SOLUBLE EPOXIDE HYDROLASE INHIBITORS
First Claim
Patent Images
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 C6-10 cycloalkyl, substituted C6-10 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.
1 Assignment
0 Petitions
Accused Products
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.
-
Citations
51 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 C6-10 cycloalkyl, substituted C6-10 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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 17, 18, 19, 20, 21, 24, 25, 29, 30, 31, 32, 33, 34, 35, 36, 40, 41, 42, 43, 44, 47, 48, 49, 51)
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 R1a 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.
- and
-
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 R1a 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 R1a 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.
- and
-
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 R1a 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); andn 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 R1a 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.
- and
-
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.
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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)
Specification