N4-Acylcytosine Nucleosides for Treatment of Viral Infections

Abstract

The present invention is directed to a method and composition of treating or preventing viral infections, in particular, human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections, in human patients or other animal hosts, comprising the administration of N.sup.4-acyl-2′,3′-dideoxy-5-fluorocytidine or N.sup.4-acyl-2′,3′-didehyd-ro-2′,3′-dideoxy-5-fluorocytidine, and pharmaceutically acceptable salts, prodrugs, and other derivatives thereof

1 . A compound of formula (I) or (II):  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein 
 i) X is O, S, NR 5 , CH 2 , CHF or CF 2 ;  
 ii) Y is CH 2 , CHF or CF 2 ;  
 iii) R 1  is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, CN, CF 3 , N 3 , NO 2 , aryl, heteroaryl and acyl;  
 iv) R 2  is chosen from alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C 6 H 4 R 6  where R 6  is chosen from halogen (F, Cl, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy; thioalkyl, alkenyl, alkynyl, and aryl;  
 v) R 3  and R 3′  are chosen independently from H, halogen (F, Cl, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl, alkenyl, and alkynyl;  
 vi) R 4  is H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, or other pharmaceutically acceptable leaving group, which, when administered in vivo, is capable of providing a compound wherein R 3  and R 3′  are H or phosphate, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol; and  
 vii) R 5  is H, acyl, alkyl, alkenyl, alkynyl, or cycloalkyl.  
 
   
   
       2 . A pharmaceutical composition that includes an effective HIV or HBV treatment amount of a compound of  claim 1  in a pharmaceutically acceptable carrier or diluent.  
   
   
       3 . A method for the treatment of a host infected with HIV that includes administering an effective amount of a compound of  claim 1  or  17  in a pharmaceutically acceptable carrier.  
   
   
       4 . A method for the treatment of a host infected with HBV that includes administering an effective amount of a compound of  claim 1  or  17  in a pharmaceutically acceptable carrier.  
   
   
       5 . A method for the treatment of a host infected with HIV that includes administering an effective amount of a compound of  claim 1  or  17  in a pharmaceutically acceptable carrier in combination with another anti-HIV agent.  
   
   
       6 . A method for the treatment of a host infected with HBV that includes administering an effective amount of a compound of  claim 1  or  17  in a pharmaceutically acceptable carrier in combination with another anti-HIV agent.  
   
   
       7 . The compound of  claim 1  wherein R 1  is hydrogen or fluorine.  
   
   
       8 . The compound of  claim 1  wherein R 3  is H or fluorine and R 3′  is H  
   
   
       9 . The method of claims  3 ,  4 ,  5  or  6  wherein R 1  is hydrogen or fluorine.  
   
   
       10 . The method of claims  3 ,  4 ,  5 , or  6  wherein R 3  is H or fluorine and R 3′  is H.  
   
   
       11 . The compound of  claim 1  selected from the group consisting of β-D-N 4 -p-iodobenzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-fluoro-benzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-chlorobenzoyl-2′,3′-dideoxy-5-fluoro-cytidine, β-D-N 4 -p-bromobenzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-ethyl-benzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-t-butylbenzoyl-2′,3′-dideoxy-5-fluoro-cytidine.  
   
   
       12 . The compound of  claim 1  selected from the group consisting of 
 β-D-N 4 -p-bromobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,    β-D-N 4 -p-fluorobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,    β-D-N 4 -p-chlorobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,    β-D-N 4 -p-iodobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,    β-D-N 4 -p-ethylbenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine, and    β-D-N 4 -p-t-butylbenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine.    
   
   
       13 . The method of  claim 2  wherein the compound is selected from the group consisting of β-D-N 4 -p-iodobenzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-fluoro-benzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-chlorobenzoyl-2′,3′-dideoxy-5-fluoro-cytidine, β-D-N 4 -p-bromobenzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-ethyl-benzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-t-butylbenzoyl-2′,3′-dideoxy-5-fluoro-cytidine.  
   
