Derivatives of heteroaryl-alkylcarbamates, methods for their preparation and use thereof as fatty acid amido hydrolase enzyme inhibitors

Abstract

The present invention is directed to compounds and compositions for the treatment of neurological diseases that cause neurogenic and neuropathic pain, inflammatory diseases, renal ischaemia, cardiovascular disease and other pathologies caused by the presence of endogenous cannabinoids and or other substrates resulting from the metabolic activities of fatty acid amido hydrolase (FAAH). These compounds are represented by the formula (I): wherein A, n, R 1 , R 7 and R 8 are as defined herein.

1 . A compound according to the formula (I): 
     
       
         
         
             
             
         
       
     
     wherein A is selected from the group consisting of X, Y and Z; wherein
 X represents a methylene group optionally substituted by one or two C 1-6 -alkyl, C 3-7 -cycloalkyl or C 3-7 -cycloalkyl-C 1-3 -alkylene groups; 
 Y represents either a C 2 -alkenylene group optionally substituted by one or two C 1-6 -alkyl, C 3-7 -cycloalkyl or C 3-7 -cycloalkyl-C 1-3 -alkylene groups; or a C 2 -alkynylene group; 
 Z represents a group of formula: 
 
     
       
         
         
             
             
         
       
       m represents an integer ranging from 1 to 5; 
       p and q represent integers and are defined such that p+q is a number ranging from 1 to 5; 
       n represents an integer ranging from 1 to 7; 
       R 1  represents an R 2  group optionally substituted by one or more R 3  and R 4  groups; 
       R 2  represents a group chosen from a pyridyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, naphthyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 2-oxo-3,4-dihydroquinolinyl, 1-oxo-3,4-dihydroisoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, naphthyridinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl and isothiazolopyridyl; 
       R 3  represents a group chosen from halogen atoms, cyano, nitro, C 1-6 -alkyl, C 3-7 -cycloalkyl, C 1-6 -alkoxy, hydroxyl, C 1-6 -thioalkyl, C 1-6 -fluoroalkyl, C 1-6 -fluoroalkoxy, C 1-6 -fluorothioalkyl, NR 5 R 6 , NR 5 COR 6 , NR 5 CO 2 R 6 , NR 5 SO 2 R 6 , COR 5 , CO 2 R 5 , CONR 5 R 6 , SO 2 R 5 , SO 2 NR 5 R 6 , —O—(C 1-3 -alkylene)-O— and phenyl group, the phenyl group optionally being substituted by one or more halogen atoms; 
       R 4  represents a group chosen from phenyl, phenyloxy, benzyloxy, naphthyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl groups; it being possible for the R 4  group or groups to be substituted by one or more R 3  groups which are identical to or different from one another; 
       R 5  and R 6  represent, independently of one another, a hydrogen atom or a C 1-6 -alkyl group or, with the atom or atoms which carry them, form a ring chosen from the group consisting of an azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine or piperazine ring, this ring optionally being substituted by a C 1-6 -alkyl or benzyl group; 
       R 7  represents a hydrogen atom or a C 1-6 -alkyl group, and 
       R 8  represents a hydrogen atom or a C 1-6 -alkyl, C 3-7 -cycloalkyl or C 3-7 -cycloalkyl-C 1-3 -alkylene group; or a salt thereof. 
     
   
   
       2 . The compound as recited in  claim 1 , wherein:
 A is chosen from one or more groups X or Y;   X represents a methylene group;   Y represents a C 2 -alkynylene group;   n represents an integer ranging from 1 to 5;   R 2  represents a group chosen from a pyridyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl, 2-oxo-3,4-dihydroquinolinyl, indolyl, benzimidazolyl and pyrrolopyridyl;   R 3  represents a group chosen from halogen atoms or C 1-6 -alkyl, C 3-7 -cycloalkyl, C 1-6 -alkoxy, NR 5 R 6  and phenyl groups;   R 4  represents a group chosen from phenyl, naphthyl and pyridyl groups; it being possible for the R 4  group or groups to be substituted by one or more R 3  groups which are identical to or different from one another;   R 5  and R 6  represent, independently of one another, a C 1-6 -alkyl group;   R 7  represents a hydrogen atom or a C 1-6 -alkyl group; and   R 8  represents a hydrogen atom or a C 1-6 -alkyl, C 3-7 -cycloalkyl or C 3-7 -cycloalkyl-C 1-3 -alkylene group;   a salt thereof.   
   
   
       3 . The compound as recited in  claim 2  wherein R 2  is selected from the group consisting of pyridyl, oxazolyl, isoxazolyl, naphthyl, quinolinyl and isoquinolinyl. 
   
   
       4 . The compound as recited in  claim 3  wherein:
 R 7  represents a hydrogen atom; and   R 8  represents a hydrogen atom or a C 1-6 -alkyl group; or   a salt thereof.   
   
   
       5 . A process for the preparation of the compound of formula (I) as recited in  claim 1  comprising converting the carbamate ester of formula (IV): 
     
       
         
         
             
             
         
       
     
     to the compound of formula (I) by aminolysis using an amine of formula R 8 NH 2 , in which A, n, R 1  and R 7  and R 8  are as defined in  claim 1 . 
   
   
       6 . A process for the preparation of the compound of formula (I) as recited in  claim 1  comprising converting the oxazolidinedione derivative of formula (VII): 
     
       
         
         
             
             
         
       
     
     to the compound of formula (I) by aminolysis, using an amine of formula R 8 NH 2 , in which A, n, R 1 , R 7  and R 8  are as defined in  claim 1 . 
   
   
       7 . A pharmaceutical composition comprising the compound of  claim 1  or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 
   
   
       8 . A pharmaceutical composition comprising the compound of  claim 2  or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 
   
   
       9 . A pharmaceutical composition comprising the compound of  claim 3  or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 
   
   
       10 . A pharmaceutical composition comprising the compound of  claim 4  or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 
   
   
       11 . A method for the treatment of a sleep disorder comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof. 
   
   
       12 . A method for the treatment of a sleep disorder comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to  claim 2  or a pharmaceutically acceptable salt thereof. 
   
   
       13 . A method for the treatment of a sleep disorder comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to  claim 3  or a pharmaceutically acceptable salt thereof. 
   
   
       14 . A method for the treatment of a sleep disorder comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to  claim 4  or a pharmaceutically acceptable salt thereof.