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Video/image communication with watermarking |
A video communication unit (405, 450) comprising a video input (415) for receiving a video signal transmission having a number of video or image frames, wherein each video or image frame includes a number of bit planes, the video input being operably coupled to a processor, the video communication unit characterised by said processor (410, 460) replicating at least one bit plane in at least two video or image frames to provide a tamper detection means of the video or image signal transmission. This enables fraudulent tampering of images and video to be detected, and the location of such tampering to be revealed to users of the material. |
1. A video communication unit comprising a video input for receiving a video or image signal transmission having a number of video or image frames, wherein each video or image frame includes a number of bit planes, the video input being operably coupled to a processor, the video communication unit characterised by said processor replicating at least one bit plane in at least two received video or image frames to provide a means of tamper detection of the video or image signal transmission. 2. The video communication unit according to claim 1, wherein replication of at least one bit plane in subsequent video or image frames is made in consecutive video or image frames. 3. The video communication unit according to claim 1, wherein replication of at least one bit plane includes replicating a less significant bit plane of a previous frame in a more significant bit plane of a current frame. 4. The video communication unit according to claim 1, wherein replication of at least one bit plane is repeated throughout the video or image signal transmission. 5. The video communication unit according to claim 1, wherein replication of at least one bit plane includes replication of a subset of pixels within a frame. 6. The video communication unit according to claim 1, wherein the watermark is applied to at least one of the following image formats: YCbCr, RGB, or any single component of an image format. 7. The video communication unit according to claim 1, wherein a watermark is applied in a restricted area or region of an image, or throughout the entire image. 8. A video transmission system comprising a video communication unit comprising a video input for receiving a video or image signal transmission having a number of video or image frames, wherein each video or image frame includes a number of bit planes, the video input being operably coupled to a processor, the video communication unit characterised by said processor replicating at least one bit plane in at least two received video or image frames to provide a means of tamper detection of the video or image signal transmission. 9. A mobile radio device comprising a video communication unit comprising a video input for receiving a video or image signal transmission having a number of video or image frames, wherein each video or image frame includes a number of bit planes, the video input being operably coupled to a processor, the video communication unit characterised by said processor replicating at least one bit plane in at least two received video or image frames to provide a means of tamper detection of the video or image signal transmission. 10. A video communication unit, comprising a video receiver adapted for receiving, from a transmitting video communication unit according to claim 1, a watermarked video signal transmission having a number of video or image frames, wherein each video or image frame includes a number of bit planes, the receiver being operably coupled to a processor, the video communication unit characterised by said processor comparing at least one bit plane of at least two subsequent video or image frames to detect any tampering of the watermark. 11. The video communication unit according to claim 10, further characterised by said processor locating a spatial and temporal position of the tampering as the video signal is being played by the video communication unit. 12. The video communication unit according to claim 11, further characterised by said processor determining a frame position of the tampered frame by comparing an appropriate bit plane of a current frame to an expected matching bit plane of a previous frame, wherein: if said comparison shows equal bit planes, no tampering has occurred; or if said comparison shows unequal bit planes, a further comparison is made between the current frame and the next frame such that: if said comparison shows equal bit planes the tampering occurred in the previous frame; or if said comparison shows unequal bit planes, the tampering occurred in the current frame. 13. A video communication unit according to claim 6, the video communication unit comprising a processor that detects tampering of an area of an image, the video communication unit characterised by said processor visually labelling, upon detection of said tampering, said area to inform a user viewing the image or video of said tampering. 14. The video communication unit according to claim 13, wherein said visual labelling includes replacing any or all of said tampered image or video with a known value such that said tampering is visible, for example black, white, any saturated colour, and/or any non-natural colour. 15. The video communication unit according to claim 13, wherein said visual labelling includes altering only a coloured appearance of a tampered pixel such that an underlying image content remains visible but said tampered area is marked. 16. The video communication unit according to claim 13, wherein said visual labelling includes replacing one component of a tampered pixel with a known value in an image format comprising more than one component. 17. The video communication unit according to claim 13, wherein a complete frame is visually labelled when any pixel within said frame is detected as having been tampered with. 18. The video communication unit according to claim 17, wherein said complete frame and all subsequent frames in a video sequence within and following a frame in which any pixel is detected as having been tampered with are visually labelled. 19. The video communication unit according to claim 10, wherein the watermark is applied to at least one of the following image formats: YCbCr, RGB, or any single component of an image format. 20. The video communication unit according to claim 10, wherein a watermark is applied in a restricted area or region of an image, or throughout the entire image. 21. A video transmission system comprising a video communication unit comprising a video receiver adapted for receiving, from a transmitting video communication unit according to claim 10, a watermarked video signal transmission having a number of video or image frames, wherein each video or image frame includes a number of bit planes, the receiver being operably coupled to a processor, the video communication unit characterised by said processor comparing at least one bit plane of at least two subsequent video or image frames to detect any tampering of the watermark. 22. A mobile radio device comprising a video communication unit comprising a video receiver adapted for receiving, from a transmitting video communication unit according to claim 10, a watermarked video signal transmission having a number of video or image frames, wherein each video or image frame includes a number of bit planes, the receiver being operably coupled to a processor, the video communication unit characterised by said processor comparing at least one bit plane of at least two subsequent video or image frames to detect any tampering of the watermark. 23. The mobile radio device of claim 22, wherein the mobile radio device is a mobile phone, a portable or mobile PMR radio, a personal digital assistant, a lap-top computer or a wirelessly networked PC. 24. A method of watermarking a video signal transmission in a video transmission system, the method comprising the step of: receiving a video or image signal transmission having a number of video or image frames, wherein each video or image frame includes a number of bit planes; the method characterised by the step of: replicating at least one bit plane in a subsequent video or image frame to provide a means of tamper detection of the video or image signal transmission. 25. A method of watermarking a video signal transmission according to claim 24, wherein the step of replicating includes replicating at least one bit plane in a subsequent consecutive video or image frame. 26. A method of watermarking a video signal transmission according to claim 25, wherein the step of replicating includes replicating a less significant bit plane of a previous frame to a more significant bit plane of a current frame. 27. The method of watermarking a video signal transmission according to claim 24, wherein the step of replicating is repeated throughout the video or image signal transmission. 28. The method of watermarking a video signal transmission according to claim 24, wherein the step of replicating includes replicating a subset of pixels within a frame. 29. A method of detecting tampering of a watermarked image, the method comprising the step of receiving a watermarked image having a number of video or image frames, wherein each video or image frame includes a number of bit planes, at least one of which is watermarked in accordance with the method of claim 20, the method characterised by the steps of: extracting said watermarked bit plane from a previous frame; and comparing said at least one watermarked bit plane in at least two subsequent video or image frames to detect any tampering of the watermark. 30. The method of detecting tampering of a watermarked image according to claim 29, wherein the step of comparing includes comparing a bit plane on a previous frame with a different bit plane on the current frame on a pixel-by-pixel basis. 31. The method of detecting tampering of a watermarked image according to claim 29, the method further characterised by the steps of: determining a frame position of the tampered frame by comparing an appropriate bit plane of the current frame to an expected matching bit plane of the previous frame, wherein: if said comparison shows equal bit planes, no tampering has occurred; or if said comparison shows unequal bit planes, the method is further characterised by the step of: making a further comparison between the current frame and the next frame such that: if said comparison shows equal bit planes the tampering occurred in the previous frame; or if said comparison shows unequal bit planes, the tampering occurred in the current frame. 32. A method of visually labelling a video or image transmission containing an attacked watermark, the method comprising the steps of: (i) detecting tampering of an area of an image of a received image or video transmission, using the method of detecting tampering of a watermarked image of claim 25; and (ii) visually labelling said area to inform a user viewing the video of said tampering of said received image or video transmission. 33. A method of visually labelling a video or image transmission according to claim 32, the method further characterised by the step of: altering a coloured appearance of a tampered pixel to inform a user viewing the video or image transmission of said tampering. 34. The method of visually labelling a video or image transmission according to claim 33, wherein said visually labelling step includes the step of: replacing any or all of a tampered image with a known value such that tampering is visible, for example black, white, any saturated colour, and/or any non-natural colour. 35. The method of visually labelling a video or image transmission according to claim 33, wherein said visually labelling step includes the step of altering only a coloured appearance of a tampered pixel such that an underlying image content remains visible but the tampering is marked. 36. The method of visually labelling a video or image transmission according to claim 33, wherein said visually labelling step includes the step of: replacing one component of a tampered pixel with a known value in an image format comprising more than one component. 37. The method of visually labelling a video or image transmission according to claim 33, wherein said visually labelling step includes the step of: visually labelling a complete image frame within which any pixel is detected as having been tampered with. 38. A storage medium storing processor-implementable instructions for controlling one or more processors to carry out a method of watermarking a video signal transmission in a video transmission system, the method comprising the step of: receiving a video or image signal transmission having a number of video or image frames, wherein each video or image frame includes a number of bit planes; the method characterised by the step of: replicating at least one bit plane in a subsequent video or image frame to provide a means of tamper detection of the video or image signal transmission. 39. A storage medium storing processor-implementable instructions for controlling one or more processors to carry out a method of detecting tampering of a watermarked image, the method comprising the step of receiving a watermarked image having a number of video or image frames, wherein each video or image frame includes a number of bit planes, at least one of which is watermarked in accordance with the method of claim 20, the method characterised by the steps of: extracting said watermarked bit plane from a previous frame; and comparing said at least one watermarked bit plane in at least two subsequent video or image frames to detect any tampering of the watermark. 40. A storage medium storing processor-implementable instructions for controlling one or more processors to carry out a method of visually labelling a video or image transmission containing an attacked watermark, the method comprising the steps of: (i) detecting tampering of an area of an image of a received image or video transmission, using the method of detecting tampering of a watermarked image of claim 25; and (ii) visually labelling said area to inform a user viewing the video of said tampering of said received image or video transmission. 41. A video communication unit adapted to perform a method of watermarking a video signal transmission in a video transmission system, the method comprising the step of: receiving a video or image signal transmission having a number of video or image frames, wherein each video or image frame includes a number of bit planes; the method characterised by the step of: replicating at least one bit plane in a subsequent video or image frame to provide a means of tamper detection of the video or image signal transmission. 42. A video communication unit adapted to perform a method of detecting tampering of a watermarked image, the method comprising the step of receiving a watermarked image having a number of video or image frames, wherein each video or image frame includes a number of bit planes, at least one of which is watermarked in accordance with the method of claim 20, the method characterised by the steps of: extracting said watermarked bit plane from a previous frame; and comparing said at least one watermarked bit plane in at least two subsequent video or image frames to detect any tampering of the watermark. 43. A video communication unit adapted to perform a method of visually labelling a video or image transmission containing an attacked watermark, the method comprising the steps of: (i) detecting tampering of an area of an image of a received image or video transmission, using the method of detecting tampering of a watermarked image of any of claim 25; and (ii) visually labelling said area to inform a user viewing the video of said tampering of said received image or video transmission. 44. A mobile radio device comprising a video communication unit in accordance with claim 35. 45. The mobile radio device of claim 36, wherein the mobile radio device is a mobile phone, a portable or mobile PMR radio, a personal digital assistant, a lap-top computer or a wirelessly networked PC. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The ability to transmit real-time video and/or image data is a desirable characteristic of many current wireline and wireless communication systems. However, it is known that individual images/pictures, or a series of images say, in a transmitted video stream, may be subjected to ‘attacks’, i.e. the images may have been tampered with. Therefore, a need exists to protect image or video transmissions from such undesirable tampering. One known technique employed to protect still/video images or documents is by the use of “watermarks”. In the context of the present invention, the terms ‘video’ and ‘image’ are used interchangeably, with the term ‘video’ generally used to represent one or more still images. Wolfgang R, Podilchuk C, Delp E “Perceptual watermarks for digital images and video”, SPIE Conference on Security and Watermarking of Multimedia Content, January 1999 , describes some state of the art watermarking methods for use with video and images. Protection of digital media (including image and video) has also become a key standardisation topic within the multimedia industry over the last year. Police users have formally stated that they do not envisage using digitally transmitted and processed images for evidential purposes without the existence of reliable tamper detection methods. The European Broadcasting Union has issued a second call for systems that offer watermarking of multimedia transmissions for entertainment applications. In addition, the International Standards Organisation (ISO) has set up a working group known as MPEG-21, whose essential function is to investigate digital rights management including the authentication of multimedia data. In image watermarking, a known binary pattern or signature is embedded into an image at the moment of image acquisition. Such watermarks are termed “robust”, because they are designed to remain intact regardless of any post-processing of the image such as filtering, cropping, etc. While such watermarks do provide a useful degree of protection, they cannot at present be wholly relied on in a court of law. The purpose of these watermarking methods is such that they are not designed to possess the required degree of surety that an image has not been tampered with, in order for the image to be used as evidence. Thus, there exists a need in the field of the present invention to provide a video communication unit and methods, based on a watermarking system, that can be used for testing a video sequence for evidence of tampering, wherein the abovementioned disadvantages may be alleviated. Furthermore, there exists a need for a labelling method to highlight areas of a video sequence that are detected as having been tampered with. Additionally, it would be beneficial to visually label tampered video sequences such that they are rendered unusable, or valueless, to the attacker. Published prior art documents include: (i) U.S. Pat. No. 5,875,249 (Mintzer et al.); (ii) ‘Digital watermarking through quasi m-arrays’, YEH et al., IEEE conference proceedings 29 Nov. 1999, pages 459-461; (iii) ‘A digital watermark’, OSBORNE et al., IEEE conference proceedings 13-16 Nov. 1994, pages 86-90. Statement of Invention The present invention provides video communication units, a video transmission system adapted to use one of the video communication units, a mobile radio device, a method of watermarking a video signal transmission in a video transmission system, a method of detecting tampering of a watermarked digital image, a method of visually labelling a video sequence that contains an attacked watermark, a storage medium storing processor-implementable instructions for controlling a processor to carry out any of the methods of the invention, a video communication unit adapted to perform any of the methods of the invention, a mobile radio device, all as claimed in the appended independent claims. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>Exemplary embodiments of the present invention will now be described, with reference to the accompanying drawings, in which: FIG. 1 shows a watermark embedding method, in accordance with the preferred embodiment of the invention. FIG. 2 shows a method of detecting frames that have been tampered with, in accordance with the preferred embodiment of the invention. FIG. 3 shows a flowchart of a decision process for determining whether tampering has occurred, in accordance with the preferred embodiment of the invention. FIG. 4 shows a block diagram of a video communication system incorporating a communication unit embedding a watermark, and a communication unit detecting a watermark, in accordance with the preferred embodiment of the invention. detailed-description description="Detailed Description" end="lead"? |
Communications method, apparatus and signal |
In a system (e.g. a IR or RF based wireless remote control system) comprising a number (N) of non-synchronized transmitters that transmit respective signals, a method of transmitting data in packets to a receiver, comprising the steps of: transmitting the respective signals, said signals having repeated burst periods that are separated by quiescent periods and repeated with mutually different repetition period, wherein the burst periods have substantially the same length, BL, and each burst period comprises a data packet. The method is characterized in that (I) where N denotes the number of transmitters, n is an index denoting a respective one of the N transmitters, RPn is the repetition period for a transmitter with index n, and BL is the length of the burst periods. |
1. In a system comprising a number (N) of non-synchronized transmitters that transmit respective signals, a method of transmitting data in packets to a receiver, comprising the steps of: transmitting the respective signals, said signals having repeated burst periods that are separated by quiescent periods and repeated with mutually different repetition periods, wherein the burst periods have substantially the same length, BL, and each burst period comprises a data packet; and wherein the repetition periods, RPn, are configured such that a succession of at most N−1 transmissions interfere with other of the respective signals; characterized in that: 2·N≦RPn/BL<2·[(N−1)2+n] where N denotes the number of transmitters, n is an index denoting a respective one of the N transmitters, RPn is the repetition period for a transmitter with index n, and BL is the length of the burst periods. 2. A method according to claim 1, wherein RPn/BL<2·[(N−1)2+n]−Dn where 1<Dn. 3. A method according to claim 1 wherein D=N−n/2±5% of RPn. 4. A method according to, claim 1, wherein repetition rates of respective signals have a mutual difference equal to or greater than two times the duration of a burst period. 5. A method according to, claim 1, wherein the respective repetition rates mutually fulfills the criterion that they are approximately equal to the length of a burst period times two times respective mutually prime numbers that are equal to or larger than the number of transmitters. 6. A method according to, claim 1, wherein the duration of a data packet is less than or equal to the duration of a burst period. 7. A method according to, claim 1, wherein the bursts comprise a fixed number of data bits repeated at a bit repetition rate, and the burst repetition period is generated from the bit repetition rate as an integer number of data bits per burst. 8. A method according to, claim 1, wherein the burst period is comprised of a data packet and an idle period in which no data are transmitted. 9. A method according to, claim 1, further comprising the step of encoding data packets of the respective signal with control data, an identity code and a check code. 10. A method according to claim 9, further comprising the steps of: receiving a respective signal; determining the identity of a transmitter by examining the identity code; and determining whether the signal is valid by examining the check code. 11. A method according to, claim 1, further comprising the step of receiving a data packet and taking the data packet as a valid data packet only if no data are received during the idle period. 12. A method according to claim 11, wherein the idle period has a length equal to or larger than a data item, wherein said data item is further composed of an opening portion, a data portion, and a closing portion. 13. A method according to, claim 1, further comprising the step of encoding digital values of block of two or more data bits, to be transmitted, by transmitting two consecutive pulses with a temporal distance, selected from a set of distances, each of which is associated with a digital value. 14. A method according to, claim 1, wherein the signals are transmitted by means of infrared light. 15. A method according to claim 1, claim 1, wherein the signals are transmitted by means of a radio frequency carrier. 16. A remote control unit having means for transmitting a respective signal. using a method according to claim 1. 17. A remote-controlled unit having means for receiving a respective signal. of the type disclosed by claim 1. 18. A signal with repetitive bursts separated by quiescent periods as disclosed in claim 1. |
Immortalization of human cells by the ectopic expression of human telomerase reverse transcriptase |
Immortalized primary adult and fetal human cells are provided that express a functional telomerase catalytic subunit from a nucleic acid sequence encoding the hTERT gene. The telomerase-immortalized human cells can be maintained in culture for at least 35 population doublings without developing a transformed phenotype, and while continuing to express proteins associated with the primary differentiated cell type. The invention is also directed to immortalized, non-transformed cell lines derived from primary human cells that express a functional telomerase catalytic subunit and to their use for transplantation to patients with hepatic disease. The invention also is directed to an improved biologic extracorporeal liver support device wherein the improvement is the use of telomerase-immortalized hepatocytes incorporated onto the scaffolding of the cell colonization chamber and use of the improved device for treating symptoms of patients with hepatic disease. |
1. An immortalized cell, wherein said cell comprises: a functional telomerase catalytic subunit, wherein said cell maintains at least one function specific to the cell type from which it was derived. 2. The immortalized cell according to claim 1, wherein said functional telomerase catalytic subunit is encoded by a human TERT gene. 3. The immortalized cell according to claim 1, wherein said cell is a transplantable cell. 4. The immortalized cell according to claim 3, wherein said cell is a hepatocyte or a pancreatic cell. 5. The immortalized cell according to claim 4, wherein said cell is a fetal cell. 6. The immortalized fetal cell according to claim 5, wherein % aid cell is transduced with a retrovirus. 7. The immortalized cell according to claim 4, wherein said cell is a hepatocyte and said function is (a) expression of one or more protein selected from the group consisting of albumin, α-fetoprotein, α1-antitrypsin, transferrin, HGF, TGFα, TGFβ1, TGFβ2, HGFR, EGFR, TGFβ1R, TGFβ2R, FGFR, IGF-1R, HNF1α, HNF1β, HNF3β, HNF4, C/EBPα, C/EBPβ, GAPDH; (b) inducibility of cytochrome P450 2E1 and (c) ureagenesis. 8. The immortalized cell according to claim 4, wherein said cell is a pancreatic cell and said function is expression of at least one protein selected from the group consisting of GLUT2, insulin, glucagon, and IDX-1. 9. A non-senescent, non-transformed immortalized human cell, wherein said cell has been cultured for at least about 35 population doublings. 10. An immortalized human cell according to claim 9, wherein said cell maintains a telomere length of at least about 6 kb. 11. A bioartificial organ comprising: a pluarility of said immortalized cell according to claim 1. 12. A method of obtaining an immortalized human cell, said method comprising the steps of: transducing a human cell with a nucleic acid encoding a functional telomerase catalytic subunit, whereby a transduced human cell is obtained; and growing said transduced human cell so that said nucleic acid is expressed, whereby an immortalized human cell is obtained that maintains at least one function specific to said human cell from which it was derived. 13. The method according to claim 12, wherein said human cell is a hepatocyte or a pancreatic cell. 14. The method according to claim 12 or claim 13, wherein said human cell is a fetal cell. 15. The method according to claim 12, wherein said fetal human cell is step of transducing is with a retrovirus. 16. A bioartificial organ comprising: a capsule and a plurality of said immortalized human cell according to claim 1. 17. A method of ameliorating at least one symptom of a metabolic disease in an individual in need thereof, said method comprising the step of: perfusing blood of said individual through a bioartificial organ according to claim 16, whereby at least one symptom is ameliorated. 18. A method of ameliorating at least one symptom of hepatic disease in an individual in need thereof, said method comprising the step of: transplanting to said individual a plurality of immortalized human hepatocytes that express a functional telomerase catalytic subunit and maintain at least one specific hepatic function, whereby at least one symptom of said hepatic disease is ameliorated. 19. An immortalized pancreatic cell comprising: a progenitor cell that expresses a functional telomerase catalytic subunit and maintains at least one specific pancreatic cell function. 20. The immortalized pancreatic cell according to claim 19, wherein said progenitor cell is derived from a nestin-positive islet cell. 21. The immortalized pancreatic cell according to claim 19, wherein said immortalized cell produces biologically active insulin. 22. The immortalized pancreatic cell according to claim 21, wherein said biologically active insulin is produced in response to glucose stimulation. 23. An immortalized pancreatic cell line comprising: a plurality of said immortalized pancreatic cell according to claim 22. 24. An immortalized pancreatic cell line comprising a plurality of said immortalized pancreatic cell according to claim 21. 25. A method of treating at least one symptom of diabetes in a patient in need thereof said method comprising: transplanting into said patient a plurality of said immortalized pancreatic cell according to claim 21. |
<SOH> INTRODUCTION <EOH>1. Field of the Invention The invention relates to primary adult or fetal human cells made immortal through expression of a functional telomerase catalytic subunit. The invention is exemplified by immortalization of human fetal pancreatic islet cells and fetal hepatocytes through transduction with a human gene encoding a human telomerase reverse transcriptase catalytic subunit. 2. Background Extracorporeal bioartificial organ support devices and cellular transplantation offer the possibility of effective treatment for many inherited and acquired organ disorders. Such therapeutic modalities could alleviate the crucial shortage of donor organs for whole organ transplantation. However, limited in vitro primary human cell proliferation has mandated that eeither less than adequate cell lines or animal cells be used for the development of extracorporeal organ support and cellular transplantation systems. Furthermore, the lack of donor organs or tissues makes it difficult to obtain enough viable human primary cells for the further advancement of cell-based transplantation therapies. Various culture systems have already been evaluated, for instance complex media supplemented with mitogens (Block et al. (1996) J Cell Biol 132 (6): 1133-49; Runge et al., (2000) Biochem Biophys Res Commun 269: 46-53), dimethyl sulfoxide supplementation (Cable and Isom (1997) Hepatology 26: 1444-57), collagen gel sandwich techniques (Kono et al., (1995) Exp Cell Res 221: 478-85), and co-culture systems with non-parenchymal cells (Rojkind et al., (1995) Am J Pathol 146 (6): 1508-20). Cancer-derived cell lines, (Aden et al., (1979) Nature 282: 615-6; Sussmann et al., (1992) Hepatology 16 (1): 60-65), provide an endless supply of cells but often lack important metabolic and synthetic properties due to genetic alterations and carry the risk of tumor seeding to the patient (Javitt (1990) FASEB J 4: 161-68, Nyberg et al., (1994) Ann Surg 220(1):59-67). One of the fundamental problems of in vitro primary cell propagation is that proliferation induces cellular dedifferentiation (i.e. specific functions associated with the differentiated cell are lost; for example, with cultured hepatocytes, the functions of albumin synthesis, cytochrome P450 oxidation, and ureagenesis are lost (Block, 1996, supra)). Non-human animal primary cells have the disadvantage that xenogenic proteins and enzymes enter the human blood circulation as well as posing a danger of xenozoonosis—the potential for transmission of animal virues, such as porcine viruses, including porcine endogenous retrovirus or hepatitis E virus (Patience et al., (1997) Nat Med 3(3):282-86, Meng et al., (1997) Proc Natl Acad Sci USA 94:9860-65). In addition, a small number of patients manifest a spontaneous cytotoxicity to animal derived cells such as porcine cells caused by natural xenoreactive IgM antibodies (Takahashi, et al. (1993) ASAIO J 39: M242-46). Another alternative is to immortalize human primary cells by genetic engineering. Currently, different immortalization techniques are being investigated, for instance the introduction of the Simian virus 40 large T-antigen (Kobayashi et al., (2000) Science 287: 1258-62, Nakamura et al., (1997) Transplantation 63 (11): 1541-47), transfection of antisense constructions against p53 and retinoblastoma protein (Werner et al., (2000) Biotechnol Bioeng 68 (1): 59-70), transgenic introduction of a truncated Met protein (Amicone et al., (1997) EMBO J. 16 (3): 495-503), and expression of a hepatitis C virus core protein (Ray et al., (2000) Virology 271: 197-204). Human cellular transplantation has been tried with varying degrees of success by several investigators. Most studies have employed the technique as a bridge to whole organ transplantation (see, for example, Mito, et al. (1993) Transplant 2: 65-74. Strom, et al. (1997) Transplant Proc 29: 2103-2106.). In several cases, the cellular transplantation has been associated with symptomatic improvement prior to organ transplantation. However, it is very difficult to assess whether the cellular transplantation was responsible for the improvements that occurred or whether the patients' native organs recovered and provided the improved function. A major issue in the human studies, as in the animal experiments, is the limited ability of most normal adult cells to proliferate and the limitation this creates when only a limited cell mass can be transplanted into a patient. In the circumstances of acute organ failure, an effective extracorporeal organ support system that provides the patient with a bridge to organ transplantation, would dramatically improve the chances of survival. A few bioartificial organ system s have been shown to be safe in clinical trials, but their efficacy has not been proven. It therefore is of interest do develop extracorporeal bioartificial liver support devices and cells for transplantation that retain differentiated cell function and long-term cell-division capacities and do not carry the dangers associated with transformation or xenogenic sources. Relevant Literature Totsugawa, et al. published abstract for a poster presentation (#43) at the 47th American Society for Artificial Internal Organs (ASAIO) annual conference (Jun. 7-9, 2001 in New York, N.Y.) reporting transduction of human hepatocytes with an adenoviral vector that expressed the hTERT gene. No details on the transduction are provided. Initial clinical trials using non-immortalized human hepatocytes to repopulate diseased livers and correct metabolic disease are discussed in Ng, et al. (2000) Clin Liver Dis, 4: 929-945. See also Gupta, et al. (1999) J Gene Med 1: 386-392. Bodnar, et al. report that expression of the human telomerase reverse transcriptase (hTERT) extends the life span of human fibroblasts and retinal pigment epithelial cells beyond senescence without causing neoplastic transformation (Science (1998) 279: 349-352). Yang, et al. disclose that introduction of the gene for hTERT into human large vessel and microvascular endothelial cells enables the cells to bypass replicative senescence without affecting their differentiation or causing the cells to exhibit a transformed phenotype (J Biol Chem (1999) 274: 26141-26148). Dickson, et al. disclose that human keratinocytes that express hTERT bypass a cell cycle checkpoint yet retain normal growth and differentiation characteristics (Mol Cell Biol 20: 1436-1447). Jiang, et al. report expression of the human telomerase catalytic component in human skin fibroblasts and retinal pigment epithelial cells, and that the cells retain normal growth control (Nature Genet (1999) 21: 111). |
<SOH> SUMMARY OF THE INVENTION <EOH>The subject invention is directed to cells that have been immortalized by transduction with nucleic acid encoding a functional telomerase catalytic subunit together with methods of making and using the immortalized cells. The method of making the immortalized cells includes the steps of transducing isolated cells with a nucleic acid encoding a functional telomerase catalytic subunit and then growing the transduced cells in culture so that a functional telomerase catalytic subunit is expressed. A biologic extracorporeal cell support apparatus or bioartificial organ also is provided which contains the telomerase-immortalized cells. Also provided are methods of using the device to provide extracorporeal organ function to an individual in need thereof, the method including the step of perfusing whole blood, plasma or ultrafiltrate from the individual through the cell colonization chamber. Methods of treating the symptoms of an organ related disease in an individual include use of the bioartificial organ or directly transplanting the immortalized cells into the individual. The invention finds use in organ transplantation and in bioartificial organ assist devices as well as in differentiation and drug metabolism studies. |
Wide band gap semiconductor composite detector plates for x-ray digital radiography |
An imaging composition for radiation detection systems which includes an admixture of at least one non-heat treated, non-ground particulate semiconductor with a polymeric binder. The non-heat treated, non-ground particulate semiconductor is selected from mercuric iodide, lead iodide, bismuth iodide, thallium bromide and cadmium-zinc-telluride (CZT), and at least 90% of the semiconductor particulates have a grain size of less than 100 microns in their largest dimension. A radiation detector plate (10) for an imaging system includes a substrate (12) which serves as an electrode, at least one imaging composition layer (16) applied onto the substrate (12), and a second electrode (18) which is in electrical connection with the imaging composition (16) and connected (20, 22) to a high voltage bias. |
