A method for controlling the hang time of a tubular parison formed from a thermoplastic resin is provided with a second higher melting thermoplastic resin as an additive, and blow molding the resulting resin at a temperature below the glass transition temperature (Tg) of the higher melting component. In the case where the lower melting base resin is PBT and the higher melting additive resin is PET, the temperature of molding is below the Tg of the PET additive.

The present invention generally relates to blow-molding processes used to form hollow articles of a blow-moldable resin. More specifically, the present invention relates to processes whereby a polybutylene terephthalate resin is blow-molded to form hollow articles thereof.
Crystalline thermoplastic polybutylene terephthalate (PBT) resins have been used extensively as an engineering plastic in various fields owing to their excellent mechanical and electrical properties, as well as their physical and chemical characteristics. PBT resins have typically not been employed as a feedstock for blow-molding operations since the intermediate hollow parison that is formed during the blow-molding process is undesirably xe2x80x9cdrawn-downxe2x80x9d due to the poor melt tension that conventional PBT resin exhibits. Thus, hollow blow-molded articles have typically not been produced from PBT resins. Instead, PBT resins are conventionally thought of as an injection-moldable resin from which hollow injection-molded articles may be produced.
Prior attempts at forming hollow articles of PBT resins by blow-molding techniques have included increasing the molecular weight of the PBT resin so as to obtain a corresponding increase in melt strength (melt tension) and melt viscosity, since greater molecular weight typically results in a greater melt strength for a given resin. However, merely increasing the molecular weight of PBT resin to thereby increase its melt viscosity does not achieve the needed melt strength sufficient to employ PBT resins in blow-molding processes. Furthermore, the addition of inorganic filler materials has also been attempted as a means to increase the melt viscosity and melt strength of PBT resins sufficiently to allow blow-molding of hollow articles. Again, however, simply adding an inorganic filler to PBT resins (even those having an increased molecular weight) does not achieve the necessary melt strength properties necessary to allow the resin to be processed by blow molding techniques. U.S. Pat. No. 5,232,773 to Itoh et al describes blow-moldable PBT resins comprised of a PBT base polymer and an effective amount of between 0.01 to 5 parts by weight (based on 100 parts by weight of the PBT base polymer) of at least one organosilane compound.
PBT resin is desirably improved for blow molding by enhancing the melt tension characteristics.
PBT resins are desirable for blow-molding processes which typically produce hollow articles. A blow-moldable PBT resins comprises a PBT base polymer and an effective amount of between 0.1 to 20 parts by weight (based on 100 parts by weight of the PBT base polymer) of polyethylene terephthalate (PET). PET is melt-blended with the PBT base polymer prior to blow molding.
The hang time of a tubular parison formed from a thermoplastic resin, for example, PBT, is controlled by providing a second higher melting thermoplastic resin, for example, PET, as an additive and blow molding the resulting resin at a temperature below melt temperature (Tm) of the higher melting component. In the case where the lower melting base resin is PBT and the higher melting additive resin is PET, the temperature of molding is below the Tm of the PET additive.
When small quantities of a high melting point semi-crystalline resin are added to polymers, either amorphous or semi crystalline with lower melt temperatures, and subsequent processing is done at temperatures below the high Tm, significant enhancement to the base polymers""s melt strength is achieved. Improved processing in processes such as blow molding, thermoforming and profile extrusion can be achieved where resin melt strength (resistance to sag) is important.
An example, the addition of small quantities of PET resin to PBT resin or PBT blends increases resistance to sag. By processing the resulting material above the PBT Tm but below the Tm of PET significant improvements in melt strength are observed and the material flow is adequate for the application. Other high Tm resins such as nylon 6,6, PPS etc., which are high melting semicrystalline materials, can be added to either amorphous or semicrystalline resins to get the desired effect.
The presence of the high melting point crystals is desirable. If the Tm of the high melting point material is exceeded during processing, the melt strength is lost. To date these materials have been utilized in profile extrusion and extrusion blow molding with excellent results. The level of high melting crystalline resin is dependent on the process being targeted and the specific resins being used. It is desirable to have a large temperature difference between the high melting point semi-crystalline resin and the low melting resin to provide a wide process temperature window possible.
Improved melt strength in traditionally low melt strength resins greatly expands the types of polymers that can be used in polymer conversion processes requiring improved melt strength. More resins are under experimentation to determine what other desirable combinations can be utilized. This technology potentially has a large impact on the thermoforming, blow molding and profile extrusion communities.
The polybutylene terephthalate base polymers used in the compositions of the present invention include polyesters comprised mainly of recurring butylene terephthalate units. In particular, the preferred base polymers are polyesters obtained by condensing 1,4-butanediol with terephthalic acid or its lower alcohol ester. The polybutylene terephthalate base polymer is not limited strictly to PBT homopolymers, but also includes copolymers mainly comprised of polybutylene terephthalate units. The term xe2x80x9ccopolymersxe2x80x9d as used herein thus refers to polymers obtained by the polycondensation of terephthalic acid or its lower alcohol ester as the main dibasic acid component with 1,4-butanediol as the main glycol component in the presence of 40 molar % or less of an ester-forming monomer. The comonomer components usable herein include dibasic acid components such as isophthalic acid, orthophthalic acid, adipic acid, sebacic acid, succinic acid and oxalic acid as well as their lower alcohol esters; and glycol components such as ordinary alkylene glycols other than 1,4-butanediol, e.g. ethylene glycol, diethylene glycol, propylene glycol, trimethylene glycol, hexamethylene glycol, neopentyl glycol and cyclohexanedimethanol as well as aromatic diols, e.g. bisphenol A and ethylene oxide (2 mol) adduct of bisphenol A.
Hydroxy acids such as hydroxybenzoic acid and hydroxynaphthoic acid and their ester-forming derivatives may also be used as suitable comonomers. Furthermore, comonomers having halogen substituents are also usable and are effective in imparting flame retardancy to the resulting blow-molded articles.
In addition, copolyesters having a branched structure obtained by the polycondensation of a polyfunctional comonomeric compound having three or more reactive groups may also be employed as the PBT base polymer. The polyfunctional compounds usable herein include trimesic acid, trimellitic acid, pyromellitic acid and alcoholic esters thereof as well as glycerol, trimethylolethane, trimethylolpropane and pentaerythritol.
The PBT base polymer that may be used in the present invention is preferably one having an intrinsic viscosity (IV) within the range of 0.7 to 2.0, particularly 1.0 to 1.6. PBT resins having an intrinsic viscosity of less than 0.7 exhibit insufficient melt tension and cannot be blow-molded. On the contrary, an intrinsic viscosity exceeding 2.0 is unfavorable because the fluidity of the resin composition is poor. Furthermore, the extrusion moldability property of PBT resins having an IV of greater than 2.0 is impaired due to overloading of the extruder motor and pressure increases at the die.
The blow-moldable PBT resin compositions and the hollow blow-molded articles produced by such blow-molding processes include PET. The amount of the PET compound to be melt-blended with the PBT base polymer in the compositions is from about 1 to about 15 parts by weight based on the weight of PBT, preferably from about 3 to about 10 parts by weight, per 100 parts by weight of the PBT base polymer. When PET is present in an amount less than 1 part by weight, the intended effect to increase melt tension cannot be obtained. On the other hand, when excess amounts of PET is employed, melt-blending and/or blow-molding abnormally increases the composition""s viscosity.
A processing temperature of at least about 5 to about 15 degrees below the melting point of the highest melting thermoplastic component (that is, the temperature at which the last crystalline material melts as the polymer is heated) is desirable. The process temperature should be above the melting point of the lowest melting component. In the case of a PBT/PET blend, PBT, which is a substantially crystalline polymer and has an equilibrium melting point of about 227 degrees C., is the lowest melting component. Therefore, the processing temperature should be above about 227 degrees Centigrade. In the case of PET, after crystallization, the equilibrium melting point is about 256 degrees C., so that the operating range processing should be below about 256 degrees or in the range of about 241 to about 251 degrees C.
Known additives usually incorporated in synthetic resin compositions can be added to the PBT resin compositions of the present invention depending on the desired properties to be attained. Suitable known additives include stabilizers such as antioxidants and ultraviolet absorbers; antistatic agents; flame retardants; colorants such as dyes and pigments, lubricants, releasers, crystallization accelerators and nucleating agents.
The process for blow-molding the PBT compositions of this invention may be practiced using conventional blow-molding apparatus. In this connection, the PBT resin composition is plasticized with an extruder or the like, and is extruded or injected through an annular die to form a tubular intermediate parison. The tubular parison is then clamped between mold parts forming a mold cavity and a pressurized fluid (e.g. air) is injected into the interior of the clamped parison so that it inflates and conforms to the walls of the mold cavity. The PBT composition is then allowed to cool and solidify at which time the mold is parted and the hollow blow-molded article is removed.
During blow-molding, temperatures of the extruder cylinder and the die are each preferably maintained at between about 225 degrees to about 280 degrees C., more preferably between about 230 degrees to about 250 degrees C. The mold temperature is preferably between about 40 degrees to about 120 degrees C., and more preferably between about 60 degrees to about 100 degrees C. Although air is most preferably used as the inflation gas due to economic considerations, nitrogen or any other inert gas may be used, if desired. The pressure of the inflation fluid is preferably between 4 to 10 kg/cm.sup.2.
The present invention makes it possible to blow-mold PBT resin which has traditionally been extremely difficult to blow-mold. As a result, hollow blow-molded articles having stable qualities and shapes may be obtained. The PBT resin compositions of this invention may thus be used for the production of hollow articles having excellent physical properties which are inherent in the PBT base polymer and may be used under severe operating conditions. For example, the blow-molded articles may be used as automotive parts, components for chemical apparatus and tools, vessels and the like whereby chemical and heat resistance properties are required; and containers for food and drinks due to the gas-barrier properties, and odorless qualities of the PBT base polymer.
U.S. Pat. No. 5,779,959 to Coyle and Teustch illustrate a blow molding process and apparatus that may be used with the compositions described. According to the patent, a pair of mating annular members defining a resin inlet on the periphery of the module, a coaxial bore having an inner cylindrical surface, an annular extrusion outlet opening into the cylindrical surface; each of said module or modules have a channel for receiving and distributing polymer extending from the inlet to the outlet and defining a flow path for the polymer to flow from the inlet to the annular extrusion outlet through which the polymer is extruded in annular form. The channel extends symmetrically around the longitudinal axis of the extrusion module or modules in a manner so as to subject all of the polymer flowing from said inlet to said extrusion outlet to substantially the same process conditions along said flow path whereby the polymer is distributed at the annular extrusion outlet with properties which are substantially symmetrical around the axis for all resin distributed through said outlet.
With the parison head, the modules coaxially extend over spaced sections of a tapered stepped mandrels as to extrude their respective layers into a tubular extrusion channel defined between the inner surfaces of the modules and the outer surface of the mandrel. The extrudate exits the abovedescribed die into a container blow mold according to conventional techniques. As illustrated in FIG. 10 of the patent, parison 32 exits into a container blow mold 200. Container blow mold 200 can be a conventional split mold which is divided into halves 200a and 200b along its longitudinal axis and has a shape selected for the particular container desired. The extruded parison 32 is then processed according to conventional blow molding techniques. See, for example, xe2x80x9cBlow Moldingxe2x80x9d, Modern Plastics, October 1991, pp. 222-224. For example, after parison 32 exits into container blow mold 200 halves 200a and 200b of the mold come together, thereby pinching the bottom of parison 32 to form a seal. The sealed bottom of the parison will become the bottom of the finished container. Shortly after the bottom of the parison is pinched, a conventional cutting blade (not shown) severs the parison from the extrudate exiting the annular die 130. The container blow mold 200 is then removed from under annular die 130 and replaced with another mold 300 to repeat the process described above. This particular process is known as a single-station shuttle process. After the container blow mold is removed from under extrusion head 10, container blow mold 200 is shuttled to calibration station 310. A blow pin 311 is then inserted into container blow mold 200 and parison 32 to inflate the-parison into a container schematically illustrated as 312 in FIG. 10. Container blow mold 200 is not illustrated at calibration station 310 in order to better illustrate container 312. The blown container 312 is then separated from mold 200 and trimmed using standard techniques.
The following non-limiting Examples will further illustrate the present invention.


