Claims
- 1. A method for the treatment of degenerative diseases which comprises administering to a patient in need of such treatment a medicament containing an effective proteolytic enzyme inhibiting amount of a compound having the formula ##STR5## wherein: L is --O--, --S--, --SO-- or --SO.sub.2 --;
- m and n are each independently 0 or 1;
- R.sub.1 is 1H-(5-tetrazolyl), 5-oxo-1-tetrazolinyl or, when R.sub.2 as defined below is other than phenylthio, 5-thioxo-1-tetrazolinyl,
- or said 1H-(5-tetrazolyl), 5-oxo-1-tetrazolinyl or 5-thioxo-1-tetrazolinyl substituted on any available nitrogen atom by lower-alkyl, hydroxy-lower-alkyl, cycloalkyl, 2-, 3- or 4-pyridinyl, carboxy-lower-alkyl, lower-alkoxycarbonyl-lower-alkyl, aminocarbonyl-lower-alkyl, lower-alkylaminocarbonyl-lower-alkyl, di-lower-alkylamino-carbonyl-lower-alkyl, amino-lower-alkyl, lower-alkylamino-lower-alkyl, di-lower-alkyl-amino-lower-alkyl, 4-morpholinyl-lower-alkyl, 1-piperidinyl-lower-alkyl, 1-pyrrolidinyl-lower-alkyl or phenyl or phenyl substituted by amino, lower-alkyl-amino, di-lower-alkylamino, lower-alkanamido, N-lower-alkyl-lower-alkanamido, carboxy-lower-alkanamido, carboxy, lower-alkoxycarbonyl, lower-alkoxy, halo or carboxy-lower-alkanoylamino,
- or said 1H-(5-tetrazolyl), 5-oxo-1-tetrazolinyl or 5-thioxo-1-tetrazolinyl substituted on any available carbon atom by nitro, lower-alkyl, amino, lower-alkylamino, di-lower-alkylamino, cycloalkylamino, mercapto, lower-alkylthio, amino-lower-alkylthio, lower-alkylamino-lower-alkylthio, di-lower-alkyl-amino-lower-alkylthio, 4-morpholinyl-lower-alkylthio, 1-piperidinyl-lower-alkylthio, 1-pyrrolidinyl-lower-alkylthio, lower-alkoxycarbonyl, di-lower-alkylamino-lower-alkyl, 4-morpholinyl-lower-alkylamino, cyano, 1-piperidinyl-lower-alkyl, hydroxy-lower-alkyl, phenylsulfonyl, toluenesulfonyl, halo, tri-lower-alkylsilyl, carboxyl or alkali metal salt thereof, furyl, trifluoromethyl, 2-benzothiazolyl, lower-alkylsulfonyl, aminocarbonyl, benzyl, 4-morpholinyl, pyridinyl, lower-alkoxy, pyrazinyl, lower-alkoxycarbonyl-lower-alkyl, di-lower-alkylaminosulfonyl, 4-morpholinylcarbonyl, lower alkanoyl, benzyloxy, hydroxy, benzoyl or benzoyl substituted by lower-alkoxy or halo, or phenyl or phenyl substituted by amino, lower-alkylamino, di-lower-alkylamino, lower-alkanamido, N-lower-alkyl-lower-alkanamido, lower-alkyl, lower-alkoxy, halo, trifluoromethyl, lower-alkoxy-poly-lower-alkoxy, methylenedioxy or lower alkoxycarbonyl;
- R.sub.2 is hydrogen, lower-alkoxycarbonyl, phenyl or phenylthio;
- R.sub.3 is hydrogen, halo, primary or secondary lower-alkyl, lower-alkoxy, lower-alkoxycarbonyl, phenyl, fluoro-lower-alkyl, lower-alkenyl, cyano or di-lower-alkylamino; and
- R.sub.4 is hydrogen or from one to three substituents selected from halo, cyano, nitro, amino, lower-alkanamido, phenyl-lower-alkanamido, diphenyl-lower-alkanamido, lower-alkylsulfonylamino, polyfluoro-lower-alkylsulfonylamino, aminosulfonyl, lower-alkyl, polyhalo-lower-alkyl, cycloalkyl, polyhalo-lower-alkoxy, hydroxy, lower-alkoxy, carboxy, hydroxymethyl, formyl, aminomethyl, lower-alkylsulfonyl, polyhalo-lower-alkylsulfonyl, lower-alkylsulfonyl-aminosulfonyl, lower-alkoxy-lower-alkoxy, lower-alkoxy-poly-lower-alkyleneoxy, carboxy-lower-alkoxy, lower-alkoxycarbonyl-lower-alkoxy or di-lower-alkylaminocarbonyloxy;
- and wherein the --CHR.sub.2 -- group is always appended either through the L moiety as defined above to a carbon atom of R.sub.1 when n is 1 or directly to a ring nitrogen atom of the R.sub.1 moiety when n is 0 with the proviso that when m is 0, n is 1, L is --S-- and R.sub.2, R.sub.3 and R.sub.4 are each hydrogen, R.sub.1 cannot be 1-phenyl-1H-(5-tetrazolyl).
