Therapeutic uses of derivatives of piperidinyl-and piperidinyl-alkyl carbamates

Abstract

Compound corresponding to the general formula (I): in which A=N or CR 2 ; R 2 ═H, F, OH, CN, CF 3 , C 1-6 -alkyl, C 1-6 -alkoxy; n=2 or 3 and m=2 when A=N; n=1, 2 or 3 and m=1 or 2 when A=CR 2 ; B=covalent bond or C 1-8 -alkylene; R 1 =optionally substituted heteroaryl; R 3 ═CHR 4 CONHR 5 ; R 4 ═H or C 1-6 -alkyl; R 5 ═H, C 1-6 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1 -C 6 -alkylene; in the form of a base, an acid-addition salt, a hydrate or a solvate. Therapeutic uses thereof.

1 . A compound corresponding to formula (I) 
       
         
           
           
               
               
           
         
         in which 
         A is a nitrogen atom or a CR 2  group in which R 2  is a hydrogen or fluorine atom or a hydroxyl, cyano, trifluoromethyl, C 1-6 -alkyl or C 1-6 -alkoxy group; 
         when A is a nitrogen atom, n is an integer equal to 3 and m is 2; 
         when A is a CR 2  group, n is an integer equal to 1, 2 or 3 and m is an integer equal to 1 or 2; 
         B is a covalent bond or a C 1-8 -alkylene group; 
         R 1  is a group selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolyl, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyridyl, oxazolopyridyl, isoxazolopyridyl and thiazolopyridyl, said R 1  group being optionally substituted with one or more groups selected from R′ and R″; 
         R′ is a halogen atom or a cyano, nitro, hydroxyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -thioalkyl, C 1-6 -fluoroalkyl, C 1-6 -fluoroalkoxy, C 1-6 -fluorothioalkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkylene, azetidinyl, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, azepinyl, NH 2 , NHR 6 , NR 6 R 7 , NR 6 COR 7 , NR 6 SO 2 R 7 , COR 6 , CO 2 R 6 , SO 2 R 6 , SO 2 NR 6 R 7  or —O—(C 1-6 -alkylene)-O— group; 
         R″ is a phenyl, imidazolyl, pyridyl or pyrimidinyl group; 
         each R″ group is optionally substituted with one or more R′groups, which may be identical to or different from each other; 
         R 3  is a group of general formula CHR 4 CONHR 5  in which:
 R 4  is a hydrogen atom or a C 1-6 -alkyl group and 
 R 5  is a hydrogen atom or a C 1-6 -alkyl, C 3-7 -cycloalkyl or C 3-7 -cycloalkyl-C 1-6 -alkylene group; and 
 
         each of R 6  and R 7  is, independently, a C 1-6 -alkyl group; 
         in the form of a base, an acid-addition salt, a hydrate or a solvate. 
       
     
     
         2 . A compound of formula (I) according to  claim 1 , wherein:
 A is a nitrogen atom;   n is 3;   m is 2;   B is a C 1-8 -alkylene group;   R 1  is a group selected from phenyl, pyridyl, pyrimidinyl, thiadiazolyl and naphthyl, said R 1  group being optionally substituted with one or more groups selected from R′ and R″;   R′ is a halogen atom or a nitro or C 1-6 -fluoroalkyl group;   R″ is a phenyl, optionally substituted with one or more groups, which may be identical to or different from each other, selected from halogen cyano, C 1-6 -alkoxy and C 1-6 -fluoroalkoxy;   R 3  is a group of general formula CHR 4 CONHR 5  in which:
 R 4  is a hydrogen atom and 
 R 5  is a hydrogen atom or a C 1-6 -alkyl, C 3-7 -cycloalkyl or C 3-7 -cycloalkyl-C 1-6 -alkylene group; 
   in the form of a base, an acid-addition salt, a hydrate or a solvate.   
     
