Piperazine compounds as inhibitors of MMP or TNF

• US 20020128270A1
• Filed: 10/22/2001
• Published: 09/12/2002
• Est. Priority Date: 12/17/1996
• Status: Active Grant

• Current Assignee: Fujisawa Pharmaceutical Co., Ltd. (Astellas Pharma Incorporated)
• Original Assignee: Fujisawa Pharmaceutical Co., Ltd. (Astellas Pharma Incorporated)
• Inventors: Neya, Masahiro, Sato, Kentaro, Yamazaki, Hitoshi, Kayakiri, Natsuko, Oku, Teruo
• Granted Patent: US 6,489,324 B2
• Time in Patent Office: Days
• US Class Current: 514/252.13
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 241/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

A compound of formula (I) wherein A is a sulfonyl or a carbonyl; R 1 is an optionally substituted aryl, an optionally substituted heterocyclic group, an optionally substituted lower alkyl or an optionally substituted lower alkenyl; R 2 is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group; R 3 is an optionally substituted lower alkyl, an optionally substituted lower alkoxy, an optionally substituted aryloxy, an optionally substitued lower alkenyl, an optionally substituted aryl, an optionally substituted heterocyclic group or an optionally substitued amino, R 4 is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group, R 5 is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group; and R 10 is a hydroxy or a protected hydroxy, and a pharmaceutically acceptable salt thereof. The compound of the present invention is useful as a medicament for prophylactic and therapeutic treatment of MMP- or TNF±-mediated diseases.

Claims

14. A method of treating and/or preventing a MMP- or TNFα

-mediated disease which comprises administering an effective amount of the compound of following formula (I) or a pharmaceutically acceptable salt thereof to a human being or an animal

15. The method of claim 14, wherein the disease is selected from the group consisting of stroke, arhtritis, cancer, tissue ulceration, decubitis ulcer, restenosis, periodontal disease, epidermolysis bullosa, scleritis, psoriasis, AIDS, sepsis, and septic shock.

16. The method of claim 14, wherein R¹ is said heterocyclic group optionally substituted by a substituent.

17. The method of claim 16, wherein

R¹ is a heterocyclic group selected fromt he group consisting of unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms and unsaturated 5- or 6-membered heteromonocyclic group containing a sulfur atom, each of which is optionally substituted by a substituent selected from the group consisting of halogen;

phenyl;

halophenyl;

hydroxyphenyl;

lower alkoxyphenyl;

lower alkyphenyl;

nitrophenyl;

bephenylyl;

phenoxy phenyl;

trihalo(lower)alkylphenyl;

cyano(lower)alkoxyphenyl;

cyano phenyl;

cyano(lower)alkyphenyl;

lower alkanoyloxyphenyl;

lower alkanoyloxy(lower)alkylphenyl;

di(lower)alkylaminosulfonylphenyl;

hydroxy(lower)alkylphenyl;

lower alkoxycarbonylphenyl;

lower alkoxycarbonyl(lower)alkoxyphenyl;

lower alkylsulfonyloxyphenyl;

phenyl substituted by halogen and hydroxy;

phenyl substituted by halogen and lower alkanoyloxy;

phenyl substituted by halogen and lower alkoxy;

heterocyclic group selected from the group consisting of unsaturated 9- or 10-membered heterobicyclic group containing 1 or 2 oxygen atoms, unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms,

unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms and

unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms;

and a lower alkyl- or (phenyl-)heterocyclic group, said heterocyclic group being unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms.

18. The method of claim 17, wherein

R¹ is a thienyl substituted by a substituent selected from the group consisting of halogen, phenyl, halophenyl, hydroxyphenyl, lower alkoxyphenyl, lower alkylphenyl, nitrophenyl, biphenylyl, phenoxy phenyl, trihalo(lower)alkylphenyl, cyano(lower)alkoxyphenyl, cyano phenyl, cyano(lower)alkylphenyl, lower alkanoyloxyphenyl, lower alkanoyloxy(lower)alkylphenyl, di(lower)alkylaminosulfonylphenyl, hydroxy(lower)alkyphenyl, lower alkoxycarbonylphenyl, lower alkoxy carbonyl(lower)alkoxyphenyl, lower alkylsulfonyloxyphenyl, phenyl substituted by halogen and hydroxy, phenyl substituted by halogen and lower alkanoyloxy, phenyl substituted by halogen, and lower alkoxy, thiazolyl, oxazolyl, pyridyl, benzodihydrofuranyl, benzodioxolenyl, lower alkyloxadiazolyl and phenyloxadiazolyl;

a thiazol substituted by phenyl or a thiadiazolyl substituted by phenyl.

19. The method of claim 18, wherein

R¹ is a thienyl, a halothienyl, a phenylthienyl, a halophenylthienyl, a hydroxyphenylthienyl, a lower alkoxyphenylthienyl, a lower alkylphenylthienyl, a nitrophenylthienyl, a bi phenylylthienyl, a phenoxyphenylthienyl, a trihalo(lower)alkyphenylthienyl, a cyano(lower)alkoxyphenylthienyl, a cyanophenylthienyl, a cyano(lower)alkyphenylthienyl, a lower alkanoyloxyphenylthienyl, a lower alkanoyloxy(lower)alkylphenylthienyl, a di(lower)alkylaminosulfonylphenylthienyl, a hydroxy(lower)alkylphenylthienyl, a lower alkoxycarbonylphenylthienyl, a lower alkoxycarbonyl(lower)alkoxyphenylthienyl, a lower alkylsulfonyloxy phenylthienyl, a phenylthienyl wherein the phenyl group being substituted by halogen and hydroxy, a phenylthienyl wherein the phenyl group being substituted by halogen and lower alkanoyloxy, or a phenylthienyl wherein the phenyl group being substituted by halogen and lower alkoxy, or a pharmaceutically acceptable salt thereof.

20. The method of claim 14, wherein the disease is stroke.

21. The method of claim 14, wherein the disease is arthritis.

22. The method of claim 14, wherein the disease is cancer.

23. The method of claim 14, wherein the disease is tissue ulceration.

24. The method of claim 14, wherein the disease is decubitis ulcer.

25. The method of claim 14, wherein the disease is restenosis.

26. The method of claim 14, wherein the disease is periodontal disease.

27. The method of claim 14, wherein the disease is epidermolysis bullosa.

28. The method of claim 14, wherein the disease is scleritis.

29. The method of claim 14, wherein the disease is psoriasis.

30. The method of claim 14, wherein the disease is AIDS.

31. The method of claim 14, wherein the disease is sepsis.

32. The method of claim 14, wherein the disease is septic shock.

33. The method of claim 14, which treats said disease.

34. The method of claim 14, which prevents said disease.

35. The method of claim 14, wherein said compound is administered to a human being.