RS20120367A2 - METHODS AND MIXTURES FOR TREATMENT OF VIRAL HEPATITIS C - Google Patents

Abstract

Invention herewith described refers to the method and the compound for the treatment of hosts infected with hepatitis C virus, which includes the application of the described 1', 2' or 3'-modified nucleoside or its pharmaceutically acceptable salt or the pro-drug in an effective dose for the treatment of hepatitis C.

Description

METHODS AND MIXTURES FOR THE TREATMENT OF VIRUS HEPATITIS C

TECHNICAL FIELD

This invention is in the field of pharmaceutical hernia, more specifically, in the field of compounds, methods and compositions for the treatment of viral hepatitis C. This application has priority over U.S. Pat. provisional application no. 60/206,585, filed May 23, 2000.

STATE OF THE ART

Hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide. (Boyer, N. et al. J. Hepatoi. 32:98-112, 2000.) HCV causes a slow viral infection and is a major cause of cirrhosis and hepatocellular carcinoma (Di Besceglie, A.M. and Bacon, B.R., Scientific American, Oct.: 80-85, (1999); Boyer, N. / others J. Hepatoi. 32:98-112, 2000) It is estimated that 170 million people worldwide are infected with HCV. (Boyer, N. et al. J. Hepatoi. 32:98-112, 2000.) 8,000-12,000 deaths per year in the United States are caused by cirrhosis secondary to chronic hepatitis C infection, and HCV infection is the main indication for liver transplantation.

It is known that HCV causes 80% of post-transfusion hepatitis and a significant proportion of sporadic acute hepatitis. Preliminary estimates also link HCV to many cases of "idiopathic" chronic hepatitis, "cryptogenic" cirrhosis, and possibly hepatocellular carcinoma unrelated to other hepatitis viruses, such as hepatitis B virus (HBV). A small part of the healthy population appears as a carrier of chronic HCV, depending on geographic and other epidemiological factors. The number of people in that population may significantly exceed that of HBV, although the information is still preliminary; it is unclear how many of these people have subclinical chronic liver disease. (The Merck Manual, ch. 69, p. 901, 16th ed., (1992)).

HCV is classified as a member of the Flaviviridae family of viruses, which includes the rhodoflaviviruses, pestiviruses, and hepaceiviruses, which include the hepatitis C viruses (Rice, C.M., Flaviviridae: The viruses and their replication. In:Fields Virology, Editors: Fields, B.N., Knipe, D.M., and Howley, P.M., Lippincott-Raven Publishers, Philadelphia, PA, Chapter 30, 931-959, 1996). HCV is a enveloped virus containing a positive-sense single-stranded RNA genome of approximately 9.4 kb. The viral genome consists of a 5' untranslated region (UTR), a long open reading backbone encoding a polyprotein precursor of about 3011 amino acids, and a short 3' (UTR). The 5' UTR is the most conserved part of the HCV genome and is necessary for initiation and control of polyprotein translation. Translation of the HCV genome is initiated by a kappa-independent mechanism known as internal ribosomal entry. This mechanism involves binding of the ribosome to an RNA sequence known as an internal ribosomal entry site (IRES). The RNA pseudoloop structure was recently determined to be an essential structural element of the HCV IRES. Viral structural proteins include the core nucleocapsid protein (C) and two envelope glycoproteins, E1 and E2. HCV also encodes two proteinases, the zinc-dependent metalloproteinase encoded by the NS2-NS3 region and the serine proteinase encoded by the NS3 region. These proteinases are necessary to cleave specific regions of the precursor polyprotein to mature peptides. The carboxyl half of nonstructural protein 5, NS5B, contains RNA-dependent RNA polymerases. The function of the remaining nonstructural proteins, NS4A and NS4B, as well as NS5A (the amino-terminal half of nonstructural protein 5) remains unknown.

A significant focus of ongoing antiviral research is directed toward the development of improved methods for the treatment of chronic HCV infections in humans (Di Besceglie, A.M. and Bacon, B.R., Scientific American, Oct.: 80-85, (1999)). Currently, there are two primary antiviral compounds, Ribavirin and interferon-alpha, used to treat chronic HCV infections in humans.

Treatment of HCV infection with Ribivarin

Ribavirin (1-|3-D-ribofuranosyl-1-1,2,4-triazole-3-carboxamide) is a synthetic, non-interferon-inducing broad-spectrum antiviral nucleoside analog, sold under the trade name Virazol (The Merck lndex, 11<th>edition, Editor: Budavari, S., Merck&Co., Inc., Rahway, NJ, p1304, 1989). U.S. Patent No. 3,798,209 and RE29,835 describe and claim Ribavirin. Ribavirin is structurally similar to guanosine, and in vitro exhibits activity against several DNA and RNA viruses, including Flaviviridae (Gray L Davis. Gastroenterology 118:S104-S114, 2000).

Ribavirin reduces serum amino transferase levels to normal values in 40% of patients, but does not reduce serum HCV-RNA levels (Gray L. Davis. Gastroenterology 118:S104-S114, 2000). Therefore, Ribavirin alone is not effective in reducing viral RNA levels. In addition, Ribavirin has significant toxicity and is known to cause anemia.

Treatment of HCV infection with Interferon

Interferons (IFNi) are compounds commercially available for the treatment of chronic hepatitis for almost a decade. IFNs are glycoproteins, produced by immune cells in response to viral infection. IFNs inhibit viral replication in many viruses including HCV, and when used alone in the treatment of hepatitis C infection, IFNs knock down serum HCV-RNA to undetectable levels. In addition, IFNs normalize the levels of serum amino transferases. Unfortunately, the effects of IFN are temporary, and a prolonged response occurs in only 8%-9% of patients chronically infected with HCV (Gary L. Davis. Gastroenterology 118:S104-S114, 2000).

Numerous patents describe the treatment of HCV using interferon-based therapies. For example, in the U.S. Patent No. 5,980,884 Blatt et al describe methods for treating patients with HCV that uniformly use interferon. U.S. Patent No. 5,942,223 to Bazer/others describes anti-HCV therapy using bovine interferon-tau. U.S. Patent No. 5,928,636 to Alber/others describes combination therapy with interleukin-12 and interferon alpha in the treatment of infectious diseases, including HCV. U.S. Patent No. 5,908,621 to Glue/others describes the use of interferon modified with polyethylene glycol in the treatment of HCV. U.S. Patent No. 5,849,696 to Chretien/others describes the use of thymosin, alone or in combination with interferon, in the treatment of HCV. U.S. Patent No. 5,830,455 to Valtunea et al describes a combination HCV therapy using interferon and a free radical scavenger. U.S. Patent No. 5,738,845 to Imakavva describes the use of human interferon tau proteins in the treatment of HCV. Other interferon-based treatments are described in U.S. Pat. Patent No. 5,676,942 to Testa/co.,U.S. Patent No. 5,372,808 to Blatt et al. Patent No. 5,849,696.

A combination of interferon and Ribavirin

The combination of IFN and Ribavirin in the treatment of HCV infection was found to be effective in the treatment of IFN natural patients (Battaglia, A.M./ associates, Ann. Pharmacother. 34:487-494, 2000). The results of treatment with this combination are promising even before hepatitis develops and when histological disease is already present (Berenguer, M./ associates Antivir. Ther.3(Suppl. 3):125-136, 1998). Adverse effects of combination therapy include hemolysis, flu-like symptoms, anemia, and exhaustion. (Gary L. Davis. Gastroenterology 118:S104-S114, 2000.)

Supplementary references describing methods for treating HCV infections

Bymock et al recapitulated numerous HCV treatments in Antiviral Chemistry & Chemotherapy, 11:2; 79-95 (2000).

The literature reports several substrate-based inhibitors of NS3 protease in which the cleaved amide bond of the cleaved substrate is replaced by an electrophile and reacted with the catalytic serine. Attvwoodet al. (1998) Antiviral peptide derivatives, 98/22496; Attvwood et al. (1999) Antiviral Chemistry and Chemotherapy 10.259-273; Attwood et al. (1999)

Preparation and use of amino acid derivatives as anti-viral agents,

German Patent Publication DE 19914474; Tunget al. (1998) Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease, WO 98/17679. These inhibitors end with an electrophile such as boric acid or phosphate. Llinas-Brunet et al. (1999) Hepatitis C inhibitory peptide analogues, WO 99/07734. Two groups of electrophile-based inhibitors, alphaketoamide and hydrazinourea, have been described.

The literature also describes a number of non-substrate-based inhibitors. For example, the investigation of the inhibitory effect of 2,4,6-trihydroxy-3-nitro-benzamide derivatives against HCV protease and other serine proteases was mentioned. Sudo, K. et al., (1997) Biochemical and Biophysical Research Communications, 238:643-647; Sudo, K. et al., (1998) Antiviral Chemistry and Chemotherapy9:186. The two most potent compounds identified using the reverse-phase HPLC technique were RD3-4082 and RD3-4078, the former substituted on the amide with a 14-carbon chain and the latter producing a p/a-phenoxyphenyl group.

Thiazolidine derivatives were determined as micromolar inhibitors, using reverse-phase HPLC technique with NS3/4A fusion protein and NS5A/5B substrate. Sudo, K. et al, (1996) Antiviral Research 32:9-18. Compound RD-1-6250, having a fused cinnamoyl moiety substituted with a long alkyl chain was the most potent against the isolated enzymes. Two other active examples were RD4 6205 and RD4 6193.

Other literature reports describe testing a relatively narrow area using the ELISA technique and list three compounds as potent inhibitors, a thiazolidine and two benzanilides. Kakiuchi N. et al., J. EBS Letters 421:217-220; Takeshita N. et al., Analytical Biochemistry 247:242-246, 1997. Several U.S. patents describe protease inhibitors in the treatment of HCV. For example, the U.S. Patent No. 6,004,933 to Spruce/ et al. describes a group of cysteine protease inhibitors in inhibiting HCV endopeptidase 2. U.S. Patent No. 5,990,276 to Zhang/al. describes synthetic inhibitors of hepatitis C viral NS3 protease. The inhibitor follows from the NS3 protease substrate or the NS4A cofactor substrate. The use of restriction enzymes in the treatment of HCV is described in U.S. Pat. Patent No. 5,538,865 according to Reves/

sar.

Phenan-trenquinone, isolated from the fermentation culture of Streptomyces sp., Sch 68631 in beef broth possesses micromolar activity against HCV protease in SDS-PAGE and autoradiographic assay. Chu M. et al, Tetrahedron Letters 37:7229-7232, 1996. In another example by the same authors, Sch 351633, which is isolated from the fungus Penicillium griscoluluum, shows micromolar activity in the scintillation proximity assay. Chu M. et al, Bioorganic and Medicinal Chemistry Letters9:1949-1952. Nanomolar activity against the HCV NS3 protease enzyme was discovered by designing selective inhibitors based on the macromolecule eglin c. Eglin c, isolated from leeches, is a potent inhibitor of several serine proteases, such as S. griseus proteases A and B, α-chymotrypsin, chymase, and subtilisin. Qasim MA et al., Biochemistn/36:1598-1607, 1997.

Also, HCV helicase inhibitors have been described. U.S. Patent No. 5,633,358 according to Diana G.D./ sar. ;PCT Application No. WO 97/36554 by Diana G.D./' et al. There are also several descriptions of HCV polymerase inhibitors: some nucleotide analogs, gliotoxin and the natural product cerulenin. Ferrari R. et al., Journal of Virology 73:1649-1654, 1999; Lohmann V. et al, Virology 249:108-118, 1998.

Antisense phosphorothioate oligodeoxynucleotides complementary to sequence inserts in the 5' non-coding regions of HCV have been reported as effective inhibitors of HCV gene expression in in vitro translation and cell culture systems of llcpG2 UCV-luciferase. Alt M. et al., Hepatology22:707-717, 1995. Subsequent studies have shown that nucleotides 326-348 including the 3' end of the NCR and nucleotides 371-388 located in the core coding region of HCV RNA are effective targets for antisense-mediated inhibition of viral translation. Alt M. et al., Archives of Virology 142:589-599, 1997. U.S. Patent No. 6,001,990 to Wands/ et al. describes oligonucleotides for inhibiting HCv replication. PCT Application No. WO 99/29350 describes compositions and methods for the treatment of hepatitis C infections, which include the use of antisense oligonucleotides that are complementary and hybridizable to HCV-RNA. U.S. Patent No. 5,922,857 to Hahn/sar. describes nucleic acids, which correspond to the sequence of the homology block of region IV of the pestivirus in the translational control of HCV. Antisense oligonucleotides as therapeutic agents have recently been reported (Galderisi U. et al., Journal of Cellular Physiology 181:251-257, 1999).

Other compounds have been reported as inhibitors of IRES-dependent translation in HCV. Japanese Patent Application JP-08268890 to Ikeda N/sar:,Japanese Patent Application JP-10101591 to Kai, Y./sar.Nuclease-resistant ribosomes were targeted in the IRES and recently reported as inhibitors in the HCV-poliovirus chimeric plaque assay. Maccjak D.J. et al., Hepatology 30abstract 995, 1999. The use of ribosomes in the treatment of HCV is also described in U.S. Pat. Patent No. 6,043,077 per Barber/ et al. and U.S. Pat.

Patent No. 5,869,253 and 5,610,054 per Draper/ sar.

