NO20121027A1 - Methods and compositions for treating hepatitis C virus - Google Patents

Abstract

A method and composition for treating a host infected with hepatitis C which comprises administering an effective hepatitis C treating amount of a described 2 ', V, 2' or 3 'modified nucleoside or a pharmaceutically acceptable salt or prodrug thereof is provided.

Description

The present invention relates to the field of pharmaceutical chemistry, and in particular to a compound, method and composition for treating hepatitis C virus.

The present patent application is separated from Norwegian patent application no. 20073151.

Hepatitis C virus (HVC) is the most important cause of chronic liver disease worldwide (Boyer, N. et al. J. Hepatol. 32:98-112, 2000). HCV causes a slow-growing viral infection and is the main cause of cirrhosis and hepatocellular carcinoma (Di Besceglie, A. M. and Bacon, B. R., Scientific American, Oet.: 80-85, (1999); Boyer, N. et la. J. Hepatol. 32 :98-112,2000). About. 170 million people are infected with HVC worldwide. (Boyer, N. et al. J. Hepatol. 32:98-112, 2000). Cirrhosis caused by chronic hepatitis C infection causes 8,000-12,000 deaths per year. years in the USA and HCV infection is the most important indication for a liver transplant.

HCV is known to cause at least 80% of post-transfusion hepatitis and a substantial proportion of sporadic acute hepatitis. Preliminary evidence also shows that HCV is implicated in 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 proportion of healthy people appear to be chronic HCV carriers, which varies with geographic and other epidemiological factors. The numbers may reach significantly higher than those for HBV, although the information is still preliminary; how many of these people have subclinical chronic liver damage is unclear. (The Merck Manual, ch. 69, p. 901, 16th ed., (1992)).

HCV has been classified as a member of the virus family Flaviviridae which includes the genera flaviviruses, pestiviruses and hapaceiviruses, which includes hepatitis C viruses (Rice, C. M., Flaviviridae: viruses and their replication. In: Field virology, editors: Fields, B.N., Knipe, D.M., and Howley, P.M., Lippincott-Raven Publishers, Philadelphia, PA, Chapter 30,931-959,1996). HCV is an enveloped virus that contains a positive-sense single-stranded RNA genome of approx. 9.4kb. The viral genome consists of a 5' untranslated region (UTR), a long open reading stem encoding a polyprotein precursor of approx. 3011 amino acids, and a short 3' UTR. The 5' UTR is the best conserved part of the HCV genome and is important for injection and control of polyprotein translation. The translation of the HCV genome is indicated by an envelope-independent mechanism known as internal ribosome entry. This mechanism involves the binding of ribosomes to an RNA sequence known as the internal ribosome entry site (IRES). An RNA pseudoknot structure has recently been determined to be an essential structural element of the HCV IRES. Viral structural proteins include a nucleocapsid core protein (C) and two envelope glycoproteins, E1 and E2. HCV also encodes two proteinases, a zinc-dependent metalloproteinase encoded by the NS2-NS3 region and a serine proteinase encoded in the NS3 region. These proteinases are required to cleave specific regions of the precursor polyprotein into mature peptides. The carboxyl moiety of the monostructural protein 5, NS5B, contains the RNA-dependent RNA polymerase. The function of the rest of the monostructural proteins, NS4A and NS4B, and that of NS5A (the amino-terminal half of the monostructural protein 5) is still unknown.

Significant focus of antiviral research today is directed toward the development of improved approaches to treat chronic HCV infections in humans (Di Besceglie, A. M. and Bacon, B. R., Scientific American, Oct. 80-85, (1999)). As of today, there are two primary antiviral compounds, ribavirin and interferon-alpha, which are used for the treatment of chronic HCV infections in humans.

Ribavirin (l-B-D-ribofuranosyl-l-l,2,4-trizol-3-carboxamide) is a synthetic non-interferon-reducing broad-spectrum antiviral nucleoside analog sold under the trade name virazol (The Merck Index, 1 lth edition, author: Budavari, S., Merck & Co., Inc., Rahway, NJ, p. 1304, 1989). US Patent Nos. 3,798,209 and RE29,835 describe ribavirin. Ribavirin is structurally close to guanosine and has in vitro activity against several DNA and RNA viruses including Flaviviridae (Gary L. Davis. Gastroenterology 118:S104-S114, 2000).

Ribavirin reduces serum aminotransferase levels to normal in 40% of patients, but does not reduce serum levels of HCV RNA (Gary L. Davis. Gastroenterology 118:S104-S114,2000). Thus, ribavirin alone is not effective in reducing viral RNA levels. In addition, ribavirin has significant toxicity and is known to induce anemia.

Interferons (IFNs) are compounds that have been commercially available in the treatment of chronic hepatitis for close to ten years. IFNs are glycoproteins produced by immune cells in response to viral infection. IFNs inhibit viral replication of many viruses, including HCV, and when used as the sole treatment for hepatitis C infection, IFNs suppress serum HCV-RNA to undetectable levels. In addition, IFN normalizes serum aminotransferase levels. Unfortunately, the effects of IFN are temporary and a sustained response occurs in only 8%-9% of patients chronically infected with HCV (Gary I. Davis, Gastroenterology 118:S104-S114,2000). A number of patents describe HCV treatments using interferon-based treatments. For example, US Patent No. 5,980,884 to Blatt et al. methods for retreatment of patients affected by HCV using consensus interferon. US Patent No. 5,942,223 to Bazer et al. describes anti-HCV treatment using ovine or bovine interferon-tau. US Patent No. 5,928,636 to Alber et al. describes combination therapy of interleukin-12 and interferon-alpha for the treatment of infectious diseases that include HCV. US Patent No. 5,908,621 to Glue et al. describes the use of polyethylene glycol-modified interferon for the treatment of HCV. US Patent No. 5,849,696 to Chretien et al. in the use of thymosins, alone or in combination with interferon, for the treatment of HCV. US Patent No. 5,830,455 to Valtuena et al. describes a combination HCV treatment that uses interferon and a free radical scavenger. US Patent No. 5,738,845 to Imakawa describes the use of human interferon tau proteins for the treatment of HCV. Other interferon-based treatments for HCV are described in US Patent No. 5,676,942 to Test et al, US Patent No. 5,372,808 to Blatt et al. and US Patent No. 5,849,696.

The combination of IFN and ribavirin for the treatment of HCV infection has been reported to be effective in the treatment of IFN naive patients (Battaglia, A.M. et al, Ann. Pharmacother. 34:487-494,2000). The results are promising for this combination treatment both before hepatitis develops and when histological disease is present (Berenguer, M. et al. Antivir. Ther. 3(Suppl. 3):125-136,1998). The side effects of combination therapy include hemolysis, flu-like symptoms, anemia and fatigue. (Gary L. Davis, Gastroenterology 118:S104-S114, 2000).

A number of HCV treatments have been reviewed by Bymock et al. in Antiviral Chemistry & Chemotherapy, 11:2, 79-95 (2000).

Several substrate-based NS3 protease inhibitors have been identified in the literature, in which the cleaved amide bond of a cleaved substrate is replaced by an electrophile, which interacts with a catalytic serine. Attwood et al. (1998) Antiviral peptide derivatives, 98/22496; Attwood et al (1999), Antiviral Chemistry and Chemotherapy 10,250-273; Attwood et al. (1999), Preparation and use of amino acid derivatives as anti-viral agents, German Patent Publication DE 19914474; Tung et al. (1998) Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease, WO 98/17679. The reported inhibitors terminate in an electrophile such as a boric acid or phosphonate. Llinas-Brunet et al. (1999) Hepatitis C inhibitor peptide analogues, WO 99/07734. Two classes of electrophile-based inhibitors have been described, alpha-ketoamides and hydrazinourea compounds.

The literature has also described a number of non-substrate-based inhibitors. For example, evaluation of inhibition effects of 2,4,6-trihydroxy-3-nitro-benzamide derivatives on HCV protease and other serine proteases has been reported. Sudo, K. et al, (1997) Biochemical and Biophysical Research Communications, 238:643-647; Sudo, K. et al.

(1998), Antiviral Chemistry and Chemotherapy 9:186. Using reverse-phase and HPLC examination, the two most potent compounds identified were RD3-4082 and RD3-4078, the former substituted on the amide with a 14 carbon chain and the latter displaying a para-phenoxyphenyl group.

Thiazolidine derivatives have been identified as micromolar inhibitors using a reversed-phase HPLC assay with an NS3/4A fusion protein and NS5A/5B substrate. Sudo, K. et al. (1996) Antiviral Research 32:9-18. Compounds RD-1-6250, which exhibits a fused cinnamoyl moiety substituted with a long alkyl chain, was most potent against the isolated enzyme. Two other active examples were RD4 6205 and RD4 6193.

Other literature reports screening a relatively small library using an ELSA assay and identifying 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 US patents describe protease inhibitors for the treatment of HCV. For example, US Patent No. 6,004,933 to Spruce et al. a class cysteine protease inhibitors to inhibit HCV endopeptidase 2. US Patent No. 5,990,276 to Zang et al. describes synthetic inhibitors of hepatitis C virus NS3 protease. The inhibitor is a subsequence of substrate of NS3 protease or a substrate of the NS4A cofactor. The use of restriction enzymes to treat HCV is described in US Patent No. 5,538,865 to Reyes et al.

Isolated from the fermentation enhancer strain of Streptomyces sp., Sch 68631, a phenane-trenequinone, exhibits micromolar activity against HCV protease in an SDS-PAGE and

autoradiographic examination. ChuM. et al, Tetrahedron Letters 37:7229-7232, 1996. In another example by the same authors, Sch 351633, isolated from the fungus Penicillium griscojuluum, shows micromolar activity in a scintillation proximity assay. Chu M. et al, Bioorganic and Medicinal Chemistry Letters 9:1949-1952. Nanomolar potency against the HCV NS3 protease enzyme has been achieved by the design of selective

inhibitors based on macromolecule eglin c. Eglin c., isolated from leech is a potent inhibitor of several serine proteases such as S. griseus protease A and B, α-chymotrypsin, chymase and subtilisin. Qasim M.A. et al, Biochemistry 36:1598-1607,1997.

