| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 31.12.02 |
| PATENT TITLE |
Preventive or therapeutic drugs for fibrosis containing chymase inhibitors as the active ingredient |
| PATENT ABSTRACT |
A medicament for the prevention or treatment containing a chymase inhibitor, as an effective component, which is a side effect-free, safe medicament for prevention or treatment of fibrosis of the skin or various viscera which suppresses the progression of the condition, prevents the progression of complications, and improves the quality of life of the patient, wherein a quinazoline derivative having the formula (I): ##STR1## or a pharmaceutically acceptable salt thereof is included therein. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | October 22, 2001 |
| PATENT CT FILE DATE | February 22, 2001 |
| PATENT CT NUMBER | This data is not available for free |
| PATENT CT PUB NUMBER | This data is not available for free |
| PATENT CT PUB DATE | This data is not available for free |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED |
Hideki Okunishi, "Angiotensin II formation by chymase in the cardiovascular tissue," Folia Pharmacologica Japonica, vol. 112, No. 3 (1998), pp. 203-212. Eiji Ikada, "Roles of ACE and chymase in kidney," Kekkan to Naihi, vol. 9, No. 2 (1999) pp. 177-184. Eiichi Kakizoe, "Activation of skin chymase in scleroderma model mice," Journal of Pharmacology, vol. 79, No. Suppl.1 (1999) p. 60P. S. Akimoto, et al, "Dermal mast cells in scleroderma: their skin density, tryptase/chymase phenotypes and degranulation," British Journal of Dermatology, vol. 138, 1998, pp. 399-406. Anne-Marie A. Irani, et al, "Mast Cell Changes in Scleroderma," Arthritis and Rheumatism, vol. 35, No. 8, Aug. 1992, pp. 933-939. Melinda Walker, et al, "Mast Cells and Their Degranulation in the Tsk Mouse Model of Scleroderma (42183)," Proceedings of the Society for Experimental Biology and Medicine, vol. 180, 1985, pp. 323-328. Eric T. Everett, et al, "The Role of mast cells in the development of skin fibrosis in tight-skin mutant mice," Comp. Biochem. Physiol., vol. 110A, No. 2, 1995, pp. 159-165. Melinda Walker, et al, "Inhibition of Fibrosis in TSK Mice by Blocking Mast Cell Degranulation," The Journal of Rheumatalogy, 14:2, 1987, pp. 299-301. Amy R. O'Brien-Ladner, et al, "Bleomycin injury of the lung in a mast-cell-deficient model," Agents Actions, vol. 39, 1993, pp. 20-24. Toshihiko Okazaki, et al, "Increase of Mast Cells in the Liver and Lung May Be Associated with but Not a Cause of Fibrosis: Demonstration Using Mast Cell-Deficient Ws/Ws Rats," Laboratory Investigation, vol. 78, No. 11, Nov. 1998, pp. 1431-1438. Juhani Saarinen, et al, "Activation of Human Interstitial Procollagenase through Direct Cleavage of the Leu.sup.83 -Thr.sup.84 Bond by Mast Cell Chymase," The Journal of Biological Chemistry, vol. 269, No. 27, 1994, pp. 18134-18140. Jussi Taipale, et al, "Human Mast Cell Chymase and Leukocyte Elastase Release Latent Transforming Growth Factor-.beta.1 from the Extracellular Matrix of Cultured Huamn Epithelial and Endothelial Cells," The Journal of Biological Chemistry, vol. 270, No. 9, 1995, pp. 4689-4696. Kevin P. Rioux, et al, "Hepatic Mucosal Mast Cell Hyperplasia in Rats With Secondary Biliary Cirrhosis," Hepatology, vol. 23, No. 4, 1996, pp. 888-895. Naotaka Shiota, MD PhD, et al, "Tranilast Suppresses Vascular Chymase Expression and Neointima Formation in Baloon-Injured Dog Carotid Artery," Circulation, 99(8), Mar. 2, 1999, pp. 1084-1090. Masatake Hara, MD, et al, "Mast Cells Cause Apoptosis of Cardiomyocytes and proliferation of Other Intramyocardial Cells In Vitro," Circulation, 100(13), Sep. 28, 1999, pp. 1443-1449. Naotaka Shiota, et al, "Chymase is activated in the hamster heart following ventricular fibrosis during the chronic stage of hypertension," FEBS Letters, 406, 1997, pp. 301-304. Thomas Armbrust, et al, "Mast cells distribution in human liver disease and experimental rat liver fibrosis. Indications for mast cell participation in development of liver fibrosis," Journal of Hepatology, vol. 26, 1997, pp. 1042-1054. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A method for the prevention or treatment of fibrosis involving extracellular matrix dysbolism comprising administering to a patient in need of such treatment a chymase inhibitor in an amount effective for prevention or treatment of said fibrosis. 2. A method for prevention or treatment according to claim 1, wherein the fibrosis involving extracellular matrix dysbolism is at least one disease selected from the group consisting of scleroderma, pulmonary fibrosis, benign prostatomegaly, myocardial fibrogenesis following myocardial infarction, myocardial fibrosis, musculoskeletal fibrosis, post-surgical adhesion, hypertropic scars and keloids, cirrhosis, hepatic fibrosis, renal fibrosis and fibrous vascular disorders. 3. A method for prevention or treatment according to claim 2, wherein siad fibrosis involving extracellular matrix dysbolism is a complication of diabetes selected from the group consisting of retinitis due to fibrous microvasculitis, neurosis, nephropathy, and peripheral arteritis. 4. A method for treatment as claimed in claim 1, wherein the chymase inhibitor is a quinazoline derivative having the following formula (I) or a pharmaceutically acceptable salt thereof: ##STR9## wherein the ring A represents an aryl group; R.sup.1 represents a hydroxyl group, an amino group, a C.sub.1 to C.sub.4 lower alkylamino group which may optionally be substituted with a carboxylic acid group, a C.sub.7 to C.sub.10 lower aralkylamino group which may optionally be substituted with a carboxylic acid group, an amino group acylated with a C.sub.1 to C.sub.4 lower aliphatic acid which may optionally be substituted with a carboxylic acid group, an amino group acylated with an aromatic ring carboxylic acid which may optionally be substituted with a carboxylic acid group, an amino group acylated with a heteroaromatic ring carboxylic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with a C.sub.1 to C.sub.4 lower alkanesulfonic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with an aromatic ring sulfonic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with a heteroaromatic ring sulfonic acid which may optionally be substituted with a carboxylic acid group, a C.sub.1 to C.sub.4 lower alkyl group substituted with a carboxylic acid group, or a C.sub.2 to C.sub.4 lower alkylene group which may optionally be substituted with a carboxylic acid group; R.sup.2 and R.sup.3 may be the same or different and represent a hydrogen atom, an unsubstituted or substituted C.sub.1 to C.sub.4 lower alkyl group, a halogen atom, a hydroxyl group, a C.sub.1 to C.sub.4 lower alkoxyl group, an amino group, an unsubstituted or substituted C.sub.1 to C.sub.4 lower alkylamino group, an unsubstituted or substituted C.sub.7 to C.sub.10 aralkylamino group, an amino group acylated with a C.sub.1 to C.sub.4 lower aliphatic acid which may optionally be substituted with a carboxylic acid group, an amino group acylated with an aromatic ring carboxylic acid which may optionally be substituted with a carboxylic acid group, an amino group acylated with a heteroaromatic ring carboxylic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with a C.sub.1 to C.sub.4 lower alkanesulfonic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with an aromatic ring sulfonic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with a heteroaromatic ring sulfonic acid which may optionally be substituted with a carboxylic acid group, or a carboxylic acid group or when the ring A is a benzene ring, R.sup.1 and R.sup.2 may form, together with the substituting benzene ring, a fused heterocyclic ring which may optionally be substituted with a carboxylic acid and in which the carbon atom in the ring may form a carbonyl group and R.sup.3 is the same as defined above; and X represents a hydrogen atom, a C.sub.1 to C.sub.4 lower alkyl group, a C.sub.1 to C.sub.4 lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, or a nitro group. 5. A method for the prevention or treatment of fibrosis involving extracellular matrix dysbolism comprising administering to a patient in need of such treatment a chymase inhibitor in an amount effective for prevention or treatment of said fibrosis, wherein the chymase inhibitor is a quinazoline derivative having the following formula (I) or a pharmaceutically acceptable salt thereof: ##STR10## wherein the ring A represents an aryl group; R1 represents a hydroxyl group, an amino group, a C.sub.1 to C.sub.4 lower alkylamino group which may optionally be substituted with a carboxylic acid group, a C.sub.7 to C.sub.10 lower aralkylamino group which may optionally be substituted with a carboxylic acid group, an amino group acylated with a C.sub.1 to C.sub.4 lower aliphatic acid which may optionally be substituted with a carboxylic acid group, an amino group acylated with an aromatic ring carboxylic acid which may optionally be substituted with a carboxylic acid group, an amino group acylated with a heteroaromatic ring carboxylic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with a C.sub.1 to C.sub.4 lower alkanesulfonic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with an aromatic ring sulfonic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with a heteroaromatic ring sulfonic acid which may optionally be substituted with a carboxylic acid group, a C.sub.1 to C.sub.4 lower alkyl group substituted with a carboxylic acid group, or a C.sub.2 to C.sub.4 lower alkylene group which may optionally be substituted with a carboxylic acid group; R.sup.2 and R.sup.3 may be the same or different and represent a hydrogen atom, an unsubstituted or substituted C.sub.1 to C.sub.4 lower alkyl group, a halogen atom, a hydroxyl group, a C.sub.1 to C.sub.4 lower alkoxyl group, an amino group, an unsubstituted or substituted C.sub.1 to C.sub.4 lower alkylamino group, an unsubstituted or substituted C.sub.7 to C.sub.10 aralkylamino group, an amino group acylated with a C.sub.1 to C.sub.4 lower aliphatic acid which may optionally be substituted with a carboxylic acid group, an amino group acylated with an aromatic ring carboxylic acid which may optionally be substituted with a carboxylic acid group, an amino group acylated with a heteroaromatic ring carboxylic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with a C.sub.1 to C.sub.4 lower alkanesulfonic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with an aromatic ring sulfonic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with a heteroaromatic ring sulfonic acid which may optionally be substituted with a carboxylic acid group, or a carboxylic acid group or when the ring A is a benzene ring, R.sup.1 and R.sup.2 may form, together with the substituting benzene ring, a fused heterocyclic ring which may optionally be substituted with a carboxylic acid and in which the carbon atom in the ring may form a carbonyl group and R.sup.3 is the same as defined above; and X represents a hydrogen atom, a C.sub.1 to C.sub.4 lower alkyl group, a C.sub.1 to C.sub.4 lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, or a nitro group. 