Other patents describe the use of immune-enhancing compounds in the treatment of HCV. For example, the U.S. Patent No. 6,001,799 by Chretien/ et al., describes a method for the treatment of hepatitis C in patients who do not respond to interferon therapy, using thymosin or a thymosin fragment in a dose to strengthen the immune system. U.S. Patents No. 5,972,347 by Eder/sari 5,969,109 by Bona/sari describe antibody-based treatments for the treatment of HCV.

U.S. Patent No. 6,034,134 to Gold/sar. describes certain NMDA receptor agonists that have immunomodulatory, antimalarial, anti-Borna virus and anti-hepatitis C activity. The described NMDA receptor agonists belong to the 1-amino-alkylcyclohexane family. U.S. Patent No. 6,030,960 to Morris-Natschke /sar. describes the use of certain alkyl lipids in inhibiting the production of antigens induced by hepatitis, including those produced by the HCV virus. U.S. Patent No. 5,922,757 to Chojkier/al. describes the use of vitamin E and other antioxidants in the treatment of liver disorders, including HCV. U.S. Patent No. 5,858,389 to Elsherby/sar. describes the use of squalene in the treatment of hepatitis C. U.S. Patent No. 5,849,800 to Smith/ et al. describes the use of amantadine in the treatment of hepatitis C. U.S. Pat. Patent No. 5,846,964 per Ozeki/ et al. describes the use of bile acids in the treatment of HCV. U.S. Patent No. 5,491,135 to Blough/col. describes the use of N-(phosphonoacetyl)-L-aspartic acid in the treatment of flaviviruses, such as HCV.

Other compounds that have been proposed for the treatment of HCV include plant extracts (U.S. Patent No. 5,837,257 to Tsai et al., U.S.

Patent No. 5,725,859 per Omer /'sar.i U.S. Patent No. 6,056,961), piperidenes (U.S. Patent No. 5,830,905 to Diana/col.), benzenedicarboxamides (U.S. Patent No. 5,633,388 to Diana/col.), polyadenylic acid derivatives (U.S. Patent No. 5,496,546 to Wang/col.), 2',3'-dideoxyinosines (U.S. Patent No. 5,496,546 to Wang/col.). Patent No. 5,026,687 to Yarchoan et al.), benzimidazoles (U.S. Patent No. 5,891,874 to Colacino et al.).

In light of the fact that ? hepatitis C has reached epidemic proportions worldwide, and has tragic consequences for the infected patient, there remains a great need to provide a new effective pharmaceutical agent for the treatment of hepatitis C, which has little toxicity to the host.

For this reason, it is an object of the present invention to provide a compound, method and composition for treating a host infected with hepatitis C virus.

EXPOSITION OF THE ESSENCE OF THE INVENTION

Compounds, methods and compositions for the treatment of hepatitis C infection are disclosed which include an effective amount of p<*->D- or p-L-nucleoside for the treatment of hepatitis C, having Formulas (I) - (XVIII) or a pharmaceutically acceptable salt or prodrug thereof.

In a first main embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt or prodrug thereof:

wherein: R<1>, R<2> and R<3> are independently H, phosphate (including mono-, di- or triphosphate and stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound in which R<1>, R<2> or R<3> are independently H or phosphate;

Y is hydrogen, bromo, chloro, fluoro, iodo, OR<4>, NR<4>R<5> or SR<*>;

X<1> and X<2> are independently selected from the group consisting of H, straight chain, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR<4>, NR<4>NR<5> or SR<5>; and R<4> and R<5> are independently hydrogen, acyl (including lower acyl) or alkyl (including but not limited to to: methyl, ethyl, propyl and cyclopropyl).

In another main embodiment, there is provided a compound of Formula II, or a pharmaceutically acceptable salt or prodrug thereof:

in which:

R1, R<2> and R<3> are independently H, phosphate (including monophosphate, diphosphate or triphosphate and stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound in which R<1>, R<2> or R<3> are independently H or phosphate;

Y is hydrogen, bromo, chloro, fluoro, iodo, OR<4>, NR<4>R<5> or SR<4>;

X<1> and X<2> are independently selected from the group consisting of H, straight chain, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR<4>, NR<4>NR<5> or SR<5>; and R<4> and R<5> are independently hydrogen, acyl (including lower acyl) or alkyl (including but not limited to: methyl, ethyl, propyl and cyclopropyl).

In a third main embodiment, there is provided a compound of Formula III, or a pharmaceutically acceptable salt or prodrug thereof:

in which:

R<1>, R<2> and R<3> are independently H, phosphate (including monophosphate, diphosphate or triphosphate and stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound in which R<1>, R<2> or R<3> are independently H or phosphate;

Y is hydrogen, bromo, chloro, fluoro, iodo, OR<*>, NR<4>R<5> or SR<4>;

X<1> and X<2> are independently selected from the group consisting of H, straight chain, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR<4>, NR<4>NR<5> or SR<5>; and R<4> and R<5> are independently hydrogen, acyl (including lower acyl) or alkyl (including but not limited to to: methyl, ethyl, propyl and cyclopropyl).

In a fourth main embodiment there is provided a compound of Formula IV, or a pharmaceutically acceptable salt or prodrug thereof:

in which:

R\ R<2> and R<3> are independently H, phosphate (including mono-, di- or triphosphate and stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound in which R<1>, R<2> or R<3> are independently H or phosphate;

Y is hydrogen, bromo, chloro, fluoro, iodo, OR<4>, NR<4>R<5> or SR<4>;

X<1> and X<2> are independently selected from the group consisting of H, straight-chain, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR<4>, NR<4>NR<5>or SR<5>; and R<4> and R<5> are independently hydrogen, acyl (including lower acyl) or alkyl (including but not limited to to: methyl, ethyl, propyl and cyclopropyl).

In a fifth main embodiment, there is provided a compound of Formula V, or a pharmaceutically acceptable salt or prodrug thereof:

in which:

R<1>, R<2> and R<3> are independently H, phosphate (including monophosphate, diphosphate or triphosphate and a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R\ R<2> or R<3> are independently H or phosphate;

Y is hydrogen, bromo, chloro, fluoro, iodo, OR<4>, NR<4>R<5> or SR<4>;

X<1> and X<2> are independently selected from the group consisting of H, straight chain, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR<4>, NR<4>NR<5> or SR<5>;

R<4> and R<6> are independently hydrogen, acyl (including lower acyl) or alkyl (including but not limited to: methyl, ethyl, propyl and cyclopropyl).

In a sixth main embodiment there is provided a compound of Formula VI, or a pharmaceutically acceptable salt or prodrug thereof:

in which:

R<1>, R<2> and R<3> are independently H, phosphate (including monophosphate, diphosphate or triphosphate and stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound in which R<1>, R<2> or R<3> are independently H or phosphate;

Y is hydrogen, bromo, chloro, fluoro, iodo, OR<4>, NR<4>R<5> or SR<4>;

X<1> and X<2> are independently selected from the group consisting of H, straight chain, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-afoxyalkyl, chloro, bromo, fluoro, iodo, OR<4>, NR<4>NR<5> or SR<5>; and R<4> and R<5> are independently hydrogen, acyl (including lower acyl) or alkyl (including but not limited to to: methyl, ethyl, propyl and cyclopropyl).

In a seventh main embodiment there is provided a compound selected from Formula VII, VIII or IX, or a pharmaceutically acceptable salt or prodrug thereof:

where:

is a purine base or a pyrimidine base, as defined herein;

R<1>, R<2> and R<3> are independently H, phosphate (including monophosphate, diphosphate or triphosphate and a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when applied in vivo can provide a compound in which R<1>, R<2> or R<3> are independently H or phosphate;

R<6>is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, 2-Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), CF3, chloro, bromo, fluoro, iodo, NO2, NH2, -NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2; and

X is O, S, SO2 or CH2.

In an eighth main embodiment, there is provided a compound selected from Formula X, XI or XII, or a pharmaceutically acceptable salt or prodrug thereof:

where:

is a purine base or a pyrimidine base, as defined herein; R\ R<2> and R<3> are independently H, phosphate (including monophosphate, diphosphate or triphosphate and a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound in which R<1>, R<2> or R<3> are independently H or phosphate; R<6>is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2, -NH2 alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2;

R<7>is hydrogen, OR<3>, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO2, NH2, - NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2; and

X is O, S, SO2 or CH2.

In a ninth main embodiment there is provided a compound selected from Formulas XIII, XIV or XV, or pharmaceutically acceptable salts or prodrugs thereof:

where:

is a purine base or a pyrimidine base, as defined herein; Ft1, Ft2 and Ft3 are independently H, phosphate (including monophosphate, diphosphate or triphosphate and a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R\ R<2> or R<3> are independently H or phosphate; R<6>is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2,

-NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2; and

X is O, S, SO2 or CH2.

In a tenth main embodiment, the invention provides a compound of Formula XVI, or a pharmaceutically acceptable salt or prodrug thereof:

where:

is a purine base or a pyrimidine base, as defined herein; R<1> and R<2> are independently H, phosphate (including monophosphate, diphosphate or triphosphate and a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound in which R<1> or R<2> are independently H or phosphate; R<6>is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2,

-NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2; and

R<7> and R<9> are independently: hydrogen, OR<2>, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO, NH2, -NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2;

R<8> and R<10> are independently: H, alkyl (including lower alkyl), chlorine, bromine or iodine; alternatively, R<7> and R<s>, R7 and R<10>, R<8> and R<9> or R8 and R<10> can join to form a pi bond; and

X is O, S, SO2 or CH2.

In an eleventh main embodiment, the invention provides a compound of Formula XVII, or a pharmaceutically acceptable salt or prodrug thereof:

where:

is a purine base or a pyrimidine base, as defined herein; R<1> and R<2> are independently H, phosphate (including monophosphate, diphosphate or triphosphate and a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound in which R<1> or R<2> are independently H or phosphate; R<6>is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2, -NH2 alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2; R<7> and R<9> are independently: hydrogen, OR<2>, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO2, NH2, -NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2;

R<10> is H, alkyl (including lower alkyl), chlorine, bromine or iodine;

alternatively, R<7> and R<9> or R7 and R<10> can join to form a pi bond; and X is O, S, SO 2 or CH 2 .

In a twelfth main embodiment, the invention provides a compound of Formula XVIII, or a pharmaceutically acceptable salt or prodrug thereof:

where:

is a purine base or a pyrimidine base, as defined herein; R<1> and R<2> are independently H, phosphate (including monophosphate, diphosphate or triphosphate and a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound in which R<1> or R<2> are independently H or phosphate; R<6>is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2, -NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2;

R<7> and R<9> are independently: hydrogen, OR<2>, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino;

R<8> is H, alkyl (including lower alkyl), chlorine, bromine or iodine;

alternatively, R<7> and R<9> or R<8> and R<9> can join to form a pi bond; X is O, S, SO 2 or CH 2 .

p-D- and (3-L-nucleosides of the present invention can inhibit the activity of HCV polymerase. The nucleosides can be tested for the ability to inhibit HCV polymerase in vitro according to screening methods, which are explained in more detail herein. The spectrum of activity can be easily determined by testing the compound using the technique described here or another confirmatory technique.

In one embodiment, the efficacy of an anti-HCV compound is measured by the concentration of the compound required to reduce the number of viral plaques in vitro by 50% (ie, the EC of the compound) in accordance with the methods described in more detail herein. In preferred embodiments, the compound exhibits an EC50 of less than 25, 15, 10, 5, or 1 micromolar.

In another embodiment, the active compound can be administered in combination or in alternation with another anti-HCV agent. In combination therapy, the effective dose of two or more agents is given together, while during alternating therapy, the effective dose of each agent is given serially. Dosages will depend on the absorption, inactivation and excretion rates of the drug, as well as other factors known to those skilled in the art. It should be emphasized that the dosage values will also vary with the severity of the condition to be alleviated. Furthermore, it should be understood that dosage regimens and schedules should be adjusted for each individual person over time, and in accordance with the individual needs and professional judgment of the person administering or supervising the administration of the mixtures.