HCV helicase inhibitors have also been reported. US Patent No. 5,633,358 to Diana G.D. et al; PCT Publication No. WO 97/36554 by Diana G.D. et al There are few reports on HCV polymerase inhibitors: some nucleotide analogues, 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 the sequence stretches in the 5' non-coding region of HCV are reported as effective inhibitors of HCV gene expression in vitro translation and IlcpG2 HCV-luciferase cell culture systems. Alt M. et al, Hepatology 22:707-717, 1995. Work has demonstrated that nucleotides 326-348 comprising 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 142:558-599, 1997. US Patent No. 6,001,990 to Wands et al. discloses oligonucleotides to inhibit replication of HCV. PCT Publication No. WO 99/29350 describes compositions and methods for treating hepatitis C infection which include the administration of antisense oligonucleotides which are complementary and hybridizable to HCV RNA. US Patent No. 5,922,857 to Han et al. describes nucleic acids corresponding to the sequence of the pestivirus homology box IV region to control translation of HCV. Antisense oligonucleotides as therapeutic agents have recently been reviewed (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 Publication JP-08268890 to Dceda N. et al; Japanese Patent Publication JP-10101591 by Kai, Y. et al. Nuclease-resistant ribozymes have been targeted by IRES and have recently been reported as inhibitors in an HCV-polio virus chimera plaque study. Maccjak D.J. et al, Hepatology 30 abstract 995,1999. Use of ribozymes to treat HCV is described in US Patent No. 6,043,077 to Barber et al, and US Patent Nos. 5,869,253 and 5,610,054 to Draper et al.

Other patents describe the use of immune system potentiating compounds for the treatment of HCV. For example, US Patent No. 6,001,799 to Chretien et al. a method of treating hepatitis C in non-responders to interferon treatment by administering an immune system potentiating dose of thymosin or a thymosin fragment. US Patent No. 5,972,347 to Eder et al and 5,969,109 to Bona et al. describes antibody-based therapies for the treatment of HCV.

US Patent No. 6,034,134 to Gold et al. describes certain NMDA receptor agonists that have immunomodulatory, antimalarial, anti-Borna virus and anti-hepatitis C activities. The described NMDA receptor antagonists belong to the family of 1-amino-alkylcyclohexanes. US Patent No. 6,030,960 to Morris-Natschke et al. describes the use of certain alkyl lipids to inhibit the production of hepatitis-induced antigens, which include those produced by the HCV virus. US Patent No. 5,922,757 to Chojkier et al. describes the use of vitamin E and other antioxidants to treat hepatitis disorders that include HCV. US Patent No. 5,858,389 to Elsherbi et al. describes the use of squalene to inhibit hepatitis C. US Patent No. 5,849,800 to Smith et al. describes the use of amantadine to treat hepatitis C. US Patent No. 5,846,964 to Ozeki et al. describes the use of bile acids to treat HCV. US Patent No. 5,491,135 to Blough et al. describes the use of N-(phosphonoacetyl)-L-aspartic acid to treat flaviviruses such as HCV.

Other compounds proposed to treat HCV include plant extracts (US Patent No. 5,837,257 to Tsai et al., US Patent No. 5,725,859 to Omer et al., and US Patent No. 6,056,961), piperidines (US- Patent No. 5,830,905 to Diana et al.), benzene carboxamides (US Patent No. 5,633,388 to Diana et al.), polyadenylic acid derivatives (US Patent No. 5,496,546 to Wang et al.), 2',3'- dideoxyinosine (US Patent No. 5,026,687 to Yarchoan et al), benzimidazoles (US Patent No. 5,891,874 to Colacino et al).

In light of the fact that hepatitis C virus has reached epidemic levels around the world, and has tragic effects on the affected patient, there is a great need to provide new effective pharmaceutical agents to treat hepatitis C that have low toxicity to the host.

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

Compounds, methods and compositions for treating hepatitis C infection are described which include an effective hepatitis C treating amount of a B-D or B-L nucleoside of formulas (I)-(XVIII), or pharmaceutically acceptable salt or prodrug thereof.

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

in which:

R<1>, R<2> and R<3> are independently H, phosphate (which includes mono-, di- or triphosphate and a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl or benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1>, R<2> or R<3> is independently H or phosphate; and Y is hydrogen, bromine, chlorine, fluorine, iodine, 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, chlorine, bromine, fluorine, iodine, OR<4> , NR<4>NR<5>or SR<5>; and

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

In a second principal embodiment there is provided a compound of formula II, or a pharmaceutically acceptable salt or prodrug thereof:

in which:

R<1>, R<2> and R3 are independently H, phosphate (which includes mono-, di- or triphosphate and a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1>, R<2> or R<3> is independently H or phosphate; and Y is hydrogen, bromine, chlorine, fluorine, iodine, 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, chlorine, bromine, fluorine, iodine, OR<4> , NR^NR<5> or SR<5>; and

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

In a third principal 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 (which includes monophosphate, diphosphate or triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition for aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or another pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1>, R<2> or R<3> is independently H or phosphate; and

Y is hydrogen, bromine, chlorine, fluorine, iodine, 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, chlorine, bromine, fluorine, iodine, OR<4> , NR^R<5> or SR<5>; and

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

In a fourth principal 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 (which includes mono-, di- or triphosphate and a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1>, R<2> or R<3> is independently H or phosphate; and Y is hydrogen, bromine, chlorine, fluorine, iodine, 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, chlorine, bromine, fluorine, iodine, OR<4> , NR<4>NR<S>or SR<5>; and

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

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

in which:

R 1 , R 0 and R " X are independently H, phosphate (which includes monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters which include alkyl or arylalkylsulfonyl which includes methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1>, R<2> or R<3> is independently H or phosphate; and Y is hydrogen, bromine, chlorine, fluorine, iodine, OR<4>, NR<4>R<5> or SR<4>;

X 1 and X 0 are independently selected from the group consisting of H, straight chain, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chlorine, bromine, fluorine, iodine, OR<4>, NR4^5 or SR<5>; and

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

In a sixth principal 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 (which includes monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1>, R<2> or R<3> is independently H or phosphate; and Y is hydrogen, bromine, chlorine, fluorine, iodine, 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, chlorine, bromine, fluorine, iodine, OR<4>, NR<4>^ <5>or SR<5>;and

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

In a seventh principal embodiment there is provided a compound of formulas VII, VIII and LX, or a pharmaceutically acceptable salt or prodrug thereof:

in which:

the base is a purine or pyrimidine base as defined herein; R<1>, R<2> and R<3> are independently H, phosphate (which includes monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1>, R<2> or R<3> is independently H or phosphate; R<6>is hydrogen, hydroxy, alkyl (which includes 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, chlorine, bromine, fluorine, iodine, N02, NH2, -NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2; and XerO, S, SO 2 or CH 2 .

In an eighth principal embodiment there is provided a compound of formulas X, XI and XII, or a pharmaceutically acceptable salt or prodrug thereof:

wherein: the base is a purine or pyrimidine base as defined herein; R<1>, R<2> and R<3> are independently H, phosphate (which includes monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1>, R<2> or R<3> is independently H or phosphate; R<6>is hydrogen, hydroxy, alkyl (which includes lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl), -0(alkyl), -0(lower alkyl), -O(alkenyl), chlorine, bromine, fluorine, iodine, N02, NH2,

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

R<7> is hydrogen, OR<3>, hydroxy, alkyl (which includes 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, fluorine, iodine, N02, NH2, - NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2; and X is O, S, SO 2 or CH 2 .

In a ninth principal embodiment there is provided a compound selected from formulas XIII, XIV and XV, or a pharmaceutically acceptable salt or prodrug thereof:

in which:

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

R<1>, R<2> and R<3> are independently H, phosphate (which includes monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1>, R<2> or R<3> is independently H or phosphate;

R<6>is hydrogen, hydroxy, alkyl (which includes 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, fluorine, iodine, N02, NH2,

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

X is O, S, SO 2 or CH 2 .

In a tenth principal embodiment, the present invention provides a compound of formula XVI, or a pharmaceutically acceptable salt or prodrug thereof:

in which:

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

R<1> and R<2> are independently H, phosphate (which includes monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> or R<2> is independently H or phosphate;

R<6>is hydrogen, hydroxy, alkyl (which includes 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, fluorine, iodine, N02, 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 (which includes 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, fluorine, iodine, N02, NH2, -NH(lower alkyl), -NH(acyl) , -N(lower alkyl)2, -N(acyl)2; and

R8 and R1<0> are independently H, alkyl (which includes lower alkyl), chlorine, bromine or iodine;

alternatively, R i and R o , R t and R in or R s and R in can be linked together to form a pi bond; and

XerO, S, SO 2 or CH 2 .

In an eleventh principal embodiment, the present invention provides a compound of formula XVII, or a pharmaceutically acceptable salt or prodrug thereof:

in which:

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

R<1> and R<2> are independently H, phosphate (which includes monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> or R<2> is independently H or phosphate;

R<6>is hydrogen, hydroxy, alkyl (which includes 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, fluorine, iodine, N02, 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 (which includes 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, fluorine, iodine, N02, NH2, -NH(lower alkyl), -NH(acyl) , -N(lower alkyl)2, -N(acyl)2; and

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

alternatively, R<7> and R<9> or R7 and R<10> can be linked together to form a pi bond; and XerO,S, SO 2 or CH 2 .