6. A method for the prevention or treatment of fibrosis involving extracellular matrix dysbolism comprising administering to a patient in need of such treatment a chymase inhibitor in an amount effective for prevention or treatment of said fibrosis, wherein said chymase inhibitor is selected from the group consisting of .alpha.-keto acid derivatives, .alpha.,.alpha.-difluoro-.beta.-keto acid derivatives, tripeptide inhibitors, phosphoric acid derivatives, trifluoromethylketone derivatives, acetoamide derivatives, triazine derivatives, phenol ester derivatives, cephem derivatives, isoxazole derivatives, imidazolidine derivatives, hydantoin derivatives and quinazoline derivatives. 7. A method for treating extracellular matrix dysbolism comprising administering to a patient in need of such treatment a chymase inhibitor in an amount effective for treating extracellular matrix dysbolism. 8. A method for treatment as claimed in claim 7, wherein the chymase inhibitor is a quinazoline derivative having the following formula (I) or a pharmaceutically acceptable salt thereof: ##STR11## wherein the ring A represents an aryl group; R.sup.1 represents a hydroxyl group, an amino group, a C.sub.1 to C.sub.4 lower alkylamino group which may optionally be substituted with a carboxylic acid group, a C.sub.7 to C.sub.10 lower aralkylamino group which may optionally be substituted with a carboxylic acid group, an amino group acylated with a C.sub.1 to C.sub.4 lower aliphatic acid which may optionally be substituted with a carboxylic acid group, an amino group acylated with an aromatic ring carboxylic acid which may optionally be substituted with a carboxylic acid group, an amino group acylated with a heteroaromatic ring carboxylic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with a C.sub.1 to C.sub.4 lower alkanesulfonic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with an aromatic ring sulfonic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with a heteroaromatic ring sulfonic acid which may optionally be substituted with a carboxylic acid group, a C.sub.1 to C.sub.4 lower alkyl group substituted with a carboxylic acid group, or a C.sub.2 to C.sub.4 lower alkylene group which may optionally be substituted with a carboxylic acid group; R.sup.2 and R.sup.3 may be the same or different and represent a hydrogen atom, an unsubstituted or substituted C.sub.1 to C.sub.4 lower alkyl group, a halogen atom, a hydroxyl group, a C.sub.1 to C.sub.4 lower alkoxyl group, an amino group, an unsubstituted or substituted C.sub.1 to C.sub.4 lower alkylamino group, an unsubstituted or substituted C.sub.7 to C.sub.10 aralkylamino group, an amino group acylated with a C.sub.1 to C.sub.4 lower aliphatic acid which may optionally be substituted with a carboxylic acid group, an amino group acylated with an aromatic ring carboxylic acid which may optionally be substituted with a carboxylic acid group, an amino group acylated with a heteroaromatic ring carboxylic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with a C.sub.1 to C.sub.4 lower alkanesulfonic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with an aromatic ring sulfonic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with a heteroaromatic ring sulfonic acid which may optionally be substituted with a carboxylic acid group, or a carboxylic acid group or when the ring A is a benzene ring, R.sup.1 and R.sup.2 may form, together with the substituting benzene ring, a fused heterocyclic ring which may optionally be substituted with a carboxylic acid and in which the carbon atom in the ring may form a carbonyl group and R.sup.3 is the same as defined above; and X represents a hydrogen atom, a C.sub.1 to C.sub.4 lower alkyl group, a C.sub.1 to C.sub.4 lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, or a nitro group. 9. A method for treating extracellular matrix dysbolism comprising administering to a patient in need of such treatment a chymase inhibitor in an amount effective for treating extracellular matrix dysbolism, wherein the chymase inhibitor is a quinazoline derivative having the following formula (I) or a pharmaceutically acceptable salt thereof: ##STR12## wherein the ring A represents an aryl group; R.sup.1 represents a hydroxyl group, an amino group, a C.sub.1 to C.sub.4 lower alkylamino group which may optionally be substituted with a carboxylic acid group, a C.sub.7 to C.sub.10 lower aralkylamino group which may optionally be substituted with a carboxylic acid group, an amino group acylated with a C.sub.1 to C.sub.4 lower aliphatic acid which may optionally be substituted with a carboxylic acid group, an amino group acylated with an aromatic ring carboxylic acid which may optionally be substituted with a carboxylic acid group, an amino group acylated with a heteroaromatic ring carboxylic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with a C.sub.1 to C.sub.4 lower alkanesulfonic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with an aromatic ring sulfonic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with a heteroaromatic ring sulfonic acid which may optionally be substituted with a carboxylic acid group, a C.sub.1 to C.sub.4 lower alkyl group substituted with a carboxylic acid group, or a C.sub.2 to C.sub.4 lower alkylene group which may optionally be substituted with a carboxylic acid group; R.sup.2 and R.sup.3 may be the same or different and represent a hydrogen atom, an unsubstituted or substituted C.sub.1 to C.sub.4 lower alkyl group, a halogen atom, a hydroxyl group, a C.sub.1 to C.sub.4 lower alkoxyl group, an amino group, an unsubstituted or substituted C.sub.1 to C.sub.4 lower alkylamino group, an unsubstituted or substituted C.sub.7 to C.sub.10 aralkylamino group, an amino group acylated with a C.sub.1 to C.sub.4 lower aliphatic acid which may optionally be substituted with a carboxylic acid group, an amino group acylated with an aromatic ring carboxylic acid which may optionally be substituted with a carboxylic acid group, an amino group acylated with a heteroaromatic ring carboxylic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with a C.sub.1 to C.sub.4 lower alkanesulfonic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with an aromatic ring sulfonic acid which may optionally be substituted with a carboxylic acid group, an amino group sulfonylated with a heteroaromatic ring sulfonic acid which may optionally be substituted with a carboxylic acid group, or a carboxylic acid group or when the ring A is a benzene ring, R.sup.1 and R.sup.2 may form, together with the substituting benzene ring, a fused heterocyclic ring which may optionally be substituted with a carboxylic acid and in which the carbon atom in the ring may form a carbonyl group and R.sup.3 is the same as defined above; and X represents a hydrogen atom, a C.sub.1 to C.sub.4 lower alkyl group, a C.sub.1 to C.sub.4 lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, or a nitro group. 10. A method for the prevention or treatment of fibrosis involving extracellular matrix dysbolism comprising administering to a patient in need of such treatment a chymase inhibitor in an amount effective for prevention or treatment of said fibrosis, wherein said chymase inhibitor is selected from the group consisting of .alpha.-keto acid derivatives, .alpha.,.alpha.-difluoro-.beta.-keto acid derivatives, tripeptide inhibitors, phosphoric acid derivatives, trifluoromethylketone derivatives, acetoamide derivatives, triazine derivatives, phenol ester derivatives, cephem derivatives, isoxazole derivatives, imidazolidine derivatives, hydantoin derivatives and quinazoline derivatives. 11. A method for treating extracellular matrix dysbolism comprising administering to a patient in need of such treatment a chymase inhibitor in an amount effective for treating extracellular matrix dysbolism, wherein said chymase inhibitor is selected from the group consisting of .alpha.-keto acid derivatives, .alpha.,.alpha.-difluoro-.beta.-keto acid derivatives, tripeptide inhibitors, phosphoric acid derivatives, trifluoromethylketone derivatives, acetoamide derivatives, triazine derivatives, phenol ester derivatives, cephem derivatives, isoxazole derivatives, imidazolidine derivatives, hydantoin derivatives and quinazoline derivatives. 