Non-limiting examples of antiviral agents that may be used in combination with the compounds described herein include: (1) interferon and/or ribavirin (Battaglia, A.M. et al., Ann. Pharmacother. 34:487-494, 2000); Berenguer, M. et al., Antivir. Ther. 3 (Suppl. 3):125-136, 1998); (2) substrate-based NS3 protease inhibitors (Attwoodet al., Antiviral peptide derivatives, PCT WO 98/22496, 1998; Attwoodet al., Antiviral Chemistry and Chemotherapy10:259-273, 1999; Attwoodet al., Preparation/on and use of amino acid derivatives as antiviral agents,

German Patent Publication DE 19914474; Tunget al., Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease, PCT VVO 98/17679), including alphaketoamides and hydrazinoreas, as well as electrophile-terminated inhibitors such as boric acid or phosphonate. Llinas-Brunet et al., Hepatitis C inhibitor peptide ana/ ogues, PCT VVO 99/07734. (3) Non-substrate-2-based inhibitors such as 2,4,6-trihydroxy-3-nitrobenzamide derivatives (Sudo K. et al, Biochemical and Biophysical Research Communications, 238:643-647, 1997; Sudo K. et al. Antiviral Chemistry and Chemotherapy9:186; 1998), including RD3-4082 and RD3-4078, the first substituted on the amide with by a chain of 14 carbons, and others producing a p/a-phenoxyphenyl group; (4) Thiazolidine derivatives showing significant inhibition in a reverse-phase HPLC assay with NS3/4A fusion protein and NS5A/5B substrate (Sudo K. et al., Antiviral Research32:9-18, 1996), especially compound RD-1-6250 having a fused cinnamoyl moiety substituted with a long alkyl chain, RD4 6205 and RD4 6193; (5) thiazolidines and benzanilides disclosed in Kakiuchi N. et al. J. EBS Letters 421:217-220; Takeshita N. et al., Analytical Biochemistry 247:242-246, 1997; (6) phenan-trenquinone has activity against HCV protease in SDS-PAGE and autoradiographic assay, isolated from the fermentation culture Streptomycessp., Sch 68631 (Chu M. et al., Tetrahedron Letters37:7229-7232, 1996) in beef broth, and Sch 351633, which is isolated from the fungus Penicillium griscofulum, shows activity in the scintillation assay proximity (Chu M. et al., Bioorganic and Medicina/ Chemistr/Letters9:1949-1952); (7) selective NS3 inhibitors, based on macromolecule elgin c, isolated from leeches (Ouasim M.A. et al., Biochemistry36:1598-1607; 1997); (8) HCV helicase inhibitors (Diana G.D. et al., Compounds, compositions and methods for treatment of hepatitis C, U.S. Patent No. 5,633,358; Diana G.D. et al, Piperidine derivatives, pharmaceutical

compositions thereof and their use in the treatment of hepatitis C, PCT

VVO 97/36554). (9) HCV polymerase inhibitors, such as nucleotide analogs, gliotoxin (Ferrari R. et al. Journal of Virology73:1649-1654, 1999) and the natural product cerulenin (Lohmann V. et al., Virology249:108-118, 1998). (10) Antisense phosphorothioate oligodeoxynucleotides (S-ODN) complementary to sequence inserts in the 5' non-coding region (NCR) of HCV (Alt M. et al., Hepatology22:707-717, 1995), or nucleotides 326-348 including the 3' end of the NCR and nucleotides 371-388 located in the core of the HCV coding region RNA (Alt M. et al, Archives of Virology 142:589-599, 1997; Galderisi U. et al., Journal of Cellular Physiology 181:251-257, 1999). (11) Inhibitors of IRES-dependent translation (Ikeda Net al, Agent for the prevention and treatment of hepatitis C, Japanese Patent Publication JP-08268890; Kai Y. et al. Prevention and treatment of viral diseases, Japanese Patent Publication JP-10101591). (12) Nuclease-resistant ribosomes (Maccjak D.J. et al., Hepatology 30abstract 995, 1999); and (13) other miscellaneous compounds include 1-amino-alkylcyclohexanes (U.S. Patent No. 6,034,134 to Gold et al.), alkyl lipids (U.S. Patent No. 5,922,757 to Chojkier et al.), vitamin E and other antioxidants (U.S. Patent No. 5,922,757 to Chojkier et al.), squalene, amantadine, bile acids (U.S. Patent No. 5,846,964 to Ozeki/sar.), N-(phosphonoacetyl)-L-aspartic acid (U.S. Patent No. 5,830,905 to Diana/sar.), benzenedicarboxamides (U.S. Patent No. 5,633,388 to Diana/'sar.), polyadenylic acid derivatives (U.S. Patent No. 5,496,546 per VVang/ et al.), 2',3'-dideoxyinosines (U.S. Patent No. 5,026,687 to Yarchoan et al.), benzimidazoles (U.S. Patent No. 5,891,874 to Colacino et al.).

BRIEF DESCRIPTION OF THE PICTURES

Figure 1 shows the structure of various non-limiting examples of nucleosides of the present invention, as well as other nucleosides, FIAU and Ribavirin used as comparative examples in the text.

Figure 2 is a line graph of the pharmacokinetics (plasma concentration) of P-D-2'-CH3-riboG administered to six Cvnomolgus monkeys over time after administration.

Figure 3 is a line graph of the pharmacokinetics (plasma concentration) of P-D-2'-CH3-riboG administered to Cvnomolgus monkeys either intravenously (3a) or orally (3b) over time after administration.

DETAILED DESCRIPTION OF THE INVENTION

The invention as described herein is a compound, method and composition for the treatment of hepatitis C in a human or animal host, comprising the administration of an effective dose for HCV treatment of P-D- or β-L-nucleosides, as described herein or pharmaceutically acceptable salts or prodrugs thereof, optionally in a pharmaceutically acceptable carrier. The compounds of the present invention either possess antiviral (ie, anti-HCV) activity or are metabolized to compounds that exhibit such activity.

Briefly, this invention includes the following features:

(a) 3-D- and β-L-nucleosides as described herein and their pharmaceutically acceptable salts and prodrugs; (b) P-D- and p-L-nucleosides as described herein and their pharmaceutically acceptable salts and prodrugs for use in the treatment or prophylaxis of HCV infection, particularly in persons diagnosed as having HCV infection or at risk of becoming infected with HCV; (c) the use of these p-D- or p-L-nucleosides and their pharmaceutically acceptable salts or prodrugs in the manufacture of drugs for the treatment of HCV infection; (d) pharmaceutical formulations comprising P-D- or <p->L-nucleosides and their pharmaceutically acceptable salts or prodrugs together with a pharmaceutically acceptable carrier or diluent; (e) P-D- or P-L-nucleosides as described herein are substantially free of enantiomers of the described nucleosides or are isolated from other chemical entities; (f) a process for making P-D- or p-L-nucleosides as described in more detail below; and (g) a process for making P-D- or P-L-nucleosides substantially in the absence of enantiomers of the described nucleosides or substantially separated from other chemical entities.

I Active compound and its physiologically acceptable salts and prodrugs

In a first main embodiment, there is provided a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof:

in which:

R\ R<2> and R<3> are independently H, phosphate (including mono-, di- or triphosphate and stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R\ R<2> or R<3> are independently H or phosphate;

Y is hydrogen, bromo, chloro, fluoro, iodo, OR<4>, NR<4>R<5> or SR<4>;

X<1> and X<2> are independently selected from the group consisting of H, straight-chain, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR<4>, NR<4>NR<5>or SR<5>; and R<4> and R<5> are independently hydrogen, acyl (including lower acyl) or alkyl (including but not limited to to: methyl, ethyl, propyl and cyclopropyl).

In a preferred embodiment, there is provided a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof wherein: R1, R<2> and R<3> are independently H or phosphate (preferably H);

X<1> is H;

X2 is H or NH2; and

Y is hydrogen, bromo, chloro, fluoro, iodo, NH 2 or OH.

In another main embodiment, there is provided a compound of Formula II, or a pharmaceutically acceptable salt or prodrug thereof:

in which:

R1, R<2>and R<3> are independently H, phosphate (including monophosphate, diphosphate or triphosphate and stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound in which R<1>, R<2> or R<3> are independently H or phosphate;

Y is hydrogen, bromo, chloro, fluoro, iodo, OR<4>, NR<4>R<5> or SR<4>;

X<1> and X<2> are independently selected from the group consisting of H, straight-chain, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR<4>, NR<4>NR<5>or SR<5>; and R<4> and R<5> are independently hydrogen, acyl (including lower acyl) or alkyl (including but not limited to to: methyl, ethyl, propyl and cyclopropyl).

In a preferred embodiment, there is provided a compound of Formula II or a pharmaceutically acceptable salt or prodrug thereof wherein: R\R<2> and R<3> are independently H or phosphate (preferably H);

X<1> is H;

X<2> is H or NH2; and

Y is hydrogen, bromo, chloro, fluoro, iodo, NH 2 or OH.

In a third main embodiment, there is provided a compound of Formula III, or a pharmaceutically acceptable salt or prodrug thereof:

in which:

R\ R<2> and R<3> are independently H, phosphate (including monophosphate, diphosphate or triphosphate and a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound in which R1, R<2> or R<3> are independently H or phosphate;

Y is hydrogen, bromo, chloro, fluoro, iodo, OR<4>, NR<4>R<5> or SR<4>;

X<1> and X<2> are independently selected from the group consisting of H, straight chain, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo; OR<4>, NR<4>NR<5>or SR<5>; and R<4> and R<5> are independently hydrogen, acyl (including lower acyl) or alkyl (including but not limited to: methyl, ethyl, propyl and cyclopropyl).

In a preferred embodiment, there is provided a compound of Formula III or a pharmaceutically acceptable salt or prodrug thereof wherein: R\ R<2> and R<3> are independently H or phosphate (preferably H);

X<1> is H;

X<2> is H or NHZ; and

Y is hydrogen, bromo, chloro, fluoro, iodo, NH 2 or OH.

In a fourth main embodiment, there is provided a compound of Formula IV, or a pharmaceutically acceptable salt or prodrug thereof:

in which:

R<1>, R<2> and R<3> are independently H, phosphate (including mono-, di- or triphosphate and stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound in which R<1>, R<2> or R<3> are independently H or phosphate;

Y is hydrogen, bromo, chloro, fluoro, iodo, OR<4>, NR<4>R<5> or SR<4>;

X<1> is selected from the group consisting of H, straight chain, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR<4>, NR4NR<5> or SR<5>; and

R<4> and R<5> are independently hydrogen, acyl (including lower acyl) or alkyl (including but not limited to: methyl, ethyl, propyl and cyclopropyl).

In a preferred embodiment, there is provided a compound of Formula IV or a pharmaceutically acceptable salt or prodrug thereof in which: R<1>, R<2> and R<3> are independently H or phosphate (preferably H);

X<1> is H or CH3; and

Y is hydrogen, bromo, chloro, fluoro, iodo, NH 2 or OH.

In a fifth main embodiment, there is provided a compound of Formula V, or a pharmaceutically acceptable salt or prodrug thereof:

which:

R<1>, R<2> and R<3> are independently H, phosphate (including monophosphate, diphosphate or triphosphate and a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound in which R<1>, R<2> or R<3> are independently H or phosphate;

Y is hydrogen, bromo, chloro, fluoro, iodo, OR<4>, NR<4>R<5> or SR<4>;

X<1> is selected from the group consisting of H, straight chain, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR<4>, NR<4>NR<5> or SR<5>; and

R<4> and R<5> are independently hydrogen, acyl (including lower acyl) or alkyl (including but not limited to: methyl, ethyl, propyl and cyclopropyl).

In a preferred embodiment, there is provided a compound of Formula V or a pharmaceutically acceptable salt or prodrug thereof wherein: R<1>, R<2> and R<3> are independently H or phosphate (preferably H);

X<1> is H or CH3; and

Y is hydrogen, bromo, chloro, fluoro, iodo, NH 2 or OH.

In a sixth main embodiment there is provided a compound of Formula VI, or a pharmaceutically acceptable salt or prodrug thereof:

in which:

R\ R<2>and R<3> are independently H, phosphate (including monophosphate, diphosphate or triphosphate and stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R\ R<2> or R<3> are independently H or phosphate; and

Y is hydrogen, bromo, chloro, fluoro, iodo, OR<4>, NR<4>R<5> or SR<4>;

X<1> is selected from the group consisting of H, straight chain, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR<4>, NR<4>NR<5> or SR<5>; and

R<4> and R<5> are independently hydrogen, acyl (including lower acyl) or alkyl (including but not limited to: methyl, ethyl, propyl and cyclopropyl).

In a preferred embodiment, there is provided a compound of Formula VI or a pharmaceutically acceptable salt or prodrug thereof wherein: R1, R<2> and R<3> are independently H or phosphate (preferably H);

X<1> is H or CH3; and

Y is hydrogen, bromo, chloro, fluoro, iodo, NH 2 or OH.

In a seventh main embodiment there is provided a compound selected from Formula VII, VIII or IX, or a pharmaceutically acceptable salt or prodrug thereof:

where:

is a purine base or a pyrimidine base, as defined herein;

R\ R<2> and R<3> are independently H, phosphate (including monophosphate, diphosphate or triphosphate and a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound in which R<1>, R<2> or R<3> are independently H or phosphate;

R<6>is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, 2-Br-ethyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), CF3, chloro, bromo, fluoro, iodo, NO2, NH2, -NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2; and

X is O, S, SO2 or CH2.

In a first preferred embodiment, there is provided a compound of Formula VII, VIII or IX, or pharmaceutically acceptable salts or prodrugs thereof, wherein: the base is a purine or pyrimidine base, as defined herein;

R\ R<2> and R<3> are independently hydrogen or phosphate;

R<6> is alkyl; and

X is O, S, SO2 or CH2.

In another preferred embodiment, there is provided a compound of Formula VII, VIII or IX, or pharmaceutically acceptable salts or prodrugs thereof, wherein: the base is a purine or pyrimidine base, as defined herein;

R<1>, R<2> and R<3> are hydrogen;

R<6> is alkyl; and

X is O, S, SO2 or CH2.

In a third preferred embodiment, there is provided a compound of Formula VII, VIII or IX, or pharmaceutically acceptable salts or prodrugs thereof, wherein: the base is a purine or pyrimidine base, as defined herein;

Ft1, Ft2 and Ft3 are independently hydrogen or phosphate;

Ft6 is alkyl; and

X is O.

