(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`1111111111111111 IIIIII IIIII 1111111111111111111111111111111111111111 IIIII IIII 111111111111111 IIII
`
`( 43) International Publication Date
`13 January 2005 (13.01.2005)
`
`PCT
`
`(10) International Publication Number
`WO 2005/003147 A2
`
`(51) International Patent Classification 7:
`
`C07H 19/00
`
`(21) International Application Number:
`PCT/US2004/012472
`
`(22) International Filing Date:
`
`21 April 2004 (21.04.2004)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/474,368
`
`30 May 2003 (30.05.2003) US
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, Fl,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
`MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
`TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
`zw.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), Euro(cid:173)
`pean (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl, FR,
`GB, GR, HU, IE, IT, LU, MC, NL, PL, PT, RO, SE, SI, SK,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`ML, MR, NE, SN, TD, TG).
`
`Published:
`without international search report and to be republished
`upon receipt of that report
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`(71) Applicant (for all designated States except US): PHAR(cid:173)
`MASSET, LTD. [US/US]; The Financial Services, Centre
`Bishop's Court Hill, P.O. Box 111, St. Michael, Barbados
`(BB).
`
`iiiiiiiiiiii
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): CLARK, Jeremy
`[US/US]; 2883 Quinbery Drive, Snellville, GA (US).
`
`(74) Agent: BRUESS, Steven C.; Merchant & Gould, P.C.,
`P.O. Box 2903, Mineapolis, MN 55402-0903 (US).
`
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`
`Q ---
`g (54) Title: MODIFlED FLUORINATED NUCLEOSIDE ANALOGUES
`M O (57) Abstract: The disclosed invention provides compositions and methods of treating a Flaviviridae infection, including hepatitis
`
`: , C virus, West Nile Virus, yellow fever virus, and a rhinovirus infection in a host, including animals, and especially humans, using a
`;;, (2'R)-2'-deoxy-2'-fluoro-2'-C-methyl nucleosides, or a pharmaceutically acceptable salt or prodrug thereof.
`
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`WO 2005/003147
`
`PCT /0S2004/0124 72
`
`MODIFIED FLUORINATED NUCLEOSIDE ANALOGUES
`
`This application is being filed on 21 April 2004 as a PCT International
`
`Patent application in the name of PHARMASSET LTD. a US resident, applicants
`
`for all designations except the US.
`
`5
`
`FIELD OF THE INVENTION
`
`(2'R)-2'-deoxy-2'-fluoro-2'-C-methyl
`includes
`invention
`The present
`nucleosides having the natural P-D configuration and methods for the treatment of
`Flaviviridae infections, especially hepatitis C virus (HCV).
`
`BACKGROUND OF THE INVENTION
`
`10
`
`Hepatitis C virus (HCV) infection is a major health problem that leads to
`
`I
`
`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.
`
`There are an estimated 4.5 million infected people in the United States alone,
`
`according to the U.S. Center for Disease Control. According to the World Health
`
`15
`
`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(cid:173)
`
`destroying cirrhosis or cancer. The viral disease is transmitted parenterally by
`
`20
`
`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-a alone or in combination with the nucleoside analog
`
`ribavirin, are of limited clinical benefit as resistancy develops rapidly. Moreover,
`
`25
`
`there is no established vaccine for HCV. Consequently, there is an urgent need for
`
`improved therapeutic agents that effectively combat chronic HCV infection.
`
`The HCV virion is an enveloped positive-strand RNA virus with a single
`
`oligoribonucleotide genomic sequence of about 9600 bases which encodes a
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`1
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`polyprotein of about 3,010 amino acids. The protein products of the HCV gene
`
`consist of the structural proteins C, El, 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
`
`5
`
`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., "Expression of Hepatitis C Virus NS5B
`
`10
`
`Protein: Characterization of Its RNA Polymerase Activity and RNA Binding,"
`
`Heptology, 29: 1227-1235 (1999); V. Lohmann, et al., "Biochemical and Kinetic
`
`Analysis of NS5B RNA-Dependent RNA Polymerase of the Hepatitis C Virus,"
`
`Virology, 249: 108-118 (1998)).
