Claims
- 1. A compound of formula (I) as a single stereoisomer or as a mixture of stereoisomers: ##STR30## wherein: m is 2, 3, 4, 5, or 6; and
- n is 0, 1, 2, 3, or 4; such that:
- when m is 2, 3 or 4; n is 1, 2, 3, or 4; and
- A is --CH.sub.2 --, --O--, or --N(R.sup.11)--, where R.sup.11 is hydrogen or alkyl;
- R.sup.1 is
- a) --CH.sub.2 --R.sup.4 where R.sup.4 is mercapto, acetylthio, carboxy, aminocarbonyl, N-hydroxyformylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, benzyloxyaminocarbonyl, or ##STR31## in which R.sup.6 is optionally substituted aryl, wherein the aryl group is quinol-2-yl, naphth-1-yl, naphth-2-yl, pyridyl or phenyl;
- b) --CH(R.sup.7)--R.sup.8 where R.sup.7 is alkyl, hydroxy, amino, alkylamino, arylamino, alkylsulphonylamino, aralkylsulphonylamino, alkoxycarbonyl, aminocarbonyl, aralkyl or carboxy; or R.sup.7 is --CH.sub.2 NHR, where R is hydrogen, alkyl, aryl, 2-benzoxazole, --SO.sub.2 R.sup.a, --SO.sub.2 NHR.sup.a, --SO.sub.2 OR.sup.a, --C(O)R.sup.a --C(O)NHR.sup.a, --C(O)OR.sup.a, where R.sup.a is alkyl, trifluoromethyl, aryl, aralkyl, aralkenyl or arylcarbonylaminoalkylaryl; and R.sup.8 is carboxy, hydroxyaminocarbonyl, alkoxycarbonyl or aralkoxycarbonyl; or
- c) --NH--CH(R.sup.9)--R.sup.10 where R.sup.9 is hydrogen, alkyl or aralkyl, and R.sup.10 is carboxy, alkoxycarbonyl or aralkoxycarbonyl, phosphonyl, dialkylphosphonyl, or methoxyphosphonyl;
- R.sup.2 is alkyl, alkenyl, trifluoromethylalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aralkoxyalkyl, aryl, aryloxyalkyl or aralkyl; and
- R.sup.3 is hydrogen, hydroxy, halo, alkyl, alkoxy or aralkoxy; when n is 0; m is 4, 5 or 6; and
- A is --CH(R.sup.12)-- where R.sup.12 is carboxy, alkoxycarbonyl or optionally substituted carbamoyl; and
- R.sup.1, R.sup.2 and R.sup.3 are as defined above;
- or a pharmaceutically acceptable salt thereof;
- and wherein alkyl is a moiety having from 1 to 6 carbon atoms;
- alkoxy is a moiety of the formula --OR.sub.a wherein R.sub.a is alkyl;
- aryl is a monovalent unsaturated aromatic carbocyclic radical having one or two rings or a monovalent unsaturated aromatic heterocyclic radical optionally substituted with aryl;
- optionally substituted aryl is a mono- di-, or tri-substituted aryl with halo, hydroxy, lower alkyl alkoxy, trifluoromethyl, aryloxy, amino, aryl, acetamido, or cyano;
- aralkyl is a moiety of the formula --R.sub.c R.sub.b wherein R.sub.c is alkylene containing 1 to 6 carbon atoms and R.sub.b is aryl; and
- cycloalkyl is a moiety having from 3 to 6 carbon atoms.
- 2. The compound or salt of claim 1 wherein n is 1, 2 or 3; m is 2 or 3; and A is --CH.sub.2 --.
- 3. The compound or salt of claim 2 wherein n is 2; R.sup.1 is --CH.sub.2 --R.sup.4 ; and R.sup.3 is hydrogen.
- 4. The compound or salt of claim 3 wherein R.sup.2 is alkyl, cycloalkyl, cycloalkylalkyl or aralkyl; and R.sup.4 is carboxy, alkoxycarbonyl or hydroxyaminocarbonyl.
- 5. The 3R,10S stereoisomer of the compound or salt of claim 4 wherein R.sup.2 is cyclopentylmethyl; and R.sup.4 is ethoxycarbonyl or isopropoxycarbonyl.
- 6. The 3R,10S stereoisomer of the compound or salt of claim 3 wherein R.sup.2 is cyclopentylmethyl; and R.sup.4 is N-methylpiperid-4-yl-oxycarbonyl or isopropoxycarbonyl.
- 7. The 3R,10S stereoisomer of the compound or salt of claim 3 wherein R.sup.2 is 2-methylpropyl; and R.sup.4 is N-methylpiperid-4-yl-oxycarbonyl, dimethylaminoethylcarbamoyl, or N-hydroxyformylamino.
- 8. The compound or salt of claim 2 wherein R.sup.1 is --CH.sub.2 --R.sup.4 ; R.sup.2 is 2-methylpropyl; and R.sup.3 is hydrogen; in which R.sup.4 is carboxy, N-hydroxyaminocarbonyl, or N-hydroxyformylamino.
