. Optionally, a surface (e.g. of the barbecue grill) on which device 100 is positioned is substantially flat.
[0044] Then, a plurality of flammable elements, such as charcoal pieces 112 , may be piled up over device 100 , to form an array of the charcoal pieces over at least a majority of the area of the outer surface of the device. For simplicity of presentation, only three charcoal pieces 112 are referenced in FIG. 4 , although the figure shows many more charcoal pieces.
[0045] A user piling up charcoal pieces 112 over device 100 , may start by piling them over the lower part of the device, so as to fill a space between that lower part and walls of barbecue grill 110 . As the piling up continues, charcoal pieces 112 begin covering device 100 higher up, finally forming an array resembling a somewhat amorphous pyramid over the device. The piling up may be done by pouring charcoal pieces 112 from a bag, by positioning them manually, by use of a hand tool, or by combination of any of the above.
[0046] Finally, device 100 may be ignited using a fire source such as a match, a portable lighter, a burning piece of paper, and/or any other means of ignition. In some embodiments, the device may be ignited by simply throwing a burning piece of paper into its inner void, such as through top rim 104 .
[0047] As device 100 catches fire, it may exhibit what is known as the chimney affect (also “stack effect”). Namely, oxygen-containing air may be drawn, due to the combustion, through the ventilation conduits (which are not referenced in FIG. 4 , merely for simplicity of illustration, but are nonetheless observable) and into the inner void of device 100 . The inner void of device 100 hence acts as its flue. Exhaust gasses resulting from the self-combustion of device 100 may be emitted to the atmosphere through top rim 104 . Accordingly, device 100 may also be referred to as a combined device, acting as a self-combustible igniter and a chimney.
[0048] The self-combustion of device 100 causes charcoal pieces 112 , or at least some thereof, to ignite as well. As device 100 self-combusts, its material (or at least a part thereof, in case its body contains also a non-combustible material) is also gradually consumed, such that the burning (or partly burning) charcoal pieces 112 gradually collapse and settle into an essentially flat formation inside barbecue grill 110 , allowing their use for barbecue grilling. FIG. 5 illustrates this; the device is no longer shown, and charcoal pieces 112 have settled into a formation which is overall lower than before.
[0049] If the charcoal pieces do not settle into a satisfactory formation, a user may manually manipulate them at his or her desire, for example using a hand tool such as a stick. A grill mesh and/or a rotisserie (not shown) may then be positioned over the settled charcoal pieces, as known in the art, for cooking food.
[0050] In the description and claims of the application, each of the words “comprise” “include” and “have”, and forms thereof, are not necessarily limited to members in a list with which the words may be associated. | A self-combusting ignition device comprising a hollow, funnel-shaped body made of a combustible material which is devoid of charcoal, said body having (a) a relatively narrow top opening and a relatively wide bottom opening, and (b) at least one ventilation conduit adjacent said relatively wide bottom opening. | 0 |
CROSS-REFERENCE
[0001] This application claims priority to U.S. Provisional Patent Application No. 60/519,986 filed 13 Nov. 2003, which is incorporated by reference herein.
FIELD OF THE INVENTION
[0002] The invention relates to the identification of a method and related compositions for inhibiting the metastatic capability of neoplastic cells in a patient. The methods and compositions comprise a PECAM-binding agent, such as an antibody, and methods of treating or preventing disease using a PECAM-binding agent to modulating invasiveness and metastatic potential of neoplastic cells.
BACKGROUND OF THE INVENTION
[0003] Oncogenesis was described by Foulds (1958) as a multistep biological process, which is presently known to occur by the accumulation of genetic damage. On a molecular level, the multistep process of tumorigenesis involves the disruption of both positive and negative regulatory effectors (Weinberg, 1989). The molecular basis for human colon carcinomas has been postulated, by Vogelstein and coworkers (1990), to involve a number of oncogenes, tumor suppressor genes and repair genes. Similarly, defects leading to the development of retinoblastoma have been linked to another tumor suppressor gene (Lee et al., 1987). Still other oncogenes and tumor suppressors have been identified in a variety of other malignancies. Unfortunately, there remains an inadequate number of treatable cancers, and the effects of cancer are catastrophic—over half a million deaths per year in the United States alone.
[0004] Cancer is fundamentally a genetic disease in which damage to cellular DNA leads to disruption of the normal mechanisms that control cellular proliferation. Two of the mechanisms of action by which tumor suppressors maintain genomic integrity is by cell arrest, thereby allowing for repair of damaged DNA, or removal of the damaged DNA by apoptosis (Ellisen and Haber, 1998; Evan and Littlewood, 1998). Apoptosis, otherwise called “programmed cell death,” is a carefully regulated network of biochemical events which act as a cellular suicide program aimed at removing irreversibly damaged cells. Apoptosis can be triggered in a number of ways including binding of tumor necrosis factor, DNA damage, withdrawal of growth factors, and antibody cross-linking of Fas receptors. Although several genes have been identified that play a role in the apoptotic process, the pathways leading to apoptosis have not been fully elucidated. Many investigators have attempted to identify novel apoptosis-promoting genes with the objective that such genes would afford a means to induce apoptosis selectively in neoplastic cells to treat cancer in a patient.
[0005] An alternative approach to treating cancer involves the suppression of angiogenesis with agent such as Endostatin™ or anti-VEGF antibodies. In this approach, the objective is to prevent further vascularization of the primary tumor and potentially to constrain the size of metastatic lesions to that which can support neoplastic cell survival without substantial vascular growth.
[0006] Platelet endothelial cell adhesion molecule (PECAM-1; CD31) is a protein found on endothelial cells and neutrophils and has been shown to be involved in the migration of leukocytes across the endothelium. The modulation of the activity of PECAM-1 for the treatment of cardiovascular conditions such as thrombosis, vascular occlusion stroke and for the treatment of or for reducing the occurrence of haemostasis disorders is disclosed in WO03055516A1. PECAM-1 has also been implicated in the inflammatory process and anti-PECAM-1 monoclonal antibody has been reported to block in vivo neutrophil recruitment (Nakada et al. (2000) J. Immunol. 164: 452-462). PECAM-1 knockout mice have been reported and appear to have normal leukocyte migration, platelet aggregaton, and vascular development, which implies that there are redundant adhesion molecules which can compensate for a loss of PECAM-1 (Duncan et al. (1999) J. Immunol. 162: 3022-3030). Monoclonal antibodies to PECAM-1 have been reported to block murine endothelial tube formation and related indicators of vascularization in a tumor transplantation model (Zhou et al. (1999) Angiogenesis 3: 181-188 and in a human skin transplantation model (Cao et al. (2002) Am. J. Physiol. Cell Physiol. 282: C1181-C1190). However, the role of PECAM-1 in tumor angiogenesis, if any, remains undefined.
[0007] Despite substantial efforts to inhibit cancer and the metastasis of tumors with anti-angiogenic strategies, to date there are no approved and marketed drugs for treating cancer solely by the inhibition of angiogenesis. Indeed the specific roles of various adhesion molecules, including PECAM-1, in the processes of neoplasia and metastasis are unknown.
[0008] There exists a need in the art for a method and related compositions for inhibiting the metastatic potential of cancer cells in patients. The present invention fulfills this need and provides related aspects desired by practitioners in the field.
[0009] The references discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention. All patent and literature publications referenced herein are incorporated by reference for all purposes as if the entire content of the disclosures were mechanically or electronically reproduced herein.
SUMMARY OF THE INVENTION
[0010] The present invention relates to the unexpected discovery that systemic administration of an antibody that binds to PECAM-1 supresses the metastatic spread of a wide variety of different tumor types which are typically fatal in humans, and this effect is achieved independent from any inhibition of angiogenesis, if any. This unexpected discovery provides a basis for the generation of novel anticancer treatments and medicaments, wherein provision of a systemic dosage of anti-PECAM antibody or a proxy that provides the same functional result is administered to a patient to inhibit or reduce the invasiveness and/or metastatic potential of neoplastic cells in the patient.
[0011] The present invention provides methods for repressing or preventing neoplastic transformation in a cell, the method comprising administering an anti-PECAM antibody systemically in an amount effective to inhibit the transformed phenotype and reduce the detectable invasiveness and/or metastatic potential of the cell. In an embodiment, the anti-PECAM antibody can bind to a PECAM located on a non-neoplastic somatic cell or it can bind to PECAM or a cross-reactive macromolecule present on a neoplastic cell.
[0012] An anti-PECAM binding species may be contacted with or introduced to a patient who has been diagnosed with a neoplasm through any of a variety of manners known to those of skill, however it is often preferred to deliver the anti-PECAM binding agent systemically. With regard to the invention, an anti-PECAM binding species can comprise an antibody, such as a humanized or human-sequence monoclonal antibody, and antibody fragment that comprises F(ab) 2 , F(ab′)2, F9ab, F(ab), Dab, Fv, scFv, Fc or a minimal recognition unit of an antibody that has the property of binding to human PECAM-1 with an affinity of at least about 1×10 8 M. Alternative binding species can also include, but are not limited to, proteinaceous binding multimers according to US20030157561A1 high-affinity peptides, and equivalents. In some embodiments, the anti-PECAM binding species is covalently linked to poly(ethylene)glycol (PEG), such as a 30K linear PEG, or 40K, 60K, or larger branched PEG—or larger linear or branched PEG moieties, either via single attachment or via multiple attachments.
[0013] In some embodiments of the present invention, the inventor's discovery that anti-PECAM binding species administered systemically is able to inhibit metastasis will be used in combination with other anti-transformation/anti-cancer therapies. These other therapies may be known at the time of this application, or may become apparent after the date of this application. For example, a humanized or human sequence anti-PECAM antibody may be used in combination with other therapeutic polypeptides, polynucleotides encoding other therapeutic polypeptides, or chemotherapeutic agents. In one representative embodiment, the chemotherapeutic agent is taxol. The anti-PECAM binding species also may be used in conjunction with radiotherapy. The type of ionizing radiation constituting the radiotherapy may be selected from the group comprising x-rays, gamma-rays, and microwaves. In certain embodiments, the ionizing radiation may be delivered by external beam irradiation or by administration of a radionuclide. The anti-PECAM binding species also may be used with gene therapy regimes.
[0014] The present invention also provides treatment methods for many human cancers. The treatment method comprises treating a patient having a diagnosed neoplasm, typically a carcinoma or sarcoma or other solid tumor type, with a systemic dosage of anti-PECAM binding species preferably delivered via subcutaneous or intravenous administration, or intrathecally into the brain to inhibit brain metastases. Preferred variations of the method include treating a patient having a diagnosed breast carcinoma, lung carcinoma, or colon carcinoma by administering an effective dose of an anti-PECAM binding species, such as a humanized or human-sequence anti-PECAM monoclonal antibody via a systemic route such as subcutaneous or intravenous.
[0015] In certain other aspects of the present invention there are provided therapeutic kits comprising in suitable container, a pharmaceutical formulation of an anti-PECAM binding species. Such a kit may further comprise a pharmaceutical formulation of a therapeutic polypeptide, polynucleotide encoding a therapeutic polypeptide, or chemotherapeutic agent. Such kits may comprise radiosensitizing agents, instructions for administration of an anti-PECAM binding species to a human patient diagnosed with a neoplasm—particularly a lung, colon, or breast neoplasm or in a variation a melanoma—via systemic delivery. In a preferred variation, the kit comprises a humanized or human sequence anti-PECAM monoclonal antibody which is PEGylated.
[0016] The invention also provides antibodies which bind to human PECAM-1 with an affinity of about at least 1×10 7 M −1 and which lack specific high affinity binding for a other PECAM-related polypeptides. Such antibodies may be used therapeutically by systemic, intracranial, or targeted delivery to neoplastic cells (e.g., by cationization or by liposome or immunoliposome delivery).
[0017] The invention also provides therapeutic agents which inhibit neoplasia, invasiveness and/or metastasis by modulating PECAM-1 function and which do not inhibit angiogenesis; such agents can be used as pharmaceuticals.
[0018] The invention provides a method for treating patients who have a diagnosed solid tumor and for whom angiogenesis inhibition would be detrimental; such as patients having recently suffered a myocardial infarction, congestive heart failure, stroke, atherosclerosis of the coronary vessels or cerebrovasculature, or who have a significant wound healing process resulting from injury or major surgery and which benefit from angiogenesis to aid healing or restore circulation.
[0019] In a variation of the invention, an immunogenic dose of a denatured human PECAM-1 or a non-human PCAM-1 such as primate, mouse, rat, dog, or pig PECAM-1 protein or a portion thereof is administered to a human patient diagnosed with a neoplasm, typically in combination with an adjuvant and/or a covalently-attached or non-attached immunostimulatory polynucleotide such as those disclosed by Dynavax or Coley Pharmaceuticals. In this way, the human patient is able to make an immune response, including an antibody response, which will crossreact with their own PECAM-1 protein which they are otherwise tolerized to.
[0020] A further understanding of the nature and advantages of the invention will become apparent by reference to the remaining portions of the specification and drawings.
[0021] Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
FIGURES
[0022] FIGS. 1A and 1B show the effects of antibody treatment in mice.
[0023] FIGS. 2A and 2B show effects of antibody treatment.
[0024] FIGS. 3A and 3B show effects of antibody treatment in mice.
[0025] FIGS. 4A and 4B show effects of antibody treatment in mice.
[0026] FIGS. 5A and 5B show effects of antibody treatment.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0027] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. For purposes of the present invention, the following terms are defined below.
[0028] The following patent documents are incorporated herein by reference: U.S. Pat. No. 5,968,511; WO0155178; U.S. Pat. No. 6,639,055; U.S. Pat. No. 6,133,426; WO03055516; WO02085405; and U.S. Pat. No. 6,627,196—including methods and materials described therein.
Definitions
[0029] The term “naturally-occurring” as used herein as applied to an object refers to the fact that an object can be found in nature. For example, a polypeptide or polynucleotide sequence that is present in an organism (including viruses) that can be isolated from a source in nature and which has not been intentionally modified by man in the laboratory is naturally-occurring. Generally, the term naturally-occurring refers to an object as present in a non-pathological (undiseased) individual, such as would be typical for the species.
[0030] The following terms are used to describe the sequence relationships between two or more polynucleotides: “reference sequence”, “comparison window”, “sequence identity”, “percentage of sequence identity”, and “substantial identity”. A “reference sequence” is a defined sequence used as a basis for a sequence comparison; a reference sequence may be a subset of a larger sequence, for example, as a segment of a full-length cDNA or gene sequence given in a sequence listing, such as a polynucleotide sequence of FIG. 2 , or may comprise a complete cDNA or gene sequence. Generally, a reference sequence is at least 20 nucleotides in length, frequently at least 25 nucleotides in length, and often at least 50 nucleotides in length. Since two polynucleotides may each (1) comprise a sequence (i.e., a portion of the complete polynucleotide sequence) that is similar between the two polynucleotides, and (2) may further comprise a sequence that is divergent between the two polynucleotides, sequence comparisons between two (or more) polynucleotides are typically performed by comparing sequences of the two polynucleotides over a “comparison window” to identify and compare local regions of sequence similarity.
[0031] A “comparison window”, as used herein, refers to a conceptual segment of at least 20 contiguous nucleotide positions wherein a polynucleotide sequence may be compared to a reference sequence of at least 20 contiguous nucleotides and wherein the portion of the polynucleotide sequence in the comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. Optimal alignment of sequences for aligning a comparison window may be conducted by the local homology algorithm of Smith and Waterman (1981) Adv. Appl. Math. 2: 482, by the homology alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48: 443, by the search for similarity method of Pearson and Lipman (1988) Proc. Natl. Acad. Sci . ( U.S.A .) 85: 2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package Release 7.0, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by inspection, and the best alignment (i.e., resulting in the highest percentage of homology over the comparison window) generated by the various methods is selected.
[0032] The term “sequence identity” means that two polynucleotide sequences are identical (i.e., on a nucleotide-by-nucleotide basis) over the window of comparison. The term “percentage of sequence identity” is calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U, or I) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity. The terms “substantial identity” as used herein denotes a characteristic of a polynucleotide sequence, wherein the polynucleotide comprises a sequence that has at least 80 percent sequence identity, preferably at least 85 percent identity and often 90 to 95 percent sequence identity, more usually at least 99 percent sequence identity as compared to a reference sequence over a comparison window of at least 20 nucleotide positions, frequently over a window of at least 25-50 nucleotides, wherein the percentage of sequence identity is calculated by comparing the reference sequence to the polynucleotide sequence which may include deletions or additions which total 20 percent or less of the reference sequence over the window of comparison. The reference sequence may be a subset of a larger sequence.
[0033] As applied to polypeptides, the term “substantial identity” means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 80 percent sequence identity, preferably at least 90 percent sequence identity, more preferably at least 95 percent sequence identity or more (e.g., 99 percent sequence identity). Preferably, residue positions which are not identical differ by conservative amino acid substitutions.
[0034] Conservative amino acid substitutions refer to the interchangeability of residues having similar side chains. For example, a group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic-hydroxyl side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; and a group of amino acids having sulfur-containing side chains is cysteine and methionine. Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, and asparagine-glutamine.
[0035] The term “fragment” as used herein refers to a polypeptide that has an amino-terminal and/or carboxy-terminal deletion, but where the remaining amino acid sequence is identical to the corresponding positions in the sequence deduced from a full-length cDNA. Fragments typically are at least 14 amino acids long, preferably at least 20 amino acids long, usually at least 50 amino acids long or longer, up to the length of a full-length naturally-occurring polypeptide.
[0036] The term “agent” is used herein to denote a chemical compound, a mixture of chemical compounds, an array of spatially localized compounds (e.g., a VLSIPS peptide array, polynucleotide array, and/or combinatorial small molecule array), a biological macromolecule, a bacteriophage peptide display library, a bacteriophage antibody (e.g., scFv) display library, a polysome peptide display library, or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Agents are evaluated for potential activity as antineoplastics, anti-inflammatories, or apoptosis modulators by inclusion in screening assays described hereinbelow. Agents are evaluated for potential activity as specific protein interaction inhibitors (i.e., an agent which selectively inhibits a binding interaction between two predetermined polypeptides but which does not substantially interfere with cell viability) by inclusion in screening assays described hereinbelow.
[0037] The term “protein interaction inhibitor” is used herein to refer to an agent which is identified by one or more screening method(s) of the invention as an agent which selectively inhibits protein-protein binding between a first interacting polypeptide and a second interacting polypeptide. Some protein interaction inhibitors may have therapeutic potential as drugs for human use and/or may serve as commercial reagents for laboratory research or bioprocess control. Protein interaction inhibitors which are candidate drugs are then tested further for activity in assays which are routinely used to predict suitability for use as human and veterinary drugs, including in vivo administration to non-human animals and often including administration to human in approved clinical trials.
[0038] The term “antineoplastic agent” is used herein to refer to agents that have the functional property of inhibiting a development or progression of a neoplasm in a human, particularly a metastasis-prone solid tumor type.
[0039] As used herein, the terms “label” or “labeled” refers to incorporation of a detectable marker, e.g., by incorporation of a radiolabeled amino acid or attachment to a polypeptide of biotinyl moieties that can be detected by marked avidin (e.g., streptavidin containing a fluorescent marker or enzymatic activity that can be detected by optical or calorimetric methods). Various methods of labeling polypeptides and glycoproteins are known in the art and may be used. Examples of labels for polypeptides include, but are not limited to, the following: radioisotopes (e.g., 3 H, 14 C, 35 S, 125 I, 131 I), fluorescent labels (e.g., FITC, rhodamine, lanthanide phosphors), enzymatic labels (e.g., horseradish peroxidase, β-galactosidase, luciferase, alkaline phosphatase), biotinyl groups, predetermined polypeptide epitopes recognized by a secondary reporter (e.g., leucine zipper pair sequences, binding sites for secondary antibodies, transcriptional activator polypeptide, metal binding domains, epitope tags). In some embodiments, labels are attached by spacer arms of various lengths to reduce potential steric hindrance.
[0040] As used herein, “substantially pure” means an object species is the predominant species present (i.e., on a molar basis it is more abundant than any other individual macromolecular species in the composition), and preferably a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all macromolecular species present. Generally, a substantially pure composition will comprise more than about 80 to 90 percent of all macromolecular species present in the composition. Most preferably, the object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single macromolecular species. Solvent species, small molecules (<500 Daltons), and elemental ion species are not considered macromolecular species.
[0041] As used herein “normal blood” or “normal human blood” refers to blood from a healthy human individual who does not have an active neoplastic disease or other disorder of lymphocytic proliferation, or an identified predisposition for developing a neoplastic disease. Similarly, “normal cells”, “normal cellular sample”, “normal tissue”, and “normal lymph node” refers to the respective sample obtained from a healthy human individual who does not have an active neoplastic disease or other lymphoproliferative disorder.
[0042] As used herein the term “physiological conditions” refers to temperature, pH, ionic strength, viscosity, and like biochemical parameters which are compatible with a viable organism, and/or which typically exist intracellularly in a viable cultured yeast cell or mammalian cell. For example, the intracellular conditions in a yeast cell grown under typical laboratory culture conditions are physiological conditions. Suitable in vitro reaction conditions for in vitro transcription cocktails are generally physiological conditions. In general, in vitro physiological conditions comprise 50-200 mM NaCl or KCl, pH 6.5-8.5, 20-45° C. and 0.001-10 mM divalent cation (e.g., Mg ++ , Ca ++ ); preferably about 150 mM NaCl or KCl, pH 7.2-7.6, 5 mM divalent cation, and often include 0.01-1.0 percent nonspecific protein (e.g., BSA). A non-ionic detergent (Tween, NP-40, Triton X-100) can often be present, usually at about 0.001 to 2%, typically 0.05-0.2% (v/v). Particular aqueous conditions may be selected by the practitioner according to conventional methods. For general guidance, the following buffered aqueous conditions may be applicable: 10-250 mM NaCl, 5-50 mM Tris HCl, pH 5-8, with optional addition of divalent cation(s) and/or metal chelators and/or nonionic detergents and/or membrane fractions and/or antifoam agents and/or scintillants.
[0043] As used herein, the terms “interacting polypeptide segment” and “interacting polypeptide sequence” refer to a portion of a hybrid protein which can form a specific binding interaction with a portion of a second hybrid protein under suitable binding conditions. Generally, a portion of the first hybrid protein preferentially binds to a portion of the second hybrid protein forming a heterodimer or higher order heteromultimer comprising the first and second hybrid proteins; the binding portions of each hybrid protein are termed interacting polypeptide segments. Generally, interacting polypeptides can form heterodimers with a dissociation constant (K D ) of at least about 1×10 3 M −1 , usually at least 1×10 4 M −1 , typically at least 1×10 5 M −1 , preferably at least 1×10 6 M −1 to 1×10 7 M −1 or more, under suitable physiological conditions.
[0044] As used herein, the term “multimer” comprises dimer and higher order complexes (trimer, tetramer, pentamer, hexamer, heptamer, octamer, etc.). “Homomultimer” refers to complexes comprised of the same subunit species. “Heteromultimer” refers to complexes comprised of more than one subunit species.
[0045] The term “recombinant” used herein refers to PECAM-1 produced by recombinant DNA techniques wherein the gene coding for protein is cloned by known recombinant DNA technology. For example, the human gene for PECAM-1 may be inserted into a suitable DNA vector, such as a bacterial plasmid, and the plasmid used to transform a suitable host. The gene is then expressed in the host to produce the recombinant protein. The transformed host may be prokaryotic or eukaryotic, including mammalian, yeast, Aspergillus and insect cells.
[0046] “Antibodies” (Abs) and “immunoglobulins” (Igs) are glycoproteins having the same structural characteristics. While antibodies exhibit binding specificity to a specific antigen, immunoglobulins include both antibodies and other antibody-like molecules which lack antigen specificity. Polypeptides of the latter kind are, for example, produced at low levels by the lymph system and at increased levels by myelomas. The term “antibody” is used in the broadest sense and specifically covers, without limitation, intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity.
[0047] “Native antibodies” and “native immunoglobulins” are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains. Each light chain has a variable domain at one end (VL) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light-chain variable domain is aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light- and heavy-chain variable domains.
[0048] The term “variable” refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. However, the variability is not evenly distributed throughout the variable domains of antibodies. It is concentrated in three segments called complementarity-determining regions (CDRs) or hypervariable regions both in the light-chain and the heavy-chain variable domains. The more highly conserved portions of variable domains are called the framework (FR) regions. The variable domains of native heavy and light chains each comprise four FR regions, largely adopting a beta-sheet configuration, connected by three CDRs, which form loops connecting, and in some cases forming part of, the beta-sheet structure. The CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., NIH Publ. No. 91-3242, Vol. I, pages 647-669 (1991)). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity.
[0049] The term “hypervariable region” when used herein refers to the amino acid residues of an antibody which are responsible for antigen-binding. The hypervariable region comprises amino acid residues from a “complementarity determining region” or “CDR” (i.e., residues 24-34 (L1), 50-56 (L2) and 89-97 (L3) in the light chain variable domain and 31-35 (H1), 50-65 (H2) and 95-102 (H3) in the heavy chain variable domain; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institute of Health, Bethesda, Md. [1991]) and/or those residues from a “hypervariable loop” (i.e., residues 26-32 (L1), 50-52 (L2) and 91-96 (L3) in the light chain variable domain and 26-32 (H1), 53-55 (H2) and 96-101 (H3) in the heavy chain variable domain; Clothia and Lesk, J. Mol. Biol., 196:901-917 [1987]). “Framework” or “FR” residues are those variable domain residues other than the hypervariable region residues as herein defined.
[0050] “Antibody fragments” comprise a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab′, F(ab′).sub.2, and Fv fragments; diabodies; linear antibodies (Zapata et al., Protein Eng., 8(10): 1057-1062 [1995]); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.
[0051] Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single antigen-binding site, and a residual “Fc” fragment, whose name reflects its ability to crystallize readily. Pepsin treatment yields an F(ab′).sub.2 fragment that has two antigen-combining sites and is still capable of cross-linking antigen.
[0052] “Fv” is the minimum antibody fragment which contains a complete antigen-recognition and -binding site. This region consists of a dimer of one heavy- and one light-chain variable domain in tight, non-covalent association. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the V.sub.H-V.sub.L dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
[0053] The Fab fragment also contains the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. Fab fragments differ from Fab′ fragments by the addition of a few residues at the carboxy terminus of the heavy chain CH1 domain including one or more cysteines from the antibody hinge region. Fab′-SH is the designation herein for Fab′ in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab′)2 antibody fragments originally were produced as pairs of Fab′ fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.
[0054] The “light chains” of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa (.kappa.) and lambda (.lambda.), based on the amino acid sequences of their constant domains.
[0055] Depending on the amino acid sequence of the constant domain of their heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA, and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are known.
[0056] The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, ie., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to conventional (polyclonal) antibody preparations which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, the monoclonal antibodies are advantageous in that they are synthesized by the hybridoma culture, uncontaminated by other immunoglobulins. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al., Nature 256:495 [1975], or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). The “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al., Nature, 352:624-628 [1991] and Marks et al., J. Mol. Biol., 222:581-597 (1991), for example.
[0057] The monoclonal antibodies herein specifically include “chimeric” antibodies (immunoglobulins) in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Pat. No. 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 [1984]).
[0058] “Humanized” forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab′, F(ab′).sub.2 or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a CDR of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity, and capacity. In some instances, Fv FR residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. These modifications are made to further refine and maximize antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fe), typically that of a human immunoglobulin. For further details, see, Jones et al., Nature, 321:522-525 (1986); Reichmann et al., Nature, 332:323-329 [1988]; and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992). The humanized antibody include PRIMATIZED™ antibody wherein the antigen-binding region of the antibody is derived from an antibody produced by immunizing macaque monkeys with the antigen of interest.
[0059] “Single-chain Fv” or “sFv” antibody fragments comprise the V.sub.H and V.sub.L domains of antibody, wherein these domains are present in a single polypeptide chain. Preferably, the Fv polypeptide further comprises a polypeptide linker between the V.sub.H and V.sub.L domains which enables the sFv to form the desired structure for antigen binding. For a review of sFv see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).
[0060] The term “diabodies” refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (V.sub.H) connected to a light-chain variable domain (V.sub.L) in the same polypeptide chain (V.sub.H-V.sub.L). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Diabodies are described more fully in, for example, EP 404,097; WO 93/11161; and Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).
[0061] An “isolated” antibody is one which has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials which would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. In preferred embodiments, the antibody will be purified (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain. Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step.
DETAILED DESCRIPTION OF THE INVENTION
[0062] The nomenclature used hereafter and the laboratory procedures in cell culture, molecular genetics, and nucleic acid chemistry and hybridization described below may involve well known and commonly employed procedures in the art. Standard techniques are used for recombinant nucleic acid methods, polynucleotide synthesis, and microbial culture and transformation (e.g., electroporation, lipofection). The techniques and procedures are generally performed according to conventional methods in the art and various general references (see, generally, Sambrook et al. Molecular Cloning: A Laboratory Manual, 2d ed. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., which is incorporated herein by reference) which are provided throughout this document.
[0063] Oligonucleotides can be synthesized on an Applied Bio Systems oligonucleotide synthesizer according to specifications provided by the manufacturer.
[0064] Methods for PCR amplification are described in the art ( PCR Technology: Principles and Applications for DNA Amplification ed. H A Erlich, Freeman Press, New York, N.Y. (1992); PCR Protocols: A Guide to Methods and Applications , eds. Innis, Gelfland, Snisky, and White, Academic Press, San Diego, Calif. (1990); Mattila et al. (1991) Nucleic Acids Res. 19: 4967; Eckert, K. A. and Kunkel, T. A. (1991) PCR Methods and Applications 1: 17; PCR, eds. McPherson, Quirkes, and Taylor, IRL Press, Oxford; and U.S. Pat. No. 4,683,202, which are incorporated herein by reference).
Production and Applications of α-PECAM Antibodies
[0065] Native human PECAM-1 proteins, fragments thereof, or analogs thereof, may be used to immunize an animal for the production of specific antibodies. These antibodies may comprise a polyclonal antiserum or may comprise a monoclonal antibody produced by hybridoma cells. For general methods to prepare antibodies, see Antibodies: A Laboratory Manual , (1988) E. Harlow and D. Lane, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., which is incorporated herein by reference.
[0066] For example but not for limitation, a recombinantly produced fragment of PECAM-1 can be injected into a mouse along with an adjuvant following immunization protocols known to those of skill in the art so as to generate an immune response. Typically, approximately at least 1-50 μg of a PECAM-1 fragment or analog is used for the initial immunization, depending upon the length of the polypeptide. Alternatively or in combination with a recombinantly produced PECAM-1 polypeptide, a chemically synthesized peptide having a PECAM-1 sequence may be used as an immunogen to raise antibodies which bind a PECAM-1 protein, such as the native PECAM-1 polypeptide having the sequence shown essentially in FIG. 1( a ), a native human PECAM-1 polypeptide, a polypeptide comprising a PECAM-1 epitope, or a PECAM-1 fusion protein. Immunoglobulins which bind the recombinant fragment with a binding affinity of at least 1×10 7 M −1 can be harvested from the immunized animal as an antiserum, and may be further purified by immunoaffinity chromatography or other means. Additionally, spleen cells are harvested from the immunized animal (typically rat or mouse) and fused to myeloma cells to produce a bank of antibody-secreting hybridoma cells. The bank of hybridomas can be screened for clones that secrete immunoglobulins which bind the recombinantly-produced PECAM-1 polypeptide (or chemically synthesized PECAM-1 polypeptide) with an affinity of at least 1×10 6 M −1 . Animals other than mice and rats may be used to raise antibodies; for example, goats, rabbits, sheep, and chickens may also be employed to raise antibodies reactive with a PECAM-1 protein. Transgenic mice having the capacity to produce substantially human antibodies also may be immunized and used for a source of α-PECAM-1 antiserum and/or for making monoclonal-secreting hybridomas.
[0067] Bacteriophage antibody display libraries may also be screened for binding to a PECAM-1 polypeptide, such as a full-length PECAM-1 protein, a PECAM-1 fragment, or a fusion protein comprising a PECAM-1 polypeptide sequence comprising a PECAM-1 epitope (generally at least 3-5 contiguous amino acids). Generally such PECAM-1 peptides and the fusion protein portions consisting of PECAM-1 sequences for screening antibody libraries comprise about at least 3 to 5 contiguous amino acids of PECAM-1, frequently at least 7 contiguous amino acids of PECAM-1, usually comprise at least 10 contiguous amino acids of PECAM-1, and most usually comprise a PECAM-1 sequence of at least 14 contiguous amino acids.
[0068] Combinatorial libraries of antibodies have been generated in bacteriophage lambda expression systems which may be screened as bacteriophage plaques or as colonies of lysogens (Huse et al. (1989) Science 246: 1275; Caton and Koprowski (1990) Proc. Natl. Acad. Sci . ( U.S.A .) 87: 6450; Mullinax et al (1990) Proc. Natl. Acad. Sci . ( U.S.A .) 87: 8095; Persson et al. (1991) Proc. Natl. Acad. Sci . ( U.S.A .) 88: 2432). Various embodiments of bacteriophage antibody display libraries and lambda phage expression libraries have been described (Kang et al. (1991) Proc. Natl. Acad. Sci . ( U.S.A .) 88: 4363; Clackson et al. (1991) Nature 352: 624; McCafferty et al. (1990) Nature 348: 552; Burton et al. (1991) Proc. Natl. Acad. Sci . ( U.S.A .) 88: 10134; Hoogenboom et al. (1991) Nucleic Acids Res. 19: 4133; Chang et al. (1991) J. Immunol. 147: 3610; Breitling et al. (1991) Gene 104: 147; Marks et al. (1991) J. Mol. Biol. 222: 581; Barbas et al. (1992) Proc. Natl. Acad. Sci . ( U.S.A .) 89: 4457; Hawkins and Winter (1992) J. Immunol. 22: 867; Marks et al. (1992) Biotechnology 10: 779; Marks et al. (1992) J. Biol. Chem. 267: 16007; Lowman et al (1991) Biochemistry 30: 10832; Lerner et al. (1992) Science 258: 1313, incorporated herein by reference). Typically, a bacteriophage antibody display library is screened with a PECAM-1 polypeptide that is immobilized (e.g., by covalent linkage to a chromatography resin to enrich for reactive phage by affinity chromatography) and/or labeled (e.g., to screen plaque or colony lifts).
[0069] PECAM-1 polypeptides which are useful as immunogens, for diagnostic detection of α-PECAM-1 antibodies in a sample, for diagnostic detection and quantitation of PECAM-1 protein in a sample (e.g., by standardized competitive ELISA), or for screening a bacteriophage antibody display library, are suitably obtained in substantially pure form, that is, typically about 50 percent (w/w) or more purity, substantially free of interfering proteins and contaminants. Preferably, these polypeptides are isolated or synthesized in a purity of at least 80 percent (w/w) and, more preferably, in at least about 95 percent (w/w) purity, being substantially free of other proteins of humans, mice, or other contaminants.
[0070] For some applications of these antibodies, such as identifying immunocrossreactive proteins, the desired antiserum or monoclonal antibody(ies) is/are not monospecific. In these instances, it may be preferable to use a synthetic or recombinant fragment of PECAM-1 as an antigen rather than using the entire native protein. Production of recombinant or synthetic fragments having such defined amino- and carboxy-termini is provided by the PECAM-1.
[0071] If an antiserum is raised to a PECAM-1 fusion polypeptide, such as a fusion protein comprising a PECAM-1 immunogenic epitope fused to β-galactosidase or glutathione S-transferase, the antiserum is preferably preadsorbed with the non-PECAM-1 fusion partner (e.g, β-galactosidase or glutathione S-transferase) to deplete the antiserum of antibodies that react (i.e., specifically bind to) the non-PECAM-1 portion of the fusion protein that serves as the immunogen. Monoclonal or polyclonal antibodies which bind to the human and/or murine PECAM-1 protein can be used to detect the presence of human or murine PECAM-1 polypeptides in a sample, such as a Western blot of denatured protein (e.g., a nitrocellulose blot of an SDS-PAGE) obtained from a lymphocyte sample of a patient. Preferably quantitative detection is performed, such as by denistometric scanning and signal integration of a Western blot. The monoclonal or polyclonal antibodies will bind to the denatured PECAM-1 epitopes and may be identified visually or by other optical means with a labeled second antibody or labeled Staphylococcus aureus protein A by methods known in the art.
[0072] One use of such antibodies is to screen cDNA expression libraries, preferably containing cDNA derived from human or murine mRNA from various tissues, for identifying clones containing cDNA inserts which encode structurally-related, immunocrossreactive proteins, that are candidate novel PECAM-1 binding factors or PECAM-1-related proteins. Such screening of cDNA expression libraries is well known in the art, and is further described in Young et al., Proc. Natl. Acad. Sci. U.S.A. 80:1194-1198 (1983), which is incorporated herein by reference) as well as other published sources. Another use of such antibodies is to identify and/or purify immunocrossreactive proteins that are structurally or evolutionarily related to the native PECAM-1 protein or to the corresponding PECAM-1 fragment (e.g., functional domain; PECAM-1-interacting protein binding domain) used to generate the antibody. The anti-PECAM-1 antibodies of the invention can be used to measure levels of PECAM-1 protein in a cell or cell population, for example in a cell explant (e.g., lymphocyte sample) obtained from a patient. The anti-PECAM-1 antibodies can be used to measure the corresponding protein levels by various methods, including but not limited to: (1) standardized ELISA on cell extracts, (2) immunoprecipitation of cell extracts followed by polyacrylamide gel electrophoresis of the immunoprecipitated products and quantitative detection of the band(s) corresponding to PECAM-1, and (3) in situ detection by immunohistochemical straining with the anti-PECAM-1 antibodies and detection with a labeled second antibody. The measurement of the ratio of PECAM-1 to control housekeeping proteins in a cell or cell population is informative regarding the invasive and metastatic status of the cell or cell population.
[0073] An antiserum which can be utilized for this purpose can be obtained by conventional procedures. One exemplary procedure involves the immunization of a mammal, such as rabbits, which induces the formation of polyclonal antibodies against PECAM-1. Monoclonal antibodies are also being generated from already immunized hamsters. This antibody can be used to detect the presence and level of the PECAM-1 protein.
[0074] It is also possible to use the proteins for the immunological detection of PECAM-1 and associations thereof with standard assays as well as assays using markers, which are radioimmunoassays or enzyme immunoassays.
[0075] The detection and determination of PECAM-1 has significant diagnostic importance. For example, the detection of a PECAM-1 decline favoring invasiveness and metastasis would be advantageous in cancer therapy and controlling hypertrophies. The detection or determination of proteins favoring metastasis and invasion will be beneficial in detecting and diagnosing cancer, neurodegenerative diseases, and ischemic cell death. Thus these proteins and their antibodies can be employed as a marker to monitor, check or detect the course of disease.
[0076] Cross-linked complexes of PECAM-1 with PECAM-1-interacting polypeptides can be used as immunogens, and the resultant antisera preadsorbed with PECAM-1 and PECAM-1-interacting polypeptide such that the remaining antisera comprises antibodies which bind conformational epitopes present on the complexes but not the monomers (e.g., complex-specific epitopes). Complex-specific hybridomas and monoclonal antibodies can be similarly generated. Such antibodies can be used diagnostically to detect and quantitate the presence of specific complexes and correlate this data with disease or cell type, and the like.
[0077] Methods for humanizing non-human antibodies are well known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as “import” residues, which are typically taken from an “import” variable domain. Humanization can be essentially performed following the method of Winter and co-workers [Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al. Science 239:1534-1536 (1988)], by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such “humanized” antibodies are chimeric antibodies (U.S. Pat. No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.
[0078] Human antibodies can also be produced using various techniques known in the art, including phage display libraries [Hoogenboom and Winter, J. Mol. Biol. 227:381 (1991); Marks et al., J. Mol. Biol. 222:581 (1991)]. The techniques of Cole et al., and Boerner et al., are also available for the preparation of human monoclonal antibodies (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boerner et al., J. Immunol., 147(1):86-95 (1991)]. Similarly, human antibodies can be made by introducing of human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in the following scientific publications: Marks et al., Bio/Technology, 10:779-783 (1992); Lonberg et al., Nature, 368:856-859 (1994); Morrison, Nature, 368:812-13 (1994); Fishwild et al., Nature Biotechnology, 14:845-51 (1996); Neuberger, Nature Biotechnology, 14:826 (1996); Lonberg and Huszar, Intern. Rev. Immunol., 13:65-93 (1995).
[0079] Therapeutic formulations of the antibody are prepared for storage by mixing the antibody having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences, 16th edition, Osol, A. ed. [1980]), in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).
[0080] The anti-PECAM binding species of the present invention can be administered to a cancer patient in conjunction with other chemotherapeutic agents and radiotherapy sensitizers.
[0081] The following examples are given to illustrate the invention, but are not to be limiting thereof. All percentages given throughout the specification are based upon weight unless otherwise indicated. All protein molecular weights are based on mean average molecular weights unless otherwise indicated.
[0082] The foregoing description of the preferred embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the invention to the precise form disclosed, and many modifications and variations are possible in light of the above teaching.
[0083] Such modifications and variations which may be apparent to a person skilled in the art are intended to be within the scope of this invention.
EXPERIMENTAL EXAMPLES
Materials and Methods
[0084] Female mice 6-8 weeks of age were used for all studies. C57B1/6 and BalbC mice were purchased from Simonson Labs, (Gilroy, Calif.), and the Nu/Nu mice were purchased from Charles River. Tumor cells were inoculated by tail vein injection. For the B16-F10 murine melanoma tumor and Lewis Lung carcinoma highly metastatic (LLC-HM) lung cancer models, each C57B1/6 mouse received 25,000 tumor cells suspended in 200 μl of culture media. For the 4T1 murine breast cancer and CT26 murine colon cancer models, each Balb/C mouse received 50,000 tumor cells tumor cells suspended in 200 μl of culture media. For the Lox cell human melanoma xenograft model, Nu/Nu mice received a total of 2.5 million Lox cells in culture media in two separate tail vein injections. The first injection was administered in the morning and the second injection four hours later. Each injection contained 1.25 million cells in 300 μl of culture media.
[0085] For the first set of experiments, groups of eight mice received 25,000 B16-F10 tumor cells by tail vein injection on day 0, and then received 5 doses of 200 μg of either rat anti-mouse anti-PECAM-1 (mAb 390) (provided by Dr. H. Delisser, University of Pennsylvania) or Rat IgG2(a) isotype control antibody (Sigma) by the following schedules. One group of mice received 5 doses of 200 μg of either rat anti-mouse anti-PECAM-1 (mAb 390) or Rat IgG2(a) isotype control antibody starting on day 0 (just after tumor cell injection), and then on days 1, 3, 6 and 8. In addition, one group of mice received 5 doses of 200 μg of either rat anti-mouse anti-PECAM-1 (mAb 390) or Rat IgG2(a) isotype control antibody starting on day 7 after tumor cell injection, and then on days 8, 10, 13 and 15. Mice bearing CT26, 4T1 B16 and Lox cells were sacrificed on days 20, 22, 23, and 28 after tumor cell inoculation, respectively.
[0086] In each case, all mice from the respective group were sacrificed when an index animal looked seriously ill or died, and significant numbers of lung tumors were documented following sacrifice and analysis of dissected lungs. Lungs from each mouse were dissected out and then weighed. The lungs then were infused intra-tracheally with 5% buffered formalin for mice bearing B16-F10 melanoma. For all other tumor-bearing mice (the 4T1, CT26, LLC-HM and Lox tumor models), the lungs were then were infused intra-tracheally with the fixative solution containing Indian ink. All lung samples were then fixed in 5% buffered formalin (50% of 10% buffered formalin (Fisher) and 50% PBS). Lung tumors were counted under a dissecting microscope by an observer blinded to which group from which they came. The potential significance of differences between various groups was assessed using an unpaired, two-sided Student's t Test.
[0087] Subsequently, the lungs were subjected to the following studies. Mitotic and apoptotic figures were counted on four-micron hematoxylin and eosin stained slides using a conventional light microscope. Actual counts of mitotic and apoptotic figures were made from the ten largest nodules. Apoptotic bodies and mitotic figures were counted according to previously described morphologic criteria (1, 2). The apoptotic and mitotic rate were calculated based on the degree of tumor cellularity, and expressed as the number of apoptotic or mitotic figures per thousand cells. In situ detection of cleaved, apoptotic DNA fragments (TUNEL) was performed using the TdT-FragEL Detection Kit (Oncogene Science) according to the manufacturer's protocol. The frequency of labeled cells was calculated by counting at least 1,000 cells in areas with the highest number of TdT labeled nuclei. Matrigel assay and Boyden chamber analysis were performed as described (3). All analyses of apoptosis, mitosis, angiogenesis and histopathology were performed by an investigator blinded to the identity of the specimens being assessed. Expression of PECAM-1 on the various tumor cell lines assessed was performed by FACS analysis.
REFERENCES
[0000]
1. Kerr, J. F., Wyllie, A. H., & Currie, A. R. (1972) Br. J. Cancer 26, 239-257.
2. van Diest, P. J., Brugal, G., & Baak, J. P. (1998) J. Clin. Pathol. 51, 716-724.
3. Desprez, P. Y., Lin, C. Q., Thomasset, N., Sympson, C. J., Bissell, M. J., & Campisi, J. (1998) Mol. Cell. Biol. 18, 4577-4588.
Results of the Anti-Metastatic Tumor Studies:
[0091] Binding of anti of anti-PECAM-1 antibody to the various tumor cell lines tested.
[0092] Binding of anti-PECAM-1 antibody to murine B16-F10 melanoma cells, murine 4T1 mammary carcinoma cells and murine Lewis Lung carcinoma-highly metastatic (LLC-HM) cells was assessed.
[0093] No PECAM-1 expression (no specific binding of anti-PECAM-1 antibody to any of these cell types was detected (data not shown)). Analysis of PECAM-1 expression on murine CT26 colon tumor cells and human LOX melanoma cells is pending.
[0094] Effects of anti-PECAM-1 on the metastatic progression of B16-F10 melanoma. We first compared the potential anti-tumor effects of five, 200 μg intravenous doses of either anti-PECAM-1 or IgG isotype control antibody, with treatment initiated either on the day of tumor injection (day 0) or 7 days after tumor cell injection (day 7). Injection of IgG isotype control antibody, beginning on either day 0 or day 7, as well as injection of anti-PECAM-1 antibody beginning on day 0 had no effect on either total lung weight (an indicator of overall metastatic burden) or the total number of metastatic lung tumors, when compared to untreated, tumor-bearing control mice. The lack of anti-tumor efficacy produced by anti-PECAM antibody therapy initiated on day 0 contrasts with the results of a prior study testing this dose and schedule of anti-PECAM antibody against locally-inoculated, sub-cutaneous B16 melanoma tumors. In this prior study, five, 200 μg intraperitoneal doses of the same anti-PECAM-1 antibody begun on the same day (day 0) as local sub-cutaneous inoculation of B16 melanoma tumors did produce significant anti-tumor activity, significantly reducing both local tumor growth, as well as significantly reducing tumor angiogenesis (Zhou et al. Angiogenesis 3: 181-188, 1999). In contrast, our studies demonstrated that injection of this same anti-PECAM-1 antibody beginning on day 0 showed no anti-tumor activity against B16 melanoma lung metastases. However, we discovered that intravenous injection of anti-PECAM-1 antibody beginning on day 7 after tumor cell injection was highly effective against metastatic B16 melanoma tumors, significantly reducing both total lung weights (p 0.005) and the total number of metastatic B16-F10 melanoma lung tumors (p<0.0001), when compared to control mice ( FIGS. 1A and 1B ). Thus, anti-tumor results obtained using IP-administered anti-PECAM antibody against local tumors can differ substantially from those obtained using intravenously-injected anti-PECAM antibody against metastatic tumors.
[0095] We then attempted to repeat these results in a follow-up experiment, again comparing the effects of either the anti-PECAM-1 antibody or the isotype control, initiated 7 days after IV injection of B16-F10 cells. We found that anti-PECAM-1 antibody significantly reduced both total lung weights (p<0.05) and the total number of lung tumors (p<0.0001) when compared to B16-F10-bearing mice treated with the same schedule and dose of isotype control antibody ( FIGS. 2A and 2B ). (We used isotype control antibody treated mice as controls in all subsequent experiments because we previously showed that total lung weights and total numbers of lung tumors do not differ between mice treated with isotype control antibody and untreated mice (see FIGS. 1A and 1B )). Anti-PECAM antibody therapy initiated on day 7 after tumor cell injection again significantly reduced overall tumor burden and the total number of lung metastatic tumors, as we had previously observed in experiment 1 above. Intraperitoneal administration of this same anti-PECAM antibody has previously been reported to significantly reduce tumor angiogenesis in subcutaneously inoculated B16 melanoma tumors. We assessed tumor angiogenesis, as well tumor apoptotic and mitotic rates in B16-F10 lung tumors from the anti-PECAM- and isotype control antibody-injected groups. Surprisingly, the number of blood vessels in lung tumors appeared higher in the anti-PECAM-treated group (17.9+4.5 tumor blood vessels/HPF (avg+S.E.)) than the isotype control-treated group (8.79+2.9), although this difference did not approach statistical significance (p=0.12). The level of tumor apoptosis (9.9+1.1) in anti-PECAM- versus isotype control-treated mice (9.7+0.8) was also comparable. However, the rate of mitosis in tumor cells was significantly higher (p<0.05) in isotype control-treated mice (4.7+0.5) versus anti-PECAM-treated mice (2.9+0.7). Histopathologically, tumor necrosis, hemorrhage, pulmonary congestion and/or intravascular emboli were noted in 7 of 9 isotype control antibody-treated mice, whereas none of these findings were noted in anti-PECAM-1 antibody-treated mice (data not shown). Overall, anti-PECAM antibody therapy significantly reduced the total numbers of metastatic B16-F10 tumors and overall tumor burden, as well as significantly reducing tumor cell mitotic rates and lung histopathologic changes. Anti-PECAM-1 antibody therapy did not reduce either tumor angiogenesis or tumor apoptosis.
[0096] To demonstrate that the anti-metastatic activity of anti-PECAM-1 antibody was specific for a broad spectrum of solid tumors, in addition to B16-F10 melanoma tumors, we then tested its potential anti-metastatic activity against a variety of other tumor cell lines injected into mice. These lines included murine 4T1 mammary carcinoma cells, murine CT26 colon tumor cells, murine Lewis Lung carcinoma-highly metastatic (LLC-HM) cells and human LOX melanoma cells. We used established protocols for generating the metastatic spread of each of these lines, as described in the materials and methods section above. We found that five, 200 μg doses of IV, anti-PECAM antibody therapy initiated on day 7 produced significant anti-metastatic activity against each of these tumor lines in tumor-bearing mice.
[0097] Specifically, anti-PECAM antibody was highly effective against the metastatic spread of 4T1 mammary carcinoma tumors, producing significant reductions of total tumor burden (p<0.005) and total metastatic lung tumors (p<0.0001), when compared to isotype control antibody-treated mice (see FIGS. 3A and 3B ). Again contrary to previous reports by others, even though anti-PECAM antibody therapy was highly effective against the metastatic spread of 4T1 tumors, it had no effect on tumor vascularity, since anti-PECAM-treated mice showed 27.8+2.5 tumor blood vessels/HPF, whereas isotype control-treated mice showed 26.5+2.1 tumor blood vessels/HPF (data not shown). Thus, unlike the anti-tumor effects of this same anti-PECAM antibody against sub-cutaneous tumors (Zhou et al. Angiogenesis 3: 181-188, 1999), anti-PECAM antibody effects against metastatic tumors does not appear to be mediated through effects on tumor angiogenesis. (The analysis the effects of anti-PECAM antibody on tumor mitotic and apoptotic rates for 4T1 tumors is in progress).
[0098] Anti-PECAM antibody was less active against the metastatic spread of CT26 colon tumors, but still significantly reduced the total number of metastatic lung tumors (p<0.05), when compared to isotype control antibody-treated mice (see FIGS. 4A and 4B ).
[0099] Anti-PECAM antibody therapy did not significantly reduce (p=0.74) lung weights in mice bearing LLC-HM tumors (0.85±0.2 gm) when compared to isotype control antibody-treated mice (0.94±0.1 gm). Since lung metastases grew largely as confluent masses rather than discrete tumors in this experiment, it was not possible to accurately count the numbers of individual lung tumors in mice. However, the number of extrapulmonary lung metastases appeared to be significantly reduced in the anti-PECAM antibody treated mice. Specifically, all eight of eight isotype control-treated mice showed discrete, bulky extrapulmonary tumors in the thoracic cavity, whereas of only 3 of 9 anti-PECAM antibody treated mice showed extrapulmonary tumors. (Note, one of the nine isotype control antibody-treated mice died with an extensive tumor burden 4 days before all other mice were sacrificed. This mouse was not included in the final analysis of metastatic LLC-HM tumors. In addition, 3 of 8 isotype control-treated mice showed liver metastases, whereas of only 1 of 9 anti-PECAM antibody treated mice showed liver tumors. Thus, while not clearly reducing the number of lung metastatic LLC-HM tumors, anti-PECAM antibody therapy did appear to significantly reduce the extrapulmonary spread of LLC-HM tumors.
[0100] Last, since anti-PECAM antibody therapy reduced the metastatic spread of four different murine solid tumors in immunocompetent, syngeneic mouse strains, we assessed whether anti-PECAM antibody therapy altered the metastatic spread of human LOX xenograft tumors in nude mice. As in the murine tumor models, anti-PECAM antibody therapy significantly reduced the metastatic spread of LOX cells in nude mice, as measured by both lungs weights (p<0.05) and the total number of lung tumors (p<0.005) when compared to LOX-bearing mice treated with isotype control antibody (see FIGS. 5A and 5B ).
[0101] Taken together, these data show that systemic, anti-PECAM antibody therapy can significantly reduce the metastatic spread of a wide variety of common fatal solid tumors (melanoma, breast, colon and lung cancer) in mouse metastasis models. Importantly, none of the tumor cells tested express detectable PECAM-1, indicating that anti-PECAM antibody does not produce its anti-metastatic tumor effects via direct binding to the tumor cells themselves. Rather, anti-PECAM antibody appears to function as an anti-tumor agent via binding to PECAM-1 expressed on vascular endothelial cells. However, anti-PECAM antibody does not appear exert anti-metastatic activity by effects on tumor blood vessel formation. Thus, unlike anti-tumor antibodies currently used to treat human cancers, anti-PECAM is neither tumor type specific, nor does it require expression of its cognate receptor on tumor cells to produce significant anti-metastatic effects. | The invention provides novel compositions, methods, kits, and uses thereof relating to antimetastatic agents useful for treating neoplastic diseases. | 0 |
DESCRIPTION
1. Technical Field
The invention relates to ultrasonic flowmeters and in particular to an ultrasonic flowmeter for viscous fluids such as heavy oil and crude oil.
2. Background Art
Ultrasonic flowmeters of the upstream-downstream type have been known for more than ten years. For example, U.S. Pat. No. 3,818,757 describes such a flowmeter wherein an acoustic path is defined between a pair of piezoelectric transducers disposed at an angle to the direction of fluid flow in a pipe. In such a flowmeter, one piezoelectric crystal acts as a transmitter while the other acts as a receiver and then roles are reversed. This provides upstream and downstream acoustic path measurements which can be compared in a way such that the difference in pulse counts provides a measure of fluid flow. One of the problems which is encountered in such flowmeters involves viscous fluids. Such fluids have relatively low relaxation frequencies such that the typical ultrasonic transducer frequency exceeds the relaxation frequency. Under such circumstances, it is not possible to transmit sound from one transducer to the other. Typically, ultrasonic acoustic waves are generated by piezoelectric crystals which have a disk or wafer shape. The vibrational mode of excitation is the compressional mode wherein opposed major surfaces of the disk are vibrating. While frequency may be changed by changing the thickness of the crystal, there are practical limits to the thickness which may be employed.
Since the disk shape for the crystal is ideal in transducer assemblies mounted in tubes joined to a pipe carrying the viscous fluid, it is difficult to change the crystal shape in order to obtain another vibrational frequency. However, it is well known that crystal frequency may be changed by exciting other vibrational modes.
An object of the invention was to devise a method of operating an upstream-and-downstream ultrasonic flowmeter for viscous fluids.
SUMMARY OF INVENTION
The above object has been achieved in an ultrasonic flowmeter of the upstream-downstream type by generating a radial vibrational mode, as well as a compression vibrational mode, in a transducer housing of the type used in prior flowmeters, thereby extending the usefulness of existing flowmeters. This result is achieved by adhering masses to either side of the piezoelectric crystal disk which generates acoustic waves. Such masses create an acoustic impedance so that the radial mode of vibration is preferred. The radial vibrational mode generally has a lower frequency, up to ten times lower than the compressional vibrational mode. Such a low frequency allows greater coupling of energy between transducers, well below the relaxation frequency of even the most viscous fluids, such that an upstream-downstream ultrasonic flowmeter may be used with the usual expected accuracy in viscous fluids, such as heavy oils.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a plan view of a piezoelectric crystal with mass loading suitable for use in an ultrasonic flowmeter transducer.
FIG. 2 is a sectional view of a piezoelectric crystal assembly of the type illustrated in FIG. 1, mounted in a housing, forming a transducer assembly for an ultrasonic flowmeter.
FIG. 3 is a plan view of an ultrasonic flowmeter employing upstream-downstream transducer assemblies of the type illustrated in FIG. 2.
FIG. 4 is a plot of the relaxation frequency in a viscous fluid, showing variations in absorption of the acoustic signal versus frequency for different temperatures.
BEST MODE FOR CARRYING OUT THE INVENTION
With reference to FIG. 1, a piezoelectric crystal 11 is shown sandwiched between two mass loading members 13 and 15. Crystal 11 is a disk or wafer which is approximately the size of a U.S. dime or somewhat smaller. The typical output frequency is 1.1 mHz when used in usual configurations for ultrasonic flowmeters of the type described in U.S. Pat. No. 3,818,757. An a.c. signal applied by wires 17 and 19 electrically excites the crystal into a vibrational mode. In the prior art, this vibrational mode has been the compressional mode with acoustic waves coming from major opposed surfaces 12 and 14 of the crystal. Wires 17 and 19 are affixed to the crystal by means of solder joints 21 and 23.
While the nominal frequency of 1.1 mHz is adequate for ordinary fluids, it is inadequate for very viscous fluids, such as heavy oils. The reason for this is that the relaxation frequency of such heavy oils does not allow good transmission of acoustic waves through the medium in a flowmeter. Relaxation frequency is a function of molecular size and for viscous hydrocarbons, i.e. large molecular size, the relaxation frequency is relatively low. It is difficult to transmit acoustic waves having a frequency which is higher than the relaxation frequency of the transmission medium.
To obtain a crystal having a frequency in the compression mode below the relaxation frequency for heavy oil would be quite difficult. Such a crystal would have unusual dimensions and would be difficult and costly to obtain.
By using an ordinary crystal, but forcing oscillations in the radial mode, frequencies ten times lower than compressional mode frequencies have been obtained. This is done by mass loading of crystal 11 by means of the mass loading members 13 and 15 which are aluminum blocks. These mass loading members are selected such that the amplitude of the radial mode oscillation is equal to the amplitude of the radial mode. These mass loading members are also selected so that there is less acoustic impedance in the forward direction of transmission than in the rearward direction. Thus, mass loading member 15, facing the direction of acoustic wave transmission, is less thick than mass loading member 13. Ordinarily, the mass loading members are adhered to major surfaces of crystal 11 by means of adhesives, such as epoxy, but for high-temperature work, the members may be held in place by a spring as shown in U.S. Pat. No. 4,162,111. Note that each mass loading member has a notch 25 and 27, for accommodating a respective solder joint 21 and 23. The thickness of mass loading member 15, i.e. in the direction of acoustic wave transmission, is approximately one-fourth the wavelength of waves at the radial mode crystal frequency. The thickness of mass loading member 13 is approximately one-half the same wavelength.
FIG. 2 shows the crystal 11 with the mass loading members 13 and 15 mounted in a tubular holder 31 having a closed end 33. The closed end should be generally transparent to acoustic waves generated by crystal 11. Mass loading member 15 is adhered to closed end 33 by an adhesive or, in high temperature applications, is held in place by a spring, as previously mentioned. Wires 17 and 19 are brought through the tubular housing rearwardly and may be held in place by a potting compound 35 used to plug the rearward end of the tubular housing. A material absorptive of acoustic waves, such as cotton wad 37, may be an intermediate filler material. The potting compound is a structural adhesive, such as epoxy. The material of the housing 31 may be a polymer, such as a material sold under the trademark Ryton. The upper portion of the housing comprises an annular flange 39 which serves to mount the entire transducer assembly of FIG. 2 in a pipe which opens into a larger pipe having viscous fluid flow inside.
This is more clearly illustrated in FIG. 3 wherein the transducer assemblies 41 and 43 are shown to be suitable for mounting in corresponding pipes 51 and 53. These pipes open into the large diameter pipe 45 carrying a viscous fluid in the direction of arrow A. In an upstream-downstream ultrasonic flowmeter of the type described in U.S. Pat. No. 3,818,757, an ultrasonic acoustic signal is transmitted first from one transducer assembly toward the other which receives the signal. An example would be from transducer assembly 41 to transducer assembly 43, which is the upstream direction relative to arrow A. Once a pulse or wave train is received, the process is reversed and the signal is transmitted from transducer assembly 43 to transducer assembly 41 in the downstream direction. From these upstream and downstream transmissions, flow velocity may be determined using an apparatus of the type described in U.S. Pat. No. 4,203,322, illustrated schematically by means of measurement box 47. Signals to the measurement box are carried along wires 55 and 57 from the respective transducer assemblies 41 and 43.
Since the relaxation frequency through a viscous fluid is highly temperature dependent, a heating coil 59 may be provided for raising the temperature of the viscous fluid to bring it into the range for which the flowmeter is designed. The flowmeter can be designed for any temperature range, but sometimes a flowmeter is designed for one temperature range, typically a high range such as 200° C. and the associated process is sometimes run at a lower temperature, thus requiring heating prior to the run through the flowmeter. The heating coil 59 is typically a resistive element powered by an energy source 61 and having a switch 63 so that the coil may be disconnected when not in use.
The temperature dependence and mode of operation of a flowmeter employing the present invention may be seen with respect to FIG. 4, a plot of acoustic signal absorption versus frequency.
In FIG. 4, two frequencies F1 and F2 are shown. F1 represents the radial mode of vibration of the transducer assembly of FIG. 2, while F2 represents the compressional mode. F2 might be approximately 1.1 mHz, while F1 might be approximately 120 kHz. The curves which are plotted represent relaxation frequencies for a viscous fluid at different temperatures. The dashed line 65 represents an absorption level, above which a useful signal is not received. For example this might be a level at which 75% of the acoustic energy transmitted is not detected at the receiver. Thus, the dashed line 61 is termed a threshold level such that energy coupled into the viscous fluid must hit the curve representing relaxation frequency below the threshold level. For curve 71 labeled T 0 this occurs for frequency F1, but not F2. If the viscous fluid is heated by a temperature increment, Δt, the same thing occurs, as indicated by curve 73. If the fluid is heated by a temperature increment 2Δt, as indicated by curve 75, T 0 +2Δt, both frequencies F1 and F2 can couple energy into the viscous fluid. The same is true for curves 77 and 79 representing the relaxation frequency at temperatures T 0 +3Δt and T 0 +4Δt, respectively. Thus, it is seen that by heating the material, there is a greater chance of transmitting both frequencies through the fluid. As the material is heated, it becomes less viscous and transmits acoustic energy more readily at higher frequencies. Depending on the temperature of the material, it is desirable to have both frequencies, F1 and F2, available for use. For this reason, the loading members attached to the crystal are such that both the compression and radial modes of vibration are excited. Both frequencies are directed into the medium. Depending on the temperature of the viscous medium, as well as the molecular size of the material involved, both frequencies may or may not be detected. At least the lower frequency, i.e. the radial mode frequency, should be detectable. For higher temperature viscous fluids, both should be detectable and filters, either mechanical or electrical, associated with the receiving transducer can select the desired signal. Alternatively, the electronics may be tuned to detect the desired signal.
While the viscous fluid described therein has been described as heavy oil or crude oil, the invention is not restricted to such materials. Other viscous fluids, such as butter or sludge may exhibit similar properties and hence be suitable for measurement by a flowmeter operated in accord with the present invention. | An ultrasonic flowmeter of the upstream-downstream type having piezoelectric crystals operated in the radial mode, as well as the compression mode, or primarily the radial mode. If both modes are used, one of the two may be selected in order to optimize the received signal. Selection would depend upon the molecular weight and temperature of the viscous fluid in the flowmeter. The selected frequency would be below the relaxation frequency of the flowing material. Radial mode oscillations are achieved by mass loading members adhered to either side of the crystal, thereby creating acoustic impedances which dampen the compressional mode, but enhance the radial mode of vibration. The mass loading member rearward of the crystal is significantly larger than the forward member so that most of the energy to be transmitted is directed in a forward direction. The forward end of the crystal is mounted in a tubular housing which is inserted into a pipe opening into a larger pipe where fluid flow occurs. | 1 |
[0001] This application claims priority from U.S. Provisional Application No. 61/120438, filed Dec. 6, 2008, the contents of which are hereby incorporated by reference in their entirety.
TECHNICAL FIELD
[0002] The present invention relates to optionally substituted 3-amino-4,5-dihydro-(1H or 2H)-pyrazolo[3,4-d]pyrimidin-6(7H)-ones and their 4-imino or 4-thioxo derivatives, e.g., 3-amino-4-(thioxo or imino)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-ones, 3-amino-4-(thioxo or imino)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-ones, 3-amino-4-(thioxo or imino)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidin-6(7H)-ones, preferably, a compound of Formula I as described below, processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising them. Of particular interest are novel compounds useful as inhibitors of phosphodiesterase 1 (PDE1), e.g., in the treatment of diseases involving disorders of the dopamine D1 receptor intracellular pathway, such as Parkinson's disease, depression, narcolepsy, damage to cognitive function, e.g., in schizophrenia, or disorders that may be ameliorated through enhanced progesterone-signaling pathway, e.g., female sexual dysfunction.
BACKGROUND OF THE INVENTION
[0003] Eleven families of phosphodiesterases (PDEs) have been identified but only PDEs in Family I, the Ca 2+ -calmodulin-dependent phosphodiesterases (CaM-PDEs), have been shown to mediate both the calcium and cyclic nucleotide (e.g. cAMP and cGMP) signaling pathways. The three known CaM-PDE genes, PDE1A, PDE1B, and PDE1C, are all expressed in central nervous system tissue. PDE is expressed throughout the brain with higher levels of expression in the CA1 to CA3 layers of the hippocampus and cerebellum and at a low level in the striatum. PDE1A is also expressed in the lung and heart. PDE1B is predominately expressed in the striatum, dentate gyrus, olfactory tract and cerebellum, and its expression correlates with brain regions having high levels of dopaminergic innervation. Although PDE1B is primarily expressed in the central nervous system, it may be detected in the heart. PDE1C is primarily expressed in olfactory epithelium, cerebellar granule cells, and striatum. PDE1C is also expressed in the heart and vascular smooth muscle.
[0004] Cyclic nucleotide phosphodiesterases decrease intracellular cAMP and cGMP signaling by hydrolyzing these cyclic nucleotides to their respective inactive 5′-monophosphates (5′AMP and 5′GMP). CaM-PDEs play a critical role in mediating signal transduction in brain cells, particularly within an area of the brain known as the basal ganglia or striatum. For example, NMDA-type glutamate receptor activation and/or dopamine D2 receptor activation result in increased intracellular calcium concentrations, leading to activation of effectors such as calmodulin-dependent kinase II (CaMKII) and calcineurin and to activation of CaM-PDEs, resulting in reduced cAMP and cGMP. Dopamine D1 receptor activation, on the other hand, leads to activation of nucleotide cyclases, resulting in increased cAMP and cGMP. These cyclic nucleotides in turn activate protein kinase A (PKA; cAMP-dependent protein kinase) and/or protein kinase G (PKG; cGMP-dependent protein kinase) that phosphorylate downstream signal transduction pathway elements such as DARPP-32 (dopamine and cAMP-regulated phosphoprotein) and cAMP responsive element binding protein (CREB). Phosphorylated DARPP-32 in turn inhibits the activity of protein phosphates-1 (PP-1), thereby increasing the state of phosphorylation of substrate proteins such as progesterone receptor (PR), leading to induction of physiologic responses. Studies in rodents have suggested that inducing cAMP and cGMP synthesis through activation of dopamine D1 or progesterone receptor enhances progesterone signaling associated with various physiological responses, including the lordosis response associated with receptivity to mating in some rodents. See Mani, et al., Science (2000) 287: 1053, the contents of which are incorporated herein by reference.
[0005] CaM-PDEs can therefore affect dopamine-regulated and other intracellular signaling pathways in the basal ganglia (striatum), including but not limited to nitric oxide, noradrenergic, neurotensin, CCK, VIP, serotonin, glutamate (e.g., NMDA receptor, AMPA receptor), GABA, acetylcholine, adenosine (e.g., A2A receptor), cannabinoid receptor, natriuretic peptide (e.g., ANP, BNP, CNP), DARPP-32, and endorphin intracellular signaling pathways.
[0006] Phosphodiesterase (PDE) activity, in particular, phosphodiesterase 1 (PDE 1) activity, functions in brain tissue as a regulator of locomotor activity and learning and memory. PDE1 is a therapeutic target for regulation of intracellular signaling pathways, preferably in the nervous system, including but not limited to a dopamine D1 receptor, dopamine D2 receptor, nitric oxide, noradrenergic, neurotensin, CCK, VIP, serotonin, glutamate (e.g., NMDA receptor, AMPA receptor), GABA, acetylcholine, adenosine (e.g., A2A receptor), cannabinoid receptor, natriuretic peptide (e.g., ANP, BNP, CNP), endorphin intracellular signaling pathway and progesterone signaling pathway. For example, inhibition of PDE should act to potentiate the effect of a dopamine D1 agonist by protecting cGMP and cAMP from degradation, and should similarly inhibit dopamine D2 receptor signaling pathways, by inhibiting PDE1 activity. Chronic elevation in intracellular calcium levels is linked to cell death in numerous disorders, particularly in neurodegerative diseases such as Alzheimer's, Parkinson's and Huntington's Diseases and in disorders of the circulatory system leading to stroke and myocardial infarction. PDE1 inhibitors are therefore potentially useful in diseases characterized by reduced dopamine D1 receptor signaling activity, such as Parkinson's disease, restless leg syndrome, depression, narcolepsy and cognitive impairment. PDE1 inhibitors are also useful in diseases that may be alleviated by the enhancement of progesterone-signaling such as female sexual dysfunction.
[0007] There is thus a need for compounds that selectively inhibit PDE1 activity, especially PDE1A and/or PDE1B activity.
SUMMARY OF THE INVENTION
[0008] The invention provides optionally substituted 3-amino-(optionally 4-imino or 4-thioxo)-4,5-dihydro-(1H or 2H)-pyrazolo[3,4-d]pyrimidin-6(7H)-ones and their 4-imino and 4-thioxo derivatives, e.g., 3-amino-4-(thioxo or imino)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-ones, 3-amino-4-(thioxo or imino)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6(7H)-ones or 3 -amino-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6(7H)-ones, preferably (optionally 1 or 2 and/or 5 and/or 7 substituted)-3-amino-(optionally 4-imino or 4-thioxo)-4,5-dihydro-(1H or 2H)-pyrazolo[3,4-d]pyrimidin-6-ones, more preferably a compound of formula II:
[0000]
[0000] wherein
(i) Q is —C(═S)—, —C(═N(R 6 ))— or —C(R 14 )(R 15 )—; (ii) R 1 is H or C 1-6 alkyl (e.g., methyl or ethyl); (iii) R 2 is
H, C 1-6 alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl or 2,2-dimethylpropyl) wherein said alkyl group is optionally substituted with one or more halo (e.g., fluoro) or hydroxy (e.g., hydroxyC 1-6 alkyl, for example 1-hydroxyprop-2-yl or 3-hydroxy-2-methylpropyl), haloC 1-6 alkyl (e.g., trifluoromethyl or 2,2,2-trifluoroethyl), N(R 14 )(R 15 )—C 1-6 alkyl (e.g., 2-(dimethylamino)ethyl or 2-aminopropyl), arylC 0-6 alkyl (e.g., phenyl or benzyl), wherein said aryl is optionally substituted with one or more C 1-6 alkoxy, for example, C 1-6 alkoxyarylC 0-6 alkyl (e.g., 4-methoxybenzyl), heteroarylC 0-6 alkyl (e.g., pyridinylmethyl), wherein said heteroaryl is optionally substituted with one or more C 1-6 alkoxy (e.g., C 1-6 alkoxyheteroarylC 1-6 alkyl); -G-J wherein G is a single bond or C 1-6 alkylene (e.g., methylene) and J is C 3-8 cycloalkyl or heteroC 3-8 cycloalkyl (e.g., oxetan-2-yl, pyrrolidin-3-yl, pyrrolidin-2-yl) wherein the cycloalkyl and heterocycloalkyl group are optionally substituted with one or more C 1-6 alkyl or amino, for example,
—C 0-4 alkyl-C 3-8 cycloalkyl (e.g., —C 0-4 alkyl-cyclopentyl, —C 0-4 alkyl-cyclohexyl or —C 0-4 alkyl-cyclopropyl), wherein said cycloalkyl is optionally substituted with one or more C 1-6 alkyl or amino (for example, 2-aminocyclopentyl or 2-aminocyclohexyl), —C 0-4 alkyl-C 3-8 heterocycloalkyl (e.g., —C 0-4 alkyl-pyrrolidinyl, for example, —C 0-4 alkylpyrrolidin-3-yl) wherein said heterocycloalkyl is optionally substituted with C 1-6 alkyl (e.g., methyl), for example, 1-methylpyrrolidin-3-yl, 1-methyl-pyrrolindin-2-yl, 1-methyl-pyrrolindin-2-yl-methyl or 1-methyl-pyrrolindin-3-yl-methyl);
(iv) R 3 is
1) -D-E-F wherein:
D is a single bond, C 1-6 alkylene (e.g., methylene), or arylC 1-6 alkylene (e.g., benzylene or —CH 2 C 6 H 4 —); E is
a single bond, C 1-4 alkylene (e.g., methylene, ethynylene, prop-2-yn-1-ylene), C 0-4 alkylarylene (e.g., phenylene or —C 6 H 4 —, -benzylene- or —CH 2 C 6 H 4 —), wherein the arylene group is optionally substituted with halo (e.g., Cl or F), heteroarylene (e.g., pyridinylene or pyrimidinylene), aminoC 1-6 alkylene (e.g., —CH 2 N(H)—), amino (e.g., —N(H)—); C 3-8 cycloalkylene optionally containing one or more heteroatom selected from N or O (e.g., piperidinylene),
F is
H, halo (e.g., F, Br, Cl), C 1-6 alkyl (e.g., isopropyl or isobutyl), haloC 1-6 alkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), C 3-8 cycloalkyl optionally containing one or more atom selected from a group consisting of N, S or O (e.g., cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydro-2H-pyran-4-yl, or morpholinyl), and optionally substituted with one or more C 1-6 alkyl (e.g., methyl or isopropyl), for example, 1-methylpyrrolidin-2-yl, pyrrolidin-l-yl, pyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl, heteroaryl (e.g., pyridyl (for example, pyrid-2-yl), pyrimidinyl (for example, pyrimidin-2-yl), thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for example, pyrazol-1-yl) or imidazolyl (for example, imidazol-1-yl, 4-methylimidazolyl, 1-methylimidazol-2-yl)), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkyloxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), wherein said heteroaryl is optionally substituted with one or more C 1-6 alkyl, halo (e.g., fluoro) or haloC 1-6 alkyl; C 1-6 alkoxy, —O-haloC 1-6 alkyl (e.g., —O—CF 3 ), C 1-6 alkylsulfonyl (for example, methylsulfonyl or —S(O) 2 CH 3 ), —C(O)—R 13 , wherein R 13 is —N(R 14 )(R 15 ), C 1-6 alkyl (e.g., methyl), —OC 1-6 alkyl (e.g., —OCH 3 ), haloC 1-6 alkyl (trifluoromethyl), aryl (e.g., phenyl), or heteroaryl; —N(R 14 )(R 15 );
or
2) a substituted heteroarylC 1-6 aklyl, e.g., substituted with haloC 1-6 alkyl;
or
3) attached to one of the nitrogens on the pyrazolo portion of Formula I and is a moiety of Formula A
[0000]
wherein:
X, Y and Z are, independently, N or C, R 8 , R 9 , R 11 and R 12 are independently H or halogen (e.g., Cl or F); and R 10 is halogen (e.g., fluoro or chloro), C 1-6 alkyl, C 3-8 cycloalkyl, heteroC 3-8 cycloalkyl (e.g., pyrrolidinyl or piperidinyl), haloC 1-6 alkyl (e.g., trifluoromethyl), aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl, (for example, pyrid-2-yl) or e.g., thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl, triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkyloxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more C 1-6 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-6 alkyl (e.g., trifluoromethyl), hydroxy, carboxy, —SH, or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl), C 1-6 alkyl sulfonyl (e.g., methyl sulfonyl), arylcarbonyl (e.g., benzoyl), heteroarylcarbonyl, C 1-6 alkoxycarbonyl, (e.g., methoxycarbonyl), Aminocarbonyl, —N(R 14 )(R 15 ); preferably R 10 is phenyl, pyridyl, piperidinyl or pyrrolidinyl optionally substituted with the substituents previously defined, e.g. optionally substituted with halo or alkyl; provided that when X, Y or X is nitrogen, R 8 , R 9 or R 10 , respectively, is not present;
(v) R 4 and R 5 are independently:
H, C 1-6 alkyl (e.g., methyl, isopropyl, isobutyl, n-propyl), C 3-8 cycloalkyl (e.g., cyclopentyl or cyclohexyl), C 3-8 heterocycloalkyl (e.g., pyrrolidinyl (for example pyrrolidin-3-yl or pyrrolidin-1-yl), piperidinyl (for example, piperidin-1-yl), morpholinyl), —C 0-6 alkylaryl (e.g., phenyl or benzyl) or —C 0-6 alkylheteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or heteroaryl is optionally substituted with one or more halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkyl, C 1-6 alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
(vi) R 6 is H, C 1-6 alkyl (e.g., methyl or ethyl) or C 3-8 cycloalkyl;
(vii) R 14 and R 15 are independently H or C 1-6 alkyl,
in free or salt form.
[0062] In a particular embodiment, the invention further provides compounds of Formula II as follows:
2.1 Formula II or 2.1, wherein Q is —C(═S)—, —C(═N(R 6 ))— or —C(R 14 )(R 15 )—; 2.2 Formula II or 2.1, wherein Q is —C(═S)—; 2.3 Formula II or 2.1, wherein Q is —C(═N(R 6 ))—; 2.4 Formula II, wherein Q is —C(R 14 )(R 15 )—; 2.5 Formula II or any of 2.1-2.4, wherein R 1 is H or C 1-6 alkyl (e.g., methyl or ethyl); 2.6 Formula II or any of 2.1-2.5, wherein R 1 is H; 2.7 Formula II or any of 2.1-2.5, wherein R 1 is C 1-6 alkyl (e.g., methyl or ethyl); 2.8 Formula II or any of 2.4-2.7, wherein R 2 is:
H, C 1-6 alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl or 2,2-dimethylpropyl) wherein said alkyl group is optionally substituted with one or more halo (e.g., fluoro) or hydroxy (e.g., hydroxyC 1-6 alkyl, for example 1-hydroxyprop-2-yl or 3 -hydroxy-2-methylpropyl), haloC 1-6 alkyl (e.g., trifluoromethyl or 2,2,2-trifluoroethyl), N(R 14 )(R 15 )—C 1-6 alkyl (e.g., 2-(dimethylamino)ethyl or 2-aminopropyl), arylC 0-6 alkyl (e.g., phenyl or benzyl), wherein said aryl is optionally substituted with one or more C 1-6 alkoxy, for example, C 1-6 alkoxyarylC 0-6 alkyl (e.g., 4-methoxybenzyl), heteroarylC 0-6 alkyl (e.g., pyridinylmethyl), wherein said heteroaryl is optionally substituted with one or more C 1-6 alkoxy (e.g., C 1-6 alkoxyheteroarylC 1-6 alkyl); -G-J wherein G is a single bond or C 1-6 alkylene (e.g., methylene) and J is C 3-8 cycloalkyl or heteroC 3-8 cycloalkyl (e.g., oxetan-2-yl, pyrrolidin-3-yl, pyrrolidin-2-yl) wherein the cycloalkyl and heterocycloalkyl group are optionally substituted with one or more C 1-6 alkyl or amino, for example,
C 0-4 alkyl-C 3-8 cycloalkyl (e.g., —C 0-4 alkyl-cyclopentyl, —C 0-4 alkyl-cyclohexyl or —C 0-4 alkyl-cyclopropyl), wherein said cycloalkyl is optionally substituted with one or more C 1-6 alkyl or amino (for example, 2-aminocyclopentyl or 2-aminocyclohexyl), —C 0-4 alkyl-C 3-8 heterocycloalkyl (e.g., —C 0-4 alkyl-pyrrolidinyl, for example, —C 0-4 alkylpyrrolidin-3-yl) wherein said heterocycloalkyl is optionally substituted with C 1-6 alkyl (e.g., methyl), for example, 1-methylpyrrolidin-3-yl, 1-methyl-pyrrolindin-2-yl, 1-methyl-pyrrolindin-2-yl-methyl or 1-methyl-pyrrolindin-3-yl-methyl);
2.9 Formula II or any of 2.4-2.8, wherein R 2 is:
C 1-6 alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl or 2,2-dimethylpropyl) wherein said alkyl group is optionally substituted with one or more halo (e.g., fluoro) or hydroxy (e.g., hydroxyC 1-6 alkyl, for example 1-hydroxyprop-2-yl or 3-hydroxy-2-methylpropyl), haloC 1-6 alkyl (e.g., trifluoromethyl or 2,2,2-trifluoroethyl), N(R 14 )(R 15 )—C 1-6 alkyl (e.g., 2-(dimethylamino)ethyl or 2-aminopropyl), arylC 0-6 alkyl (e.g., phenyl or benzyl), wherein said aryl is optionally substituted with one or more C 1-6 alkoxy, for example, C 1-6 alkoxyarylC 0-6 alkyl (e.g., 4-methoxybenzyl), heteroarylC 0-6 alkyl (e.g., pyridinylmethyl), wherein said heteroaryl is optionally substituted with one or more C 1-6 alkoxy (e.g., C 1-6 alkoxyheteroarylC 1-6 alkyl); -G-J wherein G is a single bond or C 1-6 alkylene (e.g., methylene) and J is C 3-8 cycloalkyl or heteroC 3-8 cycloalkyl (e.g., oxetan-2-yl, pyrrolidin-3-yl, pyrrolidin-2-yl) wherein the cycloalkyl and heterocycloalkyl group are optionally substituted with one or more C 1-6 alkyl or amino, for example, —C 0-4 alkyl-C 3-8 cycloalkyl (e.g., —C 0-4 alkyl-cyclopentyl, —C 0-4 alkyl-cyclohexyl or —C 0-4 alkyl-cyclopropyl), wherein said cycloalkyl is optionally substituted with one or more C 1-6 slkyl or amino (for example, 2-aminocyclopentyl or 2-aminocyclohexyl), —C 0-4 alkyl-C 3-8 heterocycloalkyl (e.g., —C 0-4 alkyl-pyrrolidinyl, for example, —C 0-4 alkylpyrrolidin-3-yl) wherein said heterocycloalkyl is optionally substituted with C 1-6 alkyl (e.g., methyl), for example, 1-methylpyrrolidin-3-yl, 1-methyl-pyrrolindin-2-yl, 1-methyl-pyrrolindin-2-yl-methyl or 1-methyl-pyrrolindin-3-yl-methyl);
2.10 Formula II or any of 2.4-2.8, wherein R 2 is H; 2.11 Formula II or any of 2.4-2.9, wherein R 2 is C 1-6 alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl or 2,2-dimethylpropyl) wherein said alkyl group is optionally substituted with one or more halo (e.g., fluoro) or hydroxy (e.g., hydroxyC 1-6 alkyl, for example 1-hydroxyprop-2-yl or 3-hydroxy-2-methylpropyl); 2.12 Formula II or any of 2.4-2.9, wherein R 2 is haloC 1-6 alkyl (e.g., trifluoromethyl or 2,2,2-trifluoroethyl); 2.13 Formula II or any of 2.4-2.9, wherein R 2 is N(R 14 )(R 15 )—C 1-6 alkyl (e.g., 2-(dimethylamino)ethyl, 2-aminopropyl); 2.14 Formula II or any of 2.4-2.9, wherein R 2 is arylC 0-6 alkyl (e.g., phenyl or benzyl), wherein said aryl is optionally substituted with one or more C 1-6 alkoxy, for example, C 1-6 alkoxyarylC 0-6 alkyl (e.g., 4-methoxybenzyl); 2.15 Formula II or any of 2.4-2.9, wherein R 2 is heteroarylC 0-6 alkyl (e.g., pyridinylmethyl), wherein said heteroaryl is optionally substituted with one or more C 1-6 alkoxy (e.g., C 1-6 alkoxyheteroarylC 1-6 alkyl); 2.16 Formula II or any of 2.4-2.9, wherein R 2 is -G-J wherein G is a single bond or C 1-6 alkylene (e.g., methylene) and J is C 3-8 cycloalkyl or heteroC 3-8 cycloalkyl (e.g., oxetan-2-yl, pyrrolidin-3-yl, pyrrolidin-2-yl) wherein the cycloalkyl and heterocycloalkyl group are optionally substituted with one or more C 1-6 alkyl or amino, for example:
—C 0-4 alkyl-C 3-8 cycloalkyl (e.g., —C 0-4 alkyl-cyclopentyl, —C 0-4 alkyl-cyclohexyl or —C 0-4 alkyl-cyclopropyl), wherein said cycloalkyl is optionally substituted with one or more C 1-6 alkyl or amino (for example, 2-aminocyclopentyl or 2-aminocyclohexyl), —C 0-4 alkyl-C 3-8 heterocycloalkyl (e.g., —C 0-4 alkyl-pyrrolidinyl, for example, —C 0-4 alkylpyrrolidin-3-yl) wherein said heterocycloalkyl is optionally substituted with C 1-6 alkyl (e.g., methyl), for example, 1-methylpyrrolidin-3-yl, 1-methyl-pyrrolindin-2-yl, 1-methyl-pyrrolindin-2-yl-methyl or 1-methyl-pyrrolindin-3-yl-methyl);
2.17 Formula II or any of 2.4-2.9, wherein R 2 is -G-J wherein G is a single bond and J is C 3-8 cycloalkyl or heteroC 3-8 cycloalkyl (e.g., oxetan-2-yl, pyrrolidin-3-yl, pyrrolidin-2-yl) wherein the cycloalkyl and heterocycloalkyl group are optionally substituted with one or more C 1-6 alkyl or amino; 2.18 Formula II or any of 2.4-2.9, wherein R 2 is -G-J wherein G is C 1-6 alkylene (e.g., methylene) and J is C 3-8 cycloalkyl or heteroC 3-8 cycloalkyl (e.g., oxetan-2-yl, pyrrolidin-3-yl, pyrrolidin-2-yl) wherein the cycloalkyl and heterocycloalkyl group are optionally substituted with one or more C 1-6 alkyl or amino; 2.19 Formula II or any of 2.4-2.9, wherein R 2 is
—C 0-4 alkyl-C 3-8 cycloalkyl (e.g., —C 0-4 alkyl-cyclopentyl, —C 0-4 alkyl-cyclohexyl or —C 0-4 alkyl-cyclopropyl), wherein said cycloalkyl is optionally substituted with one or more C 1-6 alkyl or amino (for example, 2-aminocyclopentyl or 2-aminocyclohexyl), C 0-4 alkyl-C 3-8 heterocycloalkyl (e.g., —C 0-4 alkyl-pyrrolidinyl, for example, —C 0-4 alkylpyrrolidin-3-yl) wherein said heterocycloalkyl is optionally substituted with C 1-6 alkyl (e.g., methyl), for example, 1-methylpyrrolidin-3-yl, 1-methyl-pyrrolindin-2-yl, 1-methyl-pyrrolindin-2-yl-methyl or 1-methyl-pyrrolindin-3-yl-methyl);
2.20 Formula II or any of 2.4-2.9, wherein R 2 is 2,2-dimethylpropyl; 2.21 Formula II or any of 2.4-2.9, wherein R 2 is isobutyl; 2.22 Formula II or any of 2.4-2.9, wherein R 2 is 1-hydroxyprop-2-yl or 3-hydroxy-2-methylpropyl; 2.23 Formula II or any of 2.4-2.9, wherein R 2 is cyclopentyl; 2.24 Formula II or any of 2.4-2.9, wherein R 2 is —C 0-4 alkyl-pyrrolidinyl wherein the pyrrolidnyl is optionally substituted with one or more C 1-6 alkyl, e.g., 1-methylpyrrolidin-3-yl, 1-methyl-pyrrolindin-2-yl, 1-methyl-pyrrolindin-2-yl-methyl or 1-methyl-pyrrolindin-3-yl-methyl); 2.25 Formula II or any of 2.4-2.24, wherein R 3 is -D-E-F wherein:
D is
a single bond, C 1-6 alkylene (e.g., methylene), or arylC 1-6 alkylene (e.g., benzylene or —CH 2 C 6 H 4 —);
E is
a single bond, C 1-4 alkylene (e.g., methylene, ethynylene, prop-2-yn-1-ylene), C 0-4 alkylarylene (e.g., phenylene or —C 6 H 4 —, -benzylene- or —CH 2 C 6 H 4 —), wherein the arylene group is optionally substituted with halo (e.g., Cl or F), heteroarylene (e.g., pyridinylene or pyrimidinylene), aminoC 1-6 alkylene (e.g., —CH 2 N(H)—), amino (e.g., —N(H)—); C 3-8 cycloalkylene optionally containing one or more heteroatom selected from N, S or O (e.g., piperidinylene),
F is
H, halo (e.g., F, Br, Cl), C 1-6 alkyl (e.g., isopropyl or isobutyl), haloC 1-6 alkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), C 3-8 cycloalkyl optionally containing one or more atom selected from a group consisting of N, S or O (e.g., cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydro-2H-pyran-4-yl, or morpholinyl), and optionally substituted with one or more C 1-6 alkyl (e.g., methyl or isopropyl), for example, 1-methylpyrrolidin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl, heteroaryl (e.g., pyridyl (for example, pyrid-2-yl), pyrimidinyl (for example, pyrimidin-2-yl), thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for example, pyrazol-1-yl) or imidazolyl (for example, imidazol-1-yl, 4-methylimidazolyl, 1-methylimidazol-2-yl)), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkyloxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), wherein said heteroaryl is optionally substituted with one or more C 1-6 alkyl, halo (e.g., fluoro) or haloC 1-6 alkyl; C 1-6 alkoxy, —O-haloC 1-6 alkyl (e.g., —O—CF 3 ), C 1-6 alkylsulfonyl (for example, methylsulfonyl or —S(O) 2 CH 3 ), —C(O)—R 13 , wherein R 13 is —N(R 14 )(R 15 ), C 1-6 alkyl (e.g., methyl), —OC 1-6 alkyl (e.g., —OCH 3 ), haloC 1-6 alkyl (trifluoromethyl), aryl (e.g., phenyl), or heteroaryl, —N(R 14 )(R 15 );
2.26 Formula 2.25, wherein R 13 is —N(R 14 )(R 15 ), C 1-6 alkyl (e.g., methyl), —OC 1-6 alkyl (e.g., —OCH 3 ), haloC 1-6 alkyl (trifluoromethyl), aryl (e.g., phenyl), or heteroaryl; 2.27 Formula 2.25, wherein D is C 1-6 alkylene (e.g., methylene), E is C 3-8 cycloalkylene optionally containing one or more heteroatom selected from N, S or O (e.g., piperidinylene) and F is C 1-6 alkyl (e.g., isopropyl or isobutyl), for example, R 3 is isopropylpiperidin-1-ylmethyl; 2.28 Formula II or any of 2.4-2.24, wherein R 3 is a substituted heteroarylC 0-6 aklyl, e.g., substituted with haloC 1-6 alkyl, for example; 2.29 Formula II or any of 2.4-2.24, wherein R 3 is attached to one of the nitrogens on the pyrazolo portion of Formula I and is a moiety of
[0000]
wherein:
X, Y and Z are, independently, N or C, R 8 , R 9 , R 11 and R 12 are independently H or halogen (e.g., Cl or F); and R 10 is
halogen (e.g., fluoro or chloro), C 1-6 alkyl, C 3-8 cycloalkyl, heteroC 3-8 cycloalkyl (e.g., pyrrolidinyl or piperidinyl), haloC 1-6 alkyl (e.g., trifluoromethyl), aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl, (for example, pyrid-2-yl) or e.g., thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl, triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkyloxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more C 1-6 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-6 alkyl (e.g., trifluoromethyl), hydroxy, carboxy, —SH or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl) C 1-6 alkyl sulfonyl (e.g., methyl sulfonyl), arylcarbonyl (e.g., benzoyl), heteroarylcarbonyl, C 1-6 alkoxycarbonyl, (e.g., methoxycarbonyl), aminocarbonyl —N(R 14 )(R 15 );
preferably R 10 is phenyl or pyridyl, e.g., 2-pyridyl, optionally substituted with one or more C 1-6 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-6 alkyl (e.g., trifluoromethyl), hydroxy, carboxy, -SH or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl); provided that when X, Y or X is nitrogen, R 8 , R 9 or R 10 , respectively, is not present;
2.30 Formula 2.29, wherein X, Y and/or Z are independently nitrogen and R 8 , R 9 , R 11 and R 12 are H provided that when X, Y or Z are nitrogen, R 8 , R 9 and R 10 , respectively, are not present;
2.31 Formula 2.29, wherein R 3 is X, Y and Z are C, R 8 , R 9 , R 11 and R 12 are H;
2.32 Formulae 2.29, 2.30 or 2.31, wherein R 10 is
halogen (e.g., fluoro or chloro), C 1-6 alkyl, C 3-8 cycloalkyl, heteroC 3-8 cycloalkyl (e.g., pyrrolidinyl or piperidinyl), haloC 1-6 alkyl (e.g., trifluoromethyl), aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl, (for example, pyrid-2-yl) or e.g., thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl, triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkyloxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more C 1-6 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-6 alkyl (e.g., trifluoromethyl), hydroxy, carboxy, -SH or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl), C 1-6 alkyl sulfonyl (e.g., methyl sulfonyl), arylcarbonyl (e.g., benzoyl), heteroarylcarbonyl, C 1-6 alkoxycarbonyl, (e.g., methoxycarbonyl), aminocarbonyl, —N(R 14 )(R 15 );
2.33 Any of formulae 2.29-2.32, wherein R 10 is halogen (e.g., fluoro or chloro);
2.34 Any of formulae 2.29-2.32, wherein R 10 is haloC 1-6 alkyl (e.g., trifluoromethyl);
2.35 Any of formulae 2.29-2.32, wherein R 10 is C 3-8 cycloalkyl;
2.36 Any of formulae 2.29-2.32, wherein R 10 is C 1-6 alkyl sulfonyl (e.g., methyl sulfonyl);
2.37 Any of formulae 2.29-2.32, wherein R 10 is arylcarbonyl (e.g., benzoyl);
2.38 Any of formulae 2.29-2.32, wherein R 10 is heteroarylcarbonyl;
2.39 Any of formulae 2.29-2.32, wherein R 10 is C 1-6 alkoxycarbonyl, (e.g., methoxycarbonyl);
2.40 Any of formulae 2.29-2.32, wherein R 10 is aminocarbonyl;
2.41 Any of formulae 2.29-2.32, wherein R 10 is aryl (e.g., phenyl), wherein said aryl is optionally substituted with one or more C 1-6 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-6 alkyl (e.g., trifluoromethyl), hydroxy, carboxy, —SH or an additional aryl or heteroaryl (e.g., biphenyl);
2.42 Any of formulae 2.29-2.32, wherein R 10 is heteroaryl (e.g., pyridyl, (for example, pyrid-2-yl) or e.g., thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl, triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkyloxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), wherein said heteroaryl is optionally substituted with one or more C 1-6 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-6 alkyl (e.g., trifluoromethyl), hydroxy, carboxy, —SH or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl);
2.43 Any of formulae 2.29-2.33, wherein R 10 is triazolyl (e.g., 1,2,4-triazol-1-yl);
2.44 Any of formulae 2.29-2.33, wherein R 10 is pyridyl (e.g., pyrid-2-yl);
2.45 Any of formulae 2.29-2.32, wherein R 10 is —N(R 14 )(R 15 );
2.46 Formula II or any of 2.1-2.45, wherein R 4 and R 5 are independently:
H, C 1-6 alkyl (e.g., methyl, isopropyl, isobutyl, n-propyl), C 3-8 cycloalkyl (e.g., cyclopentyl or cyclohexyl), C 3-8 heterocycloalkyl (e.g., pyrrolidinyl (for example pyrrolidin-3-yl or pyrrolidin-1-yl), piperidinyl (for example, piperidin-1-yl), morpholinyl), —C 0-6 alkylaryl (e.g., phenyl or benzyl) or —C 0-6 alkylheteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or heteroaryl is optionally substituted with one or more halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkyl, C 1-6 alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
2.47 Formula II or any of 2.1-2.46, wherein R 4 and R 5 as described in Formula II above.
2.48 Formula 2.47, wherein R 4 or R 5 is H;
2.49 Formula 2.47 or 2.48, wherein R 4 or R 5 is C 1-6 alkyl (e.g., methyl, isopropyl, isobutyl, n-propyl);
2.50 Any of formulae 2.47-2.49, wherein either R 4 or R 5 is C 3-8 cycloalkyl (e.g., cyclopentyl or cyclohexyl);
2.51 Any of formulae 2.47-2.50, wherein either R 4 or R 5 is C 3-8 heterocycloalkyl (e.g., pyrrolidinyl (for example pyrrolidin-3-yl or pyrrolidin-1-yl), piperidinyl (for example, piperidin-1-yl), morpholinyl);
2.52 Any of formulae 2.47-2.51, wherein either R 4 or R 5 is —C 0-6 alkylaryl (e.g., phenyl or benzyl) or —C 0-6 alkylheteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or heteroaryl is optionally substituted with one or more halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
2.53 Formula 2.47, wherein R 4 or R 5 is H or C 1-6 alkyl (e.g., methyl, isopropyl, isobutyl, n-propyl), and the other is
C 1-6 alkyl (e.g., methyl, isopropyl, isobutyl, n-propyl), C 3-8 cycloalkyl (e.g., cyclopentyl or cyclohexyl), C 3-8 heterocycloalkyl (e.g., pyrrolidinyl (for example pyrrolidin-3-yl or pyrrolidin-1-yl), piperidinyl (for example, piperidin-1-yl), morpholinyl), C 0-6 alkylaryl (e.g., phenyl or benzyl) or —C 0-6 alkylheteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or heteroaryl is optionally substituted with one or more halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkyl, C 1-6 alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
2.54 Any of formulae 2.47-2.53, wherein either R 4 or R 5 is phenyl optionally substituted with one or more halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkyl, C 1-6 alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
2.55 Any of formulae 2.47-2.53, wherein either R 4 or R 5 is 4-fluorophenyl;
2.56 Any of formulae 2.47-2.53, wherein either R 4 or R 5 is 4-hydroxyphenyl;
2.57 Any of formulae 2.47-2.53, wherein either R 4 or R 5 is C 3-8 cycloalkyl (e.g., cyclopentyl or cyclohexyl),
2.58 Any of formulae 2.47-2.53, wherein either R 4 is H and R 5 is phenyl optionally substituted with one or more halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkyl, C 1-6 alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
2.59 Any of the preceding formulae wherein R 6 is H, C 1-6 alkyl (e.g., methyl or ethyl) or C 3-8 cycloalkyl;
2.60 Any of the preceding formulae wherein R 6 is C 3-8 cycloalkyl;
2.61 Any of the preceding formulae wherein R 6 is H;
2.62 Any of the preceding formulae wherein R 6 is C 1-6 alkyl (e.g., methyl or ethyl);
2.63 Any of the preceding formulae wherein the compound is selected from any of the following:
[0000]
2.64 Any of formulae 2.1-2.62, wherein the compound is selected from any of the following:
[0000]
2.65 Any of formulae 2.1-2.62, wherein the compound is selected from any of the following:
[0000]
2.66 any of the preceding formulae wherein the compounds inhibit phosphodiesterase-mediated (e.g., PDE1-mediated, especially PDE1B-mediated) hydrolysis of cGMP, e.g., with an IC 50 of less than 1 μM, preferably less than 500 nM, preferably less than 200 nM in an immobilized-metal affinity particle reagent PDE assay, for example, as described in Example 5;
[0213] In another aspect, the Compound of the Invention is a Compound of Formula II, wherein
(i) Q is —C(═S)—, —C(═N(R 6 ))— or —C(R 14 )(R 15 )—; (ii) R 1 is H or C 1-6 alkyl (e.g., methyl or ethyl); (iii) R 2 is C 1-6 alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl or 2,2-dimethylpropyl) wherein said alkyl group is optionally substituted with one or more halo (e.g., fluoro) or hydroxy (e.g., hydroxyC 1-6 alkyl, for example 1-hydroxyprop-2-yl or 3-hydroxy-2-methylpropyl), (iv) R 3 is attached to one of the nitrogens on the pyrazolo portion of Formula I and is a moiety of Formula A
[0000]
wherein:
X, Y and Z are, independently, N or C, R 8 , R 9 , R 11 and R 12 are independently H or halogen (e.g., Cl or F); and R 10 is
halogen (e.g., fluoro or chloro), C 1-6 alkyl, C 3-8 cycloalkyl, heteroC 3-8 cycloalkyl (e.g., pyrrolidinyl or piperidinyl), haloC 1-6 alkyl (e.g., trifluoromethyl), aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl, (for example, pyrid-2-yl) or e.g., thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl, triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkyloxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more C 1-6 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-6 alkyl (e.g., trifluoromethyl), hydroxy, carboxy, —SH or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl) C 1-6 alkyl sulfonyl (e.g., methyl sulfonyl), arylcarbonyl (e.g., benzoyl), heteroarylcarbonyl, C 1-6 alkoxycarbonyl, (e.g., methoxycarbonyl), Aminocarbonyl, —N(R 14 )(R 15 ); preferably R 10 is phenyl or pyridyl, e.g., 2-pyridyl, optionally substituted with one or more C 1-6 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-6 alkyl (e.g., trifluoromethyl), hydroxy, carboxy, —SH or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl); provided that when X, Y or X is nitrogen, R 8 , R 9 or R 10 , respectively, is not present;
(v) R 4 and R 5 are independently:
H, C 1-6 alkyl (e.g., methyl, isopropyl, isobutyl, n-propyl), C 3-8 cycloalkyl (e.g., cyclopentyl or cyclohexyl), C 3-8 heterocycloalkyl (e.g., pyrrolidinyl (for example pyrrolidin-3-yl or pyrrolidin-1-yl), piperidinyl (for example, piperidin-1-yl), morpholinyl), C 0-6 alkylaryl (e.g., phenyl or benzyl) or —C 0-6 alkylheteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or heteroaryl is optionally substituted with one or more halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkyl, C 1-6 alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
(vi) R 6 is H, C 1-6 alkyl (e.g., methyl or ethyl) or C 3-8 cycloalkyl;
(vii) R 14 and R 15 are independently H or C 1-6 alkyl,
in free or salt form (hereinafter, Formula II(a)).
[0245] In another aspect, the Compound of the Invention is a Compound of Formula II, wherein:
(i) Q is —C(═S)—, —C(═N(R 6 ))— or —C(R 14 )(R 15 )—; (ii) R 1 is H or C 1-6 alkyl (e.g., methyl or ethyl); (iii) R 2 is C 1-6 alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl or 2,2-dimethylpropyl) wherein said alkyl group is optionally substituted with one or more halo (e.g., fluoro) or hydroxy (e.g., hydroxyC 1-6 alkyl, for example 1-hydroxyprop-2-yl or 3-hydroxy-2-methylpropyl), (iv) R 3 is attached to one of the nitrogens on the pyrazolo portion of Formula I and is a moiety of Formula A
[0000]
wherein:
X, Y and Z are, independently, N or C, R 8 , R 9 , R 11 and R 12 are independently H or halogen (e.g., Cl or F); and R 10 is phenyl or pyridyl, e.g., 2-pyridyl, or pyrrolidinyl optionally substituted with one or more C 1-6 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-6 alkyl (e.g., trifluoromethyl), hydroxy, carboxy, —SH or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl); provided that when X, Y or X is nitrogen, R 8 , R 9 or R 10 , respectively, is not present;
(v) R 4 and R 5 are independently:
H, C 1-6 alkyl (e.g., methyl, isopropyl, isobutyl, n-propyl),
C 3-8 cycloalkyl (e.g., cyclopentyl or cyclohexyl), C 3-8 heterocycloalkyl (e.g., pyrrolidinyl (for example pyrrolidin-3-yl or pyrrolidin-1-yl), piperidinyl (for example, piperidin-1-yl), morpholinyl),
C 0-6 alkylaryl (e.g., phenyl or benzyl) or —C 0-6 alkylheteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or heteroaryl is optionally substituted with one or more halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkyl, C 1-6 alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
(vi) R 6 is H, C 1-6 alkyl (e.g., methyl or ethyl) or C 3-8 cycloalkyl;
(vii) R 14 and R 15 are independently H or C 1-6 alkyl,
in free or salt form (hereinafter, Formula II(b)).
[0263] In another aspect, the Compound of the Invention is a Compound of Formula II wherein:
(i) Q is —C(═S)—, —C(═N(R 6 ))— or —C(R 14 )(R 15 )—; (ii) R 1 is H or C 1-6 alkyl (e.g., methyl or ethyl); (iii) R 2 is C 1-6 alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl or 2,2-dimethylpropyl) wherein said alkyl group is optionally substituted with one or more halo (e.g., fluoro) or hydroxy (e.g., hydroxyC 1-6 alkyl, for example 1-hydroxyprop-2-yl or 3-hydroxy-2-methylpropyl), (iv) R 3 is attached to one of the nitrogens on the pyrazolo portion of Formula I and is a moiety of Formula A
[0000]
wherein:
X, Y and Z are, independently, N or C, R 8 , R 9 , R 11 and R 12 are independently H or halogen (e.g., Cl or F); and R 10 is phenyl or pyridyl, e.g., 2-pyridyl, pyrrolidinyl optionally substituted with one or more C 1-6 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-6 alkyl (e.g., trifluoromethyl), hydroxy, carboxy, —SH or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl); provided that when X, Y or X is nitrogen, R 8 , R 9 or R 10 , respectively, is not present;
(v) R 4 and R 5 are independently:
H, C 1-6 alkyl (e.g., methyl, isopropyl, isobutyl, n-propyl), C 3-8 cycloalkyl (e.g., cyclopentyl or cyclohexyl), C 3-8 heterocycloalkyl (e.g., pyrrolidinyl (for example pyrrolidin-3-yl or pyrrolidin-1-yl), piperidinyl (for example, piperidin-1-yl), morpholinyl), C 0-6 alkylaryl (e.g., phenyl or benzyl) or —C 0-6 alkylheteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or heteroaryl is optionally substituted with one or more halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkyl, C 1-6 alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
(vi) R 6 is H or C 1-6 alkyl (e.g., methyl or ethyl);
(vii) R 14 and R 15 are independently H or C 1-6 alkyl,
in free or salt form (hereinafter, Formula II(c)).
