Antiviral nucleoside derivatives

A method for treating a disease caused by the Hepatitis C Virus (HCV) comprising administering to a mammal in need thereof, a therapeutically effective quantity of a compound of formula I

• wherein:
• R1 and R2 are independently selected from the group consisting of hydrogen, COR5, C(═O)OR5, C(═O)SR5, C(═O)NHR5 and COCH(R6)NHR7;
• R3 and R4 are independently selected from the group consisting of hydrogen, COR5, C(═O)OR5, C(═O)SR5 and COCH(R6)NHR7;
• or, R3 and R4 taken together are selected from the group consisting of CH2, C(CH3)2 and CHPh;
• R5 is independently selected from the group consisting of C1-18 unbranched or branched alkyl, C1-18 unbranched or branched alkenyl, C1-18 unbranched or branched alkynyl, C1-18 lower haloalkyl, C3-8 cycloalkyl, alkyl substituted C3-8 cycloalkyl phenyl, phenyl optionally substituted with one to three substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, lower thioalkyl, lower alkyl sulfinyl, lower alkyl sulfonyl, nitro, cyano, CH2Ph wherein in phenyl ring is optionally substituted as described above, and CH2OPh wherein in phenyl ring is optionally substituted as described above;
• R6 is independently selected from the group consisting of the side chains of naturally occurring amino acids and C1-5 unbranched or branched alkyl;
• R7 is selected from the group consisting of hydrogen, R5OCO;
• or,
• R6 and R7 taken together are (CH2)3;
• and,
• hydrates, solvates, clathrates and acid addition salts thereof;
• with the proviso that at least one of R1, R2, R3, or R4 is other than hydrogen.

A pharmaceutical composition comprising a therapeutically effective quantity of a compound of formula I

• wherein:
• R1 and R2 are independently selected from the group consisting of hydrogen, COR5, C(═O)OR5, C(═O)SR5, C(═O)NHR5 and COCH(R6)NHR7;
• R3 and R4 are independently selected from the group consisting of hydrogen, COR5, C(═O)OR5, C(═O)SR5 and COCH(R6)NHR7;
• or, R3 and R4 taken together are selected from the group consisting of CH2, C(CH3)2 and CHPh;
• R5 is independently selected from the group consisting of C1-8 unbranched or branched alkyl, C1-18 unbranched or branched alkenyl, C1-18 unbranched or branched alkynyl, C1-18 lower haloalkyl, C3-8 cycloalkyl, alkyl substituted C3-8 cycloalkyl phenyl, phenyl optionally substituted with one to three substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, lower thioalkyl, lower alkyl sulfinyl, lower alkyl sulfonyl, nitro, cyano, CH2Ph wherein in phenyl ring is optionally substituted as described above, and CH2OPh wherein in phenyl ring is optionally substituted as described above;
• R6 is independently selected from the group consisting of the side chains of naturally occurring amino acids and C1-5 unbranched or branched alkyl;
• R7 is selected from the group consisting of hydrogen, R5OCO;
• or,
• R6 and R7 taken together are (CH2)3;
• and,
• hydrates, solvates, clathrates and acid addition salts thereof;
• in combination with one or more pharmaceutically acceptable carriers and excipients, with the proviso that at least one of R1, R2, R3, or R4 is other than hydrogen.

A process for converting an N-acyl cytidine compound IVa to a cytidine compound IVb by selective cleavage of an N-acyl moiety from IVa wherein:

• R is independently selected from the group consisting of hydrogen, COR5, C(═O)OR5, C(═O)SR5, C(═O)NHR5 and COCH(R6)NHR7;
• R5 is independently selected from the group consisting of C1-18 unbranched or branched alkyl, C1-18 unbranched or branched alkenyl, C1-18 unbranched or branched alkynyl, C1-18 lower haloalkyl, C3-8 cycloalkyl, alkyl substituted C3-8 cycloalkyl phenyl, phenyl optionally substituted with one to three substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, lower thioalkyl, lower alkyl sulfinyl, lower alkyl sulfonyl, nitro, cyano, CH2Ph wherein in phenyl ring is optionally substituted as described above, and CH2OPh wherein in phenyl ring is optionally substituted as described above;
• R6 is independently selected from the group consisting of the side chains of naturally occurring amino acids and C1-5 unbranched or branched alkyl;
• R7 is selected from the group consisting of hydrogen, R5OCO;
• or,
• R6 and R7 together are (CH2)3;
• said process comprising contacting a solution of said N-acyl pyrimidine nucleoside with ZnBr2 in a protic solvent RbOH wherein Ra is hydrogen or C1-4 alkyl.