NZ541594A

NZ541594A - Anti-viral 4'-substituted nucleoside analogs and methods for treating viral infections, especially HIV infections

Info

Publication number: NZ541594A
Application number: NZ541594A
Authority: NZ
Inventors: Hiromichi Tanaka; Masanori Baba; Yung-Chi Cheng
Original assignee: Univ Yale; Hiromichi Tanaka; Masanori Baba
Priority date: 2003-02-19
Filing date: 2004-02-18
Publication date: 2009-01-31

Abstract

Disclosed is a compound of formula (I), wherein the substituents are as defined in the specification. The compounds are useful for the treatment of viral infections, including retroviruses such as HIV.

Description

<div class="application article clearfix" id="description"> WO 2005/011709 * 1 005693945 2* PCT/US2004/004713 Anti-Viral Nucleoside Analogs and Methods For Treating Viral Infections, Especially HIV Infections Related Applications This application claims the benefit of provisional application number 60/448,554, filed February 19,2003, the entirety of which is incorporated by reference herein. Field of the Invention The present invention relates to novel 2',3'-dideoxy and didehydro nucleoside analogs and related prodrugs and their use in the treatment of a number of viral infections and disease states, especially including HIV and its related condition AIDS, among numerous others, and in particular, retroviruses. This work was supported by Public Health Service grant AI-38204 from the National Institutes of Health. The government retains certain rights in the invention. Background of the invention Human immunodeficiency virus (HTV/AIDS) has become the leading infectious cause of death worldwide surpassing malaria and tuberculosis. WHO AIDS Epidemic Update, data for December 2002, lists 3.1 million deaths and 42 million people currently living with AIDS. The need for new therapeutic agents with better efficacy is evident. Dideoxy nucleosides are an important group of antiviral compounds(16, 26, 27). A member of this group, 3'-Azido-3'-deoxythymidine (AZT, Retovir, Zidovudine) was the first drug approved for the treatment of HTV. Its dose limiting adverse effect is myelosuppression (14, 36, 39), which may be worsened by the concurrent administration of other drugs that cause bone marrow suppression or that are hepatically metabolized. 2', 3Didehydro-3 deoxythymidine (D4T, Stavudine, Zerit) was then approved because of better bioavailability and lower acute toxicity (1). D4T is limited by a long-term delayed toxicity, peripheral sensory neuropathy (4) which is related to mitochondrial damage (3, 5, 6, 13, 18, 22, 30, 33, 34). 2\ 3'-Dideoxyinosine (ddl, Didanosine, Videx) and 2\ 3'-dideoxycytidine (ddC, Zalcitabine) are dideoxynucleoside anti HTV compounds that also have peripheral neuropathy as their leading adverse effect, In the search to find anti-HTV nucleoside analogs that had less neuropathy, many classes of compounds were synthesized and assessed for their antiviral 1 WO 2005/011709 PCT/US2004/004713 activity and cytotoxicity including their impact on mitochondrial DNA. Dideoxynucleosides in the unnatural L conformation represented by (3-L-2', 3'-dideoxy-3'- thiacytidine (3TC, Lamivudine), its 5- fluoro analog (FTC, Emtricitabine) and P-L-2', 3'-dideoxy-2',3'-didehydro-5- fluorocytidine (LFd4C, Elvucitabine), have been shown by us (2, 11, 12, 23-25) and others (8, 9,15, 37) to have good antiviral activity and low mitochondrial toxicity. However, even with compounds relatively non-toxic to mitochondria there is a lack of a durable response. This condition can be caused by either the rapid emergence of resistant virus or by host changes that cause differences in drug metabolism (10, 19, 35). One approach to combat this problem is to develop compounds with less toxicity and lack of cross-resistance to other antiviral drugs. When used in combinations these compounds may decrease the dosage of existing drugs needed to achieve the same antiviral effect with less toxicity. Futhermore, these compounds could even delay the onset of resistance, which could be based on the decreased viral load during treatment. In the search for a new antiviral compounds, others have looked at 4'-substituted dThd analogs (29) (32), while we synthesized a series of 4'-substituted D4T analogs. Screening revealed the 4'-ethynyl D4T to be the most active among those tested (17). In the studies described within we describe the structure activity relationship of this class of compounds and characterize 4'-ethynyl D4T in more detail with respect to its mode of action against HIV and its interaction with key cellular enzymes that mediate its activity. Objects of the Invention It is an object of the invention to provide compounds for the treatment of viral infections or cancer; and/or to provide pharmaceutical compositions which can be used to treat viral infections or cancer; and/or to provide compounds and pharmaceutical compositions which can be used in combination therapy with known anti-viral agents; and/or I INTELLECTUAL PROPERTY ! I OFFICE OF N.2. j 1 ? SEP 2008 WO 2005/011709 PCT/US2004/004713 -to provide prodrug forms of compounds according to the present invention which are formulated in combination with other anti-viral agents; and/or to provide therapeutic methods for the treatment of a variety of viruses as otherwise described herein, or cancer; and/or to provide methods of synthesizing compounds according to the present invention; and/or to provide the public with a useful choice. These atid/or other objects of the invention may be readily gleaned from the description of the invention which follows. Brief Description of the Figures Figure 1 depicts a number of preferred compounds according to the present invention. Figure 2 depicts anti-HIV compounds L(-)Fd4C, L(-)SddC, ddC and D4T. Figure 3 depicts preferred dinucleoside compounds according to the present invention. Figure 4 shows the chemical synthesis of TDK-4-152 in Scheme A. Figure 5 shows the chemical synthesis of TDK-4-114 in Scheme B. Figure 5A shows an alternative chemical synthesis of TDK4-114 . Figure 5B shows an alternative preparation of acyloxy nucleoside compound inten-nediates according to the invention, which may be used to produced TKD-4-114 of Figure 5A. Figure 6 shows a chemical synthesis of KMA-23-153. 3 INTELLECTUAL PROPERTY OFFICE OF N.Z. 17 SEP 2008 RECEIVED WO 2005/011709 PCT/US2004/004713 Figure 7 A shows the synthesis of 4'ethynyl-2'-deoxynucleosides from 2'-deoxynucleosides according to the methodology of Nomura, et al. J. Med. Chem., 42,2901-2908 (1999). Note that SiR.3 is a terNbutyldimethylsilyl group and SiR'3 is a tert-butyldiphenylsilyl group. X is a halogen atom, such as chlorine and B is a nucleoside base such as uracil, adenine, guanine or cytosine, among others. Figure 7B shows the synthesis of 4 '-ethynyl-2 '-deoxynucleosides from a blocked sugar precursor according to the methodology of Ohrui, et al., J. Med. Chem. 43,4516-4525 (2000). Note that B is a nucleoside base. Figure 7C shows a general chemical synthesis of 2',3'-didehydro nucleoside compounds from the corresponding 2' deoxynucleoside analogs according to the present invention. Figure 8 shows the anti-HTV Activity of 4'Substituted D4T analogs: the anti viral activity of 4'-ethynyl D4T, D4T, 4'-ethynyImethly D4T and 4'-cyano D4T were determined in the MT-21 HTV" IHB system as describe in the Material and Methods section in the examples. Inhibition is determined by comparison of readings at O.D. 595nm to that of uninfected untreated (UIUT) control MT-2 cells. Figure 9 shows the reversal of the Anti-HTV effect of 4'-ethynyl D4T. dThd (10 ]uM), dThd (lj-iM) and dCyd (10 juM) in the presence ofTHU (5 jiM) were added to the standard antiviral assay. Inhibition is determined by comparison of readings at O.D. 595nm to that of uninfected untreated (UIUT) control MT-2 cells. Figure 10 shows antiviral isobolograms of D4T and 4'-ethynyl D4T in combination with: A) 3TC and B) LFd4C data obtained in the MT-2/ HTV IHB system. The numbers along each axis are proportions of the EC50 (taken as 1) for the drug indicated as a single agent. [EC50 for single agents are 1.4 jjM D4T, 0.5 liM 4'-ethynyl D4T, 1.0 p.M 3TC and 0.18 |_iM LFd4C] Each datum point represents a combination that produces an effect equivalent to that of the EC50 for either drug alone. Synergy Index (SI) is calculated as the fractional part of the 45° line to the line indicating that the drug interaction is additive, the total distance being 1.0. 4 Figure 11 shows thymidine phosphorylase treatment of D4T Analogs: dThd, D4T and 4'-ethynyl D4T were incubated with a partially purified preparation of TP from human liver extract. Then the ratio of base to nucleoside was determined by reverse phase HPLC on a Beckman ODS column as described in the materials and methods section. Summary of the Invention The present invention provides a compound according to the formula: Hv /X ,c=cv C=CX H or X R is H, F, CI, Br, I, C1-C4 alkyl, -C^N, -C=C-Ra, X is H, C1-C4 alkyl, F, CI, Br or I; R1 is H, an acyl group, a Ci—C20 alkyl or an ether group; R2 is H, an acyl group, a Ci—C20 alkyl or ether group, a phosphate, diphosphate, triphosphate, phosphodiester group or a Nu- O II P — o- OR8 OR8 O II Nu C- group; INTELLECTUAL PROPERTY OFFICE OF N.2. 11 SEP 2008 RECEIVED Nu is a radical of a biologically active antiviral compound such that an amino group or hydroxyl group from said biologically active antiviral compound forms a phosphate, phosphoramidate, carbonate or urethane group with the adjacent moiety; R8 is H or a Q-C20 alkyl or ether group; R3 is a C3 or C4 alkyl group, -(CH2)n-C=C-Ra, ; R3a and R3b are each independently H, F, CI, Br or I; Ra is H, F, CI, Br, 1, or -C1-C4 alkyl; Y is H, F, CI, Br, I or -C1-C4 alkyl; k is 0, 1 or 2; and n is 0, 1, 2, 3, 4 or 5; or an anomer, pharmaceutical^ acceptable salt, polymorph or solvate thereof. Also described are compounds according to the general formulas I, II, III, IV or V: oh oh oh R3a R3b I n m IV v wherein B is nucleoside base according to the structure: 5a INTELLECT^ OFFICE Qi 1? SEP R is H, F, CI, Br, I, C1-C4 alkyl (preferably CH3), -C=N, -C=C-Ra , Hs /x /H c=cx c=cx /S H or X j X is H, C1-C4 alkyl (preferably, CH3), F, CI, Br or I; 5b INTELLECTUAL PROPER"! ■ OFFICE OF N.2, 1 ? SEP 2008 REOFU/Fr WO 2005/011709 PCT/US2004/004713 Z is O or CH2, with the proviso that Z is CH2 and not O when the compound is according to general formula It, R3 is -C=C-H and R2 is H or a phosphate, diphosphate, triphosphate or phosphotriester group; R1 is H, an acyl group, a Ci—C20 alkyl or an ether group; R2 is H, an acyl group, a Ci—C20 alkyl or ether group, a phosphate, diphosphate, triphosphate, phosphodiester group or a nu- O I! ■p—0-ORs 0 O II , II • c~ r or8 k group; Nu is a radical of a biologically active antiviral compound such that an amino group or hydroxyl group from said biologically active antiviral compound forms a phosphate, phosphoramidate, carbonate or urethane group with the adjacent moiety; R8 is H, or a C1-C20 alkyl or ether group, preferably a C1-C12 alkyl group; k is 0-12, preferably, 0-2; R3 is selected from a C1-C4 alkyl (preferably, CH3), -(CH2)n-C=C-Ra, h ,y h h (CH2% \j or (CHj^ \y 5 R3a and R3b are independently selected from H, F, CI, Br or I; R4 and R5 are independently selected from H, F, CI, Br, I, OH, C1-C4 alkyl (preferably, CH3), h ,y h h -4-(ch2% h or , . -(CH2)n-C=C-Ra, with the proviso that R and R are not both H; 6 WO 2005/011709 PCT/US2004/004713 Ra is H, F, CI, Br, I, or -C1-C4 alkyl, preferably H or CH3; Y is H, F, CI, Br, I or -C1-C4 alkyl, preferably H or CH3; and n is 0, 1, 2,3, 4 or 5, preferably 0,1 or 2; and their anomers, pharmaceutical^ acceptable salts, solvates, or polymorphs thereof. Preferably, B is a thymine base (i.e., a uracil base with 5-methyl substitution) or an unsubstituted adenine base. R1 and R2 are preferably H. R3 is preferably CH3, -C=CH or -(CH2)n-CH=CH2, where n is 1. In other preferred aspects of the present invention, the biologically active antiviral agent is a nucleoside compound selected from ddC, ddl, ddA, B-LFd4C, B-LFddC, AZT, abacavir, 3TC, D4T and FTC, wherein the biological active agent is attached to a phosphate, phosphoramidate, carbonate or urethane moiety through a hydioxyl group at the 5' position of the sugar synthon of the nucleoside. In another embodiment according to the present invention, pharmaceutical compositions comprise an effective amount of one or more compounds as described above, optionally in combination with a pharmaceutically acceptable carrier, excipient or additive. Methods of treatment of viral infections, and/or preventing or delaying the onset of conditions related to viral infections are also described. The compounds may be used to treat infections or conditions associated with viruses, including, for example, human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2) including drug resistant strains, human T-cell leukemia viruses 1 and 2 (HTLV-1 and HTLV-2), respiratory syncytial virus (RSV), human papilloma virus (HPV), adenovirus, hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), human herpes virus 8 (HHV-8, also known as Kaposi's sarcoma-associated virus) and flaviviruses, including Yellow Fever virus, Dengue virus, Japanese Encephalitis and West Nile viruses. Preferably, compounds according to the present invention may be used to treat HIV infections. In addition, the INTELLci OFFIO t / Stc WO 2005/011709 PC T/U S2004/004713 present compounds may be used to prevent and/or reduce the likelihood of a virus infection such as an HIV infection or a condition which may occur secondary to a "viral infection, such as AIDS, EBV-related lymphoma or HHV-8 associated cancer (sarcoma) will actually occur. Detailed Description of the Invention The term "compound", as used herein, unless otherwise indicated, refers to any specific chemical compound disclosed herein. Within its use in context, the term generally refers to a single compound preferably, (3 anomers, but in certain instances may also refer to stereoisomers and/or optical isomers (including racemic mixtures), preferably well as specific enantiomers, in particular, fi-D or p-L, preferably (i-D nucleoside analogs or enantiomerically enriched mixtures of disclosed compounds. In the present invention in certain instances, especially in the dual antagonist/dinucleoside prodrug aspect of the present invention, a compound according to the present invention is chemically linked through a phosphate (including polyphosphate), phosphoramidate, carbonate or urethane moiety to a biologically active antiviral agent through an amine or hydroxyl group of the biologically active antiviral agent. The term "dual antagonist" (within context, "dinucleoside") refers to a prodrug compound comprising two active agents, one being an active nucleoside compound according to the present invention and the other being a known active agent, preferably a known anti-viral agent, more preferably an anti-HTV agent having a free amino group or hydroxyl group which can be used to link the agent to a compound according to the present invention through a phosphate or carbonate group. In this dual antagonist aspect of the invention, a biologically active agent having a free hydroxyl or amino group may be used to link a compound according to the present invention through a phosphate or carbonate moiety to produce prodrug compounds which exhibit biological activity, preferably antiviral activity. In this aspect, a nucleoside analog according to the present invention is linked to the bioactive agent, preferably through a primary alcohol at the 5' OH position of the sugar synthon to produce a phosphate, phosphoramidate, carbonate or urethane moiety. Alternatively, a secondary alcohol or a free amine group from the present nucleoside compounds may be used to form the linker with the other bioactive agent in this dual antagonist aspect of the present invention. Preferably, P-D or P-L nucleoside analogs may be used as the bioactive agent and linked to nucleoside compounds of the present invention 8 WO 2005/011709 PCT/US2004/004713 (which themselves may be enantiomerically enriched P-D or P-L nucleoside compounds, racemates or diastereomeric mixtures) to form dinucleoside prodrugs, depending upon the activity of the nucleoside compound chosen for use. In preferred aspects of the invention, the biologically active antiviral agent is preferably another anti-viral nucleoside agent such as ddC, abacavir, ddl, ddA, 3TC, AZT, D4T, FTC, FddC and Fd4C. Preferred dinucleoside compounds are set forth in attached Figure 3. The term "comprising" as used in this specification means "consisting at least in part of'. When interpreting each statement in this specification that includes the term "comprising", features other than that or those prefaced by the term may also be present. Related terms such as "comprise" and "comprises" are to be interpreted in the same manner. Exemplary bioactive agents, especially anti-HIV agents, which nxay be used in this dual antagonist aspect of the present invention include, for example (compound name and active moiety through which linking with nucleoside compound according to the present invention occurs): Atazanavir (BMS-232632) using the free secondaiy hydroxyl group; Bis(POM)-PMEA (Adefovir dipivoxyl) using the free amine group; Bis(POC)-PMPA (Tenofovir disoproxil) using the free amine group; Etecavir using the primary hydroxyl group on the carbocyclic sugar synthon; Indinavir (Crixivan, MK-639 L-735,524 from Merck) using the free secondary hydroxyl group; KH3-227 (Kynostatin of Nikko Kyodo Co.) using the free secondary hydroxyl group: 2-[3-[3-(S)-[[(Tetrahydrofuranyloxy)carbonyl]amino]-4-phenyl-2(R)-hydroxybutyl]]-N-( 1,1 -dimethylethyl)decahydro-3 -isoquinolinecarboxamide (IsoquinCON furanyl urethane analog from Merck) using the free secondary hydroxyl group; Carbamic acid,[3-{[(4-methoxyphenyl)sulfonyl](cyclopenyhnethyl)amino]-2-hydroxy-l-(phenylmetliyl)propyl]tetrahydrofuranyl ester (VB-11,328 of Vertex) using the free secondary hydroxyl group; KNI-174 from Nikko Kyodo Co. using the free secondary hydroxyl (or free amine) group; Val-Val-Sta from Sandoz (Austria) using the free secondary hydroxyl group; CPG53820 from Ciba-Geigy using the free secondary hydroxyl group; bis-Val HOEt-N2 aza-peptide isostere using die free secondary hydroxyl group; C2-Sym Pliosphinic amide derivative from Hoechst AG using the free amine group; 2,5,-Diamino-N,TSt'-bis(N-benzyloxycarbonyluelyl)-l,6-diphenyl-3(S)s4(S)-hexanediol BzOCValPhe[diCHOH(SS]PheValBzOC from Abbott using the free se< hydroxyl group; 9 ■undaty— INTELLECTUAL Ph OFFICE OF N.