Modified 2' and 3'-nucleoside prodrugs for treating Flaviviridae infections

Abstract

2′ and / or 3′ prodrugs of 1′, 2′, 3′ or 4′-branched nucleosides, and their pharmaceutically acceptable salts and derivatives are described. These prodrugs are useful in the prevention and treatment of Flaviviridae infections, including HCV infection, and other related conditions. Compounds and compositions of the prodrugs of the present invention are described. Methods and uses are also provided that include the administration of an effective amount of the prodrugs of the present invention, or their pharmaceutically acceptable salts or derivatives. These drugs may optionally be administered in combination or alteration with further anti-viral agents to prevent or treat Flaviviridae infections and other related conditions.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. application Ser. No. 10 / 608,907, filed Jun. 27, 2003, which claims the benefit of priority to U.S. Provisional application No. 60 / 392,350, filed Jun. 28, 2002; U.S. Provisional Application No. 60 / 466,194, filed Apr. 28, 2003; and U.S. Provisional Application No. 60 / 470,949, filed May 14, 2003, the disclosures of each of which are incorporated herein by reference.FIELD OF THE INVENTION [0002] This invention is in the area of pharmaceutical chemistry, and is in particular, a 2′ and / or 3′ prodrug of 6-modified, 1′, 2′, 3′ or 4′-branched pyrimidine nucleoside or 8-modified, 1′, 2′, 3′ or 4′-branched purine nucleoside for the treatment of a Flaviviridae infection, such as a hepatitis C virus infection. BACKGROUND OF THE INVENTION Flaviviridae Viruses [0003] The Flaviviridae family of viruses comprises at least three distinct genera: pestiviruses, which cause disease in cattle and pigs; flaviviruses...

AI Technical Summary

Benefits of technology

[0052] 2′ and 3′-prodrugs of 1′, 2′, 3′ or 4′-branched β-D or β-L nucleosides, or their pharmaceutically acceptable salts or pharmaceutically acceptable formulations containing these compounds are useful in the prevention and treatment of Flaviviridae infections and other related conditions such as anti-Flaviviridae antibody positive and Flaviviridae—positive conditions, chronic liver inflammation caused by HCV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue. These compounds or formulations can also be used prophylactically to prevent or retard the progression of clinical illness in individuals who are anti-Flaviviridae antibody or Flaviviridae-antigen positive or who have been exposed to a Flaviviridae.

[0097] The β-D- and β-L-nucleosides of this invention may inhibit Flaviviridae polymerase activity. Nucleosides can be screened for their ability to inhibit Flaviviridae polymerase activity in vitro according to screening methods set forth more particularly herein. One can readily determine the spectrum of activity by evaluating the compound in the assays described herein or with another confirmatory assay.

Problems solved by technology

Pestivirus infections of domesticated livestock (cattle, pigs and sheep) cause significant economic losses worldwide.

However, serological surveys indicate considerable pestivirus exposure in humans.

Unfortunately, the effect of IFN is temporary and a sustained response occurs in only 8%-9% of patients chronically infected with HCV (Gary L. Davis. Gastroenterology 118:S104-S114, 2000).

Most patients, however, have difficulty tolerating interferon treatment, which causes severe flu-like symptoms, weight loss, and lack of energy and stamina.

Thus, ribavirin alone is not effective in reducing viral RNA levels.

Additionally, ribavirin has significant toxicity and is known to induce anemia.

However, as with monotherapy, significant side effects develop during combination therapy, including hemolysis, flu-like symptoms, anemia, and fatigue.

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