     
         3 . A compound of formula (I) according to  claim 1 , wherein:
 A is a CR 2  group in which R 2  is a hydrogen or fluorine atom or a hydroxyl group;   each of m and n is an integer equal to 1 or 2;   B is a covalent bond or a C 1-4 -alkylene group;   R 1  is a group selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridyl, thienopyrimidinyl, imidazopyrimidinyl, benzothiazolyl, benzimidazolyl and benzoxazolyl, said R 1  group being optionally substituted with one or more groups selected from R′ and R″;   R′ is a halogen atom, or a cyano or C 1-6 -alkyl, a C 1-6 -alkoxy, C 1-6 -fluoroalkyl, C 1-6 -fluoroalkoxy, C 3-7 -cycloalkyl, pyrrolidinyl, NH 2 , NR 6 R 7  or COR 6  group;   R″ is phenyl, imidazolyl or pyridyl;   each R″ group is optionally substituted with one or more R′ groups selected from chlorine and fluorine atoms;   R 3  is a group of general formula CHR 4 CONHR 5  in which
 R 4  is a hydrogen atom or a C 1-6 -alkyl group, and 
 R 5  is a hydrogen atom or a C 1-6 -alkyl, C 3-7 -cycloalkyl or C 3-7 -cycloalkyl-C 1 -C 6 -alkylene group; and 
   each of R 6  and R 7  is, independently, a C 1-6 -alkyl group;   in the form of a base, an acid-addition salt, a hydrate or a solvate.   
     
     
         4 . A compound of formula (I) according to  claim 1 , wherein:
 A is CH;   each of m and n is equal to 2;   B is an ethyl group;   R 1  is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridyl, thienopyrimidinyl, imidazopyrimidinyl, benzothiazolyl, benzimidazolyl and benzoxazolyl, said R 1  group being optionally substituted with one or more groups selected from R′ and R″;   R′ represents a halogen atom or a cyano or C 1-6 -alkyl, a C 1-6 -alkoxy, C 1-6 -fluoroalkyl, C 1-6 -fluoroalkoxy, C 3-7 -cycloalkyl, pyrrolidinyl, NH 2 , NR 6 R 7  or COR 6  group;   R″ represents a phenyl, imidazolyl or pyridyl;   each R″ group is optionally substituted with one or more R′ groups selected from chlorine and fluorine atoms;   R 3  is a group of general formula CH2CONHR 5  in which   R 5  is a hydrogen atom or a C 1 -C 6 -alkyl group; and   each of R 6  and R 7  is, independently, a C 1-6 -alkyl group;   in the form of the base, an acid-addition salt, a hydrate or a solvate.   
     
     
         5 . A process for preparing a compound of formula (I) according to  claim 1 , comprising the step of
 subjecting a carbamate ester of general formula (Ia)   
       
         
           
           
               
               
           
         
         in which n, m, A, B, R 1  and R 4  are as defined in  claim 1  and R represents a methyl or ethyl group, 
         to aminolysis using an amine of general formula R 5 NH 2  in which R 5  is as defined in  claim 1 . 
       
     
     
         6 . A process for preparing a compound of formula (I) according to  claim 1 , comprising the step of
 subjecting an oxazolidinedione derivative of general formula (V)   
       
         
           
           
               
               
           
         
         in which n, m, A, B, R 1  and R 4  are as defined in  claim 1 , 
         to aminolysis using an amine of general formula R 5 NH 2  in which R 5  is as defined in  claim 1 . 
       
     
     
         7 . A compound corresponding to the general formula (Ia) 
       
         
           
           
               
               
           
         
       
       in which
 A is a nitrogen atom or a CR 2  group in which R 2  is a hydrogen or fluorine atom or a hydroxyl, cyano, trifluoromethyl, C 1-6 -alkyl or C 1-6 -alkoxy group; 
 when A is a nitrogen atom, n is an integer equal to 3 and m is 2; 
 when A is a CR 2  group, n is an integer equal to 1, 2 or 3 and m is an integer equal to 1 or 2; 
 B is a covalent bond or a C 1-8 -alkylene group; 
 R 1  is a group selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolyl, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyridyl, oxazolopyridyl, isoxazolopyridyl and thiazolopyridyl, said R 1  group being optionally substituted with one or more groups selected from R′ and R″; 
 R′ is a halogen atom or a cyano, nitro, hydroxyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -thioalkyl, C 1-6 -fluoroalkyl, C 1-6 -fluoroalkoxy, C 1-6 -fluorothioalkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkylene, azetidinyl, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, azepinyl, NH 2 , NHR 6 , NR 6 R 7 , NR 6 COR 7 , NR 6 SO 2 R 7 , COR 6 , CO 2 R 6 , SO 2 R 6 , SO 2 NR 6 R 7  or —O—(C 1-6 -alkylene)-O— group; 
 R″ is a phenyl, imidazolyl, pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl group; 
 each R″ group is optionally substituted with one or more R′groups, which may be identical to or different from each other; 
 R 4  is a hydrogen atom or a C 1-6 -alkyl group; 
 each of R 6  and R 7  is, independently, a C 1-6 -alkyl group; and 
 R is a methyl or ethyl group. 
 
