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 processes 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.

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         10 . A compound selected from the group consisting of: 
 Cis-2-hydroxymethyl-5-(N 4 ′-acetyl-cytosin-1′-yl)-1,3-oxathiolane, trans-2-hydroxymethyl-5-(N 4 ′-acetyl-cytosin-1′-yl)-1,3-oxathiolane, and mixtures thereof;    Cis-2-hydroxymethyl-5-(N-dimethylamino-methylene cytosin-1′-yl)-1,3-oxathiolane;    Bis-Cis-2-succinyloxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane;    Cis-2-benzoyloxymethyl-5-(6′-chloropurin-N-9′-yl 1,3-oxathiolane, trans-2-benzoyloxymethyl-5-(6′-chloropurin-N-9′-yl)-1,3-oxathiolane, and mixtures thereof;    Cis-2-hydroxymethyl-5-(6′-hydroxypurin-N-9′-yl)-1,3-oxathiolane, trans-2-hydroxymethyl-5-(6′-hydroxypurin-N-9′-yl)-1,3-oxathiolane, and mixtures thereof;    Cis-2-benzoyloxymethyl-5-(uracil-N−1′-yl)-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-(uracil-N-1′-yl)-1,3-oxathiolane, and mixtures thereof;    Cis-2-benzoyloxymethyl-5-(thymin-N-1′-yl)-1,3-oxathione, trans-2-benzoyloxymethyl-5-(thymin-N-1′-yl)-1,3-oxathiolane, and mixtures thereof;    Cis-2-benzoyloxymethyl-5-(N 4 ′-acetyl-5′-fluorocytosin-1′-yl)-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-(N 4 ′-acetyl-5′-fluorocytosin-1′-yl)-1,3-oxathiolane, and mixtures thereof;    Cis-2-hydroxymethyl-5-(N-dimethylamino methylene cytosin-1′-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(N-dimethylamino methylene cytosin-1′-yl)-1,3-dioxolane, and mixtures thereof; 
 and pharmaceutically acceptable derivatives thereof in the form of a racemic mixture or single enantiomer.  
   
     
     
         11 . A compound selected from the group consisting of: 
 Cis-2-benzoyloxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane, and mixtures thereof;    Cis-2-benzoyloxymethyl-5-(N 4 ′-acetyl-cytosin-1′-yl)-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-(N 4 ′-acetyl-cytosin-1′-yl)-1,3-oxathiolane, and mixtures thereof; and    Cis-2-hydroxymethyl-5-(cytosin-1′-yl)-3-oxo-1,3-oxathiolane;    Cis-2-hydroxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane; trans-2-hydroxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane; and mixtures thereof;    Cis-2-hydroxymethyl-5-(uracil-N-1′-yl)-1,3-oxathiolane;    Cis-2-hydroxymethyl-5-(adenin-9′-yl)-1,3-oxathiolane, trans-2-hydroxymethyl-5-(adenin-9′-yl)-1,3-oxathiolane and mixtures thereof;    Cis-2-hydroxymethyl-5-(inosin-9′-yl)-1,3-oxathiolane, trans-2-hydroxymethyl-5-(inosin-9′-yl)-1,3-oxathiolane, and mixtures thereof;    Cis-2-hydroxymethyl-5-(thymin-N-1′-yl)-1,3-oxathiolane; and pharmaceuetically acceptable derivatives thereof in the form of a racemic mixture or single enantiomer.    
     
     
         12 . A compound selected from the group consisting of: 
 Cis-2-acetoxymethyl-4-(thymin-1′-yl)-1,3-dioxolane, trans-2-acetoxymethyl-4-(thymin-1′-yl)-1,3-dioxolane, and mixtures thereof;    Cis-2-hydroxymethyl-4-(thymin-1′-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(thymin-1′-yl)-1,3-dioxolane, and mixtures thereof;    Cis-2-benzoyloxymethyl-4-(cytosin-1′-yl)-1,3 dioxolane, trans-2-benzoyloxymethyl-4-(cytosin-1′-yl)-1,3 dioxolane, and mixtures thereof;    Cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-dioxolane, and mixtures thereof;    Cis-2-benzoyloxymethyl-4-(adenin-9′-yl)-1,3-dioxolane, trans-2-benzoyloxymethyl-4-(adenin-9′-yl)-1,3-dioxolane, and mixtures thereof;    Cis-2-hydroxymethyl-4-(adenin-9′-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(adenin-9′-yl)-1,3-dioxolane, and mixtures thereof;    Cis-2-benzoyloxylmethyl-4-(2′-amino-6′-chloro-(purin-9′-yl)-1,3-dioxolane, trans-2-benzoyloxymethyl-4-(2′-amino-6′-chloro-(purin-9′-yl)-1,3-dioxolane, and mixtures thereof;    Cis-2-hydroxymethyl-4-(2′-amino-6′-chloro-(purin-9′-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(2′-amino-6′-chloro-(purin-9′-yl)-1,3-dioxolane, and mixtures thereof;    Cis-2-hydroxymethyl-4-(2′-amino-purin-9′-yl)-1,3-dixolane, trans-2-hydroxymethyl-4-(2′-amino-purin-9′-yl)-1,3,-dioxolane, and mixtures thereof;    Cis-2-hydroxymethyl-4-(2′,6′-diamino-purin-9′-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(2′,6′-diamino-purin-9′-yl)1,3-dioxolane, and mixtures thereof;    Cis-2-hydroxymethyl-4-(guanin-9′-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(guanin-9′-yl)-1,3-dioxolane, and mixtures thereof; 
 and pharmaceutically acceptable derivatives thereof in the form of a racemic mixture or single enantiomer.  
   
     
     
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         15 . A compound according to  claim 10  in the form of a racemic mixture.  
     
     
         16 . A compound according to  claim 10  substantially in the form of a single enantiomer.  
     
     
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         19 . A pharmaceutical formulation comprising a compound of formula (I) as defined in  claim 10  or a pharmaceutically acceptable derivative thereof together with a pharmaceutically acceptable carrier thereof.  
     
     
         20 . A pharmaceutical formulation according to  claim 19  additionally comprising a further therapeutic agent.  
     
     
         21 . The ester of formula (IV), the geometric and optical isomers thereof, and mixtures of those isomers:  
       
         
           
           
               
               
           
         
       
       wherein: 
 W is PO 4   − , SPO 3   − , or —O—C—(CH 2 ) n —C—O— where n is an integer of 1 to 10;  
 J is any nucleoside or nucleoside analog or derivative thereof;  
 Z is O, S, S═O, or SO 2 ; and  
 R 2  is a purine or pyrimidine base or analogue or derivative thereof.  
 
     
     
         22 . A compound according to  claim 21  wherein J is:  
       
         
           
           
               
               
           
         
       
     
     
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         35 . The intermediate compound selected from: 
 2-thiobenzoylacetaldehyde diethylacetal.    
     
     
         36 . An intermediate selected from: 
 cis- and trans-2-chloromethyl-4-(m-chloro-benzoyloxy)-1,3-dioxolane;    cis- and trans-2-benzoyloxymethyl-1,3-dioxolane-4-carboxylic acid; and    cis- and trans-2-benzoyloxymethyl-4-(m-chlorobenzoyloxy)-1,3-dioxolane.    
     
     
         37 . A compound selected from the group consisting of: 
 cis- and trans-2-benzoyloxymethyl-5-hydroxy-1,3-oxathiolane;    cis- and trans-2-benzoyloxymethyl-5-acetoxy-1,3-oxathiolane;    cis- and tran-2-ethoxycarbonyl-5-(uracil-1′-yl)-1,3-oxathiolane;    cis- and trans-2-t-butyldimethylsilyloxy-methyl-5-(uracil-1′-yl)-1,3-oxathiolane;    cis- and trans-2-t-butyldimethylsilyloxy-methyl-5-(cytosin-1′-yl)-1,3-oxathiolane;    cis- and trans-2-t-butyldiphenylsilyloxy-methyl-5-(cytosin-1′-yl)-1,3-oxathiolane;    cis- and trans-2-t-butyldiphenylsilyloxy-methyl-5-(N-acetylcytosin-1′-yl)-1,3-oxathiolane;    cis- and trans-2-benzoyloxymethyl-4-(2-methoxyethoxy)-1,3-dioxolane;    cis- and trans-2-benzoyloxymethyl-4-acetyl-1,3-dioxolane; and    cis- and trans-2-benzoyloxymethyl-4-acetoxy-1,3-dioxolane.    
     
