4′-Substituted nucleoside derivatives as inhibitors of HCV RNA replication
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 hepatitis C virus (HCV) infection comprising administering to a patient in need thereof an effective amount of a compound of formula I
wherein the compound of formula I is in the D configuration, and;
R is hydrogen;
R 1 is alkyl, alkenyl, alkynyl, haloalkyl, alkylcarbonyl, hydroxyalkyl, alkoxyalkyl, alkoxy, cyano, azido, hydroxyiminomethyl, alkoxyiminomethyl, halogen, alkylcarbonylamino, alkylaminocarbonyl, or aminomethyl, alkylaminomethyl, dialkylaminomethyl or heterocyclyl;
R 2 is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxy, halogen or cyano;
R 3 and R 4 (i) independently are hydrogen, hydroxy, alkoxy, halogen or hydroxyalkyl, provided that at least one of R 3 and R 4 is hydrogen; or
(ii) together represent ═CH 2 or ═N—OH, or
(iii) both represent fluorine;
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;
and pharmaceutically acceptable salts thereof.
2. The method of claim 1 wherein
R 1 is alkyl, alkenyl, alkynyl, haloalkyl, alkylcarbonyl, alkoxy, hydroxymethyl, cyano, azidoalkoxyiminomethyl, alkylcarbonylamino, alkylaminomethyl or dialkylaminomethyl;
R 2 is hydrogen, hydroxy, alkoxy, or halogen;
R 3 and R 4 (i) are independently hydrogen, hydroxy, alkoxy, halogen or hydroxyalkyl, provided that at least one of R 3 and R 4 is hydrogen; or
(ii) together are ═CH 2 ; or,
(ii) both represent fluorine.
3. The method of claim 2 wherein:
R 1 is C 2-6 alkynyl, azido or hydroxymethyl;
R 2 is hydrogen, hydroxyl, alkoxy or halogen;
R 3 and R 4 (i) independently are hydrogen, hydroxyl, alkoxy or halogen, or
(ii) both are fluorine;
R 5 is hydrogen or amino;
R 6 is hydrogen amino or hydroxyl;
R 7 is hydrogen.
4. 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.