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<SOH> BACKGROUND ART <EOH>Over the past two decades, treatment of diseases by the transluminal placement of a prosthesis has garnered increasing attention. In the field of vascular disease, this therapeutic modality now represents the intervention of choice for most occlusive lesions. The satisfactory results obtained with this treatment strategy has encouraged its application for the management of lesions such as aneurysms which are characterized by partial or complete loss of structural integrity rather than hindrance to blood flow. Multiple endoluminal grafts have been described for the purpose, only a few of which have survived the rigours of clinical use. Experience with these prostheses has demonstrated that while they do have therapeutic value, all suffer from a common drawback. They are too bulky to be implanted without creating a surgical vascular access, thereby negating one of the major advantages of the transluminal approach. This characteristic also make them difficult to implant in patients with tortuous blood vessels. Another limitation associated with their use is the inability to treat lesions involving the craniocerebral or visceral branches of the aorta. That all the endoluminal grafts in use have the same disadvantage is not a coincidence because all are based on the same underlying design: a flexible non-porous tube braced by an expandable metallic skeleton. Reducing the metallic skeleton to a single, sturdy metallic collar has been proposed as one way to reduce the bulk of a endovascular graft during introduction (PCT International Application WO 97/48350). While this modification certainly makes for a more streamlined device, it does not eliminate the need for surgically creating a vascular access because the introducer catheter required has an outer diameter of approximately 5 mm (15 Fr). Furthermore, clinical experience indicates that the absence of support along the longitudinal axis of the device is likely to increase the risk of complications associated with its use such as migration (Resch T. et. al. J Vasc Intervent Radiol 1999; 10:257-64). Deployment of the tubular component of the prosthesis and its metallic skeleton in sequence offers the possibility of reducing the calibre of the introducer system necessary for deployment. Two implantable devices based on this concept have been described thus far (U.S. Pat. No. 5,776,186, U.S. Pat. No. 6,015,422). However neither can be compacted to the degree necessary for percutaneous implantation. Thus there exists a need for a prosthesis for transluminal implantation that has a low enough profile to be introduced into the body by the non-surgical, percutaneous, approach and yet has sufficient longitudinal rigidity to minimise the risk of complications, and sufficient longitudinal flexibility to accommodate geometrical changes that often occur in tubular organs such as the aorta. The prosthesis should preferably not have a metal skeleton with multiple bent struts, which carries with it the risk of the type of structural failure that contributed to the AneuRx endovascular graft being withdrawn from the market (FDA Public Health Notification, Apr. 21, 2001). Likewise the prosthesis should be free of hooks eliminating the chances of severe vascular trauma observed with the Ancure device (FDA Public Health Notification, Apr. 21, 2001). These requirements are fulfilled by the invention under consideration. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>To facilitate understanding, throughout the description, the adjective “leading” identifies the end or edge of an object, such as a prosthesis or device, that precedes the rest of said object, when said object is being introduced into another object such as the human body. FIG. 1 is a perspective view of the preferred embodiment of the implantable prosthesis. FIG. 2 is a perspective view of the bifurcated embodiment of the implantable prosthesis. FIG. 3 is a perspective view of an alternative embodiment of the implantable prosthesis characterized by a trailing end narrower than the rest of the prosthesis. FIG. 4 is a perspective view of the bifurcated embodiment of the implantable prosthesis characterized by one distal limb. FIG. 5 is a perspective view partly in section of the introducer catheter with the dilator in situ. FIG. 6 is a perspective view partly in section of the introducer catheter with the pusher in situ. FIG. 7 is a perspective view of the anchor. FIG. 8 is a perspective view of an alternative embodiment of the implantable prosthesis characterized by a circumferential slit in the graft. FIG. 9 is a perspective view partly see-through view of an alternative embodiment of the implantable prosthesis provided with an internal helical support. FIG. 10 is a perspective view partly see-through view of an alternative embodiment of the implantable prosthesis provided with an internal helical support and short supporting struts. FIG. 11 is a perspective view partly in section of a loading cartridge containing an the alternative embodiment of the prosthesis provided with an internal helical support. FIG. 12 is a longitudinal sectional view of the anchor within a cannula. FIG. 13 is a perspective view partly in section of the loading cartridge with the prosthesis and anchor in situ. FIG. 14 is a perspective view partly in section of the loading cartridge with the prosthesis and anchor and pusher in situ. FIG. 15 is a perspective view of the trailing end of the loading cartridge. FIGS. 16 to 21 are longitudinal sectional views illustrating implantation of a prosthesis in an abdominal aorta with an aneurysm according to the invention. detailed-description description="Detailed Description" end="lead"? |
IMAGE RECORDAL AND GENERATION APPARATUS |
An apparatus for recording and generating images includes a printing unit. The printing unit includes a carrier that is dimensioned to approximate a PCMCIA memory card. A media supply is receivable in the carrier. A page width print head assembly is mounted in the carrier to print images on the media. The page width print head assembly includes at least one print head chip and a suitable printing microprocessor that is configured to control operation of the print head chip. An ink supply mechanism is operatively arranged with respect to the print head assembly to supply the print head assembly with ink. A media feed mechanism is positioned in the carrier to feed media to and from the print head chip. The apparatus includes an image recordal apparatus that includes a housing in which the carrier is received. The housing is dimensioned to define a sleeve for the carrier so that at least half the carrier is received in the housing. An image sensing device is positioned on the housing to sense an image to be generated. An image sensing microprocessor is positioned in the housing and is operatively arranged with respect to the image sensing device to control operation of the image sensing device. Both the printing unit and the image recordal apparatus have complementary releasable data connectors so that the image sensing microprocessor can communicate image data to the printing microprocessor of the printing unit. |
1. An apparatus for recording and generating images, the apparatus comprising a printing unit that comprises a carrier that is dimensioned to approximate a PCMCIA memory card, a media supply being receivable in the carrier; a page width print head assembly that is mounted in the carrier to print images on the media, the page width print head assembly including at least one print head chip and a suitable printing microprocessor that is configured to control operation of the print head chip; an ink supply mechanism that is operatively arranged with respect to the print head assembly to supply the print head assembly with ink; and a media feed mechanism positioned in the carrier to feed media to and from the print head chip; and an image recordal apparatus that comprises a housing in which the carrier is received, the housing being dimensioned to define a sleeve for the carrier so that at least half the carrier is received in the housing; an image sensing device that is positioned on the housing to sense an image to be generated; and an image sensing microprocessor that is positioned in the housing and is operatively arranged with respect to the image sensing device to control operation of the image sensing device; wherein both the printing unit and the image recordal apparatus have complementary releasable data connectors so that the image sensing microprocessor can communicate image data to the printing microprocessor of the printing unit. 2. An apparatus as claimed in claim 1, in which the carrier includes an elongate, substantially rectangular support structure, with the page width print head assembly and the ink supply mechanism being mounted on an end portion of the support structure and the media feed mechanism being positioned intermediate the end portion and a remaining portion of the support structure. 3. An apparatus as claimed in claim 2, in which the carrier includes a media cartridge that is releasably mounted on said remaining portion of the support structure. 4. An apparatus as claimed in claim 3, in which the media cartridge is configured to hold sheets of media. 5. An apparatus as claimed in claim 4, in which the media feed mechanism is in the form of a roller feed mechanism that is configured to be engageable with a lowermost sheet of media in the cartridge when the cartridge is positioned on the support structure. 6. An apparatus as claimed in claim 1, in which the printing unit includes a data bus connected across the complementary data connector of the printing unit, the printing microprocessor, the print head assembly and the media feed mechanism. 7. An apparatus as claimed in claim 1, in which the image sensing device is in the form of a CMOS device that defines an active pixel sensor. 8. An apparatus as claimed in claim 1, in which the image recordal apparatus includes a data bus connected across the image sensing device, the image sensing microprocessor and the complementary data connector of the image recordal apparatus. 9. An apparatus as claimed in claim 1, in which the data connectors of the image recordal apparatus and the printing unit are both in the form of PCMCIA-type connectors. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The Applicant has developed print head assemblies that are capable of generating images having a resolution of up to 1600 dpi. Furthermore, the print head assemblies that the Applicant has developed are of a relatively small size, allowing them to be incorporated into a camera-based device such as that described in U.S. patent application Ser. No. 09/113,053. Details of such a print head assembly can be found in U.S. patent application Ser. No. 09/113,053. The relatively small size has been largely the result of the development of an ink jet print head that is the subject of U.S. patent application Ser. No. 09/425,419. The ink jet print head has allowed the Applicant to develop a compact portable printer that is directly engageable with a PCMCIA slot in a laptop or notebook computer. This compact portable printer is the subject matter of the above referenced U.S. patent application Ser. No. 09/436,509. The Applicant has identified that it would be highly desirable to provide an image recordal and generation assembly or apparatus that is capable of generating the high-resolution images mentioned above and yet is of a size that is comparable to pocket sized cameras that are presently available. |
<SOH> SUMMARY OF THE INVENTION <EOH>According to the invention, there is provided an apparatus for recording and generating images, the apparatus comprising a printing unit that comprises a carrier that is dimensioned to approximate a PCMCIA memory card, a media supply being receivable in the carrier; a page width print head assembly that is mounted in the carrier to print images on the media, the page width print head assembly including at least one print head chip and a suitable printing microprocessor that is configured to control operation of the print head chip; an ink supply mechanism that is operatively arranged with respect to the print head assembly to supply the print head assembly with ink; and a media feed mechanism positioned in the carrier to feed media to and from the print head chip; and an image recordal apparatus that comprises a housing in which the carrier is received, the housing being dimensioned to define a sleeve for the carrier so that at least half the carrier is received in the housing; an image sensing device that is positioned on the housing to sense an image to be generated; and an image sensing microprocessor that is positioned in the housing and is operatively arranged with respect to the image sensing device to control operation of the image sensing device; wherein both the printing unit and the image recordal apparatus have complementary releasable data connectors so that the image sensing microprocessor can communicate image data to the printing microprocessor of the printing unit. The invention is now described, by way of example, with reference to the accompanying drawings. It is to be noted that the following specific description is for the purposes of illustrating a particular embodiment of the invention and the manner in which it is to be performed and is not intended to limit the broad scope of the preceding summary. |
Residue removal from nozzle guard for ink jet printhead |
A nozzle guard (80) for an ink jet printer printhead with an array (14) of nozzles (10). The nozzle guard (80) has an array of apertures (84) individually corresponding to the nozzle array (14). The ink droplets are ejected through the apertures (84) and onto the media to be printed. A wiper blade (143) sweeps dust and residual ink (144) stuck to the exterior surface (142) of the nozzle guard (82) characterized in that the exterior surface (142) has a recess (146) individually associated with each of the apertures (86) for preventing residual matter (144) carried by the wiper blade (143) from lodging within the aperture (84). |
1. An apertured nozzle guard for an ink jet printer printhead having an array of nozzles for ejecting colorant onto a substrate to be printed, wherein, the nozzle guard is adapted to be positioned on the printhead such that it extends over the exterior of the nozzles to inhibit damaging contact with the nozzles while permitting colorant ejected from the nozzles to pass through the apertures and onto the substrate to be printed; the nozzle guard including: an exterior surface that, when in use, faces the media; the exterior surface being configured for engagement with a wiper blade that periodically sweeps the surface to remove residual matter; wherein, the exterior surface has a recess individually associated with each of the apertures for preventing residual matter carried by the wiper blade from lodging within the aperture. 2. A nozzle guard according to claim 1 wherein the exterior surface further includes a deflector ridge in each of the recesses, the deflector ridge positioned to engage the wiper blade before the blade passes over the aperture associated with the recess. 3. A nozzle guard according to claim 2 wherein the deflector ridge is arcuate and positoned with respect to the wiping direction to deflect residual material away from the aperture and toward the edge of the recess. 4. A nozzle guard according to claim 1 further including fluid inlet openings for directing fluid over the nozzle array and out through the passages in order to inhibit the build up of foreign particles on the nozzle array. 5. A nozzle guard according to claim 4 further including an integrally formed pair of spaced support elements one support element from the pair being arranged at each end of the nozzle guard 6. A nozzle guard according to claim 5 wherein the fluid inlet openings are arranged in one of the support elements. 7. A nozzle guard according to claim 6 wherein the fluid inlet openings are arranged in the support element remote from a bond pad of the nozzle array. 8. A nozzle guard according to claim 2 wherein the exterior surface is flat except for the recesses and the deflector ridges. 9. A nozzle guard according to claim 1 wherein the guard is formed from silicon. |
<SOH> BACKGROUND TO THE INVENTION <EOH>Ink jet printers are a well-known and widely used form of printed media production. Colorants, usually ink, are fed to an array of micro-processor controlled nozzles on a printhead. As the print head passes over the media, colorant is ejected from the array of nozzles to produce the printing on the media substrate. Printer performance depends on factors such as operating cost, print quality, operating speed and ease of use. The mass, frequency and velocity of individual ink drops ejected from the nozzles will affect these performance parameters. Recently, the array of nozzles has been formed using micro electro mechanical systems (MEMS) technology, which have mechanical structures with sub-micron thicknesses. This allows the production of printheads that can rapidly eject ink droplets sized in the picolitre (x 10 −12 litre) range. While the microscopic structures of these printheads can provide high speeds and good print quality at relatively low costs, their size makes the nozzles extremely fragile and vulnerable to damage from the slightest contact with fingers, dust or the media substrate. This can make the printheads impractical for many applications where a certain level of robustness is necessary. Furthermore, a damaged nozzle may fail to eject the colorant being fed to it. As colorant builds up and beads on the exterior of the nozzle, the ejection of colorant from surrounding nozzles may be affected and/or the damaged nozzle will simply leak colorant onto the printed substrate. Both situations are detrimental to print quality. To address this, an apertured guard may be fitted over the nozzles to shield them against damaging contact. Ink ejected from the nozzles passes through the apertures on to the paper or other substrate to be printed. However, to effectively protect the nozzles the apertures need to be as small as possible to maximize the restriction against the ingress of foreign matter while still allowing the passage of the ink droplets. Ideally, each nozzle would eject ink through its own individual aperture in the guard. As the apertures in the guard are generally microscopic they can be easily clogged. Therefore, it is often desirable to keep the exterior of the nozzle guard clean especially in environments with relatively high levels of dust and other airborne particulates. This is conveniently achieved using a wiper blade that periodically sweeps across the exterior face of the guard to remove dust or ink residues. However, the residual matter on the wiper often becomes lodged on the exterior rim especially the portion of the rim facing into the wipers' direction of travel. This build up of residue tends not to get removed by the wiper and can soon clog the aperture. |
<SOH> SUMMARY OF THE INVENTION <EOH>Accordingly, the present invention provides an apertured nozzle guard for an ink jet printer printhead having an array of nozzles for, ejecting colorant onto a substrate to be printed; wherein, the nozzle guard is adapted to be positioned on the printhead such that it extends over the exterior of the nozzles to inhibit damaging contact with the nozzles while permitting colorant ejected from the nozzles to pass through the apertures and onto the substrate to be printed; the nozzle guard including: an exterior surface that, when in use, faces the media; the exterior surface being configured for engagement with a wiper blade that periodically sweeps the surface to remove residual matter; wherein, the exterior surface has a recess individually associated with each of the apertures to prevent the wiper blade from engaging the exterior surface immediately adjacent the aperture. In this specification the term “nozzle” is to be understood as an element defining an opening and not the opening itself. Preferably, the exterior surface further includes a deflector ridge in each of the recesses, the deflector ridge positioned to engage the wiper blade before the blade passes over the aperture associated with the recess. In one convenient form, the deflector ridge is arcuate and positioned with respect to the wiping direction to deflect residual material away from the aperture and toward the edge of the recess. The nozzle guard may further include fluid inlet openings for directing fluid over the nozzle array and out through the passages in order to inhibit the build up of foreign particles on the nozzle array. The nozzle guard may include an integrally formed pair of spaced support elements one support element from the pair being arranged at each end of the guard. In this embodiment, the fluid inlet openings may be arranged in one of the support elements. It will be appreciated that, when air is directed through the openings, over the nozzle array and out through the passages, the build up of foreign particles on the nozzle array is inhibited. The fluid inlet openings may be arranged in the support element remote from a bond pad of the nozzle array. To optimize the effectiveness of the wiper blade, the exterior surface is flat except for the recesses and deflector ridges. By forming the guard from silicon, its coefficient of thermal expansion substantially matches that of the nozzle array. This will help to prevent the array of apertures in the guard from falling out of register with the nozzle array. Using silicon also allows the shield to be accurately micro-machined using MEMS techniques. Furthermore, silicon is very strong and substantially non-deformable. |
Wheel lock apparatus |
A wheel lock apparatus for a wheeled vehicle, said vehicle having a tire, the wheel lock apparatus comprising at least one tooth, wherein the at least one tooth is moveable between a first position, against the tire, and a second position, remote therefrom, such that, in the first position, the at least one tooth is oriented to substantially prevent forward rotation of the tire by engaging the tire, whilst in the second position, the tire is free to rotate. |
1. A wheel lock apparatus for a wheeled vehicle, said vehicle having a tire, the wheel lock apparatus comprising at least one tooth and a locking assembly, wherein the at least one tooth is moveable between a first position, against the tire, and a second position, remote therefrom, such that, in the first position, the at least one tooth is oriented to substantially prevent forward rotation of the tire by engaging the tire, whilst in the second position, the tire is free to rotate and wherein the at least one tooth is lockable in at least the first position by way of the locking assembly, thereby allowing the wheeled vehicle to be secured against unauthorised use. 2. A wheel lock apparatus according to claim 1, where the tire comprises a tread portion interposed between two wall portions, wherein the at least one tooth is moveable between a first position, against the tread portion of the tire, and a second position, remote therefrom, such that, in the first position, the at least one tooth is oriented to substantially prevent forward rotation of the tire by engaging the tread portion thereof. 3. A wheel lock apparatus according to claim 1, wherein when in the first position, an edge of the at least one tooth contacts the tread of the tire and a body of the at least one tooth extends from the edge of the tooth in a direction between normal to the tread of the tire and tangential to the tread of the tire such that forward rotation of the tire causes the tooth to engage the tread of the tire. 4. A wheel lock apparatus according to claim 1, wherein the wheel lock apparatus comprises at least one further tooth, wherein the at least one further tooth is moveable between a first position, against the tread portion of the tire of the trailer, and a second position, remote therefrom, such that, in the first position, the at least one further tooth is oriented to substantially prevent rearward rotation of the tire by engaging the tread portion thereof, whilst in the second position, the tire is free to rotate. 5. A wheel lock apparatus according to claim 4, wherein, when in the first position, an edge of the at least one further tooth contacts the tread of the tire and a body of the or each further tooth extends from the edge of the further tooth in a direction between normal to the tread of the tire and tangential to the tread of the tire such that rearward rotation of the tire causes the further tooth to engage the tread of the tire. 6. A wheel lock apparatus according to claim 4, wherein the at least one tooth and the at least one further tooth are provided on a plate, wherein the plate is moveable between a first position, wherein the at least one tooth and the at least one further tooth are positioned against the tread portion of the tire, and a second position, remote therefrom. 7. A wheel lock apparatus according to claim 6, wherein the or each tooth and the or each further tooth, are provided integrally with the plate. 8. A wheel lock apparatus according to claim 7, wherein the wheel lock apparatus comprises one tooth, and one further tooth, the tooth and further tooth being provided integrally with the plate in the form of a concave member. 9. A wheel lock apparatus according to claim 1, wherein the wheel lock apparatus comprises an arm member, having a first end and a second end, wherein the first end of the arm member is pivotally attached to the trailer, and the or each tooth, and the or each further tooth where provided, is provided about the second end of the arm member, wherein the arm member may be pivoted between a first position, where the or each tooth is against the tread portion of the tire, and a second position, where the or each tooth is remote therefrom. 10. A wheel lock apparatus according to claim 9, wherein the plate is pivotally attached to the second end of the arm member. 11. A wheel lock apparatus according to claim 1, wherein the wheel lock assembly comprises a mounting plate, wherein the mounting plate is attached to the bodywork of the vehicle proximate the tire thereof, such that the mounting plate faces the tread portion of the tire, the mounting plate having an inner face proximate the tire and an outer face remote therefrom, defining an interior, proximate the tire, and an exterior remote therefrom. 12. A wheel lock apparatus according to claim 11, wherein, where the vehicle is provided with a wheel arch, the mounting plate may be provided in the form of a portion of the wheel arch. 13. A wheel lock apparatus according to claim 11, wherein the first end of the arm member is pivotally attached to the inner face of the mounting plate. 14. A wheel lock apparatus according to claim 1, wherein the wheel lock apparatus comprises a biasing assembly such that, when the or each tooth is not locked in the first position, the or each tooth is biased toward the second position. 15. A wheel lock apparatus according to claim 9, wherein the wheel lock apparatus comprises an actuator assembly, wherein the actuator assembly is adapted to act on the arm member such that operation of the actuator assembly causes the arm member to be moved between the first position and the second position. 16. A wheel lock apparatus according to claim 15, wherein the actuator assembly comprises a plunger, having a first end and a second end, such that the first end of the plunger pivotally engages the arm member at a point intermediate the first and second ends thereof, and the second end is located exterior to the mounting plate. 17. A wheel lock apparatus according to claim 16, wherein an aperture is provided through the mounting plate, the plunger extending through the aperture. 18. A wheel lock apparatus according to claim 16, wherein the locking assembly is provided in the form of one or more indentations or apertures provided along the length of the plunger, and a pin member slidably mounted to the trailer, wherein the or each aperture or indentation is adapted to at least partially receive the pin member, the sliding movement of the pin member being governed by a lock. 19. A wheel lock assembly according to claim 16, wherein the biasing assembly is provided in the form of a spring, wherein the spring is provided about the portion of the plunger exterior to the mounting plate, between the outer face of the mounting plate and a flared second end of the plunger. 20. A wheel lock apparatus according to claim 16, wherein, where the actuator assembly is provided in the form of a plunger, the arm member is formed from a flexibly resilient material such that, in use, pressure on the plunger causes deformation of the arm member, in turn providing pressure to maintain the contact of the or each tooth with the tire tread. 21. A wheel lock apparatus according to claim 1, wherein the actuator assembly comprises a cam and lever assembly, having a lever portion operatively interconnected with a cam portion, wherein the cam and lever assembly is adapted to pivot between a first position where the cam portion acts on the arm member and causes such to assume the first position, and a second position, where the cam portion allows the arm member to assume the second position. 22. A wheel lock apparatus according to claim 21, wherein the cam assembly is pivotally attached to the mounting plate, with an aperture being provided through the mounting plate such that, when the cam and lever assembly is in the first position, the cam portion extends through the aperture to act on the arm member. 23. A wheel lock apparatus according to claim 21, wherein the cam portion acts on the arm member at a point intermediate the first and second ends thereof. 24. A wheel lock apparatus according to claim 21, wherein, the arm member is formed from a flexibly resilient material such that, in use, the cam portion causes deformation of the arm member, in turn providing pressure to maintain the contact of the or each tooth with the tire tread. 25. A wheel lock apparatus according to claim 21, wherein the cam portion and the lever portion of the cam and lever assembly are provided integrally. 26. A wheel lock apparatus according to claim 21, wherein the locking assembly is provided in the form of first and second projections provided from the mounting plate, each having an aperture provided therethrough, and an aperture is provided through the cam and lever assembly such that, when the cam and lever assembly is in the first position, the aperture of the cam and lever assembly is substantially aligned with the aperture through the first projection and, when the cam and lever assembly is in the second position, the aperture of the cam and lever assembly is aligned with the second projection, whereby the cam and lever assembly may be conveniently locked in either the first or second positions. 27. (canceled) |
