Fluorophenyl-substituted alkenylcarboxylic acid guanidides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them

Abstract

This invention relates to fluorophenyl-substituted alkenylcarboxylic acid guanidides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them. An embodiment of the invention embraces compounds of the formula I: and the pharmaceutically tolerated salts thereof. The disclosed compounds are valuable inhibitors of the cellular sodium/proton exchanger (Na + /H + exchanger). They are therefore outstandingly suitable for the treatment of all diseases attributable to increased Na + /H + exchange.

1 . A compound of the formula I:  
                   
       in which: 
 R(6) is hydrogen, (C 1 -C 8 )-alkyl, (C 3 -C 8 )-cycloalkyl or phenyl, the phenyl group being unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR(9)-R(10);  
 R(9) and R(10) are hydrogen, (C 1 -C 4 )-alkyl or (C 1 -C 4 ) -perfluoroalkyl;  
 R(7) is independently defined in the same way as R(6); and  
 R(1), R(2), R(3), R(4) and R(5) independently of one another are hydrogen or F, wherein at least one of the radicals R(1), R(2), R(3), R(4) and R(5) is fluorine;  
 or a pharmaceutically tolerated salt thereof.  
 
     
     
         2 . A compound of the formula I as claimed in    claim 1    wherein: 
 R(6) is hydrogen, (C 1 -C 4 )-alkyl or (C 3 -C 6 )-cycloalkyl;  
 R(7) is independently defined in the same way as R(6); and  
 R(1), R(2), R(3), R(4) and R(5) independently of one another are hydrogen or F, wherein at least one of the radicals R(1), R(2), R(3), R(4) and R(5) is fluorine.  
 
     
     
         3 . A compound of the formula I as claimed in    claim 1    wherein: 
 R(6) is hydrogen or CH 3 ;  
 R(7) is hydrogen; and  
 R(1), R(2), R(3), R(4) and R(5) independently of one another are hydrogen or F, wherein at least one of the radicals R(1), R(2), R(3), R(4) and R(5) is fluorine.  
 
     
     
         4 . A process for the preparation of a compound of the formula I as claimed in    claim 1   , which comprises reacting a compound of the formula II:  
                   
       with guanidine, wherein R(1) to R(7) are defined as in    claim 1    and L is a leaving group readily susceptible to nucleophilic substitution.  
     
     
         5 . A process as claimed in    claim 4    wherein the leaving group L is selected from the group consisting of alkoxy, phenoxy, phenylthio, methylthio, 2-pyridyl-thio, and a nitrogen heterocycle.  
     
     
         6 . A method of treating arrhythmia comprising administering to a host in need of said treatment an effective amount of a compound of the formula I as claimed in    claim 1   .  
     
     
         7 . A method of treating arrhythmia, which comprises combining an effective amount of a compound I as claimed in    claim 1    with a conventional additive to form a composition and administering the composition in a form suitable for administration.  
     
     
         8 . Amethod of treating cardiac infarction comprising administering to a host in need of said treatment an effective amount of a compound of the formula I as claimed in    claim 1   .  
     
     
         9 . A method of treating angina pectoris comprising administering to a host in need of said treatment an effective amount of a compound of the formula I as claimed in    claim 1   .  
     
     
         10 . A method of treating ischemic heart conditions comprising administering to a host in need of said treatment an effective amount of a compound of the formula I as claimed in    claim 1   .  
     
     
         11 . A method of treating ischemic conditions of the peripheral and central nervous system and stroke comprising administering to a host in need of said treatment an effective amount of a compound of the formula I as claimed in    claim 1   .  
     
     
         12 . A method of treating ischemic conditions of peripheral organs and extremities comprising administering to a host in need of said treatment an effective amount of a compound of the formula I as claimed in    claim 1   .  
     
     
         13 . A method of treating shock conditions comprising administering to a host in need of said treatment an effective amount of a compound of the formula I as claimed in    claim 1   .  
     
     
         14 . A method of protecting organs during surgical operations and organ transplants comprising administering an effective amount of a compound of the formula I as claimed in    claim 1   .  
     
     
         15 . A method of preserving or storing transplants for surgical procedures comprising administering an effective amount of a compound of the formula I as claimed in    claim 1   .  
     
     
         16 . A method of treating diseases where cell proliferation is a primary or secondary cause comprising administering to a host in need of said treatment an effective amount of a compound of the formula I as claimed in    claim 1   .  
     
     
         17 . A method for combating late diabetic complications, carcinosis, fibrotic diseases, and hyperplasia of the prostate comprising administering to a host in need of said treatment administering an effective amount of a compound of the formula I as claimed in    claim 1   .  
     
     
         18 . A method of inhibiting the Na + /H +  exchanger for the diagnosis of hypertonia and proliferative diseases comprising administering an effective amount of a compound of the formula I as claimed in    claim 1    as a diagnostic agent.  
     
     
         19 . A pharmaceutical composition comprising an effective amount of a compound of the formula I as claimed in    claim 1   .