12. A method according to claim 5, wherein the aryl group represented by the ring A is selected from the group consisting of a benzene ring and a naphthalene ring. 13. A method according to claim 5, wherein the C.sub.1 to C.sub.4 lower alkylamino group which may optionally be substituted with the carboxylic acid group is selected from the group consisting of a methylamino group, an ethylamino group, a propylamino group, a butylamino group, a carboxymethylamino group, a carboxyethylamino group, a carboxypropylamino group, and a carboxybutylamino group. 14. A method according to claim 5, wherein the C.sub.7 to C.sub.12 lower aralkylamino group which may be substituted with the carboxylic acid group represented by R.sup.1 is selected from the group consisting of a benzylamino group, a phenetylamino group, a phenylpropylamino group, a phenylbutylamino group, a carboxybenzylamino group, a carboxyphenetylamino group, a carboxyphenylpropylamino group, and a carboxyphenylbutylamino group. 15. A method according to claim 5, wherein the amino group acylated with a C.sub.1 to C.sub.4 lower aliphatic acid which may be substituted with a carboxylic acid group, the amino group acylated with an aromatic ring carboxylic acid which may be substituted with a carboxylic acid group, and the amino group acylated with a heteroaromatic ring carboxylic acid which may be substituted with a carboxylic acid group represented by R.sup.1 are each independently selected from the group consisting of a formylamino group, an acetylamino group, a propionylamino group, a butyrylamino group, a benzoylamino group, a naphthoylamino group, a pyridinecarbonylamino group, a pyrrolecarbonylamino group, a carboxyacetylamino group, a carboxypropionylamino group, a carboxybutyrylamino group, a carboxybenzoylamino group, a carboxynaphthoylamino group, a carboxypyridinecarbonylamino group, and a carboxypyrrolecarbonylamino group. 16. A method according to claim 5, wherein the amino group sulfonylated with a C.sub.1 to C.sub.4 lower alkanesulfonic acid which may be substituted with a carboxylic acid group, the amino group sulfonylated with an aromatic ring sulfonic acid which may be substituted with a carboxylic acid group, and the amino group sulfonylated with a heteroaromatic ring sulfonic acid which may be substituted with a carboxylic acid group represented by R.sup.1 are each independently selected from the group consisting of a methanesulfonylamino group, an ethanesulfonylamino group, a propanesulfonylamino group, a butanesulfonyl amino group, a benzenesulfonylamino group, a naphthalenesulfonylamino group, a pyridinesulfonylamino group, a pyrrolesulfonylamino group, a carboxymethanesulfonylamino group, a carboxyethanesulfonylamino group, a carboxypropanesulfonylamino group, a carboxybutane-sulfonylamino group, a carboxybenzenesulfonylamino group, a carboxynaphthalenesulfonylamino group, a carboxypyridinesulfonylamino group, and a carboxypyrrolesulfonylamino group. 17. A method according to claim 5, wherein the C.sub.1 to C.sub.4 lower alkyl group substituted with a carboxylic acid group represented by R.sup.1 is selected from the group consisting of an acetic acid group, a propionic acid group, a butyric acid group, and a valeric acid group. 18. A method according to claim 5, wherein the C.sub.2 to C.sub.4 lower alkylene group substituted with a carboxylic acid group represented by R.sup.1 is selected from the group consisting of an acrylic acid group and a crotonic acid group. 19. A method according to claim 5, wherein the unsubstituted or substituted C.sub.1 to C.sub.4 lower alkyl group represented by R.sup.2 or R.sup.3 is selected from the group consisting of a straight-chain alkyl group and a branched alkyl group. 20. A method according to claim 19, wherein the branched alkyl group is selected from the group consisting of an isopropyl group, a sec-butyl group, and a t-butyl group. 21. A method according to claim 5, wherein the substituent group of the C.sub.1 to C.sub.4 lower alkyl group is selected from the group consisting of a carboxylic acid group, a halogen atom, a C.sub.1 to C.sub.4 lower alkoxy group, an amino group, a methylamino group, a dimethylamino group, a carboxymethylamino group, and a carboxyethylamino group. 22. A method according to claim 5, wherein the halogen atom represented by R.sup.2 or R.sup.3 is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. 23. A method according to claim 5, wherein the C.sub.1 to C.sub.4 lower alkoxyl group represented by R.sup.2 or R.sup.3 is selected from the group consisting of a straight-chain alkyloxy group and a branched alkyloxy group. 24. A method according to claim 23, wherein the straight-chain alkyloxy group is selected from the group consisting of a methoxy group, an ethoxy group, a n-propyloxy group, and a n-butoxy group. 25. A method according to claim 23, wherein the branched alkyloxy group is selected from the group consisting of an isopropyloxy group, a sec-butoxy group, and a t-butoxy group. 26. A method according to claim 5, wherein the unsubstituted or substituted C.sub.1 to C.sub.4 lower alkylamino group represented by R.sup.2 or R.sup.3 is selected from the group consisting of a methylamino group, an ethylamino group, a propylamino group, and a butylamino group. 27. A method according to claim 5, wherein the substituent group of the C.sub.1 to C.sub.4 lower alkylamino group is selected from the group consisting of a carboxylic acid group, a halogen atom, and a C.sub.1 to C.sub.4 lower alkoxyl group. 28. A method according to claim 5, wherein the unsubstituted or substituted C.sub.7 to C.sub.12 lower aralkylamino group represented by R.sup.2 or R.sup.3 is selected from the group consisting of a benzylamino group, a phenetylamino group, a phenylpropylamino group, and a phenylbutylamino group. 29. A method according to claim 5, wherein the substituent group of the aralkylamino group is selected from the group consisting of a carboxylic acid group, a halogen atom, and a C.sub.1 to C.sub.4 lower alkoxyl group. 30. A method according to claim 5, wherein the amino group acylated with a C.sub.1 to C.sub.4 lower aliphatic acid which may be substituted with a carboxylic acid group, the amino group acylated with an aromatic ring carboxylic acid which may be substituted with a carboxylic acid group, and the amino group acylated with a heteroaromatic ring carboxylic acid which may be substituted with a carboxylic acid group represented by R.sup.2 or R.sup.3 are each independently selected from the group consisting of a formylamino group, an acetylamino group, a propionylamino group, a butyrylamino group, a benzoylamino group, a naphthoylamino group, a pyridinecarbonylamino group, a pyrrolecarbonylamino group, a carboxyacetylamino group, a carboxypropionylamino group, a carboxybutyrylamino group, a carboxybenzoylamino group, a carboxynaphthoylamino group, a carboxypyridinecarbonylamino group, and a carboxypyrrolecarbonylamino group. 31. A method according to claim 5, wherein the amino group sulfonylated with a C.sub.1 to C.sub.4 lower alkanesulfonic acid which may be substituted with a carboxylic acid group, the amino group sulfonylated with an aromatic ring sulfonic acid which may be substituted with a carboxylic acid group, and the amino group sulfonylated with a heteroaromatic ring sulfonic acid which may be substituted with a carboxylic acid group represented by R.sup.2 or R.sup.3 are each independently selected from the group consisting of a methanesulfonylamino group, an ethanesulfonylamino group, a propanesulfonylamino group, a benzenesulfonylamino group, a naphthalenesulfonylamino group, a pyridinesulfonylamino group, a pyrrolesulfonylamino group, a carboxymethanesulfonylamino group, a carboxyethanesulfonylamino group, a carboxypropanesulfonylamino group, a carboxybenzenesulfonylamino group, a carboxynaphthalenesulfonylamino group, a carboxypyridine-sulfonylamino group, and a carboxypyrrolesulfonylamino group. 32. A method according to claim 5, wherein the fused heterocyclic ring which may be substituted with a carboxylic acid and in which the carbon atom in the ring may form a carbonyl group which R.sup.1 and R.sup.2 form together with the substituting benzene ring when the ring A is a benzene ring, is selected from the group consisting of a tetrahydroquinoline, a benzoxazine, a quinoxaline, a benzodioxane, a carboxytetrahydroquinoline, a carboxybenzoxazine, a carboxyquinoxaline, and a carboxybenzodioxane. 33. A method according to claim 5, wherein the C.sub.1 to C.sub.4 lower alkyl group represented by X is selected from the group consisting of a methyl group, an ethyl group, a n-propyl group, a n-butyl group, an isopropyl group, a sec-butyl group, and a t-butyl group. 34. A method according to claim 5, wherein the C.sub.1 to C.sub.4 lower alkoxyl group represented by X is selected from the group consisting of a methoxy group, an ethoxy group, a n-propyloxy group, a n-butoxy group, an isopropyloxy group, a sec-butoxy group, and a t-butoxy group. 35. A method according to claim 5, wherein the halogen atom represented by X, is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. 36. A method according to claim 5, wherein the pharmaceutically acceptable salt is selected from the group consisting of an acid salt and an alkali metal salt. 37. A method according to claim 5, wherein the pharmaceutically acceptable salt is selected from the group consisting of a hydrochloric acid salt, a methanesulfonic acid salt, a trifluoroacetic acid salt, a sodium salt and a potassium salt. 38. A method according to claim 9, wherein the aryl group represented by the ring A is selected from the group consisting of a benzene ring and a naphthalene ring. 39. A method according to claim 9, wherein the C.sub.1 to C.sub.4 lower alkylamino group which may optionally be substituted with the carboxylic acid group is selected from the group consisting of a methylamino group, an ethylamino group, a propylamino group, a butylamino group, a carboxymethylamino group, a carboxyethylamino group, a carboxypropylamino group, and a carboxybutylamino group. 