Sirtuin modulating compounds

• US 7,345,178 B2
• Filed: 08/04/2006
• Issued: 03/18/2008
• Est. Priority Date: 08/04/2005
• Status: Expired due to Fees

• Current Assignee: GlaxoSmithKline LLC (GSK plc)
• Original Assignee: Sirtris Pharmaceuticals, Inc. (GSK plc)
• Inventors: Disch, Jeremy S., Ng, Pui Yee, Vu, Chi B., Bemis, Jean, Xie, Roger, Milne, Jill, Nunes, Joseph J.
• Primary Examiner(s): Saeed; Kamal A.
• Assistant Examiner(s): HAVLIN, ROBERT H
• Application Number:
  US11/499,919
• Publication Number:
  US 20070043050A1
• Time in Patent Office: 592 Days
• Field of Search: 548/154
• US Class Current: 548/154
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• 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 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• 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 3/02 : Nutrients, e.g. vitamins, minerals
• 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 35/02 : specific for leukemia
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 39/00 : General protective or antinoxious agents
• CPC Class Codes: A61P 41/00 : Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• 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 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 7/08 : Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock artificial tears A61P27/04
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 : Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• 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 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• 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 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:

9. The compound of claim 1, having the formula:

10. The compound according to claim 1, wherein:

11. The compound according to claim 1, wherein:

R³¹ is selected from phenyl, pyrazolyl, furyl, pyridyl, pyrimidinyl, thienyl, naphthyl, benzopyrazolyl, benzofuryl, quinolinyl, quinoxalinyl, or benzothienyl and wherein R³¹ is optionally substituted.

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

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

26. A packaged pharmaceutical comprising a compound of claim 1.

2. A compound of the formula:

12. The compound according to claim 2, wherein:

13. The compound according to claim 2, wherein:

R³¹ is selected from phenyl, pyrazolyl, furyl, pyridyl, pyrimidinyl, thienyl, naphthyl, benzopyrazolyl, benzofuranyl, quinolinyl, quinoxalinyl, or benzothienyl and wherein R³¹ is optionally substituted.

17. A composition comprising a compound of claim 2, wherein the composition is pyrogen-free.

22. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of claim 2.

27. A packaged pharmaceutical comprising a compound of claim 2.

3. A compound of the formula:

14. The compound according to claim 3, wherein:

R³² is selected from pyrrolyl, pyrazolyl, pyrazinyl, furyl, pyridyl, pyrimidinyl, or thienyl, and R³² is optionally substituted and is optionally benzofused.

15. The compound according to claim 3, wherein

R³² is selected from benzofuryl, methylfuryl, benzothienyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, wherein said methyfuryl, pyridyl, pyrazinyl, pyrimidinyl or pyrazolyl is optionally benzofused and wherein R³² is optionally substituted or further substituted.

18. A composition comprising a compound of claim 3, wherein the composition is pyrogen-free.

23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of claim 3.

28. A packaged pharmaceutical comprising a compound of claim 3.

4. A compound of the formula:

19. A composition comprising a compound of claim 4, wherein the composition is pyrogen-free.

24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of claim 4.

29. A packaged pharmaceutical comprising a compound of claim 4.

5. A compound of the formula:

20. A composition comprising a compound of claim 5, wherein the composition is pyrogen-free.

25. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of claim 5.

30. A packaged pharmaceutical comprising a compound of claim 5.

6. A composition comprising a compound of the formula:

7. A pharmaceutical composition comprising:

a) a compound of the formula;

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