Inhibitors Of Fatty Acid Amide Hydrolase And Monoacylglycerol Lipase For Modulation Of Cannabinoid Receptors

Abstract

Disclosed are compounds and compositions that inhibit the action of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL), methods of inhibiting FAAH and MGL, methods of modulating cannabinoid receptors, and methods of treating various disorders related to modulation of cannabinoid receptors.

1 . A method of modulating a cannabinoid receptor in a biological sample, the method comprising:
 (a) measuring the level of a cannabinergic ligand in the biological sample;   (b) contacting the sample with a compound having formula R—X—Y, the compound inhibiting an enzyme that hydrolyzes the cannabinergic ligand,   wherein Y is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         wherein:
 W 1  is either CH or N if it is not bonded to X or Y 1 , or W 1  is C if it is bonded to X or Y 1 ; if W 1  is N, then it can occupy position 2, 3, 4, or 5 in I 3; 
 W 2  is either CH or N if it is not bonded to X or Y 1 , or W 2  is C if it is bonded to X or Y 1 ; if W 2  is N, then it can occupy position 2, 3, 4, or 5 in I 3; 
 W 3  is CH or N if it is not bonded to X, or W 3  is C if it is bonded to X; if W 3  is N then it can occupy position 4, 5, 6, or 7 in I 4; 
 W 4  is CH or N if it is not bonded to X, or W 4  is C if it is bonded to X; if W 4  is N then it can occupy position 4, 5, 6, or 7 in I 4; 
 W 5  is CH or N if it is not bonded to X, or W 5  is C if it is bonded to X; if W 5  is N then it can occupy position 4, 5, 6, or 7 in I 5; 
 W 6  is CH or N if it is not bonded to X, or W 6  is C if it is bonded to X; if W 6  is N then it can occupy position 4, 5, 6, or 7 in I 5; 
 Q 1  is CH 2 , O, or NH if Q 1  is not bonded to X or Y 1 , or Q 1  is CH or N if Q 1  is bonded to X or Y 1 ; 
 Q 2  is CH 2  or NH if Q 2  is not bonded to Y 1 , or Q 2  is CH or N if Q 2  is bonded to Y 1 ; 
 Y 1  is selected from the group consisting of: 
 
       
       
         
           
           
               
               
           
         
         wherein:
 Y 2  and Y 3  are each independently H, alkyl, cycloalkyl, aryl, heteroaryl, —C 1-5 -alkyl-Y 4 , -cycloalkyl-Y 4 , -aryl-Y 4 , or -heteroaryl-Y 4 , or Y 2  and Y 3  together comprise part of a 5-7 membered saturated heterocyclic ring which can be substituted or unsubstituted and can contain up to one additional heteroatom selected from the group consisting of N, O, and S, with or without substitution on the heteroatom wherein the substituent is alkyl, aryl, heteroaryl, alkyl-aryl or alkyl-heteroaryl; 
 Y 4  is —F, —Cl, Br, —I, —OH, —SH, —NH 2 , —CN, —N 3 , —NCS, —CONH 2 , —CONR 13 R 14 , —SO 2 NR 13 R 14 , —COOH, —COOMe, —COOEt, COCF 3 , —NO 2 , —CF 3 , —SO 3 H, SO 2 R 13 , —P(O)(OH) 2 , —PO(OR 1 ) 2 , —C≡CH, or —CH═CH 2 ; 
 R 13  and R 14  are each independently H or C 1 -C 5 -alkyl; 
 
         wherein X is —(CH 2 ) n — or —(CH 2 ) j -A-(CH 2 ) k —, wherein:
 A is —CH═CH—, —C═O, O, S, NH, —C(O)NH, —NHC═O, —NHC(O)NH—, OC(O)NH—, NHC(O)O, or —OC(O)O—;
 n is an integer from 0 to 15; 
 j is an integer from 0 to 10; 
 k is an integer from 0 to 10; and 
 if n, j, or k is independently 0, the structural portion modified by that integer is absent, the adjacent subunits are directly connected; 
 
 
         wherein:
 R is selected from the group consisting of: 
 
       
       
         
           
           
               
