Acyl piperidine inhibitors of soluble epoxide hydrolase

Patent metadata

Field	Value
Publication number	US-2016200683-A1
Application number	US-201615075981-A
Country	US
Kind code	A1
Filing date	Mar 21, 2016
Priority date	Jan 29, 2010
Publication date	Jul 14, 2016
Grant date	—

Abstract

Inhibitors of the soluble epoxide hydrolase (sEH) are provided that incorporate multiple pharmacophores and are useful in the treatment of diseases.

First claim

What is claimed is:

1 . A compound selected from the group consisting of:
1-(4-Methoxyphenyl)-3-(1-propionylpiperidin-4-yl)urea, 1-(4-Phenoxyphenyl)-3-(1-propionylpiperidin-4-y)urea, 1-(4-Fluorophenyl)-3-(1-propionylpiperidin-4-yl)urea, 1-(4-Chlorophenyl)-3-(1-propionylpiperidin-4-yl)urea, 1-(4-Iodophenyl)-3-(1-propionylpiperidin-4-yl)urea, 1-(3,5-Dichlorophenyl)-3-(1-propionylpiperidin-4-yl)urea, 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(1-propionylpiperidin-4-y)urea, 1-(4-Perfluoroisopropylphenyl)-3-(1-propionylpiperidin-4-y)urea, 1-(1-(2-methylbutyryl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(1-(3, 3,3-trifluoropropionyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(1-(4,4,4-trifluorobutyryl)piperidin-4-yl)-3-(4-(trifluorometityl)phenyl)urea, 1-(1-Propionylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea, 1-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-3-(4-(trifluoromeithoxy)phenyl)urea, 1-(1-(Trifluoroacetyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea, 1-(1-(propylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(1-(butylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(1-(cyclopropylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(1-(2,2,2-trifluoroethylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(1-(3,3,3-trifluoropropylsulfonyppiperidin-4-yl)-3-(4-(triflubromethyl)phenyl)urea, 1-(1-(Methylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea, and 1-(1-(Ethyl sulfonyppiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea,
or salts and isomers thereof.

2 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

3 . A method for inhibiting a soluble epoxide hydrolase, the method comprising contacting the soluble epoxide hydrolase with an amount of a compound of claim 1 sufficient to inhibit the soluble epoxide hydrolase.

4 . A method for monitoring the activity of a soluble epoxide hydrolase, the method comprising contacting the soluble epoxide hydrolase with an amount of a compound of claim 1 sufficient to produce a detectable change in the fluorescence of the soluble epoxide hydrolase by interacting with one or more tryptophan residues present in the catalytic site of said sEH.

5 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
1-(1-cyclopropanecarbonylpiperidin-4-yl)-3-(4-trifluoromethyl)phenyl)urea, 1-(1-(2-methylbutyryl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(1-(3,3,3-trifluoropropionyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea, and 1-(1-(4,4,4-trifluorobutyryl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea.

6 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
1-(1-Propionylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea, 1-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea, and 1-(1-(Trifluoroacetyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea.

7 . The compound of claim 1 , wherein the compound is
1-(1-cyclopropanecarbonylpiperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea.

8 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
1-(1-(propylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(1-(butylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(1-(cyclopropylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(1-(2,2,2-trifluoroethylsulfonyl)piperidin-4-yl)-3-(4-(trifluromethyl)phenyl)urea, and 1-(1-(3,3,3-trifluoropropylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea.

9 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
1-(1-(Methylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea, and 1-(1-(Ethylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea.

10 . A method for inhibiting a soluble epoxide hydrolase, the method comprising contacting the soluble epoxide hydrolase with an amount of 1-(1-cyclopropanecarbonylpiperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea sufficient to inhibit the soluble epoxide hydrolase.

11 . A method for monitoring the activity of a soluble epoxide hydrolase, the method comprising contacting the soluble epoxide hydrolase with an amount of 1-(1-cyclopropanecarbonylpiperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea sufficient to produce a detectable change in the fluorescence of the soluble epoxide hydrolase by interacting with one or more tryptophan residues present in the catalytic site of said sEH.

Assignees

• Univ California

Inventors

• Hammock Bruce D
• Rose Tristan
• Morisseau Christophe
• Lee Kin Sing

Classifications

• C07D211/58 Primary

  attached in position 4 · CPC title

• C12N9/14

  Hydrolases (3) · CPC title

• G01N21/6486

  Measuring fluorescence of biological material, e.g. DNA, RNA, cells (G01N21/6428 takes precedence) · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K31/445

  Non condensed piperidines, e.g. piperocaine · CPC title