In a twelfth principal embodiment, the present invention provides a compound of formula XVIII, or a pharmaceutically acceptable salt or prodrug thereof:

in which;

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

R<1> and R<2> are independently H, phosphate (which includes monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> or R<2> is independently H or phosphate;

R 6 is hydrogen, hydroxy, alkyl (which includes 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, fluorine, iodine, N02, NH2,

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

R<7>and R<9> are independently hydrogen, OR<2>, alkyl (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO 2 , amino, lower alkylamino or di(lower alkyl)amino;

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

alternatively, R<7> and R<9> or R<8> and R<9> may together form a pi bond; and XerO,S, SO 2 or CH 2 .

The B-D and B-L nucleosides according to the invention can inhibit HCV polymerase activity. The nucleosides can be screened for their ability to inhibit HCV polymerase activity in vitro according to screening procedures set forth in more detail herein. One can easily determine the spectrum of activity by evaluating the connection in the investigations described here or with other confirmatory investigations.

In one embodiment, the effectiveness of the anti-HCV compound is measured according to the concentration of the compound required to reduce the plaque count of the virus in vitro according to the methods set forth specifically herein, by 50% (ie, the EC50 of the compound). In preferred embodiments, the compounds exhibit an EC 50 of less than 25, 15, 10, 5 or 1 micromolar.

In another embodiment, the active compound may be administered in combination or alternately with another anti-HCV agent. In combination therapy, an effective dosage of two or more agents is administered together, while during an alternating treatment, an effective dose of each agent is administered one after the other. Dosage will depend on absorption, inactivation and excretion rates from the drug as well as other factors known to those skilled in the art. It should be noted that dosage values will also vary with the severity of the condition to be alleviated. It is further understood that for any particular object, specific dosage regimens and protocols should be adjusted over time according to the individual need and the professional judgment of the person teaching or supervising the administration of the compositions.

Non-limiting examples of antiviral agents that can be used in combination with the compound described herein include: (1) An 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 (Attwood et al, Antiviral peptide derivatives, PCT WO 98/22496,1998; Attwood et al, Antiviral Chemistry and Chemotherapy 10.259-273, 1999; Attwood et al., Preparation and use of amino acid derivatives as antiviral agents, German patent publication DE 19914474; Tung et al Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease, PCT WO 98/17679), which include alphaketoamides and hydrazinoureas, and inhibitors terminating in an electrophile such as a boric acid or phosphonate . Llinas-Brunet et al, Hepatitis C inhibitor peptide analogues, PCT WO 99/07734. (3) Non-substrate-based inhibitors such as 2,4,6-trihydroxy-3-nitro-benzamide derivatives (Sudo K. et al, Biochemical and Biophysical Research Communications, 238:643-647,1997; Sudo K. et al Antiviral Chemistry and Chemotherapy 9:186,1998), which include RD3-4082 and RD3-4078, wherein the former is substituted on the amide with a 14 carbon chain and the latter exhibits an aro-phenoxyphenyl group; (4) Thiazolidine derivatives showing relevant inhibition in a reversed-phase HPLC assay with an NS3/4A fusion protein and NS5A/5B substrate (Sudo K. et al. Antiviral Research 32:9-18, 1996), particularly compound RD-1-6250 , which exhibit a fused cinnamoyl moiety substituted with a long alkyl chain, RD4 6205 and RD4 6193; (5) Thiazolidines and benzanilides identified in Kakiuchi N. et al, J. EBS Letters 421:217-220; TakeshitaN. et al. Analytical Biochemistry 247:242-246, 1997; (6) A phenan-trenquinone exhibiting activity against HCV protease in an SDS-PAGE and autoradiographic examination isolated from the culture broth of Streptomyces sp., Sch 68631 (ChuM. et al, Tetrahedron Letter sil.-1229-1212, 1996), and Sch 351633, isolated from the fungus Penicillium griscofuluum, which demonstrates activity in a scintillation proximity assay (Chu M. et al, Bioorganic and Medicinal Chemistry Letters 9:1949-1952); (7) Selective NS3 inhibitors based on macromolecule elgin c, isolated from leech (QasimM.A. et al, Biochemistry 36:1598-1607,1997); (8) HCV helicase inhibitors (Diana G.D. et al, Compounds, compositions and methods for treatment of hepatitis C, US 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 WO 97/36554); (9) HCV polymerase inhibitors such as nucleotide analogues, gliotoxin (Ferrari R. et al, Journal of Virology 73:1649-1654, 1999) and the natural product cerulenin (LohmannV. et al, Virology 249:108-118, 1998); (10) Antisense phosphorothioate oligodeoxynucleotides (S-ODN) complementary to the sequence features of the 5' non-coding region (NCR) of HCV (Alt M., et al, Hepatology 22:707-717, 1995), or nucleotides 326-348 which include 3 ' the end of the NCR and nucleotide 371-388 located in the core 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 N. et 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 10101591); (12) Nuclease-resistant ribozymes (Maccjak D.J. et al, Hepatology 30 abstract995,1999); and (13) Other optional compounds that include 1-amino-alkylcyclohexanes (US Patent No. 6,034,134 to Gold et al.), alkyl lipids (US Patent No. 5,922,757 to Chojkier et al.), vitamin E, and other antioxidants (US Patent No. 5,922,757 to Chojkier et al.), squalene, amantadine, bile acid (US Patent No. 5,846,964 to Ozeki et al.), N-(phosphonoacetyl)-L-aspartic acid, (US Patent No. 5,830,905 to Diana et al.), benzene carboxamides (US Patent No. 5,633,388 to Diana et al.), polyadenylic acid derivatives (US Patent No. 5,496,546 to Wang et al.), 2',3'-dideoxynosine ( US Patent No. 5,026,687 to Yarchoan et al) and

benzimidazoles (US Patent No. 5,891,874 to Colacino et al).

Figure 1 provides the structure of various non-limiting examples of nucleosides according to the invention, as well as other known nucleosides, FLAU and ribavirin, which are used as comparative examples in the text. Figure 2 is a graph of pharmacokinetics (plasma concentrations) of B-D-2'-CH3-riboG administered in six cynomolgus monkeys over time after administration. Figures 3a and 3b are graphs of pharmacokinetics (plasma concentrations) of fl'D-2'-CH3-riboG administered to cynomolgus monkeys either intravenously (3a) or orally (3b) over time after administration.

The invention as described herein is a compound, method and composition for the treatment of hepatitis C in humans or other animal hosts, which includes the administration of an effective HCV therapeutic amount of B-D or B-L nucleoside as described herein or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier. Compounds according to the invention either exhibit antiviral (ie anti-HCV) activity, or are metabolized to a compound exhibiting such activity.

In sum, the present invention includes the following features:

(a) B-D and B-L nucleosides, as described herein, and pharmaceutically acceptable salts and prodrugs thereof; (b) B-D and B-L nucleosides, as described herein, and pharmaceutically acceptable salts and prodrugs thereof for use in the treatment of prophylaxis of an HCV infection, particularly in individuals diagnosed as having an HCV infection or at risk of being infected with HCV; (c) using these B-D and B-L nucleosides, and pharmaceutically acceptable salts and prodrugs thereof for the manufacture of a medicament for treating an HCV infection; (d) pharmaceutical formulations comprising B-D or B-L nucleosides or pharmaceutically acceptable salts or prodrugs thereof together with a pharmaceutically acceptable carrier or diluent; (e) B-D and B-L nucleosides, as described herein substantially free of enantiomers of the described nucleoside, or substantially isolated from other chemical constituents; (f) methods for preparing B-D and B-L nucleosides, as described in more detail below; (g) methods for preparing B-D and B-L nucleosides substantially in the absence of enantiomers of the described nucleoside, or substantially isolated from other chemical constituents.

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

in which:

R<1>, R<2> and R<3> are independently H, phosphate (which includes mono-, di- or triphosphate and a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl or benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R , R , or R is independently H or phosphate; and Y is hydrogen, bromine, chlorine, fluorine, iodine, OR<4>, NRV 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, chlorine, bromine, fluorine, iodine, OR<4> , NR<4>NR<5>or SR<5>; and

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

In a preferred sub-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 or phosphate (preferred H);

^erH;

X 2 is either NH 2 ; and

Y is hydrogen, bromine, chlorine, fluorine, iodine, NH2 or OH.

In a second principal embodiment there is provided a compound of formula II, or a pharmaceutically acceptable salt or prodrug thereof:

in which:

R<1>, R<2> and R<3> are independently H, phosphate (which includes mono-, di- or triphosphate and a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1>, R<2> or R<3> is independently H or phosphate; and Y is hydrogen, bromine, chlorine, fluorine, iodine, OR<4>, NR^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, chlorine, bromine, fluorine, iodine, OR<4> , NR^NR<5> or SR<5>; and

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

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

X 1 is R;

X 2 is either NH 2 ; and

Y is hydrogen, bromine, chlorine, fluorine, iodine, NH2 or OH.

In a third principal 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 (which includes monophosphate, diphosphate or triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition for aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or another pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1>, R<2> or R<3> is independently H or phosphate; and

Y is hydrogen, bromine, chlorine, fluorine, iodine, 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, chlorine, bromine, fluorine, iodine, OR<4> , NR<4>NR<5>or SR<5>; and

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

In a preferred sub-embodiment there is provided a compound of formula III, or a pharmaceutically acceptable salt or prodrug thereof wherein: R 1 , R 2 and R 3 are independently H or phosphate (preferred H);

X is H;

X<2> is either NH2; and

Y is hydrogen, bromine, chlorine, fluorine, iodine, NH2 or OH.

