3-mercaptoacetylamino-1,5-substituted-2-oxo-azepan derivatives useful as inhibitors of matrix metalloproteinase

1. A compound of the formula

wherein

R 1 is C 1 -C 6 alkyl, a W—(CH 2 ) m — group, or a Q—Z—(CH 2 ) m — group wherein W is phthalimido; Z is a bond or is oxy, NR 6 , C(O)NR 6 , NR 6 C(O), NHC(O)NR 6 , OC(O)NR 6 , HNC(O)O, or SO 2 NR 6 ; Q is hydrogen, or a Y—(CH 2 ) n — group wherein Y is hydrogen, C 6 -C 10 aryl, a cyclic or bicyclic, aromatic assemblage of three to nine carbon atoms and from 1 to 3 nitrogen, oxygen, or sulfur atoms, —C(O)OR 6 , —N(R 6 ) 2 , morpholino, piperidino, pyrrolidino, or isoindolyl;

R 2 is C 1 -C 4 alkyl, a —(CH 2 ) p —(C 3 -C 9 )heteroaryl group, or a —(CH 2 ) p —Ar 1 group wherein Ar 1 is phenyl or naphthyl optionally substituted with a substituent selected from the group consisting of halogen, C 1 -C 4 alkyl, —OR 7 , —N(R 6 ) 2 , SO 2 N(R 6 ) or —NO 2 ;

R 3 is hydrogen, C 1 -C 6 alkyl, —CH 2 SCH 2 NHCOCH 3 , a —(CH 2 ) p —A group, a —(CH 2 ) m —B group or a —CH 2 —D—R 7 group wherein A is C 6 -C 10 aryl, C 3 -C 9 heteroaryl, or cyclohexyl; B is —N(R 7 ) 2 , guanidino, nitroguanidino, —C(O)OR 6 or —C(O)NR 6 ; and D is oxy or thio;

R 4 is hydrogen or a —(CH 2 ) m —S(O) p X′(R 6 ) 2 group;

R 5 is hydrogen, C 1 -C 6 alkyl or R 4 and R 5 taken together with the nitrogen atom to which they are attached form piperidino, pyrrolidino, or isoindolyl;

R 6 is hydrogen or C 1 -C 6 alkyl;

R 7 is hydrogen, C 1 -C 4 alkyl, or a —(CH 2 ) p —Ar 2 group wherein Ar 2 is phenyl or naphthyl optionally substituted with a substituent selected from the group consisting of halogen, C 1 -C 4 alkyl, —OR 7 , —N(R 6 ) 2 , SO 2 N(R 6 ) 2 or —NO 2 ;

R 8 is hydrogen, —C(O)R 7 , a —C(O)—(CH 2 ) q —K group or a —S—G group, wherein K is selected from the group consisting of

G is selected from the group consisting of

R 9 and R 10 are each independently C 1 -C 4 alkyl or a —(CH 2 ) p —Ar 2 group;

R 11 is —CF 3 , C 1 -C 10 alkyl or a —(CH 2 ) p —Ar 2 group;

R 12 is hydrogen, C 1 -C 6 alkyl, —CH 2 CH 2 S(O) n CH 3 , or arylalkyl;

R 13 is hydrogen, hydroxy, amino, C 1 -C 6 alkyl, N-methylamino, N,N-dimethylamino,

—CO 2 R 17 or —OC(O)R 18 wherein R 17 is hydrogen, —CH 2 O—C(O)C(CH 3 ) 3 , C 1 -C 4 alkyl, a

—(CH 2 ) p —Ar 2 group or diphenylmethyl and R 18 is hydrogen, C 1 -C 6 alkyl or phenyl;

R 14 is 1 or 2 substituents independently chosen from the group consisting of hydrogen,

C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or halogen;

R 15 is hydrogen, C 1 -C 6 alkyl or a —(CH 2 ) p —Ar 2 group;

R 16 is hydrogen or C 1 -C 4 alkyl;

V 1 is O, S, or NH;

V 2 is N or CH;

V 3 is a bond or —C(O)—;

V 4 is —(CH 2 ) w′″ , O, S, NR 7 , or NC(O)R 11 ;

X and X′ are each independently CH or N;

m is an integer 2-4;

n is zero or an integer 1-4;

p is zero or an integer 1-2;

q is zero or an integer 1-5;

t is an integer 1-2;

w is an integer 1-3; and

w′ is zero or an integer 1; or

a pharmaceutically acceptable salt, stereoisomer or hydrate thereof.

2. A compound of claim 1 wherein X is CH.

3. A compound of claim 2 wherein R 2 is C 1 -C 4 alkyl or a —(CH 2 ) p —Ar group wherein Ar is phenyl optionally substituted with F, Cl, C 1 -C 4 alkyl, —NO 2 , —NHz or —OR 7 ; and R 4 is hydrogen.