In an eighth main embodiment, there is provided a compound selected from Formula X, XI or XII, or a pharmaceutically acceptable salt or prodrug thereof:

where:

is a purine base or a pyrimidine base, as defined herein;

Ft1, Ft2 and R<3> are independently H, phosphate (including monophosphate, diphosphate or triphosphate and stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound in which R<1>, R<2> or R<3> are independently H or phosphate;

R<6>is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2, -NH2 alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2;

R<7>is hydrogen, OR<3>, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO2, NH2,

-NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2; and

X is O, S, SO2 or CH2.

In a first preferred embodiment, there is provided a compound of Formula X, XI or XII, or pharmaceutically acceptable salts or prodrugs thereof, wherein: the base is a purine or pyrimidine base, as defined herein;

R<1>, R<2> and R<3> are independently hydrogen or phosphate;

R<6> is alkyl; and

X is O, S, SO2 or CH2.

In another preferred embodiment, there is provided a compound of Formula X, XI or XII, or pharmaceutically acceptable salts or prodrugs thereof, wherein: the base is a purine or pyrimidine base, as defined herein;

R, R<2> and R<3> are hydrogen;

R<6> is alkyl; and

X is O, S, SO2 or CH2.

In a third preferred embodiment, there is provided a compound of Formula X, XI or XII, or pharmaceutically acceptable salts or prodrugs thereof, wherein: the base is a purine or pyrimidine base, as defined herein;

R<1>, R<2> and R<3> are independently H or phosphate;

R<6> is alkyl; and

X is O.

In even more preferred embodiments, a compound of Formula XI or a pharmaceutically acceptable salt or prodrug thereof is provided:

where:

is a purine base or a pyrimidine base, as defined herein; optionally substituted with amine or cyclopropyl (eg, 2-amino, 2,6-diamino or cyclopropyl guanosine); and

R<1> and R<2> are independently H, phosphate (including monophosphate, diphosphate or triphosphate and a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> and R<2> are independently H or phosphate.

In a ninth main embodiment there is provided a compound selected from Formulas XIII, XIV or XV, or pharmaceutically acceptable salts or prodrugs thereof:

where:

is a purine base or a pyrimidine base, as defined herein; R<1>, R<2> and R<3> are independently H, phosphate (including monophosphate, diphosphate or triphosphate and a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R\ R<2> or R<3> are independently H or phosphate; R<6>is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2,

-NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2; and

X is O, S, SO2 or CH2.

In a first preferred embodiment, there is provided a compound of Formula XIII, XIV or XV, or pharmaceutically acceptable salts or prodrugs thereof, wherein: the base is a purine or pyrimidine base, as defined herein;

R<1>, R<2> and R<3> are independently hydrogen or phosphate;

R9 is alkyl; and

X is O, S, SO2 or CH2.

In another preferred embodiment, there is provided a compound of Formula XIII, XIV or XV, or pharmaceutically acceptable salts or prodrugs thereof, wherein: the base is a purine or pyrimidine base, as defined herein;

R<1>, R<2> and R<3> are hydrogen;

R<6> is alkyl; and

X is O, S, SO2 or CH2.

In a third preferred embodiment, there is provided a compound of Formula XIII, XIV or XV, or pharmaceutically acceptable salts or prodrugs thereof, wherein: the base is a purine or pyrimidine base, as defined herein;

R1, R<2> and R<3> are independently hydrogen or phosphate;

R<6> is alkyl; and

X is O.

In a tenth main embodiment, the invention provides a compound of Formula XVI, or a pharmaceutically acceptable salt or prodrug thereof:

where:

is a purine base or a pyrimidine base, as defined herein;

R<1> and R<2> are independently H, phosphate (including monophosphate, diphosphate or triphosphate and a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound in which R<1> or R<2> are independently H or phosphate; R<6>is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2, -NH2 alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2; R<7> and R<9> are independently: hydrogen, OR<2>, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO2, NH2, -NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2;

R<a> and R<10> are independently: H, alkyl (including lower alkyl), chlorine, bromine or iodine; alternatively, R<7> and R<9>, R<7> and R10, R<8> and R<9> or R8 and R<10> can join to form a pi bond; and

X is O, S, SO2 or CH2.

In a first preferred embodiment, there is provided a compound of Formula XVI or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H or phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; (3) R<6> is alkyl; (4) R<7> and R<9> are independently: OR<2>, alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (5) R<8> and R<10> are independently: H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O, S, SO 2 or CH 2 .

In another preferred embodiment, there is provided a compound of Formula XVI or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H or phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; (3) R<6>is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO?, amino, lower alkylamino or di(lower alkyl)amino; (4) R<7> and R<9> are independently OR<2>; (5) R<8> and R<10> are independently: H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O, S, SO 2 or CH 2 .

In a third preferred embodiment, there is provided a compound of Formula XVI or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H or phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; (3) R<6>is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (4) R<7> and R<9> are independently: OR<2>, alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (5) R<8> and R<10> are H; and (6) X is O, S, SO, or CH 2 .

In a fourth preferred embodiment, there is provided a compound of Formula XVI or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H or phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; (3) R<6>is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (4) R<7> and R<9> are independently: OR<2>, alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (5) R<8> and R<10> are independently: H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O.

In a fifth preferred embodiment, there is provided a compound of Formula XVI or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H or phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; (3) R<6> is alkyl; (4) R<7> and R<9> are independently OR<1>; (5) R<8> and R<10> are independently: H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O, S, SO 2 or CH 2 .

In a sixth preferred embodiment, there is provided a compound of Formula XVI or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H or phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; (3) R<6> is alkyl; (4) R<7> and R<9> are independently: OR<2>, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (5) R<8> and R<10> are H; and (6) X is O, S, SO, or CH 2 .

In a seventh preferred embodiment, there is provided a compound of Formula XVI or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H or phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound in which R<1> is independently H or phosphate; (3) R<6> is alkyl; (4) R<7> and R<9> are independently: OR<2>, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (5) R<8> and R<10> are independently: H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O.

In an eighth preferred embodiment, there is provided a compound of Formula XVI or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H or phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; (3) R<6>is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (4) R<7> and R<9> are independently OR<2>; (5) R<8> and R<10> are hydrogen; and (6) X is O, S, SO 2 or CH 2 .

In a ninth preferred embodiment, there is provided a compound of Formula XVI or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H or phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; (3) R<6>is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (4) R<7> and R<9> are independently OR<2>; (5) <R8> and R<10> are H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O.

In a tenth preferred embodiment, there is provided a compound of Formula XVI or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H or phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound in which R<1> is independently H or phosphate; (3) R<6>is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (4) R<7> and R<9> are independently: OR<2>, alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (5) R8 and R<10> are hydrogen; and (6) X is O.

In an eleventh preferred embodiment, there is provided a compound of Formula XVI or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1> is independently H or phosphate; (3) R<6>is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (4) R<7>and R<9>codependent OR<2>; (5) R<8> and R<10> are hydrogen; and (6) X is O, S, SO 2 or CH 2 .

In a twelfth preferred embodiment, there is provided a compound of Formula XVI or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1> is independently H or phosphate; (3) R<6> is alkyl; (4) R<7> and R<9> are independently OR<2>; (5) R<8> and R<10> are hydrogen; and (6) X is O, S, SO 2 or CH 2 .

In a thirteenth preferred embodiment, there is provided a compound of Formula XVI or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1> is independently H or phosphate; (3) R<6> is alkyl; (4) R<7> and R<9> are independently OR<2>; (5) R<8> and R<10> are independently H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O.

In a fourteenth preferred embodiment, there is provided a compound of Formula XVI or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1> is independently H or phosphate; (3) R<6> is alkyl; (4) R<7> and R<9> are independently: OR<2>, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (5) R<8> and R<10> are hydrogen; and (6) X is O.

In an even more preferred embodiment, there is provided a compound of Formula XVI or a pharmaceutically acceptable salt or prodrug thereof, wherein: (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R8 and R<10> are hydrogen; and (6) X is O; (1) The base is guanine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R8 and R<10> are hydrogen; and (6) X is O; (1) The base is cytosine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R8 and R<10> are hydrogen; and (6) X is O; (1) The base is thymine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R<8> and R<10> are hydrogen; and (6) X is O; (1) The base is uracil; (2) F<T>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R8 and R<10> are hydrogen; and (6) X is O; (1) The base is adenine; (2) R<1>is phosphate; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R<8> and R<10> are hydrogen; and (6) X is O; (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is ethyl; (4) R<7> and R<9> are hydroxyl; (5) R8 and R<10> are hydrogen; and (6) X is O; (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is propyl; (4) R<7> and R<9> are hydroxyl; (5) R<8> and R<10> are hydrogen; and (6) X is O; (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is butyl; (4) R<7> and R<9> are hydroxyl; (5) R<8> and R<10> are hydrogen; and (6) X is O; (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> is hydrogen and R<9> is hydroxyl; (5) R<8> and R<10> are hydrogen; and (6) X is O; (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R8 and R<10> are hydrogen; and (6) X is S; (1) The base is adenine; (2) R<1>is hydrogen; (3) R<e>is methyl; (4) R<7> and R<9> are hydroxyl; (5) R8 and R<10> are hydrogen; and (6) X is SOa; (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R6 and R<10> are hydrogen; and (6) X is CH 2 .

In an eleventh main embodiment, the invention provides a compound of Formula XVII, or a pharmaceutically acceptable salt or prodrug thereof:

where:

is a purine base or a pyrimidine base, as defined herein; R<1> is H; phosphate (including monophosphate, diphosphate or triphosphate and stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; R<6>is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2, -NH2 alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2; R<7> and R<9> are independently: hydrogen, OR<2>, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO2, NH2, -NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2;

R<10> is H, alkyl (including lower alkyl), chlorine, bromine or iodine;

alternatively, R<7> and R<9> or R<7> and R<10> can join to form a pi bond; and X is O, S, SO 2 or CH 2 .

In a first preferred embodiment, there is provided a compound of Formula XVII or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H; phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; (3) R<6>is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (4) R<7> and R<9> are independently hydrogen, OR<2>, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (5) R<10>is H; and (6) X is O, S, SO 2 or CH 2 .

In another preferred embodiment, there is provided a compound of Formula XVII or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H; phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; (3) R<6>is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (4) R<7> and R<9> are independently OR2; (5) R<10> is H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O, S, SO 2 or CH 2 .

In a third preferred embodiment, there is provided a compound of Formula XVII or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H; phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; (3) R<6>is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (4) R<7> and R<9> are independently hydrogen, OR<2>, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (5) R<10>is H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O.

In a fourth preferred embodiment, there is provided a compound of Formula XVII or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H; phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; (3) R<6>is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (4) R<7> and R<9> are independently OR2; (5) R<10> is H; and (6) X is O, S, SO 2 , CH 2 .

In a fifth preferred embodiment, there is provided a compound of Formula XVII or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H; phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; (3) R<6>is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lower alkylamino or di(lower)alkylamino; (4) R<7> and R<9> are independently OR2; (5) R<10> is H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O.

In a sixth preferred embodiment, there is provided a compound of Formula XVII or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H; phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; (3) R<6>is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (4) R<7> and R<9> are independently hydrogen, OR<2>, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (5) R<10>is H; and (6) X is O.

In a seventh preferred embodiment, there is provided a compound of Formula XVII or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H; phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; (3) R<6>is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (4) R<7> and R<9> codependent OR<2>; (5) R<t0>is H; and (6) X is 0.

In an eighth preferred embodiment, there is provided a compound of Formula XVII or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1> is independently H or phosphate; (3) R<6> is alkyl; (4) R<7> and R<9> are independently hydrogen, OR<2>, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (5) R<10>is H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O, S, SO 2 or CH 2 .

In a ninth preferred embodiment, there is provided a compound of Formula XVII or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1> is independently H or phosphate; (3) R<6>is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (4) R<7> and R<9> are independently OR<2>;

(5) R<10>is H; and (6) X is O, S, SO 2 , CH 2 .

In a tenth preferred embodiment, there is provided a compound of Formula XVII or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1> is independently H or phosphate; (3) R<6> is alkyl; (4) R7 and R<9> are independently OR<2>; (5) R<10>is H; and (6) X is O, S, SO 2 , CH 2 .

In an even more preferred embodiment, there is provided a compound of Formula XVII or a pharmaceutically acceptable salt or prodrug thereof, wherein: (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R<10>is hydrogen; and (6) X is O; (1) The base is guanine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R<10>is hydrogen; and (6) X is O; (1) The base is cytosine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R<10>is hydrogen; and (6) X is O; (1) The base is thymine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R<10>is hydrogen; and (6) X is O; (1) The base is uracil; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R<10>is hydrogen; and (6) X is O; (1) The base is adenine; (2) R<1>is phosphate; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R<10>is hydrogen; and (6) X is O; (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is ethyl; (4) R<7> and R<9> are hydroxyl; (5) R<10>is hydrogen; and (6) X is O; (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is propyl; (4) R<7> and R<9> are hydroxyl; (5) R<10>is hydrogen; and (6) X is O; (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is butyl; (4) R<7> and R<9> are hydroxyl; (5) R<10>is hydrogen; and (6) X is O; (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R<10>is hydrogen; and (6) X is S; (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R<10>is hydrogen; and (6) X is SO 2 ; (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R<10>is hydrogen; and (6) X is CH 2 .