„. 1? SEP 2008 WO 2005/011709 PCT/US2004/004713 2,5 ,-Diamino-N ,N' -bis(N-bcnzyloxycarbonyluelyl)-1,6-diphenyl-3 (R),4(R)-hexanediol BzOCValPhe[diCHOH(RR]PheValBzOC from Abbott using the free secondary hydroxyl group; bis(S-acetyl-2-thioethyl)phosphotriester of ddA or [bis(SATE)ddAMP] using Hie free amine; BRA 2186 BS (Bio-Mega/Boehringer Ingelheim) using the free secondary hydroxyl group; Agenerase (Amprenavir; VX-478; 141W94) of Vertex/Kissei/Glaxo Wellcome at the free secondary hydroxyl or amine group; A-98881 (Azacyclic urea derivative) of Abbott using the free secondary hydroxyl group or phenolic hydroxyl group; A-83962 (Rifonavir derivative) of Abbott using the free secondary hydroxyl group; A-80987 (Rifonavir derivative) of Abbott using the free secondary hydroxyl group; (2-Naphthalcarbonyl)Asn[decarbonylPhe-hydroxyethyl]ProOtertButyl or 2NaphCOAsnPhe[CHOHCH2]Pro-OtBu of Roche using the free secondary hydroxyl; 2-Aminobenzylstatine Valyl Cbz derivative of Sandoz using the free secondary hydroxyl or amine; 2-Aminobenzylstatine Valyl Cbz deriative of Sandoz using the free hydroxyl; 10H-2(Cbz-ValNH)3PhPr [14]paracyclophane derivative of Sandoz using the free seondary hydroxyl; 10H-2(Cbz-ValNH)3PhPr [13]paracyclophane derivative of Sandoz using the free seondary hydroxyl; 10H-2(Cbz-ValNH)3PhPr [13]xnetacyclophane derivative of Sandoz using the free seondary hydroxyl; 10H-2(Cbz-Tle)3PhPr [14]paracyclophane derivative of Sandoz using the free seondary hydroxyl; l-(20HPr)~4-substituted-piperazine (cyclopropyl), thieneyl carbamate deriv. (from Merck) using the free secondary hydroxyl group; l-(20HPr)-4-substituted-piperazine (cyclobutyl), thienyl carbamate derive, (from Merck) using the free secondary hydroxyl group; l-(20HPr)-4-substituted-piperazine (3-pentyl), thienyl carbamate derive, (from Merck) using the free secondary hydroxyl group; 10H-2(Cbz-ValNH)3PhPr[17]paracyclophane derivative (from Sandoz) using the free second hydroxyl group; A-81525 (from Abbott) using the free secondary hydroxyl group; XM323 (DMP-323 from DuPont Merck) using the free primary or secondary hydroxyl groups; 10 WO 2005/011709 PCT/US2004/004713 Tipranavir (U-140690 or PHU-140690 from Pharmacia & Upjohn) using the phenolic hydroxyl group; ThienopyridCON thienyl urethane derivatives (HOCH2CH2 isostere from Lilly) (the benzyl substituted derivative or the methyl mercaptophenyl substituted derivatives) using the free secondary hydroxyl groups; SDZ PRI053 (Sandoz) using the free secondary hydroxyl group; SD146 (DuPont Merck) using either of the free secondary hydroxyl groups; Telinavir (SC-52151 from Searle/Monsanto) using the free secondary hydroxyl group or amine; (R)2QuinCOAsnPhe[CHOHCH2JPipCONHtBu (from Roche) using the free secondary hydroxyl group or amine; Saquinavir (Invirase or RO 31-8959 from Roche) using the free secondary hydroxyl group or amine; Saqiiinavir/Melfinavir derivative (from Lilly) using the free secondary hydroxyl group; IsoquinCON Thf-Thf Urethane Analog (from Merck) using the free secondary hydroxyl group; IsoquinCON thienyl urethane analog (from Merck) using the free secondary hydroxyl group; R-87366 (AHPBA analog from Sankyo) using the free amine group; DMP 460 (Dupont Merck/Avid) using the free secondary hydroxyl groups or either of the aniline amine groups; L685,434 (Merck) using the free secondary hydroxyl group; L685,434-6-Hydroxyl derivative (Merck) using the free secondary hydroxyl group; L685,434-OEtNMe2 (Merck) using the free secondary hydroxyl group; L685,434-OPrMorph derivative (Merck) using the free secondary hydroxyl group; L689,502 (Merck) using the free secondary hydroxyl group; Lasinavir (CGP 61755 from CIBA/Novartis) using the free secondary hydroxyl group; Aluviran (Lopinavir, ABT-378, RS-346 A157378 of Abbott) using the free secondary hydroxyl group; Nelfinavir-octaliydro-thienopyridine analog (from Lilly) using the free secondary hydroxyl group; P9941 (from DuPot Merck) using either of the free secondary hydroxyl groups; 11 WO 2005/011709 PCT/US2004/004713 Palinavir (BDLA 2011 BS from BIO-MEGA/Boehringer Ingelheim) using the free secondary hydroxyl group; Penicillin, 2Isoquin-OHPrNH2 analog (from Glaxo Wellcome) using the free secondary hydroxyl group, among numerous odiers. The above active compounds, and other relevant bioactive agents for use in the dual antagonist aspect of the present invention may be found at the NIH website at http://www.niaid.nih.gov/daids/dtpdb/, relevant portions of which are incorporated by reference herein. Although not necessary or critical, it is preferred in the dual antagonist aspect of the present invention that the two active agents which form the dual antagonist have different mechanisms of action such as reverse transcriptase inhibition, protease inhibition, zinc finger inhibition, TAT inhibition, integrase inhibition or other inhibitory activity. Noted here is the fact that each of the above-described agents, without limitation, may be co-administered with any one or more of the compounds according to the present invention without being chemically linked. The term "effective" is used herein, unless otherwise indicated, to describe an amount of a compound which, in context, is used to produce or effect an intended result, whether that result relates to the treatment of a viral disease state, disorder or condition associated with a viral disease or alternatively, is used to produce another compound, agent or composition. This term subsumes all other effective amount or effective concentration terms which are otherwise described in the present application. The term "patient" is used throughout the specification to describe an animal, generally a mammal and preferably a human, to whom treatment, including prophylactic treatment, with the 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 term patient refers to that specific animal. The term "virus" shall be used to describe all types of viruses, the growth or replication of which may be inhibited or disease states of which may be treated using one or more methods according to the present invention. Viruses which may be treated according to the present invention include, for example, human immunodeficiency viruses 1 and 2 (HTV-1 and HIV-2), human T-cell leukemia viruses 1 and 2 (HTLV-1 and HTLV-2), respiratory 12 WO 2005/011709 PCT/US2004/004713 syncytial virus (RSV), human papilloma virus (HPV), adenovirus, hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), human herpes virus 8 (HHV-8, also known as Kaposi's sarcoma-associated vims) and flaviviruses, including Yellow Fever virus, Dengue virus, Japanese Encephalitis and West Nile viruses, among numerous others. The term "human immunodeficiency virus" shall be used to describe human immunodeficiency virus (HTV) and its infections, which term shall be used to embrace both human immunodeficieny virus 1 (HTV-1) and human immunodeficiency virus 2 (HTV-2). The term "human T-cell leukemia virus" shall be used to describe human T-cell leukemia virus and its infections, which term shall be used to embrace both human T-cell leukemia virus 1 (HTLV-1) and human T-cell leukemia virus 2 (HTLV-2). The term "Hepatitis B Virus (HBV)" is used to describe the virus (serum hepatitis virus) which produces viral heptatis type B in humans. This is a viral disease with a long incubation period (about 50 to 160 days) in contrast to Hepatitis A virus (infectious hepatitis virus) which has a short incubation period. The virus is usually transmitted by injection of infected blood or blood derivatives or merely by use of contaminated needles, lancets or other instruments. Clinically and pathologically, the disease is similar to viral hepatitis type A; however, there is no cross-protective immunity. Viral antigen (HBAg) is found in the serum after infection. The term "Herpes Simplex Virus" (HSV) is used throughout the specification to describe HSV1 and HSV 2 which are the causative viral agents of Herpes infections, including genital Herpes infections. The term "Hepatitis C Virus (HCV)" is used throughout the specification to describe the hepatitis virus which is the causative agent of non-A, non-B hepatitis. The disease in the acute stage is, in general, milder than hepatitis B, but a greater proportion of such infections become chronic. 13 WO 2005/011709 PCT/US2004/004713 The term "Epstein-Bap- virus (EBV)" is used throughout the specification to describe a herpetovirus found in cell cultures of Burlatts lymphoma. EBV is the causative agent in infectious mononucleosis, as well as in a number of other related conditions/disease states, including EBV-associated lymphomas. The term "Varicella-Zoster virus (VZV)" is used to describe Herpes virus variceltae, also known as chicken pox or herpes zoster. Varicella results from a primary infection with the virus; herpes zoster results from secondary invasion by the same or by reactivation of infection which in many instances may have been latent for a number of years. Both the primary and secondary infections of VZV may be treated using compositions according to the present invention. The term "respiratory syncytial virus (RSV)" is used throughout the specification to describe an RNA-containing virus of the genus Pneumovirus that causes minor respiratory infection with rhinitis and cough in adults, but is capable of causing bronchitis and bronchopneumonia in young children. The virus is named for the tendency to form syncytia in tissue culture. The term "adenovirus" is used throughout the specification to describe a virus of the family adenoviridae which are double-stranded DNA-containing viruses, which infect mammals and birds. The virion is 70 to 90 ttm in diameter and is naked (has no envelope). The virus develops in nuclei of infected cells; isolation requires tissue cultures since laboratory animals are not susceptible to apparent infection. The family includes two genera, Mastadenovirus and Acviadenovirus. The term "Human Herpes Virus 8 (HHV-8)" is used throughout the specification to describe a herpetovirus which is believed to be the causative agent of Kaposis sarcoma in AIDS patients. The term "Human Papilloma Virus (HPV)" is used throughout the specification to describe a virus which causes genital warts. Also known as infectious warts virus, HPV is a universal, common, often recurrent viral infection with a large number of serotypes. HPV infection can lead to the formation of genital warts which can, in turn, lead to genital and/or cervical cancer. Genital warts caused by HPV types 1, 2, 6,11,16 and 18 are generally 14 WO 2005/011709 PCT/US2004/004713 transmitted sexually and are often associated with cervical and/or genital cancer. HPV may mature to produce a papillary tumor or wart, which is a circumscribed benign epithelial tumor projecting from the surrounding surface. It is generally a benign epithelial neoplasm consisting of villous or arborescent outgrowths of fibrovascular stroma covered by neoplastic cells. The term "flavivirus" is used throughout the specification to describe viruses belonging to the genus Flavivirus of the family Togaviridae. According to virus taxonomy, about 50 viruses including Hepatitis C virus (HCV), Yellow Fever virus, Dengue Virus, Japanese Encephalitis virus, West Nile virus and related flaviviruses are members of this genus. The viruses belonging to the genus Flavivirus are simply called flaviviruses. These viruses were formerly classified as group B arboviruses. The flaviviruses are agents of infectious disease and predominate in East, Southeast and South Asia and Africa, although they may be found in other parts of the world as well. The term "Yellow Fever virus" is used to describe the flavivirus which is the causative agent of yellow fever. Yellow fever is a tropical mosquito-borne viral hepatitis, due to Yellow Fever virus (YFV), with an urban form transmitted by Aedes aegypti, and a rural, jungle or sylvatic form from tree-dwelling mammals by various mosquitos of the Haemagogiis species complex. Yellow fever is characterized clinically by fever, slow pulse, albuminuria, jaundice, congesion of the face and hemorrhages, especially hematemesis (black vomit). It is fatal in about 5-10% of the cases. The term "Dengue virus" is used throughout the specification to descibe the flavivirus which is the causative agent(s) of dengue fever/dengue hemorrhagic fever. Dengue is a disease of tropical and subtropical regions occurring epidemically and caused by Dengue virus, one of a group of arboviruses which causes the hemorrhagic fever syndrome. Four grades of severity are recognized: grade I: fever and constitutional symptoms, grade II: grade I plus spontaneous bleeding (of skin, gums or gastrointestinal tract), grade HI: grade II plus agitation and circulatory failure and grade IV: profound shock. The disease is transmitted by a mosquito of the genus Aedes (generally A aegyptil, but frequently, A. albopictus). Also called Aden, bouquet, breakbone, dandy, date, dengue (hemorrhagic) or polka, solar fever, stiffneclc fever, scarlatina rheumatica or exanthesis arthorosia. 15 WO 2005/011709 PCT/US2004/004713 Hemorrhagic dengue is a more pathogenic epidemic form of dengue which has erupted in a number of epidemic outbreaks in the Pacific region in recent years. I The term "pharmaceutically acceptable salt" is used throughout the specification to describe a salt fonn of one or more of the compositions (and in particularly preferred aspects according to the present invention, phosphate salts) herein which are presented to increase the solubility of the compound in saline for parenteral delivery or in the gastric juices of the patient's gastrointestinal tract in order to promote dissolution and the bioavailability of the compounds. 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, magnesium and ammonium salts, among numerous other acids well known in the pharmaceutical art. Sodium and potassium salts are particularly preferred as neutralization salts of carboxylic acids and free acid phosphate containing compositions according to the present invention. The term "salt" shall mean any salt consistent with the use of the compounds according to the present invention. In the case where the compounds are used in pharmaceutical indications, including the treatment of neoplasia, including cancer, the term "salt" shall mean a pharmaceutically acceptable salt, consistent with the use of the compounds as pharmaceutical agents. The term "pharmaceutically acceptable derivative" is used throughout the specification to describe any pharmaceutically acceptable prodrug form (such as an ester or ether or other prodrug group) which, upon administration to a patient, provides directly or indirectly the present compound or an active metabolite of the present compound. The term "alkyl" shall mean within its context a C1-C20, preferably a C1-C10 linear, branch-chained or cyclic fully saturated hydrocarbon radical. The term "ether" shall mean a Ci to C20 ether group, formed from an oxygen and an alkyl group at a position on the sugar moiety of compounds according to the present invention, or alternatively, may also contain at least one oxygen group within the alkyl chain. The term "acyl" is used throughout the specification to describe a group at the 5' position of the nucleoside analog (i.e., at the free hydroxyl position in the sugar synthon) which contains a Ci to C20 linear, branched or cyclic alkyl chain. The acyl group at the 5' 16 WO 2005/011709 PCT/US2004/004713 position, in combination with the 5' hydroxyl group results in an ester, which, after administration, may be cleaved to produce the free nucleoside form of the present invention. Acyl groups according to the present invention are represented by the structure: O II R4C- where R4 is a Q to C20 linear, branched or cyclic alkyl group, alkoxyalkyl, aiyloxyalkyl, such as phenoxymethyl, aiyl, allcoxy, among others. Preferred acyl groups are those where R4 is a Ci to C10 alkyl group. Acyl groups according to the present invention also include, for example, those acyl groups derived from benzoic acid and related acids, 3-chlorobenzoic acid, succinic, capric and caproic, lauric, myristic, palmitic, stearic and oleic groups, among numerous others including mesylate groups. One of ordinary skill in the art will recognize the acyl groups which will have utility in the present invention, either to synthesize the target pharmaceutical compounds or as prodrug forms of the nucleosides according to the present invention. The term "phosphate ester" or "phosphodiester" is used throughout the specification to describe mono-phosphate groups at the 5' position of the dioxanyl moiety or sugar synthon which are diesterified such that the phosphate group is rendered neutral, i.e., has a neutral charge. Phosphate esters for use in the present invention include those represented by the structures: 0 O II II Nucleoside - P-O-R5 or Nucleoside - P-O-Rs 1 I OR5 N-CH-R7 I 0=C-0R" where R5, R^ and R" are selected from a Ci to C20 linear, branched or cyclic alkyl group, alkoxyalkyl, aryloxyalkyl, such as phenoxymethyl, aryl and allcoxy, among others, and R7 is a Ci to C20 linear, branched or cyclic alkyl or acyl group, alkoxyalkyl, aryloxyallcyl, such as phenoxymethyl, aiyl and alkoxy, among others. Preferred monophosphate esters for use in prodrug forms according to the present invention are those where R5 is a Ci to C20 is a linear or branched chain alkyl group, more preferably a Ci to C3 alkyl group. 