Pressure vessel assembly for a pressurized fluid system, comprises an enclosed outer casing, at least one internal tube extending within the casing, at least one fluid accumulator disposed within the at least one internal tube, and at least one cooling passage provided within the at least one internal tube and defined by a clearance between the at least one hydraulic fluid accumulator and the at least one internal tube. The pressure vessel assembly further includes a fluid storage compartment formed between the outer casing and the at least one internal tube. The fluid storage compartment is at least partially filled with a working fluid. The pressurized fluid system also includes a cooling fan allowing forced airflow through the cooling passage for forced cooling of the at least one hydraulic fluid accumulator and the working fluid in the storage compartment of the pressure vessel assembly.

1. Field of the Invention
The present invention relates to integrated pressurized fluid systems in general, such as for hydraulic regenerative drive systems, and, more particularly, to an integrated pressurized fluid system including a pressure vessel assembly containing at least one hydraulic fluid accumulator.
2. Description of the Prior Art
In conventional integrated pressurized fluid systems the recovered energy is normally accumulated in flywheel accumulators, in electrochemical batteries or in hydraulic fluid accumulators. The latter are of known technology and, in comparison with the other recovery and accumulation arrangements, they are more flexible in use, notably in connection with a vehicular transmission to which they are connected. On the other hand they remain less efficient in terms of mass and volume and consequently raise serious problems for fitting onto motor vehicles. In addition to penalizing the energy savings obtained, these problems of dead weight and bulk lead to high costs linked either with the hydraulic fluid accumulator itself or, mainly, with the modifications that have to be made to the vehicle to fit the accumulator. The result is that the motor vehicles equipped with the hydraulic fluid accumulator are no longer standard in any way and are therefore much more expensive to produce and maintain and that, furthermore, the equipment used for this installation cannot be transposed to another vehicle or modulated in size, which increases the overall cost of such an installation.
Accordingly, it is the intent of this invention to overcome these shortcomings of the prior art by providing a compact pressure vessel assembly combining all the accumulation functions and capable of being fitted without any substantial modification to various types of pressurized fluid systems, including standard motor vehicles equipped with hydraulic regenerative drive system designed for charging and discharging the hydraulic fluid accumulators.

Pressure vessel assembly for integrated pressurized fluid system


An assembly for positioning and removably supporting cargo on the exterior of a vehicle, wherein the cargo is preferably mounted on a mobile carrier assembly such as a hand truck. A hoist assembly includes a winch and lifting cable and is concurrently supported, along with the mobile carrier, on a base which is removably secured to a hitch structure mounted on the vehicle. A support assembly is secured to the base and is structured to independently but concurrently support both the hoist assembly and the mobile carrier, with or without the cargo thereon. Upon removal of the mobile carrier from the vehicle, the cargo supported thereon can be transported over the ground or other support surface to an intended location for use without requiring repeated loading and unloading of the cargo from the mobile carrier.

1. Field of the Invention
This invention relates to an assembly for positioning a mobile carrier or other load in a supported position on the exterior of a vehicle and comprises a hoist assembly and a support assembly. Both the load and the hoist assembly are concurrently mounted on the vehicle, preferably by being interconnected to the vehicle""s hitch structure, wherein the mobile carrier may be positioned in and removed from its supported position without the cargo being repeatedly loaded on and unloaded from the carrier.
2. Description of the Related Art
It is common practice to carry various types of loads, cargo, etc. on the interior of vehicles. Depending on the weight of the load or cargo intended to be transported, it is also known to use some type of lifting device. Typically such lifting devices are structured to lift and position the intended load into some part of the interior of the vehicle. By way of example only, pick-up trucks are specifically designed to use the truck bed as a support platform for the positioning of a variety of different loads on the truck. Also, with the increased popularity of sport utility vehicles (SUV) the interior cargo area associated with such vehicles is also, in many cases, specifically designed for the containment of a variety of different types of cargo.
In addition to the above, more conventional motor vehicles, such as passenger automobiles and the like may in some instances be adapted for the mounting and support of a variety of different loads, cargo, etc. on the exterior thereof. In such instances the use of auxiliary article carriers attached to some portion of the exterior of the vehicle has been attempted. However, the known or conventional mounting of carrier structures specifically designed to be secured to the exterior portion of a vehicle, for the transport thereof, typically requires that such article carriers be at least partially dismantled or otherwise modified in order to accomplish their secure mounting on the vehicle. The resulting problems and disadvantages associated with such known or conventional auxiliary article carriers are obvious and significant. More specifically, it is extremely inconvenient to the user of such known structures to assemble and or disassemble various portions of the auxiliary carrier when it is desired to either load or unload the carrier onto the vehicle.
In addition to the above, such carrying devices are normally not capable of having an intended load or cargo maintained thereon during the loading and unloading procedure. As a result, each time an auxiliary carrier is secured to a vehicle or removed therefrom the user must remove the intended cargo from the carrier, place it in a convenient location and then re-load the cargo once the vehicle and supported carrier reaches an intended designation. The above procedure, in addition to being extremely inconvenient, also defeats the primary purpose of using article carriers since the user must repeatedly load and unload the cargo from the carrier, as set forth above.
By way of example only, a user who enjoys the sport of fishing frequently employs the use of a mobile carrier assembly such as, but not limited to, various types of hand propelled carts or the like. These devices are used to move various equipment, devices, and supplies which may be required during a day of fishing. Such mobile carrier assemblies are commonly used in the transport of the various equipment, supplies, etc. from a vehicle to a fixed land object where, such as a pier, jetty, etc. where the fishing is to be conducted. Obviously, to assist the transport of the aforementioned equipment and supplies to and from the vehicle to the fishing site the mobile carrier assembly is extremely helpful. However, often times such carrier assemblies, as generally set forth above, are difficult to load onto and remove from the transporting vehicle. Therefore as with known or conventional auxiliary article carriers, it is not uncommon for the user to repeatedly load and unload all of the supplies during the mounting and removal of the carrier on and from the vehicle.
In addition to the time and inconvenience associated with such loading and unloading it is also well recognized that such equipment, supplies etc. involve a considerable amount of weight generally in the range of 200 pounds of more. Accordingly, it is readily apparent that the continuous and repeated handling of such equipment becomes a significant burden which seriously detracts from the intended enjoyment of fishing.
In an attempt to overcome the problems associated with the lifting, positioning and supporting of a variety of different loads, other than but including fishing supplies and equipment, the prior art has attempted to utilize a variety of lifting devices or winch assemblies. However, such known attempts typically involve situations where the winch is utilized to lift heavier than normal loads off the ground or other supporting surface and into or on an area or support platform specifically intended to store and support cargo. Therefore, known lifting devices are typically associated with pick-up trucks, vans, SUV""s, etc. Such devices are not easily adaptable for use with conventional passenger cars. To the contrary, such passenger vehicles are best suited to have a mobile carrier assembly, along with the cargo associated therewith secured to an exterior portion of the vehicle. Also, known lifting devices, of the type set forth above, frequently require their disassembly, once the cargo is loaded, in order that the vehicle may travel safely between intended locations.
Therefore it is well recognized that there are long existing and significant problems relating to lifting, positioning and supporting of a variety of different cargos on a vehicle for the transport thereof between intended locations. Accordingly, a need exists for an assembly capable of facilitating the storage of a mobile carrier assembly on the exterior of virtually any type of motor vehicle in a manner which eliminates the requirement or need for removing the cargo Jet from the mobile carrier assembly during the loading and unloading procedure. In addition such an improved and preferred assembly should include the utilization of an effectively structured hoist assembly which also may be mounted to the exterior of the vehicle concurrently to the mounting and support of the aforementioned mobile carrier assembly and cargo associated therewith. Utilization of such an improved assembly, would therefore eliminate most if not all of the problems and disadvantages associated with the transporting of various supplies and equipment between locations, by means of a motor vehicle, and also eliminate the unnecessary requirement of repeated loading and unloading of mobile carrier assemblies used to transport an intended cargo to a site or location for use. Finally, such an improved assembly should be durable, safe in its construction and use and be capable of being connected to the exterior of the vehicle without requiring any unusual or significant structural modifications of the vehicle, thereby enabling the use of such an improved assembly available for a variety of different applications.
The present invention is directed to an assembly structured to position a load preferably, but not necessarily, in the form of a mobile carrier assembly such as a hand truck, in a supported position on the exterior of a vehicle. In such a supported position the load can be transported to various locations and upon arrival at an intended designation, the load can be quickly and easily removed from its supported position on the vehicle. Once so removed the mobile carrier assembly or hand truck can travel over the ground or other supporting surface so as to further transport the cargo mounted thereon to an intended site of use. The cargo remains secured to the hand truck during all phases of it being mounted on and removed from the exterior of the vehicle. The need to repeatedly load and unload the cargo from the hand truck, as is common in conventional mobile carrier assemblies, is eliminated.
As will be described in greater detail hereinafter, the versatility of the assembly of the present invention allows for the positioning a variety of different loads and associated cargos in a supported position on the vehicle. As such, the load and or cargo may weigh several hundred pounds, wherein the weight limit is determined not only by the structural features of the assembly of the present invention, but also by the load restrictions of the hitch structure secured to the vehicle.
More specifically, the assembly of the present invention comprises a base which is connected to the exterior of a motor vehicle, preferably by means of interconnecting the base to a hitch structure. Further, the base is preferably removably connected to the hitch structure of the vehicle but, due to its relatively compact structure, may be left in place even when a load is not intended to be mounted on and transported by the vehicle.
In addition, at least one preferred embodiment of the assembly of the present invention includes a hoist assembly comprising a winch and a lifting cable connected thereto. The hoist assembly further includes a stanchion and a boom connected in outwardly extending relation to the stanchion, wherein the boom defines at least a portion of the path of travel of the cable between the winch and the load, to which the cable is attached.
Another feature of the assembly of the present invention includes the provision of a support assembly connected to the base and including individual support portions for concurrently supporting the hoist assembly and the load or mobile carrier assembly on the vehicle. More specifically, the support assembly includes at least a first support portion specifically structured to removably retain a portion of the hand truck or carrier assembly in a position or orientation which does not require the removal of cargo from the hand truck. Also, the support assembly includes at least a second support portion for the independent support of the hoist assembly, and in particular the stanchion associated therewith. The second support portion is further structured to maintain the stanchion, the boom, the winch and the connecting cable all in a substantially operative position, concurrently to the support of the hand truck, on the exterior of the vehicle. The positioning of both the hoist assembly and the concurrently supported hand truck is such as to facilitate travel of the vehicle and secure attachment of the assembly on an exterior thereof in a safe manner.
Also, the versatility of the present invention is demonstrated by the ability to mount and support a variety of different loads, other than a hand truck or like mobile carrier, on the vehicle. Accordingly, the structure of the load may vary and be of different weights, sizes and configurations. However, when the load is in the form of a hand truck or like carrier, it may be mounted on and removed from the vehicle without necessitating the repetitive loading and unloading of the cargo therefrom.
Therefore, one feature of the present invention includes the structuring of the boom to have a selectively variable length, so as to extend outwardly from the stanchion into different positions. The boom, as set forth above, defines at least a portion of the path of travel of the connecting cable and as such serves to position the connecting cable relative to the load. More specifically, the point of attachment of the connecting cable to the load may be varied dependent, at least in part, on the location of the center of gravity of the hand truck and or cargo. Proper alignment of the cable and the center of gravity is important in maintaining a proper orientation of the hand truck and the cargo, so as to facilitate its positioning into and out of a preferred supported position on the vehicle by virtue of an interconnection of the base to the hitch structure associated with the vehicle.
In addition, the length of the boom may be selectively varied into different preferred positions depending on whether the hand truck and cargo are being mounted on or removed from the support assembly. Also, further adjustment of the boom, resulting in selective positioning of the connecting cable relative to the load, can be easily accomplished to accommodate a variety of different cargos mounted on the hand truck. Therefore, proper orientation of the load and cargo can be easily accomplished when the center of gravity of a particular cargo significantly differs from the last cargo mounted on and transported by the hand truck or like mobile carrier assembly.
It is emphasized that the structural components of the assembly of the present invention are such that a variety of different load/cargo combinations may be positioned, mounted and supported on the base of the assembly, other than a hand truck or like mobile carrier assembly as is continuously referred to in the description of the most preferred embodiment provided hereinafter.
These and other objects, features and advantages of the present invention will become more clear when the drawings as well as the detailed description are taken into consideration.