- 9. The compound or salt of claim 2 wherein R.sup.1 is --CH.sub.2 --R.sup.4 ; R.sup.2 is 2-methylpropyl; and R.sup.3 is hydrogen; in which R.sup.4 is mercapto or acetylthio.
- 10. The compound or salt of claim 2 wherein R.sup.1 is ##STR32## where R.sup.6 is optionally substituted aryl, wherein the aryl group is quinol-2-yl, naphth-1-yl, naphth-2-yl, pyridyl or phenyl.
- 11. The compound or salt of claim 10 wherein n is 2 and R.sup.6 is quinol-2-yl.
- 12. The compound or salt of claim 2 wherein R.sup.1 is --CH(R.sup.7)--R.sup.8, where R.sup.7 is --CH.sub.2 NHR.
- 13. The compound or salt of claim 12 wherein n is 2; R is hydrogen, --C(O)OR.sup.a, --SO.sub.2 R.sup.a or --C(O)NHR.sup.a, where R.sup.a is alkyl; R.sup.2 is 2-methylpropyl; R.sup.3 is hydrogen; and R.sup.8 is carboxy.
- 14. The compound of claim 2 where R.sup.1 is --CH(R.sup.7)--R.sup.8, where R.sup.7 is alkyl, or alkoxycarbonyl.
- 15. The compound or salt of claim 14 wherein R.sup.2 is 2-methylpropyl; R.sup.3 is hydrogen; and R.sup.8 is hydroxyaminocarbonyl.
- 16. The compound of claim 2 wherein R.sup.1 is --CH(R.sup.7)--R.sup.8 where R.sup.8 is hydroxyaminocarbonyl.
- 17. The compound of claim 16 wherein R.sup.7 is hydroxy, R.sup.2 is isobutyl and R.sup.3 is hydrogen.
- 18. The compound or salt of claim 2 wherein R.sup.1 is --NH--CH(R.sup.9)--R.sup.10, where R.sup.10 is carboxy, alkoxycarbonyl or aralkoxycarbonyl.
- 19. The compound or salt of claim 18 wherein R.sup.9 is alkyl and R.sup.10 is carboxy or alkoxycarbonyl.
- 20. The compound or salt of claim 1 wherein n is 2 or 3; m is 4; A is --N(R.sup.11)--, where R.sup.11 is hydrogen or alkyl; R.sup.2 is alkyl; and R.sup.3 is hydrogen, halo or alkoxy.
- 21. The compound of claim 20 wherein R.sup.2 is 2-methylpropyl; R.sup.3 is hydrogen and R.sup.11 is methyl.
- 22. The compound of claim 21 wherein R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is carboxy, hydroxyaminocarbonyl, N-hydroxyformylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, or benzyloxyaminocarbonyl.
- 23. The compound of claim 22 wherein n is 2 and R.sup.1 is --CH.sub.2 --C(O)NHOH.
- 24. The compound of claim 1 wherein m is 2; n is 2; and A is oxygen.
- 25. The compound of claim 24 wherein R.sup.1 is --CH.sub.2 --R.sup.4 and R.sup.3 is hydrogen.
- 26. The compound of claim 25 wherein R.sup.2 is hydrogen, alkyl or cycloalkylalkyl.
- 27. The compound of claim 25 wherein R.sup.2 is aryl.
- 28. The compound of claim 27 wherein R.sup.4 is carboxy, or a pharmaceutically acceptable salt thereof such as the acetate, trifluoroacetate or hydrochloride salt.
- 29. The compound of claim 25 wherein R.sup.2 is aryloxyalkyl.
- 30. The compound of claim 25 wherein R.sup.2 is aralkyl.
- 31. A pharmaceutical composition comprising a compound or salt of claim 1 and a pharmaceutically acceptable excipient.
- 32. A method of treating a mammal having a disease state that is alleviated by treatment with a matrix metalloprotease inhibitor, which comprises administering a therapeutically effective amount of a compound or salt of claim 1 to a mammal in need thereof.
- 33. The method of claim 32 wherein the disease state is arthritic disease.
- 34. The method of claim 32 wherein the disease state is osteoporosis.
- 35. (3R,9S)-N-hydroxy-2-hydroxy-5-methyl-3-(8-oxo-1,7-diazatricyclo �9.6.1.0.sup.12,17 !octadeca-11(18),12(17),14, 16-tetraen-9-ylcarbamoyl) hexanamide or its (2S, 3R,9S) stereoisomer.
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of U.S. application Ser. No. 08/382,818, filed Feb. 3, 1995, pending, which is a continuation-in-part of U.S. application Ser. No. 08/102,655, filed Aug. 5, 1993 abandoned, the disclosures of which are incorporated by references herein.
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Continuation in Parts (2)
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Number |
Date |
Country |
Parent |
382818 |
Feb 1995 |
|
Parent |
102655 |
Aug 1993 |
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