[0281] In another aspect, the Compound of the Invention is a Compound of Formula II wherein:
(i) Q is —C(═S)—, —C(═N(R 6 ))— or —C(R 14 )(R 15 )—; (ii) R 1 is H or C 1-6 alkyl (e.g., methyl or ethyl); (iii) R 2 is C 1-6 alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl or 2,2-dimethylpropyl) wherein said alkyl group is optionally substituted with one or more halo (e.g., fluoro) or hydroxy (e.g., hydroxyC 1-6 alkyl, for example 1-hydroxyprop-2-yl or 3-hydroxy-2-methylpropyl), (iv) R 3 is attached to one of the nitrogens on the pyrazolo portion of Formula I and is a moiety of Formula A
[0000]
wherein:
X, Y and Z are, independently, N or C, R 8 , R 9 , R 11 and R 12 are independently H or halogen (e.g., Cl or F); and R 10 is phenyl or pyridyl, e.g., 2-pyridyl, pyrrolidinyl optionally substituted with one or more C 1-6 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-6 alkyl (e.g., trifluoromethyl), hydroxy, carboxy, —SH or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl); provided that when X, Y or X is nitrogen, R 8 , R 9 or R 10 , respectively, is not present;
(v) R 4 is H and R 5 is:
H, C 1-6 alkyl (e.g., methyl, isopropyl, isobutyl, n-propyl), C 3-8 cycloalkyl (e.g., cyclopentyl or cyclohexyl), C 3-8 heterocycloalkyl (e.g., pyrrolidinyl (for example pyrrolidin-3-yl or pyrrolidin-1-yl), piperidinyl (for example, piperidin-1-yl), morpholinyl), —C 0-6 alkylaryl (e.g., phenyl or benzyl) or —C 0-6 alkylheteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or heteroaryl is optionally substituted with one or more halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkyl, C 1-6 alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
(vi) R 6 is H, C 1-6 alkyl (e.g., methyl or ethyl);
(vii) R 14 and R 15 are independently H or C 1-6 alkyl,
in free or salt form (hereinafter, Formula II(d)).
[0299] In another aspect, the Compound of the Invention is a Compound of Formula II, wherein:
(i) Q is —C(═S)—, —C(═N(R 6 ))— or —C(R 14 )(R 15 )—; (ii) R 1 is H or C 1-6 alkyl (e.g., methyl or ethyl); (iii) R 2 is C 1-6 alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl or 2,2-dimethylpropyl) wherein said alkyl group is optionally substituted with one or more halo (e.g., fluoro) or hydroxy (e.g., hydroxyC 1-6 alkyl, for example 1-hydroxyprop-2-yl or 3-hydroxy-2-methylpropyl), (iv) R 3 is attached to one of the nitrogens on the pyrazolo portion of Formula I and is a moiety of Formula A
[0000]
wherein:
X, Y and Z are, independently, N or C, R 8 , R 9 , R 11 and R 12 are independently H or halogen (e.g., Cl or F); and R 10 is phenyl or pyridyl, e.g., 2-pyridyl, or pyrrolidinyl optionally substituted with one or more C 1-6 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-6 alkyl (e.g., trifluoromethyl), hydroxy, carboxy, —SH or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl); provided that when X, Y or X is nitrogen, R 8 , R 9 or R 10 , respectively, is not present;
(v) R 4 is H and R 5 phenyl optionally substituted with one or more halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkyl, C 1-6 alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
(vi) R 6 is H or C 1-6 alkyl (e.g., methyl or ethyl);
(vii) R 14 and R 15 are independently H or C 1-6 alkyl,
in free or salt form (hereinafter, Formula II(e)).
[0312] In another aspect, the Compound of the Invention is a Compound of Formula I:
[0000]
[0000] wherein
(i) Q is —C(═S)—, —C(═N(R 6 ))— or —C(R 14 )(R 15 )—; (ii) R 1 is H or C 1-6 alkyl (e.g., methyl or ethyl); (iii) R 2 is
H, C 1-6 alkyl (e.g., isopropyl, isobutyl, neopentyl, 2-methylbutyl, 2,2-dimethylpropyl) wherein said alkyl group is optionally substituted with halo (e.g., fluoro) or hydroxy (e.g., 1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl), —C 0-4 alkyl-C 3-8 cycloalkyl (e.g., cyclopentyl, cyclohexyl) optionally substituted with one or more amino (e.g., —NH 2 ), for example, 2-aminocyclopentyl or 2-aminocyclohexyl), wherein said cycloalkyl optionally contains one or more heteroatom selected from N and O and is optionally substituted with C 1-6 alkyl (e.g., 1-methyl-pyrrolindin-2-yl, 1-methyl-pyrrolindin-3-yl, 1-methyl-pyrrolindin-2-yl-methyl or 1-methyl-pyrrolindin-3-yl-methyl), C 3-8 heterocycloalkyl (e.g., pyrrolidinyl, for example, pyrrolidin-3-yl) optionally substituted with C 1-6 alkyl (e.g., methyl), for example, 1-methylpyrrolidin-3-yl, C 3-8 cycloalkyl-C 1-6 alkyl (e.g., cyclopropylmethyl), haloC 1-6 alkyl (e.g., trifluoromethyl, 2,2,2-trifluoroethyl), —N(R 14 )(R 15 )—C 1-6 alkyl (e.g., 2-(dimethylamino)ethyl, 2-aminopropyl), hydroxyC 1-6 alkyl (e.g., (e.g., 3-hydroxy-2-methylpropyl, 1-hydroxyprop-2-yl), arylC 0-6 alkyl (e.g., benzyl), heteroarylC 1-6 alkyl (e.g., pyridinylmethyl), C 1-6 alkoxyarylC 1-6 alkyl (e.g., 4-methoxybenzyl); -G-J wherein:
G is a single bond or, alkylene (e.g., methylene); J is cycloalkyl or heterocycloalkyl (e.g., oxetan-2-yl, pyrolyin-3-yl, pyrolyin-2-yl) optionally substituted with C 1-6 alkyl (e.g., (1-methylpyrolidin-2-yl));
(iv) R 3 is
1) -D-E-F wherein:
D is a single bond, C 1-6 alkylene (e.g., methylene), or arylalkylene (e.g., benzylene or —CH 2 C 6 H 4 —); E is
a single bond, C 1-4 alkylene (e.g., methylene, ethynylene, prop-2-yn-1-ylene), —C 0-4 alkylarylene (e.g., phenylene or —C 6 H 4 —, -benzylene- or —CH 2 C 6 H 4 —), wherein the arylene group is optionally substituted with halo (e.g., Cl or F), heteroarylene (e.g., pyridinylene or pyrimidinylene), aminoC 1-6 alkylene (e.g., —CH 2 N(H)—), amino (e.g., —N(H)—); C 3-8 cycloalkylene optionally containing one or more heteroatom selected from N or O (e.g., piperidinylene),
F is
H, halo (e.g., F, Br, Cl), C 1-6 alkyl (e.g., isopropyl or isobutyl), haloC 1-6 alkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), C 3-8 cycloalkyl optionally containing at least one atom selected from a group consisting of N or O (e.g., cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydro-2H-pyran-4-yl, or morpholinyl), and optionally substituted with C 1-6 alkyl (e.g., methyl or isopropyl), for example, 1-methylpyrrolidin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl, heteroaryl optionally substituted with C 1-6 alkyl, (e.g., pyridyl, (for example, pyrid-2-yl), pyrimidinyl (for example, pyrimidin-2-yl), thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for example, pyrazol-1-yl) or imidazolyl (for example, imidazol-1-yl, 4-methylimidazolyl, 1-methylimidazol-2-yl), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), wherein said heteroaryl is optionally substituted with halo (e.g., fluoro) or haloC 1-6 alkyl; amino (e.g., —NH 2 ), C 1-6 alkoxy, —O-haloC 1-6 alkyl (e.g., —O—CF 3 ), C 1-6 alkylsulfonyl (for example, methylsulfonyl or —S(O) 2 CH 3 ), —C(O)—R 13 , —N(R 14 )(R 15 ); or
2) a substituted heteroarylaklyl, e.g., substituted with haloalkyl; or 3) attached to one of the nitrogens on the pyrazolo portion of Formula I and is a moiety of Formula A
[0000]
wherein X, Y and Z are, independently, N or C, and R 8 , R 9 , R 11 and R 12 are independently H or halogen (e.g., Cl or F); and R 10 is halogen, alkyl, cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, (for example, pyrid-2-yl) or e.g., thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl, triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), alkyl sulfonyl (e.g., methyl sulfonyl), arylcarbonyl (e.g., benzoyl), or heteroarylcarbonyl, alkoxycarbonyl, (e.g., methoxycarbonyl), aminocarbonyl; preferably phenyl or pyridyl, e.g., 2-pyridyl; provided that when X, Y or X is nitrogen, R 8 , R 9 or R 10 , respectively, is not present;
(v) R 4 and R 5 are independently
H, C 1-6 alkyl (e.g., methyl, isopropyl), C 3-8 cycloalkyl (e.g., cyclopentyl), C 3-8 heterocycloalkyl (e.g., pyrrolidin-3-yl), aryl (e.g., phenyl) or heteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or heteroaryl is optionally substituted with halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkyl, C 1-6 alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
(vi) R 6 is H, C 1-6 alkyl (e.g., methyl) or C 3-8 cycloalkyl;
(vii) R 13 is —N(R 14 )(R 15 ), C 1-6 alkyl (e.g., methyl), —OC 1-6 alkyl (e.g., —OCH 3 ), haloC 1-6 alkyl (trifluoromethyl), aryl (e.g., phenyl), or heteroaryl; and
(viii) R 14 and R 15 are independently H or C 1-6 alkyl,
in free, salt or prodrug form.
[0366] The invention further provides compounds of Formula I as follows:
1.1 Formula I, wherein Q is —C(═S)—; 1.2 Formula I, wherein Q is —C(═N(R 6 ))—; 1.3 Formula I, wherein Q is —C(R 14 )(R 15 )—; 1.4 Formula I, or any of 1.1-1.3, wherein R 3 is -D-E-F; 1.5 Formula 1.4, D is a single bond, C 1-6 alkylene (e.g., methylene), or arylalkylene (e.g., benzylene or —CH 2 C 6 H 4 —); 1.6 Formula 1.4, wherein D is a single bond; 1.7 Formula 1.4, wherein D is C 1-6 alkylene (e.g., methylene); 1.8 Formula 1.4, wherein D is methylene; 1.9 Formula 1.4, wherein D is arylalkylene (e.g., benzylene or —CH 2 C 6 H 4 —); 1.10 Formula 1.4, wherein D is benzylene or —CH 2 C 6 H 4 —; 1.11 Any of formulae 1.4-1.10, wherein E is a single bond, C 1-4 alkylene (e.g., methylene, ethynylene, prop-2-yn-1-ylene), —C 0-4 alkylarylene (e.g., phenylene or —C 6 H 4 —, -benzylene- or —CH 2 C 6 H 4 —), wherein the arylene group is optionally substituted with halo (e.g., Cl or F); heteroarylene (e.g., pyridinylene or pyrimidinylene), aminoC 1-6 alkylene (e.g., —CH 2 N(H)—), amino (e.g., —N(H)—), C 3-8 cycloalkylene optionally containing one or more heteroatom selected from N or O (e.g., piperidinylene); 1.12 Any of formulae 1.4-1.10, wherein E is a single bond; 1.13 Any of formulae 1.4-1.10, wherein E is C 1-4 alkylene (e.g., methylene, ethynylene, prop-2-yn-1-ylene); 1.14 Any of formulae 1.4-1.10, wherein E is methylene; 1.15 Any of formulae 1.4-1.10, wherein E is ethynylene; 1.16 Any of formulae 1.4-1.10, wherein E is prop-2-yn-1-ylene; 1.17 Any of formulae 1.4-1.10, wherein E is —C 0-4 alkylarylene (e.g., phenylene or —C 6 H 4 —, -benzylene- or —CH 2 C 6 H 4 —), wherein the arylene group is optionally substituted with halo (e.g., Cl or F); 1.18 Any of formulae 1.4-1.10, wherein E is phenylene or —C 6 H 4 —; 1.19 Any of formulae 1.4-1.10, wherein E is heteroarylene (e.g., pyridinylene or pyrimidinylene); 1.20 Any of formulae 1.4-1.10, wherein E is pyridinylene; 1.21 Any of formulae 1.4-1.10, wherein E is pyrimidinylene; 1.22 Any of formulae 1.4-1.10, wherein E is aminoC 1-6 alkylene (e.g., —CH 2 N(H)—); 1.23 Any of formulae 1.4-1.10, wherein E is amino (e.g., —N(H)—); 1.24 Any of formulae 1.4-1.10, wherein E is C 3-8 cycloalkylene optionally containing one or more heteroatom selected from N or O (e.g., piperidinylene); 1.25 Any of formulae 1.4-1.24, wherein F is H, halo (e.g., F, Br, Cl), C 1-6 alkyl (e.g., isopropyl or isobutyl), haloC 1-6 alkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), C 3-8 cycloalkyl optionally containing at least one atom selected from a group consisting of N or P (e.g., cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydro-2H-pyran-4-yl, or morpholinyl), and optionally substituted with C 1-6 alkyl (e.g., methyl or isopropyl), for example, 1-methylpyrrolidin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl; heteroaryl optionally substituted with C 1-6 alkyl (e.g., pyridyl, (for example, pyrid-2-yl), pyrimidinyl (for example, pyrimidin-2-yl), thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for example, pyrazol-1-yl) or imidazolyl (for example, imidazol-1-yl, 4-methylimidazolyl, 1-methylimidazol-2-yl), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), amino (e.g., —NH 2 ), C 1-6 alkoxy, —O-haloC 1-6 alkyl (e.g., —O—CF 3 ), C 1-6 alkylsulfonyl (for example, methylsulfonyl or —S(O) 2 CH 3 ), C(O)—R 13 or —N(R 14 )(R 15 ); 1.26 Any of formulae 1.4-1.25, wherein F is H; 1.27 Any of formulae 1.4-1.25, wherein F is halo (e.g., F, Br, Cl); 1.28 Any of formulae 1.4-1.25, wherein F is fluoro; 1.29 Any of formulae 1.4-1.25, wherein F is C 1-6 alkyl (e.g., isopropyl or isobutyl); 1.30 Any of formulae 1.4-1.25, wherein F is isopropyl; 1.31 Any of formulae 1.4-1.25, wherein F is isobutyl; 1.32 Any of formulae 1.4-1.25, wherein F is haloC 1-6 alkyl (e.g., trifluoromethyl); 1.33 Any of formulae 1.4-1.25, wherein F is trifluoromethyl; 1.34 Any of formulae 1.4-1.25, wherein F is aryl (e.g., phenyl); 1.35 Any of formulae 1.4-1.25, wherein F is phenyl; 1.36 Any of formulae 1.4-1.25, wherein F is C 3-8 cycloalkyl optionally containing at least one atom selected from a group consisting of N or O (e.g., cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl tetrahydro-2H-pyran-4-yl, morpholinyl); and optionally substituted with C 1-6 alkyl (e.g., methyl or isopropyl), for example, 1-methylpyrrolidin-2-yl), for example, 1-methylpyrrolidin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl; 1.37 Any of formulae 1.4-1.25, wherein F is cyclopentyl or cyclohexyl; 1.38 Any of formulae 1.4-1.25, wherein F is 1-methylpyrrolidin-2-yl; 1.39 Any of formulae 1.4-1.25, wherein F is heteroaryl optionally substituted with C 1-6 alkyl (e.g., pyridyl, (for example, pyrid-2-yl), pyrimidinyl (for example, pyrimidin-2-yl), thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for example, pyrazol-1-yl) or imidazolyl (for example, imidazol-1-yl, 4-methylimidazolyl, 1-methylimidazol-2-yl,), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), wherein said heteroaryl is optionally substituted with halo (e.g., fluoro) or haloC 1-6 alkyl; 1.40 Any of formulae 1.4-1.25, wherein F is pyrid-2-yl optionally substituted with halo (e.g., fluoro); 1.41 Any of formulae 1.4-1.25, wherein F is 6-fluoro-pyrid-2-yl; 1.42 Any of formulae 1.4-1.25, wherein F is pyrimidinyl (for example, pyrimidin-2-yl); 1.43 Any of formulae 1.4-1.25, wherein F is triazolyl (e.g., 1,2,4-triazol-1-yl); 1.44 Any of formulae 1.4-1.25, wherein F is diazolyl (e.g., pyrazolyl (for example, pyrazol-1-yl) or imidazolyl (for example, imidazol-1-yl, 4-methylimidazolyl, 1-methylimidazol-2-yl); 1.45 Any of formulae 1.4-1.25, wherein F is C- 1-6 alkyl-oxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazolyl); 1.46 Any of formulae 1.4-1.25, wherein F is amino (e.g., —NH 2 ); 1.47 Any of formulae 1.4-1.25, wherein F is C 1-6 alkoxy; 1.48 Any of formulae 1.4-1.25, wherein F is —O-haloC 1-6 alkyl (e.g., —O—CF 3 ); 1.49 Any of formulae 1.1-1.25, wherein F is —C(O)—R 13 ; 1.50 Any of formulae 1.1-1.25, wherein F is —N(R 14 )(R 15 ); 1.51 Any of formulae 1.1-1.25, wherein F is C 1-6 alkylsulfonyl; 1.52 Any of formulae 1.1-1.25, wherein F is methylsulfonyl or —S(O) 2 CH 3 ; 1.53 Formula I or any of 1.1-1.24, wherein R 3 is a substituted heteroarylaklyl, e.g., substituted with haloalkyl; 1.54 Formula I or any of 1.1-1.24, wherein R 3 is attached to one of the nitrogens on the pyrazolo portion of Formula I and is a moiety of Formula A
[0000]
wherein X, Y and Z are, independently, N or C, and R 8 , R 9 , R 11 and R 12 are independently H or halogen (e.g., Cl or F); and R 10 is halogen, alkyl, cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, (for example, pyrid-2-yl) or e.g., thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl, triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), alkyl sulfonyl (e.g., methyl sulfonyl), arylcarbonyl (e.g., benzoyl), or heteroarylcarbonyl, alkoxycarbonyl, (e.g., methoxycarbonyl), aminocarbonyl; preferably phenyl or pyridyl, e.g., 2-pyridyl; provided that when X, Y or X is nitrogen, R 8 , R 9 or R 10 , respectively, is not present;
1.55 Formula 1.54, wherein R 3 is a moiety of Formula A, R 8 , R 9 , R 11 and R 12 are each H and R 10 is phenyl;
1.56 Formula 1.54, wherein R 3 is a moiety of Formula A, R 8 , R 9 , R 11 and R 12 are each H and R 10 is pyridyl or thiadizolyl;
1.57 Formula 1.54, wherein R 3 is a moiety of Formula A, R 8 , R 9 , R 11 and R 12 are each H and R 10 is pyrid-2-yl optionally substituted with halo (e.g., fluoro);
1.58 Formula 1.54, wherein R 3 is a moiety of Formula A and X, Y and Z are all C;
1.59 Formula 1.54, wherein R 10 is pyrimidinyl;
1.60 Formula 1.54, wherein R 10 is 5-fluoropynnidinyl;
1.61 Formula 1.54, wherein R 10 is pyrazol-1-yl;
1.62 Formula 1.54, wherein R 10 is 1,2,4-triazol-1-yl;
1.63 Formula 1.54, wherein R 10 is aminocarbonyl;
1.64 Formula 1.54, wherein R 10 is methylsulfonyl;
1.65 Formula 1.54, wherein R 10 is 5-methyl-1,2,4-oxadiazol-3-yl;
1.66 Formula 1.54, wherein R 10 is 5-fluoropyrimidin-2-yl;
1.67 Formula 1.54, wherein R 10 is trifluoromethyl;
1.68 Formula 1.54, wherein R 3 is a moiety of Formula A, X and Z are C, and Y is N;
1.69 Formula I or any of 1.1-1.68, wherein R 2 is H; C 1-6 alkyl (e.g., isopropyl, isobutyl, neopentyl, 2-methylbutyl, 2,2-dimethylpropyl) wherein said alkyl group is optionally substituted with halo (e.g., fluoro) or hydroxy (e.g., 1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl); —C 0-4 alkyl-C 3-8 cycloalkyl (e.g., cyclopentyl, cyclohexyl) optionally substituted with one or more amino (e.g., —NH 2 ), for example, 2-aminocyclopentyl or 2-aminocyclohexyl), wherein said cycloalkyl optionally contains one or more heteroatom selected from N and O and is optionally substituted with C 1-6 alkyl (e.g., 1-methyl-pyrrolindin-2-yl, 1-methyl-pyrrolindin-3-yl, 1-methyl-pyrrolindin-2-yl-methyl or 1-methyl-pyrrolindin-3-yl-methyl); C 3-8 heterocycloalkyl (e.g., pyrrolidinyl, for example, pyrrolidin-3-yl) optionally substituted with C 1-6 alkyl (e.g., methyl), for example, 1-methylpyrrolidin-3-yl; C 3-8 cycloalkyl-C 1-6 alkyl (e.g., cyclopropylmethyl); haloC 1-6 alkyl (e.g., trifluoromethyl, 2,2,2-trifluoroethyl); —N(R 14 )(R 15 )—C 1-6 alkyl (e.g., 2-(dimethylamino)ethyl, 2-aminopropyl); hydroxyC 1-6 alkyl (e.g., (e.g., 3-hydroxy-2-methylpropyl, 1-hydroxyprop-2-yl); arylC 0-6 alkyl (e.g., benzyl); heteroarylC 1-6 alkyl (e.g., pyridinylmethyl); C 1-6 alkoxyarylC 1-6 alkyl (e.g., 4-methoxybenzyl); -G-J wherein: G is a single bond or, alkylene (e.g., methylene) and J is cycloalkyl or heterocycloalkyl (e.g., oxetan-2-yl, pyrolyin-3-yl, pyrolyin-2-yl) optionally substituted with C 1-6 alkyl (e.g., (1-methylpyrolidin-2-yl));
1.70 Formula 1.69, wherein R 2 is H;
1.71 Formula 1.69, wherein R 2 is C 1-6 alkyl (e.g., isopropyl, isobutyl, neopentyl, 2-methylbutyl, 2,2-dimethylpropyl) wherein said alkyl group is optionally substituted with halo (e.g., trifluoroethyl) or hydroxy (e.g., 1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl);
1.72 Formula 1.69, wherein R 2 is isobutyl;
1.73 Formula 1.69, wherein R 2 is 3-hydroxy-2-methylpropyl;
1.74 Formula 1.69, wherein R 2 is 1-hydroxypropan-2-yl;
1.75 Formula 1.69, wherein R 2 is —C 0-4 alkyl-C 3-8 cycloalkyl (e.g., cyclopentyl, cyclohexyl) optionally substituted with one or more amino (e.g., —NH 2 ), for example, 2-aminocyclopentyl or 2-aminocyclohexyl), wherein said cycloalkyl optionally contains one or more heteroatom selected from N and O and is optionally substituted with C 1-6 alkyl (e.g., 1-methyl-pyrrolindin-2-yl, 1-methyl-pyrrolindin-3-yl, 1-methyl-pyrrolindin-2-yl-methyl or 1-methyl-pyrrolindin-3-yl-methyl);
1.76 Formula 1.69, wherein R 2 is 1-methyl-pyrrolindin-2-yl, 1-methyl-pyrrolindin-3-yl, 1-methyl-pyrrolindin-2-yl-methyl or 1-methyl-pyrrolindin-3-yl-methyl;
1.77 Formula 1.69, wherein R 2 is C 3-8 heterocycloalkyl (e.g., pyrrolidinyl, for example, pyrrolidin-3-yl) optionally substituted with C 1-6 alkyl (e.g., methyl), for example, 1-methylpyrrolidin-3-yl;
1.78 Formula 1.69, wherein R 2 is 1-methylpyrrolidin-3-yl;
1.79 Formula 1.69, wherein R 2 is C 3-8 cycloalkyl-C 1-6 alkyl (e.g.,cyclopropylmethyl);
1.80 Formula 1.69, wherein R 2 is —N(R 14 )(R 15 )—C 1-6 alkyl (e.g., 2-(dimethylamino)ethyl, 2-aminopropyl);
1.81 Formula 1.69, wherein R 2 is heteroarylC 1-6 alkyl (e.g., pyridinylmethyl),
1.82 Formula 1.69, wherein R 2 is C 1-6 alkoxyarylC 1-6 alkyl (e.g., 4-methoxybenzyl;
1.83 Formula 1.69, wherein R 2 is arylC 0-6 alkyl (e.g., benzyl);
1.84 Formula 1.69, wherein R 2 is cyclopentyl or cyclohexyl;
1.85 Formula I or any of 1.1-1.68, wherein R 2 is -G-J; G is a single bond or, alkylene (e.g., methylene); and J is cycloalkyl or heterocycloalkyl (e.g., oxetan-2-yl, pyrolyin-3-yl, pyrolyin-2-yl) optionally substituted with C 1-6 alkyl (e.g., (1-methylpyrolidin-2-yl));
1.86 Formula 1.85, wherein G is alkylene (e.g., methylene);
1.87 Formula 1.85, wherein G is methylene;
1.88 Formula 1.85, wherein J is cycloalkyl or heterocycloalkyl (e.g., oxetan-2-yl, pyrolyin-3-yl, pyrolyin-2-yl) optionally substituted with alkyl (e.g., 1-methylpyrolidin-2-yl);
1.89 Formula 1.85, wherein J is oxetan-2-yl, pyrolyin-3-yl, pyrolyin-2-yl;
1.90 Formula 1.85, wherein J is (1-methylpyrolidin-2-yl);
1.91 Any of the preceding formulae wherein R 4 and R 5 are independently H, C 1-6 alkyl (e.g., methyl, isopropyl), C 3-8 cycloalkyl (e.g., cyclopentyl), C 3-8 heterocycloalkyl (e.g., pyrrolidin-3-yl), or aryl (e.g., phenyl) or heteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or heteroaryl is optionally substituted with halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkoxy C 1-6 alkyl, or C 1-6 alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
1.92 Formula 1.91, wherein either R 4 or R 5 is H;
1.93 Formula 1.91, wherein either R 4 or R 5 is C 1-6 alkyl (e.g., methyl, isopropyl);
1.94 Formula 1.91, wherein either R 4 or R 5 is isopropyl;
1.95 Formula 1.91, wherein either R 4 or R 5 is C 3-8 cycloalkyl (e.g., cyclopentyl);
1.96 Formula 1.91, wherein either R 4 or R 5 is C 3-8 heterocycloalkyl (e.g., pyrrolidin-3-yl);
1.97 Formula 1.91, wherein either R 4 or R 5 is aryl (e.g., phenyl) optionally substituted with halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkyl, C 1-6 alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
1.98 Formula 1.91, wherein either R 4 or R 5 is 4-hydroxyphenyl;
1.99 Formula 1.91, wherein either R 4 or R 5 is 4-fluorophenyl;
1.100 Formula 1.91, wherein either R 4 or R 5 is heteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) optionally substituted with halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkyl, C 1-6 alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
1.101 Formula 1.91, wherein either R 4 or R 5 is phenyl;
1.102 Any of the foregoing formulae, wherein R 6 is H, C 1-6 alkyl (e.g., methyl) or C 3-8 cycloalkyl;
1.103 Formula 1.102, wherein R 6 is H;
1.104 Formula 1.102, wherein R 6 is C 1-6 alkyl (e.g., methyl);
1.105 Formula 1.102, wherein R 6 is methyl;
1.106 Any of the foregoing formulae, wherein R 13 is —N(R 14 )(R 15 ), C 1-6 alkyl (e.g., methyl), —OC 1-6 alkyl (e.g., —OCH 3 ), haloC 1-6 alkyl, aryl (for example phenyl), or heteroaryl;
1.107 Formula 1.106, wherein R 13 is —N(R 14 )(R 15 );
1.108 Formula 1.106, wherein R 13 is C 1-6 alkyl (e.g., methyl);
1.109 Formula 1.106, wherein R 13 is —OC 1-6 alkyl (e.g., —OCH 3 ),
1.110 Formula 1.106, wherein R 13 is —OCH 3 ;
1.111 Formula 1.106, wherein R 13 is haloC 1-6 alkyl (e.g., trifluoromethyl);
1.112 Formula 1.106, wherein R 13 is trifluoromethyl;
1.113 Formula 1.106, wherein R 13 is aryl (e.g., phenyl);
1.114 Formula 1.106, wherein R 13 is heteroaryl (e.g., pyridiyl);
1.115 Any of the preceding formulae, wherein R 14 and R 15 are independently H or C 1-6 alkyl (e.g., methyl);
1.116 Formula I or any of 1.1-1.115, wherein either R 14 or R 15 is independently H;
1.117 Formula I or any of 1.1-1.115, wherein either R 14 or R 15 is C 1-6 alkyl (e.g., methyl);
1.118 Formula I or any of 1.1-1.115, wherein either R 14 or R 15 is methyl;
1.119 any of the preceding formulae wherein the compound of formula I is
[0000]
1.120 any of the preceding formulae wherein compound of formula I is
[0000]
1.121 any of the preceding formulae wherein compound of formula I is selected from a group consisting of:
[0000]
1.122 any of the preceding formulae wherein the compounds inhibit phosphodiesterase-mediated (e.g., PDE1-mediated, especially PDE1B-mediated) hydrolysis of cGMP, e.g., with an IC 50 of less than 1 μM, preferably less than 500 nM, preferably less than 200 nM in an immobilized-metal affinity particle reagent PDE assay, for example, as described in Example 5,
in free, salt or prodrug form.
[0491] In a particular embodiment, the compound of the present invention is the compound of the present invention is a 3-amino-4-(thioxo)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-ones, e.g., a compound of Formula I or II, wherein Q is C(═S) and the rest of the substituents are as defined in any of the formulae above. In another preferred embodiment, 7-Isobutyl-5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-4-thioxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one or 7-Isobutyl-5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-4-(imino)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one, in free, or salt form. In still another embodiment, the compound of the invention is 2-(4-(1H-1,2,4-triazol-1-yl)benzyl)-5-methyl-7-neopentyl-3-(phenylamino)-4-thioxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one.
[0492] In still another particular embodiment, the Compound of the Invention is a Compound of Formula I wherein
(i) Q is —C(═S)—, —C(═N(R 6 ))— or —C(R 14 )(R 15 )—; (ii) R 1 is H or alkyl (e.g., methyl); (iii) R 2 is H, alkyl (e.g., isobutyl, 2-methylbutyl, 2,2-dimethyl propyl), cycloalkyl (e.g., cyclopentyl, cyclohexyl), haloalkyl (e.g., trifluoromethyl, 2,2,2-trifluoroethyl), alkylaminoalkyl (e.g., 2-(dimethylamino)ethyl), hydroxyalkyl (e.g., 3-hydroxy-2-methyl propyl), arylalkyl (e.g., benzyl), heteroarylalkyl (e.g., pyridylmethyl), or alkoxyarylalkyl (e.g., 4-methoxybenzyl); (iv) R 3 is a substituted heteroarylaklyl, e.g., substituted with haloalkyl or R 3 is attached to one of the nitrogens on the pyrazolo portion of Formula 1 and is a moiety of Formula A
[0000]
[0000] wherein X, Y and Z are, independently, N or C, and R 8 , R 9 , R 11 and R 12 are independently H or halogen (e.g., Cl or F); and R 10 is halogen, alkyl, cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, (for example, pyrid-2-yl) or e.g., thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl, triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), alkyl sulfonyl (e.g., methyl sulfonyl), arylcarbonyl (e.g., benzoyl), or heteroarylcarbonyl, alkoxycarbonyl, (e.g., methoxycarbonyl), aminocarbonyl; preferably phenyl or pyridyl, e.g., 2-pyridyl; provided that when X, Y or X is nitrogen, R 8 , R 9 or R 10 , respectively, is not present;
(v) R 4 is aryl (e.g., phenyl) or heteroaryl; (vi) R 5 is H, alkyl, cycloalkyl (e.g., cyclopentyl), heteroaryl, aryl, p-benzylaryl (e.g., biphenyl-4-ylmethyl); (vii) R 6 is H, C 1-6 alkyl (e.g., methyl) or C 3-8 cycloalkyl; (viii) R 13 is —N(R 14 )(R 15 ), C 1-6 alkyl (e.g., methyl), —OC 1-6 alkyl (e.g., —OCH 3 ), haloC 1-6 alkyl (trifluoromethyl), aryl (e.g., phenyl), or heteroaryl; and (ix) R 14 and R 15 are independently H or C 1-6 alkyl,
in free, salt or prodrug form (hereinafter, Compound of Formula I(i)).
[0504] In still another embodiment, the Compound of the Invention is a Compound of Formula I wherein
(i) R 1 is H or alkyl (e.g., methyl); (ii) R 2 is H, alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl, 2,2-dimethyl propyl), cycloalkyl (e.g., cyclopentyl, cyclohexyl), haloalkyl (e.g., trifluoromethyl, 2,2,2-trifluoroethyl), alkylaminoalkyl (e.g., 2-(dimethylamino)ethyl), hydroxyalkyl (e.g., 3-hydroxy-2-methyl propyl), arylalkyl (e.g., benzyl), heteroarylalkyl (e.g., pyridylmethyl), or alkoxyarylalkyl (e.g., 4-methoxybenzyl);
(iii) R 3 is D-E-F wherein 1. D is single bond, alkylene (e.g., methylene), or arylalkylene (e.g., benzylene or —CH 2 C 6 H 4 —); 2. E is a alkylene (e.g., methylene, ethynylene, prop-2-yn-1-ylene), arylene (e.g., phenylene or —C 6 H 4 —), alkylarylene (e.g., —benzylene- or —CH 2 C 6 H 4 —), aminoalkylene (e.g., —CH 2 N(H)—) or amino (e.g., —N(H)—); and 3. F is alkyl (e.g., isobutyl), aryl (e.g., phenyl), heteroaryl (e.g., pyrid-2-yl, 1,2,4-triazolyl), heteroC 3-8 cycloalkyl (e.g., pyrolidin-1-yl), amino (e.g., —NH 2 ), C 1-6 alkoxy, or —O-haloalkyl (e.g., —O—CF 3 );
(iv) R 4 is aryl (e.g., phenyl), heteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) or heterocycloalkyl (e.g., pyrrolidin-3-yl); and (v) R 5 is H, alkyl, cycloalkyl (e.g., cyclopentyl), heteroaryl, aryl, p-benzylaryl (e.g., biphenyl-4-ylmethyl); (vi) R 6 is H, C 1-6 alkyl (e.g., methyl) or C 3-8 cycloalkyl; (vii) R 13 is —N(R 14 )(R 15 ), C 1-6 alkyl (e.g., methyl), —OC 1-6 alkyl (e.g., —OCH 3 ), haloC 1-6 alkyl (trifluoromethyl), aryl (e.g., phenyl), or heteroaryl; and (viii) R 14 and R 15 are independently H or alkyl,
wherein “alk”, “alkyl”, “haloalkyl” or “alkoxy” refers to C 1-6 alkyl and “cycloalkyl” refers to C 3-8 cycloalkyl unless specifically specified; in free, salt or prodrug form (hereinafter, Compound of Formula I(ii)).
[0516] If not otherwise specified or clear from context, the following terms herein have the following meanings:
(a) “Alkyl” as used herein is a saturated or unsaturated hydrocarbon moiety, preferably saturated, preferably having one to six carbon atoms, which may be linear or branched, and may be optionally mono-, di- or tri- substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy, or carboxy. (b) “Cycloalkyl” as used herein is a saturated or unsaturated nonaromatic hydrocarbon moiety, preferably saturated, preferably comprising three to eight carbon atoms, at least some of which form a nonaromatic mono- or bicyclic, or bridged cyclic structure, and which may be optionally substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy, or carboxy. Wherein the cycloalkyl optionally contains one or more atoms selected from N and O and/or S, said cycloalkyl may optionally be a heterocycloalkyl. (c) “Heterocycloalkyl” is, unless otherwise indicated, saturated or unsaturated nonaromatic hydrocarbon moiety, preferably saturated, preferably comprising three to nine carbon atoms, at least some of which form a nonaromatic mono- or bicyclic, or bridged cyclic structure, wherein at least one carbon atom is replaced with N, O or S, which heterocycloalkyl may be optionally substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy, or carboxy. (d) “Aryl” as used herein is a mono or bicyclic aromatic hydrocarbon, preferably phenyl, optionally substituted, e.g., with alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloalkyl (e.g., trifluoromethyl), hydroxy, carboxy, or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl). (e) “Heteroaryl” as used herein is an aromatic moiety wherein one or more of the atoms making up the aromatic ring is sulfur or nitrogen rather than carbon, e.g., pyridyl or thiadiazolyl, which may be optionally substituted, e.g., with alkyl, halogen, haloalkyl, hydroxy or carboxy. (f) Wherein E is phenylene, the numbering is as follows:
[0000]
(g) It is intended that wherein the substituents end in “ene”, for example, alkylene, phenylene or arylalkylene, said substitutents are intended to bridge or be connected to two other substituents. Therefore, methylene is intended to be —CH 2 — and phenylene intended to be —C 6 H 4 — and arylalkylene is intended to be —C 6 H 4 —CH 2 — or —CH 2 —C 6 H 4 —.
[0524] Compounds of the Invention may exist in free or salt form, e.g., as acid addition salts. In this specification unless otherwise indicated, language such as “Compounds of the Invention” is to be understood as embracing the compounds described herein, e.g., 3-amino-4,5-dihydro-(1H or 2H)-pyrazolo[3,4-d]pyrimidin-6(7H)-ones and their 4-imino and 4-thioxo derivatives, e.g., optionally substituted 3-amino-4-(thioxo or imino)-4,5-dihydro-(1H or 2H)-pyrazolo[3,4-d]pyrimidin-6(7H)-ones or 3-amino-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6(7H)-ones, a Compound of Formula I, or any of 1.11.122, a Compound of Formula I(i) or I(ii), a Compound of Formula II, e.g., any of 2.1-2.64, or any of Compound of Formula II(a)-II(e), in any form, for example free or acid addition salt form, or where the compounds contain acidic substituents, in base addition salt form. The Compounds of the Invention are intended for use as pharmaceuticals, therefore pharmaceutically acceptable salts are preferred. Salts which are unsuitable for pharmaceutical uses may be useful, for example, for the isolation or purification of free Compounds of the Invention or their pharmaceutically acceptable salts, are therefore also included.
[0525] Compounds of the Invention may in some cases also exist in prodrug form. A prodrug form is compound which converts in the body to a Compound of the Invention. For example, when the Compounds of the Invention contain hydroxy (or carboxy) substituents, these substituents may form physiologically hydrolysable and acceptable esters, e.g., C 1-4 alkyl carboxylic acid ester. As used herein, “physiologically hydrolysable and acceptable ester” means esters of Compounds of the Invention which are hydrolysable under physiological conditions to yield acids (in the case of Compounds of the Invention which have hydroxy substituents) or alcohols (in the case of Compounds of the Invention which have carboxy substituents) which are themselves physiologically tolerable at doses to be administered. Therefore, wherein the Compound of the Invention contains a hydroxy group, for example, Compound-OH, the acyl ester prodrug of such compound, i.e., Compound-O—C(O)—C 1-4 alkyl, can hydrolyze in the body to form physiologically hydrolysable alcohol (Compound-OH) on the one hand and acid on the other (e.g., HOC(O)—C 1-4 alkyl). Alternatively, wherein the Compound of the Invention contains a carboxylic acid, for example, Compound-C(O)OH, the acid ester prodrug of such compound, Compound-C(O)O—C 1 alkyl can hydrolyze to form Compound-C(O)OH and HO—C 1-4 alkyl. As will be appreciated, the term thus embraces conventional pharmaceutical prodrug forms.
[0526] The invention also provides methods of making the Compounds of the Invention and methods of using the Compounds of the Invention for treatment of diseases and disorders as set forth below (especially treatment of diseases characterized by reduced dopamine D1 receptor signaling activity, such as Parkinson's disease, Tourette's Syndrome, Autism, fragile X syndrome, ADHD, restless leg syndrome, depression, cognitive impairment of schizophrenia, narcolepsy and diseases that may be alleviated by the enhancement of progesterone-signaling such as female sexual dysfunction), or a disease or disorder such as psychosis or glaucoma). This list is not intended to be exhaustive and may include other diseases and disorders as set forth below.
[0527] In another embodiment, the invention further provides a pharmaceutical composition comprising a Compound of the Invention, e.g., 3-amino-4,5-dihydro-(1H or 2H)-pyrazolo[3,4-d]pyrimidin-6(7H)-ones and their 4-imino and 4-thioxo derivatives, e.g., optionally substituted 3-amino-4-(thioxo or imino)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-ones, optionally substituted 3-amino-4-(thioxo or imino)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6(7H)-ones, 3-amino-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6(7H)-ones, a Compound of Formula I, or any of 1.11.122, a Compound of Formula I(i) or I(ii), a Compound of Formula II, e.g., any of 2.1-2.64, or any of the Compound of Formula II(a)-II(e), in free, pharmaceutically acceptable salt or prodrug form, in admixture with a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
Methods of Making Compounds of the Invention
[0528] The Compounds of the Invention and their pharmaceutically acceptable salts may be made using the methods as described and exemplified herein and by methods similar thereto and by methods known in the chemical art. Such methods include, but not limited to, those described below. In the description of the synthetic methods described herein, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. Therefore, at times, the reaction may require to be run at elevated temperature or for a longer or shorter period of time. It is understood by one skilled in the art of organic synthesis that functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. If not commercially available, starting materials for these processes may be made by procedures, which are selected from the chemical art using techniques which are similar or analogous to the synthesis of known compounds. In particular, the intermediates and starting materials for the Compounds of the Invention may be prepared by methods and processes as described in PCT/US2007/070551. All references cited herein are hereby incorporated by reference in their entirety.
[0529] The Compounds of the Invention include their enantiomers, diastereoisomers, tautomers and racemates, as well as their polymorphs, hydrates, solvates and complexes. Some individual compounds within the scope of this invention may contain double bonds. Representations of double bonds in this invention are meant to include both the E and the Z isomer of the double bond. In addition, some compounds within the scope of this invention may contain one or more asymmetric centers. This invention includes the use of any of the optically pure stereoisomers as well as any combination of stereoisomers.
[0530] It is also intended that the Compounds of the Invention encompass their stable and unstable isotopes. Stable isotopes are nonradioactive isotopes which contain one additional neutron compared to the abundant nuclides of the same species (i.e., element). It is expected that the activity of compounds comprising such isotopes would be retained, and such compound would also have utility for measuring pharmacokinetics of the non-isotopic analogs. For example, the hydrogen atom at a certain position on the Compounds of the Invention may be replaced with deuterium (a stable isotope which is non-raradioactive). Examples of known stable isotopes include, but not limited to, deuterium, 13 C, 15 N, 18 O. Alternatively, unstable isotopes, which are radioactive isotopes which contain additional neutrons compared to the abundant nuclides of the same species (i.e., element), e.g., 1231 , 131 1, 125 1, 11 C, 18 F, may replace the corresponding abundant species of I, C and F. Another example of useful isotope of the compound of the invention is the 11 C isotope. These radio isotopes are useful for radio-imaging and/or pharmacokinetic studies of the compounds of the invention.
[0531] Melting points are uncorrected and (dec) indicates decomposition. Temperature are given in degrees Celsius (° C.); unless otherwise stated, operations are carried out at room or ambient temperature, that is, at a temperature in the range of 18-25° C. Chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) is carried out on silica gel plates. NMR data is in the delta values of major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard. Conventional abbreviations for signal shape are used. Coupling constants (J) are given in Hz. For mass spectra (MS), the lowest mass major ion is reported for molecules where isotope splitting results in multiple mass spectral peaks Solvent mixture compositions are given as volume percentages or volume ratios. In cases where the NMR spectra are complex, only diagnostic signals are reported.
[0532] Terms and abbreviations:
[0533] BuLi=n-butyllithium
[0534] Bu t OH=tert-butyl alcohol,
[0535] CAN=ammonium cerium (IV) nitrate,
[0536] DIPEA=diisopropylethylamine,
[0537] DMF=N,N-dimethylforamide,
[0538] DMSO=dimethyl sulfoxide,
[0539] Et 2 O=diethyl ether,
[0540] EtOAc=ethyl acetate,
[0541] equiv.=equivalent(s),
[0542] h=hour(s),
[0543] HPLC=high performance liquid chromatography,
[0544] LDA=lithium diisopropylamide
[0545] MeOH=methanol,
[0546] NBS=N-bromosuccinimide
[0547] NCS=N-chlorosuccinimide
[0548] NaHCO 3 =sodium bicarbonate,
[0549] NH 4 OH=ammonium hydroxide,
[0550] Pd 2 (dba) 3 =tris[dibenzylideneacetone]dipalladium(0)
[0551] PMB=p-methoxybenzyl,
[0552] POCl 3 =phosphorous oxychloride,
[0553] SOCl 2 =thionyl chloride,
[0554] TFA=trifluoroacetic acid,
[0555] THF=tetrahedrofuran.
[0556] The synthetic methods in this invention are illustrated below. The significances for the R groups are as set forth in any of the formulae above, e.g., for formula I, I(i), I(ii), II, II(a)-II(e) unless otherwise indicated.
[0557] In an aspect of the invention, intermediate compounds of formula IIb can be synthesized by reacting a compound of formula IIa with a dicarboxylic acid, acetic anhydride and acetic acid mixing with heat for about 3 hours and then cooled:
[0000]
[0558] wherein R 1 is H or C 1-4 alkyl [e.g., methyl].
[0559] Intermediate IIc can be prepared by for example reacting a compound of IIb with for example a chlorinating compound such as POCl 3 , sometimes with small amounts of water and heated for about 4 hours and then cooled:
[0000]
[0560] Intermediate IId may be formed by reacting a compound of IIc with for example a P 1 -L in a solvent such as DMF and a base such as K 2 CO 3 at room temperature or with heating:
[0000]
[0000] wherein P 1 is a protective group [e.g., p-methoxybenzyl group (PMB)]; L is a leaving group such as a halogen, mesylate, or tosylate.
[0561] Intermediate IIe may be prepared by reacting a compound of IId with hydrazine or hydrazine hydrate in a solvent such as methanol and refluxed for about 4 hours and then cooled:
[0000]
[0562] Intermediate IIf can be synthesized by reacting a compound of IIe with for example an aryl isothiocyanate or isocyanate in a solvent such as DMF and heated at 110° C. for about 2 days and then cooled:
[0000]
wherein R 4 is, e.g., (hetero)aryl or (hetero)arylmethyl [e.g., phenyl or benzyl].
[0564] Intermediate IIg may be formed by reacting a compound of IIf with for example a R 3 -L in a solvent such as DMF and a base such as K 2 CO 3 at room temperature or with heating:
[0000]
wherein R 3 is as defined previously in Formula I or II [e.g. -D-E-F or moiety of Formula A]; L is a leaving group such as a halogen, mesylate, or tosylate.
[0566] Intermediate IIh may be synthesized from a compound of IIg by removing the protective group P 1 with an appropriate method. For example, if P 1 is a p-methoxybenzyl group, then it can be removed with AlCl 3 in the presence of anisole at room temperature:
[0000]
[0567] Intermediate I may be formed by reacting a compound of IIh with for example a R 2 -L and/or R 5 -L in a solvent such as DMF and a base such as K 2 CO 3 at room temperature or with heating:
[0000]
wherein R 2 and R 5 are as defined previously [e.g. R 2 is a cyclopentyl group and R 5 is phenyl]; L is a leaving group such as a halogen, mesylate, or tosylate.
[0569] There is an alternative approach for the synthesis of Intermediate I.
[0570] Intermediate IIIa may be formed by reacting a compound of IIc with for example a R 2 -L in a solvent such as DMF and a base such as K 2 CO 3 at room temperature or with heating:
[0000]
[0571] wherein R 2 is as defined in any of the formulae disclosed herein and L is a leaving group such as halogen, mesylate, or tosylate
[0572] Intermediate IIIb may be prepared by reacting a compound of IIIa with hydrazine or hydrazine hydrate in a solvent such as methanol and heated for about several hours and then cooled:
[0000]
[0573] Intermediate IIIc can be synthesized by reacting a compound of IIIb with for example an aryl isothiocyanate or isocyanate in a solvent such as DMF and heated at 110° C. for about 2 days and then cooled:
[0000]
[0574] Compound I may be formed by reacting a compound of IIIc with for example a R 3 -L in a solvent such as DMF and a base such as K 2 CO 3 at room temperature or with heating. The obtained product (IIId) may further react with for example a R 5 -L under basic condition to give compound I wherein R 5 and R 3 are as previously defined in any of the formulae disclosed herewith, and L is a leaving group such as halogen, mesylate or tosylate:
[0000]
[0575] The compound of Formula (I)-A shown below can be synthesized using similar synthetic methods described above. In general, N-1 substituted compound is obtained as a minor product of N-alkylation reaction, as shown here.
[0000]
[0576] The third approach for making compound I is described below.
[0577] Intermediate IVa may be formed by for example reacting a compound of Mb with POCl 3 and DMF.
[0000]
[0578] Intermediate IVb may be formed by reacting a compound of IVa with for example a R 3 -L in a solvent such as DMF and a base such as K 2 CO 3 at room temperature or with heating.
[0000]
[0000] wherein R 3 is as previously defined in any of the formulae disclosed herewith, and L is a leaving group such as halogen, mesylate or tosylate.
[0579] Intermediate IVc may be formed by reacting a compound of IVb with for example NCS, NBS or I 2 in a solvent such as THF and a base such as LDA or BuLi at low temperature.
[0000]
[0580] Compound I may be formed by the amination of IVc, IVd, or IIIc, e.g., with R 4 NH 2 or R 5 NH 2 under basic conditions. An appropriate catalyst such as Pd 2 (dba) 3 may be required in order to get good yields, particularly when R 4 NH 2 or R 5 NH 2 is an aryl amine or hetereoaryl amine.
[0000]
[0581] The 4-thioxo Compounds of the Invention, e.g., Compounds of Formula I or II wherein Q is C(═S) may then be prepared by reacting Intermediate I or any of the with P 4 S 1o in a microwave vial in the presence of a base, e.g., pyridine, and heating the mixture to an elevated temperature, e.g., in a microwave, e.g., to about 150° C. The 4-imino Compounds of the Invention, e.g., Compounds of Formula I or II, wherein Q is C(═N(R 6 )) may in turn be converted from the thioxo derivative (i.e., Compounds of Formula I or II, wherein with Q is X(═S)) by reacting the 4-thioxo derivative with NH 2 (R 6 ) in the presence of HgCl 2 , e.g., in a solvent such as THF, and heating the reaction mixture to an elevated temperature, e.g., in a microwave, e.g., to about 110° C.
[0582] The Compounds of the Invention, e.g., Compounds of Formula I or II wherein Q is C(R 14 )(R 15 ) may also be prepared by reacting Intermediate I with a reducing agent, e.g., diisobutylaluminum hydride (DIBAL-H), lithium aluminum hydride, sodium borohydride, preferably, DIBAL-H.
[0583] The invention thus provides methods of making a 4-thioxo Compounds of the Invention, e.g., Compound of Formula I or II, wherein Q of is C(═S) as hereinbefore described, for example, comprising reacting a 7-R 2 -5-R 3 -3-(N(R4)(R5))-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione of Formula I with P 4 S 10 in the presence of a base, e.g., pyridine, and heating the reaction mixture to an elevated temperature, e.g., to >50° C., e.g., >100° C., e.g., >150° C., for example, in a microwave to about 150° C.
[0584] The invention also provides methods of making 4-imino Compounds of the Invention, e.g., Compounds of Formula I or II, wherein Q of Formula I is C(═N(R 6 )) as hereinbefore described, for example, comprising reacting a the Compound of Formula I or II, wherein Q is C(═S), with NH 2 (R 6 ) in the presence of HgCl 2 , e.g., in a solvent such as THF, and heating the reaction mixture in a microwave, e.g., to >50° C., e.g., >75° C., e.g., >100° C., for example, in a microwave to about 110° C.
[0585] The invention also provides methods of making pyrazolo[3,4-d]pyrimidin-6-one Compounds of the Invention, e.g., Compounds of Formula I or II, wherein Q is CH 2 comprising reacting Intermediate I with a reducing agent, e.g., diisobutylaluminum hydride (DIBAL-H), lithium aluminum hydride, sodium borohydride, preferably, DIBAL-H.
[0586] Alternatively, the Compounds of the Invention, e.g., Compounds of Formula I or II wherein Q is C(═S), C(═N(R 6 )) or CH 2 , may be prepared first before attaching on R 1 , R 2 , R 3 and/or R 5 . Therefore, the Compounds of the Invention may be prepared as follows:
[0000]
[0587] Compound of Formula (I) may be formed by the amination of IVc-A, IVd-A, or IIIc-A under basic conditions. An appropriate catalyst such as Pd 2 (dba) 3 may be required in order to get good yields.
Methods of Using Compounds of the Invention
[0588] The Compounds of the Invention are useful in the treatment of diseases characterized by disruption of or damage to cAMP and cGMP mediated pathways, e.g., as a result of increased expression of PDE1 or decreased expression of cAMP and cGMP due to inhibition or reduced levels of inducers of cyclic nucleotide synthesis, such as dopamine and nitric oxide (NO). By preventing the degradation of cAMP and cGMP by PDE1B, thereby increasing intracellular levels of cAMP and cGMP, the Compounds of the Invention potentiate the activity of cyclic nucleotide synthesis inducers.
[0589] The invention provides methods of treatment of any one or more of the following conditions:
(1) Neurodegenerative diseases, including Parkinson's disease, restless leg, tremors, dyskinesias, Huntington's disease, Alzheimer's disease, and drug-induced movement disorders; (ii) Mental disorders, including depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar illness, anxiety, sleep disorders, e.g., narcolepsy, cognitive impairment, dementia, Tourette's syndrome, autism, fragile X syndrome, psychostimulant withdrawal, and drug addiction; (iii) Circulatory and cardiovascular disorders, including cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonary hypertension, and sexual dysfunction; (iv) Respiratory and inflammatory disorders, including asthma, chronic obstructive pulmonary disease, and allergic rhinitis, as well as autoimmune and inflammatory diseases; (v) Any disease or condition characterized by low levels of cAMP and/or cGMP (or inhibition of cAMP and/or cGMP signaling pathways) in cells expressing PDE1; and/or (vi) Any disease or condition characterized by reduced dopamine D1 receptor signaling activity,
comprising administering an effective amount of a Compound of the Invention, e.g., a compound according to any of Formula I or 1-1.122, or a composition comprising a Compound of the Invention, e.g., a compound according to any of Formula I or 1-1.122, to a human or animal patient in need thereof. This method also encompasses administering an effective amount of a compound of formula I(i) or I(ii), in free or pharmaceutically acceptable salt form. In another aspect, the invention provides a method of treatment of the conditions disclosed above comprising administering a therapeutically effective amount of a Compound of Formula II, e.g., any of 2.1-2.64, or any of Compound of Formula II(a)-II(e), in free or pharmaceutically acceptable salt form, or a composition comprising the same, to a human or animal patient in need thereof.
[0596] In an especially preferred embodiment, the invention provides methods of treatment or prophylaxis for narcolepsy. In this embodiment, PDE 1 Inhibitors may be used as a sole therapeutic agent, but may also be used in combination or for co-administration with other active agents. Thus, the invention further comprises a method of treating narcolepsy comprising administering simultaneously, sequentially, or contemporaneously administering therapeutically effective amounts of
(i) a PDE 1 Inhibitor of the Invention, e.g., a compound according to any of Formula I or 1.1-1.122, or I(i) or I(ii); and (ii) a compound to promote wakefulness or regulate sleep, e.g., selected from (a) central nervous system stimulants-amphetamines and amphetamine like compounds, e.g., methylphenidate, dextroamphetamine, methamphetamine, and pemoline; (b) modafinil, (c) antidepressants, e.g., tricyclics (including imipramine, desipramine, clomipramine, and protriptyline) and selective serotonin reuptake inhibitors (including fluoxetine and sertraline); and/or (d) gamma hydroxybutyrate (GHB),
in free or pharmaceutically acceptable salt form, to a human or animal patient in need thereof. In another embodiment, the invention provides methods of treatment or prophylaxis for narcolepsy as herein before described, wherein the PDE1 inhibitor is in a form of a pharmaceutical composition. In still another embodiment, the methods of treatment or prophylaxis for narcolepsy as hereinbefore described, comprises administering a therapeutically effective amount of a Compound of Formula II, e.g., any of 2.1-2.64, or any of Formula II(a)-II(e), in free or pharmaceutically acceptable salt form, as a sole therapeutic agent or use in combination for co-administered with another active agent.
[0599] In another embodiment, the invention further provides methods of treatment or prophylaxis of a condition which may be alleviated by the enhancement of the progesterone signaling comprising administering an effective amount of a Compound of the Invention, e.g., a compound according to any of Formula 1-1.122 or Formula I, I(i) or I(ii) in free, pharmaceutically acceptable salt or prodrug form, to a human or animal patient in need thereof. The invention also provides methods of treatment as disclosed here, comprising administering a therapeutically effective amount of a Compound of Formula II, e.g., any of 2.1-2.64, or any of Formula II(a)-II(e), in free or pharmaceutically acceptable salt form. Disease or condition that may be ameliorated by enhancement of progesterone signaling include, but are not limited to, female sexual dysfunction, secondary amenorrhea (e.g., exercise amenorrhoea, anovulation, menopause, menopausal symptoms, hypothyroidism), pre-menstrual syndrome, premature labor, infertility, for example infertility due to repeated miscarriage, irregular menstrual cycles, abnormal uterine bleeding, osteoporosis, autoimmmune disease, multiple sclerosis, prostate enlargement, prostate cancer, and hypothyroidism. For example, by enhancing progesterone signaling, the PDE 1 inhibitors may be used to encourage egg implantation through effects on the lining of uterus, and to help maintain pregnancy in women who are prone to miscarriage due to immune response to pregnancy or low progesterone function. The novel PDE 1 inhibitors, e.g., as described herein, may also be useful to enhance the effectiveness of hormone replacement therapy, e.g., administered in combination with estrogen/estradiol/estriol and/or progesterone/progestins in postmenopausal women, and estrogen-induced endometrial hyperplasia and carcinoma. The methods of the invention are also useful for animal breeding, for example to induce sexual receptivity and/or estrus in a nonhuman female mammal to be bred.
[0600] In this embodiment, PDE 1 Inhibitors may be used in the foregoing methods of treatment or prophylaxis as a sole therapeutic agent, but may also be used in combination or for co-administration with other active agents, for example in conjunction with hormone replacement therapy. Thus, the invention further comprises a method of treating disorders that may be ameliorated by enhancement of progesterone signaling comprising administering simultaneously, sequentially, or contemporaneously administering therapeutically effective amounts of
(i) a PDE 1 Inhibitor, e.g., a compound according to any of Formula 1.1-1.122 or Formula I, and (ii) a hormone, e.g., selected from estrogen and estrogen analogues (e.g., estradiol, estriol, estradiol esters) and progesterone and progesterone analogues (e.g., progestins)
in free or pharmaceutically acceptable salt form, to a human or animal patient in need thereof. In another embodiment, the invention provides the method described above wherein the PDE 1 inhibitor is a Compound of Formula II, e.g., any of 2.1-2.64, or any of Formula II(a)-II(e), in free or pharmaceutically acceptable salt form.
[0603] The invention also provides a method for enhancing or potentiating dopamine D1 intracellular signaling activity in a cell or tissue comprising contacting said cell or tissue with an amount of a Compound of the Invention sufficient to inhibit PDE activity.
[0604] The invention also provides a method for enhancing or potentiating progesterone signaling activity in a cell or tissue comprising contacting said cell or tissue with an amount of a Compound of the Invention sufficient to inhibit PDE1B activity.
[0605] The invention also provides a method for treating a PDE 1-related, especially PDE 1 B-related disorder, a dopamine D1 receptor intracellular signaling pathway disorder, or disorders that may be alleviated by the enhancement of the progesterone signaling pathway in a patient in need thereof comprising administering to the patient an effective amount of a Compound of the Invention that inhibits PDE1B, wherein PDE1B activity modulates phosphorylation of DARPP-32 and/or the GluR1 AMPA receptor.
[0606] “The Compound of the Invention” referred to above includes a Compound of Formula I, e.g., any of 1.1-1.122, I(i) or I(ii), or a Compound of Formula II, e.g., any of 2.1-2.64, or any of Formula II(a)-II(e), in free or pharmaceutically acceptable salt form.
[0607] In another aspect, the invention also provides a method for the treatment for glaucoma or elevated intraocular pressure comprising topical administration of a therapeutically effective amount of a phospodiesterase type I (PDE1) Inhibitor of the Invention, e.g., a Compound of Formula I, e.g., any of 1.1-1.122, I(i) or I(ii), or a Compound of Formula II, e.g., any of 2.1-2.64, or any of Formula II(a)-II(e), in free or pharmaceutically acceptable salt form, in an opthalmically compatible carrier to the eye of a patient in need thereof. However, treatment may alternatively include a systemic therapy. Systemic therapy includes treatment that can directly reach the bloodstream, or oral methods of administration, for example.
[0608] The invention further provides a pharmaceutical composition for topical ophthalmic use comprising a PDE1 inhibitor; for example an ophthalmic solution, suspension, cream or ointment comprising a PDE1 Inhibitor of the Invention, e.g., a Compound of Formula I, e.g., any of 1.1-1.122, I(i) or I(ii), or a Compound of Formula II, e.g., any of 2.1-2.64, or any of Formula II(a)-II(e), in free or ophthamalogically acceptable salt form, in combination or association with an ophthamologically acceptable diluent or carrier.
[0609] Optionally, the PDE1 inhibitor may be administered sequentially or simultaneously with a second drug useful for treatment of glaucoma or elevated intraocular pressure. Where two active agents are administered, the therapeutically effective amount of each agent may be below the amount needed for activity as monotherapy. Accordingly, a subthreshold amount (i.e., an amount below the level necessary for efficacy as monotherapy) may be considered therapeutically effective and also may also be referred alternatively as an effective amount. Indeed, an advantage of administering different agents with different mechanisms of action and different side effect profiles may be to reduce the dosage and side effects of either or both agents, as well as to enhance or potentiate their activity as monotherapy.
[0610] The invention thus provides the method of treatment of a condition selected from glaucoma and elevated intraocular pressure comprising administering to a patient in need thereof an effective amount, e.g., a subthreshold amount, of an agent known to lower intraocular pressure concomitantly, simultaneously or sequentially with an effective amount, e.g., a subthreshold amount, of a PDE1 Inhibitor of the Invention, e.g., a Compound of Formula I, e.g., any of 1.1-1.122, I(i) or I(ii), or a Compound of Formula II, e.g., any of 2.1-2.64, or any of Formula II(a)-II(e), in free or pharmaceutically acceptable salt form, such that amount of the agent known to lower intraocular pressure and the amount of the PDE1 inhibitor in combination are effective to treat the condition. In one embodiment, one or both of the agents are administered topically to the eye. Thus the invention provides a method of reducing the side effects of treatment of glaucoma or elevated intraocular pressure by administering a reduced dose of an agent known to lower intraocular pressure concomitantly, simultaneously or sequentially with an effective amount of a PDE1 inhibitor. However, methods other than topical administration, such as systemic therapeutic administration, may also be utilized.
[0611] The optional additional agent or agents for use in combination with a PDE1 inhibitor may, for example, be selected from the existing drugs comprise typically of instillation of a prostaglandin, pilocarpine, epinephrine, or topical beta-blocker treatment, e.g. with timolol, as well as systemically administered inhibitors of carbonic anhydrase, e.g. acetazolamide. Cholinesterase inhibitors such as physostigmine and echothiopate may also be employed and have an effect similar to that of pilocarpine. Drugs currently used to treat glaucoma thus include, e.g.,
1. Prostaglandin analogs such as latanoprost (Xalatan), bimatoprost (Lumigan) and travoprost (Travatan), which increase uveoscleral outflow of aqueous humor. Bimatoprost also increases trabecular outflow. 2. Topical beta-adrenergic receptor antagonists such as timolol, levobunolol (Betagan), and betaxolol, which decrease aqueous humor production by the ciliary body. 3. Alpha 2 -adrenergic agonists such as brimonidine (Alphagan), which work by a dual mechanism, decreasing aqueous production and increasing uveo-scleral outflow. 4. Less-selective sympathomimetics like epinephrine and dipivefrin (Propine) increase outflow of aqueous humor through trabecular meshwork and possibly through uveoscleral outflow pathway, probably by a beta 2 -agonist action. 5. Miotic agents (parasympathomimetics) like pilocarpine work by contraction of the ciliary muscle, tightening the trabecular meshwork and allowing increased outflow of the aqueous humour. 6. Carbonic anhydrase inhibitors like dorzolamide (Trusopt), brinzolamide (Azopt), acetazolamide (Diamox) lower secretion of aqueous humor by inhibiting carbonic anhydrase in the ciliary body. 7. Physostigmine is also used to treat glaucoma and delayed gastric emptying.
[0619] For example, the invention provides pharmaceutical compositions comprising a PDE1 Inhibitor of the Invention and an agent selected from (i) the prostanoids, unoprostone, latanoprost, travoprost, or bimatoprost; (ii) an alpha adrenergic agonist such as brimonidine, apraclonidine, or dipivefrin and (iii) a muscarinic agonist, such as pilocarpine. For example, the invention provides ophthalmic formulations comprising a PDE-1 Inhibitor of the Invention together with bimatoprost, abrimonidine, brimonidine, timolol, or combinations thereof, in free or ophthamalogically acceptable salt form, in combination or association with an ophthamologically acceptable diluent or carrier. In addition to selecting a combination, however, a person of ordinary skill in the art can select an appropriate selective receptor subtype agonist or antagonist. For example, for alpha adrenergic agonist, one can select an agonist selective for an alpha 1 adrenergic receptor, or an agonist selective for an alpha 2 adrenergic receptor such as brimonidine, for example. For a beta-adrenergic receptor antagonist, one can select an antagonist selective for either β 1 , or β 2 , or β 3 , depending on the appropriate therapeutic application. One can also select a muscarinic agonist selective for a particular receptor subtype such as M 1 -M 5 .
[0620] The PDE 1 inhibitor may be administered in the form of an ophthalmic composition, which includes an ophthalmic solution, cream or ointment. The ophthalmic composition may additionally include an intraocular-pressure lowering agent.
[0621] In yet another example, the PDE-1 Inhibitors disclosed may be combined with a subthreshold amount of an intraocular pressure-lowering agent which may be a bimatoprost ophthalmic solution, a brimonidine tartrate ophthalmic solution, or brimonidine tartrate/timolol maleate ophthalmic solution.
[0622] In addition to the above-mentioned methods, it has also been surprisingly discovered that PDE1 inhibitors are useful to treat psychosis, for example, any conditions characterized by psychotic symptoms such as hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, e.g., schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disorder, delusional disorder, and mania, such as in acute manic episodes and bipolar disorder. Without intending to be bound by any theory, it is believed that typical and atypical antipsychotic drugs such as clozapine primarily have their antagonistic activity at the dopamine D2 receptor. PDE1 inhibitors, however, primarily act to enhance signaling at the dopamine D1 receptor. By enhancing D1 receptor signaling, PDE1 inhibitors can increase NMDA receptor function in various brain regions, for example in nucleus accumbens neurons and in the prefrontal cortex. This enhancement of function may be seen for example in NMDA receptors containing the NR2B subunit, and may occur e.g., via activation of the Src and protein kinase A family of kinases.
[0623] Therefore, the invention provides a new method for the treatment of psychosis, e.g., schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disorder, delusional disorder, and mania, such as in acute manic episodes and bipolar disorder, comprising administering an effective amount of a phosphodiesterase-1 (PDE1) Inhibitor of the Invention, e.g., a Compound of Formula
[0624] I, e.g., any of 1.1-1.122, I(i) or I(ii), or a Compound of Formula II, e.g., any of 2.1-2.64, or any of Formula II(a)-II(e), in free or pharmaceutically acceptable salt form, to a patient in need thereof.
[0625] PDE 1 Inhibitors may be used in the foregoing methods of treatment prophylaxis as a sole therapeutic agent, but may also be used in combination or for co-administration with other active agents. Thus, the invention further comprises a method of treating psychosis, e.g., schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disorder, delusional disorder, or mania, comprising administering simultaneously, sequentially, or contemporaneously administering therapeutically effective amounts of:
(i) a PDE 1 Inhibitor of the invention, e.g., a Compound of Formula I, e.g., any of 1.1-1.122, I(i) or I(ii), or a Compound of Formula II, e.g., any of 2.1-2.64, or any of Formula II(a)-II(e), in free or pharmaceutically acceptable salt form; and (ii) an antipsychotic, e.g.,
Typical antipsychotics, e.g.,
Butyrophenones, e.g. Haloperidol (Haldol, Serenace), Droperidol (Droleptan); Phenothiazines, e.g., Chlorpromazine (Thorazine, Largactil), Fluphenazine (Prolixin), Perphenazine (Trilafon), Prochlorperazine (Compazine), Thioridazine (Mellaril, Melleril), Trifluoperazine (Stelazine), Mesoridazine, Periciazine, Promazine, Triflupromazine (Vesprin), Levomepromazine (Nozinan), Promethazine (Phenergan), Pimozide (Orap); Thioxanthenes, e.g., Chlorprothixene, Flupenthixol (Depixol, Fluanxol), Thiothixene (Navane), Zuclopenthixol (Clopixol, Acuphase);
Atypical antipsychotics, e.g.,
Clozapine (Clozaril), Olanzapine (Zyprexa), Risperidone (Risperdal), Quetiapine (Seroquel), Ziprasidone (Geodon), Amisulpride (Solian), Paliperidone (Invega), Aripiprazole (Abilify), Bifeprunox; norclozapine,
in free or pharmaceutically acceptable salt form, to a patient in need thereof.
[0635] In a particular embodiment, the Compounds of the Invention are particularly useful for the treatment or prophylaxis of schizophrenia.
[0636] Compounds of the Invention, e.g., a Compound of Formula I, e.g., any of 1.1-1.122, I(i) or I(ii), or a Compound of Formula II, e.g., any of 2.1-2.64, or any of Formula II(a)-II(e), in free or pharmaceutically acceptable salt form, are particularly useful for the treatment of Parkinson's disease, schizophrenia, narcolepsy, glaucoma and female sexual dysfunction.
[0637] In still another aspect, the invention provides a method of lengthening or enhancing growth of the eyelashes by administering an effective amount of a prostaglandin analogue, e.g., bimatoprost, concomitantly, simultaneously or sequentially with an effective amount of a PDE1 inhibitor of the Invention, e.g., a Compound of Formula I, e.g., any of 1.1-1.122, I(i) or I(ii), or a Compound of Formula II, e.g., any of 2.1-2.64, or any of Formula II(a)-II(e), in free or pharmaceutically acceptable salt form, to the eye of a patient in need thereof.
[0638] In yet another aspect, the invention provides a method for the treatment of traumatic brain injury comprising administering a therapeutically effective amount of a Compound of Formula I, e.g., any of 1.1-1.122, I(i) or I(ii), or a Compound of Formula II, e.g., any of 2.1-2.64, or any of Formula II(a)-II(e), in free or pharmaceutically acceptable salt form, to a patient in need thereof. Traumatic brain injury (TBI) encompasses primary injury as well as secondary injury, including both focal and diffuse brain injuries. Secondary injuries are multiple, parallel, interacting and interdependent cascades of biological reactions arising from discrete subcellular processes (e.g., toxicity due to reactive oxygen species, overstimulation of glutamate receptors, excessive influx of calcium and inflammatory upregulation) which are caused or exacerbated by the inflammatory response and progress after the initial (primary) injury. Abnormal calcium homeostasis is believed to be a critical component of the progression of secondary injury in both grey and white matter. For a review of TBI, see Park et al., CMAJ (2008) 178(9):1163-1170, the contents of which are incorporated herein in their entirety. Studies have shown that the cAMP-PKA signaling cascade is downregulated after TBI and treatment of PDE IV inhibitors such as rolipram to raise or restore cAMP level improves histopathological outcome and decreases inflammation after TBI. As Compounds of the present invention is a PDE1 inhibitor, it is believed that these compounds are also useful for the treatment of TBI, e.g., by restoring cAMP level and/or calcium homeostasis after traumatic brain injury.
[0639] The present invention also provides
(i) a Compound of the Invention for use as a pharmaceutical, for example for use in any method or in the treatment of any disease or condition as hereinbefore set forth, (ii) the use of a Compound of the Invention in the manufacture of a medicament for treating any disease or condition as hereinbefore set forth, (iii) a pharmaceutical composition comprising a Compound of the
[0643] Invention in combination or association with a pharmaceutically acceptable diluent or carrier, and
(iv) a pharmaceutical composition comprising a Compound of the Invention in combination or association with a pharmaceutically acceptable diluent or carrier for use in the treatment of any disease or condition as hereinbefore set forth.
[0645] Therefore, the invention provides use of a Compound of the Invention, e.g., a Compound of Formula I, e.g., any of 1.1-1.122, I(i) or I(ii), or a Compound of Formula II, e.g., any of 2.1-2.64, or any of Formula II(a)-II(e), in free or pharmaceutically acceptable salt form, for the manufacture of a medicament for the treatment or prophylactic treatment of the following diseases: Parkinson's disease, restless leg, tremors, dyskinesias, Huntington's disease, Alzheimer's disease, and drug-induced movement disorders; depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar illness, anxiety, sleep disorder, narcolepsy, cognitive impairment, dementia, Tourette's syndrome, autism, fragile X syndrome, psychostimulant withdrawal, and/or drug addiction; cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonary hypertension, and/or sexual dysfunction; asthma, chronic obstructive pulmonary disease, and/or allergic rhinitis, as well as autoimmune and inflammatory diseases; and/or female sexual dysfunction, exercise amenorrhoea, anovulation, menopause, menopausal symptoms, hypothyroidism, pre-menstrual syndrome, premature labor, infertility, irregular menstrual cycles, abnormal uterine bleeding, osteoporosis, multiple sclerosis, prostate enlargement, prostate cancer, hypothyroidism, estrogen-induced endometrial hyperplasia or carcinoma; and/or any disease or condition characterized by low levels of cAMP and/or cGMP (or inhibition of cAMP and/or cGMP signaling pathways) in cells expressing PDE1, and/or by reduced dopamine D1 receptor signaling activity; and/or any disease or condition that may be ameliorated by the enhancement of progesterone signaling; comprising administering an effective amount of a Compound of the Invention, or a pharmaceutical composition comprising a Compound of the Invention, to a patient in need of such treatment.
[0646] The invention also provides use of a Compound of the Invention for the manufacture of a medicament for the treatment or prophylactic treatment of:
a) glaucoma or elevated intraocular pressure, b) psychosis, for example, any conditions characterized by psychotic symptoms such as hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, e.g., schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disorder, delusional disorder, and mania, such as in acute manic episodes and bipolar disorder, or c) traumatic brain injury.
[0650] The invention further provides use of the Compound of the Invention for lengthening or enhancing growth of the eyelashes.
[0651] The words “treatment” and “treating” are to be understood accordingly as embracing prophylaxis and treatment or amelioration of symptoms of disease as well as treatment of the cause of the disease.
[0652] Compounds of the Invention are in particular useful for the treatment of Parkinson's disease, narcolepsy and female sexual dysfunction.
[0653] For methods of treatment, the word “effective amount” is intended to encompass a therapeutically effective amount to treat a specific disease or disorder.
[0654] The term “pulmonary hypertension” is intended to encompass pulmonary arterial hypertension.
[0655] The term “patient” include human or non-human (i.e., animal) patient. In particular embodiment, the invention encompasses both human and nonhuman. In another embodiment, the invention encompasses nonhuman. In other embodiment, the term encompasses human.
[0656] The term “comprising” as used in this disclosure is intended to be open-ended and does not exclude additional, unrecited elements or method steps.
[0657] Compounds of the Invention may be used as a sole therapeutic agent, but may also be used in combination or for co-administration with other active agents. For example, as Compounds of the Invention potentiate the activity of D1 agonists, such as dopamine, they may be simultaneously, sequentially, or contemporaneously administered with conventional dopaminergic medications, such as levodopa and levodopa adjuncts (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists, and anticholinergics, e.g., in the treatment of a patient having Parkinson's disease. In addition, the novel PDE 1 inhibitors of the Invention, e.g., the Compounds of the Invention as described herein, may also be administered in combination with estrogen/estradiol/estriol and/or progesterone/progestins to enhance the effectiveness of hormone replacement therapy or treatment of estrogen-induced endometrial hyperplasia or carcinoma.
[0658] Dosages employed in practicing the present invention will of course vary depending, e.g. on the particular disease or condition to be treated, the particular Compound of the Invention used, the mode of administration, and the therapy desired. Compounds of the Invention may be administered by any suitable route, including orally, parenterally, transdermally, or by inhalation, but are preferably administered orally. In general, satisfactory results, e.g. for the treatment of diseases as hereinbefore set forth are indicated to be obtained on oral administration at dosages of the order from about 0.01 to 2.0 mg/kg. In larger mammals, for example humans, an indicated daily dosage for oral administration will accordingly be in the range of from about 0.75 to 150 mg, conveniently administered once, or in divided doses 2 to 4 times, daily or in sustained release form. Unit dosage forms for oral administration thus for example may comprise from about 0.2 to 75 or 150 mg, e.g. from about 0.2 or 2.0 to 50, 75 or 100 mg of a Compound of the Invention, together with a pharmaceutically acceptable diluent or carrier therefor.
[0659] Pharmaceutical compositions comprising Compounds of the Invention may be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus oral dosage forms may include tablets, capsules, solutions, suspensions and the like.
EXAMPLES
[0660] The synthetic methods for various Compounds of the Present Invention are illustrated below. Other compounds of the Invention and their salts may be made using the methods as similarly described below and/or by methods similar to those generally described in the detailed description and by methods known in the chemical art.
Example 1
7-Isobutyl-5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-4-thioxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one
[0661]
[0662] 7-Isobutyl-5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (116 mg, 0.241 mmol) and P 2 S 10 (214 mg, 0.284 mmol) are placed in a Biotage microwave vial, and then 2.3 mL of pyridine is added. The reaction mixture is heated in a microwave at 150° C. for 2.5 h. Pyridine is removed under high vacuum. The crude product is purified by silica gel flash chromatography to give 43.4 mg of pure product as pale yellow solids. MS (ESI) m/z 497.3 [M+H] +
Example 2
7-Isobutyl-5-methyl-4-(methylimino)-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one
[0663]
[0664] 7-Isobutyl-5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-4-thioxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one (15 mg, 0.030 mmol) and HgCl 2 (16.4 mg, 0.060 mmol) are suspended in THF, and then 2.0 M methylamine solution in THF (240 μL, 0.12 mmol) is added. The reaction mixture is heated in a Biotage microwave at 110° C. for 5 hours. After routine workup, the mixture is purified by a semi-preparative HPLC to give pure product as white solids. MS (ESI) m/z 494.3 [M+H] + .
Example 3
2-(4-(1H-1,2,4-triazol-1-yl)benzyl)-5-methyl-7-neopentyl-3-(phenylamino)-4-thioxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one
[0665]
[0000] The synthetic procedure of this compound is analogous to EXAMPLE 1 wherein 2-(4-(1H-1,2,4-triazol-1 -yl)benzyl)-5-methyl-7-neopentyl-3 -(phenylamino)-2H-pyrazolo[3,4-d]pyrimidin-4,6(5H,7H)-dione is used instead of 7-Isobutyl-5-methyl-3 -(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione. MS (ESI) m/z 501.2 [M+H] + .
Example 4
2-(4-(1H-1,2,4-triazol-1-yl)benzyl)-4-imino-5-methyl-7-neopentyl-3-(phenylamino)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one
[0666]
[0667] 2-(4-(1H-1,2,4-triazol-1-yl)benzyl)-5-methyl-7-neopentyl-3-(phenylamino)-4-thioxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one (60 mg, 0.12 mmol) and HgCl 2 (65 mg, 0.24 mmol) are suspended in 2 mL of 7N NH 3 in methanol. The reaction mixture is heated in a Biotage microwave at 110° C. for 3 hours. After routine workup, the mixture is purified by a semi-preparative HPLC to give 52 mg of pure product as off-white solids (yield: 90%). MS (ESI) m/z 484.3 [M+H] + .
Example 5
Measurement of PDE1B Inhibition in Vitro Using IMAP Phosphodiesterase Assay Kit
[0668] Phosphodiesterase 1B (PDE1B) is a calcium/calmodulin dependent phosphodiesterase enzyme that converts cyclic guanosine monophosphate (cGMP) to 5′-guanosine monophosphate (5′-GMP). PDE can also convert a modified cGMP substrate, such as the fluorescent molecule cGMP-fluorescein, to the corresponding GMP-fluorescein. The generation of GMP-fluorescein from cGMP-fluorescein can be quantitated, using, for example, the IMAP (Molecular Devices, Sunnyvale, Calif.) immobilized-metal affinity particle reagent.
[0669] Briefly, the IMAP reagent binds with high affinity to the free 5′-phosphate that is found in GMP-fluorescein and not in cGMP-fluorescein. The resulting GMP-fluorescein—IMAP complex is large relative to cGMP-fluorescein. Small fluorophores that are bound up in a large, slowly tumbling, complex can be distinguished from unbound fluorophores, because the photons emitted as they fluoresce retain the same polarity as the photons used to excite the fluorescence.
[0670] In the phosphodiesterase assay, cGMP-fluorescein, which cannot be bound to IMAP, and therefore retains little fluorescence polarization, is converted to GMP-fluorescein, which, when bound to IMAP, yields a large increase in fluorescence polarization (Δmp). Inhibition of phosphodiesterase, therefore, is detected as a decrease in Δmp.
[0671] Enzyme Assay
Materials: All chemicals are available from Sigma-Aldrich (St. Louis, Mo.) except for IMAP reagents (reaction buffer, binding buffer, FL-GMP and IMAP beads), which are available from Molecular Devices (Sunnyvale, Calif.). Assay: 3′,5′-cyclic-nucleotide-specific bovine brain phosphodiesterase (Sigma, St. Louis, Mo.) is reconstituted with 50% glycerol to 2.5 U/ml. One unit of enzyme will hydrolyze 1.0 μmole of 3′,5′-cAMP to 5′-AMP per min at pH 7.5 at 30° C. One part enzyme is added to 1999 parts reaction buffer (30 μM CaCl 2 , 10 U/ml of calmodulin (Sigma P2277), 10 mM Tris-HCl pH 7.2, 10 mM MgCl 2 , 0.1% BSA, 0.05% NaN 3 ) to yield a final concentration of 1.25 mU/ml. 99 μl of diluted enzyme solution is added into each well in a flat bottom 96-well polystyrene plate to which 1 μl of test compound dissolved in 100% DMSO is added. Selected Compounds of the Invention are mixed and pre-incubated with the enzyme for 10 min at room temperature.
[0674] The FL-GMP conversion reaction is initiated by combining 4 parts enzyme and inhibitor mix with 1 part substrate solution (0.225 μM) in a 384-well microtiter plate. The reaction is incubated in dark at room temperature for 15 min. The reaction is halted by addition of 60 μl of binding reagent (1:400 dilution of IMAP beads in binding buffer supplemented with 1:1800 dilution of antifoam) to each well of the 384-well plate. The plate is incubated at room temperature for 1 hour to allow IMAP binding to proceed to completion, and then placed in an Envision multimode microplate reader (PerkinElmer, Shelton, Conn.) to measure the fluorescence polarization (Amp).
[0675] A decrease in GMP concentration, measured as decreased Δmp, is indicative of inhibition of PDE activity. IC 50 values are determined by measuring enzyme activity in the presence of 8 to 16 concentrations of compound ranging from 0.0037 nM to 80,000 nM and then plotting drug concentration versus ΔmP, which allows IC 50 values to be estimated using nonlinear regression software (XLFit; IDBS, Cambridge, Mass.).
[0676] The Compounds of the Invention may be selected and tested in this assay to show PDE1 inhibitory activity. Exemplified compounds are shown to have IC 50 activities of less than 10 μM, e.g., Example 2 are shown to have an IC 50 of less than 200 nM.
Example 4
PDE1 Inhibitor Effect on Sexual Response in Female Rats
[0677] The effect of PDE1 inhibitors on Lordosis Response in female rats is measured as described in Mani, et al., Science (2000) 287: 1053. Ovariectomized and cannulated wild-type rats are primed with 2 μg estrogen followed 24 hours later by intracerebroventricular (icv) injection of progesterone (2 μg), PDE1 inhibitors of the present invention (0.1 mg, 1.0 mg or 2.5 mg) or sesame oil vehicle (control). The rats are tested for lordosis response in the presence of male rats. Lordosis response is quantified by the lordosis quotient (LQ=number of lordosis/10 mounts×100). The LQ for estrogen-primed female rats receiving Compounds of the Invention, at 0.1 mg, will likely be similar to estrogen-primed rats receiving progesterone and higher than for estrogen-primed rats receiving vehicle. | The present invention relates to optionally substituted 3-amino-4,5-dihydro-(1H or 2H)-pyrazolo[3,4-d]pyrimidin-6(7H)-ones and their 4-imino or 4-thioxo derivatives, e.g., 3-amino-4-(thioxo or imino)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-ones, 3-amino-4-(thioxo or imino)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-ones, 3-amino-4-(thioxo or imino)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6(7H)-ones, processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising them. | 0 |
[0001] incorporate one or more light-emitting diodes, a trigger mechanism, circuitry to both recognize trigger signals and to display varying illumination sequences and a battery for energizing the diode(s).
[0002] In order to maximize battery life, the diode(s) in the shoe should illuminate only when the user is active, such as when dancing, running, jumping, etc. The diode(s) should not illuminate when the shoe is “at rest”. A shoe is at rest when it is either not being worn or is worn but the user's feet are inactive (such as when the user is sitting down). Accordingly, such a shoe might incorporate a trigger mechanism and switch to connect the diodes to the battery when pressure is applied or when the shoe is set in motion through impact, acceleration or otherwise.
[0003] Prior art in this area has developed along two lines: 1) the development of a trigger and circuit switching mechanism and 2) the development of increasingly complicated light displays and illumination patterns. A motivating factor in motion sensor development for apparel, toys and other such items, has been the constant pressure to reduce the costs and complexity of the sensor and switch mechanism. Most such devices include a method of biasing part of a circuit in a position that creates either an open or a closed circuit. Movement causes that piece of the circuit to move away from its biased position, thus closing or opening the circuit based upon the prior position of the device. The change in state from open to closed, or closed to open, triggered the targeted event.
[0004] The state of earlier prior art technology is demonstrated in U.S. Pat. No. 6,087,951 (the '951 patent), to Ramsden. That technology uses a fixed magnet, a moveable magnet and an activator switch. The moveable magnet is biased such that it rests in contact with the fixed magnet. A pre-defined amount of force caused by movement, is sufficient to caused the moveable magnet to move away from the fixed magnet, sliding towards an activator switch. The moveable magnet pushes the activator switch with sufficient force to trigger the switch.
[0005] Some of the disadvantages of that type of design are described in U.S. Pat. No. 5,965,855 (the '855 patent), by Tanazawa. According to the '855 patent, the moveable magnet design requires a relatively large amount of force to activate the sensor switch and correspondingly larger equipment to sense the activation of the switch. The '855 patent incorporates a metal ball enclosed in a chamber and surrounded by four parallel electrode pins. The ball is biased by a magnet. Movement breaks the contact between the ball and the magnet and allows the ball to contact two of the electrode pins. Contact between the metal ball and the electrode pins completes a circuit and triggers a change of state signal. The pins are positioned such that contact between any two pins defines upward, downward, right and left movements.
[0006] The second area of development regards the nature of the light displays. Technology in this area started with the display of a single light and later advanced to display a row of lights, blinking in a defined sequence. This prior art further developed to the point of pseudo-animation by having different scenes portrayed on a film attached to the shoe. A series of lights flash behind the scenes to cause the entirety of the graphical presentation on the shoe to appear animated.
[0007] Such a shoe incorporates several lights and an automatic circuit for flashing the lights in a desired sequence. One example of such a shoe is found in U.S. Pat. No. 5,457,900. This shoe can flash a fixed message, such as “hi”. Another example is found in U.S. Pat. No. 6,112,437 (the '437 patent), issued to Lovitt, for An Article With Animated Display. This shoe displays light in a sequence that illuminates sequential panels of a film, to show a person running.
[0008] The combined goal of the two areas of development has been to make a switch device that is smaller, cheaper, has a longer battery life and produces an interesting and novel visual display. The present invention addresses each of these development goals.
SUMMARY OF THE INVENTION
[0009] It is an object of the present invention to provide a motion sensitive switch that can be used in apparel, small devices and toys and that is cheaper and better than currently existing motion sensitive switches. It is a related object to provide circuitry to accompany the switch that allows for multiple patterns of random and ordered output. In accordance with these objects and with others which will be described and which will become apparent, an exemplary embodiment of a motion sensitive switch in accordance with the present invention comprises a housing unit that contains, among its basic elements, a motion sensitive switch mechanism, a battery and electrical circuitry.
[0010] The switch mechanism is contained within a smaller housing unit and comprises a magnet, two electrically conductive contact strips/pins (one being positively charged and the other being negatively charged) and an electrically conductive ball. The pins or contact strips are positioned between the magnet and the ball. The magnetic attraction biases the ball towards the magnet and into contact with the pins. Because the ball is electrically conductive, it completes a circuit between the two pins. Thus, in the biased position, the circuit is closed.
[0011] On motion, the contact between the pins and the ball is temporarily broken and the ball moves away from the electrically conductive pins. The circuit is broken and a change of state signal is sent to the electrical circuitry. When the ball again makes contact with the contact strips, a second change of state signal is sent. Upon receipt of the second change of state, the electrical circuitry activates the output device. The output device could be based upon illumination, audio output, any other form of electrically stimulated output or a combination of these. When the switch comes to rest, the ball again moves to its biased position, creating a closed circuit that positions the switch to detect a new change of state sequence.
[0012] In another exemplary embodiment of a motion sensitive switch in accordance with the present invention, the sensor switch does not include a magnet. In this embodiment, the electrically conductive ball is magnetized and the pins are comprised of a Ferro-magnetic, electrically conductive material. The ball is therefore attracted to the pins. In its biased position, the ball is at rest against the pins. On motion, the magnetic attraction and the circuit are temporarily broken. On returning to the biased position, the circuit is re-established and the change of state triggers the output device.
[0013] It is an advantage of the present invention that the motion sensitive switch contains fewer components than prior art. It is therefore less expensive and provides less opportunity for functional failure. This invention therefore provides a means by which a motion sensor switch can be more economically placed in wearing apparel, shoes and small devices.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] For a further understanding of the objects and advantages of the present invention, reference should be had to the following detailed description, taken in conjunction with the accompanying drawing, in which like parts are given like reference numbers and wherein:
[0015] [0015]FIG. 1 is a top elevation of one embodiment of the printed circuit board showing the motion sensor switch, the battery housing, the circuits and the connectors to outside electrical devices;
[0016] [0016]FIG. 2 is a cut away elevation of the motion sensor switch housing showing the motion sensor switch, the battery housing, the circuits and the connectors to outside electrical devices;
[0017] [0017]FIG. 3 is a perspective of the motion sensor switch with the electrically conductive pins extending outside of the housing and connected to the PC Board;
[0018] [0018]FIG. 4 is an exploded view of the motion sensor switch with a magnet; and
[0019] [0019]FIG. 5 is an exploded view of the motion sensor switch without a magent.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0020] A novel motion sensitive switch and electrical circuitry are described. In the following description, for the purposes of explanation, specific component arrangements and constructions and other details are set forth in order to provide a more thorough understanding of the present invention. It will be apparent to those skilled in the art, however, that the present invention may be practiced without these specific details. In other instances, well known manufacturing methods and structures have not been described in detail so as to refrain from obscuring the present invention unnecessarily. Referring first to FIG. 1, the invention comprises several basic components including a motion sensor switch housing 10 , a power source 30 , electrical circuitry generally printed on a circuit board 36 and output device(s) 50 that generally comprise one or more illumination devices such as light emitting diodes. Additionally, the motion sensor switch housing 10 , power source 30 and electrical circuitry generally printed on a circuit board 36 are positioned such that they are hidden from view, such as within the sole of a shoe, while the output device 50 is located such that the output is observable on the outside surface of the shoe.
[0021] Referring next to FIG. 2, which illustrates in cut-away elevation a preferred embodiment of a motion sensitive switch in accordance with the present invention shown generally by the reference number 10 . In FIG. 2, the circuit is in a closed position, with a moveable object having an electrically conductive surface and a magnetically attractable portion, generically referred to herein as an electrically conductive ball 20 , resting against two electrically conductive members (pins) supported in said housing 16 , 18 . Referring also to FIG. 4, an exploded view of the motion sensor switch 10 is shown.
[0022] The motion sensor switch 10 is contained within an electrically non-conductive housing unit 12 . The switch 10 includes a positively charged electrically conductive pin 16 , a negatively charged electrically conductive pin 18 , an electrically conductive ball 20 and a magnet 24 . The pins 16 , 18 are connected to the circuit in such a manner that contact by the ball 20 concurrently with both pins 16 , 18 forms a closed circuit. The magnet is positioned within the chamber so that it attracts the ball 20 towards and in contact with the pins 16 , 18 when the device is inactive.
[0023] In one embodiment of the invention, the housing 12 is essentially cylindrical in shape, having a top surface 26 and an opposing bottom surface 28 . When assembled, the magnet 24 is positioned within the housing 12 against the top surface 26 . Two electrically conductive pins 16 , 18 are positioned adjacent to the magnet 24 and between the magnet 24 and the bottom surface 28 . Pins 16 , 18 are positioned close enough together such that the ball 20 is not allowed to pass between the pins 16 , 18 and is therefore not allowed to directly contact the magnet 24 . The ball 20 is moveably positioned between the two pins 16 , 18 and the bottom surface 28 .
[0024] The height of the housing 12 is roughly equivalent to, but slightly greater than, the combined heights of the ball 20 , the pins 16 , 18 and the magnet 24 . Thus, there is sufficient space between the pins 16 , 18 and the magnet 24 such that the pins 16 , 18 and the magnet 24 are not in contact with each other. Additionally, there is sufficient additional space between the pins 16 , 18 and the bottom surface 28 such that when the ball 20 is in contact with the bottom surface 28 , the ball 20 is not in contact with the pins 16 , 18 .
[0025] When the device 10 is at rest, the ball 20 is biased towards the magnet 24 and rests against the pins 16 , 18 . When the ball is in this position, the circuit is closed. When the device 10 moves, the motion produces sufficient force to break the magnetic bond between the ball 20 and the magnet 24 , allowing the ball 20 to momentarily move freely within the housing unit 12 . While the ball 20 is not in contact with the pins 16 , 18 , the circuit is open.
[0026] Referring next to FIG. 3, the two pins 16 , 18 extend beyond the wall of the motion sensor housing 12 and are connected to the remaining electronic circuitry. To prevent movement, the pins 16 , 18 rest in notches in the housing 12 when the switch 10 is fully assembled.
[0027] Referring next to FIG. 5, another embodiment of the motion sensitive switch 10 is shown. In this embodiment, the electrically conductive ball 20 is magnetized and is therefore attracted to the Ferro-magnetic, electrically conductive pins 16 and 18 . In its biased position, the ball 20 is at rest against the pins, 16 and 18 . On motion, the magnetic attraction of the ball 20 and the circuit are temporarily broken. On returning to the biased position, the circuit is re-established and the change of state, as described above, triggers the output device. This alternative embodiment is capable of carrying out its intended function of breaking and re-making the circuit in the absence of a separate magnet 24 .
[0028] Another major component of the invention is the electrical circuitry, generally placed on a printed circuit board. Referring also back to FIG. 1, the sensor switch housing is coupled to a printed circuit board 30 . Also coupled to the printed circuit board 30 are a small battery 30 , a microprocessor 46 , memory, circuits 32 and connectors 34 for wiring to lights and/or other electrical devices. The change from closed to open causes a state change within the electrical circuitry. A second state change occurs when the ball 20 re-establishes contact with the pins 16 , 18 . The second state change causes a trigger signal to be sent to an output device 50 . In the preferred embodiment, the output device 50 produces lights and/or sounds. In the case where the output device 50 comprises a series of lights, the trigger signal consisting of the two state changes closely timed together, causes the lights connected to the circuitry to illuminate.
[0029] The illumination pattern used in the preferred embodiment is an initial illumination pattern sequence followed by a second illumination pattern sequence. Starting from the end of the initial trigger cycle and within the defined “delay” period of two seconds, if any additional trigger signal is detected, the LED 50 will continue it's flashing sequence. When no additional trigger signals are present after the two second “delay” period , the microprocessor selects a random “end-cycle” pattern of either 1 or 2 additional flashing sequences (end-cycles) and return to stand-by mode until a new trigger occurs. This end cycle consists of two different flash duration's for the purpose of extending battery life: (i) one complete cycle (80% probability) or (ii) two complete cycles (20% probability).
[0030] In the preferred embodiment, the microprocessor 46 begins lighting the first LED 50 in response to a triggering event. The LEDs 50 illuminate in sequence, in a “lighting cycle,” beginning with the LED 50 at one end of the strip and ending with the LED 50 at the opposite end. Each LED 50 turns off in sequence before the next LED 50 turns on. When the last LED 50 is turned off it creates the “end of the lighting cycle.” If the triggering event still exists at the end of the cycle, the microprocessor 46 causes the beginning of another lighting cycle. If no triggering event exists at the end of the cycle, the microprocessor 46 selects and performs an “end cycle.” The number of end cycles is selected according to a random process (done by the microprocessor 46 ) from the number {1, 2, or 3}, so that one, two, or three complete end cycles follow. Lighting stops at the end of the final end cycle.
[0031] In the preferred embodiment, several different flashing sequences are programmed into the electronic circuitry. The table below, identifies the flashing sequence of the preferred embodiment. The illumination pattern used in the preferred embodiment is a pre-defined initial signal sequence followed by a pre-defined sequential signal sequence followed by a randomly selected closing signal sequence. Only the last “randomly selected closing signal” was incorporated into the circuit design. However, it should be noted that the invention is not limited to these specific lighting sequences.
REF NO. LED's SEQUENCE RS3627B-5R- 5 1&5>2&4>3>2&4>1&5>2&4>3>2&4>1&5 066-00A (end 9-flashes) > random end cycle RS3627B-5R- 5 1>2>3>4>5>4>3>2>1>2>3>4>5 066-00B (end 13-flashes) > random end cycle RS3627B-3R- 3 1>2>3>2>1>2>3>2>1 066-00C (end 9-flashes) > random end cycle RS3627B- 6 1>2>3>4>5>6>1>2>3>4>5>6>1>2>3>4>5>6 3R3G-066-00D (end 18-flashes) > random end cycle RS3627-7R- 7 1>2>3>4>5>6>7 200-00E (end 7-flashes) > random end cycle
[0032] As noted above, the end cycle is randomly chosen from one of two different selections. The end cycle consists of two different flash duration's of either one or two complete cycles. In an embodiment where the output device(s) 50 consist of audio devices, the trigger signal causes a series of sounds to be emitted instead of illuminated LED output.
[0033] Now referring also to FIGS. 1 and 2, in the biased position, the metallic ball 20 will remain contacted against the pins 16 and 18 . A trigger event occurs when the ball 20 moves away from and then re-contacts pins 16 and 18 . The momentary break in continuity and the re-contact of the pins 16 and 18 forms the trigger cycle that the microprocessor 46 accepts in order to start the LED 50 flashing sequence. Each trigger cycle is considered to be “one-shot” or non-re-occurring. When the trigger cycle is completed and output is sent from the microprocessor 46 , the LED's 50 will then begin to flash. To prevent the microprocessor 46 from processing multiple trigger inputs, any trigger input received between the “start” and “end” of a flash sequence is disregarded. After the end of a flash sequence, a “delay” period (defined in one embodiment to be between 0.02 and 2.0 seconds) will occur before the device will accept any new trigger inputs to start another flash sequence. If no trigger is received, microprocessor 46 will select a random end cycle to flash. During the end cycle, any trigger inputs are disregarded until the cycle is completed.
[0034] Upon triggering, the LEDs 50 will flash for a single cycle sequence. Starting from the end of the initial trigger cycle and within the defined “delay” period of two seconds, if any additional trigger signal is detected, the LED 50 will continue its flashing sequence. When no additional trigger signals are present after the “delay” period, the microprocessor 46 will then select a random “end-cycle” pattern of 1 or 2 additional flashing sequences and return to stand-by mode until a new trigger occurs.
[0035] The type of power source used in the preferred embodiment is a small battery. The exact type of battery is not significant to the invention except that it should be small enough to conveniently fit into the item to which the invention is attached. The type of electrical circuitry capable of functioning in the manner described is readily available and familiar to those in the industry.
[0036] While the foregoing detailed description has described several embodiments of a motion sensitive switch in accordance with the present invention, the above description is illustrative only and not limiting of the disclosed invention. Indeed, it will be appreciated that the embodiments discussed above and the virtually infinite embodiments that are not mentioned could easily be within the scope and spirit of the present invention. Thus, the present invention is limited only by the claims set forth below. | A motion sensitive device for causing an electronic signal to be sent to one or more output devices, comprising a printed circuit board, a battery connected to the printed circuit board, electrical circuitry connected to the printed circuit board, a motion sensitive switch connected to the printed circuit board, electrical output devices such as light emitting diodes connected to the printed circuit board and electrical circuits all providing means whereby the motion sensitive switch causes a signal to be transmitted to the output device when movement is sensed by the switch. The device is small enough to be used in wearing apparel and can provide safety vis-à-vis increased visibility for the user. | 0 |
The present application claims priority from the filing date of the provisional patent application Ser. No. 60/083,290 filed Apr. 28, 1998, entitled “Method and Apparatus for Die Cutting and Making Laminate Articles.”
BACKGROUND
1. Field of the Invention
The present invention relates to a method and an apparatus for making shaped and laminate articles, and more particularly, to an apparatus that recovers excess material or flash for recycling as a part of the shaping and laminating process.
2. Background of the Invention
Rotary dies and methods of using such dies are conventionally used in this art to produce shaped and laminated articles of continuous lengths or discrete shapes. Examples of such articles include seals and gaskets, expandable articles for automotive uses, diapers, edible items such as cereal, printed matter such as labels and cardboard boxes, and other sheet goods.
U.S. Pat. Nos. 4,427,481; 5,266,133; 5,373,027; 5,678,826; 5,040,803; 4,874,650; and EP 0 730 998B1 disclose methods and apparatus that fabricate automotive expandable sealants. U.S. Pat. Nos. 5,411,390; 5,417,132; and 5,515,757 illustrate examples of conventional shaping and laminating methods and apparatus, the disclosure of each of which is hereby incorporated by reference. While conventional methods and apparatus are useful for making articles, there is a need in the art for methods and apparatus that reduce material cost without compromising the efficiency of the apparatus or the quality of the produced articles.
Conventional shaping and lamination apparatus typically do not recycle unused raw material as a part of the manufacturing process. Often the raw material is shaped and formed into a final product and cut-away portions of material, known as flash, are collected as an afterthought. The typical apparatus do not recover the flash in a systematic manner that facilitates recycling. Thus, much of the unused raw material is thrown away and wasted.
Laminate products present additional obstacles to recycling. Even if an apparatus recovers the flash from a laminate product, often the multiple layers of varying materials are inseparable and incompatible with recycling operations. Thus, if the apparatus collects the laminate flash at the end of the manufacturing process, the flash cannot be recycled.
In addition to inadequate flash removal, the rotary die apparatus known in the art present three other significant drawbacks. First, conventional apparatus typically use individual rotary processing stations. Therefore, when the machines must be re-tooled to accommodate new products, the single individual station must be taken out of service for extended periods of time. The prior art apparatus do not provide means to quickly change shaping or laminating functions without curtailing production.
Second, conventional rotary die apparatus regulate web tension with nip or pinch rollers. In conveying the web material, these rollers must contact the top of the web material. Often, the pinching action of these rollers damages the web material and diminishes the quality of the final product. The prior art apparatus do not provide means to consistently convey the web material without excessive, deleterious handling.
Finally, in facilitating flash removal, conventional rotary die apparatus spray lubricant on the entire web material and rotary die. Such a method uses excessive amounts of lubricant and degrades the quality of the web material because of over-saturation. The prior art apparatus do not provide means to apply minimal amounts of lubricant to the specific locations at which lubrication is needed for effective flash removal.
For the foregoing reasons, there remains a need for an apparatus that cuts and segregates flash from a web material before the material is laminated to another web material. The apparatus should effectively remove flash using careful handling and lubrication means to avoid degrading the quality of the final product. Further, the apparatus should provide means to easily and quickly change the shaping or lamination functions without hindering production.
SUMMARY OF THE INVENTION
The present invention provides a method and apparatus for die cutting and making shaped and laminated articles in a process that efficiently recovers unused recyclable flash material without adversely impacting production speed or quality. The present invention reduces material waste in the shaping of a web of material or the laminating of at least two films, layers or web stock and also permits changing or modifying the product being produced without stopping production.
To shape and laminate product material while continuously separating flash, the apparatus uses a novel, multi-station arrangement of stepped anvil rollers, regular anvil rollers, vacuum conveyor belts, and lubrication systems.
For the shaping configuration, a web material is fed between an anvil roller and rotary die. Depending on the number of layers in the web and the desired cut, the anvil roller is either stepped to produce a through-cut or is regular to produce a kiss-cut. A kiss-cut is a cut through part, but not all of a multi-layered article, wherein the cutting die gently or lightly cuts the web material without cutting the liner or substrate. After the die and anvil roller cut the web, a flash removal mechanism, e.g., conveyor belt, vacuum nozzle, or web rewind, removes the web flash and delivers the flash to a recycling operation. To ease removal of the flash, a lubrication system applies lubricant directly to the blades of the rotary die before the die contacts the web material.
For the lamination configuration, two anvil rollers are positioned adjacent to and on opposite sides of a rotary die. The two anvil rollers are referred to hereinafter as the first anvil roller and second anvil roller. This die and anvil roller configuration enables the feeding of two web materials. In the horizontal plane, a primary web material is fed between the rotary die and second anvil roller. From above the apparatus, a secondary web material, e.g., a film, is fed between the rotary die and first anvil roller.
The first anvil roller and rotary die cut the secondary web material into two portions, secondary web flash and secondary web product, before the secondary web product contacts the primary web material. Thus, the secondary web flash is removed before the materials are laminated and no longer suitable for recycling. The secondary web product meets the primary web material as both materials enter between the rotary die and second anvil roller. As the materials meet, they are laminated and the primary web material is cut into two portions: primary web flash and primary web product. The primary web flash is removed for recycling and the primary web product continues on a horizontal conveyor for further processing or packaging.
Like the shaping configuration, in the lamination configuration, a lubricant system improves flash removal by applying lubricant directly to the blades of the rotary die before the die contacts the secondary web material or primary web material. Additionally, the first and second anvil rollers can be either stepped or regular to produce the desired cut and the flash removal mechanism can be tailored to meet recycling requirements, e.g., conveyed, vacuumed, or rewound.
A further embodiment of the present invention incorporates the above-described shaping and lamination configurations in a multi-station system in which successive die and anvil roller assemblies are positioned along a production line. The die and anvil roller assemblies are mounted on lifting mechanisms, e.g., pneumatic cylinders, that allow the assemblies to be raised and taken out of service. When raised, the rotary die does not contact the primary web material and therefore does not shape or laminate. In this manner, the shaping and lamination functions can be stopped and started while the web materials are continuously fed.
Accordingly, it is an object of the present invention to provide a means for cutting a web material and removing flash before the web material contacts another web material in a lamination process.
It is another object of the present invention to deliver a web material to a rotary die without contacting or handling the top of the web material so as to reduce the possibility of damaging the web material.
It is another object of the present invention to enable quick changes between shaping and lamination functions in a die cutting apparatus.