Assembly for removably supporting cargo on a vehicle


A semiconductor device which permits reduction in the number of pins and in size thereof is provided. The semiconductor device comprises a sealing body formed of an insulating resin, the sealing body having an upper surface, a lower surface opposite to the upper surface, and side faces which connect the upper and lower surfaces with each other; an electrically conductive tab sealed within the sealing body; tab suspending leads contiguous to the tab and partially exposed to the lower surface and the side faces of the sealing body; a semiconductor chip fixed to a lower surface of the tab; a plurality of electrically conductive leads, the electrically conductive leads each having an inner end portion positioned within the sealing body, an outer end portion exposed to the lower surface and a side face of the sealing body, and a projecting portion projecting into the sealing body from a side face of each of the electrically conductive leads; a projecting portion projecting from a side face of each of the tab suspending leads and positioned within the sealing body; and electrically conductive wires positioned within the sealing body and connecting electrodes formed on a lower surface of the semiconductor chip with the projecting portions of the electrically conductive leads and the tab suspending leads.

The present invention relates to a semiconductor device and a method of manufacturing the same. Particularly, the present invention is concerned with a technique applicable effectively to the manufacture of a semiconductor device (non-leaded semiconductor device) such as SON (Small Outline Non-leaded package) and QFN (Quad Flat Non-leaded package) wherein external electrode terminals are exposed to a mounting surface side without intentional projection thereof on a side of a package.
A lead frame is used in manufacturing a resin-sealed type semiconductor device. The lead frame is fabricated by patterning a metallic plate into a desired pattern by punching with use of a precision press or by etching. The lead frame has a support portion called tab or die pad for fixing a semiconductor element (semiconductor chip) thereto and plural leads whose front ends (inner ends) face around the support portion. The tab is supported by tab suspending leads which extend from a frame portion of the lead frame.
In manufacturing the resin-sealed type semiconductor device with use of such a lead frame, a semiconductor chip is fixed to the tab in the lead frame and electrodes on the semiconductor chip and front ends of the leads are connected with each other through electrically conductive wires, thereafter inner end sides of the leads, including the wires and the semiconductor chip, are sealed with an insulating resin to form a sealing body (package), and then unnecessary lead frame portions are cut off. Where required, the leads projecting from the sealing body are subjected to a forming work.
On the other hand, as a resin-sealed type semiconductor device manufactured by using a lead frame there is known a semiconductor device (non-leaded semiconductor device) wherein a single-side molding is performed for one surface of a lead frame to form a package and leads as external electrode terminals are exposed to one surface of the package without intentional projection thereof from the peripheral surface of the package. As semiconductor devices of this type there are known SON wherein leads are exposed to both side edges of one surface of a package and QFN wherein leads are exposed to four sides of a quadrangular package. There also is known a semiconductor device wherein an upper surface of a tab is exposed to an upper surface of a sealing body (see, for example, Patent Literature 1).
In Patent Literature 1 is disclosed a semiconductor package wherein lower surfaces of leads are exposed to the peripheral portion of a lower surface of a resin capsule (sealing body). According to the structure disclosed therein, lower surfaces of lead inner ends are half-etched and the half-etched surfaces and electrodes on a lower surface of a semiconductor chip are connected with each other through wires. Further, electrodes on the semiconductor chip and pads are electrically connected with each other through ground wires.
[Patent Literature 1]
Japanese Unexamined Patent Publication
No. 2002-134676


Individual substituted [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one compounds and their pharmaceutically-acceptable salts are disclosed, as are libraries of such compounds. Methods of preparing and using the libraries of compounds as well as individual compounds of the libraries are also disclosed.

