MXPA00001593A - Nucleosides analogues, such as antivirals including inhibitors of retroviral reverse transcriptase and the dna polymerase of hepatitis b virus (hbv) - Google Patents

Abstract

A compound of the formula (I), wherein:nuc is the residue of a nucleoside analogue bonded through its single hydroxy group on the cyclic or acyclic saccharide moiety, R1 is hydroxy, amino or carboxy;optionally having esterified/amide bonded thereon;a C4-C22 saturated or unsaturated, optionally substituted fatty acid or alcohol, or an aliphatic L-amino acid;R2 is the residue of an aliphatic L-amino acid;L1 is a trifunctional linker group;L2 is absent or a difunctional linker group;and pharmaceutically acceptable salts thereof have favourable pharmacological properties and are antivirally active.

Description

ANALOGUES OF NUCLEOSIDES, SUCH AS ANTIVIRALS INCLUDING RETROVIRAL REVERSE TRANSCRIPTASE INHIBITORS AND DNA-POLYMERASE OF HEPATITIS B VIRUS (VHB) Technical Field This invention relates to the field of nucleoside analogues, such as antivirals including retroviral reverse transcriptase inhibitors and the DNA polymerase of Hepatitis B virus (HBV). The invention provides novel compounds with favorable pharmaceutical parameters, methods for their preparation, pharmaceutical compositions comprising these compounds and methods that are employed after the inhibition of viral and neoplastic diseases including HBV and HIV. Background of the Invention The International Patent application no. WO 88/00050 describes the anti-retroviral and anti-HBV activity of a series of 3 'fluorinated nucleosides, including the compounds 2', 3'-dideoxy, 3'-fluoroguanosine (FLG) and 3'-fluorothymidine (FLT). The last compound subjected to clinical evaluation as an anti-HIV agent and although its antiviral and pharmacokinetic activity was good, unexpected toxicity was shown (Flexner et al., J. Inf. Dis 170 (6) 1394-403 (1994). FLG compound is very active in vitro, however, the present inventors have detected that its bioavailability is very poor, about 4%, than the in vivo utility of the compound thus made in a limited manner in animal models intraperitoneally or subcutaneously US Patent No. 4,963,662 generically describes a series of corresponding 3 'fluorinated nucleosides and triphosphates and specifically describes the preparation of the 5'-O-palmitoyl derivative of FLT, without reporting any improvement in bioavailability. WO 93 13778 describes FLG derivatives modified at the 6-position of the base, in particular with n-propoxy, cyclobutoxy, cyclopropanylamino, piperidino or pyrrolid No, the international patent application no. 93 14103 describes FLG derivatives wherein the oxygen at the 6-position of guanine is replaced with amino, ether, halo or sulfonate. BRIEF DESCRIPTION OF THE INVENTION In accordance with one aspect of the invention, compounds of the formula I are provided: wherein R-i is selected from hydroxy, amino or carboxy; optionally having the esterification / amide bond therein; fatty acid or optionally substituted, saturated or unsaturated C-C22 alcohol, or an aliphatic L-amino acid; R2 is the residue of an aliphatic L-amino acid; L? it is a trifunctional ligature group; L2 is absent or is a difunctional ligature group; and pharmaceutically acceptable salts thereof.

The invention further provides pharmaceutical compositions comprising the compounds and salts of formula I and pharmaceutically acceptable carriers or diluents thereof. Additional aspects of the invention provide methods for the inhibition of HBV and retroviruses such as HIV, which comprise contacting a compound or salt of formula I with a retrovirus or HBV, for example, by administering an effective amount of the compound or salt, to an individual suffering from retroviruses or HBV. The invention also extends the use of the compounds or salts of formula I in therapy, for example, in the preparation of a medicament for the treatment of retroviral or HBV infections. In the treatment conditions caused by retroviruses such as HIV or HBV, the compounds or salts of the formula I are preferably administered from 50 to 1,500 mg one, two or three times per day, especially 100 to 700 mg two to three times daily . It is convenient to achieve serum levels of the active metabolite from 0.01 to 100 μg / ml, especially from 0.1 to 5 μg / ml. Where Ri is a fatty acid residue, preferably it has a total of a uniform number of carbon atoms, advantageously decanoyl (Cio), lauryl (C12), myristoyl (C? 4), palmitoyl (C16), stearoyl (C18) , eicosanoyl (C20) or behenoyl (C22). The fatty acid preferably has a total of 10 to 22, and more preferably from 16 to 20 carbon atoms, especially 18. The fatty acid can be unsaturated and have from one to three double bonds, especially a double bond. Unsaturated fatty acids include those derived from monounsaturated acids, myristoleic, myristic, palmitoleic, palmitelaidic, n6-octadecenoic, oleic, elaidic, gandoic, erucic, brasidic acids or a multiplicity of unsaturated fatty acids such as linoleic,? -linolenic, arachidonic acid and a-linolenic acid. Preferably, however, R1 is a saturated fatty acid such as those compounds that tend to have superior stability and shelf life. R-i is a fatty alcohol residue which preferably corresponds to one of the fatty acids described above. Alternatively, the fatty alcohol may comprise residues of short alcohols, such as methanol, ethanol or propanol. R1 is a saturated or unsaturated fatty acid or alcohol that can be optionally substituted with up to five similar or different substituents, independently selected from the group consisting of hydroxy, C1-C2 alkyl, C6-C6 alkoxy, C6 alkoxy C6, C? -C6 alkyl, Ci-Ce alkanoyl, amino, halo, cyano, azido, mercapto and nitro, and the like. Suitable aliphatic amino acids for R2 and, if present R1: include L-alanine, L-leucine, L-isoleucine and most preferably L-valine. For ease of synthesis, it is preferred that both R2 and Ri are aliphatic amino acid residues, preferably the same residue. The term "trifunctional" in the context of the first ligature of the group L ,, means that the ligation has at least three functional groups, including at least two functional groups derived from respective hydroxy, amine or carboxyl groups, the functions of the amine and hydroxy are available for the esterification / amide bond with the carboxy functions of R. ^ and R2 while a carboxy function is available on the bond for the amide bond with the free a-amine function of R2, or Ri according to the case, or esterification with Ri as a fatty alcohol. Where R-i, by itself, defines a hydroxy, amine or carboxy group, the hydroxy group currently being favored of the three functions, one of said functions on the trifunctional ligation that simply comprises these hydroxy, amine or carboxy groups. The trifunctional ligature further comprises a third functional group for ligating with the second optionally interlaced group L2 illustrated in greater detail below, or the hydroxy group at the 50th position of the parent nucleoside, such as 2 ', 3'-dideoxy-3'-fluoroguanosine . A suitable third functional group could depend on the nature of the cooperating function on ligation of the L2 group if present, and may include amino, hydroxy, carbonyl, sulfonyl, phosphoryl, phosphonyl, carbamoyl and the like. If L2 is absent, this third functional group on the L1 linkage can normally comprise a carboxyl function that can be esterified with the 5'-O group of the nucleoside analogue. Preferably, the functional groups on the trifunctional ligation that cooperate with R-y and R 2 are hydroxyl functions and the ligation is an ester ligation with the carboxyl functions of an acid R-1 degree, if provided, and R 2. A further preferred embodiment comprises a free hydroxy group such as R and a hydroxyl function on the esterified linkage in the carboxy function of R2. An alternative embodiment comprises a carboxyl group (optionally protected) as R-i and a hydroxyl function on the esterified linkage in a carboxy function on R2. The trifunctional L-i group useful, especially for directly esterifying the nucleoside, includes ligatures of the formula lia and llb: Where A and A 'define a respective ester bond between a hydroxy on the ligation and the carboxy on Rf or R2 or an ester ligation between a carboxy on the ligation and the hydroxy on Ri as a fatty alcohol, or a bond of amide between an amine on the ligation and a carboxy on Rt or R2, or an amide bond between a carboxy on the ligation an amine on Ri or R2, or one of A and A 'are as defined and the other is hydroxy , amino or carboxy in the event that Ri by itself is a hydroxy, amino or free carboxy group. Rx is H or C1-C3 alkyl, T is a ligation, -O- or -NH-; Alk is absent, is optionally substituted d-C alkyl or C2-C alkenyl as described above; and m and n are independently 0, 1 or 2. In a preferred embodiment of this aspect of the invention, the Ri and R2 groups are each esterified with each other of the hydroxy functional groups on the left (viz A and A '). ) of the Formula Ia, while the carbonyl portion is esterified to the right, optionally via a second ligature of the L2 group, in the 5'-O group of the nucleoside. Alternatively, the group L1 may comprise a ligation of formula IIb; -A- () "\ O Ar- Alk- T II / () r llb wherein Ar is preferably a saturated or unsaturated carbo-monocycle or heterocycle with 5 or 6 ring atoms; and A, A ', T, Alk, m and n are as defined above. In formula 11b, Ar is preferably an aromatic group such as pyridine, or especially phenyl, as well as aromatic portions wherein the extremities have the groups Ri and R2 which are respectively for and ortho, meta and ortho, both ortho, or preferably for and goal, both for or both goal in the rest of the ligatures. In the formulas lia and llb, the following combinations of m, n and Alk are currently favored: m n Alk 0 methylene 0 ethylene 1 absent 1 methylene 1 ethylene 1 propylene 2 absent 2 methylene 1 ethylene 1 propylene so that Ri and R2 may have different structures, it will be evident that most of the Li groups, particularly those of the formula lia, will be able to define the chiral structures and the invention includes all the enantiomers thereof, as racemates or as preparations of a compound > 80%, preferably > 95% enantiomerically pure. A particularly preferred group of trifunctional ligatures comprise glycerol derivatives of the formula I have wherein A is hydrogen, the acyl residue of an aliphatic L-amino acid ester or the acyl residue of a fatty acid ester, A 'is the acyl residue of an aliphatic amino acid residue and d is a dicarboxylic acid residue saturated or unsaturated C2-C6-The trifunctional ligatures of the formula lie are hydrolyzed or somehow decomposed in vivo to liberate the glycerol compounds of identical nature, the L-amino acid, the fatty acid (if present) are present and dicarboxylic acid, each of which is generally metabolized and / or excreted safely from the body. Preferably A and A 'are residues of an aliphatic amino acid, more preferably the same residue, particularly residues of L-valine or L-isoleucine. In the case that the portion of dicarboxylic acids in the derivative of the formula lie, is directly esterified in the 5 'hydroxy function (or equivalent) on the nucleoside, an alternative analysis could be defined in the glycerol portion as the trifunctional ligature Li and the portion of dicarboxylic acid as the difunctional ligature L2. Particularly preferred dicarboxylic acid residues include those derived from oxalic, malonic, tartronic, succinic, maleic, fumaric, malic, tartaric, glutaric, glutaconic, citraconic, itaconic, etidin-malonic, mesaconic, adipic, allylmalonic, propylidenemalonic, hydromuconic acids. , pirocincónico and mucónico and similars. The dicarboxylic acid residue can optionally be substituted, for example, with the substituents listed above with respect to R ^ as a fatty acid. The hydroxy substituents can, in turn, be esterified with an additional L-amino acid or a fatty acid residue. Several of the dicarboxylic acids mentioned above can themselves define a trifunctional ligature. For example, hydroxy-substituted dicarboxylic acids such as tartaric acid or malic acid, offer a number of configurations within the scope of the invention. By taking tartaric acid as an example, a carboxyl function is available for esterification with the 5-hydroxyl function of a nucleoside (optionally via moon difunctional ligature L2). Hydroxy functions are available for esterification with the respective carboxyl functions of R 2 of a fatty acid of Ri while the remaining carboxy group can be free, or optionally protected, for example, with a conventional pharmaceutically acceptable ester such as the methyl ester. or ethyl. Alternatively, the optional protection of the free carboxy function can, by itself, compress an ester with a fatty alcohol of R-i, with one or both hydroxyl functions being esterified in R2: The favored ligatures of the above tartaric acid series can be described generically as the formula He: R ^ lie and the isomers where Ri and R2 are inverted, where R ^ and R2 are as shown above, p, q and r are each independently from 0 to 5, preferably 0 or 1 and Ry is the free acid, a R1 ester or conventional pharmaceutically acceptable carboxy-protecting group, such as methyl, benzyl or especially the ethyl ester. The favored crosslinkers of the malic acid series have the formula llf: Phew where Ry, p, q and R2 are as defined above, preferably those where p and q are zero. Preferred compounds of this aspect of the invention include, therefore: 5'-O- [3-methoxycarbonyl-2-valyloxy-propionyl] -2 ', 3'-d-deoxy-3'-fluoroguanosine, 5'- O- [3-benzyloxycarbonyl-2-valyloxy-propionyl] -2 ', 3'-dideoxy-3'-fluoroguanosine, 5'-O- [3-methoxycarbonyl-2-isoleucoxy-propionyl] -2', 3'- dideoxy-3'-fluoroguanosine, 5, -O- [3-benzyloxycarbonyl-2-isoleucyloxy-propionyl] -2 ', 3'-dideoxy-3'-fluoroguanosine, 5'-O- [4-methoxycarbonyl] -2,3-bis-valyloxy-butyryl] -2 ', 3'-dideoxy-3'-fluoroguanosine, 5'-O- [4-benzyloxycarbonyl-2,3-bis-valyloxy-butyryl] -2' , 3'-dideoxy-3'-fluoroguanosine, 5'-O- [4-methoxycarbonyl-2,3-bis-isoleucyloxy-butyryl] -2 ', 3, -d'-deoxy-3'- Fluoroguanosine, 5'-O- [4-benzyl-oxy-carbon-2, 3-b-is-isoleucyloxy-butyryl] -2 ', 3'-dideoxy-3'-fluoroguanosine, particularly those derived from L-malic acid and L-tartaric; and corresponding derivatives employing conventional pharmaceutically acceptable esters on the carboxy terminal function. Particularly favored compounds include: 5, -O- [3-ethoxycarbonyl-2-valyloxy-propionyl] -2 ', 3'-dideoxy-3'-fluoroguanosine, 5'-O- [3-ethoxycarbonyl-2-isoleucyloxy- propionl] -2 ', 3'-dideoxy-3'-fluoroguanosine, 5'-O- [4-ethoxycarbonyl-2,3-bis-valyloxy-butyryl] -2', 3'-dideoxy-3'- fluoroguanosine, 5'-O- [4-ethoxycarbonyl-2,3-bis-isoleucyloxy-butyryl] -2 ', 3'-dideoxy-3'-fluoroguanosine, especially the isomers derived from L-malic acid and L-tartaric acid .

In a related alternative aspect of the invention one of Rt and R2 is omitted. Compounds representative of this aspect of the invention include those of the formula la: wherein Alk is an optionally substituted C? -C alkyl or C2-C4 alkenyl and Rz is the ester residue of an aliphatic L-amino acid or a fatty acid as defined for Ri and R2 above. Ligatures of this aspect of the invention are conveniently prepared from α-hydroxycarboxylic acids such as a carbonic acid, glycolic acid, hydroxypropanoic acid, hydroxybutyric acid, hydroxyvaleric acid, hydroxycaproic acid. Representative compounds of the Formula include: 2 ', 3'-dideoxy-3'-fluoro-5'-O- [3- (L-valyloxy) -propionyl] guanosine, 2', 3'-dideoxy-3'-fluoro-5'-O- [5- (L-valyloxy) -pentanoyl] guanosine, 2 ', 3'-dideoxy-3'-fluoro-5'-O- [6- (L-valyloxy) -hexanoyl] guanosine, 2', 3'- dideoxy-3'-fluoro-5'-O- [3- (L-isoleucyloxy) -propionyl] guanosine, 2,, 3'-dideoxy-3'-fluoro-5'-O- [5- (L-isoleucyloxy ) -pentanoyl] guanosine, 2 ', 3'-d-deoxy-3'-fluoro-5'-O- [6- (L-isoleucyloxy) -hexanoyl] guanosine, and pharmaceutically acceptable salts thereof.

Particularly favored compounds of the formula include: 2 ', 3'-dideoxy-3'-fluoro-5'-O- [4- (L-valyloxy) -butyryl] guanosine, 2', 3'-dideoxy-3 '-fluoro-5'-O- [4- (L-isoleucyloxy) -butyryl] guanosine and pharmaceutically acceptable salts thereof. In these compounds the hydrolysis and the removal of the R2 group in vivo allow a reactive terminal radical that could tend to cyclize or cause the effective release of the mother nucleoside. In a related alternative aspect of the invention, Ri is a fatty acid residue which by itself is used as the ligation, with the aliphatic L-amino acid residue of R2 being the esterification / amine bond in an amino, hydroxy or carboxy on the alkaline fatty acid chain, for example on coal ß. In this embodiment, the fatty acid of R1 is directly esterified on the 5'-hydroxy function (or equivalent) of the nucleoside, generally with the group R2 around the esterification / amide linkage thereof. Alternatively, the functionalized fatty acid (the carboxy / hydroxy / amino function being appropriately protected) can be first esterified at the nucleoside and deprotected prior to coupling with R2. The ligatures according to a preferred embodiment of this aspect have the formula lid: R.