`
`Inhibition of HCV NS5B polymerase prevents
`
`formation of the double-stranded HCV RNA and therefore constitutes an attractive
`
`15
`
`approach to the development ofHCV-specific antiviral therapies.
`
`HCV belongs to a much larger family of viruses that share many common
`
`features.
`
`Flaviviridae Viruses
`
`The Flaviviridae family of viruses comprises at least three distinct genera:
`
`20
`
`pestiviruses, which cause disease in cattle and pigs; flavivruses, which are the
`
`primary cause of diseases such as dengue fever and yellow fever; and hepdciviruses,
`
`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.
`Viral, 1993,70,37-43). Clinical symptoms vary and include fever, encephalitis and
`
`25
`
`hemorrhagic fever (Fields Virology, Editors: Fields, B. N., Knipe, D. M., and
`
`Howley, P. M., Lippincott-Raven Publishers, Philadelphia, PA, 1996, Chapter 31,
`
`931-959). Flaviviruses of global concern that are associated with human disease
`
`include the Dengue Hemorrhagic Fever viruses (DHF), yellow fever virus, shock
`
`30
`
`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, 64 1-643).
`
`2
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`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
`
`5
`
`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
`
`10
`
`considerable pestivirus exposure in humans.
`
`Pestiviruses and hepaciviruses are closely related virus groups within the
`
`Flaviviridae family. Other closely related viruses in this family include the 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
`
`15
`
`of closely related but genotypically distinguishable viruses that infect humans. There
`
`are at least 6 HCV genotypes and more than 50 subtypes. 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.
`
`20
`
`The genetic organization of pestiviruses and hepaciviruses is very similar.
`
`These positive stranded 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 polyprotein that is co- and post-translationally processed by both
`
`cellular and virus-encoded proteinases to yield the mature viral proteins. The viral
`
`25
`
`proteins responsible for the replication of the viral genome RNA are located within
`
`approximately the carboxy-terminal.
`
`Two-thirds of the ORF are
`
`termed
`
`nonstructural (NS) proteins. The genetic organization and polyprotein processing of
`
`the nonstructural protein portion of the ORF for pestiviruses and hepaciviruses is
`very similar. For both the pestiviruses and hepaciviruses, the mature nonstructural
`
`30
`
`(NS) proteins, in sequential order from the amino-terminus of the nonstructural
`
`protein coding region to the carboxy-terminus of the ORF, consist ofp7, NS2, NS3,
`
`NS4A, NS4B, NS5A, and NS5B.
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`3
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`The NS proteins of pestiviruses and hepaciviruses share sequence domains
`
`that are characteristic of specific protein functions. For example, the NS3 proteins of
`
`viruses in both groups possess amino acid sequence motifs characteristic of serine
`
`proteinases and of helicases (Gorbalenya et al. (1988) Nature 333:22; Bazan and
`
`5
`
`Fletterick (1989) Virology 171:637-639; Gorbalenya et al. (1989) Nucleic Acid Res.
`
`17.3889-3897). Similarly, the NS5B proteins of pestiviruses and hepaciviruses have
`
`the motifs characteristic of RNA-directed RNA polymerases (Koonin, E.V. and
`
`Dolja, V.V. (1993) Crir. Rev. Biochem. Malec. Biol. 28:375-430).
`
`The actual roles and functions of the NS proteins of pestiviruses and
`
`10
`
`hepaciviruses in the lifecycle of the viruses are directly analogous. In both cases, the
`
`NS3 serine proteinase is responsible for all proteolytic processing of polyprotein
`
`precursors downstream of its position in the ORF (Wiskerchen and Collett (1991)
`
`Virology 184:341-350; Bartenschlager et al. (1993) J. Viral. 67:3835-3844; Eckart et
`
`al. (1993) Biochem. Biophys. Res. Comm. 192:399-406; Grakoui et al. (1993) J.
