3'-or 2'-hydroxymethyl substituted nucleoside derivatives for treatment of hepatitis virus infections Number:7,094,770 from the United States Patent and Trademark Office (PTO) owispatent

Title: 3'-or 2'-hydroxymethyl substituted nucleoside derivatives for treatment of hepatitis virus infections

Abstract: The present invention relates to a composition for and a method of treating hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, hepatitis D virus (HDV) infection or a proliferative disorder in a patient using an effective amount of a compound selected from the group consisting of formulas [I] [IV] below and mixtures of two or more thereof: ##STR00001## wherein the substituents are as defined herein. Pharmaceutical compositions comprising these compounds in combination with other HBV, HCV, or HDV agents is also disclosed.

Patent Number: 7,094,770 Issued on 08/22/2006 to Watanabe,   et al.

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Inventors:	Watanabe; Kyoichi A. (Stone Mountain, GA), Pai; S. Balakrishna (Chamblee, GA)
Assignee:	Pharmasset, Ltd. (St. Michael, BB)
Appl. No.:	09/834,596
Filed:	April 13, 2001

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Current U.S. Class:	514/49 ; 514/50; 514/51; 514/52
Current International Class:	A01N 43/04 (20060101); A61K 31/70 (20060101)
Field of Search:	514/45,46,47,48,49,50,51 536/28.1,28.2,28.4

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References Cited [Referenced By]

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	WO 01/10882		Feb., 2001		WO
	WO 01/16671		Mar., 2001		WO
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	WO 01/60315		Aug., 2001		WO
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	WO 03/072757		Sep., 2003		WO
	WO 03/093290		Nov., 2003		WO

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Primary Examiner: Wilson; James O.
Assistant Examiner: McIntosh, III; Traviss C.
Attorney, Agent or Firm: Merchant & Gould

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Parent Case Text

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CROSS-REFERENCE TO RELATED APPLICATIONS AND CLAIM FOR BENEFIT

This application claims priority to U.S. provisional patent application Ser. No. 60/197,068, filed on Apr. 13, 2000, and U.S. provisional patent application Ser. No. 60/202,663, filed on May 8, 2000.

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Claims

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The invention claimed is:

1. A method for the treatment of hepatitis C virus (HCV) infection comprising administering to a host in need thereof an anti-HCV effective amount of a compound selected from the group consisting of formulas [I] [IV] below and mixtures of two or more thereof: ##STR00077## wherein: R is selected from the group consisting of: ##STR00078## or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier.

2. The method of claim 1, further comprising administering the compound in combination or alternation with one or more additional anti-HCV agents.

3. The method of claim 2, wherein the additional HCV agent is selected from the group consisting of interferon, macrokine, heptazyme, ribavarin, amantadine, ofloxacin, zadaxin and reticulose.

4. A method for the treatment of hepatitis D virus (HDV) infection comprising administering to a host in need thereof an anti-HDV effective amount of a compound selected from the group consisting of formulas [I] [IV] below and mixtures of two or more thereof: ##STR00079## wherein: R is selected from the group consisting of: ##STR00080## or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier.

5. The method of claim 4, further comprising administering the compound in combination or alternation with one or more additional anti-HDV agents.

6. The method of claim 5, wherein the additional HDV agent is selected from the group consisting of FTC, L-FMAU, interferon, beta-D-dioxolanyl-guanine (DXG), beta-D-dioxolanyl-2,6-diaminopurine (DAPD), beta-D-dioxolanyl-6-chloropurine (ACP), beta-D-dioxolanyl-2-aminopurine (ADP), famciclovir, penciclovir, bis-POM PMEA (adefovir dipivoxil); lobucavir, ganciclovir, ribavarin, lamivudine (3TC), L-thymidine (L-dT), L-2'-deoxycytidine (L-dT), L-2'-deoxycytidine-3', 5'-diO-valyl (D or L), entecavir (BMS-200475), adefovir, L-D4FC, D-D4FC, and mycophenolic acid (an IMPDH inhibitor).