4. A compound of claim 3 wherein R 3 is hydrogen, C 1 -C 6 alky, phenyl, benzyl, 1-naphthyl, 2-naphthyl, cyclohexylmethyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hyroxyphenyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 3,4-dihydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-bromophenyl, 3,4-dibromophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3-tolyl, 4-tolyl, 4-ethylphenyl, 4-isopropylphenyl, 3-aminophenyl, 4-aminophenyl, 3,4-diaminophenyl, N-methyl-4-aminophenyl, 2-nitrophenyl, 4-nitrophenyl, 4-aminobenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 3-chlorobenzyl, 4-fluorobenzyl, 3,4-dichlorobenzyl, 4-bromobenzyl, 4-methylbenzyl, or is a compound of the formula

5. A compound of claim 4 wherein R 5 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl and R 8 is hydrogen.

6. A compound of claim 2 wherein R 1 is a W—(CH 2 ) m — group.

7. A compound of claim 3 wherein R 1 is a W—(CH 2 ) m — group.

8. A compound of claim 5 wherein R 1 is a W—(CH 2 ) m — group.

9. A compound of claim 2 wherein R 1 is C 1 -C 6 alkyl.

10. A compound of claim 3 wherein R 1 is C 1 -C 6 alkyl.

11. A compound of claim 5 wherein R 1 is a C 1 -C 6 alkyl.

12. A compound of claim 2 wherein R 1 is a Q—Z—(H 2 ) m — group.

13. A compound of claim 3 wherein R 1 is a Q—Z—(H 2 ) m — group.

14. A compound of claim 5 wherein R 1 is a Q—Z—(H 2 ) m — group.

15. A compound of claim 1 wherein X is N.

16. A compound of claim 15 wherein R 2 is C 1 -C 4 alkyl or a —(CH 2 ) p —Ar group wherein Ar is phenyl optionally substituted with F, Cl, C 1 -C 4 alkyl, —NO 2 , —NH 2 or —OR 8 ; and R 4 is hydrogen.

17. A compound of claim 16 wherein R 3 is hydrogen, C 1 -C 6 alkyl, phenyl, benzyl, 1-naphthyl, 2-naphthyl, cyclohexylmethyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hyroxyphenyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 3,4-dihydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-bromophenyl, 3,4-dibromophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3-tolyl, 4-tolyl, 4-ethylphenyl, 4-isopropylphenyl, 3-aminophenyl, 4-aminophenyl, 3,4-diaminophenyl, N-methyl-4-aminophenyl, 2-nitrophenyl, 4-nitrophenyl, 4-aminobenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 3-chlorobenzyl, 4-fluorobenzyl, 3,4-dichlorobenzyl, 4-bromobenzyl, 4-methylbenzyl, or is a compound of the formula

18. A compound of claim 17 wherein R 5 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl and R 8 is hydrogen.

19. A compound of claim 16 wherein R 1 is a W—(CH 2 ) m — group.

20. A compound of claim 17 wherein R 1 is a W—(CH 2 ) m — group.

21. A compound of claim 19 wherein R 1 is a W—(CH 2 ) m — group.

22. A compound of claim 16 wherein R 1 is C 1 -C 6 alkyl.

23. A compound of claim 17 wherein R 1 is C 1 -C 6 alkyl.

24. A compound of claim 19 wherein R 1 is a C 1 -C 6 alkyl.

25. A compound of claim 16 wherein R 1 is a Q—Z—(H 2 ) m — group.

26. A compound of claim 17 wherein R 1 is a Q—Z—(H 2 ) m — group.

27. A compound of claim 19 wherein R 1 is a Q—Z—(H 2 ) m — group.

28. A compound of claim 1 wherein X is CH; R 2 is phenyl, methyl or ethyl; R 3 is phenyl, benzyl, cyclohexylmethyl, isopropyl, isobutyl, 3-pyridylmethyl, 4-fluorobenzyl or 4-aminobenzyl; R 4 is hydrogen; R 5 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl and R 8 is hydrogen.

29. A compound of claim 28 wherein R 1 is a W—(CH 2 ) m — group.

30. A compound of claim 1 wherein X is N; R 2 is phenyl, methyl or ethyl; R 3 is phenyl, benzyl, cyclohexylmethyl, isopropyl, isobutyl, 3-pyridylmethyl, 4-fluorobenzyl or 4-aminobenzyl; R 4 is hydrogen; R 5 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl and R 8 is hydrogen.

31. A compound of claim 30 wherein R 1 is a W—(CH 2 ) m — group.

32. A compound of claim 1 wherein said compound is 2H-Isoindole-2-hexanamide, N-[hexahydro-1-[2-(methylamino)-2-oxo-1-(phenylmethyl)ethyl]-2-oxo-5-phenyl-1H-azepin-3-yl]-1,3-dihydro-α-mercapto-1,3-dioxo-, [3S-[1(R*), 3α, 5α]]-.

33. A compound of claim 1 wherein said compound is 2H-Isoindole-2-hexanamide, N-[hexahydro-1-[2-(methylamino)-2-oxo-1-(phenylmethyl)ethyl]-2-oxo-5-phenyl-1H-azepin-3-yl]-1,3-dihydro-α-mercapto-1,3-dioxo-, [3S-[1(R*), 3α, 5β]]-.

34. A compound of claim 1 wherein said compound is 2H-Isoindole-2-hexanamide, N-[hexahydro-4-[2-(methylamino)-2-oxo-1-(phenylmethyl)ethyl]-5-oxo-1-(phenylmethyl)-1H-1,4-diazepin-6-yl]-1,3-dihydro-α-mercapto-1,3-dioxo-, [6S-[4(R*), 6R*(R*)]]-.

35. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

36. A method of treating rheumatoid arthritis in a patient in need thereof which comprises administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of claim 1 .

37. A method of treating osteoarthritis in a patient in need thereof which comprises administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of claim 1 .

38. A method of treating a chronic inflammatory disorder in a patient in need thereof which comprises administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of claim 1 .

39. A method of treating atherosclerosis in a patient in need thereof which comprises administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of claim 1 .

40. A method of treating corneal ulceration in a patient in need thereof which comprises administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of claim 1 .

41. A method of treating gingivitis or periodontal disease in a patient in need thereof which comprises administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of claim 1 .

42. A method of treating chronic obstructive pulmonary disorder in a patient in need thereof which comprises administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of claim 1 .