H3C - () P. _ () < wherein R2 is the residue of an aliphatic L-amino acid, p is 0, 1 or 2-20 (optionally including a double bond) and q is 0-5, preferably 0. Representative compounds include 2 ', 3'-dideoxy -3'-fluoro 5'-O- [2-L-valyloxy) -butyryl] guanosine, 2 ', 3'-dideoxy-3'-fluoro-5'-O- [2-L-valyloxy) -hexanoyl] guanosine , 2 ', 3'-dideoxy-3'-fluoro-5'-O- [2-L-valyloxy) -octanoyl] guanosine, oxy) -decanoyl] guanosine, 2', 3'-d-deoxy-3'- fluoro • 5'-O- [2-L-valyloxy) dodecanoyl] guanosine, 2 ', 3'-dideoxy-3, -fluoro-5'-O- [2-L-valyloxy) -myristoyl] guanosine, 2', 3'-dideoxy-3'-fluoro 5'-O- [2-L-valyloxy) -palmitoyl] guanosine, 2 ', 3'-dideoxy-3'-fluoro • 5'-O- [2-L-valyloxy ) -stearoyl] guanosine, 2 ', 3'-dideoxy-3'-fluoro • 5'-O- [2-L-valyloxy) -docosanoyl] guanosine, 2', 3'-dideoxy-3'-fluoro • 5, -O- [2-L-valyloxy) -eicosanoyl] guanosine, 2,, 3'-dideoxy-3'-fluoro • 5'-O- [2-L-isoleucyloxy) -butyryl] guanosine, 2 ', 3'-dideoxy-3'-fluoro • 5'-O- [2-L-isoleucyloxy) -hexanoyl] guanosine, 2 ', 3'-dideoxy-3'-flu gold • 5'-O- [2-L-isoleucyloxy) -octanoyl] guanosine, 2 ', 3, -dideoxy-3'-fluoro-5'-O- [2-L-isoleucyloxy) -decanoyl] guanosine, 2 ', 3'-dideoxy-3'-fluoro • 5'-O- [2-L-isoleucyloxy) -dodecanoyl] guanosine, 2', 3'-dideoxy-3'-fluoro-5, -O- [2- (L-Isoleucyloxy) -miristoyl] guanosine, 2 ', 3'-dideoxy-3'-fluoro-5'-O- [2- (L-isoleucyloxy) -palmitoyl] guanosine, 2', 3'-dideoxy-3 '-fluoro-5'-O- [2- (L-isoleucyloxy) -estearoyl] guanosine, 2'13, -dideoxy-3'-fluoro-5'-O- [2- (L-isoleucyloxy) -docosanoyl] guanosine, 2 ', 3'-dideoxy-3'-fluoro-5'-O- [2- (L-isoleucyloxy) -eicosanoyl] guanosine, and the n-3 and n-6 monounsaturated analogs, such as 6 or 9 octadecenoyl derivatives. In the formula lid, p and q are preferably 0, therefore defining the lactic acid derivatives, preferably the L-lactic acid derivatives, such as 2 ', 3, -dideoxy-3'-fluoro-5'-O- [ 2- (L-valyloxy) -proponyl] guanosine; and 2 ', 3'-dideoxy-3'-fluoro-5'-O- [2- (L-isoleucyloxy) -propionyl] guanosine and pharmaceutically acceptable salts thereof, such as the decomposition products, lactic acid and the amino acid They are physiologically well accepted. The bifunctional expression, in the context of the second ligature of the group L2, means that the ligature has two functions that allow acting in a separator or bridge between the first ligature of the group t and the group 5'-O of the nucleoside. For example, the optional group L2 may comprise a ligation of the formula Illa: Illa wherein R4 and R4 'are hydrogen or C? -C4 alkyl. In the formula Illa, R4 is preferably hydrogen, methyl, ethyl, or isopropyl and R4 'is hydrogen. Ligations of the Illa formula are convenient as most nucleosides such as the FLG parent compound can first be phosphorylated by cellular enzymes before they can inhibit the viral polymerase. An initial hydrolysis or sequence of the compounds of the invention can release a monophosphorylated nucleoside in vivo that is available for immediate conversion to the di- and triphosphate. A bifunctional ligature of the optional L2 group can comprise the structure of the formula IIIb: R O I ?? -O OR O- I R4 ' wherein R 4 and R 4 'independently are H or C 1 -C 4 alkyl. Yet another additional group of bifunctional ligatures have the lile formula R.-O-lile As described above, a preferred group of bifunctional linkages comprises C2-C6 alkyl derivatives, α-dicarboxylics, such as succinic acid, which are optionally substituted (for example with the substituents defined above for Ri). as a fatty acid) and / or optionally mono or polyunsaturated, such as n-3 or n-6 monounsaturated. Preferred portions within this class were listed above. Although the above description has been concentrated on Li groups of glycerol in conjunction with L2 dicarboxylic groups, it will be appreciated that a wide variety of trifunctional linkages are suitable with L2 dicarboxylic groups, for example structures of the above formula Ia and llb lacking right carbonyl . The invention further includes dual prodrugs comprising L ^ 2 derivatives of R? (R2) of conventional FLG prodrugs, which conventional prodrugs release FLG in vivo, such as the prodrug derivatives at positions 2 and 6 of the guanine base. of FLG. Examples of such conventional FLG drugs include compounds of formula IV: wherein R ^ and R2, Li and L2 are as defined above; and R3 is H, N3, NH2 or OH or pharmaceutically acceptable ether or ester thereof; and R3 'is an aromatic ligature or hydrogen.

Potential pharmaceutically acceptable esters of R3 include the fatty acids described in relation to above R1, such as stearolyl, oleolyl, etc., or short esters such as acetyl or butyryl. Potential different esters include R2 amino acid derivatives or phosphoric acid esters, such as monophosphate. Alternative esters include the fatty acid or alkylaryl carbonate, carbamate or corresponding sulfonic esters. Suitable pharmaceutically acceptable ethers for R3 include C6-C6 alkyl, cycloalkyl, C6-C2 alkaryl such as benzyl or methylpyridyl, any of which may optionally be substituted as for Ri above. Suitable ethers include those described in WO 93 13778 mentioned above such as n-propoxy, cyclobutoxy, cyclopropanylamino, piperidino or pyrrolidino and the like. The invention has therefore been described with reference to FLG of the monohydroxylated nucleoside, however it will be apparent that the corresponding derivatives can be prepared from other monohydroxylated nucleoside analogues, particularly those wherein the monohydroxy groups correspond to the 5 'hydroxy function of a nucleoside . Therefore, a further aspect of the invention provides compounds of the formula le.

R, L1L2-0-nuc R, it wherein Ri, R2, - \ and L2 are as defined above and -O-nuc is the residue of a monohydroxy having the nucleoside analogue D or L. The representative nucleosides according to this aspect of the invention include analogs of nucleic acid acyclics such as acyclovir nucleoside analogs and cyclics such as ddl (didanosine), ddC (zalcitabine), d4T (stavudine), FTC, lamivudine (3TC), 1592U89 (4- [2-amino-6- (cyclopropylamino) - 9H-purin-9-yl] -2-cyclopentene-1-methanol), AZT (zidovudine), DAPD (D-2,6-diaminopurine dioxolane), F-ddA and the like, each of which is well known in the nucleoside technique. A number of monohydric L-nucleosides are under development and the invention also finds utility in the indications corresponding to the parent compounds, for example herpesvirus infections for acyclovir derivatives, HIV for ddI, stavudine, ddC, lamivudine, AZT and 1592U89, HBV for lamivudine, FTC, etc. A favored group within the Formula comprises monohydric nucleoside derivatives of the formula le ': le' where A, A ', Alk and O-nuc are as defined above. The formula above describes the compounds wherein A and A 'depend on positions 1 and 3 of the glycerol portion and L2 depends on the glycerol position 2. In the alternative isomers A and A 'they depend on 1 and 2 or 2 and 3 and L2 of 3 or 2 respectively. Representative compounds within this aspect of the invention include 4'-O- [3 - ((2,3-bis-L-vayloxy) -1-propyloxycarbon I) propionyl] acyclovir, 4'-O- [3 - ((2-hydroxy-3-L-valyloxy) -1-propyloxycarbonyl) propionyl] acyclovir, 4'-O- [3 - ((2,3-bis-L-isoleucyloxy) ) -1-propyloxycarbonyl) propionyl] acyclovir, 4'-O- [3 - ((2-hydroxy-3-L-isoleucyloxy) -1-propyloxycarbonyl) propionyl] acyclovir, 4'-O- [3- ( (1,3-bis-L-valyloxy) -2-propyloxycarbonyl) propionyl] acyclovir, 4'-O- [3 - ((1-hydroxy-3-L-valyloxy) -2-propyloxycarbonyl) propionyl] acyclovir, 4'-O- [3 - ((1,3-bis-L-isoleucyloxy) - 2-propyloxycarbonyl) propionyl] acyclovir, 4'-O- [3 - ((1-hydroxy-3-L-isoleucyloxy) -2-propyloxycarbonyl) propionyl] acyclovir, 5'-O- [3 - ((2,3- bis-L-valyloxy) -1-propyloxycarbonyl) propionyl] lamivudine, '-O- [3 - ((2-hydroxy-3-L-valyloxy) -1-propyloxycarbonyl) propionyl] lamivudine, 5'-O- [3 - ((2,3-bis-L-isoleucyloxy) -1 -propyloxycarbonyl) propionyl] lamivudine, 5'-O- [3 - ((1,3-bis-L-valyloxy) -2-propyloxycarbonyl) propionyl] lamivudine, '-O- [3 - ((1-hydroxy-3-L-valyloxy) -2-propyloxycarbonyl) propionyl] lamivudine, 5'-O- [3 - ((1,3-bis-L-isoleucyloxy) -2 -propyloxycarbonyl) propionyl] lamivudine, 5'-O- [3 - ((1-hydroxy-3-L-isoleucyloxy) -2-propyloxycarbonyl) propionyl] lamivudine, 5'-O- [3 - ((2,3-bis -L-valyloxy) -1-propyloxycarbonyl) propionyl] DAPD, '-O- [3 - ((2-hydroxy-3-L-valyloxy) -1-propyloxycarbonyl) propionyl] DAPD, '-O- [3 - ((2,3-bis-L-isoleucyloxy) -1-propyloxycarbonyl) propionyl] DAPD, '-O- [3 - ((2-hydroxy-3-L-isoleucyloxy) -1-propyloxycarbonyl) propionyl] DAPD, 5'-O- [3 - ((1,3-bis-L-valyloxy) -2-propyloxycarbonyl) propionyl] DAPD, '-O- [3 - ((1-hydroxy-3-L-valyloxy) -2-propyloxycarbonyl) propionyl] DAPD, '-O- [3 - ((1,3-bis-L-isoleucyloxy) -2-propyloxycarbonyl) propionyl] DAPD, '-O- [3 - ((1-hydroxy-3-L-isoleucyloxy) -2-propyloxycarbonyl) propionyl] DAPD, 5'-O- [3 - ((2,3-bis-L-valyloxy) -1-propyloxycarbonyl) propionyl] -2 ', 3'-dideoxyinosine 5'-O- [3 - ((2 -hydroxy-3-L-valyloxy) -1-propyloxycarbonyl) propionyl] -2 ', 3'-dideoxyinosine 5'-O- [3 - ((2,3-bis-L-isoleucyloxy) -1-propyloxycarbonyl) propionyl] -2 ', 3'-dideoxyinosine 5'-O- [3 - ((3-hydroxy-3-L-isoleucyloxy) -1-propyloxycarbonyl) propionyl] -2', 3'-dideoxyinosine 5'- O- [3 - ((1,3-bis-L-valyloxy) -2-propyloxycarbonyl) propionyl] -2 ', 3'-dideoxyinosine 5'-O- [3 - ((1-hydroxy-3-L- valyloxy) -2-propyloxycarbonyl) propionyl] -2 ', 3'-dideoxyinosine 5'-O- [3 - ((1,3-bis-L-isoleucyloxy) -2-propyloxycarbonyl) propionyl] -2', 3 ' -dideoxyinosine 5'-O- [3 - ((1-hydroxy-3-L-isoleucyloxy) -2-propyloxycarbonyl) propionyl] -2 ', 3'-dideoxyinosine 5'-O- [3- ( (2,3-bis-L-valyloxy) -1-propyloxycarbonyl) propionyl] stavudine, '-O- [3 - ((2-hydroxy-3-L-valyloxy) -1-propyloxycarbonyl) propionyl] stavudine, 5'-O- [3 - ((2,3-bis-L-isoleucyloxy) - 1-propyloxycarbonyl) propionyl] stavudine, 5'-O- [3 - ((2-hydroxy-3-L-isoleucyloxy) -1-propyloxycarbonyl) propionyl] stavudine, 5'-O- [3 - ((1,3 -bis-L-valyloxy) -2-propyloxycarbonyl) propionyl] stavudine, 5'-O- [3 - ((1-hydroxy-3-L-valyloxy) -2-propyloxycarbonyl) propionyl] stavudine, 5'- O- [3 - ((1,3-bis-L-isoleucyloxy) -2-propyloxycarbonyl) propionyl] stavudine, 5'-O- [3 - ((1-hydroxy-3-L-isoleucyloxy) -2 propyloxycarbonyl) propionyl] stavudine, the corresponding derivatives of 4- [2-amino-6 (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol, and pharmaceutically acceptable salts thereof. An alternative sub-group of the compounds within this aspect of the invention comprises those of the formula Id: O Rz- O- - A Ailkk- JL or O - nuc Id where Rz and Alk are as defined for the formula la and O-nuc are as defined above. Representative compounds of the formula Id include 4'-O- [4- (L-valyloxy) -propionl] acyclovir, 4'-O- [5- (L-valyloxy) -pentanoyl] acyclovir, 4'- O- [6- (L-valyloxy) -hexanoyl] acyclovir, 4'-O- [4- (L-Isoleucyloxy) -propionyl] acyclovir, 4'-O- [4- (L-valyloxy) -butyryl] acyclovir, 4 * -O- [5 - ((L-isoleucyloxy) pentanoyl] acyclovir, 4'-O- [6 - ((L-isoleucyloxy) hexanoyl] acyclovir, '-O- [4 - ((L-valyloxy) -propionyl] ddl, 5'-O- [5 - ((L-valyloxy) -pentanoyl] ddl, 5'-O- [6 - ((L- valyloxy) -hexanoyl] ddl, 5'-O- [4 - ((L-isoleucyloxy) -propionyl] ddl, 5'-O- [4 - ((L-valyloxy) -butyryl] ddl, 5'-O- [5 - ((L-isoleucyloxy) pentanoyl] ddl, 5'-O- [6 - ((L-isoleucyloxy) hexanoyl] ddl, 5'-O- [4 - ((L-valyloxy) -propionyl] ddl, 5'-O- [5 - ((L-valyloxy) -pentanoyl] stavudine, '-O- [6 - ((L-valyloxy) -hexanoyl] stavudine, '-O- [4 - ((L-isoleucyloxy) -propionyl] stavudine, '-O- [4 - ((L-valyloxy) -butyryl] stavudine, 5'-O- [5 - ((L-isoleucyloxy) pentanoyl] stavudine, '-O- [6 - ((L-isoleucyloxy) hexane i I] stavudine, '-O- [4 - ((L-valyloxy) -propionyl] ddl, 5'-O- [5 - ((L-valyloxy) -pentanoyl] DAPD, 5'-O- [6 - ((L- valyloxy) -hexanoyl] DAPD, 5'-O- [4 - ((L-isoleucyloxy) -propionyl] DAPD, 5'-O- [4 - ((L-valyloxy) -butyryl] DAPD, 5'-O- [5 - ((L-Isoleucyloxy) pentanoyl] DAPD, 5'-O- [6 - ((L-isoleucyloxy) hexanoyl] DAPD, 5'-O- [5 - ((L-valyloxy) -pentanoyl] lamivudine, 5'-O- [6- (L-valyloxy) -hexanoyl] lamivudine, 5'-O- [4- (L-isoleucyloxy) -propionyl] lamivudine, 5'-O- [4- (L-valyloxy) - butyryl] lamivudine, 5'-O- [5- (L-isoleucyloxy) pentanoyl] lamivudine, 5'-O- [6- (L-isoleucyloxy) hexanoyl] lamivudine, and the corresponding derivatives of 4- [2-amino- 6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol Particularly preferred compounds within Formula Id include: 4'-O- [4- (L-valyloxy) -butyr I] acyclovir, 4'-O- [3- ((L-isoleucyloxy) -butyryl] acyclovir, 5'-O- [4- (L-valyloxy) -butyryl] ddl, 5'-O- [3- (( L-Isoleucyloxy) -butyryl] ddl, 5'-O- [4- (L-valyloxy) -butyryl] stavudine, 5'-0- [3- (L-isoleucyloxy) -butyryl] stavudine, 5'-O- [4- (L-valyloxy-butyryl] DAPD, 5'-O- [3- (L-isoleucyloxy) -butyryl] DAPD, 5'-O- [4- ((L-valyloxy) -butyryl] lamivudine, 5'-O- [3- (L-isoleucyloxy) -butyryl] lamivudine, and the corresponding derivatives of 4- [amino-6- (cyclopropylamino) -9r-purin-9-yl] -2-cyclopentane-1- methanol and pharmaceutically acceptable salts thereof In these compounds the hydrolysis and removal of the R2 group in vivo allow a reactive terminal radical which tends to cyclize and cause the effective release of the parent nucleoside, similarly the invention extends to the compounds of the formula If: R, If where Ri, R2, Ry, p, q, r and o-nuc are as defined above. Preferred compounds of this aspect of the invention include: 5'-O- [3-ethoxycarbonyl-2-valyloxy-propionyl] -ddl, 5'-O- [3-ethoxycarbonyl-2-isoleucyloxy-propionyl] -ddl 5 ' -O- [4-ethoxycarbonyl-2,3-bis-valyloxy-butyryl] -ddl, 5'-O- [4-ethoxycarbonyl-2,3-bis-isoleucyloxy-butyryl] -ddl, 4'-O [3 -e toxic rbonyl -2-valyloxy-propionylj-acyclovir, 4'-O [3-ethoxycarbonyl-2-isoleucyloxy-propionyl] -aciclovir, 4'-O [4-ethoxycarbonyl-2,3-bis-valyloxy-butyryl] -aciclovir, 4-O [4-ethoxycarbonyl-2,3-bis-isoleucyloxy-butyryl] -aciclovir, 5'-O- [3-ethoxycarbonyl-2-valyloxy-propionyl] -DAPD, 5'-O- [3 -ethoxycarbonyl-2-isoleucyloxy-propionyl] -DAPD, 5'-O- [4-ethoxycarbonyl-2,3-bis-valyloxy-butyryl] -DAPD, 5'-O- [4-ethoxycarbonyl-2,3-bis -isoleucyloxy-butyryl] -DAPD, 5'-O- [3-ethoxycarbonyl-2-valyloxy-propionyl] -stavudine, 5'-O- [3-ethoxycarbonyl-2-isoleucyloxy-propionyl] -stavudine, 5 ' -O- [4-ethoxycarbonyl-2,3-bis-valyloxy-butyryl] -stavudine, 5'-O- [3-ethoxycarbonyl-2-valyloxy-propionyl] -lamivudine, 5'-O- [3-ethoxycarbonyl- 2- isoleucyloxy-propionyl] -lamivudine, 5'-O- [4-ethoxycarbonyl-2,3-bis-valoxy-butyryl] -lamivudine, 5'-O- [4-ethoxycarbonyl-2,3-bis-isoleucyl] loxi-butyryl] -lamivudine, and the corresponding malic and tartaric acid derivatives of 4-2-amino-6 (cyclopropylamino) -9r-purin-9-yl] -2-cyclopentene-1-methanol and pharmaceutically acceptable salts thereof; in each case the isomers derived from L-tartrate and L-maleate derivatives being preferred. The invention also extends to compounds of the formula Ig: wherein R2, p, q and O-nuc are as defined above.