7. A pharmaceutical composition for the treatment of HCV comprising an anti-HCV agent and an anti-HCV effective amount of a compound selected from the group consisting of formulas [I] [IV] below and mixtures of two or more thereof: ##STR00081## wherein: R is independently selected from the group consisting of: ##STR00082## or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier.

8. A pharmaceutical composition for the treatment of HDV comprising an anti-HDV agent and an anti-HDV effective amount of a compound selected from the group consisting of formulas [I] [IV] below and mixtures of two or more thereof: ##STR00083## wherein: R is independently selected from the group consisting of: ##STR00084## or a pharmaceutically acceptable salt or prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier.

9. A process for stereospecifically preparing a 5'-modified pyrimidine .beta.-nucleoside comprising: a. applying the Mitsunobu reaction to a chiral compound of the formula; ##STR00085## b. selectively protecting the 3'.beta.-position of the resulting nucleoside of step (a) with a benzoyl protecting group or an acid labile protecting group; c. subjecting the resulting 3'.beta.-protected anhydro derivative of step (b) to mild alkaline hydrolysis, followed by phosphorylating the ring-opened, 3'.beta.-protected product with a phosphorylating agent; d. Saponifiction of the benzoyl group of the resulting product of step (c) to give the desired .beta.-nucleoside 5'-phosphate; and e. Optionally oxidizing the 5'-phosphate to obtain the 5'-phosphite.

10. The process of claim 9, wherein the acid labile agent is selected from the group consisting of tetrahydropyranyl (THP), a trityl group, or dimethyl-t-butylsilyl (DBMS).

11. The method of claim 1, wherein the compound is Formula I.

12. The method of claim 1, wherein the compound is Formula II.

13. The method of claim 1, wherein the compound is Formula III.

14. The method of claim 1, wherein the compound is Formula IV.

15. The method of claim 11, wherein R is H.

16. The method of claim 12, wherein R is H.

17. The method of claim 13, wherein R is H.

18. The method of claim 14, wherein R is H.

19. The method of claim 4, wherein the compound is Formula I.

20. The method of claim 4, wherein the compound is Formula II.

21. The method of claim 4, wherein the compound is Formula III.

22. The method of claim 4, wherein the compound is Formula IV.

23. The method of claim 19, wherein R is H.

24. The method of claim 20, wherein R is H.

25. The method of claim 21, wherein R is H.

26. The method of claim 22, wherein R is H.

27. The pharmaceutical composition of claim 7, wherein the compound is Formula I.

28. The pharmaceutical composition of claim 7, wherein the compound is Formula II.

29. The pharmaceutical composition of claim 7, wherein the compound is Formula III.

30. The pharmaceutical composition of claim 7, wherein the compound is Formula IV.

31. The pharmaceutical composition of claim 27, wherein R is H.

32. The pharmaceutical composition of claim 28, wherein R is H.

33. The pharmaceutical composition of claim 29, wherein R is H.

34. The pharmaceutical composition of claim 30, wherein R is H.

35. The pharmaceutical composition of claim 8, wherein the compound is Formula I.

36. The pharmaceutical composition of claim 8, wherein the compound is Formula II.

37. The pharmaceutical composition of claim 8, wherein the compound is Formula III.

38. The pharmaceutical composition of claim 8, wherein the compound is Formula IV.

39. The pharmaceutical composition of claim 35, wherein R is H.

40. The pharmaceutical composition of claim 36, wherein R is H.

41. The pharmaceutical composition of claim 37, wherein R is H.

42. The pharmaceutical composition of claim 38, wherein R is H.

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Description

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FIELD OF THE INVENTION

The present invention relates to a process for preparing a 3'- or 2'-hydroxymethyl substituted nucleoside derivative, and a composition for and a method of treating a hepatitis virus infection or a proliferative disorder using a 3'- or 2'-hydroxymethyl substituted nucleoside derivative. More particularly, the present invention is directed to a composition for and method of treating hepatitis B, C, or D virus or a proliferative disorder such as cancer.

