Indol-2-one derivatives disubstituted in the 3-position, preparation thereof and therapeutic use thereof

Abstract

The present invention relates to 3-disubstituted indol-2-one derivatives, to their preparation and to their therapeutic application.

1 . A compound corresponding to formula (I): 
       
         
           
           
               
               
           
         
       
       in which:
    represents a single or double bond, 
 X represents —N<, —CH<or 
 
       
         
           
           
               
               
           
         
         Y represents >N— or >CH—, it being understood that at least one from among X and Y represents N; 
         Ar represents an aryl or heteroaryl group optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and (C1-6)alkyl, (C1-6)haloalkyl, perhalo(C1-3)alkyl, (C1-6)alkoxy, perhalo(C1-3)alkoxy and aryl groups; 
         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 represents a (C1-6)alkyl or (C2-6)alkenyl group; and 
         n represents 1 or 2; 
         in the form of the base or of an acid-addition salt; with the exclusion of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-[2-(4-methylpiperazin-1-yl)acet-amido]indol-2-one. 
       
     
     
         2 . The compound of  claim 1  wherein:
    represents a single or double bond;   X represents —CH<, —N<or   
       
         
           
           
               
               
           
         
         Y represents >N— or >CH—, it being understood that at least one from among X and Y represents N; 
         Ar represents an aryl or heteroaryl group optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and (C1-6)alkyl, perhalo(C1-3)alkyl, (C1-6)alkoxy and aryl groups; 
         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, a (C1-6)alkyl, perhalo(C1-3)alkyl, CN, aryl, heteroaryl, OH, (C1-6)alkoxy, perhalo(C1-3)alkoxy, aminocarbonyl, (C1-6) (C1-6)alkylaminocarbonyl or di(C1-6)alkylaminocarbonyl group, it being understood that at least one from among R2, R3 and R4 is other than H; 
         R5 represents a (C1-6)alkyl group; 
         n represents 1 or 2; 
         in the form of the base or of an acid-addition salt. 
       
     
     
         3 . The compound of  claim 2  wherein:
    represents a single or double bond;   X represents —N<, —CH<or   
       
         
           
           
               
               
           
         
         Y represents >N— or >CH—; 
         it being understood that at least one from among X and Y represents N; 
         Ar represents an aryl group optionally substituted with one or more substituents chosen from halogen atoms, preferentially chlorine or bromine, and (C1-6)alkoxy, (C1-6)alkyl, aryl, trifluoromethyl and trifluoromethoxy groups; 
         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, preferentially chlorine or bromine, 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 represents a (C1-6)alkyl group; 
         n represents 1 or 2; 
         in the form of the base or of an acid-addition salt. 
       
     
     
         4 . The compound of  claim 3  wherein:
    represents a single or double bond;   X represents —N<, —CH<or   
       
         
           
           
               
               
           
         
         Y represents >N— or >CH—; it being understood that at least one from among X and Y represents N; 
         Ar represents a phenyl or naphthyl group optionally substituted with one or more substituents chosen from halogen atoms, preferentially chlorine or bromine, and methoxy, methyl, tert-butyl, phenyl, trifluoromethyl and trifluoromethoxy groups; 
         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 trifluoromethyl group, it being understood that at least one from among R2, R3 and R4 is other than H; 
         R5 represents a methyl, ethyl or 2-propyl group; 
         n represents 1 or 2; 
         in the form of the base or of an acid-addition salt. 
       
     
     
         5 . The compound of  claim 2  wherein:
 Ar represents a heteroaryl group optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and (C1-6)alkoxy, aryl, perhalo(C1-3)alkyl and (C1-6)alkyl groups.   
     
     
         6 . The compound of  claim 1  wherein the compound is selected from the group consisting of:
 (+)-N-[5,6-dichloro-3-(4-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-methylpiperazin-1-yl)acetamide   (+)-N-[4,6-dichloro-3-(4-trifluoromethylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(1-ethylpiperid-4-yl)acetamide   N-[4,6-dichloro-3-(4-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-methylpiperazin-1-yl)acetamide   N-[4-trifluoromethyl-6-cyano-3-(4-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-ethylpiperazin-1-yl)acetamide   (+)-N-[1-benzoyl-5,6-dichloro-3-(4-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-methylpiperazin-1-yl)acetamide   3-(4-chlorophenyl)-3-[2-(4-ethylpiperazin-1-yl)acetylamino]-2-oxo-4-trifluoromethyl-2,3-dihydro-1H-indole-6-carboxamide   N-[6-chloro-3-(4-chlorophenyl)-1,5-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-methylpiperazin-1-yl)acetamide   (+)-N-[4,6-dichloro-3-(4-trifluoromethylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(1-ethyl-1,2,3,6-tetrahydropyrid-4-yl)acetamide   N-[4,6-dichloro-3-(3,4-dichlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-ethylpiperazin-1-yl)acetamide   N-[4,6-dichloro-3-(3-fluoro-4-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-ethylpiperazin-1-yl)acetamide   N-[4,6-dichloro-3-(3-trifluoromethyl-4-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-ethylpiperazin-1-yl)acetamide   N-[4,6-dichloro-1-ethyl-3-(2-methylbenzo[b]thiophen-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(1-ethylpiperid-4-yl)acetamide   N-[4,6-dichloro-1-ethyl-3-(2-methyl-5-benzofuryl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-ethylpiperazin-1-yl)acetamide   N-[4,6-dichloro-3-(4-trifluoromethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-ethylpiperazin-1-yl)acetamide   
       in the form of the base or of an acid-addition salt. 
     
