Substituted 3-benzofuranyl-indol-2-one-3-acetamididopiperazine derivatives, preparation thereof, and therapeutic use thereof

Abstract

The invention relates to disubstituted 3-benzofuranyl-indol-2-one-3-acetamidopiperazine derivatives of the general formula (I) where R1, R2, R3, R4, R5, R6, R7, R8, R9 and n are such as defined in claim 1 , to a method for preparing same, and to the therapeutic use of said compounds.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R1 represents a hydrogen atom or a (C1-6)alkyl, —C(═O)(C1-6)alkyl or —C(═O)aryl group; 
         R2, R3 and R4, which may be identical or different, located on any of the available positions of the phenyl nucleus, independently represent a hydrogen atom, a halogen atom, CN, OH, a (C1-6)alkyl group optionally substituted with a halogen atom or an OH; perhalo(C1-3)alkyl, (C1-6)alkoxy, perhalo(C1-3)alkoxy, aminocarbonyl, (C1-6)alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, aryl, aryloxy; heteroaryl; 
         the aryl, aryloxy or heteroaryl group possibly being optionally substituted with a halogen atom, CN, OH or a (C1-6)alkyl, perhalo(C1-3)alkyl or (C1-6)alkoxy group; it being understood that at least one from among R2, R3 and R4 is other than H and that the aryl, aryloxy or heteroaryl group may be optionally substituted with a halogen atom, CN, OH or a (C1-6)alkyl, perhalo(C1-3)alkyl or (C1-6) alkoxy group; 
         R5 and R6, which may be identical or different, represent a hydrogen atom or a group (C1-6)alkyl or R5 and R6 together form a C3-C6 ring; 
         R7 represents a group (C1-C6)alkyl or a group (C2-6)alkenyl; 
         R8 and R9, which are located on any of the available positions of the piperazine nucleus, represent a hydrogen atom, a group (C1-C6)alkyl or a group (C2-6)alkenyl, it being understood that at least one from among R8 and R9 is other than H; 
         or two from among R7, R8 and R9 together form a C3-C6 ring; 
         it being understood that R8 and R9 may be in the geminal position on the same carbon atom; 
         n represents 1 or 2; 
         in the form of the base or of an acid-addition salt. 
       
     
     
         2 . The compound according to  claim 1 , wherein:
 R1 represents a hydrogen atom or a (C1-6)alkyl, —C(═O)(C1-6)alkyl or —C(═O)aryl group;   R2, R3 and R4, which may be identical or different, located on any of the available positions of the phenyl nucleus, independently represent a hydrogen atom, a halogen atom, CN, OH or a (C1-6)alkyl, perhalo(C1-3)alkyl, (C1-6)alkoxy, perhalo(C1-3)alkoxy, aminocarbonyl, (C1-6)alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, aryl, aryloxy or heteroaryl group, it being understood that at least one from among R2, R3 and R4 is other than H;   R5 and R6, which may be identical or different, represent a hydrogen atom or a group (C1-6)alkyl or R5 and R6 together form a C3-C6 ring;   R7 represents a group (C1-C6)alkyl;   R8 and R9, which are located on any of the available positions of the piperazine nucleus, represent a hydrogen atom, a group (C1-C6)alkyl, it being understood that at least one from among R8 and R9 is other than H;   or two from among R7, R8 and R9 together form a C3-C6 ring;   n represents 1 or 2;   in the form of the base or of an acid-addition salt.   
     
     
         3 . The compound according to  claim 1 , wherein
 R1 represents a hydrogen atom or a —C(═O)(C1-6)alkyl, —C(═O)aryl or (C1-6)alkyl group;   R2, R3 and R4, which may be identical or different, located on any of the available positions of the phenyl nucleus, independently represent a hydrogen atom, a halogen atom, or a (C1-6)alkyl or trifluoromethyl group, it being understood that at least one from among R2, R3 and R4 is other than H;   R5 and R6, which may be identical or different, represent a hydrogen atom or a group (C1-6)alkyl;   R7 represents a group (C1-C6)alkyl;   R8 and R9, which are located on positions 2 and 6 of the piperazine nucleus, represent a hydrogen atom, a group (C1-C6)alkyl, it being understood that at least one from among R8 and R9 is other than H;   or two from among R7, R8 and R9 together form a C3-C6 ring;   n represents 1 or 2;   in the form of the base or of an acid-addition salt.   
     
     
         4 . The compound according to  claim 1 , wherein
 R1 represents a hydrogen atom or a —C(═O)methyl, —C(O)phenyl or methyl group;   R2, R3 and R4, which may be identical or different, located on any of the available positions of the phenyl nucleus, independently represent a hydrogen atom, a halogen atom, or a methyl or trifluoromethyl group, it being understood that at least one from among R2, R3 and R4 is other than H;   R5 and R6, which may be identical or different, represent a hydrogen atom or a group (C1-6)alkyl;   R7 represents a methyl or ethyl group;   R8 and R9, which are located on positions 2 and 6 of the piperazine nucleus, represent a hydrogen atom or a methyl or ethyl group, it being understood that at least one from among R8 and R9 is other than H;   or two from among R7, R8 and R9 together form a C3-C6 ring;   n represents 1 or 2;   in the form of the base or of an acid-addition salt.   
     
     
         5 . The compound according to  claim 1 , chosen from the following compounds:
 Compound No. 1: (+)-N-[4,6-dichloro-3-(benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-ethylpiperazin-1-yl)acetamide;   Compound No. 2: (+)-N-[4,6-dichloro-3-(benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-ethylpiperazin-1-yl)propionamide;   in the form of the base or of an acid-addition salt.   
     