`
`15
`
`Viral. 67:2832-2843; Grakoui et al. (1993) Proc. Natl. Acad Sci. USA 90:10583-
`
`10587; Hijikata et al. (1993) J. Viral. 67:4665-4675; Tome et al. (1993) J. Viral.
`
`67:4017-4026). The NS4A protein, in both cases, acts as a cofactor with the NS3
`
`serine protease (Bartenschlager et al. (1994) J. Viral. 68:5045-5055; Failla et al.
`
`(1994) J. Viral. 68: 3753-3760; Xu et al. (1997) J. Viral. 71:53 12-5322). The NS3
`
`20
`
`protein of both viruses also functions as a helicase (Kim et al. (1995) Biochem.
`
`Biophys. Res. Comm. 215: 160-166; Jin and Peterson (1995) Arch. Biochem.
`
`Biophys., 323:47-53; Warrener and Collett (1995) J. Viral. 69:1720-1726). Finally,
`
`the NS5B proteins of pestiviruses and hepaciviruses have the predicted RNA(cid:173)
`
`directed RNA polymerases activity (Behrens et al. (1996) EMBO. 15:12-22;
`
`25
`
`Lechmann et al. (1997) J. Viral. 71:8416-8428; Yuan et al. (1997) Biochem.
`
`Biophys. Res. Comm. 232:231-235; Hagedorn, PCT WO 97/12033; Zhong et al.
`(1998) J. Viral. 72.9365-9369).
`
`Treatment of HCV Infection with Interferon
`
`Interferons (IFNs) have been commercially available for the treatment of
`
`30
`
`chronic hepatitis for nearly a decade. IFNs are glycoproteins produced by immune
`
`cells in response to viral infection. IFNs inhibit replication of a number of viruses,
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`including HCV, and when used as the sole treatment for hepatitis C infection, IFN
`
`can in certain cases suppress serum HCV-RNA to undetectable levels. Additionally,
`
`IFN can normalize serum amino transferase levels. Unfortunately, the effect of lFN
`
`is temporary and a sustained response occurs in only 8%-9% of patients chronically
`
`5
`
`infected with HCV (Gary L. Davis. Gastroenterology 18:Sl04-S114, 2000). Most
`
`patients, however, have difficulty tolerating interferon treatment, which causes
`
`severe flu-like symptoms, weight loss, and lack of energy and stamina.
`
`A number of patents disclose Flaviviridae, including HCV, and treatments
`
`using interferon-based therapies. For example, U.S. Patent No. 5,980,884 to Blatt et
`
`10
`
`al. discloses methods for retreatment of patients afflicted with HCV using consensus
`
`interferon. U.S. Patent No. 5,942,223 to Bazer et al. discloses an anti-HCV therapy
`
`using ovine or bovine interferon-tau. U.S. Patent No. 5,928,636 to Alber et al.
`
`discloses the combination therapy of interleukin-12 and interferon alpha for the
`
`treatment of infectious diseases including HCV. U.S. Patent No. 5,849,696 to
`
`15
`
`Chretien et al. discloses the use of thymosins, alone or in combination with
`
`interferon, for treating HCV. U.S. Patent No. 5,830,455 to Valtuena et al. discloses a
`
`combination HCV therapy employing interferon and a free radical scavenger. U.S.
`
`Patent No. 5,738,845 to Imakawa discloses the use of human interferon tau proteins
`
`for treating HCV. Other interferon-based treatments for HCV are disclosed in U.S.
`
`20
`
`Patent No. 5,676,942 to Testa et al., U.S. Patent No. 5,372,808 to Blatt et al., and
`
`U.S. Patent No. 5,849,696. A number of patents also disclose pegylated forms of
`
`interferon, such as U.S. Patent Nos. 5,747,646, 5,792,834 and 5,834,594 to
`
`Hoffmann-La Roche; PCT Publication No. WO 99/32139 and WO 99/32140 to
`
`Enzon; WO 95/13090 and U.S. Patent Nos. 5,738,846 and 5,711,944 to Schering;
`
`25
`
`and U.S. Patent No. 5,908,621 to Glue et al.