<SOH> BACKGROUND ART <EOH>Trailers, including those for boats, caravans and the like are particularly susceptible to theft, and instances of theft of trailers and caravans are occurring with increasing frequency. The security provisions commonly applied to cars are typically not suitable for trailers. For example, immobiliser type systems rely on interfering with the supply of power from the engine of a vehicle and, accordingly, have no utility in the protection of unpowered trailers from theft. Unpowered anti-theft devices, such as devices that interfere with the steering wheel of a motor vehicle, obviously have no application to trailers and the like. Further, it is anticipated that a considerable portion of the market for anti-theft systems for trailers will be owners of existing trailers. Accordingly, the ease of installation of such devices to an existing trailer is of great importance. The background to the present invention is discussed in the context of preventing/deterring theft of trailers. However, it should be understood that the application of the present invention extends to preventing/deterring theft of other wheeled vehicles, such as cars and motorcycles, as an alternative or complement to existing anti-theft systems. The preceding discussion of the background to the invention is intended to facilitate an understanding of the present invention. However, it should be appreciated that the discussion is not an acknowledgement or admission that any of the material referred to was part of the common general knowledge in Australia as at the priority date of the application. Throughout the specification, unless the context requires otherwise, the word “comprise” or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. Throughout this specification, unless the context requires otherwise, the word “trailer” will be understood to include all devices designed or arranged to be towed by a motor vehicle or truck, including but not limited to boat trailers, bike trailers, car trailers, caravans and horse floats. A tyre may be rotated in two directions, one corresponding to the forward motion of the trailer and one to the rearward motion of the trailer. For the purposes of concise description, the former will be referred to as forward rotation, and the latter as rearward rotation. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>The wheel lock apparatus of the present invention will now be described, by way of example only, with reference to two embodiments thereof and the accompanying drawings, in which:— FIG. 1 is a side elevation showing a portion of a trailer comprising a wheel arch and a wheel, the trailer being fitted with a wheel lock device according to the first embodiment, the wheel lock device being in a disengaged state; FIG. 2 is a side elevation showing a portion of a trailer and wheel lock apparatus of FIG. 1 , the wheel lock apparatus being in an engaged state; FIG. 3 is a perspective view of the portion of the trailer and wheel lock apparatus of FIGS. 1 and 2 ; FIG. 4 is a side elevation showing a portion of a trailer comprising a wheel arch and a wheel, the trailer being fitted with a wheel lock device according to a second embodiment, the wheel lock device being in a disengaged state; FIG. 5 is a side elevation showing a portion of a trailer and wheel lock apparatus of FIG. 4 , the wheel lock apparatus being in an engaged state; and FIG. 6 is a perspective view of the portion of the trailer and wheel lock apparatus of FIGS. 4 and 5 . detailed-description description="Detailed Description" end="lead"? |
Shock-proof electric marine engine, e.g. engine or generator |
The invention relates to a shock-proof electric marine engine e.g. an engine or generator, for a marine (Navy) ship, comprising a stator and a rotor in a housing, whereby the stator and the rotor are connected in such a way that they are rotatably displaceable in a counter direction and in a radial/axial manner with limited slack. Said rotor and stator form a displaceable unit in relation to the housing, which can be displaced away from the housing with a higher vibration overshoot range. Said housing is elastically connected to the marine(navy) ship. |
1. A shock-resistant electrical machine, comprising: a housing elastically connected to a marine vessel; a unit, including a stator and a rotor, located in the housing and adapted to move with respect to the housing, wherein the rotor is connected to a propulsion shaft and the stator and rotor are at least one of radially and axially connected to one another with restricted play so as to be rotateable with respect to one another, wherein the unit is adapted to flex further with respect to the housing than a normal extent of noise-inducing vibration oscillation, wherein the rotor includes a tube-like mounting body and an active part mounted on the mounting body, the rotor being elastically supported on the propulsion shaft, and wherein the stator is mounted on the mounting body of the rotor and is elastically supported on the housing. 2. The shock-resistant electrical machine as claimed in claim 1, wherein the housing includes a streamlined housing arranged like a gondola on a lower surface of the hull of the marine vessel, with at least one propeller being coupled to the propulsion shaft that is connected to the rotor, and with the stator being fixed on the rotor via rotating bearings, and wherein the unit is elastically supported both on the housing and on the propulsion shaft, with an air gap of 0.5 to 50 mm being formed between the rotor and stator. 3. The shock-resistant electrical machine as claimed in claim 1, wherein the housing of the machine is arranged on an elastically mounted base frame inside the vessel, with the propulsion shaft including an elastic coupling to at least one of a propeller shaft and a water jet impeller shaft. 4. The shock-resistant electrical machine as claimed in claim 1, wherein the support for the rotor on the propulsion shaft is relatively soft in the axial and radial directions, and is relatively torsionally stiff in the circumferential direction. 5. The shock-resistant electrical machine as claimed in claim 1, wherein the rotating bearings are in the form of roller bearings. 6. The shock-resistant electrical machine as claimed in claim 1, wherein the bearings for bearing the propulsion shaft are in the form of sliding bearings. 7. The shock-resistant electrical machine as claimed in claim 1, wherein the motor is water-cooled. 8. The shock-resistant electrical machine as claimed in claim 7, wherein the stator includes a cooling apparatus in which the cooling water for cooling the motor is passed via cooling channels. 9. The shock-resistant electrical machine as claimed in claim 8, wherein the cooling channels are in the form of radial channels. 10. The shock-resistant electrical machine as claimed in claim 8, wherein the cooling channels are in the form of circumferential channels which run on the circumference of the stator. 11. The shock-resistant electrical machine as claimed in claim 8, wherein the cooling channels are in the form of axial channels. 12. The shock-resistant electrical machine as claimed in claim 8, wherein the cooling channels are connected to at least one water chamber, acting as a distributor. 13. The shock-resistant electrical machine as claimed in claim 1, wherein the stator includes a winding with end windings around which cooling air flows. 14. The shock-resistant electrical machine as claimed in claim 1, wherein the motor is in the form of a motor with permanent-magnet excitation. 15. The shock-resistant electrical marine machine as claimed in claim 14, wherein the stator is designed to be rotateable via slide rings in the housing, for example by means of a stator yoke which can rotate. 16. The shock-resistant electrical marine machine as claimed in claim 1, wherein the machine is at least one of a motor and generator for a navy vessel. 17. The shock-resistant electrical marine machine as claimed in claim 2, wherein the support for the rotor on the propulsion shaft is relatively soft in the axial and radial directions, and is relatively torsionally stiff in the circumferential direction. 18. The shock-resistant electrical marine machine as claimed in claim 3, wherein the support for the rotor on the propulsion shaft is relatively soft in the axial and radial directions, and is relatively torsionally stiff in the circumferential direction. 19. The shock-resistant electrical marine machine as claimed in claim 8, wherein the cooling channels are in the form of meandering channels which run on the circumference of the stator. 20. The shock-resistant electrical marine machine as claimed in claim 14, wherein the stator is designed to be rotateable via slide rings in the housing, by way of a rotateable stator yoke. 21. A unit for a shock-resistant machine of a marine vessel, comprising: a stator; and a rotor, wherein the stator and rotor are at least one of radially and axially connected to one another with restricted play so as to be rotateable with respect to one another, wherein the rotor includes a tube-like mounting body and an active part mounted on the mounting body, the rotor being elastically supported on a propulsion shaft of the marine vessel, and wherein the stator is mounted on the mounting body of the rotor. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Vibration-damped electrical marine machines, for example motors, are known, for example from WO 02/30742 A1. In order to damp vibration, the rotor and the stator in the known motors are supported on one another, and the stator is supported on the motor housing via vibration-damping spring elements. The known design in its own right provides decoupling between the housing and the rotor/stator unit, but this is not sufficient for navy vessels if they are hit. In this case, it must be possible not only to absorb and dissipate vibration but also high shock accelerations, allowing the unit that is formed by the stator and rotor to flex essentially within further limits than those provided by the known vibration damping elements. |
<SOH> SUMMARY OF THE INVENTION <EOH>An object may be achieved by the stator and motor being radially/axially connected to one another with restricted but great play such that they can rotate with respect to one another. Further, they may form a unit which can move with respect to the housing, and which can flex further than the normal extent of vibration oscillation. The housing may be elastically connected to the navy vessel. In conjunction with a large gap between the stator and rotor, which is also provided according to an embodiment of the invention, this results in an embodiment which is also insensitive to bending of the rotor shaft. The proposed measures allow shock accelerations on the housing or on other vessel parts of more than 100 g to be withstood, so that the rotor and stator cannot strike one another during operation. This striking is a feature in the event of shock acceleration; the components intrinsically withstand accelerations of more than 100 g. Flexing movements of a number of millimeters, and in the extreme case of a number of centimeters, are necessary and achieved in order to dissipate the shock accelerations. An embodiment of the shock-resistant electrical marine machine provides in particular for the motor to be arranged on the lower surface of the hull of a vessel in a streamlined housing which is in the form of a gondola, with at least one propeller being coupled to the propulsion shaft that is connected to the rotor. Further, the stator is fixed on the rotor via rotating bearings. In addition, the unit formed from the stator and rotor is elastically supported both on the housing and on the propulsion shaft. Finally, an air gap of up to about 50 mm is formed between the rotor and stator. An electrical marine machine in an electrical steering propeller is subject to particularly severe shock accelerations since, in some circumstances, a mine or a torpedo may explode directly underneath the electrical steering propeller. The shock-resistant electrical marine propulsion system must continue to operate even in this situation, which involves accelerations of considerably more than 100 g for the steering propeller housing, and this is achieved by the measures described above in conjunction with the elastic connection which is provided between the steering propeller and stern of the vessel. In another refinement, an embodiment of the invention provides for the housing to be arranged on an elastically mounted base frame inside the vessel, with the propulsion shaft having an elastic coupling to a propeller shaft or a water jet impeller shaft. This results in an embodiment of a marine machine which, even when mounted in the interior of the vessel, can withstand, for example, a mine explosion or the impact of a missile, which causes severe vibration in the vessel. This therefore avoids generator failure when the shock-resistant electrical marine machine is in the form of a generator. This therefore results in twice as much elasticity with respect to the hull of the vessel both for the electrical marine machine in the interior of the vessel and for the marine machine which is arranged in an electrical steering propeller. In the case of the electrical steering propeller, this is achieved by way of a flexibly elastic steering propeller casing. Further, in the case of a machine which is installed in the interior of the vessel, this is achieved by way of an elastic base frame. In all situations, this results in a design for a shock-resistant electrical marine machine which has no problems in withstanding both large shock waves and the springing-back processes. The splitting of the rotor into a tube-like mounting body and an active part which is mounted on the mounting body and is elastically supported on the propulsion shaft, with the stator being mounted on the mounting body for the rotor and being elastically supported on the housing, results in the unit that is important according to the invention. This allows the important joint flexing movement of the rotor and stator in response to shock acceleration. The support for the rotor on the propulsion shaft is soft in the axial and radial directions, and is torsionally stiff in the circumferential direction. Depending on the requirement, the bearings are in the form of roller bearings or sliding bearings. This results in a stiff structure that is appropriate for the invention, with sliding bearings being used when particularly high shock accelerations have to be expected. The electric motor or generator according to an embodiment of the invention in its own right provides good damping of structure-borne sound by virtue of its elastically sprung installation or mounting. However, enemy forces can still locate the vessel via the radiating infrared emission. In order to reduce this and also to allow high loads to be placed on the motor despite its small cross section, the invention provides for the motor to be liquid-cooled. The water cooling is in this case advantageously provided by way of conventional closed-cycle cooling. For water cooling of the shock-resistant motor, the stator is advantageously designed as a cooling apparatus, with the cooling water flowing through the stator via cooling channels. The cooling channels may be in the form of radial channels, thus resulting in particularly effective cooling, or else in the form of circumferential channels, which run in a meandering shape on the circumference of the stator as a particularly simple solution, or else as axial channels which pass longitudinally through the stator. The cooling is also particularly effective in this case. Overall, this results in a considerable reduction in the radiated IR emission, which is particularly important for the steering propeller propulsion machine, and in an increased load capacity with a small physical size in comparison to simpler air cooling. An embodiment of the invention provides for the cooling channels to have at least one water chamber, which acts as a distributor. The individual cooling channels can thus be supplied with cooling water without any need to provide a large number of individual connections in the motor or generator. A further refinement of an embodiment of the invention provides for the stator to have a winding with end windings around which cooling air flows. This highly advantageously also results in cooling of that part of the stator which is not covered for cooling purposes by the cooling channels. Although cooling channels can also be provided for the end windings, passing through the end windings or surrounding the end winding. This results in major design difficulties, however, in particular for a shock-damped machine. Thus, this approach is generally not adopted. The end windings can thus be cooled by a circulating air flow, which is connected to a closed-cycle cooler in the vessel or on deck. The air/end winding cooling advantageously means that there is no need to change the physical size of the machine since free space is available in the end winding area. In one particularly advantageous embodiment of the shock-resistant electrical machine, this machine is in the form of a machine with permanent-magnet excitation. This results in a particularly simple machine, whose rotor has no slip-rings, etc. The rotor and stator may therefore simply be in the form of intrinsically compact units, with a relatively large gap between them, and in which the stator may be in the form of an air gap winding. Overall, this results in a particularly robust, shock-resistant configuration, especially for an electrical steering propeller motor. For electric motors of this type, which are installed in the vessel, an embodiment of the invention advantageously provides for the stator to be designed such that it can rotate in the housing via slide rings, for example by way of a stator yoke which can rotate. It is thus possible to carry out any necessary repairs that may be required, for example on the cooling system, without having to completely disassemble the machine, and without the machine having to be removed as an assembly and disassembled. This is particularly advantageous for a shock-resistant electrical marine machine for a navy vessel, since this makes it possible to avoid dockyard time. There is no need to remove the machine in order to work on the stator. |
Novel synthetic ganglioside derivatives and compositions thereof |
Novel synthetic gangliosides and pharmaceutical compositions containing such synthetic gangliosides are described. Methods of making the novel synthetic ganglioside compounds and compositions as well as their use in the field of neuroprotection and cancer treatment is also described. |
1. A compound having the formula: wherein Z is a member selected from O, S, C(R2)2 and NR2; X is a member selected from H, —OR3, —NR3R4, —SR3, and —CHR3R4; R1, R2 and R3 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, —C(═M)R5, —C(═M)-Z-R5, —SO2R5, and —SO3; wherein M and Z are members independently selected from O, NR6 or S; and Y is a member selected from H, —OR7, —SR7, —NR7R8, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl wherein R5, R6, R7 and R8 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl. 2. The compound according to claim 1, with the proviso that when X is NHR4, in which R4 is a member selected from H and —C(═O)R5, in which R5 is substituted or unsubstituted alkyl; Y is OH; and Z is O, R5 is other than a member selected from substituted or unsubstituted alkyl. 3. The compound according to claim 1, wherein R1 has the formula: in which R9, R10, R11, R12 and R13 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl substituted or unsubstituted heterocycloalkyl, NR14R15, OR14, —CN, and —C(═L)R14 wherein L is a member selected from O, S, and NR16; R14 and R15 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, C(O)R17, OR17, SR17 and NR17R18 wherein R16, R17 and R18 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, and wherein a member selected from R9 and R10; R9 and R11; R9 and R12; R9 and R13; R10 and R11; R10 and R12; R10 and R13; R11 and R12; R11 and R13; and R12 and R13, together with the atom to which they are attached, are optionally joined to form a ring, wherein said ring is a member selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroalkyl. 4. The compound according to claim 1, wherein R1 has the formula: wherein R11, R12 and R13 are members independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, NR14R15, OR14, —CN, —C(═L)R14 wherein L is a member selected from O, S, and NR16; R14 and R15 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, C(O)R17, OR17 and NR17R18 wherein R16, R17 and R18 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, and wherein a member selected from R11 and R12; R11 and R13; and R12 and R13, together with the atom to which they are attached, are optionally joined to form a ring, wherein said ring is a member selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroalkyl. 5. A compound according to claim 1, wherein R1 has the formula: R9, R10, R11, R13, R19, R20 and R21 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, NR14R15, OR14, —CN, and —C(═L)R14 wherein L is a member selected from O, S, and NR16; R14 and R15 are members independently selected from H substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, C(O)R17, OR17, SR17 and NR17R18 wherein R16, R17 and R18 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, and wherein a member selected from R9 and R10; R9 and R11; R9 and R13; R9 and R21; R9 and R19; R9 and R20; R9 and R21; R10 and R11; R10 and R13; R10 and R19; R10 and R20; R10 and R21; R11 and R13; R11 and R19; R11 and R20; R11 and R21; and R13 and R19; R13 and R20; R13 and R21; R19 and R20; R19 and R21; and R20 and R21 together with the atom to which they are attached, are optionally joined to form a ring, wherein said ring is a member selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroalkyl. 6. The compound according to claim 3, wherein R5 is CH3. 7. The compound according to claim 1, wherein the saccharide has a formula that is selected from the group consisting of: 8. The compound according to claim 7, wherein the saccharide is deacetylated. 9. The compound according to claim 1, having the formula: 10. The compound according to claim 1, having the formula: 11. The compound according to claim 1, having the formula: 12. The compound according to claim 1, having the formula: 13. The compound according to claim 1, having the formula: 14. The compound according to claim 1, having the formula: 15. The compound according to claim 1, having the formula: 16. The compound according to claim 1, having the formula: 17. The compound according to claim 1, having the formula: 18. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. 19. A method for the prevention or treatment of a disorder of the nervous system in an animal or human comprising the step of administering to an animal or human in need thereof a therapeutically effective amount of the compound of claim 1. 20. The method of claim 19, wherein said disorder of the nervous system is selected from the group consisting of Parkinson's disease, ischemia, stroke, Alzheimer's disease, depression, anxiety, encephalitis, meningitis, amyotrophic lateral sclerosis, trauma, spinal cord injury, nerve injury, and nerve regeneration. 