It is another object of the present invention to provide a lubrication system for a die cutting apparatus that minimizes wasted lubricant and reduces degradation of the web material from over-saturation.
These and other objects of the present invention are described in greater detail in the detailed description of the invention, the appended drawings and the attached claims.
DESCRIPTION OF THE DRAWINGS
FIG. 1 a is a side view of one aspect of the die cutting apparatus of the present invention.
FIG. 1 b is a top view of the apparatus shown in FIG. 1 a.
FIG. 1 c is a rear view of the apparatus shown in FIG. 1 a.
FIG. 1 d is a front view of the apparatus shown in FIG. 1 a.
FIG. 2 is a schematic of a section of a third portion of the die cutting apparatus illustrated in FIG. 1 in a shaping configuration.
FIG. 2 a is a schematic of a multi-layered primary web material.
FIG. 3 is a detail side view, partially in section, of a second aspect of the die cutting apparatus illustrated in FIG. 1 in a lamination configuration.
FIG. 3 a is an elevation view of the flash removal vacuum nozzle system components illustrated in FIG. 3 .
FIG. 4 is a detail side view, partially in section, of a portion the die cutting apparatus illustrated in FIG. 1 in a laminating configuration.
FIG. 5 is an enlarged front view of the anvils and rotary die of the sections illustrated in FIGS. 3 and 4.
FIG. 6 is an exploded view of the rotary die illustrated in FIG. 5 .
DETAILED DESCRIPTION OF THE INVENTION
Referring to the drawings, the present invention comprises an apparatus and a method for forming a shaped or laminate product, using at least one rotary die, at least one anvil roller and at least one support or drive roller. FIGS. 1 a - 1 d illustrate the preferred embodiment of the present invention as a part of a larger, manufacturing apparatus. The present invention processes web material in two configurations: shaping and lamination. FIG. 2 depicts the preferred embodiment of the present invention in the shaping configuration. FIGS. 3-4 show the preferred embodiment of the present invention in the lamination configuration. In each configuration, as the process materials are cut, excess material known as flash is recovered for recycling.
FIG. 2 shows the die cutting apparatus configured to produce shaped products, in which primary web material 202 , in sheet or web form, enters the apparatus between rotary die 201 and anvil roller 203 , at which point rotary die 201 cuts primary web material 202 into primary web flash 207 and primary web product 205 . As explained below, primary web material 202 is preferably carried on a continuing web-like liner. Primary web flash 207 is removed by primary web flash removal mechanism 208 , which conveys primary web flash 207 away from the apparatus to a recycling apparatus (not shown). Primary web product 205 exits the apparatus and continues in the manufacturing process to become the final product 206 . In the shaping configuration, the present invention produces a shaped or continuous two-dimensional article.
Rotary die 201 and anvil roller 203 rotate in opposite directions so that primary web material 202 is drawn into the apparatus upon contact with rotary die 201 and anvil roller 203 . Support roller 204 drives anvil roller 203 and longitudinally supports and stabilizes the drums of anvil roller 203 and rotary die 201 to ensure even feeding of primary web material 202 .
Primary web material 202 can be made of more than one layer, e.g., a product layer 202 P attached to a liner 202 L, as shown in FIG. 2 a . In shaping this multi-layered primary web material, rotary die 201 is mated with a regular anvil to produce kiss-cut in which only the top or product layer 202 P of primary web material 202 is cut, leaving liner 202 L intact. As primary web material 202 exits between rotary die 201 and anvil roller 203 , primary web flash 207 , which is outside of the shape of primary web product 205 , is removed from liner 202 L and recycled. As a result, primary web product 205 remains on liner 202 L and exits the die cutting apparatus as final product 206 . Examples of suitable liners include paper (coated or uncoated), polyethylene, polyester, aluminum foil, brass foil, copper foil, or other similar substrates.
The use of a product layer 202 P on a liner 202 L according to the present invention is particularly useful when final product 206 is a tacky material adhered to a liner, e.g., when a temporary, removable layer is applied to primary web product 205 to provide protection until primary web product 205 is ready for use. In this application, a tacky material such as a mastic is extruded as a web upon liner 202 L and, thereafter, introduced together as primary web material 202 into the die cutting apparatus wherein rotary die 201 cuts through or shapes the mastic portion without cutting the underlying liner 202 L. An example of a product on a liner is rubber butyl based mastic laminated with a non-tacky rubber butyl web, for use in such applications as seals for automotive or other general-purpose uses.
The web materials and liners can be fabricated by many different methods, e.g., extrusion, spraying material onto a liner, and immersion. In each case, in the preferred embodiment of the present invention, the die and anvil roller is customized to produce the cut required by the web materials, liners, and the desired final product. Customizing the cut includes, but is not limited to, such factors as the shape of the cut and the number of layers to be cut, i.e., whether a through-cut or kiss-cut is required.
FIGS. 3 and 4 illustrate the die cutting apparatus configured to produce laminate products. Laminate products are constructed of multiple layers of material, which are indistinguishable when joined in the final product. Examples of layers that can be laminated together include rubber butyl based-mastic, polyethylene, polyester, metal foils, MYLAR®, or other similar materials. FIGS. 3 and 4 depict the same laminating process but with different means of flash removal. FIG. 3 show flash removal by vacuum and conveyor whereas FIG. 4 shows flash removal by rewinding to a core.
For the laminating configuration, the die and anvil assembly comprises rotary die 301 positioned between first anvil roller 309 and second anvil roller 303 . Both first anvil roller 309 and also second anvil roller 303 rotate in one direction, while rotary die 301 rotates in the opposite direction. This rotational sequence of the die and anvil assembly draws secondary web material 310 in between first anvil roller 309 and rotary die 301 from one side of the die and anvil assembly. From the opposite side of the die and anvil assembly, rotary die 301 and second anvil roller 303 draw primary web material 302 into the apparatus.
As secondary web material 310 enters the apparatus between first anvil roller 309 and rotary die 301 , rotary die 301 cuts secondary web material 310 into secondary web flash 312 and secondary web product 311 . Secondary web flash removal mechanism 313 removes secondary web flash 312 from the apparatus and delivers secondary web flash 312 to a recycling apparatus (not shown). Secondary web product 311 adheres to rotary die 301 and rotates around with the rotary die 301 to enter between rotary die 301 and second anvil roller 303 . In this way, secondary web flash 312 is removed prior to lamination.
As secondary web product 311 rotates with rotary die 301 , secondary web product 311 joins primary web material 302 as both secondary web product 311 and primary web material 302 are drawn into the apparatus between rotary die 301 and second anvil roller 303 . Primary web material 302 and secondary web product 311 fuse together between rotary die 301 and second anvil roller 303 , forming final product 306 in which the primary and secondary layers are indistinguishable. At this point, rotary die 301 also cuts primary web material 302 into primary web flash 308 and primary web product 305 . Primary web product 305 joins secondary web product 311 to form final product 306 . Primary web flash removal mechanism 307 removes primary web flash 308 from the apparatus, conveying primary web flash 308 to a recycling apparatus (not shown).
The preferred embodiment of the laminating apparatus is particularly useful for laminated products in which the layers of final product 306 cannot be effectively separated for recycling. Instead of attempting to recycle cut-away portions of the final laminated product, the die cutting apparatus separates the flash portions of each laminate layer for recycling before the layers are fused into a final laminated product. The rotary die 301 cuts each of the layers to matching size and shape so that the layers, when fused together, form the final laminated product requiring no further cutting or shaping. Since the same die, rotary die 301 , cuts both of the pieces to be fused, a precise size match is assured.
In either the shaping or lamination configurations, there are additional structural components of the present invention that drive and add stability to the die and anvil roller(s) to ensure the proper feeding and processing of the primary and secondary web material. The structural components and their applications are typical of both the shaping and lamination configurations; for brevity, only the lamination configuration as shown in FIG. 3 is addressed herein. In the preferred embodiment of the present invention, a support roller 304 supports, stabilizes, and minimizes the deflection of the adjacent second anvil roller 303 . Support roller 304 is driven by any suitable means, such as by gear and chain. In turn, support roller 304 can be configured to drive first anvil roller 309 , rotary die 301 , and second anvil roller 303 .
Positioned above the die and anvil assembly is a truck assembly 315 that guides first anvil roller 309 and transfers a downward pressure on rotary die 301 to cut secondary web material 310 and shape primary web material 302 . Examples of suitable means for applying the downward pressure include a pair of pneumatic cylinders, hydraulic jackscrews, or any conventional means for applying downward force to the die. The preferred embodiment of the present invention uses a pneumatic cylinder.
On both sides of the first anvil roller 309 , nip rollers 318 contact, support, and drive the feeding of the secondary web material 310 and secondary web flash 312 . Preferably, the nip rollers 318 are pneumatically controlled.
Above the truck assembly 315 , a removable bridge plate 317 spans the die cutting apparatus to provide additional stability to rotary die 301 , first anvil roller 309 , and second anvil roller 303 . The length of removable bridge plate 317 matches the width of the apparatus, e.g., 12 or 21 inches. Removable bridge plate 317 also permits convenient die changes.
The compressive force or downward pressure to the rotary die 301 may be applied to the bearer surfaces 506 or journals 507 of rotary die 301 , as shown in FIG. 5 . The bearer surfaces 506 of the rotary die are located at both ends of the cylindrical die and extend radially outward beyond the cutting surface of the die. The journals 507 are located on the outside of the apparatus, on both sides, where the axle of the rotary die exits the casing of the apparatus. In the preferred embodiment of the present invention, as shown in FIG. 5, the downward pressure is applied to the bearer surfaces 506 to prevent the rotary die 301 from lifting up off of the primary web material 302 as the primary web material 302 is being cut or laminated.
In the preferred embodiment of either the shaping or lamination configuration, the die cutting apparatus is equipped with one or more stations at which dies are located. FIGS. 1 a - 1 b , 2 , and 4 show a second station 102 . The first and second stations can be identical or different depending upon the requirements of the manufacturing process. One die can be removed or changed without affecting the operation of the other die. As shown in FIG. 2, a lifting mechanism 210 is used to lift and hold a die out of service. Preferably, the lift mechanism 210 uses pneumatic cylinders; however, any other suitable lifting system, e.g., a crane system, may be used for die removal or installation.
In either the shaping or lamination configuration of the preferred embodiment of the present invention, a lubricant system is used to ease removal of the primary and/or secondary web flash. FIG. 3 illustrates an applicator 316 that lubricates the rotating rotary die 301 before the die contacts secondary web material 310 . While any suitable lubrication means can be used, the preferred embodiment delivers the lubricant with a roll applicator. The roll applicator system applies the lubricant to the blades of rotary die 301 instead of to the entire secondary web material 310 or primary web material 302 , thereby minimizing the amount of lubricant used. Additionally, using minimal lubricant prevents the web material from becoming damaged by over-saturation. While any suitable lubricant that is compatible with the laminate product and apparatus can be used, examples of desirable lubricants include aqueous soap mixtures, non-silicone-containing lubricants, and like fluids. To keep the flash and product portions from sticking to the press, the lubricating system is located to dispense the correct amount of lubricant where required. For best results, the lubricant is applied to rotary die 301 just before the location where secondary web material 310 contacts rotary die 301 .
As an alternative to lubricant, another preferred embodiment applies adhesive with applicator 316 to handle web materials that are not inherently tacky. Instead of lubricating the die for easy removal of sticky flash, the applicator applies just enough adhesive to the die to keep a slippery web material on the die, but not so much adhesive that the material is difficult to remove.
To efficiently handle web material as it enters and exits the apparatus, the preferred embodiment of the present invention uses vacuum belts, or any other type of holding belt, to convey the web materials and final products while also applying the requisite amount of web tension. These belts carry primary web material 302 into the apparatus and convey final product 306 out of the apparatus to subsequent manufacturing processes or to packaging for shipment. Optionally, a single vacuum belt can be used on the outgoing side of the apparatus to pull a web material and liner in between the rotary die and anvil roller and to pull the final product out.
By using vacuum belts, the apparatus does not have to touch the top of the primary web material 302 or the top of final product 306 , thereby eliminating the handling damage often inflicted by the nip or pinch rollers known in the art. The belt may be driven independently, or by the motor that drives the support roller 304 . In the preferred embodiment, the motor driving the rotary die 301 also drives the belt, thereby providing enhanced process control. The adjustable speed control customizes the apparatus for different lengths of processed material.
For the shaping and lamination configurations, the flash removal mechanisms remove primary web flash and secondary web flash from the apparatus. As shown in FIGS. 3 and 3A, the preferred embodiment of the present invention uses vacuum nozzle 314 . Vacuum nozzle 314 applies a vacuum to rotary die 301 and withdraws secondary web flash 312 before it contacts primary web material 302 . Vacuum nozzle 314 is especially useful when removing flash of undulating or varying configurations. FIG. 3A depicts the preferred vortex nozzle, showing a plan view 350 , a front view 351 , and a side view 352 .
A second embodiment of the flash removal system is a cotton belt conveyor. To prevent the flash material from sticking to the belt, a soapy water solution can be applied to the belt.
For both the shaping and lamination configurations, in the preferred embodiment of the present invention, the rotary die and anvil roller are configured to provide specific cuts or shaping. As illustrated in FIG. 5, a stepped anvil roller 502 can be stepped down so as to touch the blades of rotary die 501 and cut through the primary or secondary web material to produce what is known as a through-cut. Alternatively, regular anvil roller 503 is offset from the cutting surface of the rotary die 501 , thereby only cutting a portion of the material it contacts to produce what is known as a kiss-cut. Manufacturing processes use the kiss-cut to cut only a portion of a multi-layered material, e.g., cutting a primary web material but leaving an attached liner intact.
For the kiss-cut, rotary die 501 is configured to substantially the height needed to press the secondary web material onto the primary web material without cutting the liner. Alternately, foam 505 is located in the cavity of rotary die 501 to press the secondary web material to the primary web material. In addition to the preferred foam, any other like material could be used. Side nip rollers located on the stepped anvil roller 502 can be used to drive the secondary web flash though the press.
In the lamination configuration as shown in FIG. 3, the preferred embodiment of the present invention uses a rotary die 301 with an internal vacuum system to hold secondary web product 311 to the rotary die 301 while the secondary web flash removal mechanism 313 is removing secondary web flash 312 . In FIG. 3, the shaded region of the rotary die 301 indicates where the vacuum is applied. FIG. 6 shows preferred construction of the rotary die vacuum system.
Referring to FIG. 6, a vacuum probe 601 having an open channel (a shoe or boat-like structure) is inserted into rotary die 602 . Rotary die 602 incorporates vacuum holes 603 that extend from inside vacuum probe 601 , through vacuum channels (interior to rotary die 602 and not shown), and out to the exterior surface of the rotary die 602 . As the rotary die 602 rotates on vacuum probe 601 , vacuum holes 603 will either align with the probe vacuum channels or a solid surface on the opposite side of vacuum probe 601 . When the holes align with the probe vacuum channels a vacuum will be drawn through rotary die 602 , and correspondingly, when the vacuum holes 603 align with the remaining part of the probe, no vacuum will be drawn.
Instead of a vacuum system, such a configuration of holes and channels could also supply coolant, e.g., brine or water, to the apparatus in an effort to inhibit the tacky material from sticking to the die.
To enhance the operation of the die cutting apparatus, a preferred embodiment of the present invention uses sensors, tension devices, and speed control devices to control and synchronize production speed, web tension, and web sheet height. These sensors, tension devices, and speed control devices well known in the art and commercially available. The speed at which material is introduced and removed from the die cutting apparatus is controlled and synchronized. Normally, the speed is increased or decreased in response to one or more sensors. The first sensor monitors the height of a continuous sheet of tacky material that is formed before entering the press, e.g., when a tacky material is extruded onto a liner and conveyed to the press where prior to entering the press (on the left hand side of FIG. 1 a ) the sheet height is lower than the operating plane of the apparatus. Normally, the sheet will be lower than the die apparatus and form a depression or loop prior to entering the apparatus. A relatively low web sheet height indicates that material is being supplied at too fast a rate or that the apparatus is operating too slowly.
The web height is monitored by using any suitable detection means such as an ultra sonic sensor. The motor driving the sheet rate into the die cutting apparatus responds to the sheet height by either increasing or decreasing support roller speed. The support roller can be driven by any suitable means such as by gear and chain. The material flow rate through the die cutting apparatus is synchronized with the support roller drive, flash removal and finish product removal belt to avoid applying tension to the materials being processed. The apparatus processes about 400 inches per minute and in some cases up to about 1,200 feet per minute. The sheet height can also be maintained manually using a manual speed control located on the press. Normally, a certain amount of tension is required to keep the sheet relatively straight as the sheet enters the apparatus. A small vacuum chamber or any other type of tension device may be used to apply small amount of tension to the web.
The die cutting apparatus and method are not limited to the components and processes described above, and can be employed with or incorporated into a wide array of systems. If desired, a plurality of rotary die presses can be employed for making a multi-layered laminate product. The materials combined to form the laminate product can be obtained from any suitable source, e.g., a roll of film, an extruder that is optionally functionally connected to the rotary die press apparatus, or other desirable sources. The laminate product can be further processed to enhance or modify the characteristics of the product, e.g., by exposure to a source of radiation, chemically treated, physically modified, for example, by heating or stretching, among other conventional material treatment methods. The apparatus for modifying the laminate product can also be functionally connected to the rotary die press or remote therefrom.
The foregoing disclosure of embodiments of the present invention has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many variations and modifications of the embodiments described herein will be obvious to one of ordinary skill in the art in light of the above disclosure. The scope of the invention is to be defined only by the claims appended hereto, and by their equivalents. | A method and apparatus that produces shaped and laminate articles and recovers the excess material or flash as a part of the manufacturing process. The apparatus uses a combination of rotary die and anvil roller assemblies in successive multiple stations to cut and separate each raw material into final product portions and recyclable flash portions as each raw material enters the apparatus. The apparatus separately reclaims each raw material flash portion and delivers the flash of each material in a recyclable form to an auxiliary recycling operation. In recovering the flash, the apparatus does not adversely affect the speed or quality of production of the final shaped or laminated product. To ease removal of the flash, the apparatus applies lubricant to the blades of the rotary die. To avoid damage to web material, the apparatus uses vacuum belts to convey the web material and web product through the apparatus. | 1 |
This application is a divisional of application Ser. No. 08/415,847, filed Apr. 3, 1995, now U.S. Pat. No. 5,643,965 on Jul. 1, 1997.
FIELD OF THE INVENTION
This invention concerns benzamide compounds, pharmaceutical compositions containing these compounds, and their use to treat or protect against neurodegenerative conditions.
BACKGROUND INFORMATION
Neurodegenerative disease encompasses a range of seriously debilitating conditions including Parkinson's disease, amyotrophic lateral sclerosis (ALS, "Lou Gehrig's disease"), multiple sclerosis, Huntington's disease, Alzheimer's disease, diabetic retinopathy, multi-infarct dementia, macular degeneration and the like. These conditions are characterized by a gradual but relentless worsening of the patient's condition over time. The mechanisms and causes of these diseases are becoming better understood and a variety of treatments have been suggested. One of these neurodegenerative conditions, Parkinson's disease, is associated with abnormal dopamine depletion in selected regions of the brain.
Recent summaries of the state of understanding of Parkinson's disease are provided by Marsden, C. D., in "Review Article--Parkinson's Disease" Lancet (Apr. 21, 1990) 948-952 and Calne, D. B., in "Treatment of Parkinson's Disease" NEJM (Sep. 30, 1993) 329:1021-1027. As these reviews point out, dopamine deficiency was identified as a key characteristic of Parkinson's disease, and the destruction of the dopaminergic nigrostriatal pathway paralleled dopamine depletion in Parkinson's patients.
Rapid development of Parkinson's-like symptoms in a small population of illicit drug users in the San Jose, Calif. area was linked to trace amounts of a toxic impurity in the home-synthesized drugs. Subsequent studies in animal models, including monkeys, demonstrated that 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) was the cause of the Parkinson's-like symptoms which developed in the illicit drug users, as reported by J. W. Langston et al., in "Chronic Parkinsonism in Humans Due to a Product of Meperidine-Analog Synthesis" Science (Feb. 25, 1983) 219, 979-980. These early findings and the many studies that they stimulated led to the development of reliable models for Parkinson's disease, as reported by Heikkila, R. E., et al., in "Dopaminergic Neurotoxicity of 1-Methyl-4-Phenyl-1,2,5,6-Tetrahydropyridine in Mice" Science (Jun. 29, 1984) 224:1451-1453; Burns, R. S., et al., in "A Primate Model of Parkinsonism . . . " Proc. Natl. Acad. Sci USA (1983) 80:4546-4550; Singer, T. P., et al., "Biochemical Events in the Development of Parkinsonism . . . " J. Neurochem. (1987) 1-8; and Gerlach, M. et al., "MPTP Mechanisms of Neurotoxicity and the Implications for Parkinson's Disease" European Journal of Pharmacology (1991) 208:273-286. These references and others describe studies to help explain the mechanism of how the administration of MPTP to animals gives rise to motor defects characteristic of Parkinson's disease. They clearly indicate that MPTP was the cause of the Parkinson's-like symptoms that developed in the humans who had used the tainted illicit drugs and that similar motor deficits were found in other primates and other test animals which had been dosed directly with MPTP. They further point out that the administration of MPTP induces a marked reduction in the concentration of dopamine in the test subjects.
These findings have led to the development of an assay for agents effective in treating dopamine-associated neurodegenerative disorders, such as Parkinson's disease. In this assay, test animals are given an amount of MPTP adequate to severely depress their dopamine levels. Test compounds are administered to determine if they are capable of preventing the loss of dopamine in the test animals. To the extent that dopamine levels are retained, a compound can be considered to be an effective agent for slowing or delaying the course of neurodegenerative disease, e.g., Parkinson's disease.
Mitochondrial function is associated with many neurodegenerative diseases such as ALS, Huntington's disease, Alzheimer's disease, cerebellar degeneration, and aging itself (Beal, M. F. in Mitochondrial Dysfunction and Oxidative Damage in Neurodegenerative Diseases, R. G. Landes Publications Austin, Tex., 1995 at, for example, pages 53-61 and 73-99). Mitochondrial damage is the mechanism by which MPTP depletes dopamine concentrations in the striatum (Mizuno, Y., Mori, H., Kondo, T. in "Potential of Neuroprotective Therapy in Parkinson's Disease" CNS Drugs (1994) 1:45-46). Thus, an agent which protects from mitochondrial dysfunction caused by MPTP could be useful in treating diseases of the central nervous system in which the underlying cause is mitochondrial dysfunction.
While other benzamide compounds are known, their utility heretofore has generally been as intermediates in chemical syntheses or in fields unrelated to the present invention. Slight structural changes yielded large differences in efficacy and toxicity. The vast majority of benzamide compounds have little or no activity in our screens. However, there are reports of biological activity for other, structurally different benzamides. These reports include:
El Tayar et al., "Interaction of neuroleptic drugs with rat striatal D-1 and D-2 dopamine receptors: a quantitative structure--affinity relationship study" Eur. J. Med. Chem. (1988) 23:173-182;
Monkovic et al., "Potential non-dopaminergic gastrointestinal prokinetic agents in the series of substituted benzamides" Eur. J. Med. Chem. (1989) 24:233-240;
Banasik et al., "Specific inhibitors of poly(ADP-Ribose) synthetase and mono(ADP-ribosyl)transferase" J. Biol. Chem. (1992) 267:1569-1575;
Bishop et al., "Synthesis and in vitro evaluation of 2,3-dimethoxy-5-(fluoroalkyl)-substituted benzamides: high-affinity ligands for CNS dopamine D 2 receptors" J. Med. Chem. (1991) 34:1612-1624;
Hogberg et al., "Potential antipsychotic agents. 9. Synthesis and stereoselective dopamine D-2 receptor blockade of a potent class of substituted (R)-N- benzyl-2-pyrrolidinyl)methyl!benzamides. Relations to other side chain congeners" J. Med. Chem. (1991) 34:948-955;
Katopodis et al., "Novel substrates and inhibitors of peptidylglycine α-amidating monooxygenase" Biochemistry (1990) 29:4541-4548; and
Rainnie et al., "Adenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousal" Science (1994) 263:689-690.
Other benzamide-containing pharmaceutical compositions and their use to treat or protect against neurodegenerative conditions were disclosed in commonly owned U.S. Pat. No. 5,472,983 issued Dec. 5, 1995, the disclosure of which is incorporated herein by reference in its entirety.
Statement of the Invention
It has now been found that a family of novel acetamidobenzamide compounds of the Formula I below exhibit strong activity against Parkinson's disease as measured by their ability to prevent MPTP-induced reduction of dopamine levels. ##STR1## where R' is a straight, branched or cyclic saturated alkyl of from 3 to 5 carbon atoms and n is 1 or 2.
It has also been found that the novel nitro- and aminobenzamide compounds N-tert-amyl-4-nitrobenzamide (CPI1033), N-1,2-dimethylpropyl-4-nitrobenzamide (CPI1085), N-n-butyl-3-nitrobenzamide (CPI1135), N-n-pentyl-4-nitrobenzamide (CPI1140), N-2-methylbutyl-4-nitrobenzamide (CPI1146), N-n-butyl-3,5-dinitrobenzamide (CPI1147), N-methylcyclopropyl-4-nitrobenzamide (CPI1164), N-n-butyl-2-nitrobenzamide (CPI1173), N-n-pentyl-2-nitrobenzamide (CPI1174), and N-methylcyclopropyl-4-aminobenzamide (CPI1240) are useful as intermediates for preparing the acetamide compounds of Formula I above and as pharmaceutical agents.
These nitro- and aminobenzamide compounds and the acetamidobenzamide compounds of Formula I constitute one aspect of the invention.
The invention can also take the form of pharmaceutical compositions based on one or more of the compounds of Formula II below: ##STR2## where R' is a saturated alkyl of from 3 to 5 carbon atoms, each R is independently --NH--CO--CH 3 , --NO 2 or --NH 2 , and n is 1 or 2, with the following provisos: 1) when n is 1 and R is --NO 2 at the 4 position of the ring, R' is not tert-butyl, iso-butyl, or propyl; 2) when n is 1 and R is --NO 2 at the 2 position of the ring, R' is not iso-butyl or propyl; and 3) when n is 2 and R' is tert-butyl and both Rs are --NO 2 , the R groups are not at the 3 and 5 positions of the ring.
The invention can further take the form of methods of treating neurodegenerative conditions using these materials.
Thus, in one aspect this invention provides the novel acetamidobenzamide compounds of the Formula I and the novel nitro- and aminobenzamides described above.
In another aspect this invention provides pharmaceutical compositions which include one or more benzamide compounds of the Formula II in a pharmaceutically acceptable carrier. This carrier is preferably an oral carrier but can be an injectable carrier as well. These pharmaceutical compositions can be in bulk form but more typically are presented in unit dosage form.
In another aspect this invention provides a method for treating a patient suffering from a dopamine-associated neurodegenerative condition. This method involves administering to the patient an effective neurodegenerative condition-treating amount of one or more of the pharmaceutical compositions just described.
In another aspect this invention provides a method for treating a patient suffering from a condition characterized by progressive loss of central nervous system function. This method involves administering to the patient with loss of central nervous system function an effective amount of one or more of the pharmaceutical compositions just described.
In a most important aspect this invention provides a method for treating a patient suffering from a progressive loss of central nervous system function associated with Parkinson's disease. This method involves administering (preferably orally) to the patient with loss of progressive central nervous system function an effective amount of one or more of the pharmaceutical compositions just described.
In another aspect this invention provides a method for treating a patient suffering from a condition characterized by progressive loss of nervous system function due to mitochondrial dysfunction. This method involves administering to the patient with loss of central nervous system function an effective amount of one or more of the pharmaceutical compositions just described.
In a further aspect, this invention provides methods for preparing the compounds of Formula I and II. These methods generally involve condensing an alkyl amine of from 3 to 5 carbon atoms with a mono or dinitro benzoyl halide having the nitro configuration corresponding to the nitro, amine or acetamide substitution desired in the final compound, optionally, reducing the nitro groups, and, optionally, converting the amino benzamides to acetoamidobenzamides by reaction with an acetylhalide.
DETAILED DESCRIPTION OF THE INVENTION
The Compounds
This invention provides novel acetamidobenzamide compounds of the Formula I below and their use as active pharmaceutical agents. ##STR3## where R' is a saturated alkyl of from 3 to 5 carbon atoms and n is 1 or 2.
The acetamido group may be found anywhere on the ring. Preferred embodiments include when n is 1 and the R group is at the 2, 3 or 4 position of the ring and when n is 2 and the R groups are at the 2 and 3, 2 and 4, 2 and 5, 2 and 6, 3 and 4, or 3 and 5 positions of the ring.
With respect to the alkyl substituents, compounds wherein R' is an alkyl which does not have a hydrogen on the alpha carbon, that is, the carbon which bonds to the nitrogen of the ring, are preferred. Examples of these preferred R' groups are tert-butyl and tert-amyl.
The benzamide of the Formula I above which is N-tert-butyl-4-acetamidobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1189.
The benzamide of the Formula I above which is N-iso-propyl-4-acetamidobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1232.
The benzamide of the Formula I above which is N-tert-amyl-4-acetamidobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1233.
The benzamide of the Formula I above which is N-tert-butyl-3-acetamidobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1234.
The benzamide of the Formula I above which is N-methylcyclopropyl-4-acetamidobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1241.
The compounds N-tert-butyl 4-acetamidobenzamide (CPI1189), N-iso-propyl-4-acetamidobenzamide (CPI1232), N-tert-amyl-4-acetamidobenzamide CPI1233), N-tert-butyl-3-acetamidobenzamide (CPI1234), and N-methylcyclopropyl-4-acetamidobenzamide (CPI1241) are the most preferred compounds of the Formula I at this time.
The invention also provides the following novel nitro- and aminobenzamide compounds which are useful both as intermediates in preparing the compounds of the Formula I and as active pharmaceutical agents: N-tert-amyl-4-nitrobenzamide (CPI1033), N-1,2-dimethylpropyl-4-nitrobenzamide (CPI1085), N-n-butyl-3-nitrobenzamide (CPI1135), N-n-pentyl-4-nitrobenzamide (CPI1140), N-2-methylbutyl-4-nitrobenzamide (CPI1146), N-n-butyl-3,5-dinitrobenzamide (CPI1147), N-methylcyclopropyl-4-nitrobenzamide (CPI1164), N-n-butyl-2-nitrobenzamide (CPI1173), N-n-pentyl-2-nitrobenzamide (CPI1174), and N-methylcyclopropyl-4-aminobenzamide (CPI1240).
The benzamide which is N-tert-amyl-4-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1033.
The benzamide which is N-1,2-dimethylpropyl-4-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1085.
The benzamide which is N-n-butyl-3-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1135.
The benzamide which is N-n-pentyl-4-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1140.
The benzamide which is N-2-methylbutyl-4-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1146.
The benzamide which is N-n-butyl-3,5-dinitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1147.
The benzamide which is N-methylcyclopropyl-4-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1164.
The benzamide which is N-n-butyl-2-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1173.
The benzamide which is N-n-pentyl-2-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1174.
The benzamide which is N-methylcyclopropyl-4-aminobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1240.
When the benzamide compound contains an amino group, such as CPI 1240, this functionality can be present as such or as a pharmaceutically acceptable salt. When these "compounds" are referred to it is to be understood that these salts are included as well.
Commonly owned U.S. patent application Ser. No. 08/227,777, referred to above, discloses several benzamides useful in treating neurodegenerative diseases based on their protective action in the MPTP mouse model of Parkinson's disease. The compound N-tert-butyl 4-acetamidobenzamide (CPI1189) of the present invention is an in vivo biotransformation product of one of these benzamides (N-tert-butyl 4-nitrobenzamide (CPI1020)) which is found in the blood of rats and mice to which CPI1020 has been administered orally. This compound is likely formed in the body by reduction of the ring nitro of CPI1020 to an amino moiety (CPI1160) followed by acetylation of the amino function.
The compounds of the present invention, as exemplified by CPI1189, are much more potent than CPI1020 (approximately 10 times as potent) in protecting mice from dopamine reduction in the striatum induced by s.c. treatment with MPTP. Based on structurally similar molecules such as acetaminophen which contain an acetamido functionality, they should also be safer than CPI1020 because they would not be metabolized in the body to result in metabolites containing hydroxylamines (likely to be Ames positive) nor would they be likely to result in amino metabolites which may have cardiovascular and/or anorexic effects.
Pharmaceutical Compositions
The benzamide compounds of the Formula II below: ##STR4## where R' is a straight or branched chain saturated alkyl of from 3 to 5 carbon atoms, each R is independently --NH--CO--CH 3 , --NO 2 or --NH 2 , and n is 1 or 2, with the following provisos: 1) when n is 1 and R is --NO 2 at the 4 position of the ring, R' is not tert-butyl, iso-butyl, or propyl; 2) when n is 1 and R is --NO 2 at the 2 position of the ring, R' is not iso-butyl or propyl; and 3) when n is 2 and R' is tert-butyl and both Rs are --NO 2 , the R groups are not at the 3 and 5 positions of the ring, are formulated into pharmaceutical compositions suitable for oral or other appropriate routes of administration.
The benzamide of the Formula II above which is N-iso-propyl-4-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1026.
The benzamide of the Formula II above which is N-tert-butyl-3-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1034.
The benzamide of the Formula II above which is N-tert-butyl-2-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1035.
The benzamide of the Formula II above which is N-n-butyl-4-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1045.
The benzamide of the Formula II above which is N-n-propyl-4-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1047.
The benzamide of the Formula II above which is N-tert-butyl-3,5-dinitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1049.
The benzamide of the Formula II above which is N-1-methylpropyl-4-nitrobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1084.
The benzamide of the Formula II above which is N-tert-butyl-4-aminobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1160.
The benzamide of the Formula II above which is N-tert-butyl-3-aminobenzamide is referred to elsewhere in this specification by the internal compound designation number CPI1248.
When R is --NH 2 , the compounds of the Formula II may be used as salts in which the amine group is protonated to the cation form, in combination with a pharmaceutically acceptable anion, such as chloride, bromide, iodide, hydroxyl, nitrate, sulfonate, methane sulfonate, acetate, tartrate, oxalate, succinate, or palmoate.
Pharmaceutical compositions using the compounds N-tert-butyl 4-acetamidobenzamide (CPI1189), N-tert-butyl-3-acetamidobenzamide (CPI1234), N-tert-amyl-4-acetamidobenzamide (CPI1233), N-tert-butyl-4-aminobenzamide (CPI1160), N-tert-butyl-3-nitrobenzamide (CPI1034), and N-tert-butyl-3-aminobenzamide (CPI1248) are most preferred at this time.
The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in a unit dosage form to facilitate accurate dosing. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the benzamide compound is usually a minor component (0.1 to say 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form. A liquid form may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
A solid form may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
In the case of injectable compositions, they are commonly based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. Again the active benzamide is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
These components for orally administrable or injectable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa. which is incorporated by reference.
One can also administer the compounds of the invention in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in the incorporated materials in Remington's Pharmaceutical Sciences.
Conditions Treated and Treatment Regimens
The conditions treated with the benzamide-containing pharmaceutical compositions may be classed generally as neurodegenerative conditions. These include conditions characterized by protracted low grade stress upon the central nervous system and gradual progressive loss of central nervous system function. These conditions include Parkinson's disease, amyotrophic lateral sclerosis (ALS, "Lou Gehrig's disease"), multiple sclerosis, Huntington's disease, Alzheimer's disease, diabetic retinopathy, multi-infarct dementia, macular degeneration and the like. Each of these conditions is characterized by a progressive loss of function. The benzamide compound-containing pharmaceutical compositions of this invention, when administered orally or by injection such as intravenously, can slow and delay and possibly even to some extent reverse the loss of function.
Injection dose levels for treating these conditions range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
With these neurodegenerative conditions, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 1 to about 20 mg/kg of benzamide, with preferred doses each providing from about 1 to about 10 mg/kg and especially about 1 to about 5 mg/kg.
Of course, one can administer the benzamide compound as the sole active agent or one can administer it in combination with other agents, including other active benzamide compounds.
Methods of Preparation of Compounds
The benzamide compounds of this invention can be prepared using commonly available starting materials and readily achievable reactions.
One representative preparation route, which is illustrated with tert-butyl amine, but which may be used with any alkyl amine, involves the following reactions: ##STR5## where X is halo such as I, Br, F or Cl. ##STR6##
In step (A) the N-tert-butyl nitrobenzamides (III) are formed. This reaction must be carried out at temperatures below 10° C.
This step (A) yields as benzamides III, the compounds of the invention where R is --NO 2 .
In step (B) the nitro groups in the mono- or di-nitro benzamide III are subjected to reduction. This is commonly carried out with a reducing agent such as hydrazine and an appropriate catalyst such as a heterogeneous platinum, iron oxide hydroxide, palladium or nickel catalyst, typically on a support, or with hydrogen gas and a catalyst.
This step (B) yields as benzamides IV, the compounds of the invention where R is NH 2 .
In step (C) the amino-benzamides IV are converted to acetamidobenzamides V by reaction with an acetyl halide such as acetylchloride. This reaction is carried out in the presence of a mild base and at low to ambient temperatures such as -20° C. to +20° C. This yields the compounds of the invention where R is acetamido.
Alternate synthetic schemes may also be used to prepare the compounds of the present invention. Examples of these alternate routes are set forth below using CPI1189 as the representative compound. Other compounds may be prepared using these alternate methods by starting with appropriate starting materials, such as 2- or 3- amino- or nitro-benzonitrile or 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- diamino- or dinitro-benzonitrile and the appropriate alcohol (Alternate Route 1) or similarly substituted toluene compounds and the appropriate alkyl amine (Alternate Route 3).
Alternate Route 1
This route begins with acetylation of, for example, 4-aminobenzonitrile (A) to compound (B) using standard methods. Acid hydrolysis of tert-butanol in the presence of 4-acetamidobenzonitrile (B), provides a feasible synthetic pathway to CPI1189. ##STR7## Alternate Route 2
Acetylation, using standard methods, of the inexpensive starting material PABA (C) affords a cheap method to produce 4-acetamidobenzoic acid (D). Conversion of (D) to the acid chloride (E) using standard methods (e.g., SOCl 2 ) and subsequent amidation using standard methods, such as those described previously, produces CPI1189 from inexpensive raw materials. ##STR8## Alternate Route 3
Another method for the preparation of the compounds of the present invention begins with acetylation, using standard methods, of, for example, paratoluidine (F) to 4-acetamidotoluene (G). The synthetic intermediate (G) may be converted to 4-acetamidobenzoic acid (D) with common oxidizing agents (e.g., KMnO 4 ) and subsequently transformed to CPI1189 as outlined in Alternate Route 2. ##STR9##
EXAMPLES
The invention will be further described by the following Examples. These are provided to illustrate several preferred embodiments of the invention but are not to be construed as limiting its scope which is, instead, defined by the appended claims. Examples 1 to 19 demonstrate the preparation of acetamidobenzamides, as well as nitro- and aminobenzamides, which are representative of the benzamide compounds employed in the compositions and methods of this invention. Examples 20 to 24 demonstrate the preparation of pharmaceutical compositions based on the compounds. Thereafter biological test results illustrating the activity of the compositions of the invention are provided.
Example 1
Preparation of N-tert-butyl-4-aminobenzamide (CPI1160)
tert-Butyl amine (14.6 g, 0.200 mole) was stirred in ethyl acetate (150 mL, purified by washing with 5% sodium carbonate solution, saturated sodium chloride solution, drying over anhydrous magnesium sulfate, and filtering through fluted filter paper) and cooled to 5° C. with an ice bath. 4-nitrobenzoyl chloride (18.6 g, 0.100 mole) in purified ethyl acetate (75 mL) was added dropwise at such a rate to maintain the temperature below 10° C. The ice bath was removed upon complete addition of benzoyl chloride solution and the reaction stirred for 4 hours. The reaction mixture was then filtered on a Buchner funnel, the filtrate washed three times with 5% HCl, once with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered through fluted filter paper, and the solvent stripped off leaving white crystalline product. The product was dried in a vacuum oven at 24 mm and 45° C. for 14 hours. This procedure produced 17.13 g of crystals of N-tert-butyl-4-nitrobenzamide (CPI1020) (77% yield), mp 162-163° C. Proton nuclear magnetic resonance (89.55 MHz in CDCl 3 ) showed absorptions at 8.257 ppm (d, 8.8 Hz, 2H; 3,5-aryl H); 7.878 ppm (d, 8.8 Hz, 2H; 2,6-aryl H); 6.097 ppm (bs, 1H; N--H); 1.500 ppm (s, 9H; tert-butyl H).
Palladium on carbon (5%, 75 mg) was added to CPI-1020 (5 g, 22.5 mmole) in 95% ethanol at 55° C. A solution of hydrazine (1.2 mL) in 95% ethanol (10 mL) was added dropwise over 30 min. and more Pd/C added (75 mg). The reaction was refluxed 3 hours, hydrazine (0.5 g) in 95% ethanol (5 mL) was added and the reaction was refluxed for another hour. The reaction was filtered on a buchner funnel, the volume of solvent reduced under vacuum, and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and solvent stripped, leaving 3.90 g of N-tert-butyl-4-aminobenzamide (CPI1160) (90% yield), melting point 125-127° C. 90 MHz proton NMR (in CDCl 3 ) showed absorbances at 7.290 ppm (2H, d, 8.8 Hz; 2,6 aryl H); 6.368 ppm (2H, d, 8.8 Hz; 3,5 aryl H); 5.45 ppm (1H, bs; NHC═O); 3.727 ppm (2H, bs; aryl-NH 2 ); 1.186 ppm (9H, s; t-butyl H).
Example 2
Preparation of N-tert-butyl-4-acetamidobenzamide (CPI1189)
Acetyl chloride (0.45 g, 5.7 mmole) in ethyl acetate (25 mL) was added dropwise to CPI-1160 (1.0 g, 5.2 mmole) and triethyl amine (0.58 g, 5.7 mmole) in ethyl acetate at 3° C. at such a rate to maintain the temperature below 10° C. The reaction was allowed to warm to room temperature, stirred 1 hour, and washed with 5% HCl. Recrystallization from acetone gave 1.08 g N-tert-butyl-4-acetamidobenzamide (CPI1189)(89% yield), melting point 119-121° C. 90 MHz proton NMR (in DMSO-d6) showed absorbances at 9.726 ppm (1H, bs, N--H); 7.715 ppm (4H, dd, 4.4 Hz; aryl H); 7.295 ppm (1H, bs; NH); 2.844 ppm (3H, s; CH 3 CO); 1.448 ppm (9H, s; t-butyl H).
Example 3
Preparation of N-tert-butyl-3-acetamidobenzamide (CPI1234)
The amidation procedures of Example 1 were followed using 3-nitrobenzoyl chloride instead of 4-nitrobenzoyl chloride. This gave N-tert-butyl-3-nitrobenzamide (CPI1034) in 92% yield, melting point 123-125° C. Proton NMR (in CDCl 3 ) showed absorptions at 8.517 ppm (2-aryl H, s, 1H); 8.337 ppm (4-aryl H, d, 8.8 Hz, 1H); 8.121 ppm (6-aryl H, d, 6.4 Hz, 1H); 7.618 ppm (5-aryl H, m, 1H); 6.032 ppm (N--H, bs, 1H); 1.484 ppm (t-butyl H, s, 9H).
Iron (III) oxide hydroxide catalyzed hydrazine reduction produced N-tert-butyl-3-aminobenzamide (CPI1248) in 53% yield, melting point 118-120° C. Proton NMR (in CDCl 3 ) showed absorbances at 7.088 ppm (4-6-aryl H, m, 3H); 6.794 ppm (2-aryl H, s, 1H); 5.902 ppm (N--H, bs, 1H); 3.145 ppm (aryl N--H, bs, 2H); 1.458 ppm (t-butyl H, s, 9H).
Acetylation of CPI1248 as described in Example 2 gave N-tert-butyl-3-acetamidobenzamide (CPI1234) in 75% yield, melting point 194-195° C. Proton NMR (in CDCl 3 ) showed absorptions at 7.778 ppm (4-6-aryl H, m, 3H); 7.392 ppm (2-aryl H, s, 1H); 6.08 ppm (N--H, bs, 1H); 2.174 ppm (acetyl CH 3 , s, 9H); 1.500 ppm (t-butyl H, s, 9H).
Example 4
Preparation of N-tert-butyl-2-acetamidobenzamide
The method of Example 3 is repeated using 2-nitrobenzoyl chloride in the amidation step. This yields N-tert-butyl-2-nitrobenzamide (CPI1035).
Reduction of the nitrobenzamide with hydrazine yields N-tert-butyl-2-aminobenzamide.
Acetylation of the aminobenzamide yields N-tert-butyl-2-acetamidobenzamide.
Example 5
Preparation of N-iso-propyl-4-acetamidobenzamide (CPI1232)
The method of Example 3 is repeated using 4-nitrobenzoyl chloride and iso-propyl amine in the amidation step. This yields N-iso-propyl-4-nitrobenzamide (CPI1026).
Reduction of the nitrobenzamide with hydrazine yields N-iso-propyl-4-aminobenzamide.
Acetylation of the aminobenzamide yields N-iso-propyl-4-acetamidobenzamide (CPI1232).
Example 6
Preparation of N-tert-amyl-4-acetamidobenzamide (CPI1233)
The method of Example 3 is repeated using 4-nitrobenzoyl chloride and tert-amyl amine in the amidation step. This yields N-tert-amyl-4-nitrobenzamide (CPI1033).
Reduction of the nitrobenzamide with hydrazine yields N-tert-amyl-4-aminobenzamide.
Acetylation of the aminobenzamide yields N-tert-amyl-4-acetamidobenzamide (CPI1233).
Example 7
Preparation of N-iso-butyl-4-acetamidobenzamide
The method of Example 3 is repeated using 4-nitrobenzoyl chloride and iso-butyl amine in the amidation step. This yields N-iso-butyl-4-nitrobenzamide (CPI1044).
Reduction of the nitrobenzamide with hydrazine yields N-iso-butyl-4-aminobenzamide.
Acetylation of the aminobenzamide yields N-iso-butyl-4-acetamidobenzamide.
Example 8
Preparation of N-n-butyl-4-acetamidobenzamide
The method of Example 3 is repeated using 4-nitrobenzoyl chloride and n-butyl amine in the amidation step. This yields N-n-butyl-4-nitrobenzamide (CPI1045).
Reduction of the nitrobenzamide with hydrazine yields N-n-butyl-4-aminobenzamide.
Acetylation of the aminobenzamide yields N-n-butyl-4-acetamidobenzamide.
Example 9
Preparation of N-n-propyl-4-acetamidobenzamide
The method of Example 3 is repeated using 4-nitrobenzoyl chloride and n-propyl amine in the amidation step. This yields N-n-propyl-4-nitrobenzamide (CPI1047).
Reduction of the nitrobenzamide with hydrazine yields N-n-propyl-4-aminobenzamide.
Acetylation of the aminobenzamide yields N-n-propyl-4-acetamidobenzamide.
Example 10
Preparation of N-1,2-dimethylpropyl-4-acetamidobenzamide
The method of Example 3 is repeated using 4-nitrobenzoyl chloride and 1,2-dimethylpropyl amine in the amidation step. This yields N-1,2-dimethylpropyl-4-nitrobenzamide (CPI1085).
Reduction of the nitrobenzamide with hydrazine yields N-1,2-dimethylpropyl-4-aminobenzamide.
Acetylation of the aminobenzamide yields N-1,2-dimethylpropyl-4-acetamidobenzamide.
Example 11
Preparation of N-n-pentyl-4-acetamidobenzamide
The method of Example 3 is repeated using 4-nitrobenzoyl chloride and n-pentyl amine in the amidation step. This yields N-n-pentyl-4-nitrobenzamide (CPI1140).
Reduction of the nitrobenzamide with hydrazine yields N-n-pentyl-4-aminobenzamide.
Acetylation of the aminobenzamide yields N-n-pentyl-4-acetamidobenzamide.
Example 12
Preparation of N-2-methylbutyl-4-acetamidobenzamide
The method of Example 3 is repeated using 4-nitrobenzoyl chloride and 2-methylbutyl amine in the amidation step. This yields N-2-methylbutyl-4-nitrobenzamide (CPI1146).
Reduction of the nitrobenzamide with hydrazine yields N-2-methylbutyl-4-aminobenzamide.
Acetylation of the aminobenzamide yields N-2-methylbutyl-4-acetamidobenzamide.
Example 13
Preparation of N-n-pentyl-2-acetamidobenzamide
The method of Example 3 is repeated using 2-nitrobenzoyl chloride and n-pentyl amine in the amidation step. This yields N-n-pentyl-2-nitrobenzamide (CPI1174).
Reduction of the nitrobenzamide with hydrazine yields N-n-pentyl-2-aminobenzamide.
Acetylation of the aminobenzamide yields N-n-pentyl-2-acetamidobenzamide.
Example 14
Preparation of N-tert-butyl-2,3-diacetamidobenzamide
The method of Example 3 is repeated using 2,3-dinitrobenzoyl chloride in the amidation step. This yields N-tert-butyl-2,3-dinitrobenzamide.
Reduction of the nitrobenzamide with hydrazine yields N-tert-butyl-2,3-diaminobenzamide.
Acetylation of the aminobenzamide yields N-tert-butyl-2,3-diacetamidobenzamide.
Example 15
Preparation of N-tert-amyl-2,4-diacetamidobenzamide
The method of Example 3 is repeated using 2,4-dinitrobenzoyl chloride and tert-amyl amine in the amidation step. This yields N-tert-amyl-2,4-dinitrobenzamide.
Reduction of the nitrobenzamide with hydrazine yields N-tert-amyl-2,4-diaminobenzamide.
Acetylation of the aminobenzamide yields N-tert-amyl-2,4-diacetamidobenzamide.
Example 16
Preparation of N-tert-butyl-2,5-diacetamidobenzamide
The method of Example 3 is repeated using 2,5-dinitrobenzoyl chloride in the amidation step. This yields N-tert-butyl-2,5-dinitrobenzamide.
Reduction of the nitrobenzamide with hydrazine yields N-tert-butyl-2,5-diaminobenzamide.
Acetylation of the aminobenzamide yields N-tert-butyl-2,5-diacetamidobenzamide.
Example 17
Preparation of N-tert-butyl-2,6-diacetamidobenzamide
The method of Example 3 is repeated using 2,6-dinitrobenzoyl chloride in the amidation step. This yields N-tert-butyl-2,6-dinitrobenzamide.
Reduction of the nitrobenzamide with hydrazine yields N-tert-butyl-2,6-diaminobenzamide.
Acetylation of the aminobenzamide yields N-tert-butyl-2,6-diacetamidobenzamide.
Example 18
Preparation of N-tert-butyl-3,4-diacetamidobenzamide
The method of Example 3 is repeated using 3,4-dinitrobenzoyl chloride in the amidation step. This yields N-tert-butyl-3,4-dinitrobenzamide.
Reduction of the nitrobenzamide with hydrazine yields N-tert-butyl-3,4-diaminobenzamide.
Acetylation of the aminobenzamide yields N-tert-butyl-3,4-diacetamidobenzamide.
Example 19
Preparation of N-tert-butyl-3,5-diacetamidobenzamide
The method of Example 3 is repeated using 3,5-dinitrobenzoyl chloride in the amidation step. This yields N-tert-butyl-3,5-dinitrobenzamide.
Reduction of the nitrobenzamide with hydrazine yields N-tert-butyl-3,5-diaminobenzamide.
Acetylation of the aminobenzamide yields N-tert-butyl-3,5-diacetamidobenzamide.
Preparation of Pharmaceutical Compositions
Example 20
The compound of Example 1 is admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active benzamide) in a tablet press. If these tablets were administered to a patient suffering from a dopamine-associated neurodegenerative condition on a daily, twice daily or thrice daily regimen they would slow the progress of the patient's disease.
Example 21
The compound of Example 2 is admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active benzamide). If these capsules were administered to a patient suffering from a dopamine-associated neurodegenerative condition on a daily, twice daily or thrice daily regimen they would slow the progress of the patient's disease.
Example 22
The compound of Example 3 is suspended in a sweetened flavored aqueous medium to a concentration of approximately 50 mg/ml. If 5 mls of this liquid material was administered to a patient suffering from a dopamine-associated neurodegenerative condition on a daily, twice daily or thrice daily regimen they would slow the progress of the patient's disease.
Example 23
The compound of Example 4 is admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active benzamide) in a tablet press. If these tablets were administered to a patient suffering from a dopamine-associated neurodegenerative condition on a daily, twice daily or thrice daily regimen they would slow the progress of the patient's disease.
Example 24
The compound of Example 14 is dissolved in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/ml. If 50 mls of this liquid material was administered to a patient suffering from a dopamine-associated neurodegenerative condition such as Parkinson's disease on a daily, twice daily or thrice daily regimen this dose would slow the progress of the patient's disease.
It will be appreciated that any of the compounds of Formula II could be employed in any of these representative formulations, and that any of these formulations could be administered in any of these manners so as to treat any of the neurodegenerative conditions described in this specification.
Parkinson's Disease Screening Methods
Dopamine Depletion Studies.
C57BL/6J mice were pretreated with either vehicle (1% methyl cellulose) or a drug (p.o.) 30 min before MPTP. MPTP was dissolved in isotonic saline (0.9%) and given subcutaneously as a single dose of 15 mg free base/kg body weight to produce a reduction in striatal dopamine to about 0.5 nanomoles/mg protein. Groups of mice (n=8-10 per group) received either vehicle plus saline, vehicle plus MPTP, or drug plus MPTP. Seventy two hours after receiving MPTP, mice were sacrificed using cervical dislocation and the striata were excised. The tissue was homogenized in 0.4 N perchloric acid, centrifuged, and the supernatant analyzed by high performance liquid chromatography/electro-chemical detection (HPLC/ED) for dopamine levels. Supernatants were stored in a -90° C. freezer between the time of collection and analysis.
The drugs were combined with methyl cellulose and were homogenized in water for dosing. The dosage amount ranged from 10 to 50 mg/kg for CPI1160, CPI1189 and CPI1234, and from 50 to 100 mg/kg for CPI1020.
The results of representative experiments are provided in Tables 1 and 2. The results in Table 1 demonstrate that the compositions of this invention, as exemplified by CPI1160, CPI1189, and CPI1234 were effective in preventing dopamine depletion following MPTP challenge.
TABLE 1______________________________________Efficacy of CPI Compounds 1189, 1160, and 1234 at 30 mg/kgin the 15 mg/kg MPTP Model NANOMOLES DOPAMINE PER % NON-MPTPCOMPOUND MG PROTEIN ± S.E.M. CONTROL______________________________________methyl 0.72 ± .05 54.1celluloseCPI1160 1.25 ± .05 93.9CPI1234 1.02 ± .05 76.7methyl 0.56 ± .07 36.4celluloseCPI1189 1.37 ± .14 89.7______________________________________
For comparison purposes the same tests were run on compositions based on CPI1020, a closely related benzamide compound. Results are shown in Table 2. At 50 mg/kg, CPI1189 offered complete protection from the neurotoxic action of MPTP (105% of control) while CPI1020 was not as effective (65% of control).
TABLE 2______________________________________Comparison of the Efficacies of CPI1189 and CPI1020 at 50 mg/kgin the 15 mg/kg MPTP Model NANOMOLES DOPAMINE PERCOMPOUND MG PROTEIN ± S.E.M.______________________________________CPI1020 0.58 ± .14CPI1189 1.57 ± .11______________________________________ | A group of benzamide compounds are disclosed which are useful for treating neurodegenerative disorders. Methods for making these compounds are provided. These materials are formed into pharmaceutical compositions for oral or intravenous administration to patients suffering from conditions such as Parkinson's disease which can exhibit themselves as progressive loss of central nervous system function. The compounds can arrest or slow the progressive loss of function. | 0 |
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This claims the benefit of U.S. Provisional Patent Application Ser. No. 60/399,004, filed Jul. 26, 2002 and entitled, “Suspension Restraint Device,” which is incorporated by reference herein in its entirety. It is specifically noted that certain of the information from the referenced Provisional Patent Application has been omitted herein. However, the above incorporation is intended as antecedent basis for explicitly setting forth such text herein or in a continuing application should it be desired.
FIELD OF THE INVENTION
[0002] This invention relates to overall balance, traction and power transfer available to the rear wheel of a motocross motorcycle. More particularly, assemblies are provided to lower and temporarily lock the suspension fork of such a motorcycle in a position to improve starting with respect to traction and control.
BACKGROUND
[0003] In general, when a rider leaves the starting gate in a motocross event or practice, the throttle of the motorcycle is held wide open and the clutch is dumped causing the front of the bike to rise into a wheelie. The rider then has to manipulate the throttle to control the front end of the motorcycle—often by backing off the throttle slightly. As a solution to this problem, it is known to temporarily lock down the front fork of the motorcycle using a simple hook interfacing with a corresponding hole in one of the plastic fork guards. While effective, the setup was unacceptable from the perspective of wear-and-tear on the fork guard (rubbing or scoring along the length of the fork guard because of the hook, as well as compressive damage to the opening created in the fork guard) and the potential for inadvertent engagement since the hook remains jutting outward after disengagement from a fork guard.
[0004] An improved solution is offered by the present invention. It is improved not only in terms of better wear-and-tear and safety, but as potentially offering superior tunability as well as configurations suited for use with a greater variety of fork styles.
SUMMARY OF THE INVENTION
[0005] Devices of the present invention are adapted to provide a starting device to help hold the front end down of a motorcycle to the ground, especially in a “hole shot” or starting application. Generally, this goal is accomplished by a rider compressing the suspension fork of the motorcycle down by about 3 to about 4 inches and pushing in a spring loaded lock button while the fork struts are compressed so as to lock an interface member associated with the push button onto or into an interface member mounted on the fork. The fork interface member may be a ring (with or without an interface groove) clamped to the fork. Alternatively, it may be a feature integrated with the fork.
[0006] In any case, thus locked, it becomes difficult to wheelie the motorcycle of the start while holding the throttle wide open. When the rider dives into the first corner of a racetrack and applies the front brake to slow down, the braking action compresses the forks slightly—driving the ring or other fork interface portion towards the ground, releasing the lock interface member. This release causes the spring loaded push button to pop back providing clearance between the interface members, thereby allowing the rider the full range of available suspension for the remainder of the race.
[0007] One variation of the invention contemplates providing a plurality (preferably only two) push buttons incorporated in a single lock-down device. Alternately, or additionally, the fork interface member may include a plurality of engagement positions or multiple fork-side engagement members may be provided. However configured, such provisions allow a rider to choose the button and/or fork interface position that is optimal for given track conditions.
[0008] As conditions change throughout the day, a rider might choose to select a setup with a different degree for fork compression and temporary lockdown. For example, with a two-button device, if the conditions are tacky in the first moto, then the rider should choose the lower button. If the conditions dry out throughout the days racing, the rider can use the upper button for the 2nd moto. If the start is concrete, then the rider can use the upper button all the time—or no lockdown. The rider can easily try both positions before each moto and see which works best without switching fork guards and purchasing extra button devices. The invention includes such methodology in addition to the various devices described.
BRIEF DESCRIPTION OF THE FIGURES
[0009] While certain figures are proportionally drawn or indicative of actual hardware, they may equally be regarded as diagrammatic in the information they convey. To facilitate understanding, the same reference numerals have been used (where practical) to designate similar elements that are common to the figures. Some such numbers have, however, been omitted.
[0010] FIGS. 1A and 1B are perspective views of a first variation of the invention installed on different styles of motorcycle forks. FIG. 2 is a side view of multi-button variation of the invention. FIGS. 3A and 3B are side and top views, respectively, of a fork-side interface member as may be used with any of the variations of the invention.
[0011] FIGS. 4A and 4B are top and side views, respectively, showing the base of the variation of the invention in FIGS. 1A and 1B . FIGS. 5A and 5B are top and side views, respectively, showing the base of the variation of the invention in FIG. 2 . FIG. 6 is a side view assembly drawing of components to interfit with the aforementioned base members.
[0012] FIGS. 7A and 7B are top and side views, respectively of supplemental bracket member for use with a fork guard as shown in FIG. 1A .
DETAILED DESCRIPTION
[0013] It is to be understood that this invention is not limited to particular variations set forth and may, of course, vary. Various changes may be made to the invention described and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process act(s) or step(s), to the objective(s), spirit or scope of the present invention. All such modifications are intended to be within the scope of the claims made herein.
[0014] Methods recited herein may be carried out in any order of the recited events which is logically possible, as well as the recited order of events. Furthermore, where a range of values is provided, it is understood that every intervening value, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. Also, it is contemplated that any optional feature of the inventive variations described may be set forth and claimed independently, or in combination with any one or more of the features described herein.
[0015] All existing subject matter mentioned or referenced in the attached pages/herein (e.g., articles, publications, advertisements and hardware) is incorporated by reference herein in its entirety except insofar as the subject matter may conflict with that of the present invention (in which case what is present herein shall prevail). The referenced items are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such material by virtue of prior invention.
[0016] Reference to a singular item, includes the possibility that there are plural of the same items present. More specifically, as used herein and in the appended claims, the singular forms. “a,” “and,” “said” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation. Unless defined otherwise herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
[0000] Methodology
[0017] The subject devices shown in the figures are installed with a base attached either on a fork guard or a supplemental strap member. Yet, it is contemplated that the base members/portions may be incorporated into such structure.
[0018] In addition, the figures also show situations where a supplemental interface or engagement ring is attached to the fork (on a stanchion or slider) to interact with the pin(s) provided in a given base. Again, however, it is contemplated that the fork interface members/portions may be incorporated into such structure.
[0019] The manner of attaching the various components will depend on those selected and the style of fork chosen (be it a standard or inverted in style). Completing the necessary assembly is well within the abilities of those with ordinary skill in the art. As guidance, however, it is noted that the precise position for mounting components should take into consideration the amount of sag the rider has in the front suspension, along with riding ability. The faster the rider, the further down the rider may want to mount the device in order to compress the suspension further. Still further, placement may vary depending on typical conditions. If the starting ground condition is hard packed, dry slick or concrete, lower down buttons will generally not work as well as the buttons mounted up higher. The lower placement of the devices take too much traction from the rear wheel in these conditions. In tacky conditions, however, the lower down the compression, the better the bike got off the start.
[0020] As for use of the subject devices, when loading, calking or activating them, it is recommended that the motorcycle engine first be OFF. Then, holding the front brake while sitting on bike, the front end is compressed or pushed down with a rocking motion. When the forks compress, the user or a second person pushes in the pin/button on the device to engage it. As the fork rebounds, the components engage—holding the forks firmly in place and compressed as desired.
[0021] The device disengages automatically the first time the suspension compresses below the lock-out position. This event will generally occur during braking when the bike is running and in motion.
[0022] It is recommended not to engage the subject devices until at the starting line. Also, one should not activate the device while the motorcycle is sitting on a stand. Once activated, the forks apply pressure by trying to rebound and this can damage components if left connected for a period of time. Also, one should avoid locating his or her head directly on or near handlebars while the device is latched. Finally, it is recommended that one check the conditions at the starting gate. It is important for one to “farm” the area behind the gate ensuring a smooth ramp of dirt over the starting gate when down. If there is a large bump, this can deactivate the device by inadvertent compression when the front wheel hits the bump, thereby defeating the purpose of the device which is to allow the motorcycle forks to remain in a compressed state though the entire start of a race.
[0000] Devices
[0023] As to specific hardware that may be used in the invention, the figures provide various examples. Turning to FIGS. 1A and 1B , a front end 2 of a motorcycle is shown. It includes a fork 4 , and wheel 6 .
[0024] With specific reference to FIG. 1A , the fork is an inverted-style fork. Its lower tubes 8 are slidingly received within upper tubes mounted to the motorcycle. A guard 12 is provided in front of the lower tubes. The subject invention comprises base assembly 20 and interface ring 22 —either in packaged combination or installed as shown. The same holds true for other variations of the invention.
[0025] Generally, only one combination of parts forming a restraint device is installed on a single side of the fork. While not necessary, it still may be desired to have redundant latching systems by providing and identical set of parts at the same height on both fork legs. Alternatively, it may be desired to have restraint device(s) set at different heights on each leg to provide different height latching positions.
[0026] In any case, the base assembly in FIGS. 1A and 1B illustrate a push button 24 design. A spring 26 is interposed between a base or housing member 28 and the button. It is optionally secured with screws/bolts 30 from behind.
[0027] The fork-side interface member used in each design (though other options are possible) is in the form of a ring. The ring is a split-ring, clamped where desired using a screw/bolt 32 . The ring preferably includes a slot 40 to interface with a pin or piston member 42 .
[0028] Note that the variation of the invention in FIG. 1B differs in its final assembled configuration from that in FIG. 1B in that additional components are provided that are not available on a stock fork or motorcycle. Particularly, an extension member or strap 50 is provided. Its proximal end 52 is secured to a clamp 54 on the upper tube by screws/bolts 56 . Another pinch-bolt 32 may be provided to secure clamp 54 . A distal end 58 of strap 50 is set to overlap lower tube 8 and any potentially interfering structure such as ring 22 to avoid inadvertent catching it upon compression of the fork.
[0029] FIG. 2 shows another variation of the invention in which a multi-button/pin base design is in preparation for lock-down. More particularly, base 60 is adapted to slidingly receive two pins 42 . A multi-button device allows a rider to have a choice of fork compression at the start without the need to install multiple lock-down components.
[0030] In either case, the choice of adjustable height offered may be used simply to accommodate various rider weights, suspension sag, ability and/or to account for starting area conditions. Significant adjustment options are provided by pin spacing of between about 1 and about 2 inches apart (in a vertical direction—i.e., along the axis of the fork). It may be desired to have the pins locations about 1.5 inches apart. Also, more or less of a range than specifically noted may be desired (e.g., as in between about 0.5 and 3.5 inches, possibly in two, three or four steps for greater spreads).
[0031] Another feature illustrated by FIG. 2 is the manner in which a recess 70 may be provided in the pin to prevent lateral movement of the components when engaged with complementary feature 72 of the fork interface member 22 . While such features are highly advantageous, they need not—however—be provided.
[0032] FIGS. 3A and 3B better illustrate recess 40 and wall 72 defining the same. FIG. 3B also clearly illustrates the split-ring design, as well as the manner in which the recess may be offset to accommodate ideal placement relative to a guard or other Original Equipment (OE/OEM) structure, especially in view of available clearance.
[0033] Returning to FIG. 2 , however, it clearly illustrates the manner in which pin 26 is preferably fully recessed (see upper pin) when not engaged or advanced. The bias provided by the spring draws the part fully within corresponding recessed area(s) 74 . The base recess features 74 accommodating a distal end of the pin 76 are also apparent in the views of base pieces in FIGS. 4B and 5B . FIGS. 4A and 4B show views of the designs looking from the front of the fork.
[0034] FIG. 6 is a partial assembly drawing of a preferred pin/spring arrangement or assembly. In it, button/cap 24 is secured to plunger 42 via complementary threadings 82 . A socket 84 may be provided in one piece (or each piece) to facilitate tightening them relative to one another. As shown, member 42 includes a head 86 having a diameter larger than that of the barrel section 88 . Accordingly, by virtue of the size of a bore 90 in which the barrel is received in the base piece(s), head 86 serves as a stop on one end, and the button head 92 (in conjunction with spring 26 on the other, thereby effectively trapping the pin assembly within bore 90 .
[0035] To facilitate smooth and consistent action, as well as handle the torsional loads applied the pin by virtue of holding down a heavily sprung fork, bore 90 should have an adequate length (shown as “L”). This length may range from about 0.25 inches upward.
[0036] Finally, the optional hardware in FIGS. 7A and 7B is noted. This bracket member 100 may be used at the base of a fork guard 12 such as shown in FIG. 1A . Its purpose is to provide an improved bolt interface so that repeated strain by virtue of use of the subject restraint device(s) do not damage the guard material—which is often plastic. Bracket 100 fits many fork guards with extension section 102 facing toward the guard. With the bracket configuration shown, the stock bolt otherwise provided to hold the base of the fork guard is replaced with a shoulder bolt to account for the length of bore 104 . The piece shown is CNC machined, but where a bent strip of metal or a composite piece is to be used, one may simply use the stock bolts to secure the bracket.
[0037] Regarding material as used in producing other parts of the invention, each of the components (save for the spring and strap) are advantageously machined from aluminum alloy, such as 6061-T6. Of course, other material or constructional techniques may be used. Strap 50 may be plastic that is die cut or otherwise trimmed to shape. Any of these production details are believed to fall within the design abilities of those with ordinary skill in the art.
[0038] Though the invention has been described in reference to certain examples, optionally incorporating various features, the invention is not to be limited to the set-ups described. The invention is not limited to the uses noted or by way of the exemplary description provided herein. It is to be understood that the breadth of the present invention is to be limited only by the literal or equitable scope of the following claims. | Starting devices are provided that are adapted to help hold the front end of a motorcycle down, especially in a “hole shot” or starting applications. The devices allow a rider to compress the suspension fork of the motorcycle down by about 3 to about 4 inches and temporarily lock the fork in a given position. Certain variations provide for selection one of a number of positions. Lock-down and automatic release are accomplished by pushing in a spring loaded lock button while the fork struts are compressed. A pin member interfaces with a stop member located on the fork to prevent decompression of the fork. Upon further compression of the fork (e.g., due to braking) the pin is released and the spring member draws the pin out of the way to allow clearance for free fork travel. | 1 |
FIELD OF THE INVENTION
The present invention is concerned with small functionalised amide molecules that exhibit antifouling and/or antibacterial activity and their use in the control of bacterial films and organism growth in the marine environment.
BACKGROUND
Marine fouling refers to the settlement and growth of organisms on submerged, manufactured surfaces and has been has been a problem since the dawn of maritime history. Colonization of submerged surfaces by marine organisms occurs within days to weeks of the surface entering the marine environment and, given the ever-increasing presence of maritime structures (underwater cables, generators, pipelines etc), the battle against fouling organisms is becoming an increasingly significant challenge. The need for effective methods to control marine fouling is of paramount importance to the international shipping industry.
Antifouling coatings prevent the settlement of marine organisms, generally by killing larval foulers through the action of broad spectrum biocides such as organotin or copper compounds. Although extremely effective, environmental degradation resulting from the use of organotin compounds was so severe that marine paint companies voluntarily withdrew these paints from the market in 2003, and the IMO banned their use in 2008 (International Convention on the Control of Harmful Anti-fouling Systems on Ships, entered into force 17 Sep. 2008). Although copper and biocide booster containing paints are still widely available, their use is not desirable since they have the potential to accumulate in the marine environment (Voulvoulis, 2006).
Current commercial marine coatings can be divided into two classes: antifouling and foul-release. Antifouling coatings use broad-spectrum biocides which kill foulers by oxidation or, more usually, exposure to toxic metal ions. Foul-release coatings are mainly silicon based polymers that are easy to clean, however the best of these usually also contain additives and catalysts that kill organisms. As noted above, legislation and agreements, based on the recognition of the environmentally unacceptable consequences of toxic antifouling agents such as tributyl tin in coatings, have prompted interest to develop new less environmentally pernicious coatings.
An approach reported by Teo et al (an inventor of the present application) in U.S. Ser. No. 11/265,833, is the use of pharmaceuticals as antifouling agents. It has been demonstrated that pharmaceuticals may disrupt the metamorphosis of fouling organisms. Commercially available pharmaceuticals, with their known synthesis, chemical properties and primary mechanism of action in vertebrates and in humans, were screened as potential sources of antifouling agents. Whilst eight pharmaceuticals with promising bioactivity were reported, there remains the problem that these pharmaceuticals may accumulate in the marine environment. Furthermore, some of these pharmaceuticals suffer from delivery problems because of poor solubility in sea water.
A further alternative to broad spectrum biocides is small, biodegradable organic molecules that inhibit the settlement of marine organisms. Such molecules should not be recalcitrant in the environment and should be “benign by design”. To this end, Teo et al recently demonstrated the antifouling potential of a family of simple α,α-disubstituted amides (selected examples shown below) on larval barnacles and bacterial biofilms (PCT/SG2009/000175). These molecules are predicted to breakdown rapidly in the marine environment.
Numerous organic biocides have been used as additives into tin-free paints, however, the direct incorporation of small molecules into coating systems presents a number of issues. First, the release of the organic antifoulants must be sustained for several years in order to minimize the requirement for repainting of the vessel prior to scheduled dry-docking. In addition, many currently employed organic antifoulants are toxic to marine foulers, which, with increased use could have an unfavorable impact on the marine ecosystem in the event of accumulation. The physical properties of the organic antifoulants can also have a profound impact on the integrity of a commercially available coating system, which in the absence of metal-based binders may require reformulation of coating systems.
Crucially, the mechanism by which the small molecule is incorporated into the coating system should permit retention of the activity of the small molecule. It is to be expected that structural modifications of the small molecule to impact on activity so that incorporating any active molecule into a coating system would be challenging.
SUMMARY OF THE INVENTION
The present inventors have sought to address the problem of providing an environmentally benign biocide that is suitable for incorporation into coating systems, and coating systems including such biocides.
At its most general, the present invention proposes that certain aryl-containing α,α-disubstituted amides should be provided with one or more selected substituents on the aryl, which substituents are suitable for attachment to a component, e.g. a polymer, of a coating composition. Surprisingly, amide compounds modified in this particular way retain useful activity.
In particular, derivatives of the small molecule antifouling additives described in PCT/SG2009/000175 are disclosed herein, which derivatives possess functionality that enables covalent attachment to, for example, self-polishing coating systems. The ability to covalently link additives to an existing coating system has potential to facilitate their controlled release, thus extending coating lifetime and enhancing antifouling properties. Further work has identified structural modifications that permit a stable bond to coating systems without significantly compromising biological potency, thereby enabling the release of bioactive molecules via pre-existing release chemistry.
In particular, the present application describes the synthesis and biological testing of a range of α-aryl amides bearing functionality to serve as a point of attachment to a marine coating system. A number of molecules are described which retain desirable antifouling properties (high potency against barnacle cyprid settlement yet low toxicity), while including ester or ether linkages that will enable covalent attachment to existing coating systems.
Compounds
The present invention pertains generally to a class of compounds referred to herein as “antifouling amide compounds”, which compounds have the following general α,α-disubstituted structure:
wherein one or both of R A and R B is an aryl and wherein R C and R D independently represent optionally substituted alkyl or together form a ring.
The present invention proposes that the aryl group of one or both of R A and R B of such compounds should be functionalised with one or more groups tailored to permit connection to coating systems (e.g. a polymer). Furthermore, the present invention proposes that such compounds having an aryl substituent that is a product of the cleavage of such a group from a coating system (e.g. a polymer) can retain useful activity.
The present invention pertains to such antifouling amide compounds, which exhibit biocidal or biostatic properties. Therefore, the antifouling amide compounds may also be referred to as “biocidal compounds” or “biostatic compounds”.
Embodiments of the invention have the potential to enhance antifouling properties of existing marine coating systems. In particular, embodiments preferably have one or more of the following advantages: highly potent against barnacle settlement, low toxicity and are likely to degrade rapidly in the marine environment (environmentally benign).
Substitution of the aryl group with different functional groups can be employed as a point of attachment to tailor properties for different coatings and for different applications.
An advantage of this system lies in the potential to incorporate these molecules into an existing coating system and the release of the antifoulant will be directly linked to the lifetime of the coating.
In a first aspect the present invention provides a compound of formula (I) or a salt thereof:
wherein
each of R 1 and R 2 is independently selected from
(A) aryl substituted with at least one of OH, R S1 OH, OR S2 , R S1 OR S2 , OC(O)H, OC(O)R S2 , R S1 OC(O)H, R S1 OC(O)R S2 , C(O)OH, C(O)OR S2 , R S1 C(O)OH, R S1 C(O)OR S2 , OR S1 OH, OR S1 OR S2 , OR S1 OC(O)H, OR S1 OC(O)R S2 , OR S1 C(O)OH and OR S1 C(O)OR S2 ,
wherein, if present, each R S1 is independently optionally substituted C 1 to C 5 alkylene, and wherein, if present, each R S2 is independently selected from optionally substituted C 1 to C 5 alkyl, C 2 to C 5 alkenyl and C 1 to C 5 silyl-C 1 to C 5 alkylene.
and (B) optionally substituted C 3 to C 12 alkyl with the proviso that at least one of R 1 and R 2 (A);
and
each of R 3 and R 4 are independently optionally substituted C 1 to C 6 alkyl, or R 3 and R 4 together form an optionally substituted 5 to 12-membered heterocycle which incorporates the nitrogen to which they are attached.
Whilst it is possible for both R 1 and R 2 to be (A), i.e. aryl, it is preferred that one of R 1 and R 2 is (B), i.e. C 3 to C 12 alkyl.
As described herein, C 3 to C 12 alkyl includes saturated and unsaturated, branched and unbranched C 3 to C 12 alkyl. In some preferred embodiments, the alkyl is unsaturated alkyl. In particular, preferably at least one of R 1 and R 2 is unsaturated C 3 to C 12 alkyl, preferably unsaturated C 3 to C 10 alkyl, preferably unsaturated C 3 to C 8 alkyl and most preferably unsaturated C 3 to C 6 alkyl. Thus, preferably at least one of R 1 and R 2 is C 3 to C 12 alkenyl, more preferably C 3 to C 10 alkenyl, more preferably C 3 to C 8 alkenyl and most preferably C 3 to C 6 alkenyl. Indeed, the addition of unsaturation can provide activity comparable to the saturated alkyl.
In such embodiments, preferably there is one carbon-carbon double bond in the alkenyl, for example one carbon-carbon double bond in C 3 to C 10 alkenyl, or one carbon-carbon double bond in C 3 to C 6 alkenyl. Suitably the carbon-carbon double bond is at the end of the alkenyl group, i.e. a terminal carbon-carbon double bond between the C n and C n-1 carbons. C 6 alkenyls are particularly preferred. A particularly preferred alkenyl is C 6 alkenyl, most preferably 5-hexenyl (—CH 2 —(CH 2 ) 3 —CH═CH 2 ).
In embodiments, at least one of R 1 and R 2 is C 3 to C 5 alkyl. Alkyl groups, especially saturated alkyls, on the alpha carbon having between 3 and 5 carbon atoms in combination with one or more of the specified substituents on the aryl are particularly useful in providing antifouling activity whilst also exhibiting desirable solubility in sea water and degradability.
In embodiments at least one of R 1 and R 2 is C 4 alkyl, more preferably n-butyl. A C 4 alkyl group, and in particular n-butyl, on the alpha carbon, in combination with one or more of the specified substituents on the aryl, can provide surprisingly high levels of antifouling activity and is degraded at an appropriate rate.
It is preferred that R 1 is C 3 to C 8 alkyl, preferably C 3 to C 6 alkyl, more preferably C 4 to C 6 alkyl and most preferably C 4 alkyl or C 6 alkyl. Suitably R 2 is (A).
As described herein, one of R 1 and R 2 is (A), i.e. aryl (preferably C 5 to C 15 aryl, more preferably phenyl, as discussed below) and the other is C 3 to C 12 alkyl (preferably C 3 to C 6 alkyl, more preferably n-butyl or 5-hexenyl). The tests conducted by the present inventors demonstrate that desirable levels of antifouling activity are possible with this substitution pattern in conjunction with one or more of the specified substituents on the aryl.
Thus, it is preferred that one of R 1 and R 2 is selected from saturated C 3 to C 5 alkyl and C 3 to C 10 alkenyl. The alkyl (saturated or unsaturated) is optionally substituted, however, it is preferred that it is unsubstituted.
Suitably the aryl of (A) is C 5 to C 15 aryl, preferably C 6 to C 12 aryl, more preferably C 6 to C 10 aryl, and most preferably C 6 aryl. The aryl can be carboaryl or heteroaryl, but carboaryl is preferred. Especially preferred is phenyl.
Preferably R 1 is (B) and R 2 is
wherein each of R A1 , R A2 , R A3 , R A4 and R A5 is independently selected from OH, R S1 OH, OR S2 , R S1 OR S2 , OC(O)H, OC(O)R S2 , R S1 OC(O)H, R S1 OC(O)R S2 , C(O)OH, C(O)OR S2 , R S1 C(O)OH, R S1 C(O)OR S2 , OR S1 OH, OR S1 OR S2 , OR S1 OC(O)H, OR S1 OC(O)R S2 , OR S1 C(O)OH, OR S1 C(O)OR S2 , H and R S2 ,
wherein, if present, each R S1 is independently optionally substituted C 1 to C 5 alkylene, and wherein, if present, each R S2 is independently selected from optionally substituted C 1 to C 5 alkyl, C 2 to C 5 alkenyl and C 1 to C 5 alkylsilyl-C 1 to C 5 alkylene, with the proviso that at least one of R A1 , R A2 , R A3 , R A4 and R A5 is not H or R S2 .
Suitably each R S1 is independently optionally substituted C 1 to C 3 alkylene, preferably optionally substituted C 1 to C 2 alkylene and most preferably methylene. Suitably R S1 is unsubstituted.
Suitably each R S2 is independently selected from optionally substituted C 1 to C 3 alkyl, C 2 to C 3 alkenyl and C 1 to C 3 silyl-C 1 to C 3 alkylene. For the avoidance of doubt, silyl-alkylene referred to herein is an alkylene (e.g. —CH 2 —CH 2 —) substituted with a silyl such as Si(Me) 3 .
Preferably each R S2 is independently selected from optionally substituted C 1 to C 2 alkyl, C 2 to C 3 alkenyl and C 1 alkylsilyl-C 1 to C 3 alkylene. Especially preferred is that each R S2 is independently selected from methyl, CH 2 ═CH— and (Me) 3 S 1 —CH 2 —CH 2 —.
In particularly preferred embodiments each of R A1 , R A2 , R A3 , R A4 and R A5 is independently selected from OH, OMe, C(O)OH, CH 2 OH, CH 2 OAc, OC(O)CH 3 , OCH 2 C(O)OH, OCH 2 C(O)OCH 3 , OCH 2 CH 2 OH, OCH 2 CH 2 OC(O)CH 3 , OCH 2 CH 2 Si(Me) 3 , OC(O)CH═CH 2 and H, with the proviso that at least one of R A1 , R A2 , R A3 , R A4 and R A5 is not H.
In especially preferred embodiments each of R A1 , R A2 , R A3 , R A4 and R A5 is independently selected from OH, OMe, CH 2 OH, OC(O)CH 3 , OCH 2 CH 2 OH, OCH 2 CH 2 Si(Me) 3 , OC(O)CH═CH 2 and H, with the proviso that at least one of R A1 , R A2 , R A3 , R A4 and R A5 is not H.
In even more preferred embodiments each of R A1 , R A2 , R A3 , R A4 and R A5 is independently selected from OH, OMe, OC(O)CH═CH 2 and H, with the proviso that at least one of R A1 , R A2 , R A3 , R A4 and R A5 is not H.
Whilst multiple substituents on the aryl are possible, it is preferred that at least two of R A1 , R A2 , R A3 , R A4 and R A5 are H, more preferably that at least three of R A1 , R A2 , R A3 , R A4 and R A5 are H. Thus, mono and di-substituted aryls (e.g. phenyl) are preferred.
The substituents can be at any of the 1- to 5-positions, i.e. ortho, meta or para substituents. However, the 3-position (meta) is preferred. Thus, suitably R A3 is not H.
Suitably R 3 and R 4 together form an optionally substituted 5 to 10-membered heterocycle, preferably a 5 to 7-membered heterocycle and most preferably a 6-membered heterocycle. It is especially preferred that the heterocycle is piperidine.
In particularly preferred embodiments R 3 and R 4 together form an optionally substituted 6-membered heterocycle which incorporates the nitrogen to which they are attached according to formula (II):
wherein each of R 5 and R 6 are independently selected from hydroxyl, optionally substituted C 1 to C 6 alkyl, optionally substituted phenyl and H. It is preferred that each of R 5 and R 6 are independently selected from hydroxyl, optionally substituted C 1 to C 6 alkyl and H. It is particularly preferred that R 5 and R 6 are H.
In other embodiments, each of R 3 and R 4 is independently selected from optionally substituted C 1 to C 6 alkyl, more preferably C 1 to C 3 alkyl.
Suitably R 3 and R 4 are unsubstituted. It is also preferred that each of R 3 and R 4 is saturated alkyl.
R 3 and R 4 can be the same or different. It is preferred that they are the same.
In embodiments, R 3 and R 4 are both methyl.
Suitably the compound is a compound of formula (III) or formula (IV)
wherein each of R A1 , R A2 , R A3 , R A4 and R A5 is independently selected from OH, R S1 OH, OR S2 , R S1 OR S2 , OC(O)H, OC(O)R S2 , R S1 OC(O)H, R S1 OC(O)R S2 , C(O)OH, C(O)OR S2 , R S1 C(O)OH, R S1 C(O)OR S2 , OR S1 OH, OR S1 OR S2 , OR S1 OC(O)H, OR S1 OC(O)R S2 , OR S1 C(O)OH, OR S1 C(O)OR S2 , H and R S2 ,
wherein, if present, each R S1 is independently optionally substituted C 1 to C 5 alkylene, and wherein, if present, each R S2 is independently selected from optionally substituted C 1 to C 5 alkyl, C 2 to C 5 alkenyl and C 1 to C 5 alkylsilyl-C 1 to C 5 alkylene, with the proviso that at least one of R A1 , R A2 , R A3 , R A4 and R A5 is not H or R S2 .
In embodiments, if present, each R S1 is independently optionally substituted C 1 to C 3 alkylene, and wherein, if present, each R S2 is independently selected from optionally substituted C 1 to C 3 alkyl and C 2 to C 3 alkenyl and C 1 to C 3 alkylsilyl-C 1 to C 3 alkylene.
Suitably the compound is selected from compounds 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 16.10, 16.11, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8 and 17.9.
Preferably the compound is selected from compounds 15.3, 15.4, 15.5, 16.11, 17.1, 17.3, 17.4, 17.6, 17.8, 15.1, 16.1, 16.2, 16.4, 16.5, 16.6, 16.10 and 17.5. More preferably the compound is selected from compounds 15.3, 15.4, 15.5, 16.11, 17.1, 17.3, 17.4, 17.6 and 17.8.
In preferred embodiments these compounds (and polymers described herein) are incorporated into coatings in such a way that they are protected from premature degradation but released at a predetermined target time, after which they are degraded by bacteria in the environment. The skilled reader will be aware that the state of the art in polymer/coating chemistry provides several ways to deliver molecules in this way, depending on the requirements of the application.
In preferred embodiments, these compounds (and polymers described herein) are incorporated into conventional antifouling coatings as antifouling agents for the prevention of marine growth. For example, the compounds can be blended into existing acrylate paints and are therefore practical alternatives to the current coating options. In particular, these compounds may be offered as environmentally safer alternatives to reduce use of existing booster biocides in existing coating formulations, as a replacement for poorly-degradable existing booster biocides, and/or augment existing coating formulations to improve performance. In this connection, a number of the compounds are oils and suitably compatible for incorporation into coatings, for example silicon-based foul-release coatings. In embodiments, this compatibility may impart the coatings with increased effectiveness such that the coated substrate benefits from additional protection.
Furthermore, these compounds (and polymers described herein) may be applied in such way to reduce or replace copper/metal present in conventional antifouling coatings, thereby reducing the environmental impact of antifouling coatings.
Suitably, the compounds (and polymers described herein) may be used in the removal of marine organisms in seawater treatment processes such as in ballast water treatment and for control of marine growth in cooling water and desalination processes. The compounds (and polymers described herein) are particularly suited to processes where rapid degradation/removal of the active agent is necessary to prevent environmental contamination and for compliance purposes.
Polymers
The present invention also pertains generally to a class of polymers referred to herein as “antifouling polymers”, which polymers comprise an antifouling amide compound, for example as a pendant group.
In a further aspect, the present invention provides a polymer comprising at least one repeating unit formed from an antifouling compound according to the first aspect.
In embodiments, the compound is incorporated into the polymer via free radical polymerisation or polymerisation of silyl-containing groups. Thus, preferably the polymer is selected from a polymer formed from one or more monomers having an unsaturated carbon-carbon bond, for example a vinyl or (meth)acrylate monomer; and a silicone polymer.
Suitably the polymer is a (meth)acrylate polymer. Suitably the polymer comprises repeating units derived from one or more of methylmethacrylate (MMA), hydroxyethyl acrylate (HEA) and vinyl pyrrolidinone (VP). Preferably the polymer is a copolymer.
In embodiments, the polymer comprises a pendant group according to formula X
wherein
R 1 is optionally substituted C 3 to C 12 alkyl
each of R 3 and R 4 are independently optionally substituted C 1 to C 6 alkyl, or R 3 and R 4 together form an optionally substituted 5 to 12-membered heterocycle which incorporates the nitrogen to which they are attached,
each R AX is independently selected from the options for any one of R A1 to R A5 described herein,
n is an integer in the range 0 to 4,
and wherein
R L is a linker group.
The optional and preferred features in respect of R 1 , R 3 and R 4 are as described above for the first aspect.
Preferably R L is a 1 to 5 atom chain, preferably a 1 to 3 atom chain, more preferably a 2 atom chain. Suitably the atoms of the chain are selected from C and O. Preferably the linker group comprises one or more of —O—, —C(O)— and —CH 2 — units. Particularly preferred is a linker group having the structure: {[—O—] a [—C(O)] b [—CH 2 —] c } d , wherein each of a, b, c and d are independently selected from an integer in the range 0 to 4, more preferably 0 to 2.
In embodiments, R L is selected from —O—, R L1 O, OR L2 , R L1 OR L2 , OC(O), OC(O)R L2 , R L1 OC(O), R L1 OC(O)R L2 , C(O)O, C(O)OR L2 , R L1 C(O)OR L2 , OR L1 O, OR L1 OR L2 , OR L1 OC(O), OR L1 OC(O)R L2 , OR L1 C(O)O and OR L1 C(O)OR L2
wherein, if present, each R L1 is independently optionally substituted C 1 to C 5 alkylene, and wherein, if present, each R L2 is independently optionally substituted C 1 to C 5 alkylene.
Thus, linker group R L can correspond to, e.g. be a radical formed from, the substituent R A1 , R A2 , etc of the corresponding “free” compound.
Preferably R L is —OC(O)—.
Suitably n is 0 or 1, preferably n is 0 (i.e. the aryl has no further substituents).
Suitably the pendant group is releasable from the polymer in the marine environment. In particular, it is preferred that the pendant group is releasable from the polymer by hydrolysis. For example, this permits the pendant (bioactive) group to be released in an aqueous environment.
In a further aspect, the present invention provides a polymer according to formula (XI):
wherein Pol is the polymer backbone, and wherein each of R 1 , R 3 , R 4 , R AX , n and R L is as defined in respect of formula (X).
Preferably the Tg of the polymer is higher than room temperature.
Preferably the molecular weight of the polymer, as measured by GPC, is at least 5 KDa, preferably at least 10 KDa.
Suitably the polymer is a slow release or sustained release polymer whereby an antifouling compound, preferably an antifouling compound of the first aspect, is released from the polymer in use.
In a further aspect, the present invention provides use of a compound of formula (I) or a salt thereof in a method of making a polymer.
In a further aspect, the present invention provides a polymer made by copolymerising a compound of formula (I) or a salt thereof with a comonomer. Preferably the comonomer is selected from a (meth)acrylate and vinyl monomer.
In a further aspect, the present invention provides use of a compound, polymer or coating composition as described herein in a method of reducing or preventing fouling.
Suitably the method of reducing or preventing fouling is a method of reducing or preventing biofilm formation by one or more of bacteria, fungi, algae and protozoans.
In a further aspect, the present invention provides a method of preventing or reducing fouling of a substrate, wherein the method comprises the step of applying a compound, polymer or coating as described herein to the substrate.
Suitably the antifouling amide compound or polymer is applied at in an amount and at a concentration effective to prevent or reduce fouling. Preferably the antifouling amide compound or polymer is provided at a standard concentration.
In a further aspect, the present invention provides a coating composition comprising a compound or a polymer as described herein.
In a further aspect, the present invention provides an antifouling composition comprising an antifouling amide compound or polymer as described herein.
In a further aspect, the present invention provides a coating composition comprising an antifouling amide compound or a polymer as described herein. Suitably the coating composition comprises conventional additives, for example a binder. Suitably the coating composition is a paint composition. For example, the composition can include an acrylate resin. Suitably the coating composition is a self-polishing paint, preferably an acrylic self polishing paint, or a silicone coating.
In a further aspect, the present invention provides a coating comprising an antifouling amide compound as described herein.
In a further aspect, the present invention provides a substrate having a coating applied thereto, wherein the coating comprises an antifouling amide compound or polymer as described herein. For example, the substrate may be a vessel, for example a boat.
In a further aspect, the present invention provides a bacteriostatic composition comprising an antifouling amide compound or polymer as described herein.
In a further aspect, the present invention provides a bacteriocidal composition comprising an antifouling amide compound or polymer as described herein.
In a further aspect, the present invention provides a biocidal composition comprising an antifouling amide compound or polymer as described herein.
In a further aspect, the present invention provides a biostatic composition comprising an antifouling amide compound or polymer as described herein.
In a further aspect, the present invention provides an antifoulant composition comprising an antifouling amide compound or polymer as described herein.
Any one or more of the optional and preferred features of any of the aspects may apply, singly or in combination, to any one of the other aspects.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows average percentage settlement of barnacles in wells coated with polymers containing repeating units derived from a compound (16.11) of the present invention. Settlement on the control coating was similar to that for uncoated polystyrene. Whereas when increased amounts of P(MMA-co-16.11-co-VP) resulted in decline in barnacle settlement, with no settlement for test treatments >40 μl.
DETAILED DESCRIPTION OF THE INVENTION
Chemical Terms
The term “saturated,” as used herein, pertains to compounds and/or groups which do not have any carbon-carbon double bonds or carbon-carbon triple bonds.
The term “unsaturated,” as used herein, pertains to compounds and/or groups which have at least one carbon-carbon double bond or carbon-carbon triple bond. Compounds and/or groups may be partially unsaturated or fully unsaturated.
The term “carbo,” “carbyl,” “hydrocarbo,” and “hydrocarbyl,” as used herein, pertain to compounds and/or groups which have only carbon and hydrogen atoms.
The term “hetero,” as used herein, pertains to compounds and/or groups which have at least one heteroatom, for example, multivalent heteroatoms (which are also suitable as ring heteroatoms) such as boron, silicon, nitrogen, phosphorus, oxygen, sulfur, and selenium (more commonly nitrogen, oxygen, and sulfur) and monovalent heteroatoms, such as fluorine, chlorine, bromine, and iodine.
The phrase “optionally substituted,” as used herein, pertains to a parent group which may be unsubstituted or which may be substituted.
Unless otherwise specified, the term “substituted,” as used herein, pertains to a parent group which bears one or more substitutents. The term “substituent” is used herein in the conventional sense and refers to a chemical moiety which is covalently attached to, or if appropriate, fused to, a parent group. A wide variety of substituents are well known, and methods for their formation and introduction into a variety of parent groups are also well known.
Alkyl: The term “alkyl,” as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, and which may be saturated or unsaturated (e.g., partially unsaturated, fully unsaturated). Thus, the term “alkyl” includes the sub-classes alkenyl, alkynyl, cycloalkyl, cycloalkyenyl, cylcoalkynyl, etc., discussed below.
In the context of alkyl groups, the prefixes (e.g., C 1 to C 4 , C 1 to C 5 , etc.) denote the number of carbon atoms, or range of number of carbon atoms. For example, the term “C 1 to C 4 alkyl,” as used herein, pertains to an alkyl group having from 1 to 4 carbon atoms. Examples of groups of alkyl groups include C 1 to C 4 alkyl (“lower alkyl”), and C 2 to C 6 alkyl. Note that the first prefix may vary according to other limitations; for example, for unsaturated alkyl groups, the first prefix must be at least 2; for cyclic and branched alkyl groups, the first prefix must be at least 3; etc.
Examples of (unsubstituted) saturated alkyl groups include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ), butyl (C 4 ), pentyl (C 5 ) and hexyl (C 6 ).
Examples of (unsubstituted) saturated linear alkyl groups include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), n-butyl (C 4 ), n-pentyl (amyl) (C 5 ) and n-hexyl (C 6 ).
Examples of (unsubstituted) saturated branched alkyl groups include iso-propyl (C 3 ), iso-butyl (C 4 ), sec-butyl (C 4 ), tert-butyl (C 4 ), iso-pentyl (C 5 ), and neo-pentyl (C 5 ).
Alkenyl: The term “alkenyl,” as used herein, pertains to an alkyl group having one or more carbon-carbon double bonds. Examples of groups of alkenyl groups include C 2-4 alkenyl, C 2-7 alkenyl, C 2-20 alkenyl.
Examples of (unsubstituted) unsaturated alkenyl groups include, but are not limited to, ethenyl (vinyl, —CH═CH 2 ), 1-propenyl (—CH═CH—CH 3 ), 2-propenyl (allyl, —CH—CH═CH 2 ), isopropenyl (1-methylvinyl, —C(CH 3 )═CH 2 ), butenyl (C 4 ), pentenyl (C 5 ), and hexenyl (C 6 ).
Hydroxy-C 1 -C 6 alkyl: The term “hydroxy-C 1 -C 6 alkyl,” as used herein, pertains to a C 1 -C 6 alkyl group in which at least one hydrogen atom (e.g., 1, 2, 3) has been replaced with a hydroxy group. Examples of such groups include, but are not limited to, —CH 2 OH, —CH 2 CH 2 OH, and —CH(OH)CH 2 OH.
Hydrogen: —H. Note that if the substituent at a particular position is hydrogen, it may be convenient to refer to the compound or group as being “unsubstituted” at that position.
Aryl: The term “aryl,” as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified). Preferably, each ring has from 5 to 7 ring atoms.
In this context, the prefixes (e.g., C 3-20 , C 5-7 , C 5-6 , etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term “C 5-6 aryl,” as used herein, pertains to an aryl group having 5 or 6 ring atoms. Examples of groups of aryl groups include C 3-20 aryl, C 5-20 aryl, C 5-15 aryl, C 5-12 aryl, C 5-10 aryl, C 5-7 aryl, C 5-6 aryl, C 5 aryl, and C 6 aryl.
The ring atoms may be all carbon atoms, as in “carboaryl groups.” Examples of carboaryl groups include C 3-20 carboaryl, C 5-20 carboaryl, C 5-15 carboaryl, C 5-12 carboaryl, C 5-10 carboaryl, C 5-7 carboaryl, C 5-6 carboaryl, C 5 carboaryl, and C 6 carboaryl.
Examples of carboaryl groups include, but are not limited to, those derived from benzene (i.e., phenyl) (C 6 ), naphthalene (C 10 ), azulene (C 10 ), anthracene (C 14 ), phenanthrene (C 14 ), naphthacene (C 18 ), and pyrene (C 16 ).
Examples of aryl groups which comprise fused rings, at least one of which is an aromatic ring, include, but are not limited to, groups derived from indane (e.g., 2,3-dihydro-1H-indene) (C 9 ), indene (C 9 ), isoindene (C 9 ), tetraline (1,2,3,4-tetrahydronaphthalene (C 10 ), acenaphthene (C 12 ), fluorene (C 13 ), phenalene (C 13 ), acephenanthrene (C 15 ), and aceanthrene (C 16 ).
Alternatively, the ring atoms may include one or more heteroatoms, as in “heteroaryl groups.” Examples of heteroaryl groups include C 3-20 heteroaryl, C 5-20 heteroaryl, C 5-15 heteroaryl, C 5-12 heteroaryl, C 5-10 heteroaryl, C 5-7 heteroaryl, C 5-6 heteroaryl, C 5 heteroaryl, and C 6 heteroaryl.
Halo (or halogen): —F, —Cl, —Br, and —I.
Hydroxy: —OH.
Silyl: —SiR 3 , where R is a silyl substituent, for example, —H, a C 1-7 alkyl group, a C 3-20 heterocyclylgroup, or a C 5-20 aryl group, preferably —H, a C 1-7 alkyl group, or a C 5-20 aryl group. Examples of silyl groups include, but are not limited to, —SiH 3 , —SiH 2 (CH 3 ), —SiH(CH 3 ) 2 , —Si(CH 3 ) 3 , —Si(Et) 3 , —Si(iPr) 3 , —Si(tBu)(CH 3 ) 2 , and —Si(tBu) 3 .
Oxysilyl: —Si(OR) 3 , where R is an oxysilyl substituent, for example, —H, a C 1-7 alkyl group, a C 3-20 heterocyclylgroup, or a C 5-20 aryl group, preferably —H, a C 1-7 alkyl group, or a C 5-20 aryl group. Examples of oxysilyl groups include, but are not limited to, —Si(OH) 3 , —Si(OMe) 3 , —Si(OEt) 3 , and —Si(OtBu) 3 .
Siloxy (silyl ether): —OSiR 3 , where SiR 3 is a silyl group, as discussed above.
Oxysiloxy: —OSi(OR) 3 , wherein OSi(OR) 3 is an oxysilyl group, as discussed above.
Silyl-alkylene: -alkylene-SiR 3 , where R is a silyl substituent as discussed above. For example, —CH 2 —CH 2 —Si(Me) 3 .
Includes Other Forms
Unless otherwise specified, included in the above are the well known ionic, salt, solvate, and protected forms of these substituents. For example, a reference to carboxylic acid (—COOH) also includes the anionic (carboxylate) form (—COO − ), a salt or solvate thereof, as well as conventional protected forms. Similarly, a reference to an amino group includes the protonated form (—N + HR 1 R 2 ), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group. Similarly, a reference to a hydroxyl group also includes the anionic form (—O − ), a salt or solvate thereof, as well as conventional protected forms.
Salts
It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound, for example, an environmentally-acceptable salt.
Examples of suitable salts are discussed in Berge et al., 1977, “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19.
For example, if the compound is anionic, or has a functional group which may be anionic (e.g., —COOH may be —COO − ), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al +3 . Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH 3 ) 4 + .
If the compound is cationic, or has a functional group which may be cationic (e.g., —NH 2 may be —NH 3 + ), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
Unless otherwise specified, a reference to a particular compound also includes salt forms thereof.
Solvates
It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the active compound. The term “solvate” is used herein in the conventional sense to refer to a complex of solute (e.g., active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
Unless otherwise specified, a reference to a particular compound also include solvated forms thereof.
Certain Preferred Substituents
In one preferred embodiment, the substituent(s), often referred to herein as R, are independently selected from: halo; hydroxy; ether (e.g., C 1-7 alkoxy); formyl; acyl (e.g., C 1-7 alkylacyl, C 5-20 arylacyl); acylhalide; carboxy; ester; acyloxy; amido; acylamido; thioamido; tetrazolyl; amino; nitro; nitroso; azido; cyano; isocyano; cyanato; isocyanato; thiocyano; isothiocyano; sulfhydryl; thioether (e.g., C 1-7 alkylthio); sulfonic acid; sulfonate; sulfone; sulfonyloxy; sulfinyloxy; sulfamino; sulfonamino; sulfinamino; sulfamyl; sulfonamido; C 1-7 alkyl (including, e.g., unsubstituted C 1-7 haloalkyl, C 1-7 hydroxyalkyl, C 1-7 carboxyalkyl, C 1-7 aminoalkyl, C 5-20 aryl-C 1-7 alkyl); C 3-20 heterocyclyl; or C 5-20 aryl (including, e.g., C 5-20 carboaryl, C 5-20 heteroaryl, C 1-7 alkyl-C 5-20 aryl and C 5-20 haloaryl)).
In one preferred embodiment, the substituent(s), often referred to herein as R, are independently selected from:
—F, —Cl, —Br, and —I;
—OH;
—OMe, —OEt, —O(tBu), and —OCH 2 Ph;
—SH;
—SMe, —SEt, —S(tBu), and —SCH 2 Ph;
—C(═O)H;
—C(═O)Me, —C(═O)Et, —C(═O)(tBu), and —C(═O)Ph;
—C(═O)OH;
—C(═O)OMe, —C(═O)OEt, and —C(═O)O(tBu);
—C(═O)NH 2 , —C(═O)NHMe, —C(═O)NMe 2 , and —C(═O)NHEt;
—NHC(═O)Me, —NHC(═O)Et, —NHC(═O)Ph, succinimidyl, and maleimidyl;
—NH 2 , —NHMe, —NHEt, —NH(iPr), —NH(nPr), —NMe 2 , —NEt 2 , —N(iPr) 2 , —N(nPr) 2 , —N(nBu) 2 , and —N(tBu) 2 ;
—CN;
—NO 2 ;
-Me, -Et, -nPr, -iPr, -nBu, -tBu;
—CF 3 , —CHF 2 , —CH 2 F, —CBr 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , and —CH 2 CF 3 ;
—OCF 3 , —OCHF 2 , —OCH 2 F, —OCCl 3 , —OCBr 3 , —OCH 2 CH 2 F, —OCH 2 CHF 2 , and —OCH 2 CF 3 ;
—CH 2 OH, —CH 2 CH 2 OH, and —CH(OH)CH 2 OH;
—CH 2 NH 2 , —CH 2 CH 2 NH 2 , and —CH 2 CH 2 NMe 2 ; and,
optionally substituted phenyl.
In one preferred embodiment, the substituent(s), often referred to herein as R, are independently selected from: —F, —Cl, —Br, —I, —OH, —OMe, —OEt, —SH, —SMe, —SEt, —C(═O)Me, —C(═O)OH, —C(═O)OMe, —CONH 2 , —CONHMe, —NH 2 , —NMe 2 , —NEt 2 , —N(nPr) 2 , —N(iPr) 2 , —CN, —NO 2 , -Me, -Et, —CF 3 , —OCF 3 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , and -Ph.
In one preferred embodiment, the substituent(s), often referred to herein as R, are independently selected from: hydroxy; ether (e.g., C 1-7 alkoxy); ester; amido; amino; and, C 1-7 alkyl (including, e.g., unsubstituted C 1-7 haloalkyl, C 1-7 hydroxyalkyl, C 1-7 carboxyalkyl, C 1-7 aminoalkyl, C 5-20 aryl-C 1-7 alkyl).
In one preferred embodiment, the substituent(s), often referred to herein as R, are independently selected from:
—OH;
—OMe, —OEt, —O(tBu), and —OCH 2 Ph;
—C(═O)OMe, —C(═O)OEt, and —C(═O)O(tBu);
—C(═O)NH 2 , —C(═O)NHMe, —C(═O)NMe 2 , and —C(═O)NHEt;
—NH 2 , —NHMe, —NHEt, —NH(iPr), —NH(nPr), —NMe 2 , —NEt 2 , —N(iPr) 2 , —N(nPr) 2 , —N(nBu) 2 , and —N(tBu) 2 ;
-Me, -Et, -nPr, -iPr, -nBu, -tBu;
—CF 3 , —CHF 2 , —CH 2 F, —CBr 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , and —CH 2 CF 3 ;
—CH 2 OH, —CH 2 CH 2 OH, and —CH(OH)CH 2 OH; and,
—CH 2 NH 2 , —CH 2 CH 2 NH 2 , and —CH 2 CH 2 NMe 2 .
Other Terms
As used herein, the term “fouling” refers to the attachment and growth of microorganisms and small organisms to a substrate exposed to, or immersed in, a liquid medium, for example an aqueous medium, as well as to an increase in number of the microorganisms and/or small organisms in a container of the liquid medium.
Accordingly “foulers” or “microfoulers” are used interchangeably and refer to the organisms that foul a substrate. Fouling may occur in structures exposed to or immersed in fresh water as well as in sea water. In particular, the term may be used to refer to a solid medium or substrate exposed to, or immersed in sea water.
Accordingly, the term “antifouling” refers to the effect of preventing, reducing and/or eliminating fouling. Antifouling agents or compounds are also called “antifoulants”.
An antifoulant compound is usually applied at a standard concentration which is the concentration that is effective for its purpose. Accordingly, a concentration less than or below the standard concentration is one where the antifoulant is not effective when it is used alone.
