MXPA97006942A - Quimi compounds - Google Patents

Abstract

The present invention relates to masked monophosphate nucleoside analogs, with their preparation and their therapeutic use in the treatment of viral infections including HIV infection. In particular, the invention relates to 2 ', 3'-deidesoxy and 2', 3'-dideoxydideshydro phosphoroamidate of nucleoside analogues and of PM

Description

? > M? RegTQg Q? Í «ICQg DESCRIPTION OF THE INVENTION The present invention relates to a novel class of nucleoside analogs and their therapeutic use in the prophylaxis and treatment of viral infections, for example, by human immunodeficiency virus (HIV) which is considered to be the etiological agent in immunodeficiency syndrome human acquired (AIDS). There has been much interest in the use of nucleoside analogs as HIV inhibitors. The 2 ', 3'-dideoxy-2', 3 '-dideshidrotimidine (d4T) and 3'-azido-3'-deoxythymidine (AZT) compounds are both HIV inhibitors [Hitchcoc et al. , Antiviral Chem. Chemother. (1991). 2, 125; Mansuri et al. , Antimicrob. Agents Chemother., (1990), 34. 637.]. The inhibition of HIV by these and other nucleoside analogs is conventionally considered to depend on the conversion of the nucleoside analogue in vivo to the corresponding 5'-triphosphate by enzymes kinases (host cell). However, this absolute dependence on kinase-mediated activation (host cell) can lead to low activity, emergence of resistance and clinical toxicity.

REF: 25641 In order to reduce reliance on kinase enzymes, the use of masked phosphate pro-drugs of the bioactive nucleotide form of various chemotherapeutic nucleoside analogues has been suggested [McGuigan et al. , Nucleic Acids Res., (1989), 17, 6065; McGuigan et al. , Ibid., (1989), 17, 7195; Cha la et al., J.

Med. Chem. (1984), 21, 1733; Sergheraert et al. , J. Med.

Chem. (1993), 1 £, 826-830.]. In particular, McGuiaan et al [J. Med. Chem. 1 £, 1048-1052 (1993)] has reported the preparation of aryl ester-phosphoramidate derivatives of AZT.

The in vitro evaluation of these compounds reveals that the compounds have activity against HIV. However, in "normal" cells rich in thymidine kinase (TK +), the activity of such compounds is at least an order of magnitude lower than that of the original AZT nucleoside.

Only in cells deficient in TK (TK "), and which the activity of the arylester phosphoramidate derivatives is virtually maintained, but the activity of AZT, have an activity of derivatives that exceed that of AZT. It has also been reported by McGuigan et al [Bioorganic & Medical Chemistry Letters, 3. (6). 1203-1206 (1993)] the preparation of d4T triester phosphate derivatives. Again, the in vitro evaluation of these compounds reveals that although the compounds have significant anti-HIV activity, the activity is lower than that of the original d4T nucleoside in TK + cells. Abraham and Wagner (Nucleosides and Nucleotides 13 (9), 1891-1903 (1994)) have reported the preparation of diesters and triesters of nucleoside phosphoramidate but do not report any biological activity. The acyclic nucleoside analogue 9 (2-phosphonomethoxyethyl) adenine (PMEA) and analogs thereof have been shown to exhibit activity against herpes simplex viruses and retroviruses including HIV (Calió et al., Antiviral Res., (1994), 23 (1) .77-89; Balzarini et al. AIDS, (1991), 5 (1) .21-28). To date, attempts to provide masked phosphate pro-drugs have not been able to improve the antiviral activity of the original nucleoside analogs such as AZT and d4T on TK + cells. In addition, the emergence of resistance to nucleoside analogues and their bioactive form 5'-triphosphate has returned to the reported masked phosphate pro-drugs and their original nucleoside analogs potentially ineffective. It has now been found that a particular class of masked nucleoside analogs are highly potent viral inhibitors in TK "and TK * cells and still require activity against nucleotide-resistant viruses (e.g. d4T.) In accordance with the present invention, a compound of the formula (1) wherein Ar is an aryl group and is an oxygen or sulfur group; X1 is selected from 0, NR3, S, CR3R4, CR3 ** 1 and CWXW2 wherein R3 and R4 are independently selected from hydrogen, alkyl and aryl groups; and W1 and w2 are heteroatoms; X2-Xß may be absent; or Xs is CH2 and X2 is selected (independently of X1) from 0, NR3, S, CR3R4, CR3WX and CWXW2 wherein R3 and R4 are independently selected from hydrogen, alkyl and aryl groups; and W1 and W2 are heteroatoms; X3 is an alkyl group of Cx. <; X4 is oxygen or CH2; X5 may be absent or is CH2; Z is selected from 0, NRS, S, alkyl and aryl groups, wherein Rs is selected from hydrogen, alkyl and aryl groups; J is selected from hydrogen, alkyl, aryl, heterocyclic and polycyclic groups; Q is selected from 0, NRS, S, CR * R7, CR6W3 and CW3W \ in which Rβ and R7 are independently selected from hydrogen, alkyl and aryl groups; and W3 and w4 are heteroatoms; T1 and T2 are independently selected from hydrogen and CH2Rβ, wherein Rβ is selected from H, OH and F; or T1 and T2 join together are selected from the groups = ^ I &C-C ^ R11 H 'H 12 wherein R * are selected from H, halogen, CN, NH2, CO-alkyl and alkyl; and R10, R ", R12 are independently selected from H, N3 / halogen, CN, NH2, CO-alkyl and alkyl, B is a purine or pyrimidine base, or a pharmaceutically acceptable derivative or metabolite thereof. invention are powerful antiviral agents, in particular, they are highly active against HIV in both TK "and TK + cells. Particularly surprising is the activity of the compounds of the present invention against nucleoside-resistant HIV. These observations indicate that the activity of these compounds does not completely depend on the conventional mode of action (which requires hydrolysis of the aryl phosphate ester and the P-X1 bonds followed by kinase-dependent conversions to the 5'-triphosphate derivative), but arise from a completely different mode of action. The experimental data presented herein indicate that the compounds and metabolites in the present invention act directly as reverse transcriptase (RT) inhibitors by means of a previously unrecognized metabolic pathway and mechanism of action. The reference in the present specification to an alkyl group means a branched or unbranched, cyclic or acyclic, unsaturated saturated (eg alkenyl or alkynyl) furrocarbyl radical. In which the cyclic, the alkyl group is preferably C3 to C12, more preferably Cs to C10; more preferably Cs to C7. When it is acyclic, the alkyl group is preferably Cj. to C1S, more preferably Cx to Cs, more preferably methyl. The reference in the present application to alkoxy and aryloxy groups means alkyl-0-aryl-0- groups, respectively. The reference to alkyl and aroyl groups means alkyl-CO- and aryl-CO-, respectively. The reference in the present specification to an aryl group, means an aromatic group, such as phenyl or naphthyl, or a heteroaromatic group containing one or more, preferably a heteroatom such as pyridyl, pyrrolyl, furanyl and thiophenyl. Preferably, the aryl group comprises phenyl or substituted phenyl. The alkyl and aryl groups can be substituted or unsubstituted, preferably unsubstituted. When substituted, they generally have 1 to 3 substituents present, preferably 1 substituent. The substituents may include halogen atoms and halomethyl groups such as CF3 and CC13; oxygen-containing groups such as oxo, hydroxy, carboxy, carboxyalkyl, alkoxy, alkyl, alkoxy, aryloxy, aryloyl and aryloyloxy; nitrogen-containing groups such as amino, alkylamino, dialkylamino, cyano, azide and nitro; sulfur-containing groups, such as thiol, alkylthiol, sulfonyl and sulfoxide. Heterocyclic groups which themselves may be substituted, alkyl groups which may themselves be substituted; and aryl groups themselves may be substituted; such as phenyl and substituted phenyl. Alkyl includes substituted and unsubstituted benzyl. The reference in the present specification to heterocyclic groups means groups containing one or more of pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxindolyl, isoindolyl , indazolyl, indolinyl, 7-azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, naphthyridinyl, cinolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxadinyl, chromenyl, chromanyl, isochromanyl and carbolinyl. References in the present specification to polycyclic groups means a group comprising two or more carbocyclic or non-aromatic heterocyclic rings which may themselves be substituted.

The reference in the present specification to halogen means a fluorine, chlorine, bromine or iodine radical, preferably a fluorine or chlorine radical. The group Ar comprises a substituted or unsubstituted aryl group, in which the term "aryl group" and the possible substitution of the group is as defined in the foregoing. Preferably, Ar is a substituted or unsubstituted phenyl group. Particularly preferred substituents are groups that extract electrons such as halogen (preferably chlorine or fluorine), trihalomethyl (preferably trifluoromethyl), cyano and nitro groups. Preferably, Ar is phenyl, 3,5-dichlorophenyl, g-trifluoromethylphenyl, p-cyanophenyl or β-nitrophenyl. And it can be oxygen or sulfur. Preferably Y is oxygen. X1 is 0, NR3, S, CR3R \ CR3WX and CWH2 where R3 and R4 are independently selected from hydrogen, alkyl and aryl groups; and W1 and W2 are heteroatoms. Preferably, X1 is selected from O, S and NR3. Preferably, X1 is NR3. When present, R3 is preferably H. When present, W1 and W2 can independently comprise any heteroatom such as a halogen, preferably fluorine.

X-Xß may be absent; or Xß is CH2 and X2 is selected (independently of X1) from O, NR3, S, CR3R4, CR3WX and CWXW2 wherein R3 and R4 are independently selected from H, alkyl and aryl groups; and W1 and W2 are heteroatoms. When present, X2 is preferably oxygen. When present, R3 is preferably H. When present, W1 and w2 independently may comprise any heteroatom such as halogen, preferably fluorine. X4 is oxygen or CH2. Preferably X4 is oxygen. Xs may be absent or is CH2. Z may comprise O, NR5, S, alkyl or aryl groups, wherein Rs is selected from H, alkyl and aryl groups. Preferably Z is O, or NR5. Preferably, R5 is hydrogen. More preferably, Z is oxygen. J is selected from hydrogen, alkyl, aryl, heterocyclic and polycyclic groups. Preferably, J is a substituted or unsubstituted alkyl group. Preferably, J is a substituted or unsubstituted C ^ alkyl group, preferably a benzyl or methyl group. X3 is an alkyl group of C1-s. X3 can be a substituted or unsubstituted, branched or unbranched C ^ methylene chain, preferably X3 is a CRXR2 group in which R1 and R2 are independently selected from hydrogen, alkyl and aryl groups. Preferably, at least one of R1 and R2 is hydrogen.

It will be appreciated that if R1 and R2 are different, the carbon atom to which they are attached is an asymmetric center. The stereochemistry at this site can be R or S or mixed.

When one of R3 and R4 is hydrogen, the stereochemistry is preferably S.Q is selected from 0, NRβ, S, CRSR7, CR6W3 and CW3W4, wherein Rβ and R7 are independently selected from hydrogen, alkyl and aryl groups; and W2 and W3 are heteroatoms such as halogen atoms, preferably fluorine. Preferably, Q is 0, S, CH2 or CF2. More preferably, Q is oxygen. Tx and T2 are independently selected from hydrogen and CH2Rβ in which Rβ is selected from H, OH and F; or t2 and T2 are joined together, and together they are selected from the groups: Xc = c / Í &C-C ^ 11 H H 7 12 where R 9 is selected from H, halogen, CN, NH 2, CO-alkyl, and alkyl, preferably R 9 is H or F; and R10, R11 and R12 are independently selected from H, N3, halogen, CN, NH2, CO-alkyl and alkyl, preferably R10, R11 and R12 are independently selected from H, F and N3. It will be appreciated that R9 corresponds to the position 3'-Q! and R10 corresponds to the position 3 '- / ?. Preferably, T1 and T2 joined together and together form the group: B comprises a purine base or pyrimidine, such as adenine, thymine, uracil, cytosine or guanine and derivatives thereof. The derivatives thereof include substituted purine base or pyrimidine in which the substituents are as defined above. Examples of substituted bases include 5-substituted pyrimidine. Preferably, B is adenine or thymine. Preferably, the present invention provides a compound of formula (2) wherein Ar, R \ J, X2, X5, Xβ, Q, T1, T2 and B are as defined in the foregoing; or a pharmaceutically acceptable derivative or metabolite thereof. It will be appreciated that the -NH-CHR1-C02J group corresponds to a protected carboxy a-amino acid. Preferably, the group R1 corresponds to the side chain of an amino acid that occurs naturally as Alanine, Arginine, Asparagine, Aspartic acid, Cysteine, Cystine, Glycine, Glutamic acid, Glutamine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, Valine. Preferably, R1 is Me or PhCH2 which corresponds to the side chain of alanine or phenylalanine, respectively. Preferably, the stereochemistry in the asymmetric center -CHR1- corresponds to an L-amino acid.

According to a preferred embodiment, the present invention provides a compound of formula (3): Where Ar, Y, X1, X2, X3, X4, Z, Q and B are as defined in the above. More preferably, the invention provides a compound according to formula (3), of formula (4): wherein Ar, R1 and J are as defined in the above; or a pharmaceutically acceptable derivative or metabolite thereof. Preferably, the invention provides a compound of formula (4) in which Ar, R1 and J are as defined in accordance with Table 1.

Table 1 Compound of Ar R1 Reference 323 4-EtPh Me Me 324 Ph Me Me 327 4-FPh Me Me 526 3-CF3Ph Me Me 546 3.5-Cl2PH Me Me 730 Ph Me Bzl 776 2.4-Br2Ph Me Me 779 F5Ph Me Me 862 Ph Me Hexyl 863 Ph Bzl Me 864 Ph Ch2iPr Me 865 Ph iPr Me 866 Ph H Me 867 Ph [CH2] 2SMe Me 868 2.4Br2Ph Me Bzl 877 Ph Bzl Bzl 878 Ph Bzl tBu 892 Ph Me Ciciohexyl 893 Ph Me tBu 1078 Ph CH2C02H Me 1214 Ph CH2CH2CH2NHC [NH2] NH Me 1218 Ph Me n-Pent 1219 Ph Me neo-Pent 1226 Ph Me 1-naphthyl 1227 Ph Me 2 -naphthyl According to a further preferred embodiment, the present invention provides a compound of formula (5) i where Ar, Y, X1, X2, X3, X4, Z, J, R9, R10, R11, R12, Q and B are as defined in the foregoing. More preferably, the invention provides a compound according to formula (5) of formula (6): wherein Ar, R1, J, R9, R10, R11, R12 and B are as defined in the foregoing. According to a further preferred embodiment, the present invention provides a compound of formula (7): wherein Ar, Y, X1, X3, X4, Z, J. Q and B are as defined in the foregoing and T1 and T2 are independently selected from H and CH2Rβ, wherein Rβ is as defined in the foregoing . Preferably, B is a purine base. More preferably, B is adenine. Preferably, T1 is hydrogen. Preferably, T2 is CH2Rβ. These compounds are analogues of the acyclic nucleoside analog 9- (2-phosphonylmethoxyethyl) adenine (PMEA) which has been shown to have activity against the herpes virus and retroviruses (Calió et al. Antiviral Res., (1994), 23 (1). 77-89; Balzarini et al. AIDS, (1991), 5 (1). 21-28). More preferably, the invention provides a compound according to formula (7), of formula (8): where Ar, R1, J, T1, T2 and B are as defined in the above.