40. A method according to claim 9, wherein the C.sub.7 to C.sub.12 lower aralkylamino group which may be substituted with the carboxylic acid group represented by R.sup.1 is selected from the group consisting of a benzylamino group, a phenetylamino group, a phenylpropylamino group, a phenylbutylamino group, a carboxybenzylamino group, a carboxyphenetylamino group, a carboxyphenylpropylamino group, and a carboxyphenylbutylamino group. 41. A method according to claim 9, wherein the amino group acylated with a C.sub.1 to C.sub.4 lower aliphatic acid which may be substituted with a carboxylic acid group, the amino group acylated with an aromatic ring carboxylic acid which may be substituted with a carboxylic acid group, and the amino group acylated with a heteroaromatic ring carboxylic acid which may be substituted with a carboxylic acid group represented by R.sup.1 are each independently selected from the group consisting of a formylamino group, an acetylamino group, a propionylamino group, a butyrylamino group, a benzoylamino group, a naphthoylamino group, a pyridinecarbonylamino group, a pyrrolecarbonylamino group, a carboxyacetylamino group, a carboxypropionylamino group, a carboxybutyrylamino group, a carboxybenzoylamino group, a carboxynaphthoylamino group, a carboxypyridinecarbonylamino group, and a carboxypyrrolecarbonylamino group. 42. A method according to claim 9, wherein the amino group sulfonylated with a C.sub.1 to C.sub.4 lower alkanesulfonic acid which may be substituted with a carboxylic acid group, the amino group sulfonylated with an aromatic ring sulfonic acid which may be substituted with a carboxylic acid group, and the amino group sulfonylated with a heteroaromatic ring sulfonic acid which may be substituted with a carboxylic acid group represented by R.sup.1 are each independently selected from the group consisting of a methanesulfonylamino group, an ethanesulfonylamino group, a propanesulfonylamino group, a butanesulfonylamino group, a benzenesulfonylamino group, a naphthalenesulfonylamino group, a pyridinesulfonylamino group, a pyrrolesulfonylamino group, a carboxymethanesulfonylamino group, a carboxyethanesulfonylamino group, a carboxypropanesulfonylamino group, a carboxybutane-sulfonylamino group, a carboxybenzenesulfonylamino group, a carboxynaphthalenesulfonylamino group, a carboxypyridinesulfonylamino group, and a carboxypyrrolesulfonylamino group. 43. A method according to claim 9, wherein the C.sub.1 to C.sub.4 lower alkyl group substituted with a carboxylic acid group represented by R.sup.1 is selected from the group consisting of an acetic acid group, a propionic acid group, a butyric acid group, and a valeric acid group. 44. A method according to claim 9, wherein the C.sub.2 to C.sub.4 lower alkylene group substituted with a carboxylic acid group represented by R.sup.1 is selected from the group consisting of an acrylic acid group and a crotonic acid group. 45. A method according to claim 9, wherein the unsubstituted or substituted C.sub.1 to C.sub.4 lower alkyl group represented by R.sup.2 or R.sup.3 is selected from the group consisting of a straight-chain alkyl group and a branched alkyl group. 46. A method according to claim 45, wherein the branched alkyl group is selected from the group consisting of an isopropyl group, a sec butyl group, and a t-butyl group. 47. A method according to claim 9, wherein the substituent group of the C.sub.1 to C.sub.4 lower alkyl group is selected from the group consisting of a carboxylic acid group, a halogen atom, a C.sub.1 to C.sub.4 lower alkoxy group, an amino group, a methylamino group, a dimethylamino group, a carboxymethylamino group, and a carboxyethylamino group. 48. A method according to claim 9, wherein the halogen atom represented by R.sup.2 or R.sup.3 is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. 49. A method according to claim 9, wherein the C.sub.1 to C.sub.4 lower alkoxyl group represented by R.sup.2 or R.sup.3 is selected from the group consisting of a straight-chain alkyloxy group and a branched alkyloxy group. 50. A method according to claim 49, wherein the straight-chain alkyloxy group is selected from the group consisting of a methoxy group, an ethoxy group, a n-propyloxy group, and a n-butoxy group. 51. A method according to claim 49, wherein the branched alkyloxy group is selected from the group consisting of an isopropyloxy group, a sec-butoxy group, and a t-butoxy group. 52. A method according to claim 9, wherein the unsubstituted or substituted C.sub.1 to C.sub.4 lower alkylamino group represented by R.sup.2 or R.sup.3 is selected from the group consisting of a methylamino group, an ethylamino group, a propylamino group, and a butylamino group. 53. A method according to claim 9, wherein the substituent group of the C.sub.1 to C.sub.4 lower alkylamino group is selected from the group consisting of a carboxylic acid group, a halogen atom, and a C.sub.1 to C.sub.4 lower alkoxyl group. 54. A method according to claim 9, wherein the unsubstituted or substituted C.sub.7 to C.sub.12 lower aralkylamino group represented by R.sup.2 or R.sup.3 is selected from the group consisting of a benzylamino group, a phenetylamino group, a phenylpropylamino group, and a phenylbutylamino group. 55. A method according to claim 9, wherein the substituent group of the aralkylamino group is selected from the group consisting of a carboxylic acid group, a halogen atom, and a C.sub.1 to C.sub.4 lower alkoxyl group. 56. A method according to claim 9, wherein the amino group acylated with a C.sub.1 to C.sub.4 lower aliphatic acid which may be substituted with a carboxylic acid group, the amino group acylated with an aromatic ring carboxylic acid which may be substituted with a carboxylic acid group, and the amino group acylated with a heteroaromatic ring carboxylic acid which may be substituted with a carboxylic acid group represented by R.sup.2 or R.sup.3 are each independently selected from the group consisting of a formylamino group, an acetylamino group, a propionylamino group, a butyrylamino group, a benzoylamino group, a naphthoylamino group, a pyridinecarbonylamino group, a pyrrolecarbonylamino group, a carboxyacetylamino group, a carboxypropionylamino group, a carboxybutyrylamino group, a carboxybenzoylamino group, a carboxynaphthoylamino group, a carboxypyridinecarbonylamino group, and a carboxypyrrolecarbonylamino group. 57. A method according to claim 9, wherein the amino group sulfonylated with a C.sub.1 to C.sub.4 lower alkanesulfonic acid which may be substituted with a carboxylic acid group, the amino group sulfonylated with an aromatic ring sulfonic acid which may be substituted with a carboxylic acid group, and the amino group sulfonylated with a heteroaromatic ring sulfonic acid which may be substituted with a carboxylic acid group represented by R.sup.2 or R.sup.3 are each independently selected from the group consisting of a methanesulfonylamino group, an ethanesulfonylamino group, a propanesulfonylamino group, a benzenesulfonylamino group, a naphthalenesulfonylamino group, a pyridinesulfonylamino group, a pyrrolesulfonylamino group, a carboxymethanesulfonylamino group, a carboxyethanesulfonylamino group, a carboxypropanesulfonylamino group, a carboxybenzenesulfonylamino group, a carboxynaphthalenesulfonylamino group, a carboxypyridine-sulfonylamino group, and a carboxypyrrolesulfonylamino group. 58. A method according to claim 9, wherein the fused heterocyclic ring which may be substituted with a carboxylic acid and in which the carbon atom in the ring may form a carbonyl group which R.sup.1 and R.sup.2 form together with the substituting benzene ring when the ring A is a benzene ring, is selected from the group consisting of a tetrahydroquinoline, a benzoxazine, a quinoxaline, a benzodioxane, a carboxytetrahydroquinoline, a carboxybenzoxazine, a carboxyquinoxaline, and a carboxybenzodioxan. 59. A method according to claim 9, wherein the C.sub.1 to C.sub.4 lower alkyl group represented by X is selected from the group consisting of a methyl group, an ethyl group, a n-propyl group, a n-butyl group, an isopropyl group, a sec-butyl group, and a t-butyl group. 60. A method according to claim 9, wherein the C.sub.1 to C.sub.4 lower alkoxyl group represented by X is selected from the group consisting of a methoxy group, an ethoxy group, a n-propyloxy group, a n-butoxy group, an isopropyloxy group, a sec-butoxy group, and a t-butoxy group. 61. A method according to claim 9, wherein the halogen atom represented by X, is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. 62. A method according to claim 9, wherein the pharmaceutically acceptable salt is selected from the group consisting of an acid salt and an alkali metal salt. 63. A method according to claim 62, wherein the pharmaceutically acceptable salt is selected from the group consisting of a hydrochloric acid salt, a methanesulfonic acid salt, a trifluoroacetic acid salt, a sodium salt and a potassium salt |
| PATENT DESCRIPTION |
