Derivatives of isosorbide mononitrate and its use as vasodilating agents with reduced tolerance

Abstract

Novel derivatives of isosorbide mononitrate and its pharmaceutically acceptable salts, which have vasodilating activity with a reduced effect of tolerance, of the general formula (I) in which A and B individually represent any of the groups —ONO 2 and —Z—CO—R, wherein Z is an oxygen atom or sulphur atom and R is an alkyl C 1 -C 4 group, an aryl group or an aralkyl group, eventually substituted, or the group in which R 1 is hydrogen, or an alkyl C 1 -C 4 group, an aryl group or an aralkyl group, eventually substituted, with the proviso that one of A or B is always —ONO 2 , but never both of them at the same time, when Z is an sulphur atom R is an alkyl C 1 -C 4 group, an aryl group or an aralkyl group, eventually substituted, and when Z is an oxygen atom R is the group

1 . Compounds which are derivatives of isosorbide mononitrate, and its pharmaceutically acceptable salts, which corresponds to following general formula (I)  
       
         
           
           
               
               
           
         
       
       in which A and B individually represent any of the groups  
       
         
           
           
               
               
           
         
       
       wherein Z is an oxygen atom or sulphur atom, and R is an alkyl C 1 -C 4  group, an aryl group or an aralkyl group, eventually substituted, or the group  
       
         
           
           
               
               
           
         
       
       in which R 1  is hydrogen or an alkyl C 1 -C 4  group, an aryl group or an aralkyl group, eventually substituted; with the proviso that: 
 (a) one of A or B is always —ONO 2 , but never both of them at the same time;  
 (b) when Z is an sulphur atom R is an alkyl C 1 -C 4  group, an aryl group or an aralkyl group, eventually substituted; and  
 (c) when Z is an oxygen atom R is the group  
                     
 in which R 1  represents the groups indicated above.  
 
     
     
         2 . Compounds of    claim 1   , characterized by that that when Z is a sulphur atom, R is a short chain C 1 -C 4  alkyl group, and when Z is an oxygen atom, R 1  is a hydrogen atom or a short chain C 1 -C 4  alkyl group.  
     
     
         3 . Compounds of claims  1  or  2 , characterized by that B is the —ONO 2  group.  
     
     
         4 . The compound isosorbide 2-(2′-ethylthio)nicoti-nate 5-mononitrate and its pharmaceutically acceptable salts.  
     
     
         5 . The compound isosorbide 5-(2′-ethylthio)nicoti-nate 2-mononitrate and its pharmaceutically acceptable salts.  
     
     
         6 . The compound isosorbide 2-(2′-mercapto)nicoti-nate 5-mononitrate and its pharmaceutically acceptable salts.  
     
     
         7 . The compound isosorbide 5-(2′-mercapto)nicoti-nate 2-mononitrate and its pharmaceutically acceptable salts.  
     
     
         8 . The compound 2-acetylmercaptoisosorbide 5-mono-nitrate.  
     
     
         9 . The use of the compounds of any of the    claims 1    to    8    for the manufacture of a medicament with vasodilating effect for the treatment of dysfunctions of the circulatory system.  
     
     
         10 . The use, according to    claim 8   , of the compounds of any of the    claims 1    to    8   , for the manufacture of a medicament for the treatment of cardiovascular and coronary dysfunctions.