17 WO 2005/011709 PCT/US2004/0047I3 The term "protecting group" or "blocking group" shall mean, within its context, a chemical group or moiety which is used to prevent an otherwise active moiety such as an amine, hydroxyl or mercapto group from reacting in a given reaction scheme and which is readily removed under mild conditions which do not otherwise undesirably affect the molecule or compound to which the protecting group is bonded. In the present invention, numerous protecting groups may be used to produce compounds according to the present invention, preferred groups include the benzoate group to protect or block a primary or secondary hydroxyl group and silyl groups (in particular, a tertiaiy butyl dimethyl silyl, a tertiary butyl diphenyl silyl group or a trimetliylsilyl group or a related silyl protecting group) to block primary (or secondary) hydroxyl groups. One of ordinary skill in the art will recognize the various protecting groups which may be utilized within context in producing compounds and intermediates according to the present invention. The term "inhibitory effective concentration" or "inhibitory effective amount" is used throughout the specification to describe concentrations or amounts of compounds according to the present invention which substantially or significantly inhibit the growth or replication of susceptible viruses, especially including human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2), human T-cell leukemia viruses 1 and 2 (HTLV-1 and HTLV-2), respiratory syncytial virus (RSV), human papilloma virus (HPV), adenovirus, hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), human herpes virus 8 (HHV-8, also known as Kaposi's sarcoma-associated virus) and flaviviruses, including Yellow Fever virus, Dengue virus, Japanese Encephalitis and West Nile viruses, among numerous others. The term "preventing effective amount" is used throughout the specification to describe concentrations or amounts of compounds according to the present invention which are prophylactically effective in preventing, reducing the likelihood of infection or delaying the onset of infections in patients caused by human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2), human T-cell leukemia viruses 1 and 2 (HTLV-1 and HTLV-2), respiratory syncytial virus (RSV), human papilloma virus (HPV), adenovirus, hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), human herpes 18 WO 2005/011709 PCT/US2004/004713 virus 8 (HHV-8, also known as Kaposi's sarcoma-associated virus) and flaviviruses, including Yellow Fever virus, Dengue virus, Japanese Encephalitis and West Nile viruses, among numerous others. The term "coadministration" or "combination therapy" is used to describe a therapy in which at least two active compounds in effective amounts are used to treat a viral infection at the same time. Although tire term coadministration preferably includes the administration of two active compounds to the patient at the same time, it is not necessary that the compounds be administered to the patient at the same time, although effective amounts of the individual compounds will be present in the patient at the same time. Compounds according to the present invention may be administered with one or more anti-viral agent, including anti-HIV agents such as nucleoside reverse transcriptase inhibitors (NRTI), non-nucloeoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, among others, exemplary compounds of which may include, for example, 3TC (Lamivudine), AZT (Zidovudine), (-)-FTC, ddl (Didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA), D-D4FC (Reverset), D4T (Stavudine), Racivir, L-FddC, L-FD4C, NVP (Nevirapine), DLV (Delavirdine), EFV (Efavirenz), SQVM (Saquinavir mesylate), RTV (Ritonavir), IDV (Indinavir), SQV (Saquinavir), NFV (Nelfinavir), APV (Amprenavir), LPV (Lopinavir), fusion inhibitors such as T20, among others, fuseon and mixtures thereof, including anti-HTV compounds presently in clinical trials or in development. Coadministration also embraces the administration of dinucleoside analogs (i.e., compounds wherein at least two biologically active nucleosides are chemically linked via a chemical linker such as, for example, without limitation, phosphate groups or carboxylate groups, among others) or other dual antagonists, where at least one of the active nucleoside compounds of the dinucleoside compound is a compound as otherwise described herein. Compounds according to the present invention may be used in pharmaceutical compositions having biological/pharmacological activity for the treatment of, for example, viral infections, as well as a number of other conditions and/or disease states which may appear or occur secondary to the viral infection. These compositions comprise an effective amount of any one or more of the compounds disclosed hereinabove, optionally in combination with a pharmaceutically acceptable additive, carrier or excipient. Compounds according to the present invention may also be used as intermediates in the synthesis of 19 WO 2005/011709 PCT/US2004/004713 compounds exhibiting biological activity as well as standards for determining the biological activity of the present compounds as well as other biologically active compounds. The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol. 20 WO 2005/011709 PCT/US2004/004713 The pharmaceutical compositions of this invention may he orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. Hie pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used. For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for tqpical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyetliylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan mono stearate, polysorbate 60, cetyl esters wax, ceteaiyl alcohol, 2-octyldodecanol, benzyl alcohol and 21 WO 2005/011709 PCT/US2004/004713 water. For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as ben2ylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum. The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or otlier conventional solubilizing or dispersing agents. The amount of novel nucleoside of the instant invention that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between about 0.01 and 150, preferably about 0.5 to about 25 mg/kg of patient/day of the novel nucleoside can be administered to a patient receiving these compositions. It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease or condition being treated. 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, sub-cutaneous, 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 Hie particular agent chosen as well as the severity of 22 WO 2005/011709 PC T/US2004/004713 disease in the patient. Oral dosage forms are particularly preferred, because of ease of admnistration 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 according to the present invention is preferably intimately admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dose. A carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral. In preparing pharmaceutical compositions in oral dosage form, any of the usual pharmaceutical media may be used. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives including water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents and the like may be used. For solid oral preparations such as powders, tablets, capsules, and for solid preparations such as suppositories, suitable carriers and additives including starches, sugar carriers, such as dextrose, mannitol, lactose and related carriers, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used. If desired, the tablets or capsules may be enteric-coated or sustained release by standard techniques. The use of these dosage forms may significantly the bioavailability of the compounds in the patient. For parenteral formulations, the carrier will usually comprise sterile water or aqueous sodium chloride solution, though other ingredients, including those which aid dispersion, also may be included. Of course, where sterile water is to be used and maintained as sterile, the compositions and carriers must also be sterilized. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. Liposomal suspensions (including liposomes targeted to viral antigens) may also be prepared by conventional methods to produce pharmaceutically acceptable carriers. This may be appropriate for the delivery of free nucleosides, acyl/alkyl nucleosides or phosphate ester pro-drug forms of the nucleoside compounds according to the present invention. In particularly preferred embodiments according to the present invention, the compounds and compositions are used to treat, prevent or delay the onset of viral infections 23 WO 2005/011709 PCT/US2004/004713 of mammals and in particular HIV, HBV, HSV1 and/or II, EBV, HHV-8 and flavivirus infections, among others. In its preferred embodiments, the compounds are used to treat HIV, HSV I and/or II, HBV, EBV or HHV-8 infections, especially HTV infections in humans. Preferably, to treat, prevent or delay the onset of a viral infection, the compositions will be administered in oral dosage fonn in amounts ranging from about 250 micrograms up to about 500 mg or more at least once a day, preferably, up to four times a day, within the dosage range used for therapeutic treatment. The present compounds are preferably administered orally, but may be administered parenterally, topically, in suppository or other form. The compounds according to the present invention, because of their low toxicity to host cells, may advantageously be employed prophylactically to prevent a viral infection or to prevent the occurrence of clinical symptoms associated with the viral infection, for example AIDS secondary to HIV, lymphoma secondary to EBV or Kaposi's sarcoma secondary to HHV-8. Thus, the present invention also encompasses methods for the prophylactic treatment (preventing, reducing the likelihood or delaying the onset) of viral infections, and in particular HTV and EBV and in particular, conditions which occur secondary to those viruses. In this aspect according to the present invention, the present compositions are used to prevent reduce the likelihood of or delay the onset of a viral infection, in particular, HIV, HSV, EBV or another virus infection or a virus related disease or condition such as AIDS or EBV-related lymphoma or Kaposi's sarcoma (HHV-8). This prophylactic method comprises administering to a patient in need of such treatment or who is at risk for the devolopment of an HTV, EBV, HHV-8 or other viral infection, an amount of a compound according to the present invention effective for alleviating, preventing or delaying the onset of the the viral infection. In the prophylactic treatment according to the present invention, it is preferred that the antiviral compound utilized should be as low in toxicity and preferably non-toxic to the patient. It is particularly preferred in this aspect of the present invention that the compound which is used should be maximally effective against the virus and should exhibit a minimum of toxicity to the patient. In the case of compounds of the present invention for the prophylactic treatment of viral infections, these compounds may be administered within the same dosage range for therapeutic treatment (as described hereinabove, as a prophylactic agent to prevent the proliferation of the viral infection or alternatively, to prolong the onset of or reduce the likelihood of a patient contracting a virus infection which manifests itself in clinical symptoms. 24 WO 2005/011709 PCT/US2004/004713 In addition, compounds according to the present invention maybe administered alone or in combination with other agents, including other compounds of the present invention. Certain compounds according to the present invention may be effective for enhancing the biological activity of certain agents according to the present invention by reducing the metabolism, catabolism or inactivation of other compounds and as such, are co-administered for this intended effect. As indicated, compounds according to the present invention may be administered alone or in combination with other anti-viral agents for the treatment of a virus infection as otherwise described herein, especially including other compounds of the present invention or compounds which are otherwise disclosed as being useful for the treatment of HIV or flaviviruses, including those presently used to treat HIV such as nucleoside reverse transcriptase inhibitors (NRU), non-nucloeoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, among others, exemplary compounds of which may include, for example, 3TC (Lamivudine), AZT (Zidovudine), (-)-FTC, ddl (Didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA), D-D4FC (Reverset), D4T (Stavudine), Racivir, L-FddC, L-D4FC, NVP (Nevirapine), DLV (Delavirdine), EFV (Efavirenz), SQVM (Saquinavir mesylate), RTV (Ritonavir), EDV (Indinavir), SQV (Saquinavir), NFV (Nelfmavir). APV (Amprenavir), LPV (Lopinavir), fusion inhibitors such as T20, among others, fuseon and mixtures thereof, including anti-HTV compounds presently in clinical trials or in development, among others as well as compounds which are disclosed in inter alia, U.S. patent numbers 6,240,690; 6,316,505; 6,316,492; 6,232,120; 6,180,604; 6,114,327; 5,891,874; 5,821,242; 5,532,215; 5,491,135; 5,179,084; and 4,880,784, among others, relevant portions of which are incorporated by reference herein. The compounds disclosed in the above-referenced patents may be used in combination with the present compounds for their additive activity or treatment profile against HIV and/or other viruses and in certain instances, for their synergistic effects in combination with compounds of the present invention. Preferred secondary or additional compounds for use with the present compounds are those which do not inhibit HIV or another virus. Certain compounds according to the present invention may be effective for enhancing the biological activity of certain agents according to the present invention by reducing the metabolism or inactivation of other compounds and as such, are co-administered for this intended effect. 25 WO 2005/011709 PCT/US2004/004713 The present invention is now described, purely by way of illustration, in the following examples. It will be understood by one of ordinary skill in the art that these examples are in no way limiting and that variations of detail can be made without departing from the spirit and scope of the present invention. Chemistry The novel compounds of the instant invention were generally prepared in the manner following the general synthetic description set forth in Figures 4-7C. The remaining compounds may be readily synthesized by analogy. In general, the nucleoside analog (i.e., a compound containing the base and sugar synthon) is prepared initially and the corresponding 4' group is introduced as depicted generally in Schemes A and B and as otherwise described in the experimental, One of ordinary skill will readily be able to synthesize compounds according to the present invention by analogy following the synthesis presented in the experimental without engaging in undue experimentation. As set forth in figure 4, the 5'-iodo,3'-0-blocked 2'-deoxynucleoside is converted to a 4'5'-vinyl blocked nucleoside 2 which is then converted in a series of steps through a 4'5'-oxirane blocked nucleoside 4 to the 4'-vinyl compound TDK-4-152. As set forth in Figure 5, TKD-4-114 is synthesized from a 5'-iodo-3'-0-bloclced nucleoside compound 7 by forming the 4\5'-vinyl compound 8, introducing the ethynyl group at the 4'-position of the blocked nucleoside to form nucleoside 10a and then ultimately forming the 2',3' unsaturated double bond through elimination of a mesylated hydroxyl group at the 3' position of compound 13. Other compounds according to the present invention are synthesized by analogy using the above-described chemical schemes. Figure 5A shows an alternative synthesis of TDK-4-114 from intermediate 9 of Figure 5. In this aspect of the invention, intermediate 9 is reacted with leadbenzoate Pb(OCOPh) or lead tetraacetate Pb(OAc)4 in a scavenging base such as triethyl amine, diisopropylethvlarnine, or pyridine in an appropriate solvent to produce the 4'5'-diacyl (benzoyl or acetyl) blocked nucleoside 2 (Figure 5A), depending upon the lead (Pb) acylating agent used. Introduction of a 4'ethynyl group proceeds through intermediate blocked nucleoside 2 by action of aluminum acetylene agent EtAl(Cl)-C=SiMe3 (See Figure 5A) in a 26 WO 2005/011709 PCT/US2004/004713 solvent to produce 4'acetylene nucleoside compound 3 (Figure 5A). Synthesis of TKD-4-114 proceeds in a straightforward manner by elimination of the mesylated hydroxyl group to form the 4'-ethynyl-2'J3' unsaturated nucleoside compound 7. Note that intermediate 3 of figure 5 A (and 5B) may alternatively be synthesized from the 4',5'vinyl blocked nucleoside compound 1 of Figures 5 A and 5B (identical to compound 9 of Figure 5) by a two step reaction to form the di-O-benzoyl compound 3 (or di-O-acetyl) of Figure 5B using a first step of iodine and silver benzoate (silver acetate) in solvent to form intermediate 2 (Figure 5B) which can be reacted further with silver benzoate (silver acetate) in solvent at elevated temperature to form interm ediate 3 (or the di-O-acetyl compound by analogy). The chemical synthetic scheme in Figure 6 exemplifies the synthesis of the unsaturated carbocyclic analog KMA-23-153 (Figure 6) from cyclopentanone ester 1 (Figure 6) which proceeds through a number of intermediates to fonn intermediate 8 (Figure 6) which can be condensed with a nucleoside base to form intermediate 9 wherein the 4' ester can be converted to the 4'-ethynyl compound 10 followed by removal of the 5' blocking group to produce KMA-23-153. Figure 7A shows the chemical synthesis of 4'-ethynyl-2'-deoxy nucleoside compounds following the general method of Nomura, et al., J. Med. Chem., 42, 2901-2908 (1999) by introducing a halogenated vinyl group at the 4' position of the nucleoside which undergoes dehydrohalogenation to form the 4'-ethynyl nucleoside compound 8 (Figure 7A). Figure 7B shows the synthesis of the 4'-ethynyl-2'-deoxy nucleoside from a readily available sugar precursor 9 (Figure 7B) which proceeds through the introduction of a 4'-halogenated vinyl group to a4'-formyl group of the sugar synthon 10 to form 11 (Figure 7B) followed by dehydrohalogenation, introduction of the nucleoside base and eventual conversion of the 2' hydroxyl group in a series of steps to form compound 18. Figure 7C Scheme 3 shows the introduction of a 2',3'-double bond in a 4'-ethynyl analog by mesylating the 3'OH group followed by reacting mesylated intermediate with strong base to produce the double bond at the 2',3' position of the sugar. Following one or more of the above-described synthetic methods and using routine synthetic methods well-known in the art, one of ordinary skill may readily produce compounds according to the present invention. 