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US20090318380A1 - 2',4'-substituted nucleosides as antiviral agents - Google Patents

2',4'-substituted nucleosides as antiviral agents Download PDF

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Publication number
US20090318380A1
US20090318380A1 US12/271,388 US27138808A US2009318380A1 US 20090318380 A1 US20090318380 A1 US 20090318380A1 US 27138808 A US27138808 A US 27138808A US 2009318380 A1 US2009318380 A1 US 2009318380A1
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US
United States
Prior art keywords
alkyl
optionally substituted
group
alkenyl
alkynyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
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US12/271,388
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English (en)
Inventor
Michael Joseph Sofia
Jinfa Du
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gilead Pharmasset LLC
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Pharmasset Inc
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=40373557&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20090318380(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Pharmasset Inc filed Critical Pharmasset Inc
Priority to US12/271,388 priority Critical patent/US20090318380A1/en
Priority to CN200880125124.5A priority patent/CN101932590B/zh
Priority to ES12192594.5T priority patent/ES2534442T3/es
Priority to PCT/US2008/083787 priority patent/WO2009067409A1/en
Priority to EP08852934.2A priority patent/EP2227482B1/en
Priority to EP14171097.0A priority patent/EP2848624B1/en
Priority to SI200831917T priority patent/SI2227482T1/en
Priority to AU2008326569A priority patent/AU2008326569B2/en
Priority to PT88529342T priority patent/PT2227482T/pt
Priority to JP2010535016A priority patent/JP5492785B2/ja
Priority to ES08852934.2T priority patent/ES2663086T3/es
Priority to NO08852934A priority patent/NO2227482T3/no
Priority to ES14171097T priority patent/ES2794025T3/es
Priority to PL08852934T priority patent/PL2227482T3/pl
Priority to HK11103048.3A priority patent/HK1149017B/zh
Priority to NZ601486A priority patent/NZ601486A/xx
Priority to EP12192594.5A priority patent/EP2631239B1/en
Priority to CA2706327A priority patent/CA2706327C/en
Priority to PT121925945T priority patent/PT2631239E/pt
Priority to CL2008003431A priority patent/CL2008003431A1/es
Priority to PE2008001947A priority patent/PE20091424A1/es
Priority to UY31476A priority patent/UY31476A1/es
Priority to ARP080105024A priority patent/AR069634A1/es
Priority to PA20088804701A priority patent/PA8804701A1/es
Priority to TW097144977A priority patent/TW200936603A/zh
Assigned to PHARMASSET, INC. reassignment PHARMASSET, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DU, JINFA, SOFIA, MICHAEL J
Publication of US20090318380A1 publication Critical patent/US20090318380A1/en
Priority to IL205895A priority patent/IL205895A0/en
Priority to US13/324,068 priority patent/US8765710B2/en
Assigned to GILEAD PHARMASSET LLC reassignment GILEAD PHARMASSET LLC CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: PHARMASSET, INC.
Priority to US14/265,840 priority patent/US9296777B2/en
Priority to HK15109186.8A priority patent/HK1208468B/zh
Priority to US15/007,810 priority patent/US9676808B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
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    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
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    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
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    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/14—Pyrrolo-pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/173—Purine radicals with 2-deoxyribosyl as the saccharide radical

Definitions

  • Embodiments of the invention are directed to compounds, methods, and compositions for use in the treatment of viral infections. More specifically embodiments of the invention are 2′,4′-substituted nucleoside compounds useful for the treatment of viral infections, such as HIV, HCV, and HBV infections.
  • Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2-15% of the world's population.
  • chronic liver disease such as cirrhosis and hepatocellular carcinoma
  • According to the World Health Organization there are more than 200 million infected individuals worldwide, with at least 3 to 4 million people being infected each year. Once infected, about 20% of people clear the virus, but the rest can harbor HCV the rest of their lives.
  • Ten to twenty percent of chronically infected individuals eventually develop liver-destroying cirrhosis or cancer.
  • the viral disease is transmitted parenterally by contaminated blood and blood products, contaminated needles, or sexually and vertically from infected mothers or carrier mothers to their offspring.
  • Current treatments for HCV infection which are restricted to immunotherapy with recombinant interferon- ⁇ alone or in combination with the nucleoside analog ribavirin, are of limited clinical benefit as resistance develops rapidly.
  • the HCV virion is an enveloped positive-strand RNA virus with a single oligoribonucleotide genomic sequence of about 9600 bases which encodes a polyprotein of about 3,010 amino acids.
  • the protein products of the HCV gene consist of the structural proteins C, E1, and E2, and the non-structural proteins NS2, NS3, NS4A and NS4B, and NS5A and NS5B.
  • the nonstructural (NS) proteins are believed to provide the catalytic machinery for viral replication.
  • the NS3 protease releases NS5B, the RNA-dependent RNA polymerase from the polyprotein chain.
  • HCV NS5B polymerase is required for the synthesis of a double-stranded RNA from a single-stranded viral RNA that serves as a template in the replication cycle of HCV. Therefore, NS5B polymerase is considered to be an essential component in the HCV replication complex (K. Ishi, et al, Heptology, 1999, 29: 1227-1235; V. Lohmann, et al., Virology, 1998, 249: 108-118). Inhibition of HCV NS5B polymerase prevents formation of the double-stranded HCV RNA and therefore constitutes an attractive approach to the development of HCV-specific antiviral therapies.
  • HCV belongs to a much larger family of viruses that share many common features.
  • the Flaviviridae family of viruses comprises at least three distinct genera: pestiviruses, which cause disease in cattle and pigs; flaviviruses, which are the primary cause of diseases such as dengue fever and yellow fever; and hepaciviruses, whose sole member is HCV.
  • the flavivirus genus includes more than 68 members separated into groups on the basis of serological relatedness (Calisher et al., J. Gen. Virol, 1993, 70, 37-43). Clinical symptoms very and include fever, encephalitis and hemorrhagic fever (Fields Virology, Editors: Fields, B. N., Knipe, D. M., and Howley, P.
  • Flaviviruses of global concern that are associated with human disease include the Dengue Hemorrhagic Fever viruses (DHF), yellow fever virus, shock syndrome and Japanese encephalitis virus (Halstead, S. B., Rev. Infect. Dis., 1984, 6,251-264; Halstead, S. B., Science, 239: 476-481, 1988; Monath, T. P., New Eng. J. Med. 1988, 319, 641-643).
  • DHF Dengue Hemorrhagic Fever viruses
  • Yellow fever virus yellow fever virus
  • shock syndrome and Japanese encephalitis virus
  • the pestivirus genus includes bovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV, also called hog cholera virus) and border disease virus (BDV) of sheep (Moennig, V. et al. Adv. Vir. Res. 1992, 41, 53-98). Pestivirus infections of domesticated livestock (cattle, pigs, and sheep) cause significant economic losses worldwide. BVDV causes mucosal disease in cattle and is of significant economic importance to the livestock industry (Meyers, G. and Thiel, H. J., Advances in Virus Research, 1996, 47, 53-118; Moennig V., et al., Adv. Vir. Res. 1992, 41, 53-98). Human pestiviruses have not been as extensively characterized as the animal pestiviruses. However, serological surveys indicate considerable pestivirus exposure in humans.
  • BVDV bovine viral diarrhea virus
  • CSFV classical swine fever virus
  • BDV border disease virus
  • Pestiviruses and hepaciviruses are closely related virus groups within the Flaviviridae family.
  • Other closely related viruses in this family include GB virus A, GB virus A-like agents, GB virus-B and GB virus-C (also called hepatitis G virus, HGV).
  • the hepacivirus group (hepatitis C virus; HCV) consists of a number of closely related but genotypically distinguishable viruses that infect humans. There are at least 6 HCV genotypes and more than 50 subtypes.
  • bovine viral diarrhea virus Due to the similarities between pestiviruses and hepaciviruses, combined with the poor ability of hepaciviruses to grow efficiently in cell culture, bovine viral diarrhea virus (BVDV) is often used as a surrogate to study the HCV virus.
  • BVDV bovine viral diarrhea virus
  • RNA viruses possess a single large open reading frame (ORF) encoding all the viral proteins necessary for virus replication. These proteins are expressed as a poly protein that is a co- and post-translationally processed by both cellular and virus-encoded proteinases to yield the mature viral proteins.
  • the viral proteins responsible for the replication of the viral genome RNA are located within approximately the carboxy-terminal. Two-thirds of the ORF are termed non (NS) proteins.
  • NS non
  • the mature nonstructural (NS proteins in sequential order from the amino-terminus of the nonstructural protein coding region to the carboxy-terminus of the ORF, consist of p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B.
  • the NS proteins of pestiviruses and hepaciviruses share sequence domains that are characteristic of specific protein functions.
  • the NS3 proteins of viruses in both groups possess amino acid sequence motifs characteristic of serine proteinases and of helicases (Gorbalenya, et al., Nature, 1988, 333, 22; Bazan and Fletterick, Virology, 1989, 171, 637-639; Gorbalenyl, et al., Nucleic Acid Res., 1989, 17, 3889-3897).
  • the NS5B proteins of pestiviruses and hepaciviruses have the motifs characteristic of RNA-directed RNA polymerases (Koonin, E. V. and Dolja, V. V., Crit. Rev. Biochem. Molec. Biol., 1993, 28, 375-430).
  • NS3 serine proteinase is responsible for all proteolytic processing of polyprotein precursors down stream of its position in the ORF (Wiskerchen and Collett, Virology, 1991, 184, 341-350; Bartenschlager et al., J. Virol. 1993, 67, 3835-3844; Eckart et al., Biochem. Biophys. Res. Comm. 1993, 192, 399-406; Grakoui et al., J. Virol. 1993, 67, 2832-2843; Grakoui et al., Proc.
  • NS4A protein acts as a cofactor with the NS3 serine protease (Bartenschlager et al., J. Virol. 1994, 68, 5045-5055; failla et al., J. Virol., 1994, 68, 3753-3760; Xu et al., J. Virol., 1997, 71, 5312-5322).
  • the NS3 protein of both viruses also functions as a helicase (Kim et al., Biochem Biophys. Res. Comm., 1995, 215, 160-166; Jin and Peterson, Arch. Biochem. Biophys., 1995, 323, 47-53; Warrener and Collett, J. Virol., 1995, 69, 1720-1726).