21. A method for the treatment of a glioma in a human comprising the step of administering to the human in need thereof a therapeutically effective amount of the compound claim 1. 22. A method of synthesizing a synthetic ganglioside compound of claim 1, wherein the steps of synthesis of the saccharide moiety comprise: contacting an acceptor molecule comprising a sphingoid moiety and a glucose (Glc) with a galactosyltransferase enzyme and a galactose (Gal) donor molecule to form: contacting the with a trans-sialidase enzyme and a sialic acid (NANA) donor molecule to form: contacting the with a N-acetyl galactose (GalNAc)-transferase enzyme and a GalNAc donor molecule to form: contacting the with a galactosyltransferase enzyme and a galactose (Gal) donor molecule to form contacting the with a fatty acid moiety under conditions sufficient to form a ganglioside. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The term “carbohydrate” or “saccharide” embraces a wide variety of chemical compounds having the general formula (CH 2 O) n , such as monosaccharides, disaccharides, oligosaccharides and polysaccharides. Oligosaccharides and polysaccharides are chains composed of monosaccharide units, which are also generally referred to as sugars. The monosaccharide units of an oligo- or polysaccharide can be arranged in various orders. The linkage between any two saccharide units can occur in any of approximately ten different ways. As a result, the number of different possible stereoisomeric oligosaccharide or polysaccharide chains is enormous. Saccharides are a key component of glycosphingolipids found in cell membranes. Of interest with respect to the present invention is a certain class of glycoshingolipids known as gangliosides. Gangliosides are glycosphingolipids, often found in cell membranes, that consist of three elements. One or more sialic acid residues are attached to an oligosaccharide or carbohydrate core moiety, which in turn is attached to a hydrophobic lipid (ceramide) structure which generally is embedded in the cell membrane. The ceramide moiety includes a long chain base (LCB) portion and a fatty acid (FA) portion. Gangliosides, as well as other glycolipids and their structures in general, are discussed in, for example, Lehninger, Biochemistry (Worth Publishers, 1981) pp. 287-295 and Devlin, Textbook of Biochemistry (Wiley-Liss, 1992). Gangliosides are classified according to the number of monosaccharides in the carbohydrate moiety, as well as the number and location of sialic acid groups present in the carbohydrate moiety. Mono sialogangliosides are given the designation “GM”, disialogangliosides are designated “GD”, trisialogangliosides “GT”, and tetrasialogangliosides are designated “GQ”. Gangliosides can be classified further depending on the position or positions of the sialic acid residue or residues bound. Further classification is based on the number of saccharides present in the oligosaccharide core, with the subscript “1” designating a ganglioside that has four saccharide residues (Gal-GalNAc-Gal-Glc-Ceramide), and the subscripts “2”, “3” and “4” representing trisaccharide (GalNAc-Gal-Glc-Ceramide), disaccharide (Gal-Glc-Ceramide) and monosaccharide (Gal-Ceramide) gangliosides, respectively. Numerous types of gangliosides found in nature have been isolated and identified and vary primarily in the basic saccharide structure (e.g. G M3 , G M2 , G M1 , G D1a , G D1b and G T1 ). A variety of procedures are available for the isolation and purification of such “natural” gangliosides from organs and tissues, particularly from animal brain (Sonnino et al., 1992, J. Lipid Res., 33:1221-1226; Sonnino et al., 1988, Ind. J. Biochem. Biophys., 25:144-149; Svennerholm, 1980, Adv. Exp. Med. Biol., 125:533-44) as well as bovine buttermilk (Ren et al., 1992, J. Bio. Chem., 267:12632-12638; Takamizawa et al., 1986, J. Bio. Chem., 261:5625-5630). Gangliosides are normal components of plasma membranes and are particularly abundant in the nervous system. In humans, gangliosides are most abundant in the gray matter of the brain, particularly in nerve endings. They are believed to be present at receptor sites for neurotransmitters, including acetylcholine, and can also act as specific receptors for other biological macromolecules, including interferon, hormones, viruses, bacterial toxins, and the like. Certain gangliosides are found on the surface of human hematopoictic cells (Hildebrand et al. (1972) Biochim. Biophys. Acta 260: 272-278; Macher et al. (1981) J. Biol. Chem. 256: 1968-1974; Dacremont et al. Biochim. Biophys. Acta424: 315-322; Klock et al. (1981) Blood Cells 7:247) which may play a role in the terminal granulocytic differentiation of these cells. Nojiri et al. (1988) J Biol. Chem. 263: 7443-7446. These gangliosides, referred to as the “neolacto” series, have neutral core oligosaccharide structures having the formula [Galβ-(1,4)GlcNAcβ(1,3)] n Galβ(1,4)Glc, where n=1-4. Included among these neolacto series gangliosides are 3′-nLM 1 (NeuAcα(2,3)Galβ(1,4)GlcNAcβ(1,3)Galβ(1,4)-Glcβ(1,1)-Ceramide) and 6′-nLM 1 (NeuAcα(2,6)Galβ(1,4)GlcNAcβ(1,3)Galβ(1,4)-Glc,(1,1)-Ceramide). It has been widely demonstrated that gangliosides are able to enhance functional recovery both in the lesioned peripheral nervous system (PNS) and the central nervous system (CNS), through the involvement of specific membrane mechanisms and the interaction with trophic factors, as pointed out from studies in vitro on neuronal cultures (Ferrari, F. et al., Dev. Brain Res., 1983, 8:215-221; Doherty, P. et al., J. Neurochem., 1985, 44:1259-1265; Skaper, S. D. et al., Mol. Neurobiol., 1989, 3:173-199). Gangliosides have been used for treatment of nervous system disorders, including cerebral ischemic strokes. See, e.g., Mahadnik et al. (1988) Drug Development Res. 15: 337-360; U.S. Pat. Nos. 4,710,490 and 4,347,244; Horowitz (1988) Adv. Exp. Med. and Biol. 174: 593-600; Karpiatz et al. (1984) Adv. Exp. Med. and Biol. 174: 489-497. As a result, attempts have been made to use gangliosides in the treatment of disorders of the nervous system. This has led to the development of synthetic gangliosides as well as natural ganglioside containing compositions for use in the treatment of disorders of the nervous system (U.S. Pat. Nos. 4,476,119, 4,593,091, 4,639,437, 4,707,469, 4,713,374, 4,716,223, 4,849,413, 4,940,694, 5,045,532, 5,135,921, 5,183,807, 5,190,925, 5,210,185, 5,218,094, 5,229,373, 5,260,464, 5,264,424, 5,350,841, 5,424,294, 5,484,775, 5,519,007, 5,521,164, 5,523,294, 5,677,285, 5,792,858, 5,795,869, and 5,849,717). Gangliosides have also been implicated as playing a significant role in certain types of cancer. Neuroblastoma is a form of cancer that primarily afflicts children under the age of five. Individuals suffering from neuroblastoma may have tumors growing near the spinal cord, and very large tumors have been found to cause paralysis in such patients. Gangliosides have been shown to play a role in both the growth and the inhibition of the growth of neuroblastoma-associated tumors (Basavarajappa et al., 1997, Alcohol Clin. Exp. Res., 21(7):1199-203; Singleton et al., 2000, Int. J. Dev. Neurosci., 2000, 18(8):797-80). However, there still exists a need in the art for compounds capable of acting as neuroprotective agents in a manner similar to or better than the natural gangliosides for the prophylaxis, treatment and cure of disorders of the nervous system. Further, differences in the structure of ganglioside compounds can refine the structure-function relationship of such compounds to provide powerful tools for control of the growth of certain kinds of tumors, including neuroblastoma tumors. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention answers such a need by providing novel synthetic gangliosides of formulae (I) and (Va)-(Vd): including pharmaceutically acceptable salts, isomers, hydrates, solvates, and prodrugs thereof. The invention further provides a novel synthetic ganglioside of the formula in which Z can be O, S, C(R 2 ) 2 and NR 2 , X can be H, —OR 3 , —NR 3 R 4 , —SR 3 , and —CHR 3 R 4 , and R 1 , R 2 and R 3 can be independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, —C(═M)R 5 , —C(═M)-Z-R 5 , —SO 2 R 5 , and —SO 2 functional moieties. Further, a novel ganglioside of the present invention can have M and Z independently selected from O, NR 6 or S, and Y can be selected from H, —OR 7 , —SR 7 , —NR 7 R 8 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl moieties. Further still a novel ganglioside of the invention can have R 5 , R 6 , R 7 and R 8 independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl moieties. The present invention also provides a novel ganglioside compound as described above, with the proviso that when X is NHR 4 , in which R 4 is selected from H and —C(═O)R 5 , in which R 5 is substituted or unsubstituted alkyl, Y is OH; and Z is O, R 5 is other than a substituted or unsubstituted alkyl moiety. The present invention also provides a novel ganglioside compound in which the saccharide component can be and such saccharide moieties may or may not be deacetylated. The invention further provides pharmaceutical compositions including at least one compound of the invention and a pharmaceutically acceptable carrier. The invention still further provides a method for the prevention and/or treatment and/or cure of a disorder of the nervous system in an animal or human including the step of administering to a patient in need thereof a therapeutically effective amount of at least one compound or pharmaceutical composition of the invention. Such patients in need of a compound of the present invention may suffer from a disorder of the nervous system, including Parkinson's disease, ischemia, stroke, Alzheimer's disease, depression, anxiety, encephalitis, meningitis, amyotrophic lateral sclerosis, trauma, spinal cord injury, nerve injury, and nerve regeneration. One embodiment of the invention provides a method for the treatment of a glioma in a human and includes the step of administering to the human in need thereof a therapeutically effective amount of a compound of the present invention. The present invention also provides a method of synthesizing a synthetic ganglioside compound of the invention, wherein the steps of synthesis of the saccharide moiety include contacting a sphingoid acceptor molecule and a glucose molecule with a galactosyltransferase enzyme and a galactose donor molecule to form contacting the with a trans-sialidase enzyme and a sialic acid (NANA) donor molecule to form contacting the with a N-acetyl galactose (GalNAc)-transferase enzyme and a GalNAc donor molecule to form contacting the with a galactosyltransferase enzyme and a galactose (Gal) donor molecule to form contacting the with a fatty acid moiety under conditions sufficient to form a ganglioside. |
Information providing system, information processing apparatus and method, and information providing apparatus and method |
The present invention relates to an information providing system, information processing apparatus and method, and information providing apparatus and method, which prevents network contents from being used unduly. The broadcast contents, sent on the air toward a digital broadcast receiver 4 by the broadcast station 1-1, 1-2, has a reference to network contents to be provided by a contents server 9. The digital broadcast receiver 4 requests the contents server 9 to deliver network contents through the Internet 8. At this time, a URI of the broadcast contents is sent to the contents server 9. The contents server 9 searches through a database on the basis of the broadcast contents URI. In the case that the broadcast contents is not restricted in making reference to the network contents, the network contents are distributed to the digital broadcast receiver 4 through the Internet 8. The invention is applicable to a digital broadcast system. |
1. An information providing system comprising an information processing apparatus for receiving first information and second information to be made reference to by said first information, a first information providing apparatus for providing said first information, and a second information providing apparatus for providing said second information, said information providing system characterized by: said first information providing apparatus providing said first information for making reference to said second information to said information processing apparatus; said information processing apparatus receiving said first information from said first information providing apparatus, extracting identifying information for identifying said first information from said received first information, and requesting to provide said second information being made reference to by said received first information by attaching the identifying information to said second information providing apparatus; said second information providing apparatus determining whether or not to provide said second information to the information processing apparatus on the basis of the identifying information received from said information processing apparatus, and providing said second information to said information processing apparatus on the basis of a determination result thereof. 2. The information providing system according to claim 1, wherein said first information providing apparatus provides broadcast contents as said first information by broadcast, said second information providing apparatus provides network contents as said second information through the Internet. 3. The information providing system according to claim 2, wherein said identifying information is a URI of said broadcast contents. 4. The information providing system according to claim 3, wherein said information processing apparatus inserts said URI of said broadcast contents into an http message header, and requesting to provide said second information to said second information providing apparatus. 5. An information providing method of an information providing system comprising an information processing apparatus for receiving first information and second information to be made reference to by said first information, a first information providing apparatus for providing said first information, and a second information providing apparatus for providing said second information, said information providing method characterized by: said first information providing apparatus providing said first information for making reference to said second information to said information processing apparatus; said information processing apparatus receiving said first information from said first information providing apparatus, extracting identifying information for identifying said first information from said received first information, and requesting to provide said second information being made reference to by said received first information by attaching said identifying information to said second information providing apparatus; said second information providing apparatus determining whether or not to provide said second information to said information processing apparatus on the basis of said identifying information received from said information processing apparatus, and providing said second information to said information processing apparatus on the basis of a determination result thereof. 6. An information processing apparatus for receiving first information provided by a first information providing apparatus and second information provided by a second information providing apparatus to be made reference to by said first information, said information processing apparatus characterized by comprising: first receiving means for receiving said first information provided by said first information providing apparatus; extracting means for extracting identifying information for identifying said first information from said first information received by said first receiving means; request means for requesting to provide said second information being made reference to by said first information received by said first receiving means, by attaching said identifying information extracted by said extracting means to said second information providing apparatus; and second receiving means for receiving said second information provided by said second information providing apparatus, on the basis of a request by said request means. 7. The information processing apparatus according to claim 6, wherein said first receiving means receives broadcast contents provided by a broadcast of said first information providing apparatus as said first information, said second receiving means receives network contents provided by said second information providing apparatus through the Internet as the second information. 8. The information processing apparatus according to claim 7, wherein said extracting means extracts a URI of said broadcast contents as the identifying information. 9. The information processing apparatus according to claim 8, wherein said request means inserts said URI of said broadcast contents into an http message header, to request for providing said second information. 10. The information processing apparatus according to claim 6, further comprising display means for displaying said second information received by said second receiving means simultaneously with said first information received by said first receiving means. 11. The information processing apparatus according to claim 7, further comprising display means for displaying said broadcast contents received by said first receiving means and said network contents being made reference to by said broadcast contents, and received by said second receiving means, simultaneously on a same screen. 12. A information processing method for an information processing apparatus for receiving first information provided by a first information providing apparatus and second information provided by a second information providing apparatus to be made reference to by said first information, said information processing method characterized by comprising: a first receiving step of receiving said first information provided by said first information providing apparatus; an extracting step of extracting identifying information for identifying said first information from said first information received by a process of said first receiving step; a request step of requesting said second information providing apparatus to provide said second information being made reference to by said first information received in said first receiving step, by attaching said identifying information extracted by a process of said extracting step; and a second receiving step of receiving said second information provided by said second information providing apparatus, on the basis of a request by a process of said request step. 13. A program for an information processing apparatus for receiving first information provided by a first information providing apparatus and second information provided by a second information providing apparatus to be made reference to by said first information, a recording medium recording a program to be read by a computer characterized by comprising: a first receiving step of receiving said first information provided by said first information providing apparatus; an extracting step of extracting identifying information for identifying said first information from said first information received by a process of said first receiving step; a request step of requesting said second information providing apparatus to provide said second information being made reference to by said first information received in said first receiving step, by attaching said identifying information extracted by a process of said extracting step; and a second receiving step of receiving said second information provided by said second information providing apparatus, on the basis of a request by a process of said request step. 14. A program for making a computer for controlling an information processing apparatus for receiving first information provided by a first information providing apparatus and second information provided by a second information providing apparatus to be made reference to by said first information, to execute: a first receiving step of receiving the first information provided by said first information providing apparatus; an extracting step of extracting identifying information for identifying said first information from said first information received by a process of said first receiving step; a request step of requesting said second information providing apparatus to provide said second information being made reference to by said first information received in said first receiving step, by attaching said identifying information extracted by a process of said extracting step; and a second receiving step of receiving said second information provided by said second information providing apparatus, on the basis of a request by a process of said request step. 15. An information providing apparatus for providing second information to be made reference to by first information provided to an information processing apparatus by another information providing apparatus to said information processing apparatus, said information providing apparatus characterized by comprising: receiving means for receiving a request for providing said second information from said information processing apparatus; extracting means for extracting identifying information for identifying said first information from a request received by said receiving means; determining means for determining whether to provide said second information to said information processing apparatus or not, on the basis of said identifying information extracted by said extracting means; and providing means for providing said second information to said information processing apparatus, on the basis of a determination result by said determining means. 16. The information providing apparatus according to claim 15, wherein said providing means provides network contents as said second information to be made reference to by broadcast contents as the first information provided by broadcast of said other information providing apparatus, through the Internet. 17. The information processing apparatus according to claim 16, wherein said extracting means extracts a URI of said broadcast contents as the identifying information. 18. The information processing apparatus according to claim 17, wherein said extracting means extracts a URI of said broadcast contents from an http message header. 19. The information providing apparatus according to claim 15, further comprising storing means for storing access restricting information for restricting an access of the second information, said determining means determining whether to provide said second information to said information processing apparatus, further on the basis of said access restricting information stored in said storing means. 20. An information providing method for an information providing apparatus for providing second information to be made reference to by first information provided to an information processing apparatus by another information providing apparatus to said information processing apparatus, characterized by comprising: a receiving step of receiving a request for providing said second information from said information processing apparatus; an extracting step of extracting identifying information for identifying said first information from a request received by a process of said receiving step; a determining step of determining whether to provide said second information to said information processing apparatus or not, on the basis of said identifying information extracted by a process of said extraction step; and a providing step of providing said second information to said information processing apparatus, on the basis of a determination result by a process of determining step. 21. A program for an information providing apparatus for providing second information to be made reference to by first information provided to an information processing apparatus by another information providing apparatus to said information processing apparatus, a recording medium recording a program to be read by a computer characterized by comprising: a receiving step of receiving a request for providing said second information from said information processing apparatus; an extracting step of extracting identifying information for identifying said first information from a request received by a process of said receiving step; a determining step of determining whether to provide said second information to said information processing apparatus or not, on the basis of said identifying information extracted by a process of said extraction step; and a providing step of providing said second information to said information processing apparatus, on the basis of a determination result by a process of said determining step. 22. A program for making a computer for controlling an information providing apparatus for providing second information to be made reference to by first information provided to an information processing apparatus by another information providing apparatus to said information processing apparatus, to execute: a receiving step of receiving a request for providing said second information from said information processing apparatus; an extracting step of extracting identifying information for identifying said first information from a request received by a process of said receiving step; a determining step of determining whether to provide said second information to said information processing apparatus or not, on the basis of said identifying information extracted by a process of said extraction step; and a providing step of providing said second information to said information processing apparatus, on the basis of a determination result by a process of said determining step. |
<SOH> BACKGROUND ART <EOH>Recently, with the spread of the Internet, there is a trend toward distributing various kinds of contents through the Internet. On the other hand, digital television broadcast is toward spreading. For example, by the broadcast contents sent on the air by digital television broadcast, reference is made possible to network contents distributed through the Internet. In this case, the digital television receiver receives broadcast contents. In the case that the broadcast contents is making reference to network contents, access is made to a predetermined contents server through the Internet, to receive a provision of network contents. However, in case the broadcast contents are made allowed for a reference to network contents, there is a fear that the network contents be unduly utilized without the grant by the copyrighter. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a figure showing a configuration of an information providing system to which the present invention is applied. FIG. 2 is a block diagram showing a configuration of a digital broadcast receiver in FIG. 1 . FIG. 3 is a block diagram showing a configuration of contents server in FIG. 1 . FIG. 4 is a figure showing a database example. FIG. 5 is a flowchart explaining the processing of the digital broadcast receiver in FIG. 1 . FIG. 6 is a figure showing a URI example. FIG. 7 is a figure showing a format of an http message header. FIG. 8A is a figure showing a display example of network contents and broadcast contents. FIG. 8B is a figure showing a display example of network contents and broadcast contents. FIG. 9 is a flowchart explaining the processing of the contents server in FIG. 1 . FIG. 10 is a figure showing a format example of an access restricting file. detailed-description description="Detailed Description" end="lead"? |