BACKGROUND OF THE INVENTION

This invention relates to a process for preparing a 3'- or 2'-hydroxymethyl substituted nucleoside derivative, compounds and pharmaceutical compositions for, and a method of treating hepatitis virus infections and/or proliferative disorders in patients using 3'-hydroxymethyl and 2'-hydroxymethyl substituted nucleosides and structurally related nucleosides of general formulas [I] [IV] and their L-nucleoside counterparts.

##STR00002## wherein the substituents are as defined herein.

Hepatitis B virus (HBV) infection is the most prevalent form of hepatitis and is the second most common infectious disease worldwide. Approximately 5% of the world's population is chronically infected with HBV. The virus is transmitted through blood transfusions, contaminated needles, sexual contact and transmission from mother to child. Moreover, a significant number of people are infected by unknown means.

Carriers of the hepatitis B virus can exhibit various forms of disease, one of which is chronic hepatitis B. Approximately 50% of the carriers show chronic inflammatory changes in the liver and, of these, about 50% have histopathologic changes, which are termed "chronic active hepatitis," which may lead to fibrosis and ultimately to cirrhosis and progressive liver failure. Carriers without chronic inflammatory changes may also develop chronic active hepatitis, while liver cancer develops in about 10 to 30% of hepatitis B carriers. It has been estimated that approximately 4 million carriers of hepatitis B virus die each year from liver cancer or cirrhosis.

HBV, also known as the Dane particle, is a member of the Hepadonaviridae and is a 42 nm complex spherical particle composed of an outer lipoprotein coat (hepatitis B surface antigen HBsAg) and an inner core (hepatitis B core antigen, HBcAg). (Ganem, D., Fundamental Virology, 3.sup.rd Ed., Lippincott-Raven Pub., Philadelphia, 1996, p. 1199) This core contains partially double stranded DNA of 3.2 kb maintained as a circular structure by 5' cohesive ends. (Chu, C. K., Therapies for Viral Hepatitis, Schinazi, et al., Eds., International Medical Press, 1998) The viral minus strand is full length, while the plus strand is less than full length. The 5' ends of both strands contain short (11 nucleotide) direct repeats. These repeats are involved in priming the synthesis of their respective strands. Remarkably, viral DNA is synthesized in a reverse transcription of an RNA template. (Mason, W. S., Adv. Virus. Res., 1987, 32, 35) Following viral infection, the viral replication cycle begins with translocation of nucleocapsids from the cytoplasm to the nucleus. (Eckart, S. G., J. Virol., 1991, 65, 575) The partially duplex genomic DNA is converted to fully duplex covalently closed supercoiled DNA, which persists as an episomal minichromosome and functions as a reservoir of the viral genome. This feature provides a difficult challenge to therapeutic attack on the virus.

The episomal DNA is transcribed by the host RNA polymerase II and viral proteins are translated from the transcription products. Among the transcripts are full length pregenomic RNAs which are encapsulated by the viral structural proteins together with the viral polymerase. Synthesis of both viral DNA strands by the viral polymerase occurs within these structures. The polymerase contains both a reverse transcriptase and an RNAse H domain. Minus strand synthesis proceeds in two distinct steps (Zolim, F., J. Virol., 1994, 68, 3536). In the first, the polymerase binds to the direct repeat at the 5' end of the pregenomic RNA and serves as a covalent primer for the synthesis of a 4 nucleotide element. The priming hydroxyl group is the side chain of a tyrosine residue on the polymerase and is linked to a dGMP residue. A sequence in the bulge of a stem loop structure in the RNA template serves as the template for this step. This reaction is particular to the virus and is not mimicked in any cellular DNA synthesis reaction. Agents which target this step would have the potential for a high degree of specificity. Following this step the polymerase-nucleotide complex translocates to the other end of the RNA template and complete reverse transcription of the strand takes place. (It has been proposed that there may be proteolytic cleavage of polymerase and RNAse domains away from the portion of the polymerase bound to the tetranucleotide primer. (Bartenschlager, R., EMBO J. 1988, 7, 4185). First strand synthesis is accompanied by the degradation of the RNA in the RNA:DNA hybrid by the RNAse H of the polymerase. Synthesis of the second strand, also mediated by the viral polymerase, is generally incomplete, giving rise to the partially duplex DNA found in the virion.

It is now clear that there are three separate phases in replication and that the first reverse transcription step is of particular interest for therapeutic intervention. It should be noted that an agent that inhibits the reverse transcriptase of other retroviruses does not necessarily have activity against HBV. For example, Zidovudine (or AZT) as its 5'-triphosphate is a potent inhibitor of reverse transcriptase of human immunodeficiency virus and has been widely used in the treatment of HIV-infected patients. However, this agent is inactive against HBV. On the other hand, certain 2'-fluoro-D-arabino nucleosides, such as Fiacitabine (FIAC) and Fialuridine (FIAU), are devoid of activity against HIV although they effectively inhibit replication of HBV.

Hepatitis C virus (HCV), the second major cause of viral hepatitis, is present in an estimated 170 million carriers worldwide, 3.9 million of whom reside in the United States. HCV is considered the most common blood-borne infection in the United States, where it is one of the leading causes for liver transplantation among adults. Most people infected with HCV do not exhibit any acute signs or symptoms of hepatitis. In fact, unless they have a blood test, most people remain unaware that they are infected with HCV for the first 10 20 years.

Aside from direct blood contact, HCV is a very difficult agent to transmit. Maternal-to-fetal transmission is quite low, less than 6% of babies born to infected mothers will carry the virus. Additionally, unlike HBV and human immunodeficiency virus (HIV), evidence of direct sexual transmission of HCV is inconclusive.

HCV is a small, enveloped virus in the Flaviviridae family, with a positive single-stranded RNA genome of .about.9.6 kb within the nucleocapsid. The genome contains a single open reading frame (ORF) encoding a polyprotein ofjust over 3,000 amino acids, which is cleaved to generate the mature structural and nonstructural viral proteins. ORF is flanked by 5' and 3' non-translated regions (NTRs) of a few hundred nucleotides in length, which are important for RNA translation and replication. The translated polyprotein contains the structural core (C) and envelope proteins (E1, E2, p7) at the N-terminus, followed by the nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B). The mature structural proteins are generated via cleavage by the host signal peptidase. The junction between NS2 and NS3 is autocatalytically cleaved by the NS2/NS3 protease, while the remaining four junctions are cleaved by the N-terminal serine protease domain of NS3 complexed with NS4A. The NS3 protein also contains the NTP-dependent helicase activity which unwinds duplex RNA during replication. The NS5B protein possesses RNA-dependent RNA polymerase (RDRP) activity, which is essential for viral replication. It is emphasized here that, unlike HBV or HIV, no DNA is involved in the replication of HCV. Recently in in vitro experiments using NS5B, substrate specificity for HCV-RDRP was studied using guanosine 5'-monophosphate (GMP), 5'-diphosphate (GDP), 5'-triphosphate (GTP) and the 5'-triphosphate of 2'-deoxy and 2',3'-dideoxy guanosine (dGTP and ddGTP, respectively). The authors claimed that HCV-RDRP has a strict specificity for ribonucleoside 5'-triphosphates and requires the 2'- and 3'--OH groups. Their experiments suggest that the presence of 2'- and 3'-substituents would be the prerequisite for nucleoside 5'-triphosphates to interact with HCV-RDRP and to act as substrates or inhibitors. The present invention on the development of anti-HCV agents is based on this rationale.

Hepatitis D virus (HDV) is classified separately from other hepatitis viruses, but it is often found in association with hepatitis B virus. The host range of HDV is limited to those species that support the replication of a hepadnavirus capable of supplying a helper function. These include the chimpanzee (hepatitis B virus), the eastern woodchuck (woodchuck hepatitis virus) and possibly the Pekin duck (duck hepatitis virus). The successful replication of HDV is dependent on the replication of the helper hepadnavirus. Inhibition of hepatitis B virus, therefore, should result in inhibition of HDV. Also, while HDV appears to employ the host RNA polymerase, it is not clear if the virus causes some modification of the polymerase enabling it to replicate the HDV genome more efficiently. Thus, nucleosides that inhibit the HBV polymerase or the modified host RNA polymerase would be expected to inhibit the replication of HDV.

