1. Field of the Invention
The invention relates to compounds for treating viral infections in mammals mediated, at least in part, by a virus in the flaviviridae family of viruses. This invention is also directed to pharmaceutical compositions and methods of use utilizing these compounds.
2. References
The following publications are cited in this application as superscript numbers:    1. Giangaspero, et al., Arch. Virol. Suppl., 7: 53–62 (1993);    2. Giangaspero, et al., Int. J. STD. AIDS, 4(5): 300–302 (1993);    3. Yolken, et al., Lancet, 1(8637): 517–20 (1989);    4. Wilks, et al., Lancet, 1(8629): 107 (1989);    5. Giangaspero, et al., Lancet, 2: 110 (1988);    6. Potts, et al., Lancet, 1(8539): 972–973 (1987);    7. Cornberg, et al., “Hepatitis C: therapeutic perspectives.” Forum (Genova), 11(2):154–62 (2001);    8. Dymock, et al., Antivir. Chem. Chemother. 11(2):79–96 (2000);    9. Devos, et al., International Patent Application Publication No. WO 02/18404 A2, published 7 Mar. 2002;    10. Sommadossi, et al., International Patent Application Publication No. WO 01/90121, published 23 May, 2001;    11. Carroll, S. S., et al., International Patent Application Publication No. WO 02057287, published 25 Jul. 2002;    12. Carroll, S. S., et al., International Patent Application Publication No. WO 02057425, published 25 Jul. 2002;    13. Roberts, et al., U.S. patent application Ser. No. 10/861,090, filed Jun. 4, 2004.    14. Roberts, et al., U.S. patent application Ser. No. 10/861,311, filed Jun. 4, 2004.
All of the above publications and applications are herein incorporated by reference in their entirety to the same extent as if each individual publication or application was specifically and individually indicated to be incorporated by reference in its entirety.
State of the Art
The Flaviviridae family of viruses is composed of three genera: pestivirus, flavivirus and hepacivirus (hepatitis C virus). Of these genera, flaviviruses and hepaciviruses represent important pathogens of man and are prevalent throughout the world. There are 38 flaviviruses associated with human disease, including the dengue fever viruses, yellow fever virus and Japanese encephalitis virus. Flaviviruses cause a range of acute febrile illnesses and encephalitic and hemorrhagic diseases. Hepaciviruses currently infect approximately 2 to 3% of the world population and cause persistent infections leading to chronic liver disease, cirrhosis, hepatocellular carcinoma and liver failure. Human pestiviruses have not been as extensively characterized as the animal pestiviruses. However, serological surveys indicate considerable pestivirus exposure in humans. Pestivirus infections in man have been implicated in several diseases including, but not likely limited to, congenital brain injury, infantile gastroenteritis and chronic diarrhea in human immunodeficiency virus (HIV) positive patients.1-6 
Currently, there are no antiviral pharmaceutical drugs to prevent or treat pestivirus or flavivirus infections. For hepacivirus, i.e., hepatitis C virus (HCV) infections, interferon alpha (IFN) is currently the only approved drug in the United States. HCV is a major causative agent for post-transfusion and for sporadic non-A, non-B hepatitis. Infection by HCV is insidious in a high proportion of chronically infected (and infectious) carriers who may not experience clinical symptoms for many years.
At present, the only acceptable treatment for chronic HCV is interferon (IFN-alpha) and this requires at least six (6) months of treatment and/or ribavirin, which can inhibit viral replication in infected cells and also improve liver function in some people.
IFN-alpha belongs to a family of naturally occurring small proteins with characteristic biological effects such as antiviral, immunoregulatory and antitumoral activities that are produced and secreted by most animal nucleated cells in response to several diseases, in particular viral infections. IFN-alpha is an important regulator of growth and differentiation affecting cellular communication and immunological control. Treatment of HCV with interferon, however, has limited long term efficacy with a response rate about 25%. In addition, treatment of HCV with interferon has frequently been associated with adverse side effects such as fatigue, fever, chills, headache, myalgias, arthralgias, mild alopecia, psychiatric effects and associated disorders, autoimmune phenomena and associated disorders and thyroid dysfunction.
Ribavirin (1-β-D-ribofuranosyl-1 H-1,2,-4-triazole-3-carboxamide), an inhibitor of inosine 5′-monophosphate dehydrogenase (IMPDH), enhances the efficacy of IFN-alpha in the treatment of HCV. Despite the introduction of Ribavirin, more than 50% of the patients do not eliminate the virus with the current standard therapy of interferon-alpha (IFN) and Ribavirin. By now, standard therapy of chronic hepatitis C has been changed to the combination of PEG-IFN plus ribavirin. However, a number of patients still have significant side effects, primarily related to Ribavirin. Ribavirin causes significant hemolysis in 10–20% of patients treated at currently recommended doses, and the drug is both teratogenic and embryotoxic.
Other approaches are being taken to combat the virus. They include, for example, application of antisense oligonucleotides or ribozymes for inhibiting HCV replication. Furthermore, low-molecular weight compounds that directly inhibit HCV proteins and interfere with viral replication are considered as attractive strategies to control HCV infection. NS3/4A serine protease, ribonucleic acid (RNA) helicase, RNA-dependent RNA polymerase are considered as potential targets for new drugs.7,8 
Devos, et al.9 describes purine and pyrimidine nucleoside derivatives and their use as inhibitors of HCV RNA replication. Sommadossi, et al.10 describes 1′, 2′ or 3′-modified nucleosides and their use for treating a host infected with HCV. Carroll, et al.11,12, describes nucleosides as inhibitors of RNA-dependent RNA viral polymerase.
Recently, Roberts, et al.13,14 disclosed that certain 7-(2′-substituted-β-D-ribofuranosyl)-4-amino-5-(optionally substituted ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine compounds possess potent activity against HCV. These references are incorporated herein by reference in their entirety.
USPTO Backgrounds
USPTO Backgrounds