The present invention relates generally to the combinatorial synthesis of [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one derivatives. More specifically, the invention provides novel [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one compounds as well as novel combinatorial libraries comprised of many such compounds, and methods of synthesizing the libraries.
The process of discovering new therapeutically active compounds for a given indication involves the screening of all compounds from available compound collections. From the compounds tested one or more structure(s) is selected as a promising lead. A large number of related analogs are then synthesized to develop a structure-activity relation-ship and select one or more optimal compounds. With traditional one-at-a-time synthesis and biological testing of analogs, this optimization process is long and labor intensive.
Adding significant numbers of new structures to the compound collections used in the initial screening step of the discovery and optimization process cannot be accomplished with traditional one-at-a-time synthesis methods, except over a time frame of months or even years. Faster methods are needed that permit the preparation of up to thousands of related compounds in a matter of days or a few weeks. This need is particularly evident when it comes to synthesizing more complex compounds, such as the [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one compounds of the present invention.
Solid-phase techniques for the synthesis of peptides have been extensively developed and combinatorial libraries of peptides have been prepared with great success. During the past four years there has been substantial development of chemically synthesized combinatorial libraries (SCLs) made up of peptides.
The preparation and use of synthetic peptide combinatorial libraries has been described for example by Dooley in U.S. Pat. No. 5,367,053; Huebner in U.S. Pat. No. 5,182,366; Appel et al in WO PCt 92/09300; Geysen in published European Patent Application 0 138 855 and Pimmg in U.S. Pat. No. 5,143,854. Such SCLs provide the efficient synthesis of an extraordinary number of various peptides in such libraries and the rapid screening of the library that identifies lead pharmaceutical peptides.
Peptides have been, and remain, attractive targets for drug discovery. Their high affinities and specificities toward biological receptors as well as the ease with which large peptide libraries can be combinatorially synthesized make them attractive drug targets. The screening of peptide libraries has led to the identification of many biologically-active lead compounds. However, the therapeutic application of peptides is limited by their poor stability and bioavailability in vivo. Therefore, there is a need to synthesize and screen compounds that can maintain high affinity and specificity toward biological receptors, while exhibiting improved pharmacological properties relative to peptides.
Combinatorial approaches have recently been extended to xe2x80x9corganicxe2x80x9d or non-peptide libraries.
Significantly, many biologically active compounds contain the imidazole moiety. Such compounds are conformationally constrained scaffolds, are quite common in nature and many imidazole-containing natural products have been isolated encompassing a wide range of biological activities. The imidazole ring system is of particular importance because it is present in the essential amino acid histidine. The histidine residues are found at the active site of ribonuclease and several other enzymes. Drugs such as cimetidine were designed with histamine itself as the starting point [C. R. Ganellin, in Medicinal Chemistry, ed. S. M. Roberts and B. J. Price, Academic Press, London, 1985, p. 93; G. J. Durant, Chem Soc. Rev., 1985, 84, 375].
Several other classes of drugs are based on the imidazole ring. 2-Nitroimidazole (azomycin) is a naturally occurring antibiotic and some synthetic nitroimidazoles are active against intestinal infections (Reviews: Nitroimidazoles; Chemistry; Pharmacology and Clinical Applications, eds. A. Breccia, B. Cavalleri, and G. E. Adams, Plenum Press, New York, 1982; J. H. Boyer, Nitrazoles, VCH, Deerfield Beach, Fla., 1986).
Imidazole-containing moieties are found in many biologically active compounds and are known to have useful therapeutic implications. There is a need to further study and develop large numbers of [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one compounds and their binding to biological receptors. These compounds of the present invention are principally derived from the synthesis of dipeptides, but the dipeptides are substantially modified. In short, they are chemically modified through, acylation and cyclization via Bischler-Naprielski reaction into the subject [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one, thus providing mixtures and individual compounds of substantial diversity.
The invention provides a rapid approach for combinatorial synthesis and screening of individual compounds and libraries of [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one compounds. The present invention further provides libraries and individual compounds and their pharmaceutically-acceptable salts of Formula I. The present invention also relates to the preparation of synthetic combinatorial libraries of organic compounds and their pharmaceutically-acceptable salts of Formula I, wherein R1, R2 and R3 have the meanings provided below.
The present invention has several benefits and advantages. One benefit is the provision of a new synthesis for bicyclic [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one compounds. The present invention provides a large array of diverse [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one compounds that can be screened for biological activity, and as described below, are biologically active.
An advantage of the invention is that individual compounds can be prepared or libraries containing a plurality of compounds can be prepared.
Another benefit of the invention is that the yield of bicyclic compound produced is relatively great compared to that obtained in prior syntheses of the parental compound.
Still further benefits and advantages of the invention will be apparent to the skilled worker from the discussion that follows.
The present invention relates to the preparation and use of synthetic combinatorial libraries and individual compounds of a [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one also referred to as a imidazo-imidizol-one that correspond in structure to Formula I, and their pharmaceutically-acceptable salts:
wherein:
R1 and R2 are independently selected from the group consisting of a hydrogen atom (hydrido), C1-C10 alkyl, C1-C10 substituted alkyl, C7-C16 phenylalkyl, C7-C16 substituted phenylalkyl, phenyl, substituted phenyl, C3-C7 cycloalkyl, and a C3-C7 substituted cycloalkyl group.
R3 is selected from the group consisting of a hydrido, C1-C10 alkyl, C1-C10 substituted alkyl, C2-C10 alkenyl, C2-C10 substituted alkenyl, C2-C10 alkynyl, C2-C10 substituted alkynyl, C3-C7 substituted cycloalkyl, phenyl, C7-C16 phenylalkyl, C7-C16 phenylalkenyl, C7-C6 phenylalkenyl and a C7-C16 substituted phenylalkenyl group.
In one embodiment of the above bicyclic imidazo-imidizol-one of Formula I, wherein
R1 and R2 are independently selected from the group consisting of a hydrido, methyl, benzyl, 2-butyl, aminobutyl, N,N-dimethylaminobutyl, N-methylaminobutyl, N-methyl-N-benzylaminobutyl, 2-methylpropyl, methylsulfinylethyl, methylthioethyl, N,N-dimethylaminoethyl, N,N-dimethyl-aminopropyl, Nxe2x80x2,Nxe2x80x2,Nxe2x80x2-trimethylguanidinopropyl, Nxe2x80x2,Nxe2x80x2,Nxe2x80x2-tribenzylguanidinopropyl, Nxe2x80x2,Nxe2x80x2-dibenzylguanidinopropyl, Nxe2x80x2-methylguanidinopropyl, hydroxymethyl, 1-hydroxyethyl, 2-propyl, N-methyl-3-indolylmethyl, 4-methoxybenzyl, 4-hydroxybenzyl, propyl, butyl, cyclohexylmethyl, phenyl, 2-naphthylmethyl, and a 4-imidazolylmethyl substituent; and
R3 is selected from the group consisting of a 1-phenyl-1-cyclopropyl, 1-phenylbutyl, 2-phenylbutyl, 3-fluorobenzyl, 3-bromobenzyl, xcex1,xcex1,xcex1-trifluoro-m-xylyl, p-xylyl, 4-fluorobenzyl, 3-methoxybenzyl, 4-bromobenzyl, 4-methoxybenzyl, 4-ethoxybenzyl, 4-isobutyl-a-methyl-benzyl, 3,4-dichlorobenzyl, 3,5-bis-(trifluoromethyl)-benzyl, 2-(3,4-dimethoxyphenyl)-ethyl, 4-biphenylmethyl, xcex2-methyl-styryl, 2-(trifluoromethyl)-styryl, 3,4-dimethoxybenzyl, 3,4-dihydroxybenzyl, 2-methoxystyryl, 3,4-dihydroxystyryl, 2-hydroxystyryl, phenyl, 4-chlorostyryl, 3-methoxyphenyl, 4-isopropylphenyl, 4-vinylphenyl, 4-fluorophenyl, 4-bromophenyl, 3,4-dimethoxystyryl, 4-hydroxyphenyl, trans-styryl, 3,4-dimethylphenyl, 3-fluoro-4-methylphenyl, 3-bromo-4-methyl-phenyl, 3-iodo-4-methyl-phenyl, 3,4-dichlorophenyl, 4-biphenyl, 3,4-difluorophenyl, m-tolyl, benzyl, phenethyl, 3-methoxy-4-methylphenyl, 3-phenylpropyl, 4-butylphenyl, 3,5-dimethylphenyl, 3,5-bis-(trifluoromethyl)-phenyl, 3,4-dimethoxyphenyl, 4-ethyl-4-biphenyl, 3,4,5-triethoxyphenyl, propyl, hexyl, isopropyl, 2-butyl, isobutyl, 2-pentyl, isovaleryl, 3-heptyl, 1-propenyl, 2-propenyl, trans-2-pentenyl, 1-ethyl-1-pentenyl, p-tolyl, p-anisyl, t-butyl, neopentyl, cyclohexyl, cyclohexylmethyl, dicyclohexylmethyl, cyclohexylpropyl, cycloheptyl, methyl, 2-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclopentylethyl, 2-furyl, cyclohexylethyl, 4-methylcyclohexyl, 4-tert-butyl-cyclohexyl, 1-adamantyl, 4-methylcyclohexylmethyl, 1,3-pentadienyl, 2-buten-2-yl, 2-norbornanemethyl, 1-adamantanemethyl, and a 3-pentyl, 2-thiophene substituent.
In one of the preferred embodiments of the present invention, the R groups are those as immediately defined above.
In the above Formula the stereochemistry of the chiral R1 group can independently be in the R or S configuration, or a mixture of the two. For instance, as will be described in further detail below, the R1 group can be the side chain substituent of the xcex1-carbon of various amino acids. The amino acids can be in the L- or D-configuration, resulting in the same R group varying only in its stereochemistry. As a consequence of an R1 substituent being in one or both or two stereoconfigurations, the R1 group is usually illustrated bonded to the bicyclic ring by a wavy line.
It is also noted that a compound of Formula I can exist in two tautomeric forms; i.e., in the keto or enol forms. Those two tautomeric forms are illustrated in Formula IA, below.
For convenience, a contemplated compound of Formula I (IA) is usually depicted and discussed as being in the keto form (imidazo-imidizol-one) with the understanding that both keto and enol forms are present in equilibrium.
Formulas of the two tautomers in both stereoconfigurations are shown below.
In any of the Formulas herein, the term xe2x80x9cC1-C10 alkylxe2x80x9d denotes a straight or branched chain radical such as a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, amyl, tert-amyl, hexyl, heptyl, decyl group and the like. The term xe2x80x9clower alkylxe2x80x9d denotes a C1-C4 alkyl group. A preferred xe2x80x9cC1-C10 alkylxe2x80x9d group is a methyl group.
The term xe2x80x9cC2-C10 alkenylxe2x80x9d denotes a radical such as a vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl and a 2-decenyl group and the like, as well as dienes and trienes of straight and branched chains containing up to ten carbon atoms and at least one carbon-to-carbon (ethylenic) double bond.
The term xe2x80x9cC2-C10 alkynylxe2x80x9d denotes a radical such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, decynyl and the like, as well as di- and triynes of straight and branched chains containing up to ten carbon atoms and at least one carbon-to-carbon (acetylenic) triple bond.
The term xe2x80x9cC2-C10 substituted alkylxe2x80x9d, xe2x80x9cC2-C10 substituted alkenylxe2x80x9d and xe2x80x9cC2-C10 substituted alkenylxe2x80x9d denote that the above C1-C10 alkyl group and C2-C10 alkenyl and alkynyl groups are substituted by one or more, and preferably one or two, halogen, hydroxy, protected hydroxy, C3-C7 cycloalkyl, C3-C7 substituted cycloalkyl, naphthyl, substituted naphthyl, adamantyl, abietyl, thiofuranyl, indolyl, substituted indolyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, guanidino, (monosubstituted) guanidino, (disubstituted) guanidino, (trisubstituted) guanidino, imidazolyl pyrolidinyl, C1-C7 acyloxy, nitro, heterocycle, substituted heterocycle, C1-C4 alkyl ester, carboxy, protected carboxy, carbamoyl, carbamoyloxy, carboxamide, protected carboxamide, cyano, methylsulfonylamino, methylsulfonyl, sulfhydryl, C1-C4 alkylthio, C1-C4 alkyl sulfonyl or C1-C4 alkoxy groups. The substituted alkyl groups can be substituted once or more, and preferably once or twice, with the same or with different substituents.
Examples of the above substituted alkyl groups include the cyanomethyl, nitromethyl, chloromethyl, hydroxymethyl, tetrahydro-pyranyloxymethyl, trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, allyloxycarbonylmethyl, allylcarbonyl-aminomethyl, carbamoyloxymethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, 6-hydroxy-hexyl, 2,4-dichloro(n-butyl), 2-amino(isopropyl), 2-carbamoyloxyethyl chloroethyl, bromoethyl, fluoroethyl, iodoethyl, chloropropyl, bromopropyl, fluoropropyl, iodopropyl and the like.
