Substituted-1, 3-oxathiolanes and substituted-1, 3-dioxolanes with antiviral properties

Abstract

Disclosed are compounds of the formula wherein R<SUB>1 </SUB>is hydrogen or an acyl group having 1 to 16 carbon atoms; R<SUB>2 </SUB>is a purine or pyrimidine base or an analogue or derivative thereof; Z is O, S, S-O or SO<SUB>2</SUB>; and pharmaceutically acceptable derivatives thereof. Also, described are process for and intermediates of use in their preparation, pharmaceutical compositions containing these compounds, and the use of these compounds in the antiviral treatment of mammals.

1 - 22 . (canceled)  
     
     
         23 . A process for preparing an oxathiolane of formula (Ia), the geometric and optical isomers thereof, and mixtures of those isomers:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is selected from a group consisting of hydrogen, an acyl group having from 1 to 16 carbon atoms, and a hydroxyl protecting group;  
 R 2  is a purine or pyrimidine base or an analogue or derivative thereof;  
 Z is selected from a group consisting of S, S═O, and SO 2 ; the process comprising the steps of: 
 a) reacting a compound having the formula HSCH 2 CH(OR x ) 2 , wherein R x  is substituted or unsubstituted C 1-6  alkyl, with a compound having formula R y CO—OCH 2 CHO, wherein R y  is substituted or unsubstituted C 1-6  alkyl or substituted or unsubstituted aryl, in an inert solvent containing an acid catalyst to produce an intermediate having a formula:  
                     
 b) reacting the intermediate with a silylated pyrimidine or purine base or an analogue thereof, in the presence of a Lewis acid to produce a compound of the formula:  
                     
 c) optionally treating the resulting compound with an oxidizing agent in a suitable solvent to produce the corresponding sulfoxides of formula (Ia), wherein Z is S═O or SO 2 .  
 
 
     
     
         24 .- 27 . (canceled)  
     
     
         28 . A process for preparing a dioxolane of formula (Ib), the geometric and optical isomers thereof, and mixtures of those isomers,  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is selected from a group consisting of hydrogen, an acyl group having from 1 to 16 carbon atoms, and a hydroxyl protecting group; and  
 R 2  is a purine or pyrimidine base or an analogue or derivative thereof; the process comprising the steps of: 
 a) condensing a compound having a formula R z CH 2 CH(OR x ), wherein R z  is a halo selected from bromo, chloro, fluoro or iodo and R x  is substituted or unsubstituted C 1-6  alkyl, with glycerol in an inert solvent containing an acid catalyst to produce an intermediate having a formula  
                     
 b) oxidizing the hydroxymethyl group of the intermediate with an oxidizing agent to the acid and further oxidizing with an organic peracid to produce a compound of the following formula  
                     
  wherein R y  is substituted or unsubstituted C 1-6  alkyl or substituted or unsubstituted aryl;  
 c) treating the intermediate with a silylated pyrimidine or purine base or an analogue thereof, in the presence of a Lewis acid to produce a compound of the following formula  
                     
 d) displacing the R z  group with a salt of an acid.  
 
 
     
     
         29 .- 35 . (canceled)  
     
     
         36 . Intermediates useful for the production of oxathiolane and dioxolane compounds selected from the group consisting of: 
 cis- and trans-2-chloromethyl-4-(m-chloro-benzoyloxy)-1,3-dioxolane;    cis- and trans-2-benzoyloxymethyl-1,3-dioxolane-4-carboxyllic acid; and    cis- and trans-2-benzoyloxymethyl-4-(m-chlorobenzoyloxy)-1, e-dioxolane.    
     
     
         37 . (canceled)