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 . Compound of the formula (I) 
       
         
           
           
               
               
           
         
         in which 
         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, and salts, solvates and solvates of the salts thereof. 
       
     
     
         2 . Compound of the formula (I) according to  claim 1  in which
 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, and salts, solvates and solvates of the salts thereof. 
       
     
     
         3 . Compound of the formula (I) according to  claim 1  in which
 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 . Process for preparing a compound of the formula (I) according to  claim 1 , characterized in that 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 , 
         is coupled 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  claim 1   
         and 
         T 1  represents (C 1 -C 4 )-alkyl or benzyl, 
         to give a carboxamide of the formula (IV) 
       
       
         
           
           
               
               
           
         
         in which L, R 1 , 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 the ester radical T 1  is then removed by basic or acidic solvolysis or, in the case that T 1  represents benzyl, also by hydrogenolysis to give the carboxylic acid of the formula (I) 
         and the compounds of the formula (I) are optionally separated by methods known to the person skilled in the art into their enantiomers and/or diastereomers and/or reacted with the appropriate (i) solvents and/or (ii) bases to give their solvates, salts and/or solvates of the salts. 
       
     
     
         5 . (canceled) 
     
     
         6 . Use of a compound as defined in  claim 1  for preparing a medicament 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. 
     
     
         7 . Medicament comprising a compound as defined in  claim 1  in combination with one or inert, non-toxic, pharmaceutically suitable excipients. 
     
     
         8 . Medicament comprising a compound as defined in  claim 1  in combination with one or more further active compounds selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, stimulators of guanylate cyclase, agents having antithrombotic activity, agents lowering blood pressure, and agents altering lipid metabolisms. 
     
     
         9 . Medicament according to  claim 7  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 
     
     
         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 in humans and animals by administration of an effective amount of at least one compound according to  claim 1 .