27 WO 2005/011709 PCT/US2004/004713 Specific Examples Chemical Synthesis following Schemes A and B In Figure 5 and Figure 6 Synthesis of TKD-4-152 (Figure 4) TKD-4-152 (4-allyhhymidine) was synthesized by a series of reactions shown in Figure 5, Scheme A, starting from compound 1 which was prepared according to the published procedure: J. P. H. Verheyden and J. G. Moffatt, J. Org. Chem., 39, 3573-3579 (1974). l-[3-0-(MiutyIdimethylsilyI)-2,5-dideoxy-(3-D-.g/vcm>-pent-4-enofuranosyl|thymine (3) To an CH3CN (150 mL) solution of 1 (11.9 g, 30.19 mmol) was added DBN (11.2 mL, 90.57 mmol) at 0 °C under Ar atmosphere, and the whole was stirred at room temperature overnight. After neutralization with AcOH, the reaction mixture was evaporated to dryness and the residue was partitioned between CHCVsaturated aqueous NaHC03 (200 mL x2/50 mL). Silica gel column chromatography (hexane/AcOEt = 5/1-1/2) of the organic layer gave 2 (6.98 g, 87%) as a foam. Compound 2 (6.90 g, 25.92 mmol) was treated with saturated NH3 hi MeOH (350 mL) at 0°C overnight. The reaction mixture was evaporated to dryness and dried overnight in vacuo. To a DMF (60 mL) solution of the residue were added imidazole (5.29 g, 77.75 mmol) and ferf-butyldimethylsilyl chloride (7.81 g, 51.83 mmol) at 0°C under Ar atmosphere, and the mixture was stirred at room temperature overnight. The reaction mixture was partitioned between AcOEt/ItO (300 mL/100 mL x 5). Silica gel column chromatography (hexane/AcOEt = 10/1-3/1) of the organic layer gave 3 (7.87 g, 90%) as a foam: UV(MeOH)Amax 264 nm (el 1100),A,mm 234 nm (e4900); 'H NMR (CDC13)50.13 (6H, s, SiMe). 0.91 (9H, s, SiBu-f), 1.94 (3H, d, J6Me= 1.2 Hz, Me), 2.13-2.20 (1H, m, H-2'a), 2.40 (1H, ddd, J8em = 13.6 Hz, J2%3- « 3.4 Hz and Jv>vh= 6.2 Hz, H-2'b), 4.24 (1H, d, Jsem = 2.0 Hz, H-5'a), 4,54 (1H, d, Jmm = 2.0 Hz, H-5'b), 4.75 (1H, dd, J2',,y = 6.0 andJ2'w = 3.4 Hz, H-31), 6.49 (1H, t, 7i>,2.a = JVtVb= 6.2 Hz, II-l'), 6.98 (III, d, 7e)Me= 1-2 Hz, H-6), 8.47 (1H, br, NH); FAB-MS m/z 339 (1VT+H). Anal. Calcd for C16H26N204Si: C, 56.78; H, 7,74; N, 8.28. Found: C, 57.04; H, 7.99; N, 8.14. 28 WO 2005/011709 PCT/US2004/004713 3'-0-(r-Butyldimethylsilyl)thymidme 4',5'-epoxide (4)To a CH2CI2 (3 mL) solution of 3 (20 mg, 0.059 mmol) was added dimethyldioxirane (0.072 M in acetone, 1.2 mL, 0.089 mmol) at -30 °C under Ar atmosphere, and the reaction mixture was stirred for 30 min at —30 °C. Evaporation of the solvents gave 4 as a solid: 'HNMR (CDCI3) 50.09, 0.10 (6H, each as Sj SiMe), 0.90 (9H, s, SiBu-t), 1.95 (3H, d, J6,Me= 1-3 Hz, Me), 2.25 (1H, ddd, Jgem = 14.0 Hz, J2%y = 4.9 Hz and J\-o'a = 7.1 Hz, H-2'a), 2.52 (1H, ddd, Jsem = 14.0 Hz, J2%v= 1.6 Hz and Jy,2'b = 6.2 Hz, H-2'b), 3.07 (1H, d, Jgem = 3.3 Hz, H-5'a), 3.36 (1H, d, Jgem = 3.3 Hz, H-5'b), 4.26 (1H, dd, J2%3' = 4.9 and/2',b,3,= 1-6 Hz), 6.12 (1H, dd, Jv,va— 7.1 Hz and Jr,2'b = 6.2 Hz, H-l'), 7.27 (1H, d, J6Me= 1.3 Hz, H-6), 9.06 (1H, br, NH); FAB-MS m/z 355 (M++H). 3'-0-(*-Butyldimethylsilyl)-4'-a-aliylthymidine (5)To a CH2C12 (5 mL) solution of 3 (80 mg, 0.24 mmol) was added dimethyldioxirane (0.098 M in acetone, 3.6 mL, 0.36 mmol) at -30 °C under Ar atmosphere, and the mixture was stirred for 30 min at -30 °C. The solvents were evaporated and the residue was dried in vacuo for 1 h to give 4. To a CH2CI2 (5 mL) solution of 4 were added allyltrimethylsilane (0.11 mL, 0.71 mmol) and SnCL (1 M in CH2CI2, 0.71 mL, 0.71 mmol) at -30 °C under Ar atmosphere, and the mixture was stirred for 4 h at -30 °C. After being quenched with saturated aqueous NaHCC>3, the reaction mixture was filtered through celite pad. The filtrate was partitioned between CHCl3/saturated aqueous NaHC03 (60 mL x3/20 mL). The organic layer was evaporated to dryness and the residue was treated with saturated NH3 in MeOH (30 mL) at room temperature for 12 h. Evaporation followed by preparative TLC (hexane/EtOAc = 2/3) purification of the organic layer gave 5 (75 mg, 80%) as a foam: UV(MeOH)/Wx 267 nm (sl2700),Xmin 235 nm (s5900); 'H NMR (CDC13)80.08,0.08 (6H, each as s, SiMe), 0.89 (9H, s, SiBu-/), 1.87 (3H, d, J6Me= 1.1 Hz, Me), 2.16 (1H, dd, Jgem = 14.5 Hz andJ6-a,7-= 8.1 Hz, CHzCH^CHz), 2.27-2.39 (2H, m, H-2'), 2.44 (1H, dd, JgEm = 14.5 Hz and J6%T = 6.3 Hz, CH2CH=CH2), 2.94 (1H, br, OH), 3.52 (1H, dd, Jgem = 11-8 Hz and/5',oh= 6.1 Hz, H-5'a), 3.73 (1H, dd, Jgem = 11.8 Hz and Js',oh= 2.7 Hz, H-5'b), 4.62 (1H, dd, = 5.8 Hz and Jv,b,r= 7.0 Hz, H-3'), 5.07-5.13 (2H, m, CH2CH=CH2), 5.83-5.93 (1H, m, CH2CH=CH2), 6.11 (1H, dd, Jr,ra= 5.8 Hz andjr,2.b= 6.9 Hz, H-l1), 7.45 (1H: d, = 1.1 Hz, H-6), 9.40 (1H, br, NH); nOe experiment, H-1 VCH2CH=CH2 (0.8%), CH2-5'/H-3' (5.3%), CH2-57H-6 (0.6%), HO-5VH-3' (0.7%) and HO-5'/H-6 (1.2%); FAB-MS m/z 397 (M++H). Anal. Calcd for CifeNaOsSiD l/3HzO: C, 56.69; H, 8.18; N, 6.96. Found: C, 56.46; H, 8.18; N, 6.87. 29 WO 2005/011709 PCT/US2004/004713 TKD-4-152 (4'-aIlylthymidine) Figure 4 A mixture of 5 (59 mg, 0.149 mmol) and tetrabutylammmonium fluoride (58 mg, 0.223 mmol) in THF (3 mL) was stirred at room temperature for 12 h. Silica gel column chromatography (CHCl^/MeOH = 20/1) of the evaporated reaction mixture gave TKD-4-152 (37.7 mg, 90%) as a foam: UV (MeOH) Imax 267 nm (e 9300), 5\.miI1235 nm (s 2000); *H NMR 5 1.86 (3H, d, J6Me= 1.2 Hz, Me), 2.27-2.35 (3H, m, H-2' and CH2CHCH2), 2.42-2.48 (1H, m, CH2CH=CH2), 3.56 (1H, d, Jgem= 11.8 Hz, H-5'a), 3.64 (1H, d, Jgem= 11.8 Hz, H-5'b), 4.48 (1H, t, J2'a,3?=Jnrf=5.8 Hz, H-3'), 5.04-5.13 (2H,m, CH2CH=CH2), 5.88-5.98 (1H, m, CH2CH=CH2), 6.23 (1H, t, Jv>y = JVtVb= 6.5 Hz, H-l'), 7.89 (1H, d, J6Me= 1.2 Hz, H-6); FAB-MS m/z 283 (M^ II), 321 (M";+K). Anal. Calcd for Ci3HiSN20f *1/2H20: C, 54.16; H, 6.57; N, 9.62. Found: C, 53.87; H, 6.49; N, 9.28. TKD-4-114 (2',3'-didehydro-31-deoxy-4l-ethynylthymidine, 4'-ethynyl-d4T) was synthesized by a series of reactions shown in Scheme B, starting from compound 6 which was prepared according to the published procedure: B. V. Joshi and C. B. Reese, Tetrahedron Lett., 32, 2371-2374 (1992).l-(3-0-Acetyl-2,5-dideoxy-5-iodo-p-D-f/i/-«<»-pentofuranosyl)-thyniine (7)A mixture of 6 (5.3 g, 15.05 mmol) and Ac20 (4.3 mL, 45.15 mmol) in pyridine (30 mL) was stirred at room temperature for 13 h. The reaction mixture was partitioned between CHCl3/saturated aqueous NaHC03 (250 mL x3/50 mL). Silica gel column chromatography (hexane/EtOAc = 1/1-1/2) of the organic layer gave 7 (5.53 g, 93%) as a foam:'H NMR(CDC13)5 1.96 (3H, s, Me), 2.11 (3H, s, Ac), 2.11-2.16 (1H, m, H-2'a), 2.82 (1H, ddd, Jgem= 15.8 Hz, Jr,2'b= 8.0 Hz ansd J2%y- 5.7 Hz, H-2'b), 3.32-3.39 (2H, m, H-5'), 4.28 (1H, dt, Jy,4-= 3.3 Hz and/4',5" 7.1 Hz, H-4'), 5.48 (1H, dd, J2%y~ 5.7 Hz andJyA~ 3.3 Hz H-3'), 6.30 (1H, dd, JVy2'&= 2.8 Hz and Jv>rh= 8.0 Hz, H-l'), 7.38 (1H, d, 0.7 Hz, H-6), 8.59 (1H, br, NH); FAB-MS m/z 395(M++H). 1-(3-0-AcetyJ-2,5-dideoxy-jj-L-<£^}>ce/-0-pent-4-enof'uranosy])-t]iymine (8)To an CH3CN (40 mL) solution of 7 (5.5 g, 13.95 mmol) was added DBN (6.9 mL, 55.81 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 17 h. After neutralization with AcOH, the reaction mixture was evaporated to dryness. The residue was partitioned between CHCls/saturated aqueous NaHC03 (200 mL x3/50 mL). Silica gel column chromatography (hexane/EtOAc = 2/1-1/1) ofthe organic layer gave 8 (3.34 g, 90%) as a foam: ]H NMR(CDC13)8: 1.96 (3H, d, JSjMe=1.3 Hz, Me), 2.06 (3H, s, Ac), 2.21 (1H, dt, Jgem= 15.2Hz, 30 WO 2005/011709 PCT/US2004/004713 Jv,vz=J2%y=2.7E.z, H-2'a), 2.83 (1H, dt, Jgem=l5.2 Hz, Jy,rh= Jz%y= 7.1Hz, H-2'b), 4.51 (1H, dd, >/gem= 2.4 Hz, J3-,5-a= 0.8 Hz, H-5'a), 4.73 (1H, dd, Jgem= 2.4 Hz and J3',s'b= 0.7 Hz, H-5'b), 5.70-5.73 (1H, m, H-3'), 6.44 (1H, dd, Jr,2-a= 2.7 Hz and Jr,m= 7.1 Hz, H-l'), 7.25 1.3 Hz, H-6), 8.54 (1H, br, NH); FAB-MS m/z 267(M++H). l-[3-0-(?-Butyldimethylsilyl)-2,5-dideoxy-|3-L-,g/yccr0-pent-4-enofuranosyI]thymine (9)Compound 8 (5.2 g, 19.53 mmol) in saturated NH3 in MeOH (150 mL) was kept at room temperature for 9 h. After evaporation, the residue was dissolved inDMF (60 mL). To this were added imidazole (5.32 g, 78.12 mmol) and ter^butyldimethylsilyl chloride (8.83 g, 58.59 mmol) at 0°C. The reaction mixture was stirred at room temperature for 11 h, and then partitioned between Et0Ac/H20 (250 mL/50 mL x4). Silica gel column chromatography (hexane/EtOAc = 10/1) of the organic layer gave 9 (6.43 g, 97%) as a foam: UV (MeOH) ^max 266nm (sll600), ?umin 236nm (s5700); *H NMRfCDChjS 0.11 and0.14 (6H, each as s, SiMe), 0.88 (9H, s, SiBu-0, 1.92 (3H, d, J6,ch3=1.2Hz, Me), 2.03 (1H, dt, /gem= 10.8 Hz, Jr,2-a= 3.2Hz and JZXT= 3.2Hz, H-2'a), 2.61-2.68 (1H, m, H-2'b), 4.25 (1H, d, /gem= 2.2Hz, H-5'a), 4.57 (1H, d, Jsem= 2.2Hz, H-5'b), 4.68 (1H, dd, J2'-dy= 3.2 Hz, J2%3-= 6.8 Hz H-3'), 6.46 (1H, dd, ./r,2'a= 3.2 Hz and Jv,rb^ 7.2 Hz, H-l'), 7.44 (1H, d, J6,cm= 1.2 Hz, H-6), 9.12 (1H, br, NH); FAB-MS m/z 339(M++H). Anal. Calcd for C^H^N^Si: C, 56.78;H, 7.74;N, 8.28. Found: C, 56.61;H, 7.87;N, 8.17. l-[2-Deoxy-3-0-(/-butyldimethylsilyl)-4-ethynyl-P-D-rf»«o-pento-furanosyl]thymine (10a) and l-[2-Deo:sty-3-0-(f-butyldimethyl-silyl)-4-etliynyl-a-L-«zjyf/ira-pentofuranosyl]thymine (10b)To a solution of 9 (60 mg, 0.177 mmol) in CH2CI2 (5 mL) was added dimethyldioxirane (0.09 M in acetone, 3.0 mL, 0.266 mmol) at -30 °C. After stirring for 0.5 h, the mixture was evaporated and dried in vacuo for 1 h. The residue was dissolved in CH2CI2 (5 mL). To this solution was added triethynylaluminum (0.3 M in CH2CI2, 1.8 mL, 0.532 mmol) at -30 °C under Ar atmosphere, and the reaction mixture was stirred at room temperature for 17 h. After being quenched with saturated aqueous NH4CI, the reaction mixture was filtered through celite pad. The filtrate was partitioned between CHCVsaturated aqueous NH4CI (60 mL x3/20 mL). HPLC separation (hexane/EtOAc = 2/3) of the organic layer gave 10a (tR = 10.8 min, 39.3 mg, 58%, foam) and 10b (tR = 16.2 min, 18.8 mg, 28%, solid). Physical data for 10a: UV (MeOH):)^* 266 nm (el2100), A^in 235 nm (S6000); lHNMR (CDC13)50.11 and 0.16 (6H, each as s, SiMe), 0.90 (9H, s, SiBu-?), 1.91 31 WO 2005/011709 PCT/US2004/004713 (3H, d, /6>Me= 1.3 Hz, Me), 1.91-1.96 (1H, m, H-2'a), 2.33 (1H, br, OH), 2.62 (1H, s, ethynyl), 2.95(1H, ddd, Jgcm= 14.6 Hz, 7.9 Hz and J2%3-= 5.5 Hz, H-2'b), 3.93 (1H, d, J"gem= 11.6Hz, H-5'a), 3.99 (1H, d, Jgem= 11.6Hz, H-5'b), 4.49 (1H, dd, JTa,r= 2.0Hz and J2-b,3-= 5.5Hz, H-3'), 6.39 (1H, dd, Jr,2-a= 3.7 Hz and Jr,2'b= 7.9 Hz, H-l'), 7.65 (1H, d, Je,cn3= 1-3 Hz, H-6), 8.72 (1H, br, NH); FAB-MS m/z 381 (M++H). Anal. Calcd for CigHisNzOsSi-HjO: C, 54.24; H, 7.59; N, 7.03. Found: C, 54.46; H, 7.20; N, 6.72. Physical data for 10b: mp 96-98'C; UV (MeOH):Amax 267 nm (s9300), ^ 235 nm (el700). 'H NMR (CDC13)50.08 and 0.13 (6H, each as s, SiMe), 0.89 (9H, s, SiBu-/), 1.93 (3H, d, J6,ch3= 0.9 Hz, Me), 2.12-2.17 (1H, m, H-2'a), 2.63 (1H, br, OH), 2.71-2.77 (1H, m, H-2'b), 2.75 (1H, s, ethynyl), 3.67 (1H, d, Jgem= 11.5 Hz, H-5'a), 3.74 (1H, d,/gem= 11.5 Hz, H-5'b), 4.47 (1H, t, /2'a,3-=J2'b,3'= 5.3 Hz, H-3'), 6.30 (1H, dd, Jr,2'a=4.8Hz and Jr,rb= 6.9 Hz, H-l'), 7.80 (1H, d, \cH3= 0.9 Hz, H-6), 9.00 (1H, brs, NH); FAB-MS m/z 381 (M++H). Anal. Calcd for C]gH28N205Si: C, 56.82; H, 7.42; N, 7.36. Found: C, 56.57; H, 7.58; N, 7.19. l-[5-0-Acetyl-2-deoxy-3-0-(^-butyldimethylsilyl)-4-ethynyl-P-D-^/ifeo-pentofuranosyl]thymine (11) To a pyridine (4 mL) solution of 10a (161 mg, 0.423 mmol) was added AC2O (120 mL, 1.269 mmol) at 0 °C, and the mixture was stirred at room temperature for 11 h. The reaction mixture was partitioned between CHCl3/saturated aqueous NaHC03 (60 mL x3/20 mL). Silica gel column chromatography (hexane/EtOAc = 3/1) of the organic layer gave 11 (169.7 mg, 95%) as a foam: UV (MeOH^Xnm 266 nm (e9200), A™sn 234 nm (e2000); 'H NMR(CDC13)S0.10 and 0.14 (6H, each as s, SiMe), 0.90 (9H, s, SiBu-/), 1.90-1.94 (4H, m, H-2'a and Me), 2.14 (3H, s, Ac), 2.58 (1H, s, ethynyl), 3.01 (1H, ddd, J£sm= 14.8 Hz, J\ -,2'b= 8.3 Hz and J2'b,3'= 5.0 Hz, H-2'b), 4.37 (1H, d, Jgem= 11-1 Hz, H-5'a), 4.45 (1H, d, JTb,y= 5.0 Hz, H-3'), 4.53 (1H, d, Juem= 11.1 Hz, H-5'b), 6.40 (1H, dd, Jr>2.a= 2.8 Hz andJr,2.b= 8.3 Hz, H-l'), 7.53 (1H, d, J6,Me= 1-3 Hz, H-6), 8.04 (1H, br, NH); FAB-MS m/z 461 (M++K). Anal. Calcd for C2oH3oN206Si: C, 56.85; H, 7.16; N, 6.63. Found: C, 56.84; H, 7.35; N, 6.26. l-(5-O-Acetyl-2-deoxy-4-ethynyl-p-D-/fo-<?0-pentoluranosyI)-thymine (12) • To a THF (4 mL) solution of 11 (169.7 mg, 0.402 mmol) was added tetrabutylammonium fluoride (1M in THF, 602 }.iL, 0.602 mmol) under Ar atmosphere. After being stirred for 1 h at room temperature, the solvent was evaporated. Silica gel column chromatography 32 WO 2005/011709 PCTAJS2004/004713 (CHCl3/MeOH = 100/1) of the residue gave 12 (114.7 mg, 93%) as a foam: UV (MeOH) Xma* 265 nm (e8400), ^in 233 ran (sl700); *H NMR (CDCI3 after addition of D20)81.93 (3H, d, J6,Me= 1.3 Hz, Me), 2.14-2.18 (1H, m, H-2'a), 2.18 (3H, s, Ac), 2.59 (1H, s, ethynyl), 2.94-3.02 (1H, m, H-2'b), 4.22 (1H, d, Jsem= 11.4Hz, H-5'a), 4.31 (1H, d, J2%3- 5.5 Hz, H-3'), 4.68 (1H, d, Jgem= 11.4 Hz, H-5'b), 6.24 (1H, dd, sa/,■ 2.a= 2.9 Hz and JVXb= 9.0 Hz, H-l'), 7.60 (1H, d, \Me= 1.3 Hz, H-6); ,3C NMR (CDC13)512.52,20.84, 38.76, 63.30, 74.73,76.23, 79.85, 82.08, 85.33,111.41,137.93,150.53, 163.63,171.98; FAB-HR-MS m/z calcd for C14Hi7N206 309.1087 (MT+H), Found 309.1074. l-(5-0-Acetyl-2-deoxy-3-O-methanesulfonyl-4-ethynyl-j3-D-*Ar00-pentofuranosyl)thymine (13) To a pyridine (4 mL) solution of 12 (76 mg, 0.247 mmol) was added methanesulfonyl chloride (57 |iL, 0.74 mmol) at 0°C, and the mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between CHCl3/saturated aqueous NaHC03 (60 mL x 3/20 mL). Silica gel column chromatography (CHCl3/MeOH = 100/0-100/1) of the organic layer gave 13 (95.0 mg, 100%) as a foam: *11 NMR (CDClj)51.96 (3H, d, J6Me= 1.2 Hz, Me), 2.16 (3H, s, Ac), 2.38 (1H, ddd, /gem= 16.0 Hz, Jvpir 3.5 Hz and Jr^y- 0.7 Hz, H-2'a), 2.70 (1H, s, ethynyl), 3.11 (1H, s. Ms), 3.19 (1H, ddd, ./Bem= 16.0 Hz, Jr,2-b= 8.4 Hz and Ji%y= 5.5 Hz, H-2'b), 4.48 (1H, d, Jgem= 11.3 Hz, H-5'a), 4.53 (1H, d5/gem= 11.3 Hz, H-5'b), 5.27-5.28 (1H, m, H-3'), 6.52 (1H, dd,Jr>2-a= 3.5 Hz andJr,2't= 8.4 Hz, H-l'), 7.33 (1H, d,/6,Me= 1.2 Hz, H-6), 8.86 (1H, brs, NH); FAB-MS m/z 387(M++H). TKD-4-114 (2',3,-didehydro-3'-deoxy-4'-ethynylthymidlne) A mixture of 13 (105 mg, 0.272 nunol) and DBN (101 liL, 0.815 mmol) in CH3CN (10 mL) was refluxed for 11 h. After being quenched with AcOH, the reaction mixture was partitioned between CHCl3/saturated aqueous NaHC03 (60 mLx3/20 mL). The product, obtained after purification by silica gel column chromatography (hexane/EtOAc = 1/1) of the organic layer, was dissolved in saturated NH3 in MeOH (30 mL), and kept at room temperature for 12 h. Evaporation of the solvent followed by preparative TLC (hexane/EtOAc = 1/1) purification gave TKD-4-114 (49.6 mg, 74%) as a solid: mp 207-209°C ; UV (MeOH) A™ax 264 nm (810800), Xmin 235 nm (s4800); 'H NMR(CDC13)81.83 (3H, s, Me), 2.63 (1H, s, ethynyl), 3.47 (1H, br, OH), 3.88 (1H, d, Jsem= 12.5 Hz, H-5'a), 3.96 (1H, d, Jgem= 12.5 Hz, H-5'b), 5.91 (1H, dd, Jv,2-1.1 Hz and J2-;3>= 5.9 Hz, H-2'), 6.30 (1H, dd, Jv,r= 2.0 Hz and J2-,3.= 5.9 33 WO 2005/011709 PCT/US2004/004713 Hz, H-3'), 7.16-7.17 (1H, m, H-l'), 7.44 (1H, d, Jm^= 1.1 Hz, H-6), 9.06 (1H, br, NH); FAB-MS m/z 249 (M^+H). Anal. Calcd for Ci2H12N204.1/6H20: C, 57.37; H, 4.95; N, 11.15. Found: C, 57.36; H, 4.69; N, 10.98. ^ Alternative Chemical Synthesis of TDK-4-114 (Figure 5A) TKD-4-114 (2',3,-didehydro-3,-deoxy-4'-ethynylthymidines 4'-ethynyl-d4T) was synthesized by a series of reactions shown in the Scheme (See Figure 5A), starting from compound 1, the preparation of which has been reported previously. Preparation of Dibenzoyl compound 2 (a mixture of two diastereomers) To a toluene (70 mL) solution of 1 (3.98 mg, 11.76 mmol) was added z-Pr2NEt (5.1 mL, 29.4 mmol) and Pb(OCOPh)4 (20.33 g, 29.4 mmol) at 0 °C under Ar atmosphere, and the mixture was stirred for 4 h. The reaction mixture was quenched with sat. aqueous NaHCCb, and filtered through celite. Hie filtrate was partitioned between CHCl3/sat. aqueous NaHC03. The organic layer was purified by silica gel column chromatography (hexane/AcOEt = 2/1) to give 2 (4.84 g, 71%) as a foam: 'fl NMR (CDC13)50.02, 0.07, 0.15 and 0.20 (6H, each as s, SiMe), 0.75 and 0.93 (9H, each as s, SiBu-/), 1.69 and 1.91 (3H, each as d, Je,us = 1.2 Hz, Me-5), 1.91-2.00,2.33-2.40, 2.76-2.83 and 2.94-3.01 (2H, each asm, H-2'), 4.73 and4.95 (1H, t and d, Jvy = 6.8 and 4.4 Hz, H-3'), 4.91, 5.08, 5.11 and 5.19 (2H, each as d, Jsem -12.0 Hz, CH2-5'), 4.24 (1H, d, Jgem = 2.0 Hz), 6.34 and 6.64 (1H, d and dd, Jv,t = 6.4 and Ji',2'= 2.8, 8.2 Hz, H-l'), 7.32-7.37, 7.45-7.51, 7.58-7.67, 7.92-7.94, 8.02-8.04 and 8.04-8.13 (11H, each as m, H-6 and Ph), 8.92 (1H, br, NH); FAB-MS (m/z) 581 (M++H). Anal. Calcd for C30H36N2O8Si: C, 62.05; H, 6.25; N, 4.82. Found: C, 61.85; H, 6.37; N, 4.70. l-[5-0-BenzoyI-3-C-(/:-butyldimethyIsilyl)-2-deoxy-4-(trimethylsilyl)ethynyI-Ji-D-^/»-e<?