Photoresponsive polymer, built-up type diacetylene polymer, crystals of ammonium carboxylates, and processes for production of them |
A crystal of carboxyl acid and at least one compound selected from the group consisting of amine and ammonia are mixed in an absence of a liquid medium. The carboxyl acid is conjugated diene such as (Z,Z)-muconic acid, the conjugated diene including a carboxyl group. The at least one nitrogen-containing compound selected from the group consisting of amine and ammonia is primary amine represented by RCH2NH2, where R is an aryl group, or is a normal alkyl group that contains five or more carbon atoms. Moreover, such amine that is a bivalent group and that is represented by -Ar-N═N-Ar′-, where Ar and Ar′ are independently aromatic hydrocarbon bivalent groups, is intercalated in a layered crystal of a polymer such as polymuconic acid, the layered crystal including a carboxyl group. In this way, a novel photoresponsive polymer is obtaind. Also obtained is a crystal of ammonium carboxylate including at least one kind of carboxyl acid and at least one kind of amine, at least one kind of compound selected from (i) the at least one kind of carboxyl acid and (ii) the at least one kind of amine being a diacetylene derivative. The crystal of ammonium carboxylate is subjected to light or heat, to obtain a built-up type diacetylene polymer. |
1. A method of manufacturing a crystal of ammonium carboxylate, comprising the step of: mixing, in an absence of a liquid medium, a crystal of carboxyl acid and at least one nitrogen-containing compound selected from the group consisting of amine and ammonia. 2. The method as set forth in claim 1, wherein: the crystal of carboxyl acid is conjugated diene including a carboxyl group; and said at least one nitrogen-containing compound selected from the group consisting of amine and ammonia is primary amine represented by the following formula R1CH2NH2 where R1 is an aryl group, or is a normal alkyl group that contains five or more carbon atoms. 3. The method as set forth in claim 1, wherein: the crystal of carboxyl acid is a layered crystal of a polymer of conjugated diene including a carboxyl group. 4. The method as set forth in claim 3, wherein: said at least one nitrogen-containing compound selected from the group consisting of amine and ammonia is primary amine represented by the following formula R2NH2 where R2 is a hydrocarbon group that may include a functional group. 5. A method of manufacturing a crystal of ammonium carboxylate, comprising the steps of: (i) mixing, in an absence of a liquid medium, (a) conjugated diene including a carboxyl group and (b) primary amine represented by the following general formula R1CH2NH2 where R1 is an aryl group, or is a normal alkyl group that contains five or more carbon atoms, so as to obtain a crystal of conjugated diene including an ammonium carboxylate group; (ii) polymerizing, in a solid state, the crystal of conjugated diene including the ammonium carboxylate group, so as to obtain a layered crystal of a polymer of the conjugated diene including the ammonium carboxylate group; (iii) causing elimination of ammonium ions by heating the layered crystal of the conjugated diene including the ammonium carboxylate group, so as to obtain a layered crystal of a polymer of conjugated diene including a carboxyl group; and (iv) mixing, in an absence of a liquid medium, (c) the layered crystal of the polymer of the conjugated diene including the carboxyl group and (d) primary amine represented by the following formula R2NH2 where R2 is a hydrocarbon group that may include a functional group. 6. The method as set forth in claim 3, wherein: a compound mixed with the layered crystal of the polymer of the conjugated diene including the carboxyl group is amine that is a bivalent group and that is represented by the following general formula -Ar-N═N-Ar′- where Ar and Ar′ are independently aromatic hydrocarbon bivalent groups, respectively; and the amine is intercalated into the layered crystal. 7. A photoresponsive polymer, comprising: amine represented by the following general formula -Ar-N═N-Ar′- where Ar and Ar′ are independently aromatic hydrocarbon bivalent groups, respectively, the amine being intercalated in a layered crystal of a polymer including a carboxyl group. 8. A method of manufacturing a crystal of ammonium carboxylate, wherein: at least one kind of carboxyl acid and at least one kind of amine are used; and at least one kind of compound selected from (i) said at least one kind of carboxyl acid and (ii) said at least one kind of amine is a diacetylene derivative. 9. The method as set forth in claim 8, wherein: at least one kind of compound selected from (i) said at least one kind of carboxyl acid and (ii) said at least one kind of amine is the diacetylene derivative; and at least another kind of compound selected from (i) said at least one kind of carboxyl acid and (ii) said at least one kind of amine is a diene derivative. 10. The method as set forth in claim 9, wherein: the diene derivative is a layered crystal of a polymer of conjugated diene including a carboxyl group, and the diacetylene derivative is amine; and the amine is intercalated in the layered crystal. 11. A crystal of ammonium carboxylate, comprising: at least one kind of carboxyl acid and at least one kind of amine, at least one kind of compound selected from (i) said at least one kind of carboxyl acid and (ii) said at least one kind of amine being a diacetylene derivative. 12. The method as set forth in claim 11, wherein: if the diacetylene derivative is said at least one kind of carboxyl acid, said at least one kind of carboxyl acid is represented by general formula X1—(CH2)i—C≡C—C≡C—(CH2)j—COOH where X1 is COOH or H, and i and j are respectively integers not less than 0 and not more than 18; and if the diacetylene derivative is said at least one kind of amine, said at least one kind of amine is represented by general formula Y1—(CH2)p—C≡C—C≡C—(CH2)q—NH2 where Y1 is NH2 or H, and p and q are respectively integers not less than 0 and not more than 18. 13. The crystal of ammonium carboxylate as set forth in claim 11, wherein: if the diacetylene derivative is said at least one kind of carboxyl acid, said at least one kind of amine is represented by the following formula R6—NH2 where R6 is a hydrocarbon group that may include a functional group; and if the diacetylene derivative is said at least one kind of amine, said at least one kind of carboxyl acid is represented by the following formula R7—COOH where R7 is a hydrocarbon group that may include a functional group. 14. The crystal of ammonium carboxylate as set forth in claim 11, wherein: at least one kind of compound selected from (i) said at least one kind of carboxyl acid and (ii) said at least one kind of amine is the diacetylene derivative; and at least another kind of compound selected from (i) said at least one kind of carboxyl acid and (ii) said at least one kind of amine is a diene derivative. 15. The crystal of ammonium carboxylate as set forth in claim 14, wherein: if the diene derivative is said at least one kind of carboxyl acid, said at least one kind of carboxyl acid is represented by general formula X2—(CH2)i′—C═C—C═C—(CH2)j′—COOH where X2 is COOH or H, and i′ and j′ are respectively integers not less than 0 and not more than 18; and if the diene derivative is said at least one kind of amine, said at least one kind of amine is represented by general formula Y2—(CH2)p′—C═C—C═C—(CH2)q′—NH2 where Y2 is NH2 or H, and p′ and q′ are respectively integers not less than 0 and not more than 18. 16. The crystal of ammonium carboxylate as set forth in claim 14, wherein: the diene derivative is a layered crystal of a polymer of conjugated diene including a carboxyl group; and the diacetylene derivative is amine. 17. A built-up type diacetylene polymer, which is a polymer of a crystal of ammonium carboxylate including at least one kind of carboxyl acid and at least one kind of amine, at least one kind of compound selected from (i) said at least one kind of carboxyl acid and (ii) said at least one kind of amine being a diacetylene derivative. 18. The built-up type diacetylene polymer as set forth in claim 17, wherein: if the diacetylene derivative is said at least one kind of carboxyl acid, said at least one kind of carboxyl acid is represented by general formula X1—(CH2)i—C≡C—C≡C—(CH2)j—COOH where X1 is COOH or H, and i and j are respectively integers not less than 0 and not more than 18; and if the diacetylene derivative is said at least one kind of amine, said at least one kind of amine is represented by general formula Y1—(CH2)p—C≡C—C≡C—(CH2)q—NH2 where Y1 is NH2 or H, and p and q are respectively integers not less than 0 and not more than 18. 19. The built-up type diacetylene polymer as set forth in claim 17, wherein: if the diacetylene derivative is said at least one kind of carboxyl acid, said at least one kind of amine is represented by the following formula R6—NH2 where R6 is a hydrocarbon group that may include a functional group; and if the diacetylene derivative is said at least one kind of amine, said at least one kind of carboxyl acid is represented by the following formula R7—COOH where R7 is a hydrocarbon group that may include a functional group. 20. The built-up type diacetylene polymer as set forth in claim 17, wherein: in the crystal of ammonium carboxylate, at least one kind of compound selected from (i) said at least one kind of carboxyl acid and (ii) said at least one kind of amine is the diacetylene derivative; and at least another kind of compound selected from (i) said at least one kind of carboxyl acid and (ii) said at least one kind of amine is a diene derivative. 21. The built-up type diacetylene polymer as set forth in claim 20, wherein: in the crystal of ammonium carboxylate, if the diene derivative is said at least one kind of carboxyl acid, said at least one kind of carboxyl acid is represented by general formula X2—(CH2)i′—C═C—C═C—(CH2)j, —COOH where X2 is COOH or H, and i′ and j′ are respectively integers not less than 0 and not more than 18; and if the diene derivative is said at least one kind of amine, said at least one kind of amine is represented by general formula Y2—(CH2)p′—C═C—C═C—(CH2)q NH2 where Y2 is NH2 or H, and p′ and q′ are respectively integers not less than 0 and not more than 18. 22. The built-up type diacetylene polymer as set forth in claim 20, wherein: in the crystal of ammonium carboxylate, the diene derivative is a layered crystal of a polymer of conjugated diene including a carboxyl acid; and the diacetylene derivative is amine. 23. A method of manufacturing a built-up type diacetylene polymer, comprising the step of: radiating light onto a crystal of ammonium carboxylate or heating the crystal of ammonium carboxylate, the crystal of ammonium carboxylate including at least one kind of carboxyl acid and at least one kind of amine, at least one kind of compound selected from (i) said at least one kind of carboxyl acid and (ii) said at least one kind of amine being a diacetylene derivative. 24. The method as set forth in claim 23, wherein: in the crystal of ammonium carboxylate, at least one kind of compound selected from (i) said at least one kind of carboxyl acid and (ii) said at least one kind of amine is the diacetylene derivative; and at least another kind of compound selected from (i) said at least one kind of carboxyl acid and (ii) said at least one kind of amine is a diene derivative. 25. The method as set forth in claim 24, wherein: in the crystal of ammonium carboxylate, the diene derivative is a layered crystal of a polymer of conjugated diene including a carboxyl acid; and the diacetylene derivative is amine. |
<SOH> BACKGROUND ART <EOH>Conventionally, a crystal of ammonium carboxylate is produced by a well-known method using (a) a crystal of carboxyl acid and (b) amine. For example, inventors of the present invention reported that a crystal of muconic alkylammonium is obtained as follows. A crystal of muconic acid and normal alkylamine are dissolved and mixed in a solvent such as methanol, water, or the like. Then, the solvent is removed, and a solid substance thus obtained is recrystallized. The inventors of the present invention also reported that a polymer crystal is produced by solid-state polymerization, i.e. by radiating light, X-rays, γ-rays, or the like onto the crystal of muconic alkylammonium obtained by the foregoing method, and that a layered crystal of polymuconic acid is obtained by hydrolyzing the polymer crystal with acid, and then removing the solvent. The inventors of the present invention further reported that, by the following operation, normal alkylamine is intercalated between layers of the layered crystal of polymuconic acid obtained by the foregoing method: (1) dispersing the layered crystal in a dispersion medium such as methanol, water, or the like, (2) mixing the solution with normal alkyl amine, and (3) removing the dispersion medium. However, according to the conventional methods using a solvent or a dispersion medium, a polymer crystal having a layered structure cannot be obtained in a simple manner, because it is necessary to separate the solvent or the dispersion medium, and to cause recrystallization. Moreover, according to the method in which intercalation is induced by using a dispersion medium, there are cases in which a polymer crystal having a layered structure cannot be obtained, because a polymer crystal swells or dissolves in the dispersion medium if certain kind of amine is used. Especially, if alkyl primary amine having a branch structure or primary amine including a functional group is used, a polymer crystal in which the alkyl primary amine having a branch structure between layers of a layered crystal or the primary amine including a functional group cannot be obtained, because the layered crystal of polymuconic acid swells or dissolves in the dispersion medium during a reaction. Existence of photoresponsive low-molecular-weight compounds, photoresponsive polymers, and photoresponsive polymer materials are conventionally well-known. For example, it is well-known that an azobenzene derivative (a low-molecular-weight compound) has photoresponsiveness, i.e. that an azobenzene derivative is isomerized into a cis body when subjected to ultraviolet rays, and into a trans body when subjected to heat or visible light. Also well-known are photoresponsive polymers in which a side chain thereof is chemically bonded with a substituent including an azo group, and photoresponsive polymer materials in which a low-molecular-weight azo compound is dispersed in a polymer matrix. These are used in a solution state or in a film-shaped solid state. Many attempts have been made to intercalate amine including a photoresponsive group, such as an azo group, into a generally available inorganic layered crystal. It is well-known that, because some inorganic layered crystals, namely clay minerals, silicate, and metal oxide, have cation exchangeability due to negative charges thereof, it is relatively easy to intercalate amine into these inorganic layered crystals, i.e. clay minerals, silicate, and metal oxide (see Chemical Society of Japan ed, “Inorganic and Organic Nano Compounds”, in Kikan Kagaku Sousetsu , No. 42, Gakkai Shuppan Center (1999), p.33-44). For example, it is reported that in one case amine including an azo group was intercalated into an inorganic layered crystal (For example, “Photocontrol of the Basal Spacing of Azobenzene-Magadiite Intercalation Compound”, M. Ogawa, T. Ishii, N. Miyamoto, K. Kuroda, Adv. Mater. 13, 1107-1109 (2001), and “Preparation of a Cationic Azobenzene Derivative-Montmorillonite Intercalation Compound and the Photochemical Behavior”, M. Ogawa, Mater. Chem., 8, 1347-1349 (1996)). However, it is not easy to photoisomerize a usual azobenzene derivative (which includes no amino group) and induce a structural change of a crystalline polymer by mixing the azobenzene derivative and the crystalline polymer. Moreover, it requires considerable time and effort to chemically bond an azo group with a polymer directly. Therefore, the conventional photoresponsive polymer cannot be manufactured easily, let alone with variations. Moreover, sufficient stability and a sufficient function (photoresponsiveness) cannot be attained by simply dispersing a low-molecular-weight azo compound in a matrix. Moreover, it is not easy to use, in a solution state or in a film-shaped solid state, a photosensitive material in which amine including a photoresponsive group, such as an azo group, is intercalated in an inorganic layered crystal. Therefore, such a photosensitive material has a drawback that they can be used only for limited purposes. A well-known photofunctional polymer other than the photoresponsive polymers and the photoresponsive polymer materials is a conjugated system polymer that absorbs light of a certain wavelength band. For example, crystalline polydiacetylene obtained by polymerizing diacetylene is a colored conjugated system polymer that has high absorbance with respect to light in a visible region. Incidentally, in order to design a crystalline polymer such as polydiacetylene, topochemical polymerization is performed. Well-known examples of the topochemical polymerization are polymerization of a 1,3-diene monomer such as a muconic derivative, a sorbic derivative, or the like, and polymerization in a built-up film such as an LB (Langmuir-Blodgett) film or the like. The topochemical polymerization is one form of solid-state polymerization. In the topochemical polymerization, a reaction proceeds with minimum movements of atoms and substituents, while a center of gravity of a monomer and symmetry of a crystal are maintained. Therefore, a structure of a product obtained by the topochemical polymerization is controlled not only by chemical properties, e.g. reactivity, of the monomer, but also by an arrangement of the crystal formed by the monomer. Thus, in the topochemical polymerization, a polymerization reaction proceeds under a control of a crystalline lattice. Therefore, the topochemical polymerization makes it possible to design a polymer having stereospecificity and stereoselectivity. However, according to the conventional topochemical polymerization of diacetylene, it is not easy to predict reactivity of the polymerization reaction. Therefore, it is not easy to predict a crystalline structure of the polydiacetylene obtained by performing the topochemical polymerization. In other words, it is not easy to control an arrangement of polymer chains in the crystal of the polydiacetylene. Therefore, because the crystalline structure of the polydiacetylene obtained by performing the topochemical polymerization varies according to various conditions such as a condition of polymerization and the like, it is not easy to obtain polydiacetylene having an intended absorbing property. On the other hand, if the polydiacetylene is used as a photofunctional polymer, it is desired that the polydiacetylene have a certain crystalline structure under a certain reaction condition, in order to attain a stable function. It is therefore desired that an arrangement of the polymer chains of the polydiacetylene obtained by polymerizing diacetylene be controlled, so as to obtain polydiacetylene that has a certain absorbing property. If such polydiacetylene that has an intended absorbing property cannot be attained with high reproducibility by setting a reaction condition, it is not easy to use the polydiacetylene as a photofunctional polymer. The present invention was made to solve the foregoing conventional problems. An object of the present invention is therefore to provide a photoresponsive polymer in which amine including an azo group, which is a photoresponsive group, is intercalated as a guest compound in a layered crystalline polymer including carboxyl acid, the photoresponsive polymer being such that an absorbing property and a structure thereof can be changed by radiating light so as to cause cis/trans isomerization of the azo group. Another object is to provide a built-up type diacetylene polymer that includes polydiacetylene having a layered structure in which an arrangement of polymer chains in a crystal is controlled, the built-up type diacetylene polymer being a conjugated system polymer having high absorbaption in a visible region. Yet another object is to provide a crystal of ammonium carboxylate made of carboxyl acid and at least one nitrogen-containing compound selected from the group consisting of amine and ammonia, and to provide a method of manufacturing a crystal of ammonium carboxylate suitable for manufacturing the photoresponsive polymer and the built-up type diacetylene polymer. |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIGS. 1 ( a ) to 1 ( d ) are schematic diagrams illustrating steps for manufacturing ammonium carboxylate of one embodiment of the present invention. FIG. 2 is a schematic diagram illustrating an application of a layered crystal of a polymer of the ammonium carboxylate obtained by a manufacturing method of the present invention. FIG. 3 ( a ) is a chemical formula of a polymerization reaction of carboxyl acid as a diacetylene derivative. FIG. 3 ( b ) is a chemical formula of a polymerization reaction of amine as a diene derivative. FIG. 4 is a conceptual diagram illustrating a crystal of ammonium carboxylate, and a built-up type diacetylene polymer. FIG. 5 ( a ) is a conceptual diagram illustrating that the crystal of ammonium carboxylate of the present invention and the built-up type diacetylene polymer of the present invention are manufactured by means of intercalation. FIG. 5 ( b ) illustrates a chemical formula of a reaction between a diene polymer and the amine as a diacetylene derivative. FIGS. 6 ( a ) and 6 ( b ) are X-ray diffraction spectrums of a crystal of 2,5-polymuconic benzylammonium. FIG. 6 ( a ) is an X-ray diffraction spectrum of a crystal of 2,5-polymuconic benzylammonium obtained in one example of the manufacturing method of the present invention. FIG. 6 ( b ) is an X-ray diffraction spectrum of a crystal of 2,5-polymuconic benzylammonium obtained by a conventional manufacturing method. FIG. 7 illustrates IR spectrums of the 2,5-polymuconic benzylammonium and 2,5-polymuconic acid that are obtained in one example of the manufacturing method of the present invention. FIG. 8 illustrates IR spectrums of a layered crystal of 2,5-polymuconic acid of one example of the manufacturing method of the present invention, the IR spectrums being different before and after amine including a photoresponsive group was intercalated. FIG. 9 illustrates how an ultraviolet-visible absorption spectrum changed after ultraviolet rays were radiated onto a photoresponsive polymer of one example of the present invention. FIG. 10 illustrates how powder X-ray diffraction changed after ultraviolet rays were radiated onto the photoresponsive polymer of one example of the present invention. FIG. 11 illustrates thermogravimetry/differential thermal analysis (TG/DTA) spectrums of a built-up type diacetylene polymer obtained from 10,12-pentacosadiynecarboxyl 1-naphthylmethyl ammonium. FIG. 12 illustrates how a diffuse reflectance ultraviolet-visible absorption spectrum changed over time after ultraviolet rays were radiated onto the 10,12-pentacosadiynecarboxyl 1-naphthylmethyl ammonium. FIG. 13 illustrates how a diffuse reflectance ultraviolet-visible absorption spectrum changed over time after ultraviolet rays were radiated onto 2,4-pentadecadiynecarboxylic benzylammonium. FIG. 14 illustrates how an infrared absorption spectrum changed over time after ultraviolet rays were radiated onto 2,4-tetradecanediene 10,12-tricosadiyneammonium. FIG. 15 illustrates an infrared absorption spectrum ((a)) of polymuconic acid and an infrared absorption spectrum ((b)) of a crystal of ammonium carboxylate in which 10,12-pentacosadiynylamine was introduced into the polymuconic acid by means of intercalation. FIG. 16 ( a ) illustrates how a color of the crystal of ammonium carboxylate changed after X-rays were radiated onto the crystal. FIG. 16 ( b ) illustrates how the color of the crystal of ammonium carboxylate changed after γ-rays were radiated onto the crystal. FIG. 17 illustrates X-ray powder diffraction spectrums of the crystal of ammonium carboxylate before and after γ-rays were radiated. The solid line indicates the spectrum before radiation, and the dotted line indicates the spectrum after radiation. FIG. 18 illustrates a diffuse reflectance ultraviolet-visible spectrum ((a)) of a built-up type diacetylene polymer obtained by radiating γ-rays onto the crystal of ammonium carboxylate, a diffuse reflectance ultraviolet-visible spectrum ((b)) of a built-up type diacetylene polymer obtained by radiating ultraviolet rays onto the crystal of ammonium carboxylate, and a diffuse reflectance ultraviolet-visible spectrum ((c)) of the crystal of ammonium carboxylate. detailed-description description="Detailed Description" end="lead"? |
Oxadiazolyl-phenoxyalkylisoxazoles compositions thereof and methods for their use as anti-picornaviral agents |
Oxadiazolyl-phenoxyalkylisoxazoles and pharmaceutically acceptable salts thereof, compositions comprising oxadiazolyl-phenoxyalkylisoxazole compounds or pharmaceutically acceptable salts thereof and methods for using oxadiazolyl-phenoxyalkylisoxazole compounds or pharmaceutically acceptable salts thereof as anti-picornaviral agents are described herein. |
