Modulation of anxiety through blockade of anandamide hydrolysis

Abstract

Fatty acid amide hydrolase inhibitors of the Formula: are provided wherein X is NH, CH 2 , O, or S; Q is O or S; Z is O or N; R is an aromatic moiety selected from the group consisting of substituted or unsubstituted aryl; substituted or unsubstituted biphenylyl, substituted or unsubstituted naphthyl, and substituted or unsubstituted phenyl; substituted or unsubstituted terphenylyl; substituted or unsubstituted cycloalkyl, heteroaryl, or alkyl; and R 1 and R 2 are independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted phenyl, substituted or unsubstituted biphenylyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; with the proviso that if Z is O, one of R 1 and R 2 is absent, and that if Z is N, optionally R 1 and R 2 may optionally be taken together to form a substituted or unsubstituted N-heterocycle or substituted or unsubstituted heteroaryl with the N atom to which they are each attached. Pharmaceutical compositions comprising the compounds of Formula I and methods of using them to inhibit FAAH and/or treat appetite disorders, glaucoma, pain, insomnia, and neurological and psychological disorders including anxiety disorders, epilepsy, and depression are provided.

1 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein 
         X is O or S; 
         Q is O or S; 
         R is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted biphenylyl, substituted or unsubstituted naphthyl, and substituted or unsubstituted phenyl, substituted or unsubstituted terphenylyl, substituted or unsubstituted heteroaryl, and 
       
       
         
           
           
               
               
           
         
         
           wherein p is a number from 0 to 3; 
           m is a number from 0 to 4, and 
           n is a number from 0 to 5, 
           Z 1  and Z 2  are same or different and are independently selected from the group consisting of —O—, — 1 S—, —N(R 5 )—, —C(R 6 )═C(R 7 )—, —C(R 6 )═N— and —N═C(R 6 )— wherein R 5  is selected from H, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl and aroyl; R 6  and R 7  are independently selected from the group consisting of H or R 6  and R 7  optionally may combine to form a saturated or unsaturated carbocyclic or heterocyclic ring, optionally substituted with one or more R a  and R b  groups; 
           Y is a bond or selected from the group consisting of —O—, —S—, —N(R 5 )—, C 1 -C 4  alkylene, (Z)- or (E)-ethylene, and cycloalkyl with 3 to 6 carbon atoms; 
           each R a  and each R b  are independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, substituted aryl, arylalkyl or arakyl, substituted arylalkyl or arakyl, ketoalkyl, hydroxyalkyl, aminoalkyl, —CH 2 —NR 3 R 4 , alkoxy, aryloxy, arylalkyloxy, halo, haloalkyl, cyano, hydroxy, nitro, amino, —NR 3 R 4 , —SR  5 , carboxamido, —CONR 3 R 4 , —O-carboxamide, —O—CO—NR 3 R 4 , sulfonamido, and —SO 2 NR 3 R 4 , wherein R 3  and R 4  are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl and imino-methylamino and wherein optionally R 3  and R 4  together with the N atom to which they are attached to form a 5-7 membered cyclic ring; and 
           R 1  and R 2  are independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted cycloheteroalkyl, and optionally R 1  and R 2 , may be taken together with the N atom to which they are attached to form a substituted or unsubstituted ring; 
         
         and the pharmaceutically acceptable salts thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein X is O and Q is O. 
     
     
         3 . The compound of  claim 2 , wherein the R is selected from the group consisting of substituted or unsubstituted biphenylyl, substituted or unsubstituted naphthyl, substituted or unsubstituted terphenylyl, and substituted or unsubstituted cis-stilbyl. 
     
     
         4 . The compound of  claim 3 , wherein R is substituted or unsubstituted biphenylyl. 
     
     
         5 . The compound of  claim 4 , wherein at least one of R 1  and R 2  is H. 
     
     
         6 . The compound of  claim 5 , wherein R 1  is C 1 -C 8  hydrocarbyl selected from alkyl and cycloalkyl and wherein optionally one or more carbons of these hydrocarbyl groups may be substituted with a heteroatom selected from O, N—R 5  , and S—R 5 . 
     