1. An imaging composition for radiation detection systems which comprises an admixture of at least one non-heat treated, non-ground particulate semiconductor with a polymeric binder, said at least one non-heat treated, non-ground particulate semiconductor selected from a group consisting of mercuric iodide, lead iodide, bismuth iodide, thallium bromide and cadmium-zinc-telluride (CZT), and wherein at least 90% of said semiconductor particulates have a grain size of less than 100 microns in their largest dimension. 2. An imaging composition according to claim 1, which possesses at least one of the following features: (i) said polymeric binder is an organic polymeric binder; (ii) at least 90% of said semiconductor particulates have a grain size of less than 15 microns in their largest dimension; (iii) said composition further comprises at least one organic solvent; (iv) the weight ratio of said semiconductor particulates to said binder is from about 4.4:1 to about 26.0:1. 3. An imaging composition according to claim 2, which possesses at least one of the following features: (i) said organic polymeric binder comprises at least one polymer selected from a group consisting of polystyrene, polyurethane, alkyd polymers, cellulose polymers, and acrylic and vinyl polymers and co-polymers and mixtures thereof; (ii) at least 90% of said semiconductor particulates have a grain size of less than 10 microns in their largest dimension; (iii) said at least one organic solvent is selected from aliphatic alcohols, ethers, esters, ketones and aromatic and heterocyclic solvents; (iv) the weight ratio of said semiconductor particulates to said binder is from about 6.6:1 to about 19.8:1. 4. An imaging composition according to claim 2, which possesses at least one of the following features: (i) said organic polymeric binder comprises at least one polymer selected from a group consisting of polystyrene, polyurethane, and acrylic and vinyl homo- and co-polymers and mixtures thereof; (ii) at least 90% of said semiconductor particulates have a grain size of less than 5 microns in their largest dimension; (iii) said at least one organic solvent is selected from aliphatic alcohols, ethers, esters, ketones and aromatic and heterocyclic solvents; (iv) the weight ratio of said semiconductor particulates to said binder is from about 9:1 to about 15.4:1. 5. An imaging composition according to claim 1, wherein said semiconductor particulates are precipitated from a solution. 6. An imaging composition according to claim 5, wherein said solution has a solvent which is chosen from a group consisting of water, a non-aqueous solvent, a mixed aqueous-non-aqueous solvent and a mixed non-aqueous solvent. 7. A radiation detector plate for an imaging system including: at least one substrate, said substrate serving as an electrode; at least one imaging composition layer of an imaging composition applied onto said substrate, said composition including: at least one particulate semiconductor, said semiconductor comprising non-ground, non-heat treated particulates at least 90% of which are below 100 microns in their largest dimension and wherein said semiconductor is chosen from a group consisting of bismuth iodide, lead iodide, mercuric iodide, thallium bromide and cadmium-zinc-telluride (CZT); and a polymeric binder, said semiconductor particulates being in an admixture with said binder; and a second electrode, said second electrode in electrical connection with said composition and connected to a high voltage bias. 8. A radiation detector plate according to claim 7, which additionally comprises at least one composition layer comprising non-heat treated, non-ground particulate mercuric iodide in admixture with a polymeric binder. 9. A radiation detector plate according to claim 7, wherein said at least one composition layer comprises at least two semiconductors selected from a group consisting of bismuth iodide, lead iodide, mercuric iodide, thallium bromide and cadmium-zinc-telluride (CZT). 10. A radiation detector plate according to claim 7, wherein said at least one composition layer comprises at least two discrete composition layers, each of said discrete layers comprised of at least one semiconductor selected from a group consisting of bismuth iodide, lead iodide, mercuric iodide, thallium bromide and cadmium-zinc-telluride (CZT). 11. A radiation detector plate according to claim 10, further including an adhesive layer between said at least two discrete composition layers. 12. A radiation detector plate according to claim 10, wherein said at least two discrete composition layers comprise at least one discrete composition layer in which said semiconductor is non-heat treated, non-ground particulate lead iodide and at least one discrete composition layer in which said semiconductor is non-heat treated, non-ground particulate mercuric iodide. 13. A radiation detector plate according to claim 7, which further comprises an adhesive tie layer applied to said substrate. 14. A radiation detector plate according to claim 13, wherein said tie layer is chosen from a group consisting of polyacrylics, polyvinyls, polyurethanes, polyimides, cyanoacrylics, silanes, polyesters, and neoprene rubbers and mixtures thereof to bind said composition layer to said substrate. 15. A radiation detector plate according to claim 13, wherein said tie layer is a polyacrylic-polyvinyl mixture. 16. A radiation detector plate according to claim 13, wherein said tie layer is a silane. 17. A radiation detector plate according to claim 13, wherein said composition layer is applied onto said adhesive layer on the side of said adhesive layer distal from said substrate. 18. A radiation detector plate according to claim 7, wherein said at least one substrate is coated with a uniform, thin film of electrically conducting material selected from a group consisting of palladium, gold, platinum, indium-tin oxide (ITO) and germanium. 19. A radiation detector plate according to claim 7, wherein said second electrode comprises a uniform, thin film of electrically conducting material selected from a group consisting of carbon, palladium, gold, platinum, indium-tin oxide (ITO) and germanium. 20. A radiation detector plate according to claim 7, wherein said second electrode is applied by a method selected from a group consisting of sputtering, evaporation, spraying and painting. 21. A radiation detector plate according to claim 7, wherein said at least one substrate is chosen from a group consisting of a thin film transistor (TFT) flat panel array, a charge coupled device (CCD), complementary metal oxide semiconductor (CMOS) array and an application specific integrated circuit (ASIC). 22. A radiation detector plate according to claim 7, wherein said at least one composition layer possesses at least one of the following features: (i) said polymeric binder is an organic binder; (ii) at least 90% of said semiconductor particulates have a grain size of less than 15 microns in their largest dimension. 23. A radiation detector plate according to claim 22, wherein said at least one composition layer possesses at least one of the following features: (i) said organic polymeric binder comprises at least one polymer selected from a group consisting of polystyrene, polyurethane, alkyd polymers, cellulose polymers, and acrylic and vinyl homo- and co-polymers and mixtures thereof; (ii) at least 90% of said semiconductor particulates have a grain size of less than 10 microns in their largest dimension. 24. A radiation detector plate according to claim 22, wherein said at least one composition layer possesses at least one of the following features: (i) said organic polymeric binder comprises at least one polymer selected from a group consisting of polystyrene, polyurethane, and acrylic and vinyl homo- and co-polymers and mixtures thereof; (ii) at least 90% of said semiconductor particulates have a grain size of less than 5 microns in their largest dimension. 25. A radiation detector plate according to claim 7, wherein said at least one composition layer is prepared at room temperature. 26. A radiation detector plate according to claim 7, wherein said at least one composition layer is prepared at temperatures below 60° C. 27. A radiation detector plate according to claim 7, wherein said at least one composition layer has a thickness of 40-3000 microns. 28. A radiation detector plate according to claim 7, wherein said system can detect radiation in the 6 keV to 15 MeV range. 29. An image receptor for an imaging system, comprising at least one composition layer, said layer comprising an imaging composition as defined in claim 1, said composition layer positioned on a conductive substrate layer, said substrate layer forming a bottom electrode, and said composition layer covered by an upper conductive layer forming an upper electrode, wherein at least one of said conductive layers is provided with a plurality of conductive areas separated from each other by a plurality of non-conductive areas, and wherein a multiplicity of said conductive areas are individually, connected, via a charge-sensitive pre-amplifier, to an imaging electronic system. 30. An image receptor according to claim 29, which is further characterized by at least one of the following features: (i) said conductive areas are separated from each other by a dielectric material; (ii) said conductive substrate layer is covered with a uniform, thin film electrode layer selected from a group consisting of palladium, gold, platinum, indium-tin oxide (ITO) and germanium; (iii) said image receptor is adapted for use in an imaging system selected from X-ray and gamma ray imaging systems; (iv) in said at least one composition layer, said polymeric binder is an organic binder; (v) in said at least one composition layer, at least 90% of said semiconductor particulates have a grain size of less than 15 microns in their largest dimension; (vi) an adhesive tie layer between said composition layer and said bottom electrode, said tie layer chosen from a group consisting of polyacrylics, polyvinyls, polyurethanes, polyimides, cyanoacrylics, silanes, polyesters, and neoprene rubbers and mixtures thereof to bind said composition layer to said electrode. 31. An image receptor according to claim 30, wherein said at least one composition layer possesses at least one of the following features: (i) said organic polymeric binder comprises at least one polymer selected from a group consisting of polystyrene, polyurethane, alkyd polymers, cellulose polymers, and acrylic and vinyl homo- and co-polymers; (ii) at least 90% of said semiconductor particulates have a grain size of less than 10 microns in their largest dimension; (iii) comprises at least one polymer selected from a group consisting of polyurethane, polystyrene, and acrylic and vinyl homo- and co-polymers. 32. An image receptor according to claim 30, wherein said at least one composition layer possesses at least one of the following features: (i) said organic polymeric binder comprises at least one polymer selected from a group consisting of polystyrene, polyurethane, alkyd polymers, cellulose polymers, and acrylic and vinyl homo- and co-polymers; (ii) at least 90% of said semiconductor particulates have a grain size of less than 5 microns in their largest dimension; (iii) comprises at least one polymer selected from a group consisting of polyurethane, polystyrene, and acrylic and vinyl homo- and co-polymers. 33. An image receptor according to claim 29, which additionally comprises at least one composition layer comprising non-heat treated, non-ground particulate mercuric iodide in admixture with an organic polymeric binder. 34. An image receptor according to claim 29, wherein said at least one composition layer comprises at least two said semiconductors selected from bismuth iodide, lead iodide, mercuric iodide, thallium bromide and cadmium-zinc-telluride (CZT). 35. An image receptor according to claim 29, wherein said at least one composition layer comprises at least two discrete composition layers, each of said discrete layers comprised of at least one semiconductor selected from a group consisting of bismuth iodide, lead iodide, mercuric iodide, thallium bromide and cadmium-zinc-telluride (CZT). 36. An image receptor according to claim 35, further comprising an adhesive layer between said two discrete composition layers. 37. An image receptor according to claim 35, wherein said at least two discrete composition layers comprise at least one discrete composition layer where said semiconductor is non-heat treated, non-ground particulate lead iodide and at least one discrete composition layer where said semiconductor is non-heat treated, non-ground particulate mercuric iodide. 38. An image receptor according to claim 29, wherein said substrate is chosen from a group consisting of a thin film transistor (TFT) flat panel array, a charge coupled device (CCD), complementary metal oxide semiconductor (CMOS) array and an application specific integrated circuit (ASIC). 39. An image receptor according to claim 29, wherein said receptor is prepared at room temperature. 40. An image receptor according to claim 29, wherein said receptor is prepared at temperatures below 60° C. 41. An image receptor according to claim 29, wherein said receptor can image radiation from about 6 keV to about 15 MeV. 42. A method for preparing a radiation detector plate, said method including the steps of: providing a substrate; placing a semiconductor imaging composition onto said substrate thereby forming a composition layer, wherein the imaging composition comprises an admixture of at least one non-heat treated, non-ground particulate semiconductor with a polymeric binder, said at least one non-heat treated, non-ground particulate semiconductor selected from a group consisting of mercuric iodide, lead iodide, bismuth iodide, thallium bromide and cadmium-zinc-telluride (CZT), and wherein at least 90% of said semiconductor particulates have a grain size of less than 100 microns in their largest dimension: applying an electrode to said composition layer on the side distal from said substrate; and connecting a high voltage bias connection to said electrode. 43. A method for preparing a radiation detector plate according to claim 42, further comprising the step of applying an adhesive tie layer to said substrate prior to said placing step. 44. A method for preparing a radiation detector plate according to claim 42, wherein said placing step further comprises a step of die pressing said composition to form said composition layer. 45. A method for preparing a radiation detector plate according to claim 42, wherein said placing step further comprises a step of slot die coating said composition to form said composition layer. 46. A method for preparing a radiation detector plate according to claim 42, wherein said placing step further comprises a step of spreading said composition with a doctor blade to form said composition layer. 47. A method for preparing a radiation detector plate according to claim 42, wherein said placing step further comprises a step of spreading said composition with a Mayer rod to form said composition layer. 48. A method for preparing a radiation detector plate according to claim 42, wherein said placing step further includes the step of screen printing said composition to form said composition layer. 49. A method for preparing a radiation detector plate according to claim 42, wherein said placing step includes a series of placing steps each of said steps forming another composition layer. 50. A method for preparing a radiation detector plate according to claim 42, further comprising the step of depositing an electrically conductive material on said substrate before said placing step. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Lead iodide (Pbl 2 ), bismuth iodide (Bil 3 ), thallium bromide (TIBr) and mercuric iodide (Hgl 2 ), are well-known wide band gap semiconductors that exhibit properties which make them ideal for use in room temperature X-ray detection and imaging applications. These properties include a wide band gap (2.3, 2.2, 2.3 and 2.1 eV respectively), high atomic numbers Z, and low energy (below 5 eV) electron-hole pair formation. The wide energy band gap reduces the dark current at room temperature; the high atomic numbers permit good photon absorption and reduce radiation exposure; and the low energy for electron-hole pair formation produces a high X-ray-to-electrical charge ratio which conveys a high conversion coefficient. The use of mercuric iodide as single crystal X-ray detectors is known but limited to relatively small area detectors due to the high cost of producing large single crystals. Moreover, mercuric iodide crystals are produced from the vapor phase and large crystals require long periods of time for growth. Finally, the sawing and polishing of these crystals can result in the loss of a large percentage, even a major portion, of the crystal. For applications requiring large detection areas, such as detectors having areas in excess of 100 cm 2 , the use of polycrystalline mercuric iodide grains with their much lower production cost is very advantageous. Polycrystalline Hgl 2 and Pbl 2 have been used in X-ray detector plates. U.S. Pat. No. 5,892,227, (M. Schieber, et al.) incorporated herein by reference, describes methods for producing such plates from wide-band gap semiconductors by either direct evaporation of Hgl 2 and Pbl 2 , or in the case of Hgl 2 , by mixing the condensed iodide grains with a binder to form “composite imagers”. After deposition of the polycrystalline grains, the semiconductor is sintered to form a single, coherent, polycrystalline, continuous film. Up until now, the signal intensities obtained when converting x-rays to electrical signals are poorer for wide band gap semiconductor composite imagers than for physical vapor deposition (PVD) imagers of the same semiconductor. In some cases, the difference in electrical signals between composite and PVD imagers is almost two orders of magnitudes. Additionally, the equipment required to produce PVD imagers is large and costly. Furthermore, the substrates used with PVD coated detectors generally are required to be flat, even though for certain uses, such as non-destructive testing, curved substrates would be more desirable. A review of prior art polycrystalline Hgl 2 can be found in the following publications. R. Turchefta, et al., VLSI Readout for Imaging with Polycrvstalline Mercuric Iodide Detectors , Proceedings of the SPIE Conf., San Diego Calif., July 1998, edited by O. H. W. Siegmunds and M. A. Gummin, Vol. 3445, (1998) 356-363. R. Turchetta, et al., Imaging with Polycrystalline Mercuric Iodide Detectors using VLSI Readout , Proceedings of the Detector Workshop held at XIIth Int. Conf. Cryst. Growth, Jerusalem, Israel, July 1998, edited by R. B. James, L. Franks, P., Nucl. Inst. and Meth. A Vol. 428 (1999) 88 M. Schieber, et al, High flux X - ray response of composite mercuric iodide detectors , Hard Radiation SPIE, Denver, 1999, Vol. 3768 (1999) 296-309. M. Schieber, et al., Polycrystalline mercuric iodide detectors , Medical Imaging Proc., SPIE, Denver, 1999, Vol. 3770 (1999) 146-155. M. Schieber, et al. Polycrystalline mercuric iodide detectors , Medical Imaging Proc., SPIE, Denver, 1999, Vol. 3770 (1999) 146-155. R. Street, et al., High Resolution. Direct detection X - Ray Imagers , Proceedings of SPIE Vol. 3977 (2000) 418. M Schieber, et al., Radiological X - ray Response of Polycrystalline Mercuric Iodide Detectors , Proceedings of the SPIE Medical Imaging 2000 San Diego, Vol. 3977 (2000) 48. M. Schieber et al., Mercuric Iodide Thick Films for Radiological X - ray Detectors , Proceedings of the SPIE in Penetrating radiation, Vol 4142 (2000) 197. M. Schieber et al., Thick Films of X - ray Polycrystalline Mercuric Iodide Detectors , published in JCG (8-2000) A review of prior art polycrystalline lead iodide detectors can be found in the following publications and in the aforementioned patent. R. Street, et al., High Resolution. Direct Detection X - Ray Imagers , Proceedings of SPIE Vol. 3977 (2000) 418. R. Street, et al., X - ray Imaging using Lead Iodide as a Semiconductor Detector , Proceedings of SPIE, Vol. 3659 (1999), p. 36. R. Street, et al., Large Area X - Ray Image Sensing Using a Pbl 2 Photoconductor , Proceedings of SPIE Vol. 3336 (1998) 24. The films or crystals of lead iodide described in the above references were all prepared using vacuum sublimation, vacuum evaporation or other physical vapor deposition procedures. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention is directed toward producing wide band gap semiconductor particle-in-binder (PIB) composite detectors for X-ray digital imagers. The semiconductors discussed herein include, inter alia, Pbl2, Bil3, TIBr, Cd—Zn—Te (CZT) and Hgl2. The compositions, detectors and imaging systems prepared according to the present invention allow for better direct X-ray radiation-to-electrical signal conversion than prior art imagers. They also allow for the fabrication of detector plates and imagers with sensitivities close to the order of magnitude obtained by polycrystalline detector plates and imagers produced by PVD type processes. The materials and systems described herein permit the fabrication of low cost, large area imagers with high sensitivity. It should be noted that with respect to what is described herein as radiation detector plates, constructions other than planar constructions are contemplated. Therefore these radiation detector plates have at times been more generically described as radiation detection systems. These terms are to be construed as equivalent, both including planar and non-planar constructions. Similarly in what has been described herein, the terms particle, particulate and grain have been used interchangeably and should be deemed to be equivalents. In a like manner, particle size, particulate size and grain size are all deemed to be equivalents. In one aspect of the present invention, an imaging composition for radiation detection systems is described which comprises an admixture of one or more non-heat treated and non-ground particulate semiconductors with a polymeric binder. Ninety percent of the semiconductor particles have a grain size less than 100 microns in their largest dimension. Typically, the non-heat treated, and non-ground particulate semiconductor Is selected from a group consisting of mercuric iodide, lead iodide, bismuth iodide, thallium bromide and cadmium-zinc-telluride (CZT). In another aspect of the present invention a radiation detector plate is described which includes at least one substrate which serves as a bottom electrode. It also includes at least one composition layer prepared from an imaging composition which comprises an admixture of at least one non-heat treated, non-ground particulate semiconductor with a polymeric binder. At least ninety percent of the semiconductor particles in the detector plates have a grain size of less than 100 microns In their largest dimension. Typically, the semiconductor is chosen from a group consisting of bismuth iodide, lead iodide, mercuric iodide, thallium bromide and cadmium-zinc-telluride (CZT). The detector plate further includes an upper electrode which is in electrical connection with the composition layer and which is also connected to a high voltage bias. In a further aspect of the present invention, an image receptor for an imaging system is described. The receptor comprises at least one composition layer comprised as defined in the above described detector plate. The composition layer is positioned on a conductive substrate layer, which forms a bottom electrode. The composition layer is covered by an upper conductive layer, which forms an upper electrode. At least one of the conductive layers is provided with a plurality of conductive areas separated from each other by a plurality of non-conductive areas. A multiplicity of the conductive areas are individually connected, via a charge-sensitive pre-amplifier, to an imaging electronic system. Finally, in another aspect of the present invention, a method for preparing radiation detector plates is described. There is thus provided in accordance with the present invention, an imaging composition for radiation detection systems which comprises an admixture of one or more non-heat treated, and non-ground particulate semiconductor with a polymeric binder, wherein at least 90% of the semiconductor particles have a grain size less than 100 microns in their largest dimension. The non-heat treated, and non-ground particulate semiconductor is selected from a group consisting of mercuric iodide, lead iodide, bismuth iodide, thallium bromide and cadmium-zinc-telluride (CZT). In a preferred embodiment of the invention, the imaging composition possesses at least one of the following features: the polymeric binder is an organic polymeric binder; at least 90% of the semiconductor particles has a grain size of less than 15 microns in their largest dimension; the composition further comprises at least one organic solvent; the weight ratio of the semiconductor particulates to the binder is from about 4.4:1 to about 26.0:1. In another embodiment of the present invention, the imaging composition possesses at least one of the following features: the organic polymeric binder comprises at least one polymer selected from a group consisting of polystyrene, polyurethane, alkyd polymers, cellulose polymers, and acrylic and vinyl polymers and co-polymers and mixtures thereof; at least 90% of the semiconductor particles have a grain size of less than 10 microns in their largest dimension; the at least one organic solvent is selected from aliphatic alcohols, ethers, esters, ketones and aromatic and heterocyclic solvents; the weight ratio of the semiconductor particulates to the binder is from about 6.6:1 to about 19.8:1. In yet another embodiment, the imaging composition possesses at least one of the following features: the organic polymeric binder comprises one or more polymer selected from polystyrene, polyurethane, and acrylic and vinyl homo- and co-polymers and mixtures thereof; at least 90% of the semiconductor particles has a grain size of less than 5 microns in their largest dimension; the at least one organic solvent is selected from aliphatic alcohols, ethers, esters, ketones and aromatic and heterocyclic solvents; the weight ratio of the semiconductor particulates to the binder is from about 9:1 to about 15.4:1. In a further embodiment of the invention, the semiconductor particulates of the imaging composition are precipitated from a solution. The solution has a solvent which is chosen from a group consisting of water, a non-aqueous solvent, a mixed aqueous-non-aqueous solvent and a mixed non-aqueous solvent. Additionally there is provided in accordance with the present invention a radiation detector plate. The plate includes at least one substrate, which serves as an electrode. The detector plate further includes at least one imaging composition layer prepared from an imaging composition. The composition comprises an admixture of at least one non-heat treated, non-ground particulate semiconductor with a polymeric binder, with at least 90% of the semiconductor particles having a grain size of less than 100 microns in their largest dimension. The semiconductor is typically chosen from a group consisting of bismuth iodide, lead iodide, mercuric iodide, thallium bromide and cadmium-zinc-telluride (CZT). The composite layer is applied onto the substrate. The detector plate also includes a second electrode, which is in electrical connection with the composition layer and with a high voltage bias. In a further embodiment of the present invention, the radiation detector plate additionally comprises at least one composition layer comprising non-heat treated, non-ground particulate mercuric iodide in admixture with a polymeric binder. In another embodiment of the radiation detector plate, the at least one composition layer of the radiation detector plate comprises at least two semiconductors selected from a group consisting of bismuth iodide, lead iodide, mercuric iodide, thallium bromide and cadmium-zinc-telluride (CZT). Additionally, in an embodiment of the radiation detector plate, the at least one composition layer comprises at least two discrete composition layers, each of the discrete layers comprised of at least one semiconductor selected from a group consisting of bismuth iodide, lead iodide, mercuric iodide, thallium bromide and cadmium-zinc-telluride (CZT). In another embodiment, the detector plate further includes an adhesive layer between the discrete composition layers. In a preferred embodiment of the radiation detector plate, the at least two discrete composition layers comprise at least one discrete composition layer where the semiconductor is non-heat treated, non-ground particulate lead iodide and at least one discrete composition layer where the semiconductor is non-heat treated, non-ground particulate mercuric iodide. In another embodiment, the detector plate further includes an adhesive tie layer applied to the substrate, the adhesive chosen from a group consisting of polyacrylics, polyvinyls, polyurethanes, polyimides, cyanoacrylics, silanes, polyesters, and neoprene rubbers and mixtures thereof. In one embodiment the of the detector plate, the tie layer is a polyacrylic-polyvinyl mixture, while in another embodiment the tie layer is a silane. In a further embodiment of the detector plate, the substrate is coated with a uniform thin film of electrically conducting material selected from palladium, gold, platinum, indium-tin oxide and germanium. In yet another embodiment of the detector plate, the second electrode includes a uniform thin film of electrically conducting material selected from carbon, palladium, gold, platinum, indium-tin oxide and germanium. The second electrode can be applied by spraying, painting, sputtering and evaporation. In yet another embodiment of the detector plate, the one or more substrates is chosen from a group consisting of thin film transistor (TFT) flat panel array, a charge coupled device (CCD), complementary metal oxide semiconductor (CMOS) array and an application specific integrated circuit (ASIC). In a preferred embodiment of the radiation detector plate according to the present invention, the at least one composition layer possesses at least one of the following features: the polymeric binder is an organic binder; at least 90% of the semiconductor particles have a grain size of less than 15 microns in their largest dimension. In yet another embodiment of the radiation detector plate, the at least one composition layer possesses at least one of the following features: the organic polymeric binder comprises one or more polymers selected from polystyrene, polyurethane, alkyd polymers, cellulose polymers, and acrylic and vinyl homo- and co-polymers and mixtures thereof; at least 90% of the semiconductor particles have a grain size of less than 10 microns in their largest dimension. In another embodiment of the radiation detector plate, the at least one composition layer possesses at least one of the following features: the organic polymeric binder comprises at least one polymer selected from polystyrene, polyurethane, and acrylic and vinyl homo- and co-polymers and mixtures thereof; at least 90% of the semiconductor particles have a grain size of less than 5 microns in their largest dimension. Additionally, in an embodiment of the invention, the one or more composition layers of the detector plate is prepared at room temperature. In a further embodiment, the one or more composition layers of the detector plate is prepared at temperatures below 60° C. In an embodiment of the invention, the at least one composition layer of the detector plate has a thickness of 40-3000 microns. In another embodiment of the detector plate, the plate can detect radiation in the 6 keV to 15 MeV range. In another aspect of the present invention, there is also provided an image receptor for an imaging system. The receptor comprises at least one composition layer comprised of an imaging composition as described above. The composition layer is positioned on a conductive substrate layer, the substrate layer forming a bottom electrode. The composition layer is covered by an upper conductive layer, which forms an upper electrode. At least one of the conductive layers is provided with a plurality of conductive areas separated from each other by a plurality of non-conductive areas. A multiplicity of the conductive areas are individually connected, via a charge-sensitive pre-amplifier, to an imaging electronic system. In a preferred embodiment of the image receptor, the receptor is further characterized by at least one of the following features: the conductive areas are separated from each other by a dielectric material; the conductive substrate layer is covered with a uniform, thin film electrode layer selected from the group consisting of palladium, gold, platinum, indium-tin oxide (ITO) and germanium; the image receptor is adapted for use in an imaging system selected from X-ray and gamma ray imaging systems; in the at least one composition layer, the polymeric binder is an organic binder; in the at least one composition layer, at least 90% of the semiconductor particles have a grain size of less than 15 microns in their largest dimension; an adhesive tie layer between the composition layer and the bottom electrode, the tie layer chosen from a group consisting of polyacrylics, polyvinyls, polyurethanes, polyimides, cyanoacrylics, silanes, polyesters, and neoprene rubbers and mixtures thereof to bind the composition layer to the electrode. In another embodiment of the image receptor, the at least one composition layer possesses at least one of the following features: the organic polymeric binder comprises at least one polymer selected from polystyrene, polyurethane, alkyd polymers, cellulose polymers, and acrylic and vinyl homo- and co-polymers or mixtures thereof; at least 90% of the semiconductor particles have a grain size of less than 10 microns in their largest dimension. In another embodiment of the image receptor, the at least one composition layer possesses at least one of the following features: the organic polymeric binder comprises at least one polymer selected from polystyrene, polyurethane, alkyd polymers, cellulose polymers, and acrylic and vinyl homo- and co-polymers or mixtures thereof; at least 90% of the semiconductor particles have a grain size of less than 5 microns in their largest dimension. In a further embodiment of the image receptor, the receptor comprises additionally at least one composition layer comprising non-heat treated, non-ground particulate mercuric iodide in admixture with an organic polymeric binder. In yet another embodiment of the image receptor, the at least one composition layer comprises at least two semiconductors selected from a group consisting of bismuth iodide, lead iodide, mercuric iodide, thallium bromide and cadmium-zinc-telluride (CZT). In a further embodiment of the image receptor, the at least one composition layer comprises at least two discrete composition layers, each of the discrete layers comprised of at least one semiconductor selected from a group consisting of bismuth iodide, lead iodide, mercuric iodide, thallium bromide and cadmium-zinc-telluride (CZT). Additionally, in another preferred embodiment of the image receptor the at least two discrete composition layers comprise at least one discrete composition layer where the semiconductor is non-heat treated, non-ground particulate lead iodide and at least one discrete composition layer where the semiconductor is non-heat treated, non-ground particulate mercuric iodide. In yet another embodiment of the present invention, the image receptor further comprises an adhesive layer between the two discrete composition layers. In yet another embodiment of the image receptor, the substrate is chosen from a group consisting of a thin film transistor (TFT) flat panel array, a charge coupled device (CCD), a complementary metal oxide semiconductor (CMOS) array and an application specific integrated circuit (ASIC). In another embodiment of the receptor, the receptor is prepared at room temperature. In yet another embodiment of the receptor, the receptor is prepared at temperatures below 60° C. In another embodiment of the image receptor, the receptor can detect radiation in the 6 keV to 15 MeV range. Additionally, there is provided in accordance with the present invention a method for preparing a radiation detector plate, the method Including the steps of: providing a substrate; placing a semiconductor imaging composition onto the substrate, thereby forming a composition layer; applying an electrode to the composition layer on the side distal from the substrate; and connecting a high voltage bias connection to the electrode. In an embodiment of the invention, the above method for preparing a radiation detector plate further comprises the step of applying an adhesive tie layer to the substrate prior to the placing step. In an another embodiment of the method for preparing a radiation detector plate, the placing step further comprises a step of die pressing the composition to form the composition layer. In other embodiments of the method, the placing step further comprises a step of slot die coating the composition to form the composition layer; the placing step further comprises a step of spreading the composition with a doctor blade to form the composition layer; the placing step further comprises a step of spreading the composition with a Mayer rod to form the composition layer; the placing step further includes the step of screen printing the composition to form the composition layer. In yet another embodiment of the method, the placing step includes a series of placing steps each of the steps forming another composition layer. Finally in another embodiment of the method, the method further comprises the step of depositing an electrically conductive material on the substrate before the placing step. These and other objects, features, advantages and embodiments of the present invention will become apparent in light of the detailed description of the embodiments thereof, as illustrated in the accompanying drawings. |
Digital signal processing system and method for a telephony interface apparatus |
A signal processing method including the steps of: receiving a first audio signal; detecting the presence of one or more shrieks within an audible frequency range of said audio signal; creating one or more filters to selectively attenuate the respective one or more shrieks within the audible frequency range; filtering the audio signal using the one or more filters; and transmitting the filtered audio signal to an audio telephone device. |
1-55. (canceled). 56. A method of controlling the exposure of a listener to narrow-band signals in an audio signal including the steps of: periodically analysing the signal to determine the signal levels in particular frequency regions; detecting a narrow-band signal based on whether the ratio of the signal level in a particular frequency region to the signal level in nearby higher and lower frequency regions exceeds a pre-determined threshold; and in response to detection of a narrow-band signal, controlling the exposure of the listener to the detected narrow-band signal. 57. A method according to claim 56 wherein the periodic analyses of the signal are made at a frequency of about 125 Hz. 58. A method according to claim 56 wherein detection of a narrow-band signal is further based on whether the signal level in a particular frequency region exceeds a predetermined threshold. 59. A method according to claim 56 wherein detection of a narrow-band signal is further based on a comparison of the signal levels in particular frequency regions over a pre-determined number of periodic analyses. 60. A method according to claim 56 wherein detection of a narrow-band signal is further based on whether the frequency region in which the signal level exceeds the signal level in nearby higher and lower frequency regions does not change by more than a predetermined amount over a predetermined number of periodic analyses. 61. A method according to claim 59 wherein the predetermined number of periodic analyses is two. 62. A method according to claim 56 wherein the said nearby lower frequency region is not adjacent to the particular frequency region. 63. A method according to claim 62 wherein the said nearby lower frequency region lies within a range from 125 Hz to 375 Hz below the particular frequency region. 64. A method according to claim 56 wherein the said nearby higher frequency region is not adjacent to the particular frequency region. 65. A method according to claim 64 wherein the said nearby higher frequency region lies within a range from 125 Hz to 375 Hz above the particular frequency region. 66. A method according to claim 56 wherein the particular frequency regions lie within a range from 1 kHz to 4 kHz. 67. A method according to claim 56 further including the step of detecting additional narrow-band signals. 68. A method according to claim 67 wherein the audio signal is subdivided into a number of smaller frequency ranges and a narrow-band signal is detected in each of these ranges. 69. A method according to claim 67 wherein the frequency region of each identified narrow-band signal is stored to prevent those narrow-band signals from being detected again with the same periodic analysis. 70. A method according to claim 69 wherein the stored frequency regions are excluded from being used as the higher and lower frequency regions in the detection of narrow-band signals within the same periodic analysis. 71. A method according to claim 56 wherein the exposure of the listener is controlled by applying a filter to the signal, wherein the filter is arranged to attenuate the signal in the frequency range of a detected narrow-band signal. 72. A method according to claim 71 wherein the filter is applied for a predetermined time period. 73. A method according to claim 71 wherein the filter is applied by progressively increasing the degree of attenuation applied by the filter. 74. A method according to claim 71 wherein, following application of the filter, the degree of attenuation applied by the filter is progressively decreased. 75. A method according to claim 71 wherein the filter includes one or more band-reject filters having centre frequencies close to the centre frequency of the detected narrow-band signal. 76. A method according to claim 71 wherein the filter is an adaptive infinite impulse response filter. 77. A method according to claim 76 wherein each pole of the filter is paired with a zero located on the same radial axis on the z plane. 78. A method according to claim 76 wherein each pole of the filter has a fixed radius from the centre of the z plane and the radius of the zeros on the z-plane are progressively increased from the radial position of the poles towards the unit circle in proportion to the amount of attenuation specified. 79. A method according to claim 71 wherein a plurality of filters are applied to the audio signal. 80. A method according to claim 79 wherein the filters are applied in cascade. 81. A method according to claim 56 wherein the exposure of the listener is further controlled by attenuating the signal proportional to the amount by which its short-term level exceeds a given threshold. 82. A method according to claim 56 wherein the exposure of the listener is further controlled before the audio signal is reproduced by a transducer by being passed through a transducer specific filter being arranged to compensate for the frequency response of the transducer in combination with the ear to control the maximum sound pressure level presented to the ear of the listener. 83. A method according to claim 56 wherein the signal to which the listener is exposed is delayed relative to the analysis of the signal. 84. An apparatus for controlling the exposure of a listener to narrow-band signals in an audio signal including: analysing means to periodically analyse the signal to determine the signal levels in particular frequency regions; detection means arranged to detect a narrow-band signal based on whether the ratio of the signal level in a particular frequency region to the signal level in nearby higher and lower frequency regions exceeds a pre-determined threshold; and controlling means arranged to control the exposure of the listener in response to detection of a narrow-band signal. 85. An apparatus according to claim 84 wherein the analysing means is arranged to make periodic analyses of the signal at a frequency of about 125 Hz. 86. An apparatus according to claim 84 wherein the detection means is arranged to detect a narrow-band signal further based on whether the signal level in a particular frequency region exceeds a predetermined threshold. 87. An apparatus according to claim 84 wherein the detection means is arranged to detect a narrow-band signal further based on a comparison of the signal levels in the particular frequency regions over a pre-determined number of periodic analyses. 88. An apparatus according to claim 84 wherein the detection means is arranged to detect a narrow-band signal further based on whether the frequency region in which the signal level exceeds the signal level in nearby higher and lower frequency regions does not change by more than a predetermined amount over a predetermined number of periodic analyses. 89. As apparatus according to claim 87 wherein the predetermined number of periodic analyses is two. 90. An apparatus according, to claim 84 wherein the said nearby lower frequency region is not adjacent to the particular frequency region. 91. An apparatus according to claim 90 wherein the said nearby lower frequency region lies within a range from 125 Hz to 375 Hz below the particular frequency region. 92. An apparatus according to claim 84 wherein the said nearby higher frequency region is not adjacent to the particular frequency region. 93. A method according to claim 92 wherein the said nearby higher frequency region lies within a range from 125 Hz to 375 Hz above the particular frequency region. 94. An apparatus according to claim 84 wherein the particular frequency regions lie within a range from 1 kHz to 4 kHz. 95. An apparatus according to claim 84 wherein the detection means is arranged to detect additional narrow-band signals. 96. An apparatus according to claim 95 wherein the analysing means is arranged to subdivide the audio signal into a number of smaller frequency ranges and the detection means is arranged to detect a narrow-band signal in each of these ranges. 97. An apparatus according to claim 95 further including storage means arranged to store the frequency region of each identified narrow-band signal. 98. An apparatus according to claim 84 wherein the controlling means includes a filter arranged to attenuate the signal in the frequency range of a detected narrow-band signal. 99. An apparatus according to claim 98 wherein the filter is arranged to be applied for a predetermined time period. 100. An apparatus according to claim 98 wherein the filter is arranged to be applied progressively increasing the degree of attenuation applied by the filter. 101. An apparatus according to claim 98 wherein, following application of the filter, the filter is arranged to progressively decrease the degree of attenuation applied by the filter. 102. An apparatus according to claim 98 wherein the filter includes one or more band-reject filters having centre frequencies close to the centre frequency of a detected narrow-band signal. 103. An apparatus according to claim 98 wherein the filter is an adaptive infinite impulse response filter. 104. An apparatus according to claim 103 wherein each pole of the filter is paired with a zero located on the same radial axis on the z plane. 105. An apparatus according to claim 103 wherein each pole of the filter has a fixed radius from the centre of the z plane and the radius of the zeros on the z-plane are progressively increased from the radial position of the poles towards the unit circle in proportion to the amount of attenuation specified. 106. An apparatus according to claim 98 including a plurality of filters which are arranged to be applied to the audio signal. 107. An apparatus according to claim 106 wherein the filters are arranged to be applied in cascade. 108. An apparatus according to claim 84 wherein the controlling means is further arranged to control the exposure of the listener by attenuating the signal proportional to the amount by which its short-term level exceeds a predefined threshold. 109. An apparatus to claim 84 wherein the controlling means is further arranged to control the exposure of the listener before the audio signal is reproduced by a transducer by passing the signal through a transducer specific filter being arranged to compensate for the frequency response of the transducer in combination with the ear to control the maximum sound pressure level presented to the ear of the listener. 110. An apparatus according to claim 84 further including delay means arranged to delay the signal so that the signal to which the listener is exposed is delayed relative to the analysis of the signal. |
