Cannabinoid receptor antagonists/inverse agonists useful for treating metabolic disorders, including obesity and diabetes

• US 7,655,685 B2
• Filed: 10/31/2008
• Issued: 02/02/2010
• Est. Priority Date: 11/02/2007
• Status: Active Grant

• Current Assignee: Jenrin Discovery Inc.
• Original Assignee: Jenrin Discovery Inc.
• Inventors: Chorvat, Robert J., McElroy, John F.
• Primary Examiner(s): Saeed; Kamal A
• Assistant Examiner(s): Shterengarts; Samantha L
• Application Number:
  US12/262,765
• Publication Number:
  US 20090118345A1
• Time in Patent Office: 459 Days
• Field of Search: 514/403, 548/379.1, 548/379.4, 548/379.7
• US Class Current: 514/403
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 15/02 for disorders of the vagina
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• 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 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 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: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 231/06 having one double bond between ring members or between a ring member and a non-ring member

Abstract

The present invention provides novel pyrazoles that are useful as cannabinoid receptor antagonists and pharmaceutical compositions thereof and methods of using the same for treating obesity, diabetes, hepatic disorders, and/or cardiometabolic disorders.

Claims

1. A compound of Formula I or a stereoisomer or pharmaceutically acceptable salt thereof:

2. A compound of claim 1, wherein:

M is SO₂.

3. A compound of claim 1, wherein the compound is of formula Ia or a stereoisomer or pharmaceutically acceptable salt thereof:

4. A compound of claim 1, wherein the compound is of formula Ib or a stereoisomer or pharmaceutically acceptable salt thereof:

5. A compound of claim 1, wherein the compound is of formula Ic or a stereoisomer or pharmaceutically acceptable salt thereof:

6. A compound of claim 1, wherein the compound is a compound of formula Ia or a stereoisomer or pharmaceutically acceptable salt thereof,

7. A compound of claim 6, wherein:

Q is selected from;

(CH₂)_nCHA(CH₂)_mC(O)NR₂, (CH₂)_mCAA″

(CH₂)_mC(O)NR₂, (CH₂)_mCHA(CH₂)_mSO₂NR₂, (CH₂)_mCHA(CH₂)_mCONHCHA(CH₂)_mCONR^a₂, (CH₂)_mCAA″

(CH₂)_mCONHCHA(CH₂)_mCONR^a₂, (CH₂)_mCHA(CH₂)_mCONHCHA(CH₂)_mCONHCHA(CH₂)_mCONR^a₂, C₃-C₆-cyclic amino-(CH₂)_mCO₂R, C₃-C₆-cyclic amino-(CH₂)_mCONR^a₂, and C₃-C₆-cycloalkylene-(CH₂)_mCONR^a₂;

provided that when Q is (CH₂)_mCAA″

(CH₂)_mC(O)NR₂ then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b);

alternatively, Q is CHA(CH₂)_mC(O)NR₂ and A is OH or (CH₂)_nCO₂R^b or R is (CH₂)_m(CHR^b)_n(CH₂)_mOH or CH(CH₂OH)₂;

M is SO₂;

R is independently selected from H and C_1-4 alkyl;

R^b is independently selected from H and C_1-4 alkyl;

m is independently selected from 0, 1, and 2; and

,

n is independently selected from 1 and 2.

8. A compound of claim 1, wherein the compound is a compound of formula Ib or a stereoisomer or pharmaceutically acceptable salt thereof,

9. A compound of claim 8, wherein:

Q is selected from;

(CH₂)_nCHA(CH₂)_mC(O)NR₂, (CH₂)_mCAA″

(CH₂)_mC(O)NR₂, (CH₂)_mCHA(CH₂)_mSO₂NR₂, (CH₂)_mCHA(CH₂)_mCONHCHA(CH₂)_mCONR^a₂, (CH₂)_mCAA″

(CH₂)_mCONHCHA(CH₂)_mCONR^a₂, (CH₂)_mCHA(CH₂)_mCONHCHA(CH₂)_mCONHCHA(CH₂)_mCONR^a₂, C₃-C₆-cyclic amino-(CH₂)_mCO₂R, C₃-C₆-cyclic amino-(CH₂)_mCONR^a₂, and C₃-C₆-cycloalkylene-(CH₂)_mCONR^a₂;

provided that when Q is (CH₂)_mCAA″

(CH₂)_mC(O)NR₂ then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b);

alternatively, Q is CHA(CH₂)_mC(O)NR₂ and A is OH or (CH₂)_nCO₂R^b or R is (CH₂)_m(CHR^b)_n(CH₂)_mOH or CH(CH₂OH)₂;

M is SO₂;

R is independently selected from H and C_1-4 alkyl;

R^b is independently selected from H and C_1-4 alkyl;

m is independently selected from 0, 1, and 2; and

,

n is independently selected from 1 and 2.