Preferred compounds of the formula Ig include: 4'-O- [2- (L-valyloxy) -propionyl] acyclovir, 4'-O- [2- (L-isoleucyloxy) -propionyl] acyclovir, 5'-O- [2- (L-valyloxy) - propionyl] ddl, 5'-O- [2- (L-isoleucyloxy) -propionyl] ddl, 5'-O- [2- (L-valyloxy) -propionyl] stavudine, 5'-O- [2- (L -isoleucyloxy) -propionyl] stavudine, 5'-O- [2- (L-valyloxy) -propionyl] lamivudine, 5'-O- [2- (L-isoleucyloxy) -propionyl] lamivudine, and the corresponding derivatives of - [2-amino-6 (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol; and pharmaceutically acceptable salts thereof. The decomposition products of said compounds, lactic acid and the amino acid, are physiologically well accepted. The compounds of the invention can form salts that form a further aspect of the invention. Suitable pharmaceutically acceptable salts of the compounds of Formula I include salts of organic acids, especially carboxylic acids, including but not limited to acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, isethionate, adipate, alginate , aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, propionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate , organic sulfonic acids such as methanesulfonate acids, ethanesulfonate, 2-hydroxyethane sulfonate, camphorsulfonate, 2-naphthalenesulfonate, benzenesulfonate, p-chlorobenzenesulfonate and p-toluenesulfonate; and inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulphuric, hemisulfuric, thiocyanate, persulfate, phosphoric and sulfonic acids. The compounds of Formula I can be isolated in some cases as the hydrate. The term "N-protecting group" or "N-protected" as used herein, refers to those groups that are intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. . The commonly used N-protecting groups are described in Greene, "Protective Groups in Organic Synthesis" (John Wiley &Sons, New York, 1981), which is incorporated herein by reference. N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl , 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like, carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzylcarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, 4-nitro-4,5-di methoxybenzyloxycarbonyl, 3,4,5-trimethoxy benzyloxycarbonyl 1- (p-biphenylyl) -1-methyl ethoxycarbonyl, a, a-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzyhydryloxycarbonyl , tb or toxic rbo ni, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl, and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protected groups include formyl, acetyl, allyl, F-moc, benzoyl, pivalyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butoxycarbonyl (BOC) and benzyloxycarbonyl (Cbz). The hydroxy and / or carboxy protecting groups are also extensively reviewed in Greene and include ethers such as methyl, substituted methyl ethers such as methoxymethyl, methylthiomethyl, benzyloxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl and the like, the silyl ethers such as tr? meti Isyl ilo (TMS), t-butyldimethylsilyl (TBDMS) tri benzyl sulfone, triphenylsilyl, t-butyldiphenylsilyl, triisopropyl silyl and the like, the substituted ethyl ethers such as 1-ethoxymethyl, 1-methyl-1- methoxyethyl, t-butyl, allyl, benzyl, p-methoxybenzyl, diphenylmethyl, triphenylmethyl and the like, aralkyl groups such as trityl and pixyl (9-hydroxy-9-phenylxanthene derivatives, especially chloride). Hydroxy protecting groups include esters such as formate, benzylformate, chloroacetate, methoxyacetate, phenoxyacetate, pivaloate, adamantoate, mesitoate, benzoate and the like. The hydroxy carbonate protecting groups include methyl, vinyl, allyl, cinnamyl, benzyl and the like.In accordance with usual practice with retroviral and HBV inhibitors, it is advantageous to co-administer from one to three or more additional antivirals, such as AZT, ddI, ddC, d4T, 3TC, H2G, foscarnet, ritonavir, indinavir, saquinavir, nevirapine, delaviridine, Vertex VX 478 or Agouron AG1343 and the like in the case of HIV or lamivudine, interferon, famciclovir, etc. in the case of HBV. Said additional antivirals can normally be administered at doses related to one another which broadly reflect their respective therapeutic values. The molar ratios of 100: 1 to 1: 100, especially 25: 1 to 1:25, relative to the compounds or salt of formula I which is often convenient. The administration of additional antivirals is generally less common with those antiviral nucleosides that are intended for the treatment of herpes infections. While it is possible for the active agent to be administered alone, it is preferable to present itself as part of a pharmaceutical formulation. Said formulation may comprise the active agent defined above together with one or more acceptable carriers / excipients and optionally other therapeutic ingredients. The vehicles may be more acceptable in the sense that they are compatible with other ingredients of the formulation and do not damage the recipient. The formulations include those suitable for rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral administration (including subcutaneous, intramuscular, intravenous and intradermal), but preferably the formulation is an orally administered formulation. The formulations can conveniently be presented in a unit dosage form, v. gr. , tablets and sustained release capsules and can be prepared by any method well known in the pharmacy field. Said methods include the step of attracting in association with the active agent defined above with the vehicle. In general, the formulations will be uniformly prepared and attracted intimately in association with the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary forming the product. The invention extends to methods for the preparation of a pharmaceutical composition which comprises attracting a compound of Formula I or its pharmaceutically acceptable salt as a whole or in association with a pharmaceutically acceptable carrier or vehicle. If the manufacture of the pharmaceutical formulations involves intimately mixing the pharmaceutical excipients and the active ingredient in salt form, then it is often preferred for the use of excipients that have no basic nature, ie, are acidic or neutral. Formulations for oral administration in the present invention may be presented as discrete units such as capsules, troches or tablets each containing a predetermined amount of the active agent; like a powder or granules; as a solution or suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion and as a bolus, etc. With respect to compositions for oral administration (e.g., tablets and capsules), the term "suitable carriers" includes carriers such as common excipients, e.g., ligation agents, eg, syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydropropylmethylcellulose, sucrose and starch; fillers and vehicles, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metal stearates, glycerol stearate, stearic acid, silicone fluid, talc, waxes, oils and colloidal silica, flavoring agents such as peppermint, wintergreen essence, strawberry flavoring or the like may also be used. It may be convenient to add a coloring agent to take the easily identifiable dosage form. The tablets may also be coated by methods well known in the art. A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compression in a machine suitable for the active agent in a free-flowing form such as a powder, granules, optionally mixed with a binder, lubricant, inert diluent, preservative, active surface or dispersing agent. The molded tablets can be made by molding in a suitable machine a mixture of the powder compound with an inert liquid diluent. The tablets can optionally be coated or screened and can be formulated so as to provide slow or controlled release of the active agent.

Other formulations suitable for oral administration include pills that compress the active agent into a flavor base, usually sucrose and acacia or tragacanth; the temples compress the active agent in an inert base such as gelatin and glycerin or sucrose and acacia; and the rinses compress the active agent in a suitable liquid vehicle. In still a further aspect of the invention there is provided a method for the preparation of a compound of Formula I or that comprising the acylation of the nucleoside, represented herein by FLG, Formula V, normally in the hydroxy group. wherein R1 (R2) L1X represents an activated acid, such as carboxylic derivatives of Formula Ia or IIb, wherein Ri, R2, and L1 are as defined above or protected derivatives thereof. Alternatively the activated acid may comprise a compound of the formula R1 (R2) glycerol-DX, wherein Ri, R2 and D are as defined in the formula Me or an activated Rz-O-Alk-C (= O) X derivative in the case of the compounds of the formula la. In the latter cases the ligatures can be strengthened by first esterifying a carboxylic acid D or? -hydroxy suitably protected in the nucleoside, deprotecting the carboxy or hydroxy terminal function and esterifying the glycerol or Rz portion suitably protected therefrom. The activated derivative used in the acylation may comprise eg, acid halide, acid anhydride, activated acid ester or the acid in the presence of a coupling reagent, for example dicyclohexylcarbodiimide. Representative activated acid derivatives include the acid chloride, anhydride derivatives of alkoxycarbonyl halides such as isobutyloxycarbonyl chloride and the like, esters derived from N-hydroxysuccinamide, esters derived from N-hydroxyphthalimide, esters derived from N-hydroxy-5-norbornene -2,3-dicarboxamide, esters derived from 2,4,5-trichlorophenyl and the like. Additional activated acids include those wherein X in the formula RX represents a Por 'portion wherein R is R2 as defined herein, and R' is, for example COCH3, COCH2CH3 or COCF3 wherein X is benzotriazole.

The corresponding methodology may be applied when the invention is applied to other monohydroxylated nucleosides, ie the activated derivative is correspondingly esterified 5 'hydroxy (or equivalent) of monohydric nucleosides such as acyclovir, ddl, FTC, lamivudine, 1592U89, DAPD, F-ddA and similar. The intermediaries used in the above methods by themselves define novel compounds, especially those of the formula lie ': llc " wherein A, A 'and Alk are as defined above (A and A' are optionally protective with conventional protection groups) and X represents the free acid or an activated acid as illustrated above.

Representative compounds of the formula lie 'include: malonic acid ester of 2,3- £ > / s- (L-valoxy) -propyl, 2,2- £ > / 's- (N-CBZ-L-valyloxy) -propyl, malonic acid of 2,3- £ > / s- (N-Fmoc-L-valyloxy) -propyl, malonic ester acid of 2,3-6 / s- (N-Boc-L-valyloxy) -propyl, malonic acid of 2,3-ester or / s- (L-isoleucyloxy) -propyl, malonic acid ester of 2,3- £ > / s- (N-CBZ-L-isoleucyloxy) -propyl, malonic acid of 2,3-o / s- (N-Fmoc-L-isoleucyloxy) -propyl ester, malonic acid of 2,3-d ester / s- (N-Boc-L-isoleucyloxy) -propyl, succinic acid ester of 2,3- £ > / s- (L-valyloxy) -propyl, succinic acid of 2,3- £ > / s- (N-CBZ-L-valyloxy) -propyl, succinic acid ester of 2,3-o / 's- (N-Fmoc-L-valyloxy) -propyl, succinic acid of 2,3-ester £ > / s- (N-Boc-L-valyloxy) -propyl, succinic acid ester of 2,3-o / s- (L-isoleucyloxy) -propyl, succinic acid ester of 2,3-o / s- ( N-CBZ-L-isoleucyloxy) -propyl, succinic acid ester of 2,3-6 / s- (N-Fmoc-L-isoleucyloxy) -propyl, succinic acid of 2,3-6 s- ester (N -Boc-L-isoleucyloxy) -propyl, glutaric acid of 2,3- or s- (L-valyloxy) -propyl ester, 2,3-D / 's- (N-CBZ-L-) ester acid valyloxy) -propyl, glutaric ester acid of 2,3- £ >; / s- (N-Fmoc-L-valyloxy) -propyl, glutaric ester acid of 2,3- £ > / s- (N-Boc-L-valyloxy) -propyl, 2,3-j / s- (L-isoleucyloxy) -propyl ester glutaric acid, 2,3- £ glutaric acid ester > / s- (N-CBZ-L-isoleucyloxy) -propyl, glutaric ester acid of 2,3- / 5 / 's- (N-Fmoc-L-isoleucyloxy) -propy, ester glutaric acid of 2,3 - £ > / s- (N-Boc-L-isoleucyloxy) -propyl, and the corresponding acid halides, in particular the chloride, acid anhydrides and diesters of each of the foregoing, for example succinic acid of 2,3-D ester / 's - (N-CBZ-L-valyloxy) -propyl, ester of 4-methoxybenzyl, succinic acid ester of glutaric acid ester of 2,3- £ > / s- (N-CBZ-L-valyloxy) -propyl, 1,1-dimethylethyl ester, etc. A further preferred group of intermediates comprises those of the formula Na ': Ha' wherein Rx, Alk, m, n, and T are as described above, A and A 'represent acyl residues of L' aliphatic amino acids (N-protected as necessary) esterified at the hydroxy functions on the ligation or one of A and A 'is the acyl residue and the other is a free hydroxy group, and X represents the free acid or an activated acid as illustrated above. Preferably A and A 'are the same amino acid residue. Other novel intermediates include the free acid or activated acid precursors of compounds of the formula la such as: 3-N-Boc-L-valyloxypropanoic acid, 3-N-Fmoc-L-valyloxypropanoic acid, 3-N-CBZ-L acid -valiloxipropanóico, 3-N-Boc-L-isoleuciloxipropanóico acid, 3-N-Fmoc-L-isoleuciloxipropanóico acid, 3-N-CBZ-L-isoleuciloxipropanóico acid, 4-N-Boc-L-valiloxiburítirico, 3- N-Fmoc-valiloxibutírico, 4-N-CBZ-L-valiloxibutírico acid, 4-N-Boc-L-isoleuciloxibutírico acid, 3-N-Fmoc-L-isoleuciloxiburitirico acid, 3-N-CBZ-L-isoleuciloxibutírico and Similar; and activated derivatives, such as acid halides. Additional novel intermediates include precursors of compounds of the formula lie and llf above, specifically those derived from "natural" configurations such as acid L-malic and L-tartaric acid; for example, 3-ethoxycarbonyl-2-valyloxy-propionic acid 3-ethoxycarbonyl-2-isoleuciloxi-propionic acid 4-ethoxycarbonyl-2,3-bis-valyloxy-butyric acid 4-ethoxycarbonyl-2,3-bis-isoeluciloxi- butyric acid 3-benzyloxycarbonyl-2-valyloxy-propionic acid 3-benzyloxycarbonyl-2-isoleuciloxi-propionic acid benzyl 4- carbonyl oxy-2,3-bis-valyloxy-rich Butí 4-benzyloxycarbonyl-2,3-bis- isoleucyloxy-butyric, and the like; and the corresponding activated derivatives such as acid halides. Even the additional novel intermediates include precursors corresponding to the lid structure, such as: 2- (valyloxy) propanic acid, 2- (N-Boc-L-valyloxy) acid, 2- (N-Fmoc-L-valyloxy) acid propanic, 2- (N-CBZ-L-valyloxy) propanic acid, 2- (L-isoleucyloxy) propanic acid, 2- (N-Boc-L-isoleucyloxy) propanic acid, N- (Fmoc-L-isoleucyloxy) acid propanic, N- (CBZ-L-isoleucyloxy) propanic acid, 2- (L-varyloxy) butyric acid, 2- (N-Boc-L-varyloxy) butyric acid, 2- (N-Fmoc-L-valyloxy) acid butyric, 2- (N-CBZ-L-varyloxy) butyric acid, 2- (L-isoleucyloxy) butyric acid, 2- (N-Boc-L-isoleucyloxy) butyric acid, N- (Fmoc-L-isoleucyloxy) butyric, N- (CBZ-L-isoleucyloxy) butyric acid, and the like; and activated derivatives thereof, such as acid halides.

The preparation of the 3 'fluoronucleosides such as those of the formula V have been extensively reviewed by Hardiwijn et al., In Nucleosides and Nucleotides 8 (1) 65-96 (1989), which is incorporated herein by reference. The preparation of other monohydric nucleosides such as acyclovir, ddI (didanosine), ddC (zalcitabine), d4T (stavudine), FTC, lamivudine (3TC), 1592U89 (4- [2-amino-6- (cyclopropylamino) -9H-purin -9-yl] -2-cyclopentene-1-methanol), AZT (zidovudine), DAPD (D-2,6-diaminopurine dioxolane), F-ddA and the like are well known and described extensively in the literature. Reactive derivatives the group R1 (R2) L1L2X be pre-formed or would generate in situ by using reagents such as dlciclohexilcarbodiimida (DCC) or tetrafluoroborate 0- (1H-benzotriazol-1-yl) N, N, N ' , N'-tetramethyluronium (TBTU). When an acid halide, such as acid chloride is used, a tertiary amine catalyst, such as triethylamine, N, N'-dimethylaniline, pyridine or dimethylaminopyridine can be added in the reaction mixture to bind the liberated hydrohalic acid. The reactions were preferably carried out in a non-reactive solvent such as N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, or a halogenated hydrocarbon, such as dichloromethane. If desired, any of the tertiary amine catalysts mentioned above can be used as a solvent, taking care that a suitable excess is present. The reaction temperature can normally vary between 0 ° C and 60 ° C, but preferably it can be maintained at 5 ° C and 50 ° C. After a period of 1 to 60 hours the reaction will usually be essentially complete. The progress of the reaction was followed using thin layer chromatography (CCD) and appropriate solvent systems. In general, when the reaction is complete as determined by CCD, the product is extracted with an organic solvent and purified by chromatography and / or recrystallization from an appropriate solvent system. The byproducts wherein the acylation takes place on the basis of the nucleoside can be separated by chromatography, but said misacylation can be minimized by the controlled reaction conditions. These controlled conditions can be achieved, for example, by manipulating the reagent concentrations or the rate of addition, especially of the acylating agent, by minimizing the temperature or by choosing the solvent. The reaction can be followed by CCD to monitor the controlled conditions. It may be convenient to protect the 6-oxo group on the base and especially 2-amino with conventional protection groups in the anticipated misacylation. Compounds of Formula IV in which R3 is hydrogen can be prepared by activation 6 of the corresponding guanine compound of Formula I (wherein the exposed amino function of the R2 amino acid residue is optionally protected with conventional N-protecting groups) with an activation group such as halo. The subsequently activated 6-purine is reduced to purine, for example with a palladium catalyst and deprotects the desired compound of Formula IV or Formula V. Compounds wherein R 3 is Ri or another ester can be prepared by conventional esterification (analogs in the esterification described above) of the corresponding hydroxy compound of Formula I or Formula V, optionally after the conventional N-protection of the exposed amine function of the amino acid residue of R2 and / or R3. The compounds wherein R3 is an ether can be prepared analogously in the processes described in WO 93 13778 mentioned above again in conjunction with the optional N-protection of the exposed amine groups. Compounds wherein R3 is an amide which can be prepared as described in WO 9709052. The intermediates of the formula lid are conveniently prepared by acylation of a carboxy-protected hydroxy alkanoic acid, usually a 2-hydroxy-1-alkanoic acid, with the N2-protected and activated N2 derivative, such as N-CBZ vallyl or isoleucyl in conjunction with a conventional coupling reagent such as DMAP / DCC, or with the amino acid halide. The carboxy protecting group is then removed, for example by acid hydrolysis and the resulting intermediate is activated as described above or the free acid is not used in conjunction with a coupling reagent to esterify the nucleoside under conventional esterification conditions.