- 2. The method according to claim 1 wherein L is --S--, --SO-- or --SO.sub.2 --, n is 1 and R.sub.1 is 1-phenyltetrazol-5-yl.
- 3. The method according to claim 2 wherein L is --S--, m is 0, R.sub.2 is hydrogen, R.sub.3 is hydrogen, chloro, bromo, methyl, ethyl, propyl, isopropyl, sec.-butyl, methoxy, ethoxy, isopropoxy or phenyl and R.sub.4 is hydrogen, 7-chloro, 5-nitro, 6-nitro, 5-amino, 5-acetylamino, 5-(3,3-diphenyl-propionamido), 5-(1,1,3,3-tetramethylbutyl), 6-hydroxy, 7-hydroxy, 5-methoxy, 6-methoxy, 7-methoxy, 5,6-dimethoxy, 5,7-dimethoxy, 6,7-dimethoxy, 6-[2-(2-methoxyethoxy)ethoxy], 7-[2-(2-methoxyethoxy)ethoxy], 7-carboxymethoxy, 7-(t-butoxycarbonyl)methoxy, 7-dimethylaminocarbonyloxy, 6-propyl-7-methoxy, 5,7-dimethoxy-6-methyl or 5-hydroxy-6-methoxy.
- 4. The method according to claim 2 wherein L is --S--, m is 0, R.sub.2 is methoxycarbonyl, phenyl or phenylthio, R.sub.3 is hydrogen and R.sub.4 is hydrogen.
- 5. The method according to claim 2 wherein L is --S--, m is 1, R.sub.2 is hydrogen, R.sub.3 is hydrogen or isopropyl and R.sub.4 is hydrogen or methoxy.
- 6. The method according to claim 2 wherein L is --SO--, m is 0, R.sub.2 is hydrogen, R.sub.3 is hydrogen and R.sub.4 is hydrogen.
- 7. The method according to claim 1, wherein L is --S--, --SO-- or SO.sub.2 --, m is 0, n is 1, R.sub.1 is 1H-(5-tetrazolyl) or substituted 1H-(5-tetrazolyl) other than 1-phenyltetrazol-5-yl, R.sub.2 is hydrogen, R.sub.3 is hydrogen, halo, primary or secondary lower-alkyl or lower-alkoxy and R.sub.4 is hydrogen, amino, lower-alkanamido or lower-alkoxy.
- 8. The method according to claim 6 wherein L is S and R.sub.1 is
- 1-(3-acetamidophenyl)tetrazol-5-yl,
- 1-(3-heptanamidophenyl)tetrazol-5-yl,
- 1-methyltetrazol-5-yl,
- 1-cyclohexyltetrazol-5-yl,
- 1-(3-aminophenyl)tetrazol-5-yl,
- 1-(4-carboxyphenyl)tetrazol-5-yl,
- 1-(3,5-dimethoxycarbonylphenyl)tetrazol-5-yl,
- 1-[2-(4-morpholinyl)ethyl]tetrazol-5-yl,
- 1-(3-pyridyl)tetrazol-5-yl,
- 2-methyltetrazol-5-yl,
- 1-ethoxycarbonylmethyltetrazol-5-yl,
- 1-(2-hydroxyethyl)tetrazol-5-yl,
- 1-dimethylaminocarbonylmethyltetrazol-5-yl,
- 1-carboxymethyltetrazol-5-yl,
- 1-(3-succinoylaminophenyl)tetrazol-5-yl,
- 1-(2,5-dimethoxyphenyl)tetrazol-5-yl and
- R.sub.3 is hydrogen, chloro, methyl, ethyl, isopropyl or ethoxy and R.sub.4 is hydrogen, amino, acetylamino or methoxy.