`
`Interferon alpha-2a and interferon alpha-2b are currently approved as
`
`monotherapy for the treatment ofHCV. ROFERON®-A (Roche) is the recombinant
`
`form of interferon alpha-2a. PEGASYS® (Roche) is the pegylated (i.e. polyethylene
`
`glycol modified) form of interferon alpha-2a. INTRON®A (Schering Corporation)
`
`30
`
`is the recombinant form of Interferon alpha-2b, and PEG-INTRON® (Schering
`
`Corporation) is the pegylated form of interferon alpha-2b.
`
`5
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`Other forms of interferon alpha, as well as interferon beta, gamma, tau and
`
`omega are currently in clinical development for the treatment ofHCV. For example,
`
`INFERGEN
`
`(interferon alphacon-1) by InterMune, OMNIFERON
`
`(natural
`
`interferon) by Viragen, ALBUFERON by Human Genome Sciences, REBIF
`
`5
`
`(interferon beta-la) by Ares-Serono, Omega Interferon by BioMedicine, Oral
`
`Interferon Alpha by Amarillo Biosciences, and interferon gamma, interferon tau, and
`
`interferon gamma-lb by InterMune are in development.
`
`Ribivarin
`
`Ribavirin
`
`(l-{3-D-ribofuranosyl-1-1,2,4-triazole-3-carboxamide)
`
`is
`
`a
`
`10
`
`synthetic, non-interferon-inducing, broad spectrum antiviral nucleoside analog sold
`
`under the trade name, Virazole (The Merck Index, 11th edition, Editor: Budavari, S.,
`
`Merck & Co., Inc., Rahway, NJ, p1304, 1989). United States Patent No. 3,798,209
`
`and RE29,835 disclose and claim ribavirin. Ribavirin is structurally similar to
`
`guanosine, and has in vitro activity against several DNA and RNA viruses including
`
`15
`
`Flaviviridae (Gary L. Davis. Gastroenterology 118: 5104-51 14, 2000).
`
`Ribavirin reduces serum amino transferase levels to normal in 40% of
`
`patients, but it does not lower serum levels of HCV-RNA (Gary L. Davis, 2000).
`
`Thus, ribavirin alone is not effective in reducing viral RNA levels. Additionally,
`
`ribavirin has significant toxicity and is known to induce anemia. Ribavirin is not
`
`20
`
`approved for monotherapy against HCV. It has been approved in combination with
`
`interferon alpha-2a or interferon alpha-2b for the treatment ofHCV.
`
`Ribavirin is a known inosine monophosphate dehydrogenease inhibitor that
`
`does not have specific anti-HCV activity in the HCV replicon system (Stuyver et al.
`
`Journal of Virology, 2003, 77, 10689-10694).
`
`25
`
`Combination of Interferon and Ribavirin
`
`The current standard of care for chronic hepatitis C is combination therapy
`
`with an alpha interferon and ribavirin. The combination of interferon and ribavirin
`
`for the treatment of HCV infection has been reported to be effective in the treatment
`
`of interferon na'ive patients (Battaglia, A.M. et al., Ann. Pharmacother. 34:487-494,
`
`30
`
`2000), as well as for treatment of patients when histological disease is present
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`(Berenguer, M. et al. Antivir. Ther. 3(Suppl. 3):125-136, 1998). Studies have shown
`
`that more patients with hepatitis C respond to pegylated interferon-alpha/ribavirin
`
`combination therapy than to combination therapy with unpegylated interferon alpha.
`
`However, as with monotherapy, significant side effects develop during combination
`
`5
`
`therapy, including hemolysis, flu-like symptoms, anemia, and fatigue. (Gary L.
`
`Davis, 2000). Combination therapy with PEG-INTRON® (peginterferon alpha-2b)
`
`and REBETOL® (Ribavirin, USP) capsules are available from Schering
`
`Corporation. REBETOL® (Schering Corporation) has also been approved in
`
`combination with INTRON® A (Interferon alpha-2b, recombinant, Schering
`
`10
`
`Corporation).