-pentofuranosyljthymine (3) To a toluene (40 mL) solution of HC=CSiMe3 (3.2 mL, 22.44 mmol) was added BuLi (2.44 M in hexane) (9.2 mL, 22.44 mmol) at 0 °C under Ar atmosphere, and the mixture was stirred for 30 min. To this solution was added EtAlCl2 (0.94 M in hexane) (23.4 mL, 22.44 mmol) at 0 °C. After the mixture being stirred for 30 min, 2 (3.26 g, 5.61 mmol) in CH2CI2 (50 mL) was added at 0 °C, and the mixture was stirred overnight. The reaction mixture was , partitioned between CHCl3/sat. aqueous NaHC03. The organic layer was purified by silica gel column chromatography (hexane/EtOAc = 3/1) to give 3 (1.14 g, 37%) as a foam: 'H 34 WO 2005/011709 PCT/US2004/004713 NMR (CDC13)50.09 and 0.13 (6H, each as s, SiMe), 0.12 (9H, s, OCSiMe3), 0.89 (9H, s, SiBu-4 1.90 (3H, d, Jm6= 0.8 Hz, Me-5), 1.95 (1H, ddd, Jvxa= 2.8, J2Xy = 12 and /2-a,2'b = 14.6 Hz, H-2'a), 3.02 (1H, ddd,/r,2'b = 8.2, Jrb,3' = 5.2 and J2'a,2-b= 14.6 Hz, H-2'b), 4.50 (1H, dd,J2Xy = 1-2 andJ2.b>3'= 5.2 Hz, H-3'), 4.64 (1H, d^v'b = 10.8 Hz, H-5'a), 4.68 (1H, d, J5'a,5-b= 10.8 Hz, H-5'b), 6.40 (1H, d, /r,2.a= 2.8 and JVXb= 8.2 Hz, H-l'), 7.44-7.48, 7.57-7.61 and 8.07-8.10 (6H, each as m, H-6 and Ph), 8.24 (1H, br); FAB-MS (m/z) 557 (M++H) l-[5-0-Benzoyl-2-deoxy-4-ethynyl-p-D-^/-e<?-pentofuranosyl]thymine (4) To a THF (5 mL) solution of 3 (208.2 mg, 0.37 mmol) was added B104NF' 3H2O (290.2 mg, 1.11 mmol) at 0 °C, and the mixture was stirred for Ih. The reaction mixture was evaporated to dryness. Silica gel column chromatography (2% MeOH in CH2C12) of the residue gave 3 (115.3 mg, 84%) as a foam: NMR (CDC13 + D20)51.94 (3H, d, Jm6 = 1.2 Hz, Me-5), 2.15 (IH, dd, Jr,2.a= 3.2 and J2%vb = 15.0 Hz, H-2'a), 2.60 (1H, s, OCH), 3.01 (1H, ddd, Jv?b = 9.0, /2-b,3'= 5.2 and/2X2-b= 15.0 Hz, H-2'b), 4.34 (1H, d,/2>b>3'= 5.2 Hz, H-3'), 4.40 (1H, d, J5-a35'b — 11.2 Hz), 4.96 (IH, d, Js-a,5'b = 11.2 Hz), 6.34 (1H, d, Jx<,ra = 3.2 and Jv,Th = 9.0 Hz, H-l'), 7.46-7.51,7.61-7.65 and 8.09-8.11 (5H, each as m, Ph), 7.70 (IH, d, JUe,6 = 1.2 Hz), 8.47 (IH, br); FAB-MS (m/z) 371 (M"+H). l-[5-0-BenzoyI-2-deoxy-4-ethynyI-3-0-methanesuIfonyl~p-D-*yireo-p entofurano syl] thymin e (5) To apyridine (3.5 mL) solution of 4 (110.9 mg, 0.30 mmol) was addedMsCl(0.12 mL, 1.5 mmol) at 0 °C under Ar atmosphere, and the mixture was stirred for 6 h. The reaction mixture was partitioned between CHCl3/sat. aqueous NaHC03. Silica gel column chromatography (1.5% MeOH in CH2CI2) of the organic layer gave 5 (105.2 mg, 78%) as a foam: 'H NMR (CDC13)S1.92 (3H, d, 7Me,6= 1.2 Hz, Me-5), 2.43 (IH, dd, JV,Ta = 3.6 andJ2V>b= 16.0 Hz, H-2'a), 2.72 (IH, s, C=CH), 3.07 (3H, s, S02Me), 3.23 (IH, ddd, Jv,i'b= 8.2, J2%3>= 5.2 and Jixvb= 16.0 Hz, H-2'b), 4.72 (IH, d, J5'a,s-b = 11.2Hz), 4.76 (IH, d, 7svb = 11.2 Hz), 5.37 (IH, d,J2%y = 5.2 Hz, H-3'), 6.56 (IH, d, Jr,2.a= 3.6 and Jv?h = 98.2 Hz, H-l'), 7.36 (IH, d, JMe,6= 1.2 Hz), 7.47-7.51, 7.60-7.64 and 8.07-8.10 (5H, each asm, Ph), 8.32 (IH, br); FAB-MS (m/z) 449 (M++H). 35 WO 2005/011709 PCT/US2004/004713 5 '-O-Benzoyl-2 ',3 '-didehydro-3 '-deoxy-4'-ethynylthymidine (6) To an CH3CN (4 mL) solution of 5 (101.9 mg, 0.23 mmol) was added DBN (67 |xL, 0.54 mmol) at 0 °C under Ar atmosphere, and the mixture was stirred at 80 °C for 9 h. The reaction mixture was neutralized by adding AcOH, and partitioned between CHCVsat. aqueous NaHCOj. Silica gel column chromatography (1.5% MeOH in CH2CI2) of the organic layer gave 6 (60 mg, 74%) as solid: *HNMR (CDC13)51.42 (3H, d, JMe,6= 1.2 Hz, Me-5), 2.70 (IH, s, C=sCH),), 4.59 (IH, d, J5'a,5'b = 12.0 Hz, H-5'a), 4.76 (IH, d, /5.a,5'b = 12.0 Hz, H-5'b), 5.99 (IH, dd,Jv^ = 1.2,y2.,3 = 5.9, H-2'), 6.38 (IH, dd, Jyj—2.0 and J2-,3- = 5.9 Hz, H-3'), 6.98 (IH, d, JMe,6= 1-2 Hz), 7.12 (IH, 111, H-l'), 7.45-7.49, 7.60-7.63 and 8.00-8.03 (5H, each as m, Ph), 8.37 (IH, br); FAB-MS (m/z) 353 (M++H). 2',3'-Didehydro-3'-deoxy-4'-ethynyIthymidine (7) (TKD-4-114, 4'-EthynyI-d4T) To a MeOH (3 mL) suspension of 6 (56 mg, 0.16 mmol) was added 1 MNaOMe (0.32 mL, 0.32 mmol) at 0 °C under Ar atmosphere, and the mixture was stirred at r.t. for 0 h. The reaction mixture was neutralized by adding AcOH and chromatographed on a silica gel column (2% MeOH in CH2CI2) gave 7(35.8 mg, 90%) as solid. Physical data of 7 (TKD-4-114) as set foreth above. Chemical Synthesis of KMA-23-153: the carbocyclic analogue of TKD-4-114 (See Figure 6) KMA-23-153 was prepared as racemic a modification (a mixture of equal amount of D- and L-enantiomers) by a sequence of reactions shown in the Scheme set forth in figure 6. The Method for the preparation of starting material 2 has already been published: See, Kato, et al., Chem. Pharm. Bull, 47, 1256-1264 (1999). l-Hydroxymethyl-2-oxocyclopentanecarboxylic acid methyl ester (3 of Figure 6) To a suspension of 2 (lOg, 55.48 mmol) and HMPA (29 mL, 166.44 mmol) in THF (450 ml) was added BusSnCl (16.5 mL, 61.0 mmol) at 0° C under positive pressure of dry Ar. After stirring at 0 °C for 30 min, (CH20)n (8.32 g, 277.4 mmol) was added to the mixture and the whole reaction mixture was stirred for 48 h at room temperature. The reaction mixture was partitioned between AcOEt and brine. Hie organic layer was dried (Na2S04), evaporated, and 36 WO 2005/011709 PCT/U S2004/004713 chromatographed on a silica gel column (hexane/EtOAc = 1/1). This gave 3 (7.13 g, 77%) as an oil. 'HNMR (CDC13) 8: 1.97-2.18 (2H, m, CH2), 2.21-2.25 (IH, m, CH2), 2.29-2.53 (3H, m, OH and CH2), 2.62-2.66 (IH, m, CH2), 3.74 (3H, s, Me), 3.81 (IH, dd, J= 11.2 and 8.0 Hz, CH2OH), 3.89 (IH, dd, 7= 11.2 and 4.4 Hz, CH2OH). 1-(fer£-ButyldiphenylsilyIoxymethyl)-2-oxo-cyclopentanecarboxylic acid methyl ester (4 ol Figure 6) Amixtiire of 3 (10.35 g, 60.1 mmol), imidazole (8.18 g, 120.2 mmol), and TBDPSC1 (15.6 ml, 60.1 mmol) in DMF (40 ml) was stirred for 16 h at room temperature under positive pressure of dry Ar. The mixture was partitioned between EtOAc and sat. aqueous NaHC03. Hie organic layer was dried (Na2S04) and evaporated. The resulting syrupy residue was treated with MeOH (ca. 40 ml) to give the precipitated 4. This procedure was repeated further 3 times to give 4 (18.97 g, 77%) as a white solid. 1HNMR(CDC13) 3:1.02 (9H, s, SiBu-f), 2.03-2.11 (2H,m, CH2), 2.26-2.35 (IH, m, CH2), 2.41-2.53 (3H, m, CH2), 3.65 (3H, s, Me), 3.87 (IH, d, /= 9.6 Hz, CH2OSi), 4.09 (IH, d,J= 9.6 Hz, CH2OSi), 7.37-7.46 (6H, m, Ph), 7.61-7.65 (4H, m, Ph). l-(<ert-Butyldiphenylsilyloxymethyl)-2-oxocyclopent-3-enecarboxylic acid methyl ester (5 of Figure 6) To a stirring mixture of 4 (3.58 g, 8.72 mmol) and Et3N (6.1 ml, 43.6 mmol) was added Me3Si0S02CF3 (2.56 mL, 13.0 mmol) at 0° C under positive pressure of dry Ar. The mixture was stirred for 30 min at the same temperature, and then partitioned between CH2C12 and sat. aqueous NaHC03. The organic layer was dried (Na2S04) and evaporated. The residue was dissolved in DMSO (12 mL). To this solution was added Pd(OAc)2 (98 mg, 0.44 mmol), and the mixture was stirred for 36 k under positive pressure of 02. The mixture was partitioned between EtOAc and brine. The organic layer was dried (Na2S04), evaporated, and chromatographed on a silica gel column (hexane/EtOAc = 5/1) to give 5 (3.13 g, 88%) as a white solid. !HNMR (CDC13) 5:0.97 (9H, s, SiBu-f), 2.99-3.05 (IH, m, CH2), 3.21-3.26 (IH, m5 CH2), 3.66 (3H, s, Me), 3.98 (IH, d, /= 10.0 Hz, CH2OSi), 4.18 ((IH, d,J= 10.0 Hz, CH2OSi),6.24-6.26 (IH, m, CH=CH), 7.37-7.45 (6H, m, Ph), 7.58-7.62 (4H, m, Ph), 7.86-7.88 (IH, m, CH=CH). 37 WO 2005/011709 PCT/US2004/004713 l-(fejtf-ButyldiphenylsiIyloxymethyI)-(*ra«s-2-acetoxy)cyclopent-3-enecarboxylic acid methyl ester (6 of Figure 6) A mixture of NaBEL (628 mg, 16.6 mmol) and MeOH (50 ml) was cooled and stirred at -70°C. To this was added a mixture of 5 (3.39 g, 8.3 mmol) and CeCl3-7H20 (3.1 g, 8.3 mmol) in THF/MeOH = 1/1 (50 ml) dropwise over 15 min. The resulting suspension was stirred for 1 h at the -70 The reaction was quenched by adding AcOH (ca. 1 mL). The reaction mixture was evaporated. The residue was suspended in MeCN (15 ml). To this suspension were added DMAP (1.02 g, 8.3 mmol), z'-PrjNEt (1.45 mL, 8.3 mmol) and Ac20 (1.57 mL, 16.6 mmol). The mixture was stirred for 30 min at 0 " under positive pressure of dry Ar, and partitioned between CH2CI2 and sat. aqueous NaHC03. The organic layer was dried (Na?S04), evaporated, and chromatographed on a silica gel column (hexane/EtOAc = 4/1). This gave 6 (3.74 g, 100%) as an oil. 'HNMR (CDCI3) 5:1.02 (9H, s, SiBu-0, 1.87 (3H, s, Ac), 2.50-2.55 (lH,m, CPI2), 2.91-2.97 (IH, m, CH2), 3.71 (3H, s, Me), 3.87 (IH, d, 9.6 Hz, CH2OSi), 4.08 (IH, d,J= 9.6 Hz, CH2OSi), 5.76-5.78 (IH, m, CH=CH), 5.99-6.00 (IH, m, CH=CH), 6.07-6.08 (IH, m, AcOCH), 7.29-7.45 (4H, m, Ph), 7.61-7.65 (4H, m, Ph). l-(te/'M}utyIdiphenyIsilyIoxymethyl)-(ft,ff«s'-4-hydroxy)cyclopent-2-enecarboxylic acid methyl ester (7 of Figure 6) A mixture of 6 (1.87 g, 4.13 mmol), PdCl2(MeCN)2 (106 mg, 0.41 mmol) and^-quinone 224 mg, 2,07mmol) in THF (17 mL) was refluxed for 3 h under positive pressure of dry Ar. The mixture was partitioned between CH2C12 and sat. aqueous Na2S203. The organic layer was dried (Na2S04), evaporated. The residue was dissolved in MeOH (5 ml) and treated with K2CO3 (685 mg, 4.96 mmol) for 1 h with stirring. The mixture was partitioned between CHCI3 and brine. The organic layer was dried (Na2S04), evaporated, and chromatographed on a silica gel column (hexane/EtOAc = 6/1). This gave 7 (1.14 g, 67%) as an oil. 'HNMR (CDCI3) 5:1.02 (9H, s, SiBu-f), 1.87 (IH, dd, J= 14.4 and 2.4 Hz, CH2), 2.73 (IH, dd, J~ 14.4 and 7.2 Hz, CH2), 3.65 (3H, s, Me), 3.79 (IH, d, J= 9.6 Hz, CH2OSi), 3.85 (IH, d, J= 9.6 Hz, CH2OSi), 4.82-4.87 (IH, m, CHOH), 5.84-5.87 (IH, m, CH=CH), 6.02-6.04 (IH, m, CH=CH), 7.38-7.44 (6H, m, Ph), 7.63-7.65 (4H, m, Ph). WO 2005/011709 PCT/US2004/004713 l-(fert-Butyldiphenylsilyloxymethyl)-(ci,s-4-hydroxy)cyclopent-2-enecarboxylic acid methyl ester (8 of Figure 6) A mixture of 7 (1.08 g, 2.63 mmol) , PI13P (897 mg, 3.42 mmol) and AcOH (301 juL, 5.26 mmol) in THF (10 mL) was cooled to 0 under positive pressure of dry Ar. To this was added dropwise diethyl azodicarboxylate (2.3 M solution in toluene, 1.49 mL, 3.42 mol). After stirring for 30 min, the mixture was partitioned between CH2CI2 and sat. aqueous NaHC03. The organic layer was dried (Na2S04) and evaporated. The residue was treated with K2CO3 (727 mgs 5.26 mmol) in MeOH (5 mL) for 1 h. The mixture was partitioned between CHCI3 and brine. The organic layer was dried (Na2S04), evaporated, and chromatographed on a silica gel column (hexane/EtOAc = 4/1). This gave 8 (892 mg, 83%) as an oil. 'HNMR (CDCI3) 5:1.02 (9H, s, SiBu-f), 2.20-2.31 (3H, m, CH2 and OH), 3.70 (IH, d, J= 9.6 Hz, CH2OSi), 3.71 (3H, s, Me), 3.87 (IH, d, J= 9.6 Hz, CH2OSi), 4.76-4.81 (IH, m, CHOH), 5.88 (IH, d, J= 5.6 Hz, CH=CH), 6.03 (IH, dd, J= 5.6 and 2.4 Hz, CH=CH), 7.36-7.46 (6H, m, Ph), 7.61-7.65 (4H, m, Ph). l-[c/s,-4-(/e/f-Butyldiphenyisilyloxymethyl)-^"«HS-4-methoxycarbonylcyclopent-2-en-l-yl] thymine (9 of Figure 6) To a THF (25 mL) solution of PPh3 (2.28 g, 8.68 mmol) was added dropwise diethyl azodicarboxylate (2.3 M solution in toluene, 3.63 mL, 8.35 mol) at 0 " under positive pressure of dry Ar. After stirring for 30 min, a THF (76 mL) suspension containing 8 (1.37 g, 3.34 mmol) and A^-benzoyltliymine (1.15 g, 5.01 mmol) was added dropwise. The mixture was stirred for 70 h at room temperature, evaporated, and then treated with 2 M NaOMe in MeOH (6.7 mL) for 2 h. Neutralization of the reaction mixture with AcOH (1.15 mL) was followed by partition between CH2CI2 and sat aqueous NaHCOj. The organic layer was dried (Na2S04), evaporated, and chromatographed on a silica gel column (hexane/EtOAc = 1/1). This gave 9 (1.21 g, 70%) as a white foam. "HNMR (CDCI3) 8:1.05 (9H, s, SiBu-0,1.74 (3H, d,/= 1.2 Hz, thymine-5-Me), 1.75 (IH, dd, J= 14.0 and 6.8 Hz, CH2), 3.01 (IH, dd, J= 14.0 and 8.4 Hz, CH2), 3.70 (3H, s, Me), 3.87 (IH, d,J= 10.0 Hz, CH2OSi), 3.90 (IH, d, 10.0 Hz, CH2OSi), 5.79 (IH, dd, 5.2 and 2.0 Hz, CH=CH), 5.83-5.88 (IH, m, CHN), 6.10 (IH, dd, J= 5.2 and 2.4 Hz, CH=CH), 6.88 (IH, q, J= 1.2 Hz, thymine-H-6), 4.36-7.47 (6H, m, Ph), 7.61-7.64 (4H, m, Ph), 8.89 (IH, br, thymine-NH). 39 WO 2005/011709 PCT7US2004/004713 l-[cis-4-(terf-ButyldipfaenylsilyloxymethyI)-ft-a«s-4-ethynylcyclopent-2-en-l-yl]thymine (10 of Figure 6) To a CH2CI2 (10 mL) solution of 9 (550 mg, 1.06 mmol) was added dropwise Z-BU2AIH (1.01 M in toluene, 1.16 mL, 1.17 mmol) at-70 °C under positive pressure of dry Ar. After stirring for 20 min, an additional Z-BU2AIH (2.32 mL, 2.34 mmol) and added, and stirring was continued for further 20 min. Quenching with AcOH (200 mL) was followed by evaporation. Short silica gel column chromatography (hexane/EtOAc = 1/5) gave the trans-4-hydroxymethyl derivative (294 mg). The /ra/«-4-hydroxymethyl derivative was dissolved in CH2CI2 (10 mL), and oxidized with Dess-Martin periodinane (477 mg, 1.12 mmol). After stirring for 1.5 h, the mixture was partitioned between CH2CI2 and sat. aqueous NaHCOj. The organic layer was dried (NazSO*) and evaporated to give a crude trans-4-aldehyde (274 mg). The aldehyde was dissolved in MeOH containing K2CO3 (310 mg, 2.24 mmol), and stirred forlO min at 00 under positive pressure of dry Ar. To this was added dimethyl(l-diazo-2-oxopropyl)phosphonate* (270 mg, 1.4 mmol). The mixture was stirred for 1 h, and then partitioned between EtOAc and sat. aqueous NaHCOs. The organic layer was dried (NfoSO#), evaporated, and chromatographed on a silica gel column (hexane/EtOAc = 1/1). This gave 10 (138 mg, 27%) as a white foam. 1HNMR (CDCI3) 8:1.07 (9H, s, SiBu-?), 1.71 (3H, d, J- 1.2 Hz, thymine-5-Me), 2.02 (IH, dd, J= 13.2 and 7.6 Hz, CH2), 2.20 (IH, s, CCII), 2.70 (IH, dd, J= 13.2 and 8.0 Hz, CH2), 3.69 (IH, d, J= 9.6 Hz, CH2OSi), 3.83 (IH, d, J- 9.6 Hz, CH2OSi), 5.76 (IH, dd, J= 5.2 and 2.0 Hz, CH=CH), 5.91-5.95 (IH, m, CHN), 6.02 (IH, dd, J= 5.2 and 2.4 Hz, CH=CH), 6.98 (IH, q, /= 1.2 Hz, thymine-H-6), 7.37-7.48 (6H, m, Ph), 7.63-7.66 (4H, m, Ph), 8.20 (IH, br, thymine-NH). FAB-MS (m/z): 485 (M++H). *Fox the preparation of this reagent, see: P. Callant, L. D'Haenes, andM. Vandewalle, Synth. Commun., 14, 155-161 (1984). *The use of this reagent for the conversion of RCHO to RC=CH: I. Gillaizeau, I. M. Lagoja, S. P. Nolan, V. Aucagne, J. Rozenski, P. Herdewijn, and L. A. Agrofoglio, Eur. J. Org. Chem., 666-671 (2003). 40 WO 2005/011709 PCT/US2004/004713 l-(cw-4-Hydroxymethyl-fr-aHs-4-ethynylcyclopent-2-en-l-yl)thynrine (11, Figure 6): KMA-23-153 A mixture of 10 (101 mg, 0.21 mmol) and BU4NF (1M solution in THF, 230 |u.L, 0.23 mmol) in THF (3 mL) was stirred for 2 h at room temperature. To Ms mixture were added 4-dimethylaminopyridine (51 mg, 0.42 mmol), z'-Pr2NEt (73 |i.L, 0.42 mmol), and AC2O (80 (J.L, 0.84 mmol). The reaction mixture was stirred for 30 min, and then partitioned between CH2CI2 and sat aqueous NaHCC>3. The organic layer was dried (NazSCU), evaporated, and chromatographed on a silica gel column (AcOEt). This gave the acetate (52 mg) as a white solid. This acetate was treated with NHs/MeOH (35 ml) below 0°C for 12 h. During evaporation of the solvent, precipitation occurred. The precipitate was washed with hot benzene (50 ml) to give an analytically pure 11 (31 mg, 60%). 'HNMR (CDCI3) 5: 1.96-1.94 (5H, m, CH2, OH and thymine-5-Me), 2.30 (IH, s, G=CH), 2.81 (IH, dd, J= 13.6 and 8.8 Hz, CHZ), 3.65 (IH, dd,J= 10.0 and 7.6 Hz, Cj^OH), 3.78 (IH, dd, J= 10.0 and 4.8 Hz, CH2OH), 5.78-5.80 (IH, m, CH=CH), 5.85-5.89 (IH, m, CHN), 6.04-6.06 (IH, m, CH=CH), 7.10 (IH, q, J= 1.2 Hz, thymine-H-6), 8.09 (IH, br, thymine-NH). Anal. Calcd for C13H14N2O3.I/5 H20 : C, 62.49; H, 5.81; N, 11.21. Found: C, 62:57; H, 5.65; N, 11.22. Biological Activity Methods and Materials: Chemicals: The 4'-D4T analogs (Fig. 1) were synthesized in the laboratory of Dr. Hiromichi Tanaka, School of Pharmaceutical Sciences, Showa University, Japan. The dThd, D4T and AZT were purchased from Sigma-Aldrich Corp. St.Louis, MO. The ddl was purchased from ICN Biochemicals Inc., Aurora, OH, The 3TC was received from Triangle Pharmaceuticals, Durham, NC. The LFd4C was received from Vion Inc., New Haven, CT. All other chemicals used were of reagent grade or higher. Cell lines and virus: Both the H9 cell line, used for toxicity studies and virus propagation, and the MT-2 cell line, used for the antiviral activity studies were received from the AIDS Research and Reference Reagent Program of the National Institutes of Health and were 41 WO 2005/011709 PCT/US2004/004713 contributed by Dr. Robert Gallo and Dr. Douglas Richman respectively. The HIV-1 strain IHB was received from Dr. John Mellors. Determination of antiviral activity: Compounds were tested in MT-2 cells infected with HTV- 1 strain IBB essentially as described previously (31). Briefly, serial dilutions of drugs are placed in triplicate wells of a 96 well tissue culture plate, then MT-2 cells grown in RPMI 1640 media supplemented with 10% dialyzed fetal bovine serum and 100 ja.g/ml kanamycin are added at 104 cells/100 fil plus and minus 0.1 m.o.i. of HIV-1 LLLB. Five days later MTT dye is added to the wells and the color of the tetrazolium dye measured at 595 nm was used to quantitate the cellular viability (20). Calculations of the percent protection and isobologram combination studies are described (12). Cellular toxicity of nucleoside analogs: These dThd analogs have been evaluated in several cell lines; H9, CEM, MT-2 and HepG2. The basic procedures are similar. The cells are seeded a low concentration, then serial dilutions of test compound are added. The CEM, MT- 2 and H9 cell lines we use are grown in RPMI 1640 supplemented with 10% dialyzed fetal bovine serum and lOfig /ml kanamycin. After 48 to 96 h incubation at 37° C in a 5% CO2 humidified incubator the assay is ended. The drug treated samples are compared to the untreated controls. This is accomplished in suspension cell lines by counting cell numbers either with a hemocytometer or by using a Coulter Counter. The HepG2 cells, a human hepatoma cell line, were grown in DMEM medium supplemented with 10% dialyzed fetal bovine serum and 10 |-Lg/ml kanamycin. The effect on HepG2, a monolayer cell line, was quantified by staining with 1.0 % methylene blue dye dissolved in 50% ethanol, after decanting the growth medium. The cell layer is then solubilized in a 5% sarkosyl solution and the resulting color is measured at 595 nm on a Molecular Devices model Vmax plate reading spectrophotometer (Menlo Park, CA). The color of the untreated controls is compared to the drug treated samples. Mitochondrial DNA: The effect of nucleoside analogs on mtDNA content was assessed as described previously (2). Briefly, CEM cells maintained in RPMI 1640 supplemented with 10% dialyzed fetal bovine serum were plated at 2 X 105/ml into a 24 well tissue culture plate. Cells treated with drugs at various concentrations either as single agents or in combination were grown for four days. Cells were then harvested, treated with proteinase K and DNase 42 WO 2005/011709 PCT/US2004/004713 free RNase. Extracts were applied to nylon membranes and hybridized with an mtDNA probe. After stripping the membrane the load was normalized by rehybridizing the membrane with an Ahi probe. Blots were quantitated with a Molecular Dynamics personal densitometer SI with ImageQuaNT analysis software. Monophosphorylation of Analogs by Thymidine Kinase: All the analogs were tested for their ability to be phosphorylated by thymidine kinase (TK-1) from CEM cells. This enzyme was purified by an affinity column technique developed in this laboratory (7). Thymidine analogs (250 uM) were incubated in a mixture that contained 150 mM Tris HC1 pH 7.5,2.4 mM ATP, 2.4 mM MgC12, 0.6 mgs creatine phosphate, 5.8 units of creatine phosphokinase, 0.19 mgs albumin and 0.07 units of TK-1 in a total volume of 200 ul. At the end of the incubation time the reaction was stopped by the addition of 3 parts cold HPLC grade methanol. After incubating on ice for at least 10 min. the methanol insoluble material is precipitated by centrifugation and the methanol soluble supernatants were placed into clean microfuge tubes. These samples were brought to dryness in a Speedvac Centrifuge. The samples were dissolved in water and separated on a Shimatzu HPLC model SCL lOAvp using a gradient of water to 300mM potassium phosphate and a Whatman 10/25 particle SAX column. Km and relative Vmax studies were done in a similar fashion, using the same mixture and different amounts of substrate and enzyme. Acid stability studies: Nucleoside samples were mixed with IN HC1 and incubated at 37° C for 2.5 h. Then the samples were examined by HPLC using a Bechman ODS column employing a gradient of water to 80% methanol. Thymidine Phosphorylase Assays: Nucleoside analogs (100 uM) were incubated in 75 mM potassium phosphate buffer pH 7.3 at 37 ° C using a partially purified prepartion of human liver extract (28) as a source of the thymidine phosphoxylase (TP). After incubation, the reaction was stopped by the addition of trichloroacetic acid to a final concentration of 15 %. The samples were then incubated on ice. After the acid insoluble components were removed by centrifugation, the supernatant was neutralized by two extractions with one half volume of trioctylamine/freon (45: 55). The aqueous supernatants were examined by HPLC using the Beckman ODS column method, as described in Acid Stability Studies. 43 WO 2005/011709 PCT/U S2004/004713 Thymidine Kinase Assays: The thymidine kinase assays were the same as that described previously (21). Briefly, the assay uses [14C]-dThd (100 |j,M, 6.7mCi/mmol) in a mixture that contains 2.4 mM ATP-Mg, 156 mM Tris-HCl pH 7.5, 0.23 mg creatine phosphate, 7 |ig creatine phospho kinase, 67 fig BSA and 1.9 mM DTT in a 75 (il volume. The reactions were incubated for various amounts of time, then they were terminated by spotting 50 (al aliquots onto DE-81 anion exchange discs (Whatman Inc.,Clifton, NJ) that was immersed immediately in 95% ethanol. After two additional washes in ethanol, the discs were dried and placed in scintillation vials that contained 5 ml SafeScint Scintillation Cocktail (American Bioanalytical, Natick, MA). The amount of radioactivity, which, represents the amount of dTMP formed, was quantitated in a Beckman LS5000TD Scintillation Counter (Beckman Instruments Inc., Palo Alto, CA). Results of Biological Activity: Antiviral effect of 4'-substituted D4T analogs: Experiments were performed in the MT-2/ILLB anti HIV-1 system by adding compounds substituted at the 4' position of D4T with a methyl, vinyl, ethynyl, ethynylmethyl, ethynylchloro, allyl or cyano group (Fig.l). The results indicated that the 4'-ethynyl analog was more effective against HTV and less toxic than the parental compound D4T. Whereas, 4'-cyano D4T and 4'-ethynylmethyl D4T were less active than D4T against HIV (Fig.8) The 4'-methyl, 4'-vinyl, 4'-ethynylchloro and 4'-allyl substituted D4T analogs did not achieve a EC50 at a concentration of 100 p.M. A summary of the EC50 against HTV of these compounds together with D4T is shown in Table 1, below. Table 1: The Effect of 4'-Substituted D4T Analogs on HIV. Compound D4T EC50 (|iM)a 1.3 ±0.4 >100d ID50 (uM)u 98.0 ±10.8 4'-methyl D4T 4'-vinyI D4T 4'-ethynyl D4T >100" 0.25 ± 0.14d id >100 >100 >256° >100 4'-ethynylmethyl D4T 4'-ethynylchloro D4T 4.0+1.6 >100 >100 7.0 + 2.6 63.3 ±20.8 >100 >100 4'-allyl D4T 4'-cyano D4T 44 WO 2005/011709 PCT/US2004/004713 a) Effective concentration required to achieve 50% protection from HIV in MT-2 cells. b) Concentration required to inhibit MT-2 cell growth by 50%. c) The highest concentration tested. d) EC50 reported previously (17). To determine whether 4'-ethynyl D4T acts as a dThd analog against HIV, the effect of the addition of dThd or dCyd on the antivirial activity of 4'-ethynyl D4T was examined. To prevent the possibility that dCyd could be deaminated to dUrd in cells, a cytidine deaminase inhibitor, tetrahydro uridine, at a nontoxic level, was also added. It was observed that dThd decreased the antiviral effect of 4'-ethynyl D4T in a concentration dependent manner. However, dCyd had no significant effect on the activity of 4'-ethynyl D4T against HIV (Fig. 9). To assess its interaction with other antiviral nucleoside analogs the antiviral isobolograms of 4'ethynyl D4T in combination with 3TC, LFd4C, ddl and AZT were generated. 4' Ethynyl D4T was shown to have synergistic interactions with 3TC and LFd4C against HIV (Fig. 10), and the Synergy Index (SI) was determined by measuring the relative distance from the line indicating an additive drug effect. However, its antiviral effect with ddl and AZT was only additive (data not shown). Cellular Toxicity: The effect of the 4'-substituted D4T analogs on cell growth and mtDNA content was determined in CEM cells (Table 2a, set forth below). None of those analogs, with the exception of 4'-ethynylchloro D4T, could retard four day cell growth with an ID50 less than 100 (oM. Results of 72 h toxicity studies in HepG2 cells also showed that the ID50 for D4T, 4'-vinyl D4T and 4'-ethynyl D4T was greater than 100 juM. 4'-Ethynyl D4T could decrease intracellular mitochondrial DNA with an ID50 of 100 |liM, which is 10 times higher concentration than that of D4T. In view of the synergistic interaction of 4'-ethynyl D4T with 3TC and LFd4C against HIV, the interaction of those compounds on cell growth was also assessed. In H9 cells during a 48 h assay no significant increase in toxic interactions was observed (Table 2b, below). 45 WO 2005/011709 PCT/US2004/004713 Table 2a: Toxicity of Nucleoside Analogs in CEM Cells. Compound Cellular3 Mitochondrial DNA Contentb ID50 (pM) D4T 4'-methyl D4T 4'-vinylD4T 4'-ethynyl D4T 4'-ethynylmethyl D4T 4'-ethynylchloro D4T 4'-allyl D4T 4'-cyano D4T ddC 3TC >200 (77 ± 28) 60.0 ±18.0 >100 (114 ±2) >100 (78 ±21) >100 (77 ±16) >100 (94 ± 20) 62.6 ±10.0 >100 (60 ± 1) 5.5 ±1.8 >100 >100 (264 ±23) 0.15 ±0.12 >200 (114 ±2) >100 (94 ±4) >100 (116 ±26) 9.3 ±1.4 Procedures described in Materials and Methods: a) Toxicity determined by cell counts compared to untreated controls, b) Mitochondrial DNA content determined by Southern Blot analysis and densitometer readings compared to that of untreated CEM control cells. The numbers are means of p.M concentrations and standard deviations that cause 50 % inhibition of control cells. The numbers in parentheses represent the mean and standard deviations of percentage of untreated CEM control cells at the concentration indicated. 46 WO 2005/011709 PCT/US2004/004713 Table 2b: Toxicity of 4'-ethynyI D4T in H-9 Cells Alone and in Combination with Other Anti-HlV Compounds as Percent of Untreated Controls.* Cone, of 4'-ethynyl D4T (HM) 0 25 50 No additive 100 ±5 97 ± 7 102 ±6 Plus LFd4C (jjM) 5 73 ±9 62 ± 3 72 ± 5 10 56 ±4 58 ±4 64 ±5 Plus 3TC (pM) 5 99 ±3 98 ±2 99 ± 10 20 94 ±3 88 ±3 87 ±6 100 108 ±12 85 ±3 84 ± 6 *H-9 cells were grown as described in Materials and Methods for 48h in the presence of single compounds or in combination. Three or more wells were counted in duplicate for each condition using a Coulter Counter. Numbers represent means and standard deviations. Interaction of 4'-substituted D4T analogs with TK-1: The potential of these compounds to be phosphorylated by purified human TK-1 was assessed (Table 3a, below). AZT was converted to the monophoshate form half as fast as dThd, while the rate of 4'-methyl D4T, and 4'-vinyl D4T are similar to the rate of D4T (approximately 2 percent of dThd). The conversion rate of 4'-ethynyl D4T was superior to D4T with a confidence level of 0.06. There was no significant difference in the phosphorylation rates of 4'-ethynyl D4T and 4'-ethynylchloro D4T with a confidence level of 0.91 using a two tailed test. The Km of 4'-ethynyl D4T was assessed to be 52 (.tM, which is lower than 133 j.iM for D4T but higher than dThd. To be sure that none of these dThd analogs act as a potent inhibitor of TK-1, even if they are not substrates, dThd, AZT, D4T, and the 4'-substituted analogs of D4T were added to a thymidine kinase assay at a concentration 10 fold higher than that of the [14C]-dThd, then the amount of conversion to [14C]-dTMP was compared to reactions with no additions (Table 3b, below). Compounds that are phosphorylated well by TK-1 such as AZT can affect the amount of phosphorylayed dThd. The addition of D4T or its analogs that are poorly 47 WO 2005/011709 PCT/US2004/004713 phosphorylated, even in a 10 fold excess have less effect than AZT on [14C]-dThd phosphorylation by TK-1. Table 3a: Phosphorylation by Human Cytoplasmic Thymidine Kinase Compound Km (jaM) Relative Vmax dThd 2.6* 100 AZT - 55.5 ±9.7 D4T 133 2.1 ±0.7 4'-methyl D4T - 1.6 ±0.5 4'-vinyl D4T - 1.8 ±0.5 4'-ethynyl D4T 52 3.8 ±0.8 4'-ethynylmethyl D4T - 2.5 ±0.9 4'-ethynylchloro D4T - 3.9± 1.0 4'-allyl D4T - 0.4 ±0.2 4'-cyano D4T - 1.1 ±0.2 250 pM dThd or analog and 2.4 mM ATP were incubated with 0.07 unit of TK-1 at 37 DC for 285 min. Value published previously (21). 48 WO 2005/011709 PCT/US2004/004713 Table 3b: Effect of the Addition of Thymidine Analogs to a Thymidine Kinase Assay,* Nucleoside added Percent of Activity - 100 dThd 9.1 ±3.2 AZT 5.4 ± 2.3 D4T 106.3 ± 7.7 4'-methyl D4T 103.8 ±9.9 4'-vinyl D4T 99.5 ±6.9 4'-ethynyl D4T 83.9 ±6.1 4'-ethynylmethyl D4T 74.0 ±7.9 4'-ethynylchloro D4T 53.2 ±9.2 4'-allylD4T 110.8 ±9.0 4'-cyano D4T 71.8 ±8.2 *The assays were performed essentially as described in Material and Methods except the [14 C]-dThd concentration in the assay was reduced to 25 jjM and the concentration of the added nucleoside was 250 (J.M. Interaction with Thymidine Phosphorvlase and Acid Stability of 4'-ethvnvl D4T: Partially purified preparation of thymidine phosphorylase (TP) from human liver was utilized for these studies. dThd broke down very quickly while D4T was at least 10 times slower. The break down of 4'ethynyl D4T was below the detection level during the whole incubation period studied (Fig 11). The stability of D4T and 4'-ethynyl D4T at pH 1 and at 37" C was examined for 2.5 h. No detectable breakdown of either compound was detected. Discussion: D4T is an effective anti-HIV D-dideoxy-thymidine analog. Its limiting clinical toxicity, upon long term treatment, is peripheral neuropathy, which is associated with its action of decreasing the mitochrondrial DNA content of peripheral neurons (4, 5, 33, 34). The biochemical determinants of the action of D4T are different from those of 3TC, ddl or ddC. An analog of D4T, which has more potent anti-HIV activity and less impact on nuclear or 49 WO 2005/011709 PCT/US2004/004713 mitochondrial DNA synthesis, could have better therapeutic effect than D4T and could substitute for D4T in anti-HTV combination therapy. Thus, the synthesis ofD4T analogs with better pharmacological properties is a direction which has been taken in anti-HIV drug discovery. Among all the 4'-substituted D4T analogs, synthesized by us and others, 4'-ethynyl D4T is the most active one against HIV in culture. Maag et.al described a 4'-azido i D4T that was inactive against HIV at non-toxic levels (29) and O-Yang et.al describe three 4'-substituted D4T analogs that were non-toxic and had no anti-HTV activity (32). D4T is catabolized, rather quickly, into beta-aminoisobxityric acid and thymine by the hepatocytes of the liver (38). The enzyme responsible for this breakdown is TP, which in the presence of phosphate breaks dThd into thymine and 2-deoxy-D-ribose-l-phosphate. By incubating 4'-ethynyl D4T and D4T with a partially purified preparation of human liver TP, it was shown that 4'-ethynyl D4T was much more resistant to TP than D4T. This indicates that 4'-ethynyl has an additional advantage over D4T from a pharmacokinetic point of view. Furthermore, 4'-ethynyl D4T is also as stable as D4T in an acidic condition that mimics the stomach (data not shown). This suggests that 4'-ethynyl D4T could be an orally active agent like D4T. Detailed pharmacokinetic studies will be performed in the future. Since 4'-ethynyl D4T is more potent than D4T, it is conceivable that 4'-ethynyl D4T could have less viral drug resistance issues. When 4'-ethynyl D4T is employed at the same dosage as D4T to the patient, the viral load will be much less, thereby, decreasing the probable occurrence of resistant strains. It may also be possible to give 4'-ethynyl D4T at higher dosage than D4T, since 4'-ethynyl D4T is less inhibitory to cell growth and causes less mitochondrial DNA decrease than D4T. However, the determination of the amount of 4'-ethynyl D4T that can be safely used will require further investigation. Monotherapy allows the development of resistant strains of virus to occur more readily than combination therapy. It is therefore necessary for an antiviral compound to work in conjunction with other approved antiviral drugs which have different biochemical determinants of drug resistance. If the compounds are synergistic, or at least additive, with respect to their antiviral activity, but not to their cytotoxic effect on the host cells, improved therapy can be achieved. Indeed, combination therapy for HIV has made tremendous progress in the management of AIDS and D4T is often used as one of the drugs in combination protocols. To assess the potential use of 4'-ethynyl D4T in combination therapy, we examined the interaction of this compound with four antiviral nucleoside analogs. 4'-Ethynyl 50 WO 2005/011709 PCT/US2004/004713 D4T is synergistic with 3TC and LFd4C (Fig. 9) and additive with AZT and ddl (data not shown) with respect to Hie anti-HTV activity, but not to cytotoxicity (Table 2b). This suggests that 4'-ethynyl D4T could be a useful compound for combination therapy and could be useful against virus resistant to currently used nucleosides by increasing their effectiveness through a synergistic response. The activity of 4'-ethynyl D4T against virus resistant to other nucleoside analogs is currently being investigated. The underlying mechanism that makes 4'-ethynyl D4T more active than the other 4'-substituted D4T analogs studied against HTV is not clear. Deoxynucleoside analogs typically are converted into 5'triphosphate metabolites that are substrates for viral DNA polymerases. Triphosphate metabolites of known anti-HTV dideoxy nucleosides interact preferentially with viral reverse transcriptase and act as chain terminators when they are incorporated into a DNA strand. The formation of the monophosphate metabolite is the first step in the process to become a triphosphate metabolite. The 4' -substituted D4T compounds, like D4T, are dThd analogs, so we used purified TK-1 to test whether it could phosphorylate these analogs to their respective monophosphate forms. The results showed that 4'-ethynyl D4T was phosphoiylated twice as fast as D4T although at a much slower rate than that of dThd or AZT. It is interesting to note that the 4'-methyl D4T and 4'-vinyl D4T analogs were phosphorylated at the same rate as D4T, but neither had significant anti-HTV activity. Thus, it can be concluded that the lack of activity of some of these 4'-substituted D4T analogs against HTV is not due to their inability to be phosphorylated by TK-1. The phosphorylation of 4'-ethynyl D4T by TK-1 is an essential step, but is not sufficient to have antiviral activity. Since its antiviral effect could be neutralized by dThd but not dCyd, 4'-ethynyl D4T, like D4T, acts as a dThd analog but the antiviral mechanism of action of 4'-ethynyl D4T could still be quite different from that of D4T. Our unpublished results indicate that D4T could be more efficiently phosphorylated to the triphosphate metabolite than 4'-ethynyl D4T using a CEM cellular extract supplemented with partially purified TK-1 and recombinant human dTMP kinase. This raises the question of whether the 4'-ethynyl D4TMP is the active metabolite instead of 4'-ethynyl D4TTP and requires further investigation. In conclusion, 4'-ethynyl D4T is more potent against HTV and less toxic than D4T in cell culture. It is expected to have pharmacokinetic advantages over D4T, since it is not a substrate of Thymidine Phosphorylase. 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Claims