The term “substrate” as used herein refers to a solid medium such as surfaces of structures or vessels exposed to, or immersed in a liquid medium. The liquid medium may be fresh water or seawater and may be a body of water in a manmade container such as a bottle, pool or tank, or the liquid may be uncontained by any manmade container such as seawater in the open sea.
A “structure” as used herein refers to natural geological or manmade structures such as piers or oil rigs and the term “vessel” refers to manmade vehicles used in water such as boats and ships.
The “microorganisms” referred to herein include viruses, bacteria, fungi, algae and protozoans. “Small organisms” referred to herein can include organisms that commonly foul substrates exposed to, or immersed in, fresh water or seawater such as crustaceans, bryozoans and molluscs, particularly those that adhere to a substrate. Examples of such small organisms include barnacles and mussels and their larvae. Small organisms can also be called small animals. The term “organism” referred to herein is to be understood accordingly and includes microorganisms and small organisms.
The term “marine organism” as used herein refers to organisms whose natural habitat is sea water. The terms “marine microorganism” and “marine small organism” are to be understood accordingly.
Further, the term “microfouling” refers to fouling by microorganisMs and the term “macrofouling” refers to fouling by organisms larger than microorganisms such as small organisms defined above.
The terms “biocide” or “biocidal compound” refer to compounds that inhibit the growth of microorganisms and small organisms by killing them. The terms “biostatic” or “biostatic compound” refer to compounds that inhibit the growth of microorganisms or small organisms by preventing them from reproducing and not necessarily by killing them.
The term “degradation” as used herein refers to the chemical breakdown or modification of a compound in water, preferably sea water.
The term “growth” as used herein refers to both the increase in number of microorganisms and small organisms, as well to the development of a small organism from juvenile to adult stages. Accordingly, biocides and biostatics can be applied as a treatment to a body of liquid or to a substrate surface to inhibit the growth of microorganisms and small organisms. As such, biocides and biostatics can be antifoulants and can prevent, reduce or eliminate biofilm formation.
Accordingly, the terms “bacteriocidal” and “bacteriostatic” refer to effects of compounds on bacteria.
The term “bioactivity” as used herein refers to the effect of a given agent or compound, such as a biocidal or biostatic compound, on a living organism, particularly on microorganisms or small organisms.
A “biofilm” is a complex aggregation of microorganisms, usually bacteria or fungi, marked by the excretion of a protective and adhesive matrix. Biofilms are also often characterized by surface attachment, structural heterogeneity, genetic diversity, complex community interactions, and an extracellular matrix of polymeric substances. Biofilms may also be more resistant to antibiotics compared to unaggregated bacteria due to the presence of the matrix.
The term “pharmaceutical” as it relates to a use, agent, compound or composition, refers to the medical treatment of a disease or disorder in humans or animals. Accordingly, a pharmaceutical compound is a compound used for the medical treatment of a disease or disorder in humans or animals.
As used herein, the term “standard concentration” as it pertains to an anti-fouling agent or compound, refers to the concentration at which the agent or compound is effective against microorganisms or small organisms at which it are directed when that agent or compound is used alone. Accordingly, the term “effective” means having a desired effect and the term “below standard concentration” refers to the level at which the agent or compound is not effective when used alone.
Examples Part 1—Compounds
Synthesis of Compounds
Several methods for the chemical synthesis of compounds of the present invention are described herein. These and/or other well known methods may be modified and/or adapted in known ways in order to facilitate the synthesis of additional compounds within the scope of the present invention.
The amides may be prepared according to the following general methodologies
Method A
The synthesis of alkoxylated substituted compounds such as the 15-series compounds is based on a two step protocol in which commercially available phenylacetic acid derivatives undergo DCC mediated amide formation with piperidine (Scheme 1). Subsequent alkylation of the resultant 2-arylacetamides then proceeds upon treatment with LDA and bromobutane under standard conditions.
The same methodology was also adopted for the dialkyl amides. Thus, the synthesis of the methoxy- and hydroxyaryl congeners of the unsubstituted parent compound is based on a three or four step protocol in which commercially available phenylacetic acid derivatives are first converted to either the piperidine or dimethyl amides via the corresponding acid chlorides or benzotriazolyl esters. Subsequent LDA promoted alkylation with either 1-bromobutane or 6-bromo-1-hexene affords the desired methoxyaryl compounds in low to good yields as shown in Scheme 1.1.
Demethylation of selected methoxyaryl targets was performed using boron tribromide in dichloromethane as outlined in Scheme 1.2. Treatment of 15.1, 15.2, 15.3 and 17.2 under these conditions all proceeded smoothly to afford the corresponding hydroxyaryl derivatives in good yield and in high purity.
Method B
The synthesis of hydroxymethylated compounds and acetylated analogues were accessed from the readily synthesized amides following standard protection and alkylation protocols (Scheme 2). Acetylation of the p-derivative afforded compounds in good isolated yield.
More specifically, in order to gain access the hydroxymethylated congeners of 12.1 and their acetate derivatives, it was necessary to use different synthetic routes based on the commercial availability of the phenylacetic acid derivatives. Whilst p-hydroxymethylphenylacetic acid is commercially available and was able to be used directly in a coupling reaction with piperidine, the corresponding o-hydroxymethylphenylacetic acid was not commercially available. Hence the requisite amide was accessed by nucleophilic ring opening of commercially available isochromanone with piperidine in moderate isolated yield (Scheme 2.1 below). With the o- and p-hydroxymethylamides in hand, treatment with tert-butyldimethylsilyl (TBS) chloride in the presence of imidazole afforded the corresponding TBS ethers in moderate yield and these underwent alkylation to furnish 16.1 and 16.2 in their protected form. Treatment of the TBS ethers with TBAF in THF resulted in removal of the TBS protecting group to afford 16.1 and 16.2 in near quantitative yields. Compound 16.3 was then isolated following treatment of 16.2 with acetic anhydride in pyridine. This is shown in Scheme 2.1 below, being a modified version of Scheme 2.
The procedure to convert 16.2 directly to 17.9 was a two step process whereby Swern oxidation to the corresponding aldehyde was performed prior to treatment with Oxone®. The desired acid was obtained in moderate overall yield (Scheme 3).
The remaining targeted congeners of 12.1 could all be accessed by modification of 16.5 by treatment with an appropriate electrophile. In all cases the target compounds were obtained in moderate to excellent yield. A summary of these reactions are shown in Scheme 4.
Using the above methodologies, the compounds based on the following structure were synthesised, and are preferred embodiments (reference compound excluded):
(III)
R A1
R A2
R A3
R A4
R A5
Compound
H
H
H
H
H
12.1
(reference)
H
H
OMe
H
H
15.1
H
OMe
H
H
H
15.2
OMe
H
H
H
H
15.3
H
OMe
H
OMe
H
15.4
H
OMe
H
H
OMe
15.5
H
OMe
OMe
H
H
15.6
OMe
H
OMe
H
H
15.7
CH 2 OH
H
H
H
H
16.1
H
H
CH 2 OH
H
H
16.2
H
H
CH 2 OAc
H
H
16.3
H
H
OH
H
H
16.5
H
OH
H
H
H
17.5
OH
H
H
H
H
17.4
Additionally, the following compounds were synthesised, and are preferred embodiments.
Compound
R A1
R A2
R A3
R A4
R A5
No.
H
H
HOC(O)—
H
H
17.9
CH 2 OH
H
H
H
H
16.1
H
H
CH 2 OH
H
H
16.2
H
H
CH 2 OAc
H
H
16.3
H
H
CH 3 C(O)O—
H
H
16.4
H
H
HOC(O)CH 2 O—
H
H
16.9
H
H
CH 3 OC(O)CH 2 O—
H
H
16.7
H
H
HOCH 2 CH 2 O—
H
H
16.6
H
H
CH 3 C(O)OCH 2 CH 2 O—
H
H
16.8
H
H
(CH 3 ) 3 SiCH 2 CH 2 O—
H
H
16.10
H
H
CH 2 CHC(O)O—
H
H
16.11
Additionally, the compounds of the following structure were synthesised, and are preferred embodiments
(IV)
Compound
R A1
R A2
R A3
R A4
R A5
No.
H
H
OCH 3
H
H
17.1
H
H
OH
H
H
17.6
Additionally, the compounds of the following structure were synthesised, and are preferred embodiments
(V)
Compound
R A1
R A2
R A3
R A4
R A5
No.
H
H
OCH 3
H
H
17.2
H
H
OH
H
H
17.7
Additionally, the compounds of the following structure were synthesised, and are preferred embodiments
(VI)
Compound
R A1
R A2
R A3
R A4
R A5
No.
H
H
OCH 3
H
H
17.3
H
H
OH
H
H
17.8
These compounds were tested for bioactivity against barnacles.
Synthesis Methods and Data for Selected Amide Derivatives
Characterisation
Proton ( 1 H) and carbon ( 13 C) NMR spectra were recorded on a Bruker NMR spectrometer operating at 400 MHz for 1 H and 75.4 MHz for 13 C. Deuterochloroform (CDCl 3 ) was used as the solvent unless otherwise indicated. Chemical shifts (d) are reported as the shift in parts per million (ppm) from tetramethylsilane (TMS, 0.00 ppm). NMR spectra recorded in CDCl 3 were referenced to the residual chloroform singlet (7.26 ppm) for 1 H, and the central peak of the CDCl 3 triplet (77.00 ppm) for 13 C. 1 H NMR spectroscopic data are reported as follows: chemical shift (δ), multiplicity (s: singlet, d: doublet, t: triplet, q: quartet, qt: quintet, m: multiplet, dd; doublet of doublets, etc., br: broad), coupling constant (J Hz,) and relative integral (number of protons). 13 C spectroscopic data are reported as chemical shift (δ) and assignment where possible. Infrared spectra were recorded on a Bio-rad Excalibur Series TFS 3000MX FTIR. Samples were run as thin liquid films on NaCl plates. IR spectral data is reported as follows: frequency (ν max cm −1 ), strength (vs: very strong, s: strong, m: medium, w: weak). High resolution El mass spectra were recorded on a Thermo Finnigan MAT XP95 mass spectrometer. Analytical thin layer chromatography (tlc) was conducted on aluminium sheets coated with silica gel F 254 (Merck). The chromatograms were analysed at a wavelength of 254 nm (where appropriate) and/or developed using an acidic solution (5% H 2 SO 4 ) of potassium permanganate in water followed by heating. All solvents used were of AR grade and purified by literature procedures where appropriate (Armarego, 2003).
General Procedure—DCC Mediated Amide Bond Formation
To a cooled (0° C.) stirred solution of phenylacetic acid derivative (1 equiv.) in DMF (1.2 mL/mmol) was added DCC (1.1 equiv.) and HOBt (1.1 equiv.). The resulting mixture was allowed to stir for 1 hour, by which time a heavy colourless precipitate was evident. Piperidine (1.1 equiv.) was added to the reaction mixture and stirring was continued for a further two hours, after which time the reaction mixture was filtered. The mother liquor was taken up in EtOAc and washed successively with saturated NaHCO 3 and water (×3, 2.4 mL/mmol). The organic layer was dried (MgSO 4 ) and concentrated in vacuo to afford the crude amides, which were purified by flash column chromatography using the solvent systems specified.
General Procedure—Amide Bond Formation Via Acid Chlorides
To a cooled (0° C.) stirred solution of methoxyphenylacetic acid in DCM (0.4 mL mmol −1 ) was added thionyl chloride (0.4 mL mmol −1 ). The resulting mixture was allowed to warm to room temperature and was heated at 50° C. for 2 hours after which time the reaction mixture was cooled to room temperature and carefully poured onto ice. The organic layer was dried (MgSO 4 ) and concentrated in vacuo to afford the desired acid chloride which was used without further purification.
For piperidine amides, the appropriate amount of acid chloride (1 mol. equiv.) was dissolved in an equal amount of dry CH 2 Cl 2 and added slowly to a cooled (0° C.) solution of piperidine (2 mol. equiv.) in CH 2 Cl 2 (1 mL mmol −1 ). The resulting mixture was allowed to warm to room temperature and stirred for a further two hours. The crude reaction mixture was washed with water and the organic layer dried (MgSO 4 ) and concentrated in vacuo to afford the desired amide. No further purification was necessary.
For dimethyl amides, the appropriate amount of acid chloride was slowly added to cooled (0° C.) 40% solution of dimethylamine in water (10 mol. equiv.) and stirred for 2 hours after warming to room temperature. CH 2 Cl 2 was added to the reaction mixture and the organic layer was washed with water, dried (MgSO 4 ) and concentrated in vacuo to afford the desired amide.
General Procedure—α-Alkylation
To a cooled (−78° C.) stirred solution of freshly distilled diisopropylamide (1 equiv.) in dry THF (2 mL/mmol) was added n-butyllithium in hexanes (1 equiv). The resulting reaction mixture became pale yellow and was stirred for 10-15 minutes at −78° C. prior to the careful addition of the desired amide (0.95 equiv.). The resulting mixture was stirred for 1 hour at which point bromobutane (1 equiv.) was added. The resulting mixture was allowed to warm to room temperature over a number of hours (at least 3) and continued stirring for a further 13 hours (16 hours in total). The reaction was quenched by the careful dropwise addition of water to the reaction mixture. Following this, water was added to the reaction mixture and the aqueous phase removed. The organic layer was washed with water followed by brine, dried (MgSO 4 ) and concentrated under reduced pressure. Purification was carried out by flash column chromatography using the solvent systems specified.
Compound 15.1
2-(4-methoxy)phenyl-1-(piperidin-1-yl)ethanone
The title compound was prepared from 4-methoxyphenylacetic acid (1.0 g, 6.1 mmol) following the general procedure for amide bond formation. The product was isolated as a colourless oil (1.0 g, 65%) following purification by flash column chromatography (EtOAc, Rf=0.5). 1 H NMR (400 MHz, CDCl 3 ) 1.35 (m, 2H); 1.49 (m, 2H); 1.57 (m, 2H); 3.35 (m, 2H); 3.55 (m, 2H); 3.64 (s, 2H); 3.77 (s, 3H); 6.85 (d, J=8.4 Hz, 2H); 7.16 (d, 2 J=8.4 Hz 2H). 13 C NMR (75 MHz, CDCl 3 ) δ24.47, 25.52, 26.25, 40.26, 42.90, 47.25, 55.28, 114.08, 127.47, 129.61, 158.27, 169.60. HRMS (ESI+1 ion) m/z calcd for C 14 H 20 NO 2 234.1489. found 234.1496.
2-(4-methoxy)phenyl-(1-piperidin-1-yl)hexanone
The title compound was prepared following the general procedure outline for alkylation from 2-(4-methyoxy)phenyl-1-(piperidin-1-yl)ethanone (740 mg, 3.41 mmol). The title compound was isolated as a pale yellow oil (160 mg, 16%) following purification by flash column chromatography (20% EtOAc in hexane, Rf=0.6). 1 H NMR (400 MHz, CDCl 3 ) δ 0.83 (t, J=7 Hz, 3H); 1.03 (m, 1H); 1.14 (m, 1H); 1.2-1.6 (multiple signals, 8H); 1.68 (m, 1H); 2.05 (m, 1H); 3.31-3.45 (2×m, 3H); 3.64 (m, 2H); 3.78 (s, 3H); 6.83 (d, J=8.9 Hz, 2H); 7.18 (d, J=8.9 Hz 2H). 13 C NMR (75 MHz, CDCl 3 ) δ14.05, 22.74, 24.60, 25.60, 26.16, 30.07, 34.81, 43.15, 46.64, 47.78, 55.24, 113.98, 128.29, 133.03, 158.34, 171.67. HRMS (ESI+1 ion) m/z calcd for C 18 H 29 NO 2 290.2115. found 290.2130.
Compound 15.7
2-(2,4-dimethoxy)phenyl-1-(piperidin-1-yl)ethanone
The title compound was prepared from 2,4-dimethoxyphenylacetic acid (1.0 g, 4.7 mmol) following the general procedure outline for amide bond formation. The product was isolated as a yellow oil (690 mg, 56%) following purification by flash column chromatography (EtOAc, Rf=0.6). 1 H NMR (400 MHz, CDCl 3 ) δ 1.38 (m, 2H); 1.52 (m, 2H); 1.58 (m, 2H); 3.36 (m, 2H); 3.56 (m, 2H); 3.20 (s, 2H); 3.29 (s, 3H); 3.81 (s, 3H); 6.45 (m, 3H); 7.13 (d, J=8.6 Hz). 13 C NMR (75 MHz, CDCl 3 ) δ24.46, 25.56, 26.26, 40.72, 40.77, 42.94, 47.27, 111.24, 111.70, 120.66, 127.97, 147.80, 149.07, 169.45. HRMS (ESI+1 ion) m/z calcd for C 15 H 22 NO 3 264.1594. found 264.1605.
2-butyl-2-(2,4-dimethoxy)phenyl-1-(piperidin-1-yl)hexanone
The title compound was prepared following the general procedure outline for α-alkylation from 2-(2′,4′-dimethyoxy)phenyl-1-(piperidin-1-yl)ethanone (688 mg, 2.61 mmol). The product was isolated as a pale yellow oil (380 mg, 45%) following purification by flash column chromatography (50% EtOAc in hexane, Rf=0.7). 1 H NMR (400 MHz, CDCl 3 ) δ 0.87 (t, J=7 Hz, 3H); 0.973 (m, 1H); 1.13 (m, 1H), 1.23-1.65 (multiple signals, 9H); 2.01 (m, 1H); 3.33 (m, 3H); 3.7 (m, 1H); 3.79 (s, 3H); 3.82 (s, 3H); 4.12 (t, J=7 Hz, 1H); 6.42 (m, 3H); 7.20 (d, J=8 Hz). 13 C NMR (75 MHz, CDCl 3 ) δ14.06, 22.79, 24.73, 25.67, 26.16, 29.92, 34.04, 39.21, 43.11, 46.19, 55.32, 55.50, 98.26, 104.66, 121.93, 128.56, 156.79, 159.38, 172.45. HRMS (ESI+1 ion) m/z calcd for C 19 H 30 NO 3 320.2220. found 320.2229.
Compound 15.6
2-butyl-2-(2,4-dimethyoxy)phenyl-1-(piperidin-1-yl)hexanone
The title compound was prepared following the general procedure outline for α-alkylation from 2-(2′,4′-dimethyoxy)phenyl-1-(piperidin-1-yl)ethanone (688 mg, 2.61 mmol). The product was isolated as a pale yellow oil (380 mg, 45%) following purification by flash column chromatography (50% EtOAc in hexane, Rf=0.7). 1 H NMR (400 MHz, CDCl 3 ) δ 0.87 (t, J=7 Hz, 3H); 0.97 (m, 1H); 1.13 (m, 1H), 1.23-1.65 (multiple signals, 9H); 2.01 (m, 1H); 3.33 (m, 3H); 3.7 (m, 1H); 3.79 (s, 3H); 3.82 (s, 3H); 4.12 (t, J=7 Hz, 1H); 6.42 (m, 3H); 7.20 (d, J=8 Hz). 13 C NMR (75 MHz, CDCl 3 ) δ 14.06, 22.79, 24.73, 25.67, 26.16, 29.92, 34.04, 39.21, 43.11, 46.19, 55.32, 55.50, 98.26, 104.66, 121.93, 128.56, 156.79, 159.38, 172.45. HRMS (ESI+1 ion) m/z calcd for C 19 H 30 NO 3 320.2220. found 320.2229.
Compound 16.2
2-(4-hydroxymethyl)phenyl-1-(piperidin-1-yl)ethanone
The title compound was prepared from 4-hydroxymethylphenylacetic acid (1.0 g, 6.0 mmol) following the general procedure outlined for amide coupling. The product was isolated as a viscous, colourless oil (540 mg, 39%) following purification by flash column chromatography (EtOAc, Rf=0.5). 1 H NMR (400 MHz, CDCl 3 ) δ 1.37 (m, 2H); 1.52 (m, 2H); 1.58 (m, 2H); 3.36 (m, 2H); 3.56 (m, 2H); 3.71 (s, 2H); 4.66 (s, 2H); 7.23 (d, J=8 Hz, 2H); 7.31 (d, J=8 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) 524.39, 25.44, 25.47, 26.21, 34.91, 40.77, 42.92, 47.25, 55.77, 64.92, 127.33, 128.76, 134.65, 139.48, 169.30. HRMS (ESI+1 ion) m/z calcd for C 14 H 20 NO 2 234.1489. found 234.1489.
2-(4-tert-butyldimethylsilyloxymethyl)phenyl-1-(piperidin-1-yl)ethanone
To a cooled (0° C.) solution of 2-(4-hydroxymethyl)phenyl-1-(piperidin-1-yl)ethanone (540 mg, 2.32 mmol) and imidazole (97 mg, 1.4 mmol) in dry DCM was added a solution of TBSCl (214 mg, 1.42 mmol) in DCM (5 mL). The resulting reaction mixture was allowed to stir for 2 hours. After this time, the reaction mixture was washed successively with water (×2) and brine and the organic layer was dried (MgSO 4 ) and concentrated in vacuo. The title compound was obtained as a colourless oil (420 mg, 53%) following purification by flash column chromatography (20% EtOAc, Rf=0.6). 1 H NMR (400 MHz, CDCl 3 ) δ 0.084 (s, 6H); 0.929 (s, 9H); 1.34 (m, 2H); 1.52 (m, 2H); 1.59 (m, 2H); 3.43 (m, 2H); 3.57 (m, 2H); 3.71 (s, 2H); 4.71 (s, 2H); 7.20 (d, J=8 Hz, 2H); 7.25 (d, J=8 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) δ−5.21, 24.45, 25.59, 25.97, 26.20, 40.94, 42.89, 47.27, 64.77, 126.41, 128.40, 133.96, 139.81, 169.36. HRMS (ESI+1 ion) m/z calcd for C 20 H 34 NO 2 Si 348.2353. found 348.2354.
2-(4-tert-butyldimethylsilyloxymethyl)phenyl-1-(piperidin-1-yl)hexanone
The title compound was prepared from 2-(4-tert-butyldimethylsilyloxymethyl)phenyl-1-(piperidin-1-yl)ethanone (420 mg, 1.21 mmol) following the general procedure outlined for α-alkylation. The product was obtained as a colourless oil (260 mg, 53%) following purification by flash column chromatography (20% EtOAc in hexane, Rf=0.6). 1 H NMR (400 MHz, CDCl 3 ) δ 0.010 (s, 6H); 0.087 (t, J=7 Hz, 3H); 0.94 (s, 9H); 1.01 (m, 1H); 1.14 (m, 1H); 1.2-1.6 (multiple signals, 8H); 1.68 (m, 1H); 2.10 (m, 1H); 3.3-3.5 (m, 3H); 3.68 (m, 2H); 4.72 (s, 2H); 7.15 (m, 4H). 13 C NMR (75 MHz, CDCl 3 ) δ −5.20, 14.03, 22.75, 24.75, 25.68, 26.12, 30.40, 34.78, 43.16, 46.62, 48.47, 64.79, 126.38, 127.66, 139.52, 139.73, 171.42. HRMS (ESI+1 ion) m/z calcd for C 24 H 42 NO 2 Si 404.2979. found 404.2983.
2-(4-hydroxymethyl)phenyl-1-(piperidin-1-yl)hexanone
A solution of 2-(4-tert-butyldimethylsilyloxymethyl)phenyl-1-(piperidin-1-yl)hexanone (260 mg, 0.64 mmol) in dry THF (5 mL) was added to a flask containing a solution of TBAF in THF (1.29 mmol). The resulting reaction mixture was allowed to stir for 1 hour, by which time analysis by tlc revealed that no starting material remained. The reaction mixture was washed with water (×2) followed by brine and the organic layer was dried (MgSO 4 ) and concentrated in vacuo to afford the crude product. The title compound was isolated as a colourless oil (142 mg, 76%) following purification by flash column chromatography (50% EtOAc in hexane, Rf=0.4). 1 H NMR (400 MHz, CDCl 3 ) δ 0.87 (t, J=7 Hz, 3H); 1.04 (m, 1H); 1.14 (m, 1H); 1.9-1.7 (m, 8H); 1.71 (m, 1H); 1.91 (m, 1H); 3.34 (m, 2H); 3.47 (m, 1H); 3.63 (m, 1H); 3.69 (t, J=7 Hz, 1H); 4.66 (s, 2H); 7.25 (d, J=8 Hz, 2H); 7.30 (d, J=8 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) δ 14.02, 22.72, 24.56, 25.57, 26.12, 30.07, 34.76, 43.19, 46.64, 48.41, 65.07, 127.06, 127.99, 139.28, 140.32, 171.32. HRMS (ESI+1 ion) m/z calcd for C 18 H 28 NO 2 290.2114. found 289.2117.
Compound 16.3
2-(4-acetoxymethyl)phenyl-1-(piperidin-1-yl)hexanone
To a round bottomed flask containing DMAP (2 mg) was added a solution of 2-(4-hydroxymethyl)phenyl-1-(piperidin-1-yl)hexanone (30 mg, 0.10 mmol) in dry dichloromethane (2 mL). To the resulting mixture was added dry NEt 3 (208 μL, 1.5 mmol) followed by acetic anhydride (100 μL, 1.0 mmol). The resulting mixture was allowed to stir for 3 hours. After this time, the reaction mixture was washed with saturated NaHCO 3 , water and then brine and the organic phase was dried (Na 2 SO 4 ) and concentrated under reduced pressure. The title compound was obtained as a colourless oil (20 mg, 60%) following purification by flash column chromatography (50% EtOAc in hexane, Rf=0.7). 1 H NMR (400 MHz, CDCl 3 ) δ 0.86 (t, J=7 Hz, 3H); 1.0-1.2 (2×m, 2H); 1.2-1.5 (multiple signals, 8H); 1.68 (m, 1H); 4.53 (m+s, 4H); 3.33 (m, 1H), 3.39 (m, 1H); 3.49 (m, 1H); 3.60 (m, 1H); 3.70 (t, J=7 Hz, 1H); 5.07 (s, 2H); 7.72 (m, 4H). 13 C NMR (75 MHz, CDCl 3 ) δ14.01, 21.08, 22.72, 24.57, 25.60, 26.20, 30.09, 34.77, 43.20, 46.66, 48.38, 66.07, 128.03, 128.58, 134.24, 141.02, 171.09, 171.17. Note: Compound hydrolyses on standing, HRMS consistent with that of free alcohol.
Compound 17.1
2-(4-methoxyoxyphenyl)-1-(piperidin-1-yl)oct-7-en-1-one
The title compound was prepared following the general procedure for alkylation from 2-(4-hydroxyphenyl)-1-(piperidin-1-yl)ethanone (100 mg, 0.43 mmol) and 6-bromo-1-hexene (70 μL, 0.47 mmol). The purified compound was isolated as a pale yellow oil (26 mg, 26%) following purification by flash column chromatography (20% EtOAc in hexane, Rf=0.5). 1 H NMR (400 MHz, CDCl 3 ) δ1.1-1.5 (multiple signals, 10H); 1.65 (m, 1H); 2.01 (m, 3H); 3.35, (m, 3H); 3.63 (t, J=7 Hz, 1H); 3.65 (m, 1H); 3.78 (s, 3H); 4.89 (dm, J=10 Hz, 1H); 4.95 (dm, J=17 Hz, 1H); 5.77 (ddd, J=17, 10, 6.5 Hz, 1H); 6.83 (d, J=8.5 Hz, 2H); 7.17 (d, J=8.5 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) δ 24.69, 25.70, 26.25, 27.46, 29.07, 33.79, 35.02, 43.27, 46.75, 47.88, 55.35, 114.13, 114.34, 278.08, 128.89, 133.05, 139.19, 158.38, 171.69. HRMS (ESI+1 ion) m/z calcd for C 20 H 30 NO 2 316.2271. found 316.2265.
Compound 17.2
2-(4-methoxyphenyl)-N,N-dimethylhexanamide
The title compound was prepared following the general procedure for alkylation from 2-(4-hydroxyphenyl)-N,N-dimethylacetamide (100 mg, 0.52 mmol) and 1-bromobutane (70 μL, 0.57 mmol). The purified compound was isolated as a pale yellow oil (120 mg, 60%) following purification by flash column chromatography (EtOAc, Rf=0.7). 1 H NMR (400 MHz, CDCl 3 ) δ 0.85 (t, J=7 Hz, 3H); 1.14 (m, 1H); 1.28 (m, 3H); 1.68 (m, 1H); 2.05 (m, 1H); 2.93 (s, 3H); 2.94 (s, 3H); 3.63 (t, J=7 Hz, 1H); 3.78 (s, 3H); 6.84 (d, J=8.8 Hz, 2H); 7.20 (d, J=8.8 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) δ14.16, 22.84, 35.03, 36.02, 37.30, 48.09, 55.37, 114.14, 129.04, 132.64, 158.50, 173.75. HRMS (ESI+1 ion) m/z calcd for C 16 H 24 NO 2 262.1802. found 262.1795.
Compound 17.3
2-(4-methoxyphenyl)-N,N-dimethyloct-7-enamide
The title compound was prepared following the general procedure for alkylation from 2-(4-hydroxyphenyl)-N,N-dimethylacetamide (100 mg, 0.52 mmol) and 6-bromo-1-hexene (84 μL, 0.57 mmol). The purified compound was isolated as a pale yellow oil (120 mg, 60%) following purification by flash column chromatography (EtOAc, Rf=0.6). 1 H NMR (400 MHz, CDCl 3 ) δ1.1-1.5 (multiple signals, 4H); 1.66 (m, 1H); 2.02 (m, 3H); 2.93 (2×s, 6H); 3.63 (t, J=7 Hz, 1H); 3.78 (s, 3H); 4.90 (dm, J=10 Hz, 1H); 4.96 (dm, J=17 Hz, 1H); 5.77 (ddd, J=17, 10, 6.5 Hz, 1H); 6.85 (d, J=8.8 Hz, 2H); 7.19 (d, J=8.8 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) δ27.41, 29.02, 33.75, 35.10, 36.00, 37.27, 48.05, 55.34, 114.13, 114.35, 128.98, 132.49, 139.12, 158.49, 173.62. HRMS (ESI+1 ion) m/z calcd for C 17 H 26 NO 2 276.1958. found 276.1958.
Compound 16.5
2-(4-hydroxyphenyl)-1-(piperidin-1-yl)hexan-1-one
To a cooled (−78° C.) solution of 15.1 (1 g, 3.46 mmol) in dry DCM was added a solution of boron tribromide in DCM (10 mL, 10 mmol). The resulting mixture was allowed to warm to room temperature over a number of hours (at least 3) and continued stirring for a further 14 hours (17 hours in total). The reaction was quenched by the careful dropwise addition of ammonium hydroxide to the reaction mixture (caution: slow addition to reaction mixture at 0° C.). Following this, water was added to the reaction mixture and the aqueous phase removed. The organic layer was dried (MgSO 4 ) and concentrated in vacuo. The title compound was obtained as a pale brown solid (0.93 g, 97%). 1 H NMR (400 MHz, CDCl 3 ) δ 0.85 (t, 3H); 1.29 (m, 10H); 1.70 (m, 2H); 2.04 (m, 1H); 3.39 (m, 2H); 3.63 (t, 1H); 3.67 (m, 1H); 6.77 (d, J=8.5 Hz, 2H); 7.12 (d, J=8.5 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) δ 13.99, 22.67, 24.51, 25.55, 26.11, 29.98, 34.59, 43.32, 46.75, 47.73, 115.63, 128.83, 132.28, 154.95, 172.09. HRMS (ESI+1 ion) m/z calcd for C 17 H 26 NO 2 276.1958. found 276.1954.
Compound 17.7
2-(4-hydroxyphenyl)-N,N-dimethylhexanamide
The title compound was obtained as a pale yellow solid (6 mg, 53%) in a similar manner to that described for 16.5 from 17.2 (12 mg, 0.048 mmol). δ 0.85 (t, J=7 Hz, 3H); 1.1-1.5 (multiple signals, 4H); 1.65 (m, 1H); 2.03 (m, 1H); 2.94 (s, 3H); 3.63 (t, J=7 Hz, 1H); 6.76 (d, J=8.5 Hz, 2H); 7.16 (d, J=8.5 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) δ14.15, 22.82, 30.14, 31.10, 34.96, 48.05, 115.61, 129.22, 132.53, 154.65, 173.87. HRMS (ESI+1 ion) m/z calcd for C 14 H 23 NO 2 236.1645. found 236.1644.
Compound 17.8
2-(4-hydroxyphenyl)-N,N-dimethyloct-7-enamide
To a cooled (−78° C.) solution of 17.3 (25 mg, 0.09 mmol) in dry CH 2 Cl 2 (1 mL) was added BBr 3 (1 M solution in CH 2 Cl 2 , 0.27 mL, 0.27 mmol). The resulting mixture was allowed to warm to room temperature and was stirred for an additional 30 minutes. After this time, the reaction mixture was cooled to −78° C. and MeOH (2 mL) was added to the reaction mixture. After 5 minutes the resulting mixture was poured onto water and an additional 10 mL of CH 2 Cl 2 was added. The organic layer was washed dried and concentrated in vacuo to afford the crude product as a pale yellow solid. Purification of the crude product by flash column chromatography (50% EtOAc/hexane, Rf=0.2) afforded the title compound as a pale yellow oil which solidified upon standing (4 mg, 15%). 1 H NMR (400 MHz, CDCl 3 ) δ1.1-1.5 (multiple signals, 4H); 1.67 (m, 1H); 1.98 (m, 3H); 2.93 (s, 3H); 2.94 (s, 3H); 3.62 (t, J=7 Hz, 1H); 4.84 (s, 1H ArOH); 4.90 (dm, J=10 Hz, 1H); 4.95 (dm, J=17 Hz, 1H); 5.77 (ddd, J=17, 10, 6.5 Hz, 1H); 6.76 (d, J=8.8 Hz, 2H); 7.14 (d, J=8.8 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) δ27.29, 28.90, 33.64, 34.97, 35.94, 37.19, 47.92, 114.26, 115.51, 129.10, 132.48, 139.01, 173.55. HRMS (ESI+1 ion) m/z calcd for C 16 H 24 NO 2 262.1802. found 262.1086.
Compound 17.6
2-(4-hydroxyphenyl)-1-(piperidin-1-yl)oct-7-en-1-one
The title compound was prepared in a similar manner to that described for 17.8 from 2-(4-methoxyoxyphenyl)-1-(piperidin-1-yl)oct-7-en-1-one (50 mg, 0.18 mmol). The title compound was obtained as a colourless, low melting point solid (6 mg, 11%) following purification by flash column chromatography (50% EtOAc/hexane, Rf=0.5). 1 H NMR (400 MHz, CDCl 3 ) δ 1.0-1.5 (multiple signals, 10H); 1.66 (m, 1H); 2.02 (m, 3H); 3.38, (m, 3H); 3.62 (t, J=7 Hz, 1H); 3.65 (m, 1H); 4.88 (dm, J=10 Hz, 1H); 4.95 (dm, J=17 Hz, 1H); 5.76 (ddd, J=17, 10, 6.5 Hz, 1H); 6.76 (d, J=8.5 Hz, 2H); 7.11 (d, J=8.5 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) δ24.54, 25.58, 26.12, 27.31, 28.91, 33.66, 34.79, 43.27, 46.72, 47.72, 114.24, 115.59, 128.92, 132.59, 139.04, 154.64, 171.80. HRMS (ESI+1 ion) m/z calcd for C 19 H 28 NO 2 302.2115. found 302.2120.
2-(4-hydroxymethyl)phenyl-1-(piperidin-1-yl)ethanone
The title compound was prepared from 4-hydroxymethylphenylacetic acid (1.0 g, 6.0 mmol) following the general procedure outlined for DCC mediated amide formation. The product was isolated as a viscous, colourless oil (0.54 g, 39%) following purification by flash column chromatography (EtOAc, Rf=0.5). 1 H NMR (400 MHz, CDCl 3 ) δ 1.37 (m, 2H); 1.52 (m, 2H); 1.58 (m, 2H); 3.36 (m, 2H); 3.56 (m, 2H); 3.71 (s, 2H); 4.66 (s, 2H); 7.23 (d, J=8 Hz, 2H); 7.31 (d, J=8 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) δ24.39, 25.44, 25.47, 26.21, 34.91, 40.77, 42.92, 47.25, 55.77, 64.92, 127.33, 128.76, 134.65, 139.48, 169.30. HRMS (ESI+1 ion) m/z calcd for C 14 H 20 NO 2 234.1489. found 234.1489.
2-(4-tert-butyldimethylsilyloxymethyl)phenyl-1-(piperidin-1-yl)ethanone
To a cooled (0° C.) solution of 2-(4-hydroxymethyl)phenyl-1-(piperidin-1-yl)ethanone (540 mg, 2.32 mmol) and imidazole (97 mg, 1.4 mmol) in dry DCM was added a solution of TBSCl (214 mg, 1.42 mmol) in DCM (5 mL). The resulting reaction mixture was allowed to stir for 2 hours. After this time, the reaction mixture was washed successively with water (×2) and brine and the organic layer was dried (MgSO 4 ) and concentrated in vacuo. The title compound was obtained as a colourless oil (420 mg, 53%) following purification by flash column chromatography (20% EtOAc, Rf=0.6). 1 H NMR (400 MHz, CDCl 3 ) δ0.084 (s, 6H); 0.929 (s, 9H); 1.34 (m, 2H); 1.52 (m, 2H); 1.59 (m, 2H); 3.43 (m, 2H); 3.57 (m, 2H); 3.71 (s, 2H); 4.71 (s, 2H); 7.20 (d, J=8 Hz, 2H); 7.25 (d, J=8 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) δ-5.21, 24.45, 25.59, 25.97, 26.20, 40.94, 42.89, 47.27, 64.77, 126.41, 128.40, 133.96, 139.81, 169.36. HRMS (ESI+1 ion) m/z calcd for C 20 H 34 NO 2 Si 348.2353. found 348.2354.
2-(4-tert-butyldimethylsilyloxymethyl)phenyl-1-(piperidin-1-yl)hexanone
The title compound was prepared from 2-(4-tert-butyldimethylsilyloxymethyl)phenyl-1-(piperidin-1-yl)ethanone (420 mg, 1.21 mmol) following the general procedure outlined for α-alkylation. The product was obtained as a colourless oil (260 mg, 53%) following purification by flash column chromatography (20% EtOAc in hexane, Rf=0.6). 1 H NMR (400 MHz, CDCl 3 ) 0.010 (s, 6H); 0.087 (t, J=7 Hz, 3H); 0.94 (s, 9H); 1.01 (m, 1H); 1.14 (m, 1H); 1.2-1.6 (multiple signals, 8H); 1.68 (m, 1H); 2.10 (m, 1H); 3.3-3.5 (m, 3H); 3.68 (m, 2H); 4.72 (s, 2H); 7.15 (m, 4H). 13 C NMR (75 MHz, CDCl 3 ) δ-5.20, 14.03, 22.75, 24.75, 25.68, 26.12, 30.40, 34.78, 43.16, 46.62, 48.47, 64.79, 126.38, 127.66, 139.52, 139.73, 171.42. HRMS (ESI+1 ion) m/z calcd for C 24 H 42 NO 2 Si 404.2979. found 404.2983.
Compound 16.1
2-(4-hydroxymethyl)phenyl-1-(piperidin-1-yl)hexanone
A solution of 2-(4-tert-butyldimethylsilyloxymethyl)phenyl-1-(piperidin-1-yl)hexa none (260 mg, 0.64 mmol) in dry THF (5 mL) was added to a flask containing a solution of TBAF in THF (1.29 mmol). The resulting reaction mixture was allowed to stir for 1 hour, by which time analysis by tlc revealed that no starting material remained. The reaction mixture was washed with water (×2) followed by brine and the organic layer was dried (MgSO 4 ) and concentrated in vacuo to afford the crude product. The title compound was isolated as a colourless oil (142 mg, 76%) following purification by flash column chromatography (50% EtOAc in hexane, Rf=0.4). 1 H NMR (400 MHz, CDCl 3 ) δ 0.87 (t, J=7 Hz, 3H); 1.04 (m, 1H); 1.14 (m, 1H); 1.9-1.7 (m, 8H); 1.71 (m, 1H); 1.91 (m, 1H); 3.34 (m, 2H); 3.47 (m, 1H); 3.63 (m, 1H); 3.69 (t, J=7 Hz, 1H); 4.66 (s, 2H); 7.25 (d, J=8 Hz, 2H); 7.30 (d, J=8 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) δ 14.02, 22.72, 24.56, 25.57, 26.12, 30.07, 34.76, 43.19, 46.64, 48.41, 65.07, 127.06, 127.99, 139.28, 140.32, 171.32. HRMS (ESI+1 ion) m/z calcd for C 18 H 28 NO 2 290.2114. found 289.2117.
Compound 16.3
2-(4-acetoxymethyl)phenyl-1-(piperidin-1-yl)hexanone
To a round bottomed flask containing DMAP (2 mg) was added a solution of 2-(4-hydroxymethyl)phenyl-1-(piperidin-1-yl)hexanone (30 mg, 0.10 mmol) in dry CH 2 Cl 2 (2 mL). To the resulting mixture was added dry NEt 3 (208 pt, 1.5 mmol) followed by acetic anhydride (100 μL, 1.0 mmol). The resulting mixture was allowed to stir for 3 hours. After this time, the reaction mixture was washed with saturated NaHCO 3 , water and then brine and the organic phase was dried (Na 2 SO 4 ) and concentrated under reduced pressure. The title compound was obtained as a colourless oil (20 mg, 60%) following purification by flash column chromatography (50% EtOAc in hexane, Rf=0.7). 1 H NMR (400 MHz, CDCl 3 ) δ 0.86 (t, J=7 Hz, 3H); 1.0-1.2 (2×m, 2H); 1.2-1.5 (multiple signals, 8H); 1.68 (m, 1H); 4.53 (m+s, 4H); 3.33 (m, 1H), 3.39 (m, 1H); 3.49 (m, 1H); 3.60 (m, 1H); 3.70 (t, J=7 Hz, 1H); 5.07 (s, 2H); 7.72 (m, 4H). 13 C NMR (75 MHz, CDCl 3 ) δ14.01, 21.08, 22.72, 24.57, 25.60, 26.20, 30.09, 34.77, 43.20, 46.66, 48.38, 66.07, 128.03, 128.58, 134.24, 141.02, 171.09, 171.17. Note: Compound hydrolyses on standing, HRMS consistent with that of free alcohol.
Compound 16.11
4-(1-oxo-1-(piperidin-1-yl)hexan-2-yl)phenyl acrylate
To a cooled (0° C.) stirred solution of 16.5 (100 mg, 0.36 mmol) and triethylamine (56 μL, 0.40 mmol) in dry CH 2 Cl 2 (10 mL) was added acryloyl chloride (33 μL, 0.40 mmol). The resulting mixture was allowed to warm to room temperature and was stirred for a further 1 hour, by which time analysis by tlc (50% EtOAc/hexane) revealed complete consumption of starting material. After this time, the reaction mixture was concentrated in vacuo and purified by flash column chromatography (50% EtOAc/hexane, Rf=0.5) to afford the title compound as a colourless oil (120 mg, >95%). 1 H NMR (400 MHz, CDCl 3 ) δ 0.85 (t, J=7 Hz, 3H); 1.0-1.6 (multiple signals, 10H); 1.70 (m, 1H); 2.05 (m, 1H); 3.3-3.5 (2×m, 3H); 3.68 (m, 1H); 3.70 (t, J=7 Hz, 1H); 5.99, (d, J=10 Hz, 1H); 6.29 (dd, J=17, 10 Hz, 1H); 6.57 (d, J=17 Hz, 1H); 7.06 (d, J=8.4 Hz, 2H); 7.28 (d, J=8.4 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) 813.93, 22.63, 24.49, 25.51, 26.10, 30.00, 34.77, 43.12, 46.61, 47.96, 121.53, 127.88, 128.69, 132.42, 138.42, 149.15, 164.43, 171.06. HRMS (ESI+1 ion) m/z calcd for C 20 H 28 NO 3 330.1989. found 330.2056.
Compound 16.4
4-(1-oxo-1-(piperidin-1-yl)hexan-2-yl)phenyl acetate
Acetic anhydride (38 pt, 0.40 mmol) as added to a cooled (0° C.) stirred solution of 16.5 (100 mg, 0.36 mmol) and pyridine (32 μL, 0.40 mmol) in dry CH 2 Cl 2 (20 mL). The reaction was allowed to warm to room temperature and stirring was continued for a further 18 hours, by which time analysis by tlc (50% EtOAc/hexane) showed consumption of starting material. The crude reaction mixture was washed with dilute (0.1M) HCl followed by water. The organic layer was dried (MgSO 4 ) and concentrated in vacuo and the resulting oily residue was purified by flash column chromatography (50% EtOAc/hexane, Rf=0.26) to afford the title compound as a colourless oil (110 mg, >95%). 1 H NMR (400 MHz, CDCl 3 ) 0.86 (t, J=7 Hz, 3H); 1.0-1.7 (multiple signals, 11H); 2.1 (m, 1H); 2.28 (s, 3H); 3.37 (m, 2H); 3.48 (m, 1H); 3.59 (m, 1H); 3.72 (t, J=7 Hz, 1H); 7.04 (d, J=8.4 Hz, 2H); 7.28 (d, J=8.4 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) J13.96, 21.14, 22.67, 24.53, 25.55, 26.15, 30.04, 34.80, 43.15, 46.64, 47.97, 121.59, 128.72, 138.38, 149.29, 169.39, 171.11. HRMS (ESI+1 ion) m/z calcd for C 19 H 28 NO 3 318.2064. found 318.2060.
Compound 16.6
2-(4-(2-hydroxyethoxy)phenyl)-1-(piperidin-1-yl)hexan-1-one
A solution of 16.5 (0.50 g, 1.8 mmol) ethylene carbonate (176 mg, 2.00 mmol) and tetraethylammonium bromide (20 mg, 0.09 mmol) in dry DMF (10 mL) was heated at an oil bath temperature of 180° C. for 16 hours. After this time cold water (50 mL) was added and the resulting mixture was extracted with EtOAc (3×20 ml). The combined organic layers were washed with water, dried (MgSO 4 ) and concentrated in vacuo. The crude product was purified was purified by flash column chromatography (10% MeOH in CH 2 Cl 2 , Rf=0.4) to afford the title compound as a colourless oil (200 mg, 34%). 1 H NMR (400 MHz, CDCl 3 ) 0.84 (t, J=7 Hz, 3H); 1.05 (m, 1H); 1.17 (m, 1H); 1.2-1.6 (multiple signals, 8H); 1.7 (m, 1H); 2.08 (m, 1H); 2.39 (t, J=6 Hz, 1H (OH)); 3.35 (m, 3H); 3.62 (t, J=7 Hz, 1H); 3.64 (m, 1H); 3.92 (m, 2H); 4.05 (m, 1H); 6.83 (d, J=8.4 Hz, 2H); 7.16 (d, J=8.4 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) ( 13.96, 22.64, 24.50, 25.51, 26.09, 29.96, 34.70, 43.10, 46.58, 47.70, 61.36, 69.10, 114.59, 128.78, 133.38, 157.28, 171.55. HRMS (ESI+1 ion) m/z calcd for C 19 H 30 NO 3 320.2220. found 320.2205.
Compound 16.8
2-(4-(1-oxo-1-(piperidin-1-yl)hexan-2-yl)phenoxy)ethyl acetate
To a cooled (0° C.) stirred solution of 16.6 (100 mg, 0.31 mmol) and DMAP (85 mg, 0.34 mmol) in dry CH 2 Cl 2 (20 mL) was added acetyl chloride (50 μL, 0.34 mmol). The resulting reaction mixture was stirred at reflux for 16 hours by which time analysis by tlc (50% EtOAc/hexane) showed complete consumption of starting material. The reaction mixture was washed with HCl (0.1 M) and water and the organic layer was dried (MgSO 4 ) and concentrated in vacuo. The title compound was obtained as a colourless oil (110 mg, >95% yield) following purification by flash column chromatography (50% EtOAc/hexane, Rf=0.4). 1 H NMR (400 MHz, CDCl 3 ) 0.85 (t, J=7 Hz, 3H); 1.05-1.60 (multiple signals, 10H); 1.7 (m, 1H); 2.08 (m, 1H); 2.10 (s, 3H); 3.35-3.45 (m, 3H); 3.6-3.7 (m, 2H); 4.15 (app t, J=5 Hz, 2H); 4.40 (app t, J=5 Hz, 2H); 6.84 (d, J=8.4 Hz, 2H); 7.17 (d, J=8.4 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) 13.99, 20.89, 22.69, 24.55, 25.56, 26.15, 30.11, 34.77, 43.11, 46.61, 47.74, 62.86, 65.88, 114.68, 128.85, 133.61, 157.13, 171.00, 171.55. HRMS (ESI+1 ion) m/z calcd for C 21 H 32 NO 4 362.2326. found 362.2320.
Compound 16.7
Methyl 2-(4-(1-oxo-1-(piperidin-1-yl)hexan-2-yl)phenoxy)acetate
To a stirred solution of 16.5 (300 mg, 1.15 mmol) and K 2 CO 3 (400 mg, 2.87 mmol) in dry acetonitrile (20 mL) was added methylbromoacetate (0.18 g, 1.2 mmol). The resulting mixture was refluxed for 16 hours by which time analysis by tlc (5% MeOH in CH 2 Cl 2 ) showed that no starting material remained. Acetonitrile was removed in vacuo and the residue was taken up in EtOAc and washed with water. The organic layer was dried (MgSO 4 ) and concentrated in vacuo and the title compounds was obtained as a colourless oil (300 mg, 72%) following purification by flash column chromatography (5% MeOH in CH 2 Cl 2 , Rf=0.7). 1 H NMR (400 MHz, CDCl 3 ) 0.86 (t, J=7 Hz, 3H); 1.05-1.60 (multiple signals, 10H); 1.7 (m, 1H); 2.05 (m, 1H); 3.38 (m, 2H); 3.42 (m, 1H), 3.6-3.7 (m, 2H); 3.80 (s, 3H); 4.61 (s, 2H); 6.83 (d, J=8.4 Hz, 2H); 7.19 (d, J=8.4 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) 14.02, 22.72, 24.59, 25.60, 26.18, 30.06, 34.78, 43.15, 46.65, 47.73, 52.26, 65.45, 114.80, 128.94, 134.29, 156.51, 169.44, 171.48. HRMS (ESI+1 ion) m/z calcd for C 20 H 30 NO 4 348.2169. found 348.2157.
Compound 16.9
2-(4-(1-oxo-1-(piperidin-1-yl)hexan-2-yl)phenoxy)acetic acid
Powdered LiOH (72 mg, 3.0 mmol) was added to a solution of 16.7 (100 mg, 0.30 mmol) in THF (10 mL) and the mixture was allowed to stir at room temperature for 16 hours. After this time the reaction mixture was acidified with HCl (0.1 M) and washed with EtOAc (3×20 mL). The organic phase was dried (MgSO 4 ) and concentrated in vacuo. The title compound was obtained as a colourless oil (59 mg, 60%) following purification by flash column chromatography (10% MeOH in CH 2 Cl 2 , Rf=0.5). 1 H NMR (400 MHz, CDCl 3 ) 0.84 (t, J=7 Hz, 3H); 1.05-1.60 (multiple signals, 10H); 1.68 (m, 1H); 2.05 (m, 1H); 3.37 (m, 2H); 3.42 (m, 1H), 3.66 (m, 2H); 4.63 (s, 2H); 6.85 (d, J=8.4 Hz, 2H); 7.18 (d, J=8.4 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) δ13.96, 22.61, 24.41, 25.52, 26.10, 29.92, 34.52, 43.49, 46.82, 47.71, 65.10, 114.87, 128.89, 133.87, 156.46, 171.92, 172.03. HRMS (ESI+1 ion) m/z calcd for C 19 H 28 NO 4 334.2013. found 334.2001.
Compound 16.10
1-(piperidin-1-yl)-2-(4-(2-(trimethylsilyl)ethoxy)phenyl)hexan-1-one
To cooled (0° C.) solution of 16.5 (100 mg, 0.36 mmol), triphenylphosphine (140 mg, 0.54 mmol) and trimethylsilylethanol (80 μL, 0.54 mmol) in dry THF (10 mL) was added DIAD (110 μL) over a period of 10 minutes. The resulting reaction mixture was allowed to warm to room temperature and was stirred for a further 16 hours. After this time, the solvent was removed in vacuo and the residue was taken up in EtOAc and washed with water. The organic layer was dried (MgSO 4 ) and concentrated in vacuo and the resulting residue was purified by flash column chromatography (50% EtOAc/hexane, Rf=0.7) to afford the title compound as a pale yellow oil (40 mg, 30%). 1 H NMR (400 MHz, CDCl 3 ) 0.07 (s, 9H); 0.84 (t, J=7 Hz, 3H); 1.05 (m, 1H); 1.17 (m, 1H); 1.2-1.6 (multiple signals, 10H; app t, J=6 Hz, 2H); 1.7 (m, 1H); 2.05 (m, 1H); 3.25-3.35 (m, 3H); 3.62 (t, J=7 Hz, 1H); 3.65 (m, 1H); 4.03 (app t, J=6 Hz, 2H); 4.05 (m, 1H); 6.80 (d, J=8.4 Hz, 2H); 7.15 (d, J=8.4 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) −1.33, 14.01, 17.75, 22.71, 24.58, 25.57, 26.11, 30.03, 34.77, 43.11, 46.60, 47.80, 65.31, 114.59, 128.70, 132.75, 157.59, 171.67. HRMS (ESI+1 ion) m/z calcd for C 22 H 38 NO 2 376.2672. found 376.2666.
4-(1-oxo-1-(piperidin-1-yl)hexan-2-yl)benzaldehyde
DMSO (0.20 mL, 2.8 mmol) was added to a cooled (−78° C.) stirred solution of oxaloyl chloride (122 μL, 1.42 mmol) in dry CH 2 Cl 2 (5 mL). After 5 minutes 16.2 (300 mg, 1.29 mmol) was added and stirring was continued for 15 minutes after which time triethylamine (0.90 mL, 6.5 mmol) was added dropwise. After a further 5 minutes, the mixture was allowed to warm to room temperature. The reaction mixture was washed with HCl (0.1 M) and the organic layer was further extracted with water, dried (MgSO 4 ) and concentrated in vacuo. The title compound was obtained as a colourless oil (222 mg, 59%). No purification was necessary. 1 H NMR (400 MHz, CDCl 3 ) 0.80 (t, J=7 Hz, 3H); 1.05 (m, 1H); 1.15 (m, 1H); 1.2-1.6 (multiple signals, 8H); 1.7 (m, 1H); 2.05 (m, 1H); 3.29 (m, 2H); 3.36 (m, 1H), 3.61 (m, 1H); 3.71 (t, J=7 Hz, 1H); 7.39 (d, J=8.4 Hz, 2H); 7.76 (d, J=8.4 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) 13.97, 22.67, 24.49, 25.55, 26.21, 30.05, 34.64, 43.33, 46.69, 48.88, 128.57, 130.21, 135.08, 148.03, 170.36, 191.91. HRMS (ESI+1 ion) m/z calcd for C 18 H 26 NO 2 288.1958. found 288.1963.
Compound 17.9
4-(1-oxo-1-(piperidin-1-yl)hexan-2-yl)benzoic acid
Oxone (257 mg, 0.42 mmol) was added to a stirred solution of 4-(1-oxo-1-(piperidin-1-yl)hexan-2-yl)benzaldehyde (100 mg, 0.35 mmol) in DMF (5 mL) and the resulting mixture was stirred at room temperature for 16 hours. The DMF was removed in vacuo and the resulting residue was purified by flash column chromatography (50% EtOAc/hexane, Rf=0.4) to afford the desired compound as a pale yellow solid (68 mg. 64%). MP=142° C. 1 H NMR (400 MHz, CDCl 3 ) 0.86 (t, J=7 Hz, 3H); 1.05 (m, 1H); 1.15 (m, 1H); 1.2-1.6 (multiple signals, 8H); 1.71 (m, 1H); 2.10 (m, 1H); 3.33-3.43 (m, 3H); 3.69 (m, 1H); 3.77 (t, J=7 Hz, 1H); 7.38 (d, J=8.4 Hz, 2H); 8.02 (d, J=8.4 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ) 13.98, 22.68, 24.50, 25.55, 26.16, 30.04, 34.60, 43.32, 46.68, 48.82, 128.04, 130.50, 153.75, 170.59. HRMS (ESI+1 ion) m/z calcd for C 18 H 26 NO 3 304.1907. found 304.1917.
The remaining compounds were made by methods corresponding to those given above, with appropriate variation of starting materials.
Examples Part 2—Polymer Systems
A number of polymers were synthesised, which polymers included a pendant group corresponding to antifouling compound 16.5.
Specifically, compound 16.5 was incorporated into acrylate based polymers via the use of monomer 16.11.
The polymers were evaluated with respect to their ability to release (active) compound 16.5 in an aqueous environment in a sustained fashion. In particular, the antifouling efficacy of polymeric materials was studied in laboratory and field assays to identify anti-fouling performance and toxicity.
Synthesis of Polymers
The same polymers were designed and synthesized as the embodiments to illustrate the potential applications of our invention in marine coatings. But no limitations should be drawn from those embodiments.
Polymers containing compound 16.5 as a releasable functional unit were designed with moderately hydrophilic (to ensure hydration in water) and to possess suitable strength, solubility and compatibility with commercial marine paints. To fulfil these requirements, the Tg of the polymer should preferably be higher than room temperature and the molecular weight is targeted to be approximately 10 KDaltons.
Such polymers were synthesized by the polymerization of vinyl-containing compound 16.11 with the appropriate vinyl monomers under free radical conditions using AIBN, ABCN or benzoyl peroxide as initiators.
Polymer A
P(16.11-co-MMA-co-HEA)
The copolymer of compound 16.11 with methyl methacrylate (MMA) and hydroxyethyl acrylate (HEA) was designed to obtain the functional polymer. Thus 16.11, methyl methacrylate (MMA) and (HEA) were mixed and polymerized under standard free radical conditions.
The mass ratio was designed so that MMA would form the majority of the backbone of the polymer, imparting mechanical strength and ensuring a Tg higher than room temperature, whilst HEA would provide hydrogen bonding capabilities which can improve the hydrophilicity of the polymer.
0.54 g of the functional monomer (16.11) (heavy viscose oil-like yellow liquid) was mixed with 2.0 g of MMA, 1.0 g of 2-hydroxylethyl acrylate (HEA) and 40 mg of ABCN in 3 ml of DMF. The mixture was degassed by purging with nitrogen for 10 min. and then placed into an oil bath thermosetted at 70° C. for 16 hours. Following this, the reaction mixture was poured into 50 mL of ether. The precipitate was collected by filtration and dried under vacuum at room temperature to afford the title compounds as a colourless solid (2.5 g, 74%).
Analysis of the polymeric material by IR spectroscopy revealed the expected ester C═O stretching absorbances at ˜1730 cm −1 along with a key absorbance detected at 1621 cm −1 . Such low frequency C═O vibrations are characteristic of tertiary amides, and therefore this band is assigned to the piperidine amide linkage of the polymerized 16.11.
Polymer B
P(16.11-co-MMA-co-VP)
Polymer B was of a similar design to polymer A but vinyl pyrrolidinone (VP) was used in the place of HEA in order to increase the hydrophilicity of the polymer. Polymer B was synthesized under free radical conditions using the same monomer ratios as that described for polymer A. The structure of polymer B is shown below.
0.5 g of the functional monomer was mixed with 2.0 g of MMA, 1.0 g of vinyl pyrrolidone (VP) and 40 mg of ABCN in 3 ml of DMF and the mixture was degassed by purging with nitrogen for 10 min. Then the mixture was placed into an oil bath thermosetted at 70° C. for 16 hours. Then to the product was added 5 ml of DCM to form a clear solution. The solution was poured into hexane with stirring. The purified product was collected as a white precipitate. The pure product was collected and dried in air at room temperature to afford the title compound as a colourless solid (1.9 g, 54%).
Analysis of the polymer by IR spectroscopy revealed the expected ester carbonyl stretching absorbances at ˜1724 cm −1 along with the previously assigned piperidine amide carbonyl vibration at ˜1640 cm −1 . The incorporation of VP is evident by IR spectroscopy with a clear absorbance appearing at ˜1660 cm −1 , consistent with the presence of the γ-lactam.
GPC revealed a MW of 5300 Daltons. Finally, the soluble nature of the polymer allowed further analysis by 1 H NMR spectroscopy. Signals at 6.9-7.2 ppm are assigned to the phenyl moiety of the 16.11 units, whilst the broad peak at 4.0 ppm to 4.3 ppm was assigned to ring methylene adjacent to the N-atom of the pyrrolidinone unit. Large broad signals in the 3.5-3.8 ppm are assigned to the methyl ester of the MMA units (Brar and Kumar, 2002). The signals at 0.9 ppm-2.5 ppm are ascribed to the methylene and methine groups of the polymer backbone and the methylene and methyl groups of side chain of 16.11.
Polymer C
P(TBA-co-MMA-co-VP)
A standard co-polymer (polymer C) was also synthesized where 16.11 was replaced with t-butyl acrylate (TBA). Such a polymer was synthesised in order to ascertain if any background toxicity or anti-settlement activity existed as a function of the copolymer itself.
The free radical polymerization was carried out using the same mass ratios as for polymers A and B.
0.6 g of tert-butyl acrylate was mixed with 2.0 g of MMA, 1.0 g of vinyl pyrrolidone (VP) and 40 mg of ABCN in 3 ml of DMF and the mixture was degassed by purging with nitrogen for 10 min. Then the mixture was placed into an oil bath thermosetted at 70° C. for 16 hours. Then to the product was added 5 ml of DCM to form a clear solution. The solution was poured into hexane with stirring. The purified product was collected as a white precipitate. The pure product was collected and dried in air at room temperature to afford the desired compound as a colourless solid (3.2 g, 89%)
Analysis of the polymer by IR spectroscopy revealed the presence of key vibrational modes ester and lactam carbonyl groups at 1728 cm −1 and 1664 cm −1 . GPC indicated the desired MW of 67000 Daltons had been achieved and this was much higher than that obtained for polymer B.
1 H NMR analysis of the polymer confirmed the presence of the t-butyl moiety in the polymer, appearing at 1.4 ppm.
Examples Part 3—Biological Investigation of Compounds
Methodology
Biological assays were conducted with larval barnacles. Barnacles are dominant and tenacious members of marine fouling communities, and often serve as a substrate for less resistant organisms. Therefore, historically they have been used as a model organism for antifouling studies. To determine the biological response of larvae to test compounds, two bioassays were performed: settlement (using settlement stage cyprids), and toxicity (using nauplii). Procedures followed methods standard in the field, which were first described by Rittschof et al. (1992).
Preparation of stock solution for bioassays
Stock solutions of each compound were made at 50 mg/ml. Pure compounds were diluted in DMSO and sonicated. Stock solutions were stored at −20° C. in 4 ml amber screw cap vials until use. For bioassays, a small amount of stock solution was diluted in 1 μm filtered seawater (in a glass scintillation vial). The solution was then sonicated for 10 minutes. To obtain the desired concentration range, serial dilutions of the test solution were made. As control, a serial dilution of the equivalent amounts of DMSO in seawater was used.
Toxicity Assays
Toxicity assays employed stage II naupliar larvae of the barnacle Amphibalanus amphitrite (previously Balanus amphitrite : Pitombo, 2004). Assay procedures were modified from Rittschof et al. (1992). Adult A. amphitrite were collected from inter-tidal areas near the Kranji mangrove, Singapore. Larval culture was based on Rittschof et al. (1984). Following collection, nauplii were concentrated for use in bioassays by placing a fiber optic light source at one side of the container, and pipetting from the resulting dense cloud of nauplii.
In order to determine LD50 values for each compound, compounds were tested over a range of concentrations between 0-50 μg/ml. For each assay, each compound at each concentration was tested in triplicate with a single batch of nauplii. The overall assay was conducted twice, using two different batches of nauplii. Two controls were run along with each assay (in triplicate): filtered seawater only, and DMSO at 1 μg/ml (since DMSO was used as a solvent for test compounds, this concentration is equivalent to the concentration of DMSO in the highest test compound concentration).
For assays, approximately 20 nauplii (in 50 μl filtered seawater) were added to 1 ml test solution or control, in a 2 ml glass vial (La Pha Pack® PN 11-14-0544). Assays were run for 22-24 hours at 25-27° C. After this time, living and dead nauplii were counted using a Bogorov tray. Nauplii that were approaching death were scored as dead. Data for all assays was combined and LD50 was calculated (where possible) using a probit analysis (Libermann, 1983). If LD50 could not be calculated using probit analysis, values were extrapolated based on plotted data.
Settlement Assays
Settlement assays (using barnacle cyprids) were based on methodology described in Rittschof et al. (1992). Nauplii were cultured as described above, and then reared at 25° C. on an algal mixture of 1:1 v/v of Tetraselmis suecica and Chaetoceros muelleri (approximately density 5×10 5 cells per ml). Under these conditions, nauplii typically metamorphose to cyprids in 5 days. Cyprids were aged at 4° C. for 2 days. Settlement in filtered seawater controls after aging is generally 45-70%.
Settlement assays were conducted in 7 ml neutral glass vials (Samco® T103/V1; 34×23 mm diameter). For assays, each solution was made at twice the desired final concentration; 0.5 ml of this solution was transferred to vials. To each vial, cyprids were added by transferring 0.5 ml filtered seawater containing 20-40 aged cyprids. As in toxicity assays: each compound at each concentration was run in triplicate with cyprids from a single batch; two controls (filtered seawater and DMSO) were run along with each assays; and the overall assay was conducted twice, using two different batches of cyprids.
Assays were conducted for 24 hours, after which time the number of settled cyprids, the number of free swimming (unsettled) cyprids, and the number of dead cyprids were counted for each vial. Both metamorphosed, juvenile barnacles and cyprids that had committed to settlement (glued themselves to the vial), but had not yet metamorphosed, were counted as ‘settled’. Data was expressed as percent settlement. Data for all assays was combined and ED50 (the concentration that caused a 50% reduction in settlement as compared to controls) was calculated (where possible) using a probit analysis (Libermann, 1983). If ED50 could not be calculated using probit analysis, values were extrapolated based on plotted data.
Results
Biological activity for the compounds is shown in Tables 1 and 2. Data is from assays with batches of larvae, and three replicates of each compound per batch. Where LD 50 or ED 50 could not be calculated using probit analysis, values were estimated from plotted data. Compounds with a high LD 50 value (low toxicity), but low ED 50 (highly potency) are most desirable for anti-fouling purposes. A number of the tested compounds show a therapeutic ratio equal to, or greater than previously identified non-functionalised compounds (12.1 and 12.2; PCT/SG2009/000175)
TABLE 1
Biological activity.
Compound
LD 50 (μg/ml)
ED 50 (μg/ml)
TR (LD 50 /ED 50 )
12.1
9.11
1.50
6.07
(reference)
12.2
9.83
2.00
4.92
(reference)
15.1
22.95
0.19
120.79
15.2
>25
1.46
>17.12
15.3
3.67
2.85
1.29
15.4
8.22
3.29
2.5
15.5
8.66
2.16
4.01
15.6
33.21
9.12
3.64
15.7
>25
1.75
14.29
16.1
>50
4.11
>12.17
16.2
>50
13.4
>3.73
16.3
>50
6.35
>7.87
16.4
27.2
0.23
118.26
16.5
17.15
0.19
90.26
16.6
>50
9.25
>5.41
16.7
24.58
26.88
0.91
16.8
>50
29.05
1.72
16.9
>50
>50
NA
16.10
>50
3.49
>14.33
16.11
6.57
1.53
4.29
ED 50 values are anti-settlement (tested with barnacle cyprids); LD 50 values are toxicity (tested with barnacle nauplii).
TABLE 2
Biological activity.
Compound
LD 50 (μg/ml)
ED 50 (μg/ml)
TR (LD 50 /ED 50 )
17.1
9.27
2.37
3.91
17.2
>50
8.69
>5.75
17.3
18.61
2.85
6.53
17.4
14.62
0.65
22.49
17.5
25.14
3.44
7.31
17.6
9.82
2.14
4.59
17.7
>50
34.12
>1.46
17.8
12.46
4.29
2.90
17.9
>50
>50
1
ED 50 values are anti-settlement (tested with barnacle cyprids); LD 50 values are toxicity (tested with barnacle nauplii).
Biological screening therefore indicates that functionalized molecules retained or improve upon desirable biological activity (high potency against barnacle cyprid settlement, yet low toxicity).
Compounds with a high LD 50 value (low toxicity), but low ED 50 (highly potency) are most desirable for anti-fouling purposes. All the compounds gave therapeutic ratios greater than 1.
The above results demonstrate that these new small organic molecules can be used as environmentally benign antifouling additives. These molecules retain effective anti-settlement activity despite differing substituents and substitution patterns on the aromatic ring. Indeed, a number of the compounds display bioactivity comparable to, or better than that of the unsubstituted parent structure. These new molecules improve upon the parent structure in that they can support functionality which can be used to tether or anchor the antifouling compounds to a marine coating system.
The compounds can be blended into existing acrylate paints and are therefore practical alternatives to the current coating options. Furthermore, due to their simple structure the compounds are attractive candidates for degradation via bacterial means in the marine environment and are less likely to accumulate and pose a health risk in the future. In addition, given that existing organic biocides such as Diuron® and Sea-Nine® have been shown to bioaccumulate and cause detrimental effects in the marine environment, the compounds of the present invention represent a valuable alternative to traditional metal-based additives.
Examples Part 4—Polymeric Systems
Release Studies
Preparation of Multiwell Plates for Laboratory Assays
Two batches of polystyrene 4×6 multiwell plates (base of the well 2 cm 2 ) were prepared for laboratory assays. A stock solution of polymer was made by dissolving 50 mg of P(MMA-co-16.11-co-VP) in 1.0 ml of ethanol. The plates were coated with the desired amount of the stock solution (10 μL, 20 μL, 30 μL, 40 μL, 50 μL and 70 μL) and placed in air at 27° C. for 6 hours. Then deionised water was added into those wells. After 24 hours the water was removed completely from the wells and stored for further analysis. The polystyrene plates were then dried under a stream of dry air. Meanwhile, the control specimens were prepared in the same way without water soaking.
Settlement Assay
The coatings were tested for antifouling effects using barnacle cyprid settlement assays. Cyprids were cultured as described above. After 5 days, cyprids were obtained and they were aged at 4° C. for 2 days before the settlement experiment. For experiment, cyprids were added by transferring 1 ml filtered seawater containing 20-40 aged cyprids into each well. The multi-well plates were incubated for 24 hours, after which time the number of settled cyprids, the number of free swimming (unsettled) cyprids, and the number of dead cyprids were counted for each well.
The result of the assay is given in FIG. 1 . For all treatments, cyprid mortality was less than 10%. Settlement on the control coating, P(MMA-co-tBA-co-VP), was similar to that for uncoated polystyrene. Wells coated with P(MMA-co-16.11-co-VP) showed reduction in cyprid settlement, with no settlement observed for treatments >40 μl.
Quantification by HPLC
Aliquots of solutions obtained after soaking for 24 hours were mixed with a known volume of the internal standard and directly injected into a HPLC system and monitored at 226 nm. The amount of 16.5 released into the solutions obtained after soaking are shown below in Table 3 along with the calculated release rate. In each case, the amount of 16.5 released falls in a very narrow range (0.15-0.45 μg), representing the similar surface area exposed to the aqueous environment in each case, regardless of the quantity of polymer.
TABLE 3
Mass released and calculated release rates of
16.5 released from coated wells after 24 hours.
Volume of
P(MMA-co-
Mass of
16.11-co-VP)
P(MMA-co-
Released
Release Rate
stock solution
16.11-co-VP)
16.5 (μg)
(μg cm 2 day −1)
10 μL
500 μg
0.247
0.124
20 μL
1000 μg
0.136
0.0677
30 μL
1500 μg
0.212
0.106
40 μL
2000 μg
0.400
0.200
50 μL
2500 μg
0.242
0.121
70 μL
3500 μg
0.430
0.215
FIG. 1 shows average percentage settlement of barnacles in the coated wells. P(MMA-co-tBA-co-VP) was applied as the control coating. Settlement on this coating was similar to that for uncoated polystyrene. Increased amounts of P(MMA-co-16.11-co-VP resulted in decline in barnacle settlement, with no settlement for test treatments >40 μl. In all treatments, cyprid mortality was less than 10%.
Following successful release of active compound 16.5 from the polymer, analysis was carried out into the hydrolysis of compound 16.11 from the polymer to release compound 16.5 into solution.
Preparation of Coated Vials for Laboratory Analysis
The inner base of glass vials with an internal diameter of 12 mm was matted with coarse sandpaper and then inoculated with a stock solution of P(MMA-co-16.11-co-VP) in ethanol such that the quantity of copolymer present is 500 μg and 2500 μg of P(MMA-co-16.11-co-VP) respectively, covering a surface area of 1.13 cm 2 . The vials were allowed to cure overnight prior to the addition of 2 mL of deionised water was added to each well. After 24 hours, the water was removed and replaced by 2 mL of fresh deionised water. The process was repeated after a further 24 hours and again for a further 48 hours giving a time course of 1, 2 and 4 days. Aliquots of the collected solutions were run against an internal standard (phenol), monitoring the response ratio at 226 nm. The resulting mass of 16.5 released at the specified time points are shown in Table 4.
In each case the presence of 16.5 in the water was confirmed by analysis of the aliquots by analytical HPLC— ESI.
TABLE 4
Mass of 16.5 released from polymer coated vials after 24 hours
Mass of
P(MMA-co-
16.11-co-VP)
Mass of 16.5 released (μg)
coating
Day 1
Day 2
Day 3-4
Day 5-7
500 μg
0.482
0.0064
0.046
0.0054
0.572
0.0022
0.039
0.0086
0.534
0.0018
0.083
0.0096
2500 μg
0.067
0.0042
0.0031
0.0263
0.034
0.0051
0.0013
0.0233
0.050
0.0091
0.0053
0.0350
The average release rates for the first four days are shown in Table 5. The strikingly different release rates of the 500 μg and 2500 μg coated vials on day 1 (0.468 μg cm 2 day −1 and 0.045 μg cm 2 day −1 respectively) reflect the different surface roughness of the coatings at the start of the release studies. After day 1 it can be seen that the release rates converge and this level of release is sustained at similar levels over the next 6 days.
TABLE 5
Release rate of 16.5 from P(MMA-co-16.11-
co-VP) coated vials as a function of time.
Mass of
P(MMA-co-
16.11-co-VP)
Average release rate of 16.5 (μg cm −2 day −1 )
Coating
Day 1
Day 2
Day 4
Day 7
500 μg
0.482
0.0031
0.0089
0.0049
2500 μg
0.0448
0.0054
0.0031
0.0083
REFERENCES
A number of patents and publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
Armarego, W. L. F.; C. L. L. Chai. 2003. Purification of Laboratory Chemicals; 5th ed.; Butterwortth-Heinemann: Sydney. Brar, A. S, and R. Kumar. ‘Investigation of Microstructure of the N-Vinyl-2-pyrrolidone/Methyl Methacrylate Copolymers by NMR Spectroscopy’ Inc. J Appl Polym Sci 85: 1328-1336, 2002. Libermann H. R. ‘Estimating LD 50 using the probit technique: a basic computer program’ Drug Chem. Toxicol 1983, 6, 111-116. Pitombo F. B. 2004. Phylogenetic analysis of the Balanidae (Cirripedia, Balanomorpha). Zool. Scr. 33: 261-276. Rittschof D.; Clare, A. S.; Gerhart, D. J.; Avelin, M. Sr.; Bonaventura, J. ‘Barnacle in-vitro assays for biologically active substances: toxicity and settlement inhibition assays using mass cultured Balanus amphitrite amphitrite Darwin’ Biofouling 1992, 6, 115-122. Rittschof D.; Branscomb, E.; Costlow, J. ‘Settlement and behavior in relation to flow and surface in larval barnacles, Balanus amphitrite Darwin’ J. Exp. Mar. Biol. Ecol. 1984, 82, 131-146. Teo, L. M. S., D. Rittschof, F. Jameson, C. Chai, C. L. Chen, S. C. Lee. Antifouling compounds for use in marine environment. PCT Int. Appl. (2009), WO2009139729 A1. Voulvoulis, N. ‘Antifouling paint booster biocides: occurrence and partitioning in water and sediments’ In: Konstantinou, I. K. (ed). Antifouling Paint Biocides. The Handbook of Environmental Chemistry, 2006, Volume 5, Part O, pp. 155-170. Springer-Verlag Berlin-Heidelberg. | The present invention relates to derivatives of α,α-disubstituted amide compounds which comprise a substituted aryl at the α carbon such that the substituent provides a means for attachment or incorporation of the compound to or in a polymer. The provision of such a substituent on the aryl has surprisingly been found not only to permit attachment to or incorporation in a polymer but also retention of useful antifouling activity. In embodiments, the substituent is selected from hydroxyl, ethers, esters, carboxyls, alkylsilyls and alkenyls. Experiments demonstrate that antifouling activity can be as good or better as the corresponding unsubstituted compound and that polymers functionalized so as to include or be formed from the substituted compound can be used to reduce settlement. | 2 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] None.
STATEMENT REGARDING SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not applicable.
REFERENCE TO SEQUENCE LISTING, A TABLE, OR COMPUTER LISTING COMPACT DISC APPENDIX
[0003] Not applicable.
[0004] ©2008 Lane B. Scheiber and Lane B. Scheiber II. A portion of the disclosure of this patent document contains material, which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure, as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever.
BACKGROUND OF THE INVENTION
[0005] 1. Field of the Invention
[0006] This invention relates to any medical device that is utilized to filter the blood of a patient infected with the Human Immunodeficiency Virus with the intention of terminating T-Helper cells infected with the Human Immunodeficiency Virus genome.
[0007] 2. Description of Background Art
[0008] It is estimated by the Center for Disease Control that in the United States 55,000 to 60,000 new cases of Human Immunodeficiency Virus (HIV) are occurring each year. It is thought that there are 900,000 people currently infected with HIV in the United States, with many victims not aware that they have contracted the virus. Further, it has been estimated that the Human Immunodeficiency Virus (HIV), the pathogen that causes Acquired Immune Deficiency Syndrome (AIDS), has infected as many as 30-60 million people around the globe.
[0009] The presence of HIV was first came to the attention of those in the United States in 1981, when there appeared an outbreak of Kaposi's Sarcoma and Pneumocystis carinii pneumonia in gay men in New York and California. After over twenty-five years of research and investigation, eradicating the ever growing global humanitarian crisis posed by the HIV remains an elusive goal for the medical community. It is estimated the virus has already killed 25 million citizens of this planet.
[0010] The Human Immunodeficiency Virus has been previously referred to as human T-Lymphotrophic virus III (HTLV-III), lymphadenopathy-associated virus (LAV), and AIDS-associated retrovirus (ARV). Infection with HIV may occur by the virus being transferred by blood, semen, vaginal fluid, or breast milk. Four major means of transmission of HIV include unprotected sexual intercourse, contaminated needles, breast milk, and transmission from an infected mother to her baby at birth.
[0011] HIV is an ingeniously constructed very deadly virus, which represents the most challenging pathogen the worldwide medical community faces to date. Viruses in general, have been difficult to contain and eradicate due to the fact they are obligate parasites and tend not to carry out any biologic functions outside the cell the virus has targeted as its host. A virus when it exists outside the boundaries of a cell is generally referred to as a virion. HIV virions posses several attributes that make them very elusive and difficult to destroy.
[0012] Bacterial infections have posed an easier target for the medical community to eradicate from the body. Bacteria generally live and reproduce outside animal cells. Bacteria, like animal cells, carryout biologic functions. A large multi-celled organism such as the human body combats bacterial infections with a combined force of white cells, antibodies, complements and its lymphatic system. White cells circulate the body in search of bacteria. When a white cell encounters a bacterium, the white cell engulfs the bacterium, encapsulates the pathogen, processes the identification of the pathogen and kills the pathogen utilizing acids and destructive enzymes. The white cell then alerts the B-cells of the immune system as to the identity of the intruding bacterium. A subpopulation of B-cells is generated, dedicated to producing antibodies directed against the particular pathogen the circulating white cell encountered and identified. Antibodies, generated by B-cells, traverse the blood and body tissues in search of the bacteria they were designed to repel. Once an antibody encounters a bacterium it is targeted to attack, the antibody attaches to the bacterium's outer wall. The effect antibodies have in coating the outside of a bacterium is to assist the white cells and the other components of the immune system in recognizing the bacterium, so that appropriate defensive action can be taken against the pathogen. Some antibodies, in addition to coating the bacterium, will act to punch holes through the bacterium's outer wall. If the integrity of the bacterium's cell wall is breached, this action generally leads to the death of the bacterium. Complements are primitive protein structures that circulate the blood stream in search of anything that appears consistent with a bacteria cell wall. Complements are indiscriminant. Once the complement proteins locate any form of bacterial cell wall, the complement proteins organize, and much like antibodies, act in concert to punch one or more holes though a bacterium's cell wall to compromise the viability of the bacterium. The lymphatic system is a diffuse network of thin walled vessels that drain excess water from extracellular fluids and join to form the thoracic duct and right lymph duct, which empty into the venous system near the heart. Lymph nodes are present at different locations in the body and screen the fluid transiting the lymphatic system, called lymph, to remove pathogens. Cells in the spleen screen the blood in search of bacteria. When a bacterial pathogen is identified, such as by antibodies coating the surface, the bacterium is taken out of circulation and terminated.
[0013] Viruses pose a much different infectious vector to the body's defense system than either bacteria or cellular parasites. Since viruses do not carry out biologic processes outside their host cell, a virus can be destroyed, but they cannot be killed. A virus is simply comprised of one or more external shells and a portion of genetic material. The virus's genetic information is carried in the core of the virus. Antibodies can coat the exterior of a virus to make it easier for the white cells in the body to identify the viral pathogen, but the action of punching holes in the virus's external shell by antibodies or complement proteins does not necessarily kill the virus. Viruses also only briefly circulate in the blood and tissues of the body as an exposed entity. Using exterior probes, a virus hunts down a cell in the body that will act as an appropriate host so that the virus can replicate. Once the virus has found a proper host cell, the virus inserts its genome into the host cell. To complete its life-cycle, the virus's genetic material takes command of cellular functions and directs the host cell to make replicas of the virus.
[0014] Once the virus's genome has entered a host cell, the virus is in effect shielded from the body's immune system defense mechanisms. Inside a host cell, the presence of the virus is generally only represented as genetic information incorporated into the host cell's DNA. Once a virus has infected a cell in the body, the presence of the virus can only be eradicated if the host cell is destroyed. Antibodies and complements are generally designed not to attack the autologous tissues of the body. Circulating white cells and the immune cells which comprise lymph nodes and the spleen may or may not recognize that a cell, which has become a host for a virus, is infected with a virus's genome. If the immune system fails to identify a cell that has become infected with a virus, the virus's genetic material can proceed to force the infected cell to make copies of the virus. Since a virus is in essence simply a segment of genetic material, time is of no consequence to the life-cycle of the virus and a virus's genome may be carried for years by the host without a need to activate; such viruses are often termed latent viruses. A virus's genetic material may sit idle in a host cell for an extended period of time until the pathogen's programming senses the time is right to initiate the virus's replication process or an action of the host cell triggers the virus to replicate. The only opportunity for the immune system to destroy a latent virus is when copies of the virus leave the host cell and circulate in the blood or tissues in search of another perspective host cell.
[0015] The traditional medical approach to combating infectious agents such as bacteria and cellular parasites, therefore has limited value in managing or eradicating elusive or latent viral infections. Synthetic antibiotics, generally used to augment the body's capacity to produce naturally occurring antibodies against bacterial infections, have little success in combating latent viral infections. Stimulating the body's immune system's recognition of a virus by administering a vaccine also has had limited success in combating elusive viral infections. Vaccines generally are intended to introduce to the body pieces of a bacteria or virus, or an attenuated, noninfectious intact bacteria or virus so that the immune system is able to recognize and process the infectious agent and generate antibodies directed to assist in killing the pathogen. Once the immune system has been primed to recognize an intruder, antibodies will be produced by the immune system in great quantities in an effort to repel an invader. Over time, as the immune system down-regulates its antibody production in response to a lack of detecting the presence of the intruding pathogen, the quantity of antibodies circulating in the blood stream may decrease in number to a quantity that is insufficient to combat a pathogen. Since antibodies have limited value in combating some of the more elusive viruses that hibernate in host cells, vaccines have limited value in destroying latent viruses.
[0016] The Human Immunodeficiency Virus demonstrates four factors which make this pathogen particularly elusive and a difficult infectious agent to eradicate from the body. First: the host for HIV is the T-Helper cell. The T-Helper cell is a key element in the immune system's response since it helps coordinate the body's defensive actions against pathogens seeking to invade the body's tissues. In cases of a bacterial infection versus a viral infection, T-Helper cells actively direct which immune cells will rev-up in response to the infectious agent and engage the particular pathogen. Since HIV infects and disrupts T-Helper cells, coordination of the immune response against the virus is disrupted, thus limiting the body's capacity to mount a proper response against the presence of the virus and produce a sufficient action to successfully eradicate the virus.
[0017] Second: again, latent viruses such as HIV, have a strategic advantage. When the immune system first recognizes a pathogen and begins to generate antibodies against a particular pathogen, the response is generally robust. Once time has passed and the immune system fails to detect an active threat, the production of antibodies against the particular pathogen diminishes. When HIV infects a T-Helper cell, the viral genome may lay dormant, sometimes for years before taking command of the T-Helper cell's biologic functions. HIV may, therefore, generate a very active initial immune response to its presence, but if the virus sits dormant inside T-Helper cells for months or years, the antibody response to the virus will diminish over time. There may not be an adequate quantity of circulating antibodies to actively engage the HIV virions as they migrate from the T-Helper cell that generated the copies to uninfected T-Helper cells that will serve as a new host to support further replication. If the immune system's response is insufficient during the period while the virus is exposed and vulnerable, it becomes extremely difficult for the body to eradicate the virus.
[0018] Third, when replicas of the Human Immunodeficiency Virus are released from their host cell, during the budding process the HIV virion coats itself with an exterior envelope comprised of a portion of the plasma membrane from the T-Helper cell that acted as the host for the virus. A T-Helper cell's plasma membrane is comprised of a lipid bilayer, a double layer of lipid molecules oriented with their polar ends at the outside of the membrane and the nonpolar ends in the membrane interior. The virus thus, in part, takes on an external appearance of a naturally occurring cell in the body. Since the exterior envelope of a HIV virion has the characteristics of a T-Helper cell it is more difficult for the immune system to recognize that it is a pathogen as it migrates through the body in search of another T-Helper cell to infect.
[0019] Fourth, the Human Immunodeficiency Virus exhibits a very elusive mode of action which the virus readily utilizes to actively defeat the body's immune system. HIV carries in its genome a segment of genetic material that directs an infected T-Helper cell to create and mount on the surface the plasma membrane a FasL cell-surface receptor. Healthy T-Helper cells carry on the surface of their plasma membrane Fas cell-surface receptors. The Fas cell-surface receptor when engaged by a FasL cell-surface receptor on another cell, initiates apoptosis in the cell carrying the Fas cell-surface receptor. Apoptosis is a biologic process that causes a cell to terminate itself. A T-Helper cell infected with the HIV virus carrying a FasL cell-surface receptor is therefore capable of killing noninfected T-Helper cells that the infected T-Helper cell encounters as it circulates the body. The occurrence of AIDS is therefore propagated not only by the number of T-Helper cells that become incapacitated due to direct infection by HIV, but also by the number of noninfected T-Helper cells that are eliminated by coming in direct contact with infected T-Helper cells.
[0020] Acquired Immune Deficiency Syndrome (AIDS) occurs as a result of the number of circulating T-Helper cells declining to a point where the immune system's capacity to mount a successful response against opportunistic infectious agents is significantly compromised. The number of viable T-Helper cells declines either because they become infected with the HIV virus or because they have been killed by encountering a T-Helper cell infected with HIV. When there is an insufficient population of non-HIV infected T-Helper cells to properly combat infectious agents such as Pneumocystis carinii or cytomegalo virus or other pathogens, the body becomes overwhelmed with the opportunistic infection and the patient becomes clinically ill. In cases where the combination of the patient's compromised immune system and medical assistance in terms of synthetic antibiotics intended to combat the opportunistic pathogens, fluids, intravenous nutrition and other treatments are not sufficient to sustain life, the body succumbs to the opportunistic infection and death ensues.
[0021] The Human Immunodeficiency Virus locates its host by utilizing probes located on its envelope. The HIV virion has two types of glycoprotein probes attached to the outer surface of its exterior envelope. A glycoprotein is a structure comprised of a protein component and a lipid component. HIV utilizes a glycoprotein 120 (gp 120) probe to locate a CD4 cell-surface receptor on the plasma membrane of a T-Helper cell. The plasma membrane of the T-Helper cell is comprised of a lipid bilayer. Cell-surface receptors are anchored in the lipid bilayer. Once an HIV gp 120 probe has successfully engaged a CD4 cell-surface receptor on a T-Helper cell a conformational change occurs in the gp 120 probe and a glycoprotein 41 (gp 41) probe is exposed. The gp 41 probe's intent is to engage a CXCR4 or CCR5 cell-surface receptor on the plasma membrane of the same T-Helper cell. Once a gp 41 probe on the HIV virion engages a CXCR4 or CCR5 cell-surface receptor, the HIV virion opens an access portal through the T-Helper cell's plasma membrane.
[0022] Once the virus has gained access to the T-Helper cell by opening a portal through the cell's outer membrane the virion inserts two positive strand RNA molecules approximately 9500 nucleotides in length. Inserted along with the RNA strands are the enzymes reverse transcriptase, protease and integrase. Once the virus's genome gains access to the interior of the T-Helper cell, in the cytoplasm the pair of RNA molecules are transformed to deoxyribonucleic acid by the reverse transcriptase enzyme. Following modification of the virus's genome to DNA, the virus's genetic information migrates to the host cell's nucleus. In the nucleus, with the assistance of the integrase protein, the virus's DNA becomes inserted into the T-Helper cell's native DNA. When the timing is appropriate, the now integrated viral DNA, becomes read by the host cell's polymerase molecules and the virus's genetic information commands certain cell functions to carry out the replication process to construct copies of the human deficiency virus.
[0023] Present anti-viral therapy has been designed to target the enzymes that assist the HIV genome with the replication process. Anti-viral therapy is intended to interfere with the action of these replication enzymes. Part of the challenge of eradicating HIV is that once the virus inserts its genome into a T-Helper cell host, the viral genome may lay dormant until the proper circumstances evolve. The virus's genome may sit idle inside a T-Helper cell for years before becoming activated, causing drugs that interfere with HIV's life cycle to have limited effect on eliminating the virus from the body. Arresting the replication process does not insure that T-Helper cells infected with HIV do not continue to circulate the body killing noninfected T-Helper cells thus causing the patient to progress to a clinically apparent state of Acquired Immune Deficiency Syndrome and eventually succumbing to an opportunistic infection which eventually results in the death of the individual.
[0024] The outer layer of the HIV virion is comprised of a portion of the T-Helper cell's outer cell membrane. In the final stage of the replication process, as a copy of the HIV capsid, carrying the HIV genome, buds through the host cell's plasma membrane, the capsid acquires as its outermost shell a wrapping of lipid bilayer from the host cell's plasma membrane. Vaccines are generally comprised of pieces of a virus or bacterium, or copies of the entire virus or bacterium weakened to the point the pathogen is incapable of causing an infection. These pieces of a pathogen or copies of a nonvirulent pathogen prime the immune system such that a vaccine intent is to cause B-cells to produce antibodies that are programmed to seek out the surface characteristics of the pathogen comprising the vaccine. In the case of HIV, since the surface of the pathogen is an envelope comprised of lipid bilayer taken from the host T-Helper cell's plasma membrane, a vaccine comprised of portions of the exterior envelope of the HIV virions might not only target HIV virions, but might also have deleterious effects on the T-Helper cell population. Some antibodies produced to combat HIV infections may not be able to tell the difference between an HIV virion and a T-Helper cell, and such antibodies may act to coat and assist in the elimination of both targets. In such a scenario, since such a vaccine might cause a decline in the number of available T-Helper cells, it is conceivable that a vaccine comprised of portions of the external envelope of HIV virions might paradoxically induce clinically apparent AIDS in a patient that a vaccine has been administered.
[0025] It is clear that the traditional approach of utilizing antibiotics or providing vaccines to stimulate the immune system to produce endogenous antibodies, by themselves, is an ineffective strategy to manage a virus as elusive and deadly as HIV. Drugs that interfere with the replication process of HIV generally slow progression of the infection by the virus, but do not necessarily eliminate the virus from the body nor eliminate the threat of the clinical symptoms of AIDS. A new strategy is required in order to successfully combat the threat of HIV.
[0026] Dialysis is generally thought of as a means of removing waste products in patients whose kidneys are no longer capable of effectively filtering the blood and eliminating waste from the body. One option immediately available to reduce the load of T-Helper cells infected with the HIV genome circulating in the blood is by engaging them in a filter chamber with a specially constructed filter medium utilizing a reverse logic with regards to how an infected T-Helper cell would engage and kill a non-infected T-Helper cell, and use this action utilized by an infected T-Helper cell to identify T-Helper cells infected by HIV and terminate them. Reducing the number of HIV infected T-Helper cells would forestall, if not prevent, the onset of AIDS by eliminating T-Helper cells acting as hosts for the virus and eliminating the population of T-Helper cells that act to kill healthy T-Helper cells.
[0027] As mentioned earlier, HIV carries in its genome a segment of genetic material that directs an infected T-Helper cell to create and mount on its surface a FasL receptor. T-Helper cells carry, on the surface of their cell plasma membrane a Fas receptor. The Fas receptor, when triggered, initiates apoptosis in the cell. Apoptosis is a biologic process that causes a cell to terminate itself. A T-Helper cell infected with the HIV virus is therefore capable of killing noninfected T-Helper cells that the infected T-Helper cell encounters as it circulates the body. The occurrence of AIDS is therefore enhanced not only by the number of T-Helper cells that become incapacitated due to direct infection by the HIV virus, but also by the number of noninfected T-Helper cells that are eliminated by coming in contact with infected T-Helper cells.
[0028] Fas receptors and FasL receptors could be affixed to a filter medium composed of lipid bilayer material or any hypoallergenic material that cell-surface receptors could be affixed to the outer surface. The lipid bilayer material or the hypoallergenic surface material could be in the shape of a sheet, a strip or a sphere. A sheet could take the shape of a square, a rectangle, or the ends could be attached and the sheet could take the shape of a cylinder. A strip could take the shape of a long thin strand where the length is much greater in dimension than the width, or the shape of a coil, or if the ends are attached the strip could take the shape of a ring or circle. The sphere could take the shape of a ball or a cylinder or an ellipsoid.
[0029] A lipid bilayer filter medium or a hypoallergenic filter medium with Fas and FasL cell-surface receptors could be used as a filter medium in the filter chamber described in this text. Inside a filter chamber, as blood passed through the chamber, a Fas receptor affixed to the surface of the filter medium would engage a FasL receptor located on an infected T-Helper cell. Once the FasL receptor on the infected T-Helper cell has been engaged by a Fas receptor affixed to the filter medium, a FasL receptor affixed to the same filter medium would then engage a Fas cell-surface receptor on the same infected T-Helper cell. When the filter medium's FasL receptor engages a Fas cell-surface receptor on an infected T-Helper cell this action would cause apoptosis to be triggered in the infected T-Helper cell. Triggering apoptosis in an HIV infected T-Helper cell will cause the cell to kill itself. By terminating HIV infected T-Helper cells, the HIV infection could be prevented from proceeding because by terminating the host cells utilized by HIV, HIV would not be able to replicate itself and HIV virions would no longer emerge to infect additional T-Helper cells.
[0030] Constructing a virus-like structure, with the surface characteristics of a virus, that has affixed to its exterior cell-surface receptors intended to engage a T-Helper cell, is referred to as a Scientifically Modulated And Reprogrammed Target (SMART) virus. Such a structure could be simply a sphere of lipid bilayer material with cell-surface receptors attached to the outer surface as described previously, or such structures may carry a filler substance in order to maintain the integrity of the shape of the structure. As the size of the spheres comprised of lipid bilayer material is increased, as needed to be utilized as a filter medium, an inert filler substance may be needed to be placed inside the sphere in order for the sphere to retain their spherical shape. Copies of such a SMART virus could be placed in a filter chamber. Such a filler substance inside the virus-like structure may be represented by a protein or a genetic material that would serve no useful purpose other than acting as a filler. The diameter of the SMART virus could be increased to a size larger than the naturally occurring T-Helper cell to facilitate containing the SMART virus inside the filter chamber as the blood passes through the filter chamber. The SMART virus would be available and remain within the walls of the chamber to engage T-Helper cells as the blood transits through the filter chamber.
[0031] Bilayer lipid sheets, hypoallergenic surfaces, scientifically modified and reprogrammed treatment (SMART) viruses otherwise known as virus-like structures, can all be created to act as a filter medium and possess on their surface both Fas and FasL cell-surface receptors. These filter mediums can be fashioned such that the Fas receptor could be physically more prominent than the FasL receptor. The Fas receptor on the surface of a filter medium can be physically mounted further out from the FasL receptor, or in a manner likened as to how HIV is constructed with the gp 120 and gp 41 probes, the Fas receptor may hide the FasL receptor. On the surface of the naturally occurring HIV virion the gp 120 probe covers the gp 41 probe. When the gp 120 probe engages a CD4 cell-surface receptor a conformation change occurs in the gp 120 probe such that the gp 41 probe becomes exposed so that the gp 41 probe can engage either a CXCR4 or CCR5 cell-surface receptor located on the surface of a healthy T-Helper cell. On the surface of a filter medium the Fas receptor would be constructed to be engaged first by an infected T-Helper cell, and once engaged, the FasL receptor affixed to the filter medium would become available to engage a Fas receptor located on an infected T-Helper cell.
[0032] Cell-surface receptors are comprised of a protein portion and a lipid portion. The protein portion acts as the receptor. The lipid portion acts as the anchor to fix the cell-surface receptor into the lipid bilayer on the surface of a cell or on the surface of a HIV virion. The lipid portion of the cell-surface receptor could be altered to adjust the distance the protein portion of the cell-surface receptor is physically from the surface of the lipid bilayer. By adjusting the construction, thereby increasing the length of the lipid portion of the Fas cell-surface receptor, the Fas cell-surface receptor affixed to the filter medium could be fashioned to be engaged before a FasL cell-surface receptor affixed to the filter medium is engaged. Alternately the protein portion of the cell-surface receptor closest to the lipid portion of the cell-surface receptor could be lengthened such that increasing the length of the protein portion of the Fas cell-surface receptor, the Fas cell-surface receptor affixed to the filter medium could be fashioned to be engaged before a FasL cell-surface receptor affixed to the filter medium is engaged. Alternatively, the lipid or protein portion of the FasL cell-surface receptor affixed to the surface of a filter medium could be shortened such that the Fas cell-surface receptor affixed to the filter medium is engaged before a FasL cell-surface receptor affixed to the filter medium could be engaged. The intention of positioning the Fas and FasL cell-surface receptors as described is to evoke the action of the T-Helper cells infected with Human Immunodeficiency Virus genome engaging said cell-surface receptors found on the surface of said filter medium in the manner described will trigger apoptosis inside the T-Helper cells infected with the Human Immunodeficiency Virus genome for the purpose of terminating T-Helper cells infected with the Human Immunodeficiency Virus genome, but because the Fas cell-surface receptor affixed to the filter medium must be engaged before a FasL cell-surface receptor affixed to the filter medium can be engaged, T-Helper cells not infected with HIV and other cells expressing a Fas cell-surface receptor will not be harmed by transiting through the described medical filter device.
[0033] This technology has a much broader range of beneficial medical treatment uses beyond simply eliminating T-Helper cells infected with the HIV genome from the blood. All cells have cell-surface receptors. Many cells in the body have affixed to their surface cell-surface receptors that are unique to the specific type of cell. By utilizing the concept of mounting on a filter medium specialized cell-surface receptors that engage a unique cell-surface receptor located on the surface of a specific target cell circulating in the blood, specific target cells which also express a Fas cell-surface receptor on their surface can be caused to be terminated, with such action resulting a beneficial medical outcome. To accomplish this, on a filter medium would be affixed specialized cell surface receptors and FasL cell-surface receptors. The specialized cell-surface receptors would be constructed to be more prominent than the FasL cell-surface receptors, such that the specialized cell-surface receptors would be engage before a FasL cell-surface receptor could be engaged. As blood transits through a filter chamber with the above-mentioned filter medium contained inside, specific target cells would come in contact with the filter medium. Once the unique cell-surface receptor located on the specific target cell engaged a specialized cell-surface receptor affixed to the filter medium, then the FasL cell-surface receptor affixed to the filter medium would engage a Fas cell-surface receptor on the specific target cell. By the action of the FasL cell-surface receptor affixed to the filter medium engaging the Fas cell-surface receptor located on the specific target cell, the signal of apoptosis would be triggered in the specific target cell and the specific target cell would terminate itself. By physically constructing the cell-surface receptors on the filter medium such that the specialized cell-surface receptor must be engaged before the FasL cell-surface receptors can be engaged, facilitates that cells that do not carry the unique cell-surface receptor such as affixed to the surface of the specific target cell, will not be harmed by transiting through the medical filter device.
[0034] Such a filter device could be used to treat patients with cancers such as various forms of leukemia. Forms of leukemia flood the circulating blood with numerous leukemic cells. The presence of this abundance of leukemic cells interferes with the function of normal blood cells and blood plasma. For several forms of leukemia such as chronic lymphocytic Leukemia (CLL), the medical treatment approach has provided very limited benefit. Often for CLL patients, available chemotherapy treatment produces side effects that are worse than the effects of the CLL on the patient. Patients with CLL often suffer for years with the leukemia adversely affecting their bodies. A filter medium designed to utilize specialized cell-surface receptors to engage one or more unique cell-surface receptors on a leukemic cell, which once a leukemic cell would be engaged, then FasL receptors on the filter medium could engage one or more Fas cell-surface receptors on the leukemic cell, the result of which would be the leukemic cell would receive the signal that would tell the leukemic cell to terminate itself. Successfully terminating leukemic cells would reduce the quantity of circulating leukemic cells. A reduction in the quantity of circulating leukemic cells would improve beneficial performance of blood in such patients.
[0035] Other medical conditions such as parasitic infections, where a parasite has infected a blood cell and the infected blood cell expresses a unique cell-surface receptor and a Fas cell-surface receptor, such an infected cell could be terminated by a similar strategy as described above.
[0036] Any cell that is harmful to the body that circulated in the blood, that carries a unique cell-surface receptor and carries a Fas cell-surface receptor could be terminated by the above-mentioned strategy and thus eliminated from the body, to produce a medically beneficial effect.
[0037] A filter device could be fashioned to be placed inside the body to act to continuously filter the blood and terminate cancer cells of a particular type that transit the blood stream. Concerns regarding metastatic cancer could be treated by such a device. Metastatic cancer occurs when cells from a primary cancer site in the body leave the primary site and migrate through the blood and develop one or more secondary or satellite sites of cancer in the body. Once a person is found to have a cancer, or in an individual who is at high risk for developing metastatic cancer, a filter could be placed in a blood vessel, a vein or an artery, and such a filter would continuously filter the blood and engage only the cancer cells that transit through the filter allowing all other blood cells to pass through unharmed. Knowing the type of cancer the filter was created to engage, the filter medium could be created to have fixed to its surface specialized cell-surface receptors that engage unique cell-surface receptors on the surface of the specific type of targeted cancer cell. A cancer cell of a specific type that transits through the filter would be engaged by the specialized cell-surface receptor affixed to the filter medium. Once the specific type of cancer cell is engaged, a FasL cell-surface receptor located on the filter medium would engage a Fas cell-surface receptor located on the cancer cell and such an action would trigger apoptosis in the cancer cell and the cancer cell would terminate itself. The filter device would not need to be renewed and the filter device would not clog blood flow because the cancer cells would exit the filter chamber, cell death would ensue at a later time and such cells would then eventually be removed from circulation and re-absorb by the body. Such a device could be fashioned to be inserted in a vessel of the lymphatic system to constantly filter lymph and engage and terminate infected T-Helper cells or other specific target cells as they transit through the filter device. Cancers often spread locally from a primary site through the lymphatic system and such a filter device could be inserted into a vessel of the lymphatic system downstream to a primary site of cancer to screen and terminate any cancer cells that had migrated from the primary site of the cancer.
[0038] Similarly, a patient infected with HIV or patient at high risk for infection with HIV, could have a small filter placed inside their body. Such a filter could continuously screen the blood with the intention that any T-Helper cell infected with the HIV genome that is expressing both FasL and Fas cell-surface receptors that transit though the filter device will be engaged. Once a Fas cell-surface receptor affixed to the filter medium inside the filter device has been engaged by a FasL cell-surface receptor located on an infected T-Helper cell, a FasL cell-surface receptor affixed to the filter medium would then engage a Fas cell-surface receptor on the infected T-Helper cell. When the filter medium's FasL cell-surface receptor engages a Fas cell-surface receptor located on an infected T-Helper cell this action will cause apoptosis to be triggered in the infected T-Helper cell. Triggering apoptosis in a cell will cause the cell to kill itself. By this means infected T-Helpers, the host cell of HIV, can be continuously eliminated from the body. Such a filter would not need to be renewed and the filter would not clog blood flow because the infected T-Helper cells would exit the filter chamber, cell death would ensue at a later time and such cells would be removed from circulation and be re-absorb by the body.
BRIEF SUMMARY OF THE INVENTION
[0039] A T-Helper cell infected with the Human Immunodeficiency Virus genome express FasL cell-surface receptors and Fas cell-surface receptors on its exterior surface. This medical filter device is intended to engage T-Helper cells circulating in the blood. The filter medium contained inside the filter device has affixed to its surface Fas and FasL cell-surface receptors. The Fas cell-surface receptors affixed to the surface of the filter medium located inside the device are more prominent than the FasL cell-surface receptors located on the surface of the filter medium. As infected T-Helper cells transit the filter device, the FasL cell-surface receptors they carry will engage Fas cell-surface receptors affixed to the filter medium. Once a FasL cell-surface receptor on an infected T-Helper cell has engaged a Fas cell-surface receptor affixed to the filter medium, a FasL cell-surface receptor affixed to the filter medium will engage a Fas cell-surface receptor located on the surface of the infected T-Helper cell. By having a FasL cell-surface receptor affixed to the filter medium engage a Fas cell-surface receptor located on an infected T-Helper cell, the process of apoptosis is triggered in the T-Helper cell carrying the Fas cell-surface receptor. Activating the process of apoptosis in a cell leads to cell death. By terminating T-Helper cells that are infected with the Human Immunodeficiency Virus genome leads to an effective means for averting AIDS. A similar strategy utilizing specialized cell-surface receptors and FasL cell-surface receptors can be employed to terminate specific target cells such as cancer cells and cells harboring parasites for the purpose of achieving a beneficial medically therapeutic outcome. A medical device constructed with a filter medium can be fashioned to be placed in a vessel of the lymphatic system which would continuously screen lymph and terminate cancer cells or other target cells to result in a medically beneficial outcome.
DETAILED DESCRIPTION OF THE INVENTION
[0040] The invention described herein is intended to terminate T-Helper cells infected with Human Immunodeficiency Virus and other specific target cells such as cancer cells and host cells harboring parasites, as they circulate in fluid such as blood or lymph. The medical device may be used in an intermittent dynamic process such as where blood is actively removed from an individual, the blood transits through one or more filtering devices and the cleansed blood is then returned to the same individual. The medical device may be used in a process which is more static, where a specific quantity of blood is removed from one individual, the blood products transit through one or more filtering devices and this now cleansed blood or separate blood products are, at a later time, infused into one or more individuals in need of such blood products. The medical device may be used in a continuous dynamic process, where a filter device is inserted in a blood vessel or a lymphatic vessel inside the body, which such a medical device constantly acts to filter the blood or lymph and engage and terminate infected T-Helper cells or other specific target cells as they transit through the filter device.