It is a characteristic of the phosphate-stearyl compounds (1) of the present invention that they show markedly increased antiviral efficacy, in tests both in vitro and in vivo compared to their corresponding nucleoside analogue (9) In addition, the compounds of the present invention show markedly reduced toxicity compared to their corresponding analog (9). The compounds of the present invention therefore exhibit a markedly increased selectivity index (poroporción of CC50 (toxicity): CES0 (activity)) in comparison with its corresponding nucleoside analogue. Experiments with radiolabelled compounds of the present invention have shown that the compounds provide increased intracellular levels of 5'-triphosphate nucleoside, the increase is particularly significant in TK cells. "Therefore, the compounds of the present invention can act in part by the known metabolic pathway, however, it has been found that the compounds of the present invention show surprising activity against resistant strains. to HIV nucleosides This indicates that the compounds of the present invention also act in a pathway independent of the 5'-triphosphate metabolite It has been shown that the compounds of the present invention induce the intracellular generation of increased levels of a metabolite (10) .

The metabolite (10) can also be prepared by treatment of the corresponding compound according to formula (1) with pork liver esterase. In addition, it has been shown that the compounds of formula (10) are direct inhibitors of HIV reverse transcriptase.

According to a further aspect of the present invention, a compound of formula (10) is provided wherein Ar, Y, X1, X2, X3, X4, Xβ, T \ T2, Q, X5 and B are as defined above, or a pharmaceutically acceptable derivative or metabolite thereof. The intracellular generation of antiviral metabolites such as (10) is an important feature of the invention for several reasons. First, the direct activity of (10) on RT eliminates the need for additional nucleotide-kinase-mediated phosphorylation, which can be slow in many cases. In cases where the monophosphate nucleoside is not a substrate for the nucleotide kinases of the host, the activation will be poor and the antiviral efficacy low, even if the triphosphate is an excellent RT inhibitor. In such cases, the generation of metabolites such as (10) can lead to a very significant improvement in the antiviral action. Such compounds can act directly on their own or via a rearrangement, decomposition or a product of disproportionation or via a contaminant. In addition, the structure of metabolites such as (10) can be further designed to optimize binding to the known structure of the RT, and such modified metabolites can be delivered intracellularly using technology described herein, to further enhance the antiviral effect. By a "pharmaceutically acceptable derivative" is meant any pharmaceutically acceptable salt, ester or salt of such ester or any other compound which, by administration to a receptor, is capable of providing (directly or indirectly) a compound of formula (1) or (10). By "pharmaceutically acceptable metabolite" is meant a metabolite or residue of a compound of formula (1) or (10) which gives rise to an independent nucleoside resistance or nucleoside-independent 5 '-triphosphate inhibition of reverse transcriptase shown by the compounds of formula (1) or (10). In accordance with a further aspect of the present invention, a compound according to the present invention is provided for use in a method of treatment, preferably, in the prophylaxis or treatment of viral infections. According to a further aspect of the present invention, there is provided the use of a compound according to the present invention in the manufacture of a medicament for the prophylaxis or treatment of viral infections. According to a further aspect of the present invention, there is provided a method of prophylaxis or treatment of viral infections which comprises administering to a patient in need of such treatment an effective dose of a compound according to the present invention. The infection can comprise any viral infection such as HIV and herpes viruses, including HSV i and HSV 2, CMV, VZV, EBV, HAV, HBV, HCV, HDV, papilloma, rabies and influenza. Preferably, the viral infection comprises HIV infection, more preferably HIV-1 or HIV-II. It is a feature of the present invention that the compounds show good activity against HIV-I as HIV-II. According to a further aspect of the present invention, there is provided the use of a compound of the present invention in the manufacture of a medicament for use in the inhibition of a reverse transcriptase by an independent mode of action of nucleoside resistance or independent of nucleoside 5'-triphosphate. According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention in combination with a pharmaceutically acceptable excipient. According to a further aspect of the present invention, a method for preparing a pharmaceutical composition comprising the step of continuing a compound of the present invention with a pharmaceutically acceptable excipient is provided. The medicaments used in the present invention can be administered orally or parenterally, including intravenously, intramuscularly, intraperitoneally, subcutaneously, transdermally, airway (aerosol), rectally, vaginally or topically (including buccal and sublingual). For oral administration, the compounds of the invention will generally be provided in the form of tablets or capsules, as powders or granules, or as an aqueous solution or suspension. Tablets for oral use include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives or preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alkyl acid are suitable disintegrating agents. The binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin. or olive oil. Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate. Formulations suitable for vaginal administration may be presented as pessaries, plugs, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient carriers such as those known in the art which are appropriate. For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered at appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and tragacanth gum, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl p-hydroxybenzoate and n-propyl. The compounds of the invention can also be presented as liposome formulations. In general, a suitable dose will be in the range of 0.1 to 300 mg per kilogram of body weight in the recipient per day, preferably in the range of 6 to 150 mg per kilogram of body weight per day, and more preferably in the range from 15 to 100 mg per kilogram of body weight per day. The desired dose is preferably presented as two, three, four, five or six or more sub-doses administered at appropriate intervals during the day. These sub-doses may be administered in unit dosage forms, for example, containing 10 to 1500 mg, preferably 20 to 1000 mg, and most preferably 50 to 700 mg of the active ingredient per unit dosage form. According to a further aspect of the present invention, there is provided a process for the preparation of a compound according to the present invention, the process comprises the reaction of a compound of formula (11) with a compound of formula (12) And ArO-P-Cl The reaction can be carried out in tetrahydrofuran in the presence of N-methylimidazole. Alternatively, the compounds of the present invention may be prepared by reaction of a compound of formula (13) or a suitable derivative thereof with ArOH and a compound of formula (14) or suitable derivative thereof.

The invention will now be described with reference to the following figures and examples. It will be appreciated that the following is by way of example only and that modifications to detail can be made and still be within the scope of the invention. Figure 1 illustrates the in vivo antiviral activity of d4T (comparative) and the arylesterphosphoramidate compound 324 in mice infected with MSV. Doses of medication are 50 [low] or 200 [high] mg / kg / day administered i.p. for 4 days beginning 1 hour before inoculation with MSV.

EXPERIMENTAL PART All experiments involving water sensitive experiments are carried out under scrupulously dry conditions. The tetrahydrofuran is dried by heating under reflux over sodium and benzophenone followed by distillation and storage on active sieves. N-Methylimidazole is purified by distillation. The nucleosides are dried at high temperature in vacuo over P2Os. Nuclear Magnetic Resonance Spectra of Carbon and Phosphorus Proton (XH, 13C, 31P rn) are recorded on a Bruker Avance DPX spectrometer operated at 300 MHz, 75.5 MHz and 121.5 MHz, respectively. All nmr spectra are recorded in CDC13 at room temperature (20 ° C +/- 3 ° C). The chemical deviations of XH and 13C are noted in parts per million field down from tetramethylsilane. The values of J refer to the coupling constants and the signal shift patterns are described as singlet (s), broad singlet (sa), doublet (d), triplet (t), quartet (c), multiplet (m) ) or combinations thereof. The chemical deviations of 31P are recorded in parts per million in relation to the external phosphoric acid standard. Many NMR peaks were further divided due to the presence of diastereomers in the [chiral] phosphate center. Chromatography refers to flash column chromatography and is carried out using Merck 60H silica gel (40-60 m, 230-400 mesh) as the stationary phase. Thin layer chromatography is carried out using aluminum gel plates coated with aluminum Alugram SIL G / UV25 ?. The mass spectra are recorded by the fast atomic bombardment mode (BAR) on a VG 70--250 spectrometer. The CLAP data are recorded using an ACS quaternary system with a 0DS5 column and a water / acetonitrile eluent with 82% water 0-10 mm, and the linear gradient at 20% water, at 30 minutes, with a velocity of flow of 2 ml / min and UV detection at 265 nm.

The test compounds are isolated as mixtures of the diastereoisomers, with this isomerism arising from mixed stereochemistry in the phosphate center. The resulting oils do not provide useful microanalytical data found to be pure with broad field multinuclear NMR spectroscopy and rigorous CLAP analysis.

Preparation of the Compounds The compounds of the present invention are prepared according to the following general procedures.

Preparation of aryl phosphorodichlorhydrates (general procedure) A solution of the appropriate phenol (30.4 mmole) and triethylamine (4.25 ml, 30.5 mmole) in dry CH2C12 (25 ml) is added to a freshly distilled P0C13 solution (10 ml, 107 mmole) in CH2C12 (30 ml) at -50. ° C and the mixture is allowed to stir at room temperature overnight. The reaction mixture is filtered and the filtrate is evaporated. Ether (20 ml) is added and the precipitate is filtered again. After evaporation the residue is distilled if possible.

Phenyl N-methylalaninyl phosphorochloride A solution of triethylamine (1 ml-7.17 mmol) in 15 ml of dry CH2C12 is added dropwise to a mixture of phenyl phosphorodichlorhydrate (757.4 mg, 3.59 mmol) and L-alanine methyl ester hydrochloride (500 mg, 3.58 mmol). ) in 50 ml of dry CH2C12 at -80 ° C for 1 hour. The mixture is then stirred vigorously at -50 ° C for 5 hours and evaporated in CH2C12. 25 ml of dry ether are added and the precipitate is filtered off under nitrogen. Evaporation of the ether provides a colorless oil which is used without further purification for the next step.

Preparation of aryl phosphates of nucleoside analogues (general procedure) Phenyl N-alaninyl phosphorochlorohydrate (250 mg, 0.9 mmol, 2.0 equivalents) is added to a stirred solution of nucleoside analogue (0.45 mmol) and N-methylimidazole (0.37 mL, 143.5 μL, 1.8 mmol, 4 equivalents) in THF ( 2 ml). After 4 hours, the solvent is removed under reduced pressure. The gum is dissolved in chloroform (10 ml) and washed with 1M HCl (8 ml), sodium bicarbonate (10 ml) and water (15 ml). The organic phase is dried and the solvent is removed in vacuo. The residue is purified by column chromatography on silica with elution by chloroform-methanol (97: 3). The accumulation and evaporation of the eluent provides the product as a white solid.