     
     
         8 . A compound corresponding to the general formula (V) 
       
         
           
           
               
               
           
         
       
       in which
 A is a nitrogen atom or a CR 2  group in which R 2  is a hydrogen or fluorine atom or a hydroxyl, cyano, trifluoromethyl, C 1-6 -alkyl or C 1-6 -alkoxy group; 
 when A is a nitrogen atom, n is an integer equal to 3 and m is 2; 
 when A is a CR 2  group, n is an integer equal to 1, 2 or 3 and m is an integer equal to 1 or 2; 
 B is a covalent bond or a C 1-8 -alkylene group; 
 R 1  is a group selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolyl, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyridyl, oxazolopyridyl, isoxazolopyridyl and thiazolopyridyl, said R 1  group being optionally substituted with one or more groups selected from R′ and R″; 
 R′ is a halogen atom or a cyano, nitro, hydroxyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -thioalkyl, C 1-6 -fluoroalkyl, C 1-6 -fluoroalkoxy, C 1-6 -fluorothioalkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkylene, azetidinyl, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, azepinyl, NH 2 , NHR 6 , NR 6 R 7 , NR 6 COR 7 , NR 6 SO 2 R 7 , COR 6 , CO 2 R 6 , SO 2 R 6 , SO 2 NR 6 R 7  or —O—(C 1-6 -alkylene)-O— group; 
 R″ is a phenyl, imidazolyl, pyridyl or pyrimidinyl group; 
 each R″ group is optionally substituted with one or more R′groups, which may be identical to or different from each other; 
 R 3  is a group of general formula CHR 4 CONHR 5  in which:
 R 4  is a hydrogen atom or a C 1-6 -alkyl group; and 
 
 each of R 6  and R 7  is, independently, a C 1-6 -alkyl group. 
 
     
     
         9 . A medicament comprising a compound of formula (I) according to  claim 1 , in the form of the base or of a pharmaceutically acceptable acid-addition salt, hydrate or solvate. 
     
     
         10 . A pharmaceutical composition containing at least one compound of formula (I) according to  claim 1 , in the form of a base or of a pharmaceutically acceptable acid-addition salt, hydrate or solvate, and one or more pharmaceutically acceptable excipients. 
     
     
         11 . A method of preventing or treating a pathology in which the endogenous cannabinoids and/or any other substrate metabolized by the enzyme FAAH are involved, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) according to  claim 1 , in the form of a base or of a pharmaceutically acceptable acid-addition salt, hydrate or solvate. 
     
     
         12 . The method of  claim 11  for preventing or treating acute or chronic pain, vertigo, vomiting, nausea, eating disorders, neurological and psychiatric pathologies, acute or chronic neurodegenerative diseases, epilepsy, sleeping disorders, cardiovascular diseases, renal ischaemia, cancers, immune system disorders, allergic diseases, parasitic, viral or bacterial infectious diseases, inflammatory diseases, osteoporosis, ocular complaints, pulmonary complaints, gastrointestinal diseases or urinary incontinence. 
     
     
         13 . A compound chosen from the group consisting of; 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         in the form of a base, an acid-addition salt, a hydrate or a solvate. 
       
     
     
         14 . A medicament comprising a compound according to  claim 13 , in the form of the base or of a pharmaceutically acceptable acid-addition salt, hydrate or solvate. 
     
     
         15 . A pharmaceutical composition containing at least one compound according to  claim 13 , in the form of a base or of a pharmaceutically acceptable acid-addition salt, hydrate or solvate, and one or more pharmaceutically acceptable excipients. 
     
     
         16 . A method of preventing or treating a pathology in which the endogenous cannabinoids and/or any other substrate metabolized by the enzyme FAAH are involved, comprising administering to a patient in need thereof an effective amount of a compound according to  claim 13 , in the form of a base or of a pharmaceutically acceptable acid-addition salt, hydrate or solvate. 
     
     
         17 . The method of  claim 16  for preventing or treating acute or chronic pain, vertigo, vomiting, nausea, eating disorders, neurological and psychiatric pathologies, acute or chronic neurodegenerative diseases, epilepsy, sleeping disorders, cardiovascular diseases, renal ischaemia, cancers, immune system disorders, allergic diseases, parasitic, viral or bacterial infectious diseases, inflammatory diseases, osteoporosis, ocular complaints, pulmonary complaints, gastrointestinal diseases or urinary incontinence.