<SOH> BACKGROUND <EOH>Occasionally, intense, unwanted signals accidentally occur within the telephone network. These signals are variously called acoustic shocks, audio shocks, acoustic shrieks, or high-pitched tones and will be referred to herein as shrieks or narrow-band signals. The exact source of an individual acoustic shock is usually unknown, but various sources are possible, such as alarm signals, signalling tones, or feedback oscillation. Although these narrow-band noises can affect anyone, people using a regular hand-held telephone can quickly move the phone away from their ear, thus limiting their sound exposure to a fraction of a second. Call-centre operators, however, usually use a headset, which takes considerably longer to remove from the ear were an intense sound to occur. They thus receive a greater noise exposure than for people using hand-held phones. The problem may be exacerbated if call centres are so noisy that the operators need to have the volume controls on their telephones turned up higher than would be necessary in a quieter place. Unexpected high-level sounds have been reported to cause a variety of symptoms. Symptoms that have been reported during the exposure include discomfort and pain. Current methods to protect against acoustic shock involve limiting the voltage delivered to the headsets so that the sound level delivered to the ear is also limited in some way. Two forms of limiting are used. The first, peak clipping, acts instantaneously, but simultaneously creates distortion. The second is called compression limiting, and involves the rapid reduction of the gain of the device. Compression limiting creates less distortion, but there is a conflict between the need to reduce the gain slowly (to avoid distortion) and the need to reduce the gain quickly (to provide rapid protection from high level signals on the telephone line). One problem with current forms of limiting is that the devices limit the voltage delivered to the headset in a frequency-independent manner. Because headsets produce different sound levels at different frequencies for the same input voltage, the limiting produced at the eardrum depends on the characteristics of the headset. In particular, headsets of the type used in telephony are known to emphasise high-frequency sounds relative to low-frequency sounds. Conventional limiting systems thus limit low-frequency sounds to lower levels than they limit high-frequency sounds. As acoustic shocks are believed to be caused by high-frequency sounds, the standard solution is not well matched to the problem. An additional (and greater) problem for conventional limiting systems is that there is a severe compromise between selecting a limiting level that is low enough to protect against acoustic shock, but high enough to allow good intelligibility when phone operators listen in noisy environments to speech from callers. The literature on the acoustic startle response (which is believed to underlie the acoustic shock problem) suggests that even very low volume levels can lead to a startle if the sound (such as a high-pitched tone) is perceived by the operator to be dangerous. It is believed that with current methods of limiting it is not possible to choose any limiting level that simultaneously protects against acoustic shock and achieves good intelligibility. Prior art amplification systems avoid acoustic feedback by selectively reducing the gain of the devices in the chain that are causing the feedback oscillation. The acoustic shock problem is different, in that the headset and limiting amplifier are not necessarily part of the chain of devices that are causing the feedback. Prior art acoustic shock protection devices are generally analogue in nature and suffer from problems such as those mentioned above. Such devices also offer limited display and controllability of device settings. Also, such devices are usually configured to operate only with a particular headset and are not suited for or capable of accommodating headsets having different frequency response characteristics. |
<SOH> SUMMARY OF THE INVENTION <EOH>In a first aspect the present invention provides a method of controlling the exposure of a listener to narrow-band signals in an audio signal including the steps of: periodically analysing the signal to determine the signal levels in particular frequency regions; detecting a narrow-band signal based on whether the ratio of the signal level in a particular frequency region to the signal level in nearby higher and lower frequency regions exceeds a pre-determined threshold; and in response to detection of a narrow-band signal, controlling the exposure of the listener to the detected narrow-band signal. In a second aspect of the present invention the present invention provides an apparatus for controlling the exposure of a listener to narrow-band signals in an audio signal including: analysing means to periodically analyse the signal to determine the signal levels in particular frequency regions; detection means arranged to detect a narrow-band signal based on whether the ratio of the signal level in a particular frequency region to the signal level in nearby higher and lower frequency regions exceeds a pre-determined threshold; and controlling means arranged to control the exposure of the listener in response to detection of a narrow-band signal. One embodiment of the invention relates to an amplifying device adapted to detect the presence of one or more high-pitched narrow bandwidth signals within audio telephony signals, in isolation or in the presence of speech signals, and perform rapid, selective attenuation of the one or more narrow bandwidth signals to levels lower than those that occur at the same frequencies when speech is received in the absence of such high-pitched signals. Advantages of this embodiment include: 1. The greatly reduced level of high-pitched narrow-band signals makes them less dangerous to operators; 2. The effectiveness of the device can be demonstrated to operators, which should alleviate their concern over acoustic shock, which further reduces the likelihood of an acoustic shock occurring. Additional features of this embodiment include: Identification of the high pitched narrow band signal by computation of the frequency spectrum of the incoming sounds, and comparison of the level at each frequency with the level at nearby frequencies. Creation of band-reject filters having centre frequencies that approximately match the frequencies closest to the frequencies of the shrieks detected. Rapid but progressive fading-in and fading out of the filters. Use of a filter with frequency characteristics inverse to that of the receiving transducer used so that the maximum level at eardrum can be limited in a controlled manner as a function of frequency. Implementation of the manual volume control such that some of the gain variation occurs prior to limiting and some occurs subsequent to liming. Application of dual-speed compression limiting to the prevention of acoustic shock. Variation of the operation of the automatic volume control depending on whether the operator is speaking or silent. Presetting the gain of the automatic volume control at the start of each new call. Decreasing the gain of the automatic volume control whenever the incoming call level drops below a predetermined value. |
Photocatalyst material and method for preparation thereof |
The present invention provides a photocatalyst material, which can comprise a photocatalyst with an excellent adherence to a substrate and a high photocatalytic activity, and a production method thereof. The photocatalyst material (20) obtained by reacting crystal nuclei with a sol solution containing an organic metallic compound or the like and then carrying out gelation, solidification and heat treatment has a structure where more than one basic structures (10) are fixed to the surface of the substrate (1). The basic structure consists of abase portion (2) comprising crystal nuclei fixed to the surface of the substrate (1) and a photocatalyst crystalline body (3), which connects to and is extended from the base portion (2) and has a columnar structure having a hollow portion (5) formed therein. A cylindrical substrate may be used for the substrate (1). The above photocatalytic activity is further enhanced by the formation of an interior-exposing structure (8) in a shell portion (4). |
1. A photocatalyst material, characterized in that one or more than one columnar photocatalyst basic structure is fixed to the surface of a substrate, said columnar photocatalyst basic structure consisting of a base portion comprising crystal nuclei that are to be fixed or are fixed to the surface of the substrate, and a columnar photocatalyst crystalline body that connects to and is extended from the base portion and has a columnar structure having a hollow portion formed therein. 2. The photocatalyst material according to claim 1, characterized in that said base portion consists of crystal nuclei and the photocatalyst constituting said columnar photocatalyst crystalline body is titanium oxide. 3. The photocatalyst material according to claim 2, characterized in that said columnar photocatalyst crystalline body is formed by a shell portion consisting of a sidewall and an extension direction end and that it has a columnar shape such that a hollow portion is surrounded by said shell portion, wherein said shell portion is a polycrystalline body consisting of aggregated photocatalyst crystal grains. 4. The photocatalyst material according to claim 3, characterized in that an aggregate of photocatalyst crystal grains (hereinafter referred to as a “hollow portion polycrystalline body”) is produced in the hollow portion that is formed inside said columnar photocatalyst crystalline body. 5. The photocatalyst material according to claim 3, characterized in that the shell portion of said columnar photocatalyst crystalline body has an interior-exposing structure to expose an internal structure that is the hollow portion of said columnar photocatalyst crystalline body. 6. The photocatalyst material according to claim 3, characterized in that the surface of said substrate to which said base portion is fixed is a curved surface convex on the side of the extension direction of said columnar photocatalyst crystalline body. 7. The photocatalyst material according to claim 4, characterized in that the surface of said substrate to which said base portion is fixed is a curved surface convex on the side of the extension direction of said columnar photocatalyst crystalline body. 8. The photocatalyst material according to claim 5, characterized in that the surface of said substrate to which said base portion is fixed is a curved surface convex on the side of the extension direction of said columnar photocatalyst crystalline body. 9. The photocatalyst material according to claim 3, characterized in that the photocatalyst crystal grains (hereinafter referred to as “shell portion crystal grains”) constituting said shell portion have a diameter between 2 nm and 50 nm and said sidewall has a width between 20 nm and 100 nm in the extension direction. 10. The photocatalyst material according to claim 4, characterized in that the photocatalyst crystal grains (hereinafter referred to as “shell portion crystal grains°) constituting said shell portion have a diameter between 2 nm and 50 nm and said sidewall has a width between 20 nm and 100 nm in the extension direction. 11. The photocatalyst material according to claim 5, characterized in that the photocatalyst crystal grains (hereinafter referred to as 'shell portion crystal grains°) constituting said shell portion have a diameter between 2 nm and 50 nm and said sidewall has a width between 20 nm and 100 nm in the extension direction. 12. The photocatalyst material according to claim 6, characterized in that said substrate is a cylindrical substrate having a radius of 50 gm or shorter, and the material of said substrate is any one selected from a group consisting of a glass, a ceramic, a metal, and a metal oxide, and said crystal nucleus is any one selected from a group consisting of a powder, a single crystal, a polycrystalline body, a ceramic, a crystallized glass, a thermally-oxidized metal film, and an anodically-oxidized metal film. 13. The photocatalyst material according to claim 7, characterized in that said substrate is a cylindrical substrate having a radius of 50 μm or shorter, and the material of said substrate is any one selected from a group consisting of a glass, a ceramic, a metal, and a metal oxide, and said crystal nucleus is any one selected from a group consisting of a powder, a single crystal, a polycrystalline body, a ceramic, a crystallized glass, a thermally-oxidized metal film, and an anodically-oxidized metal film. 14. The photocatalyst material according to claim 8, characterized in that said substrate is a cylindrical substrate having a radius of 50 gm or shorter, and the material of said substrate is any one selected from a group consisting of a glass, a ceramic, a metal, and a metal oxide, and said crystal nucleus is any one selected from a group consisting of a powder, a single crystal, a polycrystalline body, a ceramic, a crystallized glass, a thermally-oxidized metal film, and an anodically-oxidized metal film. 15. The photocatalyst material according to claim 3, characterized in that said crystal nucleus has a diameter between 1 nm and 350 nm. 16. The photocatalyst material according to claim 3, characterized in that it comprises a columnar photocatalyst basic structure where said columnar photocatalyst crystalline body extends in the same direction along the growth direction of said crystal nuclei. 17. A method for producing a photocatalyst material, characterized in that it comprises: a gelation step of immersing a substrate, to which crystal nuclei are fixed for use as a base portion of a columnar photocatalyst basic structure, in a sol solution comprising an organic metallic compound or inorganic metallic compound, or applying the sol solution comprising an organic metallic compound or inorganic metallic compound to said crystal nuclei fixed to said substrate, so as to obtain a prototype of a photocatalyst material by gelation; a solidification step of drying and solidifying said prototype obtained by said gelation step: and a heat treatment step of subjecting the solidified prototype to heat treatment so as to form a columnar photocatalyst crystalline body, so that a photocatalyst material is obtained. 18. A method for producing a photocatalyst material according to claim 17, characterized in that said gelation step is: of using a substrate whose surface to which said base portion is to be fixed is a curved surface convex on the side of the extension direction of said columnar photocatalyst crystalline body, or a cylindrical substrate having a radius of 50 gm or shorter, fixing crystal nuclei for use as said base portion of said columnar photocatalyst basic structure to said substrate, immersing the substrate, to which said crystal nuclei are fixed, in a sol solution comprising an organic metallic compound or inorganic metallic compound, or applying the sol solution comprising an organic metallic compound or inorganic metallic compound to said crystal nuclei fixed to said substrate, so as to obtain a prototype of a photocatalyst material by gelation. 19. A method for producing a photocatalyst material according to claim 17, characterized in that ion etching or other types of dry etching is carried out on said columnar photocatalyst crystalline body obtained by said heat treatment step: wet etching in which said columnar photocatalyst crystalline body is treated with an etching solution that acts to dissolve titanium oxide is carried out on said columnar photocatalyst crystalline body obtained by said heat treatment step: or a polishing treatment or other treatments to mechanically eliminate a part of said shell portion is carried out on said columnar photocatalyst crystalline body obtained by said heat treatment step, so as to obtain the photocatalyst material with the shell portion having said interior-exposing structure. 20. A method for producing a photocatalyst material according to claim 17, characterized in that, in said heat treatment step, heat treatment is carried out at a temperature increase rate of from 15° C./min to 105° C./min, so as to obtain the photocatalyst material. |
<SOH> BACKGROUND ART <EOH>An oxide photocatalyst (hereinafter referred to as a “photocatalyst”) including titanium oxide as a typical example generates electrons at a conductor by photoexcitation, when it is irradiated with light at a wavelength of energy not less than its band gap. The oxide photocatalyst then generates holes in a balance band, so that it expresses a photocatalytic function. Thus, organic matter or nitrogen oxides, which come into contact with a photocatalyst, are decomposed into water or carbon dioxide gas by the strong reduction power of the electrons or the strong oxidative power of the holes. Accordingly, a photocatalyst has functions such as anti-fouling, deodorization or anti-bacterial properties. Environmental purification methods or devices, which utilize the anti-fouling, deodorizing and anti-bacterial functions of a photocatalyst, have become a focus of attention. In order to achieve the high performance and high efficiency of the photocatalyst, it is desired to enhance the photocatalytic activity of the photocatalyst itself. Since the conventional photocatalyst material is generally used in a powdered state, it is extremely difficult to treat it, and accordingly, it is difficult to incorporate it into an environmental purification device. In order to fix a powder photocatalyst, there is a method which involves mixing a power photocatalyst with an organic binder, applying the mixture onto a substrate, and fixing it under ordinary temperature or by heating. However, this method has a disadvantage in that since the organic matter covers a small or large part of the surface of a photocatalyst, the photocatalytic function of the mixture significantly decreases as compared with that of the original powder photocatalyst. In addition, this method has another disadvantage in that since the organic binder as an organic matter is decomposed by the photocatalytic function, coating strength deteriorates, and powders thereby gradually fall away. The disadvantage regarding the detachment of powders has been overcome by the solidification of the powder photocatalyst with an inorganic binder. However, since the binder covers a part of the photocatalyst, the surface area that can be effectively used for the expression of the photocatalytic function decreases. Thus, the problem regarding the significant decrease of the photocatalytic function has not been overcome. In order to solve the above problem of a powder photocatalyst, a large number of techniques for producing a photocatalyst such as the sol-gel method disclosed in Japanese Patent Laid-Open No. 10-180118 and others have been proposed in the past. Attempts have been made to solve the above described problems regarding a powder oxide photocatalyst and to improve its photocatalytic function. However, the satisfactory achievement of a high activity has not yet been obtained. It is the object of the present invention to solve the problems of the above prior art techniques and to provide a photocatalyst material that can be used to achieve a photocatalyst with an excellent ability to adhere to a substrate as well as a high photocatalytic activity, and a production method thereof. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a schematic diagram showing the appearance of the photocatalyst material of the present invention; FIG. 2 is a schematic diagram showing a longitudinal section obtained by enlargement of a portion of the photocatalyst material of the present invention; FIG. 3 is a scanning electron micrograph showing an example of the photocatalyst material of the present invention; FIG. 4 is a transmission electron micrograph showing a longitudinal section obtained by enlargement of a portion of the columnar photocatalyst crystalline body of the photocatalyst material of the present invention; FIG. 5 is a flow diagram showing the method for producing a photocatalyst material of the present invention; FIG. 6 is a schematic diagram showing the appearance of the photocatalyst material of the present invention, in which a cylindrical substrate is used; FIG. 7 is a scanning electron micrograph showing an example of the photocatalyst material of the present invention, in which a cylindrical substrate is used; FIG. 8 is a schematic diagram showing a longitudinal section of the photocatalyst material of the present invention having an interior-exposing structure. FIG. 9 is a schematic diagram showing the appearance of the photocatalyst material of the present invention having an interior-exposing structure; FIG. 10 is a schematic diagram showing a longitudinal section obtained by enlargement of a portion of the photocatalyst material of the present invention having an interior-exposing structure; FIG. 11 is a flow diagram showing the method for producing a photocatalyst material of the present invention, which uses dry etching; FIG. 12 is a scanning electron micrograph showing an example of the embodiments of the present invention, and the micrograph shows a structure to expose the internal structure of a columnar hollow crystal by dry etching; FIG. 13 is a flow diagram showing the method for producing a photocatalyst material of the present invention, which uses wet etching; FIG. 14 is a flow diagram showing the method for producing a photocatalyst material of the present invention, which uses a mechanical method; FIG. 15 is a flow diagram showing the method for producing a photocatalyst material of the present invention by controlling the heat treatment step; and FIG. 16 is a scanning electron micrograph showing an example of the embodiments of the present invention, and the micrograph shows a structure to expose the internal structure of a columnar hollow crystal by a controlling the heat treatment step. detailed-description description="Detailed Description" end="lead"? Reference codes used in each figure denote the following: 1 , 41 , 51 . . . substrate (basal plate), 2 , 42 , 52 . . . baseportion (crystal nucleus), 3 , 43 , 53 . . . columnar photocatalyst crystalline body (titanium oxide crystals with a columnar hollow structure), 4 , 54 . . . shell portion, 5 , 55 . . . hollow portion, 6 , 56 . . . hollow portion polycrystalline body (aggregate of crystal grains of hollow crystal), 8 . . . interior-exposing structure, 10 , 60 . . . columnar photocatalyst basic structure, 20 , 70 . . . photocatalyst material, 31 . . . gelation step,. 32 . . . solidification step, 33 , 34 . . . heat treatment step, 35 . . . interior-exposing structure formingstep (dryetching), 36 . . . interior-exposing structure forming step (wet etching), 37 . . . interior-exposing structure forming step (mechanical method), S 1 . . . crystal nucleus, S 2 . . . sol solution, M 3 . . . prototype of photocatalyst material, M 4 . . . immobilized prototype, M 5 . . . photocatalyst material without interior-exposing structure, P 5 , P 6 . . . photocatalyst material |
Multi-electrode cochlear implant system with distributed electronics |
An implantable tissue-stimulating device comprising a carrier member having a plurality of electrodes (11) mounted thereon, and at least one signal transmitting wire (13) extending through at least a portion of the carrier member and adapted to transmit signals through the carrier member to and/or from the electrodes (11). The number of wires (13) within the carrier member is less than the number of electrodes (11) mounted thereon. |
1. An implantable tissue-stimulating device comprising a carrier member having a plurality of electrode elements mounted thereon, and at least one signal transmitting means extending through at least a portion of the carrier member and adapted to transmit signals through the carrier member to and/or from said plurality of electrode elements, wherein the number of transmitting means within the carrier member is less than the number of electrode elements mounted thereon. 2. An implantable tissue-stimulating device of claim 1 wherein the device is an implantable component of a cochlear implant system. 3. An implantable tissue-stimulating device of claim 1 wherein the plurality of electrode elements define a longitudinal array of electrode elements. 4. An implantable tissue-stimulating device of claim 3 wherein the electrode elements each have a respective contact face exposed along a first side of the carrier member. 5. An implantable tissue-stimulating device of claim 4 wherein the contact faces are equally spaced along the carrier member. 6. An implantable tissue-stimulating device of claim 1 wherein the electrode elements are formed of a biocompatible metal. 7. An implantable tissue-stimulating device of claim 1 wherein the signal transmitting means comprise an electrically conducting wire or wires. 8. An implantable tissue-stimulating device of claim 7 wherein the wire or wires are formed of a biocompatible electrically conducting metal. 9. An implantable tissue-stimulating device of claim 1 wherein the device comprises at least five signal transmitting means. 10. An implantable tissue-stimulating device of claim 9 wherein the five signal transmitting means comprise a clock line, a data line, a first stimulation line, a second stimulation line, and a common ground line. 11. An implantable tissue-stimulating device of claim 10 wherein each electrode supported by the carrier member has associated electronic circuitry positioned proximate thereto within the carrier member. 12. An implantable tissue-stimulating device of claim 11 wherein the circuitry is associated with two or more electrodes. 13. An implantable tissue-stimulating device of claim 11 wherein the circuitry is positioned immediately adjacent the electrode. 14. An implantable tissue-stimulating device of claim 11 wherein an electrode and its associated circuitry are integrated on a common substrate to form an integrated circuit. 15. An implantable tissue-stimulating device of claim 11 wherein the electronic circuitry comprises a power rectifier, a data decoder, a control circuit, and an output switch. 16. An implantable tissue-stimulating device of claim 15 wherein DC power for an associated electrode is produced by the power rectifier by rectifying an AC power source provided to the power rectifier. 17. An implantable tissue-stimulating device of claim 16 wherein the AC power is provided on two signal transmitting means extending through the carrier member from a receiver/stimulator circuit. 18. An implantable tissue-stimulating device of claim 17 wherein the two signal transmitting means comprise the data line and the clock line. 19. An implantable tissue-stimulating device of claim 18 wherein the data and clock lines are capacitively coupled to the associated electronic circuitry of each of the electrodes in the carrier member using respective input pads. 20. An implantable tissue-stimulating device of claim 15 wherein the data decoder demodulates data and power signals transmitted from a receiver/stimulator circuit, extracts the data and decodes it to obtain the stimulation and telemetry control parameters for the associated electrode. 21. An implantable tissue-stimulating device of claim 20 wherein each electrode data decoder determines whether its associated electrode is required to output an electrical stimulation. 22. An implantable tissue-stimulating device of claim 15 wherein the control circuit configures the electrode output in accordance with stimulus and telemetry data decoded by the data decoder. 23. An implantable tissue-stimulating device of claim 15 wherein the output switch directs a stimulation current to the selected electrode and/or connects the selected electrode to a telemetry measurement circuit. 24. An implantable tissue-stimulating device of claim 23 wherein each output switch also controls the shorting of the electrodes during an inter-frame period. 25. An implantable tissue-stimulating device of claim 23 wherein each output switch also opens the electrode outputs during voltage and neural response telemetry. 26. An implantable tissue-stimulating device of claim 11 wherein the respective signal transmitting means are electrically insulated, the electrical insulation being removed at the side of electrical connection to input pads of the associated circuitry. 27. An implantable tissue-stimulating device of claim 26 wherein the signal transmitting means is gap welded to the input pads. 28. An implantable tissue-stimulating device of claim 26 wherein the input pads are insertion displacement connectors. 29. An implantable tissue-stimulating device of claim 28 wherein the connector comprises a cavity having a plurality of sharp tines formed in the surface thereof, the tines being adapted to pierce the insulation of the signal transmitting means positioned therein and so make an electrical connection thereto. 30. An implantable tissue-stimulating device comprising a carrier member having a plurality of electrode elements mounted thereon, at least one of the electrode elements having associated signal processing circuitry embedded within the carrier member proximate thereto. 31. An implantable tissue-stimulating device of claim 30 wherein the number of transmitting means within the carrier member is less than the number of electrode elements mounted thereon. 32. An implantable tissue-stimulating device of claim 30 wherein the circuitry is associated with two or more electrodes. 33. An implantable tissue-stimulating device of claim 30 wherein the circuitry is positioned immediately adjacent the electrode. 34. An implantable tissue-stimulating device of claim 30 wherein an electrode and its associated circuitry are integrated on a common substrate to form an integrated circuit. 35. An implantable tissue-stimulating device of claim 30 wherein the electronic circuitry comprises a power rectifier, a data decoder, a control circuit, and an output switch. 36. An implantable tissue-stimulating device of claim 35 wherein DC power for an associated electrode is produced by the power rectifier by rectifying an AC power source provided to the power rectifier. 37. An implantable tissue-stimulating device of claim 36 wherein the AC power is provided on two signal transmitting means extending through the carrier member from a receiver/stimulator circuit. 38. An implantable tissue-stimulating device of claim 38 wherein the two signal transmitting means comprise a data line and a clock line. 39. An implantable tissue-stimulating device of claim 38 wherein the data and clock lines are capacitively coupled to the associated electronic circuitry of each of the electrodes in the carrier member using respective input pads. 40. An implantable tissue-stimulating device of claim 35 wherein the data decoder demodulates data and power signals transmitted from a receiver/stimulator circuit, extracts the data and decodes it to obtain the stimulation and telemetry control parameters for the associated electrode. 41. An implantable tissue-stimulating device of claim 40 wherein each electrode data decoder determines whether its associated electrode is required to output an electrical stimulation. 42. An implantable tissue-stimulating device of claim 35 wherein the control circuit configures the electrode output in accordance with the stimulus and telemetry data decoded by the data decoder. 43. An implantable tissue-stimulating device of claim 35 wherein the output switch directs a stimulation current to the selected electrode and/or connects the selected electrode to a telemetry measurement circuit. 44. An implantable tissue-stimulating device of claim 43 wherein each output switch also controls the shorting of the electrodes during an inter-frame period. 45. An implantable tissue-stimulating device of claim 43 wherein each output switch also opens the electrode outputs during voltage and neural response telemetry. 46. An implantable tissue-stimulating device of claim 30 wherein the respective signal transmitting means are electrically insulated, the electrical insulation being removed at the side of electrical connection to input pads of the associated circuitry. 47. An implantable tissue-stimulating device of claim 46 wherein the signal transmitting means is gap welded to the input pads. 48. An implantable tissue-stimulating device of claim 46 wherein the input pads are insertion displacement connectors. 49. An implantable tissue-stimulating device of claim 48 wherein the connector comprises a cavity having a plurality of sharp tines formed in the surface thereof, the tines being adapted to pierce the insulation of the signal transmitting means positioned therein and so make an electrical connection thereto. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Cochlear implants have been developed to assist people who are profoundly deaf or severely hearing impaired, by enabling them to experience hearing sensation representative of the natural hearing sensation. In most of these cases, the individuals have an absence of or destruction of the hair cells in the cochlea which naturally transduce acoustic signals into nerve impulses which are interpreted by the brain as sound. The cochlear implant therefore bypasses the hair cells to directly deliver electrical stimulation to the auditory nerves with this electrical stimulation being representative of the sound. Cochlear implants have traditionally consisted of two parts, an external speech processor unit and an implanted receiver/stimulator unit. The external speech processor unit has normally been worn or carried on the body of the user and its main purpose has been to detect sound with a microphone and convert the detected sound into a coded signal through an appropriate speech processing strategy. This coded signal is then sent to the receiver/stimulator unit which is normally implanted in the mastoid bone of the user, via a transcutaneous radio frequency (RF) link. The receiver/stimulator unit includes a circuit that processes this coded signal and outputs a series of stimulation sequences. These sequences are transmitted to appropriate electrodes of an electrode array by respective electrically conducting wires. The array is positioned proximal to the modiolus of the cochlea such that an electrical stimulus output by the electrodes is then applied to the auditory nerve. As the electrode array is typically surgically implanted within the scala tympani of the cochlea of the recipient, the dimensions of the array and the manner of its insertion must be such so as to avoid damage to the sensitive structures of the cochlea. The dimensions and spiral shape of the cochlea also limit the maximum dimensions, particularly the diameter, and the stiffness of any array used as part of a cochlear implant. In existing designs, this has limited the number of electrically conducting electrodes that can be incorporated into the array, due in the main to limitations imposed on the number of wires that can extend through the array to the electrodes. Traditional electrode array designs have required one or more conductive wires to be connected to each electrode and as such for an array having, for example 22 electrodes, the minimum number of wires required would be 22. With an increased understanding of the tonotopic nature and behaviour of the cochlea, the benefits of providing an increased number of stimulating electrodes within the cochlea to stimulate more discrete sites within the cochlea are now being realised. However, it has been demonstrated that increasing the number of wires in conjunction with an increased number of electrodes unacceptably increases the dimensions and stiffness of the array. Merely reducing the diameter of the wires, in order to keep the overall dimensions unchanged, leads to an unacceptable increase in lead resistance. As a result, this limitation on the number of leads, and hence electrodes, limits the scale and type of electrical stimulations that can be applied to the auditory nerve by the electrode array. The present invention provides a solution to this problem by allowing an increase in the number of individual electrodes of an electrode array of a cochlear implant in comparison to known arrays while still allowing the array to be readily inserted within a implantee's cochlea. Further to this, the present invention in combination with new methods of manufacturing electrode arrays as described in the Applicant's co-pending International Patent Application PCT/AU02/00575, provides for significant improvements in the size and design of intra-cochlear electrode arrays than has previously been the case. Any discussion of documents, acts, materials, devices, articles or the like which has been included In the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application. |
<SOH> SUMMARY OF THE INVENTION <EOH>Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. According to a first aspect, the present invention is an implantable tissue-stimulating device comprising a carrier member having a plurality of electrode elements mounted thereon, and at least one signal transmitting means extending through at least a portion of the carrier member and adapted to transmit signals through the carrier member to and/or from said plurality of electrode elements, wherein the number of transmitting means within the carrier member is less than the number of electrode elements mounted thereon. According to a second aspect, the present invention is an implantable tissue-stimulating device comprising a carrier member having a plurality of electrode elements mounted thereon, at least one of the electrode elements having associated signal processing circuitry embedded within the carrier member proximate thereto. In a preferred embodiment, the tissue-stimulating device of both aspects can comprise an implantable component of a cochlear implant device. While having broader application, the present invention will be defined for the purposes of the present application with reference to a cochlear implant. For the purposes of the present specification, the cochlear implant is defined as including a receiver/stimulator circuit which is implanted in the mastoid bone of the implantee. The receiver/stimulator unit includes a circuit that processes a coded signal transmitted transcutaneously from an external component and outputs a series of signals through the carrier member to the electrodes and/or the embedded circuitry of the carrier member. While a typical cochlear implant will include an external component including a microphone and speech processor, it will be appreciated that the cochlear implant could be fully implantable within the implantee. In a preferred embodiment, the plurality of electrode elements define a longitudinal array of elements. In a further embodiment, the electrode elements each have a respective contact face exposed along a first, preferably longitudinal, side of the carrier member. In one embodiment, the contact faces can be equally spaced along the carrier member. In another embodiment, the spacing between respective pairs of contact faces can vary. In another embodiment, respective pairs of electrodes can be adapted to provide bipolar stimulation. In another embodiment, the electrode or electrodes can provide monopolar stimulation or common ground stimulation to the auditory nerve in the cochlea. The electrode elements can be formed of a biocompatible material, such as platinum. In a further embodiment of the first aspect, the signal transmitting means can comprise an electrically conducting wire or wires. In one embodiment, the wire or wires can also be formed of a biocompatible electrically conducting material, such as platinum. In one embodiment, the device includes at least five signal transmitting means for all of the electrodes in the carrier member This is in contrast to present known designs which normally have at least one wire for each of the electrodes of the array, eg. at least 32 wires for 32 electrodes. The five signal transmitting means can include a clock line, a data line, a first stimulation line, a second stimulation line, and a common ground line. In a further embodiment of the first aspect and in the second aspect, each electrode supported by the carrier member has associated electronic circuitry positioned proximate thereto within the carrier member. The circuitry can be associated with one or more electrodes. This circuitry can be positioned immediately adjacent the electrode. In another embodiment, the electrode and its associated circuitry are integrated on a common substrate to form an integrated circuit. The circuitry and substrate are each preferably constructed to be biocompatible, with preferably no metal interlayers being utilised. Instead, polysilicon is preferably used to provide low impedance pathways within the circuitry. The electronic circuitry can include a power rectifier, a data decoder, a control circuit, and/or an output switch. DC power for its associated electrode is preferably produced by the power rectifier by rectifying an AC power source provided to the power rectifier. The AC power is preferably provided on two signal transmitting means extending through the carrier member from the implanted receiver/stimulator circuit The two signal transmitting means can comprise the data line and the clock line as defined above. The data and clock lines are preferably capacitively coupled to the associated electronic circuitry of each of the electrodes in the carrier member using respective input pads. The data and clock lines are also preferably coupled to the electrode via small coupling capacitors formed under, and including, the data and clock bond pads. The circuitry preferably includes a ground pad. The ground pad is preferably bonded to a platinum wire that connects to the ground of the receiver/stimulator circuit, ie. the common ground line. It is also preferably connected to the common ground of the electronic circuit of the electrode. The stimulus pads of the integrated substrate are preferably constructed using standard CMOS bond pad design. These pads preferably do not require protection diodes. The data decoder preferably demodulates data and power signals transmitted from the receiver/stimulator circuit, extracts the data and decodes it to obtain the stimulation and telemetry control parameters. Each electrode data decoder preferably determines whether its associated electrode is required to output an electrical stimulation. By devolving this decoding step to circuitry embedded with the respective electrodes, the number of electrical connections between the electrodes and the receiver/stimulator passing through the carrier member can be reduced. The control circuit is preferably used to configure the electrode output in accordance with the stimulus and telemetry data decoded by the data decoder. The output switch (transmission gate) preferably directs the stimulation current to the selected electrode and/or connects the selected electrode to a telemetry measurement circuit. Each output switch also preferably controls the shorting of the electrodes during an inter-frame period, or to open the electrode outputs during voltage and neural response telemetry. The platinum electrode is preferably directly bonded to the drains of transistors within the output switch. In one embodiment, the wires forming the respective signal transmitting means extend from at least the proximal end of the carrier member for a length through the carrier member that includes the electrodes. The wires are preferably electrically insulated. A ribbon wire can be used to provide the signal transmitting means. The electrical insulation can comprise parylene. Where necessary, the insulation can be ablated using excimer laser ablation. The insulation is preferably ablated at fixed intervals corresponding to the positions of the input pads within the carrier member of each embedded circuit. In one embodiment, the wire can be gap welded to the input pads using an appropriate gap welder. In another embodiment, the input pads can be fabricated to form insertion displacement connectors. The connector can be fabricated by micromachining a cavity having a plurality of sharp tines formed in the surface thereof. On pushing the wire into this cavity, the sharp fines can pierce the insulation of the wire and so make electrical connection with the wire. The carrier member can be formed by molding a suitable biocompatible polymer around the wires, circuitry and electrodes. The carrier member can be formed to have a first configuration selected to allow said member to be inserted into an implantee's body and at least a second configuration wherein said carrier member is adapted to apply a preselected tissue stimulation with the electrodes. A stiffening element having a configuration selected for biasing said carrier member into said first configuration can pass through at least a portion of the carrier member. The stiffening element can be a metallic stylet disposed in a lumen passing through the carrier member. In a preferred embodiment, the second configuration of the carrier member is curved. More preferably, the carrier member adopts a spiral configuration when in the second configuration. In a preferred embodiment, the first configuration is preferably substantially straight. More preferably, the first configuration is straight. In a preferred embodiment, the carrier member is formed from a suitable biocompatible material. In one embodiment, the material can be a silicone, such as Silastic MDX 4-4210. In another embodiment, the carrier member can be formed from a polyurethane. In a preferred embodiment, the receiver/stimulator circuit of the cochlear implant is electrically connected to the data and clock lines. It is also preferably electrically connected to and drives four output stimulation lines. Two of these lines are preferably connected to two extra-cochlear electrodes. The other two lines, hereinafter called “stim 1 ” and “stim 2 ”, extend through the carrier member and are connected to the respective input pads of the embedded circuits. Each of the four lines can be connected, under the control of the receiver/stimulator circuit, to either VDD or to an on-chip stimulus current source. The stimulation charge, delivered to the cochlea, is preferably balanced by using a two-phase balanced stimulation scheme. During the first phase, the active electrode is connected to the current source while the reference electrode is connected to VDD. This allows the current to flow from the reference electrode, through the cochlea and other tissue, to the active electrode. During the second phase, the electrode connections are reversed allowing equal, but opposite polarity, charge to flow through the cochlea. This preferably results in a balanced (zero average) charge flow through the stimulating electrodes and the human tissue. Despite the above, precise charge balance may not be achievable in practice due to small timing errors or variation in electrode properties. To overcome this problem, the output transmission gates (switches) are preferably closed after the second stimulation phase, thereby connecting all intra-cochlea electrodes to stim 1 and stim 2 simultaneously. These electrodes can be connected to VDD via the output switches of the receiver/stimulator circuit. Depending on the desired shorting scheme, the extra-cochlear electrodes may also be shorted to VDD together with the intra-cochlea electrodes in order to simultaneously discharge any residual charge on all electrodes. The insertion of series capacitors with some, or all, of the four output lines of the receiver/stimulator circuit preferably guarantees the longer term charge balance of the system. As discussed, the implant is preferably capable of three stimulation modes. Monopolar stimulation is obtained by selecting an extra-cochlear electrode and an intracochlear electrode as the stimulating electrodes. In this mode, the post-stimulating shorting must involve the extra-cochlea electrodes. The bipolar stimulation is preferably achieved by selecting two intra-cochlear electrodes as the stimulating electrodes. The post-stimulation shorting, in this case, does not need to involve the extra-cochlear electrodes. The Common Ground stimulation is obtained by selecting an intra-cochlea electrode as an active electrode (connected to stim 1 ), while all other intra-cochlea electrodes are connected in parallel to stim 2 by simultaneously closing their output switches (transmission gates) during the stimulus phases. A telemetry circuit can reside in the receiver/stimulator circuit and be connected to the four output lines. This preferably enables the telemetry circuit to measure the voltage of any of the four lines with respect to an internal reference, or differentially between any two of the four lines. Three telemetry functions are preferably available when using the system, namely Current Source Voltage Compliance Telemetry, Voltage Telemetry, and Neural Response Telemetry. Current Source Voltage Compliance Telemetry is preferably used to measure the voltage across the stimulation current source of the receiver/stimulator circuit. This telemetry function returns one of two states indicating the voltage across the current source during stimulation. If the measured voltage falls below a design threshold, it may not then be sufficient to maintain the correct operation of the current source. This telemetry function is available for both monopolar and bipolar stimulation modes. Electrode Voltage Telemetry is preferably used to measure the voltage of an intra-cochlea electrode during stimulation. When voltage telemetry is used to measure the voltage of the active electrode, it can then be used with either monopolar or bipolar stimulation modes. However, only monopolar stimulation can facilitate using Voltage telemetry to measure the voltage of a non-stimulating intra-cochlea electrode, where one of the two lines, stim 1 and stim 2 , is used to carry the monopolar stimulation current while the other is used as a sense line to connect to the electrode to be measured. Neural Response Telemetry can preferably be used to measure the evoked potential of the auditory nerve after stimulation. This is achieved in monopolar mode by using either stim 1 or stim 2 as a sense line for the neural response electrode. To reduce the stimulation artefacts, one of the extra-cochlea electrodes can be used as a stimulation reference electrode, while the other can be used as a reference electrode for the neural response measurement. |