In preferred embodiments of the subject invention, C1-C1 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 substituted alkyl, C2-C10 substituted alkenyl, or C2-C10 substituted alkynyl, are more preferably C1-C7 or C2-C7, respectively, and more preferably, C1-C6 or C2-C6 as is appropriate for unsaturated substituents. However, it should be appreciated by those of skill in the art that one or a few carbons usually can be added to an alkyl, alkenyl, alkynyl, substituted or unsubstituted, without substantially modifying the structure and function of the subject compounds and that, therefore, such additions would not depart from the spirit of the invention.
The term xe2x80x9cC1-C4 alkoxyxe2x80x9d as used herein denotes groups that are ether groups containing up to four carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups. A preferred C1-C4 alkoxy group is methoxy.
The term xe2x80x9cC1-C7 acyloxyxe2x80x9d denotes a carboxy group-containing substituent containing up seven carbon atoms such as formyloxy, acetoxy, propanoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, benzoyloxy and the like.
Similarly, the term xe2x80x9cC1-C7 acylxe2x80x9d encompasses groups such as formyl, acetyl, propionoyl, butyroyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like.
The substituent term xe2x80x9cC3-C7 cycloalkylxe2x80x9d includes the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings. The substituent term xe2x80x9cC3-C7 substituted cycloalkylxe2x80x9d indicates an above cycloalkyl ring substituted by a halogen, hydroxy, protected hydroxy, phenyl, substituted phenyl, heterocycle, substituted heterocycle, C1-C10 alkyl, C1-C4 alkoxy, carboxy, protected carboxy, amino, or protected amino.
The substituent term xe2x80x9cC5-C7 cycloalkenylxe2x80x9d indicates a substituent that is itself a 1-, 2-, or 3-substituted cyclopentenyl ring, a 1-, 2-, 3- or 4-substituted cyclohexenyl ring or a 1-, 2-, 3-,4- or 5-substituted cycloheptenyl ring, whereas the term xe2x80x9csubstituted C3-C7 cycloalkenylxe2x80x9d denotes the above C3-C7 cycloalkenyl rings substituted by a C1-C10 alkyl radical, halogen, hydroxy, protected hydroxy, C1-C4 alkoxy, carboxy, protected carboxy, amino, or protected amino.
The term xe2x80x9cheterocyclic ringxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d denotes an optionally substituted 5-membered or 6-membered ring that has 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, in particular nitrogen either alone or in conjunction with sulfur or oxygen ring atoms. These five-membered or six-membered rings can be fully unsaturated or partially unsaturated, with fully unsaturated rings being preferred.
Preferred heterocyclic rings include pyridino, pyrimidino, and pyrazino, furano, and thiofurano rings. The heterocyles can be substituted or unsubstituted as for example, with such substituents as those described in relation to substituted phenyl or substituted naphthyl.
The term xe2x80x9cC7-C16 phenylalkylxe2x80x9d or xe2x80x9cC7-C16 aralkylxe2x80x9d denotes a C1-C10 alkyl group substituted at any position by a phenyl ring. Examples of such a group include benzyl, 2-phenylethyl, 3-phenyl(n-prop-1-yl), 4-phenyl(hex-1-yl), 3-phenyl(n-am-2-yl), 3-phenyl(sec-butyl), and the like. A preferred C7-C16 phenylalkyl group is the benzyl group.
The term xe2x80x9cC7-C16 substituted phenylalkylxe2x80x9d denotes an above C7-C16 phenylalkyl group substituted on the C1-C10 alkyl portion with one or more, and preferably one or two, groups selected from the group consisting of a halogen, hydroxy, protected hydroxy, keto, C2-C3 cyclic ketal phenyl, amino, protected amino, C1-C7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carbamoyloxy, cyano, N-(methyl-sulfonylamino) or C1-C4 alkoxy group, whose phenyl group portion can be substituted with 1 or 2 groups selected from the group consisting of a halogen, hydroxy, protected hydroxy, nitro, C1-C10 alkyl, C1-C6 substituted alkyl, C1-C4 alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, amino, (monosubstituted) amino, (disubstituted) amino, a N-(methylsulfonylamino) group, or a phenyl group that is itself substituted or unsubstituted. When either the C1-C10 alkyl portion or the phenyl portion or both are mono- or di-substituted, the substituents can be the same or different.
Examples of xe2x80x9cC7-C16 substituted phenylalkylxe2x80x9d include groups such as 2-phenyl-1-chloroethyl, 2-(4-methoxyphenyl)eth-1-yl, 2,6-dihydroxy-4-phenyl(n-hex-2-yl), 5-cyano-3-methoxy-2-phenyl(n-pent-3-yl), 3-(2,6-dimethylphenyl)n-prop-1-yl, 4-chloro-3-aminobenzyl, 6-(4-methoxyphenyl)-3-carboxy(n-hex-1-yl), 5-(4-aminomethyl-phenyl)-3-(aminomethyl)(n-pent-2-yl), 5-phenyl-3-keto-(n-pent-1-yl), 4-(4-aminophenyl)-4-(I.4-oxetanyl)(n-but-1-yl), and the like.
The term xe2x80x9cC7-C16 phenylalkenylxe2x80x9d denotes a C1-C10 alkenyl group substituted at any position by a phenyl ring. The term xe2x80x9cC7-C16 substituted phenylalkenylxe2x80x9d denotes a C7-C16 arylalkenyl group substituted on the C1-C10 alkenyl portion. Substituents can the same as those as defined above in relation to C7-C16 phenylalkyl and C7-C16 substituted phenylalkyl. A preferred C7-C16 substituted phenylalkenyl is 3-(4-nitrophenyl)-2-propenyl.
The term xe2x80x9csubstituted phenylxe2x80x9d specifies a phenyl group substituted at one or more positions, preferably at one or two positions, with moieties selected from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C1-C10 alkyl, C1-C10 substituted alkyl, C1-C4 alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected anilino, (monosubstituted)amino, protected (monosubstituted) amino, (disubstituted)amino, trifluoromethyl, N-(methylsulfonylamino), or phenyl that is itself substituted or unsubstituted such that, for example, a biphenyl group results.
Illustrative substituents embraced by the term xe2x80x9csubstituted phenyllxe2x80x9d include a mono- or di(halo)phenyl group such as 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl and the like; a mono or di(hydroxy)phenyl groups such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected hydroxy derivatives thereof and the like; a nitrophenyl group such as 3- or 4-nitrophenyl, a cyanophenyl group for example, 4-cyanophenyl; a mono- or di(lower alkyl)phenyl group such as 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl, 4-(isopropyl)phenyl, 4-ethylphenyl, 3-(n-prop-1-yl)phenyl and the like: a mono or di(alkoxyl)phenyl group for example, 2,6-dimethoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 4-(isopropoxy)phenyl, 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl, 3-(4-methylphenoxy)phenyl, and the like; 3- or 4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy)phenyl group such as 4-carboxyphenyl or 2,4-di(protected carboxy)phenyl; a mono-or di(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as 3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl) phenyl or (protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or 2,4-(protected aminomethyl) phenyl; or a mono- or di(N-(methylsulfonylamino))phenyl such as 3-(N-(methylsulfonylamino))phenyl. Also, the term xe2x80x9csubstituted phenylxe2x80x9d represents disubstituted phenyl groups wherein the substituents are different. For example, 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl and the like are contemplated.
The term xe2x80x9csubstituted naphthylxe2x80x9d specifies a naphthyl group substituted with one or more, and preferably one or two moieties selected from the group consisting of a halogen, hydroxy, protected hydroxy, cyano, nitro, C1-C10 alkyl, C1-C4 alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted)amino, (disubstituted) amino trifluoromethyl, or a N-(methylsulfonylamino) group. Examples of substituted naphthyl include 2-(methoxy)naphthyl and 4-(methoxy)naphthyl.
The term xe2x80x9csubstituted indolylxe2x80x9d specifies a indolyl group substituted, either at the nitrogen or carbon, or both, with one or more, and preferably one or two, moieties selected from the group consisting of a halogen, hydroxy, protected hydroxy, cyano, nitro, C1-C10 alkyl, C1-C10 substituted alkyl, C1-C10 alkenyl, C7-C16 phenylalkyl, C7-C16 substituted phenylalkyl, C1-C6 alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, monosubstituted amino, or a disubstituted amino group.
Examples of the term xe2x80x9csubstituted indolylxe2x80x9d includes such groups as 6-fluoro, 5-fluoro, 5-bromo, 5-hydroxy, 5-methyl, 6-methyl, 7-methyl, 1-methyl, 1-ethyl, 1-benzyl, 1-napthylmethyl, and the like. An example of a disubstituted indolyl is 1-methyl-5-methyl indolyl.
The terms xe2x80x9chaloxe2x80x9d and xe2x80x9chalogenxe2x80x9d refer to the fluoro, chloro, bromo, or iodo groups.
The term xe2x80x9c(monosubstituted)aminoxe2x80x9d refers to an amino group with one substituent selected from the group consisting of phenyl, substituted phenyl, C1-C10 alkyl, and C7-C16 arylalkyl, wherein the latter three substituent terms are as defined above. The (monosubstituted)amino can additionally have an amino-protecting group as encompassed by the term xe2x80x9cprotected (monosubstituted)amino.xe2x80x9d
The term xe2x80x9c(disubstituted)aminoxe2x80x9d refers to amino groups with two substituents selected from the group consisting of phenyl, substituted phenyl, C1-C10 alkyl, and C7-C16 arylalkyl wherein the latter three substituent terms are as described above. The two substituents can be the same or different.
The terms xe2x80x9c(monosubstituted)guanidinoxe2x80x9d, xe2x80x9c(disubstituted)guanidino.xe2x80x9d and xe2x80x9c(trisubstituted)-guanidinoxe2x80x9d are used to mean that a guanidino group is substituted with one, two, or three substituents, respectively. The substituents can be any of those as defined above in relation to (monosubstituted)-amino and (disubstituted)amino and, where more than one substituent is present, the substituents can be the same or different.
The terms xe2x80x9c(monosubstituted) imidizol-one imidazole, xe2x80x9c(disubstituted) imidizol-one imidazole.xe2x80x9d and xe2x80x9c(trisubstituted) imidizol-one imidazolexe2x80x9d mean compounds in which the imidizol-one imidazole group is substituted with one, two, or three substituents, respectively. The substituents can be any of those as defined above in relation to a (monosubstituted)-amino or (disubstituted)amino group and where more than one substituent is present. The substituents can be the same or different.
The term xe2x80x9camino-protecting groupxe2x80x9d as used herein refers to one or more selectively removable substituents on the amino group commonly employed to block or protect the amino functionality. The term xe2x80x9cprotected (monosubstituted)aminoxe2x80x9d means there is an amino-protecting group on the monosubstituted amino nitrogen atom. In addition, the term xe2x80x9cprotected carboxamidexe2x80x9d means there is an amino-protecting group present replacing the proton of the amido nitrogen so that di-N-alkylation.
Examples of such amino-protecting groups include the formyl (xe2x80x9cForxe2x80x9d) group, the trityl group (Trt), the phthalimido group, the trichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups. Urethane blocking groups, such as t-butoxy-carbonyl (xe2x80x9cBocxe2x80x9d), 2-(4-biphenylyl)propyl(2)-oxycarbonyl (xe2x80x9cBpocxe2x80x9d), 2-phenylpropyl(2)oxycarbonyl (xe2x80x9cPocxe2x80x9d), 2-(4-xenyl)-isopropoxycarbonyl, 1,1-diphenylethyl(1)oxycarbonyl, 1,1-diphenylpropyl(1)oxycarbonyl, 2-(3,5-dimethoxyphenyl) propyl(2)oxycarbonyl (xe2x80x9cDdzxe2x80x9d), 2-(p-5-toluyl)propyl-(2) oxycarbonyl, cyclo-pentanyloxycarbonyl, 1-methylcyclopentanyl-oxycarbonyl, cyclohexanyloxycarbonyl, 1-methyl-cyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, 9-fluoroenylmethoxycarbonyl (xe2x80x9cFmocxe2x80x9d), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benz-isoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl(2)propoxycarbonyl, cyclopropylmethoxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonyl, benzyloxycarbonyl (xe2x80x9cZxe2x80x9d), 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, xcex1-2,4,5,-tetramethylbenzyloxycarbonyl (xe2x80x9cTmzxe2x80x9d), 4-methoxybenzyl-oxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chloro-benzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyIioxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, and the like, the benzoylmethylsulfonyl group, dithiasuccinoyl (xe2x80x9cDtsxe2x80x99) group, the 2-(nitro)phenylsulfenyl group (xe2x80x9cNpsxe2x80x99), the diphenylphosphine oxide group, and like amino-protecting groups. The species of amino-protecting group employed is usually not critical so long as the derivatized amino group is stable to the conditions of the subsequent reactions and can be removed at the appropriate point without disrupting the remainder of the compound. Preferred amino-protecting groups are Boc and Fmoc.
