Heterocyclic modulators of nuclear receptors

• US 7,115,640 B2
• Filed: 11/18/2003
• Issued: 10/03/2006
• Est. Priority Date: 12/21/2001
• Status: Expired due to Term

• Current Assignee: Akarna Therapeutics, Ltd. (Abbvie Incorporated)
• Original Assignee: X-Ceptor Therapeutics, Inc. (Exelixis Incorporated)
• Inventors: Kahl, Jeffrey D, Martin, Richard, Wang, Tie-Lin, Flatt, Brenton T
• Primary Examiner(s): Lambkin, Deborah C.
• Application Number:
  US10/717,049
• Publication Number:
  US 20040180942A1
• Time in Patent Office: 1,050 Days
• Field of Search: 514/367, 514/369, 514/370, 548/180, 548/190
• US Class Current: 514/367
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• 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 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 277/20 having two or three double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 277/64 with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Compounds, compositions and methods for modulating the activity of nuclear receptors are provided. In particular, heterocyclic compounds are provided for modulating the activity of farnesoid X receptor (FXR), liver X receptor (LXR) and/or orphan nuclear receptors. In certain embodiments, the compounds are thiazolidinone derivatives.

Claims

1. A pharmaceutical composition, comprising:

(a) a compound of formulae I;

2. The composition of claim 1, wherein the cholesterol biosynthesis inhibitor is an HMG CoA reductase inhibitor.

3. The composition of claim 2, wherein the HMG CoA reductase inhibitor is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.

4. The composition of claim 3, wherein the HMG CoA reductase inhibitor is lovastatin or simvastatin.

5. The composition of claim 1, wherein the bile acid sequestrant is an anion exchange resin or a quaternary amine.

6. The composition of claim 1, wherein the quaternary amine is cholestyramine or colestipol.

33. A method of treating or ameliorating a disease or disorder selected from hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris, acneiform skin conditions, diabetes, Parkinson'"'"'s disease, cancer, Alzheimer'"'"'s disease, inflammation, immunological disorders, lipid disorders, obesity, conditions characterized by a perturbed epidermal barrier function, hyperlipidernia, cholestasis, peripheral occlusive disease, ischemic stroke, conditions of disturbed differentiation or excess proliferation of the epidermis or mucous membrane, and cardiovascular disorders, comprising administering a pharmaceutical composition of claim 1.

7. A pharmaceutical composition, comprising:

(a) a compound of formulae I;

8. The composition of claim 7, wherein the antihypercholesterolemic agent is a cholesterol biosynthesis inhibitor.

9. The composition of claim 8, wherein the cholesterol biosynthesis inhibitor is an hydroxymethylglutaryl CoA reductase inhibitor.

10. The composition of claim 9, wherein the hydroxymethylglutaryl CoA reductase inhibitor is lovastatin, simvastatin, pravastatin, fluvastatin, or atorvastatin.

11. The composition of claim 7, wherein the acyl-coenzyme A cholesterol acyltransferase inhibitor is melinamide.

12. The composition of claim 7, wherein the cholesterol absorption inhibitor is β

-sitosterol.

13. The composition of claim 7, wherein the bile acid sequestrant anion exchange resin is cholestyramine, colestipol or a dialkylaminoalkyl derivative of a cross-linked dextran.

14. The composition of claim 7, wherein the fibrate is clofibrate, bezafibrate, fenofibrate, or gemfibrizol.

15. The composition of claim 7, wherein the anti-oxidant vitamin is vitamin C, vitamin E or beta carotene.

16. The composition of claim 7, wherein the platelet aggregation inhibitor is a fibrinogen receptor antagonist.

17. The composition of claim 16, wherein the fibrinogen receptor antagonist is a glycoprotein IIb/IIIa fibrinogen receptor antagonist.

39. A method of treating or ameliorating atherosclerosis, comprising administering a pharmaceutical composition of claim 7.

18. A pharmaceutical composition, comprising:

(a) a compound of formulae I;

19. The composition of claim 18, wherein the sulfonylurea is chlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glynase, glimepiride, or glipizide.

20. The composition of claim 18, wherein the biguanide is metformin.

21. The composition of claim 18, wherein the thiazolidinedione is ciglitazone, pioglitazone, troglitazone, or rosiglitazone.

22. The composition of claim 18, wherein the insulin sensitizer is a selective or non-selective activator of PPARα

PPARβ

or PPAR{tilde over (γ

)}.

23. The composition of claim 18, wherein the α

-glucosidase inhibitor is acarbose, miglitol, or voglibose.