`
`Roche's PEGASYS®
`
`(pegylated
`
`interferon alpha-2a) and
`
`COPEGUS® (ribavirin), as well as Three River Pharmacetical's Ribosphere® are
`
`also approved for the treatment of HCV.
`
`PCT Publication Nos. WO 99/59621, WO 00/37110, WO 01/81359, WO
`
`02/32414 and WO 03/02446 1 by Schering Corporation disclose the use of
`
`15
`
`pegylated interferon alpha and ribavirin combination therapy for the treatment of
`
`HCV. PCT Publication Nos. WO 99/15 194, WO 99/64016, and WO 00/24355 by
`
`Hoffmann-La Roche Inc. also disclose the use of pegylated interferon alpha and
`
`ribavirin combination therapy for the treatment ofHCV.
`
`Additional Methods to Treat Flaviviridae Infections
`
`20
`
`The development of new antiviral agents for Flaviviridae infections,
`
`especially hepatitis C, is currently underway. Specific inhibitors of HCV-derived
`
`enzymes such as protease, helicase, and polymerase inhibitors are being developed.
`
`Drugs that inhibit other steps in HCV replication are also in development, for
`
`example, drugs that block production of HCV antigens from the RNA (IRES
`
`25
`
`inhibitors), drugs that prevent the normal processing of HCV proteins (inhibitors of
`
`glycosylation), drugs that block entry of HCV into cells (by blocking its receptor)
`
`and nonspecific cytoprotective agents that block cell injury caused by the virus
`
`infection. Further, molecular approaches are also being developed to treat hepatitis
`
`C, for example, ribozymes, which are enzymes that break down specific viral RNA
`
`30
`
`molecules, antisense oligonucleotides, which are small complementary segments of
`
`DNA that bind to viral RNA and inhibit viral replication, and RNA interference
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`techniques are under investigation (Bymock et al. Antiviral Chemistry &
`
`Chemotherapy, 11 :2; 79-95 (2000); De Francesco et al. in Antiviral Research, 58: 1-
`
`16 (2003); and Kronke et al., J. Viral., 78:3436-3446 (2004).
`
`Bovine viral diarrhea virus (BVDV) is a pestivirus belonging to the family
`
`5
`
`Flaviviridae and has been used as a surrogate for in vitro testing of potential
`
`antiviral agents. While activity against BVDV may suggest activity against other
`
`flaviviruses, often a compound can be inactive against BVDV and active against
`
`another flavivirus. Sommadossi and La Colla have revealed ("Methods and
`
`compositions for treating flaviviruses and pestiviruses", PCT WO 01/92282) that
`
`10
`
`ribonucleosides containing a methyl group at the 2' "up" position have activity
`
`against BVDV. However, it is unclear whether these compounds can inhibit other
`
`flaviviruses, including HCV in cell culture or at the HCV NS5B level. futerestingly
`
`while this publication discloses a large number of compounds that are 2 '-methyl-2 ' -
`
`X-ribonucleosides, where Xis a halogen, fluorine is not considered. Furthermore, a
`
`15
`
`synthetic pathway leading to nucleosides halogenated at the 2' "down" position is
`
`not shown by these inventors.
`
`Dengue virus (DENV) is the causative agent of Dengue hemorrhagic fever
`
`(DHF). According to the world Health Organization (WHO), two fifths of the world
`population are now at risk for infection with this virus. An estimated 500,000 cases
`of DHF require hospitalization each year with a mortality rate of 5% in children.
`
`20
`
`West Nile virus (WNV), a flavivirus previously known to exist only in
`
`intertropical regions, has emerged in recent years in temperate areas of Europe and
`
`North America, presenting a threat to public health. The most serious manifestation
`
`ofWNV infection is fatal encephalitis in humans. Outbreaks in New York City and
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`25
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`sporadic occurrences in the Southern United States have been reported since 1999.
