Claims
- 1. A compound having the formula ##STR54## wherein R.sub.1 and R.sub.2 are independently hydrogen or COOR, wherein R is hydrogen, benzyl;
- R.sub.3 is prolyl, pipecoloyl, alanyl, glycyl, or (CH.sub.2).sub.m C(O);
- R.sub.4 is R.sub.6 (CH.sub.2).sub.m C(O)--, R.sub.6 (CH.sub.2).sub.m CH(NHR.sub.5)C(O)--, substituted or unsubstituted naphthalene sulfonyl, wherein the substituent is dialkylamino, substituted or unsubstituted 4,5-dipenyloxazol-2-yl, or 2-amino-4,5-diphenyl imidazolyl;
- R.sub.5 is aminoiminomethyl, .alpha.-aminoacetyl, substituted naphthalene sulfonyl, unsubstituted or substituted quinoline and tetrahydro quinoline sulfonyl, wherein the substituent is dialkylamino;
- R.sub.6 is hydrogen; benzyl; phenyl, phenoxy; pyridinyl; thienyl; indol-2 or 3-yl; or cycloalkyl rings of 3 to 7 carbon atoms;
- R.sub.7 is CHO
- n is 1, 2, 3, 4, 5, or 6; and
- m is 0, 1, 2, 3, or 4; or
- pharmaceutically acceptable salts and hydrates thereof.
- 2. The compound of claim 1 which is N.sup..alpha. -[N-(3-phenylpropanoyl)-L-propyl]-L-arginine aldehyde.
- 3. The intermediate N.sup..alpha. -[N-(3-(3-pyridyl)propanoyl)-L-prolyl]-N.sup..delta. benzyloxycarbonyl-L-arginine lactam.
- 4. The intermediate N.sup..alpha. -[N-(3-(3-pyridyl)propanoyl)-L-prolyl]-N.sup..delta. -benzyloxycarbonyl-L-arginine aldehyde.
- 5. The compound of claim 1 which is N.sup..alpha. -[N-(3-(3- pyridyl)propanoyl)-L-prolyl]-L-arginine aldehyde dihydrochloride.
- 6. The intermediate N.sup..alpha. -[N-benzoyl-L-prolyl]-N.sup..delta. -benzyloxycarbonyl-L-arginine lactam.
- 7. The intermediate N.sup..alpha. -[N-benzoyl-L-prolyl]-N.sup..delta. -benzyloxycarbonyl-L-arginine aldehyde.
- 8. The compound of claim 1 which is N.sup..alpha. -[N-benzoyl-L-prolyl]-L-arginine aldehyde hydrochloride.
- 9. The intermediate N.sup..alpha. -[N-(3-(2-thienyl)propanoyl)-L-prolyl]-N.sup..delta. -benzyloxycarbonyl-L-arginine lactam.
- 10. The intermediate N.sup..alpha. -[N-(3-(2-thienyl)propanoyl)-L-prolyl]-N.sup..delta. -benzyloxycarbonyl-L-arginine aldehyde.
- 11. The compound of claim 1 which is N.sup..alpha. -[N-(3-(2-thienyl)propanoyl)-L-prolyl]-L-arginine aldehyde hydrochloride.
- 12. The intermediate N.sup..alpha. -[N-(indole-2-carbonyl)-L-prolyl]-N.sup..delta. -benzyloxycarbonyl-L-arginine lactam.
- 13. The intermediate N.sup..alpha. -[N-(indole-2-carbonyl)-L-prolyl]-N.sup..delta. -benzyloxycarbonyl-L-arginine aldehyde.
- 14. The compound of claim 1 which is N.sup..alpha. -[N-(indole-2-carbonyl)-L-prolyl]-L-arginine aldehyde hydrochloride.
- 15. The intermediate N.sup..alpha. -[N-phenylacetyl-L-prolyl]-N.sup..delta. -benzyloxycarbonyl-L-arginine lactam.
- 16. The intermediate N.sup..alpha. -[N-phenylacetyl-L-prolyl]-N.sup..delta. -benzyloxycarbonyl-L-arginine aldehyde.
- 17. The compound of claim 1 which is N.sup..alpha. -[N-phenylacetyl-L-prolyl]-L-arginine aldehyde.
- 18. The intermediate N.sup..alpha. -[N-(3-cyclohexylpropanoyl) -L-prolyl]-N.sup..delta. -benzyloxycarbonyl-L-arginine lactam.
- 19. The intermediate N.sup..alpha. -[N-(3-cyclohexylpropanoyl)-L-prolyl]-N.sup..delta. -benzyloxycarbonyl-L-arginine aldehyde.
- 20. The compound of claim 1 which is N.sup..alpha. -[N-(3-cyclohexylpropanoyl)-L-prolyl]-L-arginine aldehyde.