TECHNICAL FIELD The present invention relates to a medicament for the prevention or treatment of fibrosis involving extracellular matrix dysbolism, a pharmaceutical composition for the prevention or treatment of fibrosis involving extracellular matrix dysbolism, and a medicament for alleviation of extracellular matrix dysbolism. BACKGROUND ART Fibrosis is a disease characterized by excessive deposition of connective tissue-protein involving extracellular matrix dysbolism in the skin and other organs such as the lungs, heart, liver, and kidneys. For example, hepatic fibrosis is a disease characterized by the excessive deposition of collagen and other connective tissue proteins in the liver. Diseases leading to hepatic fibrosis include vairal hepatitis, alcoholic liver disease, schistosomiasis etc. In these diseases, the connective tissue protein gradually accumulates in the hepatic tissue. As a result, disorders in the hepatic functions occur and finally lead to cirrhosis (J. Hepatol. 8, 115, 1989). On the other hand, scleroderma and other skin fibrosis are conditions characterized by the excessive deposition of collagen and other connective tissue protein in the epidermis of the skin. The cause of skin fibrosis includes various skin diseases such as chronic inflammation and chronic autoimmune reactions, and various skin injury such as mechanical wounds and burns (J. Rheumatol. 15, 202, 1988). Further, pulmonary fibrosis is a condition characterized by the excessive deposition of collagen or other connective tissue proteins in the lungs and is induced by pneumonia medicamentosa caused by chemotherapeutic agents such as anti-tumor drugs and antibiotics (Am. J. Pathol. 259, L159, 1990). The mechanism of pathogenesis of fibrosis have not yet been sufficiently elucidated at the present. In general, the proliferation and function of fibroblasts are closely controlled in normal conditions. However, in pathological state in which inflammation or tissue injury is serious or sustained, the tissue repair mechanism goes into overdrive and the control mechanism is abrogated (Int. J. Biochem. Cell Biol. 29, 79, 1997). Excessive tissue repair is caused by over-production of connective tissue protein probably due to abnormal proliferation of fibroblasts and extracellular matrix dysbolism. The cytokines causing such a phenomenon include, fibroblast growth factor (FGF family), transforming growth factor (TGF-.beta.), platelet derived growth factor (PDGF), etc. (FASEB J. 8, 854, 1994). In recent years, numerous studies have been performed to obtain the substances inhibiting the production or the activity of such cytokines, but no inhibitors have yet been applied to human. Further, anti-inflammatory agents such as steroid have been used to treat fibrosis with the aim of suppressing chronic inflammation, but they cannot be said to be sufficiently satisfactory in terms of efficacy and side effects. A superior medicament for the treatment of fibrogenesis is therefore needed. On the other hand, chymase is a serine protease stored in mast cell granules, and widely present in tissue such as the skin, heart, vascular walls, intestines, etc. (Mast Cell Proteases in Immunology and Biology; Caughey, G. H., Ed; Marcel Dekker, Inc.; New York, 1995). Numerous findings that suggest chymase is involved in various types of fibrosis have already been reported. For example, it has been reported that administration of cromoglycate, an inhibitor for mast cell degranulation, suppresses skin fibrosis in Tsk (tight skin) mice, an animal model for scleroderma (Am. J. Pathol. 82, 493, 1976) (J. Rheumatol. 14, 299, 1987). Furthermore, it-has been reported that chymase activity is increased in Tsk mice (Jp. J. Pharmacol. 97 (sup. I) 60P, 1998), and that there is a correlation between the severity of the skin fibrosis and the number of skin mast cells in a bleomycin-induced scleroderma model in mice (Clin. Immunol. 92, 6, 1999). Regarding pulmonary fibrosis, in addition, it is known that pulmonary. fibrosis is not induced by administration of bleomycin in mast cell deficient mice, suggesting involvement of mast cells that produce chymase (Agents Actions 39, 20, 1993). Further, regarding hepatic fibrosis, the number of mast cells in human livers increases along with the fibrogenesis of livers (J. Hepatol. 26, 1042, 1997). A similar increase of mast cells is observed even in various hepatic fibrosis models (Hepatology 23, 888, 1996, J. Hepatol. 29, 112, 1998). In biliary cirrhosis model in rat, mast cell degranulation are observed in the liver, showing the involvement of mast cell granular components such as chymase in pathogenesis of fibrosis (Hepatology 23, 888, 1996). Regarding the involvement of chymase in fibrogenesis of the heart, on the other hand, it has been reported that chymase activity is 5-fold in the pressure-overloaded hamster heart in which fibrosis and apoptosis are observed (FEBS lett. 406, 301, 1997). Recently, it has been shown that rat mast cell chymase (RMCP-1) causes apoptosis of cardiomyocytes derived from neonatal rats, suggesting that chymase may play a role in cell death of cardiomyocytes and fibrogenesis during progression of heart failure (Circulation 100, 1443, 1999). Further, it has also been reported that the expression of mRNA of chymase is augmented in the end stage where fibrogenesis becomes prominent in a canine with heart failure induced by rapid right Ventricular pacing (Matsumoto et al., 73rd Scientific Sessions of American Heart Association, November 2000, New Orleans, Abs. 2191). Restenosis following PTCA is a vascular disease associated with fibrosis. It has been reported that an increase in mast cells augmentation of expression of chymase is observed in balloon-injured artery in dog, and that tranilast that inhibits mast cell degranulation suppresses neointima formation in this model (Circulation 99, 1084, 1999). However, there is also a report that bleomycin induced pulmonary fibrosis is, induced even in mast cell-deficient mice in the same way as normal mice (Lab. Invest. 78, 1431, 1998). There are still many unclear points in the role of mast cells or chymase in various types of fibrosis. There are findings suggesting the mechanism of action of chymase in fibrosis. For example, it has been reported that chymase promotes in culture the production of TGF-.beta., the major cytokine for fibrogenesis (J. Biol. Chem. 270, 4689, 1995). Further, there is a report that chymase acts in vitro on procollagen, a precursor of collagen, to promote collagen fibril formation (J. Biol. Chem. 272, 7127, 1997) and a report that chymase activates procollagenase (Biochem. J. 305, 301, 1995). At the present time, a broad search is under way for substances which can inhibit chymase activity in animal models with the aim of elucidating the role of chymase in the body. There are chymase inhibitors such as low molecular weight chymase inhibitors such as shown in print (Protease Inhibitors; Barrett et al., Eds; Elssevier Science B. V.; Amsterdam, 1996), .alpha.-keto acid derivatives reported as peptide type inhibitors (WO93-25574, Proc. Natl. Acad. Sci. USA, 1995, 92, 6738), .alpha.,.alpha.-difluoro-.beta.-keto acid derivatives (Japanese Unexamined Patent Publication (Kokai) No. 9-124691), tripeptide inhibitors (WO93-03625), phosphoric acid derivatives (Oleksyszyn et al., Biochemistry 30, 485, 1991), peptide like inhibitors such as trifluoromethylketone derivatives (WO96-33974, Japanese Unexamined Patent Publication (Kokai) No. 10-53579) and acetoamide derivatives (Japanese Unexamined Patent Publication (Kokai) No. 10-7661, Japanese Unexamined Patent Publication (Kokai) No. 10-53579, Japanese Unexamined Patent Publication (Kokai) No. 11-246437, WO99-41277, WO98-18794, WO96-39373), non-peptide type inhibitors such as triazine derivatives (Japanese Unexamined Patent Publication (Kokai) No. 8-208654 and Japanese Unexamined Patent Publication (Kokai) No. 10-245384), phenol ester derivatives (Japanese Unexamined Patent Publication (Kokai) No. 10-87567), cephem derivatives (Japanese Unexamined Patent Publication (Kokai) No. 10-87493), isoxazole derivatives (Japanese Unexamined Patent Publication (Kokai) No. 11-1479), imidazolidine derivatives (WO96-04248), hydantoin derivatives (Japanese Unexamined Patent Publication (Kokai) No. 9-31061), quinazoline derivatives (WO97-11941), etc. have been reported, but no satisfactory medicament or treatment method using inhibition of the activity of chymase as a strategy for treatment has yet been established. DISCLOSURE OF THE INVENTION The object of the present invention is to provide a side effect-free, safe medicament for prevention or treatment of fibrosis of the skin or various organs, which suppresses the progression of the disease, prevents the progression of complications, and improves the quality of life of the patient. The present inventors engaged in intensive studies to achieve this object focusing on subcutaneous fibrous layer hypertrophy involving the dysbolism of connective tissue protein and, as a result, found that a chymase inhibitor alleviates the dysbolism of collagen and suppresses the increase in the subcutaneous fibrous layer and thereby completed the present invention. That is, in accordance with the present invention, there is provided a medicament for the prevention or treatment of fibrosis involving extracellular matrix dysbolism having a chymase inhibitor as an effective ingredient. In accordance with the present invention, there is also provided a pharmaceutical composition for the prevention or treatment of fibrosis involving extracellular matrix dysbolism including an amount of a chymase inhibitor for alleviating extracellular matrix dysbolism and a pharmaceutically acceptable vehicle. In accordance with the present invention, the present invention further provides a medicament for alleviating extracellular matrix dysbolism having a chymase inhibitor as an effective ingredient. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the effects of a chymase inhibitor (Compound 18) on chymase activity in various tissues in mice in Example 2. FIG. 2 is a graph showing the results of measurement of the content of skin collagen (hydroxyproline content) in Tsk mice in Example 3. FIG. 3 is a graph showing the results of measurement of the degree of the thickness of subcutaneous fibrous layer in Tsk mice in Example 3. FIG. 4 is a graph showing the results of measurement of the mast cell density in the skin of Tsk mice in Example 3. FIG. 5 is a graph showing the results of measurement of chymase activity in the skin of Tsk mice in Example 3. FIG. 6 is a graph showing the results of measurement of the mRNA content for the skin chymase of Tsk mice in Example 3. FIG. 7 is a graph showing the results of measurement of the thickness of subcutaneous fibrous layer in Tsk mice in Example 4. FIG. 8 is a graph showing the results of measurement of the chymase activity in the skin of Tsk mice in Example 4. FIG. 9 is a graph showing the change of skin collagen content (hydroxyproline content) in the lung in bleomycin-induced pulmonary fibrosis model in mice. * and ** respectively indicate that P value of determination of significant difference (Dunnett's test) when compared with a control group (amount of administration of bleomycin of 0) is smaller than 0.05 and 0.01. FIG. 10 is a graph showing the results of measurement of the chymase activity in the lung of bleomycin-induced mice. * indicates that P value of determination of significant difference (Student's t-test), when compared with normal mice, is smaller than 0.05. FIG. 11 is a graph showing the effect of chymase inhibitor on the content of skin collagen (hydroxyproline content) in the lung of a bleomycin-induced mice pulmonary fibrosis model. # indicates that P value of determination of significant difference (Student's t-test), when compared with a group administered saline, is smaller than 0.01, while * indicates that P-value of determination of significant difference (Dunnett's test), when compared with a group administered HPC/saline, is smaller than 0.05. BEST MODE FOR CARRYING OUT THE INVENTION In this specification, the fibrosis involving extracellular matrix dysbolism includes diseases whose onset is caused by the occurrence of extracellular matrix dysbolism, diseases whose conditions are aggravated by the occurrence of extracellular matrix dysbolism, and diseases whose cure is delayed by the occurrence of extracellular matrix dysbolism. For example, these diseases include scleroderma, pulmonary fibrosis, benign prostatomegaly, myocardial fibrogenesis following myocardial infarction, myocardial fibrosis, musculoskeletal fibrosis, post-surgical adhesion, hypertropic scars and keloids, cirrhosis, hepatic fibrosis, renal fibrosis, fibrous vascular disorders, and complications of diabetes such as retinitis due to fibrous microvasculitis, neurosis, nephropathy, and peripheral arteritis or a condition related to the same. The chymase inhibitor able to be used in the present invention can be selected as a substance inhibiting chymase activity by the use of methods workable by persons skilled in the art. As the method of selection, for example, the method of the later explained Example 1 may be used. The compounds obtained in this way include known compounds previously-reported as chymase inhibitors, for example, the low molecular weight chymase inhibitors such as shown in the book (Protease Inhibitors; Barrett et al., Eds; Elssevier Science B. V.; Amsterdam, 1996), .alpha.-keto acid derivatives reported as peptide type inhibitors (WO93-25574, Proc. Natl. Acad. Sci. USA, 1995, 92, 6738), .alpha.,.alpha.-difluoro-.beta.-keto acid derivatives (Japanese Unexamined Patent Publication (Kokai) No. 9-124691), tripeptide inhibitors (WO93-03625), phosphoric acid derivatives (Oleksyszyn et al., Biochemistry 30, 485, 1991), peptide like inhibitors such as trifluoromethylketone derivatives (WO96-33974, Japanese Unexamined Patent Publication (Kokai).No. 10-53579) and acetoamide derivatives (Japanese Unexamined Patent Publication (Kokai) No. 10-7661, Japanese Unexamined Patent Publication (Kokai) No. 10-53579, Japanese Unexamined Patent Publication (Kokai) No. 11-246437, WO99-41277, WO98-18794, WO96-39373), non-peptide type inhibitors such as triazine derivatives (Japanese Unexamined Patent Publication (Kokai) No. 8-208654 and Japanese Unexamined Patent Publication (Kokai) No. 10-245384), phenol ester derivatives (Japanese Unexamined. Patent Publication (Kokai) No. 10-87567), cephem derivatives (Japanese Unexamined Patent Publication (Kokai) No. 10-87493), isoxazole derivatives (Japanese Unexamined Patent Publication (Kokai) No. 11-1479), imidazolidine derivatives (WO96-04248), hydantoin derivatives (Japanese Unexamined Patent Publication (Kokai) No. 9-31061), quinazoline derivatives (WO97-11941), etc., but as a representative example of a preferable chymase inhibitor, a compound of the following formula (I) and its pharmaceutically acceptable salts may be mentioned. ##STR2## wherein, the ring A represents an aryl group; R.sup.1 represents a hydroxyl group, an amino group, a C.sub.1 to C.sub.4 lower alkylamino group which may be substituted with a carboxylic acid group, a C.sub.7 to C.sub.10 lower aralkylamino group which may be substituted with a carboxylic acid group, an amino group acylated with a C.sub.1 to C.sub.4 lower aliphatic acid which may be substituted with a carboxylic acid group, an amino group acylated with an aromatic ring carboxylic acid which may be substituted with a carboxylic acid group, an amino group acylated with a heteroaromatic ring carboxylic acid which may be substituted with a carboxylic acid group, an amino group sulfonylated with a C.sub.1 to C.sub.4 lower alkanesulfonic acid which may be substituted with a carboxylic acid group, an amino group sulfonylated with an aromatic ring sulfonic acid which may be substituted with a carboxylic acid group, an amino group sulfonylated with a heteroaromatic ring sulfonic acid which may be substituted with a carboxylic acid group, a C.sub.1 to C.sub.4 lower alkyl group substituted with a carboxylic acid group, or a C.sub.2 to C.sub.4 lower alkylene group which may be substituted with a carboxylic acid group; R.sup.2 and R.sup.3 may be the same or different and represent a hydrogen atom, an unsubstituted or substituted C.sub.1 to C.sub.4 lower alkyl group, a halogen atom, a hydroxyl group, a C.sub.1 to C.sub.4 lower alkoxyl group, an amino group, an unsubstituted or substituted C.sub.1 to C.sub.4 lower alkylamino group, an unsubstituted or substituted C.sub.7 to C.sub.10 aralkylamino group, an amino group acylated with a C.sub.1 to C.sub.4 lower aliphatic acid which may be substituted with a carboxylic acid group, an amino group acylated with an aromatic ring carboxylic acid which may be substituted with a carboxylic acid group, an amino group acylated with a heteroaromatic ring carboxylic acid which may be substituted with a carboxylic acid group, an amino group sulfonylated with a C.sub.1 to C.sub.4 lower alkanesulfonic acid which may be substituted with a carboxylic acid group, an amino group sulfonylated with an aromatic ring sulfonic acid which may be substituted with a carboxylic acid group, an amino group sulfonylated with a heteroaromatic ring sulfonic acid which may be substituted with a carboxylic acid group, or a carboxylic acid group or when the ring A is a benzene ring, R.sup.1 and R.sup.2 may form, together with the substituting benzene ring, a fused heterocyclic ring which may be substituted with a carboxylic acid and in which the carbon atom in the ring may form a carbonyl group and R.sup.3 is the same as defined above; and X represents a hydrogen atom, a C.sub.1 to C.sub.4 lower alkyl group, a C.sub.1 to C.sub.4 lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, or a nitro group. In the general formula (I), preferable examples of the aryl group represented by the ring A are a benzene ring and a naphthalene ring. Preferable examples of the C.sub.1 to C.sub.4 lower alkylamino group which may be substituted with the carboxylic acid group and the C.sub.7 to C.sub.12 lower aralkylamino group which may be substituted with a carboxylic acid group represented by R.sup.1 are a methylamino group, an ethylamino group, a propylamino group, a butylamino group, a carboxymethylamino group, a carboxyethylamino group, a carboxypropylamino group, a carboxybutylamino group, a benzylamino group, a phenetylamino group, a phenylpropylamino group, a phenylbutylamino group, a carboxybenzylamino group, a carboxyphenetylamino group, a carboxyphenylpropylamino group, a carboxyphenylbutylamino group, etc. Preferable examples of the amino group acylated with a C.sub.1 to C.sub.4 lower aliphatic acid which may be substituted with a carboxylic acid group, the amino group acylated with an aromatic ring carboxylic acid which may be substituted with a carboxylic acid group, and the amino group acylated with a heteroaromatic ring carboxylic acid which may be substituted with a carboxylic acid group represented by R.sup.1 are a formylamino group, an acetylamino group, a propionylamino group, a butyrylamino group, a benzoylamino group, a naphthoylamino group, a pyridinecarbonylamino group, a pyrrolecarbonylamino group, a carboxyacetylamino group, a carboxypropionylamino group, a carboxybutyrylamino group, a carboxybenzoylamino group, a carboxynaphthoylamino group, a carboxypyridinecarbonylamino group, a carboxypyrrolecarbonylamino group, etc. Preferable examples of the amino group sulfonylated with a C.sub.1 to C.sub.4 lower alkanesulfonic acid which may be substituted with a carboxylic acid group, the amino group sulfonylated with an aromatic ring sulfonic acid which may be substituted with a carboxylic acid group, and the amino group sulfonylated with a heteroaromatic ring sulfonic acid which may be substituted with a carboxylic acid group represented by R.sup.1 are a methanesulfonylamino group, an ethanesulfonylamino group, a propanesulfonylamino group, a butanesulfonylamino group, a benzenesulfonylamino group, a naphthalenesulfonylamino group, a pyridinesulfonylamino group, a pyrrolesulfonylamino group, a carboxymethanesulfonylamino group, a carboxyethanesulfonylamino group, a carboxypropanesulfonylamino group, a carboxybutanesulfonylamino group, a carboxybenzenesulfonylamino group, a carboxynaphthalenesulfonylamino group, a carboxypyridinesulfonylamino group, a carboxypyrrolesulfonylamino group, etc. Preferable examples of the C.sub.1 