1. A compound of Formula I: and pharmaceutically acceptable salts thereof wherein: R1 is selected from the group consisting of C1-C5 alkyl, C1-C5 alkoxy, C3-C7 cycloalkyl, C1-C5 alkoxycarbonyl, carboxy and cyanomethyl the C1-C5 alkyl group being optionally substituted with at least one hydroxyl. C1-C5 alkoxyl, C1-C5 alkylthio, Cts alkylsulfinyl, C1-C5 alkylsulfonyl, mono (C1-C5) alkylamino or di (C1-C5) alkylamino groups and the C1-C5 alkoxy group being substituted with one or more hydroxyl groups; Y is a straight or branched alkylene moiety of 3 to 9 carbon atoms; R2 and R3 are independently selected from the group consisting of hydrogen, C1-C5 alkyl, C1-C5 alkoxy, halo, cyano, trifluoromethyl and nitro; R4 is selected from the group consisting of halo, hydrogen and C1-C5 alkyl; and BET is selected from the group consisting of: wherein Ra is selected from the group consisting of C1-C5 alkyl, C1-C5 alkoxy, C3-C7 cycloalkyl, heterocyclyl, C1-C5 alkoxycarbonyl. C1-C5 alkylthio, (4-methylphenyl)sulfonyloxymethyl, mono (C1-C5) alkylamino di (C1-C5) alkylamino, and carboxamido; the C1-C5 alkyl group being optionally substituted with at least one halo, hydroxyl, C1-C5 alkoxyl, C1-C5 alkylcarbonyloxyl, thio and C1-C5 alkylthio groups. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ra is selected from the group consisting of C1-C3 alkyl, C1-C5 alkoxy, cyclopropyl, C1-C3 alkoxycarbonyl (4-methylphenyl)sulfonyloxymethyl, mono (C1-C5) alkylamino di (C1-C5) alkylamino, and carboxamido; the C1-C3 alkyl group being substituted with one or more halo, hydroxyl, C1-C3 alkoxy and C1-C3 alkylcarbonyloxyl groups; and HET is: 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Ra is selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, cyclopropyl, C1-C3 alkoxycarbonyl, (4-methylphenyl)sulfonyloxymethyl, mono (C1-C5) alkylamino, di (C1-C5) alkylamino, and carboxamido; the C1-C3 alkyl group being substituted with one or more halo, hydroxyl, C1-C3 alkoxy and C1-C3 alkylcarbonyloxyl groups; and HET is: 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Ra is selected from the group consisting of C1-C3 allyl, C1-C3 alkoxy, cyclopropyl, C1-C3 alkoxycarbonyl, (4-methylphenyl)sulfonyloxymethyl, mono (C1-C5) alkylamino, di (C1-C5) alkylamino, and carboxamido; the C1-C3 alkyl group being substituted with one or more halo, hydroxyl, C1-C3 alkoxy and C1-C3 alkylcarbonyloxyl groups; and is: 5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: Y is alkylene of 3 to 5 carbon atoms; and Ra is selected from the group consisting of monohalomethyl; dihalomethyl; trihalomethyl; 1,1,-dihaloethyl; 1,2 dihaloethyl; 2,2-dihaloethyl; 1,1,2-trihaloethyl; 1,2,2-trihaloethyl and 2,2,2-trihaloethyl. 6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein Ra is trifluoromethyl. 7. The compound of claim 6 having the formula: or a pharmaceutically acceptable salt thereof. 8. A composition comprising compound having the formula: wherein the compound is in isolated or purified form. 9. A composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 10. The composition of claim 9 further comprising a pharmaceutically acceptable vehicle. 11. A method for treating or preventing a picornaviral infection in a patient, said method comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof. 12. A method for inhibiting the growth of a picornaviral infection in a cell said method comprising contacting a cell infected with a picornavirus with an inhibitory amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof. 13. The method of claim 11 wherein the picornavirus is selected from the group consisting of an enterovirus and a rhinovirus. 14. The method of claim 12 wherein the picornavirus is selected from the group consisting of an enterovirus and a rhinovirus. 15. The method of claim 11 wherein the compound of claim 1 has the structure: 16. The method of claim 12 wherein the compound of claim 1 has the structure. 17. The method of claim 15 wherein the compound or pharmaceutically acceptable salt thereof is an isolated or purified form. 18. The method of claim 16 wherein the compound or pharmaceutically acceptable salt thereof is an isolated or purified form. 19. The compound of claim 1, or a pharmaceutically acceptable Salt there, in admixture with a compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein the R1, R2, R3, R4, Y, HET and Ra groups of the compound of Formula II, or the pharmaceutically acceptable salt thereof, independently have the same meaning as in the compound of Formula I of claim 1, or thee pharmaceutically acceptable salt thereof. 20. A composition comprising a pharmaceutically acceptable vehicle, an antivirally effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and an antivirally effective amount of a compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein the R1, R2, R3, R4, Y, HET and Ra groups of the compound of Formula II, or the pharmaceutically acceptable salt thereof, independently have the same meaning as in the compound of Formula I of claim 1, or the pharmaceutically acceptable salt thereof. 21. A pharmaceutical composition comprising a compound of the formula: or a pharmaceutically acceptable salt thereof, in admixture with a compound of the formula: or a pharmaceutically acceptable salt thereof. 22. The composition of claim 20 wherein the compound of claim 1 has the formula: or a pharmaceutically acceptable salt thereof, and the compound of Formula II has the formula: or a pharmaceutically acceptable salt thereof. 23. A method for treating or preventing a picomaviral infection in a patient, said method comprising administering to a patient in need of such a treatment or prevention a therapeutically effective amount of a combination comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a compound of Formula II: or a pharmaceutically acceptable salt thereof. 24. A method for inhibiting the growth of a picomaviral infection in a cell, said method comprising contacting a cell infected with a picornavirus with a picornavirus Inhibiting amount of a combination comprising a compound of claim 1, or a pharmaceutically acceptable salt, thereof and compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein the R1, R2, R3, R4, Y, HET and Ra groups independently have the same meaning as in the compound of Formula I of claim 1, or the pharmaceutically acceptable salt thereof. 25. The method of claim 23 wherein the compound of claim 1 has the formula: or a pharmaceutically acceptable salt thereof, and the compound of Formula II has the formula: or a pharmaceutically acceptable salt thereof. 26. The method of claim 24 wherein the compound according to claim 1 has the formula: or a pharmaceutically acceptable salt thereof, and the compound of Formula II has the formula: or a pharmaceutically acceptable salt thereof. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Picornaviridae are a large group of single-stranded RNA viruses that cause infections such as viral meningitis, encephalitis, viral respiratory infection and viral exacerbation in asthma and colds ( Picornavindae and Their Replication ; Second Edition, edited by B. N. Fields et al., New York, 1990). Picornaviruses were among the first viruses recognized and encompass approximately 230 serotypes divided into five genera that include apthovirus, cardiovirus, enterovirus, hepatovirus and rhinovirus. Enterovirus and rhinovirus, which cause the common cold, comprise most of the known picornavirus serotypes. The replication of single-stranded RNA viruses such as picornaviruses occurs entirely in the cytoplasm and has been well characterized. Briefly, the genome of picornaviruses consists of one single-stranded (+)-sense RNA molecule that encodes a single polyprotein, typically between about 2100 amino acids and about 2400 amino acids in length. The polyprotein is processed through proteolytic cleavage to provide viral proteins such as a picornavirus protease, a virus RNA-dependent RNA polymerase and various coat proteins. The cleavage of the polyprotein into the above proteins is highly specific and may provide an attractive target for pharmaceutical intervention. A significant problem in developing effective pharmaceutical treatment of picornaviral infections, however, is the rapid mutation rate of RNA viruses. This rapid mutation rate might be caused by the absence of any error-correcting mechanisms in RNA synthesis. The cellular receptors of a number of different picornaviruses have been identified using a number of conventional techniques (for example, binding competition between different viruses, monoclonal antibodies that prevent virus binding and fluorescently labeled virus). Prevention of virus binding to cellular receptors is another attractive area for pharmaceutical intervention (Heinz et al., J. Virol., 1989, vol. 63, pp. 2476). Picornaviruses have also been characterized by X-ray crystallography (Rossman et al., Nature, 1985, 317, 145), which has been of great value in rationally designing inhibitors that interfere with virus-receptor binding. Picornaviruses, particularly those of enterovirus and rhinovirus genera cause significant numbers of human viral infections each year. Effective therapies for the majority of picornaviral infections are inadequate or simply unavailable. Thus, there is a general need for agents active against picornaviruses and a specific need for agents active against enteroviruses and rhinoviruses. U.S. Pat. No. 4,843,087 discloses diheterocylic compounds for use as anti-viral agents. U.S. Pat. Nos. 5,349,068 and 5,464,848 disclose 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as anti-picornaviral agents. Citation or identification of any reference in Section 2. of this Application is not an admission that such reference is available as prior art to the present invention. |
<SOH> 3. SUMMARY OF THE INVENTION <EOH>The present invention provides compounds of Formula I: and pharmaceutically acceptable salts thereof wherein: R 1 is selected from the group consisting of C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 3 -C 7 cycloalkyl, C 1 -C 5 alkoxycarbonyl, carboxy and cyanomethyl; the C 1 -C 5 alkyl group being optionally substituted with at least one hydroxyl, C 1 -C 5 alkoxyl, C 1 -C 5 alkylthio, C 1 -C 5 alkylsulfinyl, C 1 -C 5 alkylsulfonyl, mono (C 1 -C 5 ) alkylamino or di (C 1 -C 5 ) alkyl amino groups and the C 1 -C 5 alkoxy group being substituted with one or more hydroxyl groups; Y is a straight or branched alkylene moiety of 3 to 9 carbon atoms; R 2 and R 3 are independently selected from the group consisting of hydrogen, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, halo, cyano, trifluoromethyl and nitro; R 4 is selected from the group consisting of halo, hydrogen and C 1 -C 5 alkyl; and HET is selected from the group consisting of: wherein R a is selected from the group consisting of C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 3 -C 7 cycloalkyl, heterocyclyl, C 1 -C 5 alkoxycarbonyl, C 1 -C 5 alkylthio, (4-methylphenyl)sulfonyloxymethyl, mono (C 1 -C 5 ) alkylamino, di (C 1 -C 5 ) alkylamino, and carboxamido; the C 1 -C 5 alkyl group being optionally substituted with at least one halo, hydroxyl, C 1 -C 5 alkoxyl, C 1 -C 5 alkylcarbonyloxyl, thio and C 1 -C 5 alkylthio groups. The compounds of Formula I and pharmaceutically acceptable salts thereof are useful as anti-picornaviral agents. In a second aspect, the present invention provides compositions comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. The compositions optionally comprise a pharmaceutically acceptable vehicle. The compositions are useful for treating or preventing a picomaviral infection in a patient. In a third aspect, the present invention provides methods for treating or preventing a picornaviral infection in a patient, comprising administering to a patient in need of such treatment or prevention an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. In a fourth aspect, the present invention provides methods for inhibiting the growth of a picornavirus in a cell comprising contacting a cell infected with a picornavirus with an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. In a fifth aspect the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, in admixture with a compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , Y and HET are as previously defined in reference to the compound of Formula I. In a sixth aspect, the invention provides compositions useful for treating or preventing a picornaviral infection in a patient, the compositions comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a therapeutically effective compound of Formula U, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , Y and HET are as previously defined in reference to the compound of Formula I. The compositions optionally comprise a pharmaceutically acceptable vehicle. In a seventh aspect, the invention provides methods for treating or preventing a picornaviral infection in a patient comprising administering to a patient in need of such treatment or prevention an effective amount of a combination of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a compound of Formula II, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , Y and BET are as previously defined in reference to the compound of Formula I. In an eighth aspect, the invention provides methods for inhibiting growth of a picornavirus in a cell comprising contacting a cell infected with a picornavirus with an effective amount of a combination of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a compound of Formula II, or a pharmaceutically acceptable salt thereof, R 1 , R 2 , R 3 , R 4 , Y and HET are as previously defined in reference to the compound of Formula I. detailed-description description="Detailed Description" end="lead"? |
Oxadiazolyl-phenoxyalkylisoxazoles, compositions thereof and methods for their use as anti-picornaviral agents |
Oxadiazolyl-phenoxyalkylisoxazoles and pharmaceutically acceptable salts thereof, compositions comprising oxadiazolyl-phenoxyalkylisoxazole compounds or pharmaceutically acceptable salts thereof and methods for using oxadiazolyl-phenoxyalkylisoxazole compounds or pharmaceutically acceptable salts thereof as anti-picornaviral agents are described herein. The methods include using pleconaril as a prodrug for conversion to anti-picornaviral compounds in vivo. |
1. The compound of Formula I: or a pharmaceutically acceptable salt thereof. 2. The compound of Formula II: or a pharmaceutically acceptable salt thereof. 3. A composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 4. A composition comprising a compound according to claim 2 or a pharmaceutically acceptable salt thereof. 5. The composition according to claim 3, further comprising a pharmaceutically acceptable vehicle. 6. The composition according to claim 4, further comprising a pharmaceutically acceptable vehicle. 7. A method for treating or preventing a picornaviral infection in a patient, said method comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 8. A method for treating or preventing a picornaviral infection in a patient, said method comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of the compound according to claim 2 or a pharmaceutically acceptable salt thereof. 9. A method for inhibiting the growth of a picornaviral infection in a cell, said method comprising contacting a cell infected with a picornavirus with an inhibitory amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 10. A method for inhibiting the growth of a picornaviral infection in a cell, said method comprising contacting a cell infected with a picornavirus with an inhibitory amount of the compound according to claim 2 or a pharmaceutically acceptable salt thereof. 11. A method according to claim 7, wherein a precursor of said compound is administered in the form of a prodrug. 12. A method according to claim 8, wherein a precursor of said compound is administered in the form of a prodrug. 13. A method according to claim 11, wherein said prodrug is pleconaril. 14. A method according to claim 12, wherein said prodrug is pleconaril. 15. A method of using pleconaril as a prodrug for treating or preventing picornaviral infections in a patient, said method comprising administering to said patient a therapeutically effective amount of pleconaril or a pharmaceutically acceptable salt thereof. 16. A method of using pleconaril as a prodrug for treating a patient infected with at least one picornavirus, said method comprising administering to said patient a therapeutically effective amount of pleconaril or a salt thereof whereby said administrating results in the in vivo production of the compound of Formula I: or a salt thereof. 17. A method of using pleconaril as a prodrug for treating a patient infected with at least one picornavirus, said method comprising administering to said patient a therapeutically effective amount of pleconaril or a salt thereof whereby said administrating results in the in vivo production of the compound of Formula II: or a salt thereof. 18. The method according to claim 16, wherein more than one biologically active metabolite is produced. 19. The method according to claim 17, wherein more than one biologically active metabolite is produced. |
<SOH> 2. BACKGROUND OF THE INVENTION <EOH>Picornaviridae are a large group of single-stranded RNA viruses that cause infections such as viral meningitis, encephalitis, viral respiratory infection and viral exacerbation in asthma and colds ( Picornaviridae and Their Replication ; Second Edition, edited by B. N. Fields et al., New York, 1990). Picornaviruses were among the first viruses recognized and encompass approximately 230 serotypes divided into five genera that include apthovirus, cardiovirus, enterovirus, hepatovirus and rhinovirus. Enterovirus and rhinovirus, which cause the common cold, comprise most of the known picornavirus serotypes. The replication of single-stranded RNA viruses such as picornaviruses occurs entirely in the cytoplasm and has been well characterized. Briefly, the genome of picornaviruses consists of one single-stranded (+)-sense RNA molecule that encodes a single polyprotein, typically between about 2100 amino acids and about 2400 amino acids in length. The polyprotein is processed through proteolytic cleavage to provide viral proteins such as a picornavirus protease, a virus RNA-dependent RNA polymerase and various coat proteins. The cleavage of the polyprotein into the above proteins is highly specific and may provide an attractive target for pharmaceutical intervention. A significant problem in developing effective pharmaceutical treatment of picornaviral infections, however, is the rapid mutation rate of RNA viruses. This rapid mutation rate might be caused by the absence of any error-correcting mechanisms in RNA synthesis. The cellular receptors of a number of different picornaviruses have been identified using a number of conventional techniques (for example, binding competition between different viruses, monoclonal antibodies that prevent virus binding and fluorescently labeled virus). Prevention of virus binding to cellular receptors is another attractive area for pharmaceutical intervention (Heinz et al., J. Virol., 1989, vol. 63, pp. 2476). Picornaviruses have also been characterized by X-ray crystallography (Rossman et al., Nature, 1985, 317, 145), which has been of great value in rationally designing inhibitors that interfere with virus-receptor binding. Picornaviruses, particularly those of enterovirus and rhinovirus genera cause significant numbers of human viral infections each year. Effective therapies for the majority of picornaviral infections are inadequate or simply unavailable. Thus, there is a general need for agents active against picornaviruses and a specific need for agents active against enteroviruses and rhinoviruses. U.S. Pat. No. 4,843,087 discloses diheterocylic compounds for use as anti-viral agents. U.S. Pat. Nos. 5,349,068 and 5,464,848 disclose 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as anti-picornaviral agents. Citation or identification of any reference in Section 2. of this Application is not an admission that any such reference is available as prior art to the present invention. |
<SOH> 3. SUMMARY OF THE INVENTION <EOH>The present invention provides the compounds of Formula I and Formula II: and pharmaceutically acceptable salts thereof. The compounds of Formula I and Formula II and pharmaceutically acceptable salts thereof are useful as anti-picornaviral agents. In a second aspect, the present invention provides compositions comprising a therapeutically effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof. The compositions optionally comprise a pharmaceutically acceptable vehicle. The compositions are useful for treating or preventing a picornaviral infection in a patient. In a third aspect, the present invention provides methods for treating or preventing a picornaviral infection in a patient, comprising administering to a patient in need of such treatment or prevention an effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof. In a fourth aspect, the present invention provides methods for treating or preventing a picornaviral infection in a patient, comprising administering to a patient in need of such treatment or prevention an effective amount of pleconaril as a prodrug for compounds of Formula I or Formula II. The pleconaril prodrug preferably is administered as a pharmaceutically acceptable composition of pleconaril and/or pharmaceutically acceptable salts thereof. In a fifth aspect, the present invention provides methods for inhibiting the growth of a picornavirus in a cell comprising contacting a cell infected with a picornavirus with an effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof. Other aspects and features of the inventions are described herein below. detailed-description description="Detailed Description" end="lead"? |
Spare tire cover |
A spare tire cover is constituted by a fix-up plate 4 having a plurality of fixing holes 40a, 40b, a rear cover 2 to which the fix-up plate 4 including a slide fastener 3 is mounted, and a top cover in which a plurality of projections 10a, 10b are provided in an inner surface. The fix-up plate 4 is mounted and fixed to an inner side surface of the top cover 1 on the basis of a fitting connection between the fixing holes 40a, 40b and the projection holes 10a, 10b. The slide fastener 3 and a seamed portion of the rear cover 2 are wound up and held in the inner side of the top cover 1 by the fix-up plate 4 so as to integrally attach the rear cover 2 to the top cover 1. Accordingly, it is possible to omit a sewing of the other members with respect to a largely bulky hard top cover and it is possible to construct on the basis of a simple operation. Further, it is possible to integrally attach the rear cover to the top cover on the basis of a strong structure, and it is possible to construct a spare tire which can be easily attached and detached and has a good appearance. |
1. A spare tire cover comprising: a cup-shaped hard top cover which receives from one side surface of a tire up to a tread portion; and a flexible rear cover which covers another side surface of the tire in a defined width surface from an outer peripheral edge of the top cover up to a center opening, wherein the spare tire is provided with a rear cover in which a band-like fix-up plate having a plurality of fixing holes arranged in a longitudinal direction of a plate surface with a predetermined interval is mounted around an outer periphery, and a top cover in which a plurality of projections directed toward an inner side in a substantially center direction from an inner surface of a flange portion are provided along a circumferential direction of an inner surface in an inner side of an outer peripheral edge of the flange portion with a predetermined interval, the fix-up plate is mounted and fixed to an inner side surface of the top cover on the basis of a fitting connection between the fixing holes in the fix-up plate and the projections in the top cover, and the rear cover is integrally attached to the top cover by winding up and holding a portion around an outer periphery of the rear cover to an inner side from the outer peripheral edge of the top cover by the fix-up plate. 2. A spare tire cover comprising: a cup-shaped hard top cover which receives from one side surface of a tire up to a tread portion; a flexible rear cover which covers another side surface of the tire in a defined width surface from an outer peripheral edge of the top cover up to a center opening; and a slide fastener provided in at least a main portion between the top cover and the rear cover, or all the periphery, wherein the spare tire is provided with a rear cover in which a band-like fix-up plate having a plurality of fixing holes arranged in a longitudinal direction of a plate surface with a predetermined interval is mounted, one zipper teeth tape is sewn along one side line of the fix-up plate, another zipper teeth tape is sewn along an outer peripheral edge of the rear cover, or the remaining outer peripheral edge of the rear cover provided with no slide fastener is sewn along one side line of the fix-up plate, and the fix-up plate including the slide fastener is mounted to a portion around an outer periphery, and a top cover in which a plurality of projections directed toward an inner side in a substantially center direction from an inner surface of a flange portion are provided along a circumferential direction of an inner surface in an inner side of an outer peripheral edge of the flange portion with a predetermined interval, the fix-up plate is mounted and fixed to an inner side surface of the top cover on the basis of a fitting connection between the fixing holes in the fix-up plate and the projections in the top cover, and the rear cover is integrally attached to the top cover by winding up and holding the slide fastener or a seamed portion of the rear cover to an inner side from the outer peripheral edge of the top cover by the fix-up plate. 3. A spare tire cover according to claim 2, wherein the fix-up plate which is made of the same material as the top cover and can be welded is provided, and the fix-up plate is firmly bonded and fixed. 4. A spare tire cover according to claim 3, wherein there is provided the fix-up plate which prevents the welded projection from being in contact with the tire surface, and in which ribs having high rises commonly serving as a reinforcement are provided along a longitudinal direction of a plate surface in both sides of the fixing hole. 5. A spare tire cover according to claim 2, wherein there is provided with the top cover in which an elastic pad bearing the tire by a side wall portion is mounted to a portion near a corner portion in an inner surface of a face portion. 6. A spare tire cover according to claim 2, wherein the defined width surface covering one side surface of the tire is formed by a wide surface having one width and continuously connecting to right and left side portions from a center upper portion, and is formed by a narrow surface tapered toward right and left lower portions continuously connecting to the right and left side portions, and the rear cover separated into right and left sections from a lower center portion is provided. 7. A spare tire cover according to claim 6, wherein there is provided a slide fastener having a right slider and a left slider which run along a zipper teeth tape extending from the lower portion center to the respective right and left side portions except the center upper portion of the rear cover. |