The compounds of the formula la are also conveniently prepared by the methodology in the immediately preceding paragraph, namely the esterification of a carboxy-protected α-hydroxy, α-carboxy acid, such as glycolic acid, lactic acid, hydroxybutyric acid, etc. ., with the appropriate N-protected R2 derivative, either as a free acid in conjunction with a coupling agent or activated, for example with the corresponding acid halide. The carboxy protecting group is removed and the resulting intermediate is esterified with the nucleoside with the methodology described above. The compounds comprising the structure of the formula lie or llf are prepared by the carboxy protection of the carboxy terminal groups of the respective dicarboxylic acids, such as L-tartaric acid or L-malic acid, with conventional carboxy protecting groups such as benzoyl. The free hydroxy groups are then esterified with conventional esterification techniques, such as DMAP and DCC in DMF with the appropriate N-protected R2 amino acid, such as N-Boc-L-valyl or N-Boc-L-isoleucyl. The benzoyl carboxy protecting groups are removed and the resulting product is esterified at the 5 'hydroxy function of a monohydric nucleoside, using conventional conditions, such as those in the accompanying Examples. Finally, the free carboxy function is esterified with a R <or> group, more preferably a conventional pharmaceutically acceptable ester, such as ethyl ester.

The compounds comprise a phosphorylated portion I I which can be prepared by reacting 2 ', 3'-dideoxy-3'-fluoro-guanine-5-monophosphate with a compound of Formula VI Via wherein Ha is halo, such as chlorine, iodine or bromine, under conditions analogous to those described in 4 337 201 of E. U.A. , 5 277 506 of E. U .A. , WO 94/13682 and WO 94/13324, by Starret et al., J Med Chem 37 1857-1864 (1994) and lyer and other Tetrahedron Lett 30 7141-7144 (1989) which are incorporated herein by reference. The monophosphate can be prepared by conventional phosphorylation of FLG, as described, for example, in Herdwyn and others ibid. The corresponding methodology may be applied in monophosphates of other monohydric nucleosides. Alternatively, this esterification in the monophosphate ester could take part in two steps comprising a first reaction between FLG monophosphate and a compound of the formula VI R4 'il wherein R and R4' are as defined above and PG is a hydroxy functional protective group such as those described above, followed by deprotection and esterification in a Li group ligature whose third function on the right is a hydroxy group , two examples of said ligature of the group Li are described in the following Scheme 1 (the penultimate compounds in each of the series). In this embodiment the carbonyl to the left of the formula Va is a synonym when the carbonyl of the group is ligature of the ligation of Formula Ia. The compounds comprise an optional l2 ligature which can also be prepared by a two-step process. In particular a compound of the formula CIC (= O) OC (R4) (R ') CI can be reacted with the 5' hydroxy of FLG (optionally protected on the basis with conventional protecting groups) as is known in the art of cephalosporin. The FLG-5'-O-C (= O) OC chloride (R4) (R4 ') then reacts with an R-i and R2 allowing trifunctional ligation wherein the third function comprises a carboxyl function, such as potassium salt. It should be appreciated that the trifunctional L-t groups of the formula lia wherein n and m are 1 and Alk is absent can be prepared from glycerol by the regioselective esterification as described in the following scheme 1 by reference to a stearoyl / L-valyl combination. In Ri and short R2 they are esterified regioselectively in positions 1 and 3 of glycerol and position 2 then becomes the group -T-C (= O) - appropriate, which is then esterified at the 5 'position of the fluoronucleoside or in a cooperative function on L2 (not described). Alternatively, the hydroxy at position 2 of the glycerol derivative can be esterified with a group L2 containing a cooperating carbonyl function on its left end. The groups L ^ of the formula lia wherein m is 1, n is 0 and Alk is methylene can also be prepared from glycerol by the regioselective esterification Ri and R2 at positions 1 and 2 of glycerol, also described in the following scheme 1 , followed by the conversion of hydroxy to position 3 in the appropriate -TC (= O) group. A series to the left of the reactions on Scheme 1 show the situation where Ri is esterified at position 1 of glycerol and R2 is esterified at position 2. The corresponding arrangement in which Ri is esterified at position 2 and R2 in position 1, can be achieved by first treating glycerol with CBz-L-valine / DCC / DMAP / DMF and after protection in position 3 with pixyl chloride before esterifying the fatty acid of Ri in position 2 of glycerol, unprotecting and converting position 3 as necessary.

SCHEME 1 GBZ-L- valine DCC D P CH2CI2 / DM esterification with FLG I phosgene Through Scheme 1 is illustrated by reference for a combination wherein R ^ is stearoyl and R2 is L-valyl, it should be appreciated that this basic scheme will also be applicable in other amino acids when other fatty acids are present, or by using the groups of conventional protection, for combinations of R2 as an amino acid derivative and Ri as hydroxy. Ligations where T comprises a group -NH- can be prepared by regioselective esterification of analogues followed by conversion of the free hydroxyl to amine, reduction to azide and reaction with phosgene to form the corresponding chlorocarbamate. A variation of scheme I allows the preparation of the ligatures of the formula lie. In this variation, the phosgene step shown above is replaced by the reaction with an activated dicarboxylic acid, such as succinic anhydride. This results from a glycerol triester (which comprises the ester of R (optionally protected), the protected R2 ester and the dicarboxylic acid ester) and the free carboxy on the dicarboxylic acid then is activated and esterified in the nucleoside in a form conventional. Alternatively, ligatures of the formula He can be strengthened in situ on the nucleoside. In this variant, the dicarboxylic acid is esterified into a suitably protected glycerol derivative. This succinyl monoester is then esterified at the 5 'hydroxy function of the nucleoside in a conventional manner. Finally one or both of the protecting groups on the glycerol portion is replaced with the amino acid ester L, and if present, the remaining protecting group is replaced with a fatty acid ester or stirred to allow the free hydroxy group. This is described in Scheme IA which illustrates an example where the nucleoside in acyclovir (FLG shows in shades), the dicarboxylic acid is succinyl and Ri and R2 are vally protected with CBZ, but could, from the course be applicable in other variations of the formula him.

In each case the coupling conditions signify normal esterification conditions such as coupling reagents of DMAP, DCC, etc., or alternatively the conversion of the relevant carboxy function into an activated derivative such as the acid chloride or the activated succinic portion as well. they can comprise the anhydride. SCHEME 1A 2. Coupling conditions of N-CBZ-valine r 3. Hydrolysis of Ra In a variation of Scheme IA, the succinic anhydride is reacted directly with the nucleoside, thereby aiding the first protection and deprotection steps. A further alternative is to regioselectively esterify the glycerol portion with the portions of N-protected amino acids, generally in conjunction with the protection of the hydroxy function which the nucleoside intends to couple, followed by deprotection of the hydroxy and coupling of the nucleoside.

SCHEME II Stearoyl Cl 1 stearoyl Cl i C ^ C? ^ Pyridine CBzVal TrVa ali --O u - stearoyl estearoiilloo - O - ridine KMn04 / QBr 1 OsO¿? / Pi INaO " Bn esterification with FLG The ligatures where m and n are 1, Alk is alkylene or alkenylene and T is a ligation that can be prepared as shown in Scheme II above. Other permutations of m, n, Alk and various functions in the trifunctional ligature of the group Li of the formula Ha can be prepared analogously for the above with the corresponding starting materials, such as 1,2,4-trihydroxybutane (CA registration number 3968 -00-6), 3,4-dihydroxybutyanoic acid (1518-61-2 and 22329-74-4), (S) -3,4-dihydroxybutanoic acid (51267-44-8), (R) -3 acid , 4-dihydroxybutanoic (158800-76-1), 1, 2,5-pentanotriol (51064-73-4 and 14697-46-2), (S) -1,2,5-pentanotriol (13942-73-9) ), (R) -1, 2,5-pentanotriol (171335-70-9), 4,5-dihydroxypentanoic acid (66679-29-6 and 129725-14-0), 1,3,5-pentanotriol (4328-94-3) and 3- (2-hydroxyethyl) -1,5-pentanediol (53378-75-9). The preparation of each of these starting materials are described in the references for the respective registration number. Ohsawa et al., In Chem Pharm Bull 41 (11) 1906-1909 (1993) and Terao et al., Chem. Pharm. Bull. 39 (3) 823-825 (1991) describe the control of the stereochemistry of the ligature of trifunctional groups with lipase P. The amino acid derivative R2 and, if present, R ^ can be alternatively esterified in the ligature group with the methodology of 2-oxa-4-aza-cycloalkane-1,3-dione described in the international patent application no. WO 94/29311, the contents of which are incorporated herein by reference.

The ligation of the carboxy function of Ri and / or R2 in an amine group on the linked derivatives proceeds by conventional peptide chemistry, generally in conjunction with the protection of α-amine with conventional N-protecting groups. The formation of an amide linkage between a carboxyl function on the ligation and the a-amine group of R2 also proceeds by conventional peptide chemistry, generally in conjunction with the protection of a-carboxy function. The esterification of Ri as a fatty alcohol in the carboxy function on the ligation proceeds analogously, but inversely, in the previous esterification of R ^ as the fatty acid. BRIEF DESCRIPTION OF THE DRAWINGS Several aspects of the invention will now be described by the example form only with reference to the following Examples in the accompanying drawings in which; Figure 1 depicts viral serum DNA levels in ducks infected with DHBV treated and untreated as a function of time, as described in Biological Example 3; Figure 2 depicts the increase in weight in ducks infected with DHBV treated as a function of time, as described in Biological Example 3.

EXAMPLE 1 2- (Stearoyloxymethyl) -2- (N- (fluorenylmethoxycarbonyl) -L-valyloxymethiD-propionic acid To a solution of 2,2-bis (hydroxymethyl) propionic acid (28.16 g, 210 mmol) in water (50 ml), potassium hydroxide (11.78 g, 210 mmol) was added.After 5 minutes, the solution was evaporated in vacuo and the residue was co-evaporated with dry DMF for three times. DMF (500 mL) and benzyl bromide (3.57 mL, 30 mL) was added to the solution.After stirring for 30 minutes, the reaction mixture was filtered through Celite, poured into an aqueous solution of sodium hydrogen carbonate. The organic phase was recovered and then washed with aqueous sodium hydrogen carbonate solution, then evaporated in vacuo to give benzyl 2,2-bis (hydroxymethyl) propionate (4.37 g). 1 H-NMR (CDCl 3): 7.35 (s, 5H), 5.20 (d, 2H), 3.91-3.71 (m, 4H), 1.10 (s, 3H9. To a solution of 2,2-bis (hydroxymethyl) l) benzyl propionate (4.37 g, 19.5 mmol) in pyridine (58 ml) was added dropwise stearoyl chloride (4.13 g, 13.6 mmol) in dichloromethane for 40 minutes the reaction then maintained for 16 hours and then poured into aqueous sodium carbonate aqueous solution and extracted with dichloromethane. The organic phase was recovered and evaporated in vacuo. The benzyl-2- (hydroxymethyl) -2- (stearoyloxymethyl) propionate product was isolated by silica gel column chromatography (1.97 g). 1 H-NMR (CDCl 3): 7.34 (s, 5 H), 5.17 (d, 2 H 9, 4.28 (dd, 2 H), 3.69 (d, 2 H), 2.24 (t, 2 H), 1.57 (m, 2 H), 1.25 ( s, 28H, 1.22 (s, 3H), 0.87 (t, 3H) Benzyl-2- (hydroxymethyl) -2- (stearoyloxymethyl) propionate (1.86 g, 3.8 mmol) was dissolved in pyridine (30 ml). solution was added toluenesulfonic acid (73 mg, 0.39 mmol), N-fluorenylmethoxycarbonyl-L-valine (3.94 g, 11.6 mmol), and DCC 83.58 g, 17.4 mmol.) The reaction was maintained at 4 ° C for 16 hours and After it was filtered through Celite, the filtrates were poured into aqueous sodium hydrogen carbonate solution and extracted with dichloromethane, the organic phase was recovered and evaporated in vacuo The product, benzyl-2- (N-fluorenyl-methoxycarbonyl) ) -L-valyloxymethyl) -2- (stearoyloxymethyl) propionate, was isolated by column chromatography on silica gel. Yield: 2.38 g. H-NMR (CDCl 3): 7.78-7.25 (m, 13H), 5.29 (m, 1H), 5.15 (d, 2H), 4.28-4.23 (m, 7H), 2.19 (t, 2H), 2.10 (m, 1H), 1.55 (m, 2H), 1.24 (m, 3H), 0.94-0.83 (m, 9H). To the solution of benzyl 2- (N- (fluorenylmethoxycarbonyl) -L-valyloxymethyl) -2- (stearoyloxymethyl) propionate (1.86 g, 3.8 mmol) in a mixed solvent of THF / METANOL (16 ml / 8 ml) was added Ammonium formate (376 mg, 6 mmol), formic acid (1.87 ml) and palladium black (40 mg). The reaction was maintained at room temperature for 16 hours, and then filtered through Celite. After evaporation, the product was isolated by silica gel chromatography. Yield: 1.05 g.