Further examples of amino-protecting groups embraced to by the above term are well known in organic synthesis and the peptide art and are described by, for example T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley and Sons. New York., Chapter 7, 1991; M. Bodanzsky, Principles of Peptide Synthesis, 1st and 2nd revised eds., Springer-Verlag, New York, 1984 and 1993; and Stewart and Young, Solid Phase Peptide Synthesis, 2nd ed., Pierce Chemical Co, Rockford. IL 1984.
The related term xe2x80x9cprotected aminoxe2x80x9d defines an amino group substituted with an amino-protecting group discussed above.
The term xe2x80x9ccarboxy-protecting groupxe2x80x9d as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. Examples of such carboxylic acid protecting groups include 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylene-dioxybenzyl, benzhydryl, 4,4xe2x80x2-methoxytrityl, 4,4xe2x80x2,4xe2x80x3-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, 2,2,2-trichloroethyl, xcex2-(trimethylsilyl)ethyl, xcex2-[di(n-butyl)methylsilyl]ethyl, p-toluenesulfonylethyl, 4-nitrobenzyl-sulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)-prop-1-en-3-yl, and like moieties. The species of carboxy-protecting group employed is also usually not critical so long as the derivatized carboxylic acid is stable to the conditions of subsequent reactions and can be removed at the appropriate point without disrupting the remainder of the molecule.
Further examples of these groups are found in E. Haslam, Protective Groups in Organic Chemistry, J. G. W. McOmie Ed., Plenum Press, New York 1973, Chapter 5 and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis 2nd ed., John Wiley and Sons, New York, 1991, Chapter 5, each of which is incorporated herein by reference. A related term is xe2x80x9cprotected-carboxyxe2x80x9d, which refers to a carboxy group substituted with one of the above carboxy-protecting groups.
The term xe2x80x9chydroxy-protecting groupxe2x80x9d refers to readily cleavable groups bonded to hydroxyl groups, such as the tetrahydropyranyl, 2-methoxyprop-2-yl, 1-ethoxyeth-1-yl, methoxymethyl, xcex2-methoxyethoxymethyl, methylthiomethyl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4xe2x80x2-dimethoxytrityl, 4,4xe2x80x2,4xe2x80x3-trimethoxytrityl, benzyl, allyl, trimethylsilyl, (t-butyl)dimethylsilyl and 2,2,2-trichloroethoxycarbonyl groups, and the like. The species of hydroxy-protecting groups is also usually not critical so long as the derivatized hydroxyl group is stable to the conditions of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the compound.
Further examples of hydroxy-protecting groups are described by C. B. Reese and E Haslam, Protective Groups in Organic Chemistry, J. G. W. McOmie, Ed., Plentun Press, New York 1973, Chapters 3 and 4, respectively, and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley and Sons, New York, 1991, Chapters 2 and 3, whose disclosures are also incorporated by reference.
The substituent term xe2x80x9cC1-C4 alkylthioxe2x80x9d refers to sulfide groups such as methylthio, ethylthio, n-propylthio, isopropylthio, xcex1-butylthio, t-butylthio and like groups.
The substituent term xe2x80x9cC1-C4 alkylsulfoxidexe2x80x9d indicates sulfoxide groups such as methylsulfoxide, ethylsulfoxide, xcex1-propylsulfoxide, iso-propyl-sulfoxide, n-butylsulfoxide, sec-butylsulfoxide, and the like.
The term xe2x80x9cC1-C4 alkylsulfonylxe2x80x9d encompasses groups such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, a-butylsulfonyl, t-butylsulfonyl, and the like.
Phenylthio, phenyl sulfoxide, and phenylsulfonyl compounds are known in the art and these have their art-recognized definitions. By xe2x80x9csubstituted phenylthioxe2x80x9d, xe2x80x9csubstituted phenyl sulfoxidexe2x80x9d, and xe2x80x9csubstituted phenylsulfonylxe2x80x9d, is meant that the phenyl can be substituted as described above in relation to xe2x80x9csubstituted phenyl.xe2x80x9d
The substituent terms xe2x80x9ccyclic C2-C10 alkylenexe2x80x9d, xe2x80x9csubstituted cyclic C2-C10 alkylenexe2x80x9d, xe2x80x9ccyclic C2-C10 heteroalkylene.xe2x80x9d and xe2x80x9csubstituted cyclic C2-C10 heteroakylenexe2x80x9d defines a cyclic group bonded (xe2x80x9cfusedxe2x80x9d) to the phenyl radical. The cyclic group can be saturated or contain one or two double bonds. Furthermore, the cyclic group can have one or two methylene groups replaced by one or two oxygen, nitrogen or sulfur atoms.
The cyclic alkylene or heteroalkylene group can be substituted once or twice by substituents selected from the group consisting of hydroxy, protected-hydroxy, carboxy, protected-carboxy, keto, ketal, C1-C4 alkoxycarbonyl, C1-C4 alkanoyl, C1-C10 alkyl, carbamoyl, C1-C4 alkoxy, C1-C4, alkylthio, C1-C4 alkylsulfoxide, C1-C4 alkylsulfonyl, halo, amino, protected-amino, hydroxymethyl and a protected-hydroxymethyl group.
A cyclic alkylene or heteroalkylene group fused onto the benzene radical can contain two to ten ring members, but it preferably contains four to six members. Examples of such saturated cyclic groups include a bicyclic ring system that is a 2,3-dihydroindanyl or a tetralin ring. When the cyclic groups are unsaturated, examples occur when the resultant bicyclic ring system is a naphthyl ring or indanyl.
An example of a cyclic group that can be fused to a phenyl radical that has two oxygen atoms and that is fully saturated is dioxanyl. Examples of fused cyclic groups that each contain one oxygen atom and one or two double bonds occur when the phenyl ring is fused to a furyl, pyranyl, dihydrofuryl or dihydropyranyl ring. Cyclic groups that each have one nitrogen atom and contain one or two double more double bonds are illustrated where the phenyl is fused to a pyridino or pyrano ring. An example of a fused ring system having one nitrogen and two phenyl radicals is a carbozyl group. Examples of cyclic groups that each have one sulfur atom and contain one or two double bonds occur where the benzene ring is fused to a thieno, thiopyrano, dihydrothieno, or dihydrothiopyrano ring. Examples of cyclic groups that contain two heteroatoms selected from sulfur and nitrogen and one or two double bonds occur where the phenyl ring is fused to a thiazolo, isothiazolo, dihydrothiazolo or dihydroisothiazolo ring. Examples of cyclic groups that contain two heteroatoms selected from oxygen and nitrogen and one or two double bonds occur where the benzene ring is fused to an oxazole, isoxazole, dihydroxazole or dihydroisoxazole ring. Examples of cyclic groups that contain two nitrogen heteroatoms and one or two double bonds occur where the benzene ring is fused to a pyrazolo, imidazolo, dihydropyrazolo or dihydroimidazolo ring.
Examples of cyclic groups that each have one nitrogen atom and contain one or two double more double bonds occur when the phenyl is fused to a pyridino or pyrano ring. An example of a fused ring system having one nitrogen and two phenyl radicals is a carbozyl group. Examples of cyclic groups that each have one sulfur atom and contain one or two double bonds occur when the phenyl is fused to a thieno, thiopyrano, dihydrothieno, or dihydrothiopyrano ring.
Examples of cyclic groups that contain two heteroatoms selected from sulfur and nitrogen and one or two double bonds occur when the phenyl ring is fused to a thiazolo, isothiazolo, dihydrothiazolo or dihydroisothiazolo ring. Examples of cyclic groups that contain two heteroatoms selected from oxygen and nitrogen and one or two double bonds occur when the benzene ring, is fused to an oxazolo, isoxazolo, dihydroox-azolo or dihydroisoxazolo ring. Examples of cyclic groups which contain two nitrogen heteroatoms and one or two double bonds occur when the benzene ring is fused to a pyrazolo, Imidazolo, dihydropyrazolo or dihydroimidazolo ring.
Pharmaceutical Compositions
A pharmaceutical composition for treating infections, pain, or other indications treatable by a contemplated imidazo-imidazol-one is administered to a subject in need of the medication at dosage levels of about 0.7 to about 7000 mg per day, and preferably about 1 to about 500 mg per day, for a normal human adult of approximately 70 kg of body weight. This broadly translates into a dosage of about 0.01 to about 100 mg/kg of body weight per day of an imidizo-imidazol-one compound of Formula I as active ingredient. The specific dosages employed, however, can be varied depending upon the requirements of the patient, the severity of the condition being treated, and the activity of the compound being employed. The determination of optimum dosages for a particular situation is within the skill of the art.
One or more of the imidizo-imidazol-one compounds of Formula I can be present as a pharmaceutically-acceptable salt. The term xe2x80x9cpharmaceutically-acceptable saltxe2x80x9d encompasses those salts that form with the carboxylate anions or ammonium cations and include salts formed with the organic and inorganic cations and anions discussed below. Furthermore, the term includes salts that form by standard acid-base reactions with basic groups (such as amino groups) and organic or inorganic acids. Such acids include hydrochloric, sulfuric, phosphoric, acetic, succinic, citric lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D-glutamic, d-camphoric, glutaric, phthalic, tartaric, lauricc, stearic, salicyclic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids.
The term xe2x80x9corganic or inorganic cationxe2x80x9d refers to counterions for the carboxylate anion of a carboxylate salt. The counter-ions are chosen from the alkali and alkaline earth metals, (such as lithium, sodium, potassium, barium and calcium): ammonium; and the organic cations such as (dibenzylammonium, benzylammonium, 2-hydroxymethylammonium, bis(2-hydroxyethyl)ammonium, phenylethylbenzyl ammonium, dibebenzylethylenediammoniurn, and like cations). Other cations encompassed by the above term include the protonated form of procaine, quinine and N-methylglucosamine, and the protonated forms of basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine. Furthermore, any zwitterionic form of the instant compounds formed by a carboxylic acid and an amino group is referred to by this term. A preferred cation for the carboxylate anion is the sodium cation.
A compound of Formula I can also be present as a solvate and hydrate. Thus, these compounds can crystallize with, for example, waters of hydration, or one, a number of, or any fraction thereof of molecules of the mother liquor solvent. The solvates and hydrates of such compounds are included within the scope of this invention.
One or more of the contemplated compounds can be in the biologically active ester form, such as the non-toxic, metabolically-labile ester-form. Such ester forms induce increased blood levels and prolong the efficacy of the corresponding non-esterified forms of the compounds. Ester groups that can be used include the lower alkoxymethyl groups (C1-C4 alkoxymethyl) for example, methoxymethyl, ethoxymethyl, isopropoxymethyl and the like; the xe2x80x94(C1-C4) alkoxyethyl groups, for example methoxyethyl, ethoxyethyl, propxyethyl, iso-propoxyethyl, and the like, the 2-oxo-1,3-dioxolen-4-ylmethyl groups such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, 5-phenyl-2-oxo-1,3-dioxolen-4-ylmethyl, and the like, the C1-C3 alkylthiomethyl groups, for example methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, and the like, the acyloxymethyl groups, for example pivaloyloxymethyl, pivaloyloxyethyl, a-acetoxymethyl, and the like, the ethoxycarbonyl-1-methyl group, the a-acetoxyethyl, the 3-phthalidyl or 5,6-dimethylphtalidyl groups, the 1-(C1-C4 alkyloxycarbonyloxy)ethyl groups such as the 1-(ethoxycarbonyloxy)ethyl group, and the 1-(C1-C4 alkylaminocarbonyloxy)ethyl groups such as the 1-methylaminocarbonyloxyethyl group.
For preparing pharmaceutical compositions containing compounds of the invention, inert, pharmaceutically acceptable carriers are used. The pharmaceutical carrier can be either solid or liquid. Solid form preparations include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
A solid carrier can be one or more substances that can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
In powders, the carrier is generally a finely divided solid that is in a mixture with the finely divided active component. In tablets, the active compound is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
For preparing pharmaceutical composition in the form of suppositories, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient-sized molds and allowed to cool and solidify.
Powders and tablets preferably contain between about 5% to about 70% by weight of the active ingredient. Suitable carriers include, for example, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter and the like.
A pharmaceutical composition can include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier, which is thus in association with it. In a similar manner, cachets are also included.
Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
Liquid pharmaceutical compositions include, for example, solutions suitable for oral or parenteral administration, or suspensions, and emulsions suitable for oral administration. Sterile water solutions of the active component or sterile solutions of the active component in solvents comprising water, ethanol, or propylene glycol are examples of liquid compositions suitable for parenteral administration.
Sterile solutions can be prepared by dissolving the active component in the desired solvent system, and then passing the resulting solution through a membrane filter to sterilize it or, alternatively, by dissolving the sterile compound in a previously sterilized solvent under sterile conditions.
Aqueous solutions for oral administration can be prepared by dissolving the active compound in water and adding suitable flavorants, coloring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
Preferably, the pharmaceutical composition is in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active urea. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
Library Synthesis and Use
As used herein, a chemical or combinatorial xe2x80x9d libraryxe2x80x9d is an intentionally created collection of a plurality of structurally similar, but different molecules. By xe2x80x9cstructurally similarxe2x80x9d, it is meant that the constituent compounds of a library have the same ring structure; i.e., a bicyclic imidizo-imidazol-one ring, and at least two positions at which substituents are bonded to the ring structure. It is preferred that the member compounds of the library also have the same substitution pattern of substituent groups; i.e., that the at least two substituents be bonded to the same ring positions in each member compound. The molecule members of the library are different in that each member has at least one different substituent group from the other members of the library. A library can contain two to thousands or millions of member compounds.
A particular library can also be comprised of members whose substituent groups are all different from each other. Thus, where the shared ring structure contains substituent groups at a plurality of positions, a library can be prepared in which the member molecules contain different groups at each position.
Alternatively, a plurality of sub-libraries or sets can also be prepared in which a first set has a first substituent that is held constant for all of the members (is present in all members) of the set, whereas the groups at the other substituent positions are different and constitute a mixture of groups at each substituent position. A second set of that plurality has a second, different, first substituent, and the same mixture of different groups at the other substituent positions. A third set of that plurality has a third, different first substituent, and the same mixture of different groups at the other substituent positions, and so on until one decides to stop making sets with different first substituents. Such set pluralities of structurally similar, but different compounds are also often referred to as libraries of libraries, and are particularly useful in ascertaining which compound or compounds of a library are active in an assay of choice.
A library can be prepared by the synthetic means discussed below or otherwise herein and screened for biological activity in a variety of formats (e.g. libraries of soluble molecules). Libraries of compounds can be attached to resin beads, silica chips or other solid supports). The libraries can be screened in any variety of assays, such as those detailed below as well as others useful for assessing the biological activity of imidazo-imidazol-ones. The libraries typically contain at least one active compound and are generally prepared such that the compounds are in equimolar quantities.
The nonsupport-bound library mixtures prepared herein were screened in solution in radio-receptor inhibition assays described in detail hereinafter. Deconvolution of highly active mixtures can then be carried out by iterative, or positional scanning methods. These techniques, the iterative approach or the positional scanning approach, can be utilized for finding other active compounds within the libraries of the present invention using any one of the below-described assays or others well known in the art.
The iterative approach is well-known and is set forth in general in Houghten et al., Nature, 354, 84-86 (1991) and Dooley et al., Science, 266, 2019-2022 (1994), both of which are incorporated herein by reference. In the iterative approach, for example, sub-libraries of a molecule having three variable groups are made wherein the first variable substituent is defined (known and held constant) within the sub-library. Each of the compounds with the defined variable group is reacted separately with each of the other possibilities at the second variable group position and the third variable position is a mixture of all of the possible substituents to form a plurality of sub-libraries whose first two substituent groups are known. These sub-libraries are each assayed to define the identity of the second variable in the sub-library having the highest activity in the screen of choice.
A new sub-library with the first two variable positions defined is separately reacted with each of the other possibilities at the remaining undefined variable position. As before, the identity of the third variable position in the sub-library having the highest activity is determined.
If more variables exist, this process is repeated for all variables, yielding the compound with each variable contributing to the highest desired activity in the screening process. Promising compounds from this process can then be synthesized on larger scale in traditional single-compound synthetic methods for further biological investigation.
The positional-scanning approach has been described for various libraries as described, for example, in R. Houghten et al. PCT/US91/08694 and U.S. Pat. No. 5,556,762, both of which are incorporated herein by reference. The positional scanning approach is used as described below in the preparation and screening of the libraries.
In the positional scanning approach, sub-libraries are made defining only one variable substituent with each set of sub-libraries and all possible sub-libraries with each single variable substituent defined (and all other possibilities at all of the other variable positions) is made and tested. From the instant description one skilled in the art can synthesize libraries wherein two fixed substituent positions are defined at a time. From the assaying of each single-variable defined library, the optimum substituent at that position is determined, pointing to the optimum or at least a series of compounds having a maximum of the desired biological activity. Thus, the number of sub-libraries for compounds with a single substituent position defined is the number of different substituents desired at that position, and the number of all the compounds in each sub-library is the product of the number of substituents at each of the other variables.
The [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one libraries and compounds of Formula I can be prepared according to the general reaction Scheme 1, which for ease of description is shown using single amino acids. The reaction scheme shown forms a single compound or enantiomeric pair of compounds of Formula I. Where libraries are desired, a mixture of amino acids (Boc-R1aa-OH or Boc-R2aa-OH), or carboxylic acids (R3xe2x80x94CO2H) is used for at least one of the coupling steps.
The individual compounds and libraries are prepared using solid-phase techniques. The solid-phase resin, here, p-methylbenzhydrylamine resin (p-MBHA), is indicated in Scheme 1 by the large circle and dash.
Starting from p-methylbenzhydrylamine (MBHA) resin-bound N-tert-butyloxycarbonyl (Boc) amino acid 1 (Boc-R1aa-OH), the Boc group was removed using a mixture of trifluoroacetic acid (TFA) and dichloromethane (DCM). The resulting amine salt was neutralized, and the resulting primary amine was N-acylated with a second Boc-protected amino acid (Boc-R2aa-OH) as before, to provide the resin bound-monopeptide 2.
Following removal of the Boc protecting group using 55% of trifluoroacetic acid in dichloromethane, the resulting free amine was acylated with a carboxylic acid 3 (R3xe2x80x94CO2H) in dimethylformamide (DMF) using diisopropylcarbodiimide (DICI) and hydroxybenzotriazole (HOBt) to effect coupling. The bicyclic [3,5,7]-1H-imidazo[1,5-a]-imidazol-2(3H)-one 4 was obtained via cyclization using the conditions of Bischler-Napieralski, with 25-fold excess of phosphorus oxychloride (POCl3) in refluxing 1,4-dioxane in the presence of a 30-fold excess of anion exchange resin (AG(copyright) 3-X4) [Bischler, A.; Napieralski, B. Chem. Ber., (1893), 26, 1903; W. M. Whaley, T. R. Govindachari, Org. React., 6, 74 (1951); T. Kametani et al., Tetrahedron, 27, 5367 (1971); G. Fodor et al., Angew. Chem. Int. Ed., 11, 919 (1972); G. Fodor, S. Nagubandi, Tetrahedron, 36, 1279 (1980); idem, Heterocycles, 15, 165 (1981)]. More recent syntheses using freshly distilled POCl3 in the absence of the anion exchange resin have provided yields in the range of about 80 percent. The desired products were readily obtained following cleavage from the resin with anhydrous HF in anisole to provide compound 4.
Following the strategy described in Scheme 1, with the parallel synthesis approach, commonly referred to as the xe2x80x9ctea-bagxe2x80x9d method [Houghten et al., Nature, 354: 84-86 (1991)], libraries are synthesized with 33 different amino acids to provide the R group at R1, 33 different amino acids to provide the R group at R2, and 92 different carboxylic acids to provide the R group at R3, in which the individual building blocks were varied, while fixing the remaining two positions.
Any variety of amino acids can be used with the present invention as described above to prepare a vast array of bicyclic [3,5,7]-1H-imidazo[1,5-a]-imidazol-2(3H)-one with different R1, R2 and R3 groups. As described above, thirty-three first amino acids were coupled to the resin, which amino acids provide the R1 substituent group. The thirty-three amino acids included Ala, Phe, Gly, His(DNP), Ile, Lys(CBZ), Leu, Met, Arg(Tos), Nva, Ser(Bzl), Thr(Bzl), Val, Tyr(CHO), Tyr(BrZ), Nle, Cha, ala, phe, his(DNP), ile, lys(CBZ), leu, met, arg(Tos), ser(Bzl), thr(Bzl), val, trp(CHO), tyr(BrZ), nle, nva, cha.
After the above-described 33 reactions and removal of the BOC protecting group, a single amino acid (valine) was coupled as the second amino acid, thereby providing the R2 group. After removal of the second BOC group, a single carboxylic acid, acetic acid, was coupled to provide the R3 group for the 33 different compounds. Those compounds were thereafter cyclized to form compounds of Formula I and cleaved from the resin.
Another set or sub-library of 33 compounds was prepared by reacting a single amino acid (valine) with the resin to provide one R1 group. After removal of the BOC protecting group, each of the above 33 amino acids was then separately coupled to provide 33 resin-linked peptides with the same R1 group and one of the 33 different R2 groups. On removing the second BOC group, a single carboxylic acid (acetic acid) was bonded to the free amino group to provide a single R3 group for the resin-linked peptides. Theses compounds were also cyclized to form compounds of Formula I, and cleaved from the resin.
In a third set or sub-library preparation, a single amino acid (valine) was coupled to the resin to provide a single R1 group, the BOC group was removed and a second amino acid (valine) was coupled to provide a single R2 group and form a dipeptide. After removal of the second BOC group, the dipeptide was separately reacted with each of the 92 carboxylic acids listed in Table 2, below, to provide 92 different R3 groups. The acylated peptides were thereafter cyclized, cleaved from the solid support resin and recovered. Assays using those compounds are discussed hereinafter.
As used herein, abbreviations for the various amino acid side-chain protecting groups are as follows: xe2x80x9cTrtxe2x80x9d for trityl, xe2x80x9ctBuxe2x80x99 for tert-butyl, xe2x80x9cBocxe2x80x9d or xe2x80x9cBOCxe2x80x9d for tert-butoxycarbonyl, xe2x80x9cTosxe2x80x9d for toluenesulfonyl or tosyl, xe2x80x9cDNPxe2x80x9d for dinitrophenyl, xe2x80x9cBzlxe2x80x9d for benzyl, xe2x80x9cCHOxe2x80x9d for formyl, xe2x80x9cBrzxe2x80x9d for 2-bromobenzyloxycarbonyl and xe2x80x9cCBZxe2x80x9d for carbobenzoxy. As can be seen from the side chains exemplified in the table below, it should be appreciated from the above-described embodiments of R1 and R2 are merely illustrative of the R groups that can be present. Following usual notation, L-amino acids are referred to with an initial capital letter as in Val, whereas D-amino acids are referred to with an initial lower case letter as in ala.
A variety of carboxylic acids can also be used in the acylation step of the reaction of Scheme 1, thereby providing a wide array of substituents at the R3 position of the bicyclic [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one. Ninety-two carboxylic acids were used in preparing the [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one libraries. The ninety-two R3 groups were provided by the following carboxylic acids:

