Novel benzimidazole and imidazopyridine derivatives and use thereof as a medicament

Abstract

The invention relates to novel benzimidazole and imidazopyridine derivatives having the general Formula (I), which have a good affinity with certain subtypes of melanocortin receptors, particularly MC4 receptors. The derivatives are particularly suitable for the treatment of pathological states and diseases involving one or more melanocortin receptors. The invention also relates to pharmaceutical compositions containing said the compounds having the general Formula (I).

1 . A compound of general formula (I) 
       
         
           
           
               
               
           
         
         in racemic, enantiomeric form or any combinations of these forms and in which: 
         A represents —CH 2 —, —C(O)—, or —C(O)—C(R a )(R b )—; 
         X represents the —CH— radical or the nitrogen atom; 
         R a  and R b  represent, independently, the hydrogen atom or a (C 1 -C 6 )alkyl radical; 
         R 1  represents the hydrogen atom or a (C 1 -C 8 )alkyl radical; 
         R 2  represents a (C 1 -C 8 )alkyl radical; 
         or R 1  and R 2  form together with the nitrogen atom to which they are attached, a heterobicycloalkyl or a heterocycloalkyl optionally substituted by one or more identical or different (C 1 -C 6 )alkyl substituents; 
         R 3  represents —C(O)—Z′ 3 , —CH(OH)—Z′ 3  or —C(O)—NH—Z″ 3 ;
 Z′ 3  represents an aryl radical optionally substituted by one or more identical or different substituents comprising halo, nitro or —(CH 2 ) p″ —V′ 3 —Y′ 3 ; 
 V′ 3  represents —O—, —C(O)—, —C(O)—O—, —NH—C(O)—, —C(O)—NR′ 3 — or a covalent bond; 
 Y′ 3  represents the hydrogen atom or a (C 1 -C 6 )alkyl radical optionally substituted by one or more identical or different halo radicals; 
 R′ 3  represents the hydrogen atom, a (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy radical; 
 Z″ 3  represents the hydrogen atom or a —(CH 2 ) q -A″ 3  radical; 
 A″ 3  represents a (C 1 -C 6 )alkyl, aryl or heteroaryl radical;
 the alkyl and aryl radicals being optionally substituted by one or more identical or different substituents comprising halo or —V″ 3 —Y″ 3 ; 
 V″ 3  represents —O—, —C(O)—, —C(O)—O—, —C(O)—NH— or a covalent bond; 
 Y″ 3  represents the hydrogen atom or a (C 1 -C 6 )alkyl radical optionally substituted by one or more identical or different halo radicals; 
 p represents an integer from 0 to 6; p′ and p″ represent, independently, an integer from 0 to 4; q represents an integer from 0 to 2; 
 
 
         R 4  represents a radical of formula-(CH 2 ) s —R′ 4 ; 
         R′ 4  represents a heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C 1 -C 6 )alkyl 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound according to  claim 1 , wherein X represents the —CH— radical; or a pharmaceutically acceptable salt thereof. 
     
     
         3 . A compound according to  claim 1 , wherein R 1  represents the hydrogen atom or a (C 1 -C 8 )alkyl radical, and R 2  represents a (C 1 -C 8 )alkyl radical; or a pharmaceutically acceptable salt thereof. 
     
     
         4 . A compound according to  claim 1 , wherein R 1  represents a (C 1 -C 6 )alkyl radical; R 2  represents a (C 1 -C 6 )alkyl radical; or a pharmaceutically acceptable salt thereof. 
     
     
         5 . A compound according to  claim 1 , wherein A represents —CH 2 —; or a pharmaceutically acceptable salt thereof. 
     
     
         6 . A compound according to  claim 1 , wherein A represents —C(O)—C(R a )(R b )— and R a  and R b  represent, independently, a methyl radical; or a pharmaceutically acceptable salt thereof. 
     
     
         7 . A compound according to  claim 1 , wherein A represents —C(O)—; or a pharmaceutically acceptable salt thereof. 
     
     
         8 - 9 . (canceled) 
     
     
         10 . A compound according to  claim 1 , wherein R 4  represents a radical of formula-(CH 2 ) s —R′ 4 ;
 R′ 4  represents a heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C 1 -C 6 )alkyl; and s represents an integer from 2 to 6; or a pharmaceutically acceptable salt thereof. 
 
     
     
         11 . A compound according to  claim 10 , wherein R′ 4  represents the piperidine or pyrrolidine ring; s represents an integer from 1 to 4; or a pharmaceutically acceptable salt thereof. 
     
     
         12 - 20 . (canceled) 
     
     
         21 . A compound according to  claim 1 , wherein R 3  represents —C(O)—Z′ 3 ; or a pharmaceutically acceptable salt thereof. 
     
     
         22 . A compound according to  claim 21 , wherein Z′ 3  represents a phenyl radical optionally substituted by one or more identical or different substituents of formula —(CH 2 ) p″ —V′ 3 —Y′ 3 ;
 V′ 3  represents —O—; 
 Y′ 3  represents a (C 1 -C 6 )alkyl radical; 
 p″ represents an integer from 0 to 4; or a pharmaceutically acceptable salt thereof. 
 
     
     
         23 . A compound according to  claim 1 , wherein R 3  represents —C(O)—NH—Z″ 3  
 Z″ 3  represents a —(CH 2 ) q -A″ 3  radical; 
 A″ 3  represents a (C 1 -C 6 )alkyl, phenyl or thienyl radical; 
 the alkyl and aryl radicals being optionally substituted by one or more identical or different substituents of formula —V″ 3 —Y″ 3 ; 
 V″ 3  represents —O—, —C(O)—, —C(O)—O— or a covalent bond; 
 Y″ 3  represents the hydrogen atom or a (C 1 -C 6 )alkyl radical; 
 q represents an integer from 0 to 1; or a pharmaceutically acceptable salt thereof. 
 
     
     
         24 . A method of making a compound of formula (I) according to  claim 1 , wherein the compound of general formula: 
       
         
           
           
               
               
           
         
         in which A, X, R 1 , R 2 , R 4  are defined in  claim 1 , is treated 
         i) either with an aldehyde of general formula R 3 CHO in which R 3  has the meaning indicated in  claim 1 , in the presence of an oxidizing agent; 
         ii) or with an acid chloride of general formula R 3 COCl in which R 3  has the meaning indicated in  claim 1 , in the presence of an acid; 
         iii) or with a carboxylic acid of general formula R 3 C(O)OH in which R 3  has the meaning indicated in  claim 1 , in the presence of a coupling agent followed by treatment of the amide thus formed by an acid; 
         iv) or with a chloroacetamide derivative of general formula Z″ 3 —NH—C(O)CH 2 Cl in which Z″ 3  has the meaning indicated above, in the presence of a tertiary base and sulphur. 
       
     
     
         25 . A pharmaceutical composition comprising, as active ingredient, at least one compound according to  claim 1 , in combination with a pharmaceutically acceptable support. 
     
     
         26 . A method of treating conditions comprising weight disorders, mental disorders, neuropathic pain or sexual activity disorders comprising administering a therapeutically effective amount of a compound of  claim 1  to a subject in need thereof. 
     
     
         27 . The method of  claim 26 , wherein the weight disorders comprises obesity, cachexia or anorexia. 
     
     
         28 . The method of  claim 26 , wherein the mental disorders comprises anxiety or depression. 
     
     
         29 . The method of  claim 26 , wherein the condition is neuropathic pain. 
     
     
         30 . The method of  claim 26 , wherein the sexual activity disorders erectile disorders.