SUBSTITUTED TRIAZOLES AS MODULATORS OF PPAR AND METHODS OF THEIR PREPARATION

• US 20080108630A1
• Filed: 10/31/2007
• Published: 05/08/2008
• Est. Priority Date: 05/25/2004
• Status: Abandoned Application

• Current Assignee: Metabolix Incorporated
• Original Assignee: Metabolix Incorporated
• Inventors: Gregoire, Francine, Zhu, Yan, Rakhmanova, Vera, Cheng, Peng, Zhao, Zuchun, Ma, Jingyuan
• Application Number:
  US11/932,755
• Publication Number:
  US 20080108630A1
• Time in Patent Office: Days
• US Class Current: 514/254.07
• 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 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 249/06 with aryl radicals directly attached to ring atoms
• CPC Class Codes: C07D 409/10 linked by a carbon chain containing aromatic rings

Abstract

The present invention is directed to certain novel triazole compounds represented by Formula I and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof. The present invention is also directed to methods of making and using such compounds and pharmaceutical compositions containing such compounds to treat or control a number of diseases mediated by PPAR such as glucose metabolism, lipid metabolism and insulin secretion, specifically Type 2 diabetes, hyperinsulemia, hyperlipidemia, hyperuricemia, hypercholesteremia, atherosclerosis, one or more risk factors for cardiovascular disease, Syndrome X, hypertriglyceridemia, hyperglycemia, obesity, and eating disorders.

Claims

1. A compound having the formula:

2. A compound of claim 1, wherein Ar¹ is benzodioxole or phenyl optionally substituted with from one to three R⁷ substituents independently selected from the group consisting of halogen, halo(C₁-C₈)alkyl, heterocyclyl, heterocyclyl(C₁-C₄)alkyl, and —

OR².

3. A compound of claim 1, wherein Ar¹ is

4. A compound of claim 3, wherein Ar¹ is

5. A compound of claim 1, wherein R¹ is selected from the group consisting of (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, aryl and heterocyclyl(C₁-C₄)alkyl.

6. A compound of claim 5, wherein R¹ is selected from the group consisting of CH₃, CH(CH₃)₂, CF₃, CF₃CH₂, phenyl and

7. A compound of claim 6, wherein R¹⁰ is Cl, Oi-Pr or OCH₃.

8. A compound of claim 5, wherein R¹ is CH₃.

9. A compound of claim 1, wherein Y¹, Y², and Y³ is a member independently selected from the group consisting of (CR⁴R⁵)_p, C═

O, NR², O, and S(O)_r2;

R² is H;

each R⁴ and R⁵ is a member independently selected from the group consisting of H, (C₁-C₈)alkyl, halo(C 1-C₈)alkyl, or optionally, if both present on the same substituent, may be joined together to form a three- to eight-membered ring system or if present on adjacent carbon atoms are combined to form a double bond or triple bond between the atoms to which they are attached; and

r2 is 0.

10. A compound of claim 9, wherein Y¹ is (CR⁴R⁵)_p, Y² is CH₂ or C═

O and Y³ is NH, O, or S.

11. A compound of claim 9, wherein Y¹ is CH₂, Y² is (CH₂)₂ and Y³ is O or S.

12. A compound of claim 1, wherein at least one of m1, m2, or m3 is O.

13. A compound of claim 1, wherein L is a member selected from the group consisting of:

CH₂, (CH₂)₂, CH₂S, CH(CH₃)S, C(CH₃)₂S, (CH₂)₂S, CH(CH₃)CH₂S, —

C(CH₃)₂CH₂S, (CH₂)₃S, CH₂O, CH(CH₃)O, C(CH₃)₂O, (CH₂)₂O, CH(CH₃)CH₂O, —

C(CH₃)₂CH₂O, (CH₂)₃S and (C═

O)NH.

14. A compound of claim 1, wherein each R⁴ and R⁵ is independently H, CH₃, CF₃, or joined together to form a three- to six-membered ring system selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

15. A compound of claim 14, wherein R⁴ and R⁵ are H.

16. A compound of claim 1, wherein Z is CO₂R⁶.

17. A compound of claim 16, wherein R⁶ is H.

18. A compound of claim 1, wherein Ar² is selected from the group consisting of:

(i) pyridine, optionally substituted with from one to three R⁸ substituents;

(ii) pyrazine, optionally substituted with from one to two R⁸ substituents;

(iii) pyrimidine, optionally substituted with from one to two R⁸ substituents;

(iv) pyridazine, optionally substituted with from one to two R⁸ substituents; and

(v) triazine, optionally substituted with one R⁸ substituent

wherein each R⁸ substituent is a member independently selected from the group consisting of halogen, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl, aryl, aryl(C₁-C₄)alkyl, —

OR², —

X²OR², heterocyclyl, heterocyclyl(C₁-C₄)alkyl, —

COR², —

CO₂R², —

NR²R³, —

NO₂, X²NR²R³, —

CN and —

S(O)_r1R².