<div class="application article clearfix printTableText" id="claims"> what we claim is:

1. A compound according to the formula: Wherein B is O HN X N >\An I O NHR1 N N v/VA_P I r H \ / xc=c. H H X /H R is H, F, CI, Br, I, CrC4 alkyl, -ON, -C=C-Ra, X is H, C1-C4 alkyl, F, CI, Br or I; R1 is H, an acyl group, a Ci—C20 alkyl or an ether group; r2 is H, an acyl group, a Ci—C20 alkyl or ether group, a phosphate, diphosphate, triphosphate, phosphodiester group or a Nu- 0 II jj II p— ■0- — p OR8 OR8 Nu" O -c- group; Nu is a radical of a biologically active antiviral compound such that an amino group or hydroxyl group from said biologically active antiviral compound forms a phosphate, phosphoramidate, carbonate or urethane group with the adjacent moiety; R8 is H or a C 1-C20 alkyl or ether group; 56 INTELLECTUAL PROPERTY OFFICE OF N.Z. 17 SEP 2008 Y H H or —|—<CH2 R3 is a C3 or C4 alkyl group, -(CH2)n-C=C-Ra, * R3a and R3b are each independently H, F, CI, Br or I; Ra is H, F, CI, Br, I, or -C1-C4 alkyl; Y is H, F, CI, Br, I or -Q-C4 alkyl; k is 0, 1 or 2; and n is 0, 1, 2, 3,4 or 5; or an anomer, pharmaceutically acceptable salt, polymorph or solvate thereof.

