4'-substituted nucleoside derivatives as inhibitors of hcv rna replication

Abstract

The present invention relates to the use of nucleoside derivatives of formula I wherein B signifies a 9-purinyl residue B1 of formula or a 1-pyrimidyl residue B2 of formula wherein the symbols are as defined in the specification, and of pharmaceutically acceptable salts thereof; for the treatment of diseases mediated by the Hepatitis C Virus (HCV), for the preparation of a medicament for such treatment and to pharmaceutical compositions containing such compounds.

1 . A method of treating a disease mediated by the HCV virus comprising administering to a patient in need thereof an effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         R is hydrogen or —[P(O)(OH)—O] n H and n is 1, 2 or 3; 
         IV is alkyl, alkenyl, alkynyl, haloalkyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, alkoxy, cyano, azido, hydroxyiminomethyl, alkoxyiminomethyl, halogen, alkylcarbonylamino, alkylaminocarbonyl, azidoalkyl or aminomethyl, alkylaminomethyl, dialkylaminomethyl or heterocyclyl; 
         R 2  is hydrogen, hydroxy, amino, alkyl, hydroxyalkyl, alkoxy, halogen, cyano, or azido; 
         R 3  and R 4  are hydrogen, hydroxy, alkoxy, halogen or hydroxyalkyl, provided that at least one of R 3  and R 4  is hydrogen; or 
         R 3  and R 4  together represent ═CH 2  or ═N—OH, or 
         R 3  and R 4  both represent fluorine; 
         X is O, S or CH 2 ; 
         B signifies a 9-purinyl residue B1 of formula 
       
       
         
           
           
               
               
           
         
         wherein 
         R 5  is hydrogen, hydroxy, alkyl, alkoxy, alkylthio, NHR 8 , halogen or SH; 
         R 6  is hydroxy, NHR 8 , NHOR 9 , NHNR 8 , —NHC(O)OR 9′  or SH; 
         R 7  is hydrogen, hydroxy, alkyl, alkoxy, alkylthio, NHR 8 , halogen, SH or cyano; 
         R 8  is hydrogen, alkyl, hydroxyalkyl, arylcarbonyl or alkylcarbonyl; 
         R 9  is hydrogen or alkyl; 
         R 9′  is alkyl; or 
         B signifies a 1-pyrimidyl residue B2 of formula 
       
       
         
           
           
               
               
           
         
         wherein 
         Z is O or S; 
         R 10  is hydroxy, NHR 8 , NHOR 9 , NHNR 8 , —NHC(O)OR 9′  or SH; 
         R 11  is hydrogen, alkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, haloalkyl or halogen; 
         R 8  R 9  and R 9′  are as defined above; 
         and of pharmaceutically acceptable salts thereof. 
       
     
     
         2 . The method of  claim 1  wherein
 R is hydrogen; 
 R 1  is alkyl, alkenyl, alkynyl, haloalkyl, alkylcarbonyl, alkoxy, hydroxymethyl, cyano, azido, alkoxyiminomethyl, alkylcarbonylamino, alkylaminomethyl or dialkylaminomethyl; 
 R 2  is hydrogen, hydroxy, alkoxy, or halogen; 
 R 3  and R 4  are hydrogen, hydroxy, alkoxy, halogen or hydroxyalkyl, provided that at least one of R 3  and R 4  is hydrogen; or 
 R 3  and R 4  represent fluorine; 
 X is O or CH 2 ; and 
 B signifies a 9-purinyl residue B1 or a 1-pyrimidyl residue B2 as in  claim 1 . 
 
     
     
         3 . The method of or  claim 2  wherein the compound of formula I is 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is alkyl, alkenyl, alkynyl, haloalkyl, alkylcarbonyl, alkoxy, hydroxymethyl, cyano, azido, alkoxyiminomethyl, alkylcarbonylamino, alkylaminomethyl or dialkylaminomethyl; 
         R 2  R 2  is hydrogen, hydroxy, alkoxy, or halogen; 
         R 3  and R 4  are hydrogen, hydroxy, alkoxy, halogen or hydroxyalkyl, provided that at least one of R 3  and R 4  is hydrogen; or 
         R 3  and R 4  represent fluorine. 
         and pharmaceutically acceptable salts thereof; for the preparation of a medicament for the treatment of diseases mediated by the Hepatitis C Virus (HCV). 
       
     
     
         4 . The method of  claim 3 , wherein the compounds of formula I are
 4′-C-ethynylcytidine hydrochloride (1:1)   4′-C-ethoxycytidine   4′-C-acetylcytidine   
     
     
         5 . The method of  claim 3 , wherein the compound is 4′-C-azidocytidine. 
     
     
         6 . The method of  claim 1 , wherein the compound is delivered in a dose of between 1 and 100 mg/kg/body weight of the patient/day. 
     
     
         7 . The method of  claim 5 , wherein the compound is delivered in a dose of between 1 and 100 mg/kg/body weight of the patient/day. 
     
     
         8 . The method of  claim 1 , further comprising administering an immune system modulator. 
     
     
         9 . The method of  claim 8 , wherein the immune system modulator is an interferon, interleukin, tumor necrosis factor or colony stimulating factor, an antiviral agent or an anti-inflammatory agent. 
     
     
         10 . The method of  claim 9 , wherein the immune system modulator is an interferon. 
     
     
         11 . The use of a pharmaceutical composition comprising a compound of  claim 1  for the treatment of diseases mediated by the hepatitis C virus (HCV).