`
`There is currently no preventive treatment of HCV, Dengue virus (DENV) or
`
`West Nile virus infection. Currently approved therapies, which exist only against
`
`HCV, are limited. Examples of antiviral agents that have been identified as active
`against the hepatitis C flavivirus include:
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`30
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`1) Protease inhibitors:
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`Substrate-based NS3 protease inhibitors (Attwood et al., PCT WO 98/22496,
`
`1998; Attwood et al., Antiviral Chemistry and Chemotherapy 1999, 10, 259-273;
`
`Attwood et al., Preparation and use of amino acid derivatives as anti-viral agents,
`
`German Patent Pub. DE 19914474; Tung et al. fuhibitors of serine proteases,
`
`5
`
`particularly hepatitis C virus NS3 protease, PCT WO 98/17679), including
`
`alphaketoamides and hydrazinoureas, and inhibitors that terminate in an electrophile
`
`such as a boronic acid or phosphonate (Llinas-Brunet et al, Hepatitis C inhibitor
`
`peptide analogues, PCT WO 99/07734) are being investigated.
`
`Non-substrate-based NS3 protease inhibitors such as 2,4,6-trihydroxy-3-
`
`10
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`nitro-benzamide derivatives (Sudo K. et al., Biochemical and Biophysical Research
`
`Communications, 1997, 238, 643-647; Sudo K. et al. Antiviral Chemistry and
`
`Chemotherapy, 1998, 9, 186), including RD3-4082 and RD3-4078, the former
`
`substituted on the amide with a 14 carbon chain and the latter processing a para(cid:173)
`
`phenoxyphenyl group are also being investigated.
`
`15
`
`SCH 68631, a phenanthrenequinone, is an HCV protease inhibitor (Chu M.
`
`et al., Tetrahedron Letters 3 7:7229-7232, 1996). In another example by the same
`
`authors, SCH 351633, isolated from the fungus Penicillium griseofulvum, was
`
`identified as a protease inhibitor (Chu M. et al., Bioorganic and Medicinal
`
`Chemistry Letters 9:1949-1952). Nanomolar potency against the HCV NS3
`
`20
`
`protease enzyme has been achieved by the design of selective inhibitors based on the
`
`macromolecule eglin c. Eglin c, isolated from leech, is a potent inhibitor of several
`
`serine proteases such as S. griseus proteases A and B, a-chymotrypsin, chymase and
`
`subtilisin (Qasim M.A. et al., Biochemistry 36:1598-1607, 1997).
`
`Several U.S. patents disclose protease inhibitors for the treatment of HCV.
`
`25
`
`For example, U.S. Patent No. 6,004,933 to Spruce et al. discloses a class of cysteine
`
`protease inhibitors for inhibiting HCV endopeptidase 2. U.S. Patent No. 5,990,276
`
`to Zhang et al. discloses synthetic inhibitors of hepatitis C virus NS3 protease. The
`
`inhibitor is a subsequence of a substrate of the NS3 protease or a substrate of the
`
`NS4A cofactor. The use of restriction enzymes to treat HCV is disclosed in U.S.
`
`30
`
`Patent No. 5,538,865 to Reyes et al. Peptides as NS3 serine protease inhibitors of
`
`·HcV are disclosed in WO 02/008251 to Corvas International, Inc. and WO
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`02/08187 and WO 02/008256 to Schering Corporation. HCV inhibitor tripeptides
`
`are disclosed in U.S. Patent Nos. 6,534,523, 6,410,531, and 6,420,380 to Boehringer
`
`Ingelheim and WO 02/060926 to Bristol Myers Squibb. Diaryl peptides as NS3
`
`serine protease inhibitors of HCV are disclosed in WO 02/48172 to Schering
`
`5
`
`Corporation.
`
`Imidazoleidinones as NS3 serine protease inhibitors of HCV are
`
`disclosed in WO 02/08198 to Schering Corporation and WO 02/48157 to Bristol
`
`Myers Squibb. WO 98/17679 to Vertex Pharmaceuticals and WO 02/48116 to
`
`Bristol Myers Squibb also disclose HCV protease inhibitors.