In a twelfth main embodiment, the invention provides a compound of Formula XVIII, or a pharmaceutically acceptable salt or prodrug thereof:

where:

is a purine base or a pyrimidine base, as defined herein; R<1>is independent: H; phosphate (including monophosphate, diphosphate or triphosphate and stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; R<6>is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2, -NH2 alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2;

R<7> and R<9> are independently: hydrogen, OR<2>, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino;

R<8> is H, alkyl (including lower alkyl), chlorine, bromine or iodine;

alternatively, R<7> and R<9> or R<8> and R<9> can join to form a pi bond; and X is O, S, SO 2 or CH 2 .

In a first preferred embodiment, there is provided a compound of Formula XVIII or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H; phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; (3) R<6> is alkyl; (4) R<7> and R<9> are independently hydrogen, OR<2>, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (5) R<8>is H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O, S, SO 2 or CH 2 .

In another preferred embodiment, there is provided a compound of Formula XVIII or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H; phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; (3) R<6>is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (4) R<7> and R<9> are independently OR<2>; (5)<R8> is H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O, S, SO 2 or CH 2 .

In a third preferred embodiment, there is provided a compound of Formula XVIII or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H; phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound in which R' is independently H or phosphate; (3) R<6>is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (4) R<7> and R<9> are independently hydrogen, OR<2>, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (5) R<8>is H; and (6) X is O, S, SO 2 , CH 2 .

In a fourth preferred embodiment, there is provided a compound of Formula XVIII or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H; phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound in which R<1> is independently H or phosphate; (3) R<6>is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (4) R<7> and R<9> are independently hydrogen, OR<2>, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (5) R<8>is H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O.

In a fifth preferred embodiment, there is provided a compound of Formula XVIII or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H; phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; (3) R<6>is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lower alkylamino or di(lower)alkylamino; (4) R<7> and R<9> are independently OR<2>; (5) R<8> is H; and (6) X is O, S, SO 2 , CH 2 .

In a sixth preferred embodiment, there is provided a compound of Formula XVIII or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H; phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; (3) R<6>is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (4) R<7> and R<9> are independently OR<2>; (5) R<8>is H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O.

In a seventh preferred embodiment, there is provided a compound of Formula XVIII or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1>is independently H; phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl, provided herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol; or another, pharmaceutically acceptable leaving group, which when used in vivo can provide a compound wherein R<1> is independently H or phosphate; (3) R<6>is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (4) R<7> and R<9> are independently hydrogen, OR<2>, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (5) R<8>is H; and (6) X is O.

In an eighth preferred embodiment, there is provided a compound of Formula XVIII or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1> is independently H or phosphate; (3) R<6>is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NOx, amino, lower alkylamino or di(lower alkyl)amino; (4) R<7> and R<9> are independently OR<2>;

(5) R<8>is H; and (6) X is O, S, SO 2 or CH 2 .

In a ninth preferred embodiment, there is provided a compound of Formula XVIII or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1> is independently H or phosphate; (3) R<6> is alkyl; (4) R7 and R<9> are independently OR<2>; (5) R<8> is H; and (6) X is O, S, SO 2 , CH 2 .

In a tenth preferred embodiment, there is provided a compound of Formula XVIII or a pharmaceutically acceptable salt or prodrug thereof wherein: (1) the base is a purine or pyrimidine base, as defined herein; (2) R<1> is independently H or phosphate; (3) R<6> is alkyl; (4) R<7> and R<9> are independently OR<2>; (5) R<8> is H; and (6) X is O.

In an even more preferred embodiment, there is provided a compound of Formula XVIII or a pharmaceutically acceptable salt or prodrug thereof, wherein: (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R<3>is hydrogen; and (6) X is O; (1) The base is guanine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R<8>is hydrogen; and (6) X is O; (1) The base is cytosine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R<8>is hydrogen; and (6) X is O; (1) The base is thymine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R<8>is hydrogen; and (6) X is O; (1) The base is uracil; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R<8>is hydrogen; and (6) X is O; (1) The base is adenine; (2) R<1>is phosphate; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R<8>is hydrogen; and (6) X is O; (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is ethyl; (4) R<7> and R<9> are hydroxyl; (5) R<8>is hydrogen; and (6) X is O; (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is propyl; (4) R<7> and R<9> are hydroxyl; (5) R<8>is hydrogen; and (6) X is O; (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is butyl; (4) R<7> and R<9> are hydroxyl; (5) R<8>is hydrogen; and (6) X is O; (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R<8>is hydrogen; and (6) X is S; (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R<8>is hydrogen; and (6) X is SO 2 ; or (1) The base is adenine; (2) R<1>is hydrogen; (3) R<6> is methyl; (4) R<7> and R<9> are hydroxyl; (5) R<8>is hydrogen; and (6) X is CH 2 .

The p-D- and p-L-nucleosides of the present invention can inhibit HCV polymerase activity. The ability of nucleosides to inhibit HCV polymerase activity in vitro can be tested according to screening methods, which are detailed here. It is possible to easily determine the spectrum of activity by evaluating the compound with the assays described here, or with another confirmatory test.

In one embodiment, the efficacy of an anti-HCV compound is measured by the concentration of the compound, which is necessary to reduce the number of viral plaques in vitro, in accordance with the methods set forth in more detail herein, in an amount of 50% (ie, EC^ of the compound). In preferred embodiments, the compound exhibits an EC , which is less than 15 or 10 micromoles, when measured according to the polymerase assay described in Ferrari et al., Jnl. of Vir, 73:1649-1654, 1999: Ishiet al., Hepatology, 29:1227-1235, 1999; Lohmannet al, Jnl. of Bio. Chem., 274:10807-10815, 1999; or Yamashita et al., Jnl. of Bio. Chem., 273: 15479-15486, 1998.

The active compound can be administered in the form of any salt or prodrug, which are capable of directly or indirectly converting to the parent compound upon administration to the recipient or which themselves exhibit activity. Non-limiting examples are pharmaceutically acceptable salts (alternatively referred to as "physiologically acceptable salts") and the compound, which may be alkylated or acylated at the 5' position or on a purine or pyrimidine base (type of "pharmaceutically acceptable prodrug"). Furthermore, modifications can affect the biological activity of the compound, in some cases increasing the activity relative to the parent compound. The above can be readily assessed by making a salt or prodrug and testing its antiviral activity according to the methods described herein or other methods known to one skilled in the art.

II. Definitions

The term alkyl, as used herein, unless otherwise indicated, refers to a saturated straight, branched or cyclic, primary, secondary or tertiary hydrocarbon, having predominantly C, through C10, and particularly includes methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, /-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl. The term includes both substituted and unsubstituted alkyl groups. Moieties by which the alkyl group may be substituted are selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfuric acid, sulfate, phosphoric acid, phosphate or phosphonate, which are unprotected or, if necessary, protected, as known to those skilled in the art, and as shown in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, which is incorporated herein by reference.

The term lower alkyl, as used herein, unless otherwise indicated, refers to a C1 to C4 saturated straight, branched, or if appropriate, cyclic (eg, cyclopropyl) alkyl group, including both substituted and unsubstituted forms. Unless otherwise specifically stated in this application, when a suitable moiety is alkyl, lower alkyl is preferred. Similarly, when the suitable moiety is alkyl or lower alkyl, unsubstituted alkyl or lower alkyl is preferred.

The term alkylamino or arylamino refers to an amino group that has one or two alkyl or aryl substituents.

The term "protected", as used herein and unless otherwise defined, refers to a group added to an oxygen, nitrogen or phosphorus atom to prevent further reactions thereof or for other purposes. A wide range of oxygen and nitrogen protecting groups is known to those skilled in the art of organic synthesis.

The term aryl, as used herein, unless otherwise indicated, refers to phenyl, biphenyl or naphthyl, with phenyl being preferred. The term includes both substituted and unsubstituted groups. The aryl group may be substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfuric acid, sulfate, phosphoric acid, phosphate or phosphonate, which are unprotected or, if necessary, protected, as known to those skilled in the art, and as shown, for example, in Greene, et al, Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

The term alkaryl or alkylaryl refers to an alkyl group with an aryl substituent. The term aralkyl or arylalkyl refers to an aryl group with an alkyl substituent.

The term halo as used herein includes chloro, bromo, iodo and fluoro.

The term purine or pyrimidine base includes, but is not limited to, adenine, N<6->alkylpurine, N<6->acylpurine (where acyl is C(0)(alkyl, aryl, alkylaryl or arylalkyl), N<6->benzylpurine, N<6->halopurine, N<6->vinylpurine, N<6->acetylene purine, N<6->acyl purine, N<6->hydroxyalkyl purine, N<6->thioalkyl purine, N<2->alkylpurines, N<2->alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4-mercaptopyrimidine, uracil, 5-halouracil, including 5-fluorouracil, C<5->alkylpyrimidines, C<5->benzylpyrimidines, C<5->vinylpyrimidine, C<5->acetylenic pyrimidine, C<5->acyl pyrimidine, C<5->hydroxyalkyl purines, C<5->amidopyrimidine, C<5->cyanopyrimidine, C<5->nitropyrimidine, C<5->aminopyrimidine, N<2->alkylpurines, N<2->alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracil, triazolopyridinyl, imidazolopyridinyl. pyrrolopyrimidinyl and pyrazolopyrimidinyl. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine. The oxygen and nitrogen functional groups on the base can be protected if necessary or desirable. Suitable protecting groups are well known to those skilled in the art and include trimethylsilyl, dimethylhexylsilyl, /-butyldimethylsilyl, t-butyldiphenylsilyl, trityl, alkyl groups and acyl groups, such as acetyl and propionyl, methanesulfonyl and p-toluenesulfonyl.

The term acyl refers to a carboxylic acid ester, wherein the non-carbonyl part of the ester group is selected from straight, branched or cyclic alkyl or lower alkyl, alkoxyalkyl, including methoxymethyl, aralkyl, including benzyl, aryloxyalkyl, such as phenoxymethyl, aryl, including phenyl, which is optionally substituted with chloro, bromo, fluoro, iodo, C, to C4alkyl, or C1 to C4alkoxy, sulfonate esters, such as alkyl or aralkyl sulfonyl, including methanesulfonyl, mono, di, or triphosphate ester, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl (eg, dimethyl-t-butylsilyl), or diphenylmethylsilyl. Aryl groups in esters optimally contain a phenyl group. The term "lower acyl" refers to an acyl group in which the non-carbonyl moiety is lower alkyl.

As used herein, the term "substantially free of" or "substantially in the absence of" refers to a mixture of nucleosides that includes at least 85 or 90% by weight, preferably 95% to 98% by weight, and more preferably 99% to 100% by weight, of the enantiomer of that nucleoside in question. In a preferred embodiment, in the methods and compounds of the present invention, the compounds are substantially free of enantiomers.

Similarly, the term "isolated" refers to a mixture of nucleosides, which includes at least 85 or 90% by weight, preferably 95% to 98% by weight, and more preferably 99% to 100% by weight of nucleosides, with the remainder comprising other chemical species or enantiomers.

The term "independently" is used herein to indicate that the variable, which is applied independently, varies independently from application to application. Thus, in a compound such as R"XYR", where R" is "independently carbon or nitrogen", "both R" can be carbon, both R" can be nitrogen, or one R" can be carbon and the other R" can be nitrogen.

The term host, as used herein, refers to unicellular or multicellular organisms in which the virus can replicate, including cell lines and animals, preferably humans. Alternatively, the host may carry a portion of the hepatitis C viral genome, the replication or function of which may be altered by the compounds of the present invention. The term host specifically refers to infected cells, cells that have been transfected with all or part of the HCV genome, and animals, in particular, primates (including chimpanzees) and humans. In most animal applications of this invention, the host is a human patient. Veterinary applications, in certain indications, however, are clearly contemplated by this invention (as in the case of chimpanzees).

The term "pharmaceutically acceptable salt or prodrug" is used herein throughout the specification to describe any pharmaceutically acceptable form (such as an ester, phosphate ester, salt of an ester, or a related group) of a nucleoside compound, which, upon administration to a patient, yields a nucleoside compound. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art. Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, eg, 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 the functional part of the active compound. Prodrugs include compounds that may be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated, to produce the active compound. The compounds of the present invention possess antiviral activity against the HCV virus or are metabolized to compounds that exhibit such activity.

III. Nucleotide salt or prodrug formulations

In cases where the compounds are sufficiently basic or acidic to form stable non-toxic salts of the acid or base, administration of the compound in the form of a pharmaceutically acceptable salt may be convenient. Examples of pharmaceutically acceptable salts are salts formed by the addition of organic acids that form a physiologically acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate and α-glycerophosphate. Suitable inorganic salts may also be formed, including sulfate, nitrate, bicarbonate and carbonate salts.

Pharmaceutically acceptable salts can be prepared using standard procedures well known in the art, for example by reacting a sufficiently basic compound, such as an amine, with a suitable acid to produce a physiologically acceptable anion. Salts of carboxylic acids of alkali metals (for example, sodium, potassium or lithium) or alkaline earth metals (for example, calcium) can also be prepared.