  • the NS5B proteins of pestiviruses and hepaciviruses have the predicted RNA-directed RNA polymerase activity (Behrens et al., EMBO, 1996, 15, 12-22; Lechmann et al., J. Virol., 1997, 71, 8416-8428; Yuan et al., Biochem. Biophys. Res. Comm. 1997, 232, 231-235; Hagedorn PCT WO 97/12033; Zhong et al., J. Virol., 1998, 72, 9365-9369).
  • RNA-dependent RNA polymerase is absolutely essential for replication of the single-stranded, positive sense, RNA genome and this enzyme has elicited significant interest among medicinal chemists.
  • Inhibitors of HCV NS5B as potential therapies for HCV infection have been reviewed: Tan, S. L., et al., Nature Rev. Drug Discov., 2002, 1, 867-881; Walker, M. P. et al., Exp. Opin. Investigational Drugs, 2003, 12, 1269-1280; Ni, Z-J., et al., Current Opinion in Drug Discovery and Development, 2004, 7, 446-459; Beaulieu, P. L., et al., Current Opinion in Investigational Drugs, 2004, 5, 838-850; Wu, J., et al., Current Drug Targets-Infectious Disorders, 2003, 3, 207-219; Griffith, R.
  • Nucleoside inhibitors of NS5b polymerase can act either as a non-natural substrate that results in chain termination or as a competitive inhibitor which competes with nucleotide binding to the polymerase.
  • nucleoside analog To function as a chain terminator the nucleoside analog must be taken up by the cell and converted in vivo to a triphosphate to compete for the polymerase nucleotide binding site. This conversion to the triphosphate is commonly mediated by cellular kinases which imparts additional structural requirements on a potential nucleoside polymerase inhibitor.
  • hepatitis B virus HBV
  • hepatitis B virus infection remains a major public health problem worldwide with 400 million chronic carriers. These infected patients are exposed to a risk of developing liver cirrhosis and hepatocellular carcinoma (Lee, W. M. 1997, N. Eng. J. Med., 337, 1733-1745).
  • HBV hepatitis B virus
  • Hepatitis B virus is second to tobacco as a cause of human cancer.
  • the mechanism by which HBV induces cancer is unknown, although it is postulated that may directly trigger tumor development, or indirectly trigger tumor development through chronic inflammation, cirrhosis, and cell regeneration associated with the infection.
  • Hepatitis B virus has reached epidemic levels worldwide. After a two to six month incubation period in which the host is unaware of the infection, HBV infection can lead to acute hepatitis and liver damage, that causes abdominal pain, jaundice, and elevated blood levels of certain enzymes. HBV can cause fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which massive sections of the liver are destroyed. Patients typically recover from acute viral hepatitis. In some patients, however, high levels of viral antigen persist in the blood for an extended, or indefinite, period, causing a chronic infection. Chronic infections can lead to chronic persistent hepatitis. Patients infected with chronic persistent HBV are most common in developing countries. By mid-1991, there were approximately 225 million chronic carriers of HBV in Asia alone, and worldwide, almost 300 million carriers. Chronic persistent hepatitis can cause fatigue, cirrhosis of the liver, and hepatocellular carcinoma, a primary liver cancer.
  • HBV infection In western industrialized countries, high risk groups for HBV infection include those in contact with HBV carriers or their blood samples.
  • the epidemiology of HBV is in fact very similar to that of HIV, which accounts for why HBV infection is common among patients with AIDS or HIV-associated infections.
  • HBV is more contagious than HIV.
  • HIV human immunodeficiency virus
  • an antivirally effective nucleoside is a 2′,4′-disubstituted 2′-deoxynucleoside ( ⁇ -D or ⁇ -L), its 5′-mono-phosphate, its 5′,3′-cyclic phosphate, its 5′-diphosphate and its 5′-triphosphate or its pharmaceutically acceptable salt (acidic or basic addition salt), hydrate, solvate, crystalline form or prodrug thereof of the general formula:
  • R 2 is independently CH 3 , CH 2 F, CHF 2 , CF 3 , F, CN, C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms;
  • R is H, phosphate, including 5′-monophosphate, 5′,3′-cyclic phosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo;
  • R 3 is independently OH, H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, vinyl, N 3 , CN, Cl, Br, F, I, NO 2 , C(O)O(C 1-4 alkyl), C(O)O(C 1-4 alkyl), C(O)O(C 2-4 alkynyl), C(O)O(C 2-4 alkenyl), O(C 1-10 acyl), O(C 1-4 alkyl), O(C 2-4 alkenyl), SH, S(C 1-4 acyl), S(C 1-4 alkyl), S(C 2-4 alkynyl), S(C 2-4 alkenyl), SO(C 1-4 acyl), SO(C 1-4 alkyl), SO(C 2-4 alkynyl), SO(C 2-4 alkenyl), SO 2 (C 1-4 acyl), SO 2 (C 1-4 alkyl), SO 2 (C 2-4 alkynyl), SO(C 2-4
  • R 4 is independently H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH 2 ) p OH, where p is 1-6, including hydroxylmethyl (CH 2 OH), CH 2 F, N 3 , CH 2 CN, CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , ethynyl alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkenyl, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino;
  • R and R 3 can together form 5′,3′-cyclic phosphate including stabilized prodrugs thereof;
  • Base (B) is a naturally occurring or modified purine or pyrimidine base represented by the following structures:
  • Z is N or CR 8 ;
  • R 5 , R 6 , and R 7 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), lower alkyl of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkyl of C 1 -C 6 , lower alkenyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -C 6 , CO 2 H, CO 2 R′, CONH 2 , CONHR
  • R 8 is independently H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), NO 2 , lower alkyl of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkyl of C 1 -C 6 , lower alkenyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -C 6 , CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR
  • base (B) may be selected from a group of formula c
  • Z is independently selected from N or C-G; or, if Z is not a participant in a pi bond (double bond), Z is independently selected from O, S, Se, NR, NOR, NNR 2 , CO, CS, CNR, SO, S(O) 2 , SeO, Se(O) 2 , or C(G) 2 ; each G is independently selected from the group consisting of H, halogen, OR, SR, NR 2 , NROR, N 3 , COOR, CN, CONR 2 , C(S)NR 2 , C( ⁇ NR)NR 2 , and R; and where any two adjacent Z are not both selected from O, S, and Se, or not both selected from CO, CS, CNNR, SO, S(O) 2 , SeO and Se(O) 2 ; wherein, if X is a participant in a pi bond (double bond), X is C; or if X is a participant in a pi bond (double bond), X is C; or if
  • base may be a structure selected from the group consisting of structures o-ff
  • base (B) may be a structure gg
  • each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond) and R′′, R, and Z are defined as in structure c;
  • base (B) may be a structure hh
  • each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond), and each Z in independently CG (if a participant in a pi bond) or >C(G) 2 (if not a participant in a pi bond), wherein R′′ and G are defined as in structure c;
  • base (B) may be a structure ii
  • base may be a structure jj
  • R and G are defined as in structure c; or base may be a structure kk
  • Embodiments of the invention are directed to novel 2′,4′-substituted nucleoside derivatives for the treatment is viral infections in mammals, comprised of one or more compounds of the formula:
  • R 2 is independently CH 3 , CH 2 F, CHF 2 , CF 3 , F, CN, C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms;
  • R is H, phosphate, including 5′-monophosphate, 5′,3′-cyclic phosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo;
  • R 3 is independently OH, H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, vinyl, N 3 , CN, Cl, Br, F, I, NO 2 , C(O)O(C 1-4 alkyl), C(O)O(C 1-4 alkyl), C(O)O(C 2-4 alkynyl), C(O)O(C 2-4 alkenyl), O(C 1-10 acyl), O(C 1-4 alkyl), O(C 2-4 alkenyl), SH, S(C 1-4 acyl), S(C 1-4 alkyl), S(C 2-4 alkynyl), S(C 2-4 alkenyl), SO(C 1-4 acyl), SO(C 1-4 alkyl), SO(C 2-4 alkynyl), SO(C 2-4 alkenyl), SO 2 (C 1-4 acyl), SO 2 (C 1-4 alkyl), SO 2 (C 2-4 alkynyl), SO(C 2-4
  • R 4 is independently H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH 2 ) p OH, where p is 1-6, including hydroxylmethyl (CH 2 OH), CH 2 F, N 3 , CH 2 CN, CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , ethynyl alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkenyl, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino;
  • R and R 3 can together form 5′,3′-cyclic phosphate including stabilized prodrugs thereof;
  • Base is a naturally occurring or modified purine or pyrimidine base represented by the following structures:
  • Z is N or CR 8 ;
  • R 5 , R 6 , and R 7 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), lower alkyl of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkyl of C 1 -C 6 , lower alkenyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -C 6 , CO 2 H, CO 2 R′, CONH 2 , CONHR
  • R 8 is independently H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), NO 2 , lower alkyl of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkyl of C 1 -C 6 , lower alkenyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -C 6 , CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR
  • base may be selected from a group of formula c
  • Z is independently selected from N or C-G; or, if Z is not a participant in a pi bond (double bond), Z is independently selected from O, S, Se, NR, NOR, NNR 2 , CO, CS, CNR, SO, S(O) 2 , SeO, Se(O) 2 , or C(G) 2 ;
  • each G is independently selected from the group consisting of H, halogen, OR, SR, NR 2 , NROR, N 3 , COOR, CN, CONR 2 , C(S)NR 2 , C( ⁇ NR)NR 2 , and R; and where any two adjacent Z are not both selected from O, S, and Se, or not both selected from CO, CS, CNNR, SO, S(O) 2 , SeO and Se(O) 2;
  • each R is independently selected from the group consisting of H, CF 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted arylal
  • base may be a structure selected from the group consisting of structures o-ff
  • base may be a structure gg
  • each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond) and R′′, R, and Z are defined as in structure c;
  • base may be a structure hh
  • each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond), and each Z in independently CG (if a participant in a pi bond) or >C(G) 2 (if not a participant in a pi bond), wherein R′′ and G are defined as in structure c; base may be a structure ii
  • base may be a structure jj
  • R and G are defined as in structure c; or base may be a structure kk
  • R is C 1 -C 3 alkyl
  • X is selected from the group consisting of hydrogen, halo, and OW 2
  • Q′ is selected from the group consisting of NH, O, and S
  • G′ is selected from the group consisting of amino, aminocarbonyl, methylamino, dimethylamino, acylamino, —SO 3 H, —SO 2 NH 2 , alkoxyamino, aminocarbonylamino, oxycarbonylamino, HR′NCHR′′C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R′′ is a side-chain of an amino acid or where R′ and R′′ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group; Y is selected from the group consisting of a bond, O, and CH 2 ; and each of W, W 1 , and W 2 is independently selected from the group
  • a or “an” entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound.