In a fourth principal 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 (which includes mono-, di- or triphosphate and a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1>, R<2> or R<3> is independently H or phosphate; and

Y is hydrogen, bromine, chlorine, fluorine, iodine, OR4, 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, chlorine, bromine, fluorine, iodine, OR<4> , NR^R<5> or SR<5>; and

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

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

X 1 is H or CH 3 ;

Y is hydrogen, bromine, chlorine, fluorine, iodine, NH2 or OH.

In a fifth principal 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 (which includes monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1>, R<2> or R<3> is independently H or phosphate; and Y is hydrogen, bromine, chlorine, fluorine, iodine, 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, chlorine, bromine, fluorine, iodine, OR<4> , NR<4>NR<5>or SR<5>; and

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

In a preferred sub-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 (preferred H);

^erHellerCH/jjog

Y is hydrogen, bromine, chlorine, fluorine, iodine, Ntfe or OH.

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

wherein: R, R and R are independently H, phosphate (which includes monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1>, R<2> or R<3> is independently H or phosphate; and Y is hydrogen, bromine, chlorine, fluorine, iodine, 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, chlorine, bromine, fluorine, iodine, OR<4>,NR<4>NR <5>or SR<5>;and

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

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

X 1 is H or CH 3 ;

Y is hydrogen, bromine, chlorine, fluorine, iodine, NH2 or OH.

In a seventh principal embodiment there is provided a compound of formulas VI, VIII and IX, or a pharmaceutically acceptable salt or prodrug thereof:

wherein: the base is a purine or pyrimidine base as defined herein;

R<1>, R<2> and R<3> are independently H, phosphate (which includes monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1>, R<2> or R<3> is independently H or phosphate;

R<6>is hydrogen, hydroxy, alkyl (which includes 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, chlorine, bromine, fluorine, iodine, NO2, NH2,

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

XerO, S, SO 2 or CH 2 .

In a first preferred sub-embodiment there is provided a compound of formula VII, VIII or IX, or a pharmaceutically acceptable salt or prodrug thereof wherein: the base is a purine or pyrimidine base as defined herein;

19 1

R , R , and R are independently hydrogen or phosphate;

R<6> is alkyl; and

XerO, S, SO 2 or CH 2 .

In a second preferred sub-embodiment there is provided a compound of formula VII, VIII or IX, or a pharmaceutically acceptable salt or prodrug thereof wherein: the base is a purine or pyrimidine base as defined herein;

19 1

R , R , and R are hydrogens;

R 6 is alkyl; and

X is O, S, SO 2 or CH 2 .

In a third preferred sub-embodiment there is provided a compound of formula VII, VIII or IX, or a pharmaceutically acceptable salt or prodrug 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

XerO.

In an eighth principal embodiment there is provided a compound of formulas X, XI and XII, or a pharmaceutically acceptable salt or prodrug thereof:

in which:

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

R<1>, R<2> and R<3> are independently H, phosphate (which includes monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1>, R2 or R<3> is independently H or phosphate;

R<6>is hydrogen, hydroxy, alkyl (which includes lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, -C(0)0(alkyl), -C(0)0(lower alkyl), -O(acyl), -0(lower acyl),

-O(alkyl), -O(lower alkyl), -O(alkenyl), chlorine, bromine, fluorine, iodine, N02, NH2,

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

R<7> is hydrogen, OR<3>, hydroxy, alkyl (which includes 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, fluorine, iodine, N02, NH2,

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

XerO, S, SO 2 or CH 2 .

In a first preferred sub-embodiment there is provided a compound of formula X, XI or XI, or a pharmaceutically acceptable salt or prodrug thereof wherein: the base is a purine or pyrimidine base as defined herein;

19 ^

R , R , and R are independently hydrogen or phosphate;

R<6> is alkyl; and

XerO, S, SO 2 or CH 2 .

In a second preferred sub-embodiment there is provided a compound of formula X, XI or XII, or a pharmaceutically acceptable salt or prodrug thereof wherein: the base is a purine or pyrimidine base as defined herein;

19 1

R , R , and R are hydrogens;

R<6> is alkyl; and

X is O, S, SO 2 or CH 2 .

In a third preferred sub-embodiment there is provided a compound of formula X, XI or XII, or a pharmaceutically acceptable salt or prodrug thereof wherein: the base is a purine or pyrimidine base as defined herein;

19 ^

R , R , and R are independently H or phosphate;

R<6> is alkyl; and

XerO.

In a more preferred sub-embodiment, there is provided a compound of formula XI, or a pharmaceutically acceptable salt or prodrug thereof:

in which:

the base is a purine or pyrimidine base as defined herein; optionally substituted with an amine or cyclopropyl (for example 2-amino, 2,6-diamino or cyclopropylguanine); and

R<1> and R<2> are independently H, phosphate (which includes monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> or R<2> is independently H or phosphate.

In a ninth principal embodiment there is provided a compound selected from formulas XIII, XIV and XV, or a pharmaceutically acceptable salt or prodrug thereof:

in which:

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

R<1>, R<2> and R<3> are independently H, phosphate (which includes monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1>, R<2> or R<3> is independently H or phosphate;

R<6>is hydrogen, hydroxy, alkyl (which includes 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, fluorine, iodine, N02, NH2,

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

X is O, S, SO 2 or CH 2 .

In a first preferred sub-embodiment there is provided a compound of formula XIII, XIV or XV, or a pharmaceutically acceptable salt or prodrug 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

XerO, S, SO 2 or CH 2 .

In a second preferred sub-embodiment there is provided a compound of formula XIII, XIV or XV, or a pharmaceutically acceptable salt or prodrug thereof wherein: the base is a purine or pyrimidine base as defined herein;

R<*>, R<2> and R 3 are hydrogens;

R 6 is alkyl; and

XerO, S, SO2 or CH2.

In a third preferred sub-embodiment there is provided a compound of formula XIII, XIV or XV, or a pharmaceutically acceptable salt or prodrug thereof wherein: the base is a purine or pyrimidine base as defined herein;

R<1>, R<2> and R3 are independently hydrogen or phosphate;

R<6> is alkyl; and

XerO.

In a tenth principal embodiment, the present invention provides a compound of formula XVI, or a pharmaceutically acceptable salt or prodrug thereof:

in which:

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

R<1> and R<2> are independently H, phosphate (which includes monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> or R<2> is independently H or phosphate;

R<6>is hydrogen, hydroxy, alkyl (which includes 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, fluorine, iodine, N02, NH2,

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

R7 and R<9> are independently hydrogen, OR<2>, hydroxy, alkyl (which includes 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, fluorine, iodine, N02, NH2, -NH(lower alkyl), -NH(acyl) , -N(lower alkyl)2, -N(acyl)2; and

R<8> and R<10> are independently H, alkyl (which includes lower alkyl), chlorine, bromine or iodine;

alternatively, R7 and R<9>, R<7> and R<10> or R<8> and R<10> can be linked together to form a pi bond; and

XerO, S, SO 2 or CH 2 .

In a first preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing 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) R8 and R<10> are independently H, alkyl (which includes lower alkyl), chlorine, bromine or iodine; and (6) X is O, S, SO 2 or CH 2 .

In a second preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> is independently H or phosphate; (3) R<6> is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO2, amino, lower alkylamino

i-tq TB 1 fl

or di(lower alkyl)amino; (4) R and R are independently OR; (5) R and R are independently H, alkyl (which includes lower alkyl), chlorine, bromine or iodine; and (6) X is O, S, SO 2 or CH 2 .

In a third preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing 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, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (5) R8 and R<10> are H; (6) X is O, S, SO 2 or CH 2 .

In a fourth preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing 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 (which includes lower alkyl), chlorine, bromine or iodine; and (6) X is O.

In a fifth preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing 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>; (5) R<8> and R<10> are independently H, alkyl (which includes lower alkyl), chlorine, bromine or iodine; and (6) XerO, S, SO 2 or CH 2 .

In a sixth preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing 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 (which includes 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) XerO,S, SO 2 or CH 2 .

In a seventh preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing 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, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (5) R8 and R<10> are independently H, alkyl (which includes lower alkyl), chlorine, bromine or iodine; and (6) X is O.

In an eighth preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> is independently H or phosphate; (3) R<6> is alkyl (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, iodine, 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 sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> is independently H or phosphate; (3) R<6> is alkyl (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl) amino; (4) R7 and R<9> are independently OR<2>; (5) R<8> and R<10> are independently H, alkyl (which includes lower alkyl), chlorine, bromine or iodine; and (6) X is

O.

In a tenth preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> is independently H or phosphate; (3) R<6> is alkyl (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl) amino; (4) R<7>and R<9> are independently OR<2>, alkyl (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (5) R8 and R<10> are hydrogen; and (6) XerO.

In an eleventh preferred sub-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 (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, iodine, 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 hydrogen; and (6) X is O, S, SO 2 or CH 2 . In a twelfth preferred sub-embodiment there is provided a compound of formula XVI, or its pharmaceutically acceptable salt or prodrug, 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) R8 and R<10> are hydrogen; and (6) X is O, S, SO 2 or CH 2 .

In a thirteenth preferred sub-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) R8 and R<10> are independently H, alkyl (which includes lower alkyl), chlorine, bromine or iodine; and (6) X is O.

In a fourteenth preferred sub-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 pyriniidine 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 (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (5) R8 and R<10> are hydrogen; and (6) X is O.

