Hydroxamic acid compounds and methods of use thereof

• US 20040266818A1
• Filed: 04/01/2004
• Published: 12/30/2004
• Est. Priority Date: 04/01/2003
• Status: Active Grant

• Current Assignee: Paul A. Marks, Richard A. Rifkind, Ronald Breslow, Sandro Belvedere, Thomas Allen Miller, Victoria M. Richon
• Original Assignee: Paul A. Marks, Richard A. Rifkind, Ronald Breslow, Sandro Belvedere, Thomas Allen Miller, Victoria M. Richon
• Inventors: Rifkind, Richard A., Richon, Victoria M., Marks, Paul A., Miller, Thomas A., Belvedere, Sandro, Breslow, Ronald
• Granted Patent: US 7,199,134 B2
• Time in Patent Office: Days
• US Class Current: 514/310
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 39/06 Free radical scavengers or antioxidants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 211/02 Preparation by ring-closure or hydrogenation
• CPC Class Codes: C07D 215/38 Nitrogen atoms nitro radicals C07D215/18
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to a novel class of hydroxamic acid derivatives having at least two aryl containing groups, at least one of which is a quinolinyl, isoquinolinyl or benzyl moiety, linked to the hydroxamic acid group through a methylene chain. The hydroxamic acid compounds can be used to treat cancer, for example, brain cancer. The hydroxamic acid compounds can also inhibit histone deacetylase and are suitable for use in selectively inducing terminal differentiation, and arresting cell growth and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the compounds of the present are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The compounds of the invention are also useful in the prevention and treatment of TRX-mediated diseases, such as autoimmune, allergic and inflammatory diseases, and in the prevention and/or treatment of diseases of the central nervous system (CNS), such as neurodegenerative diseases.

Claims

1. A compound represented by the following structural formula:

2. The compound of claim 1, wherein n is 5.

3. The compound of claim 1, wherein R₁ is a substituted or unsubstituted heteroaryl group, phenyl group or naphthyl group.

4. The compound of claim 1, wherein R₁ is a substituted or unsubstituted pyridyl group, quinolinyl group or isoquinolinyl group.

5. The compound of claim 1, wherein R₁ is a substituted or unsubstituted phenyl group.

6. The compound of claim 5, wherein R₁ is an unsubstituted phenyl group.

7. The compound of claim 6, wherein n is 5.

8. The compound of claim 1, wherein R₁ is an unsubstituted pyridyl group.

9. The compound of claim 8, wherein R₁ is β

-pyridyl.

10. The compound of claim 9, wherein n is 5.

11. The compound of claim 1, wherein R₁ is an unsubstituted quinolinyl group.

12. The compound of claim 11, wherein R₁ is a 2-quinolinyl group.

13. The compound of claim 12, wherein n is 5.

14. The compound of claim 1, wherein R₁ is a substituted or unsubstituted arylalkyloxy group.

15. The compound of claim 14, wherein R₁ is substituted or unsubstituted benzyloxy group.

16. The compound of claim 15, wherein R₁ is an unsubstituted benzyloxy group.

17. The compound of claim 16, wherein n is 5.

45. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of any of claims 1, 18, 23, and 28, and a pharmaceutically acceptable carrier.

46. A method of treating cancer in a subject in need of treatment comprising administering to said subject a therapeutically effective amount the compound of any one of claims 1, 18, 23, and 28.

47. A method of selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting proliferation of such cells which comprises contacting the cells under suitable conditions with an effective amount of the compound of any one of claims 1, 18, 23, and 28.

48. A method of selectively inducing cell growth arrest of neoplastic cells and thereby inhibiting proliferation of such cells which comprises contacting the cells under suitable conditions with an effective amount of the compound of any one of claims 1, 18, 23, and 28.

49. A method of selectively inducing apoptosis of neoplastic cells and thereby inhibiting proliferation of such cells which comprises contacting the cells under suitable conditions with an effective amount of the compound of any one of claims 1, 18, 23, and 28.

50. A method of inducing terminal differentiation of tumor cells in a tumor comprising contacting the cells with an effective amount of the compound of any one of claims 1, 18, 23, and 28.

51. A method of inhibiting the activity of histone deacetylase comprising contacting the histone deacetylase with an effective amount of the compound of any one of claims 1, 18, 23, and 28 so as to inhibit the activity of histone acetylase.

52. A method of treating a thioredoxin (TRX)-mediated disease in a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of the compound of any one of claims 1, 18, 23, and 28.

53. The method according to claim 52, wherein said TRX-mediated disease is an inflammatory disease, an allergic disease, an autoimmune disease, a disease associated with oxidative stress or a disease characterized by cellular hyperproliferation.

54. A method of treating a disease of the central nervous system in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the compound of any one of claims 1, 18, 23, and 28.

55. The method according to claim 54, wherein the disease is a polyglutamine expansion disease.

18. A compound represented by the following structural formula:

19. The compound of claim 18, wherein Q₁ is an 8-quinolinyl group.

20. The compound of claim 18 wherein the pyridyl group is β

-pyridyl.

21. The compound of claim 20 wherein Q₁ is an 8-quinolinyl group.

22. The compound of claim 21, wherein n is 5.

23. A compound represented by the following structural formula:

24. The compound of claim 23, wherein Q₁ is an 8-quinolinyl group.

25. The compound of claim 23, wherein Q₂ is a 2-quinolinyl group.

26. The compound of claim 25, wherein Q₁ is an 8-quinolinyl group.

27. The compound of claim 26, wherein n is 5.

28. A compound represented by the following structural formula:

29. The compound of claim 28, wherein R₁ is a benzyl group.

30. The compound of claim 29, wherein R₂ is a substituted or unsubstituted quinolinyl group.

31. The compound of claim 30, wherein R₂ is an unsubstituted quinolinyl group.

32. The compound of claim 31, wherein R₂ is a 2-quinolinyl group.

33. The compound of claim 32, wherein n is 5.

34. The compound of claim 29, wherein R₂ is a substituted or unsubstituted arylalkyloxy group.

35. The compound of claim 34, wherein R₂ is a substituted or unsubstituted benzyloxy group.

36. The compound of claim 35, wherein R₂ is an unsubstituted benzyloxy group.

37. The compound of claim 36, wherein n is 5.

38. The compound of claim 29, wherein R₂ is a substituted or unsubstituted phenyl group.

39. The compound of claim 38, wherein R₂ is an unsubstituted phenyl group.

40. The compound of claim 39, wherein n is 5.

41. The compound of claim 29, wherein R₂ is a substituted or unsubstitued pyridyl group.

42. The compound of claim 41, wherein R₂ is an unsubstituted pyridyl group.

43. The compound of claim 42, wherein R₂ is a β

-pyridyl group.

44. The compound of claim 43, wherein n is 5.