to C.sub.4 lower alkyl group substituted with a carboxylic acid group represented by R.sup.1 are an acetic acid group, a propionic acid group, a butyric acid group, a valeric acid group, etc. Preferable examples of the C.sub.2 to C.sub.4 lower alkylene group substituted with a carboxylic acid group represented by R.sup.1 are an acrylic acid group, a crotonic acid group, etc. Preferable examples of the unsubstituted or substituted C.sub.1 to C.sub.4 lower alkyl group represented by R.sup.2 or R.sup.3 are a straight-chain alkyl group such as a methyl group, an ethyl group, a n-propyl group, and a n-butyl group and a branched alkyl group such as an isopropyl group, a sec-butyl group, and a t-butyl group. Preferable examples of the substituent group of the C.sub.1 to C.sub.4 lower alkyl group are a carboxylic acid group, a halogen atom such as a fluorine atom and a chlorine atom, a C.sub.1 to C.sub.4 lower alkoxy group, an amino group, a methylamino group, a dimethylamino group, a carboxymethylamino group, a carboxyethylamino group, etc. Preferable examples of the halogen atom represented by R.sup.2 or R.sup.3 are a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Preferable examples of the C.sub.1 to C.sub.4 lower alkoxyl group represented by R.sup.2 or R.sup.3 are a straight-chain alkyloxy group such as a methoxy group, an ethoxy group, a n-propyloxy group, and a n-butoxy group and a branched alkyloxy group such as an isopropyloxy group, a sec-butoxy group, and a t-butoxy group. Preferable examples of the unsubstituted or substituted C.sub.1 to C.sub.4 lower alkylamino group represented by R.sup.2 or R.sup.3 are a methylamino group, an ethylamino group, a propylamino group, a butylamino group, etc. Preferable examples of the substituent group of the C.sub.1 to C.sub.4 lower alkylamino group are a carboxylic acid group, a halogen atom such as a fluorine atom and a chlorine atom, a C.sub.1 to C.sub.4 lower alkoxyl group, etc. Preferable examples of the unsubstituted or substituted C.sub.7 to C.sub.12 lower aralkylamino group represented by R.sup.2 or R.sup.3 are a benzylamino group, a phenetylamino group, a phenylpropylamino group, a phenylbutylamino group, etc. Preferable examples of the substituent group of the aralkylamino group are a carboxylic acid group, a halogen atom such as a fluorine atom and a chlorine atom, a C.sub.1 to C.sub.4 lower alkoxyl group, etc. Preferable examples of the amino group acylated with a C.sub.1 to C.sub.4 lower aliphatic acid which may be substituted with a carboxylic acid group, the amino group acylated with an aromatic ring carboxylic acid which may be substituted with a carboxylic acid group, and the amino group acylated with a heteroaromatic ring carboxylic acid which may be substituted with a carboxylic acid group represented by R.sup.2 or R.sup.3 are a formylamino group, an acetylamino group, a propionylamino group, a butyrylamino group, a benzoylamino group, a naphthoylamino group, a pyridinecarbonylamino group, a pyrrolecarbonylamino group, a carboxyacetylamino group, a carboxypropionylamino group, a carboxybutyrylamino group, a carboxybenzoylamino group, a carboxynaphthoylamino group, a carboxypyridinecarbonylamino group, a carboxypyrrolecarbonylamino group, etc. Preferable examples, of the amino group sulfonylated with a C.sub.1 to C.sub.4 lower alkanesulfonic acid which may be substituted with a carboxylic acid group, the amino group sulfonylated with an aromatic ring sulfonic acid which may be substituted with a carboxylic acid group, and the amino group sulfonylated with a heteroaromatic ring sulfonic acid which may be substituted with a carboxylic acid group represented by R.sup.2 or R.sup.3 are a methanesulfonylamino group, an ethanesulfonylamino group, a propanesulfonylamino group, a benzenesulfonylamino group, a naphthalenesulfonylamino group, a pyridinesulfonylamino group, a pyrrolesulfonylamino group, a carboxymethanesulfonylamino group, a carboxyethanesulfonylamino group, a carboxypropanesulfonylamino group, a carboxybenzenesulfonylamino group, a carboxynaphthalenesulfonylamino group, a carboxypyridinesulfonylamino group, a carboxypyrrolesulfonylamino group, etc. Preferable examples of the fused heterocyclic ring which may be substituted with a carboxylic acid and in which the carbon atom in the ring may form a carbonyl group which R.sup.1 and R.sup.2 form together with the substituting benzene ring when the ring A is a benzene ring, are a tetrahydroquinoline ring and a benzoxazine ring, for example, a tetrahydroquinoline, a benzoxazine, a quinoxaline, a benzodioxane, a carboxytetrahydroquinoline, a carboxybenzoxazine, a carboxyquinoxaline, a carboxybenzodioxane, etc. Preferable examples of the C.sub.1 to C.sub.4 lower alkyl group represented by X are a straight-chain alkyl group such as a methyl group, an ethyl group, a n-propyl group, and a n-butyl group and a branched alkyl group such as an isopropyl group, a sec-butyl group, and a t-butyl group. Preferable examples of the C.sub.1 to C.sub.4 lower alkoxyl group represented by X are a straight-chain alkyloxy group such as a methoxy group, an ethoxy group, a n-propyloxy group, and a n-butoxy group and a branched alkyloxy group such as an isopropyloxy group, a sec-butoxy group, and a t-butoxy group. Preferable examples of the halogen atom represented by X, are a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Further, examples of a pharmaceutically acceptable salts are an acid salt such as a hydrochloric acid salt, a methanesulfonic acid salt, and a trifluoroacetic acid salt and an alkali metal salt such as a sodium salt and a potassium salt. The quinazoline derivative having the formula (I) according to the present invention may, for example, be synthesized by the following Synthesis Method (A) or (B). Synthesis Method (A) A compound having the formula (I-1): ##STR3## wherein the ring A is the same as defined above and R.sup.1', R.sup.2' and R.sup.3' represent R.sup.1, R.sup.2 and R.sup.3, which may be protected with a protecting group, respectively, and R.sup.1, R.sup.2 and R.sup.3 represent the same as defined above is reacted with an anthranilic acid derivative having the formula (I-2): ##STR4## wherein X' represents X, which may be protected with a protecting group, and X represents the same as defined above using the method described, for example, in JP-A-6-199839 to obtain a sulfonylurea derivative having the formula (I-3): ##STR5## wherein the ring A, R.sup.1', R.sup.2', R.sup.3' and X' represent the same as defined above, then, a condensing agent for example, 1,1'-carbonyldiimidazole (hereinafter referred to as CDI) is used to obtain the quinazoline ring, and if necessary, the protecting groups of R.sup.1, R.sup.2, R.sup.3 and X are deprotected. In this reaction, when R.sup.1, R.sup.2 or R.sup.3 represents a group containing a hydroxyl group, an amino group, or a carboxylic acid group, R.sup.1, R.sup.2 or R.sup.3 may be optionally protected by a protecting group such as a benzyloxycarbonyl group, a t-butoxycarbonyl group, a benzyl group, an allyl group, a t-butyl group, etc. When X represents a hydroxyl group or an amino group, X may be optionally protected with a protecting group such as a benzyloxycarbonyl group, a t-butoxycarbonyl group, a benzyl group, an allyl group, a t-butyl group, etc. The compound having the formula (I-1) used in this reaction includes a commercially available or known compound or a compound which can be synthesized by a known method may be used. For example, using the synthesis method described in the specification of European Patent No. 0269141, it is possible to use a compound which can be synthesized from the corresponding sulfonamide derivative using chlorosulfonyl isocyanate. For example, it is possible to use 3-allyloxycarbonylmethylbenzenesulfonyl isocyanate, 4-allyloxycarbonylmethylbenzenesulfonyl isocyanate, 4-allyloxybenzenesulfonyl isocyanate, etc. As the anthranilic acid derivative having the formula (I-2) used for this reaction, a commercially available or known compound or a compound which can be synthesized by a known method may be used. For example, anthranilic acid, 4-chloroanthranilic acid, 4-methoxyanthranilic acid, 5-chloroanthranilic acid, 4-hydroxyanthranilic acid, etc. may be used. The reaction to obtain the quinazoline ring from the sulfonylurea derivative having the formula (I-3) may be carried out using an aprotonic solvent such as, for example, an ether solvent such as tetrahydrofuran and dioxane, a halogen-containing solvent such as methylene chloride, or dimethylformamide etc. at a temperature of -50.degree. C. to 50.degree. C., preferably -20.degree. C. to room temperature. Further, for the cyclization reaction, it is possible to use an ordinary condensing agent which includes, for example, CDI, dicyclohexylcarbodiimide, and similar carbodiimide compounds, mixed anhydrides, etc. The deprotecting reaction can be carried out by an ordinary method using hydrolysis with an acid or alkali, reduction or oxidation etc. Synthesis Method (B) A compound having the formula (I-4): ##STR6## wherein the ring A, R.sup.1', R.sup.2' and R.sup.3' represent the same as defined above is condensed with an anthranilic acid derivative having the formula (I-5): ##STR7## wherein X' represents the same as defined above, Ph represents a phenyl group, and R.sup.4 represents a protecting group of the carboxyl group, which is specifically a group capable of being released by hydrolysis or hydrogenolysis, such as, for example, a methyl group, an ethyl group, or a benzyl group using, for example, 1,8-diazabicyclo[5,4,0]-7-undecene (hereinafter referred to as DBU) to form a sulfonylurea derivative having the formula (I-6): ##STR8## wherein the ring A, R.sup.1', R.sup.2', R.sup.3', R.sup.4 and X' are the same as defined above, which is then hydrolyzed with an alkali or hydrogenolyzed to derive a corresponding carboxylic acid represented by the formula (I-3), then the quinazoline ring is obtained and optionally the protecting groups of R.sup.1, R.sup.2, R.sup.3 and X are deprotected, in the same way as in Synthesis Method (A). In this reaction, when R.sup.1, R.sup.2 or R.sup.3 represents a group containing a hydroxyl group, an amino group, or a carboxylic acid group, R.sup.1, R.sup.2 or R.sup.3 may be optionally protected by a protecting group such as a benzyloxycarbonyl group, a t-butoxycarbonyl group, a benzyl group, an allyl group, a t-butyl group, etc. When X represents a hydroxyl group or an amino group, X may be optionally protected with a protecting group such as a benzyloxycarbonyl group, a t-butoxycarbonyl group, a benzyl group, an allyl group, a t-butyl group, etc. As the compound having the formula (I-4) used in the reaction, a commercially available or known compound or a compound which can be synthesized by a known method may be used. For example, 3-hydroxybenzenesulfonamide, 2-aminobenzenesulfonamide, 3-aminobenzenesulfonamide, 4-aminobenzenesulfonamide, (.