Spectral data 323 -. 323 - 5 '- (p-ethylphenylmethoxyalaninyl) phosphoramidate 2', 3 '-dideoxy-2' .3 '-dideshidrotimidine Yield = 79% 31P (CDClj): 3.43 ppm * H (CDC13): 9.25 (0.5H, s, B, NH), 9.23 (0.5H, s, A, NH), 7.34 (0.5H, S, H- 6, B), 7.33 (0.5H, s, H-6, A), 7.14 - 7.00 (5H, m, Ph, H-1 '), 6.28 (1H, m, H-3'), 5.88 (1H, m, H-2 '), . 00 (ÍH, m, H-4 '), 4.38 - 4.25 (2H, m, H-5'), 3.93 (2H, m, ala-NH, ala-CH), 3.70 (1.5H, s, OMe, A), 3.67 (1.5H, s, OMe, B), 2.60 (2H, c, CH2CH3, J = 7.5 Hz), 1.84 (1.5H, d, 5-CH3, J = 1.2 Hz), 1.80 (1.5H, d, 5-CH3, J = 1.2 Hz), 1.31 (3H, m, CH2CH3), 1.19 (3H, m, ala-CH3). 13C (CDC13): 174.25 (Wing-CO, A), 174.12 (Wing-CO, B), 164.22 (C-4, B), 164.17 (C-4, A), 151.15 (C-2, B), 151.12 (C-2, A), 148.29 (i-Ph, B), 148.16 (i-Ph, A), 141.24 (p-Ph, A), 141.19 (p-Ph, B), 136.06 (C-6, B), 135.76 ( C-6, A), 133.50 (C-3 ', A), 133.15 (C-3', B), 129.11 (o-Ph, A), 129.05 (o-Ph, B), 127.54 (C-2 ', A), 127.36 (C-2', B), 120.08 (d, m-Ph, B, J = 3.9 Hz), 119.90 (d, m-Ph, A, J = 4.9 Hz), 111.51 (C -5, A), 111.40 (C-5, B), 89.83 (Cl ', B), 89.60 (C-l', A), 84.88 (d, C-4 ', B, J = 8.8 Hz), 84.70 (d, C-4 ', A, J = 8.8 Hz), 67.11 (d, C-5', A, J = 4.9 Hz), 66.48 (d, C-5 ', B, J = 4.9 Hz) , 52.65 (OMe), 50.26 (wing-CH, B), 50.13 (wing-CH, A), 28.19 (Ph-CH2), 20.97 (D, wing-CH3, B, J = 4.9 Hz), 20.90 (d , wing-CH3, A, J = 4.9 Hz), 15.69 (Ph-CH2CH3), 12.45 (5-CH3, A), 12.41 (5-CH3, B). MS: C22H29N3OgP: 494 (MH +, 5), 368 (MH + -thimine, 25), 228 (15), 81 (CsH50, peak base) Accurate mass: expected 494.1692; found 494.1693 CLAP: TR = 27.23 and 27.48 min 324 -. 324 - 5 '- (Phenyl N-methoxy alaninyl) 2' .3 '- dideoxy-2', 3'-didehydrotimidine phosphoroamidate Yield: = 88% 31P (CDC13): 3.20 and 3.86 ppm H (CDC13): 1.32 and 1.34 (d, 3H, J = 6.8 Hz, Cli, ala); 1.81 and 1.84 (d, 3H, 5CH3); 3.69 and 3.70 (s, 3H, OMe); 3.84-4.00 (m, 2H, CH ala + NH ala); 4.32 (m, 2H, H5 '); 5.02 (m, ÍH, H4 '); 5.88 (m, ÍH, H2 '); 6.33 (m, ÍH, H3 '); 7.03 (m, ÍH, H1 '); 7.15-7.35 (m, 6H, Ar + H6); 9.22 and 9.26 (broad s, ÍH, NH) 13C (CDC13): 12.52 (5CH2); 21.02 (CH3 wing); 50.22-50.35 (CH ala); 52.74 (OMe); 66.62-67.29 (C5 '); 84.80-84.88 (C4 '); 89.69-89.93 (Cl '); 111.44-111.57 (C5); 120.13-120.31 (Ar ortho); 125.30 (Arpara); 127.49-127.65 (C2 '); 129.87-129.93 (Ar goal); 133.19-133.50 (C3 '); 135.77-136.06 (C6); 150.51 (Ar ipSO); 151-16 (C2); 164.14 (C4); 174.12 (CO wing) MS: 466 (MH * 0.7); 340 (MH ^ -base); 200 (17); 136 (47); 89 (25); 81 (C ^ O, peak base) CLAP: TR = 22.48 and 22.87 min 327 -. 327 - 5 'Phosphoramidate 5' (p-fluorophenylmethoxyalaninyl) -dideoxy-2 '.3' -dideshidrotimidine Yield = 89% 31P (CDC13): 3.16 ppm H (CDC13): 9.75 (OH, S, NH), 7.24 (0.5H, d, H-6, B, J = 1. 2 Hz), 7.17 (0.5H, d, H-6, A, J = 1.2 Hz), 7.09 (5H, m, Ph, H-l '), 6.22 (H, m, H-3'), 5.82 (ÍH, m, H-2 '), 4.94 (ÍH, m, H-4 '), 4.30-3.84 (4H, m, ala-NH, ala-CH, H-5'), 3. 63 (1.5H, S, OMe, A), 3.62 (1.5H, s, OMe, B), 1.77 (1.5H, d, 5-CH3, B, J = 1.0 Hz), 1.74 (1.5H, d, 5-CH3, A, J = 1.0 Hz, 1.29 (1.5H, d, wing-CH3, B, J = 7.0 Hz), 1.23 (1.5H, d, wing-CH3, A, J = 7.0 Hz). 13 C (CDCl 3): 174.19 (d, wing-CO, B, J = 6.8 Hz), 174.00 (d, wing-CO, A, J = 6.8 Hz), 164.25 (C-4, B), 164.20 (C- 4, A), 159.77 (d, p-Ph, J = 243.6 Hz), 151.14 (C-2), 146.25 (i-Ph), 135.99 (C-6, A), 135.70 (C-6, B) , 133.40. (C-3 ', A), 133.05 (C-3', B), 127.61 (C-2 ', B), 127.45 (C-2', A), 121.70 (m, o-Ph), 116.37 ( d, m-Ph, A, J = 23.5 Hz), 116.34 (d, m-Ph, B, J = 23.5 Hz), 111.45 (C-5, A), 111.32 (C-5, B), 89.87 ( C-l ', A), 89.63 (C-l', B), 84.66 (d, C-4 ', J = 5.9 Hz), 67.29 (d, C-5', A, J = 4.9 Hz), 66.10 (d, C-5 ', B, J = 4.9 Hz), 52.70 (OMe), 50.26 (Wing-CH, A), 50.13 (Wing-CH, B), 20. 92 (d, wing-CH3, A, J = 4. 8 Hz), 20. 88 (d, wing-CH3, B, J = 4 8 Hz), 12.45 (5-CH3, B), 12.41 (5-CH3, A). MS: C20H24N3OβPF: 484 (MH +, 11), 358 (MH * -thimine, 20), 218 (13), 154 (32), 136 (28), 81 (CsHsO, base peak). Accurate mass: expected 484.1285; found 484.1318 CLAP: TR = 25.17 and 25.40 min 526 -. 526 - 5- (m-trifluoromethylphenylmethoxy-alaninyl) phosphoroamidate of 2 '.3' -dideoxy-2 '.3'-didehydrotimidine Yield = 80% 31P (CDC13): 2.49 and 3.16 ppm lH (CDC13): 9.06 (lH, S, NH), 7.45 (5H, m, H-6, Ph), 7.03 (H, m, H-l '), 6.31 (H, m, H-3'), 5.92 (H, m, H- 2 '), 5.03 (ÍH, m, H-4'), 4.32 (2H, m, H-5 '), 3.97 (2H, m, ala-NH, ala-CH), 3.71 (1.5H, s, OMe, B), 3.70 (1.5H, s, OMe, A), 1.86 (1.5H, s, 5-CH3, B), 1.80 (1.5H, d, 5-CH3, A), 1.36 (3H, m , wing-CH3). 13C (CDC13): 174.06 (d, wing-CO, A, J = 6.8 Hz), 173.89 (d, wing-CO, B, J = 6.8 Hz), 163.91 (C-4, A), 163.86 (C- 4, B), 150.96 (C-2), 150.71 (d, a-Ph, J = 5.9 hZ), 135.86 (c-6, A), 135.66 (C-6, B), 133.30 (C-3 ' , A), 133.02 (C-3 ', B), 132.00 (9, C-PH, J = 32.0 Hz), 130.66 (e-Ph), 127.84 (C-2', B), 127.74 (C-2 ', A), 123.98 (f-Ph, A), 123.84 (9, CF3, j = 272.0 Hz), 123.79 (f-Ph. B), 122.14 (d-Ph), 117.54 (b-Ph, J = 3.9 Hz), 111.61 (C-5, B), 111.44 (C-5, A), 90.04 (C-l ', B), 89.77 (Cl', A), 84.61 (d, C-4 ', J = 7.8 Hz), 67.60 (d, C-5 ', B, J = 4.9 Hz), 66.89 (d, C-5', A, J = 4.9 Hz), 52.87 (OMe), 50.32 (d, ala- CH, A, J = 4.8 Hz), 50.26 (d, Wing-CH, B, J = 4.8 Hz), 21.11 (d, Wing-CH3, B, J = 4.9 Hz), 20.99 (d, Wing-CH3, A, J = 4.9 Hz), 12.55 (5-CH3, B), 12.47 (5-CH3, A). MS: C21H24N3OβPF3: 534 (MH +, 6), 408 MIT-thymine, 8), 268 (10), 149 (10), 81 (CsHsO, base peak). Accurate mass: expected 534.1253; found 534.1201 CLAP: TR = 30.56 min 4 6 - Phosphoramidate 5 '- (3,5'-dichlorofenylmethoxyalaninyl) dg 2' .3 '-dideoxy-2' .3'-dideshidrotimidine Yield = 70% 31P (CDClj): 2.83 and 3.42 ppm XH (CDCI3 ): 9.74 (HH, S, NH), 7.40 (HH, S, H-6), 7.29 (3H, m, Ph), 7.14 (HH, m, H-l '), 6.44 (1H, m, H -3 '), 6.04 (IH, m, H-2'), 5.14 (IH, m, H-4 '), 4.48 - 4.07 (5H, m, ala-NH, ala-CH, H-5') , 3.84 (3H, S, OMe), 1.97 (1.5H, s, 5-CH3, A), 1.92 (1.5H, s, 5-CH3, B), 1.48 (3H, m, ala-CH3). 13C (CDC13): 173.93 (ala-CO), 164.09 (C-4), 151.27 (i-Ph), 151.06 (C-2), 136.01 (m-Ph), 135.60 (C-6), 133.14 (C -3 ', B), 132.89 (C-3', A), 127.83 (C-2 '), 125.69 (p-Ph), 119.40 (O-Ph), 111.54 (C-5, A), 111.40 ( C-5, B), 90.03 (C-l ', A), 89.74 (C-l', B), 84.60 (C-4 '), 67.68 (C-5', A), 66.98 (C-5 ', B), 52.85 (OMe), 50.26 (Wing-CH), 20.93 (Wing-CH3), 12.51 (5-CH3). MS: C20H23N3OβPCl2: 534 (MH \ 8), 408 (MH + -thimine, 12), 391 (10), 149 (12), 127 (thymineH +, 12), 81 (CsHsO, base peak). Accurate mass: expected 534.0600; found 534.0589 CLAP: TR = 32.19 min 730 -. 730 - Phosphoramidate d = 2 '.3' -dideoxy-2 '.3'-dideshydrotimidin-5' - (phenyl-N-benzyloxylaninyl) Yield = 92% 31P (CDC13): 3.40 and 4.04 ppm XH (CDC13): 1.24 and 1.26 (d, 3H, J = 6.8 Hz, CH3 wing); 1.70 and 1.74 (S, 3H, 5CH3); 3.86-4.28 (m, 4H, H5 '+ CH ala + NH); 4.85 (m, ÍH, H4 '); 5.04 and 5.06 (s, 2H, CH2Ph); 5.74 (d, ÍH, H2 '); 6.16 (dd, ÍH, H3 '); 6.90 (m, ÍH, Hl '); 7.00-7.30 (m, 11H, Ar + H6); 9.61 (d, ÍH, NH) 13C (CDC13): 12.52 (5CH3); 20.98 (CH3 ala), 50.36-50.52 (CH ala); 66.70-67.18 (C5 '); 67.46 (CH2Ph); 84.63-84.76-84.88 (C4 '); 89.68-89.88 (Cl '); 111.44-111.55 (C5); 120.18-120.25-120.36-120.43 (Ar ort, OPh); 125.31 (Ar, para, OPh); 127.48-127.61 (C2 '); 128.45-128.79-128.83 (Ar, CH2Ph); 129.87-129.93 (Ar meta, OPh); 133.16-133.45 (C3 '); 135.35 (Arl, CH2Ph); 135.79-136.07 (C6); 150.44 (Arl, OPh); 151.18 (C2); 164.21-164.28 (C4); 173.42-173.51-173.65 (CO ala) CLAP: TR = 34.96 and 35.07 min MS: C2SH2ßOßN3P: 542 (MH * 0; 17); 416 (MH + ° base; 40); 81 (100). Accurate mass: expected 542.1716; found 542.1712 776 -. 776 - Phosphoramidate £ g 2 '.3' -dideoxy-2 '.3'-dideshydrotimidin-5' - (phenyl-N-benzyloxy alaninyl) Yield = 88% 31P (CDC13): 3.07 and 3.62 ppm XH (CDC13): 1.26 and 1.28 (d, 3H, J = 6.8 Hz, CH3 ala); 1.75 and 1.80 (S, 3H, 5CH3); 2.11 (s, ÍH, NH); 3.64 (s, 3H, OMe); 3. 92-4.30 (m, 3H, H5 '+ CHala); 4.98 (m, ÍH, H4 '); 5.87 (m, ÍH, H2 '); 6.26 (m, ÍH, H3 '); 6.96 (m, ÍH, Hl '); 7.30-7.60 (m, 4H, Ar + H6); 9.41 (broad s, ÍH, NH) 13 C (CDC13): 12.51 (5CH3); 21.00 (CH3 wing); 50.24 (CHala); 52.80 (OMe); 67.37-67.83 (C5 '); 84.49-84.61 (C4 '); 89.80-89.92 (Cl '); 111.60 (C5); 115.49 (Ar2); 118.26 (Ar4); 122.61-122.89 (Ar6); 127.70 (C2 '); 131.86 (Ar5); 133.06-133.21 (C3 '); 135.64 (Ar3); 135.75-135.88 (C6); 147.01 (Arl); 151.07 (C2); 164.03 (C4); 173.71-173.82 (COala) CLAP: RT = 41.17 and 41.30 min MS: C20H22O8N3PBr2: 622,624,626 (MH * 0; 3.6.3); 496,498,500 (MH * ° "base; 5,9,5); 81 (100) Accurate mass: expected 621.9516; found 621.9507 779 -. 779 - Phosphoramidate a = 2 '.3' -dideoxy -2 ', 3'-dideshydrotimidine-5' - (2.3.4.5.6-pentaf luorofenyl-N-methylalaninyl) Yield = 76% 31P (CDC13): 4.74 and 5.66 ppm lH (CDC13): 1.34 and 1.36 (d, 3H, J-6.7 Hz, CH3 ala); 1.75 and 1.81 (S, 3H, 5CH3); 3.69 (s, 3H; OMe); 3.92-4.40 (m, 4H, H5 '+ CH ala + NH); 4.97 (m, ÍH, H4 '); 5.85 (tn, ÍH, H2 '); 6.29 (m, ÍH, H3 '); 6.93 (m, ÍH, Hl '); 7.19 (m, ÍH, H6); 9.38 (s broad H, NH) 13 C (CDC13): 12.23-12.43 (5CH3); 20.83 (CH3 ala); 50.22-50.34 (CH ala); 52.99 (OMe); 67.75-68.37 (C5 '); 84.42-84.52 (C4 '); 89.87-90.17 (Cl '); 111.75 (C5); 127.69-127.93 (C2 '); 132. 86-133.13 (C3 '); 132-143 (m, Ar); 135.74-135.96 (C6); 151. 11 (C2); 164.15 (C4); 173.64-173.76 (COala) Mass (NOBA matrix): C20H19OaN3PF5: 556 (MH * °, 31); 578 (M ° * Na, 100) CLAP: TR - 35.90 min 862 -. 862 - 5 '- (Phenyl-N-hexyloxy alaninyl) 2' .3 '-dideoxy-2' .3 '-dideshidrotimidine Yield = 88% 31P (CDC13): 3.99 and 4.60 ppm XH (CDC13): 0.94 ( m, 3H, C &CHj); 1.28-1.41 (m, 9H, CH3 ala + 3xCH2); 1.65 (m, 2H, COJCHJCHJ); 1.90 and 1.93 (s, 3H, 5CH3); 4.00-4.20 (m, 4H, CH ala + NH ala + C02Cfí2); 4.37 (m, 2H, H5 '); 5.05 (m, ÍH, H4 '); 5.94 (m, ÍH, H2 '); 6.38 (m, ÍH, H3 '); 7.10 (m, ÍH, Hl '); 7.15-7.36 (m, 6H, Ar + H6); 9.48 and 9.51 (S, ÍH, NH) 13C (CDC1,): 12.76 (5CH3); 14.39 (£ H3CH2); 21.45 (CH3 wing); 22.88, 25.82, 28.82 and 31.72 (CH2); 50.63 (CH ala); 66.26 (OCH2); 66.89-67.43 (C5 '); 85.03 (C4 '); 89.97 (Cl '); 111.68-111.83 (C5); 120.55 (Ar ortho); 125.57 (Ar for); 127.86 (C2 '); 130.15 (Ar meta); 133.47-133.70 (C3 '); 136.03-136.31 (C6); 150.72 (Ar ipso); 151.37-151.39 (C2); 164.35-164.42 (C4); 174.02 (CO wing) Mass (NOBA matrix): C2SH34OßN3P: 536 (MH * °, 24); 558 (M ° + Na, 37) 863 - 2 '.3' - Dideoxy-2 ', 3'-didehydrotimidine-5' - (phenyl-N-methoxy-phenylalaninyl) phosphoamidate Yield = 89% 31P (CDC13): 3.96 and 4.35 ppm? E (CDCl3): 1.89 (S, 3H, 5CH3); 3.00 (m, 2H, CH2Ph); 3.74 (S, 3H, OMe); 3.80-4.28 (m, 4H, CH ala + NH ala + H5 '); 4.94 (m, ÍH, H4 '); 5.91 (m, ÍH, H2 '); 6.21-6.30 (m, ÍH, H3 '); 7.04-7.32 (m, 12H, Ar + Hl '+ H6); 9.35 (s, 1H, NH) 13C (CDC13): 12.54 (5CH3); 40.55 (CH2Ph); 52.63 (OMe); 55.72-56.01 (CH ala), 66.50-67.10 (C5 '); 84.78 (C4 '); 89.71-89.95 (Cl '); 111.53-111.64 (C5); 120.28 (Ar ort, OPh); 125.40 (Ar for, OPh); 127.52 (C2 '); 128.86, 29.65 and 129.98 (Ar, CH2Ph); 129.86-129.92 (Ar meta, OPh); 133.18-133.50 (C3 '); 135.72 (Ar ipSO, CH2Ph); 135.79-136.06 (C6); 150.46 (Ar ipSO, OPh); 151.13-151.17 (C2); 164.12-164.18 (C4), 173.00 (CO ala) Mass (NOBA matrix): C2SH2ßOßN3P: 542 (MH * °, 77); 564 (M ^ Na, 29) 864 -. 864 - 2 '.3' - Dideoxy-2 'phosphoramidate. '-dideshidrotimidin-5' - (phenyl-N-methoxy-leucinyl) Yield = 87% 31P (CDCI3): 4.18 and 4.83 ppm XH (CDCl3): 0.91 (m, 6H,; 1.42-1.70 (m, 3H, CH2CH (CH3) 2), 1.91 and 1.93 (s, 3H, 5CH3), 3.73 (s, 3H, OMe); 3. 76-3.98 (m, 2H, CH ala + NH ala); 4.28-4.46 (m, 2H, H5 '); . 08 (m, ÍH, H4 '); 5.96 (m, ÍH, H2 '); 6.36 (m, ÍH, H3 '); 7. 09 (m, ÍH, Hl '); 7.18-7.35 (m, 6H, Ar + H6); 9.35 (s, 1H, NH) 13 C (CDC113): 12.76 (5CH3); 22.23-23.01 ((£ H3) 2CH); 24.75 (CH (CH3) 2); 43.86-44.11 (£ H2CH (CH3) 2); 52.75 (OMe); 53.42-53.60 (CH ala), 66.92-67.55 (C5 '); 85.62 (C4 '); 89.92-90.19 (Cl '); 111.69-111.83 (C5); 120.37-120.62 (Ar ortho); 125.55-125.58 (Ar for); 127.79 (C2 '); 130.12 (Ar meta); 133.51-133.70 (C3 '); 136.00-136.36 (C6); 151.05 (Ar ipso); 151.38 (C2); 164.39-164.50 (C4); 174.55-174.88 (CO wing) Mass (NOBA matrix): C23H30O8N3P: 508 (MH + °, 62); 530 (M ° + Na, 59) 865 -. 865 - 2 '.3' Phosphoramidate-dideoxy-2 '. 3' -dideshydrotimidine-5 '- (phenyl-N-methoxy-salicylin) Yield = 86% 31P (CDClj): 4.85 and 5.40 ppm lH (CDC13): 0.92 ( m, 6H, (CH,),); 1.82 (m, 3H, CH (CH3) 2); 1.89 and 1.91 (S, 3H, 5CH3); 3.76 (S, 3H, OMe); 3.82 (m, 2H, CH ala + NH ala); 4.30-4.48 (m, 2H, H5 '); 5.07 (m, ÍH, H4 '); 5.96 (m, ÍH, H2 '); 6.38 (m, ÍH, H3 '); 7.10 (m, ÍH, Hl '); 7.18-7.35 (m, 6H, Ar + H6); 9.31 (s, ÍH, NH) 13 C (CDC13): 12.80 (5CH3); 17.77-19.24 ((CH3) 2CH); 32.43-32.62 (£ H (CH3) 2); 52.67 (OMe); 60.32-60.38 (CH ala); 66.92-67.65 (C5 '); 85.04 (C4 '); 89.98-90.24 (Cl '); 111.76-111.87 (C5); 120.45-120.56 (Ar ortho); 125.54-125.59 (Ar for); 127.81-127.86 (C2 '); 130.13-130.17 (Ar meta); 133.51-133.72 (C3 '); 136.01-136.28 (C6); 150.83 (Ar ipso); 150.87-151.34 (C2); 164.30-164.37 (C4); 173.56-173.65 (CO wing) Mass: C22H28OßN3P: 493.6 (MH + O, 100) 866 -. 866 - 2 '.3'-dideoxy-2' phosphoramidate. '-dideshidrotimidin-5' - (phenyl-N-methoglycinyl) Yield = 90% 31P (CDC13): 4.89 and 5.52 ppm XH (CDCI3): 1.79 and 1.83 (s, 3H, 5CH3); 3.69 (S, 3H, OMe); 3. 70-4.05 (m, 4H, CH2NH + CH ala + NH ala), 4.32 (m, 2H, H5 '); 4.99 (m, ÍH, H4 '); 5.92 (m, ÍH, H2 '); 6.38 (m, ÍH, H3 '); 6.98 (m, ÍH, Hl '); 7.05-7.38 (m, 6H, Ar + H6); 9.44 and 9.46 (s, ÍH, NH) 13 C (CDCl 3): 12.75 (5CH 3); 43.15 (£ H2NH); 52.94 (OMe); 66. 78-67.52 (C5 '); 84.98-85.10 (C4 '); 89.68-90.16 (Cl '); 111. 69-111.80 (C5); 120-46-120.59 (Ar ortho); 125.66 (Ar for); 127.66-127.91 (C2 '); 130.22 (Ar meta); 133.48-133.87 (C3 '); 136.11-136.40 (C6); 150.65 (Ar ipso); 151.45 (C2); 164. 46 (C4); 171.41-171.51 (CO ala) Mass (NOBA matrix): C19H22OßN3P: 452 (MH + °, 74); 474 (M ° + Na, 46) 867 - 2 '.3' Phosphoramidate-dideoxy-2 '.3' -dideshydrotimidin-5 '- (phenyl-N-methoxymethioninyl) Yield = 81% 31P (CDC13): 4.09 and 4.86 ppm H (CDCl3): 1.74 and 1.79 (S, 3H, CH3S); 1.94 and 1.97 (s, 3H, 5CH3); 1.80-2.40 (m, 5H, CHC &CIFs); 3.72 and 3.74 (s, 3H, OMe); 3.98-4.32 (m, 4H, H5 '+ CH ala + NH ala); 4.96 (m, ÍH, H4 '); 5.84 (tn, 1H, H2 '); 6.26 (m, ÍH, H3 '); 6.96 (m, ÍH, Hl '); 7.05-7.25 (m, 6H, Ar + H6); 9.58 (broad s, ÍH, NH) 13 C (CDCl 3): 12.80 (5CH 3); 15.68 (CH3S); 29.95 (CH2SCH3) 33.73-33.85 (£ H2CH2S); 53.06 (OMe); 53.81-54.07 (NH £ H) 67.05-67.70 (C5 '); 84.90-85.03 (C4 '); 89.98-90.23 (Cl ') 111.66-111.86 (C5); 120.39-120.66 (Ar ortho); 125.63 (Ar for); 127.81-127.91 (C2 '), 130.18 (Ar meta); 133.44-133.69 (C3 '); 136.00-136.38 (C6); 150.72-150.80 (Ar ipso); 151.41 (C2); 164.52 (C4); 173.61-173.94 (CO ala) Mass (NOBA matrix): C22H2ßOßN3PS: 526 (+ °, β); 548 (M ° + 6Na, 21) 868 -. 868 - yQgfPrQjm? DfltQ S. 2.3 '-dideoxy-2' .3'-dideshidrotimidin-5 '- (2,4-dibromophenyl-N-benzylalaninyl) Yield = 82% 3lP (CDCI3): 3.68 and 4.18 ppm XH (CDClj): 1.40 and 1.42 (d, 3H, J = 6.7 Hz, CH3 ala); 1.90 and 1.92 (s, 3H, 5CH3); 4.04-4.40 (m, 4H, H5 '+ CHala + NH ala); 4.98 (m, ÍH, H4 '); 5.20 (s, 2H, CH2Ph); 5.91 (m, ÍH, H2 '); 6.27 and 6.35 (m, ÍH, H3 '); 7.06 (s broad, ÍH, H1 '); 7.30-7.70 (m, 9H, Ar + H6); 9.52 (s, ÍH, NH) 13 C (CDCl 3): 12.86 (5CH 3); 21.35 (CH3 wing); 50.68-50.76 (CHala); 67.67-68.03 (C5 '); 67.88 (CH2Ph); 84.85 (C4 ') 90.10-90.20 (Cl'); 111.88-111.92 (C5); 115.76-115.91 (Ar2) 118.62-118.72 (Ar4); 122.91-123.22 (Ar6); 127.98 (C2 ') 128.75-129.01-129.12 (Ar 0, m, p, CH2Ph); 132.20 (Ar5) 133.38-133.51 (C3 '); 135.48 (Ar ipso, CH2Ph); 135.96 (Ar3) 136.21 (C6); 147.28 (Arl); 151.39 (C2); 164.34-164-38 (C4) 173.47-173.62 (COala) Mass (NOBA matrix): C2ßH2608N3PBr2: 699-700-701 (MH * 0, 27-49-29); 721-722-723 (M ° + Na, 17-21-17) 877 -. 877 - 2 '.3' Phosphoramidate-dideoxy-2 '.3' -dideshidrotimidin-5 '- (phenyl-N-methoxy-glycine) Yield = 83% 31P (CDC13): 3.91 and 4.33 ppm XH (CDC13): 1.83 and 1.85 (s, 3H, 5CH3); 3.01 (m, 2H, CHCH2Ph), 3.78-4.30 (m, 4H, H5 '+ HNCH); 4.92 (tn, ÍH, H4 '); 5.89 (m, ÍH, H2 '); 6.18 and 6.27 (m, ÍH, H3 '); 7.00-7.40 (m, 17H, Ar + Hl '+ H6); 9.35 (broad S, 1H, NH) 13 C (CDCl 3): 12.62-12.75 (5CH 3); 40.65-40.73 (CH £ H2Ph) 55. 95-56.26 (NHCH); 66.79 -67.27 (C5 '); 67.80 (£ H2Ph) 84. 87-85.05 (C4 '); 89.92-90.14 (Cl '); 111.72-111.82 (C5) 120. 45-120.52 (Ar ortho, OPh); 125.60 (Ar for, OPh); 127.73 (C2 '); 129.01- 129.07-129.11-129.91- 130.15-130.38- 135.29- 135.85 (Ar, 2xCH2Ph); 130.21 (Ar goal, OPh); 133.36-133.63 (C3 '); 136.24 (C6); 150.68-150.77 (Ar ipso, OPh); 151.31- 151.35 (C2); 164.28-164.34 (C4); 172.48-172.64 (CO wing) Mass (NOBA matrix): C32H3208N3P: 618 (MH + °, 78); 640 (M ° + Na, 52) 878 -. 878 - 2 '.3' Phosphoramidate-dideoxy-2 '. 3' -dideshidrotimidin-5 '- (phenyl-N-tert-butylphenylalaninyl) Yield = 79% 31P (CDCl3): 4.27 and 4.50 ppm XH (CDCl3): 1.40 and 1.41 (s, 9H, tBu), 1.84 and 1.87 (s, 3H, 5CH3); 3.00 (m, 2H, ClfcPh); 3.76-4.28 (m, 4H, H5 '+ HNCH); 4.95 (m, ÍH, H4 '); 5.86 and 5.91 (m, ÍH, H2 '); 6.26 and 6.30 (m, ÍH, H3 '); 7.04 (m H, H '); 7.12-7.25 (m, 11H, Ar + H6); 9.38 and 9.40 (broad s, ÍH, NH) 13 C (CDCl 3): 12.76-12.79 (5CH 3); 28.31 ((£ H3) 3C); 40.96-41.04 (£ H2Ph); 56.31-56.65 (NHCH); 66.79-67.28 (C5 '); 82.90-82.92 ((CH3) 3 £); 84.94-85.03 (C4 '); 89.93-90.11 (Cl '); 111.67-111.86 (C5); 120.45 (Ar ort, OPh); 125.52 (Ar for, OPh); 127.77 (C2 '); 127.88-128.83-128.92-136.02 (Ar, CH2PÜ); 130. 13 (Ar meta, OPh); 133.54-133.60 (C3 '); 136.31 (C6); 150.75-150.84 (Ar ipso, OPh); 151.36 (C2); 164.32-164.37 (C4); 171.89 (CO wing) Mass (NOBA matrix): C29H3408N3P: 584 (MH *, 26); 606 (M ° + Na, 41), 892 -. 892 - 5 '(3-phenyl-N-cyclohexyloxy alaninyl) phosphoamidate 2-d3-dideoxy-2' .3'-didehydrotimidine Yield = 83% 3lP (CDClj): 4.11 and 4.71 ppm. XH (CDC13): 1.08-1.82 (m, 16H, CH3 ala + 5CH3 + cyclohexyl); 3.79-4.14 (m, 2H, CH ala + NH ala); 4.27 (m, 2H, H5 '); 4.69 (m, CH-cyclohexyl); 4.96 (m, ÍH, H4 '); 5.80 (m, ÍH, H2 '); 6.24 (m, ÍH, H3 '); 6.98 (m, ÍH; Hl '); 7.04-7.32 (m, 6H, Ar + H6); 9.66 and 9.82 (broad s, ÍH, NH). 13 C (CDC113): 12.58 (5CH3); 21.18-21.32 (CH3 ala); 23.73-25.40-31.49-31.58 (CH2 cyclohexyl); 50.47-50.61 (CH ala); 66.69-67.24 (C5 '); 74.36 (HH-cyclohexyl); 84.87 (C4 '); 89.72-89.92 (Cl '); 111.48-111.63 (C5); 120.26-120.49 (Ar ortho); 125.32-125.37 (Ar for); 127.59-127.73 (C2 '); 129. 91-129.98 (Ar meta); 133.30-133.51 (C3 '); 135.89-136.16 (C6); 150.53 (Ar ipso); 150.67-151.31 (C2); 164.36-164.41 (C4); 173.23 (CO wing). Mass (NOBA matrix): C2SH3208N3P: 534 (MH * °, 56); 556 (M + Na, 42) 893 - 5 '- Phenyl-N-t-Butyloxy-alaninyl phosphonamidate 2 '.3' -dideoxy-2 '.3' -dideshidrotimidine Yield = 79% 31P (CDC113): 4.17 and 4.67 ppm. XH (CDClj): 1.34 (m, 3H, CH3 ala); 1.46 (m, 9H, CH3 tBu); 1. 87 (d, 3H, 5CH3); 3.82-4.06 (m, 2H, H5 '); 4.29-4.49 (m, 2H, CH ala + NH ala), 5.05 (m, ÍH, H4 '); 5.91 (m, ÍH, H2 '); 6. 35 (m, ÍH, H3 '); 7.06 (m, ÍH, H1 '); 7.15-7.40 (m, 6H, Ar + H6); 9.60 (broad s, ÍH, NH). 13 C (CDC13): 12.54 (5CH3); 21.19-21.35 (CH3 ala); 28.07 (C (CH3) 3); 50.80-50.89 (CH ala); 66.60-67.18 (C5 '); 82.41-82.45 (C (Me) j); 84.82 (C4 '); 89.67-89.87 (Cl '); 111.44- 111.60 (C5); 120.22-120.41 (Ar ortho); 125.28-125.31 (Ar for); 127.54-127.65 (C2 '); 129.88-129.94 (Ar meta); 133.33-133.47 (C3 '); 135.84-136.10 (C6); 150.51 (Ar ipso); 150. 65-151.20 (C4); 164.19-164.23 (C2); 172.78-172.93 (CO ala). Mass (NOBA matrix): C23H30O8N3P: 508 (MH * °, 82); 530 (M ° + Na, 48).