Any of the nucleosides described herein can be administered as a nucleoside prodrug to increase the activity, bioavailability, stability, or otherwise alter the properties of the nucleoside. A number of Uganda prodrugs of nucleotides are known. In general, alkylation, acylation, or other lipophilic modification of a nucleoside mono, di, or triphosphate will increase the stability of the nucleotide. Examples of substituent groups, which may replace one or more hydrogens on the phosphate moiety, are alkyl, aryl, steroids, carbohydrates, including sugars, 1,2-diacylglycerol and alcohols. Many such compounds are described in R. Jones and N. Bischofberger, Antiviral Research, 27 (1995) 1-17. Any of these compounds can be used in combination with the indicated nucleosides to achieve the desired effect.

The active nucleoside can also be obtained as a lipid 5'-phosphoether or a lipid 5'-ether, as shown in the following references, which are incorporated herein by reference: Kucera L.S., N. Iyer, E. Leake, A. Raben, Modest E.K., D.L.VV., and C. Piantadosi. 1990. "Novel membrane-interactive ether lipid analogs that inhibit infectious HIV-1 production and induce defective virus formation". AIDS Res. Hum. Retro Viruses.6:491-501; Piantadosi, C, J. Marasco C.J., S.L. Morris-Natschke, K.L. Meyer, F. Gumus, J.R. Surles, K.S. lshaq, LS. Kucera, N. Iyer, C.A. Wallen, S. Piantadosi and EJ. Modest. 1991. "Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HIV activity".J. Med. Chem. 34:1408.1414; Hosteller, K.Y., D.D. Richman, D.A. Carson, LM. Stuhmiller, G.M. T. van Wijk and H. van den Bosch. 1992. "Greatly enhanced inhibition of human immunodeficiency virus type 1 replication in CEM and HT4-6C cells by 3'-deoxythymidine diphosphate dimyristoylglycerol, a lipid prodrug of 3,-deoxythymidine." Antimicrob. Agents Chemother.36:2025.2029; Hostetler, K.Y., LM. Stuhmiller, H.B. Lenting, H. van den Bosch and D.D. Richman, 1990. "Synthesis and antiretroviral activity of phospholipid analogs of azidothymidine and other antiviral nucleosides."J. He was/. Chem. 265:61127.

Non-limiting examples of U.S. patents, which disclose suitable lipophilic substituents, which can be covalently attached to the nucleotide, preferably at the 5'-OH position of the nucleoside or lipophilic preparations, include U.S. Pat. Patent Nos. 5,149,794 (Sep. 22, 1992, Yatvinet al) ; 5,194,654 (Mar. 16, 1993, Hostetleret al, 5,223,263 (June 29, 1993, Hostetleret al) ); 5,256,641 (Oct. 26, 1993, Yatvinet al) ;5,411,947 (May 2, 1995, Hostetleret al) ;5,463,092 (Oct. 31, 1995, Hostetleret al) ;5,543,389 (Aug. 6, 1996, Yatvinet al.) ;

5,543,390 (Aug. 6, 1996, Yatvinet al); 5,543,391 (Aug. 6, 1996, Yatvinet al); and 5,554,728 (Sep. 10, 1996; Basava et al), all of which are incorporated herein by reference. Foreign patent applications, which show lipophilic substituents, which can be attached to the nucleosides of this invention or lipophilic preparations, include WO 89/02733, WO 90/00555, VVO 91/16920, VVO 91/18914, VVO 93/00910, VVO 94/26273, VVO 96/15132, EP 0 350 287, EP 93917054.4 and VVO 91/19721.

IV. Combined and alternating therapy

It has been recognized that drug-resistant variants of the HCV virus can develop after prolonged treatment with antiviral agents. Most often, resistance to the drug occurs due to a mutation of the gene that codes for the enzyme, which is used for virus replication. The efficacy of a drug against HCV virus infection can be prolonged, enhanced or restored by administering the compound in combination or alternately with another and possibly a third antiviral compound, which induces a mutation different from that caused by the parent drug. Alternatively, the pharmacokinetics, bioavailability or other parameters of the drug may be altered by such combined or alternating therapy. In general, combination therapy is generally preferable to alternating therapy, since it acts on the virus by causing multiple simultaneous stresses.

Non-limiting examples of antiviral agents that may be used in combination with the compounds disclosed herein include: (1) interferon and/or ribavirin (Battaglia, A.M. et al, Ann. Pharmacother. 34:487-494, 2000); Berenguer, M. et al. Antivir. Ther. 3 (Suppl. 3):125-136, 1998); (2) substrate-based NS3 protease inhibitors (Attwoodet al., Antiviral peptide derivatives, PCT VVO 98/22496, 1998; Attwoodet al., Antiviral Chemistry and Chemotherapy10.259-273, 1999; Attwoodet al., Preparation and use of amino acid derivatives as anti-viral agents, German Patent Publication DE 19914474; Tunget al. Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease, PCT VVO 98/17679), including alphaketoamides and hydrazinoreas and inhibitors, which end with an electrophile, such as boric acid or phosphonate. Llinas-Brunet et al, Hepatitis C inhibitor peptide analogues, PCT VVO 99/07734. (3) non-substrate-based inhibitors, such as 2,4,6-trihydroxy-3-nitro-benzamide derivatives (Sudo K. et al., Biochemical annd Biophysical Research Communications, 238:643-647, 1997; Sudo et al, Antiviral Chemistry and Chemotherapy9:186, 1998), including RD3-4082 and RD3-4078, previously substituted at amide with a chain of 14 carbons, and later continued with a p/a-phenoxyphenyl group; (4) thiazolidine derivatives, which show significant inhibition in a reverse-phase HPLC assay with NS3/4A fusion protein and NS5A/5B substrate (Sudo K. et al., Antiviral Research32:9-18, 1996), especially compound RD-1-6250, which has a fused cinnamoyl moiety, which is substituted with a long alkyl chain, RD-6205 and RD-6250. 6193; (5) thiazolidines and benzanilides, established in Kakiuchi N. et al. J. EBS Letters 421:217-220; Takeshita N. et al. Analytical Biochemistry 247:242-246, 1997; (6) phenan-trenequinone, which has activity against HCV virus protease in SDS-PAGE and autoradiographic assay, isolated from the broth fermentation culture of Streptomycessp., Sch 68631 (Chu M. et al, Tetrahedron Letters37:7229-7232, 1996) and Sch 351633, which is isolated from the fungus Penicillium griscofuluum, which shows activity in the scintillation proximity assay (Chu M. et al., Bioorganic and Medicinal Chemistry Letters9:1949-1952); (7) selective NS3 inhibitors, which are based on the macromolecule elgin c, which is isolated from a leech (Qasim M.A. et al, Biochemistry36:1598-1607, 1997); (8) HCV helicase inhibitors (Diana G.D. et al., Compounds, compositions and methods for treatment of hepatitis C, U.S. Patent N. 5,633,358; Diana G.D. et al, Piperidine derivatives, pharmaceutical compositions thereof and their use in the treatment of hepatitis C, PCT VVO 97/36554); (9) HCV polymerase inhibitors, such as nucleotide analogs, gliotoxin (Ferrari R. et al. Journal of Virology73:1649-1654, 1999) and the natural product cerulenin (Lohmannn V. et al., Virology249:108-118, 1998); (10) phosphorothioate antisense oligodeoxynucleotides (S-ODN), which are complementary to sequences in the 5' non-coding region (NCR) of the HCV virus (Alt M. et al, Hepatology22:707'-717', 1995) or nucleotides 326-348, which contain the 3' end of the NCR and nucleotides 371-388, which are located in the center of the coding region of IICV RNA (Alt M. et al, Archives of Virology 142:589-599, 1997; Galderisi U. et al., Journal of Cellular Physiology 181:251-257, 1999); (11) inhibitors of IRES-dependent translation (Ikeda Net al., Agent for the prevention and treatment of hepatitis C, Japanese Patent Publication JP-08268890; Kai Y. et al., Prevention and treatment of viral diseases, Japanese Patent Publication JP-10101591); (12) nuclease resistant ribosome (Maccjak D.J. et al, Hepatology 3?abstract995, 1999) and (13) other mixed compounds, including 1-amino-alkylcyclohexanes (U.S. Patent No. 6,034,134 to Goljet al.), alkyl lipids (U.S.

Patent No. 5,922,757 to Chojkieret al), vitamin E and other antioxidants (U.S. Patent No. 5,922,757 to Chojkieret al), squalene, amantadine, bile acids (U.S. Patent No. 5,846,964 to Ozekiet al), N-(phosphonoacetyl)-L-aspartic acid, (U.S. Patent No. 5,830,905 to Diana et al.), benzenedicarboxamides (U.S. Patent No. 5,633,388 to Diana et al.), polyadenylic acid derivatives (U.S. Patent No. 5,496,546 to Wanget al.), 2,3'-dideoxyinosine (U.S. Patent No. 5,026,687 to Yarcho et al.), and benzimidazoles (U.S. Patent No. 5,496,546 to Wang et al.). 5,891,874 by Colacino et al).

V. Pharmaceutical preparations

Hosts, including humans, infected with the HCV virus or a fragment of its gene can be treated by administering to the patient an effective amount of the active compound or a pharmaceutically acceptable prodrug or salt thereof, in the presence of a pharmaceutically acceptable carrier or diluent. The active materials may be administered by any convenient route, for example, orally, parenterally, intravenously, intradermally, subcutaneously or topically, in liquid or solid form.

A preferred dose of the compound for HCV will be in the range of about 1 to 50 mg/kg, preferably 1 to 20 mg/kg of body weight per day, more generally 0.1 to about 100 mg per kilogram of body weight of the recipient per day. An effective dosage range of pharmaceutically acceptable salts and prodrugs can be calculated based on the weight of the parent nucleoside to be released. If the salt or prodrug itself exhibits activity, the effective dosage can be determined as previously stated by taking the weight of the salt or prodrug, or by other means known to those skilled in the art.

The compound is conveniently administered in a unit of any suitable dosage form, including, but not limited to, that unit containing 7 to 3000 mg, preferably 70 to 1400 mg of active ingredient per unit dosage form. An oral dosage of 50-1000 mg is generally suitable.

Ideally, the active ingredient would be administered to achieve peak plasma concentrations of the active compound of about 0.2 to 70 µM, preferably about 1.0 to 10 µM. This can, for example, be achieved by intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or given as a bolus of the active ingredient.

The concentration of the active compound in the drug mixture will depend on the absorption, rate of inactivation and excretion of the drug, as well as on other factors, which are well known to those skilled in the art. It should be noted that dosage values will also vary in relation to the severity of the condition to be alleviated in this way. Further, it should be understood that specific dosage regimens should be tailored for each particular subject over time, in accordance with the individual needs and professional judgment of the person administering or supervising the administration of the mixtures, and that the concentration ranges provided herein are illustrative examples only and are not intended to limit the scope or practical requirements of the administered mixture. The active ingredient can be applied all at once or it can be divided into a certain number of smaller doses, which would be applied at different time intervals.

The preferred method of administration of the active ingredient is oral. Oral formulations will generally include an inert diluent or edible carrier. They can be molded into gelatin capsules or compressed into tablets. For purposes of oral therapeutic administration, the active compound can be combined with excipients and used in the form of tablets, lozenges or capsules. Pharmaceutically compatible binding agents and/or adjuvant materials may be included as part of the composition.

Tablets, pills, capsules, lozenges and the like may contain any of the following ingredients or compounds of a similar nature: a binding agent, such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient, such as starch or lactose, a disintegrating agent, such as alginic acid, Primogel or corn starch; a lubricant, such as magnesium stearate or Sterotes; a slip agent, such as colloidal silicon dioxide; a sweetening agent, such as sucrose or saccharin; or a flavoring agent, such as peppermint, methyl salicylate, or orange flavor. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a fatty oil. In addition, dosage unit forms may contain various other materials that modify the physical form of the dosage unit, for example, sugar coatings, shellac, or enteric agents.

The compound may be administered as a component of an elixir, suspension, syrup, wafer, chewing gum, or the like. The syrup may contain, in addition to the active compounds, sucrose, as a sweetening agent and certain preservatives, colors and coloring agents and agents to improve taste.

The compound or its pharmaceutically acceptable prodrug or salts may also be mixed with other active materials, which do not diminish the desired activity, or with materials, which supplement the desired activity, such as antibiotics, antifungal agents, anti-inflammatory or other antiviral agents, including other nucleoside compounds. Solutions or suspensions, used for parenteral, intradermal, subcutaneous or topical administration, may contain the following components: a sterile diluent, such as water for injection, saline, solid oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methyl parabens; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and tonicity adjusting agents such as sodium chloride or dextrose. A parenteral preparation may be packaged in ampoules, disposable injections, or glass or plastic vials with multiple doses.

If administered intravenously, the preferred vehicles are saline or phosphate buffered saline (PBS).

In a preferred embodiment, the active compounds are prepared with carriers that will protect the compound from rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactonic acid. Methods for making such formulations will be apparent to those skilled in the art. The materials are also commercially available through Alza Corporation.

Liposomal suspensions (including liposomes, which target infected cells with monoclonal antibodies to viral antigens) are also preferred as pharmaceutically acceptable carriers. They can be prepared according to methods well known to those skilled in the art, as described in U.S. Pat. Patent No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposomal formulations can be prepared by dissolving a suitable lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline and cholesterol) in an inorganic solvent, which is then evaporated, leaving behind a thin film of dry lipid on the surface of the container. An aqueous solution of the active compound or its monophosphate, diphosphate and/or triphosphate derivatives is then introduced into the container. The container is then manually rotated to loosen the lipid material from the walls of the container and disperse the lipid aggregates, thereby forming a liposomal suspension.