  • a compound refers to one or more compounds or at least one compound.
  • the terms “a” or (or “an”), “one or more”, and “at least one” can be used interchangeably herein.
  • both R's can be carbon, both R's can be nitrogen, or one R can be carbon and the other nitrogen.
  • alkenyl refers to an unsubstituted hydrocarbon chain radical having from 2 to 10 carbon atoms having one or two olefinic double bonds, preferably one olefinic double bond.
  • C 2-N alkenyl refers to an alkenyl comprising 2 to N carbon atoms where N is an integer having the following values: 3, 4, 5, 6, 7, 8, 9, or 10.
  • C 2-10 alkenyl refers to an alkenyl comprising 2 to 10 carbon atoms. Examples include, but are not limited to vinyl, 1-propenyl, 2-propenyl, (allyl) or 2-butenyl (crotyl).
  • halogenated alkenyl refers to an alkenyl comprising at least one of F, Cl, Br, and I.
  • alkyl refers to an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 30 carbon atoms.
  • C 1-N alkyl refers to an alkyl comprising 1 to N carbon atoms, where N is an integer having the following values: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
  • C 1-4 ” alkyl refers to an alkyl contain 1 to 4 carbon atoms.
  • low alkyl or “lower alkyl” denotes a straight or branched chain hydrocarbon residue comprising 1 to 8 carbon atoms.
  • C 1-20 alkyl refers to an alkyl comprising 1 to 20 carbon atoms.
  • C 1-10 alkyl refers to an alkyl comprising 1 to 10 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.
  • the term (ar)alkyl or (heteroaryl)alkyl indicate the alkyl group is optionally substituted by an aryl or a heteroaryl group respectively.
  • halogenated alkyl refers to an unbranched or branched chain alkyl comprising at least one of F, Cl, Br, and I.
  • C 1-3 haloalkyl refers to a haloalkyl comprising 1 to 3 carbons and at least one of F, Cl, Br, and I.
  • halogenated lower alkyl refers to a haloalkyl comprising 1 to 8 carbon atoms and at least one of F, Cl, Br, and I.
  • Examples include, but are not limited to, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, dichloromethyl, dibromomethyl, diiodomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, 1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 1-iodoethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2-dibromoethyl, 2,2-diiodoethyl, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl, 3-iodopropyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pent
  • alkynyl refers to an unbranched or branched hydrocarbon chain radical having from 2 to 10 carbon atoms, preferably 2 to 5 carbon atoms, and having one triple bond.
  • C 2-N alkynyl refers to an alkynyl comprising 2 to N carbon atoms, where N is an integer having the following values: 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • C 2-4 alkynyl refers to an alkynyl comprising 2 to 4 carbon atoms.
  • C 2-10 alkynyl refers to an alkynyl comprising 2 to 10 carbon atoms. Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, or 3-butynyl.
  • halogenated alkynyl refers to an unbranched or branched hydrocarbon chain radical having from 2 to 10 carbon atoms preferably 2 to 5 carbon atoms, and having one triple bond and at least one of F, Cl, Br, and I.
  • cycloalkyl refers to a saturated carbocyclic ring comprising 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
  • C 3-7 cycloalkyl refers to a cycloalkyl comprising 3 to 7 carbons in the carbocyclic ring.
  • alkoxy refers to an —O-alkyl group, wherein alkyl is defined above. Examples include, but are not limited to, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy. “Lower alkoxy” or “low alkoxy” or “low alkoxyl” as used herein denotes an alkoxy group with a “lower alkyl” group as previously defined. “C 1-10 alkoxy” refers to an —O-alkyl wherein alkyl is C 1-10 .
  • halogenated alkoxy refers to an —O-alkyl group in which the alkyl group comprises at least one of F, Cl, Br, and I.
  • halogenated lower alkoxy or “halogenated low alkoxy” refers to an —O-(lower alkyl) group in which the lower alkyl group comprises at least one of F, Cl, Br, and I.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • protected refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes.
  • oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.
  • Non-limiting examples include: C(O)-alkyl, C(O)Ph, C(O)aryl, CH 3 , CH 2 -alkyl, CH 2 -alkenyl, CH 2 Ph, CH 2 -aryl, CH 2 O-alkyl, CH 2 O-aryl, SO 2 -alkyl, SO 2 -aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene).
  • halo as used herein includes fluoro, chloro, bromo, and iodo.
  • purine or “pyrimidine” base includes, but is not limited to, adenine, N-alkylpurines, N 6 -acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N 6 -benzylpurine, N 6 -halopurine, N 6 -vinyulpurine, N 6 -acetylenic purine, N 6 -acyl purine, N6-hydroxyalkylpurine, N 6 -allylaminopurine, N 6 -thioallyl purine, N 2 -alkylpurines, N 2 -alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and 4-mercaptopyrimidine, uracil, 5-halouracil, including 5-fluorouracil, C 5 -alkylpyr
  • Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine. Functional oxygen and nitrogen groups on the base can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methansulfonyl, and p-toluenesulfonyl.
  • pharmaceutically acceptable salt or prodrug is used throughout the specification to describe any pharmaceutically acceptable form (such as an ester, phosphate ester, salt of an ester or related group) of a compound which upon administration to a mammal, provides the active compound.
  • Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids.
  • Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form a compound of the present invention. Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the selected compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound.
  • the compounds of this invention possess antiviral activity against the HIV, HBV and HCV viruses, or are metabolized to a compound that exhibits such activity.
  • pharmaceutically acceptable salts are organic acid addition salts formed with acids, which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, ⁇ -ketoglutarate, and ⁇ -glycerophosphate.
  • Suitable inorganic salts may also be formed, including sulfate, nitrate, bicarbonate and carbonate salts.
  • salts may be obtained, for example, by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • suitable acid affording a physiologically acceptable anion.
  • Alkali metal for example, sodium, potassium, or lithium
  • alkaline earth metal for example, calcium and magnesium
  • Any of the compounds described herein can be administered as a prodrug to increase the activity, bioavailability, stability or otherwise alter the properties of the selected compound.
  • a number of prodrug ligands are known.
  • host refers to a unicellular or multicellular organism in which the virus can replicate, including but not limited to cell lines and animals, and preferably a human. Alternatively, the host can be carrying a part of the viral genome, whose replication or function can be altered by the compounds of the present invention. The term host specifically refers to infected cells, cells transfected with all or part of the viral genome and animals.
  • the compounds of the present invention may be formulated in a wide variety of oral administration dosage forms and carriers.
  • Oral administration can be in the form of tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions, syrups, or suspensions.
  • Compounds of the present invention are efficacious when administered by suppository administration, among other routes of administration.
  • the most convenient manner of administration is generally oral using a convenient daily dosing regimen which can be adjusted according to the severity of the disease and the patient's response to the antiviral medication.
  • a compound or compounds of the present invention, as well as their pharmaceutically acceptable salts, together with one or more conventional excipients, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages.
  • the pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations or liquids such as suspensions, emulsions, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration.
  • a typical preparation will contain from about 5% to about 95% active compound or compounds (w/w).
  • preparation or “dosage form” is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the desired dose and pharmacokinetic parameters.
  • excipient refers to a compound that is used to prepare a pharmaceutical composition, and is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use.
  • the compounds of this invention can be administered alone but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice.
  • a “pharmaceutically acceptable salt” form of an active ingredient may also initially confer a desirable pharmacokinetic property on the active ingredient which was absent in the non-salt form, and may even positively affect the pharmacodynamics of the active ingredient with respect to its therapeutic activity in the body.
  • pharmaceutically acceptable salt of a compound as used herein means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, salicyclic acid, muconic acid, and the like or (2) basic addition salts formed with the conjugate bases of any of the inorganic acids listed above, wherein the conjugate bases comprise a cationic component
  • Solid form preparations include powders, tablets, pills capsules, suppositories, and dispersible granules.
  • a solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component.
  • the active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • Solid form preparations may contain, in addition to the active component colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • Liquid formulations also are suitable for oral administration include liquid formulations including emulsions, syrups, elixirs and aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
  • the compounds of the present invention may be formulated for administration as suppositories.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and to solidify.
  • the compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Suitable formulations along with pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th Edition, Easton, Pa., which is hereby incorporated by reference.
  • a skilled formulation scientist may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or comprising their therapeutic activity.
  • the modification of the present compounds to render them more soluble in water or other vehicle may be easily accomplished by minor modifications (e.g., salt formulation), which are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients.
  • the term “medicament” means a substance used in a method of treatment and/or prophylaxis of a subject in need thereof, wherein the substance includes, but is not limited to, a composition, a formulation, a dosage from, and the like, comprising a compound of formula I. It is contemplated that the use of the compound represented by formula I in the manufacture of a medicament for the treatment of any of the antiviral conditions disclosed herein can be any of the compounds contemplated in any of the aspects of the invention, either alone or in combination with other compounds of the present invention.
  • subject means a mammal, which includes, but is not limited to, cattle, pigs, sheep, chicken, turkey, buffalo, llama, ostrich, dogs, cats, and humans, preferably the subject is a human.
  • terapéuticaally effective amount means an amount required to reduce symptoms of the disease in an individual.
  • the dose will be adjusted to the individual requirements in each particular case. That dosage can vary within wide limits depending upon numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medicaments with which the patient is being treated, the route and form of administration and the preferences and experience of the medical practitioner involved.
  • a daily dosage of between about 0.1 and about 10 g, including all values in between, such as 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, and 9.5 g, per day should be appropriate in monotherapy and/or in combination therapy.
  • a preferred daily dosage is between about 0.5 and about 7.5 g per day, a more preferred dosage is between 1.5 and about 6.0 g per day.
  • treatment is initiated with a large initial “loading dose” to rapidly reduce or eliminate the virus followed by a decreasing of the dose to a level sufficient to prevent resurgence of the infection.
  • loading dose to rapidly reduce or eliminate the virus followed by a decreasing of the dose to a level sufficient to prevent resurgence of the infection.
  • Therapeutic efficacy in HBV and HCV treatment can be ascertained from tests of liver function including, but not limited to protein levels such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5′-nucleosidase, C-glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism.
  • the therapeutic effectiveness may be monitored by measuring HBV or HCV-RNA the results of these tests will allow the dose to be optimized.
  • therapeutic efficacy in HIV infection can be ascertained by measuring HIV-RNA levels from plasma samples and measuring levels of CD4 cells.
  • the disclosed compounds or their pharmaceutically acceptable derivatives or salts or pharmaceutically acceptable formulations containing these compounds are useful in the prevention and treatment of HIV infections and other related conditions such as AIDS-related complex (ARC), persistent generalized lymphadenopathy (PGL), AIDS-related neurological conditions, anti-HIV antibody positive and HIV-positive conditions, Kaposi's sarcoma, thrombocytopenia purpurea and opportunistic infections.
  • these compounds or formulations can be used prophylactically to prevent or retard the progression of clinical illness in individuals who are anti-HIV antibody or HIV-antigen positive or who have been exposed to HIV.
  • Another aspect of the present invention comprises administering a therapeutically effective amount of a compound represented by formula I and a therapeutically effective amount of another antiviral agent; wherein the administration is concurrent or alternative or sequential.
  • the time between alternative (or sequential) administration can range between 1-24 hours, which includes any sub-range in between including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, and 23 hours.
  • the another antiviral agent includes but is not limited to interferon- ⁇ , interferon-B, pegylated interferon- ⁇ , ribavirin, levovirin, viramidine, another nucleoside HIV, HBV, or HCV polymerase inhibitor, an HIV, HBV, or HCV non-nucleoside polymerase inhibitor, an HIV, HBV, or HCV protease inhibitor, an HIV, HBV, or HCV helicase inhibitor or an HIV, HBV, or HCV fusion inhibitor.
  • an active compound or its derivative or salt are administered in combination with another antiviral agent the activity may be increased over the parent compound.
  • Concurrent administration thus includes administration of the agents at the same time or at different times. Administration of two or more agents at the same time can be achieved by a single formulation containing two or more active ingredients or by substantially simultaneous administration of two or more dosage forms with a single active agent.
  • the active compound or its prodrug or pharmaceutically acceptable salt can be administered in combination or alternation with another antiviral agent, such as another active anti-HIV agent, including but not limited to those of the formulae above, others listed below or known in the art.
  • another antiviral agent such as another active anti-HIV agent
  • effective dosages of two or more agents are administered together, whereas during alternation therapy, an effective dosage of each agent is administered serially.
  • the dosage will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
  • Nonlimiting examples of antiviral agents that can be used in combination with the compounds disclosed herein include the following: Invirase®, Fortovase®, Norvir®, Crixivan®, Viracept®, Agenerase®, Kaletra®, Retrovir®, Epivir®, Combivir®, Triazivir®, Ziagen®, Hivid®, Videx®, Didex® EC, Zerit®, Viread®, CovincilTM, Viramune®, Rescriptor®, Sustiva®, Droxia®, Fuzeon®, Atazanavir®, Proleukin®, Remune®, Procrit®, Darunavir®, and Serostim®,
  • references herein to treatment extend to prophylaxis as well as to the treatment of existing conditions.
  • treatment also includes treatment or prophylaxis of a disease or a condition associated with or mediated by the viral infection, or the clinical symptoms thereof.
  • Another embodiment is directed to a process for preparing the compound represented by A or A′, to the compound A or A′ obtained by the process, and to a composition comprising A or A′ obtained by the process, the process comprising
  • R 2 is independently CH 3 , CH 2 F, CHF 2 , CF 3 , F, CN, C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms;
  • R is H, phosphate, including 5′-monophosphate, 5′,3′-cyclic phosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo;
  • R 3 is independently OH, H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, vinyl, N 3 , CN, Cl, Br, F, I, NO 2 , C(O)O(C 1-4 alkyl), C(O)O(C 1-4 alkyl), C(O)O(C 2-4 alkynyl), C(O)O(C 2-4 alkenyl), O(C 1-10 acyl), O(C 1-4 alkyl), O(C 2-4 alkenyl), SH, S(C 1-4 acyl), S(C 1-4 alkyl), S(C 2-4 alkynyl), S(C 2-4 alkenyl), SO(C 1-4 acyl), SO(C 1-4 alkyl), SO(C 2-4 alkynyl), SO(C 2-4 alkenyl), SO 2 (C 1-4 acyl), SO 2 (C 1-4 alkyl), SO 2 (C 2-4 alkynyl), SO(C 2-4
  • R 4 is independently H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH 2 ) p OH, where p is 1-6, including hydroxylmethyl (CH 2 OH), CH 2 F, N 3 , CH 2 CN, CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , ethynyl alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkenyl, NO 2 , amino, loweralkylamino, or di(loweralkyl)amino;
  • R and R 3 can together form 5′,3′-cyclic phosphate including stabilized prodrugs thereof;
  • Base is a naturally occurring or modified purine or pyrimidine base represented by the following structures:
  • Z is Nor CR 8 ;
  • R 5 , R 6 , and R 7 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), lower alkyl of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkyl of C 1 -C 6 , lower alkenyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -C 6 , CO 2 H, CO 2 R′, CONH 2 , CONHR
  • R 8 is independently H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 (two R′ can form saturated or unsaturated rings, or saturated or unsaturated heterocyclic rings), NO 2 , lower alkyl of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkyl of C 1 -C 6 , lower alkenyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 , halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -C 6 , CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR
  • base may be selected from a group of formula c
  • Z is independently selected from N or C-G; or, if Z is not a participant in a pi bond (double bond), Z is independently selected from O, S, Se, NR, NOR, NNR 2 , CO, CS, CNR, SO, S(O) 2 , SeO, Se(O) 2 , or C(G) 2 ;
  • each G is independently selected from the group consisting of H, halogen, OR, SR, NR 2 , NROR, N 3 , COOR, CN, CONR 2 , C(S)NR 2 , C( ⁇ NR)NR 2 , and R; and where any two adjacent Z are not both selected from O, S, and Se, or not both selected from CO, CS, CNNR, SO, S(O) 2 , SeO and Se(O) 2 ;
  • each R is independently selected from the group consisting of H, CF 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted arylal
  • base may be a structure selected from the group consisting of structures o-ff
  • base may be a structure gg
  • each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond) and R′′, R, and Z are defined as in structure c;
  • base may be a structure hh
  • each Z′ is independently N (if a participant in a pi bond) or NR (if not a participant in a pi bond), and each Z in independently CG (if a participant in a pi bond) or >C(G) 2 (if not a participant in a pi bond), wherein R′′ and G are defined as in structure c; base may be a structure ii
  • base may be a structure jj
  • R and G are defined as in structure c; or base may be a structure kk
  • R is C 1 -C 3 alkyl
  • X is selected from the group consisting of hydrogen, halo, and OW 2
  • Q′ is selected from the group consisting of NH, O, and S
  • G′ is selected from the group consisting of amino, aminocarbonyl, methylamino, dimethylamino, acylamino, —SO 3 H, —SO 2 NH 2 , alkoxyamino, aminocarbonylamino, oxycarbonylamino, HR′NCHR′′C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R′′ is a side-chain of an amino acid or where R′ and R′′ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group; Y is selected from the group consisting of a bond, O, and CH 2 ; and each of W, W 1 , and W 2 is independently selected from the group
  • Compound 18 also can be prepared by azizo-iodination of 14. Treatment of 14 with ICl and NaN 3 gives 4′-azido-5′-iodo-nucleoside 19 in good yield. 3′-OH protection with BzCl followed by 5′-iodo-oxidation with m-chloroperbenzoic acid in the presence of m-chlorobenzoic acid provides the protected nucleoside 20. Deprotection of 20 also affords 4′-azido-nucleosides 18.
  • Scheme 4 illustrated the preparation of 2′-(R)-4′-azido-2′-C-methyl-2′-deoxycytidine.
  • the target nucleoside 26 was prepared by treatment of 28 with triisopropylbenzenesulfonyl chloride in the presence of DMAP followed by ammonium hydroxide then methanolic ammonia.
  • Compound 26 can also be prepared through expoxide intermediate 24 by treatment of compound 23 with DMDO/acetone followed by ring-opening with TMSN 3 in the presence of SnCl 4 and conversion of uridine analog to cytidine derivative.
  • compound 70 was prepared from intermediate 64 when trimethylsilyl cyanide was used as nucleophile for the epoxide opening.
  • Compound 27 was prepared from starting nucleoside, 2′-C-methyl-2′-deoxyuridine, by treatment with I 2 /Ph 3 P and elimination catalyzed by NaOMe followed by azido-iodination with NCl/NaN 3 .
  • the methoxy compound (40 mg, 135 mmol, 1.0 eq.) was dissolved in 0.5N ammonia in dioxane (5 ml). The reaction mixture was heated to 120° C. in a microwave (250 W, 150 PSI) for 3 hours. Progress of the reaction was followed by LCMS. Upon completion of the reaction the solvent was removed and the residue was purified over silica gel eluted with DCM-EtOH from 95:5 to 80:20 to yield 16.8 mg of the desired product 26 as a syrup.
  • the compound 47 obtained was then dissolved in dioxane (100 mL) and 37% formaldehyde (3 mL, 36.96 mmol) was added. To the obtained solution was added 2N sodium hydroxide (5 mL, 10 mmol) dropwise at rt. The resulting reaction mixture was stirred at rt for 15 h and cooled. Then sodium borohydride (890 mg, 23.53 mmol) was added portionwise. The resulting mixture was stirred at rt for 6 h and AcOH-pyridine solution (2.5:7.5 mL) and water (100 mL) were added under ice-water. The mixture was then extracted with CH 2 Cl 2 (50 mL ⁇ 4) and the organic layer dried over sodium sulfate.
  • a mixture of the intermediate (70 mg, 0.14 mmol) and ammonium fluoride (260 mg, 7.09 mmol) was heated at 90° C. in a sealed flask for 15 h and concentrated in vacuo.
  • nucleosides of formula as indicated can be prepared.
  • the materials required for the assay comprise the following:
  • the HepG2- AD38 cell line The HepG2- AD38 cell line.
  • the culture medium for HepG2- AD38 comprises DMEM-F/12, 10% fetal bovine serum, 100 IU/ml/100 ug/ml of Penicillin/streptomycin, 50 ⁇ g/ml kanamycin, 0.3 ⁇ g/ml tetracycline, and 200 g/ml G418.
  • the assay medium for HepG2-AD38 comprises DMEM-F/12, 10% fetal bovine serum, 100 IU/ml/100 ⁇ g/ml of penicillin/streptomycin, 50 ⁇ g/ml kanamycin, and 200 ⁇ g/ml G418
  • Further materials comprise Phosphate buffered saline (PBS), Biocoated 96 well plates, DNeasy 96 tissue kit (Qiagen), QIAvac 96 vacuum manifold, Micro amp optical 96 well reaction plates (Applied Biosystems), Micro amp optical caps (Applied Biosystems), Tagman Universal PCR Master Mix (Applied Biosystems), and a 7700 Sequence detector (Applied Biosystems),
  • the primers and probes for HBV DNA comprise the 1125 nM forward primer (GGA CCC CTG CTC GTG TTA CA), the 1125 nM reverse primer (GAG AGA AGT CCA CCA CGA GTC TAG A), and the 250 nM probe (FAM-TGT TGA CAA GAA TCC TCA CAA TAC CAC).
  • HBV primers+probe mix for 200 wells (total 1500 ⁇ l) comprising 45 ⁇ l of primer 1 (100 ⁇ M), 45 ⁇ l of primer 2 (100 ⁇ M), 20 ⁇ l of probe (50 ⁇ M), and 1390 ⁇ l of nuclease free water.
  • Select an optical 96 well reaction plate Make the reaction mix for 100 wells comprising 1000 ⁇ l of Universal PCR Master Mix, 750 ul of HBV primers+probe mix, and 250 ⁇ l of nuclease free water. Aliquot 20 ⁇ l of the reaction mix per well. Add 5 ⁇ l per well of HBV DNA from each sample. Cover the wells with optical caps.
  • HCV replicon RNA-containing Huh 7 cells (clone A cells; Apath, LLC, St. Louis, Mo.) were kept at exponential growth in Dulbecco's modified Eagle's medium (high glucose) containing 10% fetal bovine serum, 4 mM L-glutamine and 1 mM sodium pyruvate, 1 ⁇ nonessential amino acids, and G418 (1,000 ⁇ g/ml).
  • Antiviral assays were performed in the same medium without G418. Cells were seeded in a 96-well plate at 1,500 cells per well, and test compounds were added immediately after seeding. Incubation time 4 days. At the end of the incubation step, total cellular RNA was isolated (RNeasy 96 kit; Qiagen).
  • Replicon RNA and an internal control were amplified in a single-step multiplex RT-PCR protocol as recommended by the manufacturer.
  • the HCV primers and probe were designed with Primer Express software (Applied Biosystems) and covered highly conserved 5′-untranslated region (UTR) sequences (sense, 5′-AGCCATGGCGTTAGTA(T)GAGTGT-3′, and antisense, 5′-TTCCGCAGACCACTATGG-3′; probe, 5′-FAM-CCTCCAGGACCCCCCCTCCC-TAMRA-3′).
  • the threshold RT-PCR cycle of the test compound was subtracted from the average threshold RT-PCR cycle of the no-drug control ( ⁇ CtHCV).
  • ⁇ CtHCV the threshold RT-PCR cycle of the test compound
  • a ⁇ Ct of 3.3 equals a 1-log 10 reduction (equal to the 90% effective concentration [EC 90 ]) in replicon RNA levels.
  • the cytotoxicity of the test compound could also be expressed by calculating the ⁇ CtrRNA values.
  • the ⁇ Ct specificity parameter could then be introduced ( ⁇ CtHCV- ⁇ CtrRNA), in which the levels of HCV RNA are normalized for the rRNA levels and calibrated against the no-drug control.
  • HIV screen Primary Screening of PSI compounds are tested for antiviral HIV activity at 50M.
  • the cells used are P4CCR5luc cells; they are human HIV indicator cells, which are derived from Hela cells, express CD4, CXCR4, CCR5, luciferase, and a beta-gal gene under the control of HIV-1 LTR.
  • P4CCR5 luc cells are cultivated in DMEM, 10% FBS, Penicillin, Streptomycin, and G418 at 500 ⁇ g/ml. 100 ⁇ l of P4 CCR5-luc cells are plated at 10,000 cells per well in 96 well Opaque Assay plates and incubated overnight at 37° C.
  • the media is aspirated from the plates and replaced by 100 ⁇ l of compound freshly diluted into media at 2 ⁇ 50 uM, in triplicate, for 4 hours at 37° C.
  • the cells are then infected with 100 ul NL43 virus at 5 ng of p24 per well, in the presence of 2 ⁇ 20 ug/ml of DEAE-Dextran for 40-42 hours.
  • Non infected, infected no drug and AZT controls are always present in triplicate on each plate.
  • the beta-gal is quantitated using the Galacto-Star kit from Applied Biosystems using the manufacturer instructions and the luminescence measured using a Victor apparatus from Perkin-Elmer. Results are represented as percentage inhibition compare to untreated cells.
  • the assays are performed in 2 to 3 independent experiments.
  • P4 CCR5-luc cells are plated at 10,000 cells per well (100 ⁇ l) in 96 well Opaque Assay plates and incubated overnight at 37° C. The next day, the media is aspirated from the plates and replaced by 100 ul of compound freshly diluted into appropriate media (DMEM, 10% FBS, G418 500 ⁇ g/ml, penicillin/streptomycin) at 2 ⁇ final concentrations in 5 fold dilutions, usually from 2 ⁇ 100 ⁇ M to 2 ⁇ 0.032 uM, in triplicate, for 4 hours at 37° C.
  • DMEM 10% FBS
  • G418 500 ⁇ g/ml penicillin/streptomycin
  • the cells are then infected with 100 ul NL43 wild type or mutant virus, at 5 ng to 20 ng of p24 per well, in the presence of 2 ⁇ 20 ug/ml of DEAE-Dextran, for 40-42 hours.
  • Non infected and infected no drug controls are always present in 12plicate on each plate.
  • An AZT control is tested in parallel for each experiment.
  • the beta-gal is quantitated in the cell lysate using the Galacto-Star kit from Applied Biosystems and the luminescence measured using a Victor apparatus from Perkin-Elmer.
  • the EC 50 Effective Concentration
  • the EC 50 Effective Concentration
  • the assay is performed in at least 2 independent experiments.
  • P4 CCR5-luc cells are plated at 10,000 cells per well (100 ul) in 96 well Opaque Assay plates and incubated overnight at 37° C. The next day, the media is aspirated from the plates and replaced by 200 ul of compound freshly diluted into media in 5 fold dilutions from 100 ⁇ M to 0.0062 ⁇ M. After 4 days of incubation at 37° C., the luciferase activity is measured in the cell lysate using the Bright Glow kit from Promega and the luminescence measured using a Victor apparatus from Perkin-Elmer.
  • Human cells lines Huh 7 and HepG2 (liver), BxPC3 (pancreatic) and CEM (lymphoid) are used for the MTS assays in 96 wells plates.
  • Drugs are freshly diluted in media at 2 ⁇ 100 ⁇ M, 50 ⁇ M, 25 ⁇ M, 10 ⁇ M, 5 ⁇ M, 1 ⁇ M and 50 ⁇ l is dispensed in triplicate in the plates.
  • the wells at the periphery of the plate contain 100 ul of media only and will be the blank controls. A replicate control with no drug is always performed in each plate.
  • 50 ⁇ l of cells are added to the plate, at 2000 cells per well for Huh 7, HepG2 and PxPC3, and 5000 cells per well for CEM cells.
  • the media used for Huh 7, HepG2 and BxPC3 cells is DMEM with 10% FBS, and Penicillin/streptomycin, and RPMI with 10% FBS, and Penicillin/streptomycin for CEM cells.
  • 20 ⁇ l of MTS dye from the CellTiter 96 Aqueous One Solution Cell Proliferation Assay kit from Promega is added to each well and the plate incubated for 2 h at 37° C.
  • the absorbance is then read at 490 nm using the microplate reader E1800 from Biotek.
  • the signal is calculated by subtracting the absorbance measured in the blank controls.
  • the CC 50 (Cytotoxic Concentration) value is then determined by comparing the signal obtained with the no-drug cell control with the treated cells and calculating the concentration of drug necessary to inhibit 50% of the signal in the wells treated with drugs.

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EP12192594.5A EP2631239B1 (en) 2007-11-20 2008-11-17 2',4'-substituted nucleosides as antiviral agents
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PT88529342T PT2227482T (pt) 2007-11-20 2008-11-17 Nucleósidos substituídos nas posições 2¿,4¿ como agentes antivirais
JP2010535016A JP5492785B2 (ja) 2007-11-20 2008-11-17 抗ウイルス剤としての２’，４’−置換ヌクレオシド
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ES14171097T ES2794025T3 (es) 2007-11-20 2008-11-17 Nucleósidos sustituidos en 2’,4’ como agentes antivirales
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CL2008003431A CL2008003431A1 (es) 2007-11-20 2008-11-19 Compuestos derivados de nucleosidos 2',4' sustituidos; proceso de preparacion de dichos compuestos; composicion farmaceutica que los comprende; su metodo de preparacion; y su uso para el tratamiento y/o la prevencion de cualquier condicion resultante de una infeccion por vhb, vhc o vih.
