SOLUBLE EPOXIDE HYDROLASE INHIBITORS

• US 20090082456A1
• Filed: 09/09/2008
• Published: 03/26/2009
• Est. Priority Date: 09/11/2007
• Status: Abandoned Application

• Current Assignee: Arete Therapeutics, Inc.
• Original Assignee: Arete Therapeutics, Inc.
• Inventors: Gless, Richard D. JR.
• Application Number:
  US12/207,408
• Publication Number:
  US 20090082456A1
• Time in Patent Office: Days
• US Class Current: 514/595
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2603/74 Adamantanes
• CPC Class Codes: C07C 275/26 having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings
• CPC Class Codes: C07C 275/30 being further substituted by halogen atoms, or by nitro or nitroso groups
• CPC Class Codes: C07C 311/07 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 311/20 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring

Abstract

Disclosed are amide, thioamide, urea and thiourea compounds and compositions that inhibit soluble epoxide hydrolase (sEH), methods for preparing the compounds and compositions, and methods for treating patients with such compounds and compositions. The compounds, compositions, and methods are useful for treating a variety of sEH mediated diseases, including hypertensive, cardiovascular, inflammatory, and diabetic-related diseases.

Claims

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

wherein;

A is a cycloalkyl ring;

m is 0, 1, 2 or 3;

X is selected from the group consisting of —

NR³—

CO—

, —

SO₂—

NR³—

, and —

NR³—

SO₂—

;

R¹ and R³ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

or R¹ and R³ together with the nitrogen atom bound thereto form a heterocyclic ring having 3 to 5 ring carbon atoms, 1 ring nitrogen atom, and 1 ring heteroatoms independently selected from the group consisting of O, S, and N, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy;

Q is O or S;

L is a covalent bond, —

NH—

, or —

CR′

R″

—

where R′ and

R″

are independently H or alkyl or R′ and

R″

together form a C₃-C₆ cycloalkyl ring;

each R² is independently selected from the group consisting of alkyl, haloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or two R² on the same carbon atom form an oxo (═

O);

n is 0, 1, 2, 3 or 4;

R is selected from the group consisting of C_6-10 cycloalkyl, substituted C_6-10 cycloalkyl, and

wherein R⁴ and R⁸ are independently hydrogen or fluoro;

R⁵, R⁶, and R⁷ are independently selected from the group consisting of hydrogen, halo, alkyl, acyl, acyloxy, carboxyl ester, acylamino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonylamino, (carboxyl ester)amino, aminosulfonyl, (substituted sulfonyl)amino, haloalkyl, haloalkoxy, haloalkylthio, cyano, and alkylsulfonyl.

2. A compound of claim 1, wherein

is selected from the group consisting of:

3. A compound of claim 2, wherein R³ is hydrogen.

4. A compound of claim 3, wherein

is selected from the group consisting of

wherein

R^1a is selected from the group consisting of alkyl, substituted alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

and

R² and n are as defined above.

5. A compound of claim 4, wherein

6. A compound of claim 5, wherein

is selected from the group consisting of

7. A compound of claim 5, wherein

is selected from the group consisting of

8. A compound of claim 4, wherein R^1a is alkyl or substituted alkyl.

9. A compound of claim 2, wherein n is 0.

10. A compound of claim 1, wherein R¹ is alkyl or optionally substituted phenyl and R³ is hydrogen.

15. A compound claim 1 wherein R is selected from the group consisting of adamantyl,

17. A compound of claim 1 wherein R is selected from the group consisting of trifluoromethylphenyl, fluorophenyl, trifluoromethoxy and chlorophenyl.

18. A compound of claim 17 wherein R is selected from the group consisting of 4-trifluoromethylphenyl, 4-fluorophenyl, 3-trifluoromethoxy, 4-trifluoromethoxy and 4-chlorophenyl.

19. A compound of claim 1 of Formula (II) or a pharmaceutically acceptable salt thereof:

wherein;

A is a cycloalkyl ring;

m is 0, 1, 2 or 3;

X is selected from the group consisting of —

NR³—

CO—

, —

SO₂—

NR³—

, and —

NR³—

SO₂—

;

R¹ and R³ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

or R¹ and R³ together with the nitrogen atom bound thereto form a heterocyclic ring having 3 to 5 ring carbon atoms, 1 ring nitrogen atom, and 1 ring heteroatoms independently selected from the group consisting of O, S, and N, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy;

Q is O or S;

each R² is independently selected from the group consisting of alkyl, haloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or two R² on the same carbon atom form an oxo (═

O);

n is 0, 1, 2, 3, or 4;

R⁴ and R⁸ are independently hydrogen or fluoro;

R⁵, R⁶, and R⁷ are independently selected from the group consisting of hydrogen, halo, alkyl, acyl, acyloxy, carboxyl ester, acylamino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonylamino, (carboxyl ester)amino, aminosulfonyl, (substituted sulfonyl)amino, haloalkyl, haloalkoxy, haloalkylthio, cyano, and alkylsulfonyl.