Spiropoperidine compounds as ligands for orl-1 receptor |
A compound of the formula (I) or a salt, prodrug or solvate thereof, wherein R1 and R2 groups are all hydrogen; A is a benzofuzed azahetero ring; W1—W2 is CH2—CH2; X1—X1 is CH2—CH2; and Z is methylene or carbonyl; or the like, is a ligand for ORL1-receptor and are useful for treating or preventing pain, a CNS disorder or the like in mammalian subjects. |
1-13. (Cancelled). 14. A compound of the following formula: or pharmaceutically accptable salts thereof, wherein each R1 is independently selected from hydrogen and (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; or two R1 groups taken together form —CH2— or —(CH2)2— and the remaining R1 groups are defined as above; each R2 is independently selected from hydrogen; halo; hydroxy; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra1R N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; aryl selected from phenyl and naphthyl; and four- to eight-membered heterocyclyl containing one to four hetero atoms in the ring independently selected from nitrogen, oxygen and sulfur; X1 and X2 are each CH2; or X1 and X2 taken together form CH═CH; W1 and W2 are independently selected from CRW1RW2, wherein RW1 and RW2 are independently selected from hydrogen; halo; hydroxy; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2 N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; C(═O)-[(C1-C6)alkyl] wherein said (C1-C6)alkyl is optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; C(═O)—NRW11RW12 wherein RW11 and RW12 are independently selected from hydrogen and (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra12N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; NRW13RW14 wherein RW13 and RW14 are independently selected from hydrogen and (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2 Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; aryl selected from phenyl and naphthyl; and four- to eight-membered heterocyclyl containing one to four hetero atoms independently selected from nitrogen, oxygen and sulfur; A is selected from AA; AB; AC and AE: wherein Ya is selected from (CH2)n2 wherein n2 is an integer selected from 0, 1 and 2; C(═O); NH; O and S; Yb, Yc, Yd, Ye, Yf, Yi, Yj, Yk and Ym are independently selected from C(═O); CRY1RY2; CRY3[C(═O)RY4]; CRY3[NRY5C(═O)RY4]; CRY3[C(═O)NRY6 RY7]; CRY3NRY6 RY7]; O; S; SO2; NH; N[(C1-C6)alkyl] wherein said (C1-C6)alkyl is optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; N—(CH2)n3-heterocyclyl wherein n3 is an integer selected from 0, 1, 2 and 3, and said heterocyclyl contains from four to eight ring atoms one or two of which are independently selected from nitrogen, oxygen and sulfur; N—(CH2)n4-aryl wherein n4 is an integer selected from 0, 1, 2 and 3, and said aryl is selected from phenyl and naphthyl; and N—(CH2)n5-heteroaryl wherein n5 is an integer selected from 0, 1, 2 and 3, and said heteroaryl is a five to ten membered aromatic heterocyclyl containing from one to four hetero atoms independently selected from nitrogen, oxygen and sulfur; or Yb and Yc taken together form a group selected from CRY81═CRY82; CRY83═N and N═N; and Yd, Ye and Yf are defined as above; wherein RY1, RY2 and RY5 are independently selected from hydrogen; hydroxy; non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl; [(C1-C6)alkyl]-C(═O)—; [(C1-C6)alkoxy]-C(═O)—; [(C1-C6)alkyl]-SO2—; and four- to eight-membered heterocyclyl containing one to four hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy, (C1-C6)alkyl, NH2—C(O═)—, [(C1-C6)alkyl]-NH—C(═O)—, [(C1-C6)alkyl]2-N—C(═O)—, and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7 Ra8 N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; or RY1 and RY2 taken together with the carbon atom to which they are attached form spiropyrrolidinyl or spiropiperidinyl, both of which are optionally N-substituted with a substituent selected from (C1-C6)alkyl, (C1-C6)alkyl-C(═O)—, [(C1-C6)alkyl]-C(═O)-(C1-C6)alkyl and aryl-(C═O)— wherein aryl is selected from phenyl and naphthyl; and RY5 is defined as above; RY3 is hydrogen; RY4 is selected from hydroxy; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and RY6 and RY7 are independently selected from hydrogen; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; hetrocyclyl-(CH2)n6— wherein n6 is an integer selected from 0, 1, 2, 3 and 4 and said heterocyclyl is four to eight membered containing one to three hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and hetroaryl-(CH2)n7— wherein n7 is an integer selected from 0, 1, 2, 3 and 4 and said heteroaryl is five to ten membered containing one to three hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heteroaryl is optionally substituted with one to three substituents independently selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; or RY6 and RY7 taken together with the nitrogen atom to which they are attached form a four to eight heterocyclyl optionally containing, in addition to the nitrogen atom, one to two additional hetero atoms independently selected from nitrogen, oxygen and sulfur, and said heterocyclyl is optionally substituted with one substituent selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; RY81, RY82 and RY83 are independently selected from RY811 and RY812C(═O)— wherein RY811 and RY812 are independently selected from hydrogen; hydroxy; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and said A is optionally substituted in the fused benzene rings with one to four substituents independently selected from halo; hydroxy; mercapto; phenyl; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1 —C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and Z is selected from C(═O); (CH2)n8 wherein n8 is an integer selected from 0, 1 and 2; and CHRZ1 wherein RZ1 is selected from carboxy; (C1-C6)alkoxy-C(═O)—; non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkyl]-C(═O)—O— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and [C(═O)—NRZ11RZ12] wherein RZ11 and RZ12 are independently selected from hydrogen and (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—. 15. A compound according to claim 1 wherein all R1 are hydrogen each R2 is independently selected from hydrogen and halo; X1 and X2 are each CH2; or X1 and X2 taken together form CH═CH; W1 and W2 are independently selected from CRW1RW2, wherein RW1 and RW2 are independently selected from hydrogen; halo; hydroxy; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; C(═O)-[(C1-C6)alkyl] wherein said (C1-C6)alkyl is optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; C(═O)—NRW11RW12 wherein RW11 and RW12 are independently selected from hydrogen and (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; NRW3RW14 wherein RW13 and RW14 are independently selected from hydrogen and (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; aryl selected from phenyl and naphthyl; and four- to eight-membered heterocyclyl containing one to four hetero atoms independently selected from nitrogen, oxygen and sulfur; A is AB wherein Yb and Yc are independently selected from C(═O); CRY1RY2; CRY3[C(═O)RY4]; CRY3[C(═O)NRY6 RY7]; CRY3[NRY6 RY7]; O; S; SO2; NH; N[(C1-C6)alkyl] wherein said (C1-C6)alkyl is optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra1Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; N—(CH2)n3-heterocyclyl wherein n3 is an integer selected from 0, 1, 2 and 3, and said heterocyclyl contains from four to eight ring atoms one or two of which are independently selected from nitrogen, oxygen and sulfur; N—(CH2)n4-aryl wherein n4 is an integer selected from 0, 1, 2 and 3, and said aryl is selected from phenyl and naphthyl; and N—(CH2)n5-heteroaryl wherein n5 is an integer selected from 0, 1, 2 and 3, and said heteroaryl is a five to ten membered aromatic heterocyclyl containing from one to four hetero atoms independently selected from nitrogen, oxygen and sulfur; or Yb and Yc taken together form a group selected from CRY81═CRY82; CRY83═N and N═N; and Yd, Ye, Yf, Yg and Yh are defined as above; RY1 and RY2 are independently selected from hydrogen; hydroxy; non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl; [(C1-C6)alkyl]-C(═O)—; [(C1-C6)alkoxy]-C(═O)—; [(C1-C6)alkyl]-SO2—; and four- to eight-membered heterocyclyl containing one to four hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy, (C1-C6)alkyl, NH2—C(O═)—, [(C1-C6)alkyl]-NH—C(═O)—, [(C1-C6)alkyl]2-N—C(═O)—, and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6 N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; or RY1 and RY2 taken together with the carbon atom to which they are attached form spiropyrrolidinyl or spiropiperidinyl, both of which are optionally N-substituted with a substituent selected from (C1-C6)alkyl, (C1-C6)alkyl-C(═O)—, [(C1-C6)alkyl]-C(═O)-(C1-C6)alkyl and aryl-(C═O)— wherein aryl is selected from phenyl and naphthyl; RY3 is hydrogen; RY4 is selected from hydroxy; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5 Ra6 N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and RY5, RY6 and RY7 are independently selected from hydrogen; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; hetrocyclyl-(CH2)n6— wherein n6 is an integer selected from 0, 1, 2, 3 and 4 and said heterocyclyl is four to eight membered containing one to three hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and hetroaryl-(CH2)n7— wherein n7 is an integer selected from 0, 1, 2, 3 and 4 and said heteroaryl is five to ten membered containing one to three hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heteroaryl is optionally substituted with one to three substituents independently selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; or RY6 and RY7 taken together with the nitrogen atom to which they are attached form a four to eight heterocyclyl optionally containing, in addition to the nitrogen atom, one to two additional hetero atoms independently selected from nitrogen, oxygen and sulfur, and said heterocyclyl is optionally substituted with one substituent selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; RY81, RY82 and RY83 are independently selected from RY811 and RY812C(═O)— wherein RY81 and RY812 are independently selected from hydrogen; hydroxy; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Rz1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1 —C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and said A is optionally substituted in the fused benzene rings with one to four substituents independently selected from halo; hydroxy; mercapto; phenyl; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and Z is selected from C(═O); (CH2)n8 wherein n8 is an integer selected from 0, 1 and 2; and CHRZ1 wherein RZ1 is selected from carboxy; (C1-C6)alkoxy-C(═O)—; non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkyl]-C(═O)—O— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and [C(═O)—NRZ11RZ12] wherein RZ11 and RZ12 are independently selected from hydrogen and (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—. 16. A compound according to claim 2 wherein all R1 are hydrogen each R2 is independently selected from hydrogen and halo; X1 and X2 are each CH2; or X1 and X2 are taken together form CH═CH; W1 and W2 are both CH2; A is AB wherein both Yb and Yc are independently selected from C(═O); CRY1RY2; CRY3[C(═O)RY4]; CRY3[C(═O)NRY6RY7]; and CRY3[NRY6RY7], wherein RY1 and RY2 are independently selected from hydrogen; hydroxy; non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl; [(C1-C6)alkyl]-C(═O)—; [(C1-C6)alkoxy]-C(═O)—; [(C1-C6)alkyl]-SO2—; and four- to eight-membered heterocyclyl containing one to four hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy, (C1-C6)alkyl, NH2—C(O═)—, [(C1-C6)alkyl]-NH—C(═O)—, [(C1-C6)alkyl]2-N—C(═O)—, and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; or RY1 and RY2 taken together with the carbon atom to which they are attached form spiropyrrolidinyl or spiropiperidinyl, both of which are optionally N-substituted with a substituent selected from (C1-C6)alkyl, (C1-C6)alkyl-C(═O)—, [(C1-C6)alkyl]-C(═O)-(C1-C6)alkyl and aryl-(C═O)— wherein aryl is selected from phenyl and naphthyl; RY3 is hydrogen; RY4 is selected from hydroxy; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and RY6 and RY7 are independently selected from hydrogen; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3 Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; hetrocyclyl-(CH2)n6— wherein n6 is an integer selected from 0, 1, 2, 3 and 4 and said heterocyclyl is four to eight membered containing one to three hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and hetroaryl-(CH2)n7— wherein n7 is an integer selected from 0, 1, 2, 3 and 4 and said heteroaryl is five to ten membered containing one to three hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heteroaryl is optionally substituted with one to three substituents independently selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; or RY6 and RY7 taken together with the nitrogen atom to which they are attached form a four to eight heterocyclyl optionally containing, in addition to the nitrogen atom, one to two additional hetero atoms independently selected from nitrogen, oxygen and sulfur, and said heterocyclyl is optionally substituted with one substituent selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; said A is optionally substituted in the fused benzene rings with one to four substituents independently selected from halo; hydroxy; mercapto; phenyl; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra6N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and Z is selected from C(═O); (CH2)n8 wherein n8 is an integer selected from 0, 1 and 2; and CHRZ1 wherein RZ1 is selected from carboxy; (C1-C6)alkoxy-C(═O)—; non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkyl]-C(═O)—O— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and [C(═O)—NRZ11RZ12] wherein RZ11 and RZ12 are independently selected from hydrogen and (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—. 17. A compound according to claim 3 wherein all R1 are hydrogen each R2 is independently selected from hydrogen and halo; X1 is selected from (CH2)n1 wherein n1 is an integer selected from 1, 2 and 3; O; NH; S; C(═O); SO2; and N[(C1-C4)alkyl]; X1 and X2 are each CH2; or X1 and X2 are taken together form CH═CH; W1 and W2 are both CH2; A is AB wherein Yb is CRY3[C(═O)NRY6RY7]; and Yc is selected from CRY1RY2; CRY3 [C(═O)RY4]; CRY3[C(═O)NRY6RY7]; and CRY3[NRY6 RY7], wherein RY1 and RY2 are independently selected from hydrogen; hydroxy; non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl; [(C1-C6)alkyl]-C(═O)—; [(C1-C6)alkoxy]-C(═O)—; [(C1-C6)alkyl]-SO2—; and four- to eight-membered heterocyclyl containing one to four hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy, (C1-C6)alkyl, NH2—C(O═)—, [(C1-C6)alkyl]-NH—C(═O)—, [(C1-C6)alkyl]2-N—C(═O)—, and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra1Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; or RY1 and RY2 taken together with the carbon atom to which they are attached form spiropyrrolidinyl or spiropiperidinyl, both of which are optionally N-substituted with a substituent selected from (C1-C6)alkyl, (C1-C6)alkyl-C(═O)—, [(C1-C6)alkyl]-C(═O)-(C1-C6)alkyl and aryl-(C═O)— wherein aryl is selected from phenyl and naphthyl; RY3 is hydrogen; RY4 is selected from hydroxy; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and RY5, RY6 and RY7 are independently selected from hydrogen; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; hetrocyclyl-(CH2)n6— wherein n6 is an integer selected from 0, 1, 2, 3 and 4 and said heterocyclyl is four to eight membered containing one to three hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and hetroaryl-(CH2)n7— wherein n7 is an integer selected from 0, 1, 2, 3 and 4 and said heteroaryl is five to ten membered containing one to three hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heteroaryl is optionally substituted with one to three substituents independently selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; or RY6 and RY7 taken together with the nitrogen atom to which they are attached form a four to eight heterocyclyl optionally containing, in addition to the nitrogen atom, one to two additional hetero atoms independently selected from nitrogen, oxygen and sulfur, and said heterocyclyl is optionally substituted with one substituent selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; said A is optionally substituted in the fused benzene rings with one to four substituents independently selected from halo; hydroxy; mercapto; phenyl; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, (C1-C6)alkoxy, (C1-C6)alkoxy-C(═O)— and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, (C1-C6)alkoxy, (C1-C6)alkoxy-C(═O)— and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and Z is selected from C(═O); (CH2)n8 wherein n8 is an integer selected from 0, 1 and 2; and CHRZ1 wherein RZ1 is selected from carboxy; (C1-C6)alkoxy-C(═O)—; non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkyl]-C(═O)—O— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and [C(═O)—NRZ11RZ12] wherein RZ11 and RZ12 are independently selected from hydrogen and (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—. 18. A compound according to claim 4 wherein all R1 are hydrogen each R2 is independently selected from hydrogen and halo; X1 and X2 are each CH2; or X1 and X2 are taken together form CH═CH; W1 and W2 are both CH2; A is AB wherein Yb is CRY3[C(═O)NRY6 RY7]; and Yc is selected from CRY1RY2; CRY3[C(═O)RY4]; CRY [C(═O)NRY6 RY7]; and CRY3[NRY6 RY7]; wherein RY1 and RY2 are independently selected from hydrogen; hydroxy; non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl; [(C1-C6)alkyl]-C(═O)—; [(C1-C6)alkoxy]-C(═O)—; [(C1-C6)alkyl]-SO2—; and four- to eight-membered heterocyclyl containing one to four hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy, (C1-C6)alkyl, NH2—C(O═)—, [(C1-C6)alkyl]-NH—C(═O)—, [(C1-C6)alkyl]2-N—C(═O)—, and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; or RY1 and RY2 taken together with the carbon atom to which they are attached form spiropyrrolidinyl or spiropiperidinyl, both of which are optionally N-substituted with a substituent selected from (C1-C6)alkyl, (C1-C6)alkyl-C(═O)—, [(C1-C6)alkyl]-C(═O)-(C1-C6)alkyl and aryl-(C═O)— wherein aryl is selected from phenyl and naphthyl; RY3 is hydrogen; RY4 is selected from hydroxy; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra1Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and RY5, RY6 and RY7 are independently selected from hydrogen; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; hetrocyclyl-(CH2)n6— wherein n6 is an integer selected from 0, 1, 2, 3 and 4 and said heterocyclyl is four to eight membered containing one to three hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and hetroaryl-(CH2)n7— wherein n7 is an integer selected from 0, 1, 2, 3 and 4 and said heteroaryl is five to ten membered containing one to three hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heteroaryl is optionally substituted with one to three substituents independently selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; or RY6 and RY7 taken together with the nitrogen atom to which they are attached form a four to eight heterocyclyl optionally containing, in addition to the nitrogen atom, one to two additional hetero atoms independently selected from nitrogen, oxygen and sulfur, and said heterocyclyl is optionally substituted with one substituent selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; said A is optionally substituted in the fused benzene rings with one to four substituents independently selected from halo; hydroxy; mercapto; phenyl; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, (C1-C6)alkoxy, (C1-C6)alkoxy-C(═O)— and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, (C1-C6)alkoxy, (C1-C6)alkoxy-C(═O)— and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and Z is C(═O). 19. A compound according to claim 3 wherein all R1 are hydrogen each R2 is independently selected from hydrogen and halo; X1 and X2 are each CH2; or X1 and X2 are taken together form CH═CH; W1 and W2 are both CH2; A is AB wherein Yb is CRY1RY2; and Yc is selected from CRY1RY2; CRY2; [C(═O)RY4]; CRY3[C(═O)NRY6RY7]; and CRY3[NRY6RY7]; or Yb and Yc taken together form a group selected from CH2—CH2 and CH2═CH2; RY1 and RY2 are independently selected from hydrogen; hydroxy; non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl; [(C1-C6)alkyl]-C(═O)—; [(C1-C6)alkoxy]-C(═O)—; [(C1-C6)alkyl]-SO2—; and four- to eight-membered heterocyclyl containing one to four hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy, (C1-C6)alkyl, NH2—C(O═)—, [(C1-C6)alkyl]-NH—C(═O)—, [(C1-C6)alkyl]2-N—C(═O)—, and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra1 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra1Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; or RY1 and RY2 taken together with the carbon atom to which they are attached form spiropyrrolidinyl or spiropiperidinyl, both of which are optionally N-substituted with a substituent selected from (C1-C6)alkyl, (C1-C6)alkyl-C(═O)—, [(C1-C6)alkyl]-C(═O)-(C1 —C6)alkyl and aryl-(C═O)— wherein aryl is selected from phenyl and naphthyl; RY3 is hydrogen; RY4 is selected from hydroxy; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6 Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and RY6 and RY7 are independently selected from hydrogen; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; hetrocyclyl-(CH2)n6— wherein n6 is an integer selected from 0, 1, 2, 3 and 4 and said heterocyclyl is four to eight membered containing one to three hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and hetroaryl-(CH2)n7— wherein n7 is an integer selected from 0, 1, 2, 3 and 4 and said heteroaryl is five to ten membered containing one to three hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heteroaryl is optionally substituted with one to three substituents independently selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; or RY6 and RY7 taken together with the nitrogen atom to which they are attached form a four to eight heterocyclyl optionally containing, in addition to the nitrogen atom, one to two additional hetero atoms independently selected from nitrogen, oxygen and sulfur, and said heterocyclyl is optionally substituted with one substituent selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; said A is optionally substituted in the fused benzene rings with one to four substituents independently selected from halo; hydroxy; mercapto; phenyl; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and Z is C(═O). 20. A compound according to claim 2 wherein all R1 are hydrogen each R2 is independently selected from hydrogen and halo; X1 and X2 are each CH2; or X1 and X2 are taken together form CH═CH; W1 and W2 are both CH2; A is AB wherein Yb is selected from C(═O); CRY1RY2; CRY3 [C(═O)RY4]; CRY3[NRY5C(═O)RY4]; CRY3[C(═O)NRY6RY7]; and CRY3[NRY6 RY7]; Yc is selected from O; S; SO2; NH; N[(C1-C6)alkyl] wherein said (C1-C6)alkyl is optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; N—(CH2)n3-heterocyclyl wherein n3 is an integer selected from 0, 1, 2 and 3, and said heterocyclyl contains from four to eight ring atoms one or two of which are independently selected from nitrogen, oxygen and sulfur; N—(CH2)n4-aryl wherein n4 is an integer selected from 0, 1, 2 and 3, and said aryl is selected from phenyl and naphthyl; and N—(CH2)n5-heteroaryl wherein n5 is an integer selected from 0, 1, 2 and 3, and said heteroaryl is a five to ten membered aromatic heterocyclyl containing from one to four hetero atoms independently selected from nitrogen, oxygen and sulfur; wherein RY1 and RY2 are independently selected from hydrogen; hydroxy; non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl; [(C1-C6)alkyl]-C(═O)—; [(C1-C6)alkoxy]-C(═O)—; [(C1-C6)alkyl]-SO2—; and four- to eight-membered heterocyclyl containing one to four hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy, (C1-C6)alkyl, NH2—C(O═)—, [(C1-C6)alkyl]-NH—C(═O)—, [(C1-C6)alkyl]2-N—C(═O)—, and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6) alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6 N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; or RY1 and RY2 taken together with the carbon atom to which they are attached form spiropyrrolidinyl or spiropiperidinyl, both of which are optionally N-substituted with a substituent selected from (C1-C6)alkyl, (C1-C6)alkyl-C(═O)—, [(C1-C6)alkyl]-C(═O)-(C1-C6)alkyl and aryl-(C═O)— wherein aryl is selected from phenyl and naphthyl; RY3 is hydrogen; RY4 is selected from hydroxy; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra1Ra2N—C(═O)—, wherein Ra1 Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)akyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6 Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and RY5, RY6 and RY7 are independently selected from hydrogen; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; hetrocyclyl-(CH2)m6— wherein n6 is an integer selected from 0, 1, 2, 3 and 4 and said heterocyclyl is four to eight membered containing one to three hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and hetroaryl-(CH2)n7— wherein n7 is an integer selected from 0, 1, 2, 3 and 4 and said heteroaryl is five to ten membered containing one to three hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heteroaryl is optionally substituted with one to three substituents independently selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; or RY6 and RY7 taken together with the nitrogen atom to which they are attached form a four to eight heterocyclyl optionally containing, in addition to the nitrogen atom, one to two additional hetero atoms independently selected from nitrogen, oxygen and sulfur, and said heterocyclyl is optionally substituted with one substituent selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; said A is optionally substituted in the fused benzene rings with one to four substituents independently selected from halo; hydroxy; mercapto; phenyl; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and Z is selected from C(═O); (CH2)n8 wherein n8 is an integer selected from 0, 1 and 2; and CHRZ1 wherein RZ1 is selected from carboxy; (C1-C6)alkoxy-C(═O)—; non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkyl]-C(═O)—O— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and [C(═O)—NRZ11RZ12] wherein RZ11 and RZ12 are independently selected from hydrogen and (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—. 21. A compound according to claim 1 wherein all R1 are hydrogen each R2 is independently selected from hydrogen and halo; X1 is selected from (CH2)n1 wherein n1 is an integer selected from 1, 2 and 3; O; NH; S; C(═O); SO2; and N[(C1-C4)alkyl]; X2 is selected from CH2; O; NH; S; C(═O); SO2; and N[(C1-C4)alkyl]; or X1 and X2 taken together form CH═CH; W1 and W2 are independently selected from CRW1RW2, wherein RW1 and RW2 are independently selected from hydrogen; halo; hydroxy; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; C(═O)-[(C1-C6)alkyl] wherein said (C1-C6)alkyl is optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; C(═O)—NRW11RW12 wherein RW11 and RW12 are independently selected from hydrogen and (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1Ra2 Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; NRW13RW14 wherein RW13 and RW14 are independently selected from hydrogen and (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; aryl selected from phenyl and naphthyl; and four- to eight-membered heterocyclyl containing one to four hetero atoms independently selected from nitrogen, oxygen and sulfur; A is AC wherein Yd, Ye and Yf are independently selected from C(═O); CRY1RY2; CRY3 [C(═O)RY4]; CRY3[NRY5 C(═O)RY4]; CRY3[C(═O)NRY6 RY7]; CRY3[NRY6RY7]; O; S; SO2; NH; N[(C1-C6)alkyl] wherein said (C1-C6)alkyl is optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra1, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; N—(CH2)n3-heterocyclyl wherein n3 is an integer selected from 0, 1, 2 and 3, and said heterocyclyl contains from four to eight ring atoms one or two of which are independently selected from nitrogen, oxygen and sulfur; N—(CH2)n4-aryl wherein n4 is an integer selected from 0, 1, 2 and 3, and said aryl is selected from phenyl and naphthyl; and N—(CH2)n5-heteroaryl wherein n5 is an integer selected from 0, 1, 2 and 3, and said heteroaryl is a five to ten membered aromatic heterocyclyl containing from one to four hetero atoms independently selected from nitrogen, oxygen and sulfur; RY1 and RY2 are independently selected from hydrogen; hydroxy; non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl; [(C1-C6)alkyl]-C(═O)—; [(C1-C6)alkoxy]-C(═O)—; [(C1-C6)alkyl]-SO2—; and four- to eight-membered heterocyclyl containing one to four hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy, (C1-C6)alkyl, NH2—C(O═)—, [(C1-C6)alkyl]-NH—C(═O)—, [(C1-C6)alkyl]2-N—C(═O)—, and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra1N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; or RY1 and RY2 taken together with the carbon atom to which they are attached form spiropyrrolidinyl or spiropiperidinyl, both of which are optionally N-substituted with a substituent selected from (C1-C6)alkyl, (C1-C6)alkyl-C(═O)—, [(C1-C6)alkyl]-C(═O)-(C1-C6)alkyl and aryl-(C═O)— wherein aryl is selected from phenyl and naphthyl; RY3 is hydrogen; RY4 is selected from hydroxy; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and RY5, RY6 and RY7 are independently selected from hydrogen; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; hetrocyclyl-(CH2)n6— wherein n6 is an integer selected from 0, 1, 2, 3 and 4 and said heterocyclyl is four to eight membered containing one to three hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and hetroaryl-(CH2)n7— wherein n7 is an integer selected from 0, 1, 2, 3 and 4 and said heteroaryl is five to ten membered containing one to three hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heteroaryl is optionally substituted with one to three substituents independently selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; or RY6 and RY7 taken together with the nitrogen atom to which they are attached form a four to eight heterocyclyl optionally containing, in addition to the nitrogen atom, one to two additional hetero atoms independently selected from nitrogen, oxygen and sulfur, and said heterocyclyl is optionally substituted with one substituent selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and said A is optionally substituted in the fused benzene rings with one to four substituents independently selected from halo; hydroxy; mercapto; phenyl; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3 Ra4 N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and Z is selected from C(═O); (CH2)n8 wherein n8 is an integer selected from 0, 1 and 2; and CHRZ1 wherein RZ1 is selected from carboxy; (C1-C6)alkoxy-C(═O)—; non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkyl]-C(═O)—O— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and [C(═O)—NRZ11RZ12] wherein RZ11 and RZ12 are independently selected from hydrogen and (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4 N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—. 22. A compound according to claim 1 wherein all R1 are hydrogen each R2 is independently selected from hydrogen and halo; X1 and X2 are each CH2; or X1 and X2 are taken together form CH═CH; W1 and W2 are independently selected from CRW1RW2, wherein RW1 and RW2 are independently selected from hydrogen; halo; hydroxy; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5, Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; C(═O)-[(C1-C6)alkyl] wherein said (C1-C6)alkyl is optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2 Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; C(═O)—NRW11RW12 wherein RW11 and RW12 are independently selected from hydrogen and (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; NRW13 RW14 wherein RW13 and RW14 are independently selected from hydrogen and (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; aryl selected from phenyl and naphthyl; and four- to eight-membered heterocyclyl containing one to four hetero atoms independently selected from nitrogen, oxygen and sulfur; A is AE wherein Yi, Yj, Yk and Ym are independently selected from C(═O); CRY1RY2; CRY3[C(═O)RY4]; CRY3[NRY5C(═O)RY4]; CRY [C(═O)NRY6 RY7]; CRY3[NRY6 RY7]; O; S; SO2; NH; N[(C1-C6)alkyl] wherein said (C1-C6)alkyl is optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; N—(CH2)n3-heterocyclyl wherein n3 is an integer selected from 0, 1, 2 and 3, and said heterocyclyl contains from four to eight ring atoms one or two of which are independently selected from nitrogen, oxygen and sulfur; N—(CH2)n4-aryl wherein n4 is an integer selected from 0, 1, 2 and 3, and said aryl is selected from phenyl and naphthyl; and N—(CH2)n5-heteroaryl wherein n5 is an integer selected from 0, 1, 2 and 3, and said heteroaryl is a five to ten membered aromatic heterocyclyl containing from one to four hetero atoms independently selected from nitrogen, oxygen and sulfur; RY1 and RY2 are independently selected from hydrogen; hydroxy; non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl; [(C1-C6)alkyl]-C(═O)—; [(C1-C6)alkoxy]-C(═O)—; [(C1-C6)alkyl]-SO2—; and four- to eight-membered heterocyclyl containing one to four hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy, (C1-C6)alkyl, NH2—C(O═)—, [(C1-C6)alkyl]-NH—C(═O)—, [(C1-C6)alkyl]2-N—C(═O)—, and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; or RY1 and RY2 taken together with the carbon atom to which they are attached form spiropyrrolidinyl or spiropiperidinyl, both of which are optionally N-substituted with a substituent selected from (C1-C6)alkyl, (C1-C6)alkyl-C(═O)—, [(C1-C6)alkyl]-C(═O)-(C1-C6)alkyl and aryl-(C═O)— wherein aryl is selected from phenyl and naphthyl; RY3 is hydrogen; RY4 is selected from hydroxy; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and RY5, RY6 and RY7 are independently selected from hydrogen; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; hetrocyclyl-(CH2)n6— wherein n6 is an integer selected from 0, 1, 2, 3 and 4 and said heterocyclyl is four to eight membered containing one to three hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and hetroaryl-(CH2)n7— wherein n7 is an integer selected from 0, 1, 2, 3 and 4 and said heteroaryl is five to ten membered containing one to three hetero atoms independently selected from nitrogen, oxygen and sulfur, wherein said heteroaryl is optionally substituted with one to three substituents independently selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; or RY6 and RY7 taken together with the nitrogen atom to which they are attached form a four to eight heterocyclyl optionally containing, in addition to the nitrogen atom, one to two additional hetero atoms independently selected from nitrogen, oxygen and sulfur, and said heterocyclyl is optionally substituted with one substituent selected from hydroxy; (C1-C6)alkyl; NH2—C(O═)—; (C1-C6)alkyl-NH—C(═O)—; [(C1-C6)alkyl]2-N—C(═O)—; and non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and said A is optionally substituted in the fused benzene rings with one to four substituents independently selected from halo; hydroxy; mercapto; phenyl; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and (C1-C6)alkoxy optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra5Ra6N— and Ra7Ra8N—C(═O)—, wherein Ra5, Ra6, Ra7 and Ra8 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and Z is selected from C(═O); (CH2)n8 wherein n8 is an integer selected from 0, 1 and 2; and CHRZ1 wherein RZ1 is selected from carboxy; (C1-C6)alkoxy-C(═O)—; non-, mono- and di-substituted amino wherein the substituents are independently selected from (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkyl]-C(═O)—O— and [(C1-C6)alkyl]-SO2—; (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—; and [C(═O)—NRZ11RZ12] wherein RZ11 and RZ12 are independently selected from hydrogen and (C1-C6)alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, carboxy, [(C1-C6)alkyl]-C(═O)—, (C1-C6)alkoxy, [(C1-C6)alkoxy]-C(═O)—, Ra1Ra2N— and Ra3Ra4N—C(═O)—, wherein Ra1, Ra2, Ra3 and Ra4 are independently selected from hydrogen, (C1-C6)alkyl, [(C1-C6)alkyl]-C(═O)—, [(C1-C6)alkoxy]-C(═O)— and [(C1-C6)alkyl]-SO2—. 23. A compound according to claim 1 selected from 2,3-dihydro-1′-{3-[2-(N-methylaminocarbonyl)indolin-1-yl]-3-oxopropyl} spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-[3-(2-N,N-dimethylaminocarbonylindolin-1-yl)-3-oxopropyl]spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-[3-(2-morpholinocarbonylindolin-1-yl)-3-oxopropyl]spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-[3-(2-carbamoylindolin-1-yl)-3-oxopropyl]spiro[1H-indene-1,4′-piperidine] hydrochloride; 2,3-dihydro-1′-{3-[2-(1-ethylprrolydin-3-yl)aminocarbonylindolin-1-yl]-3-oxopropyl} spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-{3-[2-(S)—(N,N-dimethylaminoethyl)aminocarbonylindolin-1-yl]-3-oxopropyl} spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-{3-[2-(S)-(2-hydroxyethyl)aminocarbonylindolin-1-yl]-3-oxopropyl}spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-{3-[2-(S)-(2-aminoethyl)aminocarbonylindolin-1-yl]-3-oxopropyl} spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-{3-[2-(S)-(2-acetamidoethyl)aminocarbonylindolin-1-yl]-3-oxopropyl} spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-{3-[2-(S)-(2-methanesulfonamidoethyl)aminocarbonylindolin-1-yl]-3-oxopropyl} spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-[3-(2-(S)-N-methylaminocarbonylindolin-1-yl)-3-oxopropyl]spiro [1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-[3-(2-(S)-N,N-dimethylaminocarbonylindolin-1-yl)-3-oxopropyl]spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-{3-[2-(S)-(4-morpholinecarbonyl)indolin-1-yl]-3-oxopropyl} spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-[3-(2-(S)-aminocarbonylindolin-1-yl)-3-oxopropyl]spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-11′-[3-(2-methoxycarbonylindolin-1-yl)-3-oxopropyl]spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-[3-(indolin-1-yl)-3-oxopropyl]spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-[3-(2-(S)-methoxycarbonylindolin-1-yl)-3-oxopropyl]spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-11′-indolyl-3-oxopropyl]spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-[3-(2-hydroxymethylindolin-1-yl)-3-oxopropyl]spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-[3-(2-methoxymethylindolin-1-yl)-3-oxopropyl]spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-[3-(benzimidazol-2-one-1-yl)propyl]spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-[3-(benzothiazol-2-one-1-yl)propyl]spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-[3-(2-oxo-1,3-benzoxazol-3(2H)-yl)propyl]spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-[3-(2-hydroxymethylbenzimidazol-1-yl)-3-oxopropyl]spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-[3-(3-ethylbenzimidazol-2-one-1-yl)propyl]spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-[3-(2-acetamidobenzimidazol-1-yl)propyl]spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-{3-[3-(2-hydroxyethyl)benzimidazol-2-one-1-yl)propyl} spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-{3-[3-(2-aminoethyl)benzimidazol-2-one-1-yl)propyl} spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-{3-[3-(2-acetamidoethyl)benzimidazol-2-one-1-yl)propyl} spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-[3-(2-oxo-3,4-dihydro-1 (2H)-quinolinyl)propyl]spiro[1H-indene-1,4′-piperidine]; 2,3-dihydro-1′-[3-(3-methyl-2-oxo-3,4-dihydro-1 (2H)-quinazolinyl)propyl]spiro[1H-indene-1,4′-piperidine]; and 2,3-dihydro-1′-[3-oxo-3-(2,3,4,5-tetrahydro-1H-benzazepin-1-yl)propyl]spiro[1H-indene-1,4′-piperidine]; or a salt thereof. 24. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier for treating a disease or medical condition mediated by ORL1-receptor and its endogeneous ligand in a mammal including a human. 25. A method for treating a disease in a mammal including a human, wherein said disease is selected from; pain; eating disorders; anxiety and stress conditions; immune system diseases; locomotor disorder; memory loss, cognitive disorders and dementia; epilepsy or convulsion and symptoms associated therewith; anti-epileotic action; disruption of spatial memory; drug abuse; cardiovascular disorders; hypotension; bradycardia; stroke; renal disorders; water excretion, sodium ion excretion; syndrome of inappropriate secretion of antidiuretic hormone (SIADH); gastrointestinal disorders; airway disorders; metabolic disorders; cirrhosis with ascites; sexual dysfunctions; altered pulmonary function, comprising administering an effective amount of a compound of claim 1 to a mammal including a human, which suffers from such disease. |
