Sirtuin modulating compounds

• US 7,855,289 B2
• Filed: 08/04/2006
• Issued: 12/21/2010
• Est. Priority Date: 08/04/2005
• Status: Expired due to Fees

• Current Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Original Assignee: Sirtris Pharmaceuticals, Inc. (GlaxoSmithKline PLC)
• Inventors: Disch, Jeremy S., Ng, Pui Yee, Vu, Chi B., Bemis, Jean, Xie, Roger, Milne, Jill, Armistead, David, Nunes, Joseph J., Salzmann, Thomas
• Primary Examiner(s): HAVLIN, ROBERT H
• Application Number:
  US11/499,876
• Publication Number:
  US 20070037809A1
• Time in Patent Office: 1,600 Days
• Field of Search: 544/235, 514/249
• US Class Current: 544/235
• 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 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:

6. The compound according to claim 1, wherein R¹⁹ is selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted thienyl or optionally substituted furyl.

7. The compound according to claim 1, wherein:

R¹⁹ is

8. The compound according to claim 7, wherein R³¹ is optionally substituted with 1 to 3 substituents independently selected from —

OCH₃, —

CH₃, —

N(CH₃)₂, phenyl, phenoxy, 3,4-dioxymethylene, fluoro, or another solubilizing group.

9. The compound according to claim 7, wherein R³¹ is selected from unsubstituted quinolinyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, 3,5-dimethylphenyl, 3,5-difluorophenyl, 3-trifluoromethoxyphenyl, unsubstituted quinoxalinyl, unsubstituted benzopyrimidinyl,

10. The compound according to claim 1, wherein R¹⁹ is selected from

11. The compound according to claim 10, wherein R³¹ is selected from phenyl, naphthyl, pyrazolyl, furyl, thienyl, pyridyl, isoxazolyl, benzopyrazolyl, benzofuranyl, benzothienyl, quinolinyl, benzoisoxazolyl, or

12. The compound according to claim 11, wherein R³¹ is optionally substituted with up to three substituents independently selected from —

OCH₃, —

CH₃, —

N(CH₃)₂, —

O-phenyl, or another solubilizing group.

13. The compound according to claim 11, wherein R³¹ is selected from unsubstituted phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3 dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-bis(trifluoromethyl)phenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2-methoxy-4-methylphenyl, 2-phenoxyphenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, unsubstituted 2-furanyl, unsubstituted 2-thienyl,

18. The compound according to claim 1, wherein R²¹ is —

NH—

C(O)—

.

23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of any of claims 1, and 6-13, and 18.

2. A compound of the formula:

14. The compound according to claim 2, wherein:

R₁′

is selected from H or optionally substituted C₁-C₃ straight or branched alkyl;

R²¹ is selected from —

NR₁′

—

C(O)—

, —

NR₁′

—

S(O)₂—

, —

NR₁′

—

C(O)—

NR₁′

—

, —

NR₁′

—

C(S)—

NR₁′

—

, —

NR₁′

—

C(S)—

NR₁′

—

CR₁′

R₁′

—

, —

NR₁′

—

C(O)—

CR₁′

R₁′

—

NR₁′

—

, —

NR₁′

—

C(═

NR₁′

)—

NR₁′

—

, —

C(O)—

NR₁′

—

, —

C(O)—

NR₁′

—

S(O)₂—

, —

NR₁′

—

, —

CR₁′

R₁′

—

, —

NR₁′

—

C(O)—

CR₁′

═

CR₁′

—

, —

NR₁′

—

S(O)₂—

NR₁′

—

, —

NR₁′

—

C(O)—

NR₁′

—

S(O)₂—

, —

NR₁′

—

CR₁′

R₁′

—

C(O)—

NR₁′

—

, —

CR₁′

R₁′

—

C(O)—

NR₁′

—

, —

NR₁′

—

C(O)—

CR₁′

—

CR₁′

—

CR₁′

R₁′

—

, —

NR₁′

—

C(═

N—

CN)—

NR₁′

—

, —

NR₁′

—

C(O)—

CR₁′

R₁′

—

O—

, —

NR₁′

—

C(O)—

CR₁′

R₁′

—

CR₁′

R₁′

—

O—

, —

NR₁′

—

S(O)₂—

CR₁′

R₁′

—

, —

NR₁′

—

S(O)₂—

CR₁′

R₁′

—

CR₁′

R₁′

—

, or —

NR₁′

—

C(O)—

CR₁′

R₁′

—

; and

R³¹ is selected from a monocyclic or bicyclic aryl or a monocyclic or bicyclic heteroaryl, and comprises a solubilizing group substituent.

15. The compound according to claim 2, wherein R³¹ is selected from phenyl, naphthyl, pyrazolyl, furyl, thienyl, pyridyl, isoxazolyl, benzopyrazolyl, benzofuranyl, benzothienyl, quinolinyl, benzoisoxazolyl, or

16. The compound according to claim 2, wherein:

R²¹ is selected from —

NH—

C(O)—

, NH—

C(O)—

CH₂—

CH(CH₃)—

O, —

NH—

C(O)—

NH—

, —

NH—

C(S)—

NH—

, —

NH—

C(S)—

NH—

CH₂—

, or —

NH—

S(O)₂—

; and

R³¹ is selected from an optionally substituted phenyl, an optionally substituted naphthyl, or an optionally substituted heteroaryl.

17. The compound according to claim 16, wherein R³¹ is selected from unsubstituted phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3 dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-bis(trifluoromethyl)phenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2-methoxy-4-methylphenyl, 2-phenoxyphenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, unsubstituted 2-furanyl, unsubstituted 2-thienyl,

19. The compound according to claim 2, wherein R²¹ is —

NH—

C(O)—

.

3. A composition comprising a compound of the formula:

20. The composition according to claim 3, wherein R²¹ is —

NH—

C(O)—

.

4. A pharmaceutical composition comprising:

a. a compound of the formula;

21. The pharmaceutical composition according to claim 4, wherein R²¹ is —

NH—

C(O)—

.

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

22. The packaged pharmaceutical according to claim 5, wherein R²¹ is —

NH—

C(O)—

.