The synthesis of some related compounds has been disclosed in the literature (Acton, E. M., et al., J. Med. Chem., 1979; 22:518; Fiandor, J., et al., Nucleosides Nucleotides, 1989; 8:1107; Bamford, M. J., et al., J. Med. Chem., 1990; 23:2494; Svansson, L., et al., J. Org. Chem., 1991; 56:2993; Sterzycki, R. Z., et al., Nucleosides Nucleotides, 1991; 10:291; Svansson, L., et al., Nucleosides Nucleotides, 1992; 11:1353; Kvamstrom, I., et al., Nucleosides Nucleotides, 1992; 11:1367; Tseng, C. K-H., et al., J. Med. Chem., 1991; 34: 343; Lin, T-S., et al., J. Med. Chem., 1993; 36:353; Wengel, J., et al., Bioorg. Med. Chem., 1995; 3:1223; Lee-Ruff, E., et al., J. Med. Chem., 1996; 39:5276; Jorgensen, P. N., et al., Nucleosides Nucleotides, 1997; 16:1063; Jeong, L. S., et al., Nucleosides Nucleotides, 1997; 16:1059;). Moreover, these references also disclose anti-viral test results of some of these compounds against herpes virus (HSV) or human immunodeficiency virus (HIV). Only 2',3'-dideoxy-3'-hydroxymethyl-cytidine and adenosine show good activity against HIV and 2',3'-dideoxy-3'-hydroxymethyl-cytidine (Sterzycki, R. Z., et al., Nucleosides Nucleotides, 1991, 10, 291) and 5-bromovinyl-1-(3-deoxy-3-hydroxymethyl-D-arabinofuranosyl)-uracil (Svansson, L., et al., J. Org. Chem., 1991, 56, 2993) are active against HSV.

Although it would not have been expected that an anti-herpes virus agent or anti-HIV agent would also be effective in the treatment of hepatitis, the compounds of the present invention have surprisingly been found to be useful as anti-hepatitis agents. Some of these compounds are particularly favorable in the treatment of hepatitis because they unexpectedly cause less toxic side effects. For example, we discovered that 3'-deoxy-3'-hydroxymethylthymidine, which, though devoid of activity against murine leukemia virus (MuLV), HIV, HSV-1, HSV-2, human cytomegalovirus (HCMV), Varicella zoster virus (VZV) and Epstein Barr virus (EBV)( Sterzycki, R. Z., et al., Nucleosides Nucleotides, 1991, 10, 291), is a potent agent against HBV.

It is therefore an object of the present invention to provide compounds and compositions useful for the treatment of hepatitis.

It is a further object of the present invention to provide a method for treating hepatitis using the compounds of the present invention.

It is another object of the present invention to provide compositions for treating hepatitis comprising the compounds of the present invention in combination with other anti-hepatitis agents.

It is another object of the present invention to provide a method for treating hepatitis using the compounds of the present invention in combination with other anti-hepatitis agents.

It is still another object of the present invention to provide compounds and compositions useful for the treatment of proliferative disorders.

It is still another object of the present invention to provide a method for treating proliferative disorders using the compounds of the present invention.

It is still another object of the present invention to provide a process for preparing 3'- or 2'-hydroxymethyl substituted nucleoside derivatives.

SUMMARY OF INVENTION

The present invention as disclosed herein relates to the compounds of general formulas [I] [IV], a composition for and a method of treating hepatitis B virus (HBV) in a subject using a nucleoside of general formula [I], and hepatitis C virus (HCV) or hepatitis D virus (HDV) infection using a nucleoside of general formulas [I IV]:

##STR00003## wherein:

E is selected from the group consisting of H, OH, OMe, SH, SMe, NH.sub.2, NHMe, N.sub.3, F, Cl, Br, CO.sub.2H, CO.sub.2-alkyl, OPh, OPhNO.sub.2, NO, NO.sub.2, SCN, OCN, NCS, NCO, SOMe, SO.sub.2Me;

X is selected from the group consisting of O, S, NH, CH.sub.2, CHF, CF.sub.2;