+-.)-2-(4-aminosulfonylphenyl)butyric acid, 3-benzyloxycarbonylamino-4-chlorobenzenesulfonamide 4-benzyloxycarbonylamino-3-chlorobenzenesulfonamide, 4-amino-3,5-dichlorobenzenesulfonamide, 3-benzyloxycarbonylamino-4-methylbenzenesulfonamide, 4-t-butoxycarbonyl-3-hydroxybenzenesulfonamide, 3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide, 4-t-butoxycarbonyl-3-hydroxybenzenesulfonamide, 3-t-butoxycarbonyl-4-hydroxybenzenesulfonamide, 3-acetamide-4-methoxybenzenesulfonamide, 3-(3-aminosulfonyl)phenylacrylic acid t-butylester, 3-amino-4-methoxybenzenesulfonamide, 4-methoxy-3-methylsulfonylaminobenzenesulfonamide, 3-carboxy-4hydroxy-2-naphthalenesulfonamide, 4-benzyloxycarbonylamino-3-t-butoxycarbonylbenzenesulfonamide, (.+-.)-3-t-butoxycarbonyl-2-oxo-1H,3H-quinoline-7-sulfonamide, (.+-.)-2-t-butoxycarbonyl-3-oxo-1,4-benzoxazine-6-sulfonamide, etc. may be used. As the anthranilic acid derivative having the formula (I-5) used in this reaction, a commercially available or known compound or a compound which can be synthesized by a known method may be used. For example, methyl 4-chloro-2-N-phenoxycarbonylanthranilate, ethyl 4-chloro-2-N-phenoxycarbonylanthranilate, benzyl 4-chloro-2-N-phenoxycarbonylanthranilate, methyl 5-chloro-2-N-phenoxycarbonylanthranilate, ethyl 5-chloro-2-N-phenoxycarbonylanthranilate, benzyl 5-chloro-2-N-phenoxycarbonylanthranilate, methyl 4-methoxy-2-N-phenoxycarbonylanthranilate, ethyl 4-methoxy-2-N-phenoxycarbonylanthranilate, benzyl 4-methoxy-2-N-phenoxycarbonylanthranilate, methyl 4-hydroxy-2-N-phenoxycarbonylanthranilate, ethyl 4-hydroxy-2-N-phenoxycarbonylanthranilate, benzyl 4-hydroxy-2-N-phenoxycarbonylanthranilate, etc. may be used. The reaction for obtaining the compound having the formula (I-4) and the anthranilic acid derivative having the formula (I-5) condense to obtain a sulfonylurea derivative having the formula (I-6), may be carried out using an aprotic solvent, for example, an ether solvent such as tetrahydrofuran or dioxane, a halogen-containing solvent such as methylene chloride, or dimethylformamide etc. at a temperature of -50.degree. C. to 50.degree. C., preferably -20.degree. C. to room temperature. Further, as the usable for the condensation reaction, an organic strong base such as DBU, inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide, or metal bases such as sodium hydride may be used. In the reaction for alkali hydrolysis or hydrogenolysis of the sulfonylurea derivative having the formula (I-6) thus obtained to obtain the sulfonylurea derivative having the formula (I-3), ordinary hydrolysis conditions or hydrogenolysis conditions for esters may be used. Note that the above reaction may be carried out while protecting the functional groups not involved in the reaction. According to the type of the protecting group, the protection is removed by chemical reduction or other ordinary protection-removing reactions. For example, when the protecting group is a t-butyl group or t-butoxycarbonyl group, trifluoroacetic acid may be used, while when it is an allyl group, palladium catalysts such as tetrakis(triphenylphosphine)palladium (0) may be used. The compound having the formula (I), wherein R.sup.1 represents an amino group acylated with a C.sub.1 to C.sub.4 lower aliphatic acid which may be substituted with a carboxylic acid, an amino group acylated with an aromatic ring carboxylic acid which may be substituted with a carboxylic acid and an amino group acylated with an heteroaromatic ring carboxylic acid which may be substituted with a carboxylic acid, can be obtained from the compound having the formula (I), wherein R.sup.1 represents an amino group, by acylating the same with carboxylic acid, carboxylic acid chloride, carboxylic acid anhydride using an ordinary method. The compound having the formula (I), wherein R.sup.1 represents an amino group sulfonylated with a C.sub.1 to C.sub.4 lower alkane sulfonic acid which may be substituted with a carboxylic acid, an amino group sulfonylated with an aromatic ring sulfonic acid which may be substituted with a carboxylic acid and an amino group sulfonylated with an heteroaromatic ring sulfonic acid which may be substituted with a carboxylic acid, can be obtained from the compound having the formula (I), wherein R.sup.1 represents an amino group, by sulfonylating the same with sulfonic acid or sulfonic acid chloride using an ordinary method. The product obtained according to the above-mentioned processes can be purified by a method such as recrystallization or column chromatography. If necessary, the compounds having the formula (I) of the present invention obtained according to the above-mentioned processes can each be reacted with one of various acids or basis to convert the compound into their salt. Exemplary acids usable for the conversion of the compound having the formula (I) into their salts can include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, citric acid, lactic acid, maleic acid, fumaric acid, tartaric acid, acetic acid, adipic acid, palmitic acid and tannic acid. Exemplary usable basis for the conversion of the compound having the formula (I) into their salts can include sodium hydroxide, lithium hydroxide and potassium hydroxide. Further, the compounds having the formula (I) according to the present invention include those containing asymmetric centers. Each racemic mixture can be isolated by one or more of various methods, whereby a single optically-active substance can be obtained. Usable methods include, for example: (1) Isolation by optically active column. (2) Isolation by recrystallization subsequent to conversion into a salt with an optically active acid or base. (3) Isolation by a combination of the above methods (1) and (2). These compounds can be evaluated according to the method of Example 4 or 7 below, with respect to the improvement in the abnormal exacerbation. To use the effective ingredient of the present invention as a medicament for the prevention or treatment of fibrosis involving extracellular matrix dysbolism, a pharmaceutical composition for the prevention or treatment of fibrosis involving extra cellular matrix dysbolism, and a medicament for alleviation of extracellular matrix dysbolism, one or more of the compounds of the present invention may be mixed and formed into a form suitable for use in the method of administration by an ordinary method. Examples of preparation forms for oral administration include capsules, tablets, granules, fine granules, syrups, dry syrups, and other preparations, while examples of preparation forms for non-oral administration include injections and besides suppositories such as rectal suppositories and vaginal suppositories, transnasal preparations such as sprays and ointments, and percutaneous preparations such as tapes for percutaneous absorption. The clinical dose of the compound according to the present invention varies according to the diseased condition, degree of seriousness, age, presence of complications, etc. and also varies according to its preparation form. In the case of oral administration, however, it may be dosed usually, in terms of effective ingredients, as 1 to 1000 mg per adult per day. In the case of non-oral administration, it is sufficient to administer 1/10 to 1/2 the amount of the case of oral administration. These dosages can be suitably adjusted according to the age, the diseased condition, and the like of the patient to be dosed. In the present invention, the chymase inhibitor can be administered alone as it is without being mixed with another effective ingredient, but considering the disease in question, the symptoms, complications, etc., it may also administered as a medicinal preparation containing other effective ingredients. Further, it may also be combined with these other effective ingredients. The amounts of the other effective ingredients used are not particularly limited, but are determined considering the minimum amounts for expression of their effects alone, the occurrence of side effects, etc. In treatment, the form of preparation and the method of combined treatment including preparations containing the chymase inhibitor alone as an effective ingredient and preparations also containing other effective ingredients are suitably selected by a physician in accordance with the age of the patient, the symptoms, etc. The toxicity of the compound according to the present invention is low. The acute toxicity values LD.sub.50 at 24 hours after oral administration to 5-week old male mice were 1 g/kg or more |
| PATENT EXAMPLES | This data is not available for free |
| PATENT PHOTOCOPY | Available on request |
|
Want more information ? Interested in the hidden information ? Click here and do your request. |