Anticholinergics which may be used as medicaments as well as processes for preparing them

Abstract

The present invention relates to new anticholinergics of general formula 1 wherein A, X − , and the groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 may have the meanings given in the claims and in the specification, processes for preparing them and their use as pharmaceutical compositions.

We claim:  
     
         1 . A compound of formula 1 
       
         
           
           
               
               
           
         
       
       wherein: 
 A is —CH 2 —CH 2 —;  
 X −  is an anion with a single negative charge;  
 R 1  and R 2 , which are identical or different, are each C 1 -C 4 -alkyl, which are optionally substituted by hydroxy or halogen;  
 R 3 , R 4 , R 5 , and R 6 , which are identical or different, are each hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 alkyloxy, hydroxy, CF 3 , CN, NO 2 , or halogen; and  
 R 7  is C 1 -C 4 -alkyl, C 1 -C 4 -alkyloxy, C 1 -C 4 -alkylene-halogen, halogen-C 1 -C 4 -alkyloxy, C 1 -C 4 -alkylene-OH, CF 3 , —C 1 -C 4 -alkylene-C 1 -C 4 -alkyloxy, —O—COC 1 -C 4 -alkyl, —O—COC 1 -C 4 -alkyl-halogen, —O—COCF 3 , or halogen.  
 
     
     
         2 . The compound of formula 1 according to  claim 1 , wherein: 
 X −  is an anion with a single negative charge selected from chloride, bromide, methylsulfate, 4-toluenesulfonate, and methanesulfonate;    R 1  and R 2 , which are identical or different, are each a group selected from methyl, ethyl, n-propyl, and isopropyl, which are optionally substituted by hydroxy or fluorine;    R 3 , R 4 , R 5 , and R 6 , which are identical or different, are each hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF 3 , or NO 2 ; and    R 7  is methyl, ethyl, methyloxy, ethyloxy, —CH 2 —F, —CH 2 —CH 2 —F, —O—CH 2 —F, —O—CH 2 —CH 2 —F, —CH 2 —OH, —CH 2 —CH 2 —OH, CF 3 , —CH 2 —OMe, —CH 2 —CH 2 —OMe, —CH 2 —OEt, —CH 2 —CH 2 OEt, —O—COMe, —O—COEt, —O—COCF 3 , —O—COCF 3 , fluorine, chlorine, or bromine.    
     
     
         3 . The compound of formula 1, according to  claim 2 , wherein: 
 X −  is an anion with a single negative charge selected from chloride, bromide, and methanesulfonate;    R 1  and R 2 , which are identical or different, are each methyl or ethyl, which are optionally substituted by hydroxy or fluorine;    R 3 , R 4 , R 5 , and R 6 , which are identical or different, are each hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, or bromine; and    R 7  is methyl, ethyl, methyloxy, ethyloxy, CF 3 , or fluorine.    
     
     
         4 . The compound of formula 1, according to  claim 3 , wherein: 
 X −  is bromide;    R 1  and R 2 , which are identical or different, are each methyl or ethyl;    R 3 , R 4 , R 5 , and R 6 , which are identical or different, are each hydrogen, methyl, methyloxy, chlorine, or fluorine; and    R 7  is methyl or fluorine.    
     
     
         5 . The compound of formula 1, according to  claim 4 , wherein: 
 X −  is bromide;    R 1  and R 2 , which are identical or different, are each methyl or ethyl;    R 3 , R 4 , R 5 , and R 6 , which are identical or different, denote hydrogen or fluorine; and    R 7  is methyl or fluorine.    
     
     
         6 . A method of treating a disease that is responsive to anticholinergic activity, comprising administering to a host in need thereof an effective amount of a compound of formula 1 according to one of  claims 1  to  5 .  
     
     
         7 . A method according to  claim 6 , wherein the disease is selected from asthma, COPD, vagally induced sinus bradycardia, heart rhythm disorders, spasms in the gastrointestinal tract, spasms in the urinary tract, and menstrual disorders.  
     
     
         8 . A pharmaceutical composition comprising one or more compounds of formula 1 according to one of  claims 1  to  5 , or a physiologically acceptable salt thereof, optionally together with one or more conventional excipients and/or carriers.  
     
     
         9 . A pharmaceutical composition according to  claim 8 , further comprising at least one additional active substance selected from the group consisting of: betamimetics, antiallergic agents, PAF-antagonists, leukotriene-antagonists, and steroids.  
     
     
         10 . A process for preparing a compound of formula 1 according to  claim 1   
       
         
           
           
               
               
           
         
       
       wherein A, X −  and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  have the meanings given in  claim 1 , characterised in that a compound of formula 3 
       
         
           
           
               
               
           
         
       
       wherein R 3 , R 4 , R 5 , R 6 , and R 7  have the meanings given in  claim 1 , and R is chlorine or a C 1 -C 4 -alkyloxy, is reacted with a compound of formula 2 
       
         
           
           
               
               
           
         
       
       wherein A and R 1  have the meanings given in  claim 1 , to obtain a compound of formula 4 
       
         
           
           
               
               
           
         
       
       wherein A and R 1 , R 3 , R 4 , R 5 , R 6 , and R 7  have the meanings given in  claim 1 , and the compound of formula 4 is then quaternized by reacting it with a compound R 2 —X, wherein R 2  and X have the meanings given in  claim 1 , to obtain a compound of formula 1.  
     
     
         11 . A compound of formula 4 
       
         
           
           
               
               
           
         
       
       wherein: 
 A is —CH 2 —CH 2 —;  
 X −  is an anion with a single negative charge;  
 R 1  and R 2 , which are identical or different, are each C 1 -C 4 -alkyl, which are optionally substituted by hydroxy or halogen;  
 R 3 , R 4 , R 5 , and R 6 , which are identical or different, are each hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 alkyloxy, hydroxy, CF 3 , CN, NO 2 , or halogen; and  
 R 7  is C 1 -C 4 -alkyl, C 1 -C 4 -alkyloxy, C 1 -C 4 -alkylene-halogen, halogen-C 1 -C 4 -alkyloxy, C 1 -C 4 -alkylene-OH, CF 3 , —C 1 -C 4 -alkylene-C 1 -C 4 -alkyloxy, —O—COC 1 -C 4 -alkyl, —O—COC 1 -C 4 -alkyl-halogen, —O—COCF 3 , or halogen.