Oxophenyl-Cyclohexyl-Propanolamine Derivatives, Production And Use Thereof In Therapeutics

Abstract

The invention relates to the compounds of general formula (I) where R 1 represents H, a (C1-C4)alkyl, —CO(C1-C4)alkyl, (C1-C4)alkylphenyl or —CO-phenyl group, said phenyl being optionally substituted, R 2 represents H, a halogen atom, an —S(O) z R 3 , —NHSO 2 R 3 , —NHSO 2 -phenyl or —NHSO 2 —(C1-C4)alkylphenyl group where z is equal to 0, 1 or 2 and where R 3 represents a (C1-C4)alkyl group, said phenyl being optionally substituted; A is chosen from where n is equal to 0, 1 or 2, R 4 and R 5 represent H, a (C1-C4)alkyl, hydroxyl, cyano, phenyl, benzyl, piperidyl, —CONH 2 , —CO-phenyl, —COOR 3 , —CH(phenyl) (OH) and —C(phenyl) 2 (OH) group, or R 4 and R 5 form together an optionally substituted 6-membered aromatic ring, R 6 represents H, a (C1-C4)alkyl, phenyl or benzyl group, and B represents a 5- or 6-membered nitrogen-containing heterocycle or homocycle optionally fused with a phenyl group or optionally substituted; their addition salts; their method of preparation and their therapeutic application.

1 . A compound corresponding to formula (I): 
     
       
         
         
             
             
         
       
       in which: 
       R 1  represents a hydrogen atom or a (C1-C4)alkyl group, a —CO(C1-C4)alkyl group, a (C1-C4)alkylphenyl group or a —CO-phenyl group, said phenyl being optionally substituted with one to three groups chosen independently of each other from halogen atoms, (C1-C4)alkyl and (C1-C4)alkoxy groups; 
       R 2  is chosen from one of the following groups:
 a hydrogen atom, 
 a halogen atom, 
 an —S(O) z R 3  group, 
 an —NHSO 2 R 3  group, 
 an —NHSO 2 -phenyl group, or 
 an —NHSO 2 —(C1-C4)alkylphenyl group, 
 
       where z is equal to 0, 1 or 2 and where R 3  represents a (C1-C4)alkyl group, said phenyl being optionally substituted with one to three groups chosen independently of each other from halogen atoms, (C1-C4)alkyl and (C1-C4)alkoxy groups; and 
       A is chosen from one of the groups of formula: 
     
     
       
         
         
             
             
         
       
       in which:
 n is equal to 0, 1 or 2, 
 R 4  and R 5  are carried either by different carbon atoms, or by the same carbon atom of the ring to which they are attached, and are chosen independently of each other from the following groups: a hydrogen atom, a (C1-C4)alkyl, hydroxyl, cyano, phenyl, benzyl, piperidyl, —CONH 2 , —CO-phenyl, —COOR 3  (where R 3  is as defined above), —CH(phenyl) (OH) and —C(phenyl) 2 (OH) group, at least one of R 4  or R 5  being different from a hydrogen atom, 
 or R 4  and R 5  are carried by adjacent carbon atoms of the ring to which they are attached and form together with the carbon atoms carrying them a 6-membered aromatic ring optionally substituted with 1 to 3 (C1-C4)alkyl or (C1-C4)alkoxy groups, 
 R 6  represents a hydrogen atom or a (C1-C4)alkyl, phenyl or benzyl group, and 
 B represents a saturated or unsaturated, 5- or 6-membered cycloalkyl group optionally containing 1 or 2 nitrogen atoms, this cycloalkyl group being itself condensed with a phenyl group or substituted with one to three groups chosen from phenyl and carbonyl groups;
 in the form of bases or addition salts with acids, and in the form of hydrates or solvates. 
 
 
     
   
   
       2 . The compound of formula (I) as claimed in  claim 1 , characterized in that R 1  represents a hydrogen atom,
 in the form of bases or addition salts with acids, and in the form of hydrates or solvates.   
   
   
       3 . The compound of formula (I) as claimed in  claim 1  or  claim 2 , characterized in that R 2  represents an —SO 2 R 3  or —NHSO 2 R 3  group, where R 3  is as defined in  claim 1 ,
 in the form of bases or addition salts with acids, and in the form of hydrates or solvates.   
   
   
       4 . The compound of formula (I) as claimed in any one of  claims 1  to  3 , characterized in that A is chosen from one of the following groups:
 a group of formula   
     
       
         
         
             
             
         
       
       in which n is equal to 0 or 1 and R 4  and R 5  are carried either by different carbon atoms, or by the same carbon atom of the ring to which they are attached and are chosen independently of each other from the following groups: a hydrogen atom, a (C1-C4)alkyl, hydroxyl, cyano, phenyl, benzyl, piperidyl, —CONH 2 , —CO-phenyl, —COOR 3  (where R 3  is as defined in  claim 1 ), —CH(phenyl) (OH) and —C(phenyl) 2 (OH) group, at least one of R 4  or R 5  being different from a hydrogen atom, 
       a group of formula 
     
     
       
         
         
             
             
         
       
       in which n is equal to 0 or 1 and the aromatic ring is optionally substituted with 1 to 3 groups chosen independently of each other from (C1-C4)alkyl and (C1-C4)alkoxy groups, 
       a group of formula 
     
     
       
         
         
             
             
         
       
       in which n is equal to 0 or 1 and R 6  represents a hydrogen atom or a benzyl group, and 
       a group of formula 
     
     
       
         
         
             
             
         
       
       in which n is equal to 0 or 1 and B represents a saturated or unsaturated 5- or 6-membered cycloalkyl group optionally containing 1 or 2 nitrogen atoms, this cycloalkyl group being itself fused with a phenyl group or substituted with one to three groups chosen from phenyl and carbonyl groups;
 in the form of bases or addition salts with acids, and in the form of hydrates or solvates. 
 
     
   
   
       5 . Method for preparing the compounds of formula (I) according to any one of  claims 1  to  4 , characterized in that a compound of formula (VI), in which R 1  and R 2  are as defined in any one of  claims 1  to  3  and Pg represents a protecting group: 
     
       
         
         
             
             
         
       
     
     is reacted with an amine of formula: 
     
       
         
         
             
             
         
       
     
     in which A is as defined in  claim 1  or  4 , in the presence of a coupling agent and a base, and in that the protecting group Pg is removed from the product thus obtained. 
   
   
       6 . A medicament, characterized in that it comprises a compound of formula (I) according to any one of  claims 1  to  4 , or an addition salt of this compound with a pharmaceutically acceptable acid, or a hydrate or a solvate of the compound of formula (I). 
   
   
       7 . Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of  claims 1  to  4 , or a pharmaceutically acceptable salt, a hydrate or a solvate of this compound, and at least one pharmaceutically acceptable excipient. 
   
   
       8 . The use of a compound of formula (I) according to any one of  claims 1  to  4 , for the preparation of a medicament intended for the treatment of diseases in which the beta-3 receptors are involved. 
   
   
       9 . The use of a compound of formula (I) as claimed in any one of  claims 1  to  4 , for the preparation of a medicament intended for the treatment of gastrointestinal diseases such as inflammatory bowel diseases, for example irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD), as modulators of intestinal motility, as lipolytics, anti-obesity, anti-diabetic, anti-glaucomatous and cicatrizing agents, as uterine contraction inhibitors, as tocolytics for preventing or delaying preterm labor, and for the treatment and/or prophylaxis of dysmenorrhea, as psychotropics or antidepressants, and for the treatment of urinary incontinence.