Substituted 3-phenylpropionic acids and the use thereof

Abstract

The present application relates to novel 3-phenylpropionic acid derivatives, 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 disorders.

1 . A compound of the formula (I) 
       
         
           
           
               
               
           
         
         in which 
         R 1A  represents hydrogen, fluorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, n-propyl, cyclopropyl or cyclobutyl, 
         R 1B  represents hydrogen or methyl, 
         R 2A  represents hydrogen, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, 2,2,2-tri-fluoroethyl or n-propyl, and 
         R 2B  represents hydrogen or methyl, 
         or 
         R 1A  and R 2A  are attached to one another and together with the carbon atoms to which they are attached form a cyclopropyl ring of the formula 
       
       
         
           
           
               
               
           
         
         
           in which R 1B  and R 2B  have the meanings mentioned above, 
         
         or 
         R 2A  and R 2B  are attached to one another and together with the carbon atom to which they are attached form a cyclic group of the formula 
       
       
         
           
           
               
               
           
         
       
       in which
 n represents the number 1, 2 or 3, and 
 R 1A  and R 1B  have the meanings mentioned above, 
 R 3  represents hydrogen, fluorine, methyl or trifluoromethyl, 
 R 4  represents hydrogen, fluorine, chlorine, cyano, methyl, trifluoromethyl or ethyl, 
 R 5A  represents methyl, trifluoromethyl or ethyl, and 
 R 5B  represents trifluoromethyl, 
 or 
 R 5A  and R 5B  are attached to one another and together with the carbon atom to which they are attached form a difluoro-substituted cycloalkyl ring of the formula 
 
       
         
           
           
               
               
           
         
         R 6  represents hydrogen, 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 7  represents hydrogen, fluorine, chlorine, cyano, methyl, trifluoromethyl, ethyl, methoxy or trifluoromethoxy, 
         or a salt, solvate or solvate of a salt thereof. 
       
     
     
         2 . The compound according to  claim 1  in which
 R 1A  represents hydrogen, methyl, trifluoromethyl, ethyl, n-propyl, cyclopropyl or cyclobutyl, 
 R 1B  represents hydrogen or methyl, 
 R 2A  represents hydrogen, methyl, trifluoromethyl, ethyl or n-propyl, 
 R 2B  represents hydrogen or methyl, 
 or 
 R 2A  and R 2B  are attached to one another and together with the carbon atom to which they are attached form a cyclic group of the formula 
 
       
         
           
           
               
               
           
         
       
       in which
 n represents the number 1 or 2, and 
 R 1A  and R 1B  have the meanings mentioned above, 
 R 3  represents hydrogen, fluorine or methyl, 
 R 4  represents hydrogen, fluorine, chlorine, cyano, methyl or trifluoromethyl, 
 R 5A  represents methyl or ethyl, 
 R 5B  represents trifluoromethyl, 
 or 
 R 5A  and R 5B  are attached to one another and together with the carbon atom to which they are attached form a difluoro-substituted cycloalkyl ring of the formula 
 
       
         
           
           
               
               
           
         
         R 6  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 7  represents hydrogen, fluorine, chlorine, methyl or methoxy, 
         or a salt, solvate or solvate of a salt thereof. 
       
     
     
         3 . The compound according to  claim 1  in which
 R 1A  represents hydrogen, methyl or ethyl, 
 R 1B  represents hydrogen, 
 R 2A  represents hydrogen, methyl, trifluoromethyl, ethyl or n-propyl, 
 R 2B  represents hydrogen or methyl, 
 or 
 R 2A  and R 2B  are attached to one another and together with the carbon atom to which they are attached form a cyclic group of the formula 
 
       
         
           
           
               
               
           
         
       
       in which
 n represents the number 1 or 2, and 
 R 1A  and R 1B  have the meanings mentioned above, 
 R 3  represents hydrogen, 
 R 4  represents fluorine, chlorine or methyl, 
 R 5A  represents methyl, 
 R 5B  represents trifluoromethyl, 
 or 
 R 5A  and R 5B  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 6  represents fluorine, chlorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, isopropyl, tert-butyl, 1,1,1-trifluoro-2-methylpropan-2-yl, vinyl, 1-fluorovinyl, cyclopropyl, 2,2-difluorocyclopropyl, cyclobutyl or 3,3-difluorocyclobutyl, 
         and 
         R 7  represents hydrogen, fluorine, chlorine or methyl, 
         or a salt, solvate or solvate of a salt thereof. 
       
