4'-SUBSTITUTED NUCLEOSIDE DERIVATIVES AS INHIBITORS OF HCV RNA REPLICATION

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).