Antiviral activity and resolution of 2-hydroxymethyl-5(5-fluorocytosin-1-yl)-1,3-oxathiolane

Abstract

A method and composition for the treatment of HIV and HBV infections in humans is disclosed that includes administering an effective amount of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane, a pharmaceutically acceptable derivative thereof, including a 5′ or N 4 alkylated or acylated derivative, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier. A process for the resolution of a racemic mixture of nucleoside enantiomers is also disclosed that includes the step of exposing the racemic mixture to an enzyme that preferentially catalyzes a reaction in one of the enantiomers.

1 - 13 . (canceled) 
   
   
       14 . A pharmaceutical composition comprising an effective amount to treat HIV infection in humans of (−)-β-L-2-hydroxymethyl-5-(5-fluorocytosine-1-yl)-1,3-oxathiolane, or a compound of the formula I: 
     
       
         
         
             
             
         
       
       wherein R 1  and R 2  are independently alkyl, acyl or an amino acid; and wherein one of R 1  and R 2  can be H, 
       or a physiologically acceptable salt thereof, in combination with a second antiviral compound, in a pharmaceutically acceptable carrier. 
     
   
   
       15 - 25 . (canceled) 
   
   
       26 . A method for treating HIV infection in humans comprising administering an effective amount of (−)-β-L-2-hydroxymethyl-5-(5-fluorocytosine-1-yl)-1,3-oxathiolane, or a compound of the formula: 
     
       
         
         
             
             
         
       
       wherein R 1  and R 2  are independently alkyl acyl or an amino acid; and wherein one of R 1  and R 2  can be H, 
       or a physiologically acceptable salt thereof, in combination with a second antiviral compound, in a pharmaceutically acceptable carrier. 
     
   
   
       27 - 34 . (canceled) 
   
   
       35 . The pharmaceutical composition of  claim 14 , wherein the composition is suitable for oral delivery. 
   
   
       36 . The pharmaceutical composition of  claim 35 , wherein the composition comprises 7 to 3000 mg of (−)-β-L-2-hydroxymethyl-5-(5-fluorocytosine-1-yl)-1,3-oxathiolane, or a compound of the formula I, or a physiologically acceptable salt thereof, per unit dosage form. 
   
   
       37 . The pharmaceutical composition of  claim 36 , wherein the composition comprises 70 to 1400 mg of (−)-β-L-2-hydroxymethyl-5-(5-fluorocytosine-1-yl)-1,3-oxathiolane, or a compound of the formula I, or a physiologically acceptable salt thereof, per unit dosage form. 
   
   
       38 . The pharmaceutical composition of  claim 36 , wherein the composition comprises 50 to 1000 mg of (−)-β-L-2-hydroxymethyl-5-(5-fluorocytosine-1-yl)-1,3-oxathiolane, or a compound of the formula I, or a physiologically acceptable salt thereof, per unit dosage form. 
   
   
       39 . The pharmaceutical composition of  claim 14 , wherein the second antiviral compound is an anti-HIV nucleoside compound. 
   
   
       40 . The pharmaceutical composition of  claim 14 , wherein the composition comprises (−)-β-L-2-hydroxymethyl-5-(5-fluorocytosine-1-yl)-1,3-oxathiolane. 
   
   
       41 . The pharmaceutical composition of  claim 14 , wherein R 2  is H. 
   
   
       42 . The pharmaceutical composition of  claim 41 , wherein R 1  is alkyl. 
   
   
       43 . The pharmaceutical composition of  claim 41 , wherein R 1  is acyl. 
   
   
       44 . The pharmaceutical composition of  claim 14 , wherein R 1  is H. 
   
   
       45 . The pharmaceutical composition of  claim 44 , wherein R 2  is alkyl. 
   
   
       46 . The pharmaceutical composition of  claim 44 , wherein R 2  is acyl. 
   
   
       47 . The method of  claim 26 , wherein the second antiviral compound is an anti-HIV nucleoside compound. 
   
   
       48 . The method of  claim 26 , wherein the composition comprises (−)-β-L-2-hydroxymethyl-5-(5-fluorocytosine-1-yl)-1,3-oxathiolane. 
   
   
       49 . The method of  claim 26 , wherein R 2  is H. 
   
   
       50 . The method of  claim 49 , wherein R 1  is alkyl. 
   
   
       51 . The method of  claim 49 , wherein R 1  is acyl. 
   
   
       52 . The method of  claim 26 , wherein R 1  is H. 
   
   
       53 . The method of  claim 52 , wherein R 2  is alkyl. 
   
   
       54 . The method of  claim 52 , wherein R 2  is acyl.