Sirtuin modulating compounds

• US 20070037827A1
• Filed: 08/04/2006
• Published: 02/15/2007
• Est. Priority Date: 08/04/2005
• Status: Active Grant

• Current Assignee: Sirtris Pharmaceuticals, Inc. (GlaxoSmithKline PLC)
• Original Assignee: Sirtris Pharmaceuticals, Inc. (GlaxoSmithKline PLC)
• Inventors: Bemis, Jean, Xie, Roger, Milne, Jill, Vu, Chi, Disch, Jeremy, Ng, Pui, Nunes, Joseph
• Granted Patent: US 8,093,401 B2
• Time in Patent Office: Days
• US Class Current: 514/253.40
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Provided herein are novel sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benfit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.

Claims

1. A compound of the formula:

2-7. -7. (canceled)

8. A compound of the formula:

9-14. -14. (canceled)

15. A compound of the formula:

16. (canceled)

17. A compound of the formula:

18-21. -21. (canceled)

22. A compound of the formula:

23. A composition comprising a compound of the formula:

24. (canceled)

25. A pharmaceutical composition comprising:

a) a compound of the formula;

or a pharmaceutically acceptable salt or prodrug thereof, wherein;

each of R²³ and R²⁴ is independently selected from H, —

CH₃ or a solubilizing group;

R²⁵ is selected from H or a solubilizing group; and

R¹⁹ is selected from;

wherein;

each Z₁₀, Z₁₁, Z₁₂ and Z₁₃ is independently selected from N, CR²⁰, or CR₁′

; and

each Z₁₄, Z₁₅ and Z₁₆ is independently selected from N, NR₁′

, S, O, CR²⁰, or CR₁′

, wherein;

zero to two of Z₁₀, Z₁₁, Z₁₂ or Z₁₃ are N;

at least one of Z₁₄, Z₁₅ and Z₁₆ is N, NR₁′

, O or S;

zero to one of Z₁₄, Z₁₅ and Z₁₆ is S or O;

zero to two of Z₁₄, Z₁₅ and Z₁₆ are N or NR₁′

;

zero to one R²⁰ is a solubilizing group; and

zero to one R₁′

is an optionally substituted C₁-C₃ straight or branched alkyl;

each R²⁰ is independently selected from H or a solubilizing group;

R²¹ is selected from —

NR₁′

—

C(O)—

, —

NR₁′

—

S(O)₂—

, —

NR₁′

—

C(O)—

NR₁′

—

, —

NR₁′

—

C(S)—

NR₁′

—

, —

NR₁′

—

C(S)—

NR₁′

—

CR₁′

R′

₁—

, —

NR₁′

—

C(O)—

CR₁′

R′

₁—

NR₁′

—

, —

NR₁′

—

C(═

NR₁′

)—

NR₁′

—

, —

C(O)—

NR₁′

—

, —

C(O)—

NR₁′

—

S(O)₂—

, —

NR₁′

—

, —

CR₁′

R′

₁—

, —

NR₁′

—

C(O)—

CR₁′

═

CR₁′

—

, —

NR₁′

—

S(O)₂—

NR₁′

—

, —

NR₁′

—

C(O)—

NR₁′

—

S(O)₂—

, —

NR₁′

—

CR₁′

R′

₁—

C(O)—

NR₁′

—

, —

CR₁′

R′

₁—

C(O)—

NR₁′

—

, —

NR₁′

—

C(O)—

CR₁′

═

CR₁′

—

CR₁′

R₁′

—

, —

NR₁′

—

C(═

N—

CN)—

NR₁′

—

, —

NR₁′

—

C(O)—

CR₁′

R′

₁—

O—

, —

NR₁′

—

C(O)—

CR₁′

R′

₁—

CR₁′

R′

₁—

O—

, —

NR₁′

—

S(O)₂—

CR₁′

R′

₁—

, —

NR₁′

—

S(O)₂—

CR₁′

R′

₁—

CR₁′

R′

₁—

, —

NR₁′

—

C(O)—

CR₁′

R′

₁—

CR₁′

R′

₁—

, —

NR₁′

—

C(S)—

NR₁′

—

CR₁′

R′

₁—

CR₁′

R′

₁—

, —

NR₁′

—

C(O)—

O—

or —

NR₁′

—

C(O)—

CR₁′

R₁′

—

; and

each R₁′

is independently selected from H or optionally substituted C₁-C₃ straight or branched alkyl; and

R³¹ is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl,

wherein when R¹⁹ is

R²¹ is —

NH—

C(O)— and

R²⁵ is —

H, R³¹ is not an optionally substituted phenyl group, and wherein said compound is not 2-chloro-N-[3-[3-(cyclohexylamino)imidazo[1,2-a]pyridin-2-yl]phenyl]-4-nitrobenzamide; and

b) a pharmaceutically acceptable carrier or diluent.

26. (canceled)

27. A packaged pharmaceutical comprising a compound of the formula:

28. (canceled)

29. A method for promoting survival of a eukaryotic cell, comprising contacting the cell with a compound of the formula:

30-34. -34. (canceled)

35. A method for treating or preventing a disease or disorder associated with cell death or aging in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula:

36. (canceled)

37. A method for treating or preventing insulin resistance, a metabolic syndrome, diabetes, or complications thereof, or for increasing insulin sensitivity in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula:

38. A method for reducing the weight of a subject, or preventing weight gain in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula:

39. (canceled)

40. A method for preventing the differentiation of a pre-adipocyte, comprising contacting the pre-adipocyte with a compound of the formula:

41. A method for prolonging the lifespan of a subject comprising administering to a subject a therapeutically effective amount of a a compound of the formula:

42. A method for treating or preventing a neurodegenerative disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula:

43. (canceled)

44. A method for treating or preventing a blood coagulation disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula:

45. (canceled)

46. A method for treating or preventing an ocular disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula:

47-51. -51. (canceled)

52. A method for treating or preventing chemotherapeutic induced neuropathy comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula:

53. (canceled)

54. A method for treating or preventing neuropathy associated with an ischemic event or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula:

55. (canceled)

56. A method for treating or preventing a polyglutamine disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula:

57-58. -58. (canceled)

59. A method for treating a disease or disorder in a subject that would benefit from increased mitochondrial activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula:

60-65. -65. (canceled)

66. A method for enhancing motor performance or muscle endurance, decreasing fatigue, or increasing recovery from fatigue, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula:

67-68. -68. (canceled)

69. A method for treating or preventing a condition wherein motor performance or muscle endurance is reduced, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula:

70. (canceled)

71. A method for treating or preventing muscle tissue damage associated with hypoxia or ischemia, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula:

72. A method for increasing muscle ATP levels in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of a compound of the formula:

73-128. -128. (canceled)