10. A compound of claim 1, wherein the compound is selected from Table B or a stereoisomer or a pharmaceutically acceptable salt thereof:

12. A pharmaceutical composition, comprising:

a compound according to claim 1 and a pharmaceutically acceptable carrier.

31. A pharmaceutical composition, comprising:

a compound according to claim 2 and a pharmaceutically acceptable carrier.

32. A pharmaceutical composition, comprising:

a compound according to claim 3 and a pharmaceutically acceptable carrier.

33. A pharmaceutical composition, comprising:

a compound according to claim 4 and a pharmaceutically acceptable carrier.

34. A pharmaceutical composition, comprising:

a compound according to claim 5 and a pharmaceutically acceptable carrier.

35. A pharmaceutical composition, comprising:

a compound according to claim 6 and a pharmaceutically acceptable carrier.

36. A pharmaceutical composition, comprising:

a compound according to claim 7 and a pharmaceutically acceptable carrier.

37. A pharmaceutical composition, comprising:

a compound according to claim 8 and a pharmaceutically acceptable carrier.

38. A pharmaceutical composition, comprising:

a compound according to claim 9 and a pharmaceutically acceptable carrier.

39. A pharmaceutical composition, comprising:

a compound according to claim 10 and a pharmaceutically acceptable carrier.

11. A compound selected from the compounds of Table A and C or a stereoisomer or a pharmaceutically acceptable salt thereof:

40. A pharmaceutical composition, comprising:

a compound according to claim 11 and a pharmaceutically acceptable carrier.

13. A compound of the formula

41. A pharmaceutical composition, comprising:

a compound according to claim 13 and a pharmaceutically acceptable carrier.

14. A compound of the formula

42. A pharmaceutical composition, comprising:

a compound according to claim 14 and a pharmaceutically acceptable carrier.

15. A compound of the formula

43. A pharmaceutical composition, comprising:

a compound according to claim 15 and a pharmaceutically acceptable carrier.

16. A compound of the formula

44. A pharmaceutical composition, comprising:

a compound according to claim 16 and a pharmaceutically acceptable carrier.

17. A compound of the formula

45. A pharmaceutical composition, comprising:

a compound according to claim 17 and a pharmaceutically acceptable carrier.

18. A compound of the formula

46. A pharmaceutical composition, comprising:

a compound according to claim 18 and a pharmaceutically acceptable carrier.

19. A compound of the formula

47. A pharmaceutical composition, comprising:

a compound according to claim 19 and a pharmaceutically acceptable carrier.

20. A compound of the formula

48. A pharmaceutical composition, comprising:

a compound according to claim 20 and a pharmaceutically acceptable carrier.

21. A compound of the formula

49. A pharmaceutical composition, comprising:

a compound according to claim 21 and a pharmaceutically acceptable carrier.

22. A compound of the formula

50. A pharmaceutical composition, comprising:

a compound according to claim 22 and a pharmaceutically acceptable carrier.

23. A compound of the formula

51. A pharmaceutical composition, comprising:

a compound according to claim 23 and a pharmaceutically acceptable carrier.

24. A compound of the formula

52. A pharmaceutical composition, comprising:

a compound according to claim 24 and a pharmaceutically acceptable carrier.

25. A compound of the formula

53. A pharmaceutical composition, comprising:

a compound according to claim 25 and a pharmaceutically acceptable carrier.

26. A compound of the formula

54. A pharmaceutical composition, comprising:

a compound according to claim 26 and a pharmaceutically acceptable carrier.

27. A compound of the formula

55. A pharmaceutical composition, comprising:

a compound according to claim 27 and a pharmaceutically acceptable carrier.

28. A compound of the formula

56. A pharmaceutical composition, comprising:

a compound according to claim 28 and a pharmaceutically acceptable carrier.

29. A compound of the formula

57. A pharmaceutical composition, comprising:

a compound according to claim 29 and a pharmaceutically acceptable carrier.

30. A compound of the formula

58. A pharmaceutical composition, comprising:

a compound according to claim 30 and a pharmaceutically acceptable carrier.