[0041] The medical device described herein, intended to terminate T-Helper cells infected with HIV genome as they exist in blood, is comprised of a chamber, where blood is introduced into the chamber at one location, the blood comes into contact with a filter medium, the blood exits the chamber at a different location than where the blood plasma entered the chamber. The filter medium inside the filter chamber may be comprised of several different materials and designs. The filter medium is intended to make available cell-surface receptors including Fas and FasL for T-Helper cells infected with HIV genome to engage. The filter medium may be comprised of a quantity of lipid bilayer sheets which are comprised of similar materials as found existing as the outer membrane of a T-Helper cell, and affixed to the said lipid bilayer sheets are glycoprotein cell-surface receptors including a quantity of Fas cell-surface receptors and FasL cell-surface receptors. Such bilayer sheets may be of any suitable shape which might include such shapes as the shape of a square, the shape of a rectangle, the sheet may be attached to itself to be the shape of a cylinder. The filter medium may be comprised of a quantity of lipid bilayer strips which are comprised of similar materials as found existing as the outer membrane of a T-Helper cell, and affixed to the said lipid bilayer strips are glycoprotein cell-surface receptors including a quantity of Fas cell-surface receptors and FasL cell-surface receptors. Such strips may be long and thin and may include any suitable shape such as a long thin strand, or the shape of a coil or one end may be attached to another end to form the shape of a ring or circle. The filter medium may be comprised of a quantity of lipid bilayer spheres which are comprised of similar materials as found existing as the outer membrane of a T-Helper cell, and affixed to the said lipid bilayer spheres are glycoprotein cell-surface receptors including a quantity of Fas cell-surface receptors and FasL cell-surface receptors. The shapes of the spheres may include any suitable shape such as the shape of a ball, the shape of cylinder, the shape of an ellipsoid. The filter medium may be comprised of a quantity of virus-like structures with cell-surface receptors to include a quantity of Fas cell-surface receptors and FasL cell-surface receptors. The filter medium may be comprised of any suitable hypoallergenic material, which can be affixed to the surface a quantity of Fas cell-surface receptors and FasL cell-surface receptors or simply the protein portion of the Fas cell-surface receptors and FasL cell-surface receptors. The shape of the hypoallergenic material may include a variety of suitable shapes including the shape of a sheet, shape of a strip or shape of a sphere.
[0042] The material to be used to create the walls of such a filter chamber may include any suitable hypoallergenic material such as glass, rigid plastic, a flexible plastic, latex, steel, aluminum or other metal or metal alloy. A tube to carry blood or blood plasma to the filter chamber would be attached to the portal where the blood or blood plasma would enter the filter chamber. A tube would be attached to the portal of the filter chamber where the blood or blood plasma would exit the chamber to carry the filtered blood or blood plasma away from the chamber. The tubing carrying blood or blood plasma to the filter chamber and the tubing carrying blood or blood plasma away from the filter chamber would be comprised of any hypoallergenic material such as a flexible plastic, rigid plastic, a flexible metal or a rigid metal or latex. A porous barrier located at the portal where the blood or blood plasma enters the filter chamber and a porous barrier located at the portal where the blood or blood plasma exits the filter chamber would be comprised of materials such as a flexible plastic, a rigid plastic, a flexible metal or a rigid metal or latex. The said porous barriers are comprised of a quantity of holes, said holes large enough to allow said blood or blood plasma to freely exit said chamber, but said holes are restrictive enough so as to retain said filter medium inside the inner boundaries of said chamber as said blood or blood plasma transits through said chamber. The filter medium contained inside the filter chamber may be free-floating within the inner boundaries of the filter chamber or may be physically fixed to the chamber such that the filter medium does not move freely inside the filter chamber and cannot exit the filter chamber.
[0043] Lipid bilayer sheets, strips, spheres can be manufactured and combinations of Fas cell-surface receptors and FasL cell-surface receptors can be affixed to the surface with the entire structure acting as a filter medium. Sheets of any suitable hypoallergenic material can be manufactured and combinations of Fas cell-surface receptors and FasL cell-surface receptors can be affixed to the surface with the structure acting as a filter medium. Sheets of any suitable hypoallergenic material can be manufactured and combinations of the protein portion of the Fas cell-surface receptors and FasL cell-surface receptors attached to the surface of the hypoallergenic surface and made available to engage either glycoprotein probes on HIV or cell-surface receptors on a T-Helper cell, with the structure acting as a filter medium.
[0044] To carry out the process to manufacture a virus-like structure, DNA or RNA code that would provide the necessary biologic instructions to generate the general physical outer structures of the virus-like structure, would be inserted into a host. The host may include devices such as a host cell or a hybrid host cell. The host may utilize DNA or RNA or a combination of genetic instructions in order to accomplish the construction of medically therapeutic virus-like structures. In some cases DNA or messenger RNA would be inserted into the host that would be coded to cause the production of cell-surface receptors that would be affixed to the surface of the virus-like structure that would target the glycoprotein probes affixed to the surface of an HIV virion or the FasL and Fas cell-surface receptors on infected T-Helper cells. The copies of the medically therapeutic virus-like structures, upon exiting the host, would be collected, stored and utilized as a filter medium in the described filter chamber as necessary.
[0045] The medically therapeutic version of the virus-like structures would be incapable of replication on its own due to the fact that the messenger RNA or DNA that would code for the replication process to produce copies of the virus-like structure would not be present in the virus-like structures.
[0046] The medical device intended to terminate T-Helper cells infected with the HIV genome is comprised of a chamber, where blood is introduced into the chamber at one location, the blood comes into contact with a filter medium, the blood exits the chamber at a different location than where the blood entered the chamber. The filter medium inside the filter chamber is fashioned to express on its surface a quantity of Fas cell-surface receptors and FasL cell-surface receptors. The Fas cell-surface receptors are mounted on the surface of the filter medium in a manner that they are to be engaged before the FasL cell-surface receptors can be engaged.
[0047] The invention described herein is intended to terminate T-Helper cells infected with the HIV genome from a fluid such as blood. The filtering process may be intermittently dynamic such as blood that is actively removed from an individual, the blood transits through one or more filtering devices and the cleansed blood is then returned to the same individual. In the filtering process as the blood from the individual makes contact with the filter medium inside the filter device terminates T-Helper cells infected with the HIV virus. Blood cleansed of HIV is returned to the same individual.
[0048] The filter device may be used in a more static process, where a specific quantity of blood is removed from one individual, the blood products transit through one or more filtering devices and this now cleansed blood or separate blood products are, at a later time, infused into one or more other individuals in need of such cleansed blood products. The blood permanently removed from the first individual makes contact with the filter medium inside the filter device terminates T-Helper cells infected with the HIV virus. Blood removed from the first individual, now cleansed of HIV infected T-Helper cells, is then provided to one or more other individuals requiring such blood.
[0049] The medical device may be used in a continuous dynamic process, where a filter device is inserted in a blood vessel inside the body, which constantly acts to constantly filter the blood and engage and terminate infected T-Helper cells as they transit through the filter device.
[0050] This technology has a much broader range of beneficial uses beyond just eliminating T-Helper cells infected with the HIV genome from the blood. All cells have surface cell receptors. Many cells in the body have affixed to their surface cell-surface receptors that are unique to the specific type of cell. By utilizing the concept of mounting on a filter medium specialized cell-surface receptors that engage a unique cell-surface receptor located on the surface of a specific target cell circulating in the blood, specific target cells can be caused to be terminated, with such action resulting a beneficial medical outcome. To accomplish this, on a filter medium would be affixed specialized cell surface receptors and FasL cell-surface receptors. The specialized cell-surface receptors would be constructed to be more prominent than the FasL cell-surface receptors, such that the specialized cell-surface receptors would be engaged before a FasL cell-surface receptor could be engaged. As blood transited through a filter chamber with the above-mentioned filter medium contained inside, specific target cells would come in contact with the filter medium. Once the unique cell-surface receptor on the specific target cell engaged a specialized cell-surface receptor on the filter medium, then the FasL cell-surface receptor on the filter medium would engage a Fas cell-surface receptor on the specific target cell. By the action of the FasL cell-surface receptor affixed to the filter medium engaging the Fas cell-surface receptor located on the specific target cell, the signal of apoptosis would be triggered in the specific target cell and the specific target cell would terminate itself. By constructing the cell-surface receptors on the filter medium such that the specialized cell-surface receptor must be engaged before the FasL cell-surface receptor can be engaged, facilitates that cells that do not carry the unique cell-surface receptor such as affixed to the surface of the specific target cell will not be harmed by transiting through the filter device.
[0051] Such a filter device could be used to treat patients with cancers such as various forms of leukemia. Forms of leukemia flood the circulating blood with numerous leukemic cells. The presence of this abundance of leukemic cells interferes with the function of normal blood cells and blood plasma. For several forms of leukemia such as chronic lymphocytic Leukemia (CLL), the medical treatment approach has provided very limited benefit. Often for CLL patients, available chemotherapy treatment produces side effects that are worse than the effects of the CLL on the patient. Patients with CLL often suffer for years with the leukemia adversely affecting their bodies. A filter medium designed to utilize specialized cell-surface receptors to engage one or more unique cell-surface receptors on a leukemic cell, which once a leukemic cell would be engaged, then FasL receptors on the filter medium could engage one or more Fas cell-surface receptors on the leukemic cell, the result of which would be the leukemic cell would receive the signal that would tell it to terminate itself. Successfully terminating leukemic cells would reduce the quantity of circulating leukemic cells. A reduction in the quantity of circulating leukemic cells would improve beneficial performance of blood.
[0052] Other medical conditions such as parasitic infections, where a parasite has infected a blood cell and the infected blood cell expresses a unique cell-surface receptor and a Fas cell-surface receptor, such an infected cell could be terminated by a similar strategy as described above.
[0053] Any cell that is harmful to the body that circulated in the blood, that carries a unique cell-surface receptor and carries a Fas cell-surface receptor could be terminated by the above-mentioned strategy and thus eliminated from the body, to produce a medically beneficial effect.
[0054] The medical device may be constructed to exist outside the body and engage in an intermittent dynamic process where blood is actively removed from an individual, the blood transits through one or more filtering devices and the cleansed blood is then returned to the same individual. The medical device may be constructed to exist outside the body and engage in a more static process where a specific quantity of blood is removed from one individual, the blood products transit through one or more filtering chambers and this now cleansed blood or separate blood products are, at a later time, is infused into one or more individuals in need of such blood products. The medical device may be constructed as a device to be inserted in a blood vessel inside the body, which the medical device constantly acts to filter the blood and engage and terminate specific target cells such as infected T-Helper cells, cancer cells, host cells infected by a parasite, as such cells transit through the filter device.
[0055] Portions of the lymphatic system can be continuously filtered with such a medical device. Utilizing the concept of mounting on a filter medium specialized cell-surface receptors that engage a unique cell-surface receptor located on the surface of a specific target cell transiting the lymph, specific target cells can be caused to be terminated, with such action resulting a beneficial medical outcome. To accomplish this, on a filter medium would be affixed specialized cell surface receptors and FasL cell-surface receptors. The specialized cell-surface receptors would be constructed to be more prominent than the FasL cell-surface receptors, such that the specialized cell-surface receptors would be engage before a FasL cell-surface receptor could be engaged. As lymph transits through a filter chamber with the above-mentioned filter medium contained inside, specific target cells would come in contact with the filter medium. Once the unique cell-surface receptor on the specific target cell engages a specialized cell-surface receptor on the filter medium, then the FasL cell-surface receptor on the filter medium would engage a Fas cell-surface receptor on the specific target cell. By the action of the FasL cell-surface receptor affixed to the filter medium engaging the Fas cell-surface receptor located on the specific target cell, the signal of apoptosis would be triggered in the specific target cell and the specific target cell would terminate itself. By constructing the cell-surface receptors on the filter medium such that the specialized cell-surface receptor must be engaged before the FasL cell-surface receptor can be engaged, facilitates that cells that do not carry the unique cell-surface receptor such as affixed to the surface of the specific target cell will not be harmed by transiting through the filter device. Such a medical device could be fashioned to be inserted in a vessel of the lymphatic system to constantly filter lymph to engage and terminate infected T-Helper cells or other specific target cells as they transit through the medical device.
DRAWINGS
[0056] None. | The Human Immunodeficiency Virus posses a significant threat to the world's population. Current strategies have not been adequate to contain and eradicate this deadly viral infection. HIV utilizes a T-Helper cell as a host to generate replicas of itself. Reversing HIV's own biologically deadly tactics and developing blood filtering techniques that incorporate filter mediums that engage the cell-surface receptors uniquely located on the surface of a T-Helper cell infected with the HIV genome can lead to terminating the infected T-Helper cells. Filter mediums possessing cell-surface receptors intended to terminate infected T-Helper cells by triggering apoptosis, is an effective means to eliminate HIV's host cells and thus provides a valuable strategy to prevent and treat AIDS. Similar techniques can be utilized to terminate other types of cells that act as hosts for pathogens as well as terminating cancer cells. | 0 |
The invention described herein was made in the course of work under a grant or award from the Department of Health and Human Services.
BACKGROUND OF THE INVENTION
Plasma contains a variety of proteins which have specific biologic functions, some known and well defined for a given protein, some still to be determined. Any plasma protein deficiency occurring either as a congenital disease or as an acquired state associated with a pathologic condition may indicate the need for replacement therapy. Because of technologic advances in the collection, storage and fractionation of plasma, a single unit of blood can now supply many concentrated, purified proteins for different therapeutic uses. For example, plasma was formerly the mainstay of hemophilia A and hemophilia B therapy; it is now used only when no other source of Factor VIII or Factor IX (the respective deficient factors) is available. It is currently considered poor practice to use unfractionated materials except in an emergency, because of the difficulty of achieving adequate and sustained therapeutic levels of the deficient materials without inducing circulatory overload. With the introduction of new techniques for protein purification and the recognition of congenital or acquired pathological states associated with specific protein deficiency, a number of plasma derivatives or concentrated fractions have been made available for the treatment of specific plasma protein deficiencies.
Prothrombin complex concentrates are clinically employed in current replacement therapy for patients with deficiencies of the vitamin K-dependent clotting Factors II, VII, IX and X. These concentrates, also referred to as Factor IX concentrates, Factor IX complex concentrates, and PPSB (prothrombin, proconvetin, Stuart factor, and antihemophilic B factor), have demonstrated efficacy in the treatment of hemophilia B (Christmas disease) by alleviating hemorrhagic episodes and preventing post-surgical complications. The efficacy of these Factor IX concentrates for replacement therapy in deficiencies of prothrombin (Factor II), Factor VII, and Factor X is also generally accepted, although the incidence of congenital deficiency of these factors is much rarer, and fewer data are available. Factor IX complex concentrates have, however, been implicated as a cause of thromboembolic complications and disseminated intravascular coagulation (DIC), particularly in patients with acquired deficiencies of the vitamin K-dependent clotting factors, especially those with liver disease. In patients with hemophilia B, thrombohemorrhagic complications occasionally result from infusions of conventional Factor IX complex concentrates. The reaction to these concentrates may be quite severe, with manifestations including superficial vein thrombosis, deep vein thrombosis, pulmonary embolism, and myocardial infarction. Fatalities believed to be directly attributable to commercial Factor IX complex concentrates have been documented.
While attempts have been made to devise reliable in vitro methods for the prediction of potential thrombogenicity in Factor IX complex concentrates and to identify the agent or agents present in these concentrates responsible for inducing thromboembolic complications, the results have been inconclusive. Experiments with animal models have demonstrated a correlation between non-activated partial thromboplastin time (NAPTT) and in vivo assays for thrombogenicity; the thrombingeneration test (TGt50) also correlates with in vivo test results. Using these and other in vitro tests, in conjunction with in vivo assays in animal models, researchers have suggested various causes of the thrombogenic activity associated with Factor IX complex concentrates prepared by standard methods, including Factors Xa, IXa, VIIa, and factors of the contact phase; Factor XIIa activation of prekallikrein; and high levels of zymogens extraneous to the deficient factor in the concentrates. Also considered as a possible factor in the adverse activity of the concentrates is Factor VIII bypassing activity. Unfortunately, available in vitro tests, including NAPPT and TGt50 are not reliably predictive of clinical thrombogenicity, and in vivo animal studies have proved inconclusive for various reasons. The lack of reliable in vitro tests and the impracticality of extensive in vivo testing has seriously hampered research attempts to isolate the causative agent or agents of the documented thromboembolic complications. As succinctly stated by Coan, et at. in "Properties of Commercial Factor IX Concentrates" (Ann. N.Y. Acad. Sci., 731-746; 734, 789, 1981), "Various investigators have proposed at one time or another than any of the activated coagulation factors are the cause of thrombogenicity. These include Factors VIIa, IXa, Xa, and XIa. There are no consistent results. The actual thrombogenic agent may be none, one, several or all of the above . . . . Results [of extended investigations] suggest that some as yet unidentified component of the Factor IX preparation may well be involved in the occurrence of thrombogenic reactions independent of the state or concentration of the major vitamin K-dependent factors."
It is accordingly highly desirable to provide concentrated plasma protein fractions useful for replacement therapy in congenital or acquired deficiencies of vitamin K-dependent clotting factors but which have little or no thrombogenic potential. From a practical standpoint, it is particularly desirable to provide a Factor IX concentrate devoid of thrombogenic agents but retaining clinical activity for the control of hemorrhage in hemophilia B patients, owing to the relatively more common incidence of this deficiency disease.
SUMMARY OF THE INVENTION
The invention is predicated on the identification of products useful in replacement therapy for congenital and acquired deficiencies of vitamin F-dependent clotting factors having little or no thrombogenic potential, as assessed by animal models based on the Wessler venous stasis technique (Wessler, et al., "Biologic Assay of a Thrombosis-inducing Activity in Human Serum", J. Appl. Physiol., 14:943-946 1959) and a modification of the method of Prowse and Williams (Prowse, et at., "A Comparison of the In Vitro and In Vivo Thrombogenic Activity of Factor IX Concentrates Using Stasis and Non-stasis Rabbit Models", Thromb. Haemostas., 44:82-86, 1980). Pursuant to the postulation that vitamin K-dependent clotting factors in conventional Factor IX complex concentrates which are extraneous to the deficient factor are responsible for thromboembolic complications in recipients of replacement therapy by overloading the coagulation mechanism, non-thrombogenic plasma protein fractions for replacement therapy have been developed which are substantially devoid of extraneous vitamin K-dependent clotting factors. In particular, it has been discovered that conventional Factor IX complex concentrate purified with respect to Factors II, VII, and X has little or no potential for causing thromboembolic complications in hemophilia B recipients based on animal safety data; similarly, Factor X concentrate purified with respect to Factors II, VII and IX exhibits little or no thrombogenic potential, again based on animal safety data. The invention accordingly provides a method for the treatment of vitamin K-dependent clotting factor deficiencies comprising a replacement therapy based on the administration of a plasma protein fraction concentrated with respect to the deficient clotting factor and substantially devoid of extraneous clotting factors. In particular, the invention provides a method for the treatment of hemophilia B comprising a replacement therapy based on the administration of a Factor IX plasma concentrate substantially devoid of Factors II, VII, and X, and a method for the treatment of a Factor X deficiency comprising a replacement therapy based on the administration of a Factor X plasma concentrate substantially devoid of Factors II, VII, and IX. The invention further provides an improved plasma concentrate of a vitamin K-dependent clotting factor suitable for clinical use in replacement therapy, and a method of preparing the improved concentrate.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a flow diagram exemplifying the preparation of Factor IX and Factor X concentrates according to the invention;
FIG. 2 is a graph of fibrinogen levels over time (non-stasis model) after administration of the concentrates of the invention; and
FIG. 3 is a graph of Wessler venous stasis scores after administration of the concentrates according to the invention.
DETAILED DESCRIPTION OF THE INVENTION
According to the invention, a Factor IX concentrate substantially devoid of Factors II, VII and X is employed in replacement therapy for the treatment of hemophilia B in humans. Suitable starting materials for the preparation of this concentrate are whole plasma, plasma cryosupernatant, or Cohn Effluent I. Such starting materials are then purified to substantially remove clotting Factors II, VII and X, for example by anion-exchange chromatography on DEAE-Sephadex or DEAE-cellulose followed by adsorption on a water-insoluble cross-linked sulfated polysaccharide gel matrix of the type described in U.S. Pat. No. 3,842,061 to Andersson, et at. Commercial Factor IX complex concentrates can also be employed as starting material, in which case the initial step of anion-exchange chromatography can usually be eliminated. A particularly useful procedure for the purification of Factor IX is described by Miletich, et at., in "The Synthesis of Sulfated Dextran Beads for Isolation of Human Coagulation Factors II, IX and X" (Anal. Biochem., 105:304-310, 1980). In the improved process of the invention for the preparation of concentrates suitable for clinical use, the Miletich procedure is modified by elimination of the initial step of barium precipitation, and omission of treatment with diisopropylfluorophosphate and benzamidine, to avoid the possibility that these toxic materials might be present in the infusion in harmful quantities. Preferably, adsorption of the starting Factor IX complex concentrate is followed by stepwise elution or gradient elution with increasing concentrations of NaCl to permit recovery of the Factor II, X and Protein C by-products. Factor X concentrates according to the invention for use in replacement therapy for deficiencies of this factor conveniently comprise the Factor X fraction eluted according to the purification scheme of the invention, exemplified in the flow diagram illustrated in FIG. 1. Since Protein C functions as an anticoagulant, it is surprising that the Factor IX concentrate purified with respect to this protein is non-thrombogenic.
The resultant purified concentrates are substantially devoid of extraneous clotting factors and exhibit substantially no thrombogenic potential as measured by the Wessler venous stasis technique in rabbits, at the therapeutic dosage levels. Preferred Factor IX concentrates for clinical use contain extraneous clotting Factors II, VII and X in amounts of less than about 1%, 0.5%, and 5% by specific activity (u/mg) of Factor IX, respectively, and, most preferably, are substantially devoid of these extraneous clotting factors. Preferred Factor X concentrates for clinical use contain Factors II, VII, and IX in amounts of less than about 1%, 0.5%, and 15% by specific activity of Factor X, respectively, and, most preferably, are substantially devoid of these extraneous clotting factors.
The reduced risk of thrombotic episodes attendant upon the clinical use of the purified Factor IX and X concentrates according to the present invention also permits infusions of these factors at higher dosage levels for more effective therapy. While dosage levels comparable to those recommended by standard clinical protocols for Factor IX complex concentrates are highly effective, if desired, dosages in excess of these levels, for example, up to twice the standard dosage, may be used, based upon the toxicity data obtained from animal trials. Generally, dosages sufficient to bring the deficient factors to a circulating level of from about 30% to about 50% of normal are recommended, usually requiring from about 30 to 50 units/kg body weight.
EXAMPLES
A. Purification of Factor IX Complex Concentrates
Example 1
Several batches of Factor IX concentrate were prepared according to the flow diagram illustrated in FIG. 1. For each liter of human cryosupernatant plasma, 1.7 g of DEAE-Sephadex A-50 (previously swollen in 0.07 M Na-Citrate, pH 6.0) was added. The mixture was stirred gently for 1 hr, the supernatant decanted and the resin collected in a polyethylene Buchner funnel (70μ porosity) and washed with 0.07 M Na-Citrate, pH 6.0 until the A 280 reached a plateau value of about 0.2 and the color of the resin changed from deep green to light blue (approximately 0.64 l/l original plasma). The Factor IX-containing fraction was then eluted with 0.2 M Na-Citrate, pH 6.0 (approximately 0.08 l/l original plasma). The DEAE-Sephadex eluate was diafiltered into 0.15 M NaCl, 0.02 M Na-Citrate, pH 6.0, to a final volume of 15 ml/l original plasma and was then loaded onto a column of sulfated dextran (previously equilibrated with 0.15 M NaCl, 0.02 M Na-Citrate, pH 6.0) which was prepared by the method of Miletich, et al. For each liter of original plasma, 10 ml of sulfated dextran was required. After the breakthrough protein eluted from the column, the NaCl concentration was increased to 0.25 M to elute the prothrombin; Factor X was eluted with 0.45 M NaCl and Factor IX was eluted with 0.8 M NaCl. All the eluting solutions contained 0.02 M Na-Citrate, pH 6.0. The stepwise elution of the clotting factors from the sulfated-dextran column yields prothrombin, a Factor X concentrate contaminated with both Protein C and a small but significant amount of Factor IX and a Factor IX concentrate essentially free of Factor X and prothrombin. A summary of a purification is shown in Table 1. The overall yield of Factor IX is 18% with an 880-fold increase in specific activity. Based on the specific activity of pure human Factor IX of 325 or 275, the resultant Factor IX concentrate is between 5 and 6% pure in terms of protein. On an activity basis, this preparation of Factor IX contains less than 1% of either prothrombin or Factor X contamination. Factor X contamination of Factor IX concentrate is typically below 4% while prothrombin contamination is typically below 1%.
B. Evaluation of Thrombogenicity of Purified Factor IX Concentrate
Example 2
Stasis Rabbit Model.
A model using the venous stasis technique of Wessler, et al., supra, was employed for testing several batches of purified Factor IX concentrate obtained according to Example 1. The jugular vein of a rabbit was ligated 10-15 seconds after injecting the sample to be tested in the marginal vein of the ear. The formation of thrombi in the isolated vein segment was determined by visual inspection after 10 minutes and scored from 0 to 4, a score of 4 indicating complete occlusion of the vessel. The results obtained on several batches of Factor IX concentrate from Example 1 are given in Table 2. Preparations were found to be non-thrombogenic with dosages of Factor IX concentrate ranging from 150 to as high as 380 units/kg of rabbit body weight. In contrast, a commercial Factor IX complex concentrate,
TABLE 1______________________________________FACTOR IX CONCENTRATE - CHARACTERISTICS Pro- Specific Units tein Activity Yield Ratio ×10.sup.-3 GM u/mg** % II:X:IX______________________________________Plasma 125* 6875 0.02 -- 1:1:1DEAE-Eluate 43* 20 2.15 34 1:0.5:0.9Sulfated-Dex-tran Fractions:Prothrombin 22.3 5.1 4.4 18 1:0.02:0Factor X 31.4 0.79 39.7 25 0.002:1:0.6Factor IX 22.9 1.3 17.6 18 0.002:0.004:1______________________________________ *Factor IX Units **A unit (u) is defined as the biological activity of a protein/ml of normal plasma.
TABLE 2______________________________________STASIS RABBIT MODEL Lot Dose (u/kg)**Preparation # IX X II Score______________________________________Commercial Factor IX -- 56.6 53.9 51.1 1Complex (containing 100.0 117.0 86.4 2Factors II, VII, IX, X )DEAE-Sephadex 16* 103.0 60.6 113.0 2A-50 EluateFactor IX 15* 150.0 4.5 0.9 0 15 201.0 6.0 1.2 0 16 201.0 0.5 0.3 0 16 380.0 0.97 0.6 0Prothrombin 16 -- -- 100.0 1 16 -- -- 200.0 3Factor X 16 12.2 139.0 0.3 1______________________________________ *Laboratory prepared lots. **A unit (u) is defined as the biological activity of a protein/ml of normal plasma.
as well as the DEAE-Sephadex eluate (obtained during the first step of the fractionation procedure of Example 1), both of which contain significant amounts of prothrombin and Factor X, induced clots with scores ranging from 1 to 2 when injecting dosages of Factor IX ranging from 56 to 100 units/kg.
Example 3
Non-Stasis Rabbit Model.
Comparable results were obtained when testing the DEAE-Sephadex eluate and the Factor IX concentrate of Example 1 using a rabbit non-stasis model. In this procedure, 3.6 to 4 kg male white rabbits were sedated with NEMBUTAL (27 mg/kg). A polyethylene cannula was introduced into the carotid artery. Blood samples were obtained from this cannula 30 minutes prior to and immediately before (0 time) the test material was injected at a rate of 2 ml/min. Blood samples were then taken at various times up to 2 hours after test sample injection. The blood samples (7 ml) were collected into plastic tubes containing 0.15 ml 1 M citrate. Three ml of the citrated blood was then placed into a second tube containing 6 mg of soybean trypsin inhibitor. The citrated sample was used for the coagulation factor assays and platelet count, while the soybean trypsin inhibitor-treated blood was used to measure fibrinogen. As shown in Table 3, the eluate containing Factor IX, prothrombin, and Factor X, when infused at 100 u/kg Factor IX, induced coagulation changes compatible with DIC as evidenced by a decrease in the platelet count, and decreased concentrations of Factors V and VIII, whereas the Factor IX concentrate, when infused at 200 u/kg, did not change the coagulation parameters apart from a slight decrease in the platelet count and a predictable rise in the Factor IX level (Table 4). Preliminary results
TABLE 3______________________________________DEAE-SEPHADEX A-50 ELUATE*NON-STASIS RABBIT MODEL Percent of Preinjection Value** Time (min) -30 0 15 30 60 90 120______________________________________Factor IX 100 98 168 165 153 121 107Factor X 100 110 460 426 347 282 287Prothrombin 100 98 620 606 478 450 398Factor VIII 100 94 92 93 59 39 26Factor V 100 105 103 94 64 39 28Fibrinogen 100 102 93 83 57 44 32Platelets 100 98 75 66 46 37 32______________________________________ *Dosage = 100 u/kg Factor IX? **Average of three (3) rabbits
TABLE 4______________________________________FACTOR IX CONCENTRATE*NON-STASIS RABBIT MODEL Percent of Preinjection Value Time (min) -30 0 30 60 90 120______________________________________Factor IX 100 89 517 288 360 306Factor X 100 100 100 93 96 92Prothrombin 100 98 92 89 91 84Factor VIII 100 101 121 103 110 100Factor V 100 100 96 96 88 88Fibrinogen 100 101 111 83 80 87Platelets 100 86 73 70 67 68______________________________________ *Dosage = 200 u/kg Factor IX **Average of three (3) rabbits
with three (3) rabbits showed that when prothrombin is tested in this model, minimal changes occur except for a decrease in platelet count and Factor VIII level. A modification of the non-statis model of Prowse, et al. (supra) and Triantaphyllopolous, "Intravascular Coagulation Following Injection of Prothrombin Complex", Am. J. Clin. Path., 57:603-610, 1972, was employed.
Example 4
Porcine Model.
Harrison, et al., (Clinical Research, 30:318a, 1982) reported that a more sensitive animal in which to assess the thrombogenicity of Factor IX concentrate is the mini-pig (small pig). The Harrison porcine model is a model developed for the evaluation of thrombogenicity of prothrombin complex concentrate. Internal jugular/superior vena cava I.V. silastic tubing was placed in 18 pigs aged 4 mos. (20-25 kgms) under general anesthesia. Catheter placement was observed for 24 hours before infusion. Sequentially obtained blood samples to monitor intravascular coagulation (IVC) including platelet count, PT, PTT, TT, procoagulant factors, fibrin monomer, and degradation products, were obtained for 24-48 hours after infusion. Postmortem examination was performed at the time of death or 14 days after infusion. Five (5) different sources of nonactivated and 2 sources of activated Factor IX complex concentrates (PCC) were infused. Seven of 8 pigs receiving >50 units/kgm as a single infusion of nonactivated PCC had 1+ to 4+ fibrin monomers at 15 minutes, whereas 7 of 8 receiving activated PCC had similar changes at doses >25 units/kgm. Evidence of severe IVC occurred in all 5 animals receiving 100 units/kgm of either material. Overt IVC was associated with decreased platelet count, fibrinogen, presence of fibrin monomers, and postmortem thrombosis. Subclinical IVC was associated with increased monomers with
TABLE 5__________________________________________________________________________Pig No. 13 treated with ARC - PTC concentrate No. 81-91at 50 u Factor IX/kg body weight__________________________________________________________________________ Pre 1 Pre 2 15.sup.+ 1 hr 2 hr 3 hr 4 hr 5 hr 6 hr__________________________________________________________________________Platelet Count* 245 265 235 270 140 185 147 140 150Capillary 8 2.6 2.5 1.8 2.1 2.1 2.1 2.0 2.0Fibrinogen** 1.8 2.6 2.6 1.8 2.1 2.1 2.1 2.0 2.0Protamine Test neg. neg. ± ± ± ± ± ± 2For FibrinMonomerProthrombin 14.7 15.3 13.5 16.5 17.0 17.0 16.9 16.9 8.8Time.sup.+ 15.9 16.0 14.3 16.8 17.8 17.8 17.3 17.3 9.8Partial Thrombo- 45.9 65.8 29.5 20.5 26.3 25.8 23.4 24.0 30.9Plastin time.sup.+ 47.3 66.0 30.8 22.3 26.4 26.5 24.3 25.3 31.3White Count* 30.5 22.6 36.0 32.3 21.3 29.0 26.2 27.2 27.2Fibrinogen.sup.++ 268 374 -35 441 222 353 342 276 308 8 hr 11 hr 24 hr 271/2 hr 30 hr 48 hr 53 hr 74 hr 95 hr__________________________________________________________________________Platelet Count* 150 165 145 160 120 165 130 204 150Capillary 2.2 2.2 2.1 2.2 2.0 1.8 2.0 2.0 2.2Fibrinogen** 2.2 2.3 2.1 2.2 2.2 2.0 2.0 2.2 2.2Protamine Test 2 2 1 1 1 + neg. neg. neg.For FibrinMonomerProthrombin 14.5 15.4 14.8 13.3 13.5 15.3 16.8 14.9 16.8Time.sup.+ 14.8 15.8 16.0 13.4 13.9 16.0 17.5 15.5 17.5Partial thrombo- 35.5 52.8 41.5 35.3 34.5 65.0 104.9 54.5 53.8Plastin time.sup.+ 36.8 64.5 44.8 37.5 35.3 69.8 113.4 58.8 68.9White Count* 23.5 28.9 24.2 20.3 16.2 19.4 18.5 23.5 19.1Fibrinogen .sup.++ 365 419 367 388 399 297 357 383 440__________________________________________________________________________ Gross autopsy results 8/31/81 revealed no scarring or regeneration relate to the PTC injection, however microscopic results indicated some evidence of thrombotic activity *X10.sup.3 /mm.sup.3 **Heatprecipitable fibrinogen, mm .sup.+ Seconds (duplicate samples) .sup.++ Clottable fibrinogen, mg/dl
variable changes in platelet count and fibrinogen, but postmortem evidence of renal injury. Control infusions (2 pigs) of albumin were negative.
Preliminary experiments were performed by these investigators with the DEAE-Sephadex eluate obtained according to Example 1, which contains Factors II, IX and X, and minor amounts of Factor VII (prior to adsorption and elution from sulfated dextran). This eluate was injected at a dose of 50 units of Factor IX/kg body weight and resulted in evidence of thrombotic activity (Table 5).
When one lot of purified Factor IX concentrate according to Example 1 was injected at a dose of 50 units/kg the gross autopsy revealed no scarring or regeneration related to the product and the microscopic results showed no abnormalities. The autopsy details are summarized in Table 6.
A purified Factor IX concentrate obtained according to Example 1 was injected at a level of 200 units/kg body weight. Autopsy results showed that all tissues were normal on gross examination, with no apparent residual scarring as a result of the infusion. Autopsy results are summarized in Table 7.
C. Preparation of Purified Factor IX Concentrate For Clinical Use
Example 5
The purified Factor IX concentrate obtained according to Example 1 was freeze-dried and stored at 1° to 10° C. The powdered concentrate was apportioned into dosages for clinical use. The dosages were reconstituted with 10 ml. of water prior to injection to provide an infusion isotonic with blood and of the following composition:
______________________________________Ingredient Ranges______________________________________Sodium Chloride 0.11 MSodium Citrate 20 mMTotal Protein 28 mg 25-31 mgFactor II (prothrombin) 2 units 1-4 unitsFactor X 4 units 2-8 unitsFactor VII <1 unitFactor IX 500 units 450-550 units ph ˜6.8______________________________________
D. Evaluation Of Thrombogenicity Of Purified Factor X Concentrate
Example 6
The Factor X fraction obtained after elution from sulfated-dextran with 0.45 M NaCl in the Factor IX purification procedure of Example 1 was tested for thrombogenicity according to the stasis and non-stasis models of Examples 2 and 3.
As illustrated in FIG. 2, in the non-stasis model (3 rabbits each) the eluate fraction containing Factors II, IX and X (DEAE), when infused at 100μ of the fraction per kilogram of body weight, induced coagulation changes compatible with DIC as evidenced by a decrease in fibrinogen level. In contrast, the purified Factor X concentrate only slightly lowered the fibrinogen level in this model. (The solid points in the graph have statistical significance at p<0.05, based on the Two-Tailed Student's t-Test.)
As illustrated in FIG. 3, in the stasis model, average scores (indicated by dotted lines) did not exceed 1 for the Factors II, IX, and X concentrates obtained according to Example 1. In contrast, the average score for the fraction containing Factors II, X, and IX (DEAE) was greater than 3.5. The average scores of the Factor IX and Factor X concentrates were the same; however, the Factor IX concentrate was administered at twice the dosage (200 u/kg) as the Factor X concentrate 100 u/kg.
TABLE 6__________________________________________________________________________Pig No. 14 treated with ARC Factor IX Concentrate Lot NO. 81-91at a level of 50 u/kg Factor IX (body weight)__________________________________________________________________________ Pre 1 Pre 2 15.sup.+ 1 hr 2 hr 3 hr 4 hr 5 hr 6 hr__________________________________________________________________________Platelet Count* 390 380 425 360 390 340 325 280 295Capillary 2.1 2.8 2.7 1.8 1.9 2.3 2.1 2.2 2.2Fibrinogen** 2.2 2.8 2.8 11 1.8 2.0 2.3 2.2 2.2 2.2Protamine Test neg. neg. neg. neg. neg. neg. neg. neg. neg.For FibrinMonomerProthrombin 13.9 14.0 15.5 18.0 17.5 19.0 18.0 18.9 14.5Time.sup.+ 14.3 14.8 15.8 18.8 19.8 20.3 19.3 20.3 14.8Partial thrombo- 31.0 30.0 57.8 26.0 26.3 25.0 26.3 32.8 29.5Plastin time.sup.+ 32.3 30.8 59.0 31.3 28.0 26.3 27.5 33.4 31.3White Count* 17.4 22.4 20.9 16.5 26.8 24.5 23.4 23.2 22.6Fibrinogen.sup.++ 369 422 516 330 297 435 423 435 281__________________________________________________________________________ 8 hr 11 hr 23 hr 27 hr 30 hr 48 hr 58 hr 74 hr 94 hr__________________________________________________________________________Platelet Count* 345 345 290 300 350 370 345 380 390Capillary 2.3 2.0 2.2 2.0 2.2 2.1 2.2 2.2 2.0Fibrinogen** 2.3 2.1 2.2 2.4 2.2 2.2 2.2 2.2 2.2Protamine Test neg. neg. neg. neg. neg. neg. neg. neg. neg.For FibrinMonomerProthrombin 15.0 16.0 14.5 15.0 15.3 13.9 15.0 14.8 14.8Time.sup.+ 15.3 16.3 14.8 15.3 15.5 14.8 15.8 14.9 15.0Partial thrombo- 31.0 43.9 58.3 49.4 46.5 49.5 46.6 49.0 32.5Plastin time.sup.+ 32.3 49.3 59.0 49.9 49.4 50.9 51.2 54.3 33.3White Count* 23.7 19.5 19.2 23.1 27.0 19.1 23.7 21.5 19.0Fibrinogen.sup.++ 393 415 367 370 339 408 374 435 472__________________________________________________________________________ Gross autopsy reults 9/1/81 revealed no scarring or regeneration related to the Factor IX concentrate injected. Commercial concentrates of PTC yield significant changes at the above dosage level. *X10.sup.3 /mm.sup.3 **Heatprecipitable fibrinogen, mm .sup.+ Seconds, duplicate samples .sup.++ Clottable Fibrinogen, mg/dl
TABLE 7__________________________________________________________________________Pig No. 17 treated with ARC Factor IX concentrate Lot 18-91at a level of 200 IU/kg body weight__________________________________________________________________________ Pre 1 Pre 2 Pre 3 15.sup.+ 30.sup.+ 1 hr 2 hr__________________________________________________________________________Platelet Count* 595 430 380 360 320 370 275Capillary -- 1.5 1.7 1.6 1.4 1.4 1.2Fibrinogen** -- 1.5 1.7 1.6 1.4 1.6 1.4Protamine Test -- neg. neg. neg. neg. neg. ±For FibrinMonomerProthrombin 16.5 15.0 13.3 18.4 16.9 17.3 16.0Time.sup.+ 16.8 -- 13.5 18.8 17.8 17.5 16.3Partial thrombo- 16.0 24.5 19.3 15.5 15.0 15.0 11.8Plastin Time.sup.+ 16.3 24.3 19.5 17.3 15.8 16.3 12.5White Count* 14.0 13.4 11.5 7.3 3.5 5.6 4.5Fibrinogen.sup.++ 300 300 340 320 280 300 260__________________________________________________________________________ 3 hr 4 hr 5 hr 6 hr 7 hr 8 hr 111/2 hr__________________________________________________________________________Platelet Count* 225 235 175 215 205 220 270Capillary 1.2 1.4 1.5 1.4 1.4 1.4 1.4Fibrinogen** 1.2 1.4 1.5 1.4 1.5 1.4 1.5Protamine Test 4+ 4+ ± ± neg. neg.For FibrinMonomerProthrombin 18.0 16.5 14.9 13.1 14.4 14.0 13.4Time.sup.+ 18.8 16.8 15.4 13.9 14.5 14.3 13.8Partial Thrombo- 57.6 14.5 22.0 16.0 18.0 18.5 17.5Plastin Time.sup.+ 62.5 15.3 22.3 16.3 18.8 19.4 18.8White Count* 4.4 4.7 5.0 4.6 6.7 7.0 6.7Fibrinogen.sup.++ 240 280 300 280 300 280 300__________________________________________________________________________ 221/2 hr 24 hr 26 hr 28 hr 49 hr 521/2 hr 77 hr 95 hr__________________________________________________________________________Platelet Count* 325 345 270 295 385 340 370 475Capillary 1.4 1.4 1.4 1.4 1.4 1.2 1.3 1.4Fibrinogen** 1.5 1.8 1.5 1.5 1.4 1.3 1.4 1.4Protamine Test neg. neg. neg. neg. neg. neg. neg. neg.For FibrinMonomerProthrombin 12.9 11.8 12.5 13.3 15.3 13.0 13.8 14.8Time.sup.+ 13.0 12.4 12.8 13.5 16.5 13.8 14.0 15.5Partial thrombo- 18.0 15.5 16.5 19.8 37.3 15.0 16.3 19.0Plastin Time.sup.+ 18.3 16.3 16.8 20.0 28.9 15.8 16.5 19.3White Count 9.3 10.6 8.3 10.3 13.2 12.9 13.7 14.2Fibrinogen.sup.++ 300 360 300 300 280 260 280 280__________________________________________________________________________ Gross autopsy results on this animal showed that all tissues were normal. There was no apparent residual scarring as a result of the infusion. Microscopic studies have not been completed. *× 10.sup.3 /mm.sup.3 **Heatprecipitable fibrinogen, mm .sup.+ Seconds, duplicate samples .sup.++ Clottable fibrinogen, ml/dl | Plasma concentrates of vitamin-K dependent clotting factors of reduced thrombogenic potential useful for clinical replacement therapy in deficiency diseases of these clotting factors are provided. Preferably, concentrates substantially devoid of zymogens extraneous to the deficient factor are employed. | 0 |
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application Ser. No. 61/419,306 filed Dec. 3, 2010, which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to novel oxadiazole derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals, as modulators of sphingosine-1-phosphate receptors. The invention relates specifically to the use of these compounds and their pharmaceutical compositions to treat disorders associated with sphingosine-1-phosphate (S1P) receptor modulation.
BACKGROUND OF THE INVENTION
Sphingosine-1 phosphate is stored in relatively high concentrations in human platelets, which lack the enzymes responsible for its catabolism, and it is released into the blood stream upon activation of physiological stimuli, such as growth factors, cytokines, and receptor agonists and antigens. It may also have a critical role in platelet aggregation and thrombosis and could aggravate cardiovascular diseases. On the other hand the relatively high concentration of the metabolite in high-density lipoproteins (HDL) may have beneficial implications for atherogenesis. For example, there are recent suggestions that sphingosine-1-phosphate, together with other lysolipids such as sphingosylphosphorylcholine and lysosulfatide, are responsible for the beneficial clinical effects of HDL by stimulating the production of the potent antiatherogenic signaling molecule nitric oxide by the vascular endothelium. In addition, like lysophosphatidic acid, it is a marker for certain types of cancer, and there is evidence that its role in cell division or proliferation may have an influence on the development of cancers. These are currently topics that are attracting great interest amongst medical researchers, and the potential for therapeutic intervention in sphingosine-1-phosphate metabolism is under active investigation.
SUMMARY OF THE INVENTION
A group of novel oxadiazole derivatives which are potent and selective sphingosine-1-phosphate modulators has been discovered. As such, the compounds described herein are useful in treating a wide variety of disorders associated with modulation of sphingosine-1-phosphate receptors. The term “modulator” as used herein, includes but is not limited to: receptor agonist, antagonist, inverse agonist, inverse antagonist, partial agonist, partial antagonist.
This invention describes compounds of Formula I, which have sphingosine-1-phosphate receptor biological activity. The compounds in accordance with the present invention are thus of use in medicine, for example in the treatment of humans with diseases and conditions that are alleviated by S1P modulation.
In one aspect, the invention provides a compound having Formula I or a pharmaceutically acceptable salt thereof or stereoisomeric forms thereof, or the geometrical isomers, enantiomers, diastereoisomers, tautomers, zwitterions and pharmaceutically acceptable salts thereof:
wherein:
A is C 6-10 aryl, heterocycle, C 3-8 cycloalkyl or C 3-8 cycloalkenyl; B is C 6-10 aryl, heterocycle, C 3-8 cycloalkyl or C 3-8 cycloalkenyl; R 1 is H, halogen, —OC 1-8 alkyl, C 1-8 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl; R 2 is H, halogen, —OC 1-8 alkyl, C 1-8 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl; R 3 is H, halogen, —OC 1-8 alkyl, C 1-8 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl; R 4 is H, halogen, —OC 1-8 alkyl, C 1-8 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl; R 5 is H, halogen, —OC 1-8 alkyl, C 1-8 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl; R 6 is H, halogen, —OC 1-8 alkyl, C 1-8 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl; R 7 is H, halogen, —OC 1-8 alkyl, C 1-8 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl; R 8 is independently halogen, —OC 1-8 alkyl, C 1-8 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl; L 1 is O, C(O), S, NH or CH 2 ; R 9 is O, S, C(O) or CH 2 ; R 10 is H or C 1-8 alkyl; L 2 is CHR 16 , O, S, NR 17 , direct bond or —C(O)—; R 11 is H, OPO 3 H 2 , carboxylic acid, PO 3 H 2 , C 1-8 alkyl, —S(O) 2 H, —P(O)MeOH, —P(O)(H)OH or OR 12 ; R 12 is H or C 1-8 alkyl; a is 0, 1 or 2; b is 0 or 1; c is 0, 1, 2 or 3; R 13 is H, C 1-8 alkyl; R 14 is H or C 1-8 alkyl; and R 15 is H or C 1-8 alkyl; R 16 is H, OH or C 1-8 alkyl; and R 17 is H or C 1-8 alkyl;
with the proviso that the compound is not of structure
In another aspect, the invention provides a compound having Formula I wherein L is CH 2 .
In another embodiment, the invention provides a compound having Formula I wherein:
In another embodiment, the invention provides a compound having Formula I wherein:
In another embodiment, the invention provides a compound having Formula I wherein:
In another aspect, the invention provides a compound having Formula I wherein
A is C 6 aryl or heterocycle;
B is C 6 aryl or C 3-8 cycloalkyl;
R 1 is H, halogen or —C 1-6 alkyl;
R 2 is H, halogen or —C 1-6 alkyl;
R 3 is H, halogen or —C 1-6 alkyl;
R 4 is H or C 1-6 alkyl,
R 5 is H or C 1-6 alkyl;
R 6 is H or C 1-6 alkyl;
R 7 is H or C 1-6 alkyl;
R 9 is C(O) or CH 2 ;
R 10 is H;
R 11 is OPO 3 H 2 , carboxylic acid or PO 3 H 2 ; a is 0; b is 0 or 1; c is 0, 1, 2 or 3; L 1 is CH 2 ; L 2 is CHR 16 or direct bond; and R 16 is H or C 1-6 alkyl.
In another aspect, the invention provides a compound having Formula I wherein
A is C 6 aryl or heterocycle;
B is C 6 aryl or C 3-8 cycloalkyl; R 1 is H, halogen, —OC 1-6 alkyl, C 1-6 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl; R 2 is H, halogen, —OC 1-6 alkyl, C 1-6 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl; R 3 is H, halogen, —OC 1-6 alkyl, C 1-6 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl; R 4 is H, halogen, —OC 1-6 alkyl, C 1-6 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl; R 5 is H, halogen, —OC 1-6 alkyl, C 1-6 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl; R 6 is H, halogen, —OC 1-6 alkyl, C 1-6 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl; R 7 is H, halogen, —OC 1-6 alkyl, C 1-6 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl; R 8 is independently halogen, —OC 1-6 alkyl, C 1-6 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl; L 1 is CH 2 ; R 9 is O, S, C(O) or CH 2 ; R 10 is H or C 1-6 alkyl; L 2 is CHR 16 , O, S, NR 17 , direct bond or —C(O)—; R 11 is H, OPO 3 H 2 , carboxylic acid, PO 3 H 2 , C 1-6 alkyl, —S(O) 2 H, —P(O)MeOH, —P(O)(H)OH or OR 12 ; R 12 is H or C 1-6 alkyl; a is 0, 1 or 2; b is 0 or 1; c is 0, 1, 2 or 3; R 13 is H, C 1-6 alkyl; R 14 is H or C 1-6 alkyl; and R 15 is H or C 1-6 alkyl; R 16 is H, OH or C 1-6 alkyl; and R 17 is H or C 1-6 alkyl;
with the proviso that the compound is not of structures
In another embodiment, the invention provides a compound having Formula I wherein:
R 1 is H, halogen, —OC 1-6 alkyl, C 1-6 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl;
R 2 is H, halogen, —OC 1-6 alkyl, C 1-6 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl;
R 3 is H, halogen, —OC 1-6 alkyl, C 1-6 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl;
R 4 is H, halogen, —OC 1-6 alkyl, C 1-6 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl;
R 5 is H, halogen, —OC 1-6 alkyl, C 1-6 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl;
R 6 is H, halogen, —OC 1-6 alkyl, C 1-6 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl;
R 7 is H, halogen, —OC 1-6 alkyl, C 1-6 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl;
R 8 is independently halogen, —OC 1-6 alkyl, C 1-6 alkyl, CN, C(O)R 13 , NR 14 R 15 or hydroxyl;
L 1 is CH 2 ;
R 9 is O, S, C(O) or CH 2 ;
R 10 is H or C 1-6 alkyl;
L 2 is CHR 16 , O, S, NR 17 , direct bond or —C(O)—;
R 11 is H, OPO 3 H 2 , carboxylic acid, PO 3 H 2 , C 1-6 alkyl, —S(O) 2 H, —P(O)MeOH, —P(O)(H)OH or OR 12 ;
R 12 is H or C 1-6 alkyl;
a is 0, 1 or 2;
b is 0 or 1;
c is 0, 1, 2 or 3;
R 13 is H, C 1-6 alkyl;
R 14 is H or C 1-6 alkyl; and
R 15 is H or C 1-6 alkyl;
R 16 is H, OH or C 1-6 alkyl; and
R 17 is H or C 1-6 alkyl.
In another embodiment, the invention provides a compound having Formula I wherein:
R 1 is H, halogen or —C 1-6 alkyl;
R 2 is H, halogen or —C 1-6 alkyl;
R 3 is H, halogen or —C 1-6 alkyl;
R 4 is H or C 1-6 alkyl,
R 5 is H or C 1-6 alkyl;
R 6 is H or C 1-6 alkyl;
R 7 is H or C 1-6 alkyl;
R 9 is C(O) or CH 2 ;
R 10 is H;
R 11 is OPO 3 H 2 , carboxylic acid or PO 3 H 2 ; a is 0; b is 0 or 1; c is 0, 1, 2 or 3; L 1 is CH 2 ; L 2 is CHR 16 or direct bond; and R 16 is H or C 1-6 alkyl.
In another embodiment, the invention provides a compound having Formula I wherein:
R 1 is H, fluoro, methyl or chloro;
R 2 is H, fluoro, methyl or chloro;
R 3 is H, fluoro, methyl or chloro;
R 4 is H or methyl;
R 5 is H or methyl;
R 6 is H or methyl;
R 7 is H or methyl;
R 9 is C(O) or CH 2 ;
R 10 is H;
R 11 is carboxylic acid or PO 3 H 2 ; a is 0; b is 0 or 1; c is 0, 1, 2 or 3; L 1 is CH 2 ; L 2 is CHR 16 or direct bond; and R 16 is H.
In another embodiment, the invention provides a compound having Formula I wherein:
R 1 is H, fluoro, methyl or chloro;
R 2 is H or chloro;
R 3 is H, fluoro, methyl or chloro;
R 4 is H;
R 5 is H or methyl;
R 6 is methyl;
R 7 is H or methyl;
R 8 is methyl;
R 9 is C(O) or CH 2 ;
R 10 is H;
R 11 is carboxylic acid or PO 3 H 2 ; a is 0 or 2; b is 0 or 1; c is 0, 1 or 2; L 1 is CH 2 ; and L 2 is direct bond.
The term “alkyl”, as used herein, refers to saturated, monovalent hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 1 to 8 carbon atoms. One methylene (—CH 2 —) group, of the alkyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, or by a divalent C 3-8 cycloalkyl. Alkyl groups can be substituted by halogen, hydroxyl, cycloalkyl, amino, non-aromatic heterocycles, carboxylic acid, phosphonic acid groups, sulphonic acid groups, phosphoric acid.
The term “cycloalkyl”, as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms, derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic. Cycloalkyl can be substituted by alkyl groups or halogen atoms.
The term “cycloalkenyl”, as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms, derived from a saturated cycloalkyl having one double bond. Cycloalkenyl groups can be monocyclic or polycyclic. Cycloalkenyl groups can be substituted by alkyl groups or halogen atoms.
The term “halogen”, as used herein, refers to an atom of chlorine, bromine, fluorine, iodine.
The term “alkenyl”, as used herein, refers to a monovalent or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one double bond. C 2-6 alkenyl can be in the E or Z configuration. Alkenyl groups can be substituted by alkyl groups.
The term “alkynyl”, as used herein, refers to a monovalent or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one triple bond. Alkynyl groups can be substituted by alkyl groups.
The term “heterocycle” as used herein, refers to a 3 to 10 membered ring, which can be aromatic or non-aromatic, saturated or non-saturated, containing at least one heteroatom selected form O or N or S or combinations of at least two thereof, interrupting the carbocyclic ring structure. The heterocyclic ring can be interrupted by a C═O; the S heteroatom can be oxidized. Heterocycles can be monocyclic or polycyclic. Heterocyclic ring moieties can be substituted by hydroxyl, alkyl groups or halogen atoms.
The term “aryl” as used herein, refers to an organic moiety derived from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms by removal of one hydrogen. Aryl can be monocyclic or polycyclic. Aryl can be substituted by halogen atoms, —OC 1-6 alkyl, C 1-6 alkyl, CN, C(O)(C 1-6 alkyl), N(C 1-6 alkyl) (C 1-6 alkyl) or NH 2 or NH(C 1-6 alkyl) or hydroxyl groups. Usually aryl is phenyl. Preferred substitution site on aryl are meta and para positions.
The term “hydroxyl” as used herein, represents a group of formula “—OH”.
The term “carbonyl” as used herein, represents a group of formula “—C(O)”.
The term “carboxyl” as used herein, represents a group of formula “—C(O)O—”.
The term “sulfonyl” as used herein, represents a group of formula “—SO 2 ”.
The term “sulfate” as used herein, represents a group of formula “—O—S(O) 2 —O—”.
The term “carboxylic acid” as used herein, represents a group of formula “—C(O)OH”.
The term “sulfoxide” as used herein, represents a group of formula “—S═O”.
The term “phosphonic acid” as used herein, represents a group of formula “—P(O)(OH) 2 ”.
The term “phosphoric acid” as used herein, represents a group of formula “—(O)P(O)(OH) 2 ”.
The term “sulphonic acid” as used herein, represents a group of formula “—S(O) 2 OH”.
The formula “H”, as used herein, represents a hydrogen atom.
The formula “O”, as used herein, represents an oxygen atom.
The formula “N”, as used herein, represents a nitrogen atom.
The formula “S”, as used herein, represents a sulfur atom.
Some compounds of the invention are:
3-[(4-{5-[1-(3-chlorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)amino]propanoic acid; {3-[(4-{5-[1-(3-chlorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)amino]propyl}phosphonic acid; 3-[(4-{5-[2-(3,4-dimethylphenyl)-1-(3-fluorophenyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)amino]propanoic acid; {3-[(4-{5-[2-(3,4-dimethylphenyl)-1-(3-fluorophenyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)amino]propyl}phosphonic acid; 3-[(4-{5-[1-(3,5-difluorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)amino]propyl}phosphonic acid; 3-(4-{5-[1-(3-chlorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-3-methylphenyl)propanoic acid
3-(4-{5-[1-(4-chlorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-3-methylphenyl)propanoic acid;
3-(4-{5-[1-(3-chlorophenyl)-2-(3-methylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-3-methylphenyl)propanoic acid; 3-[(4-{5-[1-(3-chlorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}benzoyl)amino]propanoic acid; 3-[(4-{5-[1-(3,5-difluorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)amino]propanoic acid; {3-[(4-{5-[1-(3,5-difluorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)amino]propyl}phosphonic acid; 3-{[4-(5-{2-(3,4-dimethylphenyl)-1-[3-(trifluoromethyl)phenyl]ethyl}-1,2,4-oxadiazol-3-yl)benzyl]amino}propanoic acid; 3-[(4-{5-[2-(3,4-dimethylphenyl)-1-(3,5-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)amino]propanoic acid.
Some compounds of Formula I and some of their intermediates have at least one stereogenic center in their structure. This stereogenic center may be present in an R or S configuration, said R and S notation is used in correspondence with the rules described in Pure Appli. Chem. (1976), 45, 11-13.
The term “pharmaceutically acceptable salts” refers to salts or complexes that retain the desired biological activity of the above identified compounds and exhibit minimal or no undesired toxicological effects. The “pharmaceutically acceptable salts” according to the invention include therapeutically active, non-toxic base or acid salt forms, which the compounds of Formula I are able to form.
The acid addition salt form of a compound of Formula I that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric, methylsulfonic, ethanesulfonic, benzenesulfonic, formic and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahal & Camille G. Wermuth (Eds), Verlag Helvetica Chemica Acta-Zürich, 2002, 329-345).
Compounds of Formula I and their salts can be in the form of a solvate, which is included within the scope of the present invention. Such solvates include for example hydrates, alcoholates and the like.
With respect to the present invention reference to a compound or compounds, is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof unless the particular isomeric form is referred to specifically.
Compounds according to the present invention may exist in different polymorphic forms. Although not explicitly indicated in the above formula, such forms are intended to be included within the scope of the present invention.
The compounds of the invention are indicated for use in treating or preventing conditions in which there is likely to be a component involving the sphingosine-1-phosphate receptors.
In another embodiment, there are provided pharmaceutical compositions including at least one compound of the invention in a pharmaceutically acceptable carrier.
In a further embodiment of the invention, there are provided methods for treating disorders associated with modulation of sphingosine-1-phosphate receptors. Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one compound of the invention.
These compounds are useful for the treatment of mammals, including humans, with a range of conditions and diseases that are alleviated by S1P modulation.
Therapeutic utilities of S1P modulators are: Ocular Diseases: wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal edema, geographic atrophy, glaucomatous optic neuropathy, chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome, prevention of inflammation-induced fibrosis in the back of the eye, various ocular inflammatory diseases including uveitis, scleritis, keratitis, and retinal vasculitis; Systemic vascular barrier related diseases: various inflammatory diseases, including acute lung injury, its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and ventilation-induced lung injury; Autoimmune diseases and immunosuppression: rheumatoid arthritis, Crohn's disease, Graves' disease, inflammatory bowel disease, multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis, antoimmune uveitis, renal ischemia/perfusion injury, contact hypersensitivity, atopic dermititis, and organ transplantation; Allergies and other inflammatory diseases: urticaria, bronchial asthma, and other airway inflammations including pulmonary emphysema and chronic obstructive pulmonary diseases; Cardiac functions: bradycardia, congestional heart failure, cardiac arrhythmia, prevention and treatment of atherosclerosis, and ischemia/reperfusion injury; Wound Healing: scar-free healing of wounds from cosmetic skin surgery, ocular surgery, GI surgery, general surgery, oral injuries, various mechanical, heat and burn injuries, prevention and treatment of photoaging and skin ageing, and prevention of radiation-induced injuries; Bone formation: treatment of osteoporosis and various bone fractures including hip and ankles; Anti-nociceptive activity: visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, neuropathic pains; Anti-fibrosis: ocular, cardiac, hepatic and pulmonary fibrosis, proliferative vitreoretinopathy, cicatricial pemphigoid, surgically induced fibrosis in cornea, conjunctiva and tenon; Pains and anti-inflammation: acute pain, flare-up of chronic pain, musculo-skeletal pains, visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, bursitis, neuropathic pains; CNS neuronal injuries: Alzheimer's disease, age-related neuronal injuries; Organ transplants: renal, corneal, cardiac and adipose tissue transplants.
In still another embodiment of the invention, there are provided methods for treating disorders associated with modulation of sphingosine-1-phosphate receptors. Such methods can be performed, for example, by administering to a subject in need thereof a therapeutically effective amount of at least one compound of the invention, or any combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual isomers, enantiomers, and diastereomers thereof.
The present invention concerns the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of: Ocular Diseases: wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal edema, geographic atrophy, glaucomatous optic neuropathy, chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome, prevention of inflammation-induced fibrosis in the back of the eye, various ocular inflammatory diseases including uveitis, scleritis, keratitis, and retinal vasculitis; Systemic vascular barrier related diseases: various inflammatory diseases, including acute lung injury, its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and ventilation-induced lung injury; Autoimmune diseases and immunosuppression: rheumatoid arthritis, Crohn's disease, Graves' disease, inflammatory bowel disease, multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis, antoimmune uveitis, renal ischemia/perfusion injury, contact hypersensitivity, atopic dermititis, and organ transplantation; Allergies and other inflammatory diseases: urticaria, bronchial asthma, and other airway inflammations including pulmonary emphysema and chronic obstructive pulmonary diseases; Cardiac functions: bradycardia, congestional heart failure, cardiac arrhythmia, prevention and treatment of atherosclerosis, and ischemia/reperfusion injury; Wound Healing: scar-free healing of wounds from cosmetic skin surgery, ocular surgery, GI surgery, general surgery, oral injuries, various mechanical, heat and burn injuries, prevention and treatment of photoaging and skin ageing, and prevention of radiation-induced injuries; Bone formation: treatment of osteoporosis and various bone fractures including hip and ankles; Anti-nociceptive activity: visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, neuropathic pains; Anti-fibrosis: ocular, cardiac, hepatic and pulmonary fibrosis, proliferative vitreoretinopathy, cicatricial pemphigoid, surgically induced fibrosis in cornea, conjunctiva and tenon; Pains and anti-inflammation: acute pain, flare-up of chronic pain, musculo-skeletal pains, visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, bursitis, neuropathic pains; CNS neuronal injuries: Alzheimer's disease, age-related neuronal injuries; Organ transplants: renal, corneal, cardiac and adipose tissue transplants.
The actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the condition, the age and weight of the patient, the patient's general physical condition, the cause of the condition, and the route of administration.
The patient will be administered the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like, or other routes may be desirable or necessary, particularly if the patient suffers from nausea. Such other routes may include, without exception, transdermal, parenteral, subcutaneous, intranasal, via an implant stent, intrathecal, intravitreal, topical to the eye, back to the eye, intramuscular, intravenous, and intrarectal modes of delivery. Additionally, the formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy.
In another embodiment of the invention, there are provided pharmaceutical compositions including at least one compound of the invention in a pharmaceutically acceptable carrier thereof. The phrase “pharmaceutically acceptable” means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Pharmaceutical compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a patch, a micelle, a liposome, and the like, wherein the resulting composition contains one or more compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications. Invention compounds may be combined, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form. In addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. Invention compounds are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition.
Pharmaceutical compositions containing invention compounds may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets containing invention compounds in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods. The excipients used may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
In some cases, formulations for oral use may be in the form of hard gelatin capsules wherein the invention compounds are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the invention compounds are mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
The pharmaceutical compositions may be in the form of a sterile injectable suspension. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required.
Invention compounds may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the invention compounds with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
Since individual subjects may present a wide variation in severity of symptoms and each drug has its unique therapeutic characteristics, the precise mode of administration and dosage employed for each subject is left to the discretion of the practitioner.
The compounds and pharmaceutical compositions described herein are useful as medicaments in mammals, including humans, for treatment of diseases and/or alleviations of conditions which are responsive to treatment by agonists or functional antagonists of sphingosine-1-phosphate receptors. Thus, in further embodiments of the invention, there are provided methods for treating a disorder associated with modulation of sphingosine-1-phosphate receptors. Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one invention compound. As used herein, the term “therapeutically effective amount” means the amount of the pharmaceutical composition that will elicit the biological or medical response of a subject in need thereof that is being sought by the researcher, veterinarian, medical doctor or other clinician. In some embodiments, the subject in need thereof is a mammal. In some embodiments, the mammal is human.
The present invention concerns also processes for preparing the compounds of Formula II. The compounds of Formula II according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry. The synthetic schemes set forth below, illustrate how compounds according to the invention can be made.
The following abbreviations are used in the general schemes and in the specific examples:
CDI
1,1′-Carbonyldiimidazole
THF
tetrahydrofuran
RT
room temperature
MPLC
medium pressure liquid chromatography
NMO
4-Methylmorpholine N-oxide
AcCN
acetonitrile
DCM
dichloromethane
TPAP
Tetrapropylammonium perruthenate
MeOH
methanol
NaCNBH 3
sodium cyanoborohydride
H 2 O
water
CD 3 OD
deuterated methanol
MgCl 2
magnesium chloride
NaCl
sodium chloride
DMSO-d6
deuterated dimethyl sulfoxide
A solution of substituted carboxylic acid (1 eq) and CDI (1-1.5 eq) in THF was stirred at rt for 30 min. N-Hydroxy-4-(hydroxymethyl)benzamidine (1 eq) (prepared according to Li, Zhen et al, J. Med. Chem., 2005, 48 (20), pp 6169-6173) was added and the resulting solution was stirred at rt overnight. The reaction solution was then transferred to a microwave reaction vessel and heated to 150° C. for 20 min under a microwave condition. After cooling to rt, the solvent was removed under reduced pressure. The desired alcohol was isolated by MPLC using 5 to 10% ethyl acetate in hexane. The alcohol (1 eq) was mixed with NMO (2.5 eq), molecular sieve (600 mg) in AcCN (5.00 mL) and DCM (25.00 mL). A catalytic amount of TPAP (28.00 mg) was added. The resulting reaction mixture was stirred at RT for 1 hour and evaporated to dryness. The obtained aldehyde was then purified by MPLC using 0-10% ethyl acetate in hexane.
The aldehyde (1 eq), the amino reagent (1.3 eq) and TEA (1.5 eq) were stirred with MeOH (8 ml). Upon stirring at 60° C. for 90 min, the reaction mixture was cooled to RT. NaBH 4 (3 eq) was added and the reaction solution was stirred at rt for 2 hour.
To obtain the phosphonic derivatives, the aldehyde (1 eq), 3-aminopropylphosphonic acid (1 eq) and tetra-n-butylammonium hydroxide (1.00 Min MeOH, 1 eq) were mixed in MeOH (10.00 mL). Upon stirring at 50° C. for 30 min, NaBH 3 CN (1 eq) was added and the resulting reaction mixture was stirred at 50° C. for 3 hour.
The reaction was quenched with 0.5 mL of water and concentrated to a minimal amount.
In the case of the carboxylic acid derivative, the compound was isolated by MPLC using 10 to 90% MeOH in EtOAc.
In the case of the phosphonic acid derivative, the compound was isolated by reverse phase MPLC using 10 to 90% H 2 O in AcCN.
Those skilled in the art will be able to routinely modify and/or adapt the following scheme to synthesize any compounds of the invention covered by Formula I.
DETAILED DESCRIPTION OF THE INVENTION
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise.
It will be readily apparent to those skilled in the art that some of the compounds of the invention may contain one or more asymmetric centers, such that the compounds may exist in enantiomeric as well as in diastereomeric forms. Unless it is specifically noted otherwise, the scope of the present invention includes all enantiomers, diastereomers and racemic mixtures. Some of the compounds of the invention may form salts with pharmaceutically acceptable acids or bases, and such pharmaceutically acceptable salts of the compounds described herein are also within the scope of the invention.
The present invention includes all pharmaceutically acceptable isotopically enriched compounds. Any compound of the invention may contain one or more isotopic atoms enriched or different than the natural ratio such as deuterium 2 H (or D) in place of protium 1 H (or H) or use of 13 C enriched material in place of 12 C and the like. Similar substitutions can be employed for N, O and S. The use of isotopes may assist in analytical as well as therapeutic aspects of the invention. For example, use of deuterium may increase the in vivo half-life by altering the metabolism (rate) of the compounds of the invention. These compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents.
The following examples are for illustrative purposes only and are not intended, nor should they be construed as limiting the invention in any manner. Those skilled in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention.
As will be evident to those skilled in the art, individual isomeric forms can be obtained by separation of mixtures thereof in conventional manner. For example, in the case of diasteroisomeric isomers, chromatographic separation may be employed.
Compound names were generated with ACD version 8. In general, characterization of the compounds is performed according to the following methods:
Proton nuclear magnetic resonance ( 1 H NMR) and carbon nuclear magnetic resonance ( 13 C NMR) spectra were recorded on a Varian 300 or 600 MHz spectrometer in deuterated solvent. Chemical shifts were reported as δ (delta) values in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard (0.00 ppm) and multiplicities were reported as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Data were reported in the following format: chemical shift (multiplicity, coupling constant(s) J in hertz (Hz), integrated intensity).
All the reagents, solvents, catalysts for which the synthesis is not described are purchased from chemical vendors such as Sigma Aldrich, Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, Trans World Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth, Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex, MIC-scientific, Ltd; however some known intermediates, were prepared according to published procedures.
Usually the compounds of the invention were purified by column chromatography (Auto-column) on an Teledyne-ISCO CombiFlash with a silica column, unless noted otherwise.
Compounds 1 through 13 were prepared in a similar manner to the method described in the general scheme. The starting materials and the results are tabulated below in Table 1 for each case.
TABLE 1
Comp.
Starting
1 NMR (Solvent; δ
number
IUPAC name
material
ppm)
1
4-{5-[1-(3- chlorophenyl)-2- (3,4- dimethylphenyl) ethyl]-1,2,4- oxadiazol-3- yl}benzaldehyde 3- aminopropanoic acid
1 H NMR (300 MHz, CD 3 OD) δ ppm 2.13 (s, 6 H) 2.79 (t, J = 6.74 Hz, 2 H) 3.31 (s, 3 H) 3.53 (dd, J = 13.48, 8.50 Hz, 1 H) 4.32 (s, 2 H) 4.67 (t, J = 7.90 Hz, 1 H) 6.84 (m, 1 H) 6.88-6.95 (m, 2 H) 7.23-7.34 (m, 3 H) 7.40 (m, 1 H) 7.65 (d, J = 8.20 Hz, 2 H) 8.13 (d, J = 8.20 Hz, 2 H).
2
4-{5-[1-(3- chlorophenyl)-2- (3,4- dimethylphenyl) ethyl]-1,2,4- oxadiazol-3- yl}benzaldehyde (3- aminopropyl)- phosphonic acid
1 H NMR (300 MHz, CD 3 OD) δ ppm 1.62- 1.76 (m, 2 H) 1.90- 2.04 (m, 2 H) 2.15 (s, 6 H) 3.09 (t, J = 6.15 Hz, 2 H) 3.22-3.30 (m, 1 H) 3.53 (dd, J = 13.63, 8.35 Hz, 1 H) 4.17 (s, 2 H) 4.68 (t, J = 8.06 Hz, 1 H) 6.80-6.87 (m, 1 H) 6.90-6.95 (m, 2 H) 7.24-7.35 (m, 3 H) 7.41 (s, 1 H) 7.65 (d, J = 8.20 Hz, 2 H) 8.10 (d, J = 8.20 Hz, 2 H)
3
4-(5-(1-(3- fluororophenyl)- 2-(3,4- dimethylphenyl) ethyl)-1,2,4- oxadiazol-3- yl)benzaldehyde 3- aminopropanoic acid
1 H NMR (300 MHz, CD 3 OD) δ ppm 2.15 (s, 6 H) 2.44 (t, J = 6.74 Hz, 2 H) 2.87 (t, J = 6.74 Hz, 2 H) 3.25-3.33 (m, 1 H) 3.53 (dd, J = 13.48, 8.50 Hz, 1 H) 3.86 (s, 2 H) 4.68 (t, J = 8.06 Hz, 1 H) 6.82-6.87 (m, 1 H) 6.91-7.04 (m, 3 H) 7.13-7.23 (m, 2 H) 7.32 (m, 1 H) 7.52 (d, J = 8.20 Hz, 2 H) 8.02 (d, J = 8.20 Hz, 2 H).
4
4-(5-(1-(3- fluororophenyl)- 2-(3,4- dimethylphenyl) ethyl)-1,2,4- oxadiazol-3- yl)benzaldehyde (3- aminopropyl)- phosphonic acid
1 H NMR (300 MHz, CD 3 OD) δ ppm 1.62- 1.75 (m, 2 H) 1.92- 2.02 (m, 2 H) 2.15 (s, 6 H) 3.09 (t, J = 6.30 Hz, 2 H) 3.24-3.29 (m, 1 H) 3.53 (dd, J = 13.48, 8.50 Hz, 1 H) 4.17 (s, 2 H) 4.70 (t, J = 7.91 Hz, 1 H) 6.81-6.86 (m, 1 H) 6.90-6.95 (m, 2 H) 6.96-7.04 (m, 1 H) 7.13-7.22 (m, 2 H) 7.29-7.38 (m, 1 H) 7.64 (d, J = 8.21 Hz, 2 H) 8.08-8.13 (d, J = 8.21 Hz, 2 H).
5
2-(3,5- difluorophenyl)- 3-(3,4- dimethylphenyl) propanoic acid
1 H NMR (300 MHz, CD 3 OD) δ ppm 1.63- 1.75 (m, 2 H) 1.92- 2.04 (m, 2 H) 2.15 (s, 6 H) 3.09 (t, J = 6.30 Hz, 2 H) 3.23-3.30 (m, 1 H) 3.54 (dd, J = 13.48, 8.50 Hz, 1 H) 4.17 (s, 2 H) 4.72 (t, J = 7.91 Hz, 1 H) 6.82-6.88 (m, 2 H) 6.92-6.94 (m, 2 H) 7.00-7.04 (m, 2 H) 7.65 (d, J = 8.45 Hz, 2 H) 8.09 (d, J = 8.45 Hz, 2 H)
6
2-(3- chlorophenyl)-3- (3,4- dimethylphenyl) propanoic acid 3-{4-[(Z)- amino(hydroxyimino)- methyl]-3- methylphenyl}- propanoate
1 H NMR (300 MHz, CD 3 OD) δ ppm 2.17 (s, 6 H) 2.51 (s, 3 H) 2.64 (t, J = 7.61 Hz, 2 H) 2.97 (t, J = 7.61 Hz, 2 H) 3.24-3.30 (m, 1 H) 3.53 (dd, J = 13.48, 8.50 Hz, 1 H) 4.67 (t, J = 8.01 Hz, 1 H) 6.83- 6.88 (m, 1 H) 6.91- 6.98 (m, 2 H) 7.17- 7.24 (m, 2 H) 7.27- 7.35 (m, 3 H) 7.44 (s, 1 H) 7.83 (d, J = 7.91 Hz, 1 H).
7
2-(4- Chlorophenyl)- 3-(3,4- dimethylphenyl) propanoic acid tert-butyl 3-{4- [(Z)- amino(hydroxyimino)- methyl]-3- methylphenyl}- propanoate
1 H NMR (300 MHz, CD 3 OD) δ ppm 2.14 (s, 6 H) 2.49 (s, 3 H) 2.62 (t, J = 7.61 Hz, 2 H) 2.93 (t, J = 7.61 Hz, 2 H) 3.21- 3.30 (m, 1 H) 3.49 (dd, J = 13.48, 8.50 Hz, 1 H) 4.64 (t, J = 8.06 Hz, 1 H) 6.82 (d, J = 7.91 Hz, 1 H) 6.88-6.95 (m, 2 H) 7.14-7.21 (m, 2 H) 7.28-7.39 (m, 4 H) 7.82 (d, J = 7.91 Hz, 1 H).
8
2-(3- Chlorophenyl)- 3-(3- methylphenyl) propanoic acid tert-butyl 3-{4- [(Z)- amino(hydroxyimino)- methyl]-3- methylphenyl}- propanoate
1 H NMR (300 MHz, CD 3 OD) δ ppm 2.24 (s, 3 H) 2.51 (s, 3 H) 2.64 (t, J = 7.61 Hz, 2 H) 2.94 (t, J = 7.61 Hz, 2 H) 3.25-3.35 (m, 1 H) 3.55 (dd, J = 13.48, 8.50 Hz, 1 H) 4.70 (t, J = 8.06 Hz, 1 H) 6.91-7.00 (m, 3 H) 7.05-7.12 (m, 1 H) 7.17-7.24 (m, 2 H) 7.26-7.36 (m, 3 H) 7.43 (m, 1 H) 7.83 (d, J = 7.91 Hz, 1 H).
9
2-(3- chlorophenyl)-3- (3,4- dimethylphenyl) propanoic acid 4-[(Z)-amino ((hydroxyimino) methyl]benzoe β-Alanine-t- butyl ester hydrochloride
1 H NMR (300 MHz, CD 3 OD) δ ppm 2.16 (s, 6 H) 2.66 (t, J = 6.89 Hz, 2 H) 3.25-3.33 (m, 1H) 3.54 (dd. J = 13.48, 8.50 Hz, 1 H) 3.65 (t, J = 6.89 Hz, 2 H) 4.70 (t, J = 7.91 Hz, 1 H) 6.82-6.87 (m, 1 H) 6.91-6.97 (m, 2 H) 7.27-7.34 (m, 3 H) 7.42 (m, 1 H) 7.96 (d, J = 8.20 Hz, 2 H) 8.14 (d, J = 8.20 Hz, 2 H).
10 2
available 3,5- difluorophenylacetonitrile, 3,4- dimethylbenzaldehyde, N′-hydroxy-4- (hydroxymethyl) benzimidamide
1 H NMR (300 MHz, DMSO) δ ppm 2.10 (s, 3 H) 2.11 (s, 3 H) 2.33 (t, J = 6.74 Hz, 2 H) 2.72 (t, J = 6.74 Hz, 2 H) 3.30 (dd, J = 13.92, 7.76 Hz, 1 H) 3.49 (dd, J = 13.63, 8.06 Hz, 1 H) 3.80 (s, 2 H) 4.88- 5.04 (m, 1 H) 6.83- 6.92 (m, 1 H) 6.93- 6.98 (m, 1 H) 7.01 (m, 1 H) 7.10-7.29 (m, 3 H) 7.50 (d, J = 8.20 Hz, 2 H) 7.93 (d, J = 8.50 Hz, 2H).
11
2-(3,5- difluorophenyl)- 3-(3,4- dimethylphenyl) propanoic acid
1 H NMR (300 MHz, CD 3 OD) δ ppm 1.63- 1.75 (m, 2 H) 1.92- 2.04 (m, 2 H) 2.15 (s, 6 H) 3.09 (t, J = 6.30 Hz, 2 H) 3.23-3.30 (m, 1 H) 3.54 (dd, J = 13.48, 8.50 Hz, 1 H) 4.17 (s, 2 H) 4.72 (t, J = 7.91 Hz, 1 H) 6.82-6.88 (m, 2 H) 6.92-6.94 (m, 2 H) 7.00-7.04 (m, 2 H) 7.65 (d, J = 8.45 Hz, 2 H) 8.09 (d, J = 8.45 Hz, 2 H).
12
4-(5-{2-(3,4- dimethylphenyl)- 1-[3- (trifluoromethyl) phenyl]ethyl}- 1,2,4-oxadiazol- 3- yl)benzaldehyde
1 H NMR (300 MHz, DMSO) δ ppm 2.09 (br. s, 6 H) 2.32 (t, J = 6.74 Hz, 2 H) 2.66-2.78 (m, 2 H) 3.23-3.39 (m, 1 H) 3.46-3.61 (m, 1 H) 3.80 (s, 2 H) 5.05 (m, 1 H) 6.85-6.96 (m, 2 H) 6.99 (br. s, 1 H) 7.50 (d, J = 8.50 Hz, 2 H) 7.54-7.67 (m, 2 H) 7.72-7.83 (m, 2 H) 7.92 (d, J = 8.20 Hz, 2 H).
13
4-(5-(2-(3,4- dimethylphenyl)- 1-(3,5- dimethylphenyl) ethyl)-1,2,4- oxadiazol-3- yl)benzaldehyde
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 2.09 (s, 3 H) 2.10 (s, 3 H) 2.22 (s, 6 H) 2.32 (t, J = 6.74 Hz, 2 H) 2.68-2.75 (m, 2 H) 3.16-3.29 (m, 1 H) 3.39-3.53 (m, 1 H) 3.80 (s, 2 H) 4.66- 4.77 (m, 1 H) 6.86- 6.98 (m, 3 H) 7.04 (br. s., 3 H) 7.49 (d, J = 8.20 Hz, 2 H) 7.86-7.96 (m, 2 H).
Biological Data
Compounds were synthesized and tested for S1P1 activity using the GTP γ 35 S binding assay. These compounds may be assessed for their ability to activate or block activation of the human S1P1 receptor in cells stably expressing the S1P1 receptor.
GTP γ 35 S binding was measured in the medium containing (mM) HEPES 25, pH 7.4, MgCl 2 10, NaCl 100, dithitothreitol 0.5, digitonin 0.003%, 0.2 nM GTP γ 35 S, and 5 μg membrane protein in a volume of 150 μl. Test compounds were included in the concentration range from 0.08 to 5,000 nM unless indicated otherwise. Membranes were incubated with 100 μM 5′-adenylylimmidodiphosphate for 30 min, and subsequently with 10 μM GDP for 10 min on ice. Drug solutions and membrane were mixed, and then reactions were initiated by adding GTP γ 35 S and continued for 30 min at 25° C. Reaction mixtures were filtered over Whatman GF/B filters under vacuum, and washed three times with 3 mL of ice-cold buffer (HEPES 25, pH7.4, MgCl 2 10 and NaCl 100). Filters were dried and mixed with scintillant, and counted for 35 S activity using a β-counter. Agonist-induced GTP γ 35 S binding was obtained by subtracting that in the absence of agonist. Binding data were analyzed using a non-linear regression method. In case of antagonist assay, the reaction mixture contained 10 nM S1P in the presence of test antagonist at concentrations ranging from 0.08 to 5000 nM.
Table 2 shows activity potency: S1P1 receptor from GTP γ 35 5: nM, (EC 50 ).
Activity potency: S1P1 receptor from GTP γ 35 S: nM, (EC 50 ),
TABLE 2
S1P1
EC 50
IUPAC name
(nM)
3-(4-{5-[1-(3-chlorophenyl)-2-(3,4-dimethylphenyl)ethyl]-
1060
1,2,4-oxadiazol-3-yl}-3-methylphenyl)propanoic acid
3-[(4-{5-[1-(3,5-difluorophenyl)-2-(3,4-dimethylphenyl)ethyl]-
1100
1,2,4-oxadiazol-3-yl}benzyl)amino]propanoic acid
3-[(4-{5-[2-(3,4-dimethylphenyl)-1-(3-fluorophenyl)ethyl]-
598
1,2,4-oxadiazol-3-yl}benzyl)amino]propanoic acid
3-[(4-{5-[1-(3-chlorophenyl)-2-(3,4-dimethylphenyl)ethyl]-
911
1,2,4-oxadiazol-3-yl}benzoyl)amino]propanoic acid
3-{[4-(5-{2-(3,4-dimethylphenyl)-1-[3-
336
(trifluoromethyl)phenyl]ethyl}-1,2,4-oxadiazol-3-
yl)benzyl]amino}propanoic acid
3-[(4-{5-[1-(3-chlorophenyl)-2-(3,4-dimethylphenyl)ethyl]-
312
1,2,4-oxadiazol-3-yl}benzyl)amino]propanoic acid
{3-[(4-{5-[2-(3,4-dimethylphenyl)-1-(3-fluorophenyl)ethyl]-
4.04
1,2,4-oxadiazol-3-yl}benzyl)amino]propyl}phosphonic acid
{3-[(4-{5-[1-(3,5-difluorophenyl)-2-(3,4-dimethylphenyl)ethyl]-
5.27
1,2,4-oxadiazol-3-yl}benzyl)amino]propyl}phosphonic acid
3-(4-{5-[1-(3-chlorophenyl)-2-(3-methylphenyl)ethyl]-1,2,4-
17.08
oxadiazol-3-yl}-3-methylphenyl)propanoic acid
3-(4-{5-[1-(4-chlorophenyl)-2-(3,4-dimethylphenyl)ethyl]-
89.3
1,2,4-oxadiazol-3-yl}-3-methylphenyl)propanoic acid
3-[(4-{5-[2-(3,4-dimethylphenyl)-1-(3,5dimethylphenyl)ethyl]-
535
1,2,4-oxadiazol-3-yl}benzyl)amino]propanoic acid
{3-[(4-{5-[1-(3-chlorophenyl)-2-(3,4-dimethylphenyl)ethyl]-
3.77
1,2,4-oxadiazol-3-yl}benzyl)amino]propyl}phosphonic acid
3-{[4-(5-{(3-chlorophenyl)[(3,4-
1.5
dimethylphenyl)amino]methyl}-1,2,4-oxadiazol-3-
yl)benzyl]amino}propanoic acid | The present invention relates to novel oxadiazole derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors. | 2 |
TECHNICAL FIELD
[0001] The invention the subject of this application relates to a device for performing binding assays. In particular, the invention relate to a centrifugal device for performing such assays. The invention also relates to a method of performing binding assays involving antigen-antibody binding, nucleic acid hybridization, or receptor-ligand interaction.
BACKGROUND ART
[0002] A fundamental aspect of research in the biological and medical sciences is the measurement of the binding of one chemical entity to another chemical entity. Such measurements are usually referred to as binding assays and include the measurement of the binding of an antigen to an antibody or vice versa, the bending of one nucleic acid to another nucleic acid such as in a hybridization reaction, and the binding of a ligand such as a hormone or other effecter molecule to its receptor.
[0003] There are numerous techniques available for performing binding assays with the technique employed for a particular assay usually being dictated by the types of molecules involved in the interaction. In general, however, one of the partners in the interaction is bound to a solid support such as a membrane or the walls of wells in microtitre plates. Many of the known techniques are automated and are adapted for the simultaneous assaying of multiple samples.
[0004] While known techniques permit the efficient performance of numerous assays in a given period, the techniques have limitations. The most serious limitation is that a particular technique and the apparatus associated therewith can usually only be used for a single binding assay. Many of the techniques further suffer from the complication that multiple steps are involved in which reagents have to be sequentially added and removed.
[0005] It would therefore be desirable to have available apparatus that can be used for performing a variety of binding assays—even simultaneously—under variable conditions and by which the assays can be done with avoidance of the multiplicity of steps necessary in known procedures.
[0006] The object of the invention is to provide such an apparatus and methods utilizing that apparatus.
SUMMARY OF THE INVENTION
[0007] In a first embodiment of the invention, there is provided a device for measuring the binding of a first partner in an interaction to a second partner in said interaction, said device comprising:
[0000] a) an opaque temperature-controlled chamber having a rotor therein, said rotor having at or near the periphery thereof at least one radially positioned transparent reaction well, said reaction well having on an upper surface thereof an aperture for the addition of reagents thereto, said reaction well further including on an internal surface thereof at the end closest the axis of said rotor at least one attachment zone for said second interaction partner;
b) a system for detecting light emitted or absorbed by said first interaction partner or an indicator molecule bound thereto; and
c) means for controlling the temperature of said chamber and the operation of said rotor.
[0008] In a second embodiment, the invention provides a method of measuring the binding of a first partner in an interaction to a second partner in said interaction, said method comprising the steps of:
[0000] a) delivering a quantity of second interaction partner to a reaction well of a device according to the first embodiment for attachment of said second interaction partner to an attachment zone of said reaction well;
b) combining a quantity of first interaction partner with said second interaction partner in said reaction well and incubating said mixture at a temperature and for a time to allow binding of said first interaction partner to said second interaction partner;
c) rotating said device rotor at a speed which displaces the mixture formed in step (b) away from said attachment zone; and
d) measuring the amount of said first interaction partner bound to said second interaction partner via the fluorescence or absorbance of said first interaction partner or an indicator molecule bound thereto.
[0009] Other embodiments of the invention will become apparent from a reading of the detailed description below.
BRIEF DESCRIPTION OF THE FIGURES
[0010] FIG. 1 is a semi schematic representation of a rotor of a device according to the invention with detail of a optical detection system included.
[0011] FIG. 2 is a representation of one of the reaction wells of a rotor of a device according to the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0012] The term “interaction” is used herein to denote the binding of any molecule (the first interaction partner) to another molecule (the second interaction partner) where the interaction may be a naturally occurring interaction or the binding of a synthetic molecule to a target molecule.
[0013] The interaction partners can be any pair of molecules in which a first molecule can bind to the second molecule. The term interaction partner therefore includes, but is not limited to, the following pairs of molecules:
[0000]
First Interaction Partner
Second Interaction Partner
Antibody
Antigen
Antigen
Antibody
Enzyme
Substrate
Oligopeptide
Protein (for example, an
enzyme or receptor)
Hormone
Receptor
Effector molecule
Receptor
Nucleic Acid (RNA or DNA)
Nucleic acid (RNA or DNA)
Oligonucleotide
Nucleic acid (RNA or DNA)
Synthetic organic compound
Protein (for example, an
enzyme or receptor)
[0014] The terms “comprise” and variants of the term such as “comprises” or “comprising” are used herein to denote the inclusion of a stated integer or stated integers but not to exclude any other integer or any other integers, unless in the context or usage an exclusive interpretation of the term is required.
[0015] With regard to the first embodiment of the invention as define above, the device chamber can be any suitable, typically insulated, container for the rotor and other device components. The chamber advantageously has a lid or sealable opening to allow loading of reaction wells. The chamber must be opaque—that is, impermeable to light—to allow accurate and sensitive measurement of the second interaction partner molecule or indicator molecule.
[0016] The temperature control of the device chamber is effected by providing a heater linked to a temperature sensor so that a set temperature can be maintained. Typically, heating is by a heater located within the chamber with circulation of heated air within the chamber aided by a fan. Alternatively, heated air can be supplied to the chamber from a port or ports in a chamber wall. Heating of the chamber can also be by infrared radiation.
[0017] Temperature control can also include a cooling system. For example, air supply to the chamber can be provided wherein the air is either at ambient temperature or less than ambient by passage through or over a cooling means. The temperature sensor referred to above is advantageously linked to the cooling system.
[0018] The device rotor is typically a flat disc of a plastic or metal material having reaction wells fitted therein. The reaction wells can be removable or the entire rotor with reaction wells can be a disposable item. The rotor of devices according to the invention advantageously comprise a plurality of reaction wells. The number of wells will depend on the configuration of the device but a typical range is 1 to 96 wells.
[0019] Reaction wells can be formed from any suitable transparent material such as polypropelene or polycarbonate. The wells can be cylindrical, rectangular prisms, or any other suitable shape provided that the well is of sufficient length to provide an area for the at least one attachment zone and an area into which the solution or solutions via which the interaction partners were applied can be displaced by centrifugal force.
[0020] In some embodiments, the reaction wells can be angled upwards toward the periphery of the rotor. This allow solution to migrate back to the at least one attachment zone once rotor speed has been sufficiently reduced. The function of such migration will be explained below. Transitory vibration of the rotor can also be used to effect migration of solution in a reaction well and in such instances the well does not have to be tilted and can be horizontal.
[0021] Attachment zones are typically provided by appropriately treating the surface, spotting the second interaction partner onto the attachment zone with a pin or ink-jet, and drying the spotted component. Alternatively, a magnet can be provided beneath the desired area of a reaction well. The second interaction partner is linked to a magnetic particle which is held in the attachment zone by the magnet. Attachment zones typically have a diameter, if a circular zone, of 50 μm to 3 mm. A particular reaction well can have a plurality of attachment zones allowing different second interaction partners to be delivered to that well if desired.
[0022] The rotor drive means can be any drive means used for rotor devices in scientific equipment. For example, the drive means can be direct-coupled AC motor, a DC motor, or an AC motor that drives the rotor via a gearbox or pulleys or the like. Preferably, the drive means is a direct-coupled AC motor, DC motor or stepper motor with the motor external to the chamber.
[0023] The detection system comprises a light source and a detector. These components can be any of the light sources and detectors know to those of skill in the art. For example, the light source can be an LED, a laser light source or a halogen lamp, with an appropriate filter to provide light of an appropriate wavelength for:
a) excitation of any fluorophore associated with the first interaction partner (by associated it is meant that the fluorophore is directly linked to the first interaction partner molecule or is linked to an indicator molecule); or b) absorbance by the first interaction partner or indicator molecule.
[0026] The detector will be suitable for the measurement of emitted fluroesence or absorbance. Detection systems advantageously include both types of detectors to give the device greater versatility in the types of binding assays that can be performed.
[0027] A device according to the invention can have associated therewith a computer for controlling such operations as:
[0028] Rotor speed;
[0029] Chamber temperature;
[0030] Time and temperature for annealing and polymerization steps when the binding assay is an hybridization;
[0031] Rotor braking;
[0032] Vibration of the rotor; and
[0033] Processing of data generated by the detection system.
[0034] A device that can be suitably adapted for use in the present invention is that described in International Application No. PCT/AU98/00277 (Publication No. WO 98/49340) the entire content of which is incorporated herein by cross reference.
[0035] With regard to the second embodiment of the invention, a method of performing a binding assay utilizing the device of the first embodiment, the quantities of first and second interaction partners are advantageously delivered as solutions which can contain other components such as buffers, salts, DNA or RNA polymerization reagents including a polymerase, or a blocking reagent if necessary. Solutions of interaction partners can be delivered by any of the methods known to those of skill in the art.
[0036] Temperatures and incubation times will be in accordance with the particular binding assay being performed and those parameters will be known to those of skill in the art. For example, hybridization reactions can be performed as described in Molecular Cloning: A Laboratory Manual , Second Edition (J. Sambrook et al., ed's), Cold Spring Harbour Laboratory Press, 1989. For performing a polymerase chain reaction, typical reaction mixtures and conditions are described, for example, in standard texts such as PCR: a Practical Approach (M. J. McPherson et al., ed's), IRL Press, Oxford, England, 1991, and numerous brochures provided by suppliers of amplification reagents and consumables. The entire content of the foregoing publications is incorporated herein by cross reference.
[0037] Binding of the first interaction partner to the second interaction partner can be done with the rotor spinning. The solution containing the mixture of interaction partners can usually be spun at a speed of less than 500 rpm while retaining the solution at the attachment zone. A speed of greater than 500 rpm is usually sufficient to displace solution—and hence any unbound first binding partner—away from the attachment zone. The bound first interaction partner is then measured by way of the detection system.
[0038] To allow measurement of bound first interaction partner, the partner has:
[0039] An inherent absorbance (which is different, if necessary, at the selected wavelength to the absorbance of other components of the binding assay); or
[0040] Has linked thereto a fluorescent or absorbent group.
[0041] Suitable fluorescent and absorbent groups will be known to those of skill in the art. Typical fluorophores include those abbreviated as FAM, JOE, ROX, TAMRA, Cy5, Cy3, Cy5.5, and VIC. Typical absorbent groups are Dabcyl and BH quenchers.
[0042] Alternatively, the bound first interaction partner can be measured by allowing an indicator molecule to bind thereto. This can be done as a further step after unbound first interaction partner is displaced form the attachment zone. Excess indicator molecule is similarly removed by centrifugal force after a sufficient period has been allowed at a suitable temperature for binding of the indicator molecule to the bound first interaction partner.
[0043] In instances where the first and second interaction partners form a DNA duplex or a DNA duplex is formed as a PCR product, an intercalating dye can be used to detect the duplex. Such dyes will be known to those of skill in the art. A particularly preferred dye is Sybr green.
[0044] The indicator molecule can be any molecule that is fluorescent or absorbs at an appropriate wavelength and which binds to the first interaction partner. Typically, the indicator molecule is an appropriately derivatised antibody that is specific for the first interaction partner.
[0045] Absorbance or fluorescence is measured with the rotor spinning, typically at a speed of at least 500 rpm at which speed the mixture will move away from the attachment zone. Data capture is controlled so that each attachment zone that passes over or under the detector is independently measured. Multiple detectors can be provided for use with reaction wells that include multiple attachment zones. Alternatively, a single detector can be used, with appropriate control, to scan all attachment zones.
[0046] A device according to the invention will now be described with reference to the accompanying figures. FIG. 1 shows rotor 1 of a device having a plurality of reaction wells mounted thereto, one of which wells is item 2 . A laser or diode 3 is provided as a light source, light from which is directed through a beam splitter or dichroic mirror 4 . Emitted fluorescence or absorbed light is measured by detector 5 .
[0047] FIG. 2 shows a reaction well 6 which in this instance is a rectangular prism fabricated from polypropylene. Well 6 has at its end which is closest the axis of the rotor when the well is in situ a plurality of attachment zones one of which is item 7 . The upper surface of well 6 has a loading port 8 . In use, after reagents have been added to the well, the solution thereof is displaced to end 9 of the well by centrifugal force through rotation of the rotor holding well 6 . Bound first interaction partner is then detected as schematically represented by arrow 10 .
[0048] Examples of binding assays that can be performed using the device and method of the invention will now be given.
Realtime Detection of PCR Products
[0049] A probe or a primer is bound at the attachment site, and PCR performed in the vessel. The following are done during PCR cycling:
[0000] 1) After each cycle of PCR at high rotor speed (greater than 500 rpm) the rotor is slowed so that the reaction mix covers the attachment zone (this is done at the annealing temperature of the primer/probe to the PCR product).
2) After a specified annealing time, the rotor speed is increased to remove the PCR mix from the attachment zone.
3) Fluorescence readings are taken at the attachment zone.
4) The previous steps are repeated.
Determination of Probe Melting Temperature
[0050] A primer or probe is bound to an attachment zone of a reaction well of a device according to the invention. A PCR reaction mix is added to the vessel, that includes at least one fluorescently-labeled primer. The rotor is spun at high speed to ensure no contact with the attachment zone and then the vessel cycled to perform PCR amplification. After amplification, the rotor is slowed to allow the PCR mix to come into contact with the attachment zone, so that the PCR product will hybridize specifically to the immobilized probe or primer. The temperature is reduced to below the expected melt temperature during this step to allow hybridization to occur. The rotor is then spun at high speed, the fluorescent signal at the attachment zone is sampled and the temperature of the chamber increased slowly, typically at 0.20° C. per second. The fluorescent signal captured will confirm the melt temperature of the primer/probe and PCR product.
[0051] Reference was made above to vibration of the rotor to move solution back over the attachment zone. This can also be achieved through use of a tilted reaction well. On sufficient slowing of the rotor, solution moves from an upward position at the distal end (relative to the axis of the rotor) to a lower portion over the attachment zone area of the reaction well. Rotor vibration is thus not needed in this embodiment of the device.
Determination of Antigen Levels in a Sample
[0052] An antibody specific for the antigen of interest is bound at an attachment zone of a reaction well. A sample containing an unknown amount of antigen is then allowed to react with the antibody. Solvent is removed by centrifugation and a solution containing an antibody to the antigen is applied to the attachment zone. This antibody may be the same or different to the antibody referred to above but is fluorescently labeled. Excess second antibody is then removed by centrifugation and the amount of antigen measured by fluorescence.
SNP Detection Using PCR
[0053] Synthetic probes for the mutated and wild type sequences are bound to separate attachment zones of a reaction well. The well is then loaded with a reaction mixture containing a DNA sample and a PCR master mix. The forward primer is labeled with a fluorophore. After each PCR cycle at the annealing temperature, the rotor speed is reduced and the reaction mixture allowed to overlay the immobolised probes. The rotor speed is then increased to displace reaction mixture and the fluorescence of the DNA retained at the attachment zones measured. An increase in fluorescence indicates amplification of either mutant, wild-type, or both DNAs.
[0054] Alternatively, a forward primer that is complementary to a portion of the mutated DNA is labeled with a fluorophore, for example FAM. A forward primer that is complementary to a portion of the wild-type sequence is labeled with a different fluorophore, JOE for example. A probe that is homologous to both the mutation and wild-type PCR products is bound at an attachment zone of a reaction well. By measuring the JOE to FAM ratio of PCR product hybridized with the probe the genotype can be determined.
[0055] It will be appreciated that many changes can be made to the device and method of use as exemplified above without departing from the broad ambit and scope of the invention. | The invention relates to a device for performing binding assays. In particular, the invention relates to a centrifugal device for performing such assays. The invention also relates to a method of performing binding assays involving antigen-antibody binding, nucleic acid hybridization, or receptor-ligand interaction. | 1 |
BACKGROUND OF INVENTION
This invention relates to low friction apparel and methods for producing same, wherein apparel is defined as clothing, footwear, fabrics, and the like. More particularly, the invention relates to low friction apparel which incorporates fabrics or chemicals having a low coefficient of friction either overall or in specific areas of the apparel that will minimize the development of blisters, callouses, and irritation of an apparel wearer's body surface. The invention also includes methods for producing the low friction apparel and methods for using a low friction material to reduce the coefficient of friction of a finished article of apparel or the like to reduce irritation.
Apparel is made out of many materials, natural and man-made. They include cotton, wool, silk, linen, leather, vinyl, nylon--polyamides and polyamide co-polymers, LYCRA SPANDEX™ in different filament configurations, orlon polyvinylidene fluoride, such as KYNAR™, polyester, for example, polyethylene terepthalate, glycol modified polyesters, such as PETG, KODURA™, rayon, orlon cellulosic fiber blends, and the like, as well as blends of the above.
Of course, apparel, either directly or indirectly, contacts the body surface of the wearer. The movement of the wearer causes frictional contact between the wearer's body surface and the apparel. This frictional contact can cause irritation, blisters, and callouses. This frictional contact is particularly a problem in sporting apparel wherein the formation of irritations, blisters, and callouses is exacerbated by the rapid and/or repetitious body movements related to the particular activity. Additionally, it is noted that most apparel has specific areas of high body surface/apparel contact which produces a majority of the irritations, blisters, and callouses.
It would be highly desirable to have apparel which has an overall low coefficient of friction or which has material having a low coefficient of friction in areas of high body surface/apparel contact such that irritations, blisters, and callouses are avoided or minimized.
SUMMARY OF THE INVENTION
It is a principle object of the invention to provide low friction apparel which avoids or minimizes the development of irritations, blisters, and callouses.
A further object of the invention is to provide a method for producing low friction apparel by chemically treating the fibers or yarn or the like of the material from which the apparel is made prior to or after producing the material.
Another object of the invention is to provide a method for producing low friction apparel by incorporating low friction yarns, fibers or material into the fabric from which the apparel is made.
Yet another object of the invention is to provide a method for producing low friction apparel by applying chemicals to impart a low friction coefficient directly to the fabric or apparel either overall or in areas of high body surface/apparel contact.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a preferred glove of the present invention.
FIG. 2 is a perspective view of an alternative embodiment of the glove of the present invention.
FIG. 3 is a perspective view of a sock or hosiery of the present invention.
FIG. 4 is a perspective view of a foot insert of the present invention.
FIG. 4A is a cross sectional view of the toe insert of the present invention for insertion into the footwear or onto the foot surface of the user.
FIG. 4B is a cross sectional view of the heel cup insert of the present invention for insertion into the footwear or onto the foot surface of the user.
FIG. 4C is a cross sectional view of a shoe insert of the present invention for insertion into the footwear or onto the foot surface of the user.
FIG. 4D is a cross sectional view of an alternative shoe insert of the present invention for insertion into the footwear or onto the foot surface of the user.
FIG. 5 is a perspective view of a knee bandage of the present invention.
FIG. 6 is a perspective view of an ankle bandage of the present invention.
FIG. 7 is a perspective view of an elbow bandage of the present invention.
FIG. 8 is a perspective view of an athletic wear of the present invention.
FIG. 9 is a perspective cross-sectional view of a footwear of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
As indicated above, the present invention provides low friction apparel to avoid or minimize irritations, blisters, and callouses that can result from abrasive contact between a wearer's body surface and the apparel. Low friction apparel can be made with low friction materials (10, FIGS. 1-9). These low friction materials can be fibers which inherently have a low coefficient of friction which are incorporated into the material either alone or in combination with other materials; low friction chemicals which can be applied directly to the finished fibers, material, or apparel to impart low friction properties; fibers which are treated with low friction chemicals then woven into the material either alone or in combination with other material; or any combination of the above. These low friction materials (10, FIGS. 1-9) can be incorporated into the entire piece of apparel (17, FIG. 5; 18, FIG. 7; 20, FIG. 6) or in specific high body surface/apparel contact areas (11, FIG. 1; 12, FIG. 2; 13, FIG. 3; 14, FIG. 4; 25, FIG. 4A; 35, FIG. 4B; 45, FIG. 5C; 55. FIG. 4D; 19, FIG. 8; 21, FIG. 9).
Some material fibers inherently have a low coefficient of friction. These fibers include, but are not limited to, silicone, graphite, TEFLON™, KYNAR™, boron, polypropylene, polyethylene, and GORTEX™. These materials can be incorporated directly into the apparel either overall or in specific high body surface/appeal contact areas to produce low friction apparel.
Chemicals can be used to treat material fibers or finished materials that do not inherently have a low coefficient of friction in order to impart a low coefficient of friction. Additionally, this chemical treatment can be used with materials which do inherently have a low coefficient of friction in order to impart an even lower coefficient of friction. This chemical treatment is incorporated into the material such that it is of a non-temporary nature. Most preferably, this chemical treatment is incorporated into the material such that it is functional substantially over the lifetime of the treated article. These chemicals include, but are not limited to, silicone, silicone copolymers, silicone elastomers, polytetra fluoroethylene, homopolymers and copolymers such as TEFLON™, graphite, and the like, as well as any combination of the above chemicals. The fibers can be treated with these chemicals by coextrusion when producing the fibers, blending with the fibers after production, adding in a bath form or spraying onto the fiber or material, or similar techniques. The finished material can be treated with these chemicals by adding in a bath form or spraying onto the material, or similar techniques.
In a typical application of the invention, a fiber, yarn or fabric or finished article (such as apparel) is treated with the low coefficient of friction material to reduce the coefficient of friction of the treated fiber, yarn, fabric or article to one which is below the coefficient of friction of the untreated fiber, yarn, fabric or finished article.
It is preferred that the coefficient of friction of the treated object be less than about 80% preferably less than about 60% and most preferably less than about 50% of the coefficient of friction of the untreated object.