EXAMPLE 2 1-O-stearoyl-2-O- (N-CBz-L-valyl) glycerol a) Preparation of 1-O-stearoylglycerol To a mixture of glycerol (30 g, 326 mmol) and pyridine ( 25 ml) dissolved in DMF (300 ml) was added dropwise stearoyl chloride (10 g, 33 mmol) dissolved in 100 ml of DMF. The mixture was cooled in an ice bath to complete the addition, where the reaction was maintained under an N2 atmosphere overnight. After 15 hours CH2CL2 (300 mL) was added and NaHCO3 (aq) was saturated. The phases were separated and the organic phase was washed with water (50 ml) and dried with Na 2 SO 4. The solvent and any pyridine were evaporated under vacuum. The crude product was chromatographed on a column of silica gel (CH2Cl2-MeOH, 20: 1) and recrystallized (CH2Cl2-ether) to give about 7 grams. b) Preparation of pixyl chloride Acetyl chloride (150 ml, 2.1 moles) was added in a magnetically stirred suspension of 9-hydroxy-9-phenylxanthene (20 g, 72 mmol) in benzene (100 ml). A homogeneous deep red solution was obtained. The solution was stirred for 30 minutes at 20 ° C. The volatiles were removed under reduced pressure. The excess AcCl were neutralized by careful addition of ethanol. The residue was co-evaporated with toluene (2 x 30 mL) with cyclohexane (2 x 30 mL) to obtain a crystalline residue that was hermetically stored. The pixyl chloride being alternatively available from Aldrich. c) Preparation of 1-O-stearoyl, 3-O-pixylglycerol The product of a) above (2.28 g) and pyridine (25 ml) were mixed and heated until dissolved. After cooling in ice bath pixyl chloride (1.92 g) from step b) was added. The mixture was kept under stirring and an argon atmosphere in an ice bath for half an hour and then at room temperature for 1.5 hours. The pyridine was evaporated under vacuum, the residue was dissolved in CH2Cl2 (70 ml) and washed with 0.5 M citric acid to remove the remaining pyridine. The residue was dried Na2SO4, evaporated and chromatographed (ether-hexane 1: 3) to give 1.25 g of pure product with a TLC R around 0.2. d) Preparation of 1-O-stearoyl, 2-O- (N-CBz-L-valyl), 3-O-pixylglycerol The product of step c) (237 mg, 0.39 mmol), CBz-L-valine (116 mg, 0.46 mmol), DCC 896 mg, 0.46 mmol) and DMAP (4.7 mg, 0.04 mmol) were dissolved in CH2Cl2 (4 mL). The mixture was kept under stirring under a nitrogen atmosphere overnight. For 18 hours the mixture was filtered through a glass filter and chromatographed on a column of silica gel (ether: hexane 1: 4) to give 230 mg with TLC Rf of 0.2. e) Preparation of 1-O-stearoyl-2-O- (N-CBz-L-valyl) glycerol The pixyl group in the product of step d) was removed by selective deprotection by the method described in Example 3, step d to give the title compound. 1 H-NMR (CDCl 3): d 7.35 (m, 5H), 5.3-4.9 (m, 4H), 4.35-4.25 (m, 3H), 3.8-3.6 (m, 2H), 2.31-2.25 (m, 2H) , 2.20-2.10 (m, 1H), 1.60 (m, 2H), 1.02-0.86 (m, 9H). EXAMPLE 3 1-O- (N-CBz-L-valin-2-O-stearoylglycerol a) Preparation of 1-O- (N-CBz-L-valyl) glycerol CBz-L-valine (4.35 g , 17.3 mmoles) in a fivefold excess of glycerol (8 ml, 86.9 mmol) together with dicyclohexylcarbodiimide (4.29 g, 20.8 mmol) and 4-dimethylaminopyridine (0.212 g) at room temperature. After stirring overnight, the suspension was filtered and DMF was removed in vacuo from the filtrate. The residue was redissolved in CH2CI2, washed successively with saturated NaHCO3, brine and water and then dried. The crude material was chromatographed on silica gel with 4/1 EtOAc-hexane as eluent to give 2.465 g. Rf (4/1 EtOAc-hexane) 0.17, (20/1 CH 2 Cl 2 -methanol) 0.12. b) Preparation of 1-O- (N-CBz-L-valil) -3-O-pixylglycerol The product of step a) (0.672 g, 20.1 mmol) was dissolved in dry pyridine (3.5 ml) under nitrogen, added 9-chloro-9-phenylxanthene (pixyl chloride, 0.65 g, 22.0 mmol, 1.1 eq -prepared as before) and the mixture was stirred at room temperature for 1.5 hours. MeOH (1.5 mL) was added and the mixture was partitioned between 10 mL of Et2O and 10 mL of saturated NaHCO3. The aqueous layer was extracted with more ether. The organic layers were combined, dried and concentrated several times with toluene to give a white solid. The crude material was chromatographed on silica gel with 3/1 hexane-EtOAc as eluent to give 0.681 g. Alternatively a pixyl group may be placed on the procedure described by Gaffney et al., Tetrahedron Lett 1997, 38, 2539-2542 using PxOH and acetic acid. c) Preparation of 1-O- (N-CBz-L-valyl) -2-O-stearoyl-3-O-pixyl glycerol. Stearoyl chloride (496 ml, 1.3 eq) in 1.5 ml of CH 2 Cl 2 was added dropwise to a solution of the product from step b) (0.658 g, 1.13 mmol) in 11 ml of pyridine with stirring under N 2 in an ice bath. After 15 minutes the mixture was stirred at room temperature overnight. The mixture was diluted with 20 ml of Et 2 O and washed with 10 ml of saturated NaHC 3. The aqueous layer was extracted with more Et2O. The organic layers were combined, washed with brine (20 mL), dried over Na2SO4 and concentrated several times with toluene. The crude material (1.37 g) was chromatographed on 130 g of silica gel with 6/1 hexane-EtOAc. An initial fraction of 500 ml was taken followed by 100 ml of fractions. The desired material was eluted in fractions 3-5 yield 0.748 g. d) Preparation of 1-O- (N-CBz-L-valyl) -2-O-stearoylglycerol To a solution of the product of step c) (0.748 g, 872 mmol) was dissolved in 35 ml of CH2Cl2 to form 0.025 M) was added pyrrole (16.5 mol eq) and dichloroacetic acid (5.5 mol eq) at room temperature. The CCD after 5 minutes showed complete reaction the mixture was diluted with 300 ml of CH2CI2 washed with 30 ml of saturated NaHCO3. The aqueous layer was extracted with more than CH2Cl2. The organic phases were combined, washed with brine (30 mL), dried over Na2SO and concentrated. The crude material was chromatographed on silica gel with 2/1 hexane-EtOAc (with 0.3% acetic acid) as eluent to give 0.363 g with Rf (2/1 hexane-EtOAc) 0.21. 1 H-NMR (CDCl 3): d ppm 0.86-0.99 (m, 9H), 1.25 (s, 28H), 1.61 (m, 2H), 2.16 (m, 1H), 2.32 (m, 2H); 3.74 (br s, 2H), 4.28-4.44 (m, 3H), 5.09 (m, 1H), 5.11 (s, 2H), 5.22 (d, 1H), 7.36 (m, 5H) EXAMPLE 4 1-O- stearoyl-3-O- (NCBz-L-valinolcerol) The product of Example 2, part a) (2.86 g, 7.99 mmol), DCC (0.9 g, 4.36 mmol) 4- (N, N-) was dissolved. dimethyl) aminopyridine (DMAP) (0.048 mg, 0.39 mmol) and N-CBz-L-valine (1 g, 3.98 mmol) in CH2Cl2 (60 mL) and DMF (6 mL). The reaction was maintained at room temperature for 18 hours and then filtered. The solvent was evaporated under reduced pressure. The residue was dissolved in CH2Cl2 (100 mL) and filtered. The crude title compound was purified by chromatography [SiO2, ether / hexane (1: 2)] to give 1.3 g of the desired product. 1-Unreacted stearoylglycerol was coated eluting with CH 2 Cl 2 / MeOH (20: 1). 1 H-NMR (CDCl 3): d 5.25 (d, 1H), 5.11 (s, 2H), 4.30-4.05 (m, 6H), 2.65 (d, 1H), 2.35 (t, 2H), 2.06 (m, 1H ), 1.62 (m, 2H), 1.26 (s, 28H), 1.00-0.84 (m, 9H). EXAMPLE 5 CBz-valilostearoyl To an ice-cooled solution of 1-chloroethyl chloroformate (1.89 g, 13.2 mmol) in CH 2 Cl 2 (5 mL), the compound of Example 4 in CH 2 Cl 2 (20 mL) was added followed by dry pyridine (1.2 mL, 29.6%). mmoles). The reaction mixture was stirred with cooling under an argon atmosphere to TLC (ether / hexane, 1: 2) indicating the consumption of the starting material. After 1.5 hours, the mixture was washed with water (3 x 5 mL). NaHCO3 saturated (5 mL) and dried (Na2SO4). Purification by chromatography [SiO2 (ether-hexane (1: 2)] to give the title compound (4.0 g). 1 H-NMR (CDCl 3): d 7.36-7.32 (m, 5H), 5.40 (m, 1H), 5.24 (m, 1H), 5.11 (s, 2H), 4.30 (m, 6H), 2.32 (m, 2H), 2.15 (m, 1H), 1.82 (m, 3H), 1.60 (m, 2H), 1.25 (br s, 28H), 0.97 (m, 3H), 0.86 (m, 6H) EXAMPLE 6 CBz-valilo stearoyl To a solution of the compound of Example 5 (3.4 g, 4.87 mmol) in dry acetonitrile (47 ml), sodium iodide (3.65 g, 24.3 mmol) was added. The obtained solution was heated to reflux under an argon atmosphere until NMR indicated the consumption of the starting material. After 4.5 hours, ether (50 ml) was added and the mixture was filtered. The solvent was removed by evaporation and the crude product was dissolved in ether 840 ml). The ether solution was washed with ether (2 x 10 mL) and dried (Na2SO) and evaporated under reduced pressure. Purification by chromatography [SiO2, ether-hexane (1.2)] to give the title compound (2.15 g). 1 H-NMR (CDCl 3): d 7.37 (m, 5 H), 6.75 (m, 1 H), 5.22 (m, 1 H), 5.15 (s, 1 H), 4.3 (m, 6 H), 2.32 (m, 1 H), 2.22 (m, 2H), 1.6 (m, 2H), 1.25 (s, 28H), 0.95 (m, 9H). EXAMPLE 7 O CH 3 O- O Ci CBz-valyo-o-stearoyl- or A solution of the compound of Example 3 (810 mg, 1.37 mmol) in 2.2 ml of dry dichloromethane was cooled in a wire bath with stirring under argon. 1-Chloroethyl chloroformate (298 μL, 2.74 mmol) was added, followed by dropwise addition of pyridine (665 μL, 8.22 mmol) in 2.5 mL of dichloromethane. After 2.5 hours, the mixture was diluted with 25 mL of dichloromethane and washed successively with 10 mL of water and 10 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated several times with toluene to give a yellow oil. Purification by flash column chromatography on silica gel with 40/1 dichloromethane-diethyl ether gave the title compound as an oil (96 mg, quantitative yield). 1 H-NMR (CDCl 3): d ppm 0.85-0.98 (m, 9H 9, 1.25 (s, 28H), 1.60 (m, 2H), 8.83 (d, 3H, J = 5.8 Hz), 2.17 (m, 1H9, 2.31 (t, 2H), 4.19-4.48 (m, 5H), 5.11 (s, 2H), 5.22 (d, 1H), 5.27 (m, 1H), 6.38-6.43 (m, 1H), 7.36 (m, 5H) EXAMPLE 8 CBz-Valyl Stearoyl A solution of the compound of Example 7 (1896 g, 2.71 mmol) and sodium iodide (1.80 g, 12.0 mmol) in acetonitrile (27 mL) was heated to reflux at 80 ° C under nitrogen. After 4.5 hours the reaction mixture was diluted with 100 mL 1/1 hexane-diethyl ether and washed with 25 mL of water. The aqueous phase was extracted with more solvent (25 mL). The organic phases were combined, washed successively with 5% aqueous sodium triosulfate solution (25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by flash column chromatography on silica gel with 80/1 dichloromethane-methane as eluent to give an oil (1.45 g) containing 90% of the title compound with 10% of the compound of Example 7. 1 H-NMR (CDCl 3): d ppm 0.85-0.99 (m, 9H), 1.25 (s, 28H), 1.6 (m, 2H), 2.17 (m, 1H), 2.23 (d, 3H, = 6Hz), 2.31 (t, 2H), 41.5-4.49 (m, 5H), 5.10 (s, 2H), 5.20-5.29 (m, 2H), 6.69-6.79 (m, 1H, 7.36 (m, 5H). EXAMPLE 9 4- Ben ci I oxy-2- (N-triti I- L-valil oxy 0-1 -stearoyl oxy oxybutan) Synthesis of diethyl-2- (2-benzyloxyethyl) malonate To a freshly prepared solution of sodium (0.95 g) , 41.4 mmol) in 50 ml of ethanol was added a solution of diethylmalonate (6.4 g, 40 mmol) in 10 ml of ethanol and the mixture was stirred for 15 minutes, then a solution of 2-benzyloxy-1-iodoethane (11.5 g. g, 41.35 mmole) was added dropwise. The mixture was refluxed for four hours and then evaporated in vacuo. 100 ml of water were added and the mixture was extracted three times with 50 ml portions of diethyl ether. The organic phase was dried with sodium sulfate and evaporated in vacuo and the product was isolated by silica gel column chromatography. Yield: 8: 6g 1 H-NMR (CDCl 3): 1.26 (m, 6H) 2.26 (m, 2H), 3.54 (m, 3H), 4.16 (m, 4H) 4.57 (s, 2H) 7.32 (m, 5H) . B) Synthesis of 4-benzyloxy-2-hydroxymethyl-butanol-1-. To a stirred suspension of lithium aluminum hydride (3.0 g, 80 mmol) in 100 ml of diethyl ether was added dropwise to a solution of diethyl-2- (2-benzyloxyethyl) malonate (8.5 g, 28.8 mmol) in 20 ml of diethyl ether at about 15 ° C. The mixture was refluxed for two hours. Approximately 4 ml of water were added by dripping while cooling. The mixture was filtered and washed with dioxane. The filtrate was evaporated under reduced pressure and the product was isolated by column chromatography on silica gel. Yield: 3.4 g. 1 H-NMR (CDCl 3): 1.60 (m, 2 H) 1.82 (m, 1 H) 3.00 (m, 2 H) 3.56 (t, 2 H) 3.69 (m, 4 H) 4.50 (s, 2 H) 7.32 (m, 5 H). c) Synthesis of 4-benzyloxy-2- (N-trityl-L-varyloxymethyl) -butanol-1 To a solution of N-trityl-L-valine (4.66 g, 13 mmol) and 4-benzyloxy-2-hydroxymethyl- butanol-1 (3.3 g, 15.6 mmol) in 50 ml of dichloromethane was added DCC (3.0 g, 14.5 mmol) and DMAP (0.18 g, 1.45 mmol) and the mixture was stirred for three days. The mixture was cooled to 5 ° C and the urethane was filtered. The solution was evaporated under reduced pressure and the product was isolated by column chromatography on silica gel. Yield: 2.5 g 1 H-NMR (CDCl 3): 1.00 (m, 6 H), 1.55 (m, 4 H), 1.72 (m, 1 H) 2.18 (m, 1 H) 2.70 (m, 1 H) 3.27 (m, 2 H) 3.43 (m, 3H) 3.50 (s, 2H) 7.26 (m, 20H). d) Synthesis of 4-benzyloxy-2- (N-trityl-L-valyloxymethyl) -1-stearoyloxybutane. To a solution of 4-benzyloxy-2- (N-trityl-L-valyloxymethyl) -butanol-1- (2.4 g, 4.35 mmol) in 50 ml of dichloromethane was added pyridine (1.72 g, 21.7 mmol). The solution was cooled to 10 ° C and a solution of stearoyl chloride (2.64 g, 8.7 mmol) in 10 ml of dichloromethane was added dropwise at 10 ° C to 15 ° C. The mixture was stirred overnight at room temperature, 100 ml of 55 sodium hydrogen carbonate solution was added and the mixture was stirred for 30 minutes. The organic phase was separated and the water phase was extracted twice with dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The product was isolated by column chromatography on silica gel. Performance: 3.0 g. H-NMR (CDCl 3): 0.98 (m, 9H) 1.26 (m, 28H) 1.54 (m, 2H) 1.94 (m, 1H), 2.25 (m, 2H) 3.23 (m, 2H) 3.44 (m, 2H) 3.58 (m, 1H) 3.91 (m, 2H9, 4.10 (m, 1H) 4.47 (s, 2H) 7.28 (m, 20H) EXAMPLE 10 5- (N-Trityl-L-vallyloxymethyl) - 6-stearoyloxyhexanoic a) Preparation of 2-allyl 1,3-propanediol Diethyl allyl malonate (20 ml, 101 mmol) in anhydrous ether was added dropwise to a stirred solution of lithium aluminum hydride (9.6 g, 2.53 mol) at 0 ° C. The reaction was warmed to room temperature and maintained for 5 hours. It was cooled below 0 ° C and water (12 ml) was added carefully by dripping.