VI. Processes for the production of active compounds

The nucleosides of this invention can be synthesized by any method known in the art. More specifically, the synthesis of these nucleosides can be carried out either by alkylation of the corresponding modified sugar followed by glycosylation or by glycosylation followed by alkylation of the nucleoside. The following non-limiting embodiments illustrate certain general methodology for preparing nucleosides of the present invention.

A. General synthesis of 1 '- C- branched nucleosides

1'-C-branched ribonucleosides of the following structure:

wherein the base is a purine or pyrimidine base, as defined herein; R<7> and R<8> are independently hydrogen, OR<2>, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO2, NH2, - NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2;

R<8> and R<10> are independently H, alkyl (including lower alkyl), chlorine, bromine or iodine; alternatively, R<7> and R<9>, R<7> and R<1>0, R<8> and R<9> or R<8> and R<10> can combine to form a pi bond;

R<1> and R<2> are independently H; phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol or other pharmaceutically acceptable leaving group, which is capable, when administered in vivo, of giving a compound, wherein R<1> or R<2> are independently H or phosphate; R<6> is alkyl, chloro-, bromo-, fluoro- or iodo-alkyl (i.e. CF3), alkenyl or alkynyl (i.e.

allyl); and

X is O, S, SO2 or CH2

may be prepared by one of the following general methods.

1) Modification from lactone

The key starting material for this process is a suitably substituted lactone. The lactone can be obtained or prepared by any known means, including standard epimerization, substitution, and cyclization techniques. The lactone can optionally be protected with a suitable protecting group, preferably an acyl or silyl group, by methods well known to those skilled in the art, as recommended by Greeneet al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. The protected lactone can then be coupled with a suitable coupling agent, such as an organometallic carbon nucleophile, such as a Grignard reagent, organolithium, lithium dialkylcopper or R<6->SiMe3u TBAF, with a suitable non-protic solvent, at a suitable temperature, to give the 1'-alkylated sugar.

The optionally activated sugar can then be purchased for the BASE by methods well known to those skilled in the art, as discussed in Townsend's Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, the acylated sugar can be purchased for the silylated base with a Lewis acid, such as stannous tetrachloride, titanium tetrachloride, or trimethylsilyltriflate, in a suitable solvent, at a suitable temperature.

Thereafter, the nucleoside may be deprotected by methods well known to those skilled in the art, as discussed by Greeneet al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a particular embodiment, a 1'-C-branched ribonucleoside is preferred. The synthesis of ribonucleosides is shown in Scheme 1. Alternatively, a deoxyribonucleoside is preferred. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as reviewed by Greeneet al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2'-OH can be reduced with a suitable reducing agent. Optionally, the 2'-hydroxyl can be activated to facilitate the reduction; i.e. by Barton reduction.

2. Alternative method for making 1"-C-branched nucleosides

The key starting material for this process is a suitably substituted hexose. The hexose can be obtained or prepared by any known means, including standard epimerization, such as alkali treatment, substitution, and coupling techniques. The hexose can be selectively protected to give the corresponding hexa-furanose, as reviewed by Tovvnsend Chemistrv of Nucleosides and Nucleotides, Plenum Press, 1994.

The 1'-hydroxyl can optionally be activated to a suitable leaving group, such as an acyl group or a chloro, bromo, fluoro, iodo group, by acylation or halogenation. Optionally, the activated sugar can then be purchased for the BASE, by methods well known to those skilled in the art, as discussed by Tovnsend Chemistrv of

Nucleosides and Nucleotides, Plenum Press, 1994. For example, an acylated sugar can be purchased for a silylated base with a Lewis acid, such as stannous tetrachloride, titanium tetrachloride, or trimethylsilyl triflate, in a suitable solvent, at a suitable temperature. Alternatively, the halo-sugar can be purchased for the silylated base in the presence of trimethylsilyl trihydrate.

If protected, 1'-CH2-OH can be selectively deprotected by methods well known in the art. The resulting primary hydroxyl can be functionalized to give different C-branched nucleosides. For example, a primary hydroxyl can be reduced to give a methyl using a suitable reducing agent. Alternatively, the hydroxyl can be activated prior to reduction, to facilitate the reaction; i.e. by Barton reduction. In an alternative embodiment, the primary hydroxyl can be oxidized to the aldehyde and then coupled with a carbon nucleophile, such as a Grignard reagent, organolithium, lithium dialkylcopper, or R<e->SiMe3u TBAF, with a suitable non-protic solvent, at a suitable temperature.

In a particular embodiment, a 1'-C-branched ribonucleoside is preferred. The synthesis of ribonucleosides is shown in Scheme 2. Alternatively, a deoxyribonucleoside is preferred. To obtain these nucleosides, the ribonucleoside formed can optionally be protected by methods well known to those skilled in the art, as reviewed by Greeneet al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2'-OH can be reduced with a suitable reducing agent. Optionally, the 2'-hydroxyl can be activated to facilitate the reduction; i.e. by Barton reduction.

Additionally, the L-enantiomers corresponding to the compounds of the invention can be prepared following the same general methods (1 or 2), starting with the corresponding L-sugar or L-enantiomer of the nucleoside, as starting material.

B. General synthesis of 2'-C-branched nucleosides

2'-C-branched ribonucleosides of the following structure:

wherein Base is a purine or pyrimidine base, as defined herein; R<7> and R<9> are independently hydrogen, OR<2>, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO2, NH2, - NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2;

R<10> is H, alkyl (including lower alkyl), chlorine, bromine or iodine;

alternatively, R<7> and R<9> or R7 and R<10> may combine to form a pi bond; R<1> and R<2> are independently H; phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol or other pharmaceutically acceptable leaving group, which is capable, when administered in vivo, of producing a compound, wherein R<1> or R<2> are independently H or phosphate;

R<6> is alkyl, chloro-, bromo-, fluoro-, iodo-alkyl (i.e. CF3), alkenyl or alkynyl (i.e.

allyl); and

X is O, S, SO2 or CH2

may be prepared by one of the following general methods.

/. Glycosylation of a nucleobase with a suitably modified sugar

The key starting material for this process is a suitably substituted sugar with 2'-OH and 2'-H, with a suitable leaving group (LG), for example an acyl group or a chloro, bromo, fluoro or iodo group. The sugar can be obtained or prepared by any known method, including standard epimerization, substitution, oxidation and reduction techniques. The substituted sugar can then be oxidized with a suitable oxidizing agent in a suitable solvent, at a suitable temperature, to give the 2'-modified sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid and sulfuric acid), Collins reagent (dipyridine Cr(VI) oxide, Corev's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, Mn02, ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate, which is protected on the polymer, Cl2-pyridine, H202-ammonium molybdate, NaBr02-CAN, NaOCI in HOAc, copper chromite, copper oxide, Ranevev nickel, palladium acetate, Meerwin-Pondorf-Werlev reagent (aluminum n-butoxide with another ketone) and N-bromosuccinimide.

Then, by coupling an organometallic carbon nucleophile, such as a Grignard reagent, organolithium, lithium dialkylcopper or R<6->SiMe3u in TBAF, with a ketone, with a suitable non-protic solvent, at a suitable temperature, a 2'-alkylated sugar is produced. The alkylated sugar can optionally be protected, with a suitable protecting group, preferably an acyl or silyl group, by methods well known to those skilled in the art, as shown by Greeneet al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

An optionally protected sugar may then be cleaved to the BASE by methods well known to those skilled in the art, as discussed in Tovnsend Chemistn/of Nucleosides and Nucleotides, Plenum Press, 1994. For example, the acylated sugar may be cleaved to a silylated base with a Lewis acid, such as stannous tetrachloride, titanium tetrachloride, or trimethylsilyl triflate, in a suitable solvent. at a suitable temperature. Alternatively, the halo-sugar can be purchased for the silylated base in the presence of trimethylsilyl triflate.

Accordingly, the nucleoside may be deprotected by methods well known to those skilled in the art, as shown in Greeneet et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a particular embodiment, a 2'-C-branched ribonucleoside is preferred. The synthesis of ribonucleosides is shown in Scheme 3. Alternatively, a deoxyribonucleoside is preferred. To obtain these nucleosides, the ribonucleoside formed can optionally be protected by methods well known to those skilled in the art, as shown by Greeneet al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2'-OH can be reduced with a suitable reducing agent. Optionally, the 2'-hydroxyl can be activated to facilitate the reduction; i.e. by Barton reduction.

2. Modification of the pre-formed nucleoside

The key starting material for this process is a suitably substituted nucleoside with 2'-OH and 2'-H. The nucleoside may be obtained or prepared by any known method, including standard coupling techniques. The nucleoside may optionally be protected with suitable protecting groups, preferably acyl or silyl groups, by methods well known to those skilled in the art, as shown in Greeneet et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

A suitably protected nucleoside can then be oxidized with a suitable oxidizing agent in a suitable solvent, at a suitable temperature, to give the 2'-modified sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid and sulfuric acid), Collins reagent (dipyridine Cr(VI) oxide, Corev's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, Mn02, ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate, which is protected on the polymer, Cl2-pyridine, H202-ammonium molybdate, NaBr02-CAN, NaOCI in HOAc, copper chromite, copper oxide, Ranevev nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum f-butoxide with another ketone), and /V-bromosuccinimide.

Thereafter, the nucleoside can be deprotected by methods well known to those skilled in the art, as described in Greene Greeneet al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a particular embodiment, a 2'-C-branched ribonucleoside is preferred. The synthesis of ribonucleosides is shown in Scheme 4. Alternatively, a deoxyribonucleoside is preferred. To obtain these nucleosides, the ribonucleoside formed can optionally be protected by methods well known to those skilled in the art, as shown by Greeneet al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2'-OH can be reduced with a suitable reducing agent. Optionally, the 2'-hydroxyl can be activated to facilitate the reduction; i.e. by Barton reduction.

In another embodiment of the invention, L-enantiomers are preferred. Therefore, the L-enantiomers, which may correspond to the compounds of the invention, can be prepared following the same, above-mentioned, general methods, starting with the appropriate L-sugar or L-enantiomer of the nucleoside, as starting material.

C. General synthesis of 3'-C-branched nucleosides

3'-C-branched ribonucleosides of the following structure:

wherein Base is a purine or pyrimidine base, as defined herein; R<7> and R<9> are independently hydrogen, OR<2>, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -O(alkyl), -0(lower alkyl), -O(alkenyl), chlorine, bromine, iodine, NO2, NH2, -NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2;

R<8> is H, alkyl (including lower alkyl), chlorine, bromine or iodine;

alternatively, R<7> and R<9> or R<8> and R<9> can combine to form a pi bond; R<1> and R<2> are independently H; phosphate (including monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl herein; lipid, including phospholipid; amino acid; carbohydrate; peptide; cholesterol or other pharmaceutically acceptable leaving group, which is capable, when administered in vivo, of producing a compound, wherein R<1> or R<2> are independently H or phosphate;

R<6> is alkyl, chloro-, fluoro-, bromo-, iodo-alkyl (i.e. CF 3 ), alkenyl or alkynyl (i.e.

allyl); and

X is O, S, SO2 or CH2

may be prepared by one of the following general methods.

1. Glycosylation of the nucleobase with a suitably modified sugar

The key starting material for this process is a suitably substituted sugar with 3-OH and 3'-H, with a suitable leaving group (LG), for example an acyl group or a chloro, bromo, fluoro or iodo group. The sugar can be obtained or prepared by any known method, including standard epimerization, substitution, oxidation and reduction techniques. The substituted sugar can then be oxidized with a suitable oxidizing agent in a suitable solvent, at a suitable temperature, to give the 3'-modified sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid and sulfuric acid), Collins reagent (dipyridine Cr(VI) oxide, Corev's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, Mn02, ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate, protected on a polymer, Cl2-pyridine, H202-ammonium molybdate, NaBr02-CAN, NaOCI in HOAc, copper chromite, copper oxide, Ranevev nickel, palladium acetate, Meerwin-Pondorf-Werlev reagent (aluminum /-butoxide with another ketone) and AAbromosuccinimide.

Then, by coupling an organometallic carbon nucleophile, such as a Grignard reagent, organolithium, lithium dialkylcopper or R<6->SiMe3u in TBAF, with a ketone, with a suitable non-protic solvent, at a suitable temperature, a 3'-C-branched sugar is produced. The 3'-C-branched sugar can optionally be protected, with a suitable protecting group, preferably an acyl or silyl group, by methods well known to those skilled in the art, as reviewed by Greeneet al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

An optionally protected sugar can then be purchased for the BASE, by methods well known to those skilled in the art, as reviewed by Tovnsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, the acylated sugar can be purchased for a silylated base with a Lewis acid, such as stannous tetrachloride, titanium tetrachloride, or trimethylsilyltriflate, in a suitable solvent, at a suitable temperature. Alternatively, the halo-sugar can be purchased for the silylated base in the presence of trimethylsilyl triflate.

Thereafter, the nucleoside may be deprotected by methods well known to those skilled in the art, as described in Greeneet et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a particular embodiment, a 3'-C-branched ribonucleoside is preferred. The synthesis of ribonucleosides is shown in Scheme 5. Alternatively, a deoxyribonucleoside is preferred. To obtain these nucleosides, the ribonucleoside formed can optionally be protected by methods well known to those skilled in the art, as shown by Greeneet al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2-OH can be reduced with a suitable reducing agent. Optionally, the 2'-hydroxyl can be activated to facilitate the reduction; i.e. by Barton reduction.

2. Modification of the pre-formed nucleoside

The key starting material for this process is a suitably substituted nucleoside with 3'-OH and 3'-H. The nucleoside may be obtained or prepared by any known method, including standard coupling techniques. The nucleoside may optionally be protected with suitable protecting groups, preferably acyl or silyl groups, by methods well known to those skilled in the art, as shown in Greeneet et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

A suitably protected nucleoside can then be oxidized with a suitable oxidizing agent in a suitable solvent, at a suitable temperature, to give the 2'-modified sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid and sulfuric acid), Collins reagent (dipyridine Cr(VI) oxide, Corev's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, Mn02, ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate, which is protected on the polymer, Cl2-pyridine, H202-ammonium molybdate, NaBr02-CAN, NaOCI in HOAc, copper chromite, copper oxide, Ranevev nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum /-butoxide with another ketone), and AAbromosuccinimide.

Thereafter, the nucleoside may be deprotected by methods well known to those skilled in the art, as reviewed by Greene Greeneet al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a particular embodiment, a 3'-C-branched ribonucleoside is preferred. The synthesis of ribonucleosides is shown in Scheme 6. Alternatively, a deoxyribonucleoside is preferred. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as shown by Greeneet al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2'-OH can be reduced with a suitable reducing agent. Optionally, the 2'-hydroxyl can be activated to facilitate the reduction; i.e. via Bartonova

reductions.

In another embodiment of the invention, L-enantimers are preferred. Therefore, the L-enantiomers, which may correspond to the compounds of the invention, can be prepared following the same, above-mentioned, general methods, starting with the appropriate L-sugar or L-enantiomer of the nucleoside, as starting material.

Examples

Example 1: Preparation of 1'-C-methylriboadenine via 6-amino-9-(1-deoxy-3-D-psychofuranosyl)purine

As another alternative preparation method, the title compound can also be prepared according to the published procedure (J. Farkas, and F. Sorm, "Nucleic acid components and their analogues. XCIV. Synthesis of 6-amino-9-(1-deoxy-p-D-psicofuranosyl)purine", Collect. Czech. Chem. Commun. 1967, 32, 2663-2667. J. Farkas", Collect. Czech. Chem. Commun. 1966, 31, 1535) (Scheme 7).

In a similar manner, but using the appropriate sugar and pyrimidine or purine bases, the following nucleosides of Formula I were prepared.

Alternatively, the following nucleosides of Formula IV are prepared using the appropriate sugar and a pyrimidine or purine base.

where:

Alternatively, the following nucleosides of Formula VII are prepared using the appropriate sugar and a pyrimidine or purine base.

Alternatively, the following nucleosides of Formula VIII are prepared using the appropriate sugar and a pyrimidine or purine base.

where:

Alternatively, the following nucleosides of Formula IX are produced using the appropriate sugar and pyrimidine or purine bases.

where:

Alternatively, the following nucleosides of Formula XVI are prepared using a suitable sugar and pyrimidine or purine bases.

where:

Example 2: Preparation of 2'-C-methylriboadenine

The title compound was produced according to a published procedure (R.E. Harry-0'kuru, J.M. Smith, and M.S. Wolfe, "A short, flexible route toward 2'-C-branched ribonucleosides'V-Org. Chem. 1997, 62, 1754-1759)

(Scheme 8).

continuation of Scheme 8 (cf. trans. J:

(a) Dess-Martin periodinane; (b) MeMgBr/TiCl4; (c) BzCl, DMAP, Et3N; (d) bis(trimethylsilyl)acetamide, N<6->benzoyl adenine, TMSOTf; (e) NH3/MeOH

In a similar manner, but using the appropriate sugar and pyrimidine or purine bases, the following nucleosides of Formula II were prepared.

where:

Alternatively, the following nucleosides of Formula V are prepared using the appropriate sugar and a pyrimidine or purine base.

where:__

Alternatively, the following nucleotides of Formula X are produced using the appropriate sugar and a pyrimidine or purine base.

where:

Alternatively, the following nucleosides of formula XI were prepared using the appropriate sugar and pyrimidine or purine bases.

in which:

Alternatively, the following nucleosides of Formula XII are prepared using the appropriate sugar and a pyrimidine or purine base.

where:

Alternatively, the following nucleosides of Formula XVII are prepared using the appropriate sugar and a pyrimidine or purine base.

where:

Example 3: Preparation of 3'-C-methylriboadenine

The title compound can be prepared according to a published procedure (R.F. Nutt, M.J. Dickinson, F.VV. Holly, and E. Walton, "Branched-chain sugar nucleosides. III. 3'-C-methyladenine", J. Org. Chem. 1968, 33, 1789-1795)(Scheme 9). (a) RuOVNaJCv (b) MeMgJ/TiCl4; (c) HCl/MeOH/H 2 O; (d) BzCl/pyridine; (e) AcBr, HBr/AcOH; (f) chloromercury-6-benzamidopurine; (g) NH 3 /MeOH.

In a similar manner, but using the appropriate sugar and pyrimidine or purine base, the following nucleosides of Formula III are produced.

where:

Alternatively, the following nucleosides of Formula VI are prepared using the appropriate sugar and a pyrimidine or purine base.

where:

Alternatively, the following nucleosides of Formula XIII are prepared using the appropriate sugar and a pyrimidine or purine base.

where:

Alternatively, the following nucleosides of Formula XIV are prepared using the appropriate sugar and a purine or pyrimidine base.

where:

Alternatively, the following nucleosides of Formula XV are prepared using the appropriate sugar and a pyrimidine or purine base.

where:

Alternatively, sitting nucleoside groups XViii are produced using the appropriate sugar and a pyrimidine or purine base.

where:

VII Anti-hepatitis C activity

The compounds may exert anti-hepatitis C activity by inhibiting HCV polymerase, inhibiting other enzymes required in the replication cycle, or other mechanisms. Numerous techniques for examining these activities have been published. A general method for testing total growth of HCV virus in culture is set forth in U.S. Pat. Patent No. 5,738,985 per Milesua et al. In vitro tests are published in Ferrari et al., Jnl. of Vir., 73:1649-1654, 1999; Ishiet al, Hepatology, 29:1227-1235, 1999; Lohmannet al, Jnl. of Bio. Chem., 247:10807-10815, 1999; and Yamashita et al., Jnl. of Bio. Chem., 273:15479-15486, 1998.

WO 97/12033, filed Sep. 27, 1996 by Emory University, naming C. Hagedorn and A. Reynolds as inventors and having priority to U.S.S.N. 60/004,383, filed September 1995, describes an HCV polymerase assay that can be used to test the activity of the compounds described herein. Another HCV polymerase assay was reported by Bartholomeusz/co-workers, the hepatitis C virus (HCV) RNA polymerase assay, which uses cloned non-structural proteins of HCV; Antiviral Therapy 1996:1 (Supp 4) 18-24.

Studies measuring reductions in activity by HCV drugs are described in U.S. Pat. Patent No. 6,030,785 per Katze/sar,U.S.

Patent No. 6,010,848 by Delvecchio et al., and U.S. Pat. Patent No. 5,759,795 to Jubin/sar. Assays measuring the protease inhibitory activity of proposed HCV drugs are described in U.S. Pat. Patent No. 5,861,267 per Su/sar,U.S. Patent No. 5,739,002 to De Francesco, et al., and U.S. Patent No. 5,597,691 to Houghton, et al.

Example 4: Nucleoside Phosphorylation Assay to Active Triphosphate

To determine the cellular metabolism of the compounds, HepG2 cells were obtained from the American Type Culture Collection (Rockville, MD) and grown in a 225 cm2 tissue culture flask in minimal essential medium supplemented with non-essential amino acids, 1% penicillin-streptomycin. The medium was renewed every three days, and the cells were subcultured once a week. A 10-minute exposure to the combination of trypsin-EDTA in the amount of 30 ml_ leads to the separation of the adherent mono-layer, followed by three successive washings with the medium, and then the confluent HepG2 cells are seeded at a density of 2.5 x 10<6> cells per reaction site in a plate with 6 reaction sites and exposed to 10 µM of the active compound determined by pH], (500 dpm/pmol), in certain time periods. Cells are stored at 37°C, in an atmosphere of 5% CO2. At selected time points, cells were washed three times with ice-cold phosphate-buffered saline (PBS). The intracellular active compound and its individual metabolites were isolated by incubating the cells overnight at -20°C with 60% methanol, followed by extraction with an additional 20 µL of cold methanol for one hour in an ice bath. Isolates were pooled, dried under carefully filtered air and stored at -20°C until HPLC analysis. The preliminary results of the HPLC analysis are tabulated in Table 1.

Example 5: Bioavailability test in Cvnomolgus monkeys

One week prior to initiation of the study, cynomolgus monkeys were surgically implanted with an indwelling venous catheter and a subcutaneous venous access port (VAP) to facilitate blood collection and then underwent a physical examination, including hematological and serum chemistry tests, and body weight was recorded. Each monkey (six in total) received about 250 uCi<3>H activity with each dose of active compound, primarily (3-D-2'-CH3-riboG at a dose of 10 mg/kg and a dose concentration of 5 mg/mL, either by intravenous bolus (3 monkeys, IV) or by oral route (3 monkeys, PO). Each dose syringe was weighed before dosing to gravimetrically determine the amount of formulation administered. Urine samples are collected in a urine collection container at the indicated intervals (approximately 18-0 hours pre-dose, 0-4, 4-8 and 8-12 hours post-dose) and tested.Also, blood samples are collected (pre-dose, 0.25, 0.5, 1, 2, 3, 6, 8, 12 and 24 hours post-dose) via indwelling venous catheter and VAP peripheral blood vessel if the procedure through indwelling venous catheter. Blood and urine samples are analyzed for maximum concentration (C^), time to maximum concentration (Tmax), area under the curve (AUC), dose concentration half-life (T1/2), clearance (CL), steady state volume and distribution (V.J and bioavailability (F), and the results are tabulated in Tables 2 and 3 and graphically illustrated in Figures 2 and 3, respectively.

Example 6; Bone marrow toxicity test

Human bone marrow cells were collected from normal, healthy volunteers and the mononuclear population was isolated by Ficoll-Hypaque gradient centrifugation, as described previously by Sommadossi J-P, Carlisle R. "Toxicity of 3'-azido-3'-deoxythymidine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine for normal human hematopoietic progenitor cells in vitro" Antimicrobial Agents and Chemotherapy 1987; 31:452-454; as well as Sommadossi J-P, Schinazi RF, Chu CK, Xie M-Y. "Comparison of cytotoxicity of the (-)- and (-t-)-enantiomer of 2'.3'-dideoxy-3'-thiacytidine in normal human bone marrow progenitor cells" Biochemical Pharmacology 1992; 44:1921-1925. Culture tests for CFU-GM and BFU-E were performed using two-layer soft agar or the methylcellulose method. Drugs were diluted in tissue culture medium and filtered. After 14 to 18 days at 37°C, in a humid atmosphere with 5% CO in air, colonies with more than 50 cells were counted using an inverted microscope. The results in Table 4 are shown as percent inhibition of colony formation in the presence of drug compared to solvent control cultures.

Example 7: Mitochondrial toxicity test

HepG2 cells were cultured in a 12-well plate as previously described and exposed to various drug concentrations as described by Pan-Zhou X-R, Cui L, Zhou X-J, Sommadossi J-P, Darley-Usmer VM. "Differential effects of antiretroviral nucleoside analogs on mitochondrial function in HepG2 cells" Antimicrob Agents Chemother 2000; 44:496-503. Lactic acid levels in the culture medium after 4 days of drug exposure were measured using a Boehringer lactic acid assay kit. Lactic acid levels were normalized to cell count, as measured by a hemocytometer counter. The preliminary results of this test are tabulated in Table 5.

This invention is described in its preferred embodiments. Deviations and changes of the invention will be clear to experts from the previous detailed description of the invention.

Claims (12)

1. Compound with the structure: or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof. 2. Use of a compound according to claim 1, or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a medicament for the treatment of a host infected with the hepatitis C virus. 3. Use of compounds with the structure: or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a medicament for the treatment of a host infected with the hepatitis C virus. 4. Use according to claim 2 or 3, characterized in that the compound is in the form of a dosage unit. 5. Use according to claim 4, characterized in that the dosage unit contains 50-1000 mg of the compound. 6. Use according to claim 4 or 5, characterized in that the dosage unit is tablets or capsules. 7. Use according to any of claims 2-6, characterized in that the compound or its pharmaceutically acceptable salt is administered in combination or alternately with a second or third antiviral agent. 8. Use according to patent claim 7, characterized in that the antiviral agent is an agent against the hepatitis C virus. 9. Use according to patent claim 8, characterized in that the anti-hepatitis C virus agent is selected from the group consisting of interferon, ribavirin, protease inhibitor, thiazolidine derivative, polymerase inhibitor and helicase inhibitor. 10. Use according to patent claim 9, characterized in that the anti-hepatitis C virus agent is interferon. 11. Use according to patent claim 9, characterized in that the anti-hepatitis C virus agent is ribavirin. 12. Use according to any one of claims 2-11, characterized in that the host is human.