- 9. The method according to claim 1 wherein m is 0, n is 0, R.sub.1 is 5-oxo-1-tetrazolinyl or 5-thioxo-1-tetrazolinyl or substituted 5-oxo-1-tetrazolinyl or 5-thioxo-1-tetrazolinyl, R.sub.2 is hydrogen, R.sub.3 is hydrogen or lower-alkyl and R.sub.4 is hydrogen or lower-alkoxy.
- 10. The method according to claim 1 wherein R.sub.1 is
- 4-phenyl-5-thioxotetrazolin-1-yl,
- 4-(4-carboxyphenyl)-5-thioxotetrazolin-1-yl,
- 4-(3-pyridyl)-5-thioxotetrazolin-1-yl,
- 2-methyl-5-thioxotetrazolin-1-yl or
- 4-phenyl-5-oxotetrazolin-1-yl,
- R.sub.3 is hydrogen or chloro and R.sub.4 is hydrogen or 6-methoxy.
- 11. A composition for the treatment of degenerative diseases which comprises a pharmaceutical carrier and an effective proteolytic enzyme inhibiting amount of a compound having the formula ##STR6## wherein L is --O--, --S--, --SO-- or --SO.sub.2 --;
- m and n are each independently 0 or 1;
- R.sub.1 is 1H-(5-tetrazolyl), 5-oxo-1-tetrazolinyl or, when R.sub.2 as defined below is other than phenylthio, 5-thioxo-1-tetrazolinyl,
- or said 1-H-(5-tetrazolyl), 5-oxo-1-tetrazolinyl or 5-thioxo-1-tetrazolinyl substituted on any available nitrogen atom by lower-alkyl, hydroxy-lower-alkyl, cycloalkyl, 2- 3- or 4-pyridinyl, carboxy-lower-alkyl, lower-alkoxycarbonyl-lower-alkyl, aminocarbonyl-lower-alkyl, lower-alkylaminocarbonyl-lower-alkyl, di-lower-alkylamino-carbonyl-lower-alkyl, amino-lower-alkyl, lower-alkylamino-lower-alkyl, di-lower-alkyl-amino-lower-alkyl, 4-morpholinyl-lower-alkyl, 1-piperidinyl-lower-alkyl, 1-pyrrolidinyl-lower-alkyl or phenyl or phenyl substituted by amino, lower-alkyl-amino, di-lower-alkylamino, lower-alkanamido, N-lower-alkyl-lower-alkanamido, carboxy-lower-alkanamido, carboxy, lower-alkoxycarbonyl, lower-alkoxy, halo or carboxy-lower-alkanoylamino,
- or said 1-H-(5-tetrazolyl), 5-oxo-1-tetrazolinyl or 5-thioxo-1-tetrazolinyl substituted on any available carbon atom by nitro, lower-alkyl, amino, lower-alkylamino, di-lower-alkylamino, cycloalkylamino, mercapto, lower-alkylthio, amino-lower-alkylthio, lower-alkylamino-lower-alkylthio, di-lower-alkyl-amino-lower-alkylthio, 4-morpholinyl-lower-alkylthio, 1-piperidinyl-lower-alkylthio, 1-pyrrolidinyl-lower-alkylthio, lower-alkoxycarbonyl, di-lower-alkylamino-lower-alkyl, 4-morpholinyl-lower-alkylamino, cyano, 1-piperidinyl-lower-alkyl, hydroxy-lower-alkyl, phenylsulfonyl, toluenesulfonyl, halo, tri-lower-alkylsilyl, carboxy or alkali metal salt thereof, furyl, trifluoromethyl, 2-benzothiazolyl, lower-alkylsulfonyl, aminocarbonyl, benzyl, 4-morpholinyl, pyridinyl, lower-alkoxy, pyrazinyl, lower-alkoxycarbonyl-lower-alkyl, di-lower-alkylaminosulfonyl, 