After stirring for 30 minutes, the mixture was filtered through Celite and then washed with ethanol (2 x 400 mL). The solution was dried under vacuum giving 9.5 g of product. 1 H-NMR (CDCl 3): 5.78 (m, 1H), 5.03 (m, 2H), 3.78 (m, 2H), 3.69 (m, 2H9, 2.06 (t, 2H), 1.87 (m, 1H). b) Preparation of 1-O- (N-trityl-L-valyl) -2-allyl-1,3-propanediol To a solution of N-trityl-L-valine (5.5 g, 15.2 mmol), 2-allyl- 1,3-propanediol (4.4 g, 38 mmol), N, N-dimethylamino pyridine (183 mg, 1.5 mmol) in dichloromethane (120 ml) were added DCC (3.5 g, 16.7 mmol). The reaction was maintained under reflux overnight. After filtration through Celite, the organic phase was washed with aqueous sodium hydrogen carbonate solution and dried. Column chromatography on silica gel gave 4.6 g of the intermediate 1-O- (N-trityl-L-valyl) -2-allyl-1,3-propanoidol. c) Preparation of 1-O- (N-trityl-L-valyl) -2-allyl-3-stearoyl-1,3-propanediol. To a solution of 1-O- (N-trityl-L-valyl) -2-allyl-1,3-propanediol (1.83 g, 4 mmol) in dichloromethane (40 ml) and pyridine (3.2 ml, 40 mmol) a 0 ° C, stearoyl chloride (3.62 g, 12 mmol) in dichloromethane was added dropwise. The solution was warmed to room temperature and maintained for 3 hours. It was then washed with aqueous sodium hydrogen carbonate solution and dried. The product was isolated by column chromatography on silica gel. 1.9 g- 1 H-NMR (CDCl 3): 7.30 (m, 15H), 5.70 (m, 1H), 4.99 (m, 2H), 3.93 (m, 2H), 3.55 (m, 1H), 3.I27 (m, 2H), 2.68 (m, 1H), 2.30 ( m, 2H), 2.23 (m, 1H), 2.01 (m, 2H), 1.85 (m, 1H), 1.62 (M, 2H), 1.3 (m, 28H), 0.98 (dd, 6H), 091 (t , 3H). d) Preparation of 3- (N-trityl-L-vallyoxymethyl) -4-stearoyloxy-butyraldehyde. 1-O- (N-trityl-L-valyl) -2-allyl-3-stearoyl-1,3 was dissolved. -propanediol (580 mg, 0.8 mmol) in dioxane (5 ml). To the solution was added osmium tetraoxide (20 mg, 0.08 mmol) and pyridine (0.05 ml, 0.6 mmol). A solution of sodium periodate in water (3.5 ml) was added to the reaction mixture. The reaction was maintained overnight and thereafter cooled below 0 ° C. An acid solution of sodium hydrogen sulfide was added and the mixture was extracted with dichloromethane. The organic phase was dried and purified by column chromatography on silica gel. Yield 250 mg. 1 H-NMR (CDCl 3): 9.68 (s, 1H), 7.25 (m, 15H), 3.92 (m, 2H), 3.58 (m, 1H), 2.32 (m, 2H), 2.68 (m, 1H), 2.34 (m, 7H), 1.58 (m, 2H), 1.53 (m, 28H), 0.96 (dd, 6H), 0.86 (t, 3H). f) Preparation of benzyl 3- (N-trityl-L-valoxymethyl) -4-stearoyloxyhexen-2-oate To a solution of 3- (N-trityl-L-varyloxymethyl) -4-stearoyloxy-butyraldehyde (15.8 g, 21.8 mmoles) in cyclochloromethane was added triphenylphosphonium bromide (benzyloxycarbonylmethyl) (10.7 g, 21.8 mmoles) and triethylamine (2.21 g, 21.8 mmoles). The reaction was maintained overnight at room temperature, and the mixture was evaporated. To the residue was added diethyl ether (200 ml) and it was kept at 4 ° C for two hours, then it was filtered and the filtrate was evaporated and the product was purified by silica gel column chromatography Yield 10 g 1 H-NMR (CDCl 3 ): 7.30 (m, 20H), 6.89 (m, 1H), 5.88 (d, 1H), 5.19 (d, 2H), 3.95 (m, 2H), 3.57 (m, 1H), 3.29 (, 2H), 2.68 (m, 1H), 2.23 (m, 5H), 1.93 (m, 1H), 1.60 (m, 2H), 1.32 (m, 28 H), 0.95 (dd, 6H), 0.89 (t, 3H). g) Preparation of 3- (N-trityl-L-varyloxymethyl) -4-stearoyloxyhexanoate To a solution of benzyl 3- (N-trityl-L-valyloxymethyl) -4-stearylohexen-2-oate (70 mg, 0.08 mmol) ) in methanol (3 mL) and ethyl acetate (1 mL) was added sodium hydrogen carbonate (10 mg) and black palladium (20 mg). The reaction was maintained under hydrogen at atmospheric pressure for 2 hours. The mixture was filtered and evaporated. The residue was dissolved in dichloromethane and washed successively with aqueous EDTA solution and cold aqueous citrus solution. The organic phase was evaporated to give 61 mg of product. 1 H-NMR (CDCl 3): 7.30 (m, 15H), 3.93 (m, 2H), 3.57 (m, 1H), 3.25 (m, 2H), 2.30 (dt, 4H), 2.20 (m, 1H), 1.70 (m, 1H), 1.62 (m, 4H), 1.30 (m, 28H), 0.95 (dd, 6H), 0.87 (t, 3H). EXAMPLE 11 3- (N-Benzyloxycarbonyl-1-oxoxymethyl) -4-stearoyloxy-butyric acid a) Preparation of 1-O- (N-benzyloxycarbonyl-L-valyl) -2-ailyl-1,3-propanediol To a solution of 2-allyl-1,3-propanediol (4.6 g, 40 mmol) and N-benzyloxycarbonyl valine (5.02 g, 20 mmol) in dichloromethane was added dimethylaminopyridine (244 mg, 2 mmol) and DCC (4.5 g, 22 mmol). After two hours, the mixture was filtered through Celite, evaporated and the product, 1-O- (N-benzyloxycarbonyl-L-vallyl) -2-allyl-1,3-propanediol, isolated to give 5.01 g. 1 H-NMR (CDCl 3): 7.36 (m, 5H), 5.78 (m, 1H), 5.26 (d, 1H), 5.11 (s, 2H), 5.06 (d, 2H), 4.22 (m, 3H), 3.59 (m, 2H), 2.13 (m, 3H), 1.98 (m, 2H), 0.94 (dd, 6H9, b) Preparation of 1-O- (N-benzyloxycarbonyl-L-valyl) -2-allyl-3- O-stearoyl-1,3-propanediol. To a solution of 1-O- (N-benzyloxycarbonyl-L-valyl) -2-allyl-1,3-propanediol (4.46 g, 12.7 mmol) in dichloromethane (70 ml) and pyridine (6.1 ml, 76 mmol) in an ice bath was added stearoyl chloride /.8 g, 26 mmol). The reaction mixture was warmed to room temperature and maintained for 1 hour. It was then poured into aqueous sodium hydrogen carbonate solution, the organic phase was dried and the product 1-O- (N-benzyloxycarbonyl-L-valyl) -2-allylyl-3-O-stearoyl-1,3-propanediol was purified by silica gel column chromatography. 6.7 g. 1 H-NMR (CDCl 3): 7.34 (m, 5H), 5.77 (m, 1H), 5.30 (d, 1H), 5.11 (s, 2H9, 5.08 (d, 2H), 4.32 (m, 1H), 4.10 ( m, 4H), 2.29 (t, 2H), 2.13 (m, 4H), 1.62 (m, 3H), 1.25 (m, 28H), 0.90 (m, 9H) c) Preparation of 3- (N-) acid benzyloxycarbonyl-L-valyloxymethyl) -4-stearyloxybutyric acid. Potassium permanganate (756 mg, 4.8 mmol) was dissolved in water (7.5 ml). The solution was kept under vigorous stirring for 10 minutes. A solution of 1-O- (N-benzyloxycarbonyl-L-valyl) -2-allylyl-3-O-stearoyl-1,3-propanediol (1 g, 1.6 mmol) and tetrabutylammonium bromide (77 mg, 0.24 mmol) in benzene (5 ml) were added. The slurry was stirred for 1.5 hours and dichloromethane was added. An aqueous solution of sodium bisulfite was added to the slurry until the mixture was discolored. The organic phase was acidified with acetic acid and washed with water. After evaporation, the product of 3- (N-benzyloxycarbonyl-L-varyloxymethyl) -4-stearoyloxy-butyric acid (390 mg) was isolated by silica gel column chromatography. 1 H-NMR (CDCl 3): 7.33 (m, 5H), 5.38 (d, 1H), 5.11 (s, 2H), 4.14 (m, 5H), 2.6 (m, 1H), 2.45 (m, 2H), 2.29 (t, 2H), 2.28 (m, 1H), 1.58 (m, 2H), 1.25 (m, 28H), 0.90 (m, 9H). EXAMPLE 12 2 ', 3'-d'deoxy-3'-fluoro-5'-O- [5- (L-vallyoxymethyl) -6-steroyloxyhexanoin guanosine a) Preparation of 2', 3'-dideoxy -3'-Fluoro-5'-O- [5- (N-trityl-l-valoxymethyl) -6-stearoyloxyhexanoi I] guanosine To a solution of 5- (N-trityl-L-valyloxymethyl) -6-stearoyloxyhexanoic acid (462 mg, 0.6 mmol) and 2 ', 3'-dideoxy-3'-fluoroguanosine (340 mg, 1.25 mmol) in DMF (3 mL) was added dimethylaminopyridine (7 mg, 0.06 mmol) and DCC (136 mg, 0.66 mmoles). The reaction was maintained at room temperature overnight, and then at 40 ° C for two hours. The reaction mixture was filtered through Celite and poured into dichloromethane, and washed with sodium acid carbonate solution. The product 2 ', 3'-dideoxy-3'-fluoro-5'-O- [5-N-trityl-L-valyloxymethyl) -6-stearoyloxyhexanoyl] guanosine was isolated by silica gel column chromatography (93 mg ). 1 H-NMR (DMSO d 6): 7.88 (s, 1 H), 7.29 (m, 15 H), 6.52 (s, 2 H 9, 6.17 (dd, 1 H), 5.5 (m, 1 H), 4.35 (m, 1 H), 4.20. (m, 2H), 3.82 (m, 2H), 3.50 - 2.60 (m, 6H), 2.30 (m, 4H), 2.10 (m, 1H), 1.70 (m, 1H), 1.50 (m, 4H), 1.22 (m, 28 H), 0.85 (m, 9H) b) Preparation of 2 ', 3'-dideoxy-3'-fluoro-5'-O- [5- (L-vallyoxymethyl) -6- stearoyloxyhexanoyl] guanosine. The compound of step b) (90 mg, 0.088 mmol) was N-deprotected by treatment with 80% acetic acid (5 ml) at room temperature for 30 minutes. It was evaporated and the product was purified by column chromatography on silica gel to give 72 mg of the title compound. 1 H-NMR (DMSO d 6): 7.88 (s, 1 H), 6.54 (s, 2 H), 6.18 (dd, 1 H), 5.48 (d, 1 H), 4.27 (d t, 1 H), 4.19 (m, 2 H), 3.98 (m, 4H), 3.17 - 2.55 (m, 4H), 2.29 (m, 4H), 1.95 (m, 1H), 1.75 (m, 1H), 1.50 (m, 4H), 1.21 (m, 28H), 0.84 (m, 9H). EXAMPLE 13 2'-3'-Dideoxy-3'-fluoro-5 '- [3- (L-valyloxymethyl) -4-stearoyloxy-butanoylguanosine a) Preparation of 2', 3'-dideoxy-3'-fluoro-5 '-O- [3- (N-benzyl oxycarbon and I-L-valyloxy) -4-stearoyloxy-butanoyl] guanosine To a solution of 2', 3'-dideoxy-3'-fluoroguanosine (113 mg, 0.42 mmol) ) and 3- (N-benzyloxycarbonyl-L-varyloxymethyl) -4-stearyloxy-butyric acid (140 mg, 0.21 mmol) in DMF 82 mL) was added dimethylaminopyridine (3 mg, 0.02 mmol) and DCC (52 mg, 0.25). mmoles). After two days, dichloromethane (10 ml) and a few drops of acetic acid were added and the organic phase was filtered through Celite. The filtrate was washed with aqueous sodium hydrogen carbonate solution and the product 2 ', 3'-dideoxy-3'-fluoro-5'-O- [3-N-benzyloxycarbonyl-L-valyloxymethyl) -4-stearoyloxy- butanoyl] guanosine was isolated by column chromatography on silica gel to give 51 mg. H-NMR (CDCl 3): 7.79 (d, 1H), 7.26 (m, 5H), 6.38 (s, 2H), 6.23 (t, 1H), 5.44 (m, 2H), 5.08 (s, 2H), 4.5 -4.10 (m, 8H), 3.15-2.40 (m, 5H), 2.30 (t, 2H), 2.14 (m, 1H), 1.58 (m, 2H), 1.24 (m, 28H), 0.87 (m, 9H) ). b) Preparation of 2 ', 3'-dideoxy-3'-fluoro-5'-O- [3- (L-valyloxymethyl) -4-stearoyloxy-butanoi I] guanosine The product of step a) (76 mg, 0.084 mmoles) was dissolved in a mixed solvent of methanol (3 ml), ethyl acetate (0.5 ml) and acetic acid (0.01 ml). To the solution was added black palladium (10 mg), after 2 hours, 10 mg of additional black palladium was added. After 3 hours, the mixture was filtered and evaporated. The residue was dissolved in dichloromethane and washed with aqueous EDTA solution. The organic phase was dried and co-evaporated with toluene to give the title compound as the acetate salt. Yield 65 mg. 1 H-NMR (DMSO d-6 + D 2 O): 7.87 (s, 1 H), 5.16 (dd, 1 H), 5.37 (d, 1 H), 4.24 (m, 3 H), 4.01 (m, 4 H), 3.10-2.60 (m, 3H), 2.40 (m, 2H), 2.24 (t, 2H), 1.70 (m, 1H), 1.48 (m, 2H), 1.25 (m, 28H), 0.82 (m, 9H). EXAMPLE 14 Chloroformate 3-ri- (N-CBz-L-vall) -2-stearoyl) propyl 1- (N-CBz-L-valyl) -2-stearyl) glycerol (300 mg, 0.5 mmol) was dissolved. ) in 20% phosgene in toluene (15 ml). After 18 hours, the solution was evaporated and the residue co-evaporated with toluene for several times, giving the title product as a quantitative yield. This product forms a carbonate with a nucleoside bank using normal methodology. For example, reacting the DMF / pyridine 10.1 solution at 0 ° C for 3 to 24 hours. Pour into the NaHCO3 solution and extract with dichloromethane. The amino acid was deprotected, for example with black palladium in a solution of methanol, ethyl acetate, acetic acid solution to give the nucleoside-O- [1- (L-valyl) -2-stearoyl-3-propyloxy carbonyl] 1H -NMR (CDCl 3): 7.40 (m, 5H9, 5.28 (m, 2H), 5.10 (s, 2H), 4.35 (m, 5H9, 2.35 (m, 2H9, 2.17 (m, 1H), 1.56 (m, 2H ), 2.130 (m, 28H), 0.95 (m, 9H) EXAMPLE 15 5- (N-FMOC-L-valyloxy) -4-steroyloxy-pentane-a) 4,5-dihydroxy-2 acid benzylpentenoate A mixture of DL-glycerin-dehydro (4.5 g, 50 mmol) and (benzyloxycarbonyl) triphenyl-phosphonium bromide (24.57 g, 50 mmol) in 100 ml of 1,3-epoxybutane was heated to reflux overnight. The mixture was evaporated under vacuum and the product was isolated by silica gel column chromatography Yield: 8g = 71%. 1 H-NMR (CDCl 3): 2.50 (s, 1 H) 2.96 (s, 1 H) 3.54 (m, 1 H) 3.70 (m, 1 H) 4.38 (m, 1 H) 5.12 (s, 2 H) 6.14 (m, 1 H), 6.90 (m, 1H) 7.30 (m, 5H) b) 5- (N-FMOC-L-valyloxy) -4-hydroxy-2-pentenoate of benzyl. A mixture of benzyl 4,5-dihydroxy-2-pentenoate (4.4 g, 20 mmol), N-FMOC-L-valine (5.8 g, 17 mmol) and DMAP (0.21 g, 1.7 mmol) in 100 ml of dichloromethane it was cooled to approximately 10 ° C. A solution of DCC 84.2 g, 20 mmol) in 25 ml of dichloromethane was added dropwise at the same temperature and the mixture was stirred overnight at room temperature. The mixture was cooled to 5 ° C and the urethane was filtered. The filtrate was evaporated under reduced pressure and the product was isolated by column chromatography on silica gel. Yield: 6.6 g = 71%. 1 H-NMR (CDCl 3): 0.91 (m, 6 H) 2.12 (m, 1 H) 4.38 (m, 5 H) 5.14 (s, 2 H) 5.24 (m, 1 H) 6.20 (m, 1 H) 6.92 (m, 1 H) 7.30 (m 13H) c) Benzyl-5- (N-FMOC-L-valyloxy) -4-stearoyloxy-2-pentenoate To a solution of benzyl-5- (N-FMOC-L-valyloxy) -4-hydroxy- 2-pentenoate (6.5 g, 12 mmol) and pyridine (2.0 g, 25 mmol) in 100 ml of dichloromethane at 10 ° C was added dropwise a solution of stearoyl chloride (4.55 g, 15 mmol) in 25 ml of dichloromethane. The mixture was stirred overnight. 100 ml of 5% sodium hydrogen carbonate solution was added and the mixture was stirred for 30 minutes. The organic phase was separated and the water phase was extracted twice with dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The product was isolated by column chromatography on silica gel.

Performance: 7.8g = 80%. 1 H-NMR (CDCl 3): 0.88 (m, 9 H), 1.25 (m, 28 H), 1.58 (m, 2 H) 2.14 (m, 1H) 2.32 (m, 2H), 4.22 (m, 5H) 5.19 (2, 2H) 5.24 (m, 1H) 6.12 (m, 1H) 6.85 (m, 1H) 7.35 (m, 13H). d) 5- (N-FMOC-L-valyloxy) -4-stearoyloxy-pentanoic acid. A solution of benzyl-5- (N-FMOC-L-valyloxy) -4-stearoyloxy-2-pentenoate (3.8 g, 4.69 mmol) in 50 ml of ethyl acetate is hydrogenated with 10% palladium on charcoal (0.05). g) at normal pressure for 5 hours at room temperature. The catalyst was filtered and washed with ethyl acetate and 1,4-dioxane. The solution was evaporated under reduced pressure. Yield: 3.3 g = 995. 1 H NMR (CDCl 3): 0.92 (m, 9 H) 1.25 (m, 28 H) 1.54 (m, 2 H) 1.98 (m, 2H) 2.18 (m, 1H) 2.28 (m, 2H) 2.41 (m, 2H) 4.32 (m, 5H) 5.13 (m, 1H) 5.33 (m, 1H) 7.50 (m, 8H) EXAMPLE 16 Acid 3- ( N-FMOC-L-valyloxy) -2-stearoyloxypropionic a) Benzyl 2,3-dihydroxypropionate. A mixture of D, L-glyceric acid, calcium salt dihydrate (2.9 g, 10 mmol) and benzyl bromide (3.8 g, 22 mmol) in 25 mL of DMF was stirred at 60 ° C overnight. The mixture was evaporated under reduced pressure and the product was isolated by silica gel chromatography. Performance: 4g = 100%. 1 H-NMR (CDCl 3): 3.26 (s, 1 H) 3.90 (m, 2 H) 4.32 (m, 1 H) 5.25 (s, 2 H) 7.28 (m, 5 H) b) Benzyl 3- (N-FMOC-L-valyloxy) ) -2-hydroxypropionate A solution of benzyl-2,3-dihydroxypropionate (4.0 g, 20 mmol) N-FMOC-L-valine (5.4 g, 16 mmol) and DMAP (0.2 g, 1.6 mmol) in 80 ml of dichloromethane it was cooled to approximately 10 ° C. A solution of DCC (4.12 g, 20 mmol) in 25 ml was added dropwise at the same temperature and the mixture was stirred overnight at room temperature. The mixture was cooled to 5 ° C and the urethane was filtered. The solution was evaporated under reduced pressure and the product was isolated by silica gel chromatography. Yield: 4.7 g = 45%. 1 H-NMR (CDCl 3): 0.88 (m, 6H) 2.05 (m, 1H) 4.40 (m, 6H) 5.23 (m, 3H) 7.50 (m, 13H) c) Benzyl 3- (N-FMOC-L-valyloxy) ) -2-stearoyloxypropionate. To a stirred solution of benzyl 3- (N-FMOC-L-valyloxy) -2-hydroxypropionate (4.6 g, 8.89 mmol) and pyridine (1.41 g, 17.8 mmol) in 80 ml of dichloromethane was added dropwise a solution of Stearoyl chloride (3.64 g, 12 mmol) in 20 ml of dichloromethane and the mixture was stirred overnight at room temperature. 100 ml of 5% sodium hydrogen carbonate solution was added and the mixture was stirred for 30 minutes. The organic phase was separated and the water phase was extracted twice with dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The product was isolated by silica gel chromatography. Yield: 6.1 g = 87%. 1 H-NMR (CDCl 3): 0.88 (m, 9 H) 1.26 (m, 28 H) 1.56 (m, 2 H) 2.06 (m, 1 H) 2.34 (m, 2 H) 4.36 (m, 6 H) 5.19 (s, 2 H) 5.32 (m, 1H) 7.50 (m, 13H) d) 3- (N-FMOC-L-valyloxy) -2-stearoyloxypropionic acid. A solution of benzyl 3- (N-FMOC-L-valyloxy) -2-stearoyloxypropionate (0.78 g, 1 mmol) in 20 ml of ethyl acetate was hydrogenated with 10% palladium on charcoal (0.2 g) under pressure normal for three hours at room temperature. The catalyst was filtered and washed with ethyl acetate and 1,4-dioxane. The solution was evaporated under reduced pressure. Yield: 0.63 g = 90% 1 H-NMR (CDCl 3): 0.88 (m, 9 H) 1.24 (m, 28 H) 1.40 (m, 2 H) 2.12 (m, 3 H) 4.30 (m, 5 H) 5.15 (m, 1 H ) 5.60 (m, 1H) 7.40 (m, 8H) EXAMPLE 17 1- (N-Benzyloxycarbonyl-L-valyloxymethyl) -2-stearoyloxyethoxycarbonyl chloride Bis (triclomethyl) carbonate (160 mg, 0.54 mmole) was added with stirring a solution of 1- (N-benzyloxycarbonyl-L-valyl) -3-steroylglycerol; 1- (N-benzyloxycarbonyl-L-valyloxy) -3-steroyloxy-2-propanol; preparative example 4; (660 mg, 1.12 mmol) and triethylamine (200 mg, 2.0 mmol) in dichloromethane (5 ml) at room temperature. After 1 hour, n-hexane (10 ml) was added and the triethylamine hydrochloride precipitated was filtered from a short column of silica gel, the product was eluted with an additional amount of n-hexane and the solvent was evaporated to a vacuum to give 650 mg (89%) of the title compound. 1 H-NMR (CDCl362.975 MHz): d 172.8 (stear-COO); 171.2 (val-COO); 155. 9 (CONH); 154.1 (COCÍ); 136.0 (Ph-CI-Val); 128-1-127.7 (Ph); 67.2 (CHOH); 66.7 (Ph CH2); 63.1 (ValCOOCH2); 61.8 (stear- COOCH2); 58.7 (val-aC); 33.7 (stear-C2); 31.6 (stear-C16); 31.0 (Val-ßC); 29.3-28.8 (stear-C4-15); 24.5 (stear-C3); 18.6 and 17.1 (Val2CH3); 13.8 (stear-C18). EXAMPLE 18 3- (N-CBz-L-valyloxymethyl-p-4-stearoyloxybutylchloroformate a) 3- (N-CBz-L-valyloxymethyl) -4-stearoyloxy-butanol. To a stirred solution of 4-stearoyloxy-3- (N-CBz-L-valyloxymethylbutyraldehyde (prepared analogously for preparative example 6, step d) using Cbz protected with valine) (2.0 g, 3.2 mmole) in 25 ml of methanol a 10 ° C sodium hydrochloride was added (0.6 g, 16 mmol) in small portions. The mixture was stirred for 30 minutes and then acidified with acetic acid. The mixture was diluted with water and extracted three times with dichloromethane.

