[5-carboxamido or 5-fluoro]-[2',3'-unsaturated or 3'-modified]-pyrimidine nucleosides

Abstract

A method and composition for the treatment of HIV and HBV infections in humans and other host animals is disclosed that includes the administration of an effective amount of a [5-carboxamido or 5-fluoro]-2′,3′-dideoxy-2′,3′-didehydro-pyrimidine nucleoside or a [5-carboxamido or 5-fluoro]-3′-modified-pyrimidine nucleoside, or a mixture or 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.

1 . A compound of the structure: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein
 X is O, S, CH 2 , CHF, or CF 2 ; 
 Y is O, S, CH 2 , CHF, CF 2 ; 
 Z is independently O, S or Se; 
 R 1  is independently H or F; 
 R 2  is independently H, OH, C 1  to C 6  alkyl, or C(O)(C 1  to C 6  alkyl); 
 R 3  is H, C(O)(C 1 -C 6  alkyl); alkyl, or mono-, di- or triphosphate; and 
 R 4  is independently H, F, Cl, Br, I, OH, —O(C 1 -C 6 alkyl), —SH, —S(C 1 -C 6 alkyl); or —C 1 -C 6 alkyl. 
 
   
   
       2 . The compound of  claim 1 , wherein Y is O or S; Z is O; R 1  is H; R 2  is H; and R 3  is H. 
   
   
       3 . The compound of  claim 1 , wherein X is O or S; Y is O; Z is 0; R 1  is H; R 2  is H; R 3  is H, and R 4  is independently H or Fl. 
   
   
       4 . The compound of  claim 1  in the form of a racemic mixture. 
   
   
       5 . The compound of  claim 1  in the form of a β-D-enantiomer. 
   
   
       6 . The compound of  claim 1  in the form of a β-L-enantiomer. 
   
   
       7 . The compound of  claim 1  in enantiomerically enriched form. 
   
   
       8 . The compound of  claim 1  selected from the group consisting of the racemic mixture, β-D- or β-L-enantiomer of 2-hydroxymethyl-5-(N-5′-carboxamidouracil-1′-yl)-1,3-oxathiolane; 2-hydroxymethyl-4-(N-5′-carboxamidouracil-1′-yl)-1,3-dioxolane; 2-hydroxymethyl-4-(N-5′-fluorocytosin-1′-yl)-1,3-dithiolan; 2-hydroxymethyl-4-(N-5′-carboxamidouracil-1′-yl)-1,3-dithiolan; 2-hydroxymethyl-4-(N-5′-fluorocytosin-1′-yl)-1,3-oxathiolane; 2-hydroxymethyl-4-(N-5′-carboxamidouracil-1′-yl)-1,3-oxathiolane; 2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine; 2′,3′-dideoxy-2′,3′-didehydro-5-carboxamidocytidine; 2′,3′-dideoxy-5-fluorocytidine; 2′,3′-dideoxy-5-carboxamidocytidine; 2′,3′-dideoxy-2′,3′-didehydro-2′,5-difluorocytidine; 2′,3′-dideoxy-2′,3′-didehydro-2′-fluoro-5-carboxamidocytidine, 2′,3′-dideoxy-2′,3′-didehydro-3′,5-difluorocytidine; 2′,3′-dideoxy-2′,3′-didehydro-3′-fluoro-5-carboxamidocytidine; 2′,3′-dideoxy-2′,3′-didehydro-2′,3′,5-trifluorocytidine; 2′,3′-dideoxy-2′,3′-didehydro-2′,3′-difluoro-5-carboxamidocytidine; 2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine; 2′,3′-dideoxy-2′,3′-didehydro-5-carboxamidocytidine; 2′,3′-dideoxy-5-fluorocytidine; 2′,3′-dideoxy-5-carboxamidocytidine; 2′,3′-dideoxy-2′,3′-didehydro-2′,5-difluorocytidine; 2′,3′-dideoxy-2′,3′-didehydro-2′-fluoro-5-carboxamidocytidine; 2′,3′-dideoxy-2′,3′-didehydro-3′,5-difluorouridine; 2′,3′-dideoxy-2′,3′-didehydro-3′-fluoro-5-carboxamidouridine; 2′,3′-dideoxy-2′,3′-didehydro-2′,3′,5-trifluorouridine; and 2′,3′-dideoxy-2′,3′-didehydro-2′,3′-difluoro-5-carboxamidouridine. 
   
   
       9 . The compound of  claim 1  selected from the group consisting of the racemic mixture, the β-L-enantiomer and the β-D-enantiomer of 5-carboxylic acid amide-2′,3′-dideoxy-3′-thiacytidine. 
   
   
       10 . A composition comprising an effective HIV or HBV treatment amount of a compound of  claim 1  in combination with a compound selected from the group consisting of the (−)-enantiomer of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC); the (−)-enantiomer of 2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC); carbovir, acyclovir, interferon, AZT, DDI, DDC, L-(−)-FMAU, and D4T. 
   
   
       11 . A pharmaceutical composition comprising an effective amount to treat HIV or HBV infection in humans of a compound of  claim 1  in the racemic or enantiomerically enriched form, or its physiologically acceptable salt, in a pharmaceutically acceptable carrier. 
   
   
       12 . A method for treating HIV infection in humans comprising administering an effective amount of a compound of  claim 1  or its physiologically acceptable derivative or physiologically acceptable salt, in a pharmaceutically acceptable carrier. 
   
   
       13 . A method for treating HBV infection in humans comprising administering an effective amount of a compound of  claim 1  or its physiologically acceptable derivative or physiologically acceptable salt, in a pharmaceutically acceptable carrier.