               
           
         
         wherein:
 W 7  is CH or N if W 7  is not bonded to X, R 1 , R 2 , or R 3 , or W 7  is C if W 7  is bonded to X, R 1 , R 2 , or R 3 ; if W 7  is N then it can occupy position 1, 2, 3, 4, 5 or 6 in I 10 and 4, 5, 6 or 7 in I 12; 
 W 8  is CH or N if W 8  is not bonded to X, R 1 , or R 2 , or W 8  is C if W 8  is bonded to X, R 1 , or R 2 ; if W 8  is N then it can occupy position 2, 3, 4 or 5 in I 11; 
 W 9  is CH or N if W 9  is not bonded to R 7 , R 8 , R 9 , or R 10 , or W 9  is C if W 9  is bonded to R 7 , R 8 , R 9 , or R 10 ; if W 9  is N then it can occupy position 7, 8, 9, 10, or 11 in I 13; 
 W 10  is CH or N if W 10  is not bonded to X, R 4 , R 5 , or R 6 , or W 10  is C if W 10  is bonded to X, R 4 , R 5 , or R 6 ; if W 10  is N then it can occupy position 1, 2, 3, 4, or 5 in I 13; 
 Q 3  is CH 2 , O, S, or NH if Q 3  is not bonded to X, R 1 , R 2 , or Q 3  is CH or N if Q 3  is bonded to X, R 1 , R 2 ; 
 Q 4  is CH 2 , O, S, or NH if Q 4  is not bonded to X, or Q 4  is CH or N if Q 4  is bonded to X; 
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  are each independently —H, —F, —Cl, —Br, —I, —OH, —OAc, —SH, —NH 2 , —CN, —N 3 , —NCS, —CONH 2 , —SO 2 NH 2 , —COOH, —NO 2 , —CHO, —CF 3 , —OCF 3 , —SO 3 H, —SO 2 F, —O—P(O)(OH) 2 , —O—P(O)(O-alkyl) 2 , —O—P(O)(OH)(O-alkyl), —P(O)(O-alkyl) 2 , —P(O)(OH)(O-alkyl), —Sn(alkyl) 3 , —Si(alkyl) 3 , —C≡CH, —CH═CH 2 , -alkyl-R 12 , or —Z-alkyl-R 12 ; 
 Z is —O—, —S—, —NH—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —S(O)—, —S(O) 2 —, —SO 2 NH—, —NHSO 2 —, —SO 2 O—, or —OSO 2 —; 
 R 12  is —H, —F, —Cl, —Br, —I, —OH, —OAc, —SH, —NH 2 , —CN, —N 3 , —NCS, —CONH 2 , —SO 2 NH 2 , —COOH, —NO 2 , —CHO, —CF 3 , —OCF 3 , —SO 3 H, —SO 2 F, —O—P(O)(OH) 2 , —Sn(alkyl) 3 , —Si(alkyl) 3 , —OSi(alkyl) 3 , —C≡CH, —CH 2 —C≡CH and —CH═CH 2 ; and 
 wherein if Y is I 1 or I 2 when Y 1  is —C(O)—N(CH 3 ) 2 , and X is —(CH 2 ) n — where n=1, then R can not be 1,1′-biphenyl-4-yl, 4-fluorophenyl, or 3-iodo-4-azidophenyl; and 
 
         (c) measuring the level of the cannabinergic ligand in the contacted sample, 
         the cannabinoid receptor being modulated if the level of the cannabinergic ligand in the contacted sample is the same or greater than the level of the cannabinergic ligand in the uncontacted sample. 
       
     
     
         2 . The method of  claim 1 , wherein the enzyme is fatty acid amide hydrolase. 
     
     
         3 . The method of  claim 2 , wherein the cannabinergic ligand is anandamide. 
     
     
         4 . The method of  claim 1 , wherein the enzyme is monacylglycerol lipase. 
     
     
         5 . The method of  claim 4 , wherein the cannabinergic ligand is 2-arachidonoylglycerol. 
     
     
         6 . The method of  claim 1 , wherein the cannabinoid receptor is CB1. 
     
     
         7 . The method of  claim 1 , wherein the cannabinoid receptor is CB2. 
     
     
         8 . The method of  claim 1 , wherein the compound having formula R—X—Y is a compound listed in Table 2. 
     
     
         9 . The method of  claim 1 , wherein the compound having formula R—X—Y is a compound listed in Table 3. 
     
     
         10 . The method of  claim 1 , wherein the compound having formula R—X—Y is a compound listed in Table 4.