Hydroxamic acid compounds and methods of use thereof

• US 20070155785A1
• Filed: 02/22/2007
• Published: 07/05/2007
• Est. Priority Date: 04/01/2003
• Status: Active Grant

• Current Assignee: Trustees Of Columbia University In The City Of New York (Columbia University), Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Original Assignee: Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Inventors: Miller, Thomas, Belvedere, Sandro, Marks, Paul, Breslow, Ronald, Rifkind, Richard, Richon, Victoria
• Granted Patent: US 7,799,803 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

1-27. -27. (canceled)

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 unsubstituted 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.

57. A pharmaceutical composition comprising the compound of claim 28 and a pharmaceutically acceptable carrier.

59. A method of treating cancer in a subject in need of treatment comprising administering to said subject a therapeutically effective amount of the compound of claim 28 wherein the effective amount is sufficient to inhibit the activity of histone deacetylase.

45-55. -55. (canceled)

56. A compound represented by the following structural formula selected from the group consisting of:

58. A pharmaceutical composition comprising the compound of claim 56 and a pharmaceutically acceptable carrier.