Fosf t of 2 '.3' -dideoxy-2 '.3'-didihidrotimidin-5'- (phenylmethoxy-B-alaninyl Cf 1197 Yield = 64% 31P (CDCI3): 6.44, 6.70 (1: 3) ÍH (CDCI3 ): 1.87 * (s, 3H, 5-CH3), 2.42 (t, 2H, CH2 ala), 3.22 * (m, 2H, CH2 ala), 3.62 (s, 3H, 0CH3), 4.09 (m, ÍH, H4 ') # 4.18-4.39 (m, 2H, H5'), 4.97 (s broad, ÍH, NH ala), 5.88 * (m, ÍH, H2 '), 6.32 * (m, ÍH, H3'), 6.99 (m, ÍH, Hl '), 7.08-7.38 (m, 5H, Ph and H6), 10.01 (s broad, ÍH , NH base) 13C (CDCl3): 14.52 (5-CH3), 37.80 * (CH2 ala), 39.28 * (CH2 ala), 53.91 * (OCH,), 68.57 * (d, J = 3.92 Hz, C5 ') , 86.90 (d, J = 8.38 Hz, C4 '), 91.68 * (Cl'), 113.4 * (C5), 122.34 (d, J = 4.68 Hz, ortho-Ph), 127.23 (C2 '), 129.55 * ( para-Ph), 131.81 * (meta-Ph), 135.45 * (C6), 137.99 * (C3 ') (152.60 * (d, J = 5.96 Hz, ipso-Ph), 153.44 (C2), 166.58 (C4) , 174.55 * (COO) Mass (NOBA matrix): C20H24N3O8 126 (thymine *, 5), 127 (thymineH *, 4), 242 (C10H13P04N *, 9), 243 (C10H14PO4N \ 3), 465 (M *, 4 ), 466 (MH *, 8), 467 (MHNa *, 20), 168 (MHNa *, 130, 5), 187 (MNa *, 3), 188 (MHNa *, 97), 189 (MHNa *, 13C , 21) High resolution EM: found 466.1379 (MH *), C20H2SN3O "P requires 466.1379 CLAP: TR = 22.81, 23.27 minutes (1: 1) S 2 '. 3' - Dideoxy-2 '. 3' -dideshidrotimidin-5 '- (phenylmethoxy-a-aminobutyryl) Cf 1198 Yield = 65% 31P (CDClj): 6.11, 6.66 (1: 2) XH ( CDCI3): 1.78 (m, 2H, CH2 GABA), 1.85 * (s, 3H, 5-CH3), 2.35 (t, 2H, J = 6.95 Hz, CH2 GABA), 2.97 * (m, 2H, CH2 GABA) , 3.68 (s, 3H, OCH3), 3.93 * (m, ÍH, H4 '), 4.28 * (m, ÍH, H5'), 4.35 * (m, ÍH, H5 '), 5.02 (s broad, ÍH, NH GABA), 5.82 * (m, HH, H2 '), 6.31 (m, HH, H3'), 6.98 (m, HH, H1 '), 7.11-7.37 (m, 6H, Ph and H6), 9.91 ( s broad, ÍH, NH base) 13 C (CDCl 3): 12.64 (5-CH 3), 26.72 * (CH 2 GABA), 32.25 * (CH 2 GABA), 40.98 * (CH 2 GABA), 51.94 (OCH 3), 66.93 * (C 5 '); 85.11 (d, J = 8.30 Hz, C4 '), 111.40 (C5), 120.46 * (d, J = 4.83 Hz, ortho-PH), 125.24 (C2'), 127.59 * (para-Ph), 129.88 * ( meta-Ph), 133.68 * (C6), 136.28 * (C3 '), 150.86 * (d, J = 6.45 Hz, ipSO-Ph), 151.61 (C2), 164.80 (C4), 173.86 * (COO) Mass ( NOBA matrix): C21H2SN308P: 127 (thymine H *, 28), 479 (M *, 3), 480 (MH *, 59), 481 (MH *, 13C, 17), 501 (MNa *, 3), 502 ( MHNa *, 59), 503 (MHNa *, 13C, 16) High resolution EM: found 480.1486 (MH *), C21H27N308P requires 480.1536 CLAP: TR 23.90, 24.33 minutes (1: 1) Phosphate 2 '.3' -dideoxy-2 '.3' -dideshidrotimidin-5 '- (phenylmethoxy-2-aminoisobutyryl) Cf 1200 Recess = 36% 31P (CDC13): 2.38, 3e.05 (3: 1) lE (CDClj): 1.53 * (s, 6H, CMe2), 1.91 * (s, 3H, 5-CH3), 3.71 (S, 3H, OCH3), 4.31 (m, 2H, H5 '), 4.23-4.41 (m, 3H, H4' and H5 '), 5.03 (s broad, ÍH, P-NH) 5.89 * (m, ÍH, H2'), 6.28 * (m, ÍH, H3 '), 6.99-7.31 (m, 7H, Ph, HO and H1'), 9.09 (broad s, HI, NH base) 13C (CDC13): 14.27 (5-CH3), 28.74 * ( CMg2), 54.81 * (OCH3), 58.88 * (£ Me2), 69.03 * (d, C, J = 5.58 Hz), 86.57 * (d, J = 7.88 Hz, C4 '), 91.51 * (Cl'), 113.24 * (C5), 122.01 * (d, J = 4.95 Hz, ortho-Ph), 126.88 (C2 '), 129.25 * (para-Ph), 131.57 * (metaPh), 135.19 * (C6), 137.68 * ( C3 '), 152.52 * (d, J = 3.09 Hz, ortho-Ph), 153.05 (C2), 166.12 (C4), 177.69 * (COO) EM (NOBA matrix): 354 ((MH-thymine) * base peak ), 479 (M *, 3), 480 (MH *, 64), 481 (MH *, 13C, 17), 482 (MH *, 2 X 13C, 3), 502 (MNa *, 92), 503 ( MHNa *, 24) High resolution EM: found 480.1503 (MH *), C21H27N308P requires 480.1536 CLAP: TR 24.79, 25.29 minutes (1: 1) Phosphate a = 2 '.3' -dideoxy-2 '.3' -dideshidrotimidin-5 '- (phenylmethoxy-6-aminocaproyl) Cf 1199 Yield = 80% 31P (CDC1,): 6.90, 6.30 (1: 1) XH (CDC13): 1.28 (S, 2H, CH2 caproyl), 1.45 (m, 2H, CH2 cappropyl), 1.58 (m, 2H, CH2 caproyl), 1.82 * (s, 3H, 5-CHj), 2.28 (m, 2H, CH2 capropyl), 2.87 (m, 2H, CH2 caproyl), 3.65 (s, 3H, OCH3), 3.81 (m, H, H4 '), 4.25 (m, 2H, H5'), 4.95 (broad s, ÍH, caproyl NH), 5.86 * (m, ÍH, H2 '), 6.31 * (m, ÍH, H3'), 6.98 (m, ÍH, Hl '), 7.04-7.38 * (m, 6H, Ph and H6 ), 10.12 (broad s, ÍH, NH base) 13C (CDC13): 13.47 * (5-CH3), 25.43 * (CH2 caproyl), 27.04 * (CH2 caproyl), 32.15 * (CH2 caproyl), 34.85 (CH2 caproyl) ), 42.30 * (CH2 caproyl), 52.61 (OCH3), 67.92 * (C5 '), 85.80 (d, J = 8.22 Hz), 90.68 * (C4'), 112.25 * (C5), 121.17 * (d, J = 4.58 Hz, ortho-Ph), 125.99 (C2 ') # 128.40 * (para-Ph), 130.77 (meta-Ph), 134.38 * (C6), 137.09 * (C3'), 151.69 * (d, J = 3.23 Hz, ortho-Ph), 152-26 (C2 '), 165.36 (C4'), 175.07 (COO) EM (Cl matrix): 1 27 (thymineH *, 42), 508 (MH *, 18), 509 (MH *, 13C 5) High resolution EM: found 508.1850 (MH *), C23H31N308P requires 508.1849 CLAP: TR 26.33 minutes Ammonium phosphate salt of 2 '.3' -dideoxy-2 '.3' -dideshidrotimidin-5 '- (ß-alaninyl) Cfl216 Yield = 62% 31P (D20): 8.84 LH (D20): 1.73 (3H, S, 5-CH3), 2.18 (2H, m, wing CH,), 2.65 (m, 2H, wing CH2), 3.79 (2m, H, H5 '), 4.95 (m, ÍH, H4'), 5.76 ( m H, H2 '), 6.35 (m, H, H'), 6.82 (m, H, Hl '), 7.47 (s, 1H, H6) l3C (D, 0): 11.81 (5-CHj), 38.51 (wing CH,), 39.45 (d, wing CH ,, J - 6.64 Hz), 65.41 (d, C5 ', J - 4.91 Hz), 86.40 (d, J - 9.20 HZ, C4'), 90.20 (Cl ' )., 111.07 (C5), 125.40 (C2 '), 134.66 (C3'), 138.54 (C6), 152.53 (C2), 167.00 (C4), 181.04 (COO) CLAP: TR = 32.74 minutes Salt of ammonium phosphate 2.3 - dideoxy - 2 '.3' - dideshidrotimidin -5 '(? -aminobutyl) Cf 1224 Yield = 54% 31P (D, 0): 10.03? (D, 0): 1.47 (m, 2H, GABA CH,) , 1.72 (s, 3H, 5-CH,), 1.98 (ra, 2H, GABA CH,), 2.48 (, 2H, GABA CH,), 3.72 (m, 2H, H5 '), 4. 91 (m, ÍH, H4 '), 5.72 (m, HI, H2'), 6.26 (ra, ÍH, H3 '), 6. 72 (m, ÍH, Hl '), 7.45 (s, ÍH, H6'). 13C (D, 0): 11.73 (5-CHj), 27.99 (d, J = 7.25 Hz, GABA CH2), 34.47 (GAEA CH,), 41.17 (GABA CH,), 65.35 (d, J = 4.68 Hz, C5 '), 86.38 (d, J - 9.36 HZ, C4'), 90.27 (Cl '), 111.47 (C5 '), 125.29 (C2'), 134.70 (C3 '), 138.68 (C6), 152.47 (C2), 166. 95 (C4), 182.32 (COO) .gal ammonium phosphate 2.3 -dideoxy -2 '.3' - dideshidrotimidin -5 '(caproyl) Cf 1217 Yield = 49% 31P (D, 0): 10.18? (D, 0): 1.01 (ra, 2H, caproyl CH,), 1.21 (ra, 2H, caproyl CH,), 1.32 (m, 2H,? Approba CH,), 1.78 (s, 3H, 5-CH, ), 2.05 (m, 2H, caproyl CH,), 2.58 (m, 2H, caproyl CH,), 3.78 (m, 2H, H5 '), 4.99 (S, H, H4'), 6.32 (m, H, H '), 6.82 (m, 1H, H2 '), 7.51 (s, ÍH, H6) 13C (D, 0): 11.84' (5-CHj), 25.66 (caproyl CH,), 26.46 (caproyl CH,), 31.10 (d, J = 6.82 Hz, caproyl CH,), 37.06 (caproyl CH,), 41.47 (caproyl CH,), 6.5.37 (d, J = 4.83 Hz, C5 '), 86.45 (d, J = 9.74 HZ, C4 '), 90.29 (Cl'), 111.43 (C5), 125.27 (C2 '), 134.80 (C3'), 138.89 (C6), 152.48 (C2), 166.94 (C4), 183. 15 (COO). 2,3-dideoxytidin-5 '- (phenyl-N-methoxyalaninyl) phosphoroamidate Cf 1221 Yield = 16.6% 31P. (CDClj): 3.94, 4.00? (CDClj): 1.33, 1.35 (2 x d, 3H, CH, ala); 1.92, 1.96, 2.41 (1H, 2H, 1H, 3 X m, H2 ', H3'); 3.66 (s, 3H, OMe); 3.86-4.35 (m, 5H, H4 ', H5', CH ala, NH ala); 5.63 (2 xd, J «7.4 Hz, H6), 6.02 (ra, ÍH, H-l '), 7.12-7.32 (m, 5H, Ar), 7.73 (ÍH, 2 xd, J - 7.4 Hz, H5) 13 C (CDClj): 20.98 (CH3 wing); 24.97, 25.11, 32.85 (C2 ', C3'); 50.12, 50.30 (CH3 ala); 52.55 (OMe); 67.19, 67.26, 67.50 (C5 '); 79.16, 79.27, 79.34 (C4 '); 87.29, 87.46 (Cl '); 93.48 (C5); 119.99, 120.04, 120.10, 125.05, 125.10, 129.73, 129.7.7 (CAr); 141.17 (C6); 150.48, 150.57 (C ipso Ar); 155.68 (C2); 165.44 (C4); 173.84, 173.94 (COala) Mass (ES *): C "HuN407P: 475 (tilla ', 100); CLAP: TR = 20.53, 21.22 min 2 ', 3' -dideoxy-2 ', 3 -dideshidrotimidin-5' - (f-enylme oxy-sarcosinylphosphory) Cf 1098 Yield = 65% 3IP (CDC1,): 6.80, 7.36 ppin? (CDClj): 1.72 (s, 3H, 5CH3); 2.64, 2.67 (s, 3H, NCH3); 3.62 (S, 3H, OCHj); 3.40-4.10 (m, 2H, CH :); 4.20-4.50 (m, 2H, H5 '); 4.97 (bs, ÍH, H4 '), 5.80-5.90 (m, ÍH, H2'); 6.30-6.40 (m, ÍH, H3 '); 6.97 (bs, ÍH, Hl '); 7.00-7.30 (m, 6H, Ar + H6); 9.59 (bs, ÍH, NH) 13C (CDClj): 12.35 (5CHj); 34.55-34.60-34.65 (NCHj); 50.67- • * 50.78-50.87 (CH,); 52.10-52.13 (OCHj); 62.27-66.77-66.82 (C5 '); 84.71-84.84 (C4 '); 89.52-89.82 (Cl '); 111.16-111.33 (C5); 120-150 (ra, Ar); 127.17-127.40 (C2 '); 133.25-133.62 (C3 '); 135.73-136.11 (C6); 150.85-150.90 (C2); 163.84-163.87 (C4); 170.57-170.60-170.84 (COOCH,) Mass: C20H, 4O, NjP: 488 ((M + Na) +, 100); 466 ((M + H) *, 5) CLAP: TR = 25.17 and 25.59 min 2 ', 3' -dideoxy-2 ', 3' -dideshidrotimidin-5'- (phenyl-ethoxysarcosyl phosphate) Cf 1133 Yield = 65% 31P (CDC1,): 0.87, 7.41 ppra? (CDC1,): 1.18-1.24 (m, 2H ", CH, CH2), 1.80 (s, 3H, 5CH,), 2.68, 2.71 (s, 3H, NCHj), 3.46-3.65 (ra, 2H, NCH, ), 3.91-4.45 (m, 2H, H5 '), 4.11, 4.13 (s, 3H, CHJCHJ), 5.00 (bs, ÍH, H4'), 5.82-5.88 (m, 1H, H2 '), 6.33-6.37 (m, ÍH, H '), 7.00 (bs, ÍH, Hl'), 7.10-7.50 (m, 6H, Ar + H6), 8.75 (bs, ÍH, NH), 3C (CDClj): 12.86-12.89 ( 5CHj); 14.69 (CH, CH,); 35.06-35.11 (NCHj); 51.35-51.43-51.51 (NCH,); 61.77 (CH, CH,); 66.77-67.27-67.33 (C5 '); 85.26-85.36 ( C4 '); 90.01-90.31 (Cl'); 111.69- 111.86 (C5); 120-151 (m, Ar); 127.73-127.96 (C2 '); 133.73-134.10 (C3'); 136.27-136.64 (C6); 151.61 (C2); 164.70 (C4); 170.62-170.66-17C.85 (COOCH,) Mass: C "H, 40, NjP: 502 ((M + Na) *, 100); 480 ((M + H) *, 5) CLAP: TR = 25.84 and 26.65 min 2 ', 3' -dideoxy-2 ', 3' -dideshidrotimidin-5 '- (methioninyl phosphate) Cf 1156 Yield = 52% 3IP (CDClj): 7.77 ppm? (CDClj): 1.75-1.85 (m, 2H, CH, S); 1.90 (s, 3H, SCH3); 2. 01, 2.10 (s, 3H, 5CH,); 2.30-2.50 (ra, 2H, CH., CH, S); 3.45- 3.60 (m, ÍH CÜNH); 3.94 (s, 2H, H5 '); 5.05 (bs, ÍH, H4 '); . 90-6.00 (m, ÍH, H2 '); 6.40-6.50 (m, ÍH, H3 '); 6.93 (bs, ÍH, Hl '); 7.68 (s, ÍH, H6) 13C (CDC1,): 11.91 (5CHj); 14.46 (SCH,); 29.58 (CHjSCH, CH,); 34. 69 (SCH, CH,); 56.42 (CHNH); 65.07-65.13 (C5 '); 86.39-86.52 (C4 '); 90.14 (Cl '); 111.70 (C5); 125.48 (C2 '); 134.77 (C3 '); 138. 91 (C6); 152.61 (C2); 167.18 (C4); 180.84 (COOH) Mass: CuHpO. jPS: 434 ((M-l), 100); 435 ((M), 15) CLAP TR - 31.38 min 2, 3'-dideoxy-2 ', 3'-dideshydrotimidin-5' - (glycine glycine) Cf 1163 Yield = 75% 31P (CDClj): 11.72 ppm? (CDClj): 1.83 (s, 3H, 5CH,); 3.29 (d, CH ,, J = 7.9HZ); 3.85-3.92 (m, ZH, H5 '); 5.00 (s, ÍH, H '); 5.85-5.38 (m, ÍH, H2 '); 6.38-6.41 (m, ÍH, H3 '), 6.88-6.20 (bs, ÍH H1'); 7.54 (s, ÍH, H6) 13C (CDClj): 19.09 (5CH3); 52.24 (CH,); 72.74-72.81 (C5 '); 93. 61-93.73 (C4 '); 97.57 (Cl '); 119.08 (CS); 132.80 (C2 '); 141. 