ARP080105024A AR069634A1 (es) 2007-11-20 2008-11-19 Nucleosidos 2,4-sustituidos como agentes antivirales, composiciones farmaceuticas que los contienen y procesos de preparacion
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US13/324,068 US8765710B2 (en) 2007-11-20 2011-12-13 2′,4′-substituted nucleosides as antiviral agents
US14/265,840 US9296777B2 (en) 2007-11-20 2014-04-30 2′,4′-substituted nucleosides as antiviral agents
HK15109186.8A HK1208468B (zh) 2007-11-20 2015-09-18 作為抗病毒劑的2’，4’-取代的核苷
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Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100234584A1 (en) * 2007-07-16 2010-09-16 Junbiao Chang 2'-Fluorine-4'-Substituted-Nucleoside Analogues, Preparation Methods and Uses Thereof
WO2012075140A1 (en) 2010-11-30 2012-06-07 Pharmasset, Inc. Compounds
US8507460B2 (en) 2011-10-14 2013-08-13 Idenix Pharmaceuticals, Inc. Substituted 3′,5′-cyclic phosphates of purine nucleotide compounds and pharmaceutical compositions for the treatment of viral infections
WO2013177243A1 (en) 2012-05-23 2013-11-28 Bristol-Myers Squibb Company Sulfilimine and sulphoxide methods for producing festinavir
WO2014078463A1 (en) * 2012-11-19 2014-05-22 Merck Sharp & Dohme Corp. 2 -alkynyl substituted nucleoside derivatives for treating viral diseases
WO2014172264A1 (en) 2013-04-16 2014-10-23 Bristol-Myers Squibb Company Method for producing festinavir using 5-methyluridine as starting material
US8871737B2 (en) 2010-09-22 2014-10-28 Alios Biopharma, Inc. Substituted nucleotide analogs
US8877731B2 (en) 2010-09-22 2014-11-04 Alios Biopharma, Inc. Azido nucleosides and nucleotide analogs
WO2014201122A1 (en) 2013-06-13 2014-12-18 Bristol-Myers Squibb Company Tert-butyl-sulphoxide method for producing festinavir
US8916538B2 (en) 2012-03-21 2014-12-23 Vertex Pharmaceuticals Incorporated Solid forms of a thiophosphoramidate nucleotide prodrug
US8980865B2 (en) 2011-12-22 2015-03-17 Alios Biopharma, Inc. Substituted nucleotide analogs
US9012427B2 (en) 2012-03-22 2015-04-21 Alios Biopharma, Inc. Pharmaceutical combinations comprising a thionucleotide analog
US9109001B2 (en) 2012-05-22 2015-08-18 Idenix Pharmaceuticals, Inc. 3′,5′-cyclic phosphoramidate prodrugs for HCV infection
US9187515B2 (en) 2013-04-01 2015-11-17 Idenix Pharmaceuticals Llc 2′,4′-fluoro nucleosides for the treatment of HCV
US9192621B2 (en) 2012-09-27 2015-11-24 Idenix Pharmaceuticals Llc Esters and malonates of SATE prodrugs
US9211300B2 (en) 2012-12-19 2015-12-15 Idenix Pharmaceuticals Llc 4′-fluoro nucleosides for the treatment of HCV
US9243025B2 (en) 2011-03-31 2016-01-26 Idenix Pharmaceuticals, Llc Compounds and pharmaceutical compositions for the treatment of viral infections
US9296777B2 (en) 2007-11-20 2016-03-29 Gilead Pharmasset Llc 2′,4′-substituted nucleosides as antiviral agents
US9296778B2 (en) 2012-05-22 2016-03-29 Idenix Pharmaceuticals, Inc. 3′,5′-cyclic phosphate prodrugs for HCV infection
US9309275B2 (en) 2013-03-04 2016-04-12 Idenix Pharmaceuticals Llc 3′-deoxy nucleosides for the treatment of HCV
US9339541B2 (en) 2013-03-04 2016-05-17 Merck Sharp & Dohme Corp. Thiophosphate nucleosides for the treatment of HCV
US9403863B2 (en) 2011-09-12 2016-08-02 Idenix Pharmaceuticals Llc Substituted carbonyloxymethylphosphoramidate compounds and pharmaceutical compositions for the treatment of viral infections
US9422323B2 (en) 2012-05-25 2016-08-23 Janssen Sciences Ireland Uc Uracyl spirooxetane nucleosides
US9447132B2 (en) 2013-04-12 2016-09-20 Achillion Pharmaceuticals, Inc. Highly active nucleoside derivative for the treatment of HCV
US9701706B2 (en) 2015-08-06 2017-07-11 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
US9968628B2 (en) 2000-05-26 2018-05-15 Idenix Pharmaceuticals Llc Methods and compositions for treating flaviviruses and pestiviruses
US10005779B2 (en) 2013-06-05 2018-06-26 Idenix Pharmaceuticals Llc 1′,4′-thio nucleosides for the treatment of HCV
US10202411B2 (en) 2014-04-16 2019-02-12 Idenix Pharmaceuticals Llc 3′-substituted methyl or alkynyl nucleosides nucleotides for the treatment of HCV
US10231986B2 (en) 2013-03-13 2019-03-19 Idenix Pharmaceuticals Llc Amino acid phosphoramidate pronucleotides of 2′-cyano, azido and amino nucleosides for the treatment of HCV
US10238680B2 (en) 2013-08-01 2019-03-26 Idenix Pharmaceuticals Llc D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease
US10513534B2 (en) 2012-10-08 2019-12-24 Idenix Pharmaceuticals Llc 2′-chloro nucleoside analogs for HCV infection
US10519186B2 (en) 2017-02-01 2019-12-31 Atea Pharmaceuticals, Inc. Nucleotide hemi-sulfate salt for the treatment of hepatitis C virus
US10525072B2 (en) 2002-11-15 2020-01-07 Idenix Pharmaceuticals Llc 2′-branched nucleosides and flaviviridae mutation
WO2020045628A1 (ja) * 2018-08-31 2020-03-05 ダイキン工業株式会社 核酸アナログ及び抗ｂ型肝炎ウイルス剤
US10717758B2 (en) 2012-05-22 2020-07-21 Idenix Pharmaceuticals Llc D-amino acid compounds for liver disease
US10723754B2 (en) 2012-10-22 2020-07-28 Idenix Pharmaceuticals Llc 2′,4′-bridged nucleosides for HCV infection
US10874687B1 (en) 2020-02-27 2020-12-29 Atea Pharmaceuticals, Inc. Highly active compounds against COVID-19
US10933067B2 (en) 2016-11-16 2021-03-02 National Center For Global Health And Medicine Nucleoside derivative having physiological activity such as antiviral activity
US11111264B2 (en) 2017-09-21 2021-09-07 Chimerix, Inc. Morphic forms of 4-amino-7-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide and uses thereof
US11690860B2 (en) 2018-04-10 2023-07-04 Atea Pharmaceuticals, Inc. Treatment of HCV infected patients with cirrhosis
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds
US12030903B2 (en) 2020-02-18 2024-07-09 Gilead Sciences, Inc. Antiviral compounds
US12054507B2 (en) 2020-02-18 2024-08-06 Gilead Sciences, Inc. Antiviral compounds
US12084473B2 (en) 2015-03-06 2024-09-10 Atea Pharmaceuticals, Inc. β-D-2′-deoxy-2′-α-fluoro-2′-β-C-substituted-2-modified-N6-substituted purine nucleotides for HCV treatment
US12116380B2 (en) 2021-08-18 2024-10-15 Gilead Sciences, Inc. Phospholipid compounds and methods of making and using the same
US12187758B2 (en) 2022-03-15 2025-01-07 Rome Therapeutics, Inc. Compounds and methods for treating disease
US12458656B2 (en) 2021-06-17 2025-11-04 Atea Pharmaceuticals, Inc. Advantageous anti-HCV combination therapy

Families Citing this family (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY164523A (en) 2000-05-23 2017-12-29 Univ Degli Studi Cagliari Methods and compositions for treating hepatitis c virus
PT1633766T (pt) 2003-05-30 2019-06-04 Gilead Pharmasset Llc Análogos de nucleósido fluorado modificado
JP2009510075A (ja) * 2005-09-26 2009-03-12 ファーマセット，インコーポレイティド 抗ウイルス剤としての修飾４’−ヌクレオシド
GB0625283D0 (en) 2006-12-19 2007-01-24 Cyclacel Ltd Combination
US8227431B2 (en) 2008-03-17 2012-07-24 Hetero Drugs Limited Nucleoside derivatives