     
         38 . In a method of preparing a nucleoside compound comprising coupling a sugar with a silylated purine or silylated pyrimidine compound whereby said nucleoside compound has a sugar moiety with an attached pyrimidin-1′-yl or purine-9′-yl base moiety, the improvement wherein: 
 coupling is performed in the presence of a Lewis acid,    said sugar is a 1,3-dioxolane compound capable of coupling with said silyated purine or silylated pyrimidine compound, and    said pyrimidin-1′-yl or purine-9′-yl base moiety is cytosin-1′-yl, thymin-1′-yl, 2′-amino-purin-9′-yl, adenin-9′-yl, guanin-9′-yl, 2′-amino-6′-chloro-purin-9′-yl, 2′,6′-diamino-purin-9′-yl, 7′-deazaadenin-9′-yl, 7-deaza-2′-amino-purin-9′-yl, 7′-deaza-8′-aza-2′,6′-diamino-purin-9′-yl, 7′-deazaguanin-9′-yl, or 2′ amino-6′-chloro-7′-deaza-purin-9′-yl, which in each case is unsubstituted or substituted by at least one of C 1-3  alkyl, C 1-3  alkenyl, halo, or NHR 3  wherein R 3  is H or C 1-3 -alkyl.    
     
     
         39 . In a method of preparing a nucleoside compound comprising coupling a sugar with a silylated purine or silylated pyrimidine compound whereby said nucleoside compound has a sugar moiety with an attached pyrimidin-1′-yl or purine-9′-yl base moiety, the improvement wherein: 
 coupling is performed in the presence of a Lewis acid,    said sugar is a 1,3-dioxolane compound capable of coupling with said silylated purine or silylated pyrimidine compound, and    said silylated purine or pyrimidine compound is substituted one or more times by NHR 3 , oxo, C 1-3 -alkyl, C 1-3 -alkenyl, Cl, F, or I, and R 3  is H or C 1-3 -alkyl.    
     
     
         40 . In a method of preparing a nucleoside analogue comprising coupling a modified sugar with a silylated purine or silylated pyrimidine compound whereby said nucleoside analogue has a sugar modified moiety with an attached pyrimidin-1′-yl or purine-9′-yl base moiety, the improvement wherein: 
 coupling is performed in the presence of a Lewis acid,    said modified sugar is a 2,4-disubstituted-1,3-dioxolane compound having a protected methyl group at the C-2 position and a leaving group at the C-4 position, which is capable of coupling with said silyated purine or pyrimidine compound, and 
 said pyrimidin-1′-yl or purine-9′-yl base moiety is cytosin-1′-yl, thymin-1′-yl, 2′-amino-purin-9′-yl, adenin-9′-yl, guanin-9′-yl, 2′-amino-6′-chloro-purin-9′-yl, 2′,6′-diamino-purin-9′-yl, 7′-deazaadenin-9′-yl, 7-deaza-2′-amino-purin-9′-yl, 7′-deaza-8′-aza-2′,6′-diamino-purin-9′-yl, 7′-deazaguanin-9′-yl, or 2′ amino-6′-chloro-7′-deaza-purin-9′-yl, which in each case is unsubstituted or substituted by at least one of C 1-3  alkyl, C 1-3  alkenyl, halo, or NHR 3  wherein R 3  is H or C 1-3 -alkyl.  
   
     
     
         41 . The methanesulphonic acid salt of cis-2-hydroxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane, in the form of a single enantiomer.  
     
     
         42 . A salt according to  claim 41 , wherein said salt is in the form of the (−)-enantiomer.  
     
     
         43 . A salt according to  claim 41 , wherein said salt is in the form of the (+)-enantiomer.