<SOH> BACKGROUND ART <EOH>Three types of opioid receptors, μ (mu), δ (delta) and κ (kappa) have been identified. These receptors may be indicated with combinations of OP (abbreviation for Opioid Peptides) and numeric subscripts as suggested by the International Union of Pharmacology (IUPHAR). Namely, OP 1 , OP 2 and OP 3 respectively correspond to δ-, κ- and μ-receptors. It has been found out that they belong to G-protein-coupled receptors and distribute in the central nervous system (CNS), peripheries and organs in a mammal. As ligands for the receptors, endogeneous and synthetic opioids are known. It is believed that an endogeneous opioid peptide produces their effects through an interaction with the major classes of opioid receptors. For example, endorphins have been purified as endogeneous opioid peptides and bind to both δ- and μ-receptors. Morphine is a well-known non-peptide opioid analgesic and has binding affinity mainly for μ-receptor. Opiates have been widely used as pharmacological agents, but drugs such as morphine and heroin induce some side effects such as drug addiction and euphoria. Further, Meunier et al. reported isolation of a seventeen-amino-acid-long peptide from rat brain as an endogeneous ligand for an orphan opioid receptor (Nature, Vol. 337, pp. 532-535, Oct. 12, 1995). The receptor is known as “opioid receptor-like 1 (abbreviated as ORL1-receptor)” which is believed to be almost as homologous to any of μ-, δ- and κ-receptors. In the same report, the endogeneous opioid ligand has been introduced as agonist for ORL-1 receptor and named as “nociceptine (abbreviated as NC)”. Also, the same ligand was named as “orphanin FQ (abbreviated as OFQ or oFQ)” by Reinscheid et al. (Science, Vol. 270, pp. 792-794, 1995). This receptor may be indicated as OP 4 in line with a recommendation by IUPHAR in 1998 (British Journal of Pharmacology, Vol. 129, pp. 1261-1283, 2000). Opioids and their affinity for these receptors have been researched in-vitro and in-vivo. It is possible to date to test whether an opioid has agonist or antagonist properties or a combination of both on the receptors. Use of a synthetic ORL1-receptor ligand or antagonist as an analgesic is disclosed in WO 00/27815 (Smithkline Beecham Spa) or WO 99/48492 (Japan Tobacco Inc.). Use of a synthetic ORL1-receptor antagonist for treating a CNS disorder is disclosed in WO 00/27815 (Smithkline Beecham Spa), WO 99/29696 (F. Hoffmann-La Roche A G) or British Journal of Pharmacology, Vol. 129, pp. 1261-1283, 2000 by G. Calo et al. Banyu's WO 98/54168, WO 00/31061, WO 00/34280 and Japanese Patent Publication Kokai 2000-169476 disclose use of a synthetic ORL1-receptor ligand or antagonist as an analgesic or for treating a CNS disorder. Schering's WO 01/07051 discloses use of a synthetic ORL-1 agonist in treating cough. |
Preparation of olefin polymerisation catalyst component |
A process for producing a Gp 2/transition metal olefin polymerisation catalyst component, in which a Gp 2 complex is reacted with a transition metal compound so as to produce an oil-in-oil emulsion, the disperse phase containing the preponderance of the Gp 2 metal being selectively sorbed on a carrier to provide a catalyst component of excellent morphology. Polymerisation of olefins using a catalyst containing such a component is also disclosed. |
1. A process for producing an olefin polymerisation catalyst component in the form of particles having a predetermined size range, comprising: preparing a solution of a complex of a Group 2 metal and an electron donor by reacting a compound of said Group 2 metal with said electron donor or a precursor thereof in an organic liquid reaction medium; reacting said complex, in solution, with at least one compound of a transition metal to produce a denser oil comprising more than 50 mol % of the Group 2 metal in said complex and an oil immiscible therewith; preferentially sorbing said denser oil on a carrier comprising carrier particles having an average particle size of 10 to 200 μm and a pore volume of 0.5 to 4 ml/g; solidifying said sorbed oil contained by said carrier, wherein said solidified sorbed oil comprises catalyst component particles; and recovering, washing and drying the carrier to obtain said catalyst component particles. 2. A process according to claim 1 wherein said transition metal is a Group 4 metal. 3. A process according to claim 1 or claim 2 wherein said Group 2 metal is magnesium. 4. A process according to claim 1 or claim 2 wherein said organic liquid reaction medium comprises a C6-C10 aromatic hydrocarbon or a mixture of a C6-C10 aromatic hydrocarbon and C5-C9 aliphatic hydrocarbons. 5. A process according to claim 2 wherein said Group 2 metal is magnesium and said denser oil is a TiCl4/toluene-insoluble oil having a Group 4 metal/Mg mol ratio greater than 0.1 and less than 10 and said oil immiscible therewith has a Group 4 metal/Mg mol ratio of 10 to 100. 6. A process according to claim 5 wherein the Group 4 metal/Mg mol ratio of said immiscible oil is 20 to 80. 7. A process according to claim 6 wherein the Group 4 metal/Mg mol ratio of said immiscible oil is 45 to 75. 8. A process according to claim 1 or claim 2 wherein said complex and said transition metal compound are reacted at a temperature of 10° C. to 60° C. 9. A process according to claim 1 or claim 2 wherein the solidification of said sorbed oil particles is effected by heating. 10. A process according to claim 1 or claim 2 wherein said electron donor is an aromatic carboxylic acid ester. 11. A process according to claim 10 wherein said electron donor is dioctyl phthalate. 12. A process according to claim 1 or claim 2 wherein said electron donor is formed in situ by reaction of an aromatic carboxylic acid chloride precursor with a C2-C16 alkanol and/or diol. 13. A process according to claim 1 or claim 2 wherein said liquid reaction medium comprises toluene. 14. A process according to claim 2 wherein said Group 4 metal is titanium. 15. A process according to claim 2 wherein said compound of a Group 4 metal is a halide. 16. A process according to claim 3 wherein said transition metal compound is a Group 4 metal compound and said magnesium complex and Group 4 metal compound are reacted at a temperature of greater than 20° C. to less than 50° C. 17. A process according to claim 1 or claim 2 wherein said carrier comprises a refractory inorganic oxide, a salt or an organic polymer having a softening point greater than 150° C. 18. A process according to claim 17 wherein said carrier comprises silica, magnesium chloride or cross-linked polystyrene resin. 19. A process according to claim 3 wherein said transition metal compound is a Group 4 metal compound and the Group 4 metal/Mg mol ratio of said denser oil is 2 to 4 and the Group 4 metal/Mg mol ratio of the oil immiscible therewith is 55 to 65. 20. A process according to claim 3 wherein said transition metal compound is a Group 4 metal compound and the carrier is added to the product of the reaction between said Mg complex and said Group 4 metal compound. 21. A process according to claim 3 wherein said transition metal compound is a Group 4 metal compound and the carrier is added to said Group 4 metal compound before reaction thereof with said Mg complex. 22. A process according to claim 3 wherein the mol ratio of Mg in said denser oil to Mg in said oil immiscible therewith is less than 0.1. 23. A process according to claim 1 or claim 2 wherein the carrier containing the sorbed oil is heated to a temperature of 70° C. to 150° C. to solidify said sorbed oil. 24. A process according to claim 1 or claim 2 wherein the the carrier containing the sorbed oil is heated to a temperature of 90° C. to 110° C. 25. A process according to claim 3 wherein the preparation of the magnesium complex is carried out at a temperature of 20° C. to 80° C. 26. A process according to claim 25 wherein the preparation of the magnesium complex is carried out at a temperature of 50° C. to 70° C. 27. A process according to claim 1 or claim 2 wherein said obtained catalyst component particles have an average size range of 10 to 200 μm. 28. A process according to claim 27 wherein said catalyst component particles have an average size range of 20 to 50 μm. 29. A process according to claim 3 wherein said transition metal compound is a Group 4 metal compound and wherein a surface active agent is added to the solution of the magnesium complex before reaction with the Group 4 metal compound. 30. A process according to claim 29 wherein said surface active agent is a sorbitan tristearate. 31. A process according to claim 29 wherein the magnesium complex and a compound of a tetravalent Group 4 metal are reacted in the presence of an additional electron donor. 32. An olefin polymerisation catalyst comprising a catalyst component prepared according to the process of claim 1 or claim 2 and an alkylaluminum cocatalyst. 33. The polymerisation catalyst of claim 32 wherein the polymerisation catalyst is used for the polymerisation of C2 to C10 α-olefins. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Processes for the preparation of such a catalyst component—as described, for instance, in WO 00/08073 and 00/08074—usually include a step in which a magnesium-Gp 4 metal-electron donor component is recovered by precipitation from solution, typically by contacting the solution with a large amount of an aliphatic hydrocarbon. However, such precipitation leads to a tar-like reaction product of low catalytic activity, that needs to be washed several times in order to decrease the amount of inactive Gp 4 metal complex. Aromatic hydrocarbons have also been used for the precipitation, but they lead to a very finely divided precipitate which is difficult to deposit. Worse still, it is difficult to carry out such precipitation in a controlled and reproducible manner, leading to unsatisfactory product morphology. Moreover variable and low concentrations of catalyst constituents such as butyl chloride may result, as a consequence of pre-precipitation evaporative removal of aliphatic solvent. detailed-description description="Detailed Description" end="lead"? |
Bis-aryl thiazole derivatives |
Compounds, compositions and methods are provided that are useful in the treatment or prevention of a condition or disorder mediated by an uncoupling protein. In particular, the compounds of the invention modulate the expression and/or activity of UCP3. The subject compositions are particularly useful in the treatment of obesity and type II diabetes, and associated diseases. |
1-81. (canceled) 82. A compound having the formula (I): or a pharmaceutically acceptable salt or prodrug thereof, wherein X is selected from the group consisting of CO2R1 and C(O)NR1R2; Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; Z1 is selected from the group consisting of hydrogen, (C1-C4)alkyl and halogen; Z2 is selected from the group consisting of aryl and heteroaryl, or Z1 and Z2 may be combined to form a fused 6-membered ring; and R1, R2, R3 and R are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl; with the proviso that the compound is not 1-[4-(3-(trifluoromethyl)phenyl)thiazol-2-yl]-5-methylpyrazole-4-carboxylic acid, 1-[4-(3-(trifluoromethyl)phenyl)thiazol-2-yl]-5-trifluoromethylpyrazole-4-carboxylic acid, 1-[4-(3-methoxyphenyl)thiazol-2-yl]-5-trifluoromethylpyrazole-4-carboxylic acid, 1-[4-(4-chlorophenyl)thiazol-2-yl]-5-trifluoromethylpyrazole-4-carboxylic acid, 1-[4-(4-nitrophenyl)thiazol-2-yl]-5-trifluoromethylpyrazole-4-carboxylic acid, 1-[4-(3-(trifluoromethyl)phenyl)-5-bromothiazol-2-yl]-5-trifluoromethylpyrazole-4-carboxylic acid, 1-[4-(3-methylphenyl)thiazol-2-yl]-5-trifluoromethylpyrazole-4-carboxylic acid, 1-[4-(4-(trifluoromethyl)phenyl)thiazol-2-yl]-5-trifluoromethylpyrazole-4-carboxylic acid, 1-[4-(2-(trifluoromethyl)phenyl)thiazol-2-yl]-5-trifluoromethylpyrazole-4-carboxylic acid, 1-[4-(3-chlorophenyl)thiazol-2-yl]-5-trifluoromethylpyrazole-4-carboxylic acid, or 1-[4-(3-(trifluoromethyl)phenyl)thiazol-2-yl]-5-phenylpyrazole-4-carboxylic acid. 83. The compound of claim 82, wherein X is CO2R′; Y is selected from the group consisting of hydrogen, heteroaryl, halogen, NR3R4 and CO2R3; Z1 is selected from the group consisting of hydrogen, (C1-C4)alkyl and halogen; Z2 is selected from the group consisting of aryl and heteroaryl, or Z1 and Z2 may be combined to form a fused 6-membered ring; and R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl. 84. The compound of claim 82, wherein X is CONR1R2; Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; Z1 is selected from the group consisting of hydrogen, (C1-C4)alkyl and halogen; Z2 is selected from the group consisting of aryl and heteroaryl, or Z1 and Z2 may be combined to form a fused 6-membered ring; and R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl. 85. The compound of claim 82, wherein said compound has the formula (II): or a pharmaceutically acceptable salt or prodrug thereof, wherein X is selected from the group consisting of CO2R1 and C(O)NR1R2; Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; Z1 is selected from the group consisting of hydrogen, (C1-C4)alkyl and halogen; Z2 is selected from the group consisting of aryl and heteroaryl, or Z1 and Z2 may be combined to form a fused 6-membered ring; and R1, R2, R3 and R are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl. 86. The compound of claim 82, wherein X is CO2H. 87. The compound of claim 82, wherein Y is hydrogen, (C1-C4)alkyl or fluoro(C1-C4)alkyl. 88. The compound of claim 82, wherein Z1 is hydrogen. 89. The compound of claim 82, wherein Z2 is phenyl, naphthyl, pyridyl or pyrimidinyl. 90. The compound of claim 82, wherein Z2 is phenyl and X 91. The compound of claim 82, wherein Z2 is phenyl and Y is (C1-C4)alkyl or fluoro(C1-C4)alkyl. 92. The compound of claim 82, wherein Z1 and Z2 are combined to form a fused benzene ring. 93. The compound of claim 85, wherein said compound has the formula (III): or a pharmaceutically acceptable salt or prodrug thereof, wherein Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; Z1 is selected from the group consisting of hydrogen, (C1-C4)alkyl and halogen; Z2 is selected from the group consisting of aryl and heteroaryl, or Z1 and Z2 may be combined to form a fused 6-membered ring; and R1, R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl. 94. The compound of claim 93, wherein R1 is hydrogen. 95. The compound of claim 93, wherein Z2 is phenyl. 96. The compound of claim 95, wherein said compound has the formula (IV): or a pharmaceutically acceptable salt or prodrug thereof, wherein Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; R1, R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl; W is (C1-C4)alkyl, fluoro(C1-C4)alkyl, halogen or nitro; and n is an integer from 1 to 3. 97. The compound of claim 96, wherein Y is (C1-C4)alkyl. 98. The compound of claim 85, wherein said compound has the formula (VI): or a pharmaceutically acceptable salt or prodrug thereof, wherein Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; Z1 is selected from the group consisting of hydrogen, (C1-C4)alkyl and halogen; Z2 is selected from the group consisting of aryl and heteroaryl, or Z1 and Z2 may be combined to form a fused 6-membered ring; and R1, R2, R3 and R are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl. 99. The compound of claim 98, wherein Z2 is phenyl. 100. The compound of claim 99, wherein said compound has the formula (VII): or a pharmaceutically acceptable salt or prodrug thereof, wherein Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl; W is (C1-C4)alkyl, fluoro(C1-C4)alkyl, halogen or nitro; and n is an integer from 1 to 3. 101. The compound of claim 100, wherein Y is (C1-C4)alkyl. 102. The compound of claim 82, wherein said compound is 103. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of formula (I): or a pharmaceutically acceptable salt or prodrug thereof, wherein X is selected from the group consisting of CO2R′ and C(O)NR1R2; Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; Z1 is selected from the group consisting of hydrogen, (C1-C4)alkyl and halogen; Z2 is selected from the group consisting of aryl and heteroaryl, or Z1 and Z2 may be combined to form a fused 6-membered ring; and R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl. 104. The composition of claim 103, wherein said compound has the formula (II): or a pharmaceutically acceptable salt or prodrug thereof, wherein X is selected from the group consisting of CO2R′ and C(O)NR1R2; Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; Z1 is selected from the group consisting of hydrogen, (C1-C4)alkyl and halogen; Z2 is selected from the group consisting of aryl and heteroaryl, or Z1 and Z2 may be combined to form a fused 6-membered ring; and R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl. 105. The composition of claim 103, wherein X is CO2H. 106. The composition of claim 103, wherein Y is hydrogen, (C1-C4)alkyl or fluoro(C1-C4)alkyl. 107. The composition of claim 103, wherein Z1 is hydrogen. 108. The composition of claim 103, wherein Z2 is phenyl, naphthyl, pyridyl or pyrimidinyl. 109. The composition of claim 103, wherein Z2 is phenyl and X is CO2H. 110. The composition of claim 103, wherein Z2 is phenyl and Y is (C1-C4)alkyl or fluoro(C1-C4)alkyl. 111. The composition of claim 103, wherein Z and Z2 are combined to form a fused benzene ring. 112. The composition of claim 104, wherein said compound has the formula (III): or a pharmaceutically acceptable salt or prodrug thereof, wherein Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; Z1 is selected from the group consisting of hydrogen, (C1-C4)alkyl and halogen; Z2 is selected from the group consisting of aryl and heteroaryl, or Z1 and Z2 may be combined to form a fused 6-membered ring; and R1, R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl. 113. The composition of claim 112, wherein R1 is hydrogen. 114. The composition of claim 112, wherein Z2 is phenyl. 115. The composition of claim 114, wherein said compound has the formula (IV): or a pharmaceutically acceptable salt or prodrug thereof, wherein Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; R1, R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl; W is (C1-C4)alkyl, fluoro(C1-C4)alkyl, halogen or nitro; and n is an integer from 1 to 3. 116. The composition of claim 115, wherein Y is (C1-C4)alkyl. 117. The composition of claim 104, wherein said compound has the formula (VI): or a pharmaceutically acceptable salt or prodrug thereof, wherein Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; Z1 is selected from the group consisting of hydrogen, (C1-C4)alkyl and halogen; Z2 is selected from the group consisting of aryl and heteroaryl, or Z1 and Z2 may be combined to form a fused 6-membered ring; and R1, R2, R3 and R are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl. 118. The composition of claim 117, wherein Z2 is phenyl. 119. The composition of claim 118, wherein said compound has the formula (VII): or a pharmaceutically acceptable salt or prodrug thereof, wherein Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl; W is (C1-C4)alkyl, fluoro(C1-C4)alkyl, halogen or nitro; and n is an integer from 1 to 3. 120. The composition of claim 119, wherein Y is (C1-C4)alkyl. 121. The composition of claim 103, wherein said compound is 122. A method for treating obesity or diabetes, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I): or a pharmaceutically acceptable salt or prodrug thereof, wherein X is selected from the group consisting of CO2R′ and C(O)NR1R2; Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; Z1 is selected from the group consisting of hydrogen, (C1-C4)alkyl and halogen; Z2 is selected from the group consisting of aryl and heteroaryl, or Z1 and Z2 may be combined to form a fused 6-membered ring; and R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl. 123. A method of treating a condition or disorder mediated by UCP3, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I): or a pharmaceutically acceptable salt or prodrug thereof, wherein X is selected from the group consisting of CO2R′ and C(O)NR1R2; Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; Z1 is selected from the group consisting of hydrogen, (C1-C4)alkyl and halogen; Z2 is selected from the group consisting of aryl and heteroaryl, or Z1 and Z2 may be combined to form a fused 6-membered ring; and R1, R2, R3 and R are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl. 124. A method of treating a condition or disorder mediated by RXR, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I): or a pharmaceutically acceptable salt or prodrug thereof, wherein X is selected from the group consisting of CO2R′ and C(O)NR1R2; Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; Z1 is selected from the group consisting of hydrogen, (C1-C4)alkyl and halogen; Z2 is selected from the group consisting of aryl and heteroaryl, or Z and Z2 may be combined to form a fused 6-membered ring; and R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl. 125. The method of claim 122, wherein said compound has the formula (II): or a pharmaceutically acceptable salt or prodrug thereof, wherein X is selected from the group consisting of CO2R′ and C(O)NR1R2; Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; Z1 is selected from the group consisting of hydrogen, (C1-C4)alkyl and halogen; Z2 is selected from the group consisting of aryl and heteroaryl, or Z1 and Z2 may be combined to form a fused 6-membered ring; and R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl. 126. The method of claim 122, wherein X is CO2H. 127. The method of claim 122, wherein Y is hydrogen, (C1-C4)alkyl or fluoro(C1-C4)alkyl. 128. The method of claim 122, wherein Z1 is hydrogen. 129. The method of claim 122, wherein Z2 is phenyl, naphthyl, pyridyl or pyrimidinyl. 130. The method of claim 122, wherein Z2 is phenyl and X is CO2H. 131. The method of claim 122, wherein Z2 is phenyl and Y is (C1-C4)alkyl or fluoro(C1-C4)alkyl. 132. The method of claim 122, wherein Z1 and Z2 are combined to form a fused benzene ring. 133. The method of claim 125, wherein said compound has the formula (III): or a pharmaceutically acceptable salt or prodrug thereof, wherein Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; Z1 is selected from the group consisting of hydrogen, (C1-C4)alkyl and halogen; Z2 is selected from the group consisting of aryl and heteroaryl, or Z1 and Z2 may be combined to form a fused 6-membered ring; and R1, R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl. 134. The method of claim 133, wherein R1 is hydrogen. 135. The method of claim 133, wherein Z2 is phenyl. 136. The method of claim 135, wherein said compound has the formula (IV): or a pharmaceutically acceptable salt or prodrug thereof, wherein Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; R1, R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl; W is (C1-C4)alkyl, fluoro(C1-C4)alkyl, halogen or nitro; and n is an integer from 1 to 3. 137. The method of claim 136, wherein Y is (C1-C4)alkyl. 138. The method of claim 125, wherein said compound has the formula (VI): or a pharmaceutically acceptable salt or prodrug thereof, wherein Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; Z1 is selected from the group consisting of hydrogen, (C1-C4)alkyl and halogen; Z2 is selected from the group consisting of aryl and heteroaryl, or Z1 and Z2 may be combined to form a fused 6-membered ring; and R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl. 139. The method of claim 138, wherein Z2 is phenyl. 140. The method of claim 139, wherein said compound has the formula (VII): or a pharmaceutically acceptable salt or prodrug thereof, wherein Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl; W is (C1-C4)alkyl, fluoro(C1-C4)alkyl, halogen or nitro; and n is an integer from 1 to 3. 141. The method of claim 140, wherein Y is (C1-C4)alkyl. 142. The method of claim 122, wherein said compound is 143. The method of claim 122, wherein said compound is administered in combination with a therapeutic agent selected from the group consisting of a β3 adrenergic receptor agonist, a leptin, a leptin derivative, a neuropeptide Y antagonist, insulin and derivatives thereof, a hypoglycemic agent, an antihyperglycemic agent, an α-glucosidase inhibitor, an insulin sensitizer, an RXR agonist, a cholesterol lowering agent, a calcium channel blocker, interferon alpha, interferon beta, a DNA-alkylating agent, an antimetabolite, a microtubule disruptor, a DNA intercalator, a DNA synthesis inhibitor and a hormone. 144. The method of claim 122, wherein said administering is oral or parenteral. 145. A method of modulating UCP3 expression, comprising contacting a cell with a compound of formula (I): or a pharmaceutically acceptable salt or prodrug thereof, wherein X is selected from the group consisting of CO2R1 and C(O)NR1R2; Y is selected from the group consisting of hydrogen, (C1-C4)alkyl, fluoro(C1-C4)alkyl, aryl, heteroaryl, halogen, NR3R4 and CO2R3; Z1 is selected from the group consisting of hydrogen, (C1-C4)alkyl and halogen; Z2 is selected from the group consisting of aryl and heteroaryl, or Z1 and Z2 may be combined to form a fused 6-membered ring; and R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, carboxy(C1-C4)alkyl and aryl. 146. The method of claim 145, wherein UCP3 expression is upregulated. 147. The method of claim 145, wherein UCP3 mRNA is increased. 148. The method of claim 145, wherein UCP3 is increased. 149. The method of claim 145, wherein said compound modulates RXR. 150. The method of claim 145, wherein said compound interacts with RXR. |
<SOH> BACKGROUND OF THE INVENTION <EOH>A mitochondrial protein called uncoupling protein 1 (UCP1) is thought to play an important role in the body's regulation of energy utilization. Such regulation provides widespread physiological controls, including body weight, appetite, glucose metabolism, temperature, immune responses, etc. Mechanistically, UCP1 is thought to create a pathway that allows dissipation of the proton electrochemical gradient across the inner mitochondrial membrane in brown adipose tissue, without coupling to any other energy consuming process (for review, see Nicholis & Locke (1984) Physiol. Rev. 64:1-64). Unfortunately, the role of UCP1 in physiologies, such as body weight regulation in large adult mammals, such as humans, cattle, pigs, etc., is likely to be limited, since there is little brown adipose tissue in such animals. UCP2 is a second, related uncoupling protein that is much more widely expressed in large adult mammals (see, e.g. Fleury et al. (1997) Nat. Genet. 15:269-272 and Tartaglia et al. WO 96/05861). Consistent with a role in the regulation of energy utilization in general, and in diabetes and obesity in particular, the UCP2 gene is upregulated in response to fat feeding and maps to regions of the human and mouse genomes linked to hyperinsulinaemia and obesity. More recently, a third structurally related UCP gene, UCP3 has been characterized and found to be preferentially expressed in skeletal muscle and brown adipose tissues; see Vidal-Puig et al. (1997) Biochem. Biophys. Res. Comm. 235:79-82 and Boss et al. (1997) FEBS Lett. 408:39-42. UCP3 has been linked to a number of disorders associated with the control of energy expenditure, including obesity and diabetes. The identification of compounds that modulate the activity and/or expression of UCP3 represents an attractive approach to the development of therapeutic agents for the treatment of conditions and disorders associated with energy utilization. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides methods of using bis-aryl thiazole compounds and compositions to treat conditions and disorders mediated by UCP3. In particular, the present invention provides methods for treating obesity and diabetes. The methods of the invention comprise administering to a subject in need thereof a therapeutically effective amount of a compound of formula (1): wherein X is selected from the group consisting of CO 2 R′ and C(O)NR 1 R 2 , Y is selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, fluoro(C 1 -C 4 )alkyl, aryl, heteroaryl, halogen, NR 3 R 4 and CO 2 R 3 , Z 1 is selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl and halogen, and Z 2 is selected from the group consisting of aryl and heteroaryl, or Z 1 and Z 2 may be combined to form a fused 6-membered ring. R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, carboxy(C 1 -C 4 )alkyl and aryl. The invention also provides methods for treating a condition or disorder mediated by UCP3. The invention further provides methods for treating a condition or disorder mediated by a nuclear hormone receptor transcription factor. The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient in combination with a compound of formula (I): wherein X is selected from CO 2 R 1 and C(O)NR 1 R 2 , Y is selected from hydrogen, (C 1 -C 4 )alkyl, fluoro(C 1 -C 4 )alkyl, aryl, heteroaryl, halogen, NR 3 R 4 and CO 2 R 3 , Z 1 is selected from hydrogen, (C 1 -C 4 )alkyl and halogen, and Z 2 is selected from aryl and heteroaryl, or Z 1 and Z 2 may be combined to form a fused 6-membered ring. R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, (C 1 -C 4 )alkyl, carboxy(C 1 -C 4 )alkyl and aryl. The present invention also provides compounds of formula (I): wherein X is selected from CO 2 R′ and C(O)NR 1 R 2 , Y is selected from hydrogen, (C 1 -C 4 )alkyl, fluoro(C 1 -C 4 )alkyl, aryl, heteroaryl, halogen, NR 3 R 4 and CO 2 R 3 , Z 1 is selected from hydrogen, (C 1 -C 4 )alkyl and halogen, Z 2 is selected from aryl and heteroaryl, or Z 1 and Z 2 may be combined to form a fused 6-membered ring, and R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, (C 1 -C 4 )alkyl, carboxy(C 1 -C 4 )alkyl and aryl, provided that the compound is not 1-[4-(3-(trifluoromethyl)phenyl)thiazol-2-yl]-5-methylpyrazole-4-carboxylic acid, 1-[4-(3-(trifluoromethyl)phenyl)thiazol-2-yl]-5-trifluoromethylpyrazole-4-carboxylic acid, 1-[4-(3-methoxyphenyl)thiazol-2-yl]-5-trifluoromethylpyrazole-4-carboxylic acid, 1-[4-(4-chlorophenyl)thiazol-2-yl]-5-trifluoromethylpyrazole-4-carboxylic acid, 1-[4-(4-nitrophenyl)thiazol-2-yl]-5-trifluoromethylpyrazole-4-carboxylic acid, 1-[4-(3-(trifluoromethyl)phenyl)-5-bromothiazol-2-yl]-5-trifluoromethylpyrazole-4-carboxylic acid, 1-[4-(3-methylphenyl)thiazol-2-yl]-5-trifluoromethylpyrazole-4-carboxylic acid, 1-[4-(4-(trifluoromethyl)phenyl)thiazol-2-yl]-5-trifluoromethylpyrazole-4-carboxylic acid, 1-[4-(2-(trifluoromethyl)phenyl)thiazol-2-yl]-5-trifluoromethylpyrazole-4-carboxylic acid, 1-[4-(3-chlorophenyl)thiazol-2-yl]-5-trifluoromethylpyrazole-4-carboxylic acid, or 1-[4-(3-(trifluoromethyl)phenyl)thiazol-2-yl]-5-phenylpyrazole-4-carboxylic acid. Unless otherwise indicated, the compounds provided in the above formulas are meant to include pharmaceutically acceptable salts and prodrugs thereof. Other objects, features and advantages of the present invention will become apparent to those skilled in the art from the following description and claims. |
Heatable liquid container for a motor vehicle |
A container (15) with a wall for accepting a liquid to be warmed in a vehicle, whereby the container (15) features a heating element (16), is characterized by the heating element (16) being fed from an electrical source of energy. |
1. Container (1, 15) with a wall for accepting a fluid to be heated in a vehicle, whereby the container (1, 15) features a heating element (16) characterized by the heating element (16) being fed from an electrical source of energy. 2. Container (1, 15) in accordance with claim 1, characterized by the source of energy being a vehicle battery. 3. Container (1, 15) in accordance with claim 1, characterized by a heating element (16) joined to a wall (18) of the container (1, 15). 4. Container (1, 15) in accordance with claim 3, characterized by a heating element (16) designed as a thick-film heater with a resistor element. 5. Container (1, 15) in accordance with claim 3, characterized by a heating element (16) protrudes into the container (1, 15) through an opening in the wall (18) of the container (1, 15). 6. Container (1, 15) in accordance with claim 5, characterized by an opening which is a filling opening for adding fluid to the container (1, 15). 7. Container (1, 15) in accordance with claim 1, characterized by a heating element (16) at least partially formed as a rod (19) or plate (23). 8. Container (1, 15) in accordance with claim 1, characterized by a heating element (16) shaped like a filament or spiral. 9. Container (1, 15) in accordance with claim 7, characterized by a heating element (16) including a heating rod (19) and a plate (23) placed at one free end of the heating rod (19). 10. Container (1, 15) in accordance with claim 1, characterized by a heating element (16) at least partially near a feed pump (20, 21, 22) for transporting the fluid out of the container (1, 15) or into it. 11. Container (1, 15) in accordance with claim 1, characterized by the source of energy being an electrical battery on board a motorized vehicle. 12. Container (1, 15) in accordance with claim 1, characterized by a first switch (in particular, a relay (9)) operated by means of ignition equipment for igniting an internal-combustion engine being placed in a circuit including the heating element (16) and the energy source, between the heating element (16) and the energy source. 13. Container (1, 15) in accordance with claim 1, characterized by control equipment (in particular, a second switch (10)) controllable by the fluid's level being placed in a circuit including the heating element (16) and the energy source. 14. Container (1, 15) in accordance with claim 1, characterized by a first thermostat (13) for setting the temperature being placed in the container (1, 15) or in a supply line leading to the container (1, 15) for feeding or removing the fluid. 15. Container (1, 15) in accordance with claim 14, characterized by having the first thermostat (13) open or close the supply line above a specific temperature value. 16. Container (1, 15) in accordance with claim 15, characterized by the temperature value being 35° C. 17. Container (1, 15) in accordance with claim 14, characterized by a second thermostat (serving as a safety thermostat) being inserted before the first thermostat, when a specific temperature value is exceeded, this second thermostat switches the control equipment on or off. In particular, it opens or closes a second switch. 18. Container (1, 15) in accordance with claim 17, characterized by the temperature value being 50° C. 19. Container (1, 15) in accordance with claim 1, characterized by it being formed as a blast-plastic part or as plastic injection molding part. 20. Container (1, 15) in accordance with claim 19, characterized by it featuring a lower (29) and upper part (28), with the heating element (16) placed at least in the lower part (29). 21. Container (1, 15) in accordance with claim 20, characterized by embedding at least one electrical heating filament (32) (in particular, a spiral-shaped one) in the wall of the lower part (29). 22. Container (1, 15) in accordance with claim 1, characterized by featuring a level sensor (10). |
Ionomer for use in fuel cells and method of making same |
The reaction product of a monomer comprising phthalazinone and a phenol group, and at least one sulfonated aromatic compound. The monomer comprising phthalazinone and a phenol group is used in a reaction with the sulfonated aromatic compound to produce ionomers with surprising and highly desirable properties. In one embodiment, the inventive ionomer is a sulfonated poly(phthalazinone ether ketone), hereinafter referred to as sPPEK. In another embodiment, the inventive ionomer is a sulfonated poly(phthalazinone either sulfone), herein after referred to as SPPES. In another embodiment, the inventive ionomer is other sulfonated aromatic polymeric compounds. The invention further includes the formation of these polymers into membranes and their use for polymer electrolyte membrane fuel cells (PEMFC), and in particular for direct methanol fuel cells (DMFC). The inventive polymers may be manufactured in membrane form, and can be dissolved into solution and impregnated into porous substrates to form composite polymer electrolyte membranes with improved properties. |
1. An ionomer comprising the reaction product of monomer A with monomer B and C, wherein the moles of monomers B plus C equal the moles of A, wherein R1-4 are independently H, linear or branched alkyl, aromatic, or halogen; X1 and X2 are independently a carbonyl or sulfone radical or aromatic compounds connected through a ketone or sulfone linkage; Y is independently a halogen group, and M is an alkali metal. 2. An ionomer as defined in claim 1 wherein monomer A comprises 4-(4-hydroxyphenyl)phthalazinone. 3. An ionomer as defined in claim 1 wherein monomer B comprises disodium 3,3′-sulfonyl(4,4′-difluorobenzophenone). 4. An ionomer as defined in claim 1 wherein monomer C comprises 4,4′-difluorobenzophenone. 5. An ionomer as defined in claim 1 wherein monomer A comprises 4-(4-hydroxyphenyl)phthalazinone, monomer B comprises disodium 3,3′-sulfonyl(4,4′-difluorobenzophenone), and monomer C comprises 4,4′-difluorobenzophenone. 6. An ionomer as defined in claim 1 wherein monomer B comprises disodium 3,3′-sulfonylbis(4-fluorophenyl sulfone). 7. An ionomer as defined in claim 1 wherein monomer C comprises bis(4-fluorophenyl)sulfone. 8. An ionomer as defined in claim 1 wherein monomer A comprises 4-(4-hydroxyphenyl) phthalazinone, monomer B comprises disodium 3,3′-sulfonylbis(4-fluorophenyl sulfone), and monomer C comprises bis(4-fluorophenyl)sulfone. 9. An ionomer comprising the reaction product of monomer A with monomer B and C in an azeotroping solvent mixed with an inert aprotic polar solvent containing at least 2 moles of an alkali metal base for each mole of monomer A, wherein the moles of monomers B plus C equal the moles of A, said reaction driven to completion by the azeotropic removal of water at a temperature above the azeotropic boiling point of the azeotroping solvent in the presence of water, wherein R1-4 are independently H, linear or branched alkyl, aromatic, or halogen; X1 and X2 are independently a carbonyl or sulfone radical or aromatic compounds connected through a ketone or sulfone linkage; and Y is a halogen group. 10. An ionomer comprising the reaction product of monomer A with an ionomer-contributing monomer. wherein R1-4 are independently H, linear or branched alkyl, aromatic, or halogen. 11. An ionomer as defined in claim 10 wherein said ionomer-contributing monomer comprises sulfonic acid. 12. An ionomer as defined in claim 10 wherein said ionomer-contributing monomer comprises carboxylic acid. 13. A sulfonated Poly(phthalazinone ether ketone)s, comprising repeating units of the polymers shown below: wherein R1 and R2 are selected from hydrogen atom, alkyl group, or aromatic group and M is metallic base ion. 14. A method of preparing a sulfonated poly(phthalzinone ether ketone) comprising the steps of (a) copolymerizing 4,4′-dihalo(or dinitro)-3,3′-disulfonate salt of benzophenone, dihalo(or dinitro)benzophenone, and a monomer containing phthalazinone and phenol group, in polar solvents or reaction medium containing mainly polar solvents, in the presence of a catalyst comprising a metallic base (or its salt), to obtain a product; (b) dehydrating said product at high temperature using azeotropic dehydration agents; (c) diluting said product with solvents; (d) coagulating said product using coagulation agents; (e) separating said product; (f) drying said product; and (g) performing steps (c) through (f) two additional times to obtain said sulfonated poly(phthalazinone ether ketone). 15. The preparation method of claim 14, wherein the reaction temperature is 150-220° C. and the reaction time is 4-32 hours. 16. The preparation method of claim 14, wherein the polar solvents are dimethyl sulfoxide, tetramethylene sulfone, phenyl sulfone, 1-methyl-2-pyrrolidinone, N,N-dimethylformamide. 17. The preparation method of claim 14, wherein the azeotropic dehydration agents are selected from the group consisting of toluene, xylene, and chloroform. 18. The preparation method of claim 14, wherein the coagulation agents are water and one of the group of methanol and ethanol. 19. A sulfonated poly(phthalazinone ether sulfone) comprising repeating units of the polymers shown below: wherein R1 and R2 are selected from hydrogen atom, C1-C4 linear or branch alkyl group, or aromatic group, M is sodium or potassium ion, m+n.> or =20 20. A method of preparing a sulfonated poly(phthalazinone ether sulfone), comprising the steps of (a) copolymerizing 4,4′-dihalo(or dinitro)-3,3-disulfonate salt of phenyl sulfone, dihalo(or dinitro)phenyl sulfone, and a monomer containing phthalazinone and phenol group, in polar solvents or reaction medium containing mainly polar solvents, in the presence of a catalyst comprising a metallic base (or its salt), to obtain a product; (b) dehydrating said product at high temperature using azeotropic dehydration agents; (c) diluting said product with solvents; (d) coagulating said product using coagulation agents; (e) separating said product from said agents; (f) drying said product; and (g) performing steps (c) through (f) two additional times to obtain said sulfonated poly(phthalazinone ether sulfone). 21. The preparation method of claim 20, wherein the monomer containing phthalazinone and phenol group has the following molecular structure: wherein R1 and R2 are selected from hydrogen atom, C1-C4 linear or branch alkyl group, or aromatic group. 22. The preparation method of claim 20, wherein the reaction temperature is 140-220° C. and the reaction time is 1-36 hours. 23. The preparation method of claim 20, wherein the polar solvents are dimethyl sulfoxide, tetramethylene sulfone, phenyl sulfone, 1-methyl-2-pyrrolidinone, and N,N-dimethylformamide. 24. The preparation method of claim 20, wherein the azeotropic dehydration agents are toluene, xylene, or chloroform. 25. The preparation method of claim 20, wherein the coagulation agents are water and methanol (or ethanol). 26. A method for generating electricity comprising the steps of: (a) providing an anode; (b) providing a cathode; (c) providing a polymer electrolyte membrane between said anode and said cathode and in communication with said anode and said cathode, said polymer electrolyte membrane comprising the ionomer of claim 1 in acid form (d) flowing a fuel to said cathode where said fuel is disassociated to release a proton and an electron; (e) transporting said proton across said polymer electrolyte membrane to said anode; and (f) collecting said electron at a collector to generate electricity. 27. A method as defined in claim 26 wherein said polymer electrolyte membrane comprises a polymeric support having interconnected passages and pathways that are substantially occluded by said polymer. 28. A method as defined in claim 26 wherein said polymeric support is expanded polytetrafluoroethylene. 29. A method as defined in claim 26 wherein said fuel is methanol. 30. A method as defined in claim 26 wherein said fuel is hydrogen. 31. A method as defined in claim 27 wherein said fuel is methanol. 32. A method as defined in claim 27 wherein said fuel is hydrogen. 33. A method as defined in claim 28 wherein said fuel is methanol. 34. A method as defined in claim 28 wherein said fuel is hydrogen. 35. A polymer electrolyte membrane comprising the ionomer of claim 1 in acid form. 36. A polymer electrolyte membrane as defined in claim 35 further comprising a polymeric support having interconnected passages and pathways that are substantially occluded by said ionomer. 37. A polymer electrolyte membrane as defined in claim 36 wherein said polymeric support is expanded polytetrafluoroethylene. 38. A membrane electrode assembly comprising: (a) an anode; (b) a cathode; and (c) a polymer electrolyte membrane between said anode and said cathode and in communication with said anode and said cathode, said polymer electrolyte membrane comprising the ionomer of claim 1 in acid form. 39. A membrane electrode assembly as defined in claim 38 wherein said polymer electrolyte membrane comprises a polymeric support having interconnected passages and pathways that are substantially occluded by said ionomer. 40. A membrane electrode assembly comprising: (a) an anode; (b) a cathode; and a polymer electrolyte membrane between said anode and said cathode and in communication with said anode and said cathode; wherein at least one of said anode and said cathode comprises the ionomer of claim 1. 41. A membrane electrode assembly comprising: (a) an anode; (b) a cathode; and (c) a polymer electrolyte membrane between said anode and said cathode and in communication with said anode and said cathode, said polymer electrolyte membrane comprising the ionomer of claim 1 in acid form, (d) wherein said polymer electrolyte membrane has a relative selectivity factor greater than 1.0. 42. A membrane electrode assembly as defined in claim 41 wherein said relative selectivity factor is about 1.3. 43. A membrane electrode assembly comprising: (c) an anode; (d) a cathode; and (c) a polymer electrolyte membrane between said anode and said cathode and in communication with said anode and said cathode, said polymer electrolyte membrane comprising the ionomer of claim 5 in acid form. 44. A fuel cell comprising the membrane electrode assembly of claim 38 sandwiched between a first gas diffusion medium and a second gas diffusion medium, said membrane electrode assembly being in electronic communication with a current collector. 45. A fuel cell as defined in claim 44 wherein said polymer electrolyte membrane comprises a polymeric support having interconnected passages and pathways that are substantially occluded by said ionomer. 46. A fuel cell as defined in claim 45 wherein said polymeric support is expanded polytetrafluoroethylene. 47. A fuel cell as defined in claim 44 wherein said fuel cell is a direct methanol fuel cell. 48. A fuel cell as defined in claim 44 herein said fuel cell uses hydrogen as a fuel. 49. A fuel cell as defined in claim 45 wherein said fuel cell is a direct methanol fuel cell. 50. A fuel cell as defined in claim 45 wherein said fuel cell uses hydrogen as a fuel. 51. A fuel cell as defined in claim 46 wherein said fuel cell is a direct methanol fuel cell. 52. A fuel cell as defined in claim 46 wherein said fuel cell uses hydrogen as a fuel. 53. A fuel cell as defined in claim 44 having an open circuit potential of 0.704 V. 54. A fuel cell as defined in claim 44 having an average methanol crossover measurement of about 0.124. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Solid polymer electrolytes or films have been well known in the art for many years. These polymers are typically characterized by high ionic conductivity, herein defined as greater than 1×10 −6 S/cm. Such high conductivity values make them valuable where rapid transport of ionic species, for example, protons, is useful, for example in fuel cells. Additionally, it is desirable for such ionically conducting polymers to be made in the form of membranes or thin films. In so doing, the resistance to ionic transport, which is a function of the film thickness, can be reduced. These materials must also function in the temperature range of interest, which can vary from below room temperature up to a large fraction of the melting temperature of the polymer, depending on the application. Additionally, the polymer must be robust mechanically, so that it does not crack, either during installation in a fuel cell, or during use. The use of ionomers as solid polymer electrolytes in fuel cells is well known, having been developed in the 1960s for the US Gemini space program. Historically, the industry has moved from phenol sulfonic materials, which suffered from poor mechanical and chemical stability; to polystyrene sulfonic acid polymers, which have improved mechanical stability, but still suffer chemical degradation; to poly(trifluoro-styrene)sulfonic acid, which has improved chemical stability, but poor mechanical stability; to perfluorinated sulfonic acid materials (commercially available as NAFION® membranes), which has improved mechanical and chemical stability [e.g., see A. J. Appleby and F. R. Foulkes, Fuel Cell Handbook , Van Nostrand Reinhold, New York, 1989; Table 10-1, pg. 268]. The perfluorinated sulfonic acid materials, for example those disclosed in U.S. Pat. No. 3,282,875, U.S. Pat. No. 4,358,545 and U.S. Pat. No. 4,940,525, are still far from ideal ionomers. These materials must be hydrated to conduct protons at an acceptable rate. As a result, in dry conditions or at temperatures above 100 degrees C., they work poorly in hydrogen-oxygen or hydrogen-air fuel cells. Furthermore, these fluoropolymer ionomers are expensive to produce because of the inherently high cost of the fluorinated monomers required for their preparation. Finally, as more fully described below, they tend to have a high permeability to methanol, and therefore are inefficient electrolytes for use in direct methanol fuel cells. These limitations have led to the development of several classes of ionomers that are not substantially fluorinated, but rather are based upon aromatic or linear polymers. In U.S. Pat. No. 4,083,768 a polyelectrolyte membrane is prepared from a preswollen membrane containing an insoluable cross-linked aromatic polymer. Although these membranes have low ionic resistance, the controlled penetration of the functional groups during preparation can make preparation difficult. In U.S. Pat. No. 5,525,436, U.S. Pat. No. 6,025,085 and U.S. Pat. No. 6,099,988 the preparation and use of polybenzimidizole membranes as ionomers is disclosed. These polymers are described as particularly suitable for use at temperatures above 100 degrees C. U.S. Pat. No. 6,087,031 discloses a ionomer comprising a sulfonated polyethersulfone that is suitable for use in a fuel cell. Kono et. al. discloses in U.S. Pat. No. 6,399,254 a solid electrolyte having a reduced amount of non-cross-linked monomer that can be rapidly cured through exposure to active radiation and/or heat and has high conductivity. Finally, Wang et. al. have disclosed in WO 0225764 ionomers made by direct polymerization of sulfonated polysulfones or polyimide polymers. Other substantially non-fluorinated ionomers are those in the class of sulfonated Poly(aryl ether ketone)s. It is convenient to prepare sulfonated poly(aryl ether ketone)s by post-sulfonation. However, post-sulfonation results in the placement of the sulfonic acid group ortho to the activated aromatic ether linkage, where the sulfonate groups are relatively easy to hydrolyze. Moreover, only one sulfonic acid per repeat unit can be achieved. To overcome this limitation, a new route was developed to prepare sulfonated poly(aryl ether sulfone)s with monomer containing sulfonate groups derived from sulfonating the dihalide monomer. Sulfonation of the dihalide monomer, 4,4′-dihalobenzophenone and 4,4′dihalodiphenylsulfone, results in sulfonic acid functionalization on both deactivated phenyl rings ortho to the halogen moiety, which offers them more chemical stability against desulfonation, and allows for two sulfonic acid groups per repeat unit of the resulting polymer. This approach displays other advantages, including being free from any degradation and cross-linking, and the ability to easily control the content of sulfonate groups by adjusting the ratios of the dihalide monomer to the sulfonated dihalide monomer. In order to prepare ion exchange membrane for polymer electrolyte fuel cells (PEMFC) with excellent combined physical chemical properties and of low cost, attempts have been made by utilizing sulfonated poly(aromatic ether sulfone) and sulfonated poly(aromatic ether ketone). These membranes can be made by two methods. One is direct sulfonation of polymers, as reported in Polym. V28, P1009 (1987) wherein direct sulfonation of poly(aromatic ether ketone) to prepare sulfonated poly(aromatic ether ketone) was reported. This method is straightforward, but decomposition and crosslinking also occurred. The degree of sulfonation is also difficult to control. In addition, the sulfonated group directly attached to bisphenol-A could cause sulfonated group be hydrolyzed and detached from the polymer structure after prolong service at high temperature. Another method is to prepare sulfonated monomers first, followed by polymerization afterwards. Macrom. Chem. Phy., (1997), P1421 (1998) reported this method. First, sulfonated difluoro-benzophenone was obtained by sulfonation of difluoro-benzophenone, then it was mixed with some difluoro-benzophenone and bisphenol-A, followed by a copolymerization into sulfonated poly(aromatic ether ketone). The polymer structure is characterized by the following structure: The polymerization process does not induce decomposition or crosslinking side reactions and it could control degree of sulfonation. The sulfonic acid groups located on the aromatic ring structure derived from benzophenone are much more stable than the ones on bisphenol-A rings. However, because of the existence of methyl group in the polymer structure, its anti-oxidation property is reduced. Furthermore, as the content of sulfonated group increases, swelling in water becomes very severe. Recently, bisphenol A-based and phenolphthalein-based and 4,4′-thiodiphenol-based sulfonated poly(aryl ether ketone)s were prepared by another method. Generally, most homogeneous ionomers have the problem of large swelling degree at compositions where they have reasonable conductivity. So other components are blended with the polymer in order to obtain ionomer membranes with lower swelling. One issue with many of these polymers is that the ionic conductivity is not as high as desirable. A high ionic conductivity in an ionomer is desirable because the higher the ionic conductivity, the lower the cell resistance when the polymer is used as the electrolyte in a fuel cell. Because lower cell resistance leads to higher fuel cell efficiency, lower resistance (or high conductance) is better. One approach to reducing the resistance of these ionomers is to reduce its thickness, as the resistance is directly proportional to thickness. Unfortunately, these ionomers cannot be made too thin because as they become thinner, they become more susceptible to physical or chemical damage, either during cell assembly or cell operation. One approach to deal with this issue has been disclosed in RE 37,707, RE 37,756 and RE 37,701 where ultra-thin composite membranes comprising expanded polytetrafluoroethylene and an ion exchange material impregnated throughout the membrane are disclosed. Composite ionomer membranes are also disclosed in U.S. Pat. No. 6,258,861. One further complication in the use of ionomers as solid polymer electrolytes in fuel cells is the need for the electrolyte to act as an impermeable barrier to the fuel. Should the fuel permeate through the electrolyte it reduces cell efficiency because the fuel that permeates through the electrolyte is either swept away into the outlet gas stream or chemically reacts on the oxidant side, giving rise to a mixed potential electrode. In either case, the fuel is not used for producing electricity. Furthermore, the fuel that permeates through the electrolyte may also poison the catalyst on the oxidizing side, further reducing the cell efficiency. This issue, called fuel crossover, is a particular problem when methanol is the fuel. Methanol crossover rates tend to be high in many solid polymer electrolytes because the methanol absorbs and permeates in the polymer in much the same way that water molecules do. Since many solid polymer electrolytes transport water easily, they also tend to transport methanol easily. One approach to reducing methanol crossover is to simply use thicker membranes because the methanol transport-resistance (as defined below) increases with increasing thickness. This solution has limited utility, though, because as the thickness increases the ionic resistance of the membrane increases as well. Higher ionic resistance in the membrane is detrimental to fuel cell efficiency because it results in higher internal resistance and thus higher (iR) power losses. Therefore, the ideal membrane for direct methanol fuel cells would be one that has both very high methanol transport resistance and at the same time, has low ionic resistance. The combination of these two characteristics would allow the use of thicker membranes, leading to low iR power loss due to membrane resistance, while simultaneously minimizing the effect of methanol crossover. The use of various polymers has been suggested to circumvent this methanol crossover issue. In WO 96/13872 the use of polybenzimidazole is suggested for direct methanol fuel cells. In WO 98/22989, a polymer electrolyte membrane composed of polystyrene sulfonic acid (PSSA) and poly(vinylidene fluoride) (PVDF) is reported to have low methanol crossover. In WO 00/77874 and U.S. Pat. No. 6,365,294 sulfonated polyphosphazene-based polymers are proposed as suitable ionomers for direct methanol fuel cells. Finally, poly(arylene ether sulfone) has been reported to have low methanol permeability [Y. S. Kim, F. Wang, M. Hickner, T. A. Zawodinski, and J. E. McGrath, Abstract No. 182, The Electrochemical Society Meeting Abstracts, Vol. 2002-1, The Electrochemical Society, Pennington, N.J., 2002]. Despite these attempts, a need still exists for an ionomer with lower methanol crossover rates and acceptably high ionic conductivity. It is thus an object of this invention to satisfy the long-felt need for improved ionomers for use as a polymer electrolyte membrane and as an electrode component in fuel cells. It is also an object of the present invention to provide an improved method of forming a fuel cell using the inventive polymers. It is a further object of the invention to form a composite solid polymer electrolyte with improved properties comprising the inventive polymers and a support. It is yet another object of the invention to improve performance of a direct methanol fuel cell comprising the inventive polymers. Finally, it is also an object of the new invention to provide a fuel cell wherein the electrode comprises the inventive polymer. |
<SOH> SUMMARY OF THE INVENTION <EOH>This invention involves the reaction product of a monomer comprising phthalazinone and a phenol group, and at least one sulfonated aromatic compound. The monomer comprising phthalazinone and a phenol group is used in a reaction with the sulfonated aromatic compound to produce ionomers with surprising and highly desirable properties. In one embodiment, the inventive ionomer is a sulfonated poly(phthalazinone ether ketone), hereinafter referred to as sPPEK. In another embodiment, the inventive ionomer is a sulfonated poly(phthalazinone ether sulfone), herein after referred to as sPPES. In another embodiment, the inventive ionomer is other sulfonated aromatic polymeric compounds. The invention further includes the formation of these polymers into membranes and their use for PEMFC, and in particular for DMFC. The inventive polymers may be manufactured in membrane form, and can be dissolved into solution and impregnated into porous substrates to form composite solid polymer electrolytes with improved properties. In one aspect, this invention provides an ionomer comprising the reaction product of monomer A (see below) with monomers B and C (also below), wherein the moles of monomers B plus C equal the moles of A, wherein R 1-4 are independently H, linear or branched alkyl, aromatic, or halogen; X 1 and X 2 are independently a carbonyl or sulfone radical or aromatic compounds connected through a ketone or sulfone linkage; Y is independently a halogen group, and M is an alkali metal. In another aspect, this invention provides an ionomer comprising the reaction product of monomer A with monomer B and C in an azeotroping solvent mixed with an inert aprotic polar solvent containing at least 2 moles of an alkali metal base for each mole of monomer A, wherein the moles of monomers B plus C equal the moles of A, said reaction driven to completion by the azeotropic removal of water at a temperature above the azeotropic boiling point of the azeotroping solvent in the presence of water, wherein R 1-4 are independently H, linear or branched alkyl, aromatic, or halogen; X 1 and X 2 are independently a carbonyl or sulfone radical or aromatic compounds connected through a ketone or sulfone linkage; and Y is a halogen group. In another aspect, this invention provides an ionomer comprising the reaction product of monomer A with an ionomer-contributing monomer. In another aspect, this invention provides a method of preparing a sulfonated poly(phthalazinone ether ketone) comprising the steps of (a) copolymerizing 4,4′-dihalo(or dinitro)-3,3′-disulfonate salt of benzophenone, dihalo(or dinitro)benzophenone, and a monomer containing phthalazinone and phenol group, in polar solvents or reaction medium containing mainly polar solvents, in the presence of a catalyst comprising a metallic base (or its salt), to obtain a product; (b) dehydrating the product at high temperature using azeotropic dehydration agents; (c) diluting the product with solvents; (d) coagulating the product using coagulation agents; (e) separating the product; (f) drying the product; and (g) performing steps (c) through (f) two additional times to obtain the sulfonated poly(phthalazinone ether ketone). In another aspect, this invention provides a method of preparing a sulfonated poly(phthalazinone ether sulfone), comprising the steps of (a) copolymerizing 4,4′-dihalo(or dinitro)-3,3-disulfonate salt of phenyl sulfone, dihalo(or dinitro)phenyl sulfone, and a monomer containing phthalazinone and phenol group, in polar solvents or reaction medium containing mainly polar solvents, in the presence of a catalyst comprising a metallic base (or its salt), to obtain a product; (b) dehydrating the product at high temperature using azeotropic dehydration agents; (c) diluting the product with solvents; (d) coagulating the product using coagulation agents; (e) separating the product; (f) drying the product; and (g) performing steps (c) through (f) two additional times to obtain the sulfonated poly(phthalazinone ether sulfone). In another aspect, this invention provides a method for generating electricity comprising the steps of: (a) providing an anode; (b) providing a cathode; (c) providing a polymer electrolyte membrane between the anode and the cathode and in communication with the anode and the cathode, the polymer electrolyte membrane comprising the ionomer of claim 1 in acid form (d) flowing a fuel to the cathode where the fuel is disassociated to release a proton and an electron; (e) transporting the proton across the polymer electrolyte membrane to the anode; and (f) collecting the electron at a collector to generate electricity. In other aspects, this invention provides a polymer electrolyte membrane comprising the inventive ionomer, a membrane electrode assembly comprising the inventive ionomer, and a fuel cell, particularly a direct methanol fuel cell, comprising the inventive ionomer. |
Thin film transistor array panel and method for fabricating the same |
The present invention relates to a TFT array panel and a fabricating method thereof. A gate insulating layer and a passivation layer are formed by printing organic insulating material in order to simplify the fabricating process. The inventive TFT panel includes an insulating substrate, and a gate wire formed on the insulating substrate. The gate wire includes a gate line extending in a first direction and a gate pad connected to one end of the gate line. A gate insulating layer is formed on the insulating substrate while exposing the gate pad and a portion of the gate line close to the gate pad. A semiconductor pattern is formed on the gate insulating layer. A data wire is formed on the gate insulating layer. The data wire includes a data line extending in a second direction and intersecting the gate line, a source electrode connected to the data line while contacting the semiconductor pattern, a drain electrode facing the source electrode while contacting the semiconductor pattern, and a data pad connected to one end of the data line. A passivation layer is formed on the gate insulating layer while exposing the data pad and a portion of the data line close to the data pad. |
1. A thin film transistor array panel comprising: an insulating substrate; a gate wire formed on the insulating substrate and including a gate line, and a gate pad connected to one end of the gate line; a gate insulating layer formed on the insulating substrate while exposing the gate pad and a portion of the gate line close to the gate pad; a semiconductor pattern formed on the gate insulating layer; a data wire formed on the gate insulating layer and including a data line intersecting the gate line, a source electrode connected to the data line and contacting the semiconductor pattern, a drain electrode facing the source electrodes and contacting the semiconductor pattern, and a data pad connected to one end of the data line; and a passivation layer formed on the gate insulating layer while exposing the data pad and a portion of the data line close to the data pad. 2. The thin film transistor array panel of claim 1 further comprising a common wire formed on the substrate and including a common electrode line parallel to the gate line, a common electrode connected to the common electrode line, and a common electrode pad connected to one end of the common electrode line, the gate insulating layer exposing the common electrode pad, and a portion of the common electrode line close to the common electrode pad. 3. The thin film transistor array panel of claim 1 or 2 wherein at least one of the gate insulating layer and the passivation layer is made of an organic insulating material. 4. A method of fabricating a thin film transistor array panel, the method comprising: forming a gate wire on an insulating substrate, the gate wire including a gate line, and a gate pad connected to one end of the gate line; forming a gate insulating layer made of an organic insulating material on the insulating substrate such that the gate insulating layer exposes the gate pad and a portion of the gate line close to the gate pad; forming a semiconductor pattern on the gate insulating layer; forming a data wire on the gate insulating layer, the data wire having a data line intersecting the gate line, a source electrode connected to the data line and contacting the semiconductor pattern, a drain electrode facing the source electrode and contacting the semiconductor pattern, and a data pad connected to one end of the data line; and forming a passivation layer made of an organic insulating material on the gate insulating layer such that the passivation layer exposes the data pad and a portion of the data line close to the data pad, wherein the formation of at least one of the gate insulating layer and the passivation layer is made by way of slit coating or printing. 5. The method of claim 4 further comprising flattening a surface of the gate insulating layer after the formation of the gate insulating layer. |
<SOH> BACKGROUND OF THE INVENTION <EOH>(a) Field of the Invention The present invention relates to a thin film transistor array panel and a fabricating method thereof and, more particularly, to a thin film transistor array panel for a liquid crystal display and a fabricating method thereof. (b) Description of the Related Art Currently, an LCD is one of the most widely used flat panel displays. An LCD, which includes two panels having electrodes and a liquid crystal layer interposed therebetween, controls the transmittance of light passing through the liquid crystal layer by re-arranging liquid crystal molecules in the liquid crystal layer with voltages applied to the electrodes. One of the LCDs for improving viewing angle provides one of the two panels with linear electrodes parallel to each other and thin film transistors (“TFTs”) for switching the voltages applied to the electrodes to re-arrange the liquid crystal molecules, which are initially aligned parallel to the panels. The panel with the TFTs (referred to as the “TFT array panel” hereinafter) is usually fabricated by photo etch using several masks. Although the number of the currently used masks is five or six, it is required to decrease the number in order to reduce the production cost. |
<SOH> SUMMARY OF THE INVENTION <EOH>It is an object of the present invention to provide a TFT array panel and a fabricating method thereof, which involves simplified processing steps. This and other objects may be achieved by forming a gate insulating layer or a passivation layer made of an organic insulating material by way of printing technique or slit-coating technique. In detail, an inventive TFT array panel includes: an insulating substrate; a gate wire formed on the insulating substrate and including a gate line, and a gate pad connected to one end of the gate line; a gate insulating layer formed on the insulating substrate while exposing the gate pad and a portion of the gate line close to the gate pad; a semiconductor pattern formed on the gate insulating layer; a data wire formed on the gate insulating layer and including a data line intersecting the gate line, a source electrode connected to the data line and contacting the semiconductor pattern, a drain electrode facing the source electrodes and contacting the semiconductor pattern, and a data pad connected to one end of the data line; and a passivation layer formed on the gate insulating layer while exposing the data pad and a portion of the data line close to the data pad. The TFT array panel may further include a common wire formed on the substrate and including a common electrode line parallel to the gate line, a common electrode connected to the common electrode line, and a common electrode pad connected to one end of the common electrode line, and the gate insulating layer preferably exposes the common electrode pad, and a portion of the common electrode line close to the common electrode pad. The gate insulating layer or the passivation layer is preferably made of an organic insulating material. An inventive method of fabricating a TFT array panel includes: forming a gate wire on an insulating substrate, the gate wire including a gate line, and a gate pad connected to one end of the gate line; forming a gate insulating layer made of an organic insulating material on the insulating substrate such that the gate insulating layer exposes the gate pad and a portion of the gate line close to the gate pad; forming a semiconductor pattern on the gate insulating layer; forming a data wire on the gate insulating layer, the data wire having a data line intersecting the gate line, a source electrode connected to the data line and contacting the semiconductor pattern, a drain electrode facing the source electrode and contacting the semiconductor pattern, and a data pad connected to one end of the data line; and forming a passivation layer made of an organic insulating material on the gate insulating layer such that the passivation layer exposes the data pad and a portion of the data line close to the data pad. The formation of at least one of the gate insulating layer and the passivation layer is made by way of slit coating or printing. The gate insulating layer may be surface-flattened after the formation of the gate insulating layer. |
Moraxella (branhamella) catarrhalis antigens |
The present invention relates to polypeptides of Moraxella (Branhamella) catarrhalis which may be useful for prophylaxis, diagnostic and/or therapy purposes. |
1. An isolated polynucleotide comprising a polynucleotide chosen from: (a) a polynucleotide encoding a polypeptide having at least 70% identity to a second polypeptide comprising a sequence chosen from: SEQ ID NO: 2 or 4 or fragments or analogs thereof; (b) a polynucleotide encoding a polypeptide having at least 80% identity to a second polypeptide comprising a sequence chosen from: SEQ ID NO: 2 or 4 or fragments or analogs thereof; (c) a polynucleotide encoding a polypeptide having at least 95% identity to a second polypeptide comprising a sequence chosen from: SEQ ID NO: 2 or 4 or fragments or analogs thereof; (d) a polynucleotide encoding a polypeptide comprising a sequence chosen from: SEQ ID NO: 2 or 4 or fragments or analogs thereof; (e) a polynucleotide encoding a polypeptide capable of raising antibodies having binding specificity for a polypeptide comprising a sequence chosen from: SEQ ID NO: 2 or 4 or fragments or analogs thereof; (f) a polynucleotide encoding an epitope bearing portion of a polypeptide comprising a sequence chosen from SEQ ID NO: 2 or 4 or fragments or analogs thereof; (g) a polynucleotide comprising a sequence chosen from SEQ ID NO: 1 or 3 or fragments or analogs thereof; (h) a polynucleotide that is complementary to a polynucleotide in (a), (b), (c), (d), (e), (f) or (g). 2. (canceled) 3. The polynucleotide of claim 1, wherein said polynucleotide is DNA. 4. (canceled) 5. The polynucleotide of claim 1, wherein said polynucleotide is RNA. 6. (canceled) 7. (canceled) 8. The polynucleotide of claim 1 that hybridizes under stringent conditions to either (a) a DNA sequence encoding a polypeptide or (b) the complement of a DNA sequence encoding a polypeptide; wherein said polypeptide comprises a sequence chosen from SEQ ID NO: 2 or 4 or fragments or analogs thereof. 9. (canceled) 10. The polynucleotide of claim 1 that hybridizes under stringent conditions to either (a) a DNA sequence encoding a polypeptide or (b) the complement of a DNA sequence encoding a polypeptide; wherein said polypeptide comprises at least 10 contiguous amino acid residues from a polypeptide comprising a sequence chosen from SEQ ID NO: 2 or 4 or fragments or analogs thereof. 11. (canceled) 12. A vector comprising the polynucleotide of claim 1, wherein said DNA is operably linked to an expression control region. 13. (canceled) 14. A host cell transfected with the vector of claim 12. 15. (canceled) 16. A process for producing a polypeptide comprising culturing a host cell according to claim 14 under conditions suitable for expression of said polypeptide. 17. (canceled) 18. An isolated polypeptide comprising a polypeptide chosen from: (a) a polypeptide having at least 70% identity to a second polypeptide having an amino acid sequence comprising a sequence chosen from: SEQ ID NO: 2, 4 or fragments or analogs thereof; (b) a polypeptide having at least 80% identity to a second polypeptide having an amino acid sequence comprising a sequence chosen from: SEQ ID NO: 2, 4 or fragments or analogs thereof; (c) a polypeptide having at least 95% identity to a second polypeptide having an amino acid sequence comprising a sequence chosen from: SEQ ID NO: 2, 4 or fragments or analogs thereof; (d) a polypeptide comprising a sequence chosen from SEQ ID NO: 2, 4 or fragments or analogs thereof; (e) a polypeptide capable of raising antibodies having binding specificity for a polypeptide comprising a sequence chosen from SEQ ID NO: 2, 4 or fragments or analogs thereof; (f) an epitope bearing portion of a polypeptide comprising a sequence chosen from SEQ ID NO: 2, 4 or fragments or analogs thereof; (g) the polypeptide of (a), (b), (c), (d), (e) or (f) wherein the N-terminal Met residue is deleted; (h) the polypeptide of (a), (b), (c), (d), (e), or (f) wherein the secretory amino acid sequence is deleted. 19. (canceled) 20. A chimeric polypeptide comprising two or more polypeptides having a sequence chosen from SEQ ID NO: 2, 4 or fragments or analogs thereof; provided that the polypeptides are linked as to formed a chimeric polypeptide. 21. (canceled) 22. A pharmaceutical composition comprising a polypeptide according to claim 18 and a pharmaceutically acceptable carrier, diluent or adjuvant. 23. A method for prophylactic or therapeutic treatment of Moraxella infection in a host susceptible to Moraxella infection comprising administering to said host a prophylactic or therapeutic amount of a composition according to claim 22. 24. A method according to claim 23 wherein the host is a neonate, an infant or a child. 25. A method according to claim 23 wherein the host is an immunocompromised host. 26. A method according to claim 23 wherein the host is an adult. 27. A method for therapeutic or prophylactic treatment of otitis media, sinusitis, persistent cough, acute laryngitis, suppurative keratitis, conjunctivitis neonatorum, and invasive disease comprising administering to said host a therapeutic or prophylactic amount of a composition according to claim 22. 28. A method for diagnosis of Moraxella infection in an host susceptible to Moraxella infection comprising (a) obtaining a biological sample from a host; (b) incubating an antibody or fragment thereof reactive with a polypeptide according to claim 18 with the biological sample to form a mixture; and (c) detecting specifically bound antibody or bound fragment in the mixture which indicates the presence of Moraxella. 29. A method for the detection of antibody specific to a Moraxella antigen in a biological sample containing or suspected of containing said antibody comprising (a) obtaining a biological sample from a host; (b) incubating one or more polypeptides according to claim 18 or fragments thereof with the biological sample to form a mixture; and (c) detecting specifically bound antigen or bound fragment in the mixture which indicates the presence of antibody specific to Moraxella. 30. (canceled) 31. Kit comprising a polypeptide according to claim 18 for detection or diagnosis of Moraxella infection. 32. A pharmaceutical composition comprising a chimeric polypeptide according to claim 20 and a pharmaceutically acceptable carrier, diluent or adjuvant. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Moraxella ( Branhamella ) catarrhalis is a Gram-negative diplococcus that causes respiratory tract infections in humans. M. catarrhalis is now accepted as the third most common cause of otitis media in infants and children, after Streptococcus pneumoniae and Haemophilus influenzae. M. catarrhalis has also been associated with several other types of infection, including sinusitis, persistent cough, acute laryngitis in adults, suppurative keratitis, conjunctivitis neonatorum, and invasive diseases in the immunocompromised host. Since approximately 90% of M. catarrhalis strains are resistant to antibiotics (β-lactamase positive) and that recurrent otitis media is associated with high morbidity, there is a need for the development of a vaccine that will protect hosts from M. catarrhalis infection. An infection by M. catarrhalis induces an immune response against antigens found at the surface of the bacterial cells. However, many of these surface proteins are still not characterized, nor has the immune response resulting in protection from infection by different strains been determined. To develop a vaccine that will protect hosts from M. catarrhalis infection, efforts have mainly been concentrated on outer membrane proteins such as the high-molecular-mass protein named ubiquitous surface protein A (UspA). This protein is considered a promising vaccine candidate because a monoclonal antibody and polyclonal antibodies were both shown to be bactericidal and protective in the murine pulmonary-clearance model. However, this protein was shown to be highly variable among the different strains of M. catarrhalis . In addition to this protein, other M. catarrhalis proteins have generated interest as potential vaccine candidates. The transferrin-binding protein which possesses conserved epitopes exposed on the bacterial surface. However, there was divergence in the degree of antibody cross-reactivity with the protein from one strain to another. Other investigators have also focused on the 45-kDa protein CD (OMP CD). This protein is highly conserved among strains of M. catarrhalis , however adults with chronic obstructive pulmonary disease show variability in the immune response against the OMP CD. Therefore there remains an unmet need for M. catarrhalis polypeptides which may be used to prevent, diagnose and/or treat Moraxella ( Branhamella ) catarrhalis infection. |
<SOH> SUMMARY OF THE INVENTION <EOH>According to one aspect, the present invention provides an isolated polynucleotide encoding a polypeptide having at least 70% identity to a second polypeptide comprising a sequence chosen from SEQ ID Nos: 2, 4 or fragments or analogs thereof. According to one aspect, the present invention relates to polypeptides comprising a sequence chosen from SEQ ID No: 2, 4 or fragments or analogs thereof. In other aspects, there are provided polypeptides encoded by polynucleotides of the invention, pharmaceutical compositions, vectors comprising polynucleotides of the invention operably linked to an expression control region, as well as host cells transfected with said vectors and processes for producing polypeptides comprising culturing said host cells under conditions suitable for expression. |
Process for producing perfluorovinylcarboxylic acid ester |
The present invention relates to a method for producing a perfluorovinylcarboxylic acid ester by reacting a perfluorovinylcarboxylic acid salt with an alkylating agent. The present invention provides a method to produce perfluorovinylcarboxylic acid ester, which is used as a raw material of an ion-exchange membrane for the chloro alkali process, in high yield from starting material, a compound which can be easily produced, in a simple manner. |
1. A method for producing a perfluorovinylcarboxylic acid ester, wherein a perfluorovinylcarboxylic acid salt represented by a following general formula (1): CH2═CFO(CF2)nCO2M (1) (wherein n represents an integer of 2-3; and M represents an alkaline metal, an alkaline-earth metal, a quaternary ammonium group or a quaternary phosphonium group), is reacted with an alkylating agent to obtain a perfluorovinylcarboxylic acid ester represented by a following general formula (2): CH2═CFO(CF2)nCO2R (2) (wherein n represents an integer of 2-3; and R represents an alkyl group having 1-4 carbon atoms). 2. The method for producing a perfluorovinylcarboxylic acid ester according to claim 1, wherein the perfluorovinylcarboxylic acid salt represented by the general formula (1) is produced by a thermal decomposition of perfluorodicarboxylic acid salt represented by a following general formula (3): MOCOCF(CF3)O(CF2)nCO2M (3) (wherein n represents an integer of 2-3; and M represents an alkaline metal, an alkaline-earth metal, a quaternary ammonium group or a quaternary phosphonium group). 3. The method for producing a perfluorovinylcarboxylic acid ester according to claim 2, wherein the thermal decomposition of perfluorodicarboxylic acid salt represented by the general formula (3) is carried out in the presence of an aprotic polar solvent. 4. The method for producing a perfluorovinylcarboxylic acid ester according to claim 2 or 3, wherein the perfluorodicarboxylic acid salt represented by the general formula (3) is produced from an acid fluoride represented by the following general formula (4): FCOCF(CF3)O(CF2)nCO2R′ (4) (wherein n represents an integer of 2-3; and R′ represents an alkyl group having 1-4 carbon atoms), and an alkaline substance. 5. The method for producing a perfluorovinylcarboxylic acid ester according to claim 2 or 3, wherein the perfluorodicarboxylic acid salt represented by the general formula (3) is produced by reacting an acid fluoride represented by the following general formula (4): FCOCF(CF3)O(CF2)nCO2R′ (4) (wherein n represents an integer of 2-3; and R′ represents an alkyl group having 1-4 carbon atoms), with an alkaline substance. 6. The method for producing a perfluorovinylcarboxylic acid ester according to claim 2 or 3, wherein the perfluorodicarboxylic acid salt represented by the general formula (3) is produced by reacting an acid fluoride represented by the following general formula (4): FCOCF(CF3)O(CF2)nCO2R′ (4) (wherein n represents an integer of 2-3; and R′ represents an alkyl group having 1-4 carbon atoms), with an alcohol to obtain the carboxylic acid diester and saponifying the thus-obtained carboxylic acid diester with an alkaline substance containing M shown in the general formula (3). |
<SOH> BACKGROUND ART <EOH>In the chloro alkali process, which produces caustic soda and chlorine, an ion-exchange membrane process is widely adopted, and a laminated type of membrane comprising a perfluorosulfonic acid polymer and a perfluorocarboxylic acid polymer is usually used as an ion-exchange membrane, which is a diaphragm for the process. In general, the perfluorocarboxylic acid polymer having a structure represented by the following general formula (5): (wherein k/l=3-15, m=0-1, n′=1-5, each of k, l, m and n′ is an integer, respectively), are used therein. Among them, those with n′=2-3 are usually used. This polymer can be obtained by the hydrolysis reaction of the film of the copolymer of perfluorovinylcarboxylic acid ester represented by the following general formula (6): (wherein m=0-1, n′=1-5, each of m and n′ respectively represent an integer, and R″ represents an alkyl group having 1-4 carbon atoms) and tetrafluoroethylene (TFE). Heretofore, various methods have been proposed as a method for producing perfluorovinylcarboxylic acid ester. For example, Japanese laid-open publication No. 52-78827 discloses a method for producing perfluorovinylcarboxylic acid ester represented by the following general formula (2): in-line-formulae description="In-line Formulae" end="lead"? CF 2 ═CFO(CF 2 ) n CO 2 R (2) in-line-formulae description="In-line Formulae" end="tail"? (wherein n represents an integer of 2-3, and R represents an alkyl group having 1-4 carbon atoms (i.e. m=0 and n′=2-3 in the above described general formula (6))), wherein a compound represented by the general formula (4) mentioned below, a starting material, is saponified in the acid fluoride moiety thereof to obtain its alkaline metal salt, and the alkaline metal salt is further subjected to a thermal decomposition reaction to obtain perfluorovinylcarboxylic acid ester. In this process, however, it is difficult to obtain perfluorovinylcarboxylic acid ester in a satisfying yield because various kinds of byproducts are produced. For avoiding such side reactions, for example, a method wherein a vinyl group is formed through a dehalogenation reaction of a precursor having a ICF 2 CF 2 O— structure (Japanese laid-open publication No. 55-31004), and a method wherein a vinylether compound having a terminal CH 3 OCF 2 CF 2 — group is treated with a strong acid to introduce an ester group (Japanese laid-open publication No. 60-156632) have been proposed. These methods, however, have various problems in that it is needed, for example, to use expensive raw materials requiring multiple steps. Japanese publication of examined application No. 45-22327 and Journal of Organic Chemistry 34, 1841(1969) disclose a method for obtaining perfluorovinylcarboxylic acid ester(a compound with n=1-12 in the general formula (2)), wherein a perfluorodicarboxylic acid salt (a compound with n=2-12 in the general formula (3) mentioned below) is thermally decomposed at 175-200° C. in the absence of solvent under anhydrous conditions to obtain perfluorovinylcarboxylic acid salt (a compound with n=2-12 in the following formula (1)), and subsequently the perfluorovinylcarboxylic acid salt is converted into a perfluorovinylcarboxylic acid by treating with an acid followed by reacting with an alcohol to obtain a perfluorovinylcarboxylic acid ester. In the method described in the publication of examined application, the manner to obtain the perfluorovinylcarboxylic acid ester from the perfluorovinylcarboxylic acid salt needs 2 steps of 1) producing the perfluorovinycarboxylic acid from the perfluorovinylcarboxylic acid salt by the acid treatment, and 2) producing the perfluorovinylcarboxylic acid ester by reacting the perfluorovinylcarboxylic acid with the alcohol. In addition, yield of perfluorovinylcarboxylic acid ester is very low. Further, the method has another drawback in that it requires a complicated purifying and separating process such as washing with a large volume of water to separate the perfluorovinylcarboxylic acid ester from the alcohol. The inventors, after an extended study to solve the above described problems, found out a method to obtain a high-purity perfluorovinylcarboxylic acid ester in good yield, through less steps, by reacting perfluorovinylcarboxylic acid salt represented by the general formula (1) with an alkylating agent, and accomplished the present invention. |
Method for determining the time and extent of maintenance operations |
In a method for defining the time and scope of maintenance operations for a system having a plurality of maintenance items, each of which should be carried out within an assigned tolerance range, a minimum maintenance interval between successive maintenance operations is predefined. The timing of a maintenance operation is predictively fixed at at least that tolerance range end point which is the first of the tolerance range end points of maintenance items relating to maintenance times to follow the time of a preceding maintenance operation while complying with the minimum maintenance interval. At least those maintenance operations whose tolerance range end points occur before the predicted subsequent maintenance time are defined as the scope of the imminent maintenance operation. |
1-3. (canceled) 4. A method for determining timing and scope of maintenance operations for a system having a plurality of maintenance items, said method comprising: predefining associated maintenance intervals and tolerance ranges for implementing the maintenance items; and predefining a minimum maintenance interval between an imminent maintenance operation and a subsequent maintenance operation; wherein, a time for a respective subsequent maintenance operation is predictively fixed, at the latest, at a tolerance range end point which is occurs first among tolerance range end points of maintenance items having associated maintenance times, following the time of a preceding maintenance operation, while complying with the minimum maintenance interval; and at least those maintenance items whose tolerance range end points occur before the predicted subsequent maintenance time are designated as maintenance items to be carried out during the imminent maintenance operation. 5. The method as claimed in claim 4, wherein: each maintenance item is composed of at least one maintenance secondary item; and when a maintenance sequence for a respective maintenance operation is created, maintenance secondary items for the maintenance items to be carried out are tested with respect to the possibility of combining them. 6. The method as claimed in claim 4, wherein in designating maintenance items to be carried out during an imminent maintenance operation, an optimization algorithm is implemented which includes advancing maintenance items from subsequent maintenance operations to earlier maintenance operations on a test basis, based on a secondary conditions that the predefined minimum maintenance interval is complied with, and that an amount of the maintenance costs according to a cost function is optimized. |
<SOH> BACKGROUND AND SUMMARY OF THE INVENTION <EOH>This application claims the priority of German patent document 101 29 457.3, filed 19 Jun. 2001 (PCT International Application No.: PCT/EP02/06479), the disclosure of which is expressly incorporated by reference herein. cross-reference-to-related-applications description="Cross Reference To Related Applications" end="tail"? The invention relates to a method for defining the time and scope of maintenance operations for a system having a plurality of maintenance items, each of which should be carried out within an associated flexible maintenance interval and tolerance range, with a predetermined minimum maintenance interval between successive maintenance operations. Such methods are customary, for example, for the maintenance of motor vehicles. In this application, fixed maintenance intervals in the form of corresponding time intervals or mileage intervals are conventionally predefined. In addition, there is usually a fixed predefinition of which maintenance items are to be carried out during a respective maintenance operation. With this type of predefined maintenance of motor vehicles, the respective vehicle component is maintained at fixed intervals independently of the severity of its actual wear, which may vary appreciably from vehicle to vehicle, for example due to different driving styles. German patent document DE 31 10 774 A1 discloses a method for defining maintenance times for motor vehicles in which a reference variable (for example, the state of the brake linings or the state of the engine oil), is fixed as decisive. An associated maintenance value of the reference variable is predefined and the actual value of the reference variable is sensed continuously while the vehicle is actually operating, and compared with the maintenance value. As soon as the actual value reaches the maintenance value, an indication is given that a maintenance operation should be carried out. For further operating variables which are to be maintained as a function of wear, such as clutch, carburetor setting, spark plugs, ignition times and battery voltage, their actual values are also sensed from time to time and compared with stored wear limiting values. Depending on the wear state, the respective operating variable is assigned to a maintenance operation which is determined by the reference variable, within a tolerance range which is formed as a function of the mileage, fuel consumption, time or a combination of these variables. Here, the maintenance time is defined within the tolerance range in the direction of the upper or lower range limit by reference to an evaluation of the reference variable and the respective operating variable. In addition, assuming that loading of the vehicle remains the same, the wear limit can be extrapolated from a computing unit which carries out the method. A load diagram can be created for the operating variable values which are decisive for the loading of the vehicle, from which diagram it is possible to detect whether the vehicle is being operated mainly in the partial load mode or full load mode. German patent document DE 32 34 727 A1 discloses a method for defining maintenance times for a motor vehicle in which the current wear of components that are to be maintained and the duration of operation or of the vehicle, the engine speed and the temperature of the cooling water are measured and the current wear is compared with a predefinable wear limiting value, in order to calculate the expected service life of the respective component therefrom. The shortest time period or distance in which a plurality of monitored components are subject to wear within a predefinable maximum tolerance range is then indicated, or the distance for a component which is worn by more than the predefined tolerance range before the other components is indicated. One object of the invention is to provide a method of the type described above, with which the time and scope of maintenance operations can be defined for a system having a plurality of maintenance items in a comparatively reliable, flexible and cost-effective way. This and other objects and advantages are achieved by the method according to the invention, in which, on the one hand, a minimum maintenance interval for a next maintenance operation (i.e., subsequent maintenance operation) and, on the other hand, flexible maintenance intervals and tolerance ranges for the maintenance items are predefined. The maintenance interval variable and the maintenance intervals and tolerance ranges for the maintenance items can be predefined differently. For the sake of optimization, it is possible to iterate over this variable maintenance interval. Furthermore, at least some of the maintenance items are treated as serving to define maintenance times, and are referred to below as control function maintenance items. The latter are taken into account in defining the maintenance times. Specifically, for a particular maintenance operation which is to follow a preceding maintenance operation by at least a minimum maintenance interval, the time is predictively fixed at least at the earliest tolerance range end point (among the control function maintenance items) which complies with the minimum maintenance interval. All maintenance items whose tolerance end points occur before this predicted, aimed-at subsequent maintenance time are included in the extent of the preceding maintenance operation. This procedure permits components which are subject to wear to be maintained sufficiently promptly, and thus reliably, in a very flexible way, by means of fixed or variable predefinition of the minimum maintenance interval and of the maintenance intervals and tolerance ranges which can be selected individually for each maintenance item. The maintenance intervals and tolerance ranges can be selected in a variable fashion as a function of the current conditions (in particular the current measured or predicted wear of the system component or components affected by a particular maintenance item), which permits a further improved adaptation of the subsequent maintenance operations to the current wear state of the various system components. In motor vehicles, different degrees of wear depending on the driving style can thus be taken into account in arriving at favorable maintenance times. The method according to the invention thus ensures, on the one hand, that each maintenance item is carried out sufficiently frequently so that worn system components are maintained promptly, and, on the other hand, selecting a correspondingly long minimum maintenance interval avoids premature performance of maintenance operations. In one embodiment of the invention, the maintenance items are categorized into one or more respective maintenance secondary items. When the sequence of a maintenance operation is created, the maintenance secondary items of the maintenance items which are to be processed in the maintenance operation are tested with respect to the possibility of combining them. This permits an effective maintenance sequence in which the maintenance secondary items are combined for processing in such a way that, as far as possible, each maintenance secondary item has to be carried out only once. In another advantageous embodiment of the invention, an optimization algorithm is used in which the complexity of the maintenance serves as a so-called cost function which is to be optimized. The complexity of the maintenance may be enumerated here, for example, as a specific amount of money or a cost value. It is possible to use maintenance positions (that is, the timing of maintenance items) with a control function which are extracted from the optimization algorithm in order to determine the maintenance time, while others are then merely added to the maintenance packages. It is possible to take into account fixed regulatory deadlines such as for TÜV[German standards testing authority], ASU[German exhaust gas test] and nonscheduled visits to the workshop. The optimization process also includes provisions for moving subsequent maintenance positions forward on a test basis (i.e., maintenance positions, which according to the normal criteria would not be due until a subsequent maintenance time), to a preceding maintenance operation. In this case, the predefined minimum maintenance interval functions as a secondary condition of the optimization process. This measure can be used to determine whether the performance of one or more maintenance items will lead to a lower overall degree of complexity and is therefore to be recommended. In practice, the wear of components which are to be maintained may be subject to time intervals or distance intervals and be calculated from load collectives or sensor data. On a program-internal basis, calculations are preferably carried out only with one unit (time or distance) and the result can then be presented again in both units. The possibility of incorporating various models for determining wear for this purpose ensures that a framework algorithm is provided. This permits, inter alia, wear models of suppliers to be incorporated and tested. For reasons of practicability, the system preferably permits manual correction of the optimum solution, for example in order to achieve further, less than optimum, solutions with associated maintenance deadlines, extent and cost of maintenance, as well as subsequent maintenance deadlines and costs. The user can thus predefine the time period between two maintenance deadlines in a reasonable range and control weighting which is optimized to a greater extent in terms of cost or time. Other objects, advantages and novel features of the present invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings. |
<SOH> BACKGROUND AND SUMMARY OF THE INVENTION <EOH>This application claims the priority of German patent document 101 29 457.3, filed 19 Jun. 2001 (PCT International Application No.: PCT/EP02/06479), the disclosure of which is expressly incorporated by reference herein. cross-reference-to-related-applications description="Cross Reference To Related Applications" end="tail"? The invention relates to a method for defining the time and scope of maintenance operations for a system having a plurality of maintenance items, each of which should be carried out within an associated flexible maintenance interval and tolerance range, with a predetermined minimum maintenance interval between successive maintenance operations. Such methods are customary, for example, for the maintenance of motor vehicles. In this application, fixed maintenance intervals in the form of corresponding time intervals or mileage intervals are conventionally predefined. In addition, there is usually a fixed predefinition of which maintenance items are to be carried out during a respective maintenance operation. With this type of predefined maintenance of motor vehicles, the respective vehicle component is maintained at fixed intervals independently of the severity of its actual wear, which may vary appreciably from vehicle to vehicle, for example due to different driving styles. German patent document DE 31 10 774 A1 discloses a method for defining maintenance times for motor vehicles in which a reference variable (for example, the state of the brake linings or the state of the engine oil), is fixed as decisive. An associated maintenance value of the reference variable is predefined and the actual value of the reference variable is sensed continuously while the vehicle is actually operating, and compared with the maintenance value. As soon as the actual value reaches the maintenance value, an indication is given that a maintenance operation should be carried out. For further operating variables which are to be maintained as a function of wear, such as clutch, carburetor setting, spark plugs, ignition times and battery voltage, their actual values are also sensed from time to time and compared with stored wear limiting values. Depending on the wear state, the respective operating variable is assigned to a maintenance operation which is determined by the reference variable, within a tolerance range which is formed as a function of the mileage, fuel consumption, time or a combination of these variables. Here, the maintenance time is defined within the tolerance range in the direction of the upper or lower range limit by reference to an evaluation of the reference variable and the respective operating variable. In addition, assuming that loading of the vehicle remains the same, the wear limit can be extrapolated from a computing unit which carries out the method. A load diagram can be created for the operating variable values which are decisive for the loading of the vehicle, from which diagram it is possible to detect whether the vehicle is being operated mainly in the partial load mode or full load mode. German patent document DE 32 34 727 A1 discloses a method for defining maintenance times for a motor vehicle in which the current wear of components that are to be maintained and the duration of operation or of the vehicle, the engine speed and the temperature of the cooling water are measured and the current wear is compared with a predefinable wear limiting value, in order to calculate the expected service life of the respective component therefrom. The shortest time period or distance in which a plurality of monitored components are subject to wear within a predefinable maximum tolerance range is then indicated, or the distance for a component which is worn by more than the predefined tolerance range before the other components is indicated. One object of the invention is to provide a method of the type described above, with which the time and scope of maintenance operations can be defined for a system having a plurality of maintenance items in a comparatively reliable, flexible and cost-effective way. This and other objects and advantages are achieved by the method according to the invention, in which, on the one hand, a minimum maintenance interval for a next maintenance operation (i.e., subsequent maintenance operation) and, on the other hand, flexible maintenance intervals and tolerance ranges for the maintenance items are predefined. The maintenance interval variable and the maintenance intervals and tolerance ranges for the maintenance items can be predefined differently. For the sake of optimization, it is possible to iterate over this variable maintenance interval. Furthermore, at least some of the maintenance items are treated as serving to define maintenance times, and are referred to below as control function maintenance items. The latter are taken into account in defining the maintenance times. Specifically, for a particular maintenance operation which is to follow a preceding maintenance operation by at least a minimum maintenance interval, the time is predictively fixed at least at the earliest tolerance range end point (among the control function maintenance items) which complies with the minimum maintenance interval. All maintenance items whose tolerance end points occur before this predicted, aimed-at subsequent maintenance time are included in the extent of the preceding maintenance operation. This procedure permits components which are subject to wear to be maintained sufficiently promptly, and thus reliably, in a very flexible way, by means of fixed or variable predefinition of the minimum maintenance interval and of the maintenance intervals and tolerance ranges which can be selected individually for each maintenance item. The maintenance intervals and tolerance ranges can be selected in a variable fashion as a function of the current conditions (in particular the current measured or predicted wear of the system component or components affected by a particular maintenance item), which permits a further improved adaptation of the subsequent maintenance operations to the current wear state of the various system components. In motor vehicles, different degrees of wear depending on the driving style can thus be taken into account in arriving at favorable maintenance times. The method according to the invention thus ensures, on the one hand, that each maintenance item is carried out sufficiently frequently so that worn system components are maintained promptly, and, on the other hand, selecting a correspondingly long minimum maintenance interval avoids premature performance of maintenance operations. In one embodiment of the invention, the maintenance items are categorized into one or more respective maintenance secondary items. When the sequence of a maintenance operation is created, the maintenance secondary items of the maintenance items which are to be processed in the maintenance operation are tested with respect to the possibility of combining them. This permits an effective maintenance sequence in which the maintenance secondary items are combined for processing in such a way that, as far as possible, each maintenance secondary item has to be carried out only once. In another advantageous embodiment of the invention, an optimization algorithm is used in which the complexity of the maintenance serves as a so-called cost function which is to be optimized. The complexity of the maintenance may be enumerated here, for example, as a specific amount of money or a cost value. It is possible to use maintenance positions (that is, the timing of maintenance items) with a control function which are extracted from the optimization algorithm in order to determine the maintenance time, while others are then merely added to the maintenance packages. It is possible to take into account fixed regulatory deadlines such as for TÜV[German standards testing authority], ASU[German exhaust gas test] and nonscheduled visits to the workshop. The optimization process also includes provisions for moving subsequent maintenance positions forward on a test basis (i.e., maintenance positions, which according to the normal criteria would not be due until a subsequent maintenance time), to a preceding maintenance operation. In this case, the predefined minimum maintenance interval functions as a secondary condition of the optimization process. This measure can be used to determine whether the performance of one or more maintenance items will lead to a lower overall degree of complexity and is therefore to be recommended. In practice, the wear of components which are to be maintained may be subject to time intervals or distance intervals and be calculated from load collectives or sensor data. On a program-internal basis, calculations are preferably carried out only with one unit (time or distance) and the result can then be presented again in both units. The possibility of incorporating various models for determining wear for this purpose ensures that a framework algorithm is provided. This permits, inter alia, wear models of suppliers to be incorporated and tested. For reasons of practicability, the system preferably permits manual correction of the optimum solution, for example in order to achieve further, less than optimum, solutions with associated maintenance deadlines, extent and cost of maintenance, as well as subsequent maintenance deadlines and costs. The user can thus predefine the time period between two maintenance deadlines in a reasonable range and control weighting which is optimized to a greater extent in terms of cost or time. Other objects, advantages and novel features of the present invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings. |
Diamine derivatives |
A compound represented by the general formula (1): Q1-Q2-T0-N(R1)-Q3-N(R2)-T1-Q4 (1) wherein R1 and R2 are hydrogen atoms or the like; Q1 is a saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon group which may be substituted, or the like; Q2 is a single bond or the like; Q3 is a group in which Q5 is an alkylene group having 1 to 8 carbon atoms, or the like; and T0 and T1 are carbonyl groups or the like; a salt thereof, a solvate thereof, or an N-oxide thereof. The compound is useful as an agent for preventing and/or treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing. |
1. A compound represented by the general formula (1): Q1-Q2-T0-N(R1)-Q3-N(R2)-T1-Q4 (1) wherein R1 and R2, independently of each other, represent a hydrogen atom, hydroxyl group, alkyl group or alkoxy group; Q1 represents a saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon group which may be substituted, a saturated or unsaturated, 5- to 7-membered heterocyclic group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted; Q2 represents a single bond, a saturated or unsaturated, 5- or 6-membered divalent cyclic hydrocarbon group which may be substituted, a saturated or unsaturated, 5- to 7-membered divalent heterocyclic group which may be substituted, a saturated or unsaturated, divalent bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, divalent bicyclic or tricyclic fused heterocyclic group which may be substituted; Q3 represents the following group: in which Q5 means an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms, or a group —(CH2)m—CH2-A-CH2—(CH2)n—, in which m and n are independently of each other 0 or an integer of 1-3, and A means an oxygen atom, nitrogen atom, sulfur atom, —SO—, —SO2—, —NH—, —O—NH—, —NH—NH—, —S—NH—, —SO—NH— or —SO2—NH—, and R3 and R4 are substituents on carbon atom(s), nitrogen atom(s) or a sulfur atom(s) of a ring comprising Q5 and are independently of each other a hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, cyano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may be substituted, alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group(s), N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl group which may be substituted, carbamoylalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group, 3- to 6-membered heterocyclic carbonylalkyl group which may be substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group which may be substituted, aryl group, aralkyl group, heteroaryl group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsulfonylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group, alkoxyalkylsulfonyl group, 3- to 6-membered heterocyclic sulfonyl group which may be substituted, N-alkylaminoacyl group, N,N-dialkylaminoacyl group, N,N-dialkylcarbamoylacyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkylsulfonyl group which may have a substituent on the alkyl group(s) or alkylsulfonylacyl group, or R3 and R4, together with each other, denote an alkylene group having 1 to 5 carbon atoms, alkenylene group having 2 to 5 carbon atoms, alkylenedioxy group having 1 to 5 carbon atoms or carbonyldioxy group; Q4 represents an aryl group which may be substituted, an arylalkenyl group which may be substituted, an arylalkynyl group which may be substituted, a heteroaryl group which may be substituted, a heteroarylalkenyl group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted; T0 represents a carbonyl or thiocarbonyl group; and T1 represents a carbonyl group, sulfonyl group, group —C(═O)—C(═O)—N(R′)—, group —C(═S)—C(═O)—N(R′)—, group —C(═O)—C(═S)—N(R′)—, group —C(═S)—C(═S)—N(R′)—, in which R′ means a hydrogen atom, hydroxyl group, alkyl group or alkoxy group, group —C(═O)-A1-N(R″)—, in which A1 means an alkylene group having 1 to 5 carbon atoms, which may be substituted, and R″ means a hydrogen atom, hydroxyl group, alkyl group or alkoxy group, group —C(═O)—NH—, group —C(═S)—NH—, group —C(═O)—NH—NH—, group —C(═O)-A2-C(═)—, in which A2 means a single bond or alkylene group having 1 to 5 carbon atoms, group —C(═O)-A3-C(═O)—NH—, in which A3 means an alkylene group having 1 to 5 carbon atoms, group —C(═O)—C(═NORa)—N(Rb)—, group —C(═S)—C(═NORa)—N(Rb)—, in which Ra means a hydrogen atom, alkyl group or alkanoyl group, and Rb means a hydrogen atom, hydroxyl group, alkyl group or alkoxy group, group —C(═O)—N═N—, group —C(═S)—N═N—, or thiocarbonyl group; a salt thereof, a solvate thereof, or an N-oxide thereof. 2. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to claim 1, wherein the group Q4 in the formula (1) is a group selected from the group consisting of a phenyl group which may be substituted, a naphthyl group which may be substituted, an anthryl group which may be substituted, a phenanthryl group which may be substituted, a styryl group which may be substituted, a phenylethynyl group which may be substituted, a pyridyl group which may be substituted, a pyridazinyl group which may be substituted, a pyradinyl group which may be substituted, a furyl group which may be substituted, a thienyl group which may be substituted, a pyrrolyl group which may be substituted, a thiazolyl group which may be substituted, an oxazolyl group which may be substituted, a pyrimidinyl group which may be substituted, a tetrazolyl group which may be substituted, a thienylethenyl group which may be substituted, a pyridylethenyl group which may be substituted, an indenyl group which may be substituted, an indanyl group which may be substituted, a tetrahydronaphthyl group which may be substituted, a benzofuryl group which may be substituted, an isobenzofuryl group which may be substituted, a benzothienyl group which may be substituted, an indolyl group which may be substituted, an indolinyl group which may be substituted, an isoindolyl group which may be substituted, an isoindolinyl group which may be substituted, an indazolyl group which may be substituted, a quinolyl group which may be substituted, a dihydroquinolyl group which may be substituted, a 4-oxodihydroquinolyl group (dihydroquinolin-4-on) which may be substituted, a tetrahydroquinolyl group which may be substituted, an isoquinolyl group which may be substituted, a tetrahydroisoquinolyl group which may be substituted, a chromenyl group which may be substituted, a chromanyl group which may be substituted, an isochromanyl group which may be substituted, a 4H-4-oxobenzopyranyl group which may be substituted, a 3,4-dihydro-4H-4-oxobenzopyranyl group which may be substituted, a 4H-quinolizinyl group which may be substituted, a quinazolinyl group which may be substituted, a dihydroquinazolinyl group which may be substituted, a tetrahydroquinazolinyl group which may be substituted, a quinoxalinyl group which may be substituted, a tetrahydroquinoxalinyl group which may be substituted, a cinnolinyl group which may be substituted, a tetrahydrocinnolinyl group which may be substituted, an indolizinyl group which may be substituted, a tetrahydroindolizinyl group which may be substituted, a benzothiazolyl group which may be substituted, a tetrahydrobenzothiazolyl group which may be substituted, a benzoxazolyl group which may be substituted, a benzoisothiazolyl group which may be substituted, a benzoisoxazolyl group which may be substituted, a benzimidazolyl group which may be substituted, a naphthyridinyl group which may be substituted, a tetrahydronaphthyridinyl group which may be substituted, a thienopyridyl group which may be substituted, a tetrahydrothienopyridyl group which may be substituted, a thiazolopyridyl group which may be substituted, a tetrahydrothiazolopyridyl group which may be substituted, a thiazolopyridazinyl group which may be substituted, a tetrahydrothiazolopyridazinyl group which may be substituted, a pyrrolopyridyl group which may be substituted, a dihydropyrrolopyridyl group which may be substituted, a tetrahydropyrrolopyridyl group which may be substituted, a pyrrolopyrimidinyl group which may be substituted, a dihydropyrrolopyrimidinyl group which may be substituted, a pyridoquinazolinyl group which may be substituted, a dihydropyridoquinazolinyl group which may be substituted, a pyridopyrimidinyl group which may be substituted, a tetrahydropyridopyrimidinyl group which may be substituted, a pyranothiazolyl group which may be substituted, a dihydropyranothiazolyl group which may be substituted, a furopyridyl group which may be substituted, a tetrahydrofuropyridyl group which may be substituted, an oxazolopyridyl group which may be substituted, a tetrahydrooxazolopyridyl group which may be substituted, an oxazolopyridazinyl group which may be substituted, a tetrahydrooxazolopyridazinyl group which may be substituted, a pyrrolothiazolyl group which may be substituted, a dihydropyrrolothiazolyl group which may be substituted, a pyrrolooxazolyl group which may be substituted, a dihydropyrrolooxazolyl group which may be substituted, a thienopyrrolyl group which may be substituted, a thiazolopyrimidinyl group which may be substituted, a 4-oxo-tetrahydrocinnolinyl group which may be substituted, a 1,2,4-benzothiadiazinyl group which may be substituted, a 1,1-dioxy-2H-1,2,4-benzothiadiazinyl group which may be substituted, a 1,2,4-benzoxadiazinyl group which may be substituted, a cyclopentapyranyl group which may be substituted, a thienofuranyl group which may be substituted, a furopyranyl group which may be substituted, a pyridoxazinyl group which may be substituted, a pyrazoloxazolyl group which may be substituted, an imidazothiazolyl group which may be substituted, an imidazopyridyl group which may be substituted, a tetrahydroimidazopyridyl group which may be substituted, a pyrazinopyridazinyl group which may be substituted, a benzoisoquinolyl group which may be substituted, a furocinnolyl group which may be substituted, a pyrazolothiazolopyridazinyl group which may be substituted, a tetrahydropyrazolothiazolopyridazinyl group which may be substituted, a hexahydrothiazolopyridazinopyridazinyl group which may be substituted, an imidazotriazinyl group which may be substituted, an oxazolopyridyl group which may be substituted, a benzoxepinyl group which may be substituted, a benzoazepinyl group which may be substituted, a tetrahydrobenzoazepinyl group which may be substituted, a benzodiazepinyl group which may be substituted, a benzotriazepinyl group which may be substituted, a thienoazepinyl group which may be substituted, a tetrahydrothienoazepinyl group which may be substituted, a thienodiazepinyl group which may be substituted, a thienotriazepinyl group which may be substituted, a thiazoloazepinyl group which may be substituted, a tetrahydrothiazoloazepinyl group which may be substituted, a 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group which may be substituted, and a 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group which may be substituted. 3. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to claim 1 or 2, wherein the substituent(s) on the group Q4 are 1 to 3 substituents selected from a hydroxyl group, halogen atoms, halogenoalkyl groups, an amino group, a cyano group, aminoalkyl groups, a nitro group, hydroxyalkyl groups, alkoxyalkyl groups, a carboxyl group, carboxyalkyl groups, alkoxycarbonylalkyl groups, acyl groups, an amidino group, a hydroxyamidino group, linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, linear, branched or cyclic alkoxy groups having 1 to 6 carbon atoms, amidino groups substituted by a linear, branched or cyclic alkoxycarbonyl group having 2 to 7 carbon atoms, linear, branched or cyclic alkenyl groups having 2 to 6 carbon atoms, linear or branched alkynyl groups having 2 to 6 carbon atoms, linear, branched or cyclic alkoxycarbonyl groups having 2 to 6 carbon atoms, a carbamoyl group, mono- or dialkylcarbamoyl groups substituted by a linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms on the nitrogen atom, mono- or di-alkylamino groups substituted by a linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, and 5- or 6-membered nitrogen-containing heterocyclic groups. 4. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to claim 1, wherein the group Q4 represents any of the following groups: wherein R5 and R6, independently of each other, represent a hydrogen atom, cyano group, halogen atom, alkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, or phenyl group which may be substituted by a cyano group, hydroxyl group, halogen atom, alkyl group or alkoxy group, and R7 and R8, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein R9 and R10, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein R11, R12 and R13, independently of one another, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein X1 represents CH2, CH, NH, NOH, N, O or S, and R14, R15 and R16, independently of one another, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein X2 represents NH, N, O or S, X3 represents N, C or CH, X4 represents N, C or CH, and R17 and R18, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group, excluding the cases where X3 and X4 are combinations of C and CH, and are both C or CH; wherein N indicates that 1 or 2 carbon atoms of the ring substituted by R19 have been substituted by a nitrogen atom, and R19, R20 and R21, independently of one another, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein X5 represents CH2, CH, N or NH, Z1 represents N, NH or O, Z2 represents CH2, CH, C or N, Z3 represents CH2, CH, S, SO2 or C═O, X5-Z2 indicates that X5 and Z2 are bonded to each other by a single bond or double bond, R22 and R23, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group, and R24 represents a hydrogen atom or alkyl group; wherein X6 represents O or S, and R25 and R26, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein R27 and R28, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein E1 and E2, independently of each other, represent N or CH, and R29 and R30, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein Y1 represents CH or N, Y2 represents —N(R33)—, in which R33 means a hydrogen atom or alkyl group having 1 to 6 carbon atoms, O or S, and R31 and R32, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; and wherein numerals 1 to 8 indicate positions, each N indicates that any one of carbon atoms of positions 1 to 4 and any one of carbon atoms of positions 5 to 8 has been substituted by a nitrogen atom, and R34, R35 and R36, independently of one another, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group. 5. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to claim 1, wherein the group Q4 represents any of the following groups: wherein R5 and R6, independently of each other, represent a hydrogen atom or alkyl group, R7 represents a hydrogen atom, and R8 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein R9 represents a hydrogen atom, and R10 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein R11 are R12 both represent hydrogen atoms, and R13 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein X1 represents NH, NOH, N, O or S, R14 represents a hydrogen atom, halogen atom, acyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group or alkyl group, R15 represents a hydrogen atom or halogen atom, and R16 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein X2 represents NH, O or S, X3 represents N, C or CH, X4 represents N, C or CH, R17 represents a hydrogen atom, and R18 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group, excluding the cases where X3 and X4 are combinations of C and CH, and are both C or CH; wherein N indicates that 1 or 2 carbon atoms of the ring substituted by R19 have been substituted by a nitrogen atom, R19 and R20 both represent hydrogen atoms, and R21 represents a hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group; wherein X5 represents CH2, CH, N or NH, Z1 represents N, NH or O, Z2 represents CH2, CH, C or N, Z3 represents CH2, CH, S, SO2 or C═O, X5-Z2 indicates that X5 and Z2 are bonded to each other by a single bond or double bond, R22 represents a hydrogen atom, R23 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group, and R24 represents a hydrogen atom; wherein X6 represents 0, R25 represents a hydrogen atom, and R26 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein R27 represents a hydrogen atom or halogen atom, and R28 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein E1 and E2, independently of each other, represent N or CH, R29 represents a hydrogen atom or halogen atom, and R30 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein Y1 represents CH or N, Y2 represents —N(R33)—, in which R33 means a hydrogen atom or alkyl group having 1 to 6 carbon atoms, O or S, R31 represents a hydrogen atom or halogen atom, and R32 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; and wherein numerals 1 to 8 indicate positions, each N indicates that any one of carbon atoms of positions 1 to 4 and any one of carbon atoms of positions 5 to 8 has been substituted by a nitrogen atom, R34 represents a hydrogen atom or halogen atom, R35 represents a hydrogen atom or halogen atom, and R36 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group. 6. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 3, wherein the group Q4 in the formula (1) is a 4-chlorostyryl, 4-fluorostyryl, 4-bromostyryl, 4-ethynylstyryl, 4-chlorophenylethynyl, 4-fluorophenylethynyl, 4-bromophenylethynyl, 4-ethynylphenylethynyl, 6-chloro-2-naphthyl, 6-fluoro-2-naphthyl, 6-bromo-2-naphthyl, 6-ethynyl-2-naphthyl, 7-chloro-2-naphthyl, 7-fluoro-2-naphthyl, 7-bromo-2-naphthyl, 7-ethynyl-2-naphthyl, 5-chloroindol-2-yl, 5-fluoroindol-2-yl, 5-bromoindol-2-yl, 5-ethynylindol-2-yl, 5-methylindol-2-yl, 5-chloro-4-fluoroindol-2-yl, 5-chloro-3-fluoroindol-2-yl, 3-bromo-5-chloroindol-2-yl, 3-chloro-5-fluoroindol-2-yl, 3-bromo-5-fluoroindol-2-yl, 5-bromo-3-chloroindol-2-yl, 5-bromo-3-fluoroindol-2-yl, 5-chloro-3-formylindol-2-yl, 5-fluoro-3-formylindol-2-yl, 5-bromo-3-formylindol-2-yl, 5-ethynyl-3-formylindol-2-yl, 5-chloro-3-(N,N-dimethylcarbamoyl)indol-2-yl, 5-fluoro-3-(N,N-dimethylcarbamoyl)indol-2-yl, 5-bromo-3-(N,N-dimethylcarbamoyl)indol-2-yl, 5-ethynyl-3-(N,N-dimethylcarbamoyl)indol-2-yl, 6-chloroindol-2-yl, 6-fluoroindol-2-yl, 6-bromoindol-2-yl, 6-ethynylindol-2-yl, 6-methylindol-2-yl, 5-chlorobenzothiophen-2-yl, 5-fluorobenzothiophen-2-yl, 5-bromobenzothiophen-2-yl, 5-ethynylbenzothiophen-2-yl, 5-methylbenzothiophen-2-yl, 5-chloro-4-fluorobenzothiophen-2-yl, 6-chlorobenzothiophen-2-yl, 6-fluorobenzothiophen-2-yl, 6-bromobenzothiophen-2-yl, 6-ethynylbenzothiophen-2-yl, 6-methylbenzothiophen-2-yl, 5-chlorobenzofuran-2-yl, 5-fluorobenzofuran-2-yl, 5-bromobenzofuran-2-yl, 5-ethynylbenzofuran-2-yl, 5-methylbenzofuran-2-yl, 5-chloro-4-fluorobenzofuran-2-yl, 6-chlorobenzofuran-2-yl, 6-fluorobenzofuran-2-yl, 6-bromobenzofuran-2-yl, 6-ethynylbenzofuran-2-yl, 6-methylbenzofuran-2-yl, 5-chlorobenzimidazol-2-yl, 5-fluorobenzimidazol-2-yl, 5-bromobenzimidazol-2-yl, 5-ethynylbenzimidazol-2-yl, 6-chloroquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-bromoquinolin-2-yl, 6-ethynylquinolin-2-yl, 7-chloroquinolin-3-yl, 7-fluoroquinolin-3-yl, 7-bromoquinolin-3-yl, 7-ethynylquinolin-3-yl, 7-chloroisoquinolin-3-yl, 7-fluoroisoquinolin-3-yl, 7-bromoisoquinolin-3-yl, 7-ethynylisoquinolin-3-yl, 7-chlorocinnolin-3-yl, 7-fluorocinnolin-3-yl, 7-bromocinnolin-3-yl, 7-ethynylcinnolin-3-yl, 7-chloro-2H-chromen-3-yl, 7-fluoro-2H-chromen-3-yl, 7-bromo-2H-chromen-3-yl, 7-ethynyl-2H-chromen-3-yl, 6-chloro-1,4-dihydroquinolin-4-one-2-yl, 6-fluoro-1,4-dihydroquinolin-4-one-2-yl, 6-bromo-1,4-dihydroquinolin-4-one-2-yl, 6-ethynyl-1,4-dihydroquinolin-4-one-2-yl, 6-chloro-1,4-dihydroquinazolin-4-one-2-yl, 6-fluoro-1,4-dihydroquinazolin-4-one-2-yl, 6-bromo-1,4-dihydroquinazolin-4-one-2-yl, 6-ethynyl-1,4-dihydroquinazolin-4-one-2-yl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-ethynylphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-bromo-phenyl, 3-ethynylphenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 4-bromo-2-fluorophenyl, 2-bromo-4-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,4-dibromophenyl, 4-chloro-3-methylphenyl, 4-fluoro-3-methylphenyl, 4-bromo-3-methylphenyl, 4-chloro-2-methylphenyl, 4-fluoro-2-methylphenyl, 4-bromo-2-methylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dibromophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-chloro-2-pyridyl, 4-fluoro-2-pyridyl, 4-bromo-2-pyridyl, 4-ethynyl-2-pyridyl, 4-chloro-3-pyridyl, 4-fluoro-3-pyridyl, 4-bromo-3-pyridyl, 4-ethynyl-3-pyridyl, 5-chloro-2-pyridyl, 5-fluoro-2-pyridyl, 5-bromo-2-pyridyl, 5-ethynyl-2-pyridyl, 4-chloro-5-fluoro-2-pyridyl, 5-chloro-4-fluoro-2-pyridyl, 5-chloro-3-pyridyl, 5-fluoro-3-pyridyl, 5-bromo-3-pyridyl, 5-ethynyl-3-pyridyl, 6-chloro-3-pyridazinyl, 6-fluoro-3-pyridazinyl, 6-bromo-3-pyridazinyl, 6-ethynyl-3-pyridazinyl, 5-chloro-2-thiazolyl, 5-fluoro-2-thiazolyl, 5-bromo-2-thiazolyl, 5-ethynyl-2-thiazolyl, 2-chlorothieno[2,3-b]pyrrol-5-yl, 2-fluorothieno[2,3-b]pyrrol-5-yl, 2-bromothieno[2,3-b]-pyrrol-5-yl or 2-ethynylthieno[2,3-b]pyrrol-5-yl group. 7. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 6, wherein the group Q1 in the formula (1) is a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted. 8. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 6, wherein the group Q1 in the formula (1) is a thienopyridyl group which may be substituted, tetrahydrothienopyridyl group which may be substituted, thiazolopyridyl group which may be substituted, tetrahydrothiazolopyridyl group which may be substituted, thiazolopyridazinyl group which may be substituted, tetrahydrothiazolopyridazinyl group which may be substituted, pyranothiazolyl group which may be substituted, dihydropyranothiazolyl group which may be substituted, furopyridyl group which may be substituted, tetrahydrofuropyridyl group which may be substituted, oxazolopyridyl group which may be substituted, tetrahydrooxazolopyridyl group which may be substituted, pyrrolopyridyl group which may be substituted, dihydropyrrolopyridyl group which may be substituted, tetrahydropyrrolopyridyl group which may be substituted, pyrrolopyrimidinyl group which may be substituted, dihydropyrrolopyrimidinyl group which may be substituted, oxazolopyridazinyl group which may be substituted, tetrahydrooxazolopyridazinyl group which may be substituted, pyrrolothiazolyl group which may be substituted, dihydropyrrolothiazolyl group which may be substituted, pyrrolooxazolyl group which may be substituted, dihydropyrrolooxazolyl group which may be substituted, benzothiazolyl group which may be substituted, tetrahydrobenzothiazolyl group which may be substituted, thiazolopyrimidinyl group which may be substituted, dihydrothiazolopyrimidinyl group which may be substituted, benzoazepinyl group which may be substituted, tetrahydrobenzoazepinyl group which may be substituted, thiazoloazepinyl group which may be substituted, tetrahydrothiazoloazepinyl group which may be substituted, thienoazepinyl group which may be substituted, tetrahydrothienoazepinyl group which may be substituted, 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group which may be substituted, or 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group which may be substituted. 9. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 8, wherein the substituent(s) on the group Q1 are 1 to 3 substituents selected from a hydroxyl group, halogen atoms, halogenoalkyl groups, an amino group, a cyano group, an amidino group, a hydroxyamidino group, C1-C6 alkyl groups, C3-C6 cycloalkyl C1-C6 alkyl groups, hydroxy-C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkoxy C1-C6 alkyl group, a carboxyl group, C2-C6 carboxyalkyl groups, C2-C6 alkoxycarbonyl C1-C6 alkyl groups, amidino groups substituted by a C2-C6 alkoxycarbonyl group, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C2-C6 alkoxycarbonyl groups, amino C1-C6 alkyl groups, C1-C6 alkylamino C1-C6 alkyl groups, di(C1-C6 alkyl)amino C1-C6 alkyl groups, C2-C6 alkoxycarbonylamino-C1-C6 alkyl groups, C1-C6 alkanoyl groups, C1-C6 alkanoylamino C1-C6 alkyl groups, C1-C6 alkylsulfonyl groups, C1-C6 alkylsulfonylamino C1-C6 alkyl groups, a carbamoyl group, C1-C6 alkylcarbamoyl groups, N,N-di(C1-C6 alkyl)carbamoyl groups, C1-C6 alkylamino groups, di(C1-C6 alkyl)amino groups, 5- or 6-membered heterocyclic groups containing one of nitrogen, oxygen and sulfur or the same or different two atoms thereof, 5- or 6-membered heterocyclic-C1-C4 alkyl group, and 5- or 6-membered heterocyclic-amino C1-C4 alkyl group. 10. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 9, wherein the group T1 in the formula (1) is a carbonyl group, group —C(═O)—C(═O)—N(R′)—, group —C(═S)—C(═O)—N(R′)—, group —C(═O)—C(═S)—N(R′)— or group —C(═S)—C(═S)—N(R′)—, in which R′ means a hydrogen atom, hydroxyl group, alkyl group or alkoxy group. 11. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 9, wherein the group T1 in the formula (1) is a group —C(═O)—C(═O)—N(R′)—, group —C(═S)—C(═O)—N(R′)—, group —C(═O)—C(═S)—N(R′)— or group —C(═S)—C(═S)—N(R′)—, in which R′ means a hydrogen atom, hydroxyl group, alkyl group or alkoxy group. 12. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 11, wherein the group Q3 in the formula (1) is wherein Q5 means an alkylene group having 3 to 6 carbon atoms or a group —(CH2)m—CH2-A-CH2—(CH2)n—, in which m and n are independently of each other 0 or 1, and A has the same meaning as defined above, and R3 and R4 are independently of each other a hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, amino group, hydroxyimino group, alkoxyimino group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may be substituted, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group(s), N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl group which may be substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group which may be substituted, carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), alkylsulfonylamino group, alkylsulfonylaminoalkyl group, oxo group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, carboxyacyl group, alkoxyalkyloxycarbonyl group, halogenoacyl group, N,N-dialkylaminoacyl group, acyloxyacyl group, hydroxyacyl group, alkoxyacyl group, alkoxyalkylsulfonyl group, N,N-dialkylcarbamoylacyl group, N,N-dialkylcarbamoylalkylsulfonyl group or alkylsulfonylacyl group. 13. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 11, wherein the group Q3 in the formula (1) is wherein Q5 means a group —(CH2)m—CH2-A-CH2—(CH2)n, in which m and n are independently of each other 0 or 1, and A has the same meaning as defined above, and R3 and R4 are independently of each other a hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, amino group, hydroxyimino group, alkoxyimino group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may be substituted, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group(s), N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl group which may be substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group which may be substituted, carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), alkylsulfonylamino group, alkylsulfonylaminoalkyl group, oxo group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, carboxyacyl group, alkoxyalkyloxycarbonyl group, halogenoacyl group, N,N-dialkylaminoacyl group, acyloxyacyl group, hydroxyacyl group, alkoxyacyl group, alkoxyalkylsulfonyl group, N,N-dialkylcarbamoylacyl group, N,N-dialkylcarbamoylalkylsulfonyl group or alkylsulfonylacyl group. 14. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 11, wherein the group Q3 in the formula (1) is wherein Q5 means an alkylene group having 3 to 6 carbon atoms, and R3 and R4 are independently of each other a hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, amino group, hydroxyimino group, alkoxyimino group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may be substituted, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group(s), N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl group which may be substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group which may be substituted, carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), alkylsulfonylamino group, alkylsulfonylaminoalkyl group, oxo group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, carboxyacyl group, alkoxyalkyloxycarbonyl group, halogenoacyl group, N,N-dialkylaminoacyl group, acyloxyacyl group, hydroxyacyl group, alkoxyacyl group, alkoxyalkylsulfonyl group, N,N-dialkylcarbamoylacyl group, N,N-dialkylcarbamoylalkylsulfonyl group or alkylsulfonylacyl group. 15. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 11, wherein the group Q3 in the formula (1) is wherein Q5 means an alkylene group having 4 carbon atoms, R3 is a hydrogen atom, and R4 is an N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group(s). 16. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 11, wherein the group Q3 in the formula (1) is wherein Q5 means an alkylene group having 4 carbon atoms, R3 is a hydrogen atom, and R4 is an N,N-dimethylcarbamoyl group. 17. The compound according to claim 1, which is represented by the general formula (1): Q1-Q2-T0-N(R1)-Q3-N(R2)-T1-Q4 (1) wherein R1 and R2, independently of each other, represent a hydrogen atom, hydroxyl group, alkyl group or alkoxy group; Q1 represents a saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon group which may be substituted, a saturated or unsaturated, 5- to 7-membered heterocyclic group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted; Q2 represents a single bond, a saturated or unsaturated, 5- or 6-membered divalent cyclic hydrocarbon group which may be substituted, a saturated or unsaturated, 5- to 7-membered divalent heterocyclic group which may be substituted, a saturated or unsaturated, divalent bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, divalent bicyclic or tricyclic fused heterocyclic group which may be substituted; Q3 represents the following group: in which Q5 means a group —(CH2)m—CH2-A-CH2—(CH2)n—, in which m and n are independently of each other 0 or an integer of 1-3, and A means an oxygen atom, nitrogen atom, sulfur atom, —SO—, —SO2—, —NH—, —O—NH—, —NH—NH—, —S—NH—, —SO—NH— or —SO2—NH—, and R3 and R4 are substituents on carbon atom(s), nitrogen atom(s) or a sulfur atom(s) of a ring comprising Q5 and are independently of each other a hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, cyano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may be substituted, alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group(s), N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl group which may be substituted, carbamoylalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group, 3- to 6-membered heterocyclic carbonylalkyl group which may be substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group which may be substituted, aryl group, aralkyl group, heteroaryl group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsulfonylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group, alkoxyalkylsulfonyl group, 3- to 6-membered heterocyclic sulfonyl group which may be substituted, N-alkylaminoacyl group, N,N-dialkylaminoacyl group, N,N-dialkylcarbamoylacyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkylsulfonyl group which may have a substituent on the alkyl group(s) or alkylsulfonylacyl group, or R3 and R4, together with each other, denote an alkylene group having 1 to 5 carbon atoms, alkenylene group having 2 to 5 carbon atoms, alkylenedioxy group having 1 to 5 carbon atoms or carbonyldioxy group; Q4 represents an aryl group which may be substituted, an arylalkenyl group which may be substituted, an arylalkynyl group which may be substituted, a heteroaryl group which may be substituted, a heteroarylalkenyl group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted; T0 represents a carbonyl or thiocarbonyl group; and T1 represents a carbonyl group, sulfonyl group or thiocarbonyl group; a salt thereof, a solvate thereof, or an N-oxide thereof. 18. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to claim 17, wherein the group Q1 is a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted, and Q2 is a single bond. 19. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to claim 17 or 18, wherein the group Q1 is a thienopyridyl group which may be substituted, tetrahydrothienopyridyl group which may be substituted, thiazolopyridyl group which may be substituted, tetrahydrothiazolopyridyl group which may be substituted, thiazolopyridazinyl group which may be substituted, tetrahydrothiazolopyridazinyl group which may be substituted, pyranothiazolyl group which may be substituted, dihydropyranothiazolyl group which may be substituted, furopyridyl group which may be substituted, tetrahydrofuropyridyl group which may be substituted, oxazolopyridyl group which may be substituted, tetrahydrooxazolopyridyl group which may be substituted, pyrrolopyridyl group which may be substituted, dihydropyrrolopyridyl group which may be substituted, tetrahydropyrrolopyridyl group which may be substituted, pyrrolopyrimidinyl group which may be substituted, dihydropyrrolopyrimidinyl group which may be substituted, oxazolopyridazinyl group which may be substituted, tetrahydrooxazolopyridazinyl group which may be substituted, pyrrolothiazolyl group which may be substituted, dihydropyrrolothiazolyl group which may be substituted, pyrrolooxazolyl group which may be substituted, dihydropyrrolooxazolyl group which may be substituted, benzothiazolyl group which may be substituted, tetrahydrobenzothiazolyl group which may be substituted, thiazolopyrimidinyl group which may be substituted, dihydrothiazolopyrimidinyl group which may be substituted, benzoazepinyl group which may be substituted, tetrahydrobenzoazepinyl group which may be substituted, thiazoloazepinyl group which may be substituted, tetrahydrothiazoloazepinyl group which may be substituted, thienoazepinyl group which may be substituted, tetrahydrothienoazepinyl group which may be substituted, 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group which may be substituted, or 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group which may be substituted. 20. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 17 to 19, wherein the substituent(s) on the group Q1 are 1 to 3 substituent(s) selected from a hydroxyl group, halogen atoms, halogenoalkyl groups, an amino group, a cyano group, an amidino group, a hydroxyamidino group, C1-C6 alkyl groups, C3-C6 cycloalkyl C1-C6 alkyl groups, hydroxy-C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkoxy C1-C6 alkyl groups, a carboxyl group; C2-C6 carboxyalkyl groups, C2-C6 alkoxycarbonyl-C1-C6 alkyl groups, amidino groups substituted by a C2-C6 alkoxycarbonyl group, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C2-C6 alkoxycarbonyl groups, amino C1-C6 alkyl groups, C1-C6 alkylamino C1-C6 alkyl groups, di(C1-C6 alkyl)amino C1-C6 alkyl groups, C2-C6 alkoxycarbonylamino C1-C6 alkyl groups, C1-C6 alkanoyl groups, C1-C6 alkanoylamino C1-C6 alkyl groups, C1-C6 alkylsulfonyl groups, C1-C6 alkylsulfonylamino C1-C6 alkyl groups, a carbamoyl group, C1-C6 alkylcarbamoyl groups, N,N-di(C1-C6 alkyl)carbamoyl groups, C1-C6 alkylamino groups, di(C1-C6 alkyl)amino groups, 5- or 6-membered heterocyclic groups containing one of nitrogen, oxygen and sulfur or the same or different two atoms thereof, 5- or 6-membered heterocyclic-C1-C4 alkyl group, and 5- or 6-membered heterocyclic-amino C1-C4 alkyl group. 21. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 17 to 20, wherein the group Q3 in the formula (1) is wherein Q5 means a group —(CH2)m—CH2-A-CH2—(CH2)n—, in which m and n are independently of each other 0 or 1, and A has the same meaning as defined above, and R3 and R4 are independently of each other a hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, amino group, hydroxyimino group, alkoxyimino group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may be substituted, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group(s), N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl group which may be substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group which may be substituted, carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), alkylsulfonylamino group, alkylsulfonylaminoalkyl group, oxo group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, carboxyacyl group, alkoxyalkyloxycarbonyl group, halogenoacyl group, N,N-dialkylaminoacyl group, acyloxyacyl group, hydroxyacyl group, alkoxyacyl group, alkoxyalkylsulfonyl group, N,N-dialkylcarbamoylacyl group, N,N-dialkylcarbamoylalkylsulfonyl group or alkylsulfonylacyl group. 22. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 17 to 21, wherein the group Q4 in the formula (1) is a group selected from the group consisting of a naphthyl group which may be substituted, an anthryl group which may be substituted, a phenanthryl group which may be substituted, a styryl group which may be substituted, a phenylethynyl group which may be substituted, a thienylethenyl group which may be substituted, a pyridylethenyl group which may be substituted, an indenyl group which may be substituted, an indanyl group which may be substituted, a tetrahydronaphthyl group which may be substituted, a benzofuryl group which may be substituted, an isobenzofuryl group which may be substituted, a benzothienyl group which may be substituted, an indolyl group which may be substituted, an indolinyl group which may be substituted, an isoindolyl group which may be substituted, an isoindolinyl group which may be substituted, an indazolyl group which may be substituted, a quinolyl group which may be substituted, a dihydroquinolyl group which may be substituted, a 4-oxodihydroquinolyl group (dihydroquinolin-4-on) which may be substituted, a tetrahydroquinolyl group which may be substituted, an isoquinolyl group which may be substituted, a tetrahydroisoquinolyl group which may be substituted, a chromenyl group which may be substituted, a chromanyl group which may be substituted, an isochromanyl group which may be substituted, a 4H-4-oxobenzopyranyl group which may be substituted, a 3,4-dihydro-4H-4-oxobenzopyranyl group which may be substituted, a 4H-quinolizinyl group which may be substituted, a quinazolinyl group which may be substituted, a dihydroquinazolinyl group which may be substituted, a tetrahydroquinazolinyl group which may be substituted, a quinoxalinyl group which may be substituted, a tetrahydroquinoxalinyl group which may be substituted, a cinnolinyl group which may be substituted, a tetrahydrocinnolinyl group which may be substituted, an indolizinyl group which may be substituted, a tetrahydroindolizinyl group which may be substituted, a benzothiazolyl group which may be substituted, a tetrahydrobenzothiazolyl group which may be substituted, a benzoxazolyl group which may be substituted, a benzoisothiazolyl group which may be substituted, a benzoisoxazolyl group which may be substituted, a benzimidazolyl group which may be substituted, a naphthyridinyl group which may be substituted, a tetrahydronaphthyridinyl group which may be substituted, a thienopyridyl group which may be substituted, a tetrahydrothienopyridyl group which may be substituted, a thiazolopyridyl group which may be substituted, a tetrahydrothiazolopyridyl group which may be substituted, a thiazolopyridazinyl group which may be substituted, a tetrahydrothiazolopyridazinyl group which may be substituted, a pyrrolopyridyl group which may be substituted, a dihydropyrrolopyridyl group which may be substituted, a tetrahydropyrrolopyridyl group which may be substituted, a pyrrolopyrimidinyl group which may be substituted, a dihydropyrrolopyrimidinyl group which may be substituted, a pyridoquinazolinyl group which may be substituted, a dihydropyridoquinazolinyl group which may be substituted, a pyridopyrimidinyl group which may be substituted, a tetrahydropyridopyrimidinyl group which may be substituted, a pyranothiazolyl group which may be substituted, a dihydropyranothiazolyl group which may be substituted, a furopyridyl group which may be substituted, a tetrahydrofuropyridyl group which may be substituted, an oxazolopyridyl group which may be substituted, a tetrahydrooxazolopyridyl group which may be substituted, an oxazolopyridazinyl group which may be substituted, a tetrahydrooxazolopyridazinyl group which may be substituted, a pyrrolothiazolyl group which may be substituted, a dihydropyrrolothiazolyl group which may be substituted, a pyrrolooxazolyl group which may be substituted, a dihydropyrrolooxazolyl group which may be substituted, a thienopyrrolyl group which may be substituted, a thiazolopyrimidinyl group which may be substituted, a 4-oxo-tetrahydrocinnolinyl group which may be substituted, a 1,2,4-benzothiadiazinyl group which may be substituted, a 1,1-dioxy-2H-1,2,4-benzothiadiazinyl group which may be substituted, a 1,2,4-benzoxadiazinyl group which may be substituted, a cyclopentapyranyl group which may be substituted, a thienofuranyl group which may be substituted, a furopyranyl group which may be substituted, a pyridoxazinyl group which may be substituted, a pyrazoloxazolyl group which may be substituted, an imidazothiazolyl group which may be substituted, an imidazopyridyl group which may be substituted, a tetrahydroimidazopyridyl group which may be substituted, a pyrazinopyridazinyl group which may be substituted, a benzisoquinolyl group which may be substituted, a furocinnolyl group which may be substituted, a pyrazolothiazolopyridazinyl group which may be substituted, a tetrahydropyrazolothiazolopyridazinyl group which may be substituted, a hexahydrothiazolopyridazinopyridazinyl group which may be substituted, an imidazotriazinyl group which may be substituted, an oxazolopyridyl group which may be substituted, a benzoxepinyl group which may be substituted, a benzoazepinyl group which may be substituted, a tetrahydrobenzoazepinyl group which may be substituted, a benzodiazepinyl group which may be substituted, a benzotriazepinyl group which may be substituted, a thienoazepinyl group which may be substituted, a tetrahydrothienoazepinyl group which may be substituted, a thienodiazepinyl group which may be substituted, a thienotriazepinyl group which may be substituted, a thiazoloazepinyl group which may be substituted, a tetrahydrothiazoloazepinyl group which may be substituted, a 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group which may be substituted, and a 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group which may be substituted. 23. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 17 to 21, wherein the substituent(s) on the group Q4 are 1 to 3 substituents selected from a hydroxyl group, halogen atoms, halogenoalkyl groups, an amino group, a cyano group, aminoalkyl groups, a nitro group, hydroxyalkyl groups, alkoxyalkyl groups, a carboxyl group, carboxyalkyl groups, alkoxycarbonylalkyl groups, acyl groups, an amidino group, a hydroxyamidino group, linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, linear, branched or cyclic alkoxy groups having 1 to 6 carbon atoms, amidino groups substituted by an linear, branched or cyclic alkoxycarbonyl group having 2 to 7 carbon atoms, linear, branched or cyclic alkenyl groups having 2 to 6 carbon atoms, linear or branched alkynyl groups having 2 to 6 carbon atoms, linear, branched or cyclic alkoxycarbonyl groups having 2 to 6 carbon atoms, a carbamoyl group, mono- or dialkylcarbamoyl groups substituted by a linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms on the nitrogen atom(s), mono- or di-alkylamino groups substituted by linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, and 5- or 6-membered nitrogen-containing heterocyclic groups. 24. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 17 to 21, wherein the group Q4 is wherein R5 and R6, independently of each other, represent a hydrogen atom, cyano group, halogen atom, alkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, or phenyl group which may be substituted by a cyano group, hydroxyl group, halogen atom, alkyl group or alkoxy group, and R7 and R8, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein R9 and R10, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein R11, R12 and R13, independently of one another, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein X1 represents CH2, CH, NH, NOH, N, O or S, and R14, R15 and R16, independently of one another, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein X2 represents NH, N, O or S, X3 represents N, C or CH, X4 represents N, C or CH, and R17 and R18, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group, excluding the cases where X3 and X4 are combinations of C and CH, and are both C or CH; wherein N indicates that 1 or 2 carbon atoms of the ring substituted by R19 have been substituted by a nitrogen atom, and R19, R20 and R21, independently of one another, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein X5 represents CH2, CH, N or NH, Z1 represents N, NH or O, Z2 represents CH2, CH, C or N, Z3 represents CH2, CH, S, SO2 or C═O, X5-Z2 indicates that X5 and Z2 are bonded to each other by a single bond or double bond, R22 and R23, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group, and R24 represents a hydrogen atom or alkyl group; wherein X6 represents O or S, and R25 and R26, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; or wherein numerals 1 to 8 indicate positions, each N indicates that any one of carbon atoms of positions 1 to 4 and any one of carbon atoms of positions 5 to 8 has been substituted by a nitrogen atom, and R34, R35 and R36, independently of one another, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group. 25. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 17 to 21, wherein the group Q4 represents any of the following groups: wherein R5 and R6, independently of each other, represent a hydrogen atom or alkyl group, R7 represents a hydrogen atom, and R8 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein R9 represents a hydrogen atom, and R10 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein R11 are R12 both represent hydrogen atoms, and R13 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein X1 represents NH, NOH, N, O or S, R14 represents a hydrogen atom, halogen atom, acyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group or alkyl group, R15 represents a hydrogen atom or halogen atom, and R16 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein X2 represents NH, O or S, X3 represents N, C or CH, X4 represents N, C or CH, R17 represents a hydrogen atom, and R18 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group, excluding the cases where X3 and X4 are combinations of C and CH, and are both C or CH; wherein N indicates that 1 or 2 carbon atoms of the ring substituted by R19 have been substituted by a nitrogen atom, R19 and R20 both represent hydrogen atoms, and R21 represents a hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group; wherein X5 represents CH2, CH, N or NH, Z1 represents N, NH or O, Z2 represents CH2, CH, C or N, Z3 represents CH2, CH, S, SO2 or C═O, X5-Z2 indicates that X5 and Z2 are bonded to each other by a single bond or double bond, R22 represents a hydrogen atom, R23 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group, and R24 represents a hydrogen atom; wherein X6 represents 0, R25 represents a hydrogen atom, and R26 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; or wherein numerals 1 to 8 indicate positions, each N indicates that any one of carbon atoms of positions 1 to 4 and any one of carbon atoms of positions 5 to 8 has been substituted by a nitrogen atom, R3 represents a hydrogen atom or halogen atom, R35 represents a hydrogen atom or halogen atom, and R36 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group. 26. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 17 to 21, wherein the group Q4 is a 4-chlorostyryl, 4-fluorostyryl, 4-bromostyryl, 4-ethynylstyryl, 4-chlorophenylethynyl, 4-fluorophenylethynyl, 4-bromophenylethynyl, 4-ethynylphenylethynyl, 6-chloro-2-naphthyl, 6-fluoro-2-naphthyl, 6-bromo-2-naphthyl, 6-ethynyl-2-naphthyl, 7-chloro-2-naphthyl, 7-fluoro-2-naphthyl, 7-bromo-2-naphthyl, 7-ethynyl-2-naphthyl, 5-chloroindol-2-yl, 5-fluoroindol-2-yl, 5-bromoindol-2-yl, 5-ethynylindol-2-yl, 5-methylindol-2-yl, 5-chloro-4-fluoroindol-2-yl, 5-chloro-3-fluoroindol-2-yl, 3-bromo-5-chloroindol-2-yl, 3-chloro-5-fluoroindol-2-yl, 3-bromo-5-fluoroindol-2-yl, 5-bromo-3-chloroindol-2-yl, 5-bromo-3-fluoroindol-2-yl, 5-chloro-3-formylindol-2-yl, 5-fluoro-3-formylindol-2-yl, 5-bromo-3-formylindol-2-yl, 5-ethynyl-3-formylindol-2-yl, 5-chloro-3-(N,N-dimethylcarbamoyl)indol-2-yl, 5-fluoro-3-(N,N-dimethylcarbamoyl)indol-2-yl, 5-bromo-3-(N,N-dimethylcarbamoyl)indol-2-yl, 5-ethynyl-3-(N,N-dimethylcarbamoyl)indol-2-yl, 6-chloroindol-2-yl, 6-fluoroindol-2-yl, 6-bromoindol-2-yl, 6-ethynylindol-2-yl, 6-methylindol-2-yl, 5-chlorobenzothiophen-2-yl, 5-fluorobenzothiophen-2-yl, 5-bromobenzothiophen-2-yl, 5-ethynylbenzothiophen-2-yl, 5-methylbenzothiophen-2-yl, 5-chloro-4-fluorobenzothiophen-2-yl, 6-chlorobenzothiophen-2-yl, 6-fluorobenzothiophen-2-yl, 6-bromobenzothiophen-2-yl, 6-ethynylbenzothiophen-2-yl, 6-methylbenzothiophen-2-yl, 5-chlorobenzofuran-2-yl, 5-fluorobenzofuran-2-yl, 5-bromobenzofuran-2-yl, 5-ethynylbenzofuran-2-yl, 5-methylbenzofuran-2-yl, 5-chloro-4-fluorobenzofuran-2-yl, 6-chlorobenzofuran-2-yl, 6-fluorobenzofuran-2-yl, 6-bromobenzofuran-2-yl, 6-ethynylbenzofuran-2-yl, 6-methylbenzofuran-2-yl, 5-chlorobenzimidazol-2-yl, 5-fluorobenzimidazol-2-yl, 5-bromobenzimidazol-2-yl, 5-ethynylbenzimidazol-2-yl, 6-chloroquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-bromoquinolin-2-yl, 6-ethynylquinolin-2-yl, 7-chloroquinolin-3-yl, 7-fluoroquinolin-3-yl, 7-bromoquinolin-3-yl, 7-ethynylquinolin-3-yl, 7-chloroisoquinolin-3-yl, 7-fluoroisoquinolin-3-yl, 7-bromoisoquinolin-3-yl, 7-ethynylisoquinolin-3-yl, 7-chlorocinnolin-3-yl, 7-fluorocinnolin-3-yl, 7-bromocinnolin-3-yl, 7-ethynylcinnolin-3-yl, 7-chloro-2H-chromen-3-yl, 7-fluoro-2H-chromen-3-yl, 7-bromo-2H-chromen-3-yl, 7-ethynyl-2H-chromen-3-yl, 6-chloro-1,4-dihydroquinolin-4-one-2-yl, 6-fluoro-1,4-dihydroquinolin-4-one-2-yl, 6-bromo-1,4-dihydroquinolin-4-one-2-yl, 6-ethynyl-1,4-dihydroquinolin-4-one-2-yl, 6-chloro-1,4-dihydroquinazolin-4-one-2-yl, 6-fluoro-1,4-dihydroquinazolin-4-one-2-yl, 6-bromo-1,4-dihydroquinazolin-4-one-2-yl, 6-ethynyl-1,4-dihydroquinazolin-4-one-2-yl, 2-chlorothieno[2,3-b]pyrrol-5-yl, 2-fluorothieno[2,3-b]pyrrol-5-yl, 2-bromothieno[2,3-b]-pyrrol-5-yl or 2-ethynylthieno[2,3-b]pyrrol-5-yl group. 27. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 17 to 26, wherein T1 is a carbonyl group. 28. The compound according to claim 1, which is represented by the general formula (1): Q1-Q2-T0-N(R1)-Q3-N(R2)-T1-Q4 (1) wherein R1 and R2, independently of each other, represent a hydrogen atom, hydroxyl group, alkyl group or alkoxy group; Q1 represents a saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon group which may be substituted, a saturated or unsaturated, 5- to 7-membered heterocyclic group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted; Q2 represents a single bond, a saturated or unsaturated, 5- or 6-membered divalent cyclic hydrocarbon group which may be substituted, a saturated or unsaturated, 5- to 7-membered divalent heterocyclic group which may be substituted, a saturated or unsaturated, divalent bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, divalent bicyclic or tricyclic fused heterocyclic group which may be substituted; Q3 represents the following group: in which Q5 means an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or a group —(CH2)m—CH2-A-CH2—(CH2)n—, in which m and n are independently of each other 0 or an integer of 1-3, and A means an oxygen atom, nitrogen atom, sulfur atom, —SO—, —SO2—, —NH—, —O—NH—, —NH—NH—, —S—NH—, —SO—NH— or —SO2—NH—, and R3 and R4 are substituents on carbon atom(s) of a ring comprising Q5 and are independently of each other a hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, cyano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may be substituted, alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group(s), N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl group which may be substituted, carbamoylalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group, 3- to 6-membered heterocyclic carbonylalkyl group which may be substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group which may be substituted, aryl group, aralkyl group, heteroaryl group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsulfonylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group, alkoxyalkylsulfonyl group, 3- to 6-membered heterocyclic sulfonyl group which may be substituted, N-alkylaminoacyl group, N,N-dialkylaminoacyl group, N,N-dialkylcarbamoylacyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkylsulfonyl group which may have a substituent on the alkyl group(s) or alkylsulfonylacyl group, or R3 and R4, together with each other, denote an alkylene group having 1 to 5 carbon atoms, alkenylene group having 2 to 5 carbon atoms, alkylenedioxy group having 1 to 5 carbon atoms or carbonyldioxy group; Q4 represents an aryl group which may be substituted, an arylalkenyl group which may be substituted, an arylalkynyl group which may be substituted, a heteroaryl group which may be substituted, a heteroarylalkenyl group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted; T0 represents a carbonyl or thiocarbonyl group; and T1 represents group —C(═O)—C(═O)—N(R′)—, group —C(═S)—C(═O)—N(R′)—, group —C(═O)—C(═S)—N(R′)—, group —C(═S)—C(═S)—N(R′)—, in which R′ means a hydrogen atom, hydroxyl group, alkyl group or alkoxy group, group —C(═O)-A1-N(R″)—, in which A″ means an alkylene group having 1 to 5 carbon atoms, which may be substituted, and R″ means a hydrogen atom, hydroxyl group, alkyl group or alkoxy group, group —C(═O)—NH—, group —C(═S)—NH—, group —C(═O)—NH—NH—, group —C(═O)-A2-C(═O)—, in which A2 means a single bond or alkylene group having 1 to 5 carbon atoms, group —C(═O)-A3-C(═O)—NH—, in which A3 means an alkylene group having 1 to 5 carbon atoms, group —C(═O)—C(═NORa)—N(Rb)—, group —C(═S)—C(═NORa)—N(Rb)—, in which Ra means a hydrogen atom, alkyl group or alkanoyl group, and Rb means a hydrogen atom, hydroxyl group, alkyl group or alkoxy group, group —C(═O)—N═N—, group —C(═S)—N═N—, or thiocarbonyl group, a salt thereof, a solvate thereof, or an N-oxide thereof. 29. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to claim 28, wherein the group Q1 is a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted, and Q2 is a single bond. 30. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to claim 28 or 29, wherein the group Q1 is a thienopyridyl group which may be substituted, tetrahydrothienopyridyl group which may be substituted, thiazolopyridyl group which may be substituted, tetrahydrothiazolopyridyl group which may be substituted, thiazolopyridazinyl group which may be substituted, tetrahydrothiazolopyridazinyl group which may be substituted, pyranothiazolyl group which may be substituted, dihydropyranothiazolyl group which may be substituted, furopyridyl group which may be substituted, tetrahydrofuropyridyl group which may be substituted, oxazolopyridyl group which may be substituted, tetrahydrooxazolopyridyl group which may be substituted, pyrrolopyridyl group which may be substituted, dihydropyrrolopyridyl group which may be substituted, tetrahydropyrrolopyridyl group which may be substituted, pyrrolopyrimidinyl group which may be substituted, dihydropyrrolopyrimidinyl group which may be substituted, oxazolopyridazinyl group which may be substituted, tetrahydrooxazolopyridazinyl group which may be substituted, pyrrolothiazolyl group which may be substituted, dihydropyrrolothiazolyl group which may be substituted, pyrrolooxazolyl group which may be substituted, dihydropyrrolooxazolyl group which may be substituted, benzothiazolyl group which may be substituted, tetrahydrobenzothiazolyl group which may be substituted, thiazolopyrimidinyl group which may be substituted, dihydrothiazolopyrimidinyl group which may be substituted, benzoazepinyl group which may be substituted, tetrahydrobenzoazepinyl group which may be substituted, thiazoloazepinyl group which may be substituted, tetrahydrothiazoloazepinyl group which may be substituted, thienoazepinyl group which may be substituted, tetrahydrothienoazepinyl group which may be substituted, 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group which may be substituted, or 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group which may be substituted. 31. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 28 to 30, wherein the substituent(s) on the group Q1 are 1 to 3 substituent(s) selected from a hydroxyl group, halogen atoms, halogenoalkyl groups, an amino group, a cyano group, an amidino group, a hydroxyamidino group, C1-C6 alkyl groups, C3-C6 cycloalkyl C1-C6 alkyl groups, hydroxy C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkoxy C1-C6 alkyl groups, a carboxyl group, C2-C6 carboxyalkyl groups, C2-C6 alkoxycarbonyl C1-C6 alkyl groups, amidino groups substituted by a C2-C6 alkoxycarbonyl group, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C2-C6 alkoxycarbonyl groups, amino C1-C6 alkyl groups, C1-C6 alkylamino C1-C6 alkyl groups, di(C1-C6 alkyl)amino C1-C6 alkyl groups, C2-C6 alkoxycarbonylamino-C1-C6 alkyl groups, C1-C6 alkanoyl groups, C1-C6 alkanoylamino C1-C6 alkyl groups, C1-C6 alkylsulfonyl groups, C1-C6 alkylsulfonylamino C1-C6 alkyl groups, a carbamoyl group, C1-C6 alkylcarbamoyl groups, N,N-di(C1-C6 alkyl)carbamoyl groups, C1-C6 alkylamino groups, di(C1-C6 alkyl)amino groups, 5- or 6-membered heterocyclic groups containing one of nitrogen, oxygen and sulfur or the same or different two atoms thereof, 5- or 6-membered heterocyclic-C1-C4 alkyl group, and 5- or 6-membered heterocyclic-amino-C1-C4 alkyl group. 32. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 28 to 31, wherein the group Q3 is wherein Q5 means an alkylene group having 3 to 6 carbon atoms or a group —(CH2)m—CH2-A-CH2—(CH2)n—, in which m and n are independently of each other 0 or 1, and A has the same meaning as defined above, and R3 and R4 are independently of each other a hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, amino group, hydroxyimino group, alkoxyimino group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may be substituted, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group(s), N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl group which may be substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group which may be substituted, carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), alkylsulfonylamino group, alkylsulfonylaminoalkyl group, oxo group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, carboxyacyl group, alkoxyalkyloxycarbonyl group, halogenoacyl group, N,N-dialkylaminoacyl group, acyloxyacyl group, hydroxyacyl group, alkoxyacyl group, alkoxyalkylsulfonyl group, N,N-dialkylcarbamoylacyl group, N,N-dialkylcarbamoylalkylsulfonyl group or alkylsulfonylacyl group. 33. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 28 to 31, wherein the group Q3 is wherein Q5 means an alkylene group having 4 carbon atoms, R3 is a hydrogen atom, and R4 is an N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group(s). 34. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 28 to 31, wherein the group Q3 is wherein Q5 means an alkylene group having 4 carbon atoms, R3 is a hydrogen atom, and R4 is an N,N-dimethylcarbamoyl group. 35. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 28 to 34, wherein the group Q4 is a group selected from a phenyl group which may be substituted, a pyridyl group which may be substituted, a pyridazinyl group which may be substituted, a furyl group which may be substituted, a thienyl group which may be substituted, a pyrrolyl group which may be substituted, a thiazolyl group which may be substituted, an oxazolyl group which may be substituted, a pyrimidinyl group which may be substituted and a tetrazolyl group which may be substituted, 36. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 28 to 35, wherein the substituent(s) on the group Q4 are 1 to 3 substituents selected from a hydroxyl group, halogen atoms, halogenoalkyl groups, an amino group, a cyano group, aminoalkyl groups, a nitro group, hydroxyalkyl groups, alkoxyalkyl groups, a carboxyl group, carboxyalkyl groups, alkoxycarbonylalkyl groups, acyl groups, an amidino group, a hydroxyamidino group, linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, linear, branched or cyclic alkoxy groups having 1 to 6 carbon atoms, amidino groups substituted by a linear, branched or cyclic alkoxycarbonyl group having 2 to 7 carbon atoms, linear, branched or cyclic alkenyl groups having 2 to 6 carbon atoms, linear or branched alkynyl groups having 2 to 6 carbon atoms, linear, branched or cyclic alkoxycarbonyl groups having 2 to 6 carbon atoms, a carbamoyl group, mono- or dialkylcarbamoyl groups substituted by a linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms on the nitrogen atom(s), mono- or di-alkylamino groups substituted by linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, and 5- or 6-membered nitrogen-containing heterocyclic groups. 37. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 28 to 34, wherein the group Q4 is wherein R27 and R28, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein E1 and E2, independently of each other, represent N or CH, and R29 and R30, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; or wherein Y1 represents CH or N, Y2 represents —N(R33)—, in which R33 means a hydrogen atom or alkyl group having 1 to 6 carbon atoms, O or S, and R31 and R32, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group. 38. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 28 to 34, wherein the group Q4 is wherein R27 is a hydrogen atom or halogen atom, and R28 is a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein E1 and E2, independently of each other, represent N or CH, R29 is a hydrogen atom or halogen atom, and R30 is a hydrogen atom, halogen atom, alkyl group or alkynyl group; or wherein Y1 is CH or N, Y2 is —N(R33)—, in which R33 means a hydrogen atom or alkyl group having 1 to 6 carbon atoms, O or S, and R31 is a hydrogen atom or halogen atom and R32 is a hydrogen atom, halogen atom, alkyl group or alkynyl group. 39. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 28 to 34, wherein the group Q4 is 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-ethynylphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 3-ethynylphenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 4-bromo-2-fluorophenyl, 2-bromo-4-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,4-dibromophenyl, 4-chloro-3-methylphenyl, 4-fluoro-3-methylphenyl, 4-bromo-3-methylphenyl, 4-chloro-2-methylphenyl, 4-fluoro-2-methylphenyl, 4-bromo-2-methylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dibromophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-chloro-2-pyridyl, 4-fluoro-2-pyridyl, 4-bromo-2-pyridyl, 4-ethynyl-2-pyridyl, 4-chloro-3-pyridyl, 4-fluoro-3-pyridyl, 4-bromo-3-pyridyl, 4-ethynyl-3-pyridyl, 5-chloro-2-pyridyl, 5-fluoro-2-pyridyl, 5-bromo-2-pyridyl, 5-ethynyl-2-pyridyl, 4-chloro-5-fluoro-2-pyridyl, 5-chloro-4-fluoro-2-pyridyl, 5-chloro-3-pyridyl, 5-fluoro-3-pyridyl, 5-bromo-3-pyridyl, 5-ethynyl-3-pyridyl, 6-chloro-3-pyridazinyl, 6-fluoro-3-pyridazinyl, 6-bromo-3-pyridazinyl, 6-ethynyl-3-pyridazinyl, 5-chloro-2-thiazolyl, 5-fluoro-2-thiazolyl, 5-bromo-2-thiazolyl or 5-ethynyl-2-thiazolyl. 40. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 28 to 39, wherein the group T1 is a group —C(═O)—C(═O)—N(R′)—, group —C(═S)—C(═O)—N(R′)—, group —C(═O)—C(═S)—N(R′)— or group —C(═S)—C(═S)—N(R′)—. 41. A medicine comprising the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40. 42. An activated blood coagulation factor X inhibitor comprising the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40. 43. An anticoagulant comprising the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40. 44. An agent for preventing and/or treating thrombosis or embolism, comprising the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40. 45. An agent for preventing and/or treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing, comprising the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40. 46. A medicinal composition comprising the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40, and a pharmaceutically acceptable carrier. 47. Use of the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40 for preparation of a medicine. 48. Use of the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40 for preparation of an activated blood coagulation factor X inhibitor. 49. Use of the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40 for preparation of an anticoagulant. 50. Use of the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40 for preparation of an agent for preventing and/or treating thrombosis or embolism. 51. Use of the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40 for preparation of an agent for preventing and/or treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing. 52. A method for treating thrombosis or embolism, which comprises administering an effective amount of the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40. 53. A method for treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing, which comprises administering an effective amount of the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40. 54. A compound represented by the following general formula (4): HN(R1)-Q3-N(R2)-T1-Q4 (4) wherein R1, R2 and T1 have the same meanings as defined in claim 1, Q3 represents the following group: wherein Q5, R3 and R4 have the same meanings as defined in claim 1, and Q4 represents an aryl group which may be substituted, a heteroaryl group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted; a salt thereof, a solvate thereof, or an N-oxide thereof. 55. A compound represented by the following general formula (9): Q1-Q2-C(═O)—N(R1)-Q3-NHR2 (9) wherein Q2, R1 and R2 have the same meanings as defined in claim 1, Q1 represents a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted, and Q3 represents the following group: in which Q5, R3 and R4 have the same meanings as defined in claim 1, a salt thereof, a solvate thereof, or an N-oxide thereof. 56. A compound represented by the following general formula (4): HN(R1)-Q3-N(R2)-T1-Q4 (4) wherein R1, R2 and T1 have the same meanings as defined in claim 17, Q3 represents the following group: wherein Q5, R3 and R4 have the same meanings as defined in claim 17, and Q4 represents an aryl group which may be substituted, a heteroaryl group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted; and a salt thereof, a solvate thereof, or an N-oxide thereof. 57. A compound represented by the following general formula (9): Q1-Q2-C(═O)—N(R1)-Q3-NHR2 (9) wherein Q2, R1 and R2 have the same meanings as defined in claim 17, Q1 represents a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted, and Q3 represents the following group: in which Q5, R3 and R4 have the same meanings as defined in claim 17, a salt thereof, a solvate thereof, or an N-oxide thereof. 58. A compound represented by the following general formula (4): HN(R1)-Q3-N(R2)-T1-Q4 (4) wherein R1, R2 and T1 have the same meanings as defined in claim 28, Q3 represents the following group: wherein Q5, R3 and R4 have the same meanings as defined in claim 28, and Q4 represents an aryl group which may be substituted, a heteroaryl group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted; and a salt thereof, a solvate thereof, or an N-oxide thereof. 59. A compound represented by the following general formula (9): Q1-Q2-—C(═O)—N(R1)-Q3-NHR2 (9) wherein Q2, R1 and R2 have the same meanings as defined in claim 28, Q1 represents a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted, and Q3 represents the following group: in which Q5, R3 and R4 have the same meanings as defined in claim 28, a salt thereof, a solvate thereof, or an N-oxide thereof. |
<SOH> BACKGROUND ART <EOH>In unstable angina, cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve replacement, reocclusion after angioplasty and thrombus formation during extracorporeal circulation, hypercoagulable state is a pivotal factor. Therefore, there is a demand for development of excellent anticoagulants which have good dose responsiveness, long duration, low risk of hemorrhage and little side effects and fast onset of sufficient effects even by oral administration (Thrombosis Research, Vol. 68, pp. 507-512, 1992). Based on the research of anticoagulants worked through various mechanism of action, it is suggested that FXa inhibitors are promising anticoagulants. A blood coagulation system comprises a series of reactions that a great amount of thrombin is produced through an amplification process by multi-stage enzyme reactions to form insoluble fibrin. In an endogenous system, activated factor IX activates into factor X on a phospholipid membrane in the presence of activated factor VIII and calcium ions after multi-stage reactions subsequent to activation of a contact factor. In an exogenous system, activated factor VII activates factor X in the presence of a tissue factor. More specifically, the activation of the factor X into FXa in the coagulation system is a crucial reaction in the formation of thrombin. The activated factor X (FXa) limitedly decomposes prothrombin to produce thrombin in the both systems. Since the produced thrombin activates coagulation factors in the upper stream, the formation of thrombin is more amplified. As described above, since the coagulation system in the upper stream of FXa is divided into the endogenous system and the exogenous system, production of FXa cannot be sufficiently inhibited by inhibiting enzymes in the coagulation system in the upper stream of FXa, leading to production of thrombin. Since the coagulation system comprises self-amplification reactions, inhibition of the coagulation system can be more efficiently achieved by inhibiting FXa in the upper stream of thrombin than the inhibition of thrombin (Thrombosis Research, Vol. 15, pp. 617-629, 1979). An another excellent point of FXa inhibitors is a great difference between an effective dose in a thrombosis model and a dose elongating bleeding time in an experimental hemorrhagic model. From this experimental result, FXa inhibitors are considered to be anticoagulants having low risk of hemorrhage. Various compounds have been reported as FXa inhibitors. It is known that antithrombin III and antithrombin III dependent pentasacchrides can generally not inhibit prothrombinase complexes which play a practical role in the thrombus formation in a living body (Thrombosis Research, Vol. 68, pp. 507-512, 1992; Journal of Clinical Investigation, Vol. 71, pp. 1383-1389, 1983; Mebio, Vol. 14, the August number, pp. 92-97). In addition, they do not exhibit effectiveness by oral administration. Tick anticoagulant peptide (TAP) (Science, Vol. 248, pp. 593-596, 1990) and antistasin (AST) (Journal of Biological Chemistry, Vol. 263, pp. 10162-10167, 1988) isolated from mites or leeches, which are bloodsuckers, also inhibit Fxa and exhibit anti-thrombotic effects against venous thrombosis and arterial thrombosis. However, these compounds are high-molecular weight peptides and unavailable in oral administration. As described above, development of antithrombin III independent low-molecular weight FXa inhibitors which directly inhibit coagulation factors has been conducted. It is therefore an object of the present invention to provide a novel compound which has a potent FXa-inhibiting effect and exhibits an anti-thrombotic effect quickly, sufficiently and persistently by oral administration. |
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