     
         7 . The compound of  claim 6 , wherein the C 1 -C 8  alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl. 
     
     
         8 . The compound of  claim 7 , wherein R 1  is cyclohexyl. 
     
     
         9 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of piperidinyl, furyl, furfuryl, furanyl, morpholinyl, is 2-,3-,4-piperidinyl, 2- and 3-morpholinyl, 2- and 3-furyl, furfuryl, 2- and 3-pyrryl or 2- or 3-thienyl. 
     
     
         10 . The compound of  claim 9 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
         and m is a number from 0 to 4 and n is a number from 0 to 5; 
         each R a  and each R b  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, substituted aryl, arylalkyl or arakyl, substituted arylalkyl or arakyl, ketoalkyl, hydroxyalkyl, aminoalkyl, —CH 2 —NR 3 R 4 , alkoxy, aryloxy, halo, haloalkyl, cyano, hydroxy, nitro, amino, —R 3 R 4 , carboxamido, —ONR 3 R 4 , —O-carboxamido, —O—CO—NR 3 R 4 , sulfonamido, —SO 2 NR 3 R 4 ;
 wherein R 3  and R 4  are independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl and imino-methylamino or R 3  and R 4  may combine to form a 5-7 membered cyclic ring. 
 
       
     
     
         11 . The compound of  claim 10 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
         wherein Ra 1  and Ra 2  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, substituted aryl, arylalkyl or arakyl, substituted arylalkyl or arakyl, ketoalkyl, hydroxyalkyl, aminoalkyl, CH 2 —NR 3 R 4 , alkoxy, aryloxy, halo, haloalkyl, cyano, hydroxy, nitro, amino, NR 3 R 4 , carboxamido, CONR 3 R 4 , O-carboxamido, O—CO—NR 3 R 4 , sulfonamido, and SO 2 NR 3 R 4 ;
 wherein R 3  and R 4  are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl and imino-methylamino or R 3  and R 4  may together with the N atom to which they are attached combine to form a 5-7 membered cyclic ring. 
 
       
     
     
         12 . The compound of  claim 11 , wherein at least one of Ra 1  and Ra 2  is H. 
     
     
         13 . The compound of  claim 11 , wherein Ra 1  is selected from the group consisting of —C(O)NH 2 , —C(O)CH 3 , or —(CH 2 ) 2 OH. 
     
     
         14 . The compound of  claim 11 , wherein Ra 1  and Ra 2  are each H. 
     
     
         15 . The compound of  claim 1 , wherein the compound is selected from the group consisting of n-butyl 4-benzyloxyphenyl carbamate and N-cyclohexyl 3′-carboxamido biphenyl-3-yl carbamate and the pharmaceutically acceptable salts thereof. 
     
     
         16 . The compound of  claim 1 , wherein the compound has an IC 50  for inhibiting the human fatty acid amide hydrolase of less than 1 micromolar. 
     
     
         17 . The compound of  claim 1 , wherein the compound has an IC 50  for inhibiting the human fatty acid amide hydrolase of less than 10 nanomolar. 
     
     
         18 . The compound of  claim 1 , wherein the molecular weight of the R—X— group is greater than the molecular weight of the —NR 1 R 2  group. 
     
     
         19 . The pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the formula: 
       
         
           
           
               
               
           
         
         wherein 
         X is O or S; 
         Q is O or S; 
         R is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted biphenylyl, substituted or unsubstituted naphthyl, and substituted or unsubstituted phenyl, substituted or unsubstituted terphenylyl, substituted or unsubstituted heteroaryl, and 
       
       
         
           
           
               
               