20. A compound of claim 19, wherein m is 2.

21. A compound of claim 19, wherein R³ is hydrogen and R¹ is alkyl or optionally substituted phenyl.

24. A compound of claim 19, wherein

is selected from the group consisting of:

25. A compound of claim 24, wherein R¹ is alkyl or optionally substituted phenyl and R³ is hydrogen.

29. A compound of claim 24, wherein

is selected from the group consisting of

wherein

R^1a is selected from the group consisting of alkyl, substituted alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

and

R² and n are as defined above.

30. A compound of claim 29 wherein R² is halo.

31. A compound of claim 29 wherein R² is alkyl.

32. A compound of claim 29, wherein R^1a is alkyl or substituted alkyl.

33. A compound of claim 19 wherein at least one of R⁵, R⁶ and R⁷ is selected from the group consisting of trifluoromethyl, trifluoromethoxy, fluoro, and chloro.

34. A compound of claim 33 wherein R⁴ and R⁸ are hydrogen, two of R⁵, R⁶ and R⁷ are hydrogen and the remaining one of R⁵, R⁶ and R⁷ is selected from the group consisting of trifluoromethyl, trifluoromethoxy, fluoro, and chloro.

35. A compound of claim 1 of Formula (III) or a pharmaceutically acceptable salt thereof:

wherein;

A is a cycloalkyl ring;

m is 0, 1, 2 or 3;

X is selected from the group consisting of —

NR³—

CO—

, —

SO₂—

NR³—

, and —

NR³—

SO₂—

;

R¹ and R³ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

or R¹ and R³ together with the nitrogen atom bound thereto form a heterocyclic ring having 3 to 5 ring carbon atoms, 1 ring nitrogen atom, and 1 ring heteroatoms independently selected from the group consisting of O, S, and N, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy;

Q is O or S;

each R² is independently selected from the group consisting of alkyl, haloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or two R² on the same carbon atom form an oxo (═

O); and

n is 0, 1, 2, 3, 4, or 5.

36. A compound of claim 35, wherein R¹ is alkyl or optionally substituted phenyl and R³ is hydrogen.

40. A compound of claim 35, wherein m is 2.

41. A compound of claim 35, wherein

is selected from the group consisting of:

42. A compound of claim 41, wherein R¹ is alkyl or optionally substituted phenyl.

43. A compound of claim 41, wherein R³ is hydrogen.

44. A compound of claim 41, wherein

is selected from the group consisting of

wherein

R^1a is selected from the group consisting of alkyl, substituted alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

and

R² and n are as defined above.

47. A compound of claim 1 or a pharmaceutically acceptable salt thereof selected from Table 3:

TABLE 3 Cmpd Structure Name 1 N-(4-(3-(adamantan-1-yl)ureido)cyclohexyl)-3-(trifluoromethyl)benzenesulfonamide 2 N-(4-(3-(adamantan-1-yl)ureido)cyclohexyl)acetamide 3 N-(4-(3-(4-fluorophenyl)ureido)cyclohexyl)-3-(trifluoromethyl)benzenesulfonamide 4 N-(4-(3-(4-(trifluoromethyl)phenyl)ureido)cyclohexyl)acetamide 5 N-(4-(3-(adamantan-1-yl)ureido)cyclohexyl)methanesulfonamide 6 N-(4-(3-(4-(trifluoromethyl)phenyl)ureido)cyclohexyl)methanesulfonamide 7 4-fluoro-N-(4-(methylsulfonamido)cyclohexyl)benzamide

48. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

49. A method for treating a soluble expoxide hydrolase mediated disease, said method comprising administering to a patient a compound of claim 1 or a pharmaceutically acceptable salt thereof.

51. A method for inhibiting a soluble epoxide hydrolase, comprising contacting the soluble epoxide hydrolase with an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

11-14. -14. (canceled)

16. (canceled)

22-23. -23. (canceled)

26-28. -28. (canceled)

37-39. -39. (canceled)

45-46. -46. (canceled)

50. (canceled)