3′-or 2′-hydroxymethyl substituted nucleoside derivatives for treatment of hepatitis virus infections
AssigneePharmasset, Inc.
InventorsKyoichi A. Watanabe, S. Balakrishna Pai
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Abstract
The present invention relates to a composition for and a method of treating hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, hepatitis D virus (HDV) infection or a proliferative disorder in a patient using an effective amount of a compound selected from the group consisting of formulas [I]–[IV] below and mixtures of two or more thereof: wherein the substituents are as defined herein. Pharmaceutical compositions comprising these compounds in combination with other HBV, HCV, or HDV agents is also disclosed.
Claims42
A method for the treatment of hepatitis C virus (HCV) infection comprising administering to a host in need thereof an anti-HCV effective amount of a compound selected from the group consisting of formulas [I]–[IV] below and mixtures of two or more thereof:
- wherein:
- R is selected from the group consisting of:
- or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier.
A method for the treatment of hepatitis D virus (HDV) infection comprising administering to a host in need thereof an anti-HDV effective amount of a compound selected from the group consisting of formulas [I]–[IV] below and mixtures of two or more thereof:
- wherein:
- R is selected from the group consisting of:
- or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier.
A pharmaceutical composition for the treatment of HCV comprising an anti-HCV agent and an anti-HCV effective amount of a compound selected from the group consisting of formulas [I]–[IV] below and mixtures of two or more thereof:
- wherein:
- R is independently selected from the group consisting of:
- or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier.
A pharmaceutical composition for the treatment of HDV comprising an anti-HDV agent and an anti-HDV effective amount of a compound selected from the group consisting of formulas [I]–[IV] below and mixtures of two or more thereof:
- wherein:
- R is independently selected from the group consisting of:
- or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier.
A process for stereospecifically preparing a 5′-modified pyrimidine β-nucleoside comprising:
- a. applying the Mitsunobu reaction to a chiral compound of the formula;
- b. selectively protecting the 3′β-position of the resulting nucleoside of step (a) with a benzoyl protecting group or an acid labile protecting group;
- c. subjecting the resulting 3′β-protected anhydro derivative of step (b) to mild alkaline hydrolysis, followed by phosphorylating the ring-opened, 3′β-protected product with a phosphorylating agent;
- d. Saponifiction of the benzoyl group of the resulting product of step (c) to give the desired β-nucleoside 5′-phosphate;
- and
- e. Optionally oxidizing the 5′-phosphate to obtain the 5′-phosphite.
Dependencies are inferred from the claim text.