           
         
         
           wherein p is a number from 0 to 3; 
           m is a number from 0 to 4, and 
           n is a number from 0 to 5, 
           Z 1  and Z 2  are same or different and are independently selected from the group consisting of —O—, —S—, —N(R 5 )—, —C(R 6 )═C(R 7 )—, —C(R 6 )═N— and —N═C(R 6 )— wherein R 5  is selected from H, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl and aroyl; R 6  and R 7  are H or R 6  and R 7  optionally may combine to form a saturated or unsaturated carbocyclic or heterocyclic ring, optionally substituted with one or more R a  and R b  groups; 
           Y is a bond or selected from the group consisting of —O—, —S—, —N(R 5 )—, C 1 -C 4  alkylene, (Z)- or (E)-ethylene, and cycloalkyl with 3 to 6 carbon atoms; 
           each R a  and each R b  are independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, ketoalkyl, hydroxyalkyl, aminoalkyl, —CH 2 —NR 3 R 4 , alkoxy, aryloxy, arylalkyloxy, halo, haloalkyl, cyano, hydroxy, nitro, amino, —NR 3 R 4 , —SR 5 , carboxamido, —CONR 3 R 4 , —O-carboxamido, —O—CO—NR 3 R 4 , sulfonamide, and —SO 2 NR 3 R 4 , wherein R 3  and R 4  are selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl and imino-methylamino and wherein optionally R 3  and R 4  together with the N atom to which they are attached to form a 5-7 membered cyclic ring; and 
           R 1  and R 2  are independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted cycloheteroalkyl, and optionally R 1  and R 2 , may be taken together with the N atom to which they are attached to form a substituted or unsubstituted ring; 
         
         and the pharmaceutically acceptable salts thereof. 
       
     
     
         20 . The composition of  claim 19 , wherein X is O; Q is O; and R is selected from the group consisting of substituted or unsubstituted biphenylyl, substituted or unsubstituted naphthyl, substituted or unsubstituted terphenylyl, and substituted or unsubstituted cis-stilbyl. 
     
     
         21 . The composition of  claim 20 , wherein R is substituted or unsubstituted biphenylyl. 
     
     
         22 . The composition of  claim 21 , wherein at least one of R 1  and R 2  is H. 
     
     
         23 . The composition of  claim 22 , wherein R 1  is C 1 -C 8 homoalkyl, C 1 -C 8  heteroalkyl, or C 1 -C 8  cycloalkyl. 
     
     
         24 . The composition of  claim 23 , wherein the C 1 -C 8  alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl. 
     
     
         25 . The composition of  claim 24 , wherein R 1  is cyclohexyl. 
     
     
         26 . The composition of  claim 19 , wherein R 1  is a substituted or unsubstituted piperidinyl, furyl, furfuryl, furanyl, thiofuranyl, and morpholinyl. 
     
     
         27 . The composition of  claim 24 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
         and m is a number from 0 to 4 and n is a number from 0 to 5; 
         each R a  and each R b  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, ketoalkyl, hydroxyalkyl, aminoalkyl, —CH 2 —NR 3 R 4 , alkoxy, aryloxy, halo, haloalkyl, cyano, hydroxy, nitro, amino, —R 3 R 4 , carboxamido, —ONR 3 R 4 , —O-carboxamido, —O—CO—NR 3 R 4 , sulfonamido, —SO 2 NR 3 R 4 ; and
 wherein R 3  and R 4  are independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl and imino-methylamino or R 3  and R 4  may combine to form a 5-7 membered cyclic ring. 
 
       
     
     
         28 . The composition of  claim 10 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
         wherein Ra 1  and Ra 2  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, ketoalkyl, hydroxyalkyl, aminoalkyl, CH 2 —NR 3 R 4 , alkoxy, aryloxy, halo, haloalkyl, cyano, hydroxy, nitro, amino, NR 3 R 4 , carboxamido, CONR 3 R 4 , O-carboxamido, O—CO—NR 3 R 4 , sulfonamido, and SO 2 NR 3 R 4 ;
 wherein R 3  and R 4  are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl and imino-methylamino or R 3  and R 4  may together with the N atom to which they are attached combine to form a 5-7 membered cyclic ring. 
 
       
     
     
         29 . The composition of  claim 28 , wherein one of Ra 1  and Ra 2  is H. 
     