- 21. The intermediate N.sup..alpha. -[N-(3-phenylpropanoyl)-L-prolyl]-N.sup..delta. -benzyloxycarbonyl-L-arginine lactam.
- 22. The intermediate N.sup..alpha. -[N-(3-phenylpropanoyl)-L-prolyl]-N.sup..delta. -benzyloxycarbonyl-L-arginine aldehyde.
- 23. The intermediate N.sup..alpha. -[N-phenoxyacetyl-L-prolyl]-N.sup..delta. -benzyloxycarbonyl-L-arginine lactam.
- 24. The intermediate N.sup..alpha. -[N-phenoxyacetyl-L-prolyl]-N.sup..delta. -benzyloxycarbonyl-L-arginine aldehyde.
- 25. The compound of claim 1 which is N.sup..alpha. -[N-phenoxyacetyl-L-prolyl]-L-arginine aldehyde.
- 26. The intermediate N-(N,N'-dibenzyloxycarbonylaminoiminomethyl)-D-phenylalanyl-L-proline and tert-butyl ester.
- 27. The intermediate N-(5-dimethylamino-1-naphthalenesulfonyl)-glycyl-L-proline tert-butyl ester.
- 28. The intermediate N-(5-dimethylamino-1-naphthalensulfonyl)-glycyl-L-proline.
- 29. The intermediate N-(8-quinolinesulfonyl) -glycyl-L-proline tert-butyl ester.
- 30. The intermediate N-(8-Quinolinesulfonyl)-glycyl-L-proline.
- 31. The intermediate N.sup..alpha. -[N-(3-phenyl propanoyl)glycyl]-N.sup..delta. -benzyloxycarbonyl-L-arginine aldehyde.
- 32. The compound of claim 1 which is N.sup..alpha. -[N-(3-phenyl propanoyl)-glycyl]-L-arginine aldehyde.
- 33. The compound of claim 1 which is N.sup..alpha. -[N-(3-phenyl propanoyl)-glycyl]-L-arginine alcohol.
- 34. The intermediate N.sup..alpha. -[N-(5-dimethylamino-1-naphthalenesulfonyl)-L-prolyl]-N.sup..delta. -benzyloxycarbonyl -L-arginine lactam.
- 35. The intermediate N.sup..alpha. -[N-(5-dimethylamino-1-naphthalenesulfonyl)-L-prolyl]-N.sup..delta. -benzyloxycarbonyl-L-arginine aldehyde.
- 36. The compound of claim 1 which is N.sup..alpha. [N-(5-dimethylamino-1-naphthalenesulfonyl)-L-prolyl]-L-arginine aldehyde.
- 37. The intermediate (.+-.)N.sup..alpha. -[N-(((3-(N-benzyloxycarbonylamino)-3-phenyl)propanoyl)-L-prolyl]-N.sup..delta. -benzyloxycarbonyl-L-arginine lactam.
- 38. The intermediate (.+-.)N.sup..alpha. -[N-(((3-(N-benzyloxycarbonyl)amino)-3-phenyl)propanoyl)-L-prolyl ]-N.sup..delta. -benzyloxycarbonyl-L-arginine aldehyde.
- 39. The compound of claim 1 which is (.+-.)N.sup..alpha. -[N-(3-amino-3-phenyl)propanoyl)-L-prolyl]-L-arginine aldehyde.
- 40. A method of inhibiting serine proteases which method comprises administering to a subject in need of such treatment, an effective amount of a compound of claim 1 or a pharmaceutically acceptable acid addition salt or hydrate thereof.
- 41. The method of 40 wherein the serine protease is trypsin.
- 42. The method of claim 40 wherein the serine protease is thrombin.
- 43. A pharmaceutical composition which comprises at least one compound in claim 1, or a pharmaceutically acceptable acid addition salt or hydrate thereof, in admixture with at least one pharmaceutically acceptable excipient.
- 44. A method of inhibiting clotting of blood in a subject in need of such treatment, which method comprises contacting said blood with an effective amount of a compound of claim 1.
- 45. The method of claim 44 wherein said blood is circulating within the body of the subject.
- 46. The method of claim 1 wherein said blood is circulating outside the body of the subject.
- 47. A pharmaceutical composition for inhibiting the thrombin-fibrinogen reaction containing an effective amount of a compound as defined in claim 1 as the active agent in association with a pharmaceutically acceptable carrier.
Parent Case Info
This is a continuation of application Ser. No. 07/741,023, filed Aug. 6, 1991, now abandoned.
US Referenced Citations (9)
Foreign Referenced Citations (3)
Number |
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0479489-A2 |
Aug 1992 |
EPX |
2091270-A |
Jul 1982 |
GBX |
2244994 |
Dec 1991 |
GBX |
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Continuations (1)
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Number |
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741023 |
Aug 1991 |
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