If the low friction material is incorporated into the finished article or fabric by weaving a low friction fiber or yarn into the article or fabric, the low friction fiber or yarn can be incorporated into amounts ranging from 5% to 100% by weight of the treated area. Preferably, the fiber or yarn is incorporated in amounts between 30 and 70% by weight of the treated area. Most preferably, these amounts are 30 to 50%, by weight.
The addition of the low friction material to the fiber, yarn, fabric or article can also be useful to wick away moisture from the skin to help guard against irritation, as well as wetness.
It is preferred that areas of objects treated are typically areas which would ordinarily come in contact with the skin during use. Furthermore, it would be preferred that areas treated be those areas subject to imparting frictional movement against the skin during use.
It is preferred also that the coefficient of friction between the treated area of the object and the body surface to be reduced to below about 0.9. Most preferably, the coefficient of friction is reduced to below about 0.6.
The following examples are set forth to illustrate specific embodiments of the invention.
EXAMPLE 1
In one embodiment, low friction socks or hosiery can be produced by incorporating low friction material overall or in specific high contact areas such as in the heel area, (10a, FIG. 3) the area around the pad of the sole of the foot, (10b, FIG. 3) the area extending from the pad of the foot to the right and left sides of the foot, in the region where the foot is the widest, and the area around the toes (10, FIG. 3). Areas of the foot which contact laces, buckles or straps are also contact areas where protection would be utilized. The low friction material can also be incorporated to the outside of the sock which reduces friction between the sock and the outer foot apparel, such as a shoe. The low friction material can be incorporated to the inside of the sock which reduces friction between the wearer's foot and the sock. Additionally, low friction material can be incorporated to both inside and outside of the sock which, of course, simultaneously reduces friction between the sock and the outer footwear, and the wearer's foot and the sock.
EXAMPLE 2
In another embodiment, outer footwear such as a shoe, sneaker, boot, ski boot, sandal, slipper and the like, can have low friction material incorporated into the outer footwear fabric lining at high body surface/apparel contact areas thereby reducing friction between the wearer's foot or sock and the footwear. It is also noted that in footwear which has no fabric lining, the footwear material itself, such as leather, can be treated with low friction coefficient chemicals in high body surface/apparel contact areas (10, 21, FIG. 9) to have a similar result.
The low friction material is particularly useful in areas where the product would rub against the skin and cause irritation, blisters or callouses. In feet, these areas would be the heel, sole, the pads of the feet at the wide portion of the foot as shown in FIG. 9 or the top of the foot which contacts laces, buckles or straps.
EXAMPLE 3
In a further embodiment, sporting apparel, such as warm-up pants, shorts, jogging suits, bicycle pants, wet suits, work pants and the like, can have low friction material incorporated into high body surface/apparel contact areas such as the groin area and along the seams, such as the inner thigh seam, to avoid rubbing and irritations (10, FIG. 8). Additionally, sporting apparel, such as sport shirts, warm-up shirt, and the like, can have low friction material incorporated into high body surface/apparel contact areas such as the neck and underarm areas to also avoid rubbing and irritations.
EXAMPLE 4
In yet another embodiment, work and sport gloves such as gloves used with tools, golf clubs, baseball bats, polo mallets, and tennis, squash and racquetball racquets, can have low friction material incorporated the glove (10, 11, FIG. 1; 10, 12, FIG. 2) at high body surface/apparel contact areas to avoid blisters and callouses on the hands.
EXAMPLE 5
The low friction material can be utilized in footwear inserts (10, 14, 15, FIG. 4; 10, 25, FIG. 4A; 10, 35, FIG. 4B; 10, 45, FIG. 4C; 10, 55, FIG. 4D) and other devices made to fit in traditional footwear that will help avoid blisters and callouses by reducing friction of the foot against the pressure areas of footwear such as heel cushions, (10, 25, FIG. 4A) insoles (10, 45, FIG. 4C; 10, 55, FIG. 4D), orthotics, cushions and other pads (bandages).
EXAMPLE 6
The low friction material can also be used in bandages and wraps which support torn and sore muscles, ligaments and joints and as linings for casts (10, 17, FIG. 5; 10, 20, FIG. 6; 10, 18, FIG. 7).
EXAMPLE 7
The low friction material can be incorporated into covers for sporting equipment and tools and other devices that one uses that could cause irritation, blisters, callouses or soreness from friction.
Handles of baseball bats, handles of tennis and racquetball racquets, shovels, picks, construction and garden tools, hammers, screwdrivers, pliers, etc, handles of ski poles, fishing rods, water ski rope grips and towing ropes, golf clubs, archery bows, bicycle seats, car seats and back seats, weights and exercise equipment, etc., are all areas which can be incorporated with the low friction material.
It is understood that the invention is not limited to human apparel. The invention can also be used in horse blankets, pet apparel, and the like.
It is also understood that the invention is not restricted to the detailed description of the invention, which may be modified without departure from the accompanying claims. | The present invention relates to apparel, such as clothing, footwear, fabrics, and the like, which incorporates fabrics or chemicals having a low coefficient of friction either overall or in specific areas of the apparel that will minimize the development of blisters, callouses, and irritation of the skin. The invention also includes methods for producing this low friction apparel. | 0 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The field of the invention is that of probes including a set of emitting and/or receiving elements obtained by cutting from a transducer block. Such probes are currently used especially in applications such as echography. More specifically, the invention relates to unidirectional acoustic probes, including linear elements which can be excited independently of each other by virtue of an interconnection network connected to a control circuit.
2. Description of the Related Art
One method of producing these probes consists first of all in producing an assembly of a printed circuit including an interconnection network/layer of piezoelectric material/acoustic matching plates, then in cutting out the individual piezoelectric elements. International application WO 97/17145 filed by the applicant describes such a method and more particularly a method of manufacturing a probe using a printed circuit on which conducting tracks are produced, making it possible to address the various acoustic elements.
FIG. 1 actually illustrates more specifically a piezoelectric material 13 assembled to acoustic matching plates Li 1 and Li 2 , said material being cut in two perpendicular directions by the standard sawcuts T i and T j . A flexible printed circuit 12 includes conducting tracks PI and vias, at least part of one and the same via being positioned on a conducting track and on a metallization M i of associated piezoelectric material. In this configuration, linear acoustic pathways are defined parallel to the lines T j , each acoustic pathway being subdivided into a subpathway defined parallel to the lines T i . When the previously described assembly is produced, the probe is shaped, an operation making it possible to produce curved probes which are particularly sought in the echography field. To this end, the printed circuit including its individual acoustic elements may be adhesively bonded to the surface of a solid absorbing material having a curved surface. The flexible printed circuit is then folded over the edges of the ceramic and of the absorber as illustrated in FIG. 2 . The acoustic pathways defined parallel to the axis X, are also parallel to the tracks PI, the printed circuit and conducting track assembly is, on the one hand, placed on the surface of the absorber ABS and, on the other hand, folded back vertically over the sides A and At of said absorber for reasons of compactness. In this configuration, the tracks are thus folded at 90° with a sharp angle which tends to weaken them or even break them.
BRIEF SUMMARY OF THE INVENTION
To solve this problem, the present invention provides an acoustic probe including a novel interconnection network produced on the surface of a flexible dielectric film making it possible during the shaping operation to optimize the overall size of the probe and the strength of the electrical connections.
More specifically, the subject of the invention is a unidirectional acoustic probe including linear piezoelectric transducers on the surface of a dielectric film, the dielectric film including elements for electrically connecting the piezoelectric transducers to a control device, characterized in that the connection elements include:
primary connection pads, facing the piezoelectric transducers; secondary connection pads, offset with respect to the piezoelectric transducers, so that the transducers can be connected to the control device; conducting tracks connecting the primary connection pads to the secondary connection pads, the conducting tracks being in a direction D x perpendicular to the direction D y defined by the major axis of the piezoelectric transducers.
In an advantageous variant of the invention, each piezoelectric transducer includes a control electrode and a ground electrode and the dielectric film may include:
on its upper face, first primary connection pads in contact with the control electrodes, second primary connection pads in contact with the ground electrodes and first secondary connection pads; on its lower face, third primary connection pads connected to the first primary connection pads by conducting vias, second secondary connection pads connected, on the one hand, to the first secondary connection pads by conducting vias and, on the other hand, to the third primary connection pads by conducting tracks, and fourth primary connection pads connected to the second primary connection pads by conducting vias.
Advantageously, the second secondary connection pads form part of a conducting region located on the periphery of the lower surface of the dielectric film forming the ground.
The subject of the invention is also a method of manufacturing acoustic probes.
More specifically, the subject of the invention is also a method of manufacturing unidirectional acoustic probes including linear piezoelectric transducers, characterized in that it includes the following steps:
producing, on each of the faces of a dielectric film, primary connection pads intended to face piezoelectric transducers and secondary connection pads intended to be offset with respect to the piezoelectric transducers; producing electrical tracks connecting primary connection pads and secondary connection pads on the lower face of the film; adhesively bonding a layer of piezoelectric material including metallizations, to the upper face of the dielectric film; cutting the layer of piezoelectric material in a first dielectric so as to define the linear piezoelectric transducers, the first direction being perpendicular to a second direction parallel to the conducting tracks.
Advantageously, the operation of cutting the linear acoustic elements is carried out down to the dielectric film.
The subject of the invention is also a method of collectively manufacturing acoustic probes, characterized in that it includes:
producing, on the surface of a dielectric film, a set of primary connection pads, secondary connection pads and conducting tracks connecting the primary connection pads to the secondary connection pads; assembling a set of layers of piezoelectric material and layers of acoustic matching material, over the set of connection pads so as to define a set of acoustic probes on the surface of the dielectric film; cutting layers of piezoelectric material and layers of acoustic matching material so as to define a set of probes including linear piezoelectric transducers; cutting sets of dielectric film/linear piezoelectric transducers so as to individualize the unidirectional acoustic probes.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be better understood and other advantages will become apparent on reading the following description given by way of non-limiting example with reference to the appended figures, in which:
FIG. 1 illustrates a multi-element acoustic probe according to the prior art including a printed circuit and conducting tracks parallel to the acoustic pathways defined by the acoustic elements;
FIG. 2 depicts the printed circuit of an acoustic probe shaped over an absorber and using the acoustic elements as illustrated in FIG. 1 , of the prior art;
FIG. 3 a illustrates a top view of an exemplary probe according to the invention;
FIG. 3 b illustrates a sectional view of the exemplary probe illustrated in FIG. 3 a;
FIG. 4 a illustrates a top view of a flexible printed circuit used in a probe according to the invention;
FIG. 4 b illustrates a bottom view of the same flexible printed circuit used in a probe according to the invention;
FIG. 5 illustrates a step in the method of the collective manufacture of probes according to the invention; and
FIG. 6 illustrates a probe according to the invention, shaped over an absorber.
DETAILED DESCRIPTION OF THE INVENTION
The invention will be described in the case of a particular example of a unidirectional probe including eight linear transducers but is applicable whatever the number N of linear transducers.
In general, the probe according to the invention includes a flexible dielectric film, hereinafter called a flexible printed circuit (because of the electrical connections which are produced thereon), on which various connection pads are produced making it possible to address the piezoelectric transducers. The connection pads facing the transducers are called primary connection pads, and the connection pads offset with respect to the transducers are called secondary connection pads.
Conventionally, each piezoelectric transducer includes a ground electrode E mi and a control electrode E ci , otherwise called a “hot spot” in the field of ultrasound sensors.
FIG. 3 a illustrates a probe according to the invention seen from the top. FIG. 3 b illustrates the same probe seen in section along the axis CC′. The piezoelectric transducer elements TP i consist of a piezoelectric material which may be a ceramic and are separated by cutouts T j . Their surface is partly metallized so as to define a control electrode E ci and a ground electrode E mi for each of said transducers. These electrodes are connected by conducting vias V i on the lower surface of the printed circuit CIS, as will be developed below. Conventionally, the upper surface of the ceramic is covered with acoustic matching elements Li 1 and Li 2 , the electrical properties of which are chosen to provide good acoustic matching. The transducers are adhesively bonded to the surface of a flexible printed circuit CIS including predefined electrical connections. The linear transducers are thus defined parallel to the direction Dy shown in FIG. 3 a.
FIGS. 4 a and 4 b illustrate respectively a top view of the printed circuit and bottom view of the said circuit, the surface seen from the top being in contact with the piezoelectric material.
More specifically, FIG. 4 a shows, in the central part of the flexible printed circuit CIS, first primary connection pads pppc i for electrically connecting the control electrodes Ec i of the transducers, second primary connection pads sppc i in contact with the ground electrodes Em i of the transducers TP i and first secondary connection pads ppsc i , the second primary connection pads sppc i correspond to a ground pad PM s produced at the periphery of the flexible printed circuit. This ground pad is cut during the operation of cutting the piezoelectric material into linear transducers since this cutting takes place on the matching plate/piezoelectric material assembly, the cutting extending into the flexible printed circuit and in this way leading to separating the ground pad prepared on the periphery of the upper surface of the flexible printed circuit into second primary connection pads sppc i .
The lower surface of the flexible printed circuit illustrated in FIG. 4 b comprises third primary connection pads tppc i facing the first primary connection pads pppc i and connected thereto by means of conducting vias. It also comprises second secondary connection pads spsc i connected to the pads tppc i by means of conducting tracks PI in a direction Dx and connected by means of conducting vias to the first secondary connection pads ppsc i , from which it becomes possible to address the control electrodes of the piezoelectric transducers TP i .
Moreover, conducting vias through the flexible printed circuit enable the second primary connection pads sppc i to be connected to the ground pad PM i made at the periphery of the flexible printed circuit on its lower surface and thus to provide the ground contact for the set of piezoelectric transducers TP i .
Advantageously, the dielectric film has a peripheral width l ex which is greater than its central width l c .
Such a configuration makes it possible to increase the pitch between the second connection pads with respect to the pitch between the primary connection pads.
Moreover, the connection pads in contact with the ground electrodes and the connection pads in contact with the control electrodes are distributed over the flexible dielectric film so that the conducting vias can equally advantageously be distributed in a direction Dg making an angle of about 45° with the direction D, so that there is no zone where the conducting vias overlap each other.
Assembly Step
In general, the ceramic piezoelectric material can be assembled onto the flexible printed circuit by adhesive bonding using an anisotropic conducting adhesive film (ACF). The ACE is a polymer film filled with metallized or metal polymer balls. The electrical conductivity is achieved by crushing the balls along the conducting axis when adhesively bonding the ceramic under pressure onto the printed circuit.
It may also involve a polymer resin filled with metallized or metal polymer balls. Electrical conductivity is also obtained by crushing the balls along the conducting axis when adhesively bonding under pressure.
According to another variant of the invention, the electrical contact may also be provided by using an isotropic conducting resin or an isotropic conducting film comprising a polymer filled for example to 80% with metal particles of the silver, nickel, etc. type. The electrical conductivity, which is in this case isotropic, is provided by the physical contact between the metal particles.
Cutting Step
The linear piezoelectric transducers can be cut from the piezoelectric material covered with its matching plates, using a diamond saw, in the direction Dy illustrated in FIG. 3 a.
Typically, the width of a linear transducer may vary between 50 and 500 microns. To electrically isolate the linear transducers, the cutting lines stop in the thickness of the dielectric film.
Rather than using a diamond saw, it is also possible to carry out laser cutting of the various elements.
It is also possible to combine the two types of cutting. Thus the acoustic matching plates can be cut by laser, while the piezoelectric ceramic is cut using the mechanical saw. The latter cutting method makes it possible to free the thermal stresses due to the adhesive bonding of materials having very different thermal expansion coefficients. By initially cutting the acoustic matching plates, the ceramic is freed from thermal stresses and consequently, breaking of the ceramic during the second cutting is avoided.
The preceding steps can be carried out collectively. This is because a set of primary and secondary connection pads can be prepared on a same flexible dielectric film and intended for several acoustic probes as illustrated in FIG. 5 , which shows a top view of said dielectric film.
On a dielectric film also called a flexible printed circuit CIS, various ground pads are prepared on the upper face of said flexible circuit, together with the necessary primary and secondary connection pads; in this case only the ground pads PMs are shown. Once the set of electrical connections (connection pad, metallization, conducting via) is produced on the flexible printed circuit assembly, various solid piezoelectric materials are adhesively bonded locally. As shown in FIG. 5 , an example of 6 ceramic plates can be adhesively bonded onto the flexible printed circuit, together with six pairs of acoustic matching plates on said six ceramic plates. A collective cutting step is then carried out. Typically, series of probes, which are aligned vertically in FIG. 5 , can be cut into individual elements in a single step, as illustrated by the dot-dash lines in FIG. 5 .
After the step of collectively cutting the linear piezoelectric transducers, each of the acoustic probes is cut around the ground planes PM s illustrated in FIG. 5 .
Thus the collectivization makes it possible to reduce the manufacturing costs.
Shaping Step
In general, the shaping operation is the one which makes it possible to produce curved probes. According to the invention, by virtue of the flexible dielectric film used and the prior cutting of the linear transducers, enough curvature of said dielectric film is obtained in order to assemble it on the surface of an absorber with a curved surface. In this respect, FIG. 6 shows the assembly of the flexible film CIS on the surface of the absorber ABS and also clearly illustrates that in this configuration, the electrical connection tracks PI are no longer folded with a sharp angle of 90° but are only subject to a slight curvature, so that they are no longer weakened as was the case in the prior art. | A unidirectional acoustic probe including a high-performance interconnection network, and a method of manufacturing such a probe. The unidirectional acoustic probe includes linear piezoelectric transducers on the surface of a dielectric film. The dielectric film includes a connection device to electrically connect the piezoelectric transducers to a control device. The connection device includes primary connection pads, facing the piezoelectric transducers, secondary connection pads, offset with respect to the piezoelectric transducers, so that the transducers can be connected to the control device, and conducting tracks connecting the primary connection pads to the secondary connection pads. The conducting tracks are in a direction perpendicular to the direction defined by a major axis of the piezoelectric transducers. | 1 |
BACKGROUND
(i) Field of the Invention
This invention relates generally to modified polyethylene terephthalate polymers and copolymers that may be processed into plastic containers using conventional extrusion blow molding equipment. More particularly, it relates to polymers of the branched and end-capped type, which polymers contain substantially fewer gels. It also relates to the use of specific end-capping agents for making such polymers in a reproducible manner.
(ii) Prior Art
U.S. Pat. No. 4,161,579 (Edelman 1), hereby incorporated by reference, discloses a large number of modified polyethylene terephthalate polymers (hereinafter modified PET polymers) that can be successfully processed to form a hollow container by conventional extrusion blow molding techniques using existing, conventional, extrusion blow molding equipment. The patent also describes the requirements for polymers suitable for extrusion blow molding. Essentially, such polymers must have (1) "high zero shear rate melt viscosity", and "absence of gels", in order to make a satisfactory "parison" after extrusion of the polymer from the annular die; and (2) sufficiently high "shear sensitivity", in order to be capable of being forced through the melt extrusion equipment without generating excessive pressure. All the polymers disclosed in Edelman 1 involve the use of branching agents and end-capping agents. However, as stated therein, the chain terminating agent "must have a boiling point above 200° C." (see Edelman 1, column 10, lines 30-34) and also is a monofunctional compound containing one--COOH group (or its ester).
U.S. Pat. No. 4,234,708 (Edelman 2) is similar to Edelman 1, except that it relates to a modified polyethylene iso/terephthalate copolymer. Edelman 2 also points out that it is necessary to avoid the presence of excessive amounts of isophthalic acid or dimethyl isophthalate as starting materials for the copolymers, as this will result in the formation of prepolymers which are totally amorphous. Further, such prepolymers possess a particularly low glass transition temperature. They therefore tend to stick together if solid state polymerization is attempted at normally employed temperatures (in order to increase molecular weight and give sufficiently "high zero shear rate melt viscosity"). This, in turn, reduced the surface area from which glycol can evaporate. Also, Example H shows that when a copolymer is prepared from terephthalic acid and isophthalic acid in a ratio of 75:25 by weight, the prepolymer is completely amorphous and therefore is not capable of solidstate polymerization to increase molecular weight. (See Edelman 2 at column 10, lines 15-31 and column 23, lines 27--34.)
U.S. Pat. No. 4,219,527 (Edelman 3) is similar to Edelman 1, except that it is directed to a blow molding process.
Defensive Publication No. T954,005, published Jan. 4, 1977, discloses a process for preparing containers, such as bottles, using a branched polyester of terephthalic acid, a combination of ethylene glycol and 1,4-cyclohexanedimethanol and a small amount of a polyfunctional branching compound. A molten parison of such polyester is extruded and then expanded in a container mold to form the desired container. More specifically, the polyester used for that invention can be broadly described as comprised of terephthalic acid and a diol component comprised of 10 to 40 mole percent 1,4-cyclohexanedimethanol and 90 to 60 mole percent ethylene glycol and a polyfunctional branching compound (see unexamined application at page 4, lines 18-21). Examples of the polyfunctional branching compound are given at page 4, lines 22-31 of the unexamined application, and include pentaerythritol, and trimethylolpropane. In addition, the unexamined application states the following at page 5, lines 14-31 concerning the possible use of chain terminators to prevent the formation of gels in the polyesters. "The rapid buildup of molecular weight can produce a nonuniform gel in the polyester. To control this rapid rate of polymerization and to obtain the desired degree of polymerization, it is often desirable to use a chain terminator in accordance with techniques well known in the art. By using the proper level of chain terminator the polymer can be stopped at the desired degree of polymerization. Useful terminators include monofunctional acids, esters or alcohols. It is often desirable to use a relatively nonvolatile terminator since the terminator can be lost by volatilization during polycondensation. Examples of terminators that can be used include heptadecanoic acid, stearic acid, nonadecanoic acid, benzoic acid, phenylacetic acid, 4-biphenylcarboxylic acid, phenyloctadecanoic acid, 1-heptadecanol, 1-octadecanol, and 1-nonadecanol. Lower molecular weight terminators such as acetic acid, propionic acid, methanol and ethanol can also be used."
Some of the chain terminators suggested in the defensive publication, e.g. methanol and ethanol, are well known to have boiling points far below 200° C. However, nowhere does the defensive publication disclose a solid-phase polymerization process. Further, it is believed that at least most of the copolymers described in the defensive publication are so-called "amorphous" polymers, and as such would be incapable of being commercially solid-phase polymerized to give polymers of very high molecular weight.
U.S. Pat. No. 4,246,378 (Komentani et al) discloses a thermoplastic polyester resinous composition comprising a melt blend of a thermoplastic polyester, an epoxy compound, and an organic sulfonate and/or organic sulfate salt of the following formulae:
R.sup.3 (SO.sub.3 M).sub.m and R.sup.4 (OSO.sub.3 M).sub.m
wherein M may be sodium and R 3 is a polymeric or high molecular weight organic group and R 4 is alkyl or polyalkylene oxide, and m is an integer from 1 to 3. The disclosed compositions are described as having improved melt strength and impact strength. Komentani's Comparative Example 12 and Comparative Example 13 in Table 2 show the result of evaluating resinous compositions L and M of Table 1 in which the epoxy compound was omitted, in respect to the states of parisons and blow molded bottles. The parisons had unacceptably "great drawdown" and it was "impossible to mold" bottles from the parisons. It will be noted that the glycol constituent was 1,4-butanediol.
U.S. Pat. No. 4,257,928 (Vachon et al) discloses an adhesive composition comprising "dibenzal sorbitol gelling agent and polyesters derived from components (A), (B) and (C) as follows: (A) at least one dicarboxylic acid; (B) at least one diol, at least 20 mole percent of the diol component being a poly(ethylene) glycol having the formula H(OCH 2 CH 2 ) n OH wherein n is an integer of from 2 to about 14; and (C) at least one difunctional dicarboxylic acid sulfomonomer containing a --SO 3 M group attached to an aromatic nucleus, wherein M is Na + , Li + , K + or a combination thereof, the sulfomonomer component constituting at least about 8 mole percent to about 45 mole percent of the sum of the moles of said components (A) and (C)." (See Abstract.) The copolyester useful in that invention "may be terminated with either hydroxy or carboxy end-groups. In addition, the end-group functionality of the copolyester, and therefore its crosslinkability, may be increased by reaction of the high molecular weight linear polyester with tri- or tetrafunctional hydroxy or carboxy compounds such as trimethylolpropane, pentaerythritol, or trimellitic anhydride in a manner known in the art." (See Vachon at column 3, line 68 to column 4, line 7). Notwithstanding some superficial similarities, Vachon's copolyesters are significantly different with regard to structure and end use from the invention described hereinafter.
Essentially, for the purpose of the invention claimed hereinafter, the prior art does not appear to disclose an end-capping agent for PET polymer or copolymer that is also an organic di-acid. Even less does such art relate to the relative effectiveness of isomers of sulfobenzoic acid.
SUMMARY OF THE INVENTION
In contract to the aforementioned prior art relating to polyethylene terephthalate and polyethylene iso/terephthalate, it has now been surprisingly discovered that certain organic di-acids are suitable as end-capping agents. Further, it appears that these compounds can result in polymers having even lower gel content than prior art products prepared from the monofunctional end-capping reagents used in any of the Examples of aforementioned Edelman 1, 2, or 3, particularly at high molecular weights. More specifically, the end-cap comprises the reacted component of a difunctional acid or alkali metal salt of a difunctional acid having the formula: ##STR2## wherein: X has a valency of 6 and is selected from sulfur, selenium, and tellurium; M is an alkali metal or hydrogen; and, Y is hydrogen or an aliphatic group containing from 1 to 18 carbon atoms.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The nature of the preferred embodiments of the invention is best understood by the Examples contrasted with the Comparative Examples and Control Examples hereinafter. Such Examples are not intended to limit the scope of the invention.
The following terms as used herein have the same definitions as those found in Edelman 1, particularly columns 7 and 8: "Melt strength (MS)"; "high melt strength"; "polyester"; "parison": "die swell"; and "shear sensitivity". The term "polyester" as used herein is any high molecular weight synthetic polymer composed of at least 85% by weight of an ester of a dihydric alcohol and terephthalic acid (p-HOOC--C 6 H 4 --COOH). Further, "inherent viscosity" and "intrinsic viscosity" were measured as described in Example 1 below. A "gel test" is also described in Example 1 below. It should be noted that it is a more stringent test than was used in Edelman 1, 2 or 3. In addition, the term "sublimation point" of a compound is used herein to denote the temperature at which the compound passes directly from the solid state to the vapor phase, at atmospheric pressure.
In practicing the instant invention it is preferred that the end-capped polymers have properties as shown in the claims hereinafter.
EXAMPLE 1
This Example illustrates the use of the sodium salt of m-sulfobenzoic acid as an end-capping agent in making polymers of the present invention. It is well known that this metal salt acts as m-sulfobenzoic acid in the presence of glycols, alcohols, and/or water.
The polymer was made and tested according to the following procedures. Briefly, (1) an ester interchange reaction was carried out using 96 parts by weight dimethylterephthalate, 4 parts by weight dimethyl isophthalate, ethylene glycol in a molar ratio of 2.2:1; 0.3 parts by weight pentaerythritol as branching agent, in the presence of 180 parts per million Mn(OAc) 2 .4H 2 O (as catalyst); (2) 110 parts per million polyphosphoric acid (as stabilizer) and m-sulfobenzoic acid as end-capping agent in an amount of one equivalent of end-capping agent per branching agent, (i.e. 4 moles m-sulfobenzoic acid for each mole of pentaerythritol) were added to the product of the ester interchange reaction; this mixture was then conventionally polymerized in the molten state in the presence of 480 ppm Sb 2 O 3 as catalyst; (3) the resultant molten polymer was pelletized and thereafter crystallized at a temperature of 140° C.; (4) separate samples of the crystallized prepolymer were then subjected to polymerization under vacuum at a temperature of 220° C. for periods of 0,3,5 and 7 hours; and (5) all four polymer samples were thereafter tested by dissolving the polymers and visually examining the resulting solutions for the presence of gels, particles and color changes. More specifically, each of the foregoing five steps is described in more detail hereinafter.
Catalysts were added to the reaction mixture, which yielded about 1 lb. of polymer, before beginning ester interchange. The ester interchange was conducted at atmospheric pressure in a stirred stainless steel, 1 liter reactor. It was fitted with a pipe plug in the bottom, and heated by an electric heating mantle. The mantle was controlled by means of a thermocouple, immersed in the reactive mass, connected to a temperature indicating controller which supplied power to the heating mantle as required to maintain the set point temperature in the mass. The current to the stirrer was monitored by an ammeter which indicated the amount of power consumed by the drive motor. The reactor was fitted with a long fractionating, Vigreux-type air-cooled condenser for the ester interchange portion of the reaction. Electric heating tape partially covered the column in order to control the heat loss and thus the reflux rate. The methanol evolution rate during ester interchange was controlled by the column temperature and batch temperature. To start the ester interchange (EI) process the temperature of the reaction mass was raised to about 90°-100° C. to commence dissolving the reactants. Once melted, the temperature was then steadily raised just fast enough to complete the EI reaction in about 2-3 hours. The actual ester interchange reaction began when the reactants reached about 150° C. and continued until about 100% of the theoretical yield of methanol had been obtained and the glycol started evolving. At this point, the reaction mass generally reached the temperature of about 215° C.
At this time, the end capper and stabilizer were added and the reaction converted to the polycondensation mode by quickly removing the air-cooled condenser used during ester interchange. The air cooled condenser was replaced with a special vacuum condenser, internally baffled to prevent the entrainment of solids in the ethylene glycol vapor and which also condensed ethylene glycol vapor without allowing the condensate to return to the reaction mass during polymerization. A vacuum pump with suitable trapping and a nitrogen bleed to control vacuum levels was attached to a side port on the ethylene glycol receiver. In order to prevent excessive volatilization of the product ethylene glycol, the receiver was immersed in a dry ice/methanol mixture to keep it cold and to reduce the ethylene glycol vapor pressure. The condensation reaction began as the temperature was raised from 215° C. to about 230°-240° C. at which point vacuum was gradually applied to facilitate the condensation reaction by removing the ethylene glycol by-product. The vacuum level was ramped from 1 atmosphere down to about 1 mm Hg over the period of about 30 minutes to 1 hour. Reaction mass temperature was steadly raised by application of heat to a maximum temperature of 270° C. over the course of about 1-2 hours and then during the last hour or so the vessel was held at full vacuum and the maximum temperature. The reaction was terminated when the ammeter indicated that the torque in the stirrer had reached a predetermined value corresponding to the desired molecular weight. This molecular weight was measured by a solution viscosity yielding an intrinsic viscosity of about 0.55-0.65 dl/bm. To measure this, the inherent viscosity was measured in orthochlorophenol at a concentration of 8% at 25.0° C. and via a correlation, for the intrinsic viscosity was computed.
Upon completion of the polycondensation, the reaction was halted by "breaking" the vacuum by valving off the pump and adding an inert gas purge (N 2 ). After reaching atmospheric pressure, the pipe plug in the bottom of the reactor was carefully removed and the reaction mass was drained from the vessel under a modest nitrogen pressure (1-2 psi). The strand issuing from the reactor was quenched in an ice water bath to solidify it, and then chipped into pellets. The chipped polymer was screen-classified to a uniform size. It was then crystallized to prevent the pellets from fusing together when reheated near the melting point for the solid state polymerization. The crystallization process was rapidly effected by heating the pellets for about one hour to about 140° C. This process also dried the pellets of excessive surface moisture.
To characterize the relative effectiveness of endcapping agents in preventing gelation of banched polyesters during solid state polymerization to the higher molecular weights required for good processing in conventional extrusion blow molding equipment, a severe solid state polymerization cycle was used; followed by dissolving the resins in a good solvent (1:1 by volume of trifluoroacetic acid: methylene chloride); and followed in turn by visual observation for the presence of gels. In particular, the polyester resins obtained from the conventional melt polymerization step were dried and crystallized as described earlier. Then 5 grams of the hot, crystalline resin were placed in a 50 ml round bottom flask. The polymer was placed in the flask so that the sample was in intimate contract with the glass walls and not "layered" atop other polymer particles. The flask was immersed in an oil bath controlled at 225±1° C. and sealed with a stopper container an evacuation tube which was connected to a vacuum line and maintained at less than 0.1 mm Hg internal pressure. Three such vessels were used for each resin and one vessel was removed from the hot oil bath after 3, 5, and 7 hours and allowed to cool to ambient temperature for 16 hours under 0.1 mm Hg internal pressure (vacuum) to prevent influx of air and water etc. onto the hot resin which may cause oxidation or hydrolysis and thus loss of molecular weight gained from solid state polymerization. After cooling, 1 gram of the sample was placed in 10 ml of a 1:1 solution by volume of trifluoroacetic acid:methylene chloride, a strong solvent for polyethyleneterephthalates. The solution was agitated for 16 hours in a capped 25 ml test tube. After agitation, the solution was observed in strong incandescent light for the presence of gels which are fluorescent in solution under these conditions. The samples were visually rated according to whether the solution contained any particles; and if so, the size and shape of the particles of gel. Obviously, the longer the solid phase polymerization time required for the formation of gels, the more efficient is the chain regulator in preventing gelation.
The following abbreviated terminology is used hereinafter in connection with the analysis of the final polymer samples. "s" denotes the presence of solution only. "F" denotes the presence of fibrous material in solution. "p" denotes the presence of fine particles in solution. "g" denotes the presence of small gels having diameter less than about 0.1 mm in solution. "G" denotes the presence of large gels having diameters greater than about 0.1 mm in solution. "G" denotes the presence of many very large gels in solution, where the gels appeared to have the shape and size of preexisting pellet samples.
In this Example, the use of 1.97 weight percent m-sulfobenzoic acid resulted in polymers with gel test results of s/s/s/F at 0/3/5/7 hours respectively.
COMPARATIVE EXAMPLE 1A
Example 1 was repeated, except that 2.11 weight percent of the potassium salt of p-sulfobenzoic acid was used as the end-capping agent. The resultant polymers had gel test results of s/G/G/G at 0, 3, 5, and 7 hours respectively. These results are significantly inferior to those of Example 1, and comparable to those in Control Example 1 and Control Example 2 below.
CONTROL EXAMPLE 1
Example 1 was repeated except that 1.02 weight percent benzoic acid was used as the end-capping agent. The gel test results of the resultant polymers were s/G/G/G.
CONTROL EXAMPLE 2
Example 1 was repeated except that 1.41 weight percent stearic acid was used as the end-capping agent. The resultant polymers had gel test results of s/g/G/G. | There is disclosed an improved modified polymer suitable for use in making hollow containers by conventional extrusion blow molding. It is a specific type of end-capped and branched polyethylene terephthalate polymer or copolymer. In the improvement, the end-cap comprises the reacted component of a difunctional acid or alkali metal salt of a difunctional acid having the formula: ##STR1## wherein: X has a valency of 6 and is selected from sulfur, selenium, and tellurium;
M is an alkali metal or hydrogen; and
Y is hydrogen or an aliphatic group containing from 1 to 18 carbon atoms.
The preferred difunctional acid is m-sulfobenzoic acid. The product typically contains few large gels having diameters greater than 0.1 mm. | 2 |
BACKGROUND OF THE INVENTION
This invention relates to enclosure apparatus which can be expanded or contracted to various dimensions. It relates particularly to expansible mobile trailers which can be readily transported from one site to another. With the present invention, if utilized as an expansible mobile home, camper or work trailer, it can be contracted such that it is of moderate size and easily transportable from location to location, and then expanded in height, width and length to provide a relatively spacious and commodious mobile home, camper or work trailer.
DESCRIPTION OF THE PRIOR ART
In attempting to design trailers and other forms of apparatus which are expansible, a number of approaches have been used. A common method has been to raise and lower trailers from a stored or towing position to a usable position by drums around which cables are wound, the cables being rooted to the upper portion of the trailer to raise and lower the trailer. Other references have shown different facilities such as interfitting wall portions to allow the interior dimensions of a trailer to be changed. For example, U.S. Pat. No. 2,767,013, to Spears, shows a trailer having a top which can be elevated wherein the top is mounted on a single telescoping central member. As an example of an expansible house trailer, U.S. Pat. No. 3,234,697, to Spencer, shows a vehicle that may be collapsed for transport and then substantially expanded by folding out various wall sections. U.S. Pat. No. 3,212,810, to Bass, also discloses a collapsible trailer of the house trailer type wherein a plurality of sections may be expanded by longitudinally telescoping means to provide a substantially elongated vehicle. Another example of expansible trailer construction is shown in U.S Pat. No. 3,734,559, to Touchette. This reference shows a trailer which expands vertically using cable and winch-operated interfitting wall sections. The elevating mechanism in this reference uses a system of pulleys and cables sometimes located within vertical channels which extend upwardly to form part of the walls of the trailer. Supplementary guide members are used to maintain integrity of the expansible portions. U.S. Pat. No. 3,815,949, to Ulert, also discloses an expansible mobile apparatus which uses interfitting floor, roof and wall sections and additional interfitting floor, roof and wall sections, which move relatively to one another for changing the dimensions of the apparatus. The specification shows interfitting body members which are actuated by hydraulic means to alter the dimensions of the apparatus.
Although the prior art does disclose the concept of a trailer having telescoping major body parts, none of the references discloses in combination substantially parallel and perpendicular telescoping structural elements which will expand in two or three dimensions to form the frame of an enclosure. In addition, none of the references demonstrates the kind of structural rigidity necessary for a vehicle or apparatus which must withstand the forces of weather and transport and the stresses associated therewith. A further disadvantage of many other prior art systems includes the lack of an effective means for guiding an upper portion of a trailer onto the lower portion and in sealing the two portions to prevent the ingress of wind, dust, moisture or the like.
SUMMARY OF THE INVENTION
The present invention recognizes and overcomes many of the problems encountered by the prior art in attempting to provide a utilitarian transportable expansible booth type apparatus which may be quickly changed in dimensions and effectively transported, if desired, from location to location while still maintaining sufficient structural integrity to fulfill its intended function. The expansible enclosure apparatus of this invention includes a box-like structure having six sides interconnected at their respective peripheries, the sides arranged in opposed pairs, at least two of the pairs of opposed sides being expansible; and at least two telescoping frame members, the frame members being perpendicular to each other, and each of the frame members being integral and co-planar with an expansible side of said box-like structure, each of the frame members interconnecting a pair of opposed sides, each of the frame members telescoping to move their respective pair of opposed sides, interconnected by the frame members, toward and away from each other for varying the dimensions of the enclosure in two dimensions.
It is an object of this invention to provide an expansible apparatus which may be readily and economically manufactured and which is relatively simple in construction and light in weight for use as a trailer display booth, camper or display counter.
A further object of this invention is to provide a box-like enclosure whose overall dimensions can be infinitely varied while maintaining substantial rigidity and integrity.
A still further object of this invention is to provide an enclosure that can be expanded and retracted simply and quickly while maintaining maximum flexibility.
Another object of this invention is to provide an expansible apparatus which can be fitted with side portions such that the ingress of wind, dust, moisture and debris can be substantially minimized.
Yet another object of this invention is to provide an expansible apparatus which can be operated by cable, hydraulic or other motive means.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of an expansible trailer in the open position.
FIG. 2 is a view similar to FIG. 1 but showing the expansible enclosure in a closed position.
FIG. 3 is a sectional view along the line 3--3 of FIG. 1 showing the interfitting wall sections and a portion of the cable assemblies.
FIG. 4 is a top plan view of the chassis, showing a floor extended in two directions with the cable assemblies used to vary the dimensions of the floor in a longitudinal direction.
FIG. 5 is a top plan view of the chassis showing the floor extended in two directions with the cable assemblies used to open and close the floor in a width wise direction.
FIG. 6 is a fragmentary sectional view of a tube member and corresponding interior structural member with corresponding cable and pulley assemblies.
FIG. 7 is a cross-sectional view of the tube member and interior structural member assembly along the line 7--7 of FIG. 6.
FIG. 8 shows an alternative embodiment of the invention wherein hydraulic means is used to move the interior structural member relative to the tube member.
DESCRIPTION OF THE INVENTION
An embodiment of the expansible enclosure of this invention is shown in FIG. 1 in the open position. The expansible enclosure, generally designated as 10, is shown resting on legs 12 which can be removed or retracted when the apparatus is moved. Towing assembly 14 generally allows the apparatus to be attached to another vehicle for movement from place to place.
In this expanded view of the apparatus of this invention, the expansible enclosure is being used as a booth with a window 16 on one side and a door 18 along one of the end sections. A first sidewall 16 includes two interfitting first sidewall panels 16a and 16b, which have corresponding sections on the other, i.e., opposed, side of the apparatus (not shown). Above the interfitting first sidewall panels 16a and 16b are corresponding interfitting second sidewall panels 18a and 18b which constitute a second sidewall 18. Corresponding sections to 18a and 18b (not shown) are located on the other side of the enclosure. In this embodiment, panels 20a and 20b of a first top section are shown along with panels 22a and 22b of a second top section. In this embodiment, the lower end panels are generally designated 24a and 24b and the upper end panels are generally designated 26a and 26b. Corresponding panels are included on the opposing panel.
The enclosure 10 is shown in a contracted position in FIG. 2. Although wheels are not shown under the chassis of the enclosure, in this position the enclosure could very easily be moved from place to place, including through city streets. FIG. 2 shows that the interfitting upper sidewall panels 18a and 18b have moved down past the lower sidewall sections 16a and 16b. Also, panels 18b and 16b have moved past panels 18a and 16a, respectively, as the expansible enclosure had achieved a contracted configuration. Further, FIG. 2 shows that end panels 26a and 26b have moved down over end panels 24a and 24b, respectively, as have panels 26a and 24a moved past panels 26b and 24b, respectively. Correspondingly, panels 22a and 22b of the second top section have moved past panels 20a and 20b, respectively, of the first top section. In addition, panels 20b and 22b have moved past panels 20a and 22a, respectively. Although wall panels are not required, when the invention is used as a camper, display booth, etc., the panels can be opaque, translucent or transparent. Any suitable material could be used such as plastics, metals, wood, fibrous materials, etc. The choice of an appropriate material for the outer panels is within the skill of the art.
The means for moving the interfitting wall panels past each other is shown in FIG. 3. FIG. 3 shows the section of the expansible apparatus along the line 3--3 of FIG. 1. The enclosure is shown in the fully extended position wherein, sidewall panel 18a is shown fully extended upwardly along sidewall panel 16a. The corresponding sidewall panels on the other side of the enclosure are 16a and 18a. The roof section 22a is shown fully extended along roof section 22b. Each of the interfitting wall and roof panels have U-shaped end portions 28 which in the fully extended position interlock with corresponding end portions 28 of the adjacent wall or roof panel. The U-shaped end portions 28 not only provide protection against wind debris and outside elements but also assure that the integrity of the expansible enclosure will be maintained, especially when the expansible enclosure is fully expanded. In the embodiment of the invention shown in FIG. 3, telescoping frame means 29 includes longitudinal tube member 30, shown attached to the base member 32 of the apparatus.
In this embodiment, tube member 30 has a square cross section although other cross sectional shapes such as circular and rectangular could be used. Longitudinal interior structural member 34 telescopically extends down into tube member 30. Interior structural member 34 in this embodiment has a C-shaped cross section as shown in FIG. 7. Pulley 36 is shown in FIG. 3 rotatably mounted in an opening in the wall of tube member 30 such that it extends into the interior of longitudinal interior structural member 34 which has a C-shaped cross section to accommodate pulley 36. Cable 38 is shown attached to the lower end of interior structural member 34 at point 35 and extending up through and within interior structural member 34 around cable 36 and outside of tube member 30 toward another pulley, not shown, within base member 32. Movement of cable 38 in either direction will raise or lower the top panels or roof and corresponding upper sidewall panels of the enclosure such as 18a, 18b, 18a', 18b', 26a and 26b. Although not shown in this drawing, the mechanism for extending the apparatus widthwise is contained in the base of the enclosure. Therefore, no cables per se are provided for movement of the top panels or roof section in this embodiment. Nevertheless, for widthwise movement longitudinal interior structural member 40 of the roof section moves telescopically into and out of longitudinal tube member 42 of the roof section to in turn move interfitting roof members 22a and 22b to expand or contract the enclosure.
The base of the expansible enclosure of the embodiment of FIG. 1 is shown in FIG. 4. The first base section 42 consists of a plurality of spaced apart longitudinal tube members 44. In the embodiment of FIG. 4, each of the spaced apart tube members 44 is substantially parallel to each other spaced apart tube member, and are attached by cross members 46. In FIG. 4 each of the cross members 46 is attached to the undersides of the tube members 44. A second base section 48 consists of spaced apart interior structural members 50, which are adapted to move telescopically into and out of the corresponding spaced apart longitudinal tube members 44 for the first base section. Cross member 52 is connected to the ends of each of the interior structural members 50 to provide rigidity and support. In the embodiment of FIG. 4 each of the spaced apart tube members 44 has a square cross section and each of the interior structural members 50 has a C-shaped cross section and is adapted to integrally move into and out of the corresponding tube members. Base section 42 also includes extendable spaced apart longitudinal tube members 54, which are parallel to stationary tube members 44, and which have extendable interior structural members 56 which telescopically extend into and out of corresponding tube members 54. Extendable tube members 54 are maintained in substantially parallel position to each other and to tube members 44 by rigid members 58 which are attached to an end of each of the tube members 54 and which telescopically extends into an open member of base section 42. Extendable tube members 54 are adapted to move along member 58 by being attached to collars 60 which slide along members 58 on the base section as the floor is expanded. Extendable interior structural members 56 are also adapted to extend by being attached to collars 62 which move along members 64 wherein members 64 move telescopically into and out of member 48 of the second base section. Any desired spacing of the tube members and interior structural members of the base section can be obtained by appropriate design of the spacers 66. Spacers 66, in this embodiment, are rigid members attached by ball and race mechanism to tube members 54 to maintain the substantially parallel spaced apart relationship of tube member 54 and the structural rigidity of the enclosure floor.
In the embodiment of FIG. 4 a cable system is shown for altering the dimensions of the base section in one direction. FIG. 4 shows the base section in an essentially extended lengthwise direction. Cable system 70 would be used to decrease the dimensions of the expandable enclosure, i.e., to close the base section. Cable system 70 includes cables 72a, 72b, 72c and 72d which are attached to the interior ends 74a, 74b, 74c and 74d of interior structural members 50 to retract the interior structural members 50 into tubular members 44. Each of the cables 72 moves through the interior of a corresponding tube member 44 and around a pulley 76, such as is shown in FIG. 6, toward and around a central pulley 78 mounted on one of the interior cross members 46 and subsequently attached to cable 80 of cable system 70, which in this embodiment is subsequently attached to a power driven winch, located other than in the floor of the enclosure.
The base section can be opened using cable system 82 which includes a series of cables 84 which move past a series of pulleys into connection with and at the end of the interior end 74 of each of the interior structural members 50.
The cable systems for opening and closing the expansible enclosure apparatus in a widthwise direction are shown in FIG. 5. The apparatus can be opened by cable system 86. Cable 88 of cable system 86 moves around pulley 90 which is attached to cross member 46 and around double pulley 92 where it separates into cables 88a and 88b. Cable 88a then passes through tube member 44 around pulley 94 and into attachment with the end 96 of end member 58. When cable 88 is drawn by the gear driven winch (not shown) to open the base section, it will cause cable 88a to pull end member 58 telescopically out of base section 42. Cable 88b, which also moves around double pulley 92, extends along the base section to double pulley 98. At double pulley 98, cable 88b splits into cables 88c and 88d. Cables 88c and 88d then move past pulleys into cross member 52 into attachment with the end of end members 64, such as is shown in the detail of FIG. 6.
Cable system 100 is used to close the base of the enclosure in a widthwise direction. As shown in FIG. 5, the cables of cable system 100 also move across pulleys mounted on various cross members of the base section and are subsequently attached to ends of end members, such as end 96 of end member 58, which allows the cable system 100 to retract the base section extendable members. For example, cable 102 of cable system 100 moves past pulley 104 and past pulley 106 which splits into cables 102a and 102b. Cable 102a is attached to end 104 of telescoping end member 58. The details of this structure are shown in FIG. 6 wherein cable 102a is shown passing over pulley 106 into attachment at end 104 of telescoping end member 58. Cable 108 shown in FIG. 6 is a part of cable system 86 used to open the base section of the expansible enclosure apparatus. FIG. 7 shows in cross section tubular end member 42 and the C-shaped cross section of end member 58. Also shown is clamp 112 which is used to attach cables 108 and 102a to end 104 of end member 58.
Although FIGS. 4 and 5 have shown in detail how cable systems can be used to expand and contract the expansible enclosure apparatus of the invention, any suitable means may be utilized. For example, as illustrated in FIG. 8, hydraulic pistons and cylinders, designated 114 and 116, respectively, are utilized to expand and contract the apparatus. As shown in FIG. 8, the hydraulic piston 114 would be attached to an end of one of the interior structural members located inside one of the tube members of the apparatus. The interior structural member would then ride on rollers 118, which would allow contraction and expansion of various members of the apparatus of this invention. Alternatively, a hydraulic piston could comprise an interior structural member.
No detailed description is given of the hydraulic piston and cylinder arrangement illustrated, other than that shown in FIG. 8, as any desired hydraulic system may be utilized. Parts for such a system are readily available on the market, and the technology for incorporating same are well known. Furthermore the means for extending or contracting any of the sections of the enclosure including the base section, the lower sidewalls, the upper sidewalls, or the roof section may be provided by any suitable means, for example, by mechanical means, such as pulleys, levers, cranks, and the like, or by pneumatic or vacuum means or by the utilization of electric motors. Installation and operation of all of these motive devices are well known and easily adaptable to the apparatus of this invention.
In the instant invention, the term expansible includes the ability to expand and contract. The invention allows the apparatus to adjust to a variety of dimensions to satisfy various needs. The flexibility associated with the invention and the structural rigidity provided by square cross sectioned longitudinal tube members and C-shaped cross sectioned longitudinal interior structural members in the preferred embodiment make the invention adaptable to a number of uses. For example, in addition to the uses already mentioned, the invention can be adapted to display counters for various types of merchandise to be displayed in department stores, supermarkets, boutiques, etc. The display counters could be adjusted to the desired size and shape, with overlapping glass panels used along the outer surfaces. The telescoping frame means, including tube members and interior structural members, could conveniently be made of chrome-plated metal or some other decorative material. Depending on advertising and display needs, the counter could quickly be altered in dimensions to conform to the user's needs or taste.
Although the preferred embodiment utilizes a plurality of telescoping frame means for rigidity, in each side, e.g., the floor or base section, only one telescoping frame means is required for movement in any desired direction. Therefore, for two dimensional expansions, two telescoping frame means are required. Three-dimensional expansion and contraction requires minimally three telescoping frame means, moving in mutually perpendicular directions, with each telescoping frame means connected to substantially parallel opposed sides. For example, the floor or base of the inventive apparatus could have a telescoping frame means along only one side with structural members known to the art providing additional support. Nevertheless, usually a plurality of telescoping frame means is used preferably in the base or floor, along each of the vertical corners and, as desired, in the roof, such as would be required for a three-dimensionally expansible enclosure.
Suitable latches or locking means can be provided to maintain the various sections releasably locked into position in both the contracted and expanded mode. For example, if cable means are employed, then locking can be provided with the gear-driven winches, whether manually or motor driven. It should be understood that any desired latching means may be utilized.
Although FIGS. 1 and 2 show the invention as capable of being towed in addition to being used in a stationary application, the invention can have self-contained motive means. The power source for the wheels could also be used to power the telescoping frame means, if desired.
It is to be understood that the form of this invention herewith shown and described is to be taken as a preferred example of the same, and that this invention is not to be limited to the exact arrangement of parts shown in the accompanying drawings or described in the specification as various changes in the details of construction as to shape, size and arrangement of parts may be resorted to without departing from the spirit of the invention, the scope of the novel concepts thereof, or the scope of the claims. | An expansible enclosure, suitable for use as a camper, trailer, display booth or display counter, having a box-like structure with six sides mutually interconnected at their respective peripheries, with telescoping frame facilities for expanding and contracting the enclosure by varying the distance between opposed sides, allowing expansion and contraction in three dimensions while maintaining substantial rigidity and integrity of the enclosure. | 1 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from Korean Utility Model Application No. 20-2008-0008378, filed on Jun. 30, 2008 in the Korean Intellectual Property Office, the entire disclosure of which is incorporated herein by reference.
TECHNICAL FIELD
[0002] The device relates to a skin massage apparatus capable of scrubbing a skin applied with a massage cream, then giving physical stimulus on the skin at a massage thus helping the relaxation of muscles and activating metabolism to serve an elastic healthy skin, and more particularly to a device delved to translating a rotating motion of a drive motor to a linear motion, beating a skin with a massage plate containing a finger-pressure projection to give physical stimulus to the skin, and thus helping the relaxation of muscles and activating metabolism to maintain an elastic healthy skin.
RELATED ART
[0003] In general, a skin, exposed to ultraviolet, gets thicker in horny substance, so that the skin loses its transparency, the metabolism of skin lowers and as well as fails to smoothly provide moisture and a nutriment.
[0004] As a prohibiting means to an aging promotion of skin seniled caused by the above facts, a skin care through massage is eventually used.
[0005] A skin care may be divided into two methods of one, in massage, applying a functional cosmetic on skin, and the other method giving physical stimulus to skin in a skin massage.
[0006] Of the above methods, in preventing of an ageing promotion of skin by applying a functional cosmetic and thus maintaining moisture of the skin, a moisture preservation is one of none to the second factors in keeping an elastic skin, in which if the moisture maintaining function lowers, the skin has a wrinkle due to the crumbling and no elasticity, also stretchiness.
[0007] Thus, by a functional cosmetic applied to skin, a nutriment is furnished, and as well as an applied moisture-keeping cream maintains a moisture thereof
[0008] As described above, in a skin massage of applying a functional cosmetic on skin, mainly fingers are used, in which a massage is performed scrubbing the skin by fingers, any physical stimulus to the skin would not occur, thus only expected of a massage effect by functional cosmetics.
[0009] Therefore, other than scrubbing a skin applied a functional cosmetic with fingers, by using a skin massage apparatus giving physical stimulus on the skin at a massage thus helping the relaxation of muscles and activating metabolism to serve an elastic, healthy skin, the effect can be doubled.
[0010] Continuingly, an existing skin massage apparatus constructed to give physical stimulus to the skin may be chiefly divided into a manual type and an electromotive type.
[0011] Of skin massage apparatuses divided as described above, an electromotive type skin massage apparatus that is up to date conveniently used and not laboring is widely used.
[0012] The electromotive type skin massage apparatus is constructed to beat skin by a back/forth round trip translation of a massage device with a motor as motive power.
[0013] As mentioned above, by beating the skin with a conventional massage device, an advanced massage effect is obtained over when a massage of finger rubbing is conducted to give stimulus up to a dermal layer and a hypodermal tissue composing skin, however, since a translation movement form advance to backing is performed by motive power of the motor in which a massage device of the massage apparatus is directly linked to a drive motor, in a case an overloading occurs due to the massage device overly attached to skin in a massage, the overload directly inflicts the drive motor, having a frequent fault of the motor, such a motor fault connects to a malfunction of the massage apparatus, becoming a factor of imbuing consumers with a negative recognition on products, thus making it difficult to ensure a market competition.
SUMMARY OF THE INVENTION
Problem to be Solved
[0014] The device has been made to solve disadvantages of a prior-art massage apparatus, an object of the device is to provide a skin massage apparatus in which a beating member of a massage apparatus delved to giving physical stimulus on the skin at a massage thus helping the relaxation of muscles and activating metabolism to serve an elastic, healthy skin when scrubbing a skin above applied with a massage cream in a massage is reformed to minimize an overload produced at a drive motor, thereby advantageously in effect addressing customer's disbelief, a problem caused by a fault of the drive motor, and ensuring reliability of a massage apparatus, thus promoting a massage apparatus use at home and thus solving a burden in taking care of skin searching an expertise beauty shop for accepting a massage and at the same time lessening economical burden accompanying with reducing a use time of expertise beauty shops, and also a skin care employing a break time is possible with no additional time investment, satisfying needs of the consumers.
Solution for the Problem
[0015] To achieve the above object, the present device has been proposed with a skin massage device of scrubbing a skin applied with a massage cream, then giving physical stimulus on the skin at a massage thus helping the relaxation of muscles and activating metabolism to serve an elastic, healthy skin, [ 15 ] characterized in that an operation device 15 to reciprocally translate a beating member 21 back and forth is installed at a rotating shaft 14 of a drive motor 13 to which an electric energy of a battery 100 is selectively supplied/blocked according to change of on/off of a rotary switch 12 , comprised of the beating member 21 inflicting physical stimulus while interworking with the operation device 15 .
Effect of the Invention
[0016] As described above, a skin massage apparatus of the present device has an expedient effect of reforming a beating member of a massage apparatus delved to giving physical stimulus on the skin at a massage thus helping the relaxation of muscles and activating metabolism to serve an elastic, healthy skin when scrubbing a skin above applied with a massage cream in a massage to minimize an overload produced at a drive motor, thereby addressing customer's disbelief, a problem caused by a fault of the drive motor, and ensuring reliability of a massage apparatus, thus promoting a massage apparatus use at home and thus solving a burden in taking care of skin searching an expertise beauty shop for accepting a massage and advantageously at the same time lessening economical burden accompanying with reducing a use time of expertise beauty shops, and also a skin care employing a break time is possible with no additional time investment, satisfying cravings of the consumers.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
[0017] FIG. 1 is a cross-section construction of one embodiment of a skin massage apparatus according to the present device;
[0018] FIG. 2 is an exemplary diagram showing that in FIG. 1 state, an operating device operates and thus a beating member acts;
[0019] FIG. 3 is a cross-section construction of another embodiment of a skin massage apparatus according to the present device;
[0020] FIG. 4 is an exemplary diagram showing that in FIG. 3 state, an operating device operates and thus a beating member acts;
[0021] FIG. 5 is a cross-section construction of still another embodiment of a skin massage apparatus according to the present device;
[0022] FIG. 6 is an exemplary diagram showing that in FIG. 5 state, an operating device operates and thus a beating member acts;
[0023] FIG. 7 is a cross-section construction of still another embodiment of a skin massage apparatus according to the present device;
[0024] FIG. 8 is an exemplary diagram showing that in FIG. 7 state, an operating device operates and thus a beating member acts;
[0025] FIG. 9 is a cross-section construction of still another embodiment of a skin massage apparatus according to the present device; and
[0026] FIG. 10 is an exemplary diagram showing that in FIG. 9 state, an operating device operates and thus a beating member acts.
<DESCRIPTION OF THE ACCOMPANYING DRAWINGS>
[0027] 10 : the first case 11 : the battery receiving part
[0028] 12 : a rotary switch 13 : the drive motor
[0029] 14 : the rotating shaft 15 : the operating device
[0030] 16 : the main power member 16 a: a connection part
[0031] 16 b, 17 b ; a circular plate cam 16 c, 17 c: a slanted surface
[0032] 16 d: a main power bevel gear 16 e: the empowered bevel gear
[0033] 16 f: a cam 16 g: a spiral-type groove
[0034] 16 h: a guide pipe 16 h′: the vertical guide hole
[0035] 17 : the empowered member 17 a: a connection pipe
[0036] 17 d: a guide protrusion 20 : the second case
[0037] 21 : the beating member 21 a: the head mounting circular plate
[0038] 22 : a beating head 22 a: stimulus protrusions
DETAILED DESCRIPTION
[0039] Hereinafter, a preferred embodiment of the present device will be described in more detail with reference to the accompanied drawings to the specification.
[0040] As illustrated in FIGS. 1 and 10 , a skin massage apparatus of the device is composed of a connection of a first case 10 installed with a battery receiving part 11 receiving a battery 100 and an operation device 15 equipped with a drive motor 13 and operated by the drive motor 13 ; and a second case equipped with a beating member 21 interworking with the operation device 15 .
[0041] The battery receiving part 11 of the first case 10 is installed with +, −ground plates 11 a, 11 b grounded at +electrode and −electrode of the received battery 100 supplying electric energy of the battery 100 to the drive motor 13 , and a rotary switch 12 for selectively supplying electric energy of the battery 100 is installed.
[0042] A drive motor 12 in which +,−ground terminals 13 a, 13 b are grounded for the +,−ground plates 11 a, 11 b is installed in the neighborhood.
[0043] The opposite side of the battery receiving part 11 is installed with an operating device 15 operating by the drive motor 13 .
[0044] The operating device 15 is comprised of a main power member 16 connected to the rotating shaft 14 of the drive motor 13 and an empowered member 17 interworking with the main power member 16 .
[0045] The empowered member 17 is installed inside the second case 20 to receive a repulse elastic force of a spring 18 , and the empowered member 17 is installed with a beating member 21 .
[0046] The main power member 16 is key assembled to the rotating shaft 14 of the drive motor 13 using a connection part 16 a as a medium, made of a circular plate cam 16 b formd with a slanted surface 16 c, its one side low and the other side high, and the empowered member 17 has a slanted surface 17 c corresponding to the circular plate cam 16 b slanted surface of the main power member 16 and at the same time has a circular plate cam 17 b contacting in plane facing each other, and a lower part of the circular plate cam 17 b is formed with a connection pipe 17 a connected of a connection pole 21 b formed towards the upper part of a head mounting circular plate 21 a of the beating member 21 .
[0047] The connection pipe 17 a of the circular plate cam 17 b is a repulse spring 23 inflicting an elastic repulse force to outside for enabling a round-trip movement.
[0048] The beating member 21 installed at the empowered member 17 of the operating device 15 placed inside the second case 20 , has a connection pole 21 b inserted at installation to the connection pipe 17 a of the empowered member 17 . and the head mounting circular plate 21 a formed to an end part of the connection pole 21 b is assembled molded with a beating head 22 irregularly arranged of a multiple of stimulus protrusions 22 a. [ 50 ] The beating head 22 is injection-molded by rubber material.
[0049] A main power member 16 of another embodiment of the operating device 15 is comprised of a main power bevel gear 16 d installed at the drive motor 13 , an empowered bevel gear 16 e interworking engaged with the main power bevel gear 16 d, and a cam 16 f installed on the same axis for interworking with the empowered bevel gear 16 e, and an empowered member 17 moving back/forth close to a cam 16 f of the main power member 16 and formed with a connection pipe 17 a engaged to the connection pole 21 b of the beating member 21 . and installed to receive repulse of the repulsing spring 23 for restoring after advancement.
[0050] A main power member 16 of still another embodiment of the operation device 15 is comprised of a main power bevel gear 164 installed at the drive motor 13 , an empowered bevel gear 16 e interworking engaged to the main power bevel gear 16 d and a cam 16 f installed on the same axis for interworking the empowered bevel gear 16 e, and made of a crank rod 18 , one end hinge-connected to the cam 16 f of the main power member 16 , and the other end hinge-connected to a connection pole 21 b of the beating member 21 .
[0051] In an installment of a main power member 17 of still another embodiment of the operating device 15 , a connection part 16 a is key assembled to the drive motor 13 , a spiral-type groove 16 g guided for a guide protrusion 17 d of the empowered member 17 is formed to an inner-rim surface, and a guide pipe 16 h having a vertical guide hole 16 W is placed to the inner side to be fixed to the second case 20 so that the empowered member 17 round-trip moves back/forth without circulation.
[0052] In the empowered member 17 interworking by the main power member 16 , the guide protrusion 17 d passing through the vertical guide hole 16 W of the guide pipe 16 h, and in which the end part is placed at the spiral-type groove 16 g of the main power member 16 is formed to face an outer-rim surface, and a connection pipe 17 a connecting to the connection pole 21 b of the beating member 21 is formed.
[0053] FIGS. 9 and 10 are another embodiment of the present device, possibly constructed that a connection pole 21 b of the beating member 21 moves back/forth directly connected to a piston rod of a solenoid 19 .
[0054] In a case of performing a massage on skin using a skin massage apparatus of the present device comprised of the above-described construction, first applying a massage cream on the part for a massage to moisturize the skin and then beating all around can create a doubled effect.
[0055] When beating and massaging skin with a skin massage apparatus of the present device, the rotary switch 12 rotationally operates to place from off state to on state.
[0056] As described above, when the rotary switch 12 transits from off state to on state, electric energy of a battery 100 mounted at the battery receiving part 11 is supplied to the drive motor 13 .
[0057] As such, the drive motor 13 supplied with electric energy drives, and rotational power produced by the drive of the drive motor 13 is delivered to the main power member 16 of the operating device 15 connected to the rotating shaft 14 to interwork with the empowered member 17 , so that the main power member 16 interworks with the empowered member 17 and a beating member 21 installed at the empowered member 17 round-trip moves back/forth.
[0058] As above, when the beating member reciprocally moves back/forth, the stimulus protrusion 22 a of the beating head constructing the beating member fully inflicts physical stimulus to skin, capable of helping relaxation of muscles and activating metabolism and thus serving an elastic, healthy skin.
[0059] In the following, an operation state of the operating device 15 allowing a massage of skin by reciprocally moving the beating member 21 will be described for each embodiment.
[0060] Referring to the operating device 15 exemplified in FIGS. 1 and 2 , when the rotary switch 12 described above converts from off to on state and the drive motor 13 rotationally operates by electric energy of the battery 100 , the slanted surface 16 c of the main power member 16 contacting in surface over the slanted surface 17 c of the empowered member 17 like FIG. 1 continuously repeats a procedure placed like FIG. 2 , and thus the beating member 21 installed at the empowered member 17 advances, and by repulsive power of the repulse spring 23 compressed by advance of the beating member 21 , the empowered member moves backward and thereby the beating member 21 everlastingly round-trip moves.
[0061] As mentioned above, as the beating member 21 round-trip moves, a stimulus protrusion 22 a of the beating head 22 constructing the beating member gives physical stimulus on skin, helping maintain a healthy skin recited at the upper part.
[0062] FIGS. 3 and 4 are an embodiment of another operation device, when a rotary switch 12 converts from off to on state to rotationally operate the drive motor 13 by electric energy of the battery 100 , a main power bevel gear 16 d constructing the main power member 16 inter-operates, the empowered bevel gear 16 e engaged to the interworking main power bevel gear 16 d as described above operates together.
[0063] As explained above, when the empowered bevel gear 16 e is interworking, the cam 16 f installed on the same axis of the empowered bevel gear 16 e operates together and thus the cam 16 f stayed in a FIG. 3 state positions as shown in FIG. 4 to move the empowered member 17 .
[0064] Described above, as the empowered member 17 moves, the beating member 21 installed at the connection pipe 17 a using the connection pole 21 b as a medium advances, and by means of repulse power of the repulse spring 23 compressed by the advance of the beating member 21 , the empowered member 17 moves back so that the beating member 21 continuously round-trip moves.
[0065] Explained above, as the beating member 21 moves round-trip, a stimulus protrusion 22 a of the beating head 22 constructing the beating member 21 gives physical stimulus to skin thereby to maintain a healthy skin as mentioned above.
[0066] FIGS. 5 and 6 are other embodiments of an operating device, when a rotary switch 12 converts from off to on state to rotationally operate the drive motor 13 by electric energy of the battery 100 , a main power bevel gear 16 d constructing the main power member 16 inter-operates, the empowered bevel gear 16 e engaged to the interworking main power bevel gear 16 d as described above operates together.
[0067] As described above, when the empowered bevel gear 16 e is interworking, the cam 16 f installed on the same axis of the empowered bevel gear 16 e operates together and thus the cam 16 f stayed in a FIG. 5 state positions as shown in FIG. 6 to move a crank rod 18 corresponding to the empowered member.
[0068] As such, one end of a crank rod 18 interworking by the cam 16 f hinge-connects to the cam 16 f, and the other end hinge-connects to the connection pole 21 b of the beating member 21 so that the beating member 21 continuously round-trip moves.
[0069] Explained above, as the beating member 21 moves round-trip, a stimulus protrusion 22 a of the beating head 22 constructing the beating member 21 gives physical stimulus to skin thereby to maintain a healty skin as mentioned above.
[0070] FIGS. 7 and 8 are other embodiments of an operating device, when a rotary switch 12 converts from off to on state to rotationally operate the drive motor 13 by electric energy of the battery 100 , a guide protrusion 17 d of the empowered member 17 placed at the upper part of the spiral-type groove 16 g of the main power member 16 like FIG. 7 is positioned under the spiral-type groove 16 g like FIG. 8 , so that the beating member 21 installed with the connection pole 21 b connected to the connection pipe 17 a advances forward.
[0071] At this time, moving forward of the empowered member 17 without rotation is because to a vertical guide hole 16 W of the guide pipe 16 h fixed to the second case 20 is guide protrusion 17 d guided.
[0072] As such, in an advanced state, the drive motor 13 drives in a backward direction, so that the beating member 21 continuously round-trip moves.
[0073] Explained above, as the beating member 21 moves round-trip, a stimulus protrusion 22 a of the beating head 22 constructing the beating member 21 gives physical stimulus to skin thereby to maintain a healthy skin as mentioned above.
[0074] FIGS. 9 and 10 are other embodiments of the present device, with intention that a back/forth round-trip movement of the beating member 21 is performed by the solenoid 19 , a connection pole 21 b of the beating member 21 is directly related to the piston rod of the solenoid 19 .
[0075] While the solenoid 19 connected to the beating member 21 round-trip moves back/forth by a piston rod stroke distance, the stimulus protrusion 22 a of the beating head 22 imbues physical stimulus to skin thereby to maintain a healthy skin as mentioned above. | Disclosed is a skin massage device, the proposed idea capable of a skin massage device of scrubbing a skin applied with a massage cream, then giving physical stimulus on the skin at a massage thus helping the relaxation of muscles and activating matabolism to serve an elastic, healty skin, characterized in that an operation device 15 to recipocally translate a beating member 21 back and forth is installed at a rotating shaft 14 of a drive motor 15 to which an electric energy of a battery 100 is selectively supplied/blocked according to change of on/off of a rotary switch 12, compised of the beating member 21 inflicting physical stimulus while interworking with the operation device 15. | 0 |
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is:
a divisional of U.S. patent application Ser. No. 13/222,758 filed on Aug. 31, 2011; and a divisional of U.S. patent application Ser. No. 11/971,998 filed on Jan. 10, 2008 (which application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 60/880,146 filed Jan. 12, 2007),
the complete disclosures of which are hereby incorporated by reference herein in their entireties.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0004] n/a
FIELD OF THE INVENTION
[0005] The present invention lies in the field of staple fastening, in particular, staples and instruments capable of applying a single or a plurality of staples to a material and processes therefor. More particularly, the present invention relates to a staple capable of placing a load-bearing force against the material being stapled and improvements in processes for stapling material. The device can be used, particularly, in the medical field for stapling tissue during surgical procedures, whether open, endoscopic, or laparoscopic.
BACKGROUND OF THE INVENTION
[0006] Conventional staples are, typically, U-shaped and require a staple cartridge and anvil to fasten the staple onto a material. The U-shape of the staple can be considered relatively square-cornered because of the sharp angle at which the legs extend from the bridge. On activation of a stapling device, the staple legs are advanced forward so that they penetrate a material on both sides of a slit or opening. As a staple former is advanced further, the legs of the staple bend around the anvil causing the tips of the legs to advance along an arcuate path toward each other so that the staple ultimately assumes a generally rectangular shape, thereby compressing the material that has been trapped between the staple legs, which is tissue in surgical applications. This compression of the material is the mechanism by which a closure is effected. Depending on the length of the incision or opening, a series of staples will be delivered along its length, which can ensure a blood tight closure in surgical procedures.
[0007] Because the staple has two legs that pierce the material, they are well suited for fastening two or more layers of material together when used with the opposing anvil. Whether used in an office or during a surgical procedure, most staples 1 have similar shapes—a bridge 2 connecting two relatively parallel legs 4 , which legs are disposed approximately orthogonal to the bridge 2 , which, depending on the material of the staple, results in a square-cornered U-shape. In surgical stapling devices, it is beneficial to start the legs 4 in a slight outward orientation to assist retention of the staples within the cartridge. The staple illustrated in FIG. 1 is representative of conventional surgical staples. Such staples are compressed against an anvil to bend the tips of the legs 4 inward. For purposes sufficient in surgery, the final stapled configuration has a stapling range from a “least” acceptable orientation to a “greatest” acceptable orientation. The “least” acceptable staple range is a position where the tangent defined by the tip of each leg 4 is at a negative angle to a line parallel to the bridge 2 and touching the lower portions of both legs 4 . The “greatest” acceptable staple range is a position where the legs 4 are bent into a shape similar to the letter “B.”
[0008] The staple 1 of FIG. 1 is shown in an orientation where the tips of the legs 4 are bent slightly by an anvil on the way towards a final stapled form. (This slightly bent orientation is also present with respect to the staples illustrated hereafter.) The legs 4 of such slightly bent staples have three different portions:
a connecting portion 6 (at which the legs 4 are connected to the bridge 2 ); an intermediate portion 8 (at which the staple is bent; of course it is also possible for the connection portion 6 to be bent for various fastening purposes); and a piercing portion 10 (for projecting through the material to be fastened; this portion, too, is bent when fastening).
Many stapling devices exist to deploy such staples. Some surgical stapling instruments are described in U.S. Pat. No. 5,465,895 to Knodel et al., and U.S. Pat. Nos. 6,644,532 and 6,250,532 to Green et al. When the staple 1 is bent for fastening, the polygon formed by the interior sides of the bent staple 1 defines an envelope or a central region 14 . The material to be fastened by the staple 1 resides in and is compressed within the central region 14 when stapling occurs. When the final staple orientation is B-shaped, there can be two regions in which the tissue is held and compressed.
[0012] One common feature associated with conventional staples is that there is no controllable way of adjusting the compressive force that is applied by the staple to the material being stapled. While items such as paper and cardboard can withstand a wide range of stapler compressive force without breaking or puncturing, living tissue, such as the tissue to be fastened in a surgical procedure, has a limited range of compressive force and cannot withstand force greater than a upper limit within that range without causing tissue damage. In fact, the range of optimal stapling force for a given surgical stapling procedure is relatively small and varies substantially with the type of tissue being stapled.
[0013] While it may be true that the distance between the bending point of the legs and the bridge (see, e.g., span 12 in FIG. 1 ) can be increased to impart less force on material within the staple, this characteristic does not apply when living tissue having varying degrees of hardness, composition, and flexibility is the material being stapled. Even if the staple leg bending distance 12 is increased, if more or less or harder or softer tissue than expected is actually captured within the staple, the force applied to the captured tissue will not be controlled and will not be optimal for that tissue.
[0014] When one, two, or more layers of tissue are being stapled, it is desirable for the tissue to be at a desired compressive state so that a desirous medical change can occur, but not to be at an undesired compressive state sufficient to cause tissue necrosis. Because there is no way to precisely control the tissue that is being placed within the staple, it is not possible to ensure that the tissue is stapled within an optimal tissue compression range, referred to as an OTC range. Therefore, ruling out of tissue necrosis is difficult or not possible. Further, tissue presented within one staple may not be the same tissue that is presented within an adjacent staple or is within another staple that is fired during the same stapling procedure. Thus, while one or a few of a set of staples could actually fasten within the OTC range, it is quite possible for many other staples in the same stapling procedure to fasten outside the OTC range.
[0015] What is needed, therefore, is an improved staple and improved methods of stapling that allow automatic control of the staple compression force imparted upon the material being stapled so that compression of the material remains within a desired OTC range. While prior art surgical stapling instruments have utility, and may be successfully employed in many medical procedures, it is desirable to enhance their operation with the ability to deliver a staple that can automatically tailor the compression force delivered to the tissue without external mechanics or operations.
BRIEF SUMMARY OF THE INVENTION
[0016] It is accordingly an object of the invention to provide an adjustable compression staple and methods for stapling with adjustable compression that overcome the hereinafore-mentioned disadvantages of the heretofore-known devices and methods of this general type and that automatically tailors the compression force delivered to the tissue.
[0017] When tissue is stapled, liquid is forced out of the tissue. The OTC range of the tissue is a compression range in which liquid is removed from the tissue (i.e., desiccates the tissue) without damaging or necrosing the tissue. As the liquid from the tissue exits the tissue due to compression exerted upon the tissue by the staple, however, the compressive force that is being imposed upon the tissue naturally reduces—because less mass is between the opposing staple portions. In some instances, this reduction can allow the imparted tissue compression to exit the OTC range. Staples according to the present invention each have a self-adjusting, pre-tensioned compression device that keeps compression force on the interposed tissue within the OTC compression range even after being desiccated.
[0018] The prior art staple of FIG. 1 has a stapling range that is illustrated in FIG. 17 . For purposes sufficient in surgery, the final stapled configuration of the OTC staples of the present invention has a stapling range that is illustrated, for example, in FIGS. 18 to 20 . A “least” acceptable staple range is a position where the tangent T defined by the tip of each leg 4 is at a negative angle α to a line L parallel to the bridge 2 . This orientation is illustrated with the left half of the staple in FIG. 17 merely for reasons of clarity. See also FIGS. 18 to 20 . A “greatest” acceptable staple range is a position where the legs 4 are bent 180 degrees into a shape similar to the letter “B” (see the exemplary orientation illustrated in the right-half of FIG. 17 ) but, in comparison to the prior art staple range of FIG. 17 , as described below in detail, the tips of the legs 4 of the staples according to the invention reach only up to a compressing portion and not further than this compressing portion as shown in FIG. 20 , for example. In such an orientation, the stapled tips of the legs do not interfere with the OTC device present in the staples according to the invention.
[0019] The OTC devices for staples according to the invention take many forms. The OTC device can be integral with the legs of the staple and project into a central area or can be attached to the staple to project into the central area. The OTC device can be sinusoidal in shape with a compressing portion at the end of the OTC device or can be have multiple cycles of bends between the bridge of the staple with the compressing portion at the end of the OTC device. The bending portion can be single or double, the double bends being in cycle, out of cycle, mirror-symmetrical, to name a few. The bends can be double-sinusoidal as shown in FIGS. 8 , 9 , and 11 The OTC device can be contained entirely between the two legs of the staple or can encircle one or both of the legs and, thereby, use the legs as a guide, for example, a sliding guide. The leg encirclement by the OTC device can be single or multiple. Travel of the OTC device can be limited, for example, by a star washer. The OTC device can be a compression spring(s) and a plate(s), with the plate encircling the legs and sliding thereon. The OTC device can be a compressible material secured on the legs. This material can be in the shape of a plate or a pillow.
[0020] With the foregoing and other objects in view, there is provided, in accordance with the invention, a substantially U-shaped staple having a bridge, legs, and an internally disposed compression device having a bias portion with a compression surface movably disposed between the legs and a compression resistor connected to the bridge and to the compression surface and is formed to resist movement of the compression surface towards the bridge with a force.
[0021] In accordance with another feature of the invention, the bridge is substantially rod-shaped with ends and the base end of each of the legs is integral with a respective one of the ends.
[0022] In accordance with a further feature of the invention, the bridge and legs define a bridge-leg plane and the legs extend from the bridge at an angle of between 80 and 100 degrees in the bridge-leg plane.
[0023] In accordance with an additional feature of the invention, the compression surface defines two orifices and each of the legs extends through one of the two orifices.
[0024] In accordance with yet another feature of the invention, the compression resistor defines at least one orifice pair, the compression surface defines two orifices, and each of the legs extends through one of the two orifices and one of the at least one orifice pair.
[0025] In accordance with yet a further feature of the invention, the compression resistor defines a plurality of orifice pairs, the compression surface defines two orifices, and each of the legs extends through one of the two orifices and one of each of the orifice pairs.
[0026] In accordance with yet an added feature of the invention, the bridge and the legs define a compression axis and the compression surface is movably disposed between the legs along the compression axis.
[0027] In accordance with yet an additional feature of the invention, the compression device is connected to the bridge.
[0028] In accordance with again another feature of the invention, the compression resistor connects the bridge to the compression surface.
[0029] In accordance with again a further feature of the invention, the bridge, the legs, the compression resistor, and the compression surface are integral.
[0030] In accordance with again an added feature of the invention, the compression resistor is at least partly disposed between the legs.
[0031] In accordance with again an additional feature of the invention, the compression resistor is disposed between the bridge and the compression surface.
[0032] In accordance with still another feature of the invention, the force is a pre-defined opposing force.
[0033] In accordance with still a further feature of the invention, the force is a substantially constant force.
[0034] In accordance with still an added feature of the invention, the force is a linearly increasing force.
[0035] In accordance with still an additional feature of the invention, the compression resistor has an anti-compressive spring constant imparting a substantially constant anti-compressive force over a pre-defined compression range.
[0036] In accordance with another feature of the invention, the staple and the compression device are of a biocompatible material.
[0037] In accordance with a further feature of the invention, the compression surface and the legs define a central compression region in which is to be disposed a material to be compressed between the compression surface and stapling points when distal ends of the staple legs are deformed. When the distal ends are deformed in a staple closing direction into the central compression region, the bias portion resists movement of the compression surface in the staple closing direction with a pre-defined, substantially constant force.
[0038] In accordance with an added feature of the invention, the compression surface and the bias portion are shaped to impart a pre-defined, substantially constant bias force upon material disposed between the compression surface and stapling points when the stapling points are deformed.
[0039] In accordance with a concomitant feature of the invention, when stapling points are deformed toward one another, material disposed between the compression surface and the stapling points is compressed between the stapling points and the compression surface. The compression resistor maintains a substantially constant compressive force on the material within a pre-defined range independent of a degree of compression between stapling points and the compression surface.
[0040] Although the invention is illustrated and described herein as embodied in an adjustable compression staple and method for stapling with adjustable compression, it is, nevertheless, not intended to be limited to the details shown because various modifications and structural changes may be made therein without departing from the spirit of the invention and within the scope and range of equivalents of the claims. Additionally, well-known elements of exemplary embodiments of the invention will not be described in detail or will be omitted so as not to obscure the relevant details of the invention.
[0041] Other features that are considered as characteristic for the invention are set forth in the appended claims. As required, detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which can be embodied in various forms. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one of ordinary skill in the art to variously employ the present invention in virtually any appropriately detailed structure. Further, the terms and phrases used herein are not intended to be limiting; but rather, to provide an understandable description of the invention. While the specification concludes with claims defining the features of the invention that are regarded as novel, it is believed that the invention will be better understood from a consideration of the following description in conjunction with the drawing figures. The figures of the drawings are not drawn to scale.
[0042] Before the present invention is disclosed and described, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. The terms “a” or “an”, as used herein, are defined as one or more than one. The term “plurality,” as used herein, is defined as two or more than two. The term “another,” as used herein, is defined as at least a second or more. The terms “including” and/or “having,” as used herein, are defined as comprising (i.e., open language). The term “coupled,” as used herein, is defined as connected, although not necessarily directly, and not necessarily mechanically.
[0043] As used herein, the term “about” or “approximately” applies to all numeric values, whether or not explicitly indicated. These terms generally refer to a range of numbers that one of skill in the art would consider equivalent to the recited values (i.e., having the same function or result). In many instances these terms may include numbers that are rounded to the nearest significant figure.
BRIEF DESCRIPTION OF THE DRAWINGS
[0044] Advantages of the embodiments of the present invention will be apparent from the following detailed description of the preferred embodiments thereof, which description should be considered in conjunction with the accompanying drawings in which:
[0045] FIG. 1 is a perspective view from above a side of an exemplary prior art surgical staple;
[0046] FIG. 2 is a perspective view from above a side of a first exemplary embodiment of an OTC staple according to the invention;
[0047] FIG. 3 is a perspective view from above a side of a second exemplary embodiment of an OTC staple according to the invention;
[0048] FIG. 4 is a perspective view from above a side of a third exemplary embodiment of an OTC staple according to the invention;
[0049] FIG. 5 is a perspective view from above a side of a fourth exemplary embodiment of an OTC staple according to the invention;
[0050] FIG. 6 is a perspective view from above a side of a fifth exemplary embodiment of an OTC staple according to the invention;
[0051] FIG. 7 is a perspective view from above a side of a sixth exemplary embodiment of an OTC staple according to the invention;
[0052] FIG. 8 is a perspective view from above a side of a seventh exemplary embodiment of an OTC staple according to the invention;
[0053] FIG. 9 is a perspective view from above a side of an eighth exemplary embodiment of an OTC staple according to the invention;
[0054] FIG. 10 is a perspective view from above a side of a ninth exemplary embodiment of an OTC staple according to the invention;
[0055] FIG. 11 is a perspective view from above a side of a tenth exemplary embodiment of an OTC staple according to the invention;
[0056] FIG. 11A is a fragmentary, enlarged perspective view from below a side of the OTC staple of FIG. 11 ;
[0057] FIG. 12 is a perspective view from above a side of an eleventh exemplary embodiment of an OTC staple according to the invention;
[0058] FIG. 13 is a perspective view from above a side of a twelfth exemplary embodiment of an OTC staple according to the invention;
[0059] FIG. 14 is a perspective view from above a side of a thirteenth exemplary embodiment of an OTC staple according to the invention;
[0060] FIG. 15 is a perspective view from above a side of a fourteenth exemplary embodiment of an OTC staple according to the invention;
[0061] FIG. 16 is a perspective view from above a side of a fifteenth exemplary embodiment of an OTC staple according to the invention;
[0062] FIG. 17 is a side elevational view of the prior art surgical staple of FIG. 1 with the staple tips illustrating an exemplary range of stapling;
[0063] FIG. 18 is a side elevational view of the staple of FIG. 6 with the staple tips in a first intermediate position of an exemplary stapling range;
[0064] FIG. 19 is a side elevational view of the staple of FIG. 6 with the staple tips in a second intermediate position of an exemplary stapling range; and
[0065] FIG. 20 is a side elevational view of the staple of FIG. 6 with the staple tips in a third intermediate position of an exemplary stapling range.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0066] Herein various embodiment of the present invention are described. In many of the different embodiments, features are similar. Therefore, to avoid redundancy, repetitive description of these similar features may not be made in some circumstances. It shall be understood, however, that description of a first-appearing feature applies to the later described similar feature and each respective description, therefore, is to be incorporated therein without such repetition.
[0067] Referring now to the figures of the drawings in detail and first, particularly to FIG. 2 thereof, there is shown a first exemplary embodiment of an automatic optimal tissue compression (OTC) staple 20 according to the invention. In this first embodiment, the bridge 21 has a center bridge portion 22 and an extension 23 that substantially increases the overall length of the bridge 21 —as compared to the bridge 2 of the staple 1 of FIG. 1 . As the upper bridge portion 22 transitions into the extension 23 , it curves into and within the central region 24 of the staple 20 . This extension 23 can be in any shape or of any material so long as it delivers a pre-set compressive force to the tissue at a compressing portion 25 , and as long as it allows for absorption (within the area between the compressing portion 25 and the upper bridge portion 22 ) of forces greater than this pre-set force. Therefore, the shape can be trapezoidal, triangular, sinusoidal, or any other configuration. An exemplary embodiment of relatively sinusoidal curves is shown in FIG. 2 . These curves traverse two periods in the illustrated embodiment, however, the number of wave periods can be varied (smaller or larger). The extension 23 has two mirror-symmetrical portions each starting from the upper bridge portion 22 and ending at respective ends of the compressing portion 25 . Further, it is noted that neither the extension 23 nor the compressing portion 25 directly contacts the legs 26 in this exemplary configuration.
[0068] In the embodiment of FIG. 2 , the extension 26 and the compressing portion 29 are integral with the upper bridge portion 22 and a base end 27 of the legs 26 . The legs 26 are shown as relatively circular in cross-section. The bridge 21 and all of the compressing components 22 , 23 , 25 can also be circular in cross-section. Alternatively, as shown in FIG. 2 , any portion of the extension 23 and/or the compressing portion 25 can have different cross-sectional shapes, such as ovular, rectangular, or polygonal. In the embodiment shown, the cross-section of the extension 23 after the first curve away from the upper bridge portion 22 is shaped in a “racetrack” form (two relatively straight sides with two curved ends connecting each end of the sides). The upper bridge portion 22 can also have a different cross-sectional shape. The extension 23 and compressing portion 25 are, in this embodiment, even in cross-sectional area. Different portions of these parts can, however, have varying cross-sectional areas (i.e., varying thicknesses) as desired.
[0069] When the upper bridge 22 , the extension 23 , and the compressing portion 25 are shaped to deliver the pre-set compressive force to the tissue in a substantially longitudinal direction 28 of an unbent section of the leg portions 26 and to absorb forces greater than this pre-set force, the overall effect is to create an OTC device having a given spring coefficient. In other words, the OTC device maintains the preset compressive force within the stapled area even after tissue changes states, such as expanding due to swelling and/or contracting during desiccation. Variation of the cross-section of any portion of the upper bridge 22 , the extension 23 , and the compressing portion 25 will allow for different OTC spring coefficients and, therefore, allows for adjustment of the compressive and reactive force constants of the OTC device within the staple 20 . Variation of the material making up all of the staple 20 or any of its portions also permits adjustment of the OTC force.
[0070] FIG. 3 illustrates a second exemplary embodiment of the OTC staple 30 according to the invention. In this variation, as compared to the embodiment of FIG. 2 , the OTC portion is not integral with the bridge 31 and the legs 32 . Instead, the OTC device 33 is separate therefrom and is connected to these staple portions. Specifically, the OTC device 33 has a compressing portion 34 that directly contacts the tissue being compressed and an extension 36 for providing the load-bearing force when tissue is compressed within the central region 37 of the staple 30 . The OTC device 33 also has a connecting portion 35 for attaching the OTC device 33 to the bridge 31 . The extension 36 connects the upper and lower portions 34 , 35 of the OTC device 33 . The extension 33 and the compressing portion 34 are, in this embodiment, different in cross-sectional area. Here, the cross-sectional area of the compressing portion 34 is wider than the extension 36 . Any portions of the extension 33 or the compressing portion 34 can be varied to have same or varying cross-sectional areas (i.e., varying thicknesses).
[0071] Connection of the OTC device 33 to the staple, for example, at the bridge 31 , can occur by any fastening measure. One exemplary connection method is spot welding, which is indicated in FIG. 3 by reference numeral 38 . Other exemplary methods of attaching suitable materials together include soldering and brazing. The type or types of material of the staple portions 31 , 32 and the OTC device 33 will direct a preferable attachment method. In the case of attaching two materials together that are not suited to be welded, soldered or brazed, other attachment methods can be used such as crimping and adhesive bonding. Features can be added to one or both of the two components to facilitate the crimp or bond. These features could be configured to have the components snap together. In the case of dissimilar materials, for example, if the staple material is stainless steel and the OTC device 33 is of nickel titanium alloy, then preferred attachment measures include crimping, adhesive bonding, or snapping.
[0072] In this second embodiment, the OTC device 33 behaves similar to the OTC portions of the embodiment of FIG. 2 and can be shaped with the same variations of cross-section and other spatial characteristics and can be formed with the same variations in material composition. Variation of any attribute of the OTC device 33 allows for adjustment of the compressive and reactive force constants thereof on the compressed tissue. The extension 36 can be any shape or material so long as it delivers a pre-set compressive force to the tissue at the compressing portion 34 and as long as it allows for absorption of forces greater than this pre-set force. An exemplary embodiment selected for this exemplary OTC device 33 is a relatively sinusoidal set of curves traversing less than two periods. The extension 36 has two minor-symmetrical portions each starting from the bridge 31 and ending at respective ends of the compressing portion 34 . In this exemplary embodiment, neither the extension 36 nor the compressing portion 34 directly contacts the legs 32 . Most of the cross-section of the OTC device 33 has a racetrack form. Like the embodiment of FIG. 2 , the cross-section can be varied in any desired way to deliver the pre-set compressive force to the tissue and to absorb forces greater than this pre-set force.
[0073] FIG. 4 illustrates a third exemplary embodiment of the OTC staple 40 according to the invention. In this variation, as compared to the embodiments of FIGS. 2 and 3 , the OTC portion 43 is not symmetrical with respect to the bridge 41 or the legs 42 . Also, like the embodiment of FIG. 3 , the OTC portion is not integral with either the bridge 41 or the legs 42 . The OTC device 43 is a separate part from the bridge 41 and the legs 42 and is fixedly connected to the bridge 41 at a connection location (for example, with a spot weld 48 ; other fixation/connection processes can be used). In particular, a connecting portion 45 of the OTC device 43 fixedly secures the OTC device 43 to the bridge 41 . An extension 46 of the OTC device 43 provides the load-bearing force when tissue is compressed within the central region 47 of the staple 40 and a compressing portion 44 directly contacts the tissue being compressed.
[0074] Notably different from the embodiments of FIGS. 2 and 3 is the compressing portion 44 . Here, the width of the compressing portion 44 (defined along the line between the two legs 42 of the staple 40 ) is greater than the separation distance of the two legs 42 . The compressing portion 44 is provided with orifices 49 having a shape substantially corresponding to the cross-sectional shape of the upper portion of the staple legs 42 but slightly larger. The legs 42 pass through and slidably rest within these orifices 49 . In such a configuration, movement of the OTC device 43 out of the bridge-legs plane is substantially prevented. Because the orifices 49 are shaped to be slightly larger than the cross-section of the legs 42 , the extension 46 acts as a compression spring in the bridge-legs plane as the compressing portion 44 moves up and down along the upper portion of the legs 42 (up being defined as the direction towards the bridge 41 from the piercing tips of the legs 42 ). Thus, the OTC device 43 of the third embodiment behaves different from the OTC devices of FIGS. 2 and 3 because of the form-locking and sliding connection between the connecting portion 44 and the legs 42 . A form-locking connection is one that connects two elements together due to the shape of the elements themselves, as opposed to a force-locking connection, which locks the elements together by force external to the elements.
[0075] Like the previous embodiments, the OTC device 43 can be shaped with variations in cross-section and other spatial characteristics and can be formed with a variety of material compositions. The extension 46 and compressing portion 44 are, in this embodiment, different in cross-sectional area. Here, the cross-sectional area of the compressing portion 44 is wider than the extension 46 . Any portions of the extension 46 or the compressing portion 44 can be varied to have same or varying cross-sectional areas (i.e., varying thicknesses). The extension 46 can be any shape or material so long as it delivers the pre-set compressive force to the tissue at the compressing portion 44 and as long as it allows for absorption of forces greater than this pre-set force. An exemplary embodiment selected for this OTC device 43 is a relatively sinusoidal curve traversing approximately one sinusoidal period. Virtually all of the cross-section of the OTC device 43 has a racetrack form, but can be changed as desired to other shapes (e.g., circular, ovular, polygonal, etc.). As described above, variation of any attribute of the OTC device 43 allows for adjustment of the compressive and reactive force constants thereof on the compressed tissue in the central region 47 .
[0076] FIG. 5 illustrates a fourth exemplary embodiment of the OTC staple 50 according to the invention. This variation has some of the features of the above embodiments. In this variant, like the embodiment of FIG. 2 , the OTC portion is symmetrical with respect to the bridge 51 and the legs 52 and the OTC device 53 is integral with the bridge 51 . Like the embodiment of FIG. 4 , the compressing portion 54 has a width greater than the separation distance of the two legs 52 and has ports 55 with a shape substantially corresponding to the cross-sectional shape of the upper portion of the legs 52 , but slightly larger. The legs 52 pass through these ports 55 . In this configuration, movement of the OTC device 53 out of the bridge-legs plane is substantially prevented. The extension 56 of the OTC device 53 traverses from the bridge 51 to the compressing portion 54 . Because the ports 55 are shaped to be slightly larger than the cross-section of the legs 52 , the extension 56 acts as a compression spring in the bridge-legs plane as the compressing portion 54 moves up and down along the upper portion of the legs 52 . It is the extension 56 that provides the load-bearing force when tissue is compressed within the central region 57 of the staple 50 . Because of the form-locking and sliding connection between the compressing portion 54 and the legs 52 , the OTC device 53 of the fourth embodiment behaves similar to the OTC devices of FIG. 4 .
[0077] Here, the OTC device 53 is integral with the legs 52 , the bridge 51 , and the compressing portion 54 . Because the two sides of the bridge 51 are not integral, they can separate from one another when the staple 50 is subjected to a twisting force. If desired, to substantially prevent such separation, the central portions of the bridge 51 can be fixedly connected to one another at a connection location (for example, with a spot weld 58 ; other connection processes can be used as well).
[0078] Like the previous embodiments, the OTC device 53 can be shaped with variations in cross-section and other spatial characteristics and can be formed with a variety of material compositions. Any portions of the extension 56 or the compressing portion 54 can be varied to have the same or varying cross-sectional areas (i.e., varying thicknesses). The extension 56 and compressing portion 54 are, in this embodiment, different in cross-sectional areas. Here, the cross-sectional area of the upper majority of the extension 56 is narrower than the lower portion of the extension 56 and the cross-section of the lower portion of the extension 56 gradually increases in width until it is equal to the cross-section of the compressing portion 54 .
[0079] The extension 56 can be any shape or material so long as it delivers the pre-set compressive force to the tissue at the compressing portion 54 and as long as it allows for absorption of forces greater than this pre-set force. An exemplary embodiment selected for this OTC device 53 is a relatively sinusoidal curve traversing more than one sinusoidal period. Again, only for illustrative purposes, the cross-section of the OTC device 53 has a racetrack shape, but can be changed as desired to other shapes (e.g., circular, ovular, polygonal, etc.). As described above, variation of any attribute of the OTC device 53 allows for adjustment of the compressive and reactive force constants thereof on the compressed tissue in the central region 57 .
[0080] FIG. 6 illustrates a fifth exemplary embodiment of the OTC staple 60 according to the invention. This variation has some of the features of the above embodiments. In this variant, like the embodiment of FIG. 3 , the OTC portion is symmetrical with respect to the bridge 61 and the legs 62 and the OTC device 63 is a separate part from the bridge 61 and legs 62 of the staple 60 . Like the embodiment of FIGS. 4 and 5 , the compressing portion 64 has a width greater than the separation distance of the two legs 62 and has ports 65 with a shape substantially corresponding to the cross-sectional shape of the upper portion of the legs 62 , but slightly larger. The legs 62 pass through these ports 65 . In this configuration, movement of the OTC device 63 out of the bridge-legs plane is substantially prevented. The extension 66 of the OTC device 63 traverses from the bridge 61 to the compressing portion 64 . Because the ports 65 are shaped to be slightly larger than the cross-section of the legs 62 , the extension 66 acts as a compression spring in the bridge-legs plane as the compressing portion 64 moves up and down along the upper portion of the legs 62 . It is the extension 66 that provides the load-bearing force when tissue is compressed within the central region 67 of the staple 60 . Because of the form-locking and sliding connection between the compressing portion 64 and the legs 62 , the OTC device 63 of the fifth embodiment behaves similar to the OTC devices of FIGS. 4 and 5 .
[0081] Connection of the OTC device 63 to the staple 60 , for example, at the bridge 61 , can occur by any fastening measure. One exemplary connection method is spot welding, which is indicated in FIG. 6 by reference numeral 68 . The type or types of material of the staple portions 61 , 62 and the OTC device 63 will direct a preferable attachment method. In the case of attaching two materials together that are not suited to be welded, soldered or brazed, other attachment methods can be used such as crimping and adhesive bonding. Features can be added to one or both of the two components to facilitate the crimp or bond. These features could be configured to have the components snap together. In the case of dissimilar materials, for example, if the staple material is stainless steel and the OTC device 63 is of nickel titanium alloy, then preferred attachment measures include crimping, adhesive bonding, or snapping.
[0082] Like the previous embodiments, the OTC device 63 can be shaped with variations in cross-section and other spatial characteristics and can be formed with a variety of material compositions. Any portions of the extension 66 or the compressing portion 64 can be varied to have the same or different cross-sectional areas (i.e., varying thicknesses). The extension 66 and compressing portion 64 are, in this embodiment, different in cross-sectional areas. Here, the cross-sectional area of most of the extension 66 is narrower than the lowermost portion of the extension 66 and the cross-section of this lowermost portion of the extension 66 gradually increases in width until it is equal to the cross-section of the compressing portion 64 , which is substantially wider.
[0083] The extension 66 can be any shape or material so long as it delivers the pre-set compressive force to the tissue at the compressing portion 64 and as long as it allows for absorption of forces greater than this pre-set force. An exemplary embodiment selected for this OTC device 63 is a relatively sinusoidal curve traversing more than one sinusoidal period. Again, only for illustrative purposes, the cross-section of the OTC device 63 has a racetrack shape, but can be changed as desired to other shapes (e.g., circular, ovular, polygonal, etc.). As described above, variation of any attribute of the OTC device 63 allows for adjustment of the compressive and reactive force constants thereof on the compressed tissue in the central region 67 .
[0084] FIG. 7 illustrates a sixth exemplary embodiment of the OTC staple 70 according to the invention. This variation has some of the features of the above embodiments. In this variant, like the embodiment of FIG. 3 , the OTC portion is symmetrical with respect to the bridge 71 and the legs 72 and the OTC device 73 is a separate part from the bridge 71 and legs 72 of the staple 70 . Like the embodiment of FIGS. 4 to 6 , the compressing portion 74 has a width greater than the separation distance of the two legs 72 and has ports 75 with a shape substantially corresponding to the cross-sectional shape of the upper portion of the legs 72 , but slightly larger. The legs 72 pass through these ports 75 . In this configuration, movement of the OTC device 73 out of the bridge-legs plane is substantially prevented. The extension 76 of the OTC device 73 traverses from the bridge 71 to the compressing portion 74 . Because the ports 75 are shaped to be slightly larger than the cross-section of the legs 72 , the extension 76 acts as a compression spring in the bridge-legs plane as the compressing portion 74 moves up and down along the upper portion of the legs 72 . It is the extension 76 that provides the load-bearing force when tissue is compressed within the central region 77 of the staple 70 . Because of the form-locking and sliding connection between the compressing portion 74 and the legs 72 , the OTC device 73 of the sixth embodiment behaves similar to the OTC devices of FIGS. 4 to 6 .
[0085] Connection of the OTC device 73 to the staple 70 , for example, at the bridge 71 , can occur by any fastening measure. One exemplary connection method is spot welding, which is indicated in FIG. 7 by reference numeral 78 . The type or types of material of the staple portions 71 , 72 and the OTC device 73 will direct a preferable attachment method. In the case of attaching two materials together that are not suited to be welded, soldered or brazed, other attachment methods can be used such as crimping and adhesive bonding. Features can be added to one or both of the two components to facilitate the crimp or bond. These features could be configured to have the components snap together. In the case of dissimilar materials, for example, if the staple material is stainless steel and the OTC device 73 is of nickel titanium alloy, then preferred attachment measures include crimping, adhesive bonding, or snapping.
[0086] It is noted that the extensions (i.e., springs) in each of FIGS. 2 , 3 , 5 , and 6 are in the same plane, which can be the bridge-legs plane (as shown) or out of that plane. In comparison to these embodiments, the extension 76 has the springs residing in different planes (i.e., one next to the other.
[0087] Like the previous embodiments, the OTC device 73 can be shaped with variations in cross-section and other spatial characteristics and can be formed with a variety of material compositions. Any portions of the extension 76 or the compressing portion 74 can be varied to have the same or varying cross-sectional areas (i.e., varying thicknesses). The extension 76 and the compressing portion 74 are, in this embodiment, different in cross-sectional areas. Here, the cross-sectional area of most of the extension 76 is narrower than the lowermost portion of the extension 76 and the cross-section of this lowermost portion of the extension 76 gradually increases in width until it is equal to the cross-section of the compressing portion 74 , which is substantially wider.
[0088] The extension 76 can be any shape or material so long as it delivers the pre-set compressive force to the tissue at the compressing portion 74 and as long as it allows for absorption of forces greater than this pre-set force. An exemplary embodiment selected for this OTC device 73 is a relatively sinusoidal curve traversing more than one sinusoidal period. Again, only for illustrative purposes, the cross-section of the OTC device 73 has a racetrack shape, but can be changed as desired to other shapes (e.g., circular, ovular, polygonal, etc.). As described above, variation of any attribute of the OTC device 73 allows for adjustment of the compressive and reactive force constants thereof on the compressed tissue in the central region 77 .
[0089] FIG. 8 illustrates a seventh exemplary embodiment of the OTC staple 80 according to the invention. This variation has some of the features of the above embodiments. In this variant, like the embodiment of FIG. 3 , the OTC portion is symmetrical with respect to the bridge 81 and the legs 82 , and the OTC device 83 is a separate part from the bridge 81 and legs 82 of the staple 80 . Like the embodiment of FIGS. 4 to 7 , the compressing portion 84 has a width greater than the separation distance of the two legs 82 and has ports 85 with a shape substantially corresponding to the cross-sectional shape of the upper portion of the legs 82 , but slightly larger. The legs 82 pass through these ports 85 . In this configuration, movement of the OTC device 83 out of the bridge-legs plane is substantially prevented. The extension 86 of the OTC device 83 traverses from the bridge 81 to the compressing portion 84 . Because the ports 85 are shaped to be slightly larger than the cross-section of the legs 82 , the extension 86 acts as a compression spring in the bridge-legs plane as the compressing portion 84 moves up and down along the upper portion of the legs 82 . It is the extension 86 that provides the load-bearing force when tissue is compressed within the central region 87 of the staple 80 . Because of the form-locking and sliding connection between the compressing portion 84 and the legs 82 , the OTC device 83 of the seventh embodiment behaves similar to the OTC devices of FIGS. 4 to 7 .
[0090] Like the previous embodiments, the OTC device 83 can be shaped with variations in cross-section and other spatial characteristics and can be formed with a variety of material compositions. Any portions of the extension 86 or the compressing portion 84 can be varied to have the same or varying cross-sectional areas (i.e., varying thicknesses). The extension 86 and the compressing portion 84 are, in this embodiment, different in cross-sectional areas. Here, the cross-sectional area of most of the extension 86 is smaller and narrower than the lowermost portion of the extension 86 and the cross-section of this lowermost portion gradually increases in width until it is equal to the cross-section of the compressing portion 84 , which is substantially wider. Also, the cross-sectional area of this extension 86 is smaller than previous embodiments (but it need not be).
[0091] The extension 86 can be any shape or material so long as it delivers the pre-set compressive force to the tissue at the compressing portion 84 and as long as it allows for absorption of forces greater than this pre-set force. An exemplary embodiment selected for this OTC device 83 is a relatively sinusoidal curve traversing a more than two periods and also having a second “interior” curve that traverses sinusoidal periods. In this embodiment, the OTC device 83 has an uppermost portion that is, in contrast to the embodiments of FIGS. 3 , 6 , and 7 a single bar extending along a majority of the bridge 81 .
[0092] Connection of the OTC device 83 to the staple 80 , for example, at the bridge 81 , can occur by any fastening measure. One exemplary connection method is spot welding, which is indicated in FIG. 8 by reference numeral 88 . Because there is contact over most of the bridge 81 , the OTC device 83 can be welded over the entire length thereof. The type or types of material of the staple portions 81 , 82 and the OTC device 83 will direct a preferable attachment method. In the case of attaching two materials together that are not suited to be welded, soldered or brazed, other attachment methods can be used such as crimping and adhesive bonding. Features can be added to one or both of the two components to facilitate the crimp or bond. These features could be configured to have the components snap together. In the case of dissimilar materials, for example, if the staple material is stainless steel and the OTC device 83 is of nickel titanium alloy, then preferred attachment measures include crimping, adhesive bonding, or snapping.
[0093] Only for illustrative purposes, the cross-section of the OTC device 83 has a racetrack shape, but can be changed as desired to other shapes (e.g., circular, ovular, polygonal, etc.). As described above, variation of any attribute of the OTC device 83 allows for adjustment of the compressive and reactive force constants thereof on the compressed tissue in the central region 87 .
