Sirtuin modulating compounds

• US 7,893,086 B2
• Filed: 06/20/2008
• Issued: 02/22/2011
• Est. Priority Date: 06/20/2007
• Status: Expired due to Fees

• Current Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Original Assignee: Sirtris Pharmaceuticals, Inc. (GlaxoSmithKline PLC)
• Inventors: Perni, Robert B., Disch, Jeremy S., Ng, Pui Yee, Vu, Chi B., Oalmann, Christopher, Bemis, Jean
• Primary Examiner(s): Hui; San-ming
• Assistant Examiner(s): ZAREK, PAUL E
• Application Number:
  US12/214,805
• Publication Number:
  US 20090105246A1
• Time in Patent Office: 977 Days
• Field of Search: 514/301, 514/357, 514/439, 514/444, 546/114, 546/270.1
• US Class Current: 514/301
• 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 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: 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 (II):

2. The compound of claim 1, wherein:

X¹ to X⁴ is —

CR*—

; and

R² is selected from phenyl, fluorophenyl, difluorophenyl, chlorophenyl, difluorophenylmethylthiazolyl, pyrimidinyl, pyridyl and pyrazolyl.

3. The compound of claim 2, wherein R² is selected from phenyl, fluorophenyl, difluorophenyl, chlorophenyl, 2-methylthiazol-4-yl, pyridyl and pyrazol-1-yl.

4. The compound of claim 3, wherein R² is phenyl or pyridyl.

5. The compound of claim 1, wherein one of X¹ to X⁴ are —

N—

.

6. The compound of claim 1, wherein two of X¹ to X⁴ are —

N—

.

7. The compound of claim 5, wherein X¹ is N.

8. The compound of claim 6, wherein X¹ and X² are —

N—

.

9. The compound of claim 6, wherein X¹ and X⁴ are —

N—

.

10. The compound of claim 1, wherein:

R¹ is —

CH₂—

R³; and

R³ is a nitrogen-containing heterocycle optionally substituted with one or more substituents selected from C₁-C₄ alkyl, amino, halogen, methoxy and methoxy-C₁-C₄ alkyl.

11. The compound of claim 10, wherein R² is phenyl, pyridyl or 3-fluorophenyl.

12. The compound of claim 11, wherein X² and X³ are —

CH— and

X¹ and X⁴ are independently selected from —

CR*—

or —

N—

.

13. The compound of claim 10, wherein:

R¹ is —

CH₂—

R³; and

R³ is selected from piperazin-1-yl, 4-(methoxyethy-piperazin-1-yl, 3,5-dimethylpiperazin-1-yl, morpholin-4-yl, piperidin-1-yl, 4-aminopiperidin-1-yl, pyrrolidin-1-yl, 3-fluoropyrrolidin-1-yl, —

NH—

(pyrrolidin-3-yl), and 1,4-diaza-bicyclo[2.2.1]heptan-1-yl.

14. The compound of claim 13, wherein R³ is selected from 4-(methoxyethy)-piperazin-1-yl, morpholin-4-yl, piperidin-1-yl and 4-aminopiperidin-1-yl.

15. The compound of claim 14, wherein R² is phenyl, 3-fluorophenyl or pyridyl.

16. The compound of claim 15, wherein X² and X³ are —

CH— and

X¹ and X⁴ are independently selected from —

CR*—

or —

N—

.

17. The compound of claim 1, wherein R* is H.

18. The compound of claim 1, represented by formula (IV):

19. A pyrogen-free composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof and a carrier.

22. A pharmaceutical composition comprising a compound of any of one claims 1, 20 or 21 and a pharmaceutically acceptable carrier.

23. The pharmaceutical composition of claim 22, further comprising an additional active agent.

20. A compound represented by the structural formula:

21. A compound represented by the structural formula: