Inhibitors of fatty acid amide hydrolase

Abstract

Potent inhibitors of fatty acid amide hydrolase (FAAH) are constructed having K i 's below 200 pM and activities 10 2 -10 3 times more potent than the corresponding trifluoromethyl ketones. The potent inhibitors combine several features, viz.: 1.) an α-keto heterocylic head group; 2.) a hydrocarbon linkage unit employing an optimal C12-C8 chain length; and 3.) a phenyl or other π-unsaturation corresponding to the arachidonyl Δ 8,9 /Δ 11,12 and/or oleyl Δ 9,10 positions. A preferred α-keto heterocylic head group is α-keto N4 oxazolopyridine, with incorporation of a second weakly basic nitrogen. Fatty acid amide hydrolase is an enzyme responsible for the degradation of oleamide (an endogenous sleep-inducing lipid) and anandamide (an endogenous ligand for cannabinoid receptors).

1 .- 12 . (canceled) 
   
   
       13 . An inhibitor of fatty acid amide hydrolase represented the formula:
   A-B—C   
     wherein:
 A is an α-keto heterocyclic pharmacophore for inhibiting the fatty acid amide hydrolase, wherein A is represented by the formula: 
 
     
       
         
         
             
             
         
       
       wherein “het” is selected from: 
     
     
       
         
         
             
             
         
       
       B is a chain for linking A and C, said chain having a linear skeleton with a length of 3 to 9 sequential atoms selected from the group consisting of carbon, oxygen, sulfur, and nitrogen, the linear skeleton having a first end and a second end, the first end being covalently bonded to the α-keto group of A; 
       wherein if the first end of said chain B is an α-carbon with respect to the α-keto group of A, then the α-carbon is optionally substituted with one or two fluoro, chloro, hydroxyl, alkoxy, trifluoromethyl, or alkyl groups, or a combination thereof; and 
       C is an activity enhancer for enhancing the inhibition activity of said α-keto heterocyclic pharmacophore, said activity enhancer having at least one π-unsaturation situated within a π-bond containing radical selected from a group consisting of aryl, alkenyl, alkynyl, and ring structures having at least one unsaturation, with or without one or more heteroatoms; 
       said activity enhancer C being covalently bonded to the second end of the linear skeleton of chain B wherein no π-unsaturation within the π-bond containing radical is separated from the α-keto group of A by a sequence of less than 4 atoms bonded sequentially to one another, inclusive of said linear skeleton, and wherein at least one π-unsaturation within the π-bond containing radical is separated from the α-keto group of A by a sequence of no more than 9 atoms bonded sequentially to one another, inclusive of said linear skeleton. 
     
   
   
       14 . The inhibitor of fatty acid amide hydrolase of  claim 13  wherein “het” is 
     
       
         
         
             
             
         
       
     
   
   
       15 . The inhibitor of fatty acid amide hydrolase of  claim 13  wherein “het” is 
     
       
         
         
             
             
         
       
     
   
   
       16 . The inhibitor of fatty acid amide hydrolase of  claim 13  wherein —B—C comprises a carbon chain comprising 5 to 19 carbon atoms, wherein the chain includes at least one π-unsaturation situated within a π-bond containing radical selected from a group consisting of aryl, alkenyl, alkynyl, and ring structures having at least one unsaturation. 
   
   
       17 . The inhibitor of fatty acid amide hydrolase of  claim 13  wherein —B—C is a π-bond containing alkenyl radical having one to four π-unsaturations. 
   
   
       18 . The inhibitor of fatty acid amide hydrolase of  claim 17  wherein at least one n-unsaturation is in a cis conformation. 
   
   
       19 . The inhibitor of fatty acid amide hydrolase of  claim 17  wherein at least one π-unsaturation is in a trans conformation. 
   
   
       20 . The inhibitor of fatty acid amide hydrolase of  claim 17  wherein —B—C is: 
     
       
         
         
             
             
         
       
     
   
   
       21 . The inhibitor of fatty acid amide hydrolase of  claim 13  wherein the first end of chain B is an α-carbon with respect to the α-keto group of A and the α-carbon is substituted with a fluoro, chloro, hydroxyl, alkoxy, trifluoromethyl, or alkyl group. 
   
   
       22 . The inhibitor of fatty acid amide hydrolase of  claim 13  wherein the first end of chain B is an α-carbon with respect to the o-keto group of A and the α-carbon is substituted with a combination two substituents selected from fluoro, chloro, hydroxyl, alkoxy, trifluoromethyl, and alkyl. 
   
   
       23 . The inhibitor of fatty acid amide hydrolase of  claim 20  wherein the inhibitor is: 
     
       
         
         
             
             
         
       
     
   
   
       24 . The inhibitor of fatty acid amide hydrolase of  claim 20  wherein the inhibitor is: 
     
       
         
         
             
             
         
       
     
   
   
       25 . The inhibitor of fatty acid amide hydrolase of  claim 20  wherein the inhibitor is: 
     
       
         
         
             
             
         
       
     
   
   
       26 . The inhibitor of fatty acid amide hydrolase of  claim 20  wherein the inhibitor is: 
     
       
         
         
             
             
         
       
     
   
   
       27 . The inhibitor of fatty acid amide hydrolase of  claim 20  wherein the inhibitor is: 
     
       
         
         
             
             
         
       
     
   
   
       28 . The inhibitor of fatty acid amide hydrolase of  claim 20  wherein the inhibitor is: 
     
       
         
         
             
             
         
       
     
   
   
       29 . The inhibitor of fatty acid amide hydrolase of  claim 20  wherein the inhibitor is: 
     
       
         
         
             
             
         
       
     
   
   
       30 . The inhibitor of fatty acid amide hydrolase of  claim 20  wherein the inhibitor is: 
     
       
         
         
             
             
         
       
     
   
   
       31 . The inhibitor of fatty acid amide hydrolase of  claim 20  wherein the inhibitor is: 
     
       
         
         
             
             
         
       
     
   
   
       32 . A process for enhancing SWS2 or REM sleep comprising administering to a subject a therapeutically effective amount of the fatty acid amide hydrolase inhibitor of  claim 13 , wherein SWS2 or REM sleep is thereby enhanced.