`
`2) Thiazolidine derivatives which show relevant inhibition in a reverse-phase HPLC
`
`10
`
`assay with an NS3/4A fusion protein and NS5A/5B substrate (Sudo K. et al.,
`
`Antiviral Research, 1996, 32, 9-18), especially compound RD-1-6250, possessing a
`
`I
`
`fused cinnamoyl moiety substituted with a long alkyl chain, RD4 6205 and RD4
`
`6193;
`
`3) Thiazolidines and benzanilides identified in Kakiuchi N. et al. J. EBS Letters
`
`15
`
`421, 217-220; Takeshita N. et al. Analytical Biochemistry, 1997, 247,242-246;
`
`4) A phenanthrenequinone possessing activity against protease in a SDS-P AGE and
`
`autoradiography assay isolated from the fermentation culture broth of Streptomyces
`sp., Sch 68631 (Chu M. et al., Tetrahedron Letters, 1996, 37, 7229-7232), and Sch
`351633, isolated from the fungus Penicillium griseofulvum, which demonstrates
`
`20
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`activity in a scintillation proximity assay (Chu M. et al., Bioorganic and Medicinal
`
`Chemistry Letters 9, 1949-1952);
`
`5) Helicase inhibitors (Diana G.D. et al., Compounds, compositions and methods
`
`for treatment of hepatitis C, U.S. Pat. No. 5,633,358; Diana G.D. et al., Piperidine
`
`derivatives, pharmaceutical compositions thereof and their use in the treatment of
`
`25
`
`hepatitis C, PCT WO 97 /36554);
`
`6) Nucleotide polymerase inhibitors and gliotoxin (Ferrari R. et al. Journal of
`
`Virology, 1999, 73, 1649-1654), and the natural product cerulenin (Lohmann V. et
`
`al, Virology, 1998, 249, 108-118);
`
`7) Antisense phosphorothioate oligodeoxynucleotides (S-ODN) complementary to
`
`30
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`sequence stretches in the 5' non-coding region (NCR) of the virus (Alt M. et al.,
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`10
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`Hepatology, 1995, 22, 707-717), or nucleotides 326-348 comprising the 3' end of the
`
`NCR and nucleotides 371-388 located in the core coding region of the HCV RNA
`
`(Alt M. et al., Archives of Virology, 1997, 142, 589-599; Galderisi U. et al., Journal
`
`of Cellular Physiology, 1999, 181, 251-257);
`
`5
`
`8)
`
`Inhibitors of IRES-dependent translation (Ikeda N. et al., Agent for the
`
`prevention and treatment of hepatitis C, Japanese Patent Pub. JP-8268890; Kai Y. et
`
`al. Prevention and treatment of viral diseases, Japanese Patent Pub. JP-10101591);
`
`9) Ribozymes, such as nuclease-resistant ribozymes (Maccjak, D. J. et al.,
`
`Hepatology 1999, 30, abstract 995) and those disclosed in U.S. Patent No. 6,043,077
`
`10
`
`to Barber et al., and U.S. Patent Nos. 5,869,253 and 5,610,054 to Draper et al.;
`
`10) Nucleoside analogs have also been developed for the treatment of Flaviviridae
`
`infections.
`
`Idenix Pharmaceuticals discloses the use of certain branched nucleosides in
`
`the treatment of flaviviruses (including HCV) and pestiviruses in futemational
`
`15
`
`Publication Nos. WO 01/90121 and WO 01/92282. Specifically, a method for the
`
`treatment of hepatitis C virus infection (and flaviviruses and pestiviruses) in humans
`
`and other host animals is disclosed in the Idenix publications that includes
`
`administering an effective amount of a biologically active l', 2', 3' or 4'-branched (3-
`
`D or (3-L nucleosides or a pharmaceutically acceptable salt or derivative thereof,
`
`20
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`administered either alone or in combination with another antiviral agent, optionally
`
`in a pharmaceutically acceptable carrier.