     
         6 . A process for preparing a compound according to  claim 1 , comprising reacting a compound of general formula (V): 
       
         
           
           
               
               
           
         
         in which R2, R3 and R4 may be identical or different, located on any of the available positions of the phenyl nucleus, independently represent a hydrogen atom, a halogen atom, CN, OH, a (C1-6)alkyl group optionally substituted with a halogen atom or an OH; perhalo(C1-3)alkyl, (C1-6)alkoxy, perhalo(C1-3)alkoxy, aminocarbonyl, (C1-6)alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, aryl, aryloxy; heteroaryl; 
         the aryl, aryloxy or heteroaryl group possibly being optionally substituted with a halogen atom, CN, OH or a (C1-6)alkyl, perhalo(C1-3)alkyl or (C1-6)alkoxy group; it being understood that at least one from among R2, R3 and R4 is other than H and that the aryl, aryloxy or heteroaryl group may be optionally substituted with a halogen atom, CN, OH or a C1-6)alkyl, perhalo C1-3) alkyl or C1-6) alkoxy group with a compound of general formula (VI): 
       
       
         
           
           
               
               
           
         
         in which Hal′ and Hal″, which may be identical or different, independently represent a halogen atom; 
         and then in reacting the compound of general formula (III) obtained 
       
       
         
           
           
               
               
           
         
         with a compound of general formula (IV): 
       
       
         
           
           
               
               
           
         
         in which R7 represents a group (C1-C6)alkyl or a group (C2-6)alkenyl; R8 and R9, which are located on any of the available positions of the piperazine nucleus, represent a hydrogen atom, a group (C1-C6)alkyl or a group (C2-6)alkenyl, it being understood that at least one from among R8 and R9 is other than H; 
         or two from among R7, R8 and R9 together form a C3-C6 ring; 
         it being understood that R8 and R9 may be in the geminal position on the same carbon atom; 
         n represents 1 or 2; and Hal″ represents a halogen atom; 
         optionally followed by the step that consists in reacting the product of formula (I) obtained in which R1 is equal to H, with a compound of formula (II):
   R1-Hal  (II)
 
 
         in which R1 is a (C1-6)alkyl, —C(═O)(C1-6)alkyl or —C(═O)aryl group, and Hal represents a halogen atom. 
       
     
     
         7 . (canceled) 
     
     
         8 . The process according to  claim 6 , comprising reacting the said compound of general formula (V) with a compound of general formula (VII): 
       
         
           
           
               
               
           
         
         in which R5 and R6, which may be identical or different, represent a hydrogen atom or a group (C1-6)alkyl or R5 and R6 together form a C3-C6 ring; 
         R7 represents a group (C1-C6)alkyl or a group (C2-6)alkenyl; 
         R8 and R9, which are located on any of the available positions of the piperazine nucleus, represent a hydrogen atom, a group (C1-C6)alkyl or a group (C2-6)alkenyl, it being understood that at least one from among R8 and R9 is other than H; 
         or two from among R7, R8 and R9 together form a C3-C6 ring; 
         it being understood that R8 and R9 may be in the geminal position on the same carbon atom 
         optionally followed by reacting the product of formula (I) obtained, in which R1 is equal to H, with a compound of formula (II):
   R1-Hal  (II)
 
 
         in which R1, which is other than H, is defined as in the general formula (I) and Hal represents a halogen atom. 
       
     
     
         9 . The process for preparing a compound according to  claim 1 , comprising reacting a compound of general formula (XVII): 
       
         
           
           
               
               
           
         
         in which R2, R3 and R4 may be identical or different, located on any of the available positions of the phenyl nucleus, independently represent a hydrogen atom, a halogen atom, CN, OH, a (C1-6)alkyl group optionally substituted with a halogen atom or an OH; perhalo(C1-3)alkyl, (C1-6)alkoxy, perhalo(C1-3)alkoxy, aminocarbonyl, (C1-6)alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, aryl, aryloxy; heteroaryl; 
         the aryl, aryloxy or heteroaryl group possibly being optionally substituted with a halogen atom, CN, OH or a (C1-6)alkyl, perhalo(C1-3)alkyl or (C1-6)alkoxy group; it being understood that at least one from among R2, R3 and R4 is other than H and that the aryl, aryloxy or heteroaryl group may be optionally substituted with a halogen atom, CN, OH or a (C1-6)alkyl, perhalo(C1-3)alkyl or (C1-6) alkoxy group and ALK represents an alkyl group with a compound of general formula (VII): 
       
       
         
           
           
               
               
           
         
         in which R5, R6, R7, R8, and R9 are as defined in  claim 1 . 
       
     
     
         10 . (canceled) 
     
     
         11 . The process according to  claim 6 , further comprising separating out the desired compound of general formula (I). 
     
     
         12 . A pharmaceutical composition comprising the compound of  claim 1 , or an addition salt of said compound with a pharmaceutically acceptable acid. 
     
     
         13 . A pharmaceutical composition comprising the compound of  claim 1 , or a pharmaceutically acceptable salt. 
     
     
         14 . A method of preventing or treating obesity, diabetes, appetite disorders and excess weight in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of  claim 12 . 
     
     
         15 . (canceled) 
     
     
         16 . A combination comprising one or more compounds according to  claim 1  with one or more active ingredient(s). 
     
     
         17 . The process according to  claim 9 , further comprising separating out the desired compound of general formula (I).