[0094] FIG. 9 illustrates an eighth exemplary embodiment of the OTC staple 90 according to the invention. This variation has some of the features of the above embodiments. In this variant, like the embodiment of FIG. 3 , the OTC portion is symmetrical with respect to the bridge 91 and the legs 92 , and the OTC device 93 is a separate part from the bridge 91 and legs 92 of the staple 90 . Like the embodiment of FIGS. 4 to 8 , the compressing portion 94 has a width greater than the separation distance of the two legs 92 and has ports 95 with a shape substantially corresponding to the cross-sectional shape of the upper portion of the legs 92 , but slightly larger. The legs 92 pass through these ports 95 . In this configuration, movement of the OTC device 93 out of the bridge-legs plane is substantially prevented. The extension 96 of the OTC device 93 traverses from the bridge 91 to the compressing portion 94 . Because the ports 95 are shaped to be slightly larger than the cross-section of the legs 92 , the extension 96 acts as a compression spring in the bridge-legs plane as the compressing portion 94 moves up and down along the upper portion of the legs 92 . It is the extension 96 that provides the load-bearing force when tissue is compressed within the central region 97 of the staple 90 . Because of the form-locking and sliding connection between the compressing portion 94 and the legs 92 , the OTC device 93 of the eighth embodiment behaves similar to the OTC devices of FIGS. 4 to 8 .
[0095] Like the previous embodiments, the OTC device 93 can be shaped with variations in cross-section and other spatial characteristics and can be formed with a variety of material compositions. Any portion(s) of the extension 96 or the compressing portion 94 can be varied to have the same or varying cross-sectional areas (i.e., varying thicknesses). The extension 96 and the compressing portion 94 are, in this embodiment, different in cross-sectional areas. Here, the cross-sectional area of most of the extension 96 is smaller and narrower than the lowermost portion of the extension 96 and the cross-section of this lowermost portion gradually increases in width until it is equal to the cross-section of the compressing portion 94 , which is substantially wider. Also, the cross-sectional area of this extension 96 is smaller than previous embodiments (but need not be). With such a relatively smaller cross-sectional shape, the curves of the extension 96 might tend to deform or move out of the bridge-legs plane, which tendency can increase or decrease depending upon the material of the extension 96 . To prevent such deformation and/or movement, a plurality of guiding tabs 99 are disposed at one or more of the outside ends of each periodic curve adjacent the legs 92 . These guiding tabs 99 are shaped in a similar manner to the ends of the compressing portion 94 , in that they have ports with a cross-sectional shape substantially corresponding to the cross-sectional shape of the upper portion of the legs 92 but slightly larger. The embodiment illustrated in FIG. 9 provides each guiding tab 99 with two relatively parallel plates each having one of the two ports through which the respective leg 92 is disposed Like the lower portion of the extension 96 , the cross-sectional area of the extension gradually increases in width until it is equal to the larger cross-section of the plate of the guiding tab 99 . Another alternative of the guiding tab 99 is to have only a single plate with a single port. In such an embodiment (assuming the material was the same as a dual-plate embodiment), the curves of the extension 96 would be slightly stiffer because of the absence of the exterior curve of the guiding tab 99 .
[0096] The extension 96 can be any shape or material so long as it delivers the pre-set compressive force to the tissue at the compressing portion 94 and as long as it allows for absorption of forces greater than this pre-set force. An exemplary embodiment selected for this OTC device 93 is a relatively sinusoidal curve having a second interior curve that traverses a few sinusoidal periods and, in this embodiment, has an uppermost portion that is, like the embodiment of FIG. 8 , a single bar extending along a majority of the bridge 91 . Connection of the OTC device 93 to the staple 90 , for example, at the bridge 91 , can occur by any fastening measure. One exemplary connection method is spot welding, which is indicated in FIG. 9 by reference numeral 98 . Alternatively, the weld can be over the entire span contacting the bridge 91 . The type or types of material of the staple portions 91 , 92 and the OTC device 93 will direct a preferable attachment method. In the case of attaching two materials together that are not suited to be welded, soldered or brazed, other attachment methods can be used such as crimping and adhesive bonding. Features can be added to one or both of the two components to facilitate the crimp or bond. These features could be configured to have the components snap together. In the case of dissimilar materials, for example, if the staple material is stainless steel and the OTC device 93 is of nickel titanium alloy, then preferred attachment measures include crimping, adhesive bonding, or snapping.
[0097] Again, only for illustrative purposes, the cross-section of the OTC device 93 has a racetrack shape, but can be changed as desired to other shapes (e.g., circular, ovular, polygonal, etc.). As described above, variation of any attribute of the OTC device 93 allows for adjustment of the compressive and reactive force constants thereof on the compressed tissue in the central region 97 .
[0098] FIG. 10 illustrates a ninth exemplary embodiment of the OTC staple 100 according to the invention. This variation has some of the features of the above embodiments. In this variant, like the embodiment of FIG. 3 , the OTC portion is symmetrical with respect to the bridge 101 and the legs 102 , and the OTC device 103 is a separate part from the bridge 101 and legs 102 of the staple 100 . The compressing portion 104 , however, is unlike all of the previous embodiments. Here, the compressing portion 104 is formed from two compressing plates, each of these plates being attached to a respective lower end of two halves of the OTC device 103 . The shape of the compressing portion 104 need not be a plate. It can be cylindrical, for example. Like previous embodiments, the lowermost end of the extension 106 gradually increases in cross-section until it is equal to the compressing portion 104 . Each compressing plate, then, extends towards a respective one of the legs 102 and defines a respective port 105 for receiving therein the leg 102 . The port 105 has a shape substantially corresponding to the cross-sectional shape of the upper portion of the legs 102 , but is slightly larger. The legs 102 pass through each port 105 to form the OTC device 103 . In this configuration, movement of the OTC device 103 out of the bridge-legs plane is substantially prevented. The extension 106 of the OTC device 103 traverses from the bridge 101 to the plates of the compressing portion 104 . Because the ports 105 are shaped to be slightly larger than the cross-section of the legs 102 , the extension 106 acts as a compression spring in the bridge-legs plane as the compressing portion 104 moves up and down along the upper portion of the legs 102 . It is the extension 106 that provides the load-bearing force when tissue is compressed within the central region 107 of the staple 100 .
[0099] In this embodiment, as compared to previous OTC device embodiments, the two sides of the OTC device 103 move independent from one another. Thus, if tissue varies in any characteristic within the central portion 107 (e.g., hardness, thickness, density), the optimal tissue compression force can be delivered independently and differently for each of the two differing tissue segments contacting the respective one of the sides of the OTC device 103 .
[0100] Connection of the OTC device 103 to the staple 100 , for example, at the bridge 101 , can occur by any fastening measure. One exemplary connection method is spot welding, which is indicated in FIG. 10 by reference numeral 108 . As the upper portion contacts almost all of the bridge 101 , the weld 108 , instead, can span any amount of the bridge 101 . The type or types of material of the staple portions 101 , 102 and the OTC device 103 will direct a preferable attachment method. In the case of attaching two materials together that are not suited to be welded, soldered or brazed, other attachment methods can be used such as crimping and adhesive bonding. Features can be added to one or both of the two components to facilitate the crimp or bond. These features could be configured to have the components snap together. In the case of dissimilar materials, for example, if the staple material is stainless steel and the OTC device 103 is of nickel titanium alloy, then preferred attachment measures include crimping, adhesive bonding, or snapping.
[0101] Like the previous embodiments, the OTC device 103 can be shaped with variations in cross-section and other spatial characteristics and can be formed with a variety of material compositions. Any portions of the extension 106 or the compressing portion 104 can be varied to have the same or varying cross-sectional areas (i.e., varying thicknesses). The extension 106 and the plates of the compressing portion 104 are, in this embodiment, different in cross-sectional areas. Here, the cross-sectional area of most of the extension 106 is smaller and narrower than the lowermost portion of the extension 86 and the cross-section of this lowermost portion gradually increases in width until it is equal to the cross-section of the respective plate of the compressing portion 104 , which is substantially wider.
[0102] The extension 106 can be any shape or material so long as it delivers the pre-set compressive force to the tissue at the compressing portion 104 and as long as it allows for absorption of forces greater than this pre-set force. An exemplary embodiment selected for this OTC device 103 is a relatively sinusoidal curve having almost two sinusoidal periods and, in this embodiment, has an uppermost portion that is (like the embodiments of FIGS. 8 and 9 ) a single bar extending along a majority of the bridge 101 . For illustrative purposes, the cross-section of the OTC device 103 has an ovular shape, but can be changed as desired to other shapes (e.g., circular, racetrack, polygonal, etc.). As described above, variation of any attribute of the OTC device 103 allows for adjustment of the compressive and reactive force constants thereof on the compressed tissue in the central region 107 .
[0103] FIGS. 11 and 11A illustrate a tenth exemplary embodiment of the OTC staple 110 according to the invention. This variation has some of the features of the above embodiments. In this variant, like the embodiment of FIG. 3 , the OTC portion is symmetrical with respect to the bridge 111 and the legs 112 , and the OTC device 113 is a separate part from the bridge 111 and legs 112 of the staple 110 . The compressing portion 114 is like the embodiment of FIG. 10 —it is formed from two compressing plates, each of these plates being attached to a respective lower end of two halves of the OTC device 113 . The lowermost end of the extension 116 gradually increases in cross-section until it is equal in area to the compressing portion 114 . Each compressing plate, then, extends towards a respective one of the legs 112 and defines a respective port 115 for receiving therein one of the legs 112 . In FIG. 11 , the ports 115 cannot be seen because of the presence of one-way washers 119 (described below), but the port 115 is visible in FIG. 11A .
[0104] As set forth above, each port 115 has a shape substantially corresponding to the cross-sectional shape of the upper portion of the legs 112 but is slightly larger. The legs 112 pass through each port 115 to form the OTC device 113 . Because the ports 115 are shaped to be slightly larger than the cross-section of the legs 112 , the extension 116 acts as a compression spring in the bridge-legs plane as the compressing portion 114 moves up and down along the upper portion of the legs 112 . In this configuration, movement of the OTC device 113 out of the bridge-legs plane is substantially prevented. It is the extension 116 that provides the load-bearing force when tissue is compressed within the central region 117 of the staple 110 . In this embodiment (like the embodiment of FIG. 10 ), the two sides of the OTC device 113 move independent from one another. Thus, if tissue varies in any characteristic within the central portion 117 (e.g., hardness, thickness, density), the optimal tissue compression force can be delivered independently and differently for each of the two differing tissue segments contacting the two plates of the compressing portion 114 .
[0105] Introduced for the first time in this embodiment are one-way devices 119 (one exemplary embodiment being a star washer that is illustrated in FIGS. 11 and 11A ) disposed on the leg 112 between the bridge 111 and the compressing portion 114 . These devices 119 are shaped to freely move on the leg 112 upwards towards the bridge 111 but not to move in the opposite direction. Thus, as tissue is being compressed within the central region 117 as the distal ends of the legs 112 are curved in the stapling action, the tissue presses against the compressing portion 114 and moves the compressing portion 114 up towards the bridge 111 . Once the stapling force is removed from the staple 110 (after stapling is complete), the tissue will most likely not press the washers 119 any further without any additionally supplied outside force. Thus, the washers 119 limit further movement of the compressing portion 114 from the then-current location of the washers 119 towards the first bend of the legs 112 . These washers also add some friction when the first stapling movement occurs, which friction may be used to add to and make up the compression coefficients of the OTC device 113 . If the stapled tissue swells, it is possible for the washers 119 to be moved if the force is sufficient. After such swelling ends and desiccation of the tissue occurs, the compressing portions 114 will be limited in further compression by these washers 119 .
[0106] Like the previous embodiments, the OTC device 113 can be shaped with variations in cross-section and other spatial characteristics and can be formed with a variety of material compositions. Any portions of the extension 116 or the compressing portion 114 can be varied to have the same or varying cross-sectional areas (i.e., varying thicknesses). The extension 116 and the plates of the compressing portion 114 are, in this embodiment, different in cross-sectional areas. Here, the cross-sectional area of most of the extension 116 is smaller and narrower than the lowermost portion of the extension 116 and the cross-section of this lowermost portion gradually increases in width until it is equal to the cross-section of the respective plate of the compressing portion 114 , which is substantially wider.
[0107] The extension 116 can be any shape or material so long as it delivers the pre-set compressive force to the tissue at the compressing portion 114 and as long as it allows for absorption of forces greater than this pre-set force. An exemplary embodiment selected for this OTC device 113 is a relatively sinusoidal curve traversing more than two sinusoidal periods and having a second “interior” curve. In this embodiment, the OTC device 113 has an uppermost portion that is (like the embodiments of FIGS. 8 to 10 ) a single bar extending along a majority of the bridge 111 . Connection of the OTC device 113 to the staple 110 , for example, at the bridge 111 , can occur by any fastening measure. One exemplary connection method is spot welding, which is indicated in FIG. 11 by reference numeral 118 . This process can be changed if desired. The type or types of material of the staple portions 111 , 112 and the OTC device 113 will direct a preferable attachment method. In the case of attaching two materials together that are not suited to be welded, soldered or brazed, other attachment methods can be used such as crimping and adhesive bonding. Features can be added to one or both of the two components to facilitate the crimp or bond. These features could be configured to have the components snap together. In the case of dissimilar materials, for example, if the staple material is stainless steel and the OTC device 113 is of nickel titanium alloy, then preferred attachment measures include crimping, adhesive bonding, or snapping.
[0108] For illustrative purposes, the cross-section of the OTC device 113 has a racetrack shape, but can be changed as desired to other shapes (e.g., circular, ovular, polygonal, etc.). As described above, variation of any attribute of the OTC device 113 allows for adjustment of the compressive and reactive force constants thereof on the compressed tissue in the central region 117 .
[0109] FIG. 12 illustrates an eleventh exemplary embodiment of the OTC staple 120 according to the invention. This variation is significantly different from the above embodiments. The OTC device 123 is, as above, a separate part from the bridge 121 and legs 122 of the staple 120 . Here, however, the compressing portion 124 is a C-beam having ports 125 that permit passage of a respective one of the legs 122 therethrough. Each port 125 has a shape substantially corresponding to the cross-sectional shape of the upper portion of the legs 122 but is slightly larger. The legs 122 pass through each port 125 to form the OTC device 123 . In this configuration, movement of the OTC device 123 out of the bridge-legs plane is substantially prevented.
[0110] The C-beam shape is useful for a variety of reasons. First, the C-shape provides a central cavity in which a distal end of a compression device 126 can be held or fastened. Next, the C-shape also increases resistance to bending forces as compared to a simple rectangular plate, as is known in construction. Finally, orienting the open portion of the “C” away from the tissue presents a flat compressing plate to the tissue to be compressed. With such a shape, the tissue can be compressed evenly, with no singular pressure points. Of course, the C-shape is not the only possible cross-sectional shape. The compressing portion 124 can be a rectangular plate, an I-beam, an L-beam, or any other desired shape.
[0111] The compression device 126 can take any form (see, e.g., FIG. 13 ). The exemplary embodiment of FIG. 12 illustrates the compression device 126 as a conically expanding compression spring. Connection of the spring 126 and compressing portion 124 to the staple 120 , for example, at the bridge 121 , can occur by any fastening measure. The illustrated exemplary proximal connection method is a ring of the spring material wrapping around the bridge 121 . This proximal end is secured at the center of the bridge 121 and held in place there by placing protuberances 128 on the bridge 121 . These protuberances prevent lateral movement of the proximal ring towards either of the two legs 122 . Of course, this ring can be welded or fastened to the bridge 121 by any fastening process. The distal end of the spring is a relatively circular coil lying in the same plane as the interior cavity of the C-beam and having an outer diameter just slightly less than the interior diameter of the C-shaped cavity of the compressing portion 124 . Thus, the ends of the C-shape can be used to retain the distal end of the spring 126 within the cavity. Of course, other fastening measures can be used to secure the spring distal ends to the compressing portion 124 .
[0112] It is the spring 126 that provides the load-bearing force when tissue is compressed within the central region 127 of the staple 120 . Like the previous embodiments, the OTC device 123 can be shaped with variations in cross-section, winding, and other spatial characteristics and can be formed with a variety of material compositions. Any portions of the spring 126 or the compressing portion 124 can be varied. In particular, the spring 126 can be any shape or material so long as it delivers the pre-set compressive force to the tissue through the compressing portion 124 and as long as it allows for absorption of forces greater than this pre-set force. As described above, variation of any attribute of the OTC device 123 allows for adjustment of the compressive and reactive force constants thereof on the compressed tissue in the central region 127 .
[0113] FIG. 13 illustrates a twelfth exemplary embodiment of the OTC staple 130 according to the invention. This variation is similar to the embodiment of FIG. 12 . The OTC device 133 is, as above, a separate part from the bridge 131 and legs 132 of the staple 130 and the compressing portion 134 is a C-beam having ports 135 that permit passage of a respective one of the legs 132 therethrough. Each port 135 has a shape substantially corresponding to the cross-sectional shape of the upper portion of the legs 132 but is slightly larger. The legs 132 pass through each port 135 to form the OTC device 133 . In this configuration, movement of the OTC device 133 out of the bridge-legs plane is substantially prevented.
[0114] The C-beam shape has the same benefits as described in the eleventh embodiment of FIG. 12 . Like that embodiment, the C-shape is not required; the compressing portion 134 can be a rectangular plate, an I-beam, an L-beam, or any other desired shape.
[0115] The compression device 136 can take any form. In the exemplary embodiment of FIG. 13 , the compression device 136 is a pair of compression springs 136 . Connection of these springs 136 and the compressing portion 134 to the staple 130 , for example, at the bridge 131 , can occur by any fastening measure. The illustrated exemplary proximal connection method is a narrowing of the spring diameter to be equal or less than the diameter of the legs 132 at the connection point to the bridge 131 . Thus, the springs 136 can be held by the force imparted on the legs 132 by press-fitting the narrower spring rings onto a desired location on the legs 132 . Alternatively and/or additionally, the almost ninety degree bend at the legs-bridge intersection forms a stop preventing further upward movement of the distal ends of each spring 136 . Of course, the upper ring(s) can be fastened to the staple 130 by any measure, such as welding, crimping, etc.
[0116] Like the embodiment of FIG. 12 , the distal end of the springs 136 in FIG. 13 is formed by a relatively circular coil lying in the same plane as the interior cavity of the C-beam and having an outer diameter just slightly less than the interior diameter of the C-shaped cavity of the compressing portion 134 . Thus, the ends of the C-shape can be used to retain the distal end of the spring 136 within the cavity. The coils can be welded to the C-beam, for example. Of course, other fastening measures and coil configurations can be used to secure the distal ends of the springs 136 to the compressing portion 134 .
[0117] It is the springs 136 that provide the load-bearing force when tissue is compressed within the central region 137 of the staple 130 . Like the previous embodiments, the OTC device 133 can be shaped with variations in cross-section and other spatial characteristics and can be formed with a variety of material compositions. Any portions of the springs 136 or the compressing portion 134 can be varied. In particular, the spring 136 can be any shape or material so long as it delivers the pre-set compressive force to the tissue through the compressing portion 134 and as long as it allows for absorption of forces greater than this pre-set force. As described above, variation of any attribute of the OTC device 133 allows for adjustment of the compressive and reactive force constants thereof on the compressed tissue in the central region 137 .
[0118] The spring 136 shown in FIG. 12 floats between the legs 132 and does not touch either leg 132 . In contrast, the springs 135 of FIG. 13 wrap around the legs throughout the entire length. This orientation presents the possibility of resistance (i.e., friction) imparted upon the springs 136 by the legs 132 when the springs 136 are compressed. This resistance may be desirable depending upon the desired OTC device compression coefficient. If resistance is to be reduced, then sleeves 138 can be inserted onto the legs 132 such that they “lubricate” or reduce resistance of spring compression. These sleeves 138 can be made of polytetrafluoroethylene (PTFE), for example.
[0119] FIG. 14 illustrates a thirteenth exemplary embodiment of the OTC staple 140 according to the invention. This variation is similar to the embodiments of FIGS. 12 and 13 . The OTC device 143 is, as above, a separate part from the bridge 141 and legs 142 of the staple 140 and the compressing portion 144 is a C-beam having non-illustrated ports that permit passage of a respective one of the legs 142 therethrough (in the view of FIG. 14 , the ports are blocked from view by the C-beam). Each port has a shape substantially corresponding to the cross-sectional shape of the upper portion of the legs 142 but is slightly larger. The legs 142 pass through each port to form the OTC device 143 . In this configuration, movement of the OTC device 143 out of the bridge-legs plane is substantially prevented.
[0120] The C-beam shape has the same benefits as described in the eleventh embodiment of FIG. 12 . Like that embodiment, the C-shape is not required; the compressing portion 144 can be a rectangular plate, an I-beam, an L-beam, or any other desired shape.
[0121] The compression device 146 can take any form. The exemplary embodiment of FIG. 14 is a pair of compression springs 146 . Like the single spring 136 shown in FIG. 12 , the compression springs 146 of this embodiment float between the legs 142 and do not touch either leg 142 . Connection of these springs 146 to the staple 140 , for example, at the bridge 141 , can occur by any fastening measure. The illustrated exemplary proximal connection method is a second C-beam disposed against the bridge 141 and connected thereto by any fastening measure, such as spot welds 148 , for example. With such a connection configuration, each of the springs 146 can be formed with a relatively circular coil lying in the same plane as the interior cavity of each C-beam and having an outer diameter just slightly less than the interior diameter of the respective C-shaped cavity of the compressing portion 144 . Thus, the ends of the C-shape can be used to retain the distal end of the spring 146 within the cavity. These end coils can be press-fit or slid into the C-beam cavity for connection thereto. Alternatively and/or additionally, these lower and upper loops can be fastened to the beams by welding, crimping, etc. The respective interior cavities of the two C-beams can be of different or of equal size.
[0122] It is the springs 146 that provide the load-bearing force when tissue is compressed within the central region 147 of the staple 140 . Like the previous embodiments, the OTC device 143 can be shaped with variations in cross-section, winding, and other spatial characteristics and can be formed with a variety of material compositions. Any portions of the springs 146 or the compressing portion 144 can be varied. In particular, the spring 146 can be any shape or winding or of any material so long as it delivers the pre-set compressive force to the tissue through the compressing portion 144 and as long as it allows for absorption of forces greater than this pre-set force. As described above, variation of any attribute of the OTC device 143 allows for adjustment of the compressive and reactive force constants thereof on the compressed tissue in the central region 147 .
[0123] FIG. 15 illustrates a fourteenth exemplary embodiment of the OTC staple 150 according to the invention. The OTC device 153 is, as above, a separate part from the bridge 151 and legs 152 of the staple 150 . Here, however, this variation differs from the previous embodiments because the OTC device 153 is a cushion made of a compressible material. Examples of such material include, but are not limited to, closed cell polyethylene foam, expanded polytetrafluoroethylene (PTFE), silicone rubber, silicone rubber foam, urethane, and electro-spun thermoplastic elastomers. This cushion 153 defines two channels 154 for receiving therethrough a respective one of the legs 152 . Because the staple legs 152 taper inwards slightly in a direction from the intermediate portion 155 of the staple 150 to the ends of the bridge 151 (although this taper is not a requirement), the cross-sectional area of the channels 154 are larger than the cross-section of a portion of the legs 152 disposed inside the channels 154 . By passing the legs 152 through each channel 154 , the OTC device 153 is formed.
[0124] It is this pillow 153 that provides the load-bearing force when tissue is compressed within the central region 157 of the staple 150 . Like the previous embodiments, the OTC device 153 can be shaped with variations in cross-section and other spatial characteristics and can be formed with a variety of material compositions. The exemplary embodiment illustrated in FIG. 15 is a pillow having a racetrack cross-sectional shape in the transverse direction. However, the pillow can be circular, ovular, rectangular, and polygonal in its outer transverse shape.
[0125] Any portion of the pillow 153 can be varied so long as it delivers the pre-set compressive force to the tissue at the distal end of the pillow 153 and as long as it allows for absorption of forces greater than this pre-set force. As described above, variation of any attribute of the OTC device 153 allows for adjustment of the compressive and reactive force constants thereof on the compressed tissue in the central region 157 .
[0126] FIG. 16 illustrates a fifteenth exemplary embodiment of the OTC staple 160 according to the invention. This variation is different from the previous embodiments. The OTC device 163 is, as above, a separate part from the bridge 161 and legs 162 of the staple 160 . The OTC device is a plate 163 made of a semi-compressible material having properties that will be described in detail below. Examples of such a material include, but are not limited to, polyurethane and silicone rubber. The plate 163 defines two channels 164 for receiving therethrough a respective one of the legs 162 . Because the legs 162 taper inwards slightly in the bridge-legs plane in a direction from the intermediate portion 165 of the staple 160 to the ends of the bridge 161 (although this taper is not a requirement), the cross-sectional area of each of the channels 164 in the bridge-legs plane is larger than the cross-section of the legs 162 that are to be disposed inside the channels 164 . This larger area is defined by a hole that is longer in the bridge-legs plane than in the plane orthogonal thereto along the axis of the leg 162 . In the exemplary embodiment shown in FIG. 16 , the cross-sectional shape of the channels 164 are ovular or racetrack shaped. By passing the legs 162 through each channel 164 , the OTC device 163 is formed.
[0127] It is noted that the staple 160 shown in FIG. 16 is different from the prior art staple of FIG. 1 . Specifically, the connecting portion 166 of the legs 162 tapers in width outwardly in the direction beginning from the intermediate portion towards the bridge 161 in a plane that is orthogonal to the bridge-legs plane. Because the channels 164 have a fixed width in the plane of the widening (which plane is orthogonal to the bridge-legs plane), and due to the fact that the fixed width is close in size to the lower-most portion of the connecting portion 166 (nearest to the intermediate portion 165 ), the plate 163 will not be able to move upwards towards the bridge 161 unless the material of the plate 163 is semi-compressible. Knowledge about the material's ability to compress and the resistance it provides to upward movement as the plate 163 progresses upward along the outwards taper of the leg widening can be used to set or adjust the compressive and reactive force constants thereof on the compressed tissue in the central region 167 . Any portion of the plate 163 and of the upper leg taper can be varied so long as the OTC system (plate 163 and taper of the legs 162 ) delivers the pre-set compressive force to the tissue at the distal end of the plate 163 and as long as it allows for absorption of forces greater than this pre-set force.
[0128] The OTC device of this embodiment can be shaped with variations in cross-section, taper, and other spatial characteristics and can be formed with a variety of material compositions. The exemplary embodiment illustrated in FIG. 16 is a plate 163 having a racetrack cross-sectional shape in the transverse direction. However, the pillow can be circular, ovular, rectangular, and polygonal in its outer transverse shape, for example.
[0129] The OTC staple according to the invention is applied in the same manner as a conventional staple, that is:
the staple is loaded into a staple cartridge; material to be stapled with the staple is placed between the staple cartridge and an anvil; and the anvil and staple are brought together to press the lower portion of the legs against the anvil and bend the lower portions inward to capture the material in the central region and compress it between the bent portions and the compressing portion of the staple.
[0133] Because the material to be stapled has a length less than the distance between the bent lower portions and the bridge, the captured material partially compresses the OTC device inside the staple to, thereby, effect the optimal tissue compression feature. When the staple and material are released from the staple cartridge and anvil, the OTC device is imparting a pre-set compressive force against the compressed material. Significantly, the OTC device is able to move while the material is going through its compression and expansion cycle(s) until it finally reaches a steady state size. Even after reaching the steady state, the OTC device imparts the desired compressive force (within an acceptable minimum range) so that the material is not permanently damaged due to overcompression.
[0134] For example, if the material is human tissue, when tissue is stapled, liquid is forced out of the tissue. During the desiccation period, the tissue compresses further and further. The OTC device compensates by enlarging to follow the tissue compression. At some point in time, the tissue begins to swell (due to the puncturing and compressing forces imparted thereon). During the swelling period, the OTC device compensates by reducing to follow the tissue swelling.
[0135] The foregoing description and accompanying drawings illustrate the principles, preferred embodiments and modes of operation of the invention. However, the invention should not be construed as being limited to the particular embodiments discussed above. Additional variations of the embodiments discussed above will be appreciated by those skilled in the art.
[0136] Therefore, the above-described embodiments should be regarded as illustrative rather than restrictive. Accordingly, it should be appreciated that variations to those embodiments can be made by those skilled in the art without departing from the scope of the invention as defined by the following claims. | A substantially U-shaped staple has a bridge, legs, and an internally disposed compression device with a bias portion having a compression surface movably disposed between the legs and a compression resistor connected to the bridge and to the compression surface and is formed to resist movement of the compression surface towards the bridge with a force. | 0 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is claiming the benefit of U.S. provisional patent application Ser. No. 60/862,419, filed Oct. 20, 2006 by the present inventor.
FEDERALLY SPONSORED RESEARCH
[0002] Not Applicable
SEQUENCE LISTING OR PROGRAM
[0003] Not Applicable
BACKGROUND
[0004] 1. Field of the Invention
[0005] The present invention relates to a micro-well sample plate which is commonly referred to as a microplate and which is used to hold a large number of samples in a standardized format. More specifically, the present invention relates to a microplate with modified quadrilateral edges, which bring less artificially induced inaccuracies in peripheral wells, especially in corner wells.
[0006] 2. Prior Art
[0007] Microplates are widely used for storing, filtering, incubating and detecting samples in chemical experiments, biological assays, medical tests and the like. For example, a microplate might be used as micro-containers to store, filter, prepare, or incubate multiplicate samples in different wells by a parallel way, and as well, a microplate can be used to conduct relatively tiny volume cell cultures in vitro. The sample filled microplate might eventually be subject to specific measuring methods like Enzyme Linked Immuno-Sorbent Assay (ELISA) to analyze its contents qualitatively and/or quantitatively. The most apparent advantage related to the microplate is a set of trace reactions can be conducted simultaneously.
[0008] A typical microplate based on prior arts usually comprises the following: an experimental unit 1 which consists of a plurality of micro-wells 3 in some cases numbering 48, 96, 384, or 1536, and a bottom 4 enabling a complete closure to all micro-wells from underneath; a supporting base 2 consisting of four side-walls 5 and an upper platform 6 that is able to connect the said four side-walls 5 with the said micro-wells 3 from above by known techniques like welding, meanwhile forming four non-experimental slots 7 underneath the platform 6 between the said experimental unit 1 and the said side-walls 5 ; the said side-wall might further comprise a bottom outside flange 8 .
[0009] As most microplate operators may know, an expectation when using a microplate in laboratory applications is that this sort of microplate should be able to simultaneously handle dozens of samples it contains and keep all samples going under the same protocol. To realize this, first of all, it is necessary for an operator or operating machine to feed each micro-well with exactly the same quantity of reagents whenever it needs per protocol; Secondly, each micro-well must be treated exactly under the same surrounding situations, generally inclusive of temperature, air ventilation, humidity and light exposure; At last, all micro-wells within a plate should be physically the same if considering its supramolecule binding ability, and bottom evenness, wall straightness, light penetration, and heat transmission when compared to each other. In shorts, the micro-wells have to be furnished exactly in the same way.
[0010] For better explanation purpose, in this specification, the accuracy of reagent transfer whose change may affect final results is described as one of the metrical factors. And the surrounding situations such as temperature, air ventilation, humidity, and light exposure are defined by a holistic term as environmental factors. And supramolecule-binding ability, and bottom evenness, wall straightness, light penetration, and heat transmission are defined as physical factors in this regard.
[0011] It is fortunate that depending on current pipette technologies the most accurate liquid transfer can be reached with a skillful technician and the above mentioned concerns over metrical factors could be solved very well.
[0012] However, there are some considerable limitations related to current commercially available microplates due to the influences of surrounding factors. For example, when a 96-well microplate based on prior arts is moved from 4° C. to 37° C. during an incubation process, ambient air will immediately enter the nonexperimental slots 7 , and then peripheral wells 9 will have temperatures increased faster than internal wells 10 ; And absolutely, four corner wells 11 have the first preference of thermal increase. The same temperature changing disparity will apply when it is cooling down. As a result, if the experiment itself is sensitive to temperature changes, artificially affected results will be obtained at peripheral wells, especially at corner wells. In general, surrounding factors as above exemplified by the temperature, will have peripheral preference because of the non-experimental slots in a traditional microplate, which eventually induce the peripheral artifacts.
[0013] Peripheral artifacts also appear when using micro-wells to store liquid samples. The wells at edges and corners are surrounded differently compared to internal wells, so that the former will have apparent dissimilarity in air ventilation and heat transmission. In specifics, the peripheral wells are subject to a different air-ventilating pattern by which volatile solvents evaporate faster than in internal wells. As a result, samples stored in the peripheral wells, especially the corner wells, will be more or less concentrated after a long-term storage. This peripheral artifact still exists even though the microplate is sealed during storage. A sticky sealing film used to cover the microplate is often stuck well at peripheral edges even after a long-time storage, but might be easy to pop up in the middle. This will bring a different air pattern at peripheral wells, which induces artifacts.
[0014] And physical factors sometimes effect together with surrounding factor to exaggerate incomparable performances between peripheral wells and internal wells within a conventional microplate. For example, of flat-bottom microplates, bottom evenness is currently under concerns in most of microplate manufacturers and operators. Due to the current design of conventional microplates, pressures and tensions are not as evenly distributed to edges and corners of the bottom as to the internal areas of the bottom. As a result, the plate will be finished with an invisibly curly bottom when it eventually comes out of a factory. This kind of uneven bottom might go along with problems in molecule binding ability, biased penetration and/or reflection of light, all of which might affect later-on spectrophotometric measurements. And the most likely problematic wells should be at edges and/or corners. So the peripheral artifacts found in a conventional microplate might also be owing to physical factors.
[0015] Nevertheless, even if manufacturing a totally even bottom is no longer a problem, there are still some visible differences between peripheral wells and internal wells. An internal well is surrounded by other eight wells which may absorb and bounce back light interferences, but a peripheral well is not. As a result, peripheral wells may have a different pattern of light interferences, so as to earn some artifacts when the wells are subject to a spectrophotometric measurement that is sensitive to the surrounding light exposure. For better explanation purpose, these artifacts will be described as the disparity of light exposure in this specification.
[0016] It is inevitable that the above-mentioned limitations have caused some inaccurate experimental results, for example, increase or decrease in spectrophotometric reading values, in the conventional microplates. Accordingly, there exists a need for a microplate which overcomes the above noted drawbacks associated with existing techniques.
SUMMARY
[0017] In this specification, some specific terms are defined as follows unless otherwise indicated.
[0018] “Peripheral wells” or “the first series of wells” is defined as a set of wells consisting of the first row, the last row, the first column, and the last column of regular micro-wells, exclusive of extra sham wells, in a microplate. “Internal wells”, or “internal experimental wells” is defined as all other wells within a microplate that are encircled by the “peripheral wells”. Both “peripheral wells” and “internal wells” are regular micro-wells.
[0019] “Sham wells” is defined as the wells from which any final experimental results obtained are predicted to be useless, no matter whether the said sham wells are used to host an assay, or they are just left blank without an assay. Once sham wells are in the regular micro-wells area, they are called “regular sham wells”. “Extra sham wells” is defined as some excessive wells existing in a microplate other than regular micro-wells, and these excessive wells are used as sham wells.
[0020] “Peripheral artifacts”, “lateral artifacts”, “quadrilateral artifacts”, or “edge artifacts” is defined as artificially induced difference(s) of experimental results specifically stemming from “peripheral wells” or “lateral wells” other than internal experimental wells. These artifacts are usually owing to disparities of thermal receptance, light exposure, and/or liquid evaporation between “peripheral wells” and “internal wells”. “Corner artifacts” is defined as artifacts specifically resulting from “corner wells” that are used to host an assay.
[0021] “Slot area” is defined as an area that is supposed to be a slot (slots) in there, but actually might be modified to a non-slot structure.
[0022] The present invention has been made to solve the problems noted above and provide a microplate that has fewer artifacts at peripheral wells, especially at corner wells.
[0023] A primary object of the invention is to provide a microplate eliminating the non-experimental slots that may avail physical differences, such as the thermal preference, at peripheral wells, especially at corner wells.
[0024] A second object of the invention is to provide a microplate able to retard some of the surrounding influences, i.e. thermal transmission, from the ambience via side-walls sideward to the experimental unit, and/or accelerate thermal transmission from the ambience upward and/or downward to the experimental unit.
[0025] A third object of the invention is to provide a microplate which achieves the alleviation or elimination of disparity of light interferences at peripheral wells compared to internal wells.
[0026] Other objects and advantages of the present invention will become apparent upon reading the following detailed description and upon reference to the accompanying drawings.
[0027] To realize the foregoing objects, a microplate according to the present invention, comprising a supporting base and an experimental unit as in a conventional microplate, possesses further improvements.
[0028] In a preferred embodiment, a microplate according to the present invention possesses an elongated bottom to cover, weld, and close from underneath not only all the micro-wells as in a conventional microplate, but also the non-experimental slots area until it reaches and welds into the flanges of side-walls.
[0029] In another preferred embodiment, a microplate according to the present invention further possesses enhancement(s) at the side-wall; the enhanced side-walls may retard some of the surrounding disparities, like the thermal preference, at peripheral wells.
[0030] In still another preferred embodiment, the microplate according to the present invention further possesses single or multiple air-through notch(es) at bottom outside flanges of side-walls, enabling air to flow through the lower ambience.
[0031] In a further preferred embodiment, the microplate according to the present invention further comprises sham wells, either complete or incomplete, between the side-walls and the experimental unit; the said sham wells are available or not available for loading samples.
[0032] In an alternative preferred embodiment, the microplate according to the present invention is almost equivalent to a conventional microplate, but co-packaged with a separate or affixed sheet informing microplate users of the artifacts of peripheral wells, the associated unreliability, and some preventive ways thereof.
[0033] Other preferred embodiments of the present invention will become apparent upon reading the following detailed description and upon reference to the accompanying drawings.
DRAWINGS—FIGURES
[0034] FIG. 1A is a perspective view of a conventional microplate, also showing a partial sectional view of Row H;
[0035] FIG. 1B is a top view of a conventional microplate, showing peripheral wells, corner wells, and internal wells;
[0036] FIG. 2A is a magnified partial sectional view of a conventional microplate, showing section A-A′ of FIG. 1A ;
[0037] FIG. 2B is a magnified partial sectional view, showing the same section as in FIG. 2A , of an embodiment of the microplate according to the present invention possessing an elongation of the bottom;
[0038] FIG. 2C is a magnified partial sectional view, showing the same section as in FIG. 2A , of an embodiment of the microplate according to the present invention possessing an outer layer of the peripheral well wall;
[0039] FIG. 2D is a magnified partial sectional view, showing the same section of a microplate as in FIG. 2A , of an embodiment of the microplate according to the present invention possessing extra sham wells;
[0040] FIG. 2E is a magnified partial sectional view, showing the same section of a microplate as in FIG. 2A , of an embodiment of the microplate according to the present invention possessing extra sham wells with upper closure;
[0041] FIG. 3 is a side view of an embodiment of the microplate according to the present invention, showing notches at bottom outside flange;
[0042] FIG. 4A is a top view of an embodiment of the microplate according to the present invention, showing extra sham wells;
[0043] FIG. 4B is a top view of another embodiment of the microplate according to the present invention, showing regular sham wells;
[0044] Although all drawings in this specification are illustrated with a flat bottom, it is understood that any other formats of well bottom are also applicable, such as round bottom, V-shape bottom, conical bottom, pyramid-shape bottom, etc.
[0045] In general, all specific drawings herein are intended to exemplify the current invention so as to make the invention better understandable. They are not intended to limit the invention within its scope disclosed. On the contrary, any possible modifications and variations based on the spirit and scope of the invention will be covered as defined by the claims.
DRAWINGS—NUMERALS
[0046] 1 . Experimental unit
[0047] 2 . Supporting base
[0048] 3 . Micro-wells
[0049] 4 . Bottom
[0050] 5 . Side-walls
[0051] 6 . Upper platform
[0052] 7 . Nonexperimental slots
[0053] 8 . Bottom outside flanges
[0054] 9 . Peripheral wells
[0055] 10 . Internal wells
[0056] 11 . Corner well
[0057] 12 . Peripheral well-walls
[0058] 13 . Bottom elongation
[0059] 14 . Cavity
[0060] 15 . Side-wall projection
[0061] 16 . Air-through notches
[0062] 17 . Bottom line
[0063] 18 . Bottom outside flanges
[0064] 19 . Sham wells
[0065] 20 . Complete sham wells
[0066] 21 . Incomplete sham wells
DETAILED DESCRIPTION
Preferred Embodiment 1—FIGS. 2 B and 3
[0067] FIG. 1A illustrates a typical microplate based on prior arts that usually comprises the following: 1) an experimental unit 1 which consists of a plurality of micro-wells 3 , in some cases numbering 48, 96, 384, or 1536, and a bottom 4 enabling a complete closure to all micro-wells from underneath; and 2) a supporting base 2 consisting of four side-walls 5 and an upper platform 6 that is able to connect the said four side-walls with the said micro-wells from above by known techniques like welding. The said side-wall 5 further comprises a bottom outside flange 8 . The said upper platform 6 of a microplate covers the area between side-walls 5 and peripheral well-walls. And in our embodiments the upper platform is preferred to further cover the areas in between micro-wells.
[0068] As best seen in FIG. 2A , there exist four nonexperimental slots 7 between the side-walls 5 and the experimental unit 1 . The four nonexperimental slots 7 are connected end to end into a rectangular shape if viewed from bottom. These nonexperimental slots 7 are closed by the upper platform 6 on top, but are open to the ambience on bottom. That means the air within the slots 7 is readily refreshable by outside ambient air. Instead, ambient air between internal wells 10 is less refreshable, especially when the microplate is covered by a lid or a film. Apparently, the peripheral wells 9 , with peripheral well-walls 12 adjacent to the nonexperimental slots 7 , will be bathed in more movable ambient air than internal wells 10 are. As a result, the peripheral wells 9 , especially the corner wells 11 , are more readily affected by the influences of surrounding factors. For example, when a conventional microplate is undergoing a higher temperature incubation, the peripheral wells 9 will have more chances to get in touch with higher temperature ambience at the beginning, so as to increase in situ temperature temporarily faster than internal wells 10 ; this is indicated as peripheral thermal preference, which can cause some artificially affected results at peripheral wells 9 , especially at corner wells 11 in a temperature-sensitive assay. And absolutely, it is due to the non-experimental slots 7 within the plate.
[0069] By comparison, FIG. 2B illustrates a preferred embodiment of the microplate according to the present invention possesses a bottom elongation 13 that is able to cover, weld, and close from underneath not only all the micro-wells 3 as in a conventional microplate, but also the non-experimental slots area until the said bottom elongation reaches and welds into the flanges 8 of side-walls 5 . In this embodiment, the non-experimental slots area between the side-walls and the experimental unit are closed on bottom by the elongation 13 of the bottom. And the whole bottom of the microplate will look like an entire structure with rims of side-wall projection 15 in around but without any open rectangular slots. Basically, this will also close out the influence of some surrounding factors which for example might cause the peripheral thermal preference eventually.
[0070] One apparent advantage of this embodiment is, because of the elongation 13 of the bottom 4 , the disparity of pressures and tensions which was haunting the edges and corners during manufacturing processes and which was considered to be the cause of bottom unevenness, especially unevenness at edges and corners, will affect the elongation 13 area instead; and this will at least help the regular experimentable bottom area be evener.
[0071] Although the preferred embodiment according to the current invention is illustrated with a flat bottom, it is understood that any other formats of well bottom are also applicable, such as round bottom, V-shape bottom, conical bottom, pyramid-shape bottom, etc.
[0072] In the same preferred embodiment, there will be a cavity 14 formed due to the under-closure of a non-experimental slot area. This cavity 14 might be left empty, or completely/partially stuffed.
[0073] In a further preferred embodiment, a microplate according to the present invention further possesses four side-walls able to retard some of the surrounding influences, like the thermal preference, at peripheral wells. Preferably, the side-wall is enhanced by increasing its thickness. The thickness of the side-wall, either uniform or not, is preferred to be one to three times more than whatever it is on the counterpart of a conventional microplate. And it is more preferred that the thickness is two times more than a conventional one. The thicker side-walls are able to retard or eliminate some of the surrounding influences, i.e. thermal transmission, from the ambience via side-walls sideward to the experimental unit. As a matter of fact, thermal transmission from the ambience upward and/or downward to the experimental unit is not affected.
[0074] Preferably, the said side-wall is further subject to some post-casting treatments, such as carving, etching, finishing, painting, coloring, labeling etc.
[0075] Alternatively to the increased thickness of side-walls, side-walls are enhanced by attaching a layer that is able to mask some disparities of the surrounding influences, like the light exposure, at peripheral wells; For one example, the said layer is made of one of some known light-masking materials to prevent the light exposure; The said material can be different from the materials used to make other parts of the microplate. For another example, the said layer is subject to some post-casting treatments, such as carving, etching, finishing, painting, coloring, labeling etc. to prevent the light exposure.
[0076] In an additionally further preferred embodiment, the microplate according to the present invention further possesses single or multiple air-through notches 16 at bottom outside flanges 8 of side-walls 5 , accelerating air-flowing through the lower ambience and thermal transmission from the ambience upward to the experimental unit. As best shown in FIG. 3 , the said notches are below the level of bottom line 17 .
Preferred Embodiment 2—FIG. 2 C
[0077] A preferred embodiment of the microplate according to the present invention possesses peripheral well-walls able to retard some of the surrounding influences, like the thermal preference, at peripheral wells.
[0078] Preferably, the peripheral well-wall is enhanced by increasing its thickness. The thickness of the peripheral well-wall, in a uniform format, is preferred to be one to three times more than a normal thickness of internal well-walls. A more preferred thickness is two times a normal thickness of internal well-walls. The thicker peripheral well-walls are able to retard or eliminate some of the surrounding influences, i.e. thermal transmission, from the ambience via peripheral well-walls sideward to the internal wells. As a matter of fact, thermal transmission from the ambience upward and/or downward to the experimental unit is not affected. Alternatively, turning over to FIG. 2C , the peripheral well-wall 12 is consolidated by attaching an outer layer 18 that is able to mask some of the surrounding disparities, like the light exposure, at peripheral wells; For one example, the said layer 18 is made of one of some known light-masking materials to prevent the light exposure; The said material can be different from the materials used to make other parts of the microplate. For another example, the said layer 18 is subject to some post-casting treatments, such as carving, etching, finishing, painting, coloring, labeling etc. to prevent the light exposure.
Preferred Embodiment 3—FIGS. 4 A, 4 B, 2 D, 2 E
[0079] FIG. 4 illustrates an additional preferred embodiment of the microplate according to the present invention that further comprises sham wells 19 , in a format of either complete sham well 20 or incomplete sham well 21 ; The said sham wells can occupy the nonexperimental slots area between the side-walls 5 and the experimental unit 1 , or the peripheral wells 9 in the experimental unit 1 , or both; the said sham wells are available or not available for loading samples.
[0080] Sham wells are defined as the wells from which any final experimental results obtained are predicted to be useless, no matter whether the said sham wells are used to host an assay, or they are just left blank without an assay.
[0081] The said sham wells are manufactured by the same way that an internal well 10 is made. Because of the limiting space, a sham well might be either a complete sham well 20 like an internal well, or an incomplete sham well 21 with laterally cleavage. The sham well might be equal to, or less than an internal well 10 in size. The cavity of a sham well can be partially, fully, or neither stuffed.
[0082] As best shown in FIG. 4B , for the layout of the said sham wells in the microplate, it is preferred to be on the peripheral wells 9 in the experimental unit 1 , and meanwhile allows this microplate keeping the same as a standard microplate regarding the presence of nonexperimental slots, the number of total wells, and the simplicity of side-walls etc. In this case, the said sham wells are called regular sham wells. For particular exemplification purpose, if a standard microplate has ninety-six wells, the microplate according to the present invention also has ninety-six wells in total, divided into sixty internal wells 10 and thirty-six sham wells 19 .
[0083] And it is also preferred for the said sham wells 19 to occupy the nonexperimental slots area between the side-walls and the non-experimental slots, as shown in FIG. 4A ; And in this case, the microplate has extra sham wells around the peripheral wells 9 and internal wells 1 0 , wherein the regular micro-wells number the same as in a conventional microplate. For particular exemplification purpose, if a standard microplate has ninety-six wells, the microplate according to the present invention has ninety-six micro-wells 3 too, plus forty-four extra sham wells 19 , that is, one hundred and forty wells in total.
[0084] A further modification hereinwith is that sham wells consist of both the said extra sham wells and the said regular sham wells.
[0085] FIG. 2D and FIG. 2E individually illustrate two modifications related to this additional preferred embodiment of the microplate possessing sham wells 19 . The said sham wells can be covered by the upper platform, which makes them not available to host an assay; or just open to the upper ambience as an internal well is, and by contrary they can be experimented though experimental results thereof are deemed useless. The said sham wells are more preferred to be open to the upper ambience since this will help adjacent wells expose to a balanced air ventilating pattern comparable to others.
[0086] Apparently, the preferred embodiment 3 according to the present invention has some novel advantages. First of all, the sham wells are physically located on the way of the micro-wells sideward to the ambience and acting as a buffering barrier for heating and/or cooling, so as able to retard the sideward heat transmission. Hence, the peripheral thermal preference will be prevented more or less. Second of all, the sham wells permit any of the other mico-wells they encircled, either on the edge or in the center of the circle, to possess the same physical surroundings, bringing forth the same patterns of air ventilation, liquid evaporation, and light exposure. Third but not the last, the disparity of pressures and tensions which was haunting the edges and corners during manufacturing processes and which was considered to be the cause of bottom unevenness, especially unevenness at edges and corners, will instead affect sham wells area; and this will at least help the regular experimentable bottom area be less affected and evener. Thus, all these will prevent some of the peripheral artifacts and impart better reliability of the experimental results at peripheral wells, especially corner wells.
Preferred Embodiment 4
[0087] Alternatively to the preferred embodiment 1 possessing a bottom elongation 13 , a preferred embodiment 4 according to the present invention has a releasable undercover in addition to a conventional microplate, and the said undercover is used to cover the bottom of the microplate from underneath when needed, especially when a temperature change is expected. The purpose of this undercover is to make a tight closure over the lower ambience, including the non-experimental slots, and prevent the ambient air from refreshing into the non-experimental slots. The said undercover is preferably co-packaged with the microplate as an assembly; More preferably, the said undercover is a separately-cataloged universal undercover.
[0088] In an alternative preferred embodiment, the microplate according to the present invention is similar to, or even the same as, one of any conventional microplates, but co-packaged with a separate and/or affixed sheet informing microplate users of the artifacts of peripheral wells especially such as corner wells, the relative unreliability, and/or some predictable preventive ways thereof.
OPERATION OF INVENTION
[0089] Manufacture of the preferred embodiments according to this invention is already a known art. In addition, comparative experiments are described in this chapter. The purpose of comparative experiments is to elucidate the existing differences between some particular columns and rows of micro-wells within a conventional microplate and the possible artifacts thereof, and also make comparisons between a preferred embodiment of the microplate according to the current invention and a conventional microplate. In order to realize this, three experiments, which are in common use in laboratories, were carried out based on some standard laboratory protocols. The influences of heating disparity, air ventilation, and light exposure were studied respectively.
[0090] The first experiment was designed to investigate the possibility of heating preference affecting the HRP catalysis in the peripheral wells. Both a conventional microplate (Nunc® MaxiSorp™; Rochester, N.Y.) and a preferred embodiment of the microplate according to the current invention were pre-cooled to 4° C. HRP (RDI; Flanders, N.J.; 1:5000 in ELISA carbonate coating buffer, 4° C., 100 μl per well) was used to coat micro-wells by 4° C. overnight incubation.
[0091] The micro-wells were then ashed by 4° C. 1× PBS (five times, 400 μl each time), followed by adding 4° C. TMB solution (Sigma, Saint Louis Mo.; 100 μl per well). Next the microplates were kept in a 37° C. ambience for 5, 10 minutes, then read at 650 nm immediately. Results were shown in Table 1.
[0000]
TABLE 1
Model
Position
OD at 650 nm (10 min)
Nunc ® MaxiSorp ™
Peripheral wells
2.496 ± 0.158
Internal wells
2.274 ± 0.141
Preferred embodiment 3
Peripheral wells
2.267 ± 0.144
Internal wells
2.279 ± 0.134
[0092] The second experiment was designed to investigate the possibility of air ventilation affecting the cell cultures in the peripheral wells. Both a conventional microplate (Corning Incorporated Costar®; Corning, N.Y.) and a preferred embodiment of the microplate according to the current invention were used to host 37° C. Balb/c 3T3 cell cultures in 10% FBS containing DMEM in vitro. Universal lids were used to cover the plates during incubation. Balb/c 3T3 cells, starting at the same cell density in each well, consumed the media and eventually turned its color from pink to yellow. The time when the first batch media changed its color was recorded. Once all micro-wells changed color, media was refreshed into each micro-well. Media refreshments were repeated until most wells reach cell confluence. Cell cultures were finally subject to incorporation of Thiazolyl Blue Tetrazolium Blue (MTT; Sigma; Saint Louis, Mo.) followed by colorimetry at 570 nm. Results were shown in Table 2.
[0000]
TABLE 2
Time of media
Model
Position
color change
OD at 570 nm
Costar ® microplate
Peripheral wells
18 ± 0.4 hr
1.547 ± 0.079
Internal wells
26 ± 0.5 hr
1.783 ± 0.098
Preferred
Peripheral wells
24 ± 0.5 hr
1.794 ± 0.080
embodiment 3
Internal wells
25 ± 0.4 hr
1.839 ± 0.076
[0093] The third experiment was designed to investigate the possibility of light exposure affecting the actino-sensitive reaction in the peripheral wells. Both a conventional microplate (Corning Incorporated Costar®; Corning, N.Y.) and a preferred embodiment of the microplate according to the current invention were used to host the photochemical decomposition of the iron (III) complex generating iron (II) ions. Prepare accurately a 20 ml aqueous solution of 1 mg/ml anhydrous potassium tris(oxalato)ferrate (III). After mixing well, pipette a 10 mL aliquot into a 20 ml volumetric flask, and continue by adding 8 ml of acetic acid and sodium acetate buffer (pH 4.5), 1 ml of 2,2′-dipyridyl solution (0.32% in water, w/v) and make up to the mark with water. Mix well and aliquot 200 μl each into micro-wells. Expose the microwells to a bright light for 30 min, 60 min with swirling occasionally. And record the absorbance at 522 nm. Results were shown in Table 3.
[0000]
TABLE 3
Model
Position
OD at 522 nm (60 min)
Costar ® microplate
Peripheral wells
1.257 ± 0.057
Internal wells
1.378 ± 0.081
Preferred embodiment 3
Peripheral wells
1.235 ± 0.065
Internal wells
1.276 ± 0.074
CONCLUSION, RAMIFICATIONS, AND SCOPE OF INVENTION
[0094] Thus the reader will see that at least one embodiment of the microplate provides a more reliable, less peripherally affected device that can be used in biomedical and chemical assays.
[0095] While my above description contains many specifics, these should not be construed as limitations on the scope of the invention, but rather as an exemplification of several preferred embodiments thereof. Many other modifications and variations of the present invention are possible in the light of the above teachings.
[0096] Accordingly, the scope of the invention should be determined not by the embodiments illustrated, but by the appended claims and their legal equivalents. | The current invention relates to an improved microplate. The microplate is characterized by modified quadrilateral edges, which bring less artificially induced inaccuracies in peripheral wells, especially in corner wells. Preferably, the microplate possesses a bottom that is elongated to cover the non-experimental slots. The microplate might further comprise sham wells. | 1 |
FIELD OF APPLICATION
[0001] The present invention refers to a method for the production of wine and a wine obtained from such new method
PRIOR ART
[0002] The traditional wine production method comprises the subsequent steps of the grape harvest, grape crushing, alcoholic fermentation of the must by yeasts, wine ageing, stabilization, filtering and bottling of the wine.
[0003] As it is well-known, in the course of the fermentation, yeasts (usually Saccharomyces cereuisiae ), operate the conversion of the sugars to ethyl alcohol and carbon dioxide by way of the following reaction:
[0000] C 6 H 12 O 6 →2C 2 H 5 OH+2CO 2
[0004] However, it is also well-known that reactions or fermentation processes parallel and/or subsequent to the alcoholic fermentation also take place, which are started by contaminating bacteria and yeasts, in particular malolactic fermentation, in which the lactic acid bacteria transform malic acid in lactic acid, thereby causing an increase in the pH of the must or of the wine.
[0005] It is known and widespread in the sector to resort to must sulfiting, that is, the addition of sulfur dioxide (SO 2 ) to ensure the microbiological and chemical stability of the final product.
[0006] This procedure, used in the great majority of the cases, is particularly widespread because sulfur dioxide exercises a double action: antioxidant and antibacterial. It therefore not only helps preserve over time the organoleptic characteristics (color, body, flavor) and, in particular, the scent of the wine, but also blocks the secondary reactions started by the yeasts and the lactic acid bacteria. Finally, it plays a role in the microbiological preservation of the wine itself.
[0007] Sulfur dioxide, which produces sulfites when in solution, is an additive permitted by law within certain limits (the World Health Organization (WHO) has established that the allowable daily intake (ADI) is 0 . 7 mg/Kg of body weight) and its use has come to be seen as essential in the winemaking technology.
[0008] However, even when added within the limits permitted by law, sulfur dioxide can be harmful to health because of its intrinsic toxicity and can lead to intolerance, thus causing problems in sensitive individuals.
[0009] Moreover, sulfur dioxide can interfere with the metabolism of the fermenting yeasts and interact with grape polyphenols thereby de-coloring or destabilzing the color of red wines. From an organoleptic point of view, both in white and in red wines, sulfur dioxide concentrations even lower than the upper legal limits, can give rise to unpleasant odors and metallic tastes which mask the natural scent of the wines.
[0010] In the endeavor to overcome such drawbacks, many attempts have recently been made towards limiting the use of sulfur dioxide by the use of alternative and healthier additives upon which are devolved, to a substantial extent, the anti-bacterial and antioxidant activities.
[0011] This has involved mostly the production of the so-called “organic” wines, which can claim, and which distinguish themselves for, their cultivation and production methods, which are as natural as possible and in line with tradition and in the respect of the environment and of consumer health.
[0012] However, such attempts have been generally unsuccessful, as the organoleptic properties of the wine thus obtained are considerably different from those of wine obtained by way of well-known and traditional methods that use said sulfiting step. In particular, the wine obtained from alternative production methods known in the sector is oxidized, altered in its color, of unusual flavor and/or microbiologically contaminated
[0013] The technical problem underlying the present invention is thus that of providing a method for the production of a wine having microbiological and organoleptic properties that are comparable to those of a wine obtained by a traditional method involving the addition of sulfur dioxide, so as to overcome the drawbacks mentioned above with reference to the prior art.
SUMMARY OF THE INVENTION
[0014] Such a technical problem is solved by a method for the production of wine comprising the steps of:
a) Preparing a grape must; b) Subjecting the grape must to clarification; and c) Subjecting the clarified grape must to alcoholic fermentation to obtain said wine;
characterized in that it comprises the step of adding to the clarified grape must prior to the alcoholic fermentation thereof, in sequence 1) at least one tannin and 2 ) lysozyme.
[0018] Hereunder, by the expression “grape must” is meant the product obtained from grapes pressed by crushing, draining, pressing, vertical pressing, or other method for the extraction of juice.
[0019] The grape must clarification step involves the common operations for the neutralization of the oxidizing components and the contaminating microbial load found in the grape must. Such operations include the addition to the grape must of clarifying agents such as bentonite, potassium caseinate, silica sol, gelatin, albumin, polyvinylpyrrolidone (PVPP), pectolytic enzymes and the removal of solid products obtained upon such addition by decanting, centrifugation or filtration.
[0020] Tannins are organic compounds of plant origin and they are obtained, usually, from plants such as oak, fir tree, chestnut tree, etc. The most important property of tannins in their use in winemaking, is their antioxidant activity, that is, their ability to donate electrons to free radicals thereby blocking the destructive chain reaction started by these latter.
[0021] Lysozyme (or muramidase) is an enzyme attacking the particular structure of the cell wall of Gram-positive bacteria, such as, for example, the bacteria of the genus Clostridum, Listeria, Streptococcus and the great majority of the lactic acid bacteria which are involved in the malolactic fermentation. The lysozyme hydrolyzes the β(1,4) glycosidic bond between N-acetylmuramic acid and the N-acetylglucosamine, which make up the cell wall of these bacteria.
[0022] In the present invention, by the term “lysozyme” what is meant is a lysozyme of animal or plant origin, for example an isolate or extract obtained from any suitable raw material of animal or plant origin (e.g. tissues, animal secretions, egg white, etc.), natural or genetically modified.
[0023] The present invention is based on the surprising fact that by sequentially adding tannins and lysozyme to the clarified grape must, prior to the fermentation, the complementary activities offered by the tannins and the lysozyme can be fully exploited to the extent that it is possible to obtain a wine having optimal organoleptic properties and a high chemical and microbiological stability without having to resort to additions of sulfur dioxide in the course of the preparation method. On the one hand, in fact, the tannins generate an antioxidant effect, inhibiting the formation of oxidizing reactions that are damaging to the aroma and the color of the final wine, whereas on the other hand, the lysozyme has an anti-microbial effect, which hinders the formation of secondary reactions and helps preserve the wine over time.
[0024] It follows that the method according to the present invention does not require a sulfiting step and the wine obtained according to the method will contain no added sulfites.
[0025] More in particular, it has been surprisingly found that by adding tannins and lysozyme to the clarified grape must sequentially, prior to fermentation, there is a large reduction or complete inhibition of events that would decrease the activity of the above-mentioned compounds, such as for example flocculation originating from the interaction of the tannins with lysozyme in the same solution.
[0026] In this respect it should be noted that by first adding the tannins to the clarified grape must, they will interact with oxidizing components of the grape must, thereby blocking the oxidation reactions that can adversely affect the desirable aroma and color of the final wine, thus becoming substantially unavailable for interaction with the subsequently added lysozyme. Said lysozyme will thus be able to carry out its activity in the clarified grape must thereby conferring an adequate microbiological control to the must as well as to the final wine.
[0027] It should be noted, moreover, that by adding the lysozyme to the grape must after its clarification, any complexing events of the former with solid components of the grape must, which could lead to a decrease in the activity of the lysozyme, are advantageously avoided.
[0028] According to a preferred embodiment of the method of the invention, the at least one tannin is added in a quantity comprised between 5 and 100 g/hl based on the volume of the final wine. According to a further embodiment, the at least one tannin is added in the form of an aqueous solution containing between about 3 and 50% by weight of tannin in a quantity comprised between 10 and 200 ml/hl based on the final volume, preferably between 10 and 30 ml/hl based on the final volume of the wine obtained from the method of the invention.
[0029] In the present invention, the tannins used for the preparation of the aqueous solution to be added to the grape must are preferably chosen from the plant species of tara vine, myrobalan, quercus infectoria, quebracho, sessile oak, chestnut tree and others. The tannins extracted from the above-mentioned plants, or parts of them, have in fact been shown to be particularly suitable for the purposes of the present invention as they exhibit a high specificity of action as well as an effect complementary to the use of the lysozyme of the present invention.
[0030] It has been shown, in fact, that the chosen tannins are strong oxygen acceptors and they therefore bind the dissolved oxygen in the wine thus inhibiting the oxidation of the grape polyphenols. Moreover, they can denature the oxidase enzyme proteins deriving from the grapes or from any grape parasitic microorganism. A further protective action against oxidation is given by the ability of these tannins to complex molecules of iron, copper and other metals that act as catalysts in the oxidative process.
[0031] The tannin aqueous solution is preferably prepared in situ or bought in ready for use. The quantity of tannin added to the grape must will mainly depend on the quantity of polyphenols present, the hygienic state of the grapes, the quantity of dissolved oxygen in the must, the degree of turbidity, and the concentration of metals such as iron, zinc, copper and others. Such factors that are critical for the addition of the tannins can be pre-determined by way of a suitable analysis of the grape must to be fermented, in a conventional manner.
[0032] In the method according to the invention, the lysozyme is added in a quantity comprised between 5 and 50 g/hl based on the final volume, preferably between 15 and 35 g/hl based on the final volume, even more preferably between 20 and 30 g/hl based on the final volume of the wine obtained from the method.
[0033] Preferably, in the method according to the invention, the lysozyme is in the form of a 95% pure extract from hen's egg albumen.
[0034] The lysozyme from albumen is obtained by extraction of the hen's egg white. Such extraction, itself conventional, is done by passing the albumen over ionic exchange resins followed by elution based on the fact that the lysozyme has a pI of 10.5 whereas other albumen proteins have an isoelectric point (pI) of about 5.
[0035] The eluted product undergoes a purification cycle which does not involve the use of organic solvents but rather only aqueous ones and is finally dried. The product obtained is compliant with the purity requirements established by the competent authorities for this product.
[0036] Preferably, the lysozyme is added to the grape must in the form of an aqueous solution. In this respect, prior to the addition of the grape must, it is preferably re-hydrated with water and mixed with a portion of grape must until substantially homogenized. As a non limiting example, the lysozyme can be re-hydrated in ten times its quantity in weight of water and subsequently mixed with a portion of the must until the volume is at least trebled.
[0037] In order for the lysozyme to carry out its bactericidal action, in fact, it is recommended that it be well homogenized with the grape must to be treated.
[0038] The quantity of lysozyme added to the clarified grape must will depend on factors of the must such as, mainly, its microbial load, but also its pH, degree of turbidity and polyphenol concentration.
[0039] In the method according to the invention, the fermentation involves the use of selected yeast strains in quantities variable preferably between 5 and 100 g/hl, even more preferably between 20 and 40 g/hl based on the volume of the grape must, and fermentation starter cultures to allow the chosen strain to colonize the medium thus inhibiting the proliferation of contaminant species and achieving the rapid utilization of all the dissolved O 2 that may be present. The activity of the selected yeast must, of course, operate the conversion and transformation of the sugars of the must in alcohol and other secondary compounds.
[0040] The yeast strains suitable according to the present invention are those traditionally used in the production of wine and well-known to the skilled person in the field, provided they are low sulfite producers.
[0041] A yeast strain suitable for use according to the invention is for instance commercialized under the name of “Selezione Italica 337” (Oliver Ogar).
[0042] Advantageously, given that the method of the present invention does not involve a sulfiting step, no fermentation hindering effects are established by the action of sulfites, as is the case, instead, in traditional methods. As a consequence, in the method according to the invention, the fermentation is brought to completion within a substantially shorter time, and the very profile of such fermentation is improved, causing the generation of a characteristic bouquet in the final wine, which can be considered to be superior to that obtained by the traditional methods.
[0043] Moreover, given the lack of a sulfiting step, the wine obtained by the method of the invention has a concentration of sulfites comprised between 0 and 10 mg/l, preferably between 4 and 8 mg/l.
[0044] According to a preferred embodiment, the method of the invention involves a further lysozyme addition in the above-mentioned clarified grape must fermentation step, preferably following a suitable culture inoculation for such fermentation. Preferably, the lysozyme is added during and/or at completion of the fermentation step at a rate comprised between 5 and 50 g/hl based on the final volume, to ensure protection against the occurrence of bacterial contamination.
[0045] According to another aspect of the present invention, the method of the invention involves a further addition of tannins to the wine obtained following the completion of the fermentation step at a rate comprised between 1 and 50 g/hl based on the volume of said wine.
[0046] According to yet another aspect of the present invention, the method of the invention involves a micro-oxygenation step of the wine obtained following the fermentation step. This step is particularly suited in case of red wine production.
[0047] According to a further aspect of the present invention, the method involves the inoculation of the wine obtained following the fermentation step with malolactic bacteria in order to obtain the malolactic fermentation and then the addition of 5 to 50 g/hl based on the wine obtained of lysozyme to stop the bacterial activity.
DETAILED DESCRIPTION OF THE INVENTION
[0048] Embodiments shall be hereunder described, given for indicative and non-limiting purposes, to illustrate the method for the production of a wine that is free of added sulfites according to the invention, and a wine obtained from such a method.
EXAMPLE 1
White Wine
[0049] The test involved the grape harvest of 2005. Inzolia cultivar grapes, from the province of Trapani (Italy) were used.
[0050] The must obtained from 450 quintals of grapes from grape crushing was cold clarified for 24 hours by traditional methods and exhibited low acidity, high pH and a medium microbial load (Table 1).
[0000]
TABLE 1
Composition of the must at crushing
Parameters
Values obtained
Reducing sugars
195
(g/l)
Total acidity
3.01
(Tartaric acid) (g/l)
pH
3.71
Malic acid (g/l)
1.81
Microbial load
6 × 10 3
(CFU/ml)
[0051] The clarified must was thus racked and divided in a first and a second batch of 80 hl each. The acidity of the must was adjusted in both batches with tartaric acid.
[0052] The first batch of clarified must was treated in a suitable reactor by the method of the invention while the second batch (or reference batch) was treated in another reactor, for comparison, according to a conventional method involving the addition of sulfur dioxide.
[0053] More in detail, according to the invention, 15 g/hl based on the volume of the grape must of Excellence Gold White tannin (Oliver-Ogar) were added to the first batch to prevent it from oxidation.
[0054] Separately, a solution of granular type lysozyme for winemaking was prepared in situ by dissolving 1200 g of the commercial product Lysozyme food grade with activity >95% from Fordras SA in 12 l of water. The thus prepared solution was brought to 60 l with must and then it was added to the reactor containing the first batch, after a holding time of 5 hours from the time of addition of the tannin, in a quantity such as to obtain a lysozyme concentration in the must of 25 g/hl. The addition of lysozyme to the first batch was completed within about one hour.
[0055] To both clarified must batches were added 15 g/hl of yeast and 20 g/hl of fermentation starter culture for the second batch (reference batch) and double the amount for the first batch. According to the conventional method, 3.5 g/hl of SO 2 were added to the second batch. The fermentation was left to proceed in both batches for 14 days at 18° C. at atmospheric pressure.
[0056] Such starter culture inoculum in the batch treated according to the invention enabled the fermentation to rapidly start. A higher rate of sugar use up and completion of the fermentation (reducing sugars <1 g/l) 36 hours faster than the reference batch were also observed.
[0057] At the end of the alcoholic fermentation, the wine obtained according to the invention had maintained the original quantity of malic acid more or less unaltered (please see Table 2 below) just like the wine obtained from the traditional method which was being compared, thus confirming the efficacy of the lysozyme in the control of the malolactic flora.
[0058] As far as the sulfur dioxide content is concerned, it is notably less in the wine of the invention and is originated exclusively by the metabolism of the yeasts, given that no addition of sulfur dioxide is involved in the method of production in this case.
[0000]
TABLE 2
Composition at the end of the alcoholic fermentation
Wine of the
Parameters
invention
Traditional wine
Malic acid (g/l)
1.29
1.25
Lactic acid (g/l)
0.03
0.05
Total SO 2 (mg/l)
8
99
Free SO 2 (mg/l)
—
38
Lysozyme (mg/l)
135
absent
[0059] At the end of the fermentation, 5 g/hl of SO 2 were added to the reference wine and both wines were stored for 3 months in inert atmosphere (nitrogen) and then suitably stabilized and bottled. The chemical and microbiological stability of the wines under comparison was then compared. The results are shown in Table 3 below.
[0000]
TABLE 3
Composition parameters of the wines under comparison after 3
months of storage
Units of
Wine of the
Parameters
measurement
invention
Reference wine
O.D. (Optical
nm
0.096
0.068
density) 420
O.D. 420 (55° C. × 48)
nm
0.112
0.070
pH
3.71
3.76
Total acid (tart. ac)
g/l
4.3
4.38
Volatile ac. (acet.
g/l
0.15
0.30
ac)
Malic acid (g/l)
g/l
1.15
1.21
Lactic acid (g/l)
g/l
0.05
0.05
Lactic acid bacteria
CFU/ml
3.21 × 10 3
4.56 × 10 3
Acetic acid bacteria
CFU/ml
<10
2 × 10 2
Total SO 2
mg/l
8
122
Lysozyme
mg/l
176
absent
[0060] Table 3 shows that for both wines the bacterial stability control lasted beyond the storage period without significant variations in the general acidic profile. It is worth noting that the reference wine exhibits an increase in the figure for volatile acidity, given by the increase in the level of acetic acid population in the wines. As far as the protection against oxidation is concerned, the values for optical density were similar in the wines under comparison, which shows the efficacy of the tannins in preserving the wines from oxidation, which adversely affects their aroma and color (darkening).
EXAMPLE 2
Red Wine
[0061] The test involved the grape harvest of 2006. Merlot cultivar grapes were used.
[0062] The must obtained from 450 quintals of grapes from grape crushing was brought to a temperature of 16-18° C. and was then cold clarified for 24 hours by traditional methods.
[0063] The must was then transferred to a suitable reactor and a Proantocyanidinic tannin, Excellence Vintage (by Oliver-Ogar) was then added at the bottom of the must reactor at a rate of 30 g/hl of must to prevent it from oxidation.
[0064] Separately, 25 g/hl (based on the volume of the must) of “Selezione Italica 337” yeast (Oliver-Ogar) inoculum was rehydrated in water in a 1/10 weight ratio. The obtained yeast inoculum is then added to the first 10% of the must.
[0065] Separately, a solution of granular type lysozyme for winemaking was prepared in situ by dissolving 1200 g of the commercial product Lysozyme food grade with activity >95% from Fordras SA in 12 l of water. The thus prepared solution was brought to 60 l with must and then it was added to the reactor containing the must, after a holding time of 24 hours from the time of addition of the tannin, in a quantity such as to obtain a lysozyme concentration in the must of 30 g/hl. The addition of lysozyme was carried out concomitantly with a conventional delestage protocol.
[0066] The fermentation was then started and left to proceed for 14 days at 16° C. at atmospheric pressure.
[0067] At the end of the fermentation step, 20 g/hl of lysozyme was again added to the wine obtained, followed by extended maceration and the addition of 5 g/hl (based on the volume of the wine obtained) of Proantocyanidinic tannin, Excellence Vintage (Oliver-Ogar), and of 5 g/hl (based on the volume of the wine obtained) of Quebracho tannin, Excellence Brown (Oliver-Ogar).
[0068] Micro-oxygenation was then carried out on the wine obtained, at a rate of 10 ml/l/month for 15 days.
[0069] This was followed by the inoculation with 1 g/hl based on the volume of the wine obtained of malolactic bacteria upon which the concentration of malic acid was monitored until a drop in concentration to 0.2 g/l was obtained. 40 g/hl (based on the volume of the wine) of lysozyme was then added to stop the bacterial activity and finally, one week after the addition of lysozyme, 30 g/hl of Excellence Brown (Oliver-Ogar) tannin was added to the wine.
[0070] The final concentration values of malic, lactic, acetic and total acid, sugar, SO 2 , and alcohol by volume, lysozyme and pH in the wine obtained are summarized in Table 4.
[0000]
TABLE 4
Composition parameters of the wine obtained
Unit of
Parameter
measurement
Value
Total acidity
g/l
5.90
Acetic acid
g/l
0.253
Lactic acid
g/l
1.53
Malic acid
g/l
0.061
Total SO 2
mg/l
1.28
Free SO 2
mg/l
0.64
Alcohol by volume
% vol
11.56
Total sugars
g/l
2.64
Lysozyme
mg/l
absent
pH
3.56
[0071] In conclusion, the winemaking method according to the invention has been shown to be suitable for the obtention of wines free of added SO 2 . The inoculum of the selected yeasts enabled a rapid and complete course of fermentation. The control of the lactic acid flora was ensured during both the fermentation steps and the storage and could be further enhanced by the optional subsequent addition of lysozyme at the end of the fermentation.
[0072] Moreover, the wines obtained by the methods of the present invention have a vivid color and have an appearance that is comparable to that obtained from traditional production methods that involve a sulfiting step.
[0073] Moreover, the wines possess a pleasant bouquet and a flavor that is satisfactory and typical of the type of grape from which they are obtained.
[0074] It is thus clear from the description and from the examples given above that the winemaking method of the present invention (and the wines thus obtained) offers considerable advantages over the prior art. In fact, thanks to the method of the present invention, the addition of sulfites in the winemaking production method is no longer required.
[0075] Tannins and lysozyme, added separately according to the present invention, carry out an activity having an advantageously complementary effect once they are both added in the grape must. Their combined actions, in fact, can entirely replace the traditional addition of sulfites, thus guaranteeing microbial stability and the organoleptic characteristics of the wine so that it is no longer necessary to resort to a sulfiting step.
[0076] This is advantageous in that the resulting product does not exhibit the drawbacks deriving from the addition of sulfites, such as the manifestation of their toxicity and of their intolerance.
[0077] Moreover, the product obtained will be able to be advertised as being “organic” and flaunt a production method that is essentially biological and natural. | A method is described for the production of wine, comprising the steps of:
a) preparing a grape must; b) subjecting said grape must to clarification; and c) subjecting said clarified grape must to alcoholic fermentation to obtain said wine;
characterized in that it comprises the step of adding to said clarified grape must, in sequence 1) at least one tannin and 2) a lysozyme. The use of tannin and lysozyme according to the invention enables to eliminate the sulfiting step involved in traditional methods and the sulfite-free wine thus obtained exhibits good chemical and microbiological stability. | 2 |
TECHNICAL FIELD
[0001] The present invention relates to a transition metal included tungsten carbide, tungsten carbide diffused cemented carbide and a process for producing the same.
BACKGROUND ART
[0002] Tungsten has a high melting point and modulus of elasticity and is useful as a filament material or a raw material for tungsten carbide (WC). However, the price of tungsten is showing a tendency to increase sharply in accordance with a rapid increase in the domestic demand of China, since the raw material thereof is present only in China. In order to develop materials capable of conserving tungsten resources, there is a need to replace a portion of tungsten with a transition metal element.
[0003] However, it is difficult to prepare tungsten parts by melt-casting due to the high melting point thereof. Further, in spite of using powder metallurgy for imparting a form to the powder material, there is a problem in that alloying effect is not performed in a blended elemental method of a tungsten powder and a transition metal element. In addition, an atomization method is difficult to be applied to the tungsten for preparing an alloy powder.
[0004] Meanwhile, it has been known a conventional method for preparing a tungsten alloy powder by co-precipitating a metal salt or metal hydroxide (Japanese Patent Publication 1 and 2).
[0005] [Japanese Patent Publication 1] PCT International Patent Publication No. 2002-527626
[0006] [Patent Publication 2]: U.S. Pat. No. 4,913,731
SUMMARY OF INVENTION
Technical Problem to be Solved
[0007] However, in the preparation methods disclosed in Patent Publication 1 and 2, due to the operation of “co-precipitation”, a resulting alloy powder comes to contain a phase of a transition metal element, in addition to a tungsten phase and a tungsten phase alloyed with a transition metal element, it shows that alloying is not sufficiently performed.
[0008] On the other hand, a cemented carbide made of tungsten carbide (WC) having a quite high toughness and alloying with cobalt (Co) is useful for cutting tools and molds, so a lot of cemented carbide is necessary to automobile and electric industries. However, due to mal-distribution of tungsten in China and rapid increasing domestic demand in China, tungsten material cost is escalating. Therefore, we should cut down the used amount of tungsten and cemented carbide demand necessary for the industries should be self-contained in order to sustain industry activity in Japan.
[0009] To solve the problem, an object of the present invention is to provide a novel tungsten carbide necessary for a cemented carbide material by using a tungsten alloy powder and also to provide a cemented carbide.
Solution to Problem
[0010] As a result of a variety of extensive and intensive studies to accomplish the object, the present inventors discovered that when tungsten ions and ions of transition metal are homogenized at an ionic level in an aqueous solution, subjected to drying by distillation or spray-drying, thermal decomposition and then hydrogen thermal reduction to obtain a tungsten powder. The tungsten alloy powder in which a transition metal element is thoroughly compulsorily dissolved as a solid solution can be prepared, and it has been found that the tungsten alloy powder can be used for an altemate new tungsten carbide and an alternate new cemented carbide, thus accomplished the present invention.
[0011] That is, the present invention provides a tungsten alloy carbide powder represented by Formula [1] which is carbonized from a tungsten alloy powder with a transition metal dissolved therein as a solid solution represented by Formula [2] in which at least one transition metal element selected from the group consisting of cobalt, iron, manganese and nickel is dissolved in a tungsten grating and a peak derived from a bcc tungsten phase appears in an X-ray diffraction diagram.
[0000] M-W—C Formula [1]:
[0012] wherein M represents one or more selected from Co, Fe, Mn and Ni.
[0000] M-W Formula [2]:
[0013] wherein M represents one or more selected from Co, Fe, Mn and Ni.
[0014] The tungsten alloy powder represented by Formula [2] comprises: a transition metal selected from the group consisting of cobalt, iron, nickel and manganese is dissolved in tungsten grating and a peak derived from a bcc tungsten phase appears in an X-ray diffraction diagram which means that any transition metal and any its metal compounds do not exist in the grain boundary of tungsten. Therefore, the inventive tungsten alloy powder can be used as an alternative of the ordinary tungsten. Herein, when the amount of transition metal is less than 0.3% of tungsten alloy powder, we have not any advantage of natural resource saving. On the other hand, when the amount of transition metal is more than 20.8 wt % of tungsten alloy powder, we have precipitation phenomenon of the second phase in the grain boundary of tungsten and the transition metal is not dissolved as a solid solution in the tungsten grating. In the tungsten alloy powder, cobalt can be located in a position of tungsten grating and acts as a substitute of tungsten Nickel is cheaper than Cobalt and acts in a same manner of cobalt. Iron and Manganese are cheaper elements and improve the strength of tungsten alloy powder in a same manner.
[0015] The transition metal can be dissolved in the tungsten up to the same mole of tungsten. Among them, cobalt and iron are more preferable. In case of cobalt, it is preferable that cobalt of 40 to 10 mole % can be dissolved in 60 to 90 mole % of tungsten. In case of the other transition metals, the same ratio can be applicable.
[0016] A part of cobalt can be substituted by one or more elements selected from the group consisting of iron, nickel and manganese, to obtain a complex transition metal dissolved tungsten alloy powder.
[0017] The present invention transition metal included tungsten carbide represented by the Formula [1] can be exemplified by Co—W—C/WC. In this case, a preferred composition is Co: 0.3-19.7 wt %, W: 75.3-93.6 wt %, C:4.9-6.2 wt % and a solid solution phase of Co—W—C is included therein, in which all or a part of cobalt can be substituted by one or more selected from the group consisting of iron, manganese and nickel. In case of Co substituted by Fe, it is exemplified by Fe—W—C/WC. In this case, a preferred composition is Fe: 0.3-19.7 wt %, W: 75.3-93.6 wt %, C: 4.9-6.2 wt % and a solid solution phase of Fe—W—C is included therein, in which all or a part of iron can be substituted by one or more selected from the group consisting of cobalt, manganese and nickel. Among them, Fe—Mn—W—C (Fe partially substituted by manganese) is preferable. In case of Co substituted by Ni, it is exemplified by Ni—W—C/WC. In this case, a preferred composition is Ni: 0.3-19.7 wt %, W: 75.3-93.6 wt %, C: 4.9-6.2 wt % and a solid solution phase of Ni—W—C is included therein, in which a part of nickel can be substituted by one or more selected from the group consisting of iron, cobalt, and manganese. In case of Co substituted by Mn, it is exemplified by Mn—W—C/WC. In this case, a preferred composition is Mn: 0.3-19.7 wt %, W: 75.3-93.6 wt %, C: 4.9-6.2 wt % and a solid solution phase of Mn—W—C is included therein, in which a part of manganese can be substituted by one or more selected from the group consisting of cobalt, iron and nickel.
[0018] An another object of the invention is provided a tungsten carbide diffused cemented carbide by a process of sintering the above transition metal included tungsten carbide with the transition metal. That is, it is to provide a tungsten carbide diffused cemented carbide by sinter a tungsten alloy carbide powder represented by Formula [1] which is carbonized from a tungsten alloy powder with a transition metal dissolved therein as a solid solution represented by Formula [2] in which at least one transition metal element selected from the group consisting of cobalt, iron, manganese and nickel is dissolved in a tungsten grating and a peak derived from a bcc tungsten phase appears in an X-ray diffraction diagram.
[0000] M-W—C Formula [1]:
[0019] wherein M represents one or more selected from Co, Fe, Mn and Ni.
[0000] M-W Formula [2]:
[0020] wherein M represents one or more selected from Co, Fe, Mn and Ni.
[0021] Among them, a tungsten carbide diffused cemented carbide can be exemplified by combination of: Co—W—C as transition metal included tungsten carbide and Co as a combined transition metal; Fe—W—C as transition metal included tungsten carbide and Co as a combined transition metal; Ni—W—C as transition metal included tungsten carbide and Co as a combined transition metal; Mn—W—C as transition metal included tungsten carbide and Co as a combined transition metal. In the above cases, cobalt used in the transition metal included tungsten carbide and the combined transition metal can be totally or partially substituted by one or more elements selected from the group consisting of nickel, iron and manganese.
Advantageous Effects
[0022] The tungsten alloy carbide obtained by the present invention maintains a WC-structure (skeleton) and contains a transition metal element dissolved as a solid solution in a tungsten grating, so that the tungsten alloy carbide can provide a novel tungsten carbide diffused cemented carbide having substantially the same properties as those made of the conventional tungsten carbide.
[0023] According to the present invention, there can be provided a tungsten carbide diffused cemented carbide made of Co—W—C as a transition metal included tungsten carbide and Co as a transition metal powder, a preferred composition of which is Co: 1.2-31.7 wt %, W: 64.0-92.7 t %, C: 4.2-6.1 wt %. In this case, cobalt of Co—W—C can be partially substituted by one or more elements selected from the group consisting of iron, nickel and manganese, by which there is provided the other preferred composition of Co: 0.2-12.0 wt %, Fe: 0.3-19.7 wt %, W: 64.0-92.7 wt %, C: 4.2-6.1 wt % in case of Fe—W—C as a transition metal included tungsten carbide and Co as a transition metal powder; Co: 0.9-12.0 wt %, Ni: 0.3-19.7 wt %, W: 64.0-92.7 wt %, C: 4.2-6.1 wt % in case of Ni—W—C as a transition metal included tungsten carbide and Co as a transition metal powder; Co: 0.9-12.0 wt %, Mn: 0.3-19.7 wt %, W: 64.0-92.7 wt %, C: 4.2-6.1 wt % in case of Mn—W—C as a transition metal included tungsten carbide and Co as a transition metal powder. The transition metal Co powder can be totally or partially substituted by one or more selected from the group consisting of Ni, Fe and Mn, each of the substituted compositions resulting in the same effect in case of Co.
[0024] The transition metal included tungsten carbide represented by Formula [1] can be produced by 1) mixing an aqueous solution containing tungsten ions with an aqueous solution containing at least ions of one transition metal selected from the group consisting of cobalt, iron, manganese and nickel, wherein the mixing is performed such that the tungsten ions are 60 mol % or more and the transition metal ions are 40 mol % or less, drying the mixed aqueous solution by distillation or spraying, thermally decomposing the resulting solid, followed by hydrogen thermal reduction, to prepare a transition metal-dissolved tungsten alloy powder represented by Formula [2], 2) carbonizing the resulting oxide powder or transition metal-dissolved tungsten alloy powder by heating with graphite to be mixed or gas-carburizing.
[0025] In the present invention, preferably, the aqueous solution containing tungsten ions is an ammonium paratungstate aqueous solution (5(NH 4 ) 2 O.12WO 3 .5H 2 O). The aqueous solution containing ions at least one transition metal selected from the group consisting of cobalt, iron, manganese and nickel is a transition metal complex salt aqueous solution. Examples of useful transition metal complex salts include acetates (Fe(OH)(C 2 H 3 OO) 2 , Co(C 2 H 3 O 3 ) 2 .4H 2 O, Mn(CH 3 COO) 2 .4H 2 O, and Ni(C 2 H 3 O 3 ) 2 . xH 2 O), which are soluble in water, do not produceharmful materials and low in environmental load. In addition, use of transition metal sulfates of iron, nickel and cobalt can be exemplified by such as CoSO 4 .7H 2 O, FeSO 4 .7H 2 O, and NiSO 4 .6H 2 O which are effective in realizing circulation society.
[0026] Generally, in an electrolytic refining process of copper, the transition metals of iron, nickel and cobalt are concentrated in sulfate in an electrolyte. Accordingly, waste liquid produced during the electrolytic refining of copper may be used as a raw material of the tungsten alloy powder of the present invention and the sulfate produced during drying by distillation or spray-drying may be efficiently used as a by-product.
[0027] The tungsten alloy carbon diffused cemented carbide obtained from the present invention can be produced from the present invention tungsten alloy carbide by 1) mixing an aqueous solution containing tungsten ions with an aqueous solution containing at least ions of one transition metal selected from the group consisting of cobalt, iron, manganese and nickel, wherein the mixing is performed such that the tungsten ions are 60 mol % or more and the transition metal ions are 40 mol % or less, drying the mixed aqueous solution by distillation or spraying, thermally decomposing the resulting solid, followed by hydrogen thermal reduction, to prepare a transition metal-dissolved tungsten alloy powder represented by Formula [2], 2) carbonizing the resulting oxide powder or transition metal-dissolved tungsten alloy powder by heating it with graphite to be mixed or gas-carburizing, to obtain a transition metal dissolved tungsten carbide and 3) sintering the resulting tungsten carbide with a transition metal powder.
DESCRIPTION OF EMBODIMENTS
[0028] Hereinafter, the present invention will be described with reference to representative examples. However, it will be apparent to those skilled in the art from Examples that the other tungsten carbide can be produced and the other tungsten carbide can be used with a transition metal powder to produce any other tungsten carbide diffused cemented carbide.
Preparation 1
[0029] A conventional material (No.1), materials of the present invention (Nos. 2 to 8, Nos. 11 to 14) and Comparative materials (Nos. 9 and 10) were prepared to have the chemical components (mol %) shown in Table 1, and the possibility of a compulsive solid solution and the existence of precipitation of the second phase were confirmed by X-ray diffraction and EPMA.
[0000]
TABLE 1
Chemical component (mol %) and formation of compulsive solid solution
No
Fe
Co
Mn
Ni
W
Note
1
—
20
—
—
Bal
Conventional
Powder mixing
Second phase (Co)
material
precipitation
2
—
10
—
—
Bal
Material of the
Solution method
Compulsive solid
present invention
solution
3
—
20
—
—
Bal
Material of the
Solution method
Compulsive solid
present invention
solution
4
—
30
—
—
Bal
Material of the
Solution method
Compulsive solid
present invention
solution
5
—
40
—
—
Bal
Material of the
Solution method
Compulsive solid
present invention
solution
6
10
10
—
—
Bal
Material of the
Solution method
Compulsive solid
present invention
solution
7
—
10
—
10
Bal
Material of the
Solution method
Compulsive solid
present invention
solution
8
5
10
—
1.85
Bal
Material of the
Solution method
Compulsive solid
present invention
solution
9
—
90
—
—
Bal
Comparative
Solution method
2(Co 3 W) phase
material
precipitation
10
—
50
—
—
Bal
Comparative
Solution method
2(Co 7 W 6 ) phase
material
precipitation
11
0.1
19.9
—
—
Bal
Material of the
Solution method
Compulsive solid
present invention
solution
12
5.0
15.0
—
—
Bal
Material of the
Solution method
Compulsive solid
present invention
solution
13
20
—
—
—
Bal
Material of the
Solution method
Compulsive solid
present invention
solution
14
17.4
—
2.4
—
Bal
Material of the
Solution method
Compulsive solid
present invention
solution
[0030] In Table 1, the term “solution method” is a process of the present invention which includes mixing an aqueous solution of transition metal acetate (Co(C 2 H 3 O 3 ) 2 .4H 2 O, Fe(OH)(C 2 H 3 OO) 2 , Mn(CH 3 COO) 2 .4H 2 O and/or Ni(C 2 H 3 O 3 ) 2 . xH 2 O) with an aqueous solution of ammonium paratungstate (5(NH 4 ) 2 O.12WO 3 .5H 2 O), subjecting the mixture to drying by distillation (or spray drying), thermally decomposing the resulting solid into an oxide under an atmosphere at 823 K, and subjecting the resulting product to hydrogen thermal reduction under a hydrogen gas at 1073 K for 1 h to obtain a tungsten alloy powder.
[0031] Sample No. 1 is a conventional material obtained using a blended elemental method, as a conventional powder metallurgy method, including weighing and mixing 7.42% by weight of a pure cobalt powder and the balance of a pure tungsten powder to make the chemical composition of Table 1, followed by compression molding at a pressure of 2 ton/cm 2 , and maintaining for 1 h under a hydrogen gas at 1073 K. A pure cobalt phase remained as the second phase and alloying with tungsten was not performed.
[0032] Sample No. 2 is a material of the present invention obtained by a solution method. An aqueous solution of transition metal acetate (Co(C 2 H 3 O 3 ) 2 .4H 2 O) was mixed with ammonium paratungstate. In the X-ray diffraction diagram of the resulting alloy powder, only a peak derived from a bcc W phase appeared and a W alloy powder was obtained in which Co was homogenously compulsorily dissolved as a solid solution.
[0033] Sample No. 3 is a material of the present invention obtained by a solution method. An aqueous solution of a transition metal acetate Co(C 2 H 3 O 3 ) 2 .4H 2 O was mixed with ammonium paratungstate to make the composition 80 mol % W-20 mol % Co. In the X-ray diffraction diagram of the resulting alloy powder, only a peak derived from a bcc W phase appeared and a W alloy powder was obtained in which Co was homogenously compulsorily dissolved as a solid solution. The equilibrium phases of this composition at a hydrogen thermal reduction temperature of 1073 K were a W phase and a Co 7 W 6 phase. First, it was confirmed that, when cobalt ions and tungsten ions in an aqueous solution were made homogeneous at an ion level by the solution method, cobalt was captured in a tungsten grating even after the hydrogen thermal reduction and equilibrium phase of Co 7 W 6 could not be formed. That is, it was discovered that, when a solution method is applied, an alloy powder compulsorily dissolved as a solid solution in a non-equilibrium state can be prepared.
[0034] Samples No. 4 and No. 5 are materials of the present invention obtained by a solution method. It was confirmed that a W alloy powder in which Co was homogenously compulsorily dissolved in a non-equilibrium state to make a composition of 60 mol % W-40 mol % Co could be obtained. When the solution method was applied, compulsorily dissolved alloy powder as a solid solution in a non-equilibrium state could be prepared, without forming an equilibrium phase of Co 7 W 6 to make this composition.
[0035] Sample No. 6 is a material of the present invention obtained by a solution method, in which a Co(C 2 H 3 O 3 ) 2 .4H 2 O aqueous solution is partially substituted by an Fe(OH)(C 2 H 3 OO) 2 aqueous solution. It was discovered that compulsorily dissolved alloy powder as a solid solution could be prepared, although Co was partially substituted by Fe.
[0036] Sample No. 7 is a material of the present invention obtained by a solution method, in which a Co(C 2 H 3 O 3 ) 2 .4H 2 O aqueous solution is partially substituted by an aqueous solution of Ni(C 2 H 3 O 3 ) 2 .xH 2 O. A compulsorily dissolved alloy powder as a solid solution could be prepared, although Co was partially substituted by Ni.
[0037] Sample No. 8 is a material of the present invention obtained by a solution method, in which a Co(C 2 H 3 O 3 ) 2 .4H 2 O aqueous solution is partially substituted by an aqueous solution of Fe(OH) (C 2 H 3 OO) 2 and Ni(C 2 H 3 O 3 ) 2 .xH 2 O. A compulsorily dissolved alloy powder as a solid solution could be prepared, although Co was partially substituted by Fe and Ni.
[0038] Sample No. 9 is a Comparative material obtained by the solution method. In this composition of 10 mol % W-90 mol % Co, an equilibrium phase of Co 3 W was finally precipitated as a second phase. Accordingly, when the amount of Co is greater, W atoms are readily diffused in a Co lattice in spite of using a solution method and thus a compulsory solid solution could not be prepared.
[0039] Sample No. 10 is a Comparative material obtained by a solution method. In this composition of 50 mol % W-50 mol % Co, the equilibrium phase of Co7W 6 was finally precipitated as the second phase. Accordingly, W atoms were also diffused in this composition, and a compulsory solid solution could not be thus prepared.
[0040] Sample No. 11 is a material of the present invention obtained by a solution method, in which a Co(C 2 H 3 O 3 ) 2 .4H 2 O aqueous solution was partially substituted by an Fe(OH)(C 2 H 3 OO) 2 aqueous solution. Sample No. 11 is a compulsorily dissolved alloy powder as a solid solution in which Co was partially substituted by a small amount of Fe.
[0041] Sample No. 12 is a material of the present invention obtained by a solution method, in which a Co(C 2 H 3 O 3 ) 2 .4H 2 O aqueous solution was partially substituted by an Fe(OH)(C 2 H 3 OO) 2 aqueous solution. A compulsorily dissolved alloy powder as a solution solid could be prepared, although an Ni(C 2 H 3 O 3 ) 2 .xH 2 O aqueous solution shown in Sample No.8 was not added.
[0042] Sample No. 13 is a material of the present invention obtained by a solution method, in which a Co(C 2 H 3 O 3 ) 2 .4H 2 O aqueous solution was entirely substituted by an Fe(OH)(C 2 H 3 OO) 2 aqueous solution. A compulsorily dissolved alloy powder as a solid solution could be prepared, although Co was entirely substituted by Fe.
[0043] Sample No. 14 is a material of the present invention obtained by a solution method, in which a Co(C 2 H 3 O 3 ) 2 .4H 2 O aqueous solution was entirely substituted by an Fe(OH)(C 2 H 3 OO) 2 aqueous solution and a Mn(CH 3 COO) 2 .4H 2 O aqueous solution. A compulsorily dissolved alloy powder as a solid solution could be prepared, although Co was entirely substituted by Fe and Mn.
EXAMPLE 1
[0044] A conventional material (No. 21), materials of the present invention (Nos. 22 to 27, and Nos. 30 to 33) and Comparative materials (Nos. 28 and 29) having chemical components (wt %) shown in Table 2 were prepared and the possibility of a compulsive solid solution and the existence of precipitation of the second phase were confirmed by X-ray diffraction and EPMA.
[0000]
TABLE 2
Chemical components of tungsten carbide (wt %) and formation
of metal phase or second carbide phase in the carbide
No
Fe
Co
Mn
Ni
W
C
Note
21
—
—
—
Bal
6.13
Conventional
X
material
22
—
1.20
—
Bal
6.10
Material of the
◯
present invention
23
—
7.00
—
Bal
5.70
Material of the
◯
present invention
24
—
16.71
—
Bal
5.11
Material of the
◯
present invention
25
—
19.70
—
Bal
4.20
Material of the
◯
present invention
26
3.32
3.50
—
Bal
5.91
Material of the
◯
present invention
27
—
3.50
3.48
Bal
5.91
Material of the
◯
present invention
28
—
19.76
—
Bal
4.19
Comparative
X
material
29
—
0.29
—
Bal
6.12
Comparative
X
material
30
0.033
6.96
—
—
Bal
5.70
Material of the
present invention
31
1.66
5.25
—
—
Bal
5.71
Material of the
◯
present invention
32
6.65
—
—
—
Bal
5.72
Material of the
◯
present invention
33
5.79
—
0.79
—
Bal
5.73
Material of the
◯
present invention
Metal phase is formed in carbide: ◯
Metal phase is not formed in carbide: X
[0045] The materials of the present invention of Nos. 22 to 27 shown in Table 2 were prepared by adding graphite to a tungsten alloy powder in which a transition metal was compulsorily dissolved as a solid solution by a solution method, followed by mixing. That is, a tungsten alloy powder in which a transition metal element was compulsorily dissolved as a solid solution was prepared, by 1) mixing an aqueous solution of transition metal acetate selected from the group consisting of Co(C 2 H 3 O 3 ) 2 .4H 2 O, Fe(OH)(C 2 H 3 OO) 2 , Mn(CH 3 COO) 2 .4H 2 O and/or Ni(C 2 H 3 O 3 ) 2 .xH 2 O) with an aqueous solution of ammonium paratungstate (5(NH 4 ) 2 O.12WO 3 .5H 2 O), drying by distillation (or spray drying), thermally decomposing the resulting solid with oxide under an atmosphere at 823 K, and performing hydrogen thermal reduction for 1 h under a hydrogen gas at 1073 K.
[0046] Then, 2) this tungsten alloy powder was mixed with graphite and was allowed to stand in Ar at 1473 K for 1 h to prepare tungsten carbide.
[0047] Sample No. 21 was WC carbide obtained by mixing WO 3 with graphite and carbonizing at 1473 K for 1 h in accordance with a conventional powder metallurgy method. A metal phase was not present in the WC skeleton.
[0048] Sample No. 22 to Sample No. 27 are materials of the present invention obtained by 1) a solution method and 2) carbonization. A specific structure in which a metal phase is present in the WC skeleton was obtained. This metal phase contributes to resource saving of tungsten and the improvement of mechanical properties of carbide. It was confirmed that the content of metal phase increases in accordance in the order of Sample No. 22, No. 23, No. 24, No. 25, No. 26 and No. 27.
[0049] Sample No. 26 and Sample No. 27 are carbides in which metal phase cobalt present therein is substituted by iron, iron-manganese and nickel, respectively, to reduce the cost.
[0050] Samples Nos. 28 and 29 are Comparative materials obtained by a solution method and carbonization. When the amount of cobalt is greater than that of tungsten as in Sample No. 29, tungsten is diffused in the cobalt in the process of preparing the tungsten alloy powder, to produce an equilibrium phase of Co 3 W or Co 7 W 6 . As a result, when this alloy powder is carbonized, the metal phase surrounds the carbide and the metal phase cannot be thus present in the carbide.
[0051] The materials of the present invention of Nos. 30 and 31 shown in Table 2 were prepared by adding graphite to a tungsten alloy powder in which a transition metal is compulsorily dissolved as a solid solution by a solution method, followed by mixing. That is, in the same manner as in Sample 26, a tungsten alloy powder in which a transition metal element is compulsorily dissolved as a solid solution was prepared, by mixing an aqueous transition metal acetate solution (Co(C 2 H 3 O 3 ) 2 .4H 2 O) and an aqueous solution of Fe(OH)(C 2 H 3 OO) 2 with an aqueous solution of ammonium paratungstate (5(NH 4 ) 2 O.12WO 3 .5H 2 O), drying by distillation (or spray drying), thermally decomposing the resulting solid into an oxide under an atmosphere at 823 K, and performing hydrogen thermal reduction for 1 h under hydrogen gas at 1073 K. Then, this tungsten alloy powder was mixed with graphite and was allowed to stand in Ar at 1473 K for 1 h to prepare tungsten carbide. A specific structure in which a Co—Fe solid solution phase is present in the WC skeleton was obtained.
[0052] The materials of the present invention of Nos. 32 and 33 shown in Table 2 were prepared by adding graphite to a tungsten alloy powder in which Fe and Mn were compulsorily dissolved as a solid solution by a solution method, followed by mixing. That is, the tungsten alloy powder in which a transition metal element is compulsorily dissolved as a solid solution was prepared, by mixing an aqueous solution of (Fe(OH)(C 2 H 3 OO) 2 ) and an aqueous solution of Mn(CH 3 COO) 2 .4H 2 O with an aqueous solution of ammonium paratungstate (5(NH 4 ) 2 O.12WO 3 .5H 2 O), drying by distillation (or spray drying), thermally decomposing the resulting solid into an oxide under an atmosphere at 823 K, and performing hydrogen thermal reduction for 1 h under hydrogen gas at 1073 K. Then, this tungsten alloy powder was mixed with graphite and was allowed to stand in Ar at 1473 K for 1 h to prepare tungsten carbide. When Co is entirely substituted by Fe or Fe and Mn, WC containing a Fe metal or Fe—Mn solid solution could be obtained.
[0053] FIG. 1 shows EPMA observation results of the material of the present invention of Sample No. 23. As can be seen from the X-ray image of W and C corresponding to the SEM image, the structure of WC was formed. In addition, it was found from the X-ray image of Co that a metal phase was formed in the structure of WC. That is,
[0054] (a) is an SEM image. A white part represents a WC skeleton and a black part represents a domain composed of a Co metal. The Co domain is inevitably grown when sintered at 1623 K at 3.6 ks, but is maintained at 3 mm or less.
[0055] (b) represents an X-ray image of W and shows formation of the WC skeleton.
[0056] (c) represents an X-ray image of Co and shows formation of the Co domain in a WC skeleton.
[0057] (d) represents an X-ray image of C and shows formation of the WC skeleton.
[0058] This formation of metal phase is effective in reducing the amount of tungsten used and improves mechanical properties. Accordingly, a cemented carbide, in which this novel WC carbide is dispersed, is suitable as an abrasion resistance material.
EXAMPLE 2
[0059] The cemented carbide may be prepared by sintering tungsten carbide of the present invention with a Co powder in accordance with a known preparation method. FIG. 2 shows an EPMA image of a cemented carbide, experimentally prepared by adding 5% by weight of bonded Co to the material of the present invention of Sample No. 33 and sintering at 1623 K at 3.6 ks. It can be seen that, in the cemented carbide, a Fe—Mn solid solution is formed in the WC skeleton and a bonded Co is partially distributed in this Fe—Mn solid solution during sintering. The Vickers hardness was an extremely high hardness of Hv1945. Further, it could be observed that a tip of a Vickers hardness test indentation did not crack and exhibited excellent toughness. That is,
[0060] (a) is an SEM image. A white part is a WC skeleton and a black part is a domain composed of a Fe—Mn solid solution. When sintered, the metal domain inevitably grows, but is maintained at 1 mm or less. This SEM image exhibits an indentation of a Vickers hardness test. The Vickers hardness was an extremely high hardness of Hv1945. Further, it can be seen that a tip of a Vickers hardness test indentation did not crack and exhibited excellent toughness.
[0061] (b) represents an X-ray image of W and shows formation of the WC skeleton. In addition, a part of W is distributed in the Fe—Mn solid solution domain.
[0062] (c) represents formation of the Fe—Mn solid solution domain, which is an X-ray image of Fe.
[0063] (d) is an X-ray image of Co. The bonded Co is partially distributed in the Fe—Mn solid solution domain during sintering.
[0064] (e) represents an X-ray image of C and shows formation of a WC skeleton.
[0065] (f) represents an X-ray image of Mn and shows formation of a Fe—Mn solid solution domain.
[0066] The reason why the WC carbide including a metal domain exhibits a high hardness is that in the present invention, the WC skeleton successfully creates a micro structure which constrains deformation of the metal domain.
INDUSTRIAL APPLICABILITY
[0067] As apparent from the foregoing, the alloy powder of the present invention contains a transition metal element homogenously compulsorily dissolved as a solid solution in a tungsten grating. Accordingly, the tungsten alloy powder may be widely used, as an alloy powder in which a portion of the tungsten is substituted by a transition metal element, for resource saving of tungsten such as tungsten carbide materials used for cemented carbides.
[0068] Accordingly, the inventive a transition metal included tungsten carbide can be used to make a new cemented carbide sintered with a combined phase Co in a substitute of the conventional cemented carbide. The inventive tungsten carbide phase including metal phase has a property of toughness as itself, resulting in improved mechanical property of carbide diffused cemented carbide, which provides a long life mold materials. Furthermore, a tungsten carbide sintered body including a metal phase can be also suitable for a new cemented carbide.
BRIEF DESCRIPTION OF DRAWINGS
[0069] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
[0070] FIG. 1 is an image illustrating EPMA observation results of tungsten carbide including a metal phase, for the material of the present invention of Sample No. 23. (a) is an SEM image in which a white part represents a WC skeleton and a black part represents a domain composed of a Co metal. (b) represents an X-ray image of W and shows formation of a WC skeleton. (c) represents an X-ray image of Co and shows formation of a Co domain in a WC skeleton. (d) represents an X-ray image of C and shows formation of a WC skeleton.
[0071] FIG. 2 is an image illustrating EPMA observation results of tungsten carbide including a metal phase, for the material of the present invention of Sample No. 33:(a) is an SEM image in which a white part is a WC skeleton and a black part is a domain composed of a Fe—Mn solid solution.