In even more preferred sub-embodiments, 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 R9 are hydroxyl; (5) R<8> 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) R<8> 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) R7 and R<9> are hydroxyl; (5) R<8> and R<10> are 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> 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 R9 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) 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 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 1<0>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 R9 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) R<8> and R<10> are hydrogen; and (6) X is S; (1) The base is adenine; (2) R<1> is hydrogen; (3) R<6> is methyl; (4) R7 and R<9> are hydroxyl; (5) R<8> and R<10> are hydrogen; and (6) X is SO 2 ; (1) The base is adenine; (2) R<1> is hydrogen; (3) R<6> is methyl; (4) R7 and R<9> are hydroxyl; (5) R<8> and R<10> are hydrogen; and (6) X is CH 2 ;

In an eleventh principal embodiment, the present invention provides a compound of formula XVII, or a pharmaceutically acceptable salt or prodrug thereof:

wherein: the base is a purine or pyrimidine base as defined herein; R<1> is H; phosphate (which includes monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> is independently H or phosphate; R<6>is hydrogen, hydroxy, alkyl (which includes 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, fluorine, iodine, N02, NH2, -NH(lower alkyl) , -NH(acyl), -N(lower alkyl)2, -N(acyl)2; R<7>and R<9> are independently hydrogen, OR<2>, hydroxy, alkyl (which includes 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, fluorine, iodine , NO 2 , NH 2 , -NH(lower alkyl), -NH(acyl), -N(lower alkyl) 2 , -N(acyl) 2 ;

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

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

In a first preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> is independently H or phosphate; (3) R 6 is alkyl (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, iodine, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (4) R<7>and R<9> are independently hydrogen, OR<2>, alkyl (which includes 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; (6) X is O, S, SO 2 or CH 2 .

In a second preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> is independently H or phosphate; (3) R<6> is alkyl (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, iodine, 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, alkyl (which includes lower alkyl), chlorine, bromine or iodine; (6) X is O, S, SO 2 or CH 2 .

In a third preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> is independently H or phosphate; (3) R<6> is alkyl (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, iodine, NO 2 , amino, lower alkylamino or di(lower alkyl) amino; (4) R<7>and R<9> are independently hydrogen, OR<2>, alkyl (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO 2 , amino , lower alkylamino or di(lower alkyl)amino; (5) R<10> is H, alkyl (which includes lower alkyl), chlorine, bromine or iodine; (6) X is O.

In a fourth preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> is independently H or phosphate; (3) R<6> is alkyl (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, iodine, 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; (6) X is O, S, SO 2 or CH 2 .

In a fifth preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> is independently H or phosphate; (3) R<6> is alkyl (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, iodine, NO 2 , amino, lower alkylamino or di(lower alkyl) amino; (4) R7 and R<9> are independently OR<2>; (5)R<10>is H, alkyl (which includes lower alkyl), chlorine, bromine or iodine; (6) X is O.

In a sixth preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> is independently H or phosphate; (3) R<6> is alkyl (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl) amino; (4) R<7>and R<9> are independently hydrogen, OR<2>, alkyl (which includes 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; (6) X is O.

In a seventh preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> is independently H or phosphate; (3) R<6> is alkyl (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl) amino; (4) R<7> and R<9> are independently OR<2>; (5) R10 is H; (6) X is O.

In an eighth preferred sub-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 (which includes 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 (which includes lower alkyl), chlorine, bromine or iodine; and (6) X is O, S, SO 2 or CH 2 .

In a ninth preferred sub-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 (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO2, amino, lower alkylamino or di( lower alkyl)amino; (4) R<7>and R9 are independently OR<2>; (5) R<10>is H; and (6) X is O, S, SO 2 or CH 2 .

In a tenth preferred sub-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 OR 2 ; (5) R<10> is H; and (6) X is O, S, SO 2 or CH 2 .

In even more preferred sub-embodiments, 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) R7 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> is hydrogen and R<9> is 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 ; 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<10> is hydrogen; and (6) X is CH 2 .

In a twelfth principal embodiment, the present invention provides a compound of formula XVIII, or a pharmaceutically acceptable salt or prodrug thereof:

in which:

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

R<1> and R<2> are independently H, phosphate (which includes monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> or R<2> is independently H or phosphate;

R<6>is hydrogen, hydroxy, alkyl (which includes 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, fluorine, iodine, NO2, NH2,

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

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

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

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

In a first preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing 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 (which includes 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 (which includes lower alkyl), chlorine, bromine or iodine; and (6) X is O, S, SO 2 or CH 2 .

In a second preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> is independently H or phosphate; (3) R<6> is alkyl (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl) amino; (4) R<7> and R<9> are independently OR<2>; (5) R<8>is H, alkyl (which includes lower alkyl), chlorine, bromine or iodine; and (6) X is O, S, SO 2 or CH 2 .

In a third preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> is independently H or phosphate; (3) R<6> is alkyl (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl) amino; (4) R<7>and R<9> are independently hydrogen, OR<2>, alkyl (which includes 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 a fourth preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> is independently H or phosphate; (3) R<6> is alkyl (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl) amino; (4) R<7>and R<9> are independently hydrogen, OR<2>, alkyl (which includes 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 (which includes lower alkyl), chlorine, bromine or iodine; and (6) X is O.

In a fifth preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> is independently H or phosphate; (3) R<6> is alkyl (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, iodine, 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; and (6) X is O, S, SO 2 or CH 2 .

In a sixth preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> is independently H or phosphate; (3) R<6> is alkyl (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl) amino; (4) R<7> and R<9> are independently hydrogen, OR<2>;

(5) R<8>is H, alkyl (which includes lower alkyl), chlorine, bromine or iodine; and (6) X is O.

In a seventh preferred sub-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 (which includes monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> is independently H or phosphate; (3) R 6 is alkyl (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, iodine, NO 2 , amino, lower alkylamino or di(lower alkyl)amino; (4) R<7>and R<9> are independently hydrogen, OR<2>, alkyl (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino , lower alkylamino or di(lower alkyl)amino; (5) R is H; (6) X is O.

In an eighth preferred sub-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 (which includes lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, iodine, NO 2 , amino, lower alkylamino or diØaverealkyl)amino;

(4) R7 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 sub-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 or CH 2 .

In a tenth preferred sub-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 even more preferred sub-embodiments, 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<8> is hydrogen; and (6) X is O; (1) The base is guanine; (2) R<1> is hydrogen; (3) R<6> is methyl; (4) R7 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) R7 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> is hydrogen and R<9> is 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 B-D and B-L nucleosides according to the invention can inhibit HVC polymerase activity. The nucleosides can be screened for their ability to inhibit HCV polymerase activity in vitro according to screening procedures set forth more specifically herein. One can easily determine the spectrum of activity by evaluating the compound in the assay described herein or with other confirmatory assays.

In one embodiment, the effectiveness of the anti-HVC compound is measured according to the concentration of the compound necessary to reduce the plaque count of the virus in vitro, according to methods set forth more particularly herein, by 50% (ie, the EC50 of the compound). In preferred embodiments, the compound exhibits an EC50 of less than 15 or 10 micromolar, when measured according to the polymerase assay described in Ferrari et al, Jnl of Vir., 73:1649-1654,1999; Ishii et al, Hepatology, 29:1227-1235, 1999; Lohamann et al, Jnl. ofBio. Chem., 274:10807-10815, 1999; Yamashita et al., Jnl. ofBio. Chem., 273:15479-15486, 1998.

The active compound may be administered as any salt or prodrug which, upon administration to the recipient, is capable of providing directly or indirectly the parent compound, or which exhibits activity per se. Non-limiting examples are pharmaceutically acceptable salts (alternatively referred to as "physiologically acceptable salts"), and a compound that has been alkylated or acylated at the 5' position or at the pyrine or pyrimidine base (a type of "pharmaceutically acceptable prodrug"). Furthermore, modifications can affect the biological activity of the compound, in some cases increasing the activity compared to the parent compound. This can be easily determined by preparing the salt or prodrug and testing its antiviral activity according to the methods described herein, or other methods known to those skilled in the art.

The term alkyl, as used herein, unless otherwise indicated, refers to a saturated, straight-chain, branched, or cyclic primary, secondary, or tertiary hydrocarbon typically C 10 C 10 , and specifically includes methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, f-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. The moiety with which the alkyl group may be substituted is selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate, either unprotected, or protected if necessary, which are known to those skilled in the art, for example as described in Green, et al, Protective Groups in Oreanic Synthesis. John Wiley and Sons, 2nd Edition, 1991, hereby incorporated by reference.

The term lower alkyl, as used herein, unless otherwise indicated, refers to Cityl C4 straight chain branched, or if appropriate, a cyclic (eg, cyclopropyl) alkyl group, which includes both substituted and unsubstituted forms. Unless otherwise specified in the application, when alkyl is a suitable moiety, lower alkyl is preferred. Likewise, when alkyl is lower alkyl is a suitable moiety, unsubstituted alkyl or lower alkyl is preferred.

The term alkylamino or arylamino refers to an amino group having one or two alkyl or aryl substituents, respectively.

The term "protected" as used herein and unless otherwise specifically defined refers to a group that is added to an oxygen, nitrogen or phosphorus atom to prevent its further reaction or for other purposes. A wide range of oxygen and nitrogen protecting groups are 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 and preferably phenyl. The term includes both substituted and unsubstituted moieties. 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, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate, either unprotected or unprotected if necessary, as known by the skilled person for example as described in Green, et al, Protective Groups in Organic Synthesis, John Wiley and Sons, 2nd 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, refers to chlorine, bromine, iodine or fluorine.

