L-beta-dioxolane uridine analogs and methods for treating and preventing virus infections

Abstract

The present invention relates to the discovery that certain P-L-dioxolane nucleoside analogs which contain a uracil base, and preferably, a 5-halosubstituted uracil base, exhibit unexpectedly high activity against Epstein-Barr virus (EBV), Varciella-Zoster virus (VZV) and Herpes Virus 8 (HV-8). In particular, the compounds according to the present invention show potent inhibition of the replication of the virus (viral growth) in combination with very low toxicity to the host cells (i.e., animal or human tissue). Compounds are useful for treating EBV, VZV and HV-8 infections in humans.

1 . A method for treating a viral infection in a patient caused by Epstein-Barr virus, Varicella-Zoster virus or Kaposi's Sarcoma virus comprising administering to said patient a therapeutically effective amount of a compound according to the structure:  
                   where R is H, F, Cl, Br, I, CH 3  or CF 3 ; and    R 1  is H, a C 1  to C 20  acyl or ether group, a phosphate, diphosphate, triphosphate or phosphodiester group.    
     
     
         2 . The method according to    claim 1    where R is H, Br or I.  
     
     
         3 . The method according to    claim 1    where R is Br or I.  
     
     
         4 . The method according to    claim 1    wherein said viral infection is caused by Epstein Barr virus and R is I.  
     
     
         5 . The method according to    claim 1    where R 1  is a C 1  to C 3  acyl group.  
     
     
         6 . The method according to    claim 1    wherein said viral infection is caused by Varicella-Zoster virus and R is Br.  
     
     
         7 . A method for treating an Epstein-Barr virus infection in a patient comprising administering to said patient a therapeutically effective amount of a compound according to the structure:  
                   where R is Br or I and R 1  is H.    
     
     
         8 . The method according to    claim 7    where R is I.  
     
     
         9 . A method for treating a Varicella-Zoster virus infection in a patient comprising administering to said patient a therapeutically effective amount of a compound according to the structure:  
                   where R is Br or I and R 1  is H.    
     
     
         10 . The method according to    claim 9    where R is Br.  
     
     
         11 . A method for preventing or delaying the onset of EBV-related lymphoma or cancer or Kaposi's Sarcoma in patients comprising administering to a patient at risk for an EBV-related lymphoma or cancer or Kaposi's Sarcoma a therapeutically effective amount of a compound according to the formula:  
                   where R is H, F, Cl, Br, I, CH 3  or CF 3 ; and    R 1  is H, a C 1  to C 20  acyl or ether group, a phosphate, diphosphate, triphosphate or phosphodiester group.    
     
     
         12 . The method according to    claim 11    wherein said patient is imimunodeficient.  
     
     
         13 . The method according to    claim 11    wherein said patient is an organ transplant patient.  
     
     
         14 . The method according to    claim 11    wherein said patient has had a blood transfusion.  
     
     
         15 . The method according to    claim 11    wherein R is I or Br.