Sirtuin modulating compounds

• US 20090105246A1
• Filed: 06/20/2008
• Published: 04/23/2009
• Est. Priority Date: 06/20/2007
• Status: Active Grant

• Current Assignee: GlaxoSmithKline LLC (GSK plc)
• Original Assignee: Sirtris Pharmaceuticals, Inc. (GSK plc)
• Inventors: Perni, Robert B., Disch, Jeremy S., Ng, Pui Yee, Vu, Chi B., Oalmann, Christopher, Bemis, Jean
• Granted Patent: US 7,893,086 B2
• Time in Patent Office: Days
• US Class Current: 514/234.200
• 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-(methoxyethyl-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-(methoxyethyl)-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):

21. A pyrogen-free composition comprising a compound of any one of claims 1, 19 or 20, or a pharmaceutically acceptable salt thereof and a carrier.

22. A pharmaceutical composition comprising a compound of any of one claims 1, 19 or 20 and a pharmaceutically acceptable carrier.

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

24. A method for treating a subject suffering from or susceptible to insulin resistance, a metabolic syndrome, diabetes, or complications thereof, or for increasing insulin sensitivity in a subject, comprising administering to the subject in need thereof a composition of claim 22.

25. The method of claim 24, wherein said compound increases at least one of the level or activity of a sirtuin protein.

26. The method of claim 25, wherein the compound increases deacetylase activity of the sirtuin protein.

27. The method of claim 25, wherein the sirtuin protein is a mammalian protein.

28. The method of claim 25, wherein the sirtuin protein is human SIRT1.

29. The method of claim 25, wherein the compound does not substantially have one or more of the following activities:

inhibition of PI3-kinase, inhibition of aldoreductase, inhibition of tyrosine kinase, transactivation of EGFR tyrosine kinase, coronary dilation, or spasmolytic activity, at concentrations of the compound that are effective for increasing the deacetylation activity of a SIRT1 and/or SIRT3 protein.

19. A compound represented by Structural Formula (V):

20. A compound represented by Structural Formula (VI):