<SOH> BACKGROUND ART <EOH>In general, in a type of motor vehicle such as an off-road car or the like shown in FIG. 13 , a base table having a plurality of stud bolts protruded therefrom is provided in a rear portion of a vehicle body B, and a spare tire which is attached by nuts by inserting the stud bolts to bolt holes in a tire wheel is covered by a tire cover C, whereby the spare tire is mounted to the rear portion of the vehicle body B. In conventional, as the spare tire cover, there has been proposed a structure which is constituted by a cup-shaped hard top cover receiving from one side surface of the tire up to a tread portion and a flexible rear cover provided with a rubber band elastically drawing a center opening, formed in a donut shape and covering another side surface of the tire, setting the rear cover in an outer periphery of the top cover by an outer peripheral edge so as to integrally attach to the top cover (Japanese Utility Model Application Laid-Open No. 4-60785). In the spare tire cover, since the rear cover is set in the hard top cover while handling the top cover which is largely bulky together therewith, a significantly lot of man hour is required for setting, and a seam of the rear cover is exposed to an exterior portion. Further, since it is necessary to execute an attaching and detaching operation while drawing out and expanding the center opening of the rear cover by the rubber band, a lot of man hour is required for this attaching and detaching operation. In order to make it easy to attach and detach the spare tire cover, there is proposed a spare tire cover structured such that respective zipper teeth tapes are respectively set in outer peripheral edges of a top cover and a rear cover, a slide fastener is provided, and a rubber molding covering a seam in a side of the top cover is set in so as to overlap with a side of the rear cover (Japanese Patent Application Laid-Open No. 9-71270). In the spare tire cover, since at least one of the zipper teeth tapes is set in the hard top cover even when the slide fastener is provided in all around the periphery or in a main portion except a part thereof, it is necessary to execute the sewing of the zipper teeth tape caused by handling the largely bulky hard top cover together, so that a lot of man hour is required in the same manner as the preceding prior art. A main object of the present invention is to provide a spare tire cover which can be constructed on the basis of a simple operation with omitting a sawing operation of the other members with respect to a largely bulky hard top cover, can integrally attach a rear cover to the top cover on the basis of a strong structure and has a good appearance. In addition, another object of the present invention is to provide a spare tire cover which can prevent an abnormal noise or the like from being generated due to a friction between the top cover and the tire, and can be further easily attached and detached. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a side cross sectional view showing a spare tire cover in accordance with the present invention; FIG. 2 is a perspective view showing the spare tire cover in FIG. 1 from a side of a top cover; FIG. 3 is a partly perspective view showing the top cover constituting the spare tire cover in FIG. 1 from an inner side; FIG. 4 is a bottom elevational view showing the spare tire cover in FIG. 1 ; FIG. 5 is a back elevational view showing the spare tire cover in FIG. 1 from a rear cover side; FIG. 6 is a partly perspective view showing a fix-up plate constituting the spare tire cover in FIG. 1 ; FIG. 7 is a partly perspective view showing a joint portion connecting the fix-up plate in FIG. 6 ; FIG. 8 is a schematic view showing a structure seaming the fix-up plate in FIG. 6 to a rear cover; FIG. 9 is a schematic view showing a structure seaming a slide fastener including the fix-up plate in FIG. 6 to the rear cover; FIG. 10 a is a schematic view showing the fix-up plate in FIG. 6 in a state of being assembled in an inner side of the top cover; FIG. 10 b is a schematic view showing the fix-up plate in FIG. 10 a in a state of being welded and fixed to the inner side of the top cover; FIG. 11 is a schematic view showing the spare tire cover in accordance with the present invention in a state of being opened by the slide fastener; FIG. 12 is a schematic view showing the spare tire cover in accordance with the present invention in a state of being locked by a pad lock; and FIG. 13 is a schematic view showing a type of motor vehicle in which the spare tire in accordance with a normal embodiment is mounted. detailed-description description="Detailed Description" end="lead"? |
Shower recess assembly incorporating body drier |
A drying system is provided for incorporation in a fixed shower recess. The drying system comprises; a shower recess defined by shower walls and an opening for entry into the shower recess, a water reticulation system which supplies water from a water supply to a water outlet in the shower recess; characterised in that the shower recess further comprises an air supply delivered to the space defined by the shower recess from at least one wall of the shower recess and via said water outlet The system also includes means to control the delivery of the air supply; wherein, in operation, the air supply is delivered to the recess thereby drying the body of an occupant of the shower recess. |
1. A body drying system for incorporation in a shower recess; wherein the system comprises; a shower recess defined by shower walls and an opening for entry into the shower recess; a water reticulation system which supplies water from a water supply to a stationary side water outlet in the shower recess; characterised in that the shower recess further comprises an air supply delivered to the space defined by the shower recess from at least one wall of the shower recess and via said water outlet; and means to control the delivery of the air supply; wherein, the air supply is delivered to the recess thereby drying the body of an occupant of the shower recess. 2. A drying system according claim 1 wherein, the air supply is heated via a heating means prior to delivery of said air to the recess. 3. A drying system according claim 2 wherein the air supply is heated via a heating element prior to delivery to the recess. 4. A drying system according to claim 3 wherein the air supply to the shower recess is heated by an electrical element. 5. A drying system according claim 4 wherein, air delivery outlets are located in the shower recess so as to substantially surround a user positioned within the recess through one or more walls and the shower head. 6. A drying system according claim 5 further including a user control located in the shower recess interior and including means for controlling the supply rate, temperature and volume of air delivered to the occupier via said air outlets. 7. A drying system according claim 6 wherein the system includes a delivery fan which is powered by a motor for delivery of air to the shower recess. 8. A drying system according claim 7 wherein a thermostat is electrically coupled to the heating means to control the amount of thermal energy generated by the heating means between a selected temperature range of a high and low temperature. 9. A drying system according claim 7 wherein the temperature of the air is adjusted by having a hot air stream and the cold air stream which merges into one stream according to an adjustable ratio. 10. A drying system according claim 8 or 9 wherein delivery of air is controlled and adjusted via a control which may be operated from within the shower recess for enabling a user to select between a maximum air delivery rate and a minimum air delivery rate or turn on and off the air flow. 11. A drying system according claim 10 where the hot air, is generated prior to the time when the user requires hot air for drying, and is stored in a air tank. 12. A drying system according claim 10 further comprising an air extraction system for extracting hot drying air from the shower enclosure. 13. A drying system according claim 10 further comprising an halogen heating mechanism assisting in drying up the users body and the shower room. 14. A drying system according claim 10 wherein there are infrared light generators which beam light towards the user and providing infrared therapy to the user 15. A drying system according claim 10 wherein the air pumped into the shower recess is combined with perfume so that it will provide pleasant fragrance when drying the body. 16. A drying system which combines any combination of claims 11, 12, 13, 14 and 15. 17. A drying system according claim 16 further comprising a massaging assembly capable of massaging a body via hydrotherapy wherein water jets are positioned at an appropriate location in the shower recess to approximate a body location to be massaged. 18. A drying system according to claim 16 comprising a massaging assembly capable of massaging at least part of a body of an occupier of the shower recess via mechanical vibration, wherein a massage may be provided with direct body contact with massaging pads either on walls or on a floor of the recess. 19. A drying system according to claim 16 comprising a massaging assembly wherein there is a air jet which blows air onto the user so that it will provide a massaging effect on the body. 20. A drying system according to claims comprising a massaging assembly with any combination of claims 17, 18 and 19. 21. A drying system according to any of the foregoing claims wherein the combination is formed into a compact self contained unit where it will be able to fitted into an existing shower as an additional attachment. 22. A drying system according to any of the above claims however fitted into a room not a shower. |
<SOH> BACKGROUND <EOH>The present invention relates to air dryers and more particularly relates to a full body air dryer capable of use in a shower recess and which may be activated for fill body drying after showering. The invention further relates to a drying system for use in a shower recess. |
Solid state Illuminator for bi-coloured ported water level gauges |
A solid state illuminator and display means are provided for bi-coloured ported water level gauges suitable for use in high pressure steam drums or similar water/steam devices to facilitate making an accurate determination of water level in such a device. The illuminator comprises an array of bi-coloured solid state light emitting diodes (LEDs), as the light source, and a precision lens to focus the light provided from the LEDs through a gauge body and onto the view screen. |
1. A bi-colour water level gauge for use in determining the water level in a boiler steam drum, heater, or similar water/steam device characterized by: an electronic printed circuit board (10) containing an array of high-intensity narrow beam first colour and second colour light emitting diodes (19); said electronic printed circuit board (10) being mounted on an electronics divider board (11); a lens divider board (12) comprising a plurality of viewing ports, each of said ports containing means, such as a plano-convex lens (13), for focussing light originating from said light emitting diodes (19), said ports being equal in number to, and aligned with said light emitting diodes (19); a heat divider (26) for separating said printed circuit board (10) from exposure to high temperatures existing at an external housing; and a display means (15) onto which light originating from the light emitting diodes (19) is projected for inspection by an operator. 2. A bi-colour water level gauge for use in determining the water level in a boiler steam drum, heater, or similar water/steam device characterized by: an electronic printed circuit board (10) containing an array of high-intensity narrow beam first colour and second colour light emitting diodes (19); said electronic printed circuit board (10) being mounted on an electronics divider board (11); a divider board (12) comprising a plurality of ports aligned with said light emitting diodes (19); a heat divider (26) for separating said printed circuit board (10) from high temperatures existing at an external housing; and a display means (15) onto which light originating from the light emitting diodes (19) is projected for inspection by an operator. 3. A bi-colour water level gauge illuminator for use in determining the water level in a boiler steam drum characterized by: an electronic printed circuit board (10) containing an array of high-intensity narrow beam first colour and second colour light emitting diodes (19); said electronic printed circuit board (10) being mounted on an electronics divider board (11); a lens divider board (12) comprising a plurality of ports, each of said ports containing means, such as a plano-convex lens (13), for focussing light originating from said light emitting diodes (19), equal in number to, and aligned with said light emitting diodes (19); and a heat divider (26) for separating said printed circuit board (10) from high temperatures existing at an external housing. 4. A bi-colour water level gauge illuminator for use in determining the water level in a boiler steam drum characterized by: an electronic printed circuit board (10) containing an array of high-intensity narrow beam first colour and second colour light emitting diodes (19); said electronic printed circuit board (10) being mounted on an electronics divider board (11); a divider board (12) comprising a plurality of ports aligned with said light emitting diodes (19); and a heat divider (26) for separating said printed circuit board (10) from high temperatures existing at an external housing. 5. A bi-colour water level gauge for use in determining the water level in a boiler steam drum, heater, or similar water/steam device according to claim 1, wherein said array of high-intensity narrow beam first colour and second colour light emitting diodes (19) comprises at least two light emitting diodes of said first colour arranged in parallel for independent operation and at least two light emitting diodes of said second colour arranged in parallel for independent operation. 6. A bi-colour water level gauge illuminator according to claim 3, wherein said array of high-intensity narrow beam first colour and second colour light emitting diodes (19) comprises at least two light emitting diodes of said first colour arranged in parallel for independent operation and at least two light emitting diodes of said second colour arranged in parallel for independent operation. 7. A bi-colour water level gauge for use in determining the water level in a boiler steam drum, heater, or similar water/steam device according to claim 1, wherein said first colour is red. 8. A bi-colour water level gauge for use in determining the water level in a boiler steam drum, heater, or similar water/steam device according to claim 1, wherein said second colour is green. 9. A bi-colour water level gauge illuminator for use in determining the water level in a boiler steam drum, heater, or similar water/steam device according to claim 3, wherein said first colour is red. 10. A bi-colour water level gauge illuminator for use in determining the water level in a boiler steam drum, heater, or similar water/steam device according to claim 3 wherein said second colour is green. 11. A method for determining the water level in a boiler steam heater, or similar water/steam device characterized by the steps of: projecting a first light from one or more light emitting diodes of a first colour; projecting a second light from one or more light emitting diodes of a second colour; passing said first and second lights though a column containing steam and water at a varying level on an opposing side of said column relative to said light emitting diodes; observing the position of the first and second light at varying vertical levels along the column; and determining the presence of water or steam at each of said varying vertical levels based upon the observed positions of the first and second lights. 12. A method for determining the water level in a boiler steam heater, or similar water/steam device according to claim 11 characterized in that said step of determining the presence of water or steam at each of said varying vertical levels is based upon the observed positions of the first and second lights on a projection screen. 13. A method for determining the water level in a boiler steam heater, or similar water/steam device according to claim 11, characterized in that said step of projecting a first light utilizes at least two light emitting diodes of said first colour arranged in parallel for independent operation. 14. A method for determining the water level in a boiler steam heater, or similar water/steam device according to claim 11, characterized in that said step of projecting a second light utilizes at least two light emitting diodes of said second colour arranged in parallel for independent operation. 15. A method for determining the water level in a boiler steam heater, or similar water/steam device according to claim 11, characterized in that said first colour is red. 16. A method for determining the water level in a boiler steam heater, or similar water/steam device according to claim 11, characterized in that said second colour is green. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The design and use of bi-coloured light for determining water levels in steam boilers is well taught and documented in the art. Traditionally, incandescent light is passed through coloured lenses as the light source. These designs suffer from numerous deficiencies in their fragility, efficiency, power requirements and life span. An incandescent light source utilizes a fragile filament operating at high temperature. This filament can easily become damaged and break when subjected to continued vibration. In addition, the high operating temperature of the filament limits the life span of the incandescent light. The same incandescent light source requires a high level of power to operate and only a small percentage of this power is converted to usable light. The remaining power is lost, predominantly as heat. Numerous liquid level indicators can be found in the art to which the present invention provides advances. U.S. Pat. No. 2,510,729 describes an indicating gauge in which a vertical column containing both water and steam includes a multitude of bores which pass horizontally through the column and allow for visual inspection of the contents of the column present at the corresponding level. An operator is able to inspect and determine the level at which the contents of the column shift from water to steam. In U.S. Pat. Nos. 2,024,815 and 2,115,889, indicators that utilize the reflective and refractive properties of water, steam and light are revealed. In each case, the operator inspects the individual gauges within a plurality of gauges and is able to determine the water/steam level by observing a colour change associated with the level corresponding to the change from water to steam. The device of U.S. Pat. No. 2,115,889 provides an additional means to visually inspect the gauge at a greater distance, more specifically, at a position located far below the gauge. The light is provided in each of these devices via an incandescent light source. U.S. Pat. No. 4,836,022 describes a bi-colour fluviograph for use in steam boilers and provides improvement to the intensity of light provided from the light source and includes benefits aimed at reducing the frequency of maintenance of the fluviograph. The light is provided by a flourescent lamp and the colours are introduced via a two planes, one painted red, and the other green. The fluviograph increases the intensity of the red light to allow for its operation in murky or turbulent water conditions that would render most previous devices inoperable. A further advantage is that the device need not be cleaned as frequently. Traditionally, the impurities in the water contained within the boiler would deposit on the lens and gradually reduce the effective light transmitted. This effect is lessened by increasing the light intensity. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides a gauge system that incorporates a solid state illuminator and corresponding view screen, which can help accurately determine the water level in steam boilers or similar devices, and do so in a safe, economical, and efficient manner. The use of light emitting diodes as a light source in a level gauge illuminator provides reduced operating costs in that much or virtually all power is converted to visible light. In addition, the nominal life of an LED is 100,000 hours. An LED is unaffected by continued vibration. An LED is capable of producing red and green light directly, eliminating the need for coloured glass. Finally, an LED requires minimal power to operate and the use of a solid state illuminator would be intrinsically safe in a hazardous environment. According to an aspect of the present invention, there is provided a bi-colour ported water level gauge for use in determining the water level in a steam/water environment, for instance in a boiler steam drum comprising: an electronic printed circuit board containing an array of high-intensity, narrow beam, red/green light emitting diodes; the electronic printed circuit board being mounted on an electronics divider board; a divider board comprising a plurality of viewing ports, said ports being individually aligned with the light emitting diodes, and preferably substantially equal in number thereto; a heat divider for protecting the printed circuit board from high temperatures existing at an external housing comprising rows of offset slots to reduce heat transmission; and display means, such as a view screen, onto which light originating from the light emitting diodes is projected for inspection by an operator. According to another aspect of the present invention, there is provided a bi-colour ported water level gauge illuminator for use in determining the water level in a steam/water environment, for instance in a boiler steam drum comprising: an electronic printed circuit board containing an array of high-intensity, narrow beam, red/green light emitting diodes; the electronic printed circuit board being mounted on an electronics divider board; a divider board comprising a plurality of viewing ports, said ports being individually aligned with the light emitting diodes, and preferably substantially equal in number thereto; and a heat divider for protecting the printed circuit board from high temperatures existing at an external housing comprising rows of offset slots to reduce heat transmission. According to an aspect of the present invention, there is provided a bi-colour ported water level gauge for use in determining the water level in a steam/water environment, for instance in a boiler steam drum comprising: an electronic printed circuit board containing an array of high-intensity, narrow beam, red/green light emitting diodes; the electronic printed circuit board being mounted on an electronics divider board; a lens divider board comprising a plurality of viewing ports, each containing means, such as a plano-convex lens, for focussing light originating from the light emitting diodes, said ports being individually aligned with the light emitting diodes, and preferably substantially equal in number thereto; a heat divider for protecting the printed circuit board from high temperatures existing at an external housing comprising rows of offset slots to reduce heat transmission; and display means, such as a view screen, onto which light originating from the light emitting diodes is projected for inspection by an operator. According to another aspect of the present invention, there is provided a bi-colour ported water level gauge illuminator for use in determining the water level in a steam/water environment, for instance in a boiler steam drum comprising: an electronic printed circuit board containing an array of high-intensity, narrow beam, red/green light emitting diodes; the electronic printed circuit board being mounted on an electronics divider board; a lense divider board comprising a plurality of viewing ports, each containing means, such as a plano-convex lense, for focussing light originating from the light emitting diodes, said ports being individually aligned with the light emitting diodes, and preferably substantially equal in number thereto; and a heat divider for protecting the printed circuit board from high temperatures existing at an external housing comprising rows of offset slots to reduce heat transmission. A further aspect of the invention provides a method for determining the water level in a boiler steam heater, or similar water/steam device characterized by the steps of: projecting a first light from one or more light emitting diodes of a first colour; projecting a second light from one or more light emitting diodes of a second colour; passing said first and second lights though a column containing steam and water at a varying level onto a projection screen positioned on an opposing side of said column relative to said light emitting diodes; observing the position of the first and second light on the projection screen at varying vertical levels along the column; and determining the presence of water or steam at each of said varying vertical levels based upon the observed positions of the first and second lights on the projection screen. |
Method of modifying genome in higher plant |
A genome-modification technique based on homologous recombination was established for partial modification of genomic sequences into desired sequences. The use of such a technique to achieve high efficiency and reproducibility in higher plants has been regarded as difficult. According to the present invention, endogenous genome sequences of higher plants can be targeted to efficiently and reproducibly yield homologous recombinants without changing their original loci. Moreover, the present invention enables the production of a transformed plant in which a specific gene is modified without any restrictions, and it can also contribute to the analysis of gene functions as well as to the analysis of gene expression mechanisms associated with changes in genome dynamics. |