89 (C3 '); 145.74 (C6); 159.87 (C2); 174.34 (C4); 186.03-186.15 (COOH) Mass: C12H, 40, N3P: 360 ((M-l), 100); 361 ((M), 15) CLAP: TR = 32.57 min 2 ', 3' -dideoxy-2 ', 3' -dideshydro imidin-5 '- (phenylmethoxisoleucinyl phosphate) Cf 1186 Yield = 82% 3IP (CDClj): 4.59, 5.16 ppm? (CDC1,): 0.91-0.99 (m, 6H, CH, + CH3); 1.09-1.26 (CHCH3); 1.28-1.56 (m, 2H, CH,); 1.92, 1.97 (s, 3H, 5CH,); 3.60-3.77 (m, ÍH, CHNH); 3.77 (s, 3H, OCH,); 3.88-3.99 (m, 1H, N ^ CH); 4.30-4.52 (m, 2H, H5 '); 5.11-5.13 (m, ÍH, H4 '); 5.95-6.00 (m, ÍH, H2 '); 6.35-6.45 (ra, ÍH, H '); 7.10-.7.13 (m, ÍH, Hl '); 7.16-7.45 (m, 6H, Ar + H6); 8.68 (bs, 1H, NH) 13C (CDClj); 11.90-11.92 (CH, CH,); 12.76-12.81 (5CH,); 15.64 (CHCHj); 25.06-25.14; 39.39-39.47-39.52-39.60 (CH,); 52.61 (OCH,); 59.38-59.54 (NHCH); 66.94-67.58-67.65 (C5 '); 84.91-85.04-85.16 (C4 '); 89.94-90.21 (Cl '); 111.75- 111.87 (C5 '); 120-151 (m Ar); 127.82-127.87 (C2 '); 133.49- 133.69 (C3 '); 135.99-136.28 (C6); 151.37 (C2); 164.40 (C4); 173.53-173.59-173.64 (COOCH,) Mass: CUHJQO. JP: 529.91 ((M + Na) *, 100) CLAP: TR = 30.52 and 31.14 rain 2 ', 3' -dideoxy -2 ', 3' -dideshidrotimidin-5'-phenylalaninylphosphate) Cf 1187 Performance = 68% IP (CDC1,): 7.58 ppm? (CDC1,): 1.70 (s, 3H, 5CH,); 2.64-2.80 (m, 2H, CH, Ph); 3.57-3.64 (m, ÍH, CHNH); 3.68-3.70 (m, 2H, H5 '); 4.85 (s, ÍH, H4 '); 5.73-5.75 (m, ÍH, H2 '); 6.26-6.29 (m, ÍH, H3 '); 6. 74-. 75 (m, H H, H ''); 7.02 -7.28 (m, 5H, CH, £); 7.44 (s, H, H6), JC (COCÍ,): 11.88 (5CH3); 40.92-40.97 (CH, ala); 58.27 (CH ala); 65.22-65.28 (C5'J; 86.36-86.49 (C4 '); 90.22 (Cl'); 111. 63 (C5); 125.38 (C2 '); 126-129 (m, Ar); 134.74 (C3 '); 138.31-138.48 (C5); 152.40 (C2); 166.81 (C4); 180.87-180.96 (COOH) Mass:: 450 ((M-l), 100); 451 ((W, 20) CLAP: TR = 32.11 min 2 ', 3' -dideoxy-2 ', 3' -dideshidrotimidin-5 '- (valinyl phosphate) Cf 1190 Yield = 67% 31P (CDClj): 8.35 ppm? (CDC1,): 0.72 (t, 6H, (CH,), CH, J - 7.3 Hz); 1.62-1.73 (ra, ÍH, (CHj), CH); 1.77 (s, 3H, 5CH3); 3.12 (dd, ÍH, NHCH, J = 5.6 HZ and 9.4 Hz); 3.80 (dd, 2H, H5 ', J = 3.5 Hz and 4.4 HZ); 4.92 (S, ÍH, H4 '); 5.76-5.73 (m, ÍH, H2 '); 6.31-6.35 '(m, ÍH, H3'); 6.79-6.81 (m, ÍH, Hl '); 7.53 (S, H, H6) 13C (CDC1,): 11.84 (5CH3); 17.95-18.84 ((CHj), CH); 32.30-32.38 ((CH,), CH); 62.43 (CHNH); 65.18-65.24 (C5 '); 86.43-86.58 (C4 '); 90.25 (Cl '); 111.65 (C5); 125.20 (C2 '); 134.90 (C3 '); 138.73 (C6); 152.52 (C2); 167.05 (C4); 181.27-181.31 (COOH) Mass: Cl3HpO, N3P: 402 ((M-l) \ 100); 403 ((M) \ 30) CLAP: TR = 31.90 min 2 ', 3' -dideoxy-2 ', 3' -dideshidrotimidin-5 '- (leucinyl phosphate) Cf 1192 Yield = 83% 31P (CDC1,): 7.98 ppm' H (CDC1,): 0.71 (d, 6H , (CH,) jCH, J »6.5 Hz); 1.22-1.34 (ra, 2H, CH,); 1.34-1.71 (m, ÍH, (CH,), CH); 1.80 (S, 3H, 5CH3); 3.30-3.38 (m, ÍH, CHNH); 3.82-3.85 (m, 2H, H5 '); 4.95 (s, ÍH, H4 '); 5.80-5.82 (m, ÍH, H2 '); 6.35-6.37 (m, H, H3'J, 6.81-6.82 (m, H, H '), 7.58 (s, H, H6) 13C (CDClj): 12.53 (5CH3), 22.88-22.99 ((CH3), CH); 25.28 (CH,); 45.27-45.34 ((CH,), CH); 56.38 (CHNH); 65.74-65.81 (C5 '); 87.12-87.25 (C4 '); 90.89 (Cl '); 112.30 (C5); 125.99 (C2 '); 135.49 (C3 '); 139.44. (C6); 153.12 (C2); 167.70 (C4); 183.36-183.42 (COOH) Mass: CISH240, N3P: 416 ((M-l), 100); 417 ((M \ 20) CLAP: TR = 35.02 min 2 ', 3' -dideoxy-2 ', 3' -dideshidrotimidin-5 '- (phenylmethoxyalaninyl phosphate) [fast diastereoisomer] Cf 1193 3IP (CDCl,): 4.51 ppm? (CDClj): 1.25-1.40 (m, .3H, CHCH,), 1.86-1.90 (m, 3H, 5CH3), 3.74-3.90 (ra, 4H, OCH3 + CH ala), 4.37-4.47 (m, 2H, H5 '); 5.08 (bs, HH, H'); 5.91-5.93 (m, HH, H2 '); 6.38-6.41 (m, HH, H3'); 7.07-7.09 (m, 1H, Hl ' ); 7.20-7.39 (m, 6H, Ax + H6); 9.04 (bs, ÍH, NH) l3C (CDC13): 10.85 (5CH3); 19.38-19.45 (CHCH,); 48.71 (CHCH3); 51.14 (OCH3); 64.91-64.97 (C5 '); 83.11-83.22 (C4'); 88.03 (Cl '); 109.77 (C5); 118-149 (m, Ar); 125.84 (C2'); 131.88 (C3 '); 134.44 (C6); 149.34 (C2); 162.35 (C4); 172.53-17'2.62 (CO wing); 2 ', 3' -dideoxy-2 ', 3'-dideshidrotimidin-5' - (phenylprolinyl phosphate) Cf 1194 Yield = 41% 3IP (CDCl,): 5.27 ppm? (CDCl,): 1.55 (s, 3H, 5CH3); 1.56-2.15 (m, 4H, CHCH2CH2); 3.10-3.30 (m, 2H, NCH,); 3.90-4.00 (m, ÍH, NCH); 4.20-4.50 (ra, 2H, H5 '); 5.11 (s, ÍH, H4 '); 5.89-5.91 (m, ÍH, H2 '); 6.41-6.44 (m, ÍH, H3 '); 6.76-6.78 (m, ÍH, H1 '); 6.99-7.40 (m, 6H, Ar + H6) 13 C (CDCl,): 11.84 (5CH3); 25.44-25.56 (CH, CH, N); 31.94-32.06 (CH, CHN); 47.40-47.46 (NCH,); 63.31 (CHN); 67.14-67.21 (C5 '); 85.56-85.68 (C4 '); 90.69 (Cl '); 111.00 (C5), 120-150 (m, Ar), 125.07 (C2 '), 134.13 (C3'), 138.26 (C6), 152.67 (C2), 166.64 (C4), 181.32 (COOH). Mass • j.Hj.O. jP: 476 ((M-l) \ 100); 477 ((M) \ 25) CLAP TR = 34.16 min 1001 2 '.3' phosphoroamidate-dideoxy-2 '.3' - dideshydroadenosin-5 '- (phenylmethoxyalaninyl) Yield = 67%? (draso-d6): 8.14 (H, s, H8), 8.06 (H, D, H2), 7.07-7.40 (7H, m, P eH &NH,), 6.93 - '(lH, s, Hl' ), 6.47 (HH, 2d, H3 '), 6.21 (HH, d, H3'), 5.96 (HH, n, NH), 5.11 (HH, m, H4 '), 4.10 (2H, m, H5') , 3.5-4.83 (ÍH, 2m, CH ala), 3.52 (3H, d, MeO), 1.08 (3H, 2d, CH3 ala). 3IP (dmso-d6): 4.92, 4.78. 13C (dmso-d6): 172.909-172.815 (CO ala), 154.663 (C-2), 152.238 (C-6), 149.524-149.442 (Ar-ipso), 148.782 (C-4), 138.006-137.907 (C -8), 132,286-132,205 (C-2 '), 128,621 (Ar-meta), 125,384-125,210 (Ar ara), 123,928 (C-3'), 119,067- 119.00 (Ar ortho), 118,508 (C-5). ), 87.311-87.060 (C-l '), 84.485-84.368 (C-4'), 66.093-65.324 (C-5 '), 51.477-51.429 (OMe), 49.109-48.989 (CH ala), 19.903-19.585 (CH, wing). Dough. Calculated MH +: 475,149. Found: 475,151 1093 fQS £? > rQ my tQ < S 2 '.3' -didesoxiadenosin-5 ' (phenylmethoxyalaninyl) Yield = 42% 'H (CDClj): 8.32 (H, s, H-8), 8.12 & 8.11 (ÍH, 2s, H-2), 7.22 (5H, m, Ar), 6.40 (2H, 2bs, NH2), 6.30 (ÍH, t, H-l ', J = 5.4 HZ), 4.42 (4H, m, NH, 2H5 '& H'), 4.00 (1H, 2d, Ala CH), 3.65 (3H, 2S, OMe), 2.52 (2H, m, H '), 2.13 (2H, m, H2') , 1.31 (3H, 2d, CH3 ala, J = 7.3 Hz). 3tP (CDClj): 4.26, 4.19. , 3C nmr (CDClj): 174,534, 174,468, 174,441, 174,372 (0-C = 0), 156,148 (C-2), 153,331 (C-6), 151,092 & 151,006 (2 Ar ipso), 149,674 & 149,599 (C-4), 139,211 & 139.103 (C-8), 130,040 (Ar meta), 125,325 (Ar for), 120,570 (C-5), 120,508 & 120,327 (Ar ortho), 85,994 & 85,746 (C-1 '), 80,105, 79,985 & 79,874 (C-4 '), 68,136, 68,067, 67,704 S. 67,636 (C-5'), 52,868 (OMe), 50,628 & 50,531 (Wing C-H), 32,712 (C-2 '), 26,339 & 26,106 (C-3 '), 21,337, 21,264 & 21,190 (CHj wing). Dough. Calculated MH +: 477,165. Found: 477.164 1094 phosphoramidate of 2 '.3' -dideoxy-2 '.3' - dideshydroadenosin-5 '- (f-enylbenzylalaninyl) Yield = 65%? (CDClj): 8.32 (ÍH, bs, H-8), 7.99 (ÍH, bs, H-2), 7.21 (11H, m, Ar-H & Hl '), 6.34 (ÍH, ra, H3') , 6.07 (ÍH, m, H2 '), 5.81 (2H, 2bs, NH,), 5.08 (3H, 2bs, BZ-CH, & H4'), 4.05 (4H, m, NH, CH, H5 ') , 1.24 (3H, 2d, methyl ala, J »6.9 Hz). 31P (CDClj): 4.21, 3.98 13C (CDClj): 173,700 fi. 173.601 (0-C = 0), 156.005 (C-2), 153,728 (C-6), 150,952 & 150,870 (Ar), 150,322 & 150,280 (C-4), 139,484 & 139,368 (C-3), 135,672 (Ar), 133,733 & 133,654 (C-2 '), 130,066 (Ar), 129,041, 128,895, 128,635 & 128,601 (Ar), 126,751 & 126,598 (C-3 '), 125,375 (Ar), 120,529, 120,463, 120,399, 120,119 & 120,051 (C-5 &Ar), 88,702 & 88. 476 (C-1 '), 85,907, 85,476, 85,791 & 85,736 (c-4 '), 67. 632, 67,475 & 67,403 (C-5 'and Bz-CH,), 66,805 & 66,745 (C-5 '), 50,677 & 50,542 (Wing C-H), 21,399, 21,335, 21,083 & 21. 019 (methyl Ala). Dough. Calculated MH *: 551.181. Found: 551,179. 1168 phosphoramidate 2 '.3' -dideoxy-2 '.3' - dideshydroadenosin-5 '-alaninyl Yield = 69%? nmr (D, 0): 8.09 (H, s, H8), 7.88 (H, s, H2), 6.61 (H, s, H, '), 6.33 (H, d, H3'), 6.02 (H, d , H3 '), 5.01 (HI, ra, H4'), 4.73 (2H, m, H5 '), 3.5-4.83 (HI, 2m, CH ala), 0.89 (3H, 2d, CH3 ala). 3, P (D, 0): 8.34. l3C (D, 0): 183,055 (CO wing), 155,549 (C-2), 152,745 (C-6), 148,643 (C-3), 140,928 (C-8), 134,730 (C-2 '), 124.709 (C-3 '), 118,527 (C-5), 88,299 (C-1'), 87,199 & 87,073 (C-4 '), 65,215-65,149 (C-5'), 52,564 (Alai C-H), 21. 5-21. 81 (Ala CH3). 1196 phosphoramidate of -2 '.3' -didesoxi- 2 '.3' - dideshidrotimi in '- (phenyldimethoxyglutaminyl) Yield = 33% 3IP (CDCl,) 4.14, 4.76? (CDClj) 1.81, 1.85 (5CH3); 1.91-2.18 (m, 2H, CH, Gln); 2.24-2.36 (m, 2H, CH, G n); 3.64 (s, 3H, NMe); 3.69 (s, 3H, OMe); 3.92-4.21 (m, 2H, H5 '); 4.23-4.42 (m, 2H, CH Gln, NH Gln); 5.00 (m, ÍH, H4 '); 5.91 (m, ÍH, H2 '); 6.31 (m, 1H, H3 '); 7.01 (m, ÍH, H1 '), 7.03-7.34 (m, 6H, Ph, H6); 9.49 (s, 1H, NH) 13C (CDC13) 12.32-12.36 (5CH,); 29.01-29.42 (CH, G n); 29.46 (NMe); 51.81 (CH Gln); 52.65 (OMe); 53.65-53.92 (CH, Gln); 66.63-67.33 (C5 '); 34.43-84.71 (C4 '); 89.57-89.83 (Cl '); 111.29-111.44 (CS); 119.98-120.22 (Ph); 125.21-125.26 (Ph); 127. 39-.127.50 (C2 '); 129.74-129.78 (Ph); 133.00-133.25 (C3 '); 135.60-135.90 (C6); 150.98 (C2); 164.00-164.09 (C4); 172.96-173.23 (CO, CON) Mass (ES): C23H29N409P: 536 (M *, 100); 537 (MH *, 32) 2_14 fQsforoamidatn of -2 '. V -dideanyi -2 '. V - dideshidrotimidin-5'- (phenyl dimetnxiasparasini lo) Yield = 75% 3IP (CDClj) 1.15, 2.20? (CDClj) 1.81, 1.86 (s, 3H, 5CH3); 2.49-2.92 (m, 2H, CH, Asn); 3.64 (s, 3H, NMe); 3.72 (s, 3H, OMe); 4.04-4.26 (ra, 2H, H5 '); 4.28-4.43 (m, 2H, CH Asn, NH Asn); 5.05 (m, ÍH, H4 '); 5.89 (ra, ÍH, H2 '); 6.31 (m, ÍH, H3 '); 7.01 (m, ÍH, Hl '); 7.14-7.33 (m, 6H, Ph, H6); 8.46 (s, 1H, NH) 13C (CDC13) 12.28 (5CH3); 51.01 (CH Asn); 52.09 (OMe); 52.94 (CH, Asn); 84.75 (C4 '); 89.60 (Cl '); 111.30 (C5); 125-130 (Ph); 127.32-127.48 (C2 '); 133.10-133.41 (C3 '); 135.94 (C6) Mass (ES): C22H27N409P: 522 (M \ 100); 523 (MH +, 31) 1215 phosphoramidate of -2 '.3' -dideoxy-2 '.3' - dideshidrotimidin-5 '- (phenylmethoxypropyl añyl) Yield = 100% 31P (CDClj) 4.15, 4.57? (CDC13) 1.74 (s, 3H, 5CH3); 3.16 (m, 2H, CH, Trp); 3.60 (s, 3H, OMe); 3.75-4.05 (m, 2H, H5 '); 4.10-4.33 (m, 2H, CH Trp NH Trp); 4.84 (ra, ÍH, H4 '); 5.79 (m, ÍH, H2 '); 6.15 (m, ÍH, H3 '); 6.86 (ra, 1H, H1 '); 6.91 (ra, ÍH, H6); 7.00-7.49 (ra, 10H, Ar); 8.45 (s, ÍH, NH Trp); 9.14 (s, ÍH, NH) "C (COCÍ,) 14.75 (5CH3); 32.46 (CH, Trp); 54.91 (CH Trp); 57.53-57.61 (OMe); 69 (C5 '); 87.06 (C4') 92.03-92.25 (Cl '); 111.63 (CS); 127.60 (C2'); 135.45-135.83 (C3 '); 138.11-138.62 (C6); 152.78-153.1 (C2); 166.28-166.40 (C4);; 175.85 (CO) Mass (ES): C2ßH2ßN409P: 579 (M +, 100); 580 (MH *, 43) 4fi2 phosphprpamidate e '-deSQXÍ-3' -fl-asi? Thymidine-5 '- (phenylmethylalaninyl)? (COCÍ,): 1.39 (d, 3H, J - 7.2 Hz, CH3 wing), 1.94 (s, 3H 5 Me), 2.15 (d, ÍH, J = 15.5 Hz, H2 '), 2.68-2.79 (m , ÍH, H2 '), 3.72 (S, 3H, OMe), 3.90-4.50. (Ra, 6H, H3' + H4 '+ • H5' + NH + CHala), 6.18 (dd, ÍH, J = 7.5 and 3.1 Hz, Hl '), 7.1-7.4 (m, 6H, Ph + H6), 8.82 (bs, ÍH, NH). l3C (CDCl,): 12.67 (5-Me),. 20.96, 21.29 (Wing-Me), 38.50 (C2 '), 50.16, 50.28 (CHala) -, 52.57 (OMeala), 60.74 (C3'), 64.43 (C5 '), 80.17 (C4'), 83.93 (Cl ' ), 111.21 (C5), 120.11 (Ar2), 125.18 (Ar4), 129.73 (Ar3), 135.18 (C6), 159.96 (Arl), 150.30 (C4), 163.49 (C2), 173.84 (COala). 31P (CDClj): 1.55 IR (COCÍ,): 3216, 2113, 1685 cm-1. Mass 509.1543 (MH *, 40%, calculated 509.1549), 340 (12), 250 (17), 200 (18). CLAP: TR =, 28.48 minutes 536 3 '-deoxy-3' -β-azidotimidin-5 '- phosphoramidate (m-trifluoromethylphenylmethoxyalaninyl)? (CDClj): 1.39, 1.40 (d, 3H, J = 7.2 Hz, Me-wing), 1.92, 1. 93 (s, 3H, 5-CHj), 2.15 (d, ÍH, J = 15.1 Hz, H2 '), 2.71-2.80 (m, ÍH, H2'), 3.70, 3.71 (s, 3H, OMe), 3.90 -4.50 (ra, 6H, H3 '+ H4' + H5 '+ NH + CHala), 6.19 (dd, ÍH, J = 7.7 and 3. 3 Hz, H1 '), 7.41-7.46 (m, 5H, Ph + H6), 9.52 (bs, 1H, NH).

I3C (CDCl,): 12.58 (5-Me), 20.75, 20.83 (CH, ala), 33.33, 38. 44 (C2'J, 50.15, 50.29 (CHala), 52.55 (OMeala), 60.77 (C3 '), 64.72 (C5'), 80.05, 30.35 (d, J - 6.8 Hz, C '), 83.94 (Cl '), 111.25 (CS), 117.43 (Ar2), 121.81, 121.86 (Ar4), 123. 37 (q, J = 273 Hz, CF,), 123.74 (Ar6), 130.35 (Ar5), 132. 11 (q, J - 33 Hz, Ar3), 135.11 (C6), 150.49 (C4), 150.62 (Arl), 163.78 (C2), 173.68, 173.87 (d, J = 7.8 Hz, COala). 31P: 2.69 Mass 577 (MH *, 40%), 340 (13), 268 (14), 250 (12). CLAP: TR = 30.66 minutes 550 3 '-deoxy-3' -β-azidothymidin-5 '- (3,5-dichlorophenylmethoxyalaninyl) H phosphoroamidate: 1.42 (d, 3H, J = 6.8 Hz, Me-ala), 1.94, 1.95 ( d, 3H, J = 1.2 Hz, 5-CH,), '2.17, 2.18 (d, ÍH, J = 15.1 Hz, H2'), 2.76-2.85 (m, ÍH, H2 '), 3.74, 3.75 (s) , 3H, OMe), 3.90-4.50 (m, 6H, H3 '+ H4' + H5 '+ NH + CHala), 6.20 (dd, ÍH, J m 7.7 and 3.3 HZ, Hl'), 7.19 (m, 2H , Ar2), 7.27 (s, ÍH, Ar4), 7.41, 7.42 (s, ÍH, H6), 9.04 (bs, ÍH, NH). , 3C: 12.65 (5-Me), 20.85, 20.91 (CH3 wing), 38.38, 38.48 (C2 '), 50.18, 50.29 (CHala), 52.68 (OMeala), 60.77 (C3'), 64.86, 64.93 (C5 ' ), 79.80, 80.20 (d, J »8Hz, C4 '), 83.97 (Cl'), 111.35 (C5), 117.28, 119.38 (d, J - 6Hz, Ar2), 125. 58 (Ar4), 135.10 (C6) ), 135.46, 135.50 (Ar3), 145.35 (Arl), 150.36 (C4), 163.61 (C2), 173.64, 173.79 (COala). 31P: 2.83 Mass 577, 579, 581 (MH * 5: 3: 1.) 307, 309, 311 (12: 8: 2) 289 (10) In vitro tests Cells are infected with VlH-I as previously described [Balzarini et al. AIDS (1991), £, 21-28]. Briefly, 5 x 10 cells per milliliter are infected with HIV-1 or HIV-2 at 100 CCIDS0 (infective dose of 50% cell culture) per milliliter of cell suspension. Then 100 μl of the infected cell suspension is transferred to microtiter plate wells and mixed with 100 μl of the appropriate dilutions of the test compounds. After 4 days, giant cell formation is recorded microscopically in cultures of HIV-infected cells [CEM] and after 5 days the number of viable cells is determined by trypan blue staining in a culture of HIV-infected cells [ MT4]. The 50% effective concentration (CES0) and the 50% cytotoxic concentration (CCS0) is defined as the compound concentrations needed to reduce by 50% the number of giant cells or viable cells in cultures of cells infected with or infected with virus. false, respectively. Activities against HIV-1 and toxicities of the compounds are also determined in two cell lines: C8166 cells. Cells are grown in ERPMI 1640 with 10% bovine serum. 4 x 10 * cells per well of microtitre plate are mixed with quintuple dilutions of compounds before the addition of 10 units CCID50 of HIV-1 strain III-B are incubated for 5-7 days (Betbeder et al., Antiviral Chem. Chemother, 1, 241-247, 1990). The formation of syncytia is examined 2 days after infection. The culture fluid is harvested at 5-7 days and the production of gp-120 antigen is measured by ELISA (Mahmood and Hay, J. Immunol. Meth., 151, 9-13, 1992). CES0 is the concentration of medication [in μM] needed to reduce the production of gpl20 by 50%. The viability of the infected and uninfected cells is determined by the MTT-Formazen method (Pauwels et al., J. Virol, Meth., 20, 309-321, 1988).