24. The composition of claim 18, wherein the insulin secretogogue is repaglinide, gliquidone, or nateglinide.

35. A method for decreasing hyperglycemia and/or insulin resistance, comprising administering the pharmaceutical composition of claim 18.

37. A method for treatment or amelioration of type II diabetes, comprising administering a pharmaceutical composition of claim 18.

25. A pharmaceutical composition, comprising:

(a) a compound of formulae I;

26. The composition of claim 25, wherein the gastrointestinal lipase inhibitor is orlistat.

41. A method of treating or ameliorating obesity or complications thereof, comprising administering a pharmaceutical composition of claim 25.

27. A pharmaceutical composition, comprising:

(a) a compound of formulae I;

28. The composition of claim 27, wherein the anti-infective agent is rifampin, rifadin, or rimactane.

43. A method of treating or ameliorating cholestasis, comprising administering a pharmaceutical composition of claim 27.

29. A method for decreasing hyperglycemia and/or insulin resistance, comprising administering a compound of formulae I:

30. A method for treatment or amelioration of type II diabetes, comprising administering a compound of formulae I:

31. A method of treating or ameliorating atherosclerosis, comprising administering a compound of formulae I:

32. A method of treating or ameliorating obesity, comprising administering a compound of formulae I:

34. A method of treatingr or ameliorating a disease or disorder selected from hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dystipidemia, atherosclerosis, gallstone disease, acne vulgaris, acneiform skin conditions, diabetes, Parkinson'"'"'s disease, cancer, Alzheimer'"'"'s disease, inflammation, immunological disorders, lipid disorders, obesity, conditions characterized by a perturbed epidermal barrier function, hyperlipidemia, cholestasis, peripheral occlusive disease, isehemic stroke, conditions of disturbed differentiation or excess proliferation of the epidermis or mucous membrane, and cardiovascular disorders, comprising:

(a) administering a compound of formulae I;

36. A method for decreasing hyperglycemia and/or insulin resistance, comprising:

(a) administering a compound of formulae I;

38. A method for treatment or amelioration of type II diabetes, comprising:

(a) administering a compound of formulae I;

40. A method of treating or ameliorating atherosclerosis, comprising:

(a) administering a compound of formulae I;

42. A method of treating or ameliorating obesity or complications thereof, comprising:

(a) administering a compound of formulae I;

44. A method of treating or ameliorating cholestasis, comprising:

(a) administering a compound of formulae I;

45. A method of treating or ameliorating a disease or disorder selected from hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris, acneiform skin conditions, diabetes, Parkinson'"'"'s disease, cancer, Alzheimer'"'"'s disease, inflammation, immunological disorders, lipid disorders, obesity, conditions characterized by a perturbed epidermal barrier function, hyperlipidemia, cholestasis, peripheral occlusive disease, ischemic stroke, conditions of disturbed differentiation or excess proliferation of the epidermis or mucous membrane, cardiovascular disorders, and type II diabetes, comprising administering a compound of formulae III:

46. The method of claim 45, wherein X² is S and X³ is O.

47. The method of claim 46, wherein X¹ is S.

48. The method of claim 47, wherein R¹ is substituted or unsubstituted alkyl.

49. The method of claim 48, wherein R² is substituted or unsubstituted alkyl, or substituted or unsubstituted aralkyl.

50. The method of claim 49, wherein R³ is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

51. The method of claim 46, wherein X¹ is CR⁸═

CR⁹.

52. The method of claim 51, wherein R¹ is substituted or unsubstituted alkyl.

53. The method of claim 52, wherein R² is substituted or unsubstituted alkyl, or substituted or unsubstituted aralkyl.

54. The method of claim 53, wherein R³ is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

55. A method of treating or ameliorating a disease or disorder selected from hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris, aeneiform skin conditions, diabetes, Parkinson'"'"'s disease, cancer, Alzheimer'"'"'s disease, inflammation, immunological disorders, lipid disorders, obesity, conditions characterized by a perturbed epidermal barrier function, hyperlipidemia, cholestasis, peripheral occlusive disease, ischemic stroke, conditions of disturbed differentiation or excess proliferation of the epidermis or mucous membrane, cardiovascular disorders, and type II diabetes, comprising administering a compound of formulae II:

56. The method of claim 55, wherein R¹ is substituted or unsubstituted alkyl.

57. The method of claim 56, wherein R² is substituted or unsubstituted alkyl, or substituted or unsubstituted aralkyl.

58. The method of claim 57, wherein R³ is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

59. The method of claim 56, wherein the compound has formulae VI:

60. The method of claim 55, wherein the compound has formulae VII:

61. The method of claim 55, wherein the compound has formulae VIII:

62. The method of claim 55, wherein the compound has formulae IX: