Acyl piperidine inhibitors of soluble epoxide hydrolase

Abstract

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

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.