The organic phase was dried with sodium sulfate and concentrated in vacuo. The product was isolated by column chromatography on silica gel. Performance. 1.5 g = 75%. 1 H NMR (CDCl 3): 0.88 (m, 9 H) 1.25 (m, 28 H) 1.52 (m, 4 H) 2.24 (m, 3H) 3.68 (m, 2H) 4.12 (m, 4H) 4.24 (m, 1H) 5.08 (s, 2H) 5.22 (m, 1H) 7. 36 (m, 5H) b) 3- (N-CBz-L-valyloxymethyl) -4-stearoyloxybutyl chloroformate A solution of the intermediate from step a) in 20 ml of a 20% solution of phosgene in toluene was stirred during night. The mixture was evaporated under reduced pressure to give the title compound. Performance: 1.5g = 97%. 1 H-NMR (CDCl 3): 0.88 (m, 9 H) 1.28 (m, 28 H) 1.58 (m, 2 H) 1.72 (m, 2 H) 2.15 (m, 1 H) 2.31 (m, 2 H) 4.08 - 4.42 (m, 5 H ) 5.10 (s, 2H) 5.22 (m, 1H) 7.36 (m, 5H) EXAMPLE 19 2 ', 3'-dideoxy-3'-fluoro-5'-O- [3- (L-valyloxy) -2- stearoyloxy-propyl carbonyljuanosine a) Synthesis of 2 \ 3'-dideoxy-3'-fluoro-5'-O- [3- (N-CBz-L-valyloxy) -2-stearoyloxy-3-propyloxycarbonyljuanosine. To a solution of 2 ', 3'-dideoxy-3'-fluoro-guanosine (270 mg, 1 mmol) in DMF (10 mL) and pyridine (1 mL) was added 3-chloroformate. { 1- (N-CBz-L-valyl) -2-stearoyl} propyl (619 mg, 0.5 mmol) at 0 ° C. After 3 hours, the reaction mixture was poured into sodium acid carbonate solution and extracted with dichloromethane. The organic phase was dried under vacuum, and 2 ', 3'-dideoxy-3'-fluoro-5'-O- [1- (N-CBz-L-valyloxy) -2-stearoyloxy-3-propyloxycarbonyljuanosine was isolated by column chromatography on silica gel (195 mg). 1 H-NMR (CDCl 3): 7.69 (s, 1 H), 7.31 (m, 5 H), 6.50 (m, 2 H), 6.32 (m, 1 H), 5.3 (m, 2 H), 5.09 (m, 2 H), 4.35 (m, 7H), 2.60 (m, 2H); 2.31 (t, 2H), 2.20 (m, 1H), 1.58 (m, 2H), 1.23 (m, 28H), 0.92 (m, 9H) b) Synthesis of 2 ', 3'-dideoxy-3'-fluoro-5'-O- [1- ( L-valyloxy) -2-stearoyloxy-propyloxycarbonyl] guanosine 2 ', 3'-dideoxy-3'-fluoro-5'-O- [31- (N-CBz-L-valyloxy) -2-stearoyloxy- was dissolved. 3-propyloxycarbonyl] guanosine (190 mg), was dissolved in a mixed solvent of methanol (6 ml), ethyl acetate (2 ml) and acetic acid (1 ml). Black palladium (30 mg) was added to the solution and the reaction mixture was kept under hydrogen for 2 hours. It was then filtered and the filtrate was evaporated and the title product isolated by column of silica gel. 110 mg. 1 H-NMR (DMSO d 6): 7.86 (d s, 1 H), 6.51 (s, 2 H), 6.17 (dd, 1 H), 5.48 (m, 1 H), 5.20 (m, 1 H), 4.25 (m, 7 H), 2.70 (m, 2H), 2.27 (m, 2H), 1.72 (m, 1H), 1.47 (m, 2H), 1.22 (m, 28H), 0.84 (m, 9H). EXAMPLE 20 2 ', 3'-dideoxy-3'-fluoro-5'-O-r5- (L-valloxy) -4-stearoyloxy-butanoyl-1-guanosine To a solution of 2', 3'-dideoxy-3 '-fluoroguanosine (0.27 g, 1 mmol) and 5- (N-FMOC-L-valyloxy) -4-stearoyloxypentanoic acid (0.94 g, 1.3 mmol) in 30 ml of DMF was added DMAP (16 mg, 0.13 mmol) HOBT (0.176 g, 1.3 mmol) and DCC (0.248 g, 1.2 mmol). The mixture was stirred for three days at room temperature. 4g of silica gel was added and the mixture was evaporated in vacuo. The product 2 ', 3'-dideoxy-3'-fluoro-5'-O- [5- (FMOC-L-valyloxy) -4-stearoyloxy-pentanoyl] guanosine was separated by silica gel chromatography. Yield: 0.45 g. 1 H-NMR (DMSOd-6) 0.88 (m, 9 H) 1.20 (m, 28 H) 1.45 (m, 2 H) 1.78 (m, 2 H) 2.18 (m, 2 H) 2.36 (m, 1 H) 2.62 (m, 2 H) 3.88 (m, 1H) 4.22 (m, 6H) 4.92 (m, 1H) 5.45 (m, 1H) 6.19 (m, 1H) 6.42 (s, 2H) 7.26-7.88 (m, 8H) The protected intermediate is deprotected as shown above to give the title compound. EXAMPLE 20 2 ', 3'-dideoxy-3'-fluoro-5'-O- [3- (N-FMOC-L-valyloxy) -2-stearoyloxypropanoyl] guanosine To a mixture of 3- (N-FMOC) acids -L-valyloxy) -2-staroyloxypropanoic acid (0.61 g, 0.88 mmole) in 5 ml of dry diethylether over one drop of DMF and thionyl chloride (0.52 g, 4.4 mmol). The mixture was refluxed for two hours and then evaporated under reduced pressure. The product was dissolved in dry dichloromethane and added dropwise to a solution of 2 ', 3'-dideoxy-3'-fluoroguanosine (0.215 g, 0.8 mmole) and pyridine (0.35 g, 4.4 mmole) in 20 ml of DMF. The solution was stirred overnight.

Two lumps of silica gel were added and the mixture was evaporated in vacuo. The product was isolated by silica gel chromatography.

Yield: 0.19 g = 25% 1 H-NMR (CDCl 3): 0.88 (m, 9 H) 1.25 (m, 28 H) 1.62 (m, 2 H) 2.12 (m, 1 H) 2.38 (m, 2 H) 2.58 (m, 2 H) 4.12-4-76 (m, 6H) 5.32 (m, 2H) 6.12 (m, 1H) 6.26 (m, 1H) 6.44 (m, 1H) 7.12-7.78 (m, 8H). EXAMPLE 21 monoster of 1- (N-CBz-L-val03-stearoyl-2-propyl succinate 1- (N-CBz-L-valyl) -3-stearoyl-glycerol (86 mg, 1.5 mmol) was dissolved and Succinic anhydride (450 mg, 4.5 mmol) was dissolved in a mixed solvent of DMF (15 ml) and pyridine (1 ml) The reaction was maintained at room temperature for 3 hours, and then at 60 ° C for 5 hours. The reaction mixture was poured into a solution of acetic acid and the water and extracted with dichloromethane.The organic phase was washed with water and evaporated, and the product was isolated by column chromatography on silica gel to give 900 mg. -NRM (CDCI3): d 7.43 (m, 5H), 5.27 (m, 1H), 5.09 (m, 2H), 4.21 (m, 5H), 2.54 (m, 4H), 2.29 (t, 2H), 2.13 (m, 1H), 1.59 (m, 2H), 1.25 (m, 28 H), 0.90 (m, 9H) EXAMPLE 22 2 ', 3, -dideoxy-3'-fluoro-5'-O-. { 3- [1- (L-valyloxy) -3-stearoyloxy-2-propyloxycarbonyl] -propanoyl.} Guanosine To a solution of 2 ', 3'-dideoxy-3'-fluoro-guanosine (351 mg, 1.3 mmoles) and monoester of 1- (N-CBz) -L-valyl) -3-stearoyl-2-propyl succinate (900 mg, 1.3 mmol) in DMF (15 mL) was added dimethylaminopyridine (24 mg, 0.2 mmol), 1-hydroxybenzotriazole (175 mg, 1.3 mmol), DCC (321 mg, 1.56 mmol). After 48 hours, the reaction mixture was filtered. The filtrate was poured into sodium hydrogen carbonate solution and extracted with dichloromethane. The product 2 ', 3'-dideoxy-3'-fluoro-5'-O-. { 3- [1- (N-CBz-L-valyl) -3-stearoyl glyceroloxy carbonyl] propanoyl} guanosine were isolated by silica gel column chromatography. 780 mg 1 H-NMR (DMSO-d 6): 7.89 (s, 1 H), 7.34 (m, 5 H), 6.50 (s, 2 H), 6.17 (dd, 1 H), 5.46 (m, 1 H), 5.38 (m, 1H), 5.02 (s, 2H), 4.22 (m, 7H), 3.32 (s, 4H), 280 (m, 2H), 2.57 (m, 2H), 2.31 (t, 2H), 2.05 (m, 1H) ), 1.48 (m, 2H), 1.21 (m, 28H) 0.84 (m, 9H). To the solution of 2 ', 3'-dideoxy-3'-fluoro-5'-O-. { 3- [1- (N-CBz-L-valyl) -3-stearoyl-2-propyloxycarbonyl] propanoyl} guanosine (460 mg, 0.5 mmol) in a mixed solvent of methanol (10 mL), ethyl acetate (3 mL) and acetic acid (2 mL) was added black palladium (50 mg). After the reaction under a hydrogen atmosphere for 2 hours, the mixture was filtered and the filtrate was dried. The title product was isolated by column chromatography on silica gel. 360 mg. 1 H-NMR (DMSO-d 6): 7.89 (s, 1 H), 6.41 (s, 2 H), 6.16 (dd, 1 H), 5.48 (m, 1 H), 5.17 (m, 1 H), 4.28 (m, 7 H) , 2.90 (m, 2H9, 2.58 (m, 4H), 2.28 (t, 2H), 1.85 (m, 1H), 1.49 (m, 2H), 1.22 (m, 28H), 0.85 (m, 9H). 2. 3 Bz A solution of stearoyl chloride (12.1 g, 40 mmol, 10.0 eq) in CH2Cl2 (100 ml) was added slowly (1 hour) to a solution of 2,2-bis (hydroxymethyl) propionic acid (26.8 g, 200 mmol, 5.0 eq) in pyridine (400 ml) at room temperature. The reaction mixture was stirred at room temperature overnight and then concentrated (100 ml) under vacuum. The reaction mixture was treated slowly with saturated NaHC 3 (400 mL) and then extracted with CH 2 Cl 2 (3 x 300 mL). The organic layers were combined, washed with brine, dried over Na2SO and concentrated in vacuo. The crude material was chromatographed on silica gel (500 g) with 19/1 to 4/1 CH2Cl2-MeOH as eluent, to give the mono-stearoyl ester, Rf (9/1 CH2Cl2-MeOH) 0.33. 12.5 g (78%). A solution at 0 ° C of N-CBz-L-valine (18.85 g, 75 mmol, 2.4 eq) and DMAP (855 mg, 7 mmol, 0.22 eq) in CH2Cl2 (800 ml) was cooled and treated with DCC ( 14.4 g, 70 mmol, 2.2 eq). The reaction mixture was stirred at room temperature for 30 minutes and then treated slowly (1 hour) with a solution of the above monostearoyl ester (12.5 g, 31.2 mmoles, 1 eq) in CHCl3 (200 ml, ethanol free). After stirring overnight the suspension was filtered and the filtrate was washed with brine, dried with Na2SO and concentrated in vacuo. The crude material was chromatographed on silica gel 8500 g with 19/1 to 4/1 CH2Cl2-MeOH as eluent, to give the diester described above, Rf (9/1 CH2Cl2-MeOH) 0.46. 13.8 g (70%). 1 H-NMR (250 MHz, CDCl 3): d 7.35-7.3 (m, 5H, ArH), 5.32 (d, 1h, cH), 5.10 (s, 2H, CH2PH), 4.33-4.18 (m, 4H, CH2) , 2.28 (t, 2H, CH2), 2.22-2.05 (m, 1H, CH), 1.64-1.50 (m, 2H, CH2) 1.35-1.15 (m, 31H), 1.00-0.82 (m, 9H, Me) . EXAMPLE 24 2,3'-Dideoxy-3'-fluoro-5'-O-5 - (L-valyloxy) -4-stearoyloxy-pentanoyl-guanosine a) Synthesis of 2,3'-dideoxy-3'-fluoro- 5'-O- [5- (N-FMOC-L-valyloxy) -4-stearoyloxy-pentanoyl] guanosine A d 2 ', 3'-dideoxy-3'-3'-fluoroguanosine mixture (269 mg, 1.0 mmol) , 5- (N-FMOC-L-valyloxy) -4-stearoyloxy-pentanoic acid (940 mg, 1.3 mmol), DMAP (16 mg, 0.13 mmol) and HOBT (176 mg, 1.3 mmol) were co-evaporated twice with DMF and reduced to approximately 30 ml. DCC 8248 mg, 1.2 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was filtered and the solution was evaporated under reduced pressure. Ethyl acetate (50 ml) was added and the organic phase was washed twice with 5% acetic acid. With 5% sodium carbonate acid and water. The organic phase is dried with sodium sulphate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel. Yield: 450 mg. 1 H-NMR (DMSO d-6) 0.88 (m, 9 H) 1.22 (m, 28 H) 1.45 (m, 2 H) 1.83 (m, 2 H) 2.21 (m, 2 H 2.37 (m, 1 H) 3.90 (m, 1 H) 5.36-5.58 (m, 1H) 6.18 (m, 1H) 6.50 (s, 2H) 7.28-7.91 (m, 10H) b) Synthesis of 2,3'-dideoxy-3'-fluoro-5'-O- [5- (L-valyloxy) -4-stearoyloxy-pentanoi I] guanosine. A mixture of 2,3'-dideoxy-3'-fluoro-5'-O- [5- (N-CBZ-L-valyloxy) -4-stearoyloxy-pentanoyl] guanosine (300 mg, 0.308 mmol) in 5 ml of NN-diisopropylethylamine and 5 ml of DMF was stirred for three days at room temperature. Acetic acid (5 ml) was added and the mixture was evaporated under reduced pressure. The product was isolated as the acetate salt by column chromatography on silica gel.