US8173621B2 (en) 2008-06-11 2012-05-08 Gilead Pharmasset Llc Nucleoside cyclicphosphates
AU2009329872B2 (en) 2008-12-23 2016-07-07 Gilead Pharmasset Llc Synthesis of purine nucleosides
BRPI0922508A8 (pt) 2008-12-23 2016-01-19 Pharmasset Inc Análogos de nucleosídeo
PA8855601A1 (es) 2008-12-23 2010-07-27 Forformidatos de nucleósidos
CN102686599B (zh) * 2009-09-29 2016-10-05 杨森产品有限公司 核苷的氨基磷酸酯衍生物
PL2528930T3 (pl) * 2010-01-28 2014-03-31 Riboscience Llc 4`-azydonukleozydy jako związki przeciw hcv
CA2794671C (en) 2010-03-31 2018-05-01 Gilead Pharmasset Llc Stereoselective synthesis of phosphorus containing actives
CN102351931B (zh) 2010-09-07 2014-01-22 河南省科学院高新技术研究中心 嘧啶核苷衍生物、合成方法及其在制备抗肿瘤、抗病毒药物中的应用
CN102286047A (zh) * 2011-09-14 2011-12-21 郑州大学 2’-脱氧-2’-氟-4’-三氮唑取代-β-D胞苷类似物、其制备方法及其应用
SI2794627T1 (sl) * 2011-12-22 2019-02-28 Alios Biopharma, Inc. Substituirani nukleozidi, nukleotidi in njihovi analogi
CN102603836A (zh) * 2012-02-10 2012-07-25 郑州大学 五味子丙素简化物、类似物及其制备方法和应用
US9441007B2 (en) 2012-03-21 2016-09-13 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
USRE48171E1 (en) 2012-03-21 2020-08-25 Janssen Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
WO2014033617A1 (en) 2012-08-31 2014-03-06 Novartis Ag 2'-ethynyl nucleoside derivatives for treatment of viral infections
GEP201706757B (en) 2012-12-21 2017-10-25 Alios Biopharma Inc Substituted nucleosides, nucleotides and analogs thereof
US9895442B2 (en) * 2013-05-16 2018-02-20 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
US20180200280A1 (en) 2013-05-16 2018-07-19 Riboscience Llc 4'-Fluoro-2'-Methyl Substituted Nucleoside Derivatives as Inhibitors of HCV RNA Replication
CN104086612A (zh) * 2013-07-17 2014-10-08 郑州大学 4-取代胺基-2′-脱氧-2′-氟-4′-叠氮-β-D-胞苷类核苷化合物、制备方法及其应用
SG11201602595TA (en) 2013-10-11 2016-04-28 Alios Biopharma Inc Substituted nucleosides, nucleotides and analogs thereof
EP3083654A1 (en) * 2013-12-18 2016-10-26 Idenix Pharmaceuticals LLC 4'-or nucleosides for the treatment of hcv
WO2015143712A1 (en) * 2014-03-28 2015-10-01 Merck Sharp & Dohme Corp. 4'-substituted nucleoside reverse transcriptase inhibitors
US9603863B2 (en) 2014-06-24 2017-03-28 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
MA41213A (fr) 2014-12-19 2017-10-24 Alios Biopharma Inc Nucléosides substitués, nucléotides et analogues de ceux-ci
CN104558080A (zh) * 2015-02-03 2015-04-29 西安新通药物研究有限公司 环状磷酸酯合成的新方法
JP6767011B2 (ja) * 2015-09-18 2020-10-14 ヤマサ醤油株式会社 抗ｄｎａウィルス活性などの生理活性を有するヌクレオシド誘導体
EP3352781B1 (en) 2015-09-23 2020-12-16 Merck Sharp & Dohme Corp. 4'-substituted nucleoside reverse transcriptase inhibitors and preparations thereof
WO2017197046A1 (en) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. C3-carbon linked glutarimide degronimers for target protein degradation
EP3455219A4 (en) 2016-05-10 2019-12-18 C4 Therapeutics, Inc. AMINE-RELATED C3-GLUTARIMIDE DEGRONIMERS FOR TARGET PROTEIN REDUCTION
ES2990061T3 (es) 2016-05-10 2024-11-28 C4 Therapeutics Inc Degronímeros espirocíclicos para la degradación de proteínas diana
ES2989988T3 (es) 2016-05-10 2024-11-28 C4 Therapeutics Inc Degronímeros heterorocíclicos para la degradación de proteínas diana
US10202412B2 (en) 2016-07-08 2019-02-12 Atea Pharmaceuticals, Inc. β-D-2′-deoxy-2′-substituted-4′-substituted-2-substituted-N6-substituted-6-aminopurinenucleotides for the treatment of paramyxovirus and orthomyxovirus infections
LU100724B1 (en) 2016-07-14 2018-07-31 Atea Pharmaceuticals Inc Beta-d-2'-deoxy-2'-alpha-fluoro-2'-beta-c-substituted-4'-fluoro-n6-substituted-6-amino-2-substituted purine nucleotides for the treatment of hepatitis c virus infection
CN116036114A (zh) 2016-09-07 2023-05-02 阿堤亚制药公司 用于rna病毒治疗的2’-取代的-n6-取代的嘌呤核苷酸
EP3538108A4 (en) 2016-11-10 2020-06-17 Oyagen, Inc. METHODS OF TREATING AND INHIBITING EBOLA VIRUS INFECTION
WO2018237026A1 (en) 2017-06-20 2018-12-27 C4 Therapeutics, Inc. N/o-linked degrons and degronimers for protein degradation
SG11202002431SA (en) 2017-09-21 2020-04-29 Riboscience Llc 4'-fluoro-2'-methyl substituted nucleoside derivatives as inhibitors of hcv rna replication
US11040975B2 (en) 2017-12-08 2021-06-22 Merck Sharp & Dohme Corp. Carbocyclic nucleoside reverse transcriptase inhibitors
PH12021500034A1 (en) 2019-03-06 2022-06-06 Glaxosmithkline Ip No 2 Ltd Compounds useful in hiv therapy
JP2022525818A (ja) * 2019-03-15 2022-05-19 河南真実生物科技有限公司 ２’－フルオロ－４’－置換ヌクレオシド類似体ｉの結晶形ａ及びその調製方法と応用
US11738025B2 (en) 2020-02-04 2023-08-29 Oyagen, Inc. Method for treating coronavirus infections
AU2021237718B2 (en) 2020-03-20 2023-09-21 Gilead Sciences, Inc. Prodrugs of 4'-C-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same
US12274700B1 (en) 2020-10-30 2025-04-15 Accencio LLC Methods of treating symptoms of coronavirus infection with RNA polymerase inhibitors
CN114149475B (zh) * 2021-12-14 2023-07-14 新乡拓新药业股份有限公司 一种合成阿兹夫定的工艺方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5977325A (en) * 1988-11-15 1999-11-02 Merrell Pharmaceuticals Inc. 2'-halomethylidene, 2'-ethenylidene and 2'-ethynyl cytidine, uridine and guanosine derivatives
US6403568B1 (en) * 1999-05-12 2002-06-11 Yamasa Corporation 4′-C-ethynyl pyrimidine nucleosides and pharmaceutical compositions thereof
US7094768B2 (en) * 2002-09-30 2006-08-22 Genelabs Technologies, Inc. Nucleoside derivatives for treating hepatitis C virus infection
US20070135363A1 (en) * 2003-08-27 2007-06-14 Biota, Inc. Novel tricyclic nucleosides or nucleotides as therapeutic agents
US7666856B2 (en) * 2006-10-10 2010-02-23 Medivir Ab Antiviral nucleosides

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU719122B2 (en) 1995-09-27 2000-05-04 Emory University Recombinant hepatitis C virus RNA replicase
US5856085A (en) * 1995-12-01 1999-01-05 The Penn State Research Foundation Compositions and methods of developing oligonucleotides and oligonucleotide analogs having antiviral activity
WO1998050530A2 (en) * 1997-05-09 1998-11-12 Ribozyme Pharmaceuticals, Inc. Enzymatic nucleic acids: synthesis, selection and use
ATE414520T1 (de) * 2000-04-13 2008-12-15 Pharmasset Inc 3 oder 2 hydroxymethyl substituierte nucleoside derivate und ihre verwendung zur behandlung von virusinfektionen
KR100905221B1 (ko) * 2000-10-18 2009-07-01 파마셋 인코포레이티드 바이러스 감염 및 비정상적인 세포 증식의 치료를 위한변형된 뉴클레오시드
SI1355916T1 (sl) 2001-01-22 2007-04-30 Merck & Co Inc Nukleozidni derivati kot inhibitorji RNA-odvisne RNA virusne polimeraze
GB0114286D0 (en) * 2001-06-12 2001-08-01 Hoffmann La Roche Nucleoside Derivatives
CA2488534A1 (en) * 2002-06-21 2003-12-31 Merck & Co., Inc. Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase
JP5080973B2 (ja) 2004-06-24 2012-11-21 メルク・シャープ・エンド・ドーム・コーポレイション Ｒｎａ依存性ｒｎａウイルスの感染を処置するためのヌクレオシドアリールホスホルアミダート
MX2007006961A (es) * 2004-12-10 2007-10-04 Univ Emory Analogos nucleosidos de ciclobutilo 2' y 3'-sustituidos para el tratamiento de infeccciones virales y proliferacion celular anormal.