Synthesis of [3,5,7]-1H-imidazo [1,5-a]imidazol-2 (3H)- one compounds

Torrey Pines Institute for Molecular Studies


A gelled negative electrode contains zinc powder, alkaline electrolyte, and a gelling agent. The specific surface area of the zinc powder is in the range between 0.025 and 0.045 m2/g. The gelling agent contains, as a main component, a cross-linked polymer formed by radical polymerization in a non-benzene solvent, specifically, a cross-linked poly(meth)acrylic acid (or salt) formed by radical polymerization of a (meth)acrylic acid (or slat) in a non-benzene solvent.

1. Field of the Invention
The present invention relates to a gelled negative electrode for an alkaline battery containing a gelling agent polymerized in a non-benzene solvent and an alkaline battery using it as a negative electrode.
2. Description of Related Art
In general, a gelled negative electrode, which is obtained by gelling a mixture of alkaline electrolyte and zinc powder with an gelling agent added, is used as a negative electrode of an alkaline battery. As the main component of the gelling agent, a cross-linked poly(meth)acrylic acid (or salt) formed by polymerizing a (meth)acrylic acid (or salt) is used in general, wherein the gelled negative electrode is adjusted to have a predetermined viscosity for preventing the zinc powder from sedimenting in the alkaline electrolyte.
When the added amount of the gelling agent is increased, the internal resistance of the battery increases to degrade the discharge characteristics of the battery. When the added amount of the gelling agent is reduced in contrast, sedimentation of the zinc powder is suppressed insufficiently to degrade the discharge characteristics of the battery and to shorten the lifetime thereof.
To tackle these problems, Japanese Unexamined Patent Application Publication 2003-123763 proposes a technique for enhancing the thickening effect of the gelling agent by adding ultra-fine particles of a metal oxide to the gelling agent. This reduces the added amount of the gelling agent required for attaining the predetermined viscosity and prevents degradation of the discharge characteristics caused due to an increase in internal resistance of the battery.
Japanese Unexamined Patent Application Publication 2000-306589 discloses a technique for forming a gelling agent made of a cross-linked poly(meth)acrylic acid (or salt) having a large particle diameter by aqueous solution polymerization or reverse phase suspension polymerization. This suppresses sedimentation of the zinc powder to prevent degradation of the discharge characteristics and shortening of the lifetime of the battery.

Gelled negative electrode for alkaline battery and alkaline battery


An engine driven generator (17) is provided with first and second stage fans (41,42) at one end thereof. The two-stage fan system draws in ambient air and forces it through the generator windings (38) and rotor-stator air gap (37,39) for the purpose of improving generator cooling. Stationary guide vanes (49) are disposed between the two fans (41,42) for the purpose of de-swirling the flow therebetween. The fans are of the centrifugal type and are preferably backward curved.

This invention relates generally to transport refrigeration systems and, more particularly, to the cooling of an engine driven electric generator therefor.
Generally, transport refrigeration systems such as those used on truck trailers, have employed belt driven and/or mechanically linked, shaft driven compressor units and/or belt driven, or otherwise mechanically linked, fan powering systems. That is, the unit engine, such as a diesel engine, is mechanically connected to drive both the compressor unit(s) and the unit refrigeration systems fans and other components.
A significant improvement to such an arrangement was a so called "all electric" transport refrigeration system as described in U.S. Pat. No. 6,223,546, assigned to the assignee of the present invention. In such a unit, a generator is mechanically connected to the system engine and is used to generate the electrical power needed to drive the compressor and the various refrigeration system fans and other components.
Heretofore, such an engine driven generator has been cooled by a single stage centrifugal fan disposed on one end thereof and adapted to circulate air over the stator and armature components for the cooling thereof.
Relatively low engine speeds are desired in trailer refrigeration systems in order to attain low fuel burn rates. This limitation on shaft speed results in relatively low pressure rise capability from a single stage fan. Yet, high pressure rise is needed to drive flow through the generator windings and rotor-stator air gap. System space constraints make large cooling fans or push-pull fan options impractical.
Augmentation of a cooling fan by the use of a second fan in cooling rotating machinery as shown in U.S. Pat. Nos. 6,700,235 and 7,129,604. However, the fans are mounted at opposite ends of the generator such that one of the fans is blowing cooler air across the rotating machinery, while the other fan is drawing warmer air away from the rotating machinery. This is disadvantageous since the warmer air is less dense and therefore results in reduced air mass flow rate.

Two-stage cooling fan for an electric generator