Branched 3-phenylpropionic acid derivatives and their use

Abstract

The present application relates to novel 3-phenylpropionic acid derivatives which carry a branched or cyclic alkyl substituent in the 3-position, to processes for their preparation, to their use for the treatment and/or prevention of diseases and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of cardiovascular diseases.

1 . A compound of the formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 1 , R 2  and R 3  independently of one another represent hydrogen or methyl, 
         L represents a bond or represents —CH 2 —, 
         R 4A  and R 4B  independently of one another represent methyl, trifluoromethyl or ethyl 
         or 
         R 4A  and R 4B  are attached to one another and together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring which may be substituted up to two times by fluorine, 
         R 5  represents hydrogen, fluorine, methyl or methoxy, 
         R 6  represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl, ethyl, methoxy or trifluoromethoxy, 
         R 7  represents hydrogen, fluorine, chlorine or methyl, 
         R 8A  represents methyl or ethyl, 
         R 8B  represents trifluoromethyl, 
         or 
         R 8A  and R 8B  are attached to one another and together with the carbon atom to which they are attached form an optionally difluoro-substituted cyclopentyl ring of the formula 
       
       
         
           
           
               
               
           
         
         R 9  represents fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, (C 2 -C 4 )-alkenyl, cyclopropyl or cyclobutyl, where
 (C 1 -C 4 )-alkyl and (C 2 -C 4 )-alkenyl may be substituted up to three times by fluorine 
 and 
 cyclopropyl and cyclobutyl may be substituted up to two times by fluorine, 
 
         and 
         R 10  represents hydrogen, fluorine, chlorine, methyl, trifluoromethyl, ethyl or methoxy, 
         or a salt thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein:
 R 1  represents hydrogen or methyl,   R 2  represents hydrogen,   R 3  represents hydrogen or methyl,   L represents a bond or represents —CH 2 —,   R 4A  and R 4B  both represent methyl or are attached to one another and together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring which may be substituted up to two times by fluorine,
 R 5  represents hydrogen, fluorine, methyl or methoxy, 
   R 6  represents fluorine, chlorine, methyl or ethyl,
 R 7  represents hydrogen or fluorine, 
 R 8A  represents methyl, 
 R 8B  represents trifluoromethyl, 
 or 
   R 8A  and R 8B  are attached to one another and together with the carbon atom to which they are attached form a difluoro-substituted cyclopentyl ring of the formula   
       
         
           
           
               
               
           
         
         R 9  represents fluorine, chlorine, (C 1 -C 4 )-alkyl, (C 2 -C 3 )-alkenyl, cyclopropyl or cyclobutyl, where
 (C 1 -C 4 )-alkyl and (C 2 -C 3 )-alkenyl may be substituted up to three times by fluorine 
 and 
 cyclopropyl and cyclobutyl may be substituted up to two times by fluorine, 
 
         and 
         R 10  represents hydrogen, fluorine, chlorine, methyl or methoxy, 
         or a salt thereof. 
       
     
     
         3 . The compound of  claim 1  wherein:
 R 1  and R 2  both represent hydrogen, 
 R 3  represents hydrogen or methyl, 
 L represents a bond or represents —CH 2 —, 
 R 4A  and R 4B  both represent methyl or are attached to one another and together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring which may be substituted up to two times by fluorine,
 R 5  represents hydrogen, fluorine or methyl, 
 
 R 6  represents chlorine,
 R 7  represents hydrogen, 
 R 8A  represents methyl, 
 R 8B  represents trifluoromethyl, 
 
 R 9  represents fluorine, chlorine, methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, tert-butyl, cyclopropyl or 2,2-difluorocyclopropyl, 
 and 
 R 10  represents hydrogen, fluorine, methyl or methoxy, 
 and salts, solvates and solvates of the salts thereof. 
 
     
     
         4 . A process for preparing a compound of  claim 1 , comprising
 coupling a carboxylic acid of the formula (II)   
       
         
           
           
               
               
           
         
         in which R 8A , R 8B , R 9  and R 10  have the meanings given in  claim 1 , 
         in an inert solvent with the aid of a condensing agent or via the intermediate of the corresponding carbonyl chloride in the presence of a base with an amine of the formula (III) 
       
       
         
           
           
               
               
           
         
         in which L, R 1 , R 2 , R 3 , R 4A , R 4B , R 5 , R 6  and R 7  have the meanings given in  claims 1  to  3   
         and 
         T 1  represents (C 1 -C 4 )-alkyl or benzyl, 
         to give a carboxamide of the formula (IV) 
       
       
         
           
           
               
               
           
         
         in which L, R 2 , R 3 , R 4A , R 4B , R 5 , R 6 , R 7 , R 8A , R 8B , R 9 , R 10  and T 1  have the meanings given above, 
         and removing T 1  from the compound of formula (IV) by basic or acidic solvolysis or, when T 1  represents benzyl, also by hydrogenolysis to give a compound of  claim 1 . 
       
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . A pharmaceutical composition comprising a compound of  claim 1  and an inert, non-toxic, pharmaceutically suitable excipient. 
     
     
         8 . The pharmaceutical composition of  claim 1  further comprising an active compound selected from the group consisting of an organic nitrate, an NO donor, a cGMP-PDE inhibitor, a stimulator of guanylate cyclase, an agent having antithrombotic activity, an agent lowering blood pressure, and an agent altering lipid metabolisms. 
     
     
         9 . (canceled) 
     
     
         10 . Method for the treatment and/or prevention of heart failure, angina pectoris, hypertension, pulmonary hypertension, thromboembolic disorders, ischaemias, vascular disorders, microcirculation impairments, renal insufficiency, fibrotic disorders and arteriosclerosis comprising administering an effective amount of at least one compound of  claim 1  to a human or animal in need thereof. 
     
     
         11 . A method for the treatment and/or prevention of heart failure, angina pectoris, hypertension, pulmonary hypertension, thromboembolic disorders, ischaemias, vascular disorders, microcirculation impairments, renal insufficiency, fibrotic disorders and arteriosclerosis comprising administering an effective amount of a pharmaceutical composition of  claim 7  to a human or animal in need thereof.