1. A gene construct for modifying the genome of higher plants by homologous recombination, which contains the following elements between BR (right border sequence) and BL (left border sequence) of T-DNA in the following orientation from Br: (1) a first negative selection marker gene in an expressible state; (2) a first cloning site for incorporating the 5′ region of a DNA sequence to be homologously recombined with a target DNA sequence in the host genome; (3) a positive selection marker gene in an expressible state; (4) a second cloning site for incorporating the 3′ region of the DNA sequence to be homologously recombined with the target DNA sequence in the host genome; and (5) a second negative selection marker gene in an expressible state, which may be the same as the first negative selection marker. 2. A gene construct of claim 1, which further includes (6) a transcription termination region, preferably a transcription termination region of En/Spm type transposon, in downstream of the first cloning site. 3. A gene construct of claim 1, which further includes (7) recombinase recognition sequences in upstream and downstream of the positive selection marker gene. 4. A gene construct of claim 1, wherein one or both of the cloning sites for incorporating the 5′ and 3′ regions of the DNA sequence to be homologously recombined with the target DNA sequence in the host genome are multiple cloning sites. 5. A gene construct of claim 1, wherein the first negative selection marker gene in an expressible state is located between a maize ubiquitin 1 promoter (pubi) and a cauliflower mosaic virus 35S terminator (t35S). 6. A gene construct of claim 1, wherein the positive selection marker gene is in an expressible state by being placed between a rice actin promoter (pAct) along with the 1st intron (iAct) of rice actin and a cauliflower mosaic virus 35S terminator (t35S). 7. A gene construct of claim 1, wherein the second negative selection marker gene is in an expressible state by being placed between a cauliflower mosaic virus 35S promoter (p35S) along with the 1st intron of castor bean catalase and a cauliflower mosaic virus 35S terminator (t35S). 8. A gene construct of claim 1, wherein the directions of transcription of the first and second negative selection marker genes are opposite to each other. 9. A gene construct of claim 1, wherein the positive selection marker gene is selected from the group consisting of hygromycin resistance gene, kanamycin resistance gene, neomycin resistance gene, and herbicide resistance gene (for example, bar gene), while the negative selection marker gene is selected from the group consisting of diphtheria toxin protein A chain gene (DT-A), coda gene, cytochrome P-450 gene, and barnase gene. 10. A vector for plant transformation, which contains a gene construct of claim 1. 11. A vector for plant transformation which contains a gene construct of claim 1, wherein the 5′ region of the DNA sequence to be homologously recombined with the target DNA sequence in the host genome is incorporated into the first cloning site, and the 3′ region of the DNA sequence to be homologously recombined with the target DNA sequence in the host genome is incorporated into the second cloning site. 12. A method for producing a higher plant (preferably monocotyledon) having a modified genome by means of homologous recombination, comprising the steps of: (a) introducing a vector for plant transformation of claim 11 into an Agrobacterium strain which contains Ti plasmid; (b) allowing said Agrobacterium strain to infect a cell, tissue or callus of a plant; (c) performing negative and positive selections to select a cell, tissue or callus undergoing homologous recombination; (d) culturing the cell or tissue to form a callus in the case that selection was performed with a cell or tissue; (e) culturing the callus in a regeneration medium to generate an individual plant which is heterozygous for homologous recombination in the genome; and (f) fertilizing said plant to yield a gene-modified higher plant which is homozygous for homologous recombination. 13. A method of claim 12, which includes the step of deleting the positive selection marker gene and its promoter and terminator, as well as the transcription termination region, if present, from the region of homologous recombination in the genome of the plant cell, before or after the step (d), (e) or (f). 14. A method of claim 13, wherein the deletion step comprises the Cre/lox recombination system, the R/RS recombination system, or the FLP-FRT recombination system. |
<SOH> TECHNICAL FIELD <EOH>The present invention relates to a gene construct for homologous recombination-based genome modification in higher plants, and a method for production of a higher plant having a modified genome by using a plant transformation vector carrying the gene construct. The present invention is directed to an efficient and reproducible method, in which endogenous genome sequences of plants are targeted to yield homologous recombinants without changing their original loci. |
<SOH> SUMMARY OF THE INVENTION <EOH>As stated above, there are various advantages in homologous recombination-based genome modification. However, for reasons such as an extremely low frequency of homologous recombination in higher plants, there are only two successful reports stated above (Miao Z H et al. and Yanofsky M F et al.) for modification of endogenous genome sequences in higher plants via homologous recombination. Neither of these reports discloses a reproducible and reliable method for homologous recombination. Moreover, no successful case is reported for monocotyledonous plants although they are very important to agricultural production. Thus, there has been a strong need to develop a reproducible and reliable method for homologous recombination in higher plants. In view of the foregoing, the object of the present invention is to overcome various problems arising from conventional transformation of higher plant cells including monocotyledonous plant (e.g., rice) cells. Such problems include those associated with foreign gene transfer, such as the copy number and position effect of introduced foreign genes or expression instability due to co-suppression, gene silencing, etc. Thus, the present invention provides a gene construct and a vector for plant genome modification, intended for use in a method which allows transformation without causing any change in the genome other than the gene region(s) to be modified, as well as a method for producing a whole transformed plant from the transformed cells obtained by the above method. |
Fuel cell system and method for recycling exhaust |
A fuel cell system includes a primary fuel line to the fuel cell assembly, a jet pump in the primary fuel line and adapted to be driven by the flow of primary fuel, the jet pump having a nozzle, an entrainment chamber downstream of the nozzle and a mixing tube downstream of the entrainment chamber, a fuel exhaust recycle line from the fuel cell assembly opening to the entrainment chamber for supply of fuel exhaust thereto, and a mass flow control device in the primary fuel line upstream of the jet pump for controlling the primary fuel flow rate to the jet pump. The nozzle of the jet pump has an adjustable cross-sectional area to provide a variable area flow of the primary fuel so that the ratio of fuel exhaust entrained by the primary fuel in the entrainment chamber can be varied. |
1. A fuel cell system including a fuel cell assembly for producing electricity from a fuel and an oxygen-containing gas, which comprises: a primary fuel line to the fuel cell assembly, a jet pump in the primary fuel line and adapted to be driven by the flow of primary fuel, the jet pump having a nozzle, an entrainment chamber downstream of the nozzle and a mixing tube downstream of the entrainment chamber, a fuel exhaust recycle line from the fuel cell assembly opening to the entrainment chamber for supply of fuel exhaust thereto, and a mass flow control device in the primary fuel line upstream of the jet pump for controlling the primary fuel flow rate to the jet pump, wherein the nozzle of the jet pump has an adjustable cross-sectional area to provide a variable area flow therefrom of the primary fuel whereby the ratio of fuel exhaust entrained by the primary fuel in the entrainment chamber can be varied. 2. The fuel cell system according to claim 1, wherein the jet pump nozzle comprises a nozzle bore of fixed cross-section and a tapered valve body axially adjustable relative to the nozzle bore to vary the cross-sectional area of the nozzle. 3. The fuel cell system according to claim 2, wherein the valve body and nozzle bore have a cross-section that is selected from circular, oval and finned. 4. The fuel cell system according to claim 2, wherein the nozzle bore and an inlet to the mixing tube from the entrainment chamber have substantially the same cross-sectional shape. 5. The fuel cell system according to claim 2, wherein with the valve body fully retracted from the nozzle bore, the nozzle bore has a cross-sectional area that is larger than the cross-sectional area of an inlet to the mixing tube from the entrainment chamber. 6. The A fuel cell system according to claim 1, wherein the fuel exhaust recycle line is branched from a fuel exhaust line extending from the fuel cell assembly and delivers to the jet pump only the volume of fuel exhaust to be entrained. 7. The fuel cell system according to claim 1, wherein the fuel exhaust recycle line delivers all of the fuel exhaust to the jet pump and the jet pump has an exhaust outlet from the entrainment chamber for discharge of excess fuel exhaust. 8. The fuel cell system according to claim 1, wherein the system operates at a primary fuel pressure of 40 kPa or less. 9. The fuel cell system according to claim 1, wherein a fuel source supplies fuel to the system at a first pressure and wherein the mass flow control device provided in the primary fuel line upstream of the jet pump comprises a pressure regulator, the pressure regulator being adjustable to supply the primary fuel to the jet pump in a pressure range of no more than the first pressure. 10. The fuel cell system according to claim 1, wherein the mass flow control device comprises a pump controllable by means of a flow sensor in the primary fuel line upstream of the jet pump. 11. The fuel cell system according to claim 1, wherein the fuel cell assembly is one of a plurality of fuel cell assemblies, each having a respective primary fuel line thereto with a respective said jet pump therein adapted to be driven by the flow of primary fuel, the fuel cell system further including a respective fuel exhaust recycle line from each fuel cell assembly opening to the entrainment chamber of the associated jet pump for supply of fuel exhaust thereto, wherein the cross-sectional area of each jet pump nozzle is individually adjustable to provide a variable area flow therefrom of the primary fuel whereby the ratio of fuel exhaust entrained by the primary fuel in each jet pump is consequently varied. 12. The fuel cell system according to claim 11, wherein a respective mass flow control device is provided in each primary fuel line upstream of the associated jet pump for controlling the primary fuel flow rate to said jet pump. 13. The fuel cell system according to claim 11, wherein the respective primary fuel lines branch from a common primary fuel line and the mass flow control device is disposed in the common primary fuel line. 14. The fuel cell system according to claim 11, wherein each fuel cell assembly comprises a plurality of fuel cell stacks. 15. A method of operating a fuel cell system in which fuel exhaust from a fuel cell assembly is recycled, which comprises: entraining fuel exhaust in a primary fuel stream by using a jet pump through a nozzle of which the primary fuel stream passes and is mixed with the primary fuel stream, and wherein the ratio of fuel exhaust in the mixed flow of primary fuel and fuel exhaust delivered to the fuel cell assembly is varied by adjusting the cross-sectional area of the jet pump nozzle and thereby adjusting the cross-sectional area of the primary fuel stream therethrough. 16. A method for adjusting a proportion of steam in a fuel stream delivered to a fuel cell assembly in a fuel cell system, the method comprising: recycling fuel exhaust containing steam from the fuel cell assembly by entraining and mixing the fuel exhaust in a primary fuel stream by means of a jet pump through a nozzle of which the primary fuel stream passes, wherein the ratio of fuel exhaust in the mixed flow of primary fuel and fuel exhaust delivered to the fuel cell assembly is varied by adjusting the cross-sectional area of the jet pump nozzle and thereby adjusting the cross-sectional area of the primary fuel stream therethrough. 17. The method according to claim 15, wherein the jet pump is capable of operating in a condition in which no fuel exhaust is entrained by the primary fuel stream passing through the jet pump nozzle. 18. The method according to claim 17, wherein the fuel cell assembly is purged by adjusting the jet pump nozzle to entrain no fuel exhaust and replacing the primary fuel stream with a purge gas stream. 19. The method according to claim 18, wherein fuel exhaust in an exhaust recycle line between the fuel cell assembly and the jet pump is purged by passing purge gas from the jet pump through the exhaust recycle line to an exhaust discharge outlet. 20. The method according to claim 15, wherein only the volume of fuel exhaust to be entrained in the primary fuel stream is recycled by the jet pump. 21. The method according to claim 15, wherein all of the fuel exhaust is recycled through the jet pump and excess fuel exhaust is discharged from the jet pump through an exhaust discharge outlet. 22. The method according to claim 15, wherein mass flow control of the primary fuel stream is performed upstream of the jet pump. 23. The method according to claim 22, wherein the mass flow control comprises increasing the supply pressure of the primary fuel stream to the jet pump as the primary fuel flow rate is reduced and as the cross-sectional area of the primary fuel stream through the jet pump nozzle is reduced to increase the proportion of fuel exhaust in the mixed flow. 24. The method according to claim 15, which further comprises adjusting a cross-sectional area of the jet pump nozzle to maintain a selected pressure differential range across an anode side of the fuel cells in the fuel cell assembly. 25. The method according to claim 24, wherein a variation in pressure differential across the anode side of the fuel cells through the range of operating conditions of the fuel cell assembly is no more than about 10%. 26. The method according to claim 15, which comprises shutting off the primary fuel stream by means of the jet pump. 27. The method according to claim 15, wherein the jet pump acts to provide a pressure drop between a primary fuel supply and the fuel cell assembly, thereby isolating the fuel cell assembly from variations in system exhaust pressure. 28. The method according to claim 15, wherein the fuel cell system includes a plurality of fuel cell assemblies, each with a respective jet pump for recycling fuel exhaust to the respective assembly, and wherein the cross-sectional area of each jet pump nozzle is individually adjustable to vary the cross-section of the primary fuel stream therethrough and thereby independently adjust the ratio of fuel exhaust in the mixed flow of primary fuel and fuel exhaust delivered to the respective fuel cell assembly. 29. The method according to claim 28, wherein differential adjustment of each jet pump nozzle is used to control respective primary fuel flow rates through the jet pumps. 30. The method according to claim 15, wherein each fuel cell assembly comprises a plurality of fuel cell stacks. 31. A method for adjusting the proportion of steam in a fuel stream delivered to a fuel cell assembly in a fuel cell system, the method comprising: recycling fuel exhaust containing steam from the fuel cell assembly by entraining and mixing the fuel exhaust in a primary fuel stream by using a jet pump through a nozzle of which the primary fuel stream passes, wherein the ratio of fuel exhaust in the mixed flow of primary fuel and fuel exhaust delivered to the fuel cell assembly is varied by adjusting the cross-sectional area of the jet pump nozzle and thereby adjusting the cross-sectional area of the primary fuel stream therethrough. 32. The method according to claim 16, wherein the jet pump is capable of operating when no fuel exhaust is entrained by the primary fuel stream passing through the jet pump nozzle. 33. The method according to claim 32, wherein the fuel cell assembly is purged by adjusting the jet pump nozzle to entrain no fuel exhaust and replacing the primary fuel stream with a purge gas stream. 34. The method according to claim 33, wherein fuel exhaust in an exhaust recycle line between the fuel cell assembly and the jet pump is purged by passing purge gas from the jet pump through the exhaust recycle line to an exhaust discharge outlet. 35. The method according to claim 16, wherein only a volume of fuel exhaust to be entrained in the primary fuel stream is recycled by the jet pump. 36. The method according to claim 16, wherein all of the fuel exhaust is recycled through the jet pump and excess fuel exhaust is discharged from the jet pump through an exhaust discharge outlet. 37. The method according to claim 16, wherein mass flow control of the primary fuel stream is performed upstream of the jet pump. 38. The method according to claim 37, wherein the mass flow control comprises increasing a supply pressure of the primary fuel stream to the jet pump as the primary fuel flow rate is reduced and as a cross-sectional area of the primary fuel stream through the jet pump nozzle is reduced to increase the proportion of fuel exhaust in the mixed flow. 39. The method according to claim 16, which comprises adjusting a cross-sectional area of the jet pump nozzle to maintain a selected pressure differential range across the anode side of the fuel cells in the fuel cell assembly. 40. The method according to claim 39, wherein a variation in pressure differential across the anode side of the fuel cells through the range of operating conditions of the fuel cell assembly is no more than about 10%. 41. The method according to claim 16, which further comprises shutting off the primary fuel stream by means of the jet pump. 42. The method according to claim 16, wherein the jet pump acts to provide a pressure drop between a primary fuel supply and the fuel cell assembly, thereby isolating the fuel cell assembly from variations in the system exhaust pressure. 43. The method according to claim 16, wherein the fuel cell system includes a plurality of fuel cell assemblies, each with a respective jet pump for recycling fuel exhaust to the respective assembly, and wherein the cross-sectional area of each jet pump nozzle is individually adjustable to vary the cross-section of the primary fuel stream therethrough and thereby independently adjust the ratio of fuel exhaust in the mixed flow of primary fuel and fuel exhaust delivered to the respective fuel cell assembly. 44. The method according to claim 43, wherein differential adjustment of each jet pump nozzle is used to control the respective primary fuel flow rates through the jet pumps. 45. The method according to claim 16, wherein each fuel cell assembly comprises a plurality of fuel cell stacks. 46. The fuel cell system according to claim 1, wherein the fuel cell assembly comprises a plurality of fuel cell stacks. |
<SOH> BACKGROUND OF THE INVENTION <EOH>In the purest form of the reaction, fuel cells produce electricity from hydrogen and oxygen with water as a by-product in the form of steam. Inevitably, however, hydrocarbon fuels such as natural gas or higher (C 2+ ) hydrocarbons are used as the source of hydrogen and air as the source of oxygen, with the hydrocarbon fuel being subjected to reforming upstream of the fuel cell assembly. One of the advantages of a solid oxide fuel cell assembly is that the operating temperature range of about 700 to 1000° C. is sufficiently high for internal steam reforming of the hydrocarbon fuel on a nickel catalyst on the anode side of each fuel cell. Since the anode of a solid oxide fuel cell is commonly nickel-based, for example a nickel cermet, at least some of the internal steam reforming may be performed on the anode. Internal steam reforming of the hydrocarbon fuel has advantages for the operating efficiency of the fuel cell assembly, particularly in terms of balancing the exothermic fuel cell reaction with the endothermic reforming reaction. However, full internal reforming of the hydrocarbon fuel would tend to excessively cool the fuel cells by reforming endotherm and can lead to carbon deposition during preheating of the fuel mixture, so it has been proposed to use both steam pre-reforming and internal steam reforming of the hydrocarbon fuel. Examples of such systems are described in International Patent Applications WO 01/12452 and PCT/AU02/00128 of Ceramic Fuel Cells Limited. Steam must be present in the fuel stream supplied to the fuel cell assembly in order for the internal steam reforming reaction to take place, and the proportion of steam to carbon (S/C) in the fuel supply is one of the important variables in the reforming reaction. Additionally, the presence of steam in the fuel stream tends to alleviate carbon deposition on the nickel catalyst. It has been proposed to recycle exhaust from a fuel cell assembly such as one or more fuel cell stacks to provide the steam for the internal reforming reaction. In operating a steam-self sufficient fuel cell system, exhaust gas exiting the anode side of the assembly is recirculated and mixed with the incoming primary fuel stream. This also has the advantage of improving fuel utilisation limitations of the fuel cell assembly. Recirculation of exhaust fuel gas in a fuel cell system is achieved by an arrangement which must be able to operate at high temperature. Various arrangements have been proposed by different fuel cell developers for introducing the anode exhaust gas into the inlet fuel gas stream. One proposal favoured by some fuel cell system developers has been to use a jet pump, for example as described in European Patent Application EP 0673074. In all such proposals the incoming or primary fuel stream is discharged through a fixed geometry precision machined nozzle. The resultant high velocity jet creates a vacuum in an entrainment chamber that is used to draw in the recycled fuel exhaust gas through a suction port. The two gas streams are mixed in a mixer tube of the jet pump and discharged to the anode side inlet manifold of the fuel cell assembly. Jet pumps used as described above have a single fuel utilization design condition for optimum thermal efficiency of the fuel cell system, so that the recycled exhaust gas volume drawn in by the jet pump is theoretically proportional to the volume of the primary fuel stream (subject to disproportionate variations resulting from temperature differences in the system and the associated density changes of the primary and recycle flows, as well as from a varying volume of steam in the recycle stream). This means that to operate the fuel cell system with a reduced electrical output, and consequently reduced fuel supply, there is traditionally a reduced volumetric fuel flow rate through the fuel cell assembly. The low flow rate presents challenges to maintaining an even flow distribution throughout the fuel cell assembly. An uneven fuel distribution results in an uneven fuel utilization between cells in the fuel cell assembly. The maximum localized fuel utilization is the factor that limits the safe (non-damaging) operation of the fuel cell. Advantage would be gained in having control of the amount of anode exhaust gas recirculation to follow fuel utilization. In order to maintain thermal balance in the fuel cell assembly, a fuel cell system requires variation in the fuel utilization level throughout the operating range of output power from the assembly. A change in fuel utilization changes the steam content of the anode exhaust and therefore directly impacts the ratio of recycled anode exhaust gas that is required to achieve an adequate S/C ratio. Further to this, peak shaving, as practiced by natural gas distributors around the world, can introduce a primary fuel supply of variable hydrogen to carbon ratio. This varies seasonally as the gas demand of the general market changes throughout the year. The variable hydrogen to carbon ratio also changes the anode exhaust gas recycle to primary fuel mass flow ratio requirements, but this can not be catered for by the jet pumps described above except by designing them for the worst case, which consequently leads to a reduction in efficiency. Those proposing the use of jet pumps of the type described above have faced considerable difficulty in providing for a variable recirculation rate. On line trimming of recycle is unavailable and the system has a resonance time (of steam mass flow available) during current ramp up that limits the fuel flow ramp rate. As more steam is generated by the fuel cell assembly, more needs to be recycled to satisfy the steam requirements of the increased fuel flow. Significant excess steam supply is required in normal operation to provide rapid load-following capability and a safety margin for composition variations of the system feedstock fuel gas. This is a substantial disadvantage to the thermal efficiency of a fuel cell system when using jet pumps of the type described above. Other developers of fuel cell systems have proposed the use of a hot gas blower combined with suitable mixing of recirculated exhaust and fresh fuel gas to achieve anode exhaust gas recirculation. However, the high temperature of the exhaust gas renders the use of a blower generally undesirable, particularly given a need for heat exchangers to first cool the gas upstream of the blower and then reheat the gas downstream of the blower. In addition to the difficulty of materials operating at these temperatures, such as metal creep and fatigue, a blower has disadvantages resulting from general mechanical wear, as well as from operating noise and vibration. A hot air blower may have the advantage of enabling the ratio of primary fuel to recycle fuel exhaust gas to be varied. However, when the fuel cell system is operated at high electrical turndown (low electricity production), high exhaust recycle is required to maintain a desired volumetric fuel flow to the fuel cell assembly. Such a high exhaust recycle requires the highest blower duty and thus the highest electrical load. The electrical efficiency of the fuel cell system is thus substantially reduced at turndown due to turndown being the regime when the highest blower power requirements are present. It is an aim of the present invention to alleviate the aforementioned disadvantages of known proposals for recycling fuel exhaust in fuel cell systems. This is achieved, according to the present invention, by the use of a jet pump having a variable nozzle area geometry that is adapted in use to control the cross-sectional area of the jet of primary fuel on entry to the mixing tube of the jet pump and thereby the kinetic energy imparted to the primary fuel stream. It thereby controls the ratio of recycled fuel exhaust entrained by the primary fuel stream in the jet pump. A jet pump known as an adjustable area motive hydrogen ejector has been proposed for use in a fuel cell application by the Fox Valve Development Company of Dover, N.J., United States of America, in their pamphlet “Hydrogen Ejectors for Fuel Cells”, for recycling hydrogen, steam and air at a maximum temperature of 500° F. (260° C.). However, these devices use a variable needle and seat arrangement working in a choked (sonic) flow regime for the purposes of metering high pressure motive flow. Thus, the devices are proposed for use to control mass flow at primary stream pressures of several hundred kPa. As described their use is incapable of varying the flow rate of the recirculated stream independently of the motive or primary stream flow rate, and therefore is incapable of varying the entrainment ratio of the recirculating gas. |