2. The compound according to claim 1 wherein B is H O & v/vr> I

3. The compound according to claim 1 or 2 wherein R is w H or -(CH2)„-C=C-Ri H H \ / -^chjC \y a?

4. The compound according to any one of claims 1-3 wherein R is F, CI, Br, Hv /X Hx /H Xc c\ xc c\ I, C1-C3 alkyl,-C=C-Ra, H or x and X is H, C,-C4 alkyl, F, CI, Br or I.

5. The compound according to claim 1 wherein R is CH3, R3 is -<CH2)„-C=C-Ra, n is 0 and Ra is H. 57 intellectual prope office of n.z. 17 SEP D c r. p 1 \/ F

6. The compound according to any one of claims 1-5 wherein R3a and R3b are both H.

7. The compound according to any one of claims 1-6 wherein R2 is H.

8. The compound according to claim 1 which is o h3c- N O

9. The compound according to claim 8 wherein R is H, an acyl group, a phosphate, diphosphate, triphosphate or phosphodiester group.

10. The compound according to claim 8 wherein R2 is H. NHR1 NK A.

11. The compound according to claim 1 wherein B is v/WP R

12. The compound according to claim 11 wherein R is -(CH2)n-C=C-R1 Hx /Y Hx /H ■C=cv vc=c. H or X Y X ■a? and n is 0.

13. The compound according to claim 11 or 12 wherein R is H, F, CI, 58 intellectual proper* office of n.2. 17 SEP 2008 dcp.FIX/FI Hx /X Hx /H x° °N xc Cn Br, i, CH3,-C-C-Ra, H or x and X is H, C1-C4 alkyl, F, CI, Br or I.

14. The compound according to claim 11 or 12 wherein R is CH3, R is -(CH2)n-C=C-Ra, n is 0 and Ra is H.

15. The compound according to any one of claims 11-14 wherein R3a and R3b are both H.

16. The compound according to any one of claims 11-15 wherein R2 is H.

17. A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutically acceptable carrier, additive or excipient. A" cr n'

18. The composition according to claim 17 wherein B is I

19. The composition according to claim 17 or 18 wherein R is H ^ H H H or -(CH2)n-C=C-Ra, *

20. The composition according to any one of claims 17-20 wherein R is F, CI, Hn /X Hv _ /H Br, I, C1-C3 alkyl, -C=C-Ra, H or x and X is H, C,-C4 alkyl, F, CI, Br or I.

21. The composition according to claim 17 wherein R is CH3, R3 is -(CH2)n-C=C~Ra, n is 0 and Ra is H. 59 intellectual office op v 1 J SEP 2008 RECEIVE!

22. The composition according to any one of claims 17-21 wherein R3a and R3b are both H.

23. The composition according to any one of claims 17-22 wherein R2 is H.

24. The composition according to claim 17 wherein said compound is o

25. The composition according to claim 24 wherein R is H, an acyl group, a phosphate, diphosphate, triphosphate or phosphodiester group.

26. The composition according to claim 24 or 25 wherein R2 is H. NHR1

27. The composition according to claim 17 wherein B is

28. The composition according to claim 27 wherein R3 is Hx /Y Hv /H n ,C=C, , ,c=c. ^ / \ / vc~c\ vc—c\ H or Sh Y -<CH2)n-OC-Ra, and n is 0. 60 1 ? SEP 2008

29. The composition according to claim 27 or 28 wherein R is H, F, CI, Hs /x hN /h c=cx c=cx Br, I, CH3, -C=C-Ra, H or x and X is H,Ci-C4 alkyl, F,Cl,Br or I.

30. The composition according to any one of claims 27-29 wherein R is CH3, R3 -(CH2)n-C=C-Ra, n is 0 and Ra is H.

31. The composition according to any one of claims 27-30 wherein R3a and R3b are both H.

32. The composition according to any one of claims 27-31 wherein R2 is H.

33. The composition according to claim 27 wherein said compound is Where R1 is H or an acyl group; and R2 is H, an acyl group, a phosphate, diphosphate, triphosphate or phosphodiester group.

34. The composition according to claim 33 wherein R1 is H and R2 is H. is NHR1

35. The composition o any one of claims 17-34 further comprising at least one additional anti-HIV agent. intellectual - OFFICE OF 61 I ? SEP 2uuo R C O c i i j j~

36. The composition according to claim 35 wherein said additional anti-HIV agent is selected from the group consisting of ddC, abacavir, ddl, ddA, 3TC, AZT, D4T, FTC, FddC, Fd4C, Atazanavir, Adefovir dipivoxyl, Tenofovir disoproxil, Etecavir, Indinavir, KHI-227, 2-[3-[3-(S)-[[(Tetrahydrofuranyloxy)carbonyl]amino]-4-phenyl-2(R)-hydroxybutyl]]-N-( 1,1 -dimethylethyl)decahydro-3-isoquinolinecarboxamide, VB-11,328, KNI-174, Val-Val-Sta, CPG53820, bis-Val HOEt-N2 aza-peptide isostere, C2-Sym Phosphinic amide derivative, 2,5-Diamino-N,N'-bis(N-benzyloxycarbonyluelyl)-l,6-diphenyl-3(S),4(S)-hexanediol BzOCValPhe[diCHOH(SS]PheValBzOC, 2,5,-Diamino-N,N' -bis(N-benzyloxycarbonyluelyl)-1,6-diphenyl-3(R),4(R)-hexanediol BzOCValPhe[diCHOH(RR]PheValBzOC, [bis(SATE)ddAMP], BILA 2186 BS, Amprenavir, A-98881, A-83962, A-80987, (2-Naphthalcarbonyl)Asn[decarbonylPhe-hydroxyethyl]ProOtertButyl, 2-Aminobenzylstatine Valyl Cbz derivative, 10H-2(Cbz-ValNH)3PhPr [14]paracyclophane derivative, 10H-2(Cbz-ValNH)3PhPr [13]paracyclophane derivative, 10H-2(Cbz-ValNH)3PhPr [13]metacyclophane derivative, 10H-2(Cbz-Tle)3PhPr [14]paracyclophane derivative, 1 -(20HPr)-4-substituted-piperazine (cyclopropyl), thieneyl carbamate derivative, l-(20HPr)-4-substituted-piperazine (cyclobutyl), thienyl carbamate derivative, 1 -(20HPr)-4-substituted-piperazine (3-pentyl), thienyl carbamate derivative, 10H-2(Cbz-ValNH)3PhPr[l 7]paracyclophane derivative, A-81525, XM323, Tipranavir, ThienopyridCON thienyl urethane derivatives, SDZ PRI 053, SD146, Telinavir, (R)2QuinCOAsnPhe[CHOHCH2]PipCONHtBu, Saquinavir Saquinavir/Melflnavir derivative, IsoquinCON Thf-Thf Urethane Analog , IsoquinCON thienyl urethane analog, R-87366, DMP 460, L685,434, L685,434-6-Hydroxyl derivative, L685,434-OEtNMe2 , L685,434-OPrMorph derivative , L689,502 , Lasinavir, Lopinavir, Nelfinavir-octahydro-thienopyridine analog, P9941, Palinavir, Penicillin, 2Isoquin-OHPrNH2 analog and mixtures thereof.

37. The composition according to claim 35 wherein said additional anti-HIV agent is selected from the group consisting of ddC, abacavir, ddl, ddA, 3TC, AZT, D4T, FTC, FddC and Fd4C. 62

38. A use of a compound according to claim 1 in the manufacture of a medicament for the treatment of a viral infection caused by a virus selected from the group consisting of human immunodeficiency viruses I and 2 (HIV-1 and HIV-2), human T-cell leukemia viruses 1 and 2 (HTLV-1 and HTLV-2), respiratory syncytial virus (RSV), human papilloma virus (HPV), adenovirus, hepatitis B virus (HBV), hepatitis C' virus (HCV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex viruses I and 2 (HSV-1 and HSV-2), human herpes virus 8 (HHV-8, also known as Kaposi's sarcoma-associated virus) and flaviviruses, including Yellow Fever virus, Dengue virus, Japanese Encephalitis and West Nile viruses.

39. Hie use according to claim 38 wherein said virus is HfV 1 or 2.

40. A use of a compound according to claim 1 in the manufacture of a medicament for reducing the likelihood or delaying the onset of a condition secondary to a viral infection in a patient at risk for the development of said condition.

41. The use according to claim 40 wherein said condition is AIDS and said viral infection is HIV 1 or 2.

42. A compound as claimed in claim 1, substantially as herein described with reference to any example thereof and with or without reference to the accompanying drawings.

43. A pharmaceutical composition as claimed in claim 17 substantially as herein described with reference to any example thereof and with or without reference to the accompanying drawings.

44. A use as claimed in claim 38 or 40 substantially as herein described with reference to any example thereof and with or without reference to the accompanying drawings. intellectual property OFFICE OF N.Z. 13 PEC 2DD8 RECEIVED 63 </div>