N-Phenyl Benzamide Derivatives as Sirtuin Modulators

• US 20090163476A1
• Filed: 03/03/2006
• Published: 06/25/2009
• Est. Priority Date: 03/03/2005
• Status: Abandoned Application

• Current Assignee: Sirtris Pharmaceuticals, Inc. (GSK plc)
• Original Assignee: Sirtris Pharmaceuticals, Inc. (GSK plc)
• Inventors: Vu, Chi B., Bemis, Jean, Xie, Roger, Milne, Jill, Normington, Karl D., Nunes, Joseph J., Milburn, Michael
• Application Number:
  US11/885,577
• Publication Number:
  US 20090163476A1
• Time in Patent Office: Days
• US Class Current: 514/218
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 : for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 235/18 : with aryl radicals directly attached in position 2
• CPC Class Codes: C07D 241/42 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 263/57 : Aryl or substituted aryl radicals
• CPC Class Codes: C07D 265/22 : Oxygen atoms
• CPC Class Codes: C07D 277/66 : with aromatic rings or ring systems directly attached in position 2
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : 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 benefit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.

Claims

1. A compound represented by Structural Formula (III):

or a salt thereof, where;

Ring A is optionally substituted;

R₅ and R₆ are independently —

H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group;

R₇, R₉, R₁₀ and R₁₁ are independently selected from the group consisting of —

H, halogen, —

R₅, —

OR₅, —

CN, —

CO₂R₅, —

OCOR₅, —

OCO₂R₅, —

C(O)NR₅R₆, —

OC(O)NR₅R₆, —

C(O)R₅, —

COR₅, —

SR₅, —

OSO₃H, —

S(O)_nR₅, —

S(O)_nOR₅, —

S(O)_nNR₅R₆, —

NR₅R₆, —

NR₅C(O)OR₆, —

NR₅C(O)R₆ and —

NO₂;

R₈ is a polycyclic aryl group; and

n is 1 or 2.

14. The compound according to claim 1, wherein Ring A is optionally substituted with up to 3 substituents independently selected from (C₁-C₃ straight or branched alkyl), O—

(C₁-C₃ straight or branched alkyl), N(C₁-C₃ straight or branched alkyl)₂, halo, or a 5 to 6-membered heterocycle, wherein

when R₈ is unsubstituted

 

then Ring A is;

a. not simultaneously substituted at the 2- and 6-positions with O—

(C₁-C₃ straight or branched alkyl);

b. not simultaneously substituted at the 2-, 4- and 6-positions with O—

(C₁-C₃ straight or branched alkyl);

c. not simultaneously substituted at the 2-, 3-, and 4-positions with O—

(C₁-C₃ straight or branched alkyl);

d. not substituted at the 4-position with a 5 to 6-membered heterocycle; and

e. not singly substituted at the 4-position with O—

(C₁-C₃ straight or branched alkyl), and

when R₈ is

 

then Ring A is not singly substituted at the 3-position with O—

(C₁-C₃ straight or branched alkyl).

15. The compound according to claim 14, wherein Ring A is substituted with up to 3 substituents independently selected from chloro, methyl, O-methyl, N(CH₃)₂ or morpholino.

16. The compound according to claim 15, wherein R₈ is selected from

wherein up to 2 ring carbons not immediately adjacent to the indicated attachment point are independently substituted with O—

C₁-C₃ straight or branched alkyl, C₁-C₃ straight or branched alkyl or halo; and

each of R₇, R₉, and R₁₁ is —

H; and

R₁₀ is selected from —

H, —

CH₂OH, —

CO₂H, —

CO₂CH₃, —

CH₂-piperazinyl, CH₂N(CH₃)₂, —

C(O)—

NH—

(CH₂)₂—

N(CH₃)₂, or —

C(O)-piperazinyl.

19. A composition comprising a compound of claim 1 wherein the composition is pyrogen-free.

20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of claim 1.

21. A packaged pharmaceutical comprising a compound of claim 1 and instructions for using the compound to modulate a sirtuin.