JM cells. JM cells, which are relatively resistant to the antiviral effects of AZT and numerous of its derivatives, are infected with strains of HIV-1 and the antiviral and toxic effects of the compounds are determined for C8166 cells. Both GB8 or IIIB strains of HIV-1 are used, with no detectable differences in the observed endpoints.

Each trial is carried out in duplicate, on at least two separate occasions, and the data reported is the average of each separate trial. The compounds of the present invention have been shown to be active against HIVl and HIV2 in both TK * and TK "cells, as illustrated in Table 2.

Table 2 As expected, d4T (comparative) loses kinase deficient activity (especially CEM TK ") while compound 730 of the invention retains good activity in TK * as in TK" against HIVl and HIV2. The compound 730 of the invention is > 1000 times more potent than d4T in TK cells. "Surprisingly, the compound is 100 times more potent than d4T in CEM TK * assays.

The potent activity of the compounds of the invention is further supported by the data in the Table 3, which illustrate the activity, toxicity and selectivity index of a series of compounds of the present invention. The increased antiviral potency and reduced cytotoxicity of the phosphate derivatives leads to very large improvements in the selectivity index [defined as CCS0 / CES0] which shows remarkable improvements in in vivo efficacy compared to d4T (comparative). The evidence that the compounds of the present invention are acting in a way different from that of d4T or AZT is provided by the data in Table 4. As can be seen, although the potency of d4T (comparative) is greatly reduced in strains resistant to nucleosides, the potency of the compounds of the present invention is maintained to a large extent. Therefore, it is evident that the compounds of the present invention do not act primarily via the conventional 5'-trisphosphate nucleoside derivative. CEM and MT4 cells (at 400,000 cells / ml) and PBL cells (at 2,000,000 cells / ml) are exposed at different concentrations of [3H] 324 and incubated at 37 ° C for 24 hours. The cells are then washed twice with cold PBS and 400 μl of 66% cold methanol are added to the cell pellet. After standing on ice for 10 minutes, the cell extract is centrifuged and the supernatant is analyzed in CLAP. As shown in Table 5, the levels of intracellular d4T-MP (monophosphate) increase proportionally as a function of the initial concentration of 324 in all the cell lines tested. However, the increase in d4T-tp (triphosphate) levels slowly decreases to initial concentrations of 324 so that they are greater than 25 μM (for CEM and MT4 cells) or greater than 1.0 μM (for PBL). Surprisingly, a metabolite (designated X) accumulates substantially and predominantly in all three cell types. The accumulation is proportional to the initial concentration of 324 and, again, is lower in PBL cells than in CEM and MT4. When 324 1 mM is incubated with high concentrations of pig liver at 37 ° C in Tris-HCl buffer containing 5 mM MgCl 2, formation of a time-dependent metabolite is observed. These metabolites co-elute with the predominant metabolite (X) found in cell extracts after incubation of intact cells with [3 H] 324. Metabolite X corresponds to a compound of formula (10), wherein Y is oxygen, X1 is NH, X2 is oxygen, B is thymine, R1 is Me, R2 is hydrogen.

The data in an expanded range of the compounds is presented in Table 6 (d4T analogs) and Table 7 (dideoxy and 3'-β '-substituted nucleoside analogues) in which: Cpd and Init: refer to the reference numbers of the compound; And it refers to the group: 3 'A \ Z: refers to the 3 'substituent on a deoxyribose sugar in which the substituent is in an "a" (R9) orientation unless designated "up", which refers to an "ß" (R10) orientation; B: refers to a base of heterocyclic nucleic acid present in Cl 'in β orientation; the conventional one-letter base codes are used; the pyrimidine substituents are in C5. The columns of data are, in order: HIV1 MT4: EC50 in μM for inhibition of HIV-1 in cells MT4. HIV2 MT4: CES0 in μM for inhibition of HIV-2 in cells MT4. CC50 MT4: CC50 in μM for toxicity for MT-4 cells.

HIVi CEM: CES0, in μM for inhibition of HIV-l in cells CEM. HIV2 CEM: EC50, in μM for inhibition of HIV-2 in cells CEM. HIV2 CEM-TK ": CES0 in μM for inhibition of HIV-2 in cells CEM / TK "CC50 CEM: CCS0 in μM, for toxicity to CEM cells.

EC50 MSV: CES0, in μM for MSV inhibition. MCC MSV: Minimum cytotoxic concentration in the MSV assay. When the data in Table 6 differ from those presented in Tables 2 to 5, the data from the first relate to the average result obtained from two or more repeated experiments, while the latter are related to individual experimental results.

Table 3 Input Ar Rx J Activity Toxicity Selectivity CES0 CC50 CCS0 / EC50 x 103 323 4-EtPh Me Me 0.0032 50 15.6 324 Ph Me Me 0.0032 150 46.9 327 4-FPh Me Me 0.0032 200 62.5 526 3-CFjPh Me Me 0.0008 200 250 546 3,5-Cl2Ph Me Me 0.001 100 100 | 730 Ph Me Bzl 0.0008 400 500 776 2,4-Br2Ph Me Me 0.0008 100 125 1 779 F5Ph Me Me 0.064 80 1.25 862 Ph Me Hex 0.0012 500 417 863 Ph Me Me 0.016 500 31.2 864 Ph CH2iPr Me 0.016 > 1000 > 62.5 865 Ph iPr Me 0.8 > 1000 > 1.25 866 Ph H Me 0.8 > 1000 > 1.25 867 Ph [CH2] 2SMe Me 0.0016 > 1000 > 62.5 868 2, 4Br2Ph Me Bzl 0.0032 500 156 877 Ph Bzl Bzl 0.0003 80 267 878 Ph Bzl tBu 0.16 150 0.9 892 Ph Me Ciclohex 0.0016 500 312 893 Ph Me tBu 0.2 > 1000 > 5.0 [the data are μM for HIVl in C8166 cells] For comparison, similar data for d4T: 0.08 50 0.6 Table 4 Table 5 Metabolism of [3 H] 324 after 24 hours of incubation in human CEM, MT4 and PBL cells TABLE 6 (continued) vo Z Z Z In vivo test Inhibitory effects of the test compounds in the onset of MSV-induced tumor formation in NRMI mice and in the survival of MRI mice inoculated with MSV Mice infected with the Moloney sarcoma virus [MSV] were treated daily with placebo or with d4T [at one of two doses] or with compound 324 at one of the same doses (equimolar.) Subcutaneous (sc) mice were inoculated NMRI from two to three days of age (weighing - 2 grams) in the thigh of the left paw with 50 μl of MSV (100 foil-forming units, measured by in vitro determination of virus-induced transformation of fibroblast cell mouse C3H embryo.) At 4 to 5 days post-infection, tumors developed and rapidly increased in volume as the mice grew, and in the next 10 to 12 days after infection, the mice (which at that time were weighing ~ 5 to 6 grams) died from viral infection, drug treatment started 1 hour before virus infection, and administration of additional compound was provided daily ip for 3 additional days. or the average number of days of tumor onset (± standard deviation) and the average day of survival of the mice (± standard deviation) and the statistical significance of the average delay of tumor formation and the daily average of survival in the treated groups versus the untreated group (control) using the two-tailed student's t-test. Although d4T failed to provide a detectable delay in the appearance of tumors or a death, a significant effect was observed in arabos parameters with compound 324 at high doses, and an effect on the first parameter of disease at low dose [Figure 1]. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (18)

1. A compound of the formula (I) characterized in that Ar is an aryl group, • Y is oxygen or sulfur; X1 is selected from O, NR3, S, CR3R \ CR3WX and CW1 * 2 wherein R3 and R4 are independently selected from hydrogen, alkyl and aryl groups and W1 and W2 are heteroatoms; X2-X6 may be absent; or X6 is CH2 and X2 is selected (independently of X1) from O, NR3, S, CR3R4, CR3 ** 1 and CWXW3 wherein R3 and R4 are independently selected from hydrogen, alkyl and aryl groups; and W1 and W2 are heteroatoms; X3 is an alkyl group of Cx.s; X4 is oxygen or CH2; X5 may be absent or is CH2; Z is selected from 0, NRS, S, alkyl and aryl groups, wherein Rs is selected from hydrogen, alkyl and aryl groups; J is selected from hydrogen, alkyl, aryl, heterocyclic and polycyclic groups; Q is selected from 0, NRß, S, CRßR7, CRßCW3 and CW3W4, wherein Rβ and R7 are independently selected from hydrogen, alkyl and aryl groups; and W3 and W4 are heteroatoms; T1 and T2 are independently selected from hydrogen and CH2Rβ, wherein Rβ is selected from H, OH and F; or T1 and T2 join and together they are selected from the groups I &C-C ^ 1 E 'H and 12 wherein R9 are selected from H, halogen, CN, NH2 / CO-alkyl and alkyl; and R10, R11 and R12 are independently selected from H, N3, halogen, CN, NH2, CO-alkyl and alkyl, B is a purine or pyrimidine base with the proviso that B is not a natural uracil base; or a pharmaceutically acceptable derivative or metabolite thereof.
2. 2. The compound according to claim 1, characterized in that Y is oxygen; X1 is NH; X3 is CHR1, wherein R1 is selected from H, alkyl and aryl groups X4 is oxygen, and Z is oxygen.
3. 3. A compound, characterized in that it is of formula (10) or a pharmaceutically acceptable derivative or metabolite thereof.
4. 4. The compound according to claim 3, characterized in that Y is oxygen; X1 is NH; X3 is CHR1; and X4 is oxygen.
5. 5. The compound according to any of claims 1 to 4, characterized in that X 2 is oxygen; X * is CH2; Q is oxygen; Xs is absent; and T1 and T2 together comprise the group:
6. 6. The compound according to claim 5, characterized in that B is thymine.
7. 7. The compound according to claim 6, characterized in that Ar, R1 and J are defined as follows: Compound of Ar R1 J Reference 323 4-EtPh Me Me 324 Ph Me Me 327 4-FPh Me Me 526 3-CF3Ph Me Me 546 3.5-Cl2PH Me Me 730 Ph Me Bzl 776 2.4-Br2Ph Me Me 779 FsPh Me Me 862 Ph Me Hexyl 863 Ph Bzl Me 864 Ph Ch2iPr Me 865 Ph iPr Me 866 Ph H Me 867 Ph [CH2] 2SMe Me 868 2, 4Be2Ph Me Bzl 877 Ph Bzl Bzl 878 Ph Bzl tBu 892 Ph Me Ciciohexyl 893 Ph Me tBu 1078 Ph CH2C02H Me 1214 Ph CH2CH2C? 2j ?? íe 1218 Ph Me n-Pent 1219 Ph Me neo-Pent 1226 Ph Me 1-naphthyl 1227 Ph Me 2-naphthyl
8. 8. The compound according to any of claims 1 to 4, characterized in that X 2 is oxygen; Xs is CH2; Q is oxygen; X5 is absent; and T1 and T2, together they comprise the group I &C-C ^ 1 # 'V2
9. 9. The compound according to claim 8, characterized in that B is adenine or thymine.
10. 10. The compound according to any of claims 1 to 4, characterized in that X2-Xβ is absent Q is oxygen; Xs is CH2; T1 and T2 are independently selected from hydrogen and CH2Rβ, wherein R * is selected from H, OH and F.
11. 11. The compound according to claim 9, characterized in that B is adenine.
12. 12. The compound according to any of claims 1 to 11, characterized in that it is used in a method of treatment, prophylaxis or diagnosis.
13. 13. The use of a compound according to any of claims 1 to 11, characterized in that it is used in the manufacture of a medicament for the treatment or prophylaxis of a viral infection.
14. 14. The use of a compound according to claim 13, characterized in that the viral infection comprises HIV.
15. 15. A process for the preparation of a compound of any of claims 1 to 11, characterized in that it comprises the reaction of a compound of formula (11) with a compound of formula (12) ArO-P-Cl (12) i
16. 16. A method of prophylaxis or treatment of viral infection, characterized in that it comprises administering to a patient in need of such treatment an effective dose of a compound according to any of the claims of claims 1 to 11.
17. 17. The use of a compound according to any of claims 1 to 11, characterized in that it is used in the manufacture of a medicament for use in the inhibition of a reverse transcriptase by an independent action mode of nucleoside resistance or nucleoside-independent of 5 '-triphosphate.
18. 18. A pharmaceutical composition, characterized in that it comprises a compound according to any of claims 1 to 11, in combination with a pharmaceutically acceptable excipient. RESOLUTION OF THE INVENTION The invention relates to masked monophosphate nucleoside analogs, their preparation and their therapeutic use in the treatment of viral infections including HIV infection. In particular, the invention relates to 2 ', 3' -deidesoxy and 2 ', 3'-dideoxydideshydro phosphoroamidate of nucleoside analogues and of PMEA.