AMPK MODULATORS

• US 20100009992A1
• Filed: 02/04/2009
• Published: 01/14/2010
• Est. Priority Date: 02/04/2008
• Status: Active Grant

• Current Assignee: Mercury Therapeutics, Inc.
• Original Assignee: Mercury Therapeutics, Inc.
• Inventors: Liu, Hong, Birnberg, Neal C., Salgaonkar, Paresh D., Shang, Haibo, Rajur, Sharanappa B., Kim, Hwa-Ok, Weng, Qing Ping, Yin, Pan, Peet, Norton P.
• Granted Patent: US 8,273,744 B2
• Time in Patent Office: Days
• US Class Current: 514/249
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 209/12 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 209/14 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 209/18 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/42 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 215/54 attached in position 3
• CPC Class Codes: C07D 215/56 with oxygen atoms in position 4
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 498/04 Ortho-condensed systems

Abstract

The present invention relates to compounds and pharmaceutically acceptable salts, esters and prodrugs of Formula (I) or (II):

which are useful as AMPK modulators effective in treating diabetes, obesity and cancer in a subject.

Claims

1. A compound represented by formula I or II:

2. The compound of claim 1 having the formula:

3. The compound of claim 2 wherein R₃ is hydrogen, —

CN, —

CHNOH, —

CONH₂ or —

CHO and salts thereof.

4. The compound of claim 1 wherein R₁ is hydrogen or an electron withdrawing group and salts thereof.

5. The compound of claim 1 wherein Ar₂ is a 2-hydroxyphenyl or a 2,6-dihydroxyphenyl and salts thereof.

6. The compound of claim 1 wherein Ar₂ is a 2-hydroxyheteroaryl or a o,o-dihydroxyheteroraryl and salts thereof.

16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and salts thereof, in combination with a pharmaceutically suitable carrier.

17. A method of regulating AMPK in a subject, comprising administering to said subject in need thereof a therapeutically effective amount of a compound of claim 1 and salts thereof.

18. A method of treating diabetes mellitis in a subject, comprising administering to said subject in need thereof a therapeutically effective amount of a compound of claim 1 and salts thereof.

19. A method of treating obesity in a subject, comprising administering to said subject in need thereof a therapeutically effective amount of a compound of claim 1 and salts thereof.

20. A method of treating cancer in a subject, comprising administering to said subject in need thereof a therapeutically effective amount of a compound of claim 1 and salts thereof.

7. A compound represented by formula I or II:

8. The compound of claim 7 wherein Ar₂ is a 2-hydroxyphenyl or a 2,6-dihydroxyphenyl and salts thereof.

9. A compound represented by formula I or II:

10. A compound according to claim 9 represented by formula (III):

11. A compound according to claim 9 represented by formula (IV):

12. A compound according to claim 9 represented by formula (V):

13. A compound according to claim 9 represented by formula (VI):

14. A compound according to claim 9 selected from the compounds delineated in Table A and salts thereof:

15. A compound selected from 5-(2,6-Dihydroxybiphenyl)-1H-indole-3-carbonitrile, 5-(2,6-Dihydroxybiphenyl)-1H-indole-3-carboxamide, 5-(6-(2-Hydroxyphenyl)pyridin-3-yl)-1H-indole-3-carbaldehyde, and 5-(6-(2-Hydroxyphenyl)pyridazin-3-yl)-1H-indole-3-carbaldehyde and salts thereof.