Y is selected from the group consisting of CH.sub.2, NH, NOH, NMe, NEt, NOMe, CHF, CF.sub.2;

Z is selected from the group consisting of H, OH, Ome, SH, SMe, F, Cl, Br, I, NH.sub.2, NHMe;

B is a base selected from the group consisting of

##STR00004##

R.sup.2 is selected from the group consisting of O, S, NH, NR;

R.sup.5 is selected from the group consisting of H, branched or unbranched lower alkyl having 1 5 carbon atoms, F, Cl, Br, I, CH.dbd.CH.sub.2, CH.dbd.CHBr, Ph, Ac, OMe, OPh, NO, NO.sub.2, NH.sub.2, NHR;

R.sup.6 and R.sup.8 are the same or different and are independently selected from the group consisting of H, OH, OMe, SH, SMe, F, Cl, Br, I, NH.sub.2, NHMe, NMe.sub.2;

R is independently selected from the group consisting of

##STR00005##

Compounds according to the present invention may also be used to treat human immunodeficiency virus (HIV) infection and/or proliferative disorders as well as bacterial infections.

The present invention is also directed to a process for preparing 3'- or 2'-hydroxymethyl substituted nucleoside derivatives.

DETAILED DESCRIPTION

The following terms shall be used to describe the present invention:

The terms "patient" and "host organism" are used throughout the specification to describe an animal, preferably a human, to whom treatment, including prophylactic treatment, with the compounds and pharmaceutical compositions according to the present invention is provided. For treatment of those infections, conditions or disease states which are specific for a specific animal such as a human patient, the terms patient or host refer to that specific animal. In most applications of the present invention, the patient is a human. Veterinary applications, in certain indications, however, are clearly contemplated by the present invention.

The term "therapeutically effective amount" shall mean the administration of at least one compound according to the present invention in an amount or concentration and for period of time including acute, sub-acute or chronic administration, which is effective within the context of its administration for causing an intended effect or physiological outcome in the treatment of HIV, HBV, HCV, HDV, bacterial infection or proliferative disorders such as tumors/cancer. Effective amounts of compounds, according to the present invention, include amounts which are therapeutically effective for delaying the onset of, inhibiting or alleviating the effects of the above disease states. Although effective amounts of compounds, according to the present invention, generally fall within the dosage range of about 0.1 mg/patient kg to about 100 mg/patient kg or more, amounts outside of these ranges, in certain instances, may be used, depending upon the final use of the composition.

As used herein, the term "alkyl" is defined as any straight-chained or branched alkyl, including but not limited to methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, t-butyl, isopentyl, amyl, and t-pentyl.

The term "acyl" as used herein is defined as the residue of an acid group, including but not limited to acetyl, formyl, propionyl, butyryl, pentanoyl, 3-methylbutyryl, hydrogen succinate, 3-chlorobenzoate, cyclopentyl, cyclohexyl, benzoyl, acetyl, pivaloyl, mesylate, valeryl, caproic, caprylic, capric, lauric, myristic, palmitic, stearic, oleic, amino acids including but not limited to alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaoyl, lysinyl, argininyl, and histidinyl.

The term "tumor" or "neoplasia" is used to describe the pathological process that results in the formation and growth of a neoplasm, i.e., an abnormal tissue that grows by cellular proliferation more rapidly than normal tissue and continues to grow after the stimuli that initiated the new growth cease. Neoplasia exhibits partial or complete lack of structural organization and functional coordination with the normal tissue, and usually forms a distinct mass of tissue which may be benign (benign tumor) or malignant (carcinoma). The terms "proliferative disorder" and "cancer" are used as general terms to describe any of various types of malignant neoplasms, most of which invade surrounding tissues, may metastasize to several sites, and are likely to recur after attempted removal and to cause death of the patient unless adequately treated. As used herein, the term cancer is subsumed under the term tumor or neoplasia. Cancers, which may be treated using one or more compounds according to the present invention, include stomach, colon, rectal, liver, pancreatic, lung, breast, cervix uteri, corpus uteri, ovary, prostate, testis, bladder, renal, brain/CNS, head and neck, throat, Hodgkin's disease, non-Hodgkin's leukemia, multiple myeloma leukemias, skin melanoma, acute lymphocytic leukemia, acute myelogenous leukemia, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, neuroblastoma, mouth/pharynx, esophagus, larynx, melanoma, lymphoma and kidney cancer. Compounds according to the present invention, which are used to treat tumors and/or cancer, are referred to as anti-proliferative.

The term "D-nucleoside" is used to describe a nucleoside compound, according to the present invention, which has a configuration about the nucleoside base/sugar synthon bond which is the same as the configuration of the naturally occurring nucleoside compounds.

The term "L-nucleoside" is used throughout the specification to describe those nucleoside compounds used in the present invention which have an unnatural L-configuration of the sugar synthon moiety in contrast to the natural D-configuration. Certain compounds according to the present invention do not have a D,L distinction.

The term ".beta.-anomer" or ".beta.-nucleoside" is used to describe nucleoside compounds according to the present invention which have a cis-relationship between the base and the 4'-hydroxymethyl group (i.e., a configuration in which the base and 4'-hydroxymethyl group of the sugar are in the same side of the sugar ring).

The term ".alpha.-anomer" or ".alpha.-nucleoside" is used to describe nucleoside compounds according to the present invention which have a trans-relationship between the base and the 4'-hydroxymethyl group (i.e., a configuration in which the base is oriented in the opposing plane relative to the 4'-hydroxymethyl group of the sugar synthon).

The term pharmaceutically acceptable derivative is used throughout the specification to describe any pharmaceutically acceptable salt or prodrug form (such as an ester, phosphate ester or salt of an ester or a related group) of a nucleoside compound which, upon administration to a patient, provides directly or indirectly the nucleoside compound or an active metabolite of the nucleoside compound. Pharmaceutically acceptable salts forms of the present compounds are also contemplated by the present invention. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, and ammonium among numerous other acids well known in the pharmaceutical art.

The term "enantiomerically enriched" is used throughout the specification to describe a nucleoside which includes at least about 95%, preferably at least about 96%, more preferably at least about 97%, even more preferably, at least about 98%, and even more preferably at least about 99% or more of a single enantiomer of that nucleoside. When a nucleoside of a particular configuration (D or L) is referred to in this specification, it is presumed that the nucleoside is an enantiomerically enriched nucleoside, unless otherwise stated.

The invention as described herein includes processes to prepare compounds of formulas [I] [IV]. In another embodiment, the use of these compounds for the treatment of viral hepatitis (B, C or D), HIV infections and AIDS or abnormal cellular proliferation in humans or other host animals that includes administering an effective amount of a compound of general formulas [I] [IV] to a patient in need of therapy or preventions. The compounds of this invention either possess anti-viral (anti-HBV, anti-HCV or anti-HDV) activity, anti-HIV activity, antibacterial activity or anti-proliferative activity, or are metabolized to a compound that exhibits such activity. It should be noted that compounds of formula [I] [IV] may be viewed as sugar ring expanded analogues of the anti-viral antibiotic oxetanocin-G (Presentation 1).

Presentation 1. Structural relationship between oxetanocin and compounds of present invention.

##STR00006## Oxetanocin-G: X=O, n=m=0 Formula I and II: m=0, n=1 Formula III and IV: n=1, m=0

Specifically, this invention provides processes for the preparation of a compound having the structure:

##STR00007## wherein:

E is selected from the group consisting of H, OH, OMe, SH, SMe, NH.sub.2, NHMe, N.sub.3, F, Cl, Br, CO.sub.2H, CO.sub.2-alkyl, OPh, OPhNO.sub.2, NO, NO.sub.2, SCN, OCN, NCS, NCO, SOMe, SO.sub.2Me;

X is selected from the group consisting of O, S, NH, CH.sub.2, CHF, CF.sub.2;

Y is selected from the group consisting of CH.sub.2, NH, NOH, NMe, NEt, NOMe, CHF, CF.sub.2;

Z is selected from the group consisting of H, OH, Ome, SH, SMe, F, Cl, Br, I, NH.sub.2, NHMe;