19. A compound of claim 18, wherein Ar² is selected from the group consisting of:

(i) pyridine, optionally substituted with from one to three R⁸ substituents;

(ii) pyrazine, optionally substituted with from one to two R⁸ substituents;

(iii) pyrimidine, optionally substituted with from one to two R⁸ substituents;

(iv) pyridazine, optionally substituted with from one to two R⁸ substituents; and

(v) triazine, optionally substituted with from one to two R⁸ substituents

wherein each R⁸ substituent is a member independently selected from the group consisting of halogen, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl, aryl, aryl(C₁-C₄)alkyl, —

OR², —

X²OR², heterocyclyl, heterocyclyl(C₁-C₄)alkyl, —

COR², —

CO₂R², —

NR²R³, —

NO₂, —

X²NR²R³, —

CN and —

S(O)_r1R².

20. A compound of claim 18, wherein Y¹, Y², and Y³ is a member independently selected from the group consisting of (CR⁴R⁵)_p, C═

O, NR², O, and S(O)_r2;

R² is H; and

each R⁴ and R⁵ are members independently selected from the group consisting of H, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, or optionally, if both present on the same substituent, may be joined together to form a three- to eight-membered ring system or if present on adjacent carbon atoms are combined to form a double bond or triple bond between the atoms to which they are attached.

21. A compound of claim 20, wherein Y¹ is (CR⁴R⁵)_p, Y² is CH₂ or C═

O and Y³ is NH, O, or S.

22. A compound of claim 20, wherein Y¹ is CH₂, Y² is (CH₂)₂ and Y³ is O or S.

23. A compound of claim 18, wherein at least one of m1, m2, or m3 is O.

24. A compound of claim 18, wherein L is a member selected from the group consisting of:

CH₂, (CH₂)₂, CH₂S, CH(CH₃)S, C(CH₃)₂S, (CH₂)₂S, CH(CH₃)CH₂S, —

C(CH₃)₂CH₂S, (CH₂)₃S, CH₂O, CH(CH₃)O, C(CH₃)₂O, (CH₂)₂O, CH(CH₃)CH₂O, —

C(CH₃)₂CH₂O, (CH₂)₃S and (C═

O)NH.

25. A compound of claim 18, wherein L is a member selected from the group consisting of:

CH₂, CH(CH₃), C(CH₃)₂, CH═

CH₂^E, CH═

CH₂^Z, CH═

CH, OCH₂, —

OCH(CH₃) and OC(CH₃)₂, wherein E represents the entgegen isomer and Z represents the zusammen isomer.

26. A compound of claim 18, wherein each R⁴ and R⁵ is independently H, CH₃, CF₃, or joined together to form a three- to six-membered ring system selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

27. A compound of claim 26, wherein R⁴ and R⁵ are H.

28. A compound of claim 18, wherein each R⁸ substituent is a member independently selected from the group consisting of halogen, (C₁-C₈)alkyl, heterocyclyl, heterocyclyl(C₁-C₄)alkyl, and halo(C₁-C₈)alkyl.

29. A compound of claim 18, wherein Ar² has the formula:

30. A compound of claim 18, wherein Ar² has the formula:

31. A compound of claim 1, wherein Ar² is benzene optionally substituted with from one to three R⁸ substituents each independently selected from the group consisting of halogen, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl, aryl, aryl(C₁-C₄)alkyl, —

OR², —

X²OR², heterocyclyl, heterocyclyl(C₁-C₄)alkyl, —

COR², —

CO₂R³, —

NR²R³, —

NO₂, —

X²NR²R³, —

CN and —

S(O)_r1R².

32. A compound of claim 31, wherein Ar² is benzene optionally substituted with from one to two R⁸ substituents each independently selected from the group consisting of halogen, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl, aryl, aryl(C₁-C₄)alkyl, —

OR², —

X²OR², heterocyclyl, heterocyclyl(C₁-C₄)alkyl, —

COR², —

CO₂R², —

NR²R³, —

NO₂, —

X²NR²R³, —

CN and —

S(O)_r1R².

33. A compound of claim 31, wherein Y¹, Y², and Y³ is a member independently selected from the group consisting of (CR⁴R⁵)_p, C═

O, NR², O, and S(O)_r2;

R² is H; and

each R⁴ and R⁵ are members independently selected from the group consisting of H, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, or optionally, if both present on the same substituent, may be joined together to form a three- to eight-membered ring system or if present on adjacent carbon atoms are combined to form a double bond or triple bond between the atoms to which they are attached.

34. A compound of claim 33, wherein Y¹ is (CR⁴R⁵)_p, Y² is CH₂ or C═

O and Y³ is NH, O, or S.