4-morpholinylcarbonyl, lower alkanoyl, benzyloxy, hydroxy, benzoyl or benzoyl substituted by lower-alkoxy or halo, or phenyl or phenyl substituted by amino, lower-alkylamino, di-lower-alkylamino, lower-alkanamido, N-lower-alkyl-lower-alkanamido, lower-alkyl, lower-alkoxy, halo, trifluoromethyl, lower-alkoxy-poly-lower-alkoxy, methylenedioxy or lower alkoxycarbonyl;
- R.sub.2 is hydrogen, lower-alkoxycarbonyl, phenyl or phenylthio;
- R.sub.3 is hydrogen, halo, primary or secondary lower-alkyl, lower-alkoxy, lower-alkoxycarbonyl, phenyl, fluoro-lower-alkyl, lower-alkenyl, cyano or di-lower-alkylamino; and
- R.sub.4 is hydrogen or from one to three substituents selected from halo, cyano, nitro, amino, lower-alkanamido, phenyl-lower-alkanamido, diphenyl-lower-alkanamido, lower-alkylsulfonylamino, polyfluoro-lower-alkylsulfonylamino, aminosulfonyl, lower-alkyl, polyhalo-lower-alkyl, cycloalkyl, polyhalo-lower-alkoxy, hydroxy, lower-alkoxy, carboxy, hydroxymethyl, formyl, aminomethyl, lower-alkylsulfonyl, polyhalo-lower-alkylsulfonyl, lower-alkylsulfonyl-aminosulfonyl, lower-alkoxy-lower-alkoxy, lower-alkoxy-poly-lower-alkyleneoxy, carboxy-lower-alkoxy, lower-alkoxycarbonyl-lower-alkoxy or di-lower-alkylaminocarbonyloxy;
- and wherein the --CHR.sub.2 -- group is always appended either through the L moiety as defined above to a carbon atom of R.sub.1 when n is 1 or directly to a ring nitrogen atom of the R.sub.1 moiety when n is 0 with the proviso that when m is 0, n is 1, L is --S-- and R.sub.2, R.sub.3 and R.sub.4 are each hydrogen, R.sub.1 cannot be 1-phenyl-1H-(5-tetrazolyl).
- 12. A composition according to claim 11 wherein L is --S--, --SO-- or --SO.sub.2 --, n is 1 and R.sub.1 is 1-phenyltetrazol-5-yl.
- 13. A composition according to claim 12 wherein L is --S--, m is 0, R.sub.2 is hydrogen, R.sub.3 is hydrogen, chloro, bromo, methyl, ethyl, propyl, isopropyl, sec.-butyl, methoxy, ethoxy, isopropoxy or phenyl and R.sub.4 is hydrogen, 7-chloro, 5-nitro, 6-nitro, 5-amino, 5-acetylamino, 5-(3,3-diphenyl-propionamido), 5-(1,1,3,3-tetramethylbutyl), 6-hydroxy, 7-hydroxy, 5-methoxy, 6-methoxy, 7-methoxy, 5,6-dimethoxy, 5,7-dimethoxy, 6,7-dimethoxy, 6-[2-(2-methoxyethoxy)ethoxy], 7-[2-(2-methoxyethyl)ethoxy], 7-carboxymethoxy, 7-(t-butoxycarbonyl)methoxy, 7-dimethylaminocarbonyloxy, 6-propy-7-methoxy, 5,7-dimethoxy-6-methyl or 5-hydroxy-6-methoxy.
- 14. A composition according to claim 12 wherein L is --S--, m is 0, R.sub.2 is methoxycarbonyl, phenyl or phenylthio, R.sub.3 is hydrogen and R.sub.4 is hydrogen.