     
     
         4 . The compound according to  claim 1 , wherein the compound is
 (+)-3-(3-{[(2S,3R)-2-(4-tert-butylphenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-4-chlorophenyl)propanoic acid;   3-[4-Chloro-3-({4,4,4-trifluoro-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]butanoyl}amino)phenyl]propanoic acid;   3-(4-chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)butanoic acid;   (3S)-3-(4-chloro-3-{[(4-chlorophenyl)(2,2-difluoro-cyclopentyl)acetyl]amino}phenyl)butanoic acid;   (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)propanoic acid;   (+)-(2S)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-2-methylpropanoic acid;   (+)-[1-(3-{[(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-4-fluorophenyl)-cyclopropyl]acetic acid;   [1-(4-Chloro-3-{[(3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)cyclobutyl]acetic acid;   (+)-(2S)-2-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}benzyl)butanoic acid;   3-(3-{[(3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-4-fluorophenyl)-2-methylpropanoic acid;   threo-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-4-fluorophenyl)-2-methylbutanoic acid;   2-(3-{[(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-4-fluorophenyl)-trans-cyclopropanecarboxylic acid;   (+)-2-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}benzyl)-2-methylbutanoic acid;   3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)hexanoic acid;   (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)hexanoic acid;   (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-4,4,4-trifluorobutanoic acid;   (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)pentanoic acid;   3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-2,2-dimethylpropanoic acid;   [1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)cyclobutyl]acetic acid;   [1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)cyclopropyl]acetic acid;   (2S)-3-[4-chloro-3-({4,4,4-trifluoro-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]butanoyl}amino)phenyl]-2-methylpropanoic acid;   (2S)-3-[4-chloro-3-({(2S,3R)-2-[4-(3,3-difluorocyclobutyl)phenyl]-4,4,4-trifluoro-3-methylbutanoyl}amino)phenyl]-2-methylpropanoic acid;   [1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3,3-difluorocyclobutyl]acetic acid; or   (2S)-3-(4-Chloro-3-{[(4-chlorophenyl)(3,3-difluorocyclopentyl)acetyl]amino}phenyl)-2-methylpropanoic acid.   
     
     
         5 . A process for preparing a compound according to  claim 1 , wherein
 (a) a carboxylic acid of the formula (II)   
       
         
           
           
               
               
           
         
         
           in which R 5A , R 4B , R 6  and R 7  have the meanings given in  claim 1   
           is coupled with an amine of the formula (III) 
         
       
       
         
           
           
               
               
           
         
         
           in which R 1A , R 1B , R 2A , R 3B , R 1  and R 4  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 R 1A , R 1B , R 2A , R 2B , R 3 , R 4 , R 5A , R 5B , R 6 , R 7  and T 1  have the meanings given above, 
         
         (b) the ester radical T 1  is removed to give the compound of formula (I), and 
         (c) the compound of formula (I) is optionally separated into its enantiomers and/or diastereomers, and/or optionally reacted with one or more (i) solvents and/or (ii) bases to give a solvate, salt and/or solvate of a salt thereof. 
       
     
     
         6 . The process according to  claim 5 , wherein step (a) is performed via a carbonyl chloride intermediate in the presence of a base. 
     
     
         7 . The process according to  claim 5 , wherein in step (b) the ester radical T 1  is removed by basic or acidic solvolysis and, if T 1  represents benzyl, also by hydrogenolysis. 
     
     
         8 . A pharmaceutical composition comprising a compound according to  claim 1  and an inert, non-toxic, pharmaceutically suitable excipient. 
     
     
         9 . A pharmaceutical composition comprising a compound according to  claim 2  and an inert, non-toxic, pharmaceutically suitable excipient. 
     
     
         10 . A pharmaceutical composition comprising a compound according to  claim 3  and an inert, non-toxic, pharmaceutically suitable excipient. 
     
     
         11 . A pharmaceutical composition comprising a compound according to  claim 4  and an inert, non-toxic, pharmaceutically suitable excipient. 
     
     
         12 . A pharmaceutical composition comprising a compound according to  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 metabolism. 
     
     
         13 . A pharmaceutical composition comprising a compound according to  claim 2  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 metabolism. 
     
     
         14 . A pharmaceutical composition comprising a compound according to  claim 3  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 metabolism. 
     
     
         15 . A pharmaceutical composition comprising a compound according to  claim 4  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 metabolism. 
     
     
         16 . A method for the treatment and/or prevention of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, impaired microcirculation, thromboembolic disorders or arteriosclerosis comprising administering to a human or animal in need thereof an effective amount of a compound according to  claim 1 . 
     
     
         17 . A method for the treatment and/or prevention of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, impaired microcirculation, thromboembolic disorders or arteriosclerosis comprising administering to a human or animal in need thereof an effective amount of a compound according to  claim 2 . 
     
     
         18 . A method for the treatment and/or prevention of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, impaired microcirculation, thromboembolic disorders or arteriosclerosis comprising administering to a human or animal in need thereof an effective amount of a compound according to  claim 3 . 
     
     
         19 . A method for the treatment and/or prevention of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, impaired microcirculation, thromboembolic disorders or arteriosclerosis comprising administering to a human or animal in need thereof an effective amount of a compound according to  claim 4 . 
     
     
         20 . The process according to  claim 5 , wherein step (a) is performed in the presence of an inert solvent with the aid of a condensing agent.