(b) represents an X-ray image of W and shows formation of a WC skeleton. (c) represents an X-ray image of Fe and shows formation of a Fe—Mn solid solution domain. (d) is an X-ray image of Co in which the bonded Co is partially distributed in the Fe—Mn solid solution domain during sintering. (e) represents an X-ray image of C and shows formation of a WC skeleton. (f) represents an X-ray image of Mn and shows formation of a Fe—Mn solid solution domain. | This invention is related to a powder of a transition metal dissolved tungsten alloy carbide which comprises a transition metal element forcibly dissolved as a solid solution which represented by Formula [1] of M-W—C wherein M is one or more of Co, Fe, Ni and Mn and its tungsten alloy carbide diffused cemented carbide. The diffused cemented carbide is compatible with the conventional tungsten carbide diffused cemented carbide and comprises a binder metal and a tungsten alloy carbide which is provided with a solid solution phase of at least one transition metal element selected from the group consisting of cobalt, iron, nickel and manganese, included in a tungsten carbide skeleton, which exhibits a peak derived from a bcc tungsten phase in an X-ray diffraction diagram. | 2 |
BACKGROUND OF THE INVENTION
This invention relates to a passenger lift system for mobile vehicular use such as in commercial buses and vans in which the lift system functions either as a retractable step system or a vertically movable platform for non-ambulatory passengers. The lift system includes a vertical safety barrier at the outermost edge of the platform which, when not in use, collapses to form the lowermost step in the step system. The lift is moved by hydraulically actuated motors or electro-mechanical devices or the like, whose operation is dependent upon the vehicle's propulsion system and is controlled appropriate electrical sensors which detect and correct any malfunction.
BACKGROUND OF THE INVENTION
There are a number of devices which have been proposed or actually built for assisting non-ambulatory persons in the ingress and egress from vehicles, particularly commercial buses. Such systems may include elevators or platforms which move from the street level to the floor level of the vehicle, and transport non-ambulatory persons such as those sitting in a wheelchair or other means of transportation into and out of the vehicle. Such systems must be reliable, simple to operate by the bus driver and foolproof in that they cannot stall or otherwise endanger the person being assisted into the vehicle.
OBJECTS OF THE INVENTION
It is accordingly an object of this invention to provide a wheelchair lift for vehicles to facilitate ingress and egress by non-ambulatory persons in which a plurality of rectangular steps are pivotally connected together at their longitudinal edges and can be orientated in either a retracted position as steps or an extended position in a horizontal platform. In the retracted position, the step sections are alternately horizontally and vertically aligned to form conventional steps. In extended positions, the step sections are horizontally aligned to form a platform which is moved upwardly and downwardly.
There are a number of United States patents which disclose and claim various features of wheelchair lifts of the type previously described in which folding steps may be extended to form a horizontal platform. Exemplary of these patents are U.S. Pat. No. 4,466,771 issued Aug. 21, 1984; U.S. Pat. No. 4,441,850 issued Apr. 10, 1984; U.S. Pat. No. 4,251,179 issued Feb. 17, 1981; U.S. Pat. No. 4,176,999 issued Dec. 4, 1979; U.S. Pat. No. 4,081,091 issued Mar. 28, 1978 and U.S. Pat. No. 4,027,807 issued Jun. 7, 1977.
In each of these instances, the lift is shown as a movable platform and/or stair extending between the level of a bus floor and the ground level and positioned to one side of the bus if installed in a normally located bus front or rear door. By various mechanisms the steps, which are generally rectangular sections hinged together at their adjacent longer sides, form successive steps and risers and can be extended horizontally outward to form a platform which in turn can be raised and lowered from the level of the bus floor. At that point the wheelchair is loaded onto the platform and then lowered to the ground level at which point the wheelchair is driven off the platform onto the ground. Each of the prior art examples heretofore discussed contains various methods of empowering the interlocks and accomplishing the mechanical functions of these devices.
SUMMARY OF THE INVENTION
It is accordingly an object of this invention to provide a passenger lift of the type described which functions either as a retractable step system for a vehicle or as a vertically movable elevated platform for transporting non-ambulatory passengers from an upper position level with the vehicle floor to a lower position at ground level. The lift system of this invention includes a safety barrier at the outermost edge of the platform which, when not in use, collapses to form the lowermost step of the system. The lift is powered by hydraulically actuated motors or electro-mechanical devices or the like, whose operation and motive power are dependent upon the main vehicle's propulsion system and is controlled by appropriate electrical controls operated by the bus operator.
A particular advantage of this application is the way in which the platform is moved from an upper to a lower position by means of a chain and extensible piston mechanism which, because of its way of attachment, allows for movement of the platform over a relatively large vertical distance by an extensible piston of relatively small stroke.
Other objects and advantages of the invention will be apparent to those skilled in the art from the following detailed description of a preferred embodiment thereof, with reference being made to the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a fragmentary perspective view of a vehicle showing the passenger lift system of the present invention where the apparatus is illustrated as being in the step-like stowed position;
FIG. 2 is a front elevational view of the present invention where the apparatus is illustrated as being in the step-like stowed position;
FIG. 3 is a side elevation of the passenger lift system of the present invention where the steps are in their step-like position;
FIG. 4 is a side elevation similar to that of FIG. 3 but with the steps extending to form the horizontal platform at an intermediate elevation;
FIG. 5 is a side elevation similar to that of FIG. 4 but with the platform moved upwardly to a horizontal position even with the bus floor;
FIG. 6 is a side elevation similar to that of FIG. 5 but with the platform in its lowermost position at ground level, and also illustrating the safety barrier in its downward or ramp-like position shown in solid line and in its upper safety barrier position in broken line;
FIG. 7 is a detailed side elevation view taken along line 7--7 of FIG. 2 and illustrating the control mechanism for the safety barrier;
FIG. 8 is a detailed side elevation taken along line 8--8 of FIG. 2 similar to that of FIG. 7 and illustrating the drive train and locking mechanism of the safety barrier;
FIG. 9 is a detailed side elevation taken along line 9--9 of FIG. 4 or FIG. 5 and illustrating the safety barrier locking mechanism.
FIG. 10 is an enlarged detailed side elevation of the platform in its lowermost position at ground level with the safety barrier in its downward or ramp-like position taken along line 10--10 of FIG. 11.
FIG. 11 is a fragmentary top plan view of the portions of the platform and safety barrier.
DETAILED DESCRIPTION OF THE INVENTION
Referring first to FIG. 1, the steplift of this invention is shown in perspective, partially broken away, as it would appear at the side door of a bus or van and in its stowed position. It includes an outer or main frame housing H (only one of which is shown) secured relative to the bus floor F and extending upwardly within the bus compartment. The steps themselves include a middle step 12 and a lower step 17, separated by a lower riser 15, with an upper riser 14 connecting the middle step 12 with an upper step 13. The vertical member extending from the floor F, designated by reference numeral 2, forms in effect a top riser when the steps are in the position shown in this figure. On each side of the steps is a handrail 4 which may be of any suitable shape and is supported by a vertical brace 5 which is secured to either side of the path of the steps 12, 13 and 17 as will be later seen in the detailed description.
In general, the following description describes the mechanism for moving and the sequence of moving the steps from their stowed position as shown in FIG. 1 and also shown in greater detail in FIG. 3 to an intermediate elevated position in which the steps have been extended to form a horizontal platform as shown in FIG. 4. From this intermediate extended position the steps are then moved upwardly to a horizontal position even with the bus floor F as shown in FIG. 5. In this position, the horizontal platform is held at the same level as the bus floor F and the person embarking on the platform in a wheelchair or otherwise can easily translate from the bus floor to the platform. The lift then moves to its lowermost extended position as shown in FIG. 6, with the person being carried now at ground level and waiting for the barrier 18 to move from its upward locked safety position to its horizontal position where it functions as a ramp from the platform to the ground. The sequence of this operation will now be described in more detail with reference being made to the drawings mentioned above which describe the details of the mechanism for moving the steps through their cycle.
Referring to FIG. 3, the steplift is shown in the so-called stow position with the step members folded in step position with two risers 14 and 15 separating the steps 12, 13, and 17. The outside of the inner section of the mechanism for moving the steps through their cycle is a trapezoidal frame 55 seen in FIGS. 6-8. Secured relative to that trapezoidal frame 55 and extending through it are the bottom end 60 of a link 61 which is pivotally attached to the upper step 13 at 62. Also secured to the trapezoidal frame 55 is the bottom end 63 of a link 6, and also secured relative to the trapezoidal frame 55 is the bottom end 64 of riser 15.
Referring to FIG. 3, to start raising the step members to form a horizontal platform, a hydraulic cylinder and piston combination 10 and 11 having their upper end secured as by bolts to the inner frame 33 is retracted and its retraction causes link 6, which is attached to link 61 through another link 65, to pivot (clockwise in FIG. 3) about pivot point A. This causes link 61 to follow link 6 in pivoting in a clockwise direction. As these two links (61 and 6) pivot together in a clockwise direction, their lower fixed ends 60 and 63 cause the trapezoidal frame 55 to translate upwardly and forwardly. This movement of trapezoidal frame 55 causes the bottom end 64 of riser 15 to move in an upward and outward direction, thus pivoting the lower riser 15 in a clockwise direction around its upper pivot point relative to middle step 12 until the lower riser 15 reaches a horizontal position. This movement of the trapezoidal frame 55 also causes the middle step 12 to move upwardly and outwardly as it is pivoted in the middle of link 6. At the same time, the upper riser 14, which is pivotally attached to the lower end of piston 11, is pivoted about pivot point A towards a horizontal position. As the lower riser 15 moves or pivots clockwise towards a horizontal position, the lowermost step 17 falls by gravity to a horizontal position. The barrier 18 is not carried by the lower step 17 but operates independently and will be subsequently described.
Referring to FIG. 4, the entire platform is now in horizontal position with link 6 horizontal at the level of pivot point A, and with link 61 horizontal at the level of its pivot point 62 which is slightly below pivot point A so that the two links 61 and 6 are both horizontal and closely adjacent to each other. The various steps and riser members have now reached their horizontal position and link 6 has come to rest in horizontal position outside of the steps and risers. The platform is now horizontal and the barrier 18 is in its vertical safety barrier position. This detail is best shown in FIG. 9 which shows section 9--9 from FIG. 4 or FIG. 5.
In FIG. 9, the safety barrier is pivoted at each end on bearings 19 and 20 and a stub axle extending through the bearing 20 carries a drive pulley 21 which in turn drives a timing or position sensing belt 22 past proximity switches L which signal to a controller the movement of the safety barrier 18 from its vertical barrier position where roll-off the lower step 17 is permitted to its horizontal position when the entire lift is lowered. This detail can also be seen in FIG. 7.
FIG. 9 shows the locking mechanism for keeping the safety barrier in its upper position and generally includes a pair of rods 23 and 24 pivotally attached to a yoke 25 which is pivoted about an axis 26 and may be turned by movement of the solenoid 27. As will be apparent from FIG. 9, movement of the solenoid 27 to the left causes the yoke 25 to pivot clockwise around axis 26, thus withdrawing the rods 23 and 24 from their sockets 28 and 29 in the trapezoidal frame 55 on either side of the steplift. Withdrawal of the rods 23 and 24 permits the entire safety barrier 18 to pivot from its vertical position as shown in FIG. 4 clockwise to a horizontal position.
Referring again to FIG. 4, the platform is shown in its horizontal extended position but must be raised to the level of the bus floor F. This is accomplished by extension of the hydraulic cylinder and piston combination 30 and 31 which extends from and has its top secured to the uppermost top edge of the outer frame 32. The lower end of the piston 31 carries a pulley arrangement 34 at its lower end as also seen in FIG. 5. A flexible chain 35 has one end secured relative to the support frame 32 by a chain anchor 37. Chain 35 extends downwardly and around the pulley arrangement 34, extends upwardly and around fixed pulley 38, at the uppermost top edge of the frame 32, and extends downwardly and is secured to a bracket 51 which is located behind a movable sprocket 39. Both the bracket 51 and the axis of the movable sprocket 39 are secured relative to the bottom of inner frame 33. As the cylinder and piston combination 30 and the pulley 34 31 is extended and moves downwardly, the run of chain 35 is lengthened between its start at 37 and between downwardly moving pulley arrangement 34 and fixed pulley 38 so that necessarily the end of the movable sprocket at 39 is pulled upwardly to raise the platform to the bus floor level F. This is easily visualized in FIG. 6.
Referring again to FIG. 4, a second chain 36 has its upper end secured by a chain anchor 38a. The second chain 36 extends downwardly and around movable sprocket 39, extends upwardly and around a fixed sprocket 40, and extends downwardly and is secured at a chain anchor 44 secured relative to the support frame 32. A shaft, which journals the movable sprocket 39, extends laterally across the platform to an identical sprocket and chain arrangement on the other side of the platform. The second chain 36 is a guide chain which merely keeps the sides of the platform level and moving at the same time because the movable sprocket 39 and its corresponding member on the other side are secured on the same axis so that movement of one necessarily is coordinated with movement of the other. As can be seen in FIGS. 4, 5 and 6, the inner frame 33 is guided for vertical reciprocation within the main support frame 32 by suitable slide members 41 and guide bars 42 and 43, and the fixed sprocket 40 is secured to the inner frame 33 for movement up and down with that inner frame 33.
To move the horizontal platform from its upper position shown in FIG. 5 to its lower position at ground or street level as shown in FIG. 6, the inner frame 33 is translated vertically in a downward direction as guided by the guide bars 42 and 43 and slide members 41 relative to the main frame 32. This downward movement is initiated by retraction of the piston 31 into its cylinder 30 which in turn moves the pulley arrangement 34 upwardly, thus shortening the run of the chain 35 between its fixed end at 37, the movable pulley 34, and the fixed upper pulley 38. As the movable pulley 34 moves upwardly and the run of the chain 35 is shortened, the other end of chain 35 secured at bracket 51 is pulled downwardly, thus lowering the end of the chain 35. As this end of the chain 35 is lowered, the entire horizontal platform and inner frame 33 moves downwardly towards its position as shown in FIG. 6. When the piston 31 is completely retracted within its cylinder 30, as shown in FIG. 6, the platform is resting at the ground line in its horizontal position with the barrier 18 still in its vertical erected position. The next step in the operating sequence is to lower the safety barrier 18 to its horizontal ramp position.
Referring to FIG. 9, the safety barrier 18 when actuated, is unlocked by the inward movement of the rods 23 and 24, as previously described, and then rotated around its axis at point Y by movement of a drive train separately provided for raising and lowering the safety barrier 18. This drive train is shown in detail in FIG. 8. Referring to that figure, a driven sprocket 49 secured to the stub axle extending through the bearing 19 is connected by a chain 45 which extends around a drive sprocket 46 which is secured to and coaxial with a gear sector 47. The external teeth of the gear sector 47 are meshed with a drive gear 48 directly connected to an electrical drive motor 50 which, as can be seen from this figure, when actuated, causes the gear sector 47 to be slowly rotated in counterclockwise fashion to turn the chain 45 and the sprocket 49 secured on the barrier axis so that the safety barrier 18 rotates on the stub axles in bearings 19 and 20 on each side of the safety barrier 18.
The position of the barrier is sensed by a timing belt 22 which is shown in FIG. 7 and consists of a number of proximity switches L which are appropriately programmed to sense the safety barrier in its full open or fully closed position. The proximity switches L and their actuator target 66 on the timing belt 22 can be magnetic, capacitive, photo-optic or any other type of limit switches which have appropriate capacity to sense position.
After the passenger or mobility impaired person has exited the platform in its lowermost position as shown in FIG. 6, the reverse movement of the platform to its upper and then retracted position will be performed upon signal from the vehicle driver as briefly as follows. Referring to FIG. 6, the cylinder 30 and piston 31 are now extended to lengthen the effective run of the chain 35 as the pulley arrangement 34 is pushed downwardly. This causes the lower end of the chain 35 secured at bracket 51 at the bottom of the inner frame 33 to move upwardly, pulling the inner frame 33 and platform from its lowermost position shown in FIG. 6 to its partially elevated position shown in FIG. 4. When the horizontal platform has reached the intermediate position with the safety barrier 18 in its vertical safety position, as shown in FIG. 4, the platform may be retracted and formed into the steps for storage by extending the cylinder 10 and its piston 11 so that the link 6 pivots in a counterclockwise direction about the pivot point A. This causes link 61 to follow link 6 in pivoting in a counterclockwise direction. As these two links (61 and 6) pivot together in a counterclockwise direction, their lower ends 60 and 63 cause the trapezoidal frame 55 to translate downwardly and rearwardly. This movement of trapezoidal frame 55 causes the bottom end 64 of riser 15 to move in a downward and inward direction, thus pivoting the lower riser 15 in a counterclockwise direction about the upper pivot point relative to middle step 12 until the lower riser 15 reaches a vertical position.
This movement of the trapezoidal frame 55 also causes the middle step 12 to move downwardly and inwardly as it is pivoted in the middle of link 6. At the same time, the upper riser 14 is pivoted counterclockwise about pivot point A towards a vertical position. As the lower riser 15 pivots counterclockwise towards a vertical position, the lowermost step 17 resumes its original slightly inclined position shown in FIG. 3. The safety barrier 18 is then pivoted from its vertical safety position as shown in FIG. 4 clockwise to a horizontal step position.
Although the best mode contemplated by the inventor for carrying out the present invention as of the filing date hereof has been shown and described herein, it will be apparent to those skilled in the art that suitable modifications, variations, and equivalents may be made without departing from the scope of the invention, such scope being limited solely by the terms of the following claims. | A passenger lift system for mobile vehicular use which functions either as a retractable step system for the vehicle or as a vertically movable elevator platform for non-ambulatory passengers transporting non-ambulatory passengers from an upper position level with the vehicle to a lower position at ground level. The lift system includes a vertical safety barrier at the outermost edge of the platform which, when not in use, collapses to form the lowermost step in the step system. The lift is moved by hydraulic actuated motors or electro-mechanical devices, or the like, whose operation and motive power is independent of the vehicles propulsion system and is controlled by appropriate electrical sensors which detect and correct any malfunction thereof. | 0 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The container assembly of the application relates to plastic container assemblies for liquid material, for example, which lend themselves to economical mass production techniques, and may be economically utilized in the beverage industry.
2. Description of the Prior Art
The container industry has been responsible for developing a wide range of plastic containers to accommodate the shipping, storing, displaying and dispensing of a large variety of liquid products, for example.
One area of container design in which considerable attention has been focused is in the field of beverage dispensing structures. Various structures have been developed to facilitate the dispensing of beverages in plastic containers. The structures include features to facilitate the opening of the containers to accomplish the desired dispensing function. Opening structures of the prior art include tear strips, and score lines to facilitate the fracturing of a junction of the container to provide access to the contained liquid. Typical prior art structures are illustrated in the following U.S. Pat. No. 3,215,333 to Stelzer; U.S. Pat. Nos. 3,472,367, 3,472,368, and 3,689,458 to Hellstrom; U.S. Pat. No. 3,913,734 to Siegel; and U.S. Pat. No. 185,299 to O'Connor.
While the containers illustrated and described in the above cited patents successfully accomplished certain of the stated objectives, none of the containers included an efficient, integral, inexpensive and sanitary dispensing structure.
Liquid containers having built-in drinking straws have been developed to provide an efficient and sanitary dispensing structure and are well known in the prior art. Typically, these containers include either a rigid container or a flexible pouch type container. Rigid containers of the carton-type with drinking straws are illustrated in U.S. Pat. No. 3,122,297 to Sachs, U.S. Pat. No. 3,215,329 to Pugh and U.S. Pat. No. 3,486,679 to Pfahler. Such containers are typically formed of a substantially rigid material such as treated paperboard material. The entire drinking straw is disposed within the interior of the container. Flexible containers having drinking straws contained therein are illustrated in U.S. Pat. No. 2,992,118 to Daline and U.S. Pat. No. 3,545,604 to Gunther, Sr. These containers, unlike the rigid containers, when opened, must be supported against a fixed support in order to avoid the spilling of the contents.
The U.S. Pat. No. 3,144,976 to Freshour discloses a container structure designed to overcome the spilling disadvantage of the flexible wall pouch type container. The container includes a substantially rigid supporting frame member for the associated thin flexible material which forms the liquid containing pouch. Further, the pouches of the container include a main compartment for the liquid and a dispensing compartment for housing a drinking straw. The lower portions of the two compartments are in communication through a small restricted aperture which acts to restrict the flow of liquid from the main compartment into the dispensing compartment. When the flexible pouch is laid on its side, liquid must flow through the small restriction in order to spill out of the container. Clearly, the structure does not prevent, but merely restricts, the spillage of the contained liquid.
The U.S. Pat. No. 3,799,914 to Schmit et al discloses a flexible container adopted for storing liquids having flexible side walls and a dispensing member enclosed within the container capable of being unfolded into a dispensing position.
SUMMARY OF THE INVENTION
The container of the present invention abrogates many of the problems and disadvantages of the prior art containers. Further, the present invention is directed to a container formed of plastic material which is easily and economically manufactured and results in a structure which is capable of readily dispensing liquids from the interior thereof through a sanitary spill-proof dispensing structure. The container may be supported with ease on a horizontal surface without any concern of spillage of the contents.
Another object of the invention is to produce a container formed of plastic sheet material which may be mass produced in a continuous fashion enabling selected sections or numbers of the container to be folded upon themselves to enable packaging and marketing thereof in the desired multiples.
Still another object of the invention is to produce a container formed of plastic sheet material formed to provide a main liquid containing cavity and an associated liquid dispensing conduit terminating in a drinking spout.
The above as well as other objects of the invention may be achieved by a liquid filled container assembly comprising a formed sheet of plastic material having relatively flat portions defining an open main liquid containing cavity and a spaced apart adjacent elongate open conduit having one end communicating with the interior of the main cavity and the opposite end terminating in a drinking spout; a sheet of relatively flat plastic material overlaying the formed sheet and being sealed to the flat portions thereof to hermetically seal the main cavity, and the elongate conduit; and weakening means proximate to the spout of the conduit and spaced from the main cavity for facilitating the tearing off of the outermost portion of the sealed sheets to expose the spout to allow liquid to be withdrawn from the main cavity in the conduit.
BRIEF DESCRIPTION OF THE DRAWINGS
The above objects and advantages of the invention, as well as others, will become clearly manifest to those skilled in the art from reading the following detailed description of a preferred embodiment of the invention when considered in the light of the accompanying drawings, in which:
FIG. 1 is a perspective view of a liquid filled container incorporating the features of the present invention;
FIG. 2 is a side elevational view of the container illustrated in FIG. 1;
FIG. 3 is an enlarged fragmentary view of the drinking spout structure of the container illustrated in FIGS. 1 and 2;
FIG. 4 is an enlarged fragmentary view of a modified form of the container illustrated in FIGS. 1 and 2;
FIG. 5 is an enlarged fragmentary view of a modified form of the dispensing spout of the embodiment illustrated in FIGS. 1 and 2;
FIG. 6 is a view of a continuous section of a number of liquid filled containers incorporating the features of the invention; and
FIG. 7 is a perspective view of the strip of containers illustrated in FIG. 6 after a number of containers have been folded upon a like number of containers and banded together for display and transit to the point of sale.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Referring to FIGS. 1 and 2 of the drawings, there is illustrated a container assembly for liquids embodying the novel features of the invention. The container assembly includes a bottom portion formed of a self-supporting plastic material such as polyethylene sheeting for example, which may be vacuum formed to provide a cavity 12 defined by a bottom wall 14, a pair of spaced apart upstanding side walls 16 and 18, and a pair of cooperating spaced apart end walls 20 and 22. The end wall 22 is typically of a greater dimension than the spaced apart end wall 20. The bottom wall 14 may be provided with a plurality of laterally extending strengthening ribs 24.
An elongate conduit 26 is formed to extend in parallel spaced relation from the side wall 18 and has one end thereof in communication with the cavity 12 through an opening 28 typically formed near the junction of the end wall 20 and the side wall 18. The opposite end of the elongate conduit 26 terminates in a drinking spout portion 30, which extends outwardly from the end wall 22. It will be appreciated that the cavity 12 and the elongate conduit 26 are spaced apart from one another by a flat zone or land 32, which extends from the opening 28 and terminates in the region of the junction between the end wall 22 and the associated side wall 18.
A planar flange 34 extends completely around the peripheral portions of the bottom portion 10 as is clearly apparent in FIG. 1.
Adjacent the outermost end of the spout 30 of the conduit 26 is a weakening line 36 which will be explained in more detail hereinafter.
The above described bottom portion 10 is then covered by a flexible sheet of film material 38 and typically sealed to the flat zone 32 and the peripheral planar flange 34. Typically, the film 38 is applied to the bottom portion simultaneously with the filling operation of the liquid to be contained within the container assembly. In the preferred operation, applying the covering film 38 to the bottom portion 10 is accomplished during the time that the bottom portion is disposed in such a fashion that the spout 30 is in an elevated position. Initially, the covering film is typically applied to the portion of the planar flange 34 adjacent the end wall 20 and the portions of the flange 34 adjacent the adjoining edges of the side walls 16 and 18 and the associated end wall 20. After the covering film 38 is initially sealed to the planar flange 34 as mentioned above, the liquid to be contained is introduced into the cavity 12 and simultaneously the covering film 38 is continuously applied, and the liquid introducing nozzle means, for example, is removed prior to the instant that the covering film 38 is disposed completely over the bottom portion 10. During the aforementioned operation, the covering film 38 is suitably sealed to the facing surfaces of the flat zone 32 and the planar flange 34 to hermetically seal the container. The sealing operation may be accomplished by a heating operation in the event the bottom portion 10 and the covering film 38 are formed of a thermoplastic material. Manifestly, the sealing may also satisfactorily be achieved by using suitable adhesive materials.
The filled and sealed container assembly may then be stored or transported to a point of sale. The liquid contained within the container assembly may be withdrawn by holding the container assembly in a position where the spout 30 is in an elevated position and the outer end thereof grasped to bend the uppermost end thereof about the weakening line 36 so that the end may be removed and the contents withdrawn from the then opened spout 30. It will be appreciated that the liquid contained within the container assembly illustrated in FIGS. 1 and 2 may be readily withdrawn from the interior of the cavity 12 through the conduit 26 by utilizing the opened spout 30 as a drinking straw. The material defining the cavity 12 is of sufficient flexibility to allow the withdrawal of liquid within the cavity 12 without providing an ancillary air opening to avoid the formation of a vacuum in the cavity 12, which might otherwise prevent the withdrawal of liquid. At the end of one sipping operation the walls defining the cavity 12 may be flexed inwardly and then air is admitted through the open spout 30, the conduit 26, the opening 28, and thence into the cavity 12.
Also, it will be appreciated that when the user wishes to place the container assembly at rest, the bottom wall 14 is dsposed on a supporting surface. Since the end wall 22 is of greater height than the spaced end wall 20, the spout portion 30 is elevated, thereby preventing the spillage of any liquid from the interior of the assembly.
FIG. 3 illustrates a modified version of the spout 30 of the container assembly illustrated in FIGS. 1 and 2 wherein an outer wrap 40 is employed to maintain the end of the spout 30, and especially the portion used as a straw to withdraw the contents, in a sanitary state. The wrap 40 is typically a transparent, flexible plastic film. The outer wrap 40 is generally sealed to the outermost portion of the spout 30 adjacent the portion of the peripheral flange 34, which is removed prior to dispensing the liquid within the container assembly and extends inwardly to the junction of the spout 30 and the remainder of the bottom portion 10. This arrangement provides for the covering of substantially the entire length of the spout 30 during storage or shipment.
In the event the material used in fabricating the container assembly described in connection with the illustrations of FIGS. 1 and 2 have such inherent rigidity to militate against inward flexure thereof during the dispensing liquid within the container assembly, it may be necessary to employ an air hole 42, which may be opened by grasping the end of the flange 34 and flexing the same about the weakening line 44. Thereby the interior of the cavity 12 is in communication with the atmosphere to prevent the formation of a vacuum therein.
FIG. 5 illustrates a further embodiment to the flange 34 adjacent the outermost end of the spout 30, wherein a plurality of strengthening ribs 46 are employed in the zone to be removed upon the opening of the associated container assembly.
Typically, the container assembly may be formed on a drum wherein a series of six, for example, bottom portions 10 may be formed in side-by-side relationship and joined together by spaced apart weakening lines 48. In such instances two or three of the aligned container assemblies, after being filled with the desired liquid and sealed, may be folded upon themselves and held in such condition by a paper board carrying case 50, having a handle 52.
In certain instances, the bottom portion 10 may be fabricated from a rather flexible sheet of material rather than the more dimensionally stable sheet stock as described above. By carefully controlling the rigidity of the resultant laminate formed around the peripheral portion of the container assembly in the regions where the stock forming the bottom portion 10 and the overlaying sheets 38 are sealed together, a container assembly of the above type may be formed. Among the obvious advantages of such a construction is the capability of the walls defining the liquid containing cavity to flex inwardly during withdrawal of the contained liquid, while simultaneously being self supporting so as to militate against liquid leaking out of the open spout 30 during periods that the container assembly is rested on a horizontal supporting surface.
In accordance with the provisions of the patent statutes, I have explained the principle and mode of operation of the invention, and have illustrated and described what I consider to be its best embodiments. It is understood that, within the scope of the appended claims, the invention may be practiced otherwise than as specifically illustrated and described. | A container for liquids formed of a pair of cooperating sheets of plastic material wherein one of the sheets is formed to provide a main liquid containing cavity and a cooperating conduit providing a path for the withdrawal of liquid from the main cavity. The other of the sheets is laminated to the formed sheet so as to hermetically seal the main cavity and the cooperating conduit. A fracturable opening at the outlet of the conduit is provided permitting the withdrawal of liquid therefrom. The formed sheet being formed such that the assembly may be supported, when not in use, to dispose the outlet of the conduit at a higher level than the main cavity to militate against the unintentional spillage of liquid. | 1 |
CROSS-REFERENCE TO RELATED APPLICATION
This application is related to the commonly assigned, copending U.S. application Ser. No. 06/575,010 filed Jan. 30, 1984, entitled "Calender for Pressure and Thermal Treatment of Material Webs".
BACKGROUND OF THE INVENTION
The present invention broadly relates to roll or calendering devices and, more specifically, pertains to a new and improved construction of a two-roll calender with heated calender rolls.
In its more specific aspects the roll or calendering device of the present invention relates to a two-roll calender having heated rolls for the pressure and thermal treatment of webs or sheet materials of plastic or textile or both, such as fiber webs.
In heretofore known two-roll calenders of this type the heated rolls are exposed to room or ambient temperature without heat or thermal insulation which leads to significant energy losses. These energy losses have the advantage, as far as they are uniform, that they have an equalizing effect on the temperature profile of the rolls and therefore guarantee a uniform quality of the sheet materials or webs produced, particularly with respect to their width. If the above-mentioned heat losses are prevented the required uniformity of the temperature profile over the length of the roll is no longer guaranteed.
SUMMARY OF THE INVENTION
Therefore, with the foregoing in mind it is a primary object of the present invention to provide a new and improved construction of a two-roll calender with heated rolls which does not have associated with it the aforementioned drawbacks and shortcomings of the prior art constructions.
Another and more specific object of the present invention aims at providing a new and improved construction of a two-roll calender with heated rolls of the previously mentioned type by means of which a substantial reduction in the thermal energy supplied to the rolls can be obtained without affecting the required uniformity of the temperature profile over the length of the rolls.
A further object of the invention is to provide a roll or calendering device wherein a cooling means acts in a gap or space formed between a roll member and a heat insulating protective shield to produce a cooling effect on the roll member which is adapted to equalize the temperature over the length of such roll member.
Yet a further significant object of the present invention aims at providing a new and improved construction of a two-roll calender with heated rolls which is relatively simple in construction and design, extremely economical to manufacture, highly reliable in operation, not readily subject to breakdown or malfunction and requires a minimum of maintenance and servicing.
Now in order to implement these and still further objects of the invention, which will become more readily apparent as the description proceeds, the two-roll calender with heated rolls of the present invention is manifested by the features that both heated rolls are provided with heat insulating protective shields capable of being pivoted away from the related roll and with heat insulative end covers at the ends of the related roll. Moreover, at least one of the rolls is provided with a cooling device acting in a gap or space between such at least one roll and at least one of the heat insulating protective shields thereof to produce a cooling effect which can be regulated over the length of the roll for substantially equalizing the temperature.
Since the cooling device provided according to the invention only has to equalize minimal temperature differences, the use of the heat insulating protective shields results in a significant saving of heat or thermal energy.
The cooling device is preferably a blower device for generating air flows or jets which can be regulated over the length of the roll. The blower device is supplied with air at room or ambient temperature or air which has been heated by a suitable heating device. A very simple cooling device which is adequate for most cases is obtained by this measure.
The heat insulating protective shields are preferably pivotably mounted on the side of the roll which is located opposite to the contact pressure gap or nip. This arrangement provides optimal accessibility to the rolls by very simple means when the heat insulating protective shields are pivoted away from the rolls.
The blower device can also be disposed on the side of the roll located opposite to the contact pressure gap or nip in a space between two pivotable heat insulating protective shields. This arrangement provides a long region or path over which the air flows or jets can act on the surface of the roll in the gap or space between the roll and the related heat insulating protective shield. The blower device is also optimally accessible in this arrangement. The heat insulating protective shields can be provided with a layer of insulative material as well as a heat reflecting foil on the side facing the related roll. This foil is preferably easily replaced.
In a particularly simple embodiment, the blower device can be a housing having nozzle apertures or orifices disposed in at least one row and closable, individually or in groups, by means of sliding dampers, baffles or shutters or the like. It is to be understood that this blower device can also contain a longitudinal slot extending in the direction of the length of the related roll and whose width at different positions can be varied, as required, by any suitable means.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be better understood and objects other than those set forth above, will become apparent when consideration is given to the following detailed description thereof. Such description makes reference to the annexed drawings wherein:
FIG. 1 is a schematic side view of the calender or calendering device according to the invention;
FIG. 2 is a schematic partial longitudinal section taken substantially at line II--II of FIG. 1; and
FIG. 3 is a schematic representation of a possible embodiment of the blower device.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Describing now the drawings it is to be understood that to simplify the showing of the drawings only enough of the structure of the two-roll calender or calendering device has been illustrated therein as is needed to enable one skilled in the art to readily understand the underlying principles and concepts of this invention. The illustrated exemplary embodiment of the two-roll calender will be seen to comprise an upper calender roll 1 and a lower calender roll 2. In FIG. 1, the supporting framework or roll stand of the rolls has been omitted for reasons of clarity. Both calender rolls 1 and 2 are provided with conventional heating devices known per se and thus not particularly shown in the drawings. With these standard heating devices, the heating rolls 1 and 2 can be heated to a temperature of approximately 160° C. to 250° C. In operation, a sheet of material or web 3 of, for example, plastic or of textile, for instance a fiber web, that is to be subjected to pressure and thermal treatment is entrained and guided between the two coacting calender rolls 1 and 2 and fed into or through the contact pressure gap or roll nip 5 between these calendar rolls 1 and 2 by conventional web feed means, generally indicated in FIG. 1 by reference character 40. Both of these calender rolls 1 and 2 are provided with heat insulating protective shields 4, each of which contain a layer of insulative material as well as a heat reflective foil facing the surface of the related roll, for instance aluminum foil, as generally indicated by reference character 30.
As can further be seen from FIG. 1, the heat insulating protective shields 4 are pivotably mounted in hinges or pivot means 6 on those sides of the calender rolls 1, 2 located opposite to the contact pressure gap or nip 5. This arrangement permits the heat insulating protective shields 4 to be pivoted out of their service or operating position in the direction of the arrows 7.
The lower roll 2 in the calender of FIG. 1 is provided with cooling means comprising a blower device 8 which is shown on an enlarged scale in FIG. 3. As can be also seen in FIG. 1, the blower device 8 can be supplied with air by a fan or blower 10 or equivalent structure. The air can be conducted through a suitable heating device 11 which can be operated as required and through a regulating or control valve 12.
FIG. 2 shows a partial section of the end zone or region of the upper calender roll 1 of FIG. 1. As can be seen from FIG. 2, the calender roll 1 has, in addition to the heat insulating protective shields 4 acting on its circumference, a heat insulating protective end cover 13 at each roll end. This end cover 13 is disposed as close as possible to the related lateral end face or surface of the calender roll 1 and is provided with the same insulative treatment and structure 20 as the heat insulating protective shields 4. It is to be understood that both ends of both rolls 1 and 2 are provided with such end covers 13.
According to the showing of FIG. 3 the blower device 8 comprises a housing or plenum chamber 14 whose length is relatively great in comparison to its other dimensions and whose upper side or wall is provided with nozzle apertures or orifices 15 disposed in two rows. These nozzle apertures or orifices 15 are adapted to form air flows or jets 15' directed against the surface of the corresponding roll, i.e. here the calender roll 2. The housing 14 is provided with sliding dampers or shutters 16 or equivalent structure for selectively closing and opening the nozzle apertures 15. These sliding dampers 16 or the like can, for instance, be adjusted by hand according to requirements in service. The nozzle apertures 15 of both exemplary depicted rows can be closed or the nozzle apertures 15 of one row can be open or the nozzle apertures of both rows can be open. Three sliding dampers 16 are represented in FIG. 3 illustrating each of the three positions mentioned above.
When the inventive calender or calendering device is in operation the heat insulating protective shields 4 are in the position shown in the drawings. This position greatly reduces heat losses for the rolls 1 and 2 to the ambient environment except at the processing or operating point in the region of the sheet of material or web 4 being processed. Unavoidable irregularities of the surface temperature of the calender rolls can be compensated by adjustment of the sliding dampers 16 of the blower device 8. The regulating or control valve 12 regulates the quantity of cooling air and the heating device 11 regulates its temperature. The greatest cooling effect is obtained when the regulating valve 12 is open and the heating device 11 is turned off. Throttling the regulating valve 12 or heating the air supply reduces the cooling effect.
The air flowing into the gap or space 17 between the insulative heat shields 4 and the calender roll 2 is directed towards the sheet of material or web 3 in whose proximity the gaps or spaces 17 terminate. Since the cooling effect is primarily required on that side of the calender roll 2 which is turning towards or inbound with respect to the contact pressure gap or nip 5, it is advantageous to close the gap or space 17 off between the heat insulating protective shield 4 and the calender roll 2 on the side of such roll downstream of the contact pressure gap or nip 5 by means of a closure strip or fixed baffle 18. The air current or flow is then concentrated mainly in the left-hand gap or space 17 of FIG. 1, whereby a further advantageous effect of this arrangement is achieved. The air warmed in the gap or space 17 and directed in the direction of the arrow 20 towards the sheet of material or web 3 can be employed to preheat such sheet of material or web 3 immediately before entering the contact pressure gap or nip 5. This has the effect that under otherwise identical conditions a reduced supply of heat to the contact pressure gap or nip 5 is required. Thus, for instance, the temperature of the calender roll 2 can then be lower which results in a further saving of energy.
While there are shown and described present preferred embodiments of the invention, it is to be distinctly understood that the invention is not limited thereto, but may be otherwise variously embodied and practiced within the scope of the following claims. Accordingly, | The calender rolls of a calender are provided with heat insulating protective shields which can be laterally pivoted open and with heat insulating end covers or closures at the ends of the rolls. At least one of the rolls is provided with a blower device for generating air flows or jets which can be regulated over the length of such roll to equalize the temperature over the length of this roll. | 1 |
BACKGROUND OF THE INVENTION
1. Field
Polyurethanes, which are formed by reacting an isocyanate with a reactive hydrogen providing component, such as a polyol, have been widely used in preparing rigid and flexible foams, castings, adhesives and coatings. Typically, the reaction between the isocyanate and the polyol has been catalyzed by using various components such as amines, e.g. tertiary amines and organometallics, particularly organo tin compounds such as stannous octoate, dibutyl tin laurate, tin ethylhexanoate and so forth. The effectiveness of the catalyst is often measured by the cream time, which is the time required for the isocyanate and polyol syrup to turn from a clear solution to a creamy color; the gel time, which is the time required for polymer particles to form in the syrup; rise time, which is the time required for the syrup to rise to its maximum height; and cure time which is the time to reach a tack-free state.
In some applications for polyurethanes it is desirable to effect reaction in the shortest time possible and, therefore, pg,2 catalysts having tremendous activity are desired. In some applications, though, as in the molding of intricate parts or large objects, it may be desirable to keep the polyurethane composition in a fluid state for an extended time to permit the composition to completely fill the mold or flow into the cracks and crevices of the mold. Then, once the mold is completely filled, it is desirable to effect polymerization of the polyurethane in the shortest time possible so that the finished parts can be removed and the mold recharged with new materials. In this regard, it is desirable to delay the initial reaction, but after reaction commences then catalyze the polymerization rate. To do this it is necessary to extend the cream time to permit the polyurethane composition to penetrate the cracks and crevices in the mold and to extend the gelation time as the polyurethane foam on gelling becomes intractable and resists molding. However, once the reaction begins, it is desirable to end up with a rise and cure time comparable to those achieved by active catalysts as this will permit greater productivity.
2. Description of the Prior Art
Organometallics and particularly organo tin compounds such as tin ethylhexanoate, tin isooctoate, tin napthenate, di-n-butyl tin dilaurate; dibutyl tin diacetate, and tertiary nitrogen tin compounds such as dibutyl-tin-di(pyridine-4-carboxylic acid esters) as shown in U.S. Pat. No. 3,595,734; and U.S. Pat. No. 3,164,557 have been used to catalyze urethane reactions.
Amine compounds and particularly tertiary amines or their salts have been used as catalysts for polyurethanes. Examples of amines which are suited for catalyzing polyurethane reactions are dimethyl benzylamine, triethylenediamine, trimethylamine; alkanolamines such as diethanolamine, triethanolamine, N-diethyl-ethanolamine; N-hydroxyalkyl substituted imidazoles and N-vinyl pyrrolidone as shown in U.S. Pat. Nos. 3,645,927; 3,450,648; 3,448,065 and 3,746,663.
U.S. Pat. Nos. 3,620,986 and 3,580,868 show that Mannich bases of secondary amines and phenols can be used for catalyzing an isocyanate-hydroxyl reaction. Generally, some aminoalcohol is present and the phenol radical may contain an active hydrogen atom, e.g. COOH, CONH 2 , OH, etc., which can condense into the urethane structure. Typically, these Mannich bases are formed by reacting dimethylamine, formaldehyde, aminoalcohol and a phenol, e.g. Bisphenol A, or salicylic acid amide.
Although the above references indicate the compositions have catalytic activity, a number of references have suggested similar but different compositions as being useful as delayed action catalysts (DAC), i.e. those which initially delay and then catalyze the isocyanate-hydroxyl reaction. For example, chelating agents, e.g. beta-diketones and beta carbonyls with aminefree organometallics have been used. Examples of beta-diketones useful as a delayed action catalyst in polyurethane chemistry include 2,4-hexanedione, acetylacetone, 1,cyclohexyl-1, 3 butanedione; beta-hydroxy ketones, e.g. beta hydroxy quinoline, 1hydroxy-9-fluorenone, and alpha-hydroxy ketones, e.g. benzoin, acetoin and others as shown in U.S. pat. No. 3,635,906.
Another example of a delayed action catalyst for the preparation of foamed polyurethane resins is shown in U.S. Pat. 2,932,621. This patent discloses that amine salts of dicarboxylic acids and notably the hydroxy tertiary amine salts of oxalic acid are particulary effective in delaying the initial reaction between an isocyanate and hydroxyl group, but after an appropriate lapse of time, they become fully effective and cause the reaction to proceed to completion smoothly, rapidly and efficiently.
It has also been proposed to use quaternary ammonium salts of Mannich bases as a delayed action catalyst for the reaction between an isocyanate and polyol to form polyurethanes. Initially, the quaternary ammonium salt has little catalytic effect, but during the reaction it decomposes to form tertiary amine which can assist in catalyzing the reaction. Examples of quaternary ammonium salts of Mannich bases are shown in U.S. Pat. No. 2,950,262 and are prepared by reacting a secondary amine with an aldehyde and a ketone such as cyclohexanone and then reacting the Mannich base with an organic halide to form the quaternary ammonium salt.
SUMMARY OF THE INVENTION
This invention relates to amine salts of tertiary amino acids. These amine salts are represented by the formula ##STR1##
wherein R 1 and R 2 independently are hydrogen (wherein only one of R 1 or R 2 is hydrogen at a time) alkyl and substituted alkyl groups having from 1 to 15 carbon atoms, lower alkanol groups having from 2 to 4 carbon atoms, or combined to form a piperidine, piperizine, morpholine, imidazole or imidazoline radical or substituted radical thereof;
wherein R 3 and R 4 independently are alkylene groups having from 1-6 atoms, aralkylene groups with the alkylene portion having from 1 to 6 carbon atoms, substituted alkylene and substituted aralkylene groups;
wherein R 5 is hydrogen, a lower alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, an aryl group and substituted derivatives, a cycloaliphatic or alkyl substituted cycloaliphatic group with the alkyl portion having from 1 to 6 carbons, or a keto alkyl group with the alkyl portion having from 1-6 carbon atoms;
wherein R 6 is hydrogen, or a radical selected from the group consisting of alkyl, phenyl, furfuryl, napthyl, and substituted derivatives of such groups;
wherein X is an amine salt of a carboxylic acid group;
wherein Y is a carboxylic acid group, a nitrile group, or an amine salt of an acid group;
wherein m and o independently are 0 or 1;
wherein q is 0 or 1;
wherein p is 1 or 2;
wherein s is 0 or 1; and
wherein p + q + s is 3.
Advantages of the amine of tertiary amino acid catalysts of this invention include:
the ability to delay, as compared to conventional amine catalysts, the initial reaction between an isocyanate and an active hydrogen containing compound in the formation of a polyurethane;
the ability to catalyze the reaction between an isocyanate and an active hydrogen containing compound;
the ability to form an organometallic catalyzed polyurethane molding composition having excellent flow during initial stages by extending the cream and gelation time and yet end up with a desirable rise and cure time which often is close to those obtained with conventional catalyst compositions; and
the ability, by virtue of being thermally sensitive, to generate additional reactive amine for catalyzing and enhancing the cure rate.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Broadly, the amine salts of the tertiary amino acids of this invention can be visualized as amine salts of Mannich type tertiary amino acid adducts having at least monofunctionality in terms of tertiary amine, and at least monofunctionality and preferably at least difunctionality in the form of an amine salt.
The Mannich type tertiary amino acid adducts typically are formed by reacting a primary and preferably a secondary amine with an aldehyde having sufficient capability to react with the amine hydrogen and form a terminal methylol group and an organic compound having a hydrogen atom sufficiently reactive to undergo the Mannich addition, and having pendent acid functionality or functionality which can be converted to the acid form and then reacting the thus formed Mannich tertiary amino acid adduct with an amine to form the salt. Further description of the preparation of the Mannich adduct and type can be found in copending application having U.S. Ser. No. 717,579, and a filing date of Aug. 26, 1976, now Pat. No. 4,086,213, and is incorporated by reference.
In preparing the Mannich type adducts described, suitable amines generally are lower alkyl amines having from 1 to 15 carbon atoms, and preferably 1 to 3 carbon atoms, lower alkanol amines where the alkanol portion has from 2 to 4 carbon atoms; phenyl amines such as mono and dibenzylamine, cyclic amines such as cyclohexylamine and dicyclohexylamine; piperidine; piperizine; imidazole; aralkylene amines, e.g. ethylbenzylamines; heterocyclic amines, e.g. morpholine. The amines can be substituted with various functional groups, e.g. alkyl, alkoxy, ether and hydroxyl so long as the funtionality does not interfere with the reaction or impart an adverse characteristic to the resulting polyurethane resin. The preferred substituted group is a hydroxyl group as it does not interfere with the reaction and tends to aid the delay in the initial urethane reaction and thereby lengthen the cream time. Those amines best suited for forming the Mannich type are morpholine, diethanolamine, ethanolamine, piperidine and piperizine.
The second component used in forming the Mannich adduct is an aldehyde. Aldehydes and substituted aldehydes useful in forming the Mannich adducts are well known and can be used here. As taught in the art, these aldehydes must have a pendant aldehyde group which is sufficiently reactive to form the Mannich adduct. Typically, these aldehydes are activated, as for example, by an unsaturated group in conjugated relationship with the carbonyl aldehyde. Examples of aldehydes best suited for practicing the invention are formaldehyde, benzaldehyde, furfuraldehyde, napthaldehyde, and substituted aldehydes such as nitrobenzaldehyde, nitrofurfural, cyanofurfuraldehyde and the like. For reasons of efficiency and economy, formaldehyde is the preferred aldehyde used in forming the adduct.
The remaining component necessary for forming the Mannich adduct is an organic compound having at least one hydrogen atom sufficiently reactive for undergoing a Mannich reaction. Generally in such compounds, the hydrogen atom is positioned on a methylene group alpha positioned to a carbonyl group such as a ketone, a carboxylic acid ester or an acid group. Further, the organic compound should have a pendant carboxylic acid or nitrile group or a structure, e.g. ketone or ester which permits the formation of a carboxylic acid. The acid then can be neutralized with amine and converted to the salt. Examples of organic compounds having at least one active hydrogen atom, and in some instances, two active hydrogen atoms suited for practicing the invention include disubstituted saturated acids such as malonic acid, benzyl malonic acid, lower alkyl (C 1 -C 3 ) malonic acids, furfuryl malonic acid, alkenyl malonic acids, e.g. allyl malonic acid; cyanoacetic acid and keto acids, e.g. 2 ketobutyric acid.
The amine salts of this invention can be formed by reacting the amino acids with amines such as ethanolamine, diethanolamine, triethanolamine, tri-n-propanolamine, methylamine, ethylamine, propylamine, benzylamine, triethylamine, cyclohexylamine, etc. Highly reactive tertiary amines such as bis-(dimethylaminoethyl) ether and triethylenediamine can also be used to form the amine salts and these catalysts are particularly effective for enhancing the rate of the urethane reaction. Generally, the less active amines, such as ethanol and diethanol amine result in producing a less active catalyst. Because the tertiary amine is tied to the Mannich adduct, though, the cream time is lengthened substantially over that which is obtained by using tertiary amine alone.
Examples of amine salts of Mannich type adducts include: bis-tri-n-propanolamine salt of bis(hydroxyethylamino) methyl malonic acid, diethanolamine salt of hydroxyethylamino methyl malonic acid, monomethylamine salt of bis(hydroxyethylamino) furfuryl malonic acid, bis-triethylenediamine salt of bis(hydroxyethylamino) benzyl malonic acid, bis-triethylenediamine salt of morpholino benzyl malonic acid, bis-dimethylamine salt of morpholino methyl malonic acid, methylamine salt of bis(piperidinylmethyl) acetic acid, bis-tri-n-propanolamine salt of diglycolamino methyl malonic acid, propanolamine salt of bis(piperdinylmethyl) acetic acid, triethanolamine salt of bis(imidazolo methyl) acetic acid, bis-trimethylamine salt of piperidinyl methyl malonic acid and triethylenediamine salt of morpholino benzyl cyanoacetic acid.
The amine salts of the tertiary amino acids of this invention can be utilized with other conventional polyurethane catalysts without detracting from the overall benefits. A conventional catalyst that is quite acceptable as a cocatalyst is an organometallic, suitably an organo tin composition such as dibutyl tin dilaurate, dibutyl tin diacetate, diethyl tin diacetate, dihexyl tin diacetate, stannous octoate, stannous decanoate and dioctyl tin oxide.
Representative polyisocyanates suited for producing polyurethanes in practicing this invention are the aliphatic and aromatic polyvalent isocyanates. Examples of aliphatic isocyanates include alkylene diisocyanates such as tri, tetra and hexamethylene diisocyanates; arylene diisocyanates and their alkylation products such as phenylene diisocyanate, napthylene diisocyanate, diphenylmethane diisocyanate, toluene diisocyanate, di and triisopropyl benzene diisocyanate and triphenylmethane triisocyanates; triesters or isocyanato-phenyl-triphosphoric acid; triesters of para-isocyanato phenyl phosphoric acid; aralkyl diisocyanates such as 1-(isocyanato phenol-ethyl) isocyanate or xylene diisocyanate.
Suitable reactive Zerewitinoff compounds, e.g. polyols for forming the polyurethanes include aliphatic polyether polyols prepared from the reaction of ethylene or propylene oxides or mixtures thereof with a glycol; glycols such as ethylene glycol, propylene glycol, butylene glycol, tetramethylene glycol, hexamethylene glycol, and triols such as glycerol, trimethylolpropane, trimethylol ethane, and higher polyols such as pentaerythritol, sorbitol, castor oil, polyvinyl alcohol, sucrose, dextrose, methyl glycoside and the like; amino polyols made by the condensation of alkylene oxides and alkanol amines such as tetrahydroxyethylenediamine, tetrahydroxypropyl ethylenediamine; other organic compounds having an active hydrogen atom are amines such as triethanolamine, methylamine, diethanolamine, phenylenediamine, tolylenediamine, piperizine and the like.
The polyols also can be incorporated into a polymer and reacted with the isocyanates as in the case of polyesters. A polyester, as is known, is prepared by the reaction between a dicarboxylic acid and a polyol, e.g. a glycol. Examples of conventional dicarboxylic acids suited for manufacturing polyester polyols include succinic, glutaric, adipic, sebacic, phthallic, terephthallic, maleic, fumaric, itaconic, citraconic, and the like. Glycols include, ethylene glycol, propylene glycol and butylene glycol.
In the preparation of polyurethanes, conventional additives can be utilized for their desired effect without departing or detracting from the advantageous aspects of the catalysts of this invention. For example, blowing agents such as water or a volatile organic such as dichlorodifluoromethane, dichlorofluoromethane, trichloromonofluoromethane, dichlorofluoromethane, difluorodichloroethane, methylene chloride, carbontetrachloride, butane, pentane, and the like.
Foam stabilizers or surfactants are other additives which can be added for enhancing the retention of gas generated during the polymerization reaction and such stabilizers include silicone block polymers comprising polyalkylene glycol units, n-vinyl pyrrolidone, or n-vinyl pyrrolidone-dibutyl maleic copolymers or n-vinyl pyrrolidone-dibutyl maleate (vinyl acetate). Other examples are shown in U.S. Pat. No. 3,746,663.
In preparing the polyurethanes, the amine salt of a Mannich acid adduct is added to the urethane composition in at least a sufficient or effective proportion for enhancing the cure rate of the urethane. When the catalyst is used alone, generally from about 0.1 to about 5 parts by weight per 100 parts and preferably about 0.5 to about 1.5 per 100 parts by weight of reactive Zerewitinoff hydrogen compound, e.g. polyol are included. When less than about 0.1 parts are added to the composition, the catalyst is not present in sufficient proportion to substantially influence the cure rate of the polyurethane. When more than about 3.5 parts catalyst are added to the urethane composition, too much amine may be introduced and amine odor may be observed. For reasons of economy, the catalyst concentration is preferably from about 0.5 to about 1.5 parts.
Often where the organo portion of the amine salt of tertiary amino acid is relatively small or negated by the fact that a hydroxyl or other polar group is present, it may be necessary to use a solvent to disperse the catalyst in the urethane syrup. Virtually any solvent may be used which does not compete with the isocyanate-active hydrogen to form a polyurethane, or does not adversely affect the resultant polyurethane. Conventional solvents such as glycols, e.g. propylene glycol, ethylene glycol, dipropylene glycol; ethylene carbonate, and amino-nitrile compositions such as cyanoethyldiethanolamine, which is also a catalyst, can be used as a solvent.
Organometallic catalysts may be included in polyurethane manufacture along with the amine salts in a proportion of from about 0.005 to about 0.5, and preferably 0.01 to 0.2 parts by weight per 100 parts of active Zerewitinoff hydrogen compound. Variations within this broad range are practiced depending on whether, for example, high and low density polyurethanes are prepared and seems to be no significant enhancement of catalytic activity or of other desired features to warrant the additional expenditure and usage of the catalyst.
The following examples are provided to illustrate preferred embodiments in the invention and are not intended to restrict the scope thereof. All parts are parts by weight, all percentages are expressed as weight percentages, and all temperatures are in ° C. unless otherwise specified.
EXAMPLE 1
Bis-(hydroxyethyl) amino benzyl malonic acid was prepared conventionally in a flask equipped with a stirrer and reflux condenser by first charging 0.1 mol of malonic acid, 0.1 mol of diethanol amine and 100 cc methanol. The contents were warmed to a temperature of about 20° C. and then 0.1 mol benzaldehyde were added to the flask and the reaction commenced. After refluxing the reaction mixture for 1 hour, the methanol was removed from the reaction mixture by coupling the flask to a vacuum source and heating to a temperature of about 50° C. The residue remaining in the flask then was triturated in acetone and the resulting acid isolated by filtration.
The bis-triethylenediamine salt of the acid was prepared by mixing 0.1 m of the methanolic solution of the acid with 0.2 m triethylene diamine at room temperature (25° C.) for 30 minutes, after which the methanol was removed under reduced pressure.
EXAMPLE 2
Morpholino benzyl cyanoacetic acid was prepared in the same manner as the acid of Example 1 except that morpholine was substituted for diethanolamine and cyanoacetic acid for malonic acid. The monotriethylenediamine salt of the cyanoacetic acid adduct was prepared in the same manner as the amine salt of Example 1.
EXAMPLE 3
Approximately 100 cc of water and 0.2 mols (21.1 grams) of malonic acid and 0.4 mols (27.4 grams) of imidazole were charged to a round bottom flask. Then 0.4 mols formaldehyde as a 35% aqueous solution were added over a period of time to the mixture of water, malonic acid and imidazole. The resulting mixture was stirred for about 36 hours at 25° C. after which the contents were heated to a temperature of 50° C. and the water removed by vacuum. The resulting product was bis-(imidazole methyl) acetic acid.
EXAMPLE 4
Approximately 100 cc of methanol, 0.1 mols of malonic acid, 0.1 mols of diethanolamine, and 0.1 mols of furfuraldehyde were charged to a round bottom flask. The contents were refluxed for two hours, and then the methanol removed by evacuation. The product obtained was bis-(hydroxyethyl) furfuryl malonic acid.
The triethylenediamine salt of the above product is prepared in the same procedure as the composition in Example 1.
EXAMPLE 5
Conventional high density rigid polyurethane foams were prepared from the basic formulation below in conventional manner. In preparing these polyurethane foams, the catalyst, comprising an amine salt of a Mannich adduct (as indicated), and organometallic (as indicated) and the concentration of each catalyst component were varied to determine the overall effect on the foam formulation. The polyurethane foams were evaluated for cream time, gelation time, and cure time.
The components used for preparing the high density foam were as follows:
______________________________________Component Amount, parts by weight______________________________________Mondur® MR Isocyanate 100NIAX® DAS-361 Polyol 65Thanol® G-400 Polyol 27.7Polylite® 34-400 Polyol 5.0Water 0.6DC-193 0.8Tertiary amino acid or nitrile 0.5 - 1.5 catalyst parts/100 parts polyol (php)Organometallic catalyst 0.005 - 0.5 parts/100 parts polyol (php)______________________________________
(1) Mondur MR Isocyanate is crude 4,4'methylene bisphenylisocyanate having an isocyanate equivalent of about 133, a functionality of about 2.7-2.9 and a viscosity of about 150-250 cps.
(2) NIAX DAS-361 Polyol is a sucrose/amine polyol having a hydroxyl number of 360.
(3) Thanol G-400 Polyol is a glycerol polyol having a hydroxyl number of 400.
(4) Polylite 34-400 Polyol is an amino polyol having a hydroxyl number of 790.
(5) In the examples to follow where a previous example is given, as the catalyst used but a different amine indicated as a solvent, that amine was used in place of the particular amine in the previous example; TEDA refers to triethylenediamine; DEA refers to diethanolamine; DPG refers to dipropylene glycol; PG refers to propylene glycol; T-12 refers to dibutyl tin dilaurate, php refers to the parts of catalyst (including solvent if used) per 100 parts polyol.
The results of the formulation testing is set forth in Table 1.
TABLE 1__________________________________________________________________________HIGH DENSITY RIGID FOAM Tack FreeCatalyst Organometallic Cream Time Gel Time Cure Timephp Solvent php Sec. Sec. Sec.__________________________________________________________________________Ex. 1 (0.5) (neat) -- 61 132 176Ex. 1 (0.7) (neat) -- 53 113 160Ex. 1 (1.0) (neat) -- 44 93 125Ex. 1 (0.5) (neat) T-12 (0.03) 48 77 86Ex. 1 (1.0) (neat) T-12 (0.03) 43 69 79Ex. 1 (0.5) (neat) T-12 (0.04) 46 71 78Ex. 1 (1.0) (neat) T-12 (0.04) 40 64 72Ex. 1 (0.5) (neat) T-12 (0.05) 44 63 69Ex. 1 (1.0) (neat) T-12 (0.05) 37 61 65Ex. 2 (0.5) (50% DPG) -- 75 157 227Ex. 2 (1.5) (50% DPG) -- 50 107 154Ex. 2 (0.5) (50% DPG) T-12 (0.01) 53 100 125Ex. 2 (1.5) (50% DPG) T-12 (0.01) 43 82 105Ex. 2 (1.5) (50% DPG) T-12 (0.03) 33 90 111ethylene diamine 60 197 >6 min.(0.4)diethanolamine 68 244 >6 min.(0.4)diethylenetri- 59 228 > 6 min.amine (0.4)n-butylamine 61 244 >6 min.TEDA (0.23) 67% DPG -- 34 81 106-- -- t-12 (0.04) 44 78 87-- --T-12 (0.03) 46 82 94-- -- T-12 (0.05) 33 61 68__________________________________________________________________________
EXAMPLE 6
Conventional low density rigid polyurethane foam formulations utilizing the components set forth below were prepared in conventional manner. In these polyurethane foams, the catalysts comprising an amino acid and organometallic and the concentration were varied. The basic formulation used for the low density rigid polyurethane foam was as follows:
______________________________________Component Amount, parts______________________________________Hylene® TIC.sup.(1) 105RS-6406 Polyol.sup.(2) 109DC193.sup.(3) Surfactant 1.5R11.sup.(4) Blowing Agent 47______________________________________
(1) Hylene TIC is an undistilled, technical grade of tolylene diisocyanate typically having an isocyanate content of 38.75 to 39.75%, an amine equivalent of 105.5 to 108 and a viscosity at 25° C. of 15 to 75 cps.
(2) RS-6406 Polyol is a sucrose/amine polyol having a hydroxyl number 475.
(3) DC-193 Surfactants are polysiloxane polyoxalkylene block copolymers. Examples are shown in U.S. Pat. Nos. 2,834,748 and 2,917,480.
(4) R-11 Blowing Agent is trichloromonofluoromethane.
(5) See the excerpt for high density formulations for an explanation of terms used on page 20, paragraph (5). The results are shown in Table 2.
TABLE 2__________________________________________________________________________LOW DENSITY RIGID FOAM Tack FreeCatalyst Organometallic Cream Time Gel Time Cure Timephp Solvent php Sec. Sec. Sec. Shrinkage Friability__________________________________________________________________________dimethylcyclo- -- 18 77 168 none nonehexylamine(0.8)TEDA (0.17) 67% DPG -- 30 106 164 slight moderateTEDA (0.43) 67% DPG -- 11 50 75 none none-- T-12 (0.2) 38 70 98 moderate moderatebis-DEA salt of T-12 (0.08) 39 117 230 slight- very slightmalonic acid moderate(0.05)" (1.0) T-12 (0.08) 36 123 237 moderate slight" (0.5) T-12 (0.1) 37 115 241 moderate slight" (1.0) T-12 (0.1) 34 117 245 moderate- slight severemono DEA salt T-12 (0.08) 36 114 221 slight- very slightof malonic acid moderate(0.5)" (1.0) T-12 (0.08) 34 133 259 severe slight" (0.5) T-12 (0.1) 36 103 187 sight- slight moderate" (1.0) T-12 (0.1) 33 111 208 slight slight__________________________________________________________________________
EXAMPLE 7
Conventional microcellular polyurethane foam formulations were prepared in the usual manner by mixing
87 parts of CP-4701 polyol,
13 parts of 1,4-butanediol,
1.00 parts of L-5303 Silicone Surfactant and
0.30 parts of water to form a polyol premix.
Then the tertiary amino acid (DAC) and organometallic catalyst were added and the type and concentration of each was varied as indicated.
After the catalysts were blended with the premix, 50 parts Mondur MR isocyanate were added to the premix and the resulting syrup poured into a container and evaluated as indicated in Table 2. Terms used in the table correspond to Example 5, paragraph (5) for the high density formulations. In addition
(1) CP-4701 Polyol -- is a polyol made from glycerine and propylene and ethylene oxides and is marketed by the Dow Chemical Company, and
(2) L-5303 Silicone -- is a surfactant supplied by Union Carbide Corporation.
TABL 3______________________________________MICROCELLULAR FOAM Tack Free Organo- Cream Gel CureCatalyst metallic Time Time Timephp Solvent php Sec. Sec. Sec.______________________________________TEDA (0.2) (66.6% DPG) T-12 (0.03) 27 36 49-- T-12 (0.25) 30 35 43Ex. 2 (1.0) (50% DPG) -- 272 400 600Ex. 2 (2.0) (50% DPG) -- 155 255 320Ex. 2 (0.5) (50% DPG) T-12 (0.04) 81 100 125Ex. 2 (1.0) (50% DPG) T-12 (0.04) 72 90 110Ex. 2 (2.0) (50% DPG) T-12 (0.04) 71 90 105-- -- T-12 (0.04) 360+ -- --______________________________________ | Amine salts of tertiary amino acids have been found to be effective as catalysts for polyurethane synthesis and they have been found to exhibit delayed action, in many instances, in the polymerization of urethanes. Typically, the amine salts of tertiary amino acids are formed by initially reacting a primary or secondary amine with an aldehyde and disubstituted acid to form a Mannich adduct and then reacting the resulting Mannich acid adduct with an amine. | 2 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the priority benefits to U.S. provisional patent application, Ser. No. 61/569,176 filed Dec. 9, 2011, to German patent application DE 10 2010 053 996.1, filed Dec. 9, 2010, to German patent application DE 10 2011 118 842.1, filed Nov. 18, 2011, to German patent application DE 10 2011 120 598.9, filed Dec. 9, 2011, to German patent application DE 10 2012 010 157.0, filed May 16, 2012.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not Applicable
REFERENCE TO SEQUENCE LISTING; A TABLE; OR A COMPUTER PROGRAM LISTING COMPACT DISC APPENDIX
[0003] Not Applicable
BACKGROUND OF THE INVENTION
[0004] (1) Field of the Invention
[0005] The present invention relates to vehicle signal lighting.
[0006] (2) Description of Related Art
[0007] The light-signals of a vehicle are generally known, which signals indicate the intentions of a driver to execute any manoeuvre. To these signals belong the signals “turn on right or on left”, “stop”, “further motion”.
[0008] The shortcoming of this a.m. method and devices is an essential limitation of the detectability of these signals, especially from the front side in the darkness, because the head lamps lighting (beaming) much more bright, then the relatively dim (dull) turn-intention light signals. Besides, also under the shining sun, the a.m. turn-intention light signals are relatively difficult detectable against the background of bright surrounding.
BRIEF SUMMARY OF THE INVENTION
[0009] Aim of the presented invention is to provide a more clear and easy & quick recognisable indicating of the maneuvering-intentions of a vehicle and therewith to improve the safety of traffic. This problem is solved in the listed in the claims features.
[0010] The attained by this invention advantages are, in particular, that it makes it possible to recognise the current traffic situation (situation with the vehicles in the road) certain and quickly, in spite of the usual technical obstacles to recognise the signal- and vehicle position (as, for example, in the darkness, a dazzling light of the head lamps of the vehicles which are moving in the opposite direction, or, in the day time, a bright surrounding under the shining sun, or a limited view from the driver seat, etc.).
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0011] The examples of embodiment of the invention are presented in the drawings and described below.
[0012] The figures show:
[0013] FIG. 1-FIG . 3 : Schematical representation, how looks the front view of a vehicle from the point of view of a driver, who seats in a vehicle, which moves in the opposite direction; FIG. 1 —without turn-indicating blinking lamps (Blinker); FIG. 2 —with a switched-on right turn-indicating lamp (lights); FIG. 3 —with a switched-on left turn-indicating lamp (lights);
[0014] FIG. 4 (A-C)- FIG. 7 : Possible embodiments of the Arrow-kind structure of a turn-indicating-signal lighting of a vehicle:
[0015] FIG. 4A and FIG. 4 C—possible embodiment of the Arrow-kind structure, where FIG. 4A is a front view with a switched-on right turn, FIG. 4 B—the same view with a schematic presentation of the Arrow-kind structure, and FIG. 4C is the same view with a switched-on left turn;
[0016] FIG. 5A and FIG. 5 B—possible embodiment, where FIG. 5A is one axonometric view of a vehicle, with a shown plane of symmetry, and FIG. 5B is the same view with the switched-on right turn indication;
[0017] FIG. 6A and FIG. 6 B—the same embodiment, where FIG. 6A is one other axonometric view of the vehicle, with a shown plane of symmetry, and FIG. 5B is this same view with the switched-on left turn indication;
[0018] FIG. 7 —possible Head-Part- and Foot-Part-embodiments of the Arrow-kind structure.
[0019] FIG. 8A and FIG. 8B : Possible different variants of the placing (positioning) of the arrow-kind turn-indicating-signal lights of a vehicle: FIG. 8 A—front view, FIG. 8 B—side view.
[0020] FIG. 9 : The most probable variants of combinations of the placing (positioning) of the lightlines.
[0021] FIG. 10A and FIG. 10B : Possible variant of the placing of an arrow-kind turn-indicating-signal lights of a vehicle on the back side of a vehicle: FIG. 10 A—back view with the switched-on left turn; FIG. 10 B—the same view with the switched-on right turn.
[0022] FIG. 11A and FIG. 11B : Possible variant of embodiment of turn-indicators: FIG. 11 A—front view with the switched-on right turn; FIG. 10 B—the same view with the switched-on left turn.
[0023] FIG. 12 (A-C)- FIG. 19(A-C) : Examples of embodiments of the reflection-kind indicating of a turn-intention:
[0024] FIG. 12(A-C) : front view of the vehicles with the turn-indicator lights, beaming down in the shadow area under the vehicle, where FIG. 12 A—general schematic front view; FIG. 12 B—the same view in the dark; FIG. 12 C—the same view under the bright sun;
[0025] FIG. 13 : front view of the vehicles with the turn-indicator lights, beaming down both in the shadow area under the vehicle and also down near the vehicle;
[0026] FIG. 14(A-C) : front view of the vehicles with the turn-indicator lights, beaming down both in the shadow road area under the vehicle and also to the internal part of either left or right wheel of the vehicle, where FIG. 14 A—general schematic front view, FIG. 14 B—the same view in the dark; FIG. 14 C—the same view under the bright sun;
[0027] FIG. 15 : possible variants of synchronising between the light-flashing lamp (lighting) and usual turn-intention lighting in the same vehicle;
[0028] FIG. 16 : one possible placing of the down-beaming lights (beamers) under a vehicle;
[0029] FIG. 17 : one possible placing of the down-beaming lights (beamers) under a vehicle;
[0030] FIG. 18(A-C) : one possible placing of the down-beaming lights (beamers) under a vehicle, where FIG. 18 A—axonometric view, FIG. 18 B—partial front view of the same vehicle with the switched-on right turn, FIG. 18 C—the same front view with the switched-on left turn;
[0031] FIG. 19(A-C) : one possible placing of the down-beaming lights (beamers) on edges of a vehicle, where FIG. 19 A—axonometric view, FIG. 19 B—partial front view of the same vehicle with the switched-on right turn, FIG. 19 C—the same front view with the switched-on left turn.
[0032] FIG. 20A and FIG. 20B : Possible variant of a head-lighting (head lamp) embodiment, where FIG. 20 A—front view; FIG. 20 B—side view.
[0033] FIG. 21 : Possible variant of embodiment of a stop-indicator.
[0034] FIG. 22-FIG . 30 : Possible variants of placing of lightlines
[0035] FIG. 31A and FIG. 31B : Possible variant of placing of turn-indicating lights, where FIG. 31 A—front view; FIG. 31 B—side view.
[0036] FIG. 32A and FIG. 32B : Possible variant of placing of turn-indicating lights, where FIG. 32 A—front view; FIG. 32 B—side view.
[0037] FIG. 33A and FIG. 33B : Possible variant of placing of turn-indicating lights, where FIG. 33 A—front view; FIG. 33 B—side view.
[0038] FIG. 34A and FIG. 34B : Possible variant of placing of a video-scout, where FIG. 34 A—front view; FIG. 34 B—side view.
[0039] FIG. 35 —Video-scout with a telescopic support for videocamera.
[0040] FIG. 36 —Video-scout with an adjustable for different angles in respect to the vehicle's body support for videocamera.
DETAILED DESCRIPTION OF THE INVENTION
[0041] FIG. 1 shows schematically, how looks from the front view in the darkness a vehicle without the switched-on turn-indicating lights, from the point of view of the driver of the vehicle, which moves in the opposite direction. As in the darkness there is a big and sharp difference of a light intensity between the light, which goes from head lamps surfaces 1 and from the surface of a vehicle body 2 , a driver, who moves from the opposite directions, see only two schining surfaces of the head lamps 1 . The turn-indicating lights (lamps) 3 ( FIG. 2 and FIG. 3 ), which are placed near the head lamps 1 , are also less bright shining, then the head lamps 1 . Therefor these turn-indicating lamps are basically bad recognisable. One recognises them more or less sure only 1) (main reason) because of the blinking working regime of this lights, 2) because the car body is equipped also with the other additional side-turn-indicating lights 4 , which are placed on the left (or right) side of the vehicle body, or on the right & left rear-view mirror 5 , and additionally 3 ) because these turn-indicating lights have normally the red shining color in comparison the white (all-spectrum) shining color of the vehicle head lamps.
[0042] To improve the recognisability of the turn-indicating signals, it is possible to indicate a turn-intention of a vehicle 16 by an arrow-kind lighting structure, which one is good recognisable also near an in spite of the brightly shining vehicle's head lamps.
[0043] FIG. 4A , FIG. 4B and FIG. 4C shows schematically one possible variant of embodiment of this arrow-kind lighting. The lighting lines (or lighting strips) 6 , among others (a.o.) 6 a - 6 z , (in the future called as “lightlines”) are forming an easy recognisable (also easy recognisable from the front view in the darkness) arrow-kind lighting structure 7 , together with the head lamp 1 a and with the nearby placed usual turn-indicating lamp 3 . The second, separately shining head lamp 1 b is forming a placed on the some certain distance “foot” 7 F of the arrow, and this way this head lamp also belongs to the lighting structure 7 . (Here is presented only the turn-indication on-right; the turn-indication on-left is full-symmetrical, and therefore it is not presented).
[0044] Therewith the arrow-kind turn-indicating lighting structure 7 contains two parts:
1) a head-part 17 , which one is formed by the switched-on (a.o. blinking) lightlines 6 . This head-part can also contain the blinking turn-indicating lamps 3 or 5 and a permanently (not-blinking) shining head lamp 1 a; 2) a foot-part 18 , which one is formed by the permanently (not blinking) shining head lamp 1 b (i.e. “foot” 7 F) and by the dark interval 19 between this head lamp 1 b (foot 7 F) and the axis of symmetry 20 . (Or with another words, the head lamp 1 b forms a placed on a definite distance “foot” 7 F of the arrow, and therewith the foot-part 18 contains a permanently (not blinking) shining head lamp 1 b and dark space (interval) 19 between this head lamp and axis of symmetry 20 of the vehicle.)
[0047] This way the direction of the orientation of the arrow is easy recognisable. The both head lamps are the parts of these arrow-kind lighting structure 7 . Therefor the light of head lamps does not interfere (does not disturb), but in the opposite, helps to recognise the turn-indication signaling.
[0048] Each pair of the lightlines 6 is symmetrical relatively the plane of symmetry 21 of the vehicle 16 ( FIG. 5A & FIG. 5B and FIG. 6A & FIG. 6B ). Each pair consist of the two (one left-placed and one right-placed) lightlines 6 , which lightlines indicate (show) the turn-intention of the vehicle 16 .
[0049] And to be more precise, this FIG. 5A & FIG. 5B and FIG. 6A & FIG. 6B presents schematically several possible placing of the lighting lines 6 relatively to the plane of symmetry 21 (different variants simultaneously in one picture), and more concretely: FIG. 5 B—a vehicle with the electrically switched-on turn-indication on-right; and FIG. 6 B—a vehicle with the electrically switched-on turn-indication on-left.
[0050] Therewith the turn-indicating lighting of a vehicle 16 contains at least one pair of the lighting-able lines 6 .
Where these above mentioned (a.m.) two lines 6 are symmetrical one to another relatively the plane of symmetry 21 of this vehicle 16 . (I.e. the plane of symmetry of this vehicle is the plane of symmetry of these two lines, and therewith the axis of symmetry 20 of the front view (or back view) of this vehicle is the axis of symmetry of the front view (or back view) of these a.m. lines.) Besides, these two lines has the separate, independent one from another, electrical connection. Besides, these a.m. two lines begin themselves in one common point, which point lays on the axis of symmetry 20 of the front view (or back view) of this vehicle, and after that these two a.m. lines go from this point correspondently on-left and on-right from this axis of symmetry; after that these a.m. two lines go up to (or approximately up to) the extremely left part of the external contour 22 of the vehicle and the extremely right part of the external contour of the vehicle correspondently. And after that, a.o. (among other variants), the a.m. lines can further go on, along the external contour of the correspondently left and right external contours (silhouettes) 22 of the vehicle; and after that these a.m. two lines go back to the a.m. axis of symmetry, and these lines are ending themselves in some common point on this axis of symmetry.
[0054] Or, instead of the a.m. extremely left (right) parts of the external contour 22 of the vehicle, these a.m. two lines can go up to the left (right) part of some geometrical peculiarity (feature) of the vehicle body, and after that these lines can further go along this peculiarity.
[0055] One of these a.m. two lines is shining (is lighting) during the turn-indicating, and the second one from these two lines is not switched on during this time period.
[0056] Therewith the switched-on lighting line embraces (surrounds) the external contour (Silhouette) of this vehicle, and concretely from that side of the axis of symmetry, whereto the turn-intention is intended and indicated. Whereby a.o. these lighting lines can embrace (surround) the external contour (Silhouette) of only one part of a vehicle (as f.e. radiator 23 , front window (back window) 24 , motor hood 14 , deck lid (luggage rack, boot) (or back door) 25 , etc.), also from that side of the axis of symmetry 20 , whereto the turn-intention is intended and indicated. Or one can use not only one pair of the a.m. lightlines 6 , but to use several/numerous pairs of the lighting-able lines 6 simultaneously.
[0057] Each of the a.m. two lighting-able lines, which belong to the same a.m. pair, can begin themselves approximately on the axis of symmetry and end themselves approximately on the extremely left (or right correspondently) part of the external contour of a vehicle.
[0058] Each of the a.m. two lighting-able lines, which belong to the same a.m. pair, can also begin themselves approximately on the axis of symmetry and to end themselves approximately on the left (or right correspondently) usual light source (among others head lamp 1 , turn-indicating lamp 3 or 5 , etc.) of the vehicle 16 .
[0059] And besides all these lighting lines a.o. can be also discontinuous.
[0060] The lightlines 6 can also blink, a.o. also blink together and synchron with the usual turn-intention lighting lamps 3 . Or the lightlines 6 can shine (light) such way, that this lighting is formed from the one after another following bright (lighting) and dark spaces (points), where this lighting is controlled electrically such way, that the bright and dark spaces (points) move in the direction of turn-intention. The arrow-kind structure 7 can contain also several/numerous lightlines 6 , whereby some of these lines 6 can blink, and the others from these lines 6 simultaneously can show/indicate the turn-intention through the a.m. moving of the bright light spaces/points.
[0061] In general the arrow-kind structure 7 is formed from the following most important elements:
1) Curvilinear head-part 17 of the arrow-kind lighting structure 7 :
Die lighting lines, which are lighting (a.o. also blinking lighting) from that side of the plane of symmetry 21 of a vehicle 16 , whereto the turn-intention is intended and indicated. To the head of the arrow belong also the such permanently (not blinking) shining lights (a.o. head lamps), which are also placed from the same side of the plane of symmetry. They are normally placed in the top of the curvilinear head of arrow. Also the usual blinking lamp-kind turn-intention indicators (as f.e. lamps 3 , 5 , etc.) can belong additionally to the head-part 17 of the arrow-kind lighting structure 7 .
2) Foot-part 18 of the arrow-kind lighting structure 7 is formed through:
a) the permanently (not blinking) lighting “Foot”- 7 F—of the arrow 7 , i.e. a head lamp 1 , (or also other lights 26 , which shine permanently (not blinking way), and which are placed on the vehicle body from the opposite side of the a.m. plane of symmetry 21 ;
and
b) the dark gap 19 between the a.m. foot 7 F of the arrow 7 and the axis of symmetry 20 of the vehicle on the front view (back view) of the vehicle.
[0067] In reality on see normally either a front view, or a back view of a vehicle, and therefore below will be spoken not about the plane of symmetry 21 , but about the axis of symmetry 20 of the front view (or back view).
[0068] There always exists an essential dark distance (interval, gap) 19 between the “Foot” 7 F of the arrow 7 and the axis of symmetry 20 , from which one the curvilinear head-part 17 of the arrow 7 begins itself. On the other hand, the head of the arrow contains long lighting lines, which embrace (surround) or cover a big external contour of the one from the two symmetrical opposite sides of a vehicle. One (either left or right) part of the external contour (silhouette, Ladeprofil) of the vehicle from the left (right) head lamp up to the axis of symmetry 20 remains dark. And the other part of the vehicle (i.e. a right (left) silhouette, immediate from the axis of symmetry up to the right external contour is shining, a.o. also blinking shining, and besides, a.o., it is indicated by the long lighting lines. Therefore this lighting structure 7 is easy recognisable.
[0069] Some possible variants of embodiments of the arrow-kind lighting structure 7 is presented a.o. in FIG. 7 (both for the left and for the right turn-intentions). These arrow-kind structures 7 are presented, nevertheless, also in others figures in this description, actually everywhere, where one shows schematically the views “in the Darkness”.
[0070] The lighting lines 6 are placed outside the head lamps, and concretely either on the vehicle body 2 or on (or behind of) the windows 24 of the vehicle. (One cannot place effectively any additional lights under the transparent cover of a head lamp 1 , because these additional lights could be practically bad recognisable against the bright shining background of the head lamp.) The lighting lines 6 are long; their lengths are comparable with the external dimensions of the vehicle, on which one these lines are installed. Therefore a human eye recognises surely these lines against the background of a vehicle's body with the brightly shining head lamps and back lamps.
[0071] This way one shows the turn-intention not by some point-kind (it means among others (a.o.) round, quadrangular, etc.) little lamps, but by an arrow-kind lighting structure, which one has the same (or comparable) dimensions with the dimensions of the vehicle. Besides, this arrow-kind lighting structure contains both the permanently (not blinking) shining head- and back lamps 1 , and also the lighting (a.o. also blinking lighting) lines 6 .
[0072] In some embodiments the lightlines 6 can irradiate a diffusive (scattered, dispersal) light. But in other embodiments these lightlines 6 can also irradiate a shining beam-kind (a.o. also a shining perpendicularly to the lightline or to the vehicle body) light.
[0073] Or the same lightline can also be lighting-able in the both a.m. modes: either in a diffusive light-mode (f.e. in the darkness), or in a shining (beam-kind) light-mode (f.e. in the sun weather). Such way the same lightline 6 can be not-dazzling in a darkness, but be good recognisable in a sun weather.
[0074] For the lightlines 6 one can use light sources, which work on all possible physical principles, a.o. also the LED-kind light sources.
[0075] FIG. 8A (front view) and FIG. 8B (side view) shows schematically some examples—variants of the placing of the lightlines 6 to attain the easy recognisable turn-signalling, and, among others, to realise the arrow-kind turn-signal lighting of a vehicle. All lightlines are shown only on one side of a vehicle, and concretely for the case, when a vehicle have to show a turn-intention on the left. The possible variants for the turning on the right are absolutely symmetrical, and therefore these variants are not shown. The realisation (embodiment) variants for the back lighting are the same, as also for the above described front lighting, and therefore these variants are also not shown.
[0076] The realisation (embodiment) variants are possible, in which only one of the lightlines 6 (among others 6 a - 6 z ) is used; or all possible variants, where any combinations of these lightlines 6 (among others also combinations of lines 6 a - 6 z ) are used. The most probable combinations are presented in the FIG. 9 . Nevertheless all other combinations of the lightlines 6 are also possible. The lightlines 6 a - 6 z can a.o. be placed on the edge-lines (inflection/bend-lines) of the vehicle body surface, on the vehicle body surface near these (edge-, inflection-, bend-) lines, on edges, above or under the edge-lines of the moving parts (as £e. door 13 , motor hood 14 , etc.), anywhere on the vehicle's body surface, on- or behind the glasses (but not under the head lamps covers—s. above). Also the realisation (embodiment) variants are possible, where the right or left ends of the lightlines 6 do not adjoin the head lamps, back lamps, or other lighting.
[0077] The same arrow-kind lighting is placed on the back part of a vehicle the same way. Instead of the head lamps 1 one use here the back lamps (back lighting lamps) 1 . Therefore, as it was already said above, mainly the front views are given in the drawings, because the back views are, in the subject meaning, the same. (The circumstance that the head lamps are normally round and white-lighting, and the back lamps (back lights) are normally quadrangular and red-lighting, does not play any subject role for the contents of the patent description).
[0078] Nevertheless there is an essential difference: there are no air intake on the back side, and therefore one can place there the lightlines not only parallely, i.e. along the ribs of air intake, or outside the air intake surface, but also anywhere, with a free chosen angle α between these lightlines ( FIG. 10A and FIG. 10B ). Self evidently one can place the lightlines 6 under the angle on to another also on the front side of a vehicle as well also on the flank side of a vehicle, if the geometry of a vehicle body permits it.
[0079] The most probable realisation (embodiment) variants for the back view of a vehicle are shown in the FIG. 9 , variants 33 - 37 . A lightline 6 can a.o. first be placed under the laggage hood (or back door) 25 , and then this lightline can embrace (surround) the all vehicle. Or this lightline can embrace the laggage hood (or back door). Or this lightline can embrace (surround) the back window, and to be placed either behind the window glass or on the vehicle body near the window, etc.—s. above.
[0080] The placed behind the window 24 (front window or back window or both) lightlines 6 can be used in the already produced vehicles as an additional equipment, i.e. without changing of a vehicle construction (design).
[0081] One can also switch on the lightlines 6 from the both sides of the axis of symmetry simultaneously to indicate a stop-intention. Such stop-intention indication can be used also instead of the presently existed stop-intention lighting. Nevertheless one can use such signal also additionally to the presently existing stop-lighting.
[0082] The presented in the drawings solutions can be also worded another way, namely, that one understands under the arrow-kind structure the such placing of lightlines 6 , where the end points of these lightlines are separated one from another at the one side of these lightlines, and they are placed, among others, approximately (nearly) at the central axis line of symmetry of a car body, or near it; and the end points of these lightlines of the other sides of these lightlines are placed in one point, or nearby one to another, or the both lightlines are adjoin by their left or right end points correspondently to the left or right head lamp (or correspondently to one other kind of a left or right permanently (not blinking) shining lamps, among others, back lights). Whereby all arrow-forming lightlines are electrically switched-on to shine simultaneously on that side of a vehicle, whereto this vehicle executes the turn-indication.
[0083] The lightlines 6 can be both straight and curved.
[0084] One can see that in the majority of embodiments the head of the arrow-kind structure 7 (or every part of this head) looks approximately U-shaped (or π-shaped, bzw. V-shaped), where the letter U (or π, or V) is placed horizontally (i.e. 90° turned to the its usual writing), and the both ends of the a.m letters lay on the vertical axis of a vehicle.
[0085] The lightlines 6 can be placed on the body of a vehicle, a.o. also along a window of a vehicle, or on a window of a vehicle, or behind a window of a vehicle, or a.o. on the boundary between a window edge and vehicle's body edge. There can be, as said above, also a combined placing of lightlines 6 both behind a vehicle's window and on a vehicle's body.
[0086] The shown in the FIGS. 1-5 realisation (embodiment) variants of the invention can be worded also the following way:
[0087] The turn-intention of a vehicle 16 is indicated by a lightline 6 , which one lays outside a head lamp 1 (or outside a head lamp transparent cover), whereby the both ends of this lighting line lay approximately on the axis of symmetry 20 of the front view (or back view) of this vehicle, and besides, embraces (surrounds, contains) this line the external contour (the silhouette 22 ) of this vehicle from that side of the axis of symmetry 20 , whereto the turn-intention is intended and indicated. Where this lighting line can also embrace (surround) the external contour (silhouette) of only one part of this vehicle, also from that side of the axis of symmetry, whereto the turn-intention of the vehicle is intended and indicated. (One a.m. part of the vehicle is for example a radiator grill (grate) 23 , front window (back window) 24 , motor hood 14 , laggage hood (or back door) 25 , a lower part of a vehicle's body, which part lays under the front- and back windows, a geometrical peculiarity of a vehicle's body, as for example an inflection (bend)—line 27 of the motor hood surface, etc.). Besides, these lighting line cam be, a.o., also discontinuous, i.e. inside these lighting lines also the dark (i.e. not lighting) intervals can exist, or the intervals, where the other light sources (as f.e. the head lamps, the back lamps, etc.) lay.
[0088] Here it is meant, that the case in point is a line, which one is beginning and ending itself approximately on the a.m. axis of symmetry. Therewith, in this wording one understands it so, that the line groups, which form one line (as for example, a.o. the groups 6 a & 6 b ; 6 i & 6 j & 6 h ; 6 l ,& 6 m & 6 k ; 6 u & 6 v ; etc.) present the one solely line, which consists of several parts, as for example, 6 a & 6 b , etc.
[0089] In this description normally the lightlines only from one side of a vehicle are shown, and concretely for the case, when a vehicle have to show a turn-intention either on the left, or on the right. The possible variants for the turning in the opposite direction (i.e. on the right or on the left correspondently) are absolutely symmetrical and therefore these symmetrical variants are not shown.
[0090] All variants of placing of lightlines for the front view are also suitable for the back view, and vice versa. Therefore only one view is shown (either front view or back view of the vehicle) for every variant of placing of the lightlines.
[0091] As it was already in general described, the lightlines 6 can also embrace (surround) some separate parts of the vehicle body, a.o. also head lamps, visual peculiarities of vehicle's body, as f.e. convexities (reliefs) or bends of the vehicle body, etc., where the a.m. lightlines 6 or some separate parts of the lightlines 6 can built (form) the closed curves (s. f.e. FIG. 22-FIG . 30 ).
[0092] Among other variants, the lightlines 6 can embrace (surround) some a.m. separate, big in comparison with the head lamps parts of the vehicle body (a.o. also the splash-boards/wings), but do not build (form) any closed curves, where, in some projections (f.e. from the front view) one can a.o. see visually the closed curves, or almost closed curves of lighting lines (it means that the lightlines can build (form) the closed or almost closed curves in some projections).
[0093] Furthermore, in the above described cases, the lightlines 6 can a.o. also be not connected with the axis of symmetry.
[0094] The lightlines 6 can a.o. also be placed on a splash-board/wing (s. f.e. FIG. 28-FIG . 30 ), or they can embrace (surround) the doors.
[0095] As it was already described, the lightlines 6 can embrace (surround) also the windows, and besides they can embrace (surround) not only the front windows and back windows, but also the flank windows. For these cases the all above described features are also valid, a.o. that these lightlines can be placed either behind the window or on the vehicle's body near the window, etc.—s. above.
[0096] One can describe it also such way, that a turn-intention signal (Blinker) is formed by the lightlines 6 , which lightlines embrace (surround), completely or partially, a flank window.
[0097] The lightlines 6 can also consist of the lighting points or lighting intervals or other geometrical figures.
[0098] The lightlines 6 can also build (form) a wide lighting strip (band), which width is comparable with diameters of the head lamps 1 or back lighting 1 h . Or, instead of the lightlines 6 , one can build also a wide lighting strip (band) 15 , the width of which is comparable with the diameters of the head lamps 1 or back lighting lamps 1 h ( FIG. 11A and FIG. 11B ). In this case the case in point is a pair of wide strips (bands) 15 , where the each of them adjoin itself by it's left or right end correspondently to the left or right head lamp 1 (or correspondently to one other kind of left or right permanently (not blinking) shining lighting, a.o. back lighting 1 ). And besides, these wide strips are blinking periodically, among other variants also synchron with the usual turn-intention lighting lamps together.
[0099] The strips (bands) 15 can be also both straight and curvilinear.
[0100] The embodiments also possible, where the whole vehicle's body 2 is blinking completely from the left or right side from the axis of symmetry 20 . Or a part of the vehicle's body (a wide strip (band) is shining or blinking, which part lays between the axis of symmetry and external contour (silhouette) of the vehicle.
[0101] One next example of embodiment of invention is presented in the FIGS. 12 (A-C)- 19 (A-C).
[0102] Both in the darkness and also under the shining sun, the part 11 of road surface (asphalt, ground surface etc.) immediately under the vehicle is the most dark place on & near the vehicle, because this surface part lays always in the shadow. (The shadow is caused either by day light (sunshine) or by night street lighting. Therefore one can equip a vehicle with the lights (beamers) 10 , which lights 10 are shining (beaming) down (and which lights 10 are placed, among other variants, under a vehicle, or, a.o., on edges of a vehicle), and which lights 10 light up either the left or the right part of the road surface under the vehicle (and also a bit near the vehicle) correspondently to the direction of the turn-intention (FIG. 12 (A-C)- FIG. 14(A-C) , FIG. 16-FIG . 19 (A-C)). These lights 10 can light up also the internal parts 29 of either left or right wheel of the vehicle, correspondently to the direction of a turn-intention ( FIG. 14(A-C) ). (Furthermore, self-evidently, one can light up not only the internal, but also the front parts of the a.m. correspondent wheels of a vehicle in the front side of the vehicle and the back parts of the a.m. correspondent wheels of the vehicle in the back side of the vehicle.) In contradiction to the usual lights 1 , which may not dazzle a driver, who moves in the opposite direction, the lights 10 can be infinitely bright and strong-lighting. Also in contradiction to the head lamps 1 and to the other usual lighting of a vehicle, these lights 10 can be focused exactly on the determinate places of the surface 12 of the road under (as well as a bit near) the vehicle, or these lights 10 can shine parallel-straight-lighting. As this strong light-signal is focused on the surface of a road under- or directly near the vehicle (but it does not shine parallely to the road surface into the eyes of a driver of a vehicle, which moves in the opposite direction), there is no reasons to limit the intensity of the lighting.
[0103] The lights 10 can also blink, a.o. they can blink also synchron with the usual turn-indicating lights 3 . Nevertheless the lights 10 can also blink sparkle/flash-kind (short blink time), where the every flash is high-bright and intensive-lighting. The blink frequency can be also higher, a.o. also much higher the frequency of the usual turn-intention lights (blinkers). The sparkle/flash-kind, also energy economizing, lighting techniques (or light-impulse techniques) is known a.o. from the airplane-building technologies, photocamera's producing technologies; the techniques for the multiple light flashes during a short time periods is also known from the phototechnologies, and therewith it belongs to the state of technology.
[0104] The light-flashing lights (lamps) can be also so electrically connected, that the each further series of quick-flashes is interrupted by a break (i.e dark time-period without light-beaming), where the time period of the flash-series is the same as the time period of switched-of state of a turn-intention indicator (blinker), and the time period of the a.m. break (dark pause) of the a.m. light-flashing lamp is the same as the time period of the not-lighting pause of the blinking turn-intention light, and besides the a.m. light-flashing lamp and the usual turn-intention lights are switched on and switched of synchron and simultaneously.
[0105] FIG. 15 shows some possible variants of synchronising between the light-flashing lamp (lighting) and usual turn-intention lighting in the same vehicle. Here “Iw” is the light intensity of a turn-intention lamp; “Is” is the light intensity of a light-flashing lamp, “t” is time, and “E” is the envelope curve.
[0106] As it is known, a human eye recognises the two, each after other in series happening light flashes as two different flashes only if the time period between these flashes is bigger then a definite known biologically determinated constant (in the future named as the “T eye ”). But if the a.m. time period is less then the a.m constant T eye , recognises the human eye these a.m. two flashes as one flash.
[0107] Therefore the above described light-flashing lights (lamps) can be built or installed (electrically connected) such way, that the time periods between the solely separate flashes is less then the a.m. constant T eye . In this case the street traffic members recognise the complete flash-series as one non-interrupted lighting.
[0108] Or vice versa, the above described light-flashing lights (lamps) can be built or installed (electrically connected) such way, that the time periods between the solely separate flashes are bigger then the a.m. constant T eye . In this case the members of street traffic recognise also the separate flashes.
[0109] The second a.m. working regime provides more recognisable indicating, which one can be used in the extraordinary bright surrounding (f.e. under the intensively shining sun). The first a.m. working regime provides a less aggressive indicating.
[0110] The light-flashing lights (lamps) 10 can consist both of lamps (or other point-kind sources of light, a.o. circle, square, quadrangle, triangle, etc.) 10 b , and of schining strips (bands) 10 a , which are placed under the vehicle's body 2 .
[0111] Such way one use the lights 10 as the turn-indicating lighting.
[0112] Besides, instead of the two lamps 1 , which are place on the both sides of the vehicle body (and on the both sides of the surface of the radiator opening 8 ), the usual head lamps 1 themselves can consist of one shining strip (band) 9 , which strip (band) is placed under the surface of the radiator opening 8 , and which strip (band) takes place from the left to the right boundary of the front side. Therewith one can reduce the dazzling effect for a driver, who moves in the opposite direction ( FIG. 20A and FIG. 20B ).
[0113] One can also use the above-described turn-intention lighting (both the lightlines 6 —kind lighting, and the turn-intention light-flash 10 —kind lighting) for the “Stop”- and “Furthermoving”-manoeuvre indication. For this aim one switch on simultaneously the both turn-intention lighting, which are placed from both the left and right side of the plane of symmetry 21 .
[0114] As an example, one example of embodiment is presented in the FIG. 21 . To indicate a stop-intention, one switch on simultaneously the lightlines 6 , which are placed on the right- and left-side of the axis of symmetry 20 ( FIG. 21 ). When the vehicle is going to move again, one switch off simultaneously the both lightlines. Furthermore, the lightlines 6 can shine a.o. blinking way in the turn-intention mode, but in the stop-indication-mode (i.e. when the lights a switched off simultaneously) these lights can shine a.o. permanently (not blinking way). Wie ist es oben bereits gesagt, alle möglichen Variationen der Konfigurationen der Leuchtlinien 6 sind möglich. Für die Stop-Indizierung müssen aber alle Leuchtlinien 6 an der Karosserie beidseitig (d.h. symmetrisch in Hinsicht auf die Symmetrieachse 20) leuchten.
[0115] In the first embodiments one can use the traditional lamp-kind (point-kind) turn-intention lights (lighting lamps) 3 , which one do not belong to the above-mentioned arrow-kind structure, also together and simultaneously with the lightlines 6 . But one can use the lightlines 6 also instead of the lighting lamps 3 , because these lighting lamps 3 are much less recognisable and therewith they are surplus (not necessary). Therewith the case in point are both the additional turn-intention lighting indicators and also the alternative turn-intention lighting indicators. If in some separate countries the legal rules exist to use the existing constructions of “Stop”- and “Turn-intention”-lighting, they can be used simultaneously with the above described “Turn”- and “Stop”-signals.
[0116] The turn-intention indicators, both according to this description, and also all traditional turn-intention lightings, can be built as the lighting with the possibility to regulate (control) the brightness of this lighting.
[0000] Besides, a vehicle contains also:
a devise (devices) for measurement of brightness, with which device the measuring of brightness of the head lamps, vehicle's body and brightness of surrounding can be executed; means for calculations (computer, chip, etc.); and a device (means), which change the brightness of the turn-intention lighting.
[0120] The above mentioned device for the brightness measuring transfers the actual dates to the a.m. means for calculations. These means for calculation calculate the optimal for a human eye intensity of light of turn-intention lighting (as well as of stop-signal lighting) and gives the command to the a.m. device to change the brightness of the turn-intention lighting (as well as stop-lighting). The same way one can also regulate (control) the brightness intensity of the head lamps, as well as always realise an optimal ratio between the brightness intensity of head lamps and turn-intention lights (as well as stop-signal lights).
[0121] As it was already shown above, one can indicate the turn-intentions of a vehicle through the lighting up of the correspondent (left or right) wheels of a vehicle. In this case the vehicle's wheels reflect a “light-irradiation from outside”. Nevertheless one can indicate the turn-intentions of a vehicle such way, that the vehicle's wheels have the sources of light themselves, i.e. the turn-intention lighting is placed on the vehicle's wheels or in the vehicle's wheels.
[0122] The turn-intention lighting 30 can be placed also on the upper parallely laggage splints 31 ( FIG. 31A and FIG. 31B ). These splints for the laggage carrying are oftly placed on the upper part of a vehicle's body 2 .
[0123] One can place the turn-intention-lighting 32 also on two rods (supports) 33 , where these rods 33 are placed on the upper part of the vehicle's body 2 ( FIG. 32A and FIG. 32B ). Nevertheless such placing could be suitable only if these rods 33 execute simultaneously also some other functions. And concretely:
[0000] 1) The rods 33 , or at least one of them, can execute a role of an antenna. In the old models of vehicles one used two antennas, where the each of them was placed on the vehicle's body from the right or left side. Now one used only one antenna, which one placed centrally on a vehicle's body. But one can use two antennas again, where the rods 33 could execute the both functions (antenna and carrier of a turn-intention lighting).
2) The rods 33 , or at least one of them, can also execute a role of a video-scout (vehicle's periscope)—( FIG. 34(A & B)- FIG. 36) . As a driver sits in a vehicle, he can observe the traffic situation from his position only limited. In particular. He can see only the immediate next nearest vehicle in front of him and behind him. A driver does not see the 2-nd, third, firth, etc. vehicles, which move in the line before him and behind him. The using of videocamera for the aims of vehicle's orientation is known. But these videocameras are placed directly on a vehicle's body. Therewith such cameras provide the views only to the immediate nearby moving vehicles. If one places a camera 34 on the upper top of the rod 33 , which rod is placed on the vehicles body 2 , and which a.m. upper top stays above the vehicle, the driver will be able to observe visually also the situation with the a.m. 2-nd, third, firth, etc. vehicles before and behind of him in the line. This camera 34 can be placed, self-evidently only on a long enough rod (support) 33 . One (solely) rod 33 can be placed on the vehicle's body centrally, or it can be placed on one side of the body, (optimally from that side, where the driver sits—it can be on the left or on the right side). Nevertheless if one places the cameras 34 on two rods 33 , one can see not only the further vehicles in the line, but also make measurements of the related distances. Therewith the information from the cameras 34 can be transferred not immediately to a display, but firstly to the computer, and after that this traffic situation will be presented on display, among other variants also in a form of computer simulation. The a.m. system, which contains the rods 33 , cameras 34 , vehicle's computer, can also contain an additional device (means), which compensates the occasional deviations from the vertical axis or vibrations of the camera 34 (among others compensates electronically). This function can be executed also by a vehicle's computer with the correspondent software. Under the “vehicle's computer” one understands also a board-computer, a microchip, or any other electronic device, by which the electronical signals from the videocamera can be processed.
[0124] The langs or (and) angular position of the rod (the rods, in the future—“the rods”) 33 can be also adjustable.
[0125] The rod 33 can be executed as a telescopic one, and also contain a mechanism 35 (a.o. an electro-mechanical mechanism), by which this rod can be repositioned for the definite length by a driver during a trip ( FIG. 35 ).
[0126] A.o. the rod 33 can be adjustable also for different angles or orientations in respect to the vehicle's body, and for this aim this rod can contain the correspondent mechanisms 36 , a.o. the electro-mechanical mechanisms ( FIG. 36 ).
[0127] Each rod 33 can also have two cameras, where one of these cameras is orientated forwardly (forward view), and the second is orientated on the back (back view).
[0128] Self-evidently one can use these a.m. rods 33 with the videocameras 34 as video-scouts (“vehicle's periscopes”) also separately and independently from the turn-intention indication. Nevertheless if the rod 33 is used also as a turn-indicator, the turn-indication lights 32 , can be placed on the rod 33 both as the point-kind lights ( FIG. 32A and FIG. 32B ) and as the linelights ( FIG. 33A and FIG. 33B ).
[0129] The videocameras 34 in connection with a vehicle's computer can recognise a.o. also the turn-intention lights of the ahead- back- or nearby moving vehicles (and therewith the turn-intentions of these vehicles), and to inform the driver about it (through display, a.o. also through the simulating vehicle's contours on display, or through any other light-kind, acoustic-kind or any other informating signals).
[0130] Therewith the driver can be informed about the turn-intentions not only immediate nearby moving vehicles, but also about the turn-intentions of the 2-nd, third, fourth, etc. vehicle in the vehicle line.
[0131] The videocameras 34 in connection with the vehicle's computer can recognise a.o. also the stop-signal lights of the ahead-, back-, or nearby-moving vehicles (and therewith the stop-intentions of these vehicles) and to inform timely the driver about it.
[0132] The rods 33 , or at least one of them can also simultaneously all three roles/functions of: a) carrier of the turn-intention lighting, b) antenna, and c) a.m. video-scout (vehicle's periscope).
[0133] Each videocamera 34 is equipped with a device, which one provides the horizontal placing of the camera, also when the rod 33 has an angle with the vehicle's body. These devises are known (f.e. the parallelogram-based constructions with sharniers) and belong to the state of technology.
[0134] The turn-intention indication of a vehicle, as well as the stop-indication, can be executed also through the light signals, which can be generated on some distance from the vehicle or from it's material technical parts (as f.e. vehicle's body, back-view mirror, etc.). It means that one see a light signal “in the air” near the vehicle, not immediately on it's body or on it's parts. These technologies are already used in other technical branches, as f.e. laser-show, or in computer-monitors-production or TV technologies (in tablet PCs, smartphones etc., which technologies are also known under the name “3D”-technologies, a.o. one need in some cases also the special glasses), and therewith these technologies are known and belong to the state of technology.
[0135] In the future these a.m. “in the air hanging” turn-intention lights and stop-indication lights will be named as the “virtual-image indication lights.
Among other variants (below “a.o.”) these “virtual-image indication lights” can be generated by laser irradiation, where the source-device (devices) for this radiation is placed on- or in- or behind the vehicle's body. A.o. these “virtual-image indication lights” are generated by at least two sources of laser radiation, which are placed a.o. on-, or in-, or behind the vehicle's body. A.o. these “virtual-image indication lights” are presented as a hologram. A.o. these “virtual-image indication lights” can be also generated as a result of a reflection (visualisiring) of a light beam (or several light beams) in one space through the a) dispersed liquid drops, a.o. water drops, b) with the vapor, a.o. condensations steam, or c) with any other gas-like substance, which one contains a lot of reflecting points. In this case the vehicle contains (on the vehicle's body near the turn-intention lighting source) an injector, by which injector the a.m. dispersed drops of liquid or vapor are shooted from the vehicle's body such way, that the a.m turn-indicating beam beams through the space with these a.m. liquid drops or vapor. This last variant, which requires the using of liquid drops, can be nevertheless practically efficiently used only in solely special cases. A.o., instead (or additionally to) the lamp-kind blinkers, these back-view mirrors can contain the devices (means), which can generate the a.m. “virtual-image indication lights”, a.o. the 3D-visual image, outside the mirror body or outside the vehicle's body. This way the turn-intention can be indicated through this virtual-image, a.o. in the form of a “hanging in the air” arrow. | Invention provides a more clear recognisable indicating of the maneuvering-intentions of a vehicle to improve the safety of traffic. More appropriate for human eyes way to recognise the turn- and stop-intention signals are provided. It makes it possible to estimate the current traffic situation certain and quickly, in spite of the usual technical obstacles to recognise the signal- and vehicle position (as, for example, in the darkness, a dazzling light of the head lamps of the vehicles which are moving in the opposite direction, or, in the day time, a bright surrounding under the shining sun, or a limited view from the driver seat, etc.). | 1 |
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