- 15. A composition according to claim 12 wherein L is --S--, m is 1, R.sub.2 is hydrogen, R.sub.3 is hydrogen or isopropyl and R.sub.4 is hydrogen or methoxy.
- 16. The composition according to claim 12 wherein L is --SO--, m is 0, R.sub.2 is hydrogen, R.sub.3 is hydrogen and R.sub.4 is hydrogen.
- 17. A composition according to claim 11 wherein L is --S--, --SO-- or SO.sub.2 --, m is 0, n is 1, R.sub.1 is 1H-(5-tetrazolyl) or substituted 1H-(5-tetrazolyl) other than 1-phenyltetrazol-5-yl, R.sub.2 is hydrogen, R.sub.3 is hydrogen, halo, primary or secondary lower-alkyl or lower-alkoxy and R.sub.4 is hydrogen, amino, lower-alkanamido or lower-alkoxy.
- 18. A composition according to claim 12 wherein L is S and R.sub.1 is
- 1-(3-acetamidophenyl)tetrazol-5-yl,
- 1-(3-heptanamidophenyl)tetrazol-5-yl,
- 1-methyltetrazol-5-yl,
- 1-cyclohexyltetrazol-5-yl,
- 1-(3-aminophenyl)tetrazol-5-yl,
- 1-(4-carboxyphenyl)tetrazol-5-yl,
- 1-(3,5-dimethoxycarbonylphenyl)tetrazol-5-yl,
- 1-[2-(4-morpholinyl)ethyl]tetrazol-5-yl,
- 1-(3-pyridyl)tetrazol-5-yl,
- 2-methyltetrazol-5-yl,
- 1-ethoxycarbonylmethyltetrazol-5-yl,
- 1-(2-hydroxyethyl)tetrazol-5-yl,
- 1-dimethylaminocarbonylmethyltetrazol-5-yl,
- 1-carboxymethyltetrazol-5-yl,
- 1-(3-succinoylaminophenyl)tetrazol-5-yl,
- 1-(2,5-dimethoxyphenyl)tetrazol-5-yl and
- R.sub.3 is hydrogen, chloro, methyl, ethyl, isopropyl or ethoxy and R.sub.4 is hydrogen, amino, acetylamino or methoxy.
- 19. A composition according to claim 11 wherein m is 0, n is 0, R.sub.1 is 5-oxo-1-tetrazolinyl or 5-thioxo-1-tetrazolinyl or substituted 5-oxo-1-tetrazolinyl or 5-thioxo-1-tetrazolinyl, R.sub.2 is hydrogen, R.sub.3 is hydrogen or lower-alkyl and R.sub.4 is hydrogen or lower-alkoxy.
- 20. A composition according to claim 11 wherein R.sub.1 is
- 4-phenyl-5-thioxotetrazolin-1-yl,
- 4-(4-carboxyphenyl)-5-thioxotetrazolin-1-yl,
- 4-(3-pyridyl)-5-thioxotetrazolin-1-yl, 2-methyl-5-thioxotetrazolin-1-yl or
- 4-phenyl-5-oxotetrazolin-1-yl,
- R.sub.3 is hydrogen or chloro and R.sub.4 is hydrogen or 6-methoxy.
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of our prior copending application Ser. No. 07/514,920 filed Apr. 26, 1990, now abandoned. Application Ser. No. 07/514,920 is a continuation-in-part of applications Ser. Nos. 347,125 and 347,126, both filed May 4, 1989 and both now abandoned.
US Referenced Citations (11)
Foreign Referenced Citations (2)
Number |
Date |
Country |
7200419 |
Dec 1966 |
JPX |
9013549 |
Nov 1990 |
WOX |
Non-Patent Literature Citations (4)
Entry |
Cha, Biochem. Pharmacol., 24, 2177-2185 (1975). |
Powers et al., Biochem., 24, 2048-2058 (1985). |
Svoboda et al., Coll. Czech. Chem. Commun., 51, 1133-1139 (1986). |
Teshima et al., J. Biol. Chem. 257(9), 5085-5091 (1982). |
Continuation in Parts (2)
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Number |
Date |
Country |
Parent |
514920 |
Apr 1990 |
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Parent |
347125 |
May 1989 |
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