JP2009510075A (ja) 2005-09-26 2009-03-12 ファーマセット，インコーポレイティド 抗ウイルス剤としての修飾４’−ヌクレオシド
DE102006061756A1 (de) 2006-12-28 2008-07-03 Alfred Kärcher Gmbh & Co. Kg Radialgebläse und mit einem Radialgebläse versehenes Hochdruck-Reinigungsgerät
US7964580B2 (en) 2007-03-30 2011-06-21 Pharmasset, Inc. Nucleoside phosphoramidate prodrugs
CN100532388C (zh) * 2007-07-16 2009-08-26 郑州大学 2’-氟-4’-取代-核苷类似物、其制备方法及应用
KR20100097170A (ko) 2007-11-20 2010-09-02 스미또모 가가꾸 가부시키가이샤 피리딘 화합물, 유해 생물 방제 조성물 및 유해 생물의 방제 방법
BRPI0820481A2 (pt) 2007-11-20 2015-06-16 Janssen Pharmaceutica Nv Composotos cicloalquilóxi e heterocicloalquilóxi piridina como moduladores do receptor de h3 de histamina
US20090318380A1 (en) 2007-11-20 2009-12-24 Pharmasset, Inc. 2',4'-substituted nucleosides as antiviral agents

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5977325A (en) * 1988-11-15 1999-11-02 Merrell Pharmaceuticals Inc. 2'-halomethylidene, 2'-ethenylidene and 2'-ethynyl cytidine, uridine and guanosine derivatives
US6403568B1 (en) * 1999-05-12 2002-06-11 Yamasa Corporation 4′-C-ethynyl pyrimidine nucleosides and pharmaceutical compositions thereof
US7094768B2 (en) * 2002-09-30 2006-08-22 Genelabs Technologies, Inc. Nucleoside derivatives for treating hepatitis C virus infection
US20070135363A1 (en) * 2003-08-27 2007-06-14 Biota, Inc. Novel tricyclic nucleosides or nucleotides as therapeutic agents
US7666856B2 (en) * 2006-10-10 2010-02-23 Medivir Ab Antiviral nucleosides

Cited By (76)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9968628B2 (en) 2000-05-26 2018-05-15 Idenix Pharmaceuticals Llc Methods and compositions for treating flaviviruses and pestiviruses
US10525072B2 (en) 2002-11-15 2020-01-07 Idenix Pharmaceuticals Llc 2′-branched nucleosides and flaviviridae mutation
US20100234584A1 (en) * 2007-07-16 2010-09-16 Junbiao Chang 2'-Fluorine-4'-Substituted-Nucleoside Analogues, Preparation Methods and Uses Thereof
US8835615B2 (en) * 2007-07-16 2014-09-16 Junbiao Chang 2′-fluorine-4′-substituted-nucleoside analogues, preparation methods and uses thereof
US9296777B2 (en) 2007-11-20 2016-03-29 Gilead Pharmasset Llc 2′,4′-substituted nucleosides as antiviral agents
US9676808B2 (en) 2007-11-20 2017-06-13 Gilead Pharmasset Llc 2′,4′-substituted nucleosides as antiviral agents
US8877731B2 (en) 2010-09-22 2014-11-04 Alios Biopharma, Inc. Azido nucleosides and nucleotide analogs
US8871737B2 (en) 2010-09-22 2014-10-28 Alios Biopharma, Inc. Substituted nucleotide analogs
US9346848B2 (en) 2010-09-22 2016-05-24 Alios Biopharma, Inc. Azido nucleosides and nucleotide analogs
US9278990B2 (en) 2010-09-22 2016-03-08 Alios Biopharma, Inc. Substituted nucleotide analogs
EP3042910A2 (en) 2010-11-30 2016-07-13 Gilead Pharmasset LLC 2'-spiro-nucleosides for use in the therapy of hepatitis c
WO2012075140A1 (en) 2010-11-30 2012-06-07 Pharmasset, Inc. Compounds
US9243025B2 (en) 2011-03-31 2016-01-26 Idenix Pharmaceuticals, Llc Compounds and pharmaceutical compositions for the treatment of viral infections
US9403863B2 (en) 2011-09-12 2016-08-02 Idenix Pharmaceuticals Llc Substituted carbonyloxymethylphosphoramidate compounds and pharmaceutical compositions for the treatment of viral infections
US8507460B2 (en) 2011-10-14 2013-08-13 Idenix Pharmaceuticals, Inc. Substituted 3′,5′-cyclic phosphates of purine nucleotide compounds and pharmaceutical compositions for the treatment of viral infections
US9605018B2 (en) 2011-12-22 2017-03-28 Alios Biopharma, Inc. Substituted nucleotide analogs
US8980865B2 (en) 2011-12-22 2015-03-17 Alios Biopharma, Inc. Substituted nucleotide analogs
US9856284B2 (en) 2012-03-21 2018-01-02 Alios Biopharma, Inc. Solid forms of a thiophosphoramidate nucleotide prodrug
US8916538B2 (en) 2012-03-21 2014-12-23 Vertex Pharmaceuticals Incorporated Solid forms of a thiophosphoramidate nucleotide prodrug
US9394330B2 (en) 2012-03-21 2016-07-19 Alios Biopharma, Inc. Solid forms of a thiophosphoramidate nucleotide prodrug
US9012427B2 (en) 2012-03-22 2015-04-21 Alios Biopharma, Inc. Pharmaceutical combinations comprising a thionucleotide analog
US9109001B2 (en) 2012-05-22 2015-08-18 Idenix Pharmaceuticals, Inc. 3′,5′-cyclic phosphoramidate prodrugs for HCV infection
US9296778B2 (en) 2012-05-22 2016-03-29 Idenix Pharmaceuticals, Inc. 3′,5′-cyclic phosphate prodrugs for HCV infection
US10717758B2 (en) 2012-05-22 2020-07-21 Idenix Pharmaceuticals Llc D-amino acid compounds for liver disease
WO2013177243A1 (en) 2012-05-23 2013-11-28 Bristol-Myers Squibb Company Sulfilimine and sulphoxide methods for producing festinavir
US9249171B2 (en) 2012-05-23 2016-02-02 Bristol-Myers Squibb Company Sulfilimine and sulphoxide methods for producing festinavir
US10774106B2 (en) 2012-05-25 2020-09-15 Janssen Sciences Ireland Unlimited Company Uracyl spirooxetane nucleosides
US10301347B2 (en) 2012-05-25 2019-05-28 Janssen Sciences Ireland Unlimited Company Uracyl spirooxetane nucleosides
US9422323B2 (en) 2012-05-25 2016-08-23 Janssen Sciences Ireland Uc Uracyl spirooxetane nucleosides
US10040814B2 (en) 2012-05-25 2018-08-07 Janssen Sciences Ireland Uc Uracyl spirooxetane nucleosides
US10544184B2 (en) 2012-05-25 2020-01-28 Janssen Sciences Ireland Unlimited Company Uracyl spirooxetane nucleosides
US9845336B2 (en) 2012-05-25 2017-12-19 Janssen Sciences Ireland Uc Uracyl spirooxetane nucleosides
US9192621B2 (en) 2012-09-27 2015-11-24 Idenix Pharmaceuticals Llc Esters and malonates of SATE prodrugs
US10513534B2 (en) 2012-10-08 2019-12-24 Idenix Pharmaceuticals Llc 2′-chloro nucleoside analogs for HCV infection
US10723754B2 (en) 2012-10-22 2020-07-28 Idenix Pharmaceuticals Llc 2′,4′-bridged nucleosides for HCV infection
US9732111B2 (en) 2012-11-19 2017-08-15 Merck Sharp & Dohme Corp. 2′-alkynyl substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
EP2919792A4 (en) * 2012-11-19 2016-06-01 Merck Sharp & Dohme 2 -ALKYNYL-SUBSTITUTED NUCLEOSIDE DERIVATIVES FOR THE TREATMENT OF VIRUS DISEASES
WO2014078463A1 (en) * 2012-11-19 2014-05-22 Merck Sharp & Dohme Corp. 2 -alkynyl substituted nucleoside derivatives for treating viral diseases
US9211300B2 (en) 2012-12-19 2015-12-15 Idenix Pharmaceuticals Llc 4′-fluoro nucleosides for the treatment of HCV
US9309275B2 (en) 2013-03-04 2016-04-12 Idenix Pharmaceuticals Llc 3′-deoxy nucleosides for the treatment of HCV
US9339541B2 (en) 2013-03-04 2016-05-17 Merck Sharp & Dohme Corp. Thiophosphate nucleosides for the treatment of HCV
US10231986B2 (en) 2013-03-13 2019-03-19 Idenix Pharmaceuticals Llc Amino acid phosphoramidate pronucleotides of 2′-cyano, azido and amino nucleosides for the treatment of HCV
US9187515B2 (en) 2013-04-01 2015-11-17 Idenix Pharmaceuticals Llc 2′,4′-fluoro nucleosides for the treatment of HCV
US9447132B2 (en) 2013-04-12 2016-09-20 Achillion Pharmaceuticals, Inc. Highly active nucleoside derivative for the treatment of HCV
WO2014172264A1 (en) 2013-04-16 2014-10-23 Bristol-Myers Squibb Company Method for producing festinavir using 5-methyluridine as starting material
US10005779B2 (en) 2013-06-05 2018-06-26 Idenix Pharmaceuticals Llc 1′,4′-thio nucleosides for the treatment of HCV
WO2014201122A1 (en) 2013-06-13 2014-12-18 Bristol-Myers Squibb Company Tert-butyl-sulphoxide method for producing festinavir
US10238680B2 (en) 2013-08-01 2019-03-26 Idenix Pharmaceuticals Llc D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease
US10202411B2 (en) 2014-04-16 2019-02-12 Idenix Pharmaceuticals Llc 3′-substituted methyl or alkynyl nucleosides nucleotides for the treatment of HCV
US12084473B2 (en) 2015-03-06 2024-09-10 Atea Pharmaceuticals, Inc. β-D-2′-deoxy-2′-α-fluoro-2′-β-C-substituted-2-modified-N6-substituted purine nucleotides for HCV treatment
US10407457B2 (en) 2015-08-06 2019-09-10 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
US11981700B2 (en) 2015-08-06 2024-05-14 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
US9708359B2 (en) 2015-08-06 2017-07-18 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
US9701706B2 (en) 2015-08-06 2017-07-11 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
US10941175B2 (en) 2015-08-06 2021-03-09 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
US10933067B2 (en) 2016-11-16 2021-03-02 National Center For Global Health And Medicine Nucleoside derivative having physiological activity such as antiviral activity
US10519186B2 (en) 2017-02-01 2019-12-31 Atea Pharmaceuticals, Inc. Nucleotide hemi-sulfate salt for the treatment of hepatitis C virus
US10894804B2 (en) 2017-02-01 2021-01-19 Atea Pharmaceuticals, Inc. Nucleotide hemi-sulfate salt for the treatment of hepatitis C virus
US10906928B2 (en) 2017-02-01 2021-02-02 Atea Pharmaceuticals, Inc. Nucleotide hemi-sulfate salt for the treatment of hepatitis C virus
US12006340B2 (en) 2017-02-01 2024-06-11 Atea Pharmaceuticals, Inc. Nucleotide hemi-sulfate salt for the treatment of hepatitis c virus
US11111264B2 (en) 2017-09-21 2021-09-07 Chimerix, Inc. Morphic forms of 4-amino-7-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide and uses thereof
US11690860B2 (en) 2018-04-10 2023-07-04 Atea Pharmaceuticals, Inc. Treatment of HCV infected patients with cirrhosis
WO2020045628A1 (ja) * 2018-08-31 2020-03-05 ダイキン工業株式会社 核酸アナログ及び抗ｂ型肝炎ウイルス剤
US12054507B2 (en) 2020-02-18 2024-08-06 Gilead Sciences, Inc. Antiviral compounds
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds
US12030903B2 (en) 2020-02-18 2024-07-09 Gilead Sciences, Inc. Antiviral compounds
US12264173B2 (en) 2020-02-18 2025-04-01 Gilead Sciences, Inc. Antiviral compounds
US11813278B2 (en) 2020-02-27 2023-11-14 Atea Pharmaceuticals, Inc. Highly active compounds against COVID-19
US11738038B2 (en) 2020-02-27 2023-08-29 Atea Pharmaceuticals, Inc. Highly active compounds against COVID-19
US11707480B2 (en) 2020-02-27 2023-07-25 Atea Pharmaceuticals, Inc. Highly active compounds against COVID-19
US10874687B1 (en) 2020-02-27 2020-12-29 Atea Pharmaceuticals, Inc. Highly active compounds against COVID-19
US12226429B2 (en) 2020-02-27 2025-02-18 Atea Pharmaceuticals, Inc. Highly active compounds against COVID-19
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
US12458656B2 (en) 2021-06-17 2025-11-04 Atea Pharmaceuticals, Inc. Advantageous anti-HCV combination therapy
US12116380B2 (en) 2021-08-18 2024-10-15 Gilead Sciences, Inc. Phospholipid compounds and methods of making and using the same
US12187758B2 (en) 2022-03-15 2025-01-07 Rome Therapeutics, Inc. Compounds and methods for treating disease

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