22. A method for promoting survival of a eukaryotic cell comprising contacting the cell with at least one compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

28. 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 at least one compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

30. 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 at least one compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

31. 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 at least one compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

33. A method for preventing the differentiation of a pre-adipocyte, comprising contacting the pre-adipocyte with at least one compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

34. A method for prolonging the lifespan of a subject comprising administering to a subject a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

35. 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 at least one compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

37. 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 at least one compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

39. A method for treating or preventing an ocular disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

45. A method for treating or preventing chemotherapeutic induced neuropathy comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

47. 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 at least one compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof.

49. A method for treating or preventing a polyglutamine disease comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

52. 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 at least one compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

59. 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 at least one compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

62. 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 at least one compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

64. 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 at least one compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

65. 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 claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

72. A method for treating or preventing cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

74. A method for stimulating weight gain in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

75. A method for increasing the radiosensitivity or chemosensitivity of a cell comprising contacting the cell with at least one compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

94. A method for treating or preventing chemotherapeutic induced neuropathy comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

2-13. -13. (canceled)

17-18. -18. (canceled)

23-27. -27. (canceled)

29. (canceled)

32. (canceled)

36. (canceled)

38. (canceled)

40-44. -44. (canceled)

46. (canceled)

48. (canceled)

50-51. -51. (canceled)

53-58. -58. (canceled)

60-61. -61. (canceled)

63. (canceled)

66-71. -71. (canceled)

73. (canceled)

76-81. -81. (canceled)

82. A method for promoting survival of a eukaryotic cell comprising contacting the cell with at least one compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

Ring A is optionally substituted; and

Ring B is substituted with at least one carboxy or polycyclic aryl group.

85. The method of claim 82, wherein the compound is represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

Ring A is optionally substituted; and

Ring B is substituted with at least one polycyclic aryl group.

83-84. -84. (canceled)

86. 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 at least one compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

Ring A is optionally substituted; and

Ring B is substituted with at least one polycyclic aryl group.

87. 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 at least one compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

Ring A is optionally substituted; and

Ring B is substituted with at least one polycyclic aryl group.

88. 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 at least one compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

Ring A is optionally substituted; and

Ring B is substituted with at least one polycyclic aryl group.

89. A method for preventing the differentiation of a pre-adipocyte, comprising contacting the pre-adipocyte with at least one compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

Ring A is optionally substituted; and

Ring B is substituted with at least one polycyclic aryl group.

90. A method for prolonging the lifespan of a subject comprising administering to a subject a therapeutically effective amount of at least one compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

Ring A is optionally substituted; and

Ring B is substituted with at least one polycyclic aryl group.

91. 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 at least one compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

Ring A is optionally substituted; and

Ring B is substituted with at least one polycyclic aryl group.

92. 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 at least one compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

Ring A is optionally substituted; and

Ring B is substituted with at least one polycyclic aryl group.

93. A method for treating or preventing an ocular disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

Ring A is optionally substituted; and

Ring B is substituted with at least one polycyclic aryl group.

95. 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 at least one compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

Ring A is optionally substituted; and

Ring B is substituted with at least one polycyclic aryl group.

96. A method for treating or preventing a polyglutamine disease comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

Ring A is optionally substituted; and

Ring B is substituted with at least one polycyclic aryl group.

97. 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 at least one compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

Ring A is optionally substituted; and

Ring B is substituted with at least one polycyclic aryl group.

98. 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 at least one compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

Ring A is optionally substituted; and

Ring B is substituted with at least one polycyclic aryl group.

99. 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 at least one compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

Ring A is optionally substituted; and

Ring B is substituted with at least one polycyclic aryl group.

100. 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 at least one compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

Ring A is optionally substituted; and

Ring B is substituted with at least one polycyclic aryl group.

101. 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 represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

Ring A is optionally substituted; and

Ring B is substituted with at least one polycyclic aryl group.

102. A method for treating or preventing cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

Ring A is optionally substituted; and

Ring B is substituted with at least one polycyclic aryl group.

103. A method for stimulating weight gain in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

Ring A is optionally substituted; and

Ring B is substituted with at least one polycyclic aryl group.

104. A method for increasing the radiosensitivity or chemosensitivity of a cell comprising contacting the cell with at least one compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;

Ring A is optionally substituted; and

Ring B is substituted with at least one polycyclic aryl group.

105-106. -106. (canceled)