B is a base selected from the group consisting of

##STR00008##

R.sup.2 is selected from the group consisting of O, S, NH, NR;

R.sup.5 is selected from the group consisting of H, branched or unbranched lower alkyl having 1 5 carbon atoms, F, Cl, Br, I, CH.dbd.CH.sub.2, CH.dbd.CHBr, Ph, Ac, OMe, OPh, NO, NO.sub.2, NH.sub.2, NHR;

R.sup.6 and R.sup.8 are the same or different and are independently selected from the group consisting of H, OH, OMe, SH, SMe, F, Cl, Br, I, NH.sub.2, NHMe, NMe.sub.2;

R is independently selected from the group consisting of

##STR00009## or pharmaceutically acceptable salts or prodrugs thereof.

Pharmaceutical compositions based upon the compounds of the present invention comprise the above-described compounds in a therapeutically effective amount for treating a viral infection such as an HBV, HCV, HDV or HIV infection or a proliferative disease such as a tumor or cancer, optionally in combination with a pharmaceutically acceptable additive, carrier or excipient. One of ordinary skill in the art will recognize that a therapeutically effective amount will vary with the infection or condition to be treated, its severity, the treatment regimen to be employed, the pharmacokinetics of the agent used, as well as the patient or host organism (animal or human) treated.

In the pharmaceutical aspect according to the present invention, the compound according to the present invention is formulated preferably in admixture with a pharmaceutically acceptable carrier. In general, it is preferable to administer the pharmaceutical composition in orally administrable form, but certain formulations may be administered via a parenteral, intravenous, intramuscular, transdermal, buccal, subcutaneous, vaginal, suppository or other route. Intravenous and intramulscular formulations are preferably administered in sterile saline. One of ordinary skill in the art may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity. In particular, the modification of the present compounds to render them more soluble in water or other vehicle, for example, may be easily accomplished by minor modifications (salt formulation, esterification, etc.), which are well within the ordinary skill in the art. It is also well within the ordinary artisan's skill to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients.

In certain pharmaceutical dosage forms, the prodrug form of the compounds, especially including acylated (acetylated or other) and ether derivatives, phosphate esters and various salt forms of the present compounds, are preferred. One of ordinary skill in the art will recognize how to readily modify the present compounds to prodrug forms to facilitate delivery of active compounds to a targeted site within the host organism or patient. The routineer also will take advantage of favorable pharmacokinetic parameters of the prodrug forms, where applicable, in delivering the present compounds to a targeted site within the host organism or patient to maximize the intended effect of the compound in the treatment of viral infections or proliferative diseases.

The amount of compound included within therapeutically active formulations, according to the present invention, is an effective amount for treating the infection or condition, in preferred embodiments, an HBV, HCV, HDV, or HIV infection or a proliferative disease, including cancer. In general, a therapeutically effective amount of the present compound in pharmaceutical dosage form usually ranges from about 0.1 mg/patient kg to about 100 mg/patient kg or more, depending upon the compound used, the condition or infection treated and the route of administration. In the case of proliferative diseases including cancer, the active compound is preferably administered in amounts ranging from about 0.5 mg/patient kg to more than 100 mg/kg of the patient, depending upon the pharmacokinetics of the agent in the patient. For purposes of the present invention, a prophylactically or preventively effective amount of the compositions, according to the present invention, falls within the same concentration range as set forth above for therapeutically effective amount and is usually the same as a therapeutically effective amount.

Administration of the active compound may range from continuous (intravenous drip) to several oral administrations per day (for example, Q.I.D.) and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancement agent), buccal and suppository administration, among other routes of administration. Enteric-coated oral tablets may also be used to enhance bioavailability of the compounds from an oral route of administration. The most effective dosage form will depend upon the pharmacokinetics of the particular agent chosen, as well as the severity of disease in the patient. Oral dosage forms are particularly preferred, because of ease of administration and prospective favorable patient compliance.

To prepare the pharmaceutical compositions according to the present invention, a therapeutically effective amount of one or more of the compounds is preferably intimately admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniq