SIRTUIN MODULATING COMPOUNDS

• US 20110130387A1
• Filed: 11/29/2010
• Published: 06/02/2011
• Est. Priority Date: 08/04/2005
• Status: Active Grant

• Current Assignee: GlaxoSmithKline LLC (GSK plc)
• Original Assignee: Sirtris Pharmaceuticals, Inc. (GSK plc)
• Inventors: Xie, Roger, Milne, Jill, Armistead, David, Nunes, Joseph J., Salzmann, Thomas, Disch, Jeremy S., Ng, Pui Yee, Vu, Chi B., Bemis, Jean
• Granted Patent: US 8,178,536 B2
• Time in Patent Office: Days
• US Class Current: 514/218
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 27/02 Ophthalmic agents
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07C 233/81 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 235/56 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 237/42 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• CPC Class Codes: C07D 209/14 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 209/80 [b, c]- or [b, d]-condensed
• CPC Class Codes: C07D 213/40 Acylated substituent nitrogen atom
• CPC Class Codes: C07D 215/12 with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• 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 243/08 : not condensed with other rings
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 263/57 : Aryl or substituted aryl radicals
• CPC Class Codes: C07D 265/14 : condensed with one six-membered ring
• CPC Class Codes: C07D 271/107 : with two aryl or substituted aryl radicals attached in positions 2 and 5
• CPC Class Codes: C07D 277/26 : Radicals substituted by sulfur atoms
• CPC Class Codes: C07D 277/28 : Radicals substituted by nitrogen atoms
• CPC Class Codes: C07D 277/66 : with aromatic rings or ring systems directly attached in position 2
• CPC Class Codes: C07D 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 333/20 : by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 491/04 : 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 method for promoting survival of a eukaryotic cell, comprising contacting the cell with a compound of the formula:

2-6. -6. (canceled)

7. 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:

8. The method of claim 7, wherein the aging-related disease is stroke, a cardiovascular disease, arthritis, high blood pressure, or Alzheimer'"'"'s disease.

9. 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:

10. 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:

11. The method of claim 10, wherein said subject does not reduce calorie consumption, increase activity or a combination thereof to an extent sufficient to cause weight loss in the absence of a sirtuin activating compound.

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

13. 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:

14. 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:

15. (canceled)

16. 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:

17. (canceled)

18. 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:

19-23. -23. (canceled)

24. 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:

25. (canceled)

26. 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:

27. (canceled)

28. 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:

29-30. -30. (canceled)

31. 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:

32-37. -37. (canceled)

38. 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:

39-40. -40. (canceled)

41. 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:

42. (canceled)

43. 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:

44. 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:

45-50. -50. (canceled)