   
       14 . The method of  claim 2  wherein the compound is selected from the group consisting of 
 β-D-N 4 -p-bromobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,    β-D-N 4 -p-fluorobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,    β-D-N 4 -p-chlorobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,    β-D-N 4 -p-iodobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,    β-D-N 4 -p-ethylbenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine, and    β-D-N 4 -p-t-butylbenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine.    
   
   
       15 . The method of  claim 3  wherein the compound is selected from the group consisting of β-D-N 4 -p-iodobenzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-fluoro-benzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-chlorobenzoyl-2′,3′-dideoxy-5-fluoro-cytidine, β-D-N 4 -p-bromobenzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-ethyl-benzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-t-butylbenzoyl-2′,3′-dideoxy-5-fluoro-cytidine.  
   
   
       16 . The method of  claim 3  wherein the compound is selected from the group consisting of 
 β-D-N 4 -p-bromobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,    β-D-N 4 -p-fluorobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,    β-D-N 4 -p-chlorobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,    β-D-N 4 -p-iodobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,    β-D-N 4 -p-ethylbenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine, and    β-D-N 4 -p-t-butylbenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine.    
   
   
       17 . A compound selected from the following, or its pharmaceutically acceptable salt or prodrug: 
 β-D-2′,3′-dideoxy-5-fluoro-N 4 -(4-iodobenzoyl)cytidine of the structure:                          β-D-2′,3′-dideoxy-5-fluoro-N 4 -(4-fluorobenzoyl)cytidine of the structure:                          β-D-N 4 -(4-chlorobenzoyl)-2′,3′-dideoxy-5-fluorocytidine of the structure:                          β-D-N 4 -(4-bromobenzoyl)-2′,3′-dideoxy-5-fluorocytidine of the structure:                          β-D-2′,3′-dideoxy-5-fluoro-N 4 -(3-fluorobenzoyl)cytidine of the structure:                          β-D-N 4 -(3-chlorobenzoyl)-2′,3′-dideoxy-5-fluorocytidine of the structure:                          or a pharmaceutically acceptable salt or prodrug thereof.    In one preferred embodiment, the active compound is β-D-N 4 -(3-bromobenzoyl)-2′,3′-dideoxy-5-fluorocytidine of the structure:                          β-D-2′,3′-dideoxy-5-fluoro-N 4 -(4-nitrobenzoyl)cytidine of the structure:                          β-D-2′,3′-dideoxy-5-fluoro-N 4 -p-toluoylcytidine of the structure:                          β-D-2′,3′-dideoxy-5-fluoro-N 4 -(m-toluoyl)cytidine of the structure:                          β-D-2′,3′-dideoxy-N 4 -(4-ethylbenzoyl)-5-fluorocytidine of the structure:                          β-D-2′,3′-dideoxy-5-fluoro-N 4 -(4-propylbenzoyl)cytidine of the structure:                          β-D-N 4 -(4-tert-butylbenzoyl)-2′,3′-dideoxy-5-fluorocytidine of the structure:                          β-D-2′,3′-dideoxy-5-fluoro-N 4 -(2-thiophenecarbonyl)cytidine of the structure:                          β-D-N 4 -(benzo-[b]-thiophene-2-carbonyl)-2′,3′-dideoxy-5-fluorocytidine of the structure:                          β-D-N 4 -(cyclohexane-carbonyl)-2′,3′-dideoxy-5-fluorocytidine of the structure:                          β-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-N 4 -(4-iodobenzoyl)cytidine of the structure:                          β-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-N 4 -(4-fluorobenzoyl)cytidine of the structure:                          β-D-N 4 -(4-chlorobenzoyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine of the structure:    β-D-N 4 -(4-bromobenzoyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine of the structure;                          β-D-N 4 -p-anisoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine of the structure:                          β-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-N 4 -(3-nitrobenzoyl)cytidine of the structure.                          β-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-N 4 -p-toluoylcytidine of the structure:                          β-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-N 4 -m-toluoylcytidine of the structure:                          β-D-N 4 -(4-t-butylbenzoyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine of the structure:                          or a pharmaceutically acceptable salt or prodrug thereof.    β-D-N 4 -cyclopentanecarbonyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine of the structure:                          or a pharmaceutically acceptable salt or prodrug thereof.    β-D-N 4 -(cyclohexanecarbonyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine of the structure: