Conformationally restricted urea inhibitors of soluble epoxide hydrolase
View Patent ↗Inhibitors of the soluble epoxide hydrolase (sEH) are provided that incorporate multiple pharmacophores and are useful in the treatment of diseases.
1. A compound having the formula:
wherein R 1 is a member selected from the group consisting of phenyl, cyclohexyl, cycloheptyl and adamantyl, wherein said phenyl is optionally substituted with from 1 to 2 substituents each independently selected from the group consisting of C 1 -C 8 alkyl, haloC 1 -C 8 alkyl, cyano, haloC 1 -C 8 alkoxy, C 1 -C 8 heteroalkyl, aryl, heteroaryl;
L is selected from the group consisting of —CO— and —SO 2 -;
R 4 is selected from the group consisting of H, C 1 -C 8 alkyl, arylC 0 -C 8 alkyl, and C 3 -C 12 cycloalkyl, each optionally substituted with from 1 to 2 substituents each independently selected from the group consisting of C 1 -C 8 alkyl, halo, C 1 -C 8 heteroalkyl, arylC 0 -C 8 alkyl, COR 6 , S(O) m R 6 and heteroaryl;
each R 6 is independently selected from the group consisting of H, C 1 -C 8 alkyl, C 1 -C 8 alkoxy and amino;
the subscript n is 0; and
the subscript m is an integer of from 0 to 2;
or a pharmaceutically acceptable salt thereof.
2. The compound in accordance with claim 1 having the formula:
or a pharmaceutically acceptable salt thereof.
3. The compound in accordance with claim 1 or 2 , wherein R 1 is adamantyl.
4. The compound in accordance with claim 1 or 2 , wherein R 1 is cycloheptyl or cyclohexyl.
5. The compound in accordance with claim 1 or 2 , wherein L is a —C(O)—.
6. The compound in accordance with claim 1 or 2 , wherein R 4 is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, and arylC 0 -C 8 alkyl.
7. The compound in accordance with claim 1 or 2 , wherein R 4 is C 1 -C 8 alkyl.
8. A compound according to claim 2 which compound is selected from the group consisting of:
N-(1-acetylpiperidin-4-yl)-N′-(adamant-1-yl)urea;
N-(1-propionylpiperidin-4-yl)-N′-(adamant-1-yl)urea;
N-(1-butyrylpiperidin-4-yl)-N′-(adamant-1-yl)urea;
N-(1-benzoylpiperidin-4-yl)-N′-(adamant-1-yl)urea;
4-[4-(3-adamantan-1-yl-ureido)-piperidin-1-yl]-4-oxo-butanoic acid methyl ester;
5-[4-(3-adamantan-1-yl-ureido)-piperidin-1-yl]-5-oxo-pentanoic acid methyl ester;
2-[4-(3-adamantan-1-yl-ureido)-piperidine-1-carbonyl]-benzoic acid methyl ester;
3-[4-(3-adamantan-1-yl-ureido)-piperidine-1-carbonyl]-benzoic acid methyl ester;
4-[4-(3-adamantan-1-yl-ureido)-piperidine-1-carbonyl]-benzoic acid methyl ester;
1-(1-acetyl-piperidin-4-yl)-3-(4-trifluoromethoxyphenyl)urea;
1-(1-trifluoromethylcarbonylpiperidin-4-yl)-3-(4-trifluoromethoxyphenyl)urea; and
1-(1-acetyl-piperidin-4-yl)-3-cycloheptyl urea;
or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 8 , wherein said compound is selected from the group consisting of:
N-(1-acetylpiperidin-4-yl)-N′-(adamant-1-yl)urea;
N-(1-propionylpiperidin-4-yl)-N′-(adamant-1-yl)urea;
N-(1-butyrylpiperidin-4-yl)-N′-(adamant-1-yl)urea; and
N-(1-benzoylpiperidin-4-yl)-N′-(adamant-1-yl)urea or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 8 , wherein said compound is N-(1-acetylpiperidin-4-yl)-N′-(adamant-1-yl)urea or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 8 , wherein said compound is N-(1-propionylpiperidin-4-yl)-N′-(adamant-1-yl)urea or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 8 , wherein said compound is N-(1-butyrylpiperidin-4-yl)-N′-(adamant-1-yl)urea or a pharmaceutically acceptable salt thereof.
13. The compound according to claim 8 , wherein said compound is N-(1-benzoylpiperidin-4-yl)-N′-(adamant-1-yl)urea or a pharmaceutically acceptable salt thereof.
14. A compound according to claim 2 which compound is selected from the group consisting of:
N-(1-methanesulfonylpiperidin-4-yl)-N′-(adamant-1-yl)urea;
N-(1-methanesulfonylpiperidin-4-yl)-N′-(4-trifluoromethoxyphenyl)urea;
N-(1-toluene-4-sulfonylpiperidin-4-yl)-N′-(4-trifluoromethoxyphenyl)urea; and
N-[1-(5-dimethylaminonaphthalene-1-sulfonyl)-piperidin-4-yl]-N′-(4-trifluoromethoxy -phenyl) urea;
or a pharmaceutically acceptable salt thereof.
15. The compound according to claim 14 , wherein said compound is N-(1-methanesulfonylpiperidin-4-yl)-N′-(adamant-1-yl)urea or a pharmaceutically acceptable salt thereof.
16. The compound according to claim 14 , wherein said compound is N-(1-methanesulfonylpiperidin-4-yl)-N′-(4-trifluoromethoxy-phenyl)urea or a pharmaceutically acceptable salt thereof.
17. The compound according to claim 14 , wherein said compound is N-(1-toluene-4-sulfonylpiperidin-4-yl)-N′-(4-trifluoromethoxy-phenyl)urea or a pharmaceutically acceptable salt thereof.
18. The compound according to claim 14 , wherein said compound is N-[1-(5-dimethylaminonaphthalene-1-sulfonyl)-piperidin-4-yl]-N′-(4-trifluoromethoxy-phenyl) urea or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising a compound according to any one of claims 1 and 2 and a pharmaceutically acceptable excipient.