The term purine or pyrimidine base includes, but is not limited to, adenine, N<6->alkylpurines, N<6->acylpurines (where acyl is C(0)(alkyl, aryl, alkylaryl or arylalkyl), N<6- >benzylpurine, N^halopurine, N<6->vinylpurine, N<6->acetylenic purine, N^acylpurine, N<6->hydroxyalkylpurine, N^thioalkylpurine, N<6->alkylpurines, N^alkyl-6- itopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4-mercaptopyrimidines, 5-halouracil, including 5-fluorouracil, C<5->alkylpyrimidines, C< 5->benzylpyrimidines, C<5->halopyrimidines, C<5->vinylpyrimidine, C<5->acetylenic pyrimidine, C<5->acylpyrimidine, C<5->hydroxylalkylpurine, C<5->amidopyrimidine, C< 5->cyanopyrimidine, C<5->nitropyrimidine, C5-aminopyrimidine, N<2->alkylpurines, N<2->alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl and pyrazolopyrimidinyl. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-mamin purine and 6-chloropurine. Functional oxygen and nitrogen groups on the base can be protected if necessary or desired. Desired protecting groups are well known to those skilled in the art, include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl and p-toluenesulfonyl.

The term acyl refers to carboxylic acid esters in which the non-carbonyl portion of the ester group is selected from straight, branched or cyclic alkyl or lower alkyl, alkoxyalkyl including methoxyalkyl, aralkyl including benzyl, aryloxyalkyl, such as phenoxymethyl, aryl including phenyl optionally substituted with chlorine, bromine . ) or diphenylmethylsilyl. Aryl groups in the esters optionally include a phenyl group. The term "lower acyl" refers to an acyl group in which the non-carbonyl moiety is a lower alkyl.

As used herein, the term "substantially without" or "substantially in the absence of" a nuldeoside composition that includes at least 85 or 90% by weight, preferably 95 to 98% by weight, even more preferably 99 to 100% by weight , of the indicated enantiomer of the nucleoside. In a preferred embodiment of the method and composition according to the invention, the compound is essentially without enantiomers.

Similarly, the term "isolated" refers to a nucleoside composition that includes at least 85 to 90% by weight, preferably 95 to 98% by weight, even more preferably 99 to 100% by weight of the nucleoside, with the remainder comprising other chemical constituents or enantiomers.

The term "independent" as used herein indicates that the variable that is independent varies independently from application to application. Thus, in a connection 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 a unicellular or multicellular organism in which the virus can replicate, which includes cell lines and animals, and preferably a human. Alternatively, the host carrying part of the hepatitis C viral genome, the replication or function of which can be altered by the compounds of the invention. The term host refers specifically to infected cells, cells transfected with all or part of the HCV genome and animals, particularly primates (which include chimpanzees) and humans. In most animal applications of the invention, the host is a human patient. However, veterinary applications for certain indications are clearly encompassed by the present invention (such as chimpanzees).

The term "pharmaceutically acceptable salt or prodrug" as used 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, provides the nucleoside compound. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic acids or bases. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among a number of other acids well known in the literature. Pharmaceutically acceptable prodrug refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the invention. Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional part of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to yield the active compound. The compound according to the invention displays antiviral activity against HCV, or is metabolized to a compound that displays such activity.

In the case where compounds are sufficiently basic or acidic to form stable non-toxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acid, which form a physiologically acceptable anion, for example tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, oc-ketoglutarate and α-glycerophosphate. Suitable inorganic salts may also be formed, which include sulphate, nitrate, bicarbonate and carbonate salts.

Pharmaceutically acceptable salts can be obtained using standard methods well known in the literature, for example by reacting a sufficiently basic compound such as an amine with an appropriate acid which gives a physiologically acceptable anion. Alkali metal (eg sodium, potassium or lithium) or alkaline earth metal (eg calcium) salts of carboxylic acids can also be prepared.

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

The active nucleoside may also be provided as a 5'-phosphoether lipid or a 5'-ether lipid, as described in the following references, which include references herein: Kucera, L.S., N. Lyver, E. Leake, A. Raben, Modest E.K., D.L.W. , 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 Vimses. 6:491-501; Piantadosi, C, J. Marasco C.J., S.L. Morris-Natschke, K.L. Meyer, F. Gumus, J.R. Surles, K.S. Ishaq, L.S. Kucera, N. lies, CA. Wallen, S. Piantadosi, and E.J. Modest. 1991. "Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HTV activity". J. Med. Chem. 34:1408-1414; Hosteller, K.Y., D.D. Richman, D.A. Carson, L.M. 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., L.M. 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. Biol. Chem. 265-61127.

Non-limiting examples of US patents that describe suitable lipophilic substituents that can be covalently incorporated into the nucleoside, preferably at the 5'-OH position of the nucleoside or lipophilic preparations, include US Patent No. 5,149,794 (Sep. 22,1992, Yatvin et al.); 5,194,654 (Mar. 16, 1993, Hosterier et al.), 5,223,263 (June 29, 1993, Hosterier et al.); 5,256,641 (Oct. 26, 1993, Yatvin et al.); 5,411. 947 (May 2, 1995, Hosterier et al.); 5,463,092 (Oct. 31, 1995, Hosterier et al.); 5,543,389 (Aug. 6, 1996, Yatvin et al.); 5,543. 390 (Aug. 6, 1996, Yatvin et al.); 5,543,391 (Aug. 6, 1996, Yatvin et al.); and 5,554,728 (Sep. 10, 1996; Basava et al.), for all of which are incorporated by reference.Foreign patent applications describing lipophilic substituents that can be attached to the nucleosides of the invention, or lipophilic preparations, include WO 89/02733, WO 90/00555, WO 91/16920, WO 91/18914, WO 93/ 00910, WO 94/26273, WO 96/15132, EP 0 350 287, EP 93917054.4 and WO 91/19721.

It has been shown that drug-resistant variants of HCV can emerge after prolonged treatment with an antiviral agent. Drug resistance most typically occurs by mutation of a gene that codes for an enzyme used in viral replication. The efficacy of a drug against HCV infection can be prolonged, augmented or restored by administering the compound in combination or alternation with a second, and possibly third, antiviral compound that induces a different mutation from that caused by the multiple drug. Alternatively, the pharmacokinetics, biodistribution or other parameters of the compound can be changed by such a combination or alternating treatment. In general, combination therapy is typically preferred over alternating treatment due to the fact that it induces multiple simultaneous stresses on the virus.

Non-limiting examples of antiviral agents that can be used in combination with compounds described herein include: (1) An 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 (Attwood et al, Antiviral peptide derivatives, PCT WO 98/22496, 1998; Attwood et al, Antiviral Chemistry and Chemotherapy 10.259-273, 1999; Attwood et al., Preparation and use of amino acid derivatives as anti-viral agents, German patent publication DE 19914474; Tung et al Inhibitors of senne proteases, particularly hepatitis C virus NS3 protease, PCT WO 98/17679), which include alphaketoamides and hydrazinoureas, and inhibitors terminating in an electrophile such as a boric acid or phosphonate. Llinas-Brunet et al, Hepatitis C inhibitor peptide analogues, PCT WO 99/07734. (3) Non-substrate-based inhibitors such as 2,4,6-tirhydroxy-3-nitro-benzamide derivatives (Sudo K. et al., Biochemical and Biophysical Research Communications, 238:643-647, 1997; Sudo K. et al. al. Antiviral Chemistry and Chemotherapy 9:186,1998), which include RD3-4082 and RD3-4078, wherein the former is substituted on the amide with a 14 carbon chain and the latter exhibits a β - phenoxyphenyl group; (4) Thiazolidine derivatives showing relevant inhibition in a reverse phase HPLC assay with an NS3/4A fusion protein and NS5A/5B substrate (Sudo K. et al. Antiviral Research 32:9-18, 1996), particularly compound RD-1-6250 , which exhibit a fused cinnamoyl moiety substituted with a long alkyl chain, RD4 6205 and RD4 6193; (5) Thiazolidines and benzanilides identified in Kakiuchi N. et al., J. EBS Letters 421:217-220; Takeshita N. et al. Analytical Biochemistry 247:242-246, 1997; (6) A phenan-trenquinone exhibiting activity against HCV protease in an SDS-PAGE and autoradiographic examination isolated from the culture broth of Streptomyces sp., Sch 68631 (Chu M. et al, Tetrahedron Lettersllr:7229-7232, 1996), and Sch 351633, isolated from the fungus Penicillium griscofuluum, which demonstrates activity in a scintillation proximity assay (Chu M. et al, Bioorganic and Medicinal Chemistry Letters 9:1949-1952); (7) Selective NS3 inhibitors based on macromolecule elgin c, isolated from leech (QasimM.A. et al, Biochemistry 36:1598-1607, 1997); (8) HCV helicase inhibitors (Diana G.D. et al, Compounds, compositions and methods for treatment of hepatitis C, US 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 WO 97/36554); (9) HCV polymerase inhibitors such as nucleotide analogues, gliotoxin (Ferrari R. et al, Journal of Virology 73:1649-1654, 1999) and the natural product cerulenin (LohmannV. et al, Virology 249:108-118,1998); (10) Antisense phosphorothioatoligodeoxynucleodes (S-ODN) complementary to the sequence features of the 5' non-coding region (NCR) of HCV (Alt M, et al, Hepatology 22:707-717, 1995), or nucleotides 326-348 including the 3' the end of the NCR and nucleotide 371-388 located in the core 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 (Dceda N. et 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 10101591); (12) Nuclease-resistant ribozymes (Maccjak D.J. et al, Hepatology 30 abstract 995,1999); and (13) Other optional compounds which include 1-amino-alkylcyclohexanes (US Patent No. 6,034,134 to Gold et al.,) alkyl lipids (US Patent No. 5,922,757 to Chojkier et al.), vitamin E and others antioxidants (US Patent No. 5,922,757 to Chojkier et al), squalene, amantadine, bile acid (US Patent No. 5,846,964 to Ozeki et al), N-(phosphonoacetyl)-L-aspartic acid, (US Pat. No. 5,830,905 to Diana et al.), benzene carboxamides (US Patent No. 5,633,388 to Diana et al.), polyadenylic acid derivatives (US Patent No. 5,496,546 to Wang et al.), 2',3'-dideoxyinosine (US Patent No. 5,026,687 to Yarchoan et al.) and

benzimidazoles (US Patent No. 5,891,874 to Colacino et al).