Yield: 90 mg. 1 H-NMR (DMSO d-6) 0.88 (m, 9 H) 1.24 (m, 28 H) 1.55 (m, 2 H) 1.91 (m, 2H) 2.31 (m, 2H) 2.44 (m, 1H) 2.56-3.08 (m, 2H) 3.15 (m, 1H) 4.00-4.49 (m, 5H) 5.08 (m, 1H) 5.40-5.62 (m , 1H) 6.24 (m, 1H) 6.54 (s, 2H) 7.96 (s, 1H) EXAMPLE 25 2,3'-d-Deoxy-3'-fluoro-5'-O-r3- (L-valyloxy) -2-stearoyloxy-propanol1 guanosine a) Synthesis of 2,3'-dideoxy-3'-fluoro-5'-O- [5- (N-CBZ-L-valyloxy) -2-stearoyloxy-propanoyljuanosine A mixture of 2 ', 3'-dideoxy-3'-fluoroguanosine (404 mg, 1.5 mmol), 3- (N-CBZ-L-valyloxy) -2-stearoyloxy-propanic acid (1.06 g, 1.76 mmol), DMAP (24 mg, 0.2 mmol) and HOBT (264 mg, 1.82 mmol) it was co-evaporated twice with DMF and reduced to approximately 30 ml. DCC (372 mg, 1.8 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was filtered and the solution was evaporated under reduced pressure. Ethyl acetate (50 ml) was added and the organic phase was washed twice with 5% acetic acid, with 5% sodium hydrogen carbonate and with water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel. Yield: 0.73 g. 1 H-NMR (DMSO d-6) 0.81 (m, 9 H) 1.22 (m, 28 H) 1.48 (m, 2 H) 2.31 (m, 2 H) 2.50-3.00 (m, 2 H) 3.91 (m, 1 H) 4.18-4.52 (m, 5H) 5.00 (s, 2H) 5.30-5.61 (m, 2H) 6.16 (m, 1H) 6.50 (s, 2H) 7.32 (m, 5H) 7.71 (m, 1H) 7.92 (s, 1H) 10.18 (s, 1H) b) Synthesis of 2,3'-dideoxy-3'-fluoro-5'-O- [3- (L-valyloxy) -2-stearoyl oxypropane and I] guanosine A solution of 2,3'-dideoxy-3'-fluoro-5'-O- [3- (N-CBZ-L-valyloxy) -2-stearoyloxy-propanoyl] guanosine (350 mg, 0.4 mmol) in ethyl acetate ( mi), methanol (5 ml) and acetic acid (5 ml) with black palladium (300 mg) at normal pressure for three hours. The catalyst was filtered and washed with ethyl acetate and methanol. The solution was evaporated under reduced pressure and the product was isolated as the acetate salt by column chromatography. Yield: 120 mg. 1 H-NMR (DMSO d-6) 0.84 (m, 9 H) 1.22 (m, 28 H) 1.50 (m, 2 H) 2.32 (m, 2 H) 2.50-3.00 (m, 2 H) 3.07 (m, 1 H) 4.21-4.59 (m, 5H) 5.38-5.59 (m, 2H) 6.17 (m, 1H) 6.0 (s, 2H) 7.90 (s, 1H) EXAMPLE 26 2,3'-dideoxy-3'-fluoro-5'-O- 3,3-bis- (L-valyloxymethyl) -propionic acid guanosine a) Synthesis of 4,4-bis (N-CBZ-L-valyloxymethyl) -but-1-ene. To a solution of 2-allyl-1,3-propanediol (2.32 g, 20 mmol), N-CBZ-L-valine (10.06g, 40 mmol) and DMPA (0.488 g, 4 mmol) in 120 ml of dichloromethane was added DCC (9.08 g, 44 mmol) in portions and the mixture was stirred overnight room temperature. The mixture was cooled to 5 ° C and the urethane was filtered. The filtrate was evaporated and the product isolated by silica gel column chromatography. Yield: 9.0 g H-NMR (CDCb) 0.89 (m, 12H) 5.11 (s, 2H) 5.73 (m, 1H) b) Synthesis of 3,3-bis (N-CBZ-L-valoyloxymethyl) -propionic acid. to a cooled solution of 4,4-bis (N-CBZ-L-valyloxymethyl) -but-1-ene (14.6 g, 25 mmol) and tetrabutylammonium bromide (1.3 g, 4 mmol) in 120 ml of benzene were added 100 ml of water. Under vigorous stirring potassium permanganate (15.8 g, 100 mmol) was added in portions and the mixture was stirred for 2 hours at 15 ° C to 20 ° C. An aqueous solution of sodium bisulfite was added to a slurry until the mixture became discolored. The mixture was acidified with 2N hydrochloric acid and extracted four times with ethyl acetate. The organic phase was washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel. Performance: 7.5 9- 1 H-NMR (CDCl 3) 0.89 (m, 12 H) 2.05 (m, 2 H) 2.46 (m, 2 H) 2.62 (m, 1H) 4.20 (m, 6H) 5.11 (s, 4H) 5.30 (m, 2H) 7.35 (m, 10H) c) Synthesis of 2,3'-dideoxy-3'-fluoro-5'-O- [3, 3-bis- (L-valyloxymethyl) -propionyl] guanosine A solution of 2 ', 3'-dideoxy-3'-fluoroguanosine (1.35 g, 5 mmol), 3,3-bis acid (N-CBZ) was co-evaporated. -L-valyloxymethyl) (3.6 g, 6 mmol), DMAP (0.061 g, 0.05 mmol) and HOBT (0.81 g, 6 mmol) twice with DMF and reduced to approximately 120 ml. DCC (1.24 g, 6 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was filtered and the solution was evaporated at room temperature. The mixture was filtered and the solution evaporated under reduced pressure. Ethyl acetate (200 ml) was added and the organic phase was washed twice with 5% acetic acid, 5% sodium hydrogen carbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel. Yield: 2.7 g. 1 H-NMR (DMSO d-6) 0.88 (m, 12H) 2.00 (m, 2H) 2.50-3.00 (m, 2H) 3.90-4.43 (m, 10H) 5.08 (s, 4H) 5.32-5.59 (m, 1H 6.17 (m, 1H) 6.50 (s, 2H97.28 (m, 10H) 7.72 (m, 2H) 7.90 (s, 1H) d) Synthesis of 2,3'-dideoxy-3'-fluoro-5'- O- [3,3-bis (L-valyloxymethyl) -propionic acid] guanosine A solution of 2,3'-dideoxy-3'-fluoro-5'-O- [3,3-bis (N-CBZ-L -valyloxymethyl) -propionyl] guanosine (2.6 g, 3.1 mmol) in 80 ml of ethyl acetate, 20 ml of methanol and 20 ml of acetic acid were hydrogenated with black palladium (0.3 g) for two hours under normal pressure. The catalyst was filtered and washed with ethyl acetate and methanol. The solution was evaporated under reduced pressure and the product was isolated as the bisacetate salt by column chromatography on silica gel. Yield: 1.2g 1H-NMR (DMSO d-6) 0.90 (m, 12H) 1.78 (m, 2H) 2.50-3.00 (m, 2H) 3.09 (m, 2H) 4.02-4.45 (m, 8H) 5.34-5.59 (m, 1H) 6.17 (, 1H) 6.62 (s, 2H) 7.88 (s, 1H) EXAMPLE 27 2,3'-dideoxy-3'-fluoro-5'-O-r3- (L-valyloxymethyl) -4 -stearoxyloxy-butoxycarbon and I] guanosine a) Synthesis of 2,3'-dideoxy-3'-fluoro-5'-O- [3- (N-CBZ-L-vali loxime tyl) -4-en Aroyloxy-butoxycarbonyl] guanosine A solution of 2 ', 3'-dideoxy-3'-fluoroguanosine (2.69 mg, 1. 00 mmol in absolute DMF was added pyridine (198 mg, 2.5 mmol) and a solution of 3- (N-CBZ-L-valoyloxymethyl) -4-stearoyloxy-butoxycarbonyl chloride (750 mg, 1.1 mmol) in 5 ml. dichloromethane. The mixture was stirred for three days at room temperature. The solution was evaporated under reduced pressure and the product was isolated by column chromatography. Yield: 120 mg. 1 H-NMR (DMSO d-6) 0.88 (m 9 H) 1.24 (m, 28 H) 5.08 (s, 2 H) 6.24 (m, 1 H) 8.00 (s, 1 H) b) Synthesis of 2,3'-dideoxy-3 '-fluoro-5'-O- [3- (L-valyloxymethyl) -4-stearoyloxy-butoxycarbonyl] guanosine A mixture of 2,3'-dideoxy-3'-fluoro-5'-O- [3- (N -CBZ-L-valyloxymethyl) -4-stearoyloxy-butoxycarbonyl] guanosine in 15 ml of ethyl acetate, 2 ml of methanol and 2 ml of acetic acid was hydrogenated with black palladium (40 mg) under normal pressure for two hours. The catalyst was filtered and washed with ethyl acetate and methanol. The solution was evaporated and the product was isolated as the acetate salt by column chromatography on silica gel. Yield: 78 mg 1 H-NMR (DMSO d-6) 0.87 (m, 9 H) 1.22 (m, 28 H) 1.48 (m, 2 H) 1.68 (m, 2 H) 2.12 (m, 1 H) 2.26 (m, 2 H) 2.50 -3.00 (m, 2H) 4.00-4.42 (m, 10H) 5.34-5.58 (m, 1H) 6.18 (m, 1 H) 6.42 (s, 2H) 7.82 (s, 1H) EXAMPLE 28 2,3'-dideoxy -3'-fluoro-5'-O- [2- (L-valyloxy) -estearoyl] guanosine a) Synthesis of benzyl 2-hydroxystearate To a solution of DL-2-hydroxystearic acid (3.0 g, 10 mmol) in 20 ml of dry DMF was added potassium tert-butoxide (1.23 g, 11 mmol) and the mixture was stirred for one hour at 60 ° C. Benzyl bromide (2.14 g, 12.5 mmol) was added and the mixture was stirred for six hours at 80 ° C. The mixture was evaporated under reduced pressure and 100 ml of ethyl acetate were added. The organic phase was separated and washed four times with water. The organic phase was dried with sodium sulfate and concentrated in vacuo. The product was isolated by column chromatography on silica gel. Yield: 3.3 g 1 H-NMR (CDCl 3) 0.88 (m, 3 H) 1.26 (m, 28 H) 1.62 (m, 2 H) 4.20 (m, 1 H) 5.20 (s, 2 H) 7.36 (m, 5 H). b) Synthesis of benzyl-2- (N-FMOC-L-valyloxy) stearate. To a solution of benzyl-2-hydroxystearate (3.2 g, 8.2 mmol), N-FMOC-L-valine (3.4 g, 10 mmol) and DMAP (0.12 g, 1 mmol) in 80 mL of dichloromethane was added a solution of DCC (2.5 g, 12 mmol) and the mixture was stirred overnight at room temperature. The mixture was cooled to 5 ° C and the urethane was filtered. The filtrate was evaporated and the product isolated by silica gel column chromatography. Yield: 4.5 g 1 H-NMR (CDCl 3) 0.90 (m, 6 H) 1.26 (m, 6 H) 1.82 (m, 2 H) 2.16 (m, 1 H) 4.21 (m, 1 H) 4.36 (m, 2 H) 5.10 (m, 1H) 5.18 (2, 2H) 5.28 (m, 1H) 7.20-7.80 (m, 13H) c) Synthesis of 2- (N-FMOC-L-valyloxy) stearic acid A solution of benzyl-2- (N-FMOC) -L-valyloxy) stearate (4.4 g, 6. 2 mmol) in 50 ml of ethyl acetate was hydrogenated with palladium or 10% charcoal (0.5 g) under normal pressure for two hours. The catalyst was filtered and washed with ethyl acetate and 1,4-dioxane. The solution was evaporated under reduced pressure and the product was isolated by column chromatography on silica gel. Yield: 3.4 g. 1 H-NMR (CDCl 3) 0.88 (m, 6 H 1.26 (m, 28 H) 1.82 (m, 2 H) 2.28 (m, 1 H) 4.20 (m, 1 H) 4.40 (m, 2 H) 5.00 (m, 1 H) 5.41 (m , 1H) 7.26-7.82 (m, 8H) d) Synthesis of 2,3'-dideoxy-3'-fluoro-5'-O- [2- (N-FMOC-L-valyloxy) -stearoyljuanosine A mixture of 2 ', 3'-dideoxy-3'-fluoroguanosine (404 mg, 1.5 mmol), 2- (N-FMOC-L-valyloxy) stearic acid (1.24 g, 2 mmol), DMPA (24 mg, 0.2 mmol) and HOBT (264 mg, 1.95 mmol) was coevaporated twice with DMF and reduced to about 30 ml. DCC (372 mg, 1.8 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was filtered and the solution was evaporated under reduced pressure. Ethyl acetate (50 ml) was added and the organic phase was washed twice with 5% acetic acid, with 5% sodium hydrogen carbonate and with water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated as the acetate salt by column chromatography on silica gel. Yield: 1.2g 1H-NMR (DMSO d-6) 0.80-0.90 (m, 9H) 1.22 (m, 28H) 2.12 (m, 1H) 2.50-3.00 (m, 2H) 3.98 (m, 1H) 4.96 (m, 1H) 6.17 (m, 1H) 6.50 (s, 2H) 7.32-7.95 (m, 10H) e) Synthesis of 2,3'-dideoxy-3'-fluoro-5'-O- [2- (L-valyloxy) -estearoyl] guanosine. To a solution of 2,3'-dideoxy-3'-fluoro-5'-O- [2- (L-valyloxy) -estearoyl] guanosine (800 mg, 0.89 mmol) in 15 ml of DMF was added DBU ( 1.35 g, 8.9 mmol) and the mixture was stirred for 5 minutes at room temperature. Acetic acid (2 mL) was added and the mixture was evaporated under reduced pressure. Water (20 ml) was added and the mixture was extracted three times with dichloromethane. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel. Yield: 164 mg 1 H-NMR (DMSO d-6) 0.87 (m, 9 H) 1.22 (m, 28 H) 1.70 (m, 2 H) 1.88 (m, 1 H) 2.50-3.00 (m, 2 H) 3.20 (m, 1 H ) 4.32 (m 3 H) 4.94 (m, 1H) 5.32-5.54 (m, 1H) 6.14 (m, 1H) 6.49 (s, 2H) 7.89 (s, 1H). EXAMPLE 29 2,3'-dideoxy-3'-fluoro-5'-O-3 [1,3-bis- (L-valyloxy) -2-propyloxycarbonylpropanoyljuanosine a) Synthesis of 1,3-dibenzyloxy-2 monoester -propyl succinate. A solution of 2,3-dibenzyloxypropan-2-olo (6.8 g, 25 mmol) and succinic anhydride (7.5 g, 75 mmol) and DMAP (12.2 g, 100 mmol) was stirred for one hour at 60 ° C. The mixture was evaporated under reduced pressure, acidified with 2N HCl and extracted twice with ethyl acetate. The combined organic phase was washed three times with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel. Yield: 7.8 g b) Synthesis of 2,3'-dideoxy-3'-fluoro-5'-O- [3- (1,3-dibenzyloxy-2-propyloxycarbonyl) -propanoyl] guanosine. A mixture of 2 ', 3'-dideoxy-3'-fluoroguanosine (1.61 g, 6 mmol), HOBT (0.972 g, 7.2 mmol), DMAP (73.3 mg, 0.6 mmol) and 1,3-dibenzyloxy-2-propyl monoester Succinate (2.68 g, 7.2 mmol) was co-evaporated twice with DMF and reduced to approximately 150 ml. DCC (1.55 g, 7.5 mmol) was added and the mixture was stirred 72 hours at room temperature. The mixture was filtered and the solution was evaporated under reduced pressure. Ethyl acetate (200 ml) was added and the organic phase was washed twice with 5% acetic acid, 5% sodium hydrogen carbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel. Yield: 3.3 g. c) Synthesis of 2,3'-dideoxy-3'-fluoro-5'-O- [3- (1,3-dihydroxy-2-propyloxycarbonyl) propanoyl] guanosine. A solution of 2,3'-dideoxy-3'-fluoro-5'-O- [3- (1,3-dibenzyloxy-2-propyloxycarbonyl) propanoyl] guanosine (3.2 g, 5.13 mmol) in 50 ml of acetate of ethyl, 50 ml of methanol and 10 ml of acetic acid was hydrogenated with black palladium (0.6 g) under 2.8 kg / cm2 overnight. The catalyst was filtered and washed with methanol. The solution was evaporated under reduced pressure and the product was isolated by column chromatography on silica gel. Yield: 1.64 g. d) Synthesis of 2,3'-d-deoxy-3'-fluoro-5'-O-. { 3- [1, 3-Bis (N-CBZ-L-valyloxy) -2-propyloxycarbonyl] propanoyl} guanosine A mixture of 2,3'-dideoxy-3'-fluoro-5'-O- [3- (1,3-dihydroxy-2-propyloxycarbonyl) propanoyl] guanosine (1.93 g, 2.93 mmole), N-CBZ- Valine (1.76 g, 7 mmol), HOBT (0.95 g, 7 mmol) and DMAP (85.5 mg, 0.7 mmol) were co-evaporated twice with DMF and reduced to approximately 60 ml. DCC (1.55 g, 7.5 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was heated for four hours at 60 ° C and then cooled to approximately 10 ° C. The mixture was filtered and the solution reduced under reduced pressure. Ethyl acetate (150 ml) was added and the organic phase was washed twice with 5% acetic acid, 5% sodium hydrogen carbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel. Yield: 1.6 g. e) Synthesis of 2,3'-dideoxy-3'-fluoro-5'-O-. { 3- [1, 3-bis- (L-valyloxy) -2-propyloxycarbonyl] -propanoyl} guanosine A solution of 2,3'-dideoxy-3'-fluoro-5'-O-. { 3- [1, 3-bis- (N-CBZ-L-valyloxy) -2-propyloxycarbonyl) propanoyl} guanosine (1.6 g, 1.75 mmoles) in 80 ml of ethyl acetate, 20 ml of methanol and 20 ml of acetic acid was hydrogenated with black palladium (0.3 g) for two hours at room temperature and normal pressure. The catalyst was filtered and washed with methanol. The solution was evaporated under reduced pressure and the product was isolated as the diacetate salt by column chromatography on silica gel. Yield: 1.02 g 1 H-NMR (DMSO d-6) 0.84 (m, 12 H) 1.85 (m, 2 H) 2.58 (m, 4 H) 2.60-3.10 (m, 2 H) 3.11 (m, 2 H) 3.61-4.39 (m , 7H) 5.19 (m, 1 H) 5.35-5.56 (m, 1H) 6.16 (m, 1H) 6.62 (s, 2H) 7.89 (s, 1H) EXAMPLE 30 2,3'-dideoxy-3'-fluoro- 5'-O-. { 3- [1- (L-Valyloxy) -3-hydroxy-2-propyloxycarbonyl] propanoyl} guanosine a) Synthesis of 2,3'-dideoxy-3'-fluoro-5'-O-. { 3- [1- (N-CBZ-L-valyloxy) -3-hydroxy-2-propyloxycarbonyl] -propanoyl} guanosine A mixture of 2,3'-dldeoxy-3'-fluoro-5'-O- [3- (1,3-dihydroxy-2-propyloxycarbonyl) -propanoyl] guanosine (1.3 g, 2.93 mmole), N-CBZ -L-valine (1.00 g, 4 mmol), HOBT (0.54 g, 4 mmol) and DMAP (48.8 mg, 0.4 mmol) were co-evaporated twice with DMF and reduced to approximately 60 ml. DCC (0.91 g, 4.4 mmol) was added and the mixture was stirred for 72 hours at room temperature. The mixture was filtered and the solution was evaporated under reduced pressure. Ethyl acetate (150 ml) was added and the organic phase was washed twice with 5% acetic acid, 5% sodium carbonate, and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel. Yield: 0.99 g b) Synthesis of 2,3'-dideoxy-3'-fluoro-5'-O-. { 3- [1- (L-Valyloxy) -3-hydroxy-2-propyloxycarbonyl] -propanoyl} guanosine A solution of 2,3'-dideoxy-3'-fluoro-5'-O-. { 3- [1-N-CBZ-L-valyloxy) -3-hydroxy-2-propyloxycarbonyl) -propanoyl} guanosine (0.82 g, 1.21 mmol) in 30 mL of ethyl acetate, 15 mL of methanol and 15 mL of acetic acid was hydrogenated with black palladium (0.15 g) for two hours at room temperature and normal pressure. The catalyst was filtered and washed with methanol. The solution was evaporated under reduced pressure and the product was isolated as an acetate salt by column chromatography on silica gel. Yield: 0.5 g. 1H.RMN (DMSO d-6) 0.84 (m, 6H) 1.86 (m, 1H) 2.58 (m, 4H) 2.63-3.02 (m, 2H) 3.10-4.38 (m, 9H) 5.34-5.5 (m, 1H 6.16 (m, 1H) 6.56 (s, 2H) 7.90 (s, 1H) EXAMPLE 31 5'-L-Valyl-2 ', 3'-dideoxy-3'-fluoroguanosine To a solution of 2', 3'- dideoxy-3'-fluoroguanosine (810 mg, 3 mmol) and 4-dimethylaminopyridine (73 mg, 0.6 mmol), N-CBz-valine (1.5 g, 6 mmol) and 1-hydroxybenzotriazole (810 mg, 6 mmol) in DMF (20 ml) was added DCC (1.36 g, 6.6 mmol). After 72 hours, the reaction mixture was filtered and concentrated in vacuo. 5 '- (N-CBz-L-valyl) -2'-3'-dideoxy-3'-fluoroguanosine was isolated by column chromatography on silica gel (1.15 g). This intermediate (503 mg, 1 mmol) was dissolved in a mixed solvent of ethyl acetate (10 mL), methanol (20 mL) and acetic acid (2 mL). Black palladium (100 mg) was added to the mixture and the reaction mixture was kept under hydrogen at atmospheric pressure for 3 hours. After filtration and concentration, the title product was isolated by silica gel column chromatography (370 mg). 1 H-NMR (DMSO d-6): 7.94 (s, 1 H), 6.52 (s, 2 H) 6.17 (dd, 1 H), 5.47 (dd, 1H), 4.15 (m, 3H), 3.15 (d, 1H), 3.01-2.62 (m, 2H), 1.80 (m, 1H), 0. 82 (dd, 6H). EXAMPLE 32 2, 3'-dideoxy-3'-f Ioro-5'-O-r2- (L-valyloxy) -propionic guanosine a) Synthesis of 4-methoxybenzyl-2-hydroxypropionate. To a solution of DL-2-hydroxypropionic acid (9.0 g, 100 mmol) in 100 ml of dry DMF was added potassium tert-butoxide (12.34 g, 110 mmol) and the mixture was stirred for one hour at 60 ° C. . 4-Methoxybenzyl chloride (18.8 g, 120 mmol) was added and the mixture was stirred overnight at 60 ° C for eight hours. The mixture was evaporated under reduced pressure and 250 ml of ethyl acetate were added. The organic phase was washed four times with water. The organic phase was dried with concentrated sodium sulfate in vacuo.

Yield: 16.8 g 1 H-NMR (CDCl 3) 1.40 (m, 3 H) 3.81 (s, 3 