35. A compound of claim 33, wherein Y¹ is CH₂, Y² is (CH₂)₂ and Y³ is O or S.

36. A compound of claim 31, wherein at least one of m1, m2, or m3 is O.

37. A compound of claim 31, wherein L is a member selected from the group consisting of:

CH₂, (CH₂)₂, CH₂S, CH(CH₃)S, C(CH₃)₂S, (CH₂)₂S, CH(CH₃)CH₂S, —

C(CH₃)₂CH₂S, (CH₂)₃S, CH₂O, CH(CH₃)O, C(CH₃)₂O, (CH₂)₂O, CH(CH₃)CH₂O, —

C(CH₃)₂CH₂O, (CH₂)₃S and (C═

O)NH.

38. A compound of claim 31, wherein each R⁴ and R⁵ is independently H, CH₃, CF₃, or joined together to form a three- to six-membered ring system selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

39. A compound of claim 38, wherein R⁴ and R⁵ are H.

40. A compound of claim 31, wherein each R⁸ substituent is independently selected from the group consisting of H, halogen, (C₁-C₈)alkyl, and halo(C 1-C₈)alkyl.

41. A compound of claim 31, wherein Ar² has the formula:

42. A compound of claim 41, wherein the compound is

45. A composition comprising one or more pharmaceutically acceptable carriers, diluents, or excipients and a compound of claim 1.

46. A method of modulating a condition selected from the group consisting of:

insulin resistance, leptin levels and peroxisome proliferator activated receptor, comprising the step of contacting the receptor with at least one compound of claim 1.

47. A method of treating a condition selected from the group consisting of:

hyperinsulemia, hyperlipidemia, hyperuricemia, hypercholesteremia, atherosclerosis, one or more risk factors for cardiovascular disease Syndrome X, hypertriglyceridemia, hyperglycemia, obesity, eating disorders and Type 2 diabetes in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

48. A method of decreasing fibrinogen levels or LDLc in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

49. A method of shifting LDL particle size from small dense to normal dense LDL in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

50. A method of suppressing appetite in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.

43. A compound selected from the group consisting of:

2-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-propionic acid;

3-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenyl}-acrylic-acid;

3-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenyl}-propionic acid;

2,2-Dimethyl-3-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenyl}-propionic acid;

{2-Bromo-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenyl}-acetic acid;

-2-Methyl-2-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3] triazol-4-ylmethylsulfanyl]-phenyl}-propionic acid;

{2-Chloro-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenyl}-acetic acid;

(2-Methyl-4-{1-methyl-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethylsulfanyl}-phenoxy)-acetic acid;

(2-Methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethoxy}-phenoxy)-acetic acid;

(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethoxy}-phenoxy)-acetic acid;

(2-Methyl-4-{[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethyl]-amino}-phenoxy)-acetic acid;

1-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-cyclobutanecarboxylic acid;

1-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-cyclopentanecarboxylic acid;

1-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-cyclohexanecarboxylic acid;

(2-Methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethylsulfanyl}-phenoxy)-acetic acid;

(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethylsulfanyl}-phenoxy)-acetic acid;

(2-Methyl-4-{[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazole-4-carbonyl]-amino}-phenoxy)-acetic acid;

{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenylsulfanyl}-acetic acid;

{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-3-propyl-phenyl}-acetic acid;

{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-phenyl}-acetic acid;

{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-phenyl}-propynoic acid;

2-{4-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-propionic acid;

2-{4-[5-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-propionic acid;

2-{4-[5-[4-(4-Isopropoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-propionic acid;

2-{4-[2-(2-Fluoro-4-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid; and

2-{5-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid.

44. A compound selected from the group consisting of:

2-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-propionic acid;

2-Methyl-2-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-phenoxy}-propionic acid;

2-[4-(2-Biphenyl-4-yl-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid;

2-Methyl-2-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-propionic acid;

2-Methyl-2-(2-methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethoxy}-phenoxy)-propionic acid;

(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethyl}-phenoxy)-acetic acid;

(2-Methyl-4-{1-methyl-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethylsulfanyl}-phenoxy)-acetic acid;

(2-Methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethoxy}-phenoxy)-acetic acid;

2-{4-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-2-methyl-propionic acid;

2-{4-[2-(4-Chloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid;

2-{2-Chloro-4-[2-(4-chloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-phenoxy}-2-methyl-propionic acid;

2-{2-Chloro-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-phenoxy}-2-methyl-propionic acid;

2-Methyl-2-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-phenoxy}-propionic acid;

2-[4-(2-Biphenyl-4-yl-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid; and

[4-(2-Biphenyl-4-yl-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy)-2-methyl-phenoxy]-acetic acid;

(2-Methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethoxy}-phenoxy)-acetic acid;

(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethyl}-phenoxy)-acetic acid; and

2-Methyl-2-(2-methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethoxy}-phenoxy)-propionic acid.