Hosts, including humans, infected with HCV, or a gene fragment thereof, 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 suitable route, for example oral, parenteral, intravenous, intradermal, subcutaneous or topical, in liquid or solid form.

A preferred dose of the compound for HCV will be in the range of approx. 1 to 50 mg/kg, preferably 1 to 20 mg/kg, of body weight per day, with generally 0.1 to approx. 100 mg per kg body weight of the recipient per day. The effective dosage range of the pharmaceutically acceptable salts and prodrugs can be calculated based on the weight of the parent nucleoside to be delivered. If the salt or prodrug exhibits activity in itself, the effective dose can be estimated as above by using the weight of the salt or prodrug, or by other methods known to the person skilled in the art.

The compound is usually administered in any suitable unit dosage form, including, but not limited to, one 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 usually appropriate.

Ideally, the active ingredient should be administered to achieve the peak plasma concentration of the active compound of from about 0.2 to 70 µm, preferably approx. 1.0 to 10 fim. This can be achieved, for example, by intravenous injection of a 0.1 to 5% solution of active ingredient, possibly in salt form, or administered as a bolus of the active ingredient.

The concentration of active compound in the drug composition 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 will also apply that the dosage values will also vary with the severity of the condition to be alleviated. It is further to be understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need based on the functional assessment of the person being administered or monitoring the administration of the compounds, and that the concentration ranges set forth herein are exemplary only and are not intended as limitations on the scope or practice of the compositions according to the invention. The active ingredient can be administered as a whole or can be divided into a number of smaller doses that can be administered at different time intervals.

A preferred mode of administration of active compound is oral. Oral compositions will generally include an inert diluent or edible carrier. They can be in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binders and/or adjuvant materials may be included as part of the composition.

The tablets, pills, capsules, troches and the like may contain any of the following ingredients, or compounds of similar type: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrant such as alginic acid, primogel or corn starch; a lubricant such as magnesium stearate or sterotes; a lubricant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate, or orange flavor. When the unit dosage form is a capsule, it may contain, in addition to the material of the above type, a liquid carrier such as a fatty oil. In addition, the dosage unit forms may contain various other materials that modify the physical form of the dosage unit, such as coatings of sugar, shellac, or other enteric agents.

The compound can be administered by a compound of an elixir, suspension, syrup, wafer, chewing gum or the like. In addition to the active compound, a syrup may contain sucrose as a sweetener and certain preservatives, coloring agents and flavourings.

The compound or a pharmaceutically acceptable prodrug or salt thereof may be mixed with other active materials that do not destroy the desired effect, or with materials that supplement the desired effect, such as antibiotics, antifungals, anti-inflammatory agents, or other antiviral agents, which include other nucleoside compounds. Solutions or suspensions used for parenteral, intradermal, subcutaneous or topical application may include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; gelatinizing agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for adjusting tonicity such as sodium chloride or dextrose. The parenteral preparation may be in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

If administered intravenously, preferred carriers are physiological 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 controlled release formulations, which include implants and microencapsulated delivery systems. Biodegradable biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid. Procedures for producing such formulations will be clear to the person skilled in the art. The materials can also be obtained commercially from Alza Corporation.

Liposomal suspensions (which include liposomes targeted to infected cells with monoclonal antibodies to viral antigens) are also preferred as pharmaceutically acceptable carriers. These can be produced according to methods known to those skilled in the art, for example as described in US patent no. 4,522,811 (incorporated herein by reference in its entirety).

For example, liposome formulations can be prepared by dissolving appropriate liquids (such as stearoylphosphatidylethanolamine, stearoylphosphatidycholine, arachodoylphosphatidylcholine and cholesterol) in an inorganic solvent which is then evaporated, leaving a thin film of the desired lipid on the surface of the container. An aqueous solution of active compound or its monophosphate, diphosphate and/or triphosphate derivatives is then introduced into the container. The container is then shaken by hand to release the lipid material from the sides of the container and disperse the lipid aggregates, thereby forming the liposomal suspension.

The nucleosides according to the invention can be synthesized by any method known in the literature. In particular, the synthesis of the present nucleosides can be achieved either by alkylation of the appropriately modified sugar followed by glycosylation or glycosylation followed by alkylation of the nucleoside. The following non-limiting embodiments illustrate the same general methodology for obtaining the nucleosides of the invention.

A. General synthesis of T-C-united nucleosides

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

wherein BASE is a purine or pyrimidine base as defined herein;<7>and R<9> is independently hydrogen, OR<2>, hydroxy, alkyl (which includes 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;

R8 and R1<0> are independently H, alkyl (which includes lower alkyl), chlorine, bromine or iodine;

alternatively, R<7> and R<9>, R<7> and R<10> or R<8> and R<10> can together form a pi bond;

R<1> and R<2> are independently H, phosphate (which includes monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R or R is independently H or phosphate;

R<6>is an alkyl, chloro-, bromo-, fluoro- or iodo-alkyl (ie CF3), alkenyl or alkynyl (ie

allyl); and

XerO,S, SO 2 or CH 2

can be produced by one of the following general methods.

1) Modification from lactone

The key starting material for this process is an appropriately substituted lactone. The lactone can be purchased or can be prepared by a known method which includes standard epimerization, substitution and cyldization techniques. The lactone can be optimally protected with a suitable protecting group, preferably with an acyl or silyl group, by methods known in the literature, as described by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, 2nd 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, an organolithium, lithium dialkyl copper or R<6->SiMe3i TBAF with appropriate non-protic solvent at appropriate temperature to give r-alkylated sugar.

The optionally activated sugar can then be coupled to BASE by methods well known to those skilled in the art, as described by Townsend Chemistr<y>of Nucleosides and Nucleotides. Plenum Press, 1994. For example, an acylated sugar can be coupled to a silylated base with a Lewis acid, such as tetrachloride, titanium tetrachloride or trimethylsilyl triflate in a suitable solvent at a suitable temperature.

The nucleoside can then be deprotected by methods known to those skilled in the art, as described by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, 2nd edition, 1991.

In a particular embodiment, 1'-C branched ribonucleoside is desirable. The synthesis of ribonucleoside is shown in Scheme 1. Alternatively, deoxyribonucleoside is desirable. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods known to those skilled in the art, as described by Greene et al. Protective Groups in Organic Synthesis. John Wiley and Sons, 2nd 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 the Barton reduction.

2. Alternative method for the production of 1'-C-branched nucleosides

The key starting material for this process is an appropriately substituted hexose. The hexose can be purchased or prepared by any known method including standard epimerization, such as alkaline treatment, substitution and coupling techniques. The hexose can be selectively protected to give a suitable hexa-furanose, as described by Townsend Chemistry 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 chlorine, bromine, fluorine, iodine via acylation or halogenation, respectively. Optionally, the activated sugar can then be coupled to the BASE by methods well known to those skilled in the art, as described by Townsend Chemistr<y>of Nucleosides and Nucleotides. Plenum Press, 1994. For example, acylated sugar can be coupled to a silylated base with a Lewis acid, such as stannous tetrachloride, titanium tetrachloride or trimethylsilyl triflate in suitable solvents at a suitable temperature. Alternatively, a halo sugar can be coupled to a silylated base in the presence of triethylsilyl triflate.

1'-CH2-OH, if protected, can be selectively deprotected by methods known in the literature. The resulting primary hydroxyl can be functionalized to give

different C-branched nucleosides. For example, the primary hydroxyl is reduced to give methyl, using a suitable reducing agent. Alternatively, the hydroxyl may be activated prior to reduction to facilitate the reaction; i.e. via 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, an organolithium compound, lithium dialkyl copper, or R<6->SiMe3i TBAF with a suitable non-protic solvent at a suitable temperature.

In a particular embodiment, 1'-C-branched ribonucleoside is preferred. The synthesis of a ribonucleoside is shown in Scheme 2. Alternatively, deoxyribonucleoside is preferred. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods known to those skilled in the art, as described by Greene et al. Protective Groups in Organic Synthesis. John Wiley and Sons, 2nd edition, 1991, and then the 2'-OH can be reduced via a suitable reducing agent. Optionally, the 2'-hydroxyl can be activated to facilitate the reduction: ie via Barton reduction.

In addition, the L-enantiomers corresponding to the compound according to the invention can be prepared by following the same general methods (1 or 2), starting with the corresponding L-sugar or nucleoside L-enantiomer as starting material.

R General synthesis of 2'-C-branched nucleosides

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

wherein BASE is a purine or pyrimidine base as defined herein; 7 and R<9> are independently hydrogen, OR<2>, hydroxy, alkyl (which includes 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 (which includes lower alkyl), chlorine, bromine or iodine;

alternatively, R<7> and R<9> or R7 and R<10> can together form a pi bond;

R<1> and R<2> are independently H, phosphate (which includes monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> or R<2> is independently H or phosphate;

R<6> is an alkyl, chloro-, bromo-, fluoro- or iodo-alkyl (ie CF 3 ), alkenyl or alkynyl (ie allyl); and

XerO,S, SO2 or CH2

can be produced by one of the following general methods.

1) Glycosylation of the nucleobase with a suitable modified sugar

The key starting material for this process is an appropriately substituted sugar with 2'-OH and 2'-H with the appropriate group (LG), e.g. an acyl group or a chlorine, bromine, fluorine or iodine. The sugar can be purchased or can be prepared by any method including standard epimerization, substitution, oxidation and reduction techniques. The substituted sugar can then be oxidized with the appropriate oxidizing agent in a compatible 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), Collin's reagent (dipyridine Cr(VI)oxide, Corey's reagent (dipyridine (Cr(VI)oxide, Corey's reagent (pyridine chlorochromate), pyridine dichromate, acid dichromate, potassium permanganate, Mn02, ruthenium tetroxide , phase transfer catalysts such as chromic acid or permanganate supported on a polymer, Ck-pyridine, H202-ammonium molybdate, NaBrOr2-CAN, NaOCl I HO Ac, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminium f-butoxide with another ketone) and iV-bromosuccinimide.

Then in coupling of an organometallic carbon nucleophile, such as a Grignard reagent, an organolithium compound, lithium dialkyl copper, or R<6->SiMe in TBAF with the ketone with a suitable non-protic solvent at a suitable temperature, the 2'-alkylated sugar. The alkylated sugar can optionally be protected with a suitable protecting group, preferably with an acyl or silyl group, by methods known in the literature, as described by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, 2nd Edition, 1991.

The protected sugar can then be coupled to BASE by methods well known to those skilled in the art, as described by Townsend Chemistry of Nucleosides and Nucleotides. Plenum Press, 1994. For example, the acylated sugar can be coupled to a silylated base with a Lewis acid, such as tetrachloride, titanium tetrachloride or trimethylsilyl triflate in a suitable solvent at a suitable temperature. Alternatively, a halo sugar can be coupled to a silylated base in the presence of trimethylsilyl triflate.

The nucleoside can then be deprotected by methods known in the literature, as described by Greene et al. Protective Groups in Organic Synthesis. John Wiley and Sons, 2nd edition, 1991.

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

1) Modification of a preformed nucleoside

The key starting material for this method is an appropriately substituted nucleoside with a 2'-OH and 2'-H. The nucleoside may be purchased or may be prepared by known methods including standard coupling techniques. The nucleoside can optionally be protected with a suitable protecting group, preferably with an acyl or silyl group, by methods known in the literature, as described by Greene et al. Protective Groups in Organic Synthesis. John Wiley and Sons, 2nd edition, 1991.

Appropriately protected nucleoside can then be oxidized with the appropriate oxidizing agent in a compatible solvent at a suitable temperature to give the 2'-modified sugar. Possible oxidizing agents are Jones's reagent (a mixture of chromic acid and sulfuric acid), Collin's reagent (dipyridine Cr(VI) oxide, Corey's reagent (pyridine chlorochromate), pyridine dichromate, acid dichromate, potassium permanganate, Mn02, ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, CI2-pyridine, H202-ammonium molybdate, NaBrOr2-CAN, NaOCl I HO Ac, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum/-butoxide with another ketone) and iV^bromosuccinimide .

The nucleoside can then be deprotected by methods known in the literature, as described by Greene et al. Protective Groups in Organic Synthesis. John Wiley and Sons, 2nd edition, 1991.

In a particular embodiment, 2'-C branched ribonucleoside is desirable. The synthesis of ribonucleoside is shown in Scheme 4. Alternatively, the deoxyribonucleoside is desirable. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods known in the literature, as described by Greene et al. Protective Groups in Organic Synthesis. John Wiley and Sons, 2nd 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 the Barton reduction.

In another embodiment of the present invention, L-enantiomers are desirable. Therefore, the L-enantiomers corresponding to the compound according to the invention can be prepared by following the same general procedure as above, starting with the corresponding L-sugar or nucleoside L-enantiomer as starting material.

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

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

wherein BASE is a purine or pyrimidine base as defined herein; 7 and R<9> are independently hydrogen, OR<2>, hydroxy, alkyl (which includes 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, N02, NH2, -NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, -N(acyl)2;

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

alternatively, R<7> and R<9> or R<8> and R<9> may together form a pi bond;

R<1> and R<2> are independently H, phosphate (which includes monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (which includes lower acyl); alkyl (which includes lower alkyl); sulfonate esters including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, which includes phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R<1> or R<2> is independently H or phosphate;

R<6>is an alkyl, chloro-, bromo-, fluoro- or iodo-alkyl (ie CF 3 ), alkenyl or alkynyl (ie

allyl); and

XerO.S, SO 2 or CH 2

can be produced by one of the following general methods.

1) Glycosylation of the nucleobase with a suitable modified sugar

The key starting material for this process is a suitably substituted sugar with a 3'-OH and 3'-H, with the appropriate group (LG), e.g. an acyl group or a chlorine, bromine, fluorine, iodine. The sugar can be purchased or can be prepared by methods known per se which include standard epimerization, substitution, oxidation and reduction techniques. The substituted sugar can then be oxidized with the appropriate oxidizing agent in a compatible 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), Collin's reagent (dipyridine Cr(VI) oxide, Corey's reagent (pyridine chlorochromate), pyridine dichromate, acid dichromate, potassium permanganate, Mn02, ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer . the coupling of an organometallic carbon nucleophile, such as a Grignard reagent, an organolithium compound, lithium dialkyl copper, or R<6->SiMe in TBAF with the ketone with the appropriate non-protic solvent at a suitable temperature, provides the 3'-C-branched sugar. The 3' -branched sugar can optionally be protected with a suitable protecting group, preferably with an acyl or silyl group, by methods known to those skilled in the art, as described by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, 2nd Edition, 1991.

The optionally protected sugar can then be coupled to BASE by methods well known to those skilled in the art, as described by Townsend Chemistry of Nucleosides and Nucleotides. Plenum Press, 1994. For example, an acylated sugar can be coupled to a silylated base with a Lewis acid, such as tetrachloride, titanium tetrachloride or trimethylsilyl triflate in a suitable organic solvent at a suitable temperature. Alternatively, a halo sugar can be coupled to a silylated base in the presence of trimethylsilyl triflate.

The nucleoside can then be deprotected by known methods well known in the literature, as described by Greene et al. Protective Groups in Organic Synthesis. John Wiley and Sons, 2nd edition, 1991.

In a particular embodiment, 3'-C branched ribonucleoside is desirable. The synthesis of a ribonucleoside is shown in Scheme 5. Alternatively, deoxyribonucleoside is preferred. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods known in the literature, as described by Greene et al. Protective Groups in Organic Synthesis. John Wiley and Sons, 2nd edition, 1991 and then the 2'-OH can be reduced with a suitable reducing agent. Alternatively, the 2'-hydroxyl can be activated to facilitate the reduction; i.e. via the Barton reduction.

2) Modification of a preformed nucleoside

The key starting material for this method is an appropriately substituted nucleoside with a 3'-OH and 3'-H. The nucleoside can be purchased or can be prepared using methods known per se which include standard coupling techniques. The nucleoside can optionally be protected with suitable protecting groups, for example with acyl or silyl groups, by methods known in the literature, as described by Greene et al. Protective Groups in Organic Synthesis. John Wiley and Sons, 2nd edition, 1991.

Appropriately protected nucleoside can then be oxidized using the appropriate oxidizing agent in a compatible 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), Collin's reagent (dipyridine Cr(VI) oxide, Corey's reagent (pyridine chlorochromate), pyridine dichromate, acid dichromate, potassium permanganate, Mn02, ruthenium tetroxide, phase transition catalysts such as chromic acid or permanganate supported on a polymer , Cl2-pyridine, H202-ammonium molybdate, NaBrOr2-CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum f-butoxide with another ketone) and iV-bromosuccinimide.

The nucleoside can then be deprotected by methods known in the literature, as described by Greene et al. Protective Groups in Organic Synthesis. John Wiley and Sons, 2nd edition, 1991.

In a particular embodiment, 3'-C branched ribonucleoside is desirable. The synthesis of the ribonucleoside is shown in Scheme 6. Alternatively, deoxyribonucleoside is preferred. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods known to those skilled in the art, as described by Greene et al. Protective Grou<p>s in Organic Synthesis, John Wiley and Sons, 2nd 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 the Barton reduction.

In another preferred embodiment according to the invention, the L-enantiomers are desirable. Therefore, the L-enantiomers corresponding to the compound according to the invention can be prepared by following the same method as that described above, starting from the corresponding sugar or nucleoside L-enantiomer as starting material.

Examples

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

As another alternative method of preparation, the title compound can also be prepared according to a published method (J. Farkas, and F. Sorm, "Nucleic acid components and their analogues. XCIV. Synthesis of 6-amino-9-(l-deoxy-B-D- psychofuranosyl)purine", Collect. Czech. Chem. Commtm. 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.

in which:

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

in which:

Claims (13)

1. Compound characterized by the formula: or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof. 2. Pharmaceutical composition, comprising a compound of according to claim 1, or a phosphate thereof, or a pharmaceutically acceptable salt or an ester thereof, and a pharmaceutically acceptable excipient. 3. Pharmaceutical composition according to claim 2, wherein the compound is in the form of a dosage unit. 4. Pharmaceutical composition according to claim 3, where the dosage unit contains 10 to 1500 mg of said compound. 5. Pharmaceutical composition according to claim 3, where the dosage unit is a tablet or a capsule. 6. Pharmaceutical composition according to claim 2, wherein the excipient is suitable for oral delivery. 7. Pharmaceutical composition according to claim 2, where the excipient is suitable for intravenous, parenteral, intradermal, subcutaneous or topical delivery, 8. Pharmaceutical composition according to claim 2, wherein the composition comprises one or more additional antiviral agents. 9. Pharmaceutical composition according to claim 8, wherein the additional antiviral agent is ribavirin. 10. Pharmaceutical composition according to claim 8, wherein the additional antiviral agent is an interferon. 11. Pharmaceutical composition according to claim 8, wherein the additional antiviral agents are interferon and ribavirin. 12. Pharmaceutical composition according to claim 8, wherein the additional antiviral agent is an HCV polymerase inhibitor. 13. Pharmaceutical composition according to claim 8, wherein the additional antiviral agent is an HCV helicase inhibitor.