<SOH> SUMMARY OF THE INVENTION <EOH>According to the present invention there is provided a fuel cell system including a fuel cell assembly for producing electricity from a fuel and an oxygen-containing gas, a primary fuel line to the fuel cell assembly, a jet pump in the primary fuel line and adapted to be driven by the flow of primary fuel, the jet pump having a nozzle, an entrainment chamber downstream of the nozzle and a mixing tube downstream of the entrainment chamber, a fuel exhaust recycle line from the fuel cell assembly opening to the entrainment chamber for supply of fuel exhaust thereto, and a mass flow control device in the primary fuel line upstream of the jet pump for controlling the primary fuel flow rate to the jet pump, wherein the nozzle of the jet pump has an adjustable cross-sectional area to provide a variable area flow therefrom of the primary fuel whereby the ratio of fuel exhaust entrained by the primary fuel in the entrainment chamber can be varied. Further according to the present invention there is provided a method of operating a fuel cells system in which fuel exhaust from a fuel cell assembly is recycled, wherein fuel exhaust is entrained in a primary fuel stream by means of a jet pump through a nozzle of which the primary fuel cell stream passes and is mixed with the primary fuel stream, and wherein the ratio of fuel exhaust in the mixed flow of primary fuel and fuel exhaust delivered to the fuel cell assembly is varied by adjusting the cross-sectional area of the jet pump nozzle and thereby adjusting the cross-sectional area of the primary fuel stream therethrough. The entrainment achieved by the invention is thus disproportionate to the mass flow rate of the primary fuel stream. This is unlike the behavior of typical jet pumps proposed for use in fuel cell systems, which have a fixed geometry and do not change the cross section of the primary fuel stream. When the cross-section of the primary fuel stream is fixed, the primary and entrained recycle flows remain essentially proportional throughout the range of flow. Advantageously, varying the recycle to primary fuel stream ratio changes the S/C ratio in the fuel stream to the fuel cell assembly. Thus, further according to the present invention there is provided a method for adjusting the proportion of steam in a fuel stream delivered to a fuel cell assembly in a fuel cell system, the method comprising recycling fuel exhaust containing steam from the fuel cell assembly by entraining and mixing the fuel exhaust in a primary fuel stream by means of a jet pump through a nozzle of which the primary fuel stream passes, wherein the ratio of fuel exhaust in the mixed flow of primary fuel and fuel exhaust delivered to the fuel cell assembly is varied by adjusting the cross-sectional area of the jet pump nozzle and thereby adjusting the cross-sectional area of the primary fuel stream therethrough. In a preferred embodiment, the jet pump nozzle comprises a nozzle bore of fixed cross-section and a tapered valve body axially adjustable relative to the nozzle bore to vary the cross-sectional area of the nozzle. Variable area jet pumps of this type have been proposed for use in recirculating flue gas in a furnace system in a paper by G. H. Priestman and J. R. Tippetts entitled “ The application of a variable - area jet pump to the external recirculation of hot flue gases ” in the Journal of the Institute of Energy, December 1995, 68, pp 213-219, the disclosure of which is incorporated herein by reference. The valve body and nozzle bore in the preferred embodiment of jet pump may have any suitable cross-sectional shape, but preferably such shape is selected from circular, oval and finned. Generally, the nozzle bore and at least an inlet to the mixing tube from the entrainment chamber will have substantially the same cross-sectional shape. Conveniently, the jet pump is capable of operating in a condition in which no fuel exhaust is entrained by the primary fuel stream passing through the jet pump nozzle. This can be achieved in the preferred embodiment of the jet pump, without a shut-off valve in the fuel exhaust recycle line, by providing the nozzle bore with a cross-sectional area that is larger than the cross-sectional area of an inlet to the mixing tube from the entrainment chamber when the valve body is fully retracted from the nozzle bore. This can have substantial advantage when the fuel cell assembly is purged, since the jet pump can be adjusted to entrain no fuel exhaust when the primary fuel stream is replaced with a purge gas that is non-combustible, such as an inert gas. If one or more of the fuel cells in the fuel cell assembly breaks or cracks by some means, it is possible for air to pass from the cathode-side to the anode-side of that cell, leading to anode destruction. Such anode destruction is limited to the broken or cracked cell or cells when there is no recycle of the fuel exhaust. However, with fuel exhaust recycle, the air ingress to the fuel exhaust has the potential to contaminate the whole of the fuel side of the fuel cell assembly with oxygen. Generally, the oxygen contamination will be identified before the contaminated fuel exhaust is recycled with the primary fuel stream. However, a fuel-side purge will still contaminate the fuel-side with oxygen if contaminated fuel exhaust is entrained in the purge gas. Setting the jet pump so as to entrain no fuel exhaust alleviates the risk of fuel-side contamination. Advantageously, in such a purge, fuel exhaust in the exhaust recycle line between the fuel cell assembly and the jet pump is purged by passing purge gas from the jet pump through the exhaust recycle line to an exhaust discharge outlet. In an embodiment in which the fuel exhaust recycle line is branched from a fuel exhaust line extending from the fuel cell assembly and delivers to the jet pump only the volume of fuel exhaust to be entrained, the motive purge gas can be directed both through the fuel cell assembly and in reverse flow along the fuel exhaust recycle line when the jet pump is set to entrain no fuel exhaust. This arrangement can reduce the resonance time of the purge function and can reduce the quantity of gas required for a purge. In an alternative embodiment, the fuel exhaust recycle line delivers all of the fuel exhaust to the jet pump and the jet pump has an exhaust discharge outlet from the entrainment chamber for discharge of excess fuel exhaust. When the jet pump is set to entrain no fuel exhaust, all of the fuel exhaust will be discharged through the jet pump exhaust outlet. In this embodiment, all of the motive purge gas in a purge process may be delivered by the jet pump to the fuel cell assembly and pass from there through the fuel exhaust recycle line to the jet pump exhaust discharge outlet, when the jet pump is set to not entrain the exhaust. The feature of the recycle line delivering all of the exhaust to the jet pump and the jet pump having an exhaust outlet from the entrainment chamber for discharge of excess exhaust has application to other exhaust recycle systems than fuel cell systems and is advantageous since recycling all of the exhaust directly through the entrainment chamber is simpler in construction than known recirculation systems. According to this aspect of the invention, there is provided a system for recycling exhaust, including an assembly for generating exhaust from a fuel, a primary fuel line to the assembly, a jet pump in the primary fuel line and adapted to be driven by the flow of primary fuel, a fuel exhaust recycle line from the assembly opening to an entrainment chamber of the jet pump for supply of all of the fuel exhaust from the assembly thereto, and an exhaust discharge outlet from the entrainment chamber, wherein a nozzle of the jet pump has an adjustable cross-sectional area to provide a variable area flow therefrom of the primary fuel whereby the ratio of fuel exhaust entrained by the primary fuel in the entrainment chamber can be varied, with excess fuel exhaust being discharged through the exhaust discharge outlet. It will be appreciated that the discussion above and below relating to fuel cell system usage of a jet pump is generally applicable also to any other system and assembly for generating exhaust from a fuel as described in the immediately preceding paragraph. In a fuel cell system, the present invention has advantage in allowing a variation of the mass flow of recirculated fuel exhaust as a proportion of the primary fuel flow during operation and in allowing the system to operate at a minimal recycle rate during normal operation, yet also allowing good response to ramp up fuel flow and electrical output. When reducing electrical production, and therefore when there is a lower fuel flow requirement, the variable geometry jet pump will provide higher fuel exhaust recirculation to dilute the primary fuel stream and maintain a desired fuel flow rate to the fuel cell assembly throughout the turndown range. At minimal power output, the mass fuel flow rate to the fuel cell assembly is therefore enhanced to aid fuel distribution and permit a much greater turndown range than is otherwise possible. Without this feature, low fuel flow to and poor fuel distribution within the fuel cell assembly during low power output operation will eventually produce local fuel starvation in one or more of the fuel cells and irreversible anode damage as the anode oxidizes. Preferably therefore, the method of the invention comprises adjusting the cross-sectional area of the jet pump nozzle to maintain a selected pressure differential range across the fuel cells in the fuel cell assembly. Advantageously, with the system and method of the invention, the differential pressure across the anode side under different operating conditions of the fuel cell assembly does not vary by more than about 25% from the full power operating condition to the low power output operating condition. More preferably, the differential pressure does not vary by more than about 15%, and most preferably by not more than about 10%. Any mass flow control of the primary fuel stream should be performed upstream of the jet pump. In many conditions of use of the jet pump, mass flow control of the primary fuel stream may be performed upstream of the jet pump by increasing the supply pressure of the primary fuel stream to the jet pump as the primary fuel flow rate is reduced and as the cross-sectional area of the primary fuel stream through the jet pump nozzle is reduced to increase the proportion of fuel exhaust in the mixed flow. However, there may be conditions, such as when reducing the fuel utilization, when the cross-sectional area of the primary fuel stream through the jet pump nozzle is reduced to increase the proportion of fuel exhaust in the mixed flow independently of the primary fuel flow rate. Thus, the ratio of fuel exhaust to primary fuel flow is changed to satisfy the chemical needs of the fuel cell assembly and to suit the operating conditions of the assembly. Primary fuel flow may be delivered to the jet pump by, for example, a blower or pump in the fuel cell system. Preferably, however, the primary fuel is natural gas, which may have been subjected to partial pre-reforming, that is supplied to the fuel cell system at mains pressure of, say, 40 kPa. The flow rate control device may then comprise a pressure regulator that regulates the pressure down to the pressure required at the jet pump to control the desired mass flow. Conveniently, mass flow control is performed upstream of any pre-heating, pre-reforming and/or desulphurisation of the fuel. Any suitable technique may be used to measure the actual mass flow. For example, the flow could be sensed in the cold region by a flow sensor (thermal dispersion, vortex or orifice, etc). In one embodiment, the mass flow control function may be performed by a mass flow meter that has an integrated sensor, a flow control valve and/or pressure regulator. In another embodiment the mass flow control device comprises a pump controllable by means of a flow sensor in the primary fuel line upstream of the jet pump. This embodiment is useful when the primary fuel flow pressure needs to be increased in order to maintain a desired mass flow Advantageously, the jet pump acts to provide a pressure drop between a primary fuel supply and the fuel cell assembly, thereby isolating the fuel cell assembly from variations in the fuel cell assembly exhaust pressure caused, for example, by flue effects or internal transient states. Conveniently, the primary fuel stream may be shut-off by means of the jet pump, for example, in the preferred embodiment, by inserting the tapered valve body fully into the nozzle bore. In one embodiment of the fuel cell system, the fuel cell assembly is one of a plurality of fuel cell assemblies, each having a respective primary fuel line thereto with a respective said jet pump therein adapted to be driven by the flow of primary fuel, the fuel cell system further including a respective fuel exhaust recycle line from each fuel cell assembly opening to the entrainment chamber of the associated jet pump for supply of fuel exhaust thereto, the cross-sectional area of each jet pump nozzle being individually adjustable to provide a variable area flow therefrom of the primary fuel whereby the ratio of fuel exhaust entrained by the primary fuel in each jet pump is consequently varied. With the plurality of fuel cell assemblies, a respective mass flow control device may be provided in each primary fuel line upstream of the associated jet pump for controlling the primary fuel flow rate to said jet pump. Alternatively, the respective primary fuel lines may branch from a common primary fuel line with the mass flow control device being disposed in the common primary fuel line. Correspondingly, when the fuel cell system includes a plurality of fuel cell assemblies, each with a respective jet pump for recycling fuel exhaust to the respective assembly, an advantageous method feature of the invention is to individually adjust the cross-sectional area of each jet pump nozzle to vary the cross-section of the primary fuel stream therethrough and thereby independently adjust the ratio of fuel exhaust in the mixed flow of primary fuel and fuel exhaust delivered to the respective fuel cell assembly. The fuel exhaust is preferably recycled from the respective fuel cell assembly, but it may be mixed with fuel exhaust from one or more other fuel cell assemblies with the mixed fuel exhaust being recycled to all of those fuel cell assemblies. Preferably, the or each fuel cell assembly comprises a plurality of fuel cell stacks, most preferably each comprising a plurality of solid oxide fuel cells with each adjacent pair of fuel cells being separated by a gas separator plate. Advantageously, each of a plurality of jet pumps associated with respective fuel cell assemblies is supplied with primary fuel from a common source. Without variation of the primary fuel flow rate, differential adjustment of the jet pumps will act to apportion the primary fuel flow between them. Any adjustment of a jet pump nozzle cross-sectional area will cause change to the flow resistance in that jet pump and, when the pressure drop over each jet pump is the same, the primary fuel flow will vary between each jet pump proportionally. |
Use of cyclopeta[g]quinazoline derivatives for treating cancer |
Cyclopenta[g]quinazolines of the formula (I): wherein; A is hydrogen or a group OR or NR0R1 wherein R0 and R1 are each independently hydrogen C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, C2-4 hydroxyalkyl, C1-4 halogenoalkyl or C1-4 cyanoalkyl, or R0 and R1 together with the intermediate N form a five- or six-membered heterocyclic ring, p is an integer in the range 1 to 4; R2 is hydrogen, C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, C2-4 hydroxyalkyl, C2-4 halogenoalkyl or C1-4 cyanoalkyl; Ar1 is phenylene, thiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediy which may optionally bear one or two subtituents selected from halogeno, hydroxy, amino, nitro, cyano, trifluoromethyl, C1-4 alkyl and C1-4 alkoxy; and R3 is a group the following formula: (II) and pharmaceutically acceptable salts or calers may be used in the treatment of solid tumours. |
1. Use of a cyclopenta[g]quinazoline of the formula (I): wherein: A is hydrogen or a group OR0 or NR0R1 wherein R0 and R1 are each independently hydrogen, C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, C2-4 hydroxyalkyl, C2-4 halogenoalkyl or C1-4 cyanoalkyl, or R0 and R1 together with the intermediate N form a five- or six-membered heterocyclic ring; p is an integer in the range 1 to 4; R2 is hydrogen, C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, C2-4 hydroxyalkyl, C2-4 halogenoalkyl or C1-4 cyanoalkyl; Ar1 is phenylene, thiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediyl which may optionally bear one or two substituents selected from halogeno, hydroxy, amino, nitro, cyano, trifluoromethyl, C1-4 alkyl and C1-4 alkoxy; and R3 is a group of the formula: —A5—CON(R)CH(Y4)Y5 in which A5 is a C1-6 alkylene group and R is hydrogen, C1-4 alkyl, C3-4 alkenyl or C3-4 alkynyl; Y4 is carboxy, tetrazol-5-yl, N-(C1-4 alkylsulfonyl)carbamoyl, N-(phenylsulfonyl)-carbamoyl which may optionally bear one or two substituents on the phenyl ring selected from the group consisting of halogeno, nitro, C1-4 alkyl and C1-4 alkoxy, tetrazol-5-ylthio, tetrazol-5-ylsulfinyl or tetrazol-5-ylsulfonyl; and Y5 is the residue of a naturally occurring amino acid NH2CH(CO2 H)Y5; or Y5 is a group of the formula: —A4—CO2 H in which A4 is a C2-6 alkylene group; or Y5 is a group of the formula: —A6—Ar3—A7—Y6 in which A6 is a bond between the α-carbon atom of the group —A5—CON(R)CH(Y4)— and Ar3 or is a C1-2 alkylene group; Ar3 is phenylene, tetrazolediyl, thiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediyl which in the case of phenylene may optionally bear one or two substituents on the ring selected from halogeno, nitro, C1-4 alkyl and C1-4 alkoxy; A7 is a C1-3 alkylene or C2-3 alkenylene group; and Y6 is carboxy, tetrazol-5-yl, N-(C1-4 alkylsulfonyl)carbamoyl, N-(phenylsulfonyl)carbamoyl which may optionally bear one or two substituents on the phenyl ring selected from the group consisting of halogeno, nitro, C1-4 alkyl and C1-4 alkoxy, tetrazol-5-ylthio, tetrazol-5-ylsulfinyl or tetrazol-5-ylsulfonyl; the compound (I) optionally being in the form of a pharmaceutically acceptable salt or ester; for the manufacture of a medicament for the treatment of solid tumours. 2. Use as claimed in claim 1 wherein: R0 and R1 are each independently hydrogen or C1-4 alkyl; R2 is ethyl, propyl, prop-2-enyl, prop-2-ynyl, 2-hydroxyethyl, 2-fluoroethyl, 2-bromoethyl or 2-cyanoethyl; Ar1 is 1,4-phenylene which may optionally bear one or two substituents selected from the group consisting of chloro, fluoro, thiophene-2,5-diyl, thiazole-2,5-diyl or pyridine-2,5-diyl; A5 is an ethylene group; and Y5 is the residue of a naturally occurring amino acid NH2CH(CO2 H)Y5. 3. Use as claimed in claim 2 wherein: A is hydrogen or a group OR0 in which R0 is hydrogen or methyl; R2 is ethyl or prop-2-ynyl; and Ar1 is 1,4-phenylene or 1,4-phenylene having a 2-fluoro. 4. Use as claimed in claim 3 wherein R3 is the residue of an acid NH2.CH(COOH)R3 which comprises L-Glu-γ-D-Glu, i.e. N-L-γ-glutamyl-D-glutamic acid, or L-Glu-γ-L-Glu, i.e. N-L-γ-glutamyl-L-glutamic acid wherein R3 is of formula: R3 is the corresponding N-methyl derivative of formula: or R3 is the corresponding tetrazol-5-yl derivative of formula: 5. Use as claimed in claim 1 wherein p is 1. 6. Use as claimed in claim 1 wherein the cyclopenta[g]quinazoline of formula (I) comprises: N-{N-{4-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoyl}-L-γ-glutamyl}-D-glutamic acid; (4R)-4-{N-{N-{4-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]-quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoyl}-L-γ-glutamyl}amino}-4-(tetrazol-5-yl)-butyric acid; N-{N-{4-[N-((6RS)-2-methoxymethyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta-[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoyl}-L-γ-glutamyl}-D-glutamic acid; N-{N-{4-[N-((6RS)-2-hydroxymethyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta-[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoyl}-L-γ-glutamyl}-D-glutamic acid; or N-{N-{4-[N-((6RS)-2-hydroxymethyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]-quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoyl}-L-▭-glutamyl}-N-methyl-L-glutamic acid; or a pharmaceutically acceptable salt or ester thereof. 7. Use according to claim 1 wherein the cyclopenta[g]quinazoline of formula (I) is administered together with a pharmaceutically acceptable diluent or carrier. 8. Use according to claim 1 wherein the medicament is for use in the treatment of a carcinoma of ovarian origin. 9. A method for aiding regression and palliation of solid tumours in a patient in need of such treatment which comprises administering to said patient an effective amount of a cyclopenta[g]quinazoline according to claim 1. |
Methods and cell cultures for promoting organogenesis and tissue development |
Methods of promoting liver morphogenesis prior to the functioning of blood vessels by culturing liver cells with endothelial cells is provided. Also provided are cell cultures and method of promoting vasculogenesis of liver tissue by contacting liver cells with endothelial cells. |
1. A method of promoting liver morphogenesis prior to the functioning of blood vessels comprising culturing liver cells with endothelial cells at the air-gas interface on a Transwell membrane in culture medium to permit liver tissue morphogenesis. 2. A method of promoting liver morphogenesis prior to the functioning of blood vessels comprising culturing liver cells with endothelial cells to produce interactions which permit liver tissue morphogenesis. 3. The method of claim 1 wherein the liver cells are nascent liver cells. 4. The method of claim 1 wherein the liver cells are derived from stem cells. 5. A method of promoting vasculogenesis of liver tissue comprising maintaining contact of liver cells with endothelial cells to promote vascular development of liver tissue. 6. A method of promoting vessel formation among liver cells comprising culturing hepatic cells with human endothelial cells in a mixture of hepatic cell media and endothelial cell media to result in vessel formation. 7. A cell culture comprising hepatic cells and human endothelial cells in a mixture of hepatic cell media and endothelial cell media. 8. The method of claim 2 wherein the liver cells are nascent liver cells. 9. The method of claim 2 wherein the liver cells are derived from stem cells. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The mechanisms by which tissue morphogenesis initiates from the gut endoderm are not well defined. Although genetic methods have yet to provide much insight into hepatic specification and subsequent cell interactions, experiments with transplanted tissues have revealed more information. Hepatocytes develop from the endoderm lining the presumptive ventral foregut, near the developing heart. At about 9 days gestation in the mouse, foregut endoderm in contact with cardiac mesoderm proliferates more rapidly, and first α-fetoprotein (AFP) and then serum albumin mRNAs become detectable by in situ hybridization (Shiojiri et al. 1991 . Cancer Res. 51:2611-2620) By 9.5 days gestation, hepatic endodermal cells migrate into the more posterior mesenchyme of the septum transversum, where they begin to form the liver. Each tissue has its own architectural constraints on how the vascular system must integrate with functional aspects of an organ. To construct a vascular system that is specific for the needs of a particular organ, the development of the vascular system must be carefully coordinated with the development of the parenchymal cells. Assembly into a nascent organ may be regulated through interactions between parenchymal cells and vascular endothelial cells during organ morphogenesis. Understanding vascular development coordination with organogenesis will provide insights into future efforts to reconstitute organ systems for medical purposes and to generate tissue types in vitro for research, toxicological, and pharmaceutical applications. Despite the clear importance of understanding these principles, very little is known about the earliest steps of vasculogenesis during organ development. Vasculogenesis refers to the earliest stages of vascular development, during which vascular endothelial cell precursors undergo differentiation and coalesce to form a network of primitive tubules (Risau, W. 1997. Nature 386: 671-674). This initial lattice, consisting purely of endothelial cells, is then remodeled by a process referred to as angiogenesis (Risau, W. 1997. Nature 386: 671-674), which involves the sprouting, branching, and differential growth of blood vessels to form the more mature vasculatures seen in the adult organs. Angiogenic vascular development also involves the sprouting and penetration of vessels into previously avascular regions of the embryo (Folkman, J. and D'Amore, P. A. 1996. Cell 87:1153-1155; Lindahl, et al. 1997. Science 277: 242-245). Mechanisms of vascular development during organogenesis, particularly of the liver, are unknown and vasculogenesis, angiogenesis, or both may possibly be involved. It is known that close proximity to the cardiac mesoderm with the foregut endoderm causes the foregut endoderm to develop into the liver (LeDouarin, N. M. 1975, Med. Biol. 53, 427-455). This initial induction is accompanied by the activation of liver genes and enhanced proliferation of the newly specified hepatic cells (Gualdi et al. 1996; Jung et al. 1999). In a second step, these hepatic cells migrate and/or proliferate into the adjacent septum transversum, generating the liver bud. This morphogenetic transition, from hepatic endoderm to liver bud, represents the major defining moment in converting a simple epithelium to a complex structure that establishes the foundation for organogenesis. Although it is known that mesenchyme cells in the septum transversum promote this transition (LeDouarin, N. M. 1975. Med. Biol. 53, 427-455; Rossi, J. M., Dunn, N. R., Hogan, B. L. M., and Zaret, K. S. 2001, Genes Dev. 15:1998-2009) the potential role of other cell types is unknown. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides a method of promoting vasculogenesis of liver tissue by maintaining contact of liver cells with endothelial cells and early vascular structures to promote morphogenetic development of liver cells and liver tissue. The present invention further provides a method of promoting liver organogenesis prior to the functioning of blood vessels comprising culturing liver cells with endothelial cells. The present invention further provides cell cultures and methods for promoting vessel formation among liver cells using cell cultures comprising hepatic cells and human endothelial cells in a mixture of hepatic cell media and endothelial cell media. detailed-description description="Detailed Description" end="lead"? |
C-14 oxidation of morphine derivatives |
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