     
         7 . A process for preparing a compound of formula (I) of  claim 1 , characterized in that it comprises a step that consists in reacting a compound of general formula (V): 
       
         
           
           
               
               
           
         
       
       in which R2, R3, R4 and Ar are as defined according to formula (I). 
     
     
         8 . The process of  claim 7 , further comprising the steps of:
 reacting the compound of formula (V) with a compound of 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 formula (III) obtained 
 
       
         
           
           
               
               
           
         
       
       with a compound of general formula (IV): 
       
         
           
           
               
               
           
         
       
       in which R2, R3, R4, R5, Y, Ar and n are as defined in formula (I) and Hal″ represents a halogen atom;
 optionally followed by the step that consists in reacting the product of formula (I) obtained, in which X represents —N< and 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 formula (I) and Hal represents a halogen atom. 
     
     
         9 . The process of  claim 7 , further comprising the step of reacting the compound of formula (V) with a compound of formula (VIII): 
       
         
           
           
               
               
           
         
       
       in which  , X, Y, R5 and n are as defined according to formula (I); 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 defined as in formula (I) with the proviso that R1 cannot be H, and Hal represents a halogen atom. 
     
     
         10 . A process for preparing a compound of formula (I) of  claim 1 , comprising the step of reacting a compound of formula (XXVIII): 
       
         
           
           
               
               
           
         
       
       in which R2, R3, R4 and Ar are as defined according to formula (I) and ALK represents an alkyl group. 
     
     
         11 . The process of  claim 10  further comprising the steps of:
 reacting the compound of formula (XXVIII) with a compound of formula (VI):   
       
         
           
           
               
               
           
         
       
       in which Hal′ and Hal″, which may be identical or different, independently represent a halogen atom;
 and then reacting the compound of formula (XXIX) obtained 
 
       
         
           
           
               
               
           
         
       
       with a compound of formula (IV): 
       
         
           
           
               
               
           
         
         in which R2, R3, R4, R5, Y, Ar and n are as defined in formula (I), and Hal″ represents a halogen atom. 
       
     
     
         12 . The process of  claim 10  further comprising a step that consists in reacting the compound of formula (XXVIII) with a compound of formula (VII): 
       
         
           
           
               
               
           
         
       
       in which
   , X, Y, R5 and n are as defined in formula (I). 
 
     
     
         13 . The process according to  claim 7 , further comprising a subsequent step that consists in separating out the desired compound of formula (I). 
     
     
         14 . A compound of formula (III): 
       
         
           
           
               
               
           
         
       
       in which R2, R3, R4 and Ar are as defined in formula (I) of  claim 1  and Hal represents a halogen atom, with the proviso that the compound of formula (III) cannot be 5-chloro-3-(2-chloroacetamido)-3-(2-chlorophenyl)-1,3-dihydroindol-2-one. 
     
     
         15 . The compound of  claim 14 , in which: 
       Ar represents a heteroaryl group optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and (C1-6)alkoxy, aryl, perhalo(C1-3)alkyl and (C1-6)alkyl groups. 
     
     
         16 . A compound of formula (XXVIII): 
       
         
           
           
               
               
           
         
       
       in which R2, R3, R4 and Ar are as defined according to formula (I) of  claim 1  and ALK represents an alkyl group. 
     
     
         17 . A compound of formula (XXIX): 
       
         
           
           
               
               
           
         
       
       in which R2, R3, R4 and Ar are as defined in formula (I) of  claim 1 , ALK represents an alkyl group and Hal″ represents a halogen atom. 
     
     
         18 . A medicament comprising a compound of formula (I) of  claim 1  or an addition salt of said compound with a pharmaceutically acceptable acid. 
     
     
         19 . A pharmaceutical composition comprising a compound of formula (I) of  claim 1  or a pharmaceutically acceptable salt. 
     
     
         20 . Use of a compound according to  claim 1  for the preparation of a medicament for preventing or treating obesity, diabetes, appetite disorders and excess weight. 
     
     
         21 . Use of a compound according to  claim 1  for preventing or treating obesity, diabetes, appetite disorders and excess weight. 
     
     
         22 . A combination comprising one or more compounds of  claim 1  with one or more active ingredient(s).