     
         30 . The composition of  claim 29 , wherein Ra i  is selected from the group consisting of —C(O)NH 2 , —C(O)CH3, or —(CH 2 ) 2 OH. 
     
     
         31 . The composition of  claim 30 , wherein Ra 1  and Ra 2  are each H. 
     
     
         32 . The composition of  claim 19 , wherein the compound is selected from the group consisting of n-butyl 4-benzyloxyphenyl carbamate and N-cyclohexyl 3′-carboxamido biphenyl-3-yl carbamate and the pharmaceutically acceptable salts thereof. 
     
     
         33 . The composition of  claim 19 , wherein the molecular weight of the R—X— group is greater than the molecular weight of the —NR 1 R 2  group. 
     
     
         34 . A method of inhibiting fatty acid amide hydrolase activity in a mammal, said method comprising administering to the mammal a compound of the formula 
       
         
           
           
               
               
           
         
         wherein 
         X is O or S; 
         Q is O or S; 
         R is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted biphenylyl, substituted or unsubstituted naphthyl, and substituted or unsubstituted phenyl, substituted or unsubstituted terphenylyl, substituted or unsubstituted heteroaryl, and 
       
       
         
           
           
               
               
           
         
         
           wherein p is a number from 0 to 3; 
           m is a number from 0 to 4, and 
           n is a number from 0 to 5, 
           Z 1  and Z 2  are same or different and are independently selected from the group consisting of —O—, —S—, —N(R 5 )—, —C(R 6 )═C(R 7 )—, —C(R 6 )═N— and —N═C(R 6 )— wherein R 5  is selected from H, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl and aroyl; R 6  and R 7  are each H or R 6  and R 7  optionally may combine to form a saturated or unsaturated carbocyclic or heterocyclic ring, optionally substituted with one or more R a  and R b  groups; 
           Y is a bond or selected from the group consisting of —O—, —S—, —N(R 5 )—, C 1 -C 4  alkylene, (Z)- or (E)-ethylene, and cycloalkyl with 3 to 6 carbon atoms; 
           each R a  and each R b  are independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, ketoalkyl, hydroxyalkyl, aminoalkyl, —CH 2 —NR 3 R 4 , alkoxy, aryloxy, arylalkyloxy, halo, haloalkyl, cyano, hydroxy, nitro, amino, —NR 3 R 4 , —SR  5 , carboxamido, —CONR 3 R 4 , —O-carboxamido, —O—CO—NR 3 R 4 , sulfonamido, and —SO 2 NR 3 R 4 , wherein R 3  and R 4  are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl and imino-methylamino and wherein optionally R 3  and R 4  together with the N atom to which they are attached to form a 5-7 membered cyclic ring; and 
           R 1  and R 2  are independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted cycloheteroalkyl, and optionally R 1  and R 2 , may be taken together with the N atom to which they are attached to form a substituted or unsubstituted ring; 
         
         and the pharmaceutically acceptable salts thereof. 
       
     
     
         35 . The method of  claim 34 , wherein the mammal is human. 
     
     
         36 . The method of  claim 34 , wherein the compound is administered orally. 
     
     
         37 . The method of  claim 34 , wherein R is substituted or unsubstituted biphenylyl, R 2  is H, and R 1  is C 1 -C 8  homoalkyl, C 1 -C 8  heteroalkyl, or C 1 -C 8  cycloalkyl. 
     
     
         38 . The method of  claim 37 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
         and m is a number from 0 to 4 and n is a number from 0 to 5; 
         each R a  and each R b  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, ketoalkyl, hydroxyalkyl, aminoalkyl, —CH 2 —NR 3 R 4 , alkoxy, aryloxy, halo, haloalkyl, cyano, hydroxy, nitro, amino, —R 3 R 4 , carboxamido, —ONR 3 R 4 , —O-carboxamido, —O—CO—NR 3 R 4 , sulfonamido, —SO 2 NR 3 R 4 ; and
 wherein R 3  and R 4  are independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl and imino-methylamino or R 3  and R 4  may combine to form a 5-7 membered cyclic ring.