`
`WO 2004/002422 to Idenix published January 8, 2004 discloses a family of
`
`2'-methyl nucleosides for the treatment of flavivirus infections. WO 2004/002999 to
`
`Idenix, published January 8, 2004 discloses a series of 2' or 3' prodrugs of 1', 2', 3',
`
`25
`
`or 4' branch nucleosides for the treatement of flavivirus infections including HCV
`
`infections.
`
`Other patent applications disclosing the use of certain nucleoside analogs to
`
`treat hepatitis C virus infection include: PCT/CAOO/01316 (WO 01/32153; filed
`
`November 3, 2000) and PCT/CAOI/00197 (WO 01/60315; filed February 19, 2001)
`
`30
`
`filed by BioChem Pharma, fuc. (now Shire Biochem, fuc.); PCT/USO2/01531 (WO
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`02/057425; filed January 18, 2002) and PCT/U502/03086 (WO 02/057287; filed
`
`January 18, 2002) filed by Merck & Co., Inc., PCT/EPOT/09633 (WO 02/18404;
`
`published August 21, 2001) filed by Roche, and PCT Publication Nos. WO
`
`01/79246 (filed April 13, 2001), WO 02/32920 (filed October 18, 2001) and WO
`
`5
`
`02/48 165 by Pharmasset, Ltd.
`
`WO 2004/007512 to Merck & Co. discloses a number of nucleoside
`
`compounds disclosed as inhibitors of RNA-dependent RNA viral polymerase. The
`
`nucleosides disclosed in this publication are primarily 2'-methyl-2'-hydroxy
`
`subsitituted nucleosides. WO 02/057287 to Merck et al. published July 25, 2002,
`
`10
`
`discloses a large genus of pyrimidine derivative nucleosides of the 2'-methyl-2'(cid:173)
`
`hydroxy substitutions. WO 2004/009020 to Merck et al. discloses a series of
`
`thionucleoside derivatives as inhibitors of RNA dependent RNA viral prolymerase.
`
`WO 03/105770 to Merck et al. discloses a series of carbocyclic nucleoside
`
`derivatives that are useful for the treatement of HCV infections.
`
`15
`
`PCT Publication No. WO 99/43691 to Emory University, entitled "2'- 1
`
`Fluoronucleosides" discloses the use of certain 2'-fluoronucleosides to treat HCV.
`
`U.S. Patent No. 6,348,587 to Emory University entitled "2'-fluoronucleosides"
`
`discloses a family of 2'-fluoronucleosides useful for the treatment of hepatitis B,
`
`HCV, HIV and abnormal cellular proliferation. The 2' subsitutent is disclosed to be
`
`20
`
`in either the "up" or "down" position.
`
`Eldrup et al. (Oral Session V, Hepatitis C Virus, Flaviviridae; 16th
`
`International Conference on Antiviral Research (April 27, 2003, Savannah, Ga.))
`
`described the structure activity relationship of 2'-modified nucleosides for inhibition
`
`ofHCV.
`
`25
`
`Bhat et al. (Oral Session V, Hepatitis C Virus, Flaviviridae; 16th International
`
`Conference on Antiviral Research (April 27, 2003, Savannah, Ga.); p A75) describe
`
`the synthesis and pharmacokinetic properties of nucleoside analogues as possible
`
`inhibitors of HCV RNA replication. The authors report that 2'-modified nucleosides
`
`demonstrate potent inhibitory activity in cell-based replicon assays.
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`Olsen et al. (Oral Session V, Hepatitis C Virus, Flaviviridae; 16th
`International Conference on Antiviral Research (April 27, 2003, Savannah, Ga.) p
`
`A76) also described the effects of the 2'-modified nucleosides on HCV RNA
`
`replication.
`
`5
`
`11) Other miscellaneous compounds including 1-amino-alkylcyclohexanes (U.S.
`
`Patent No. 6,034,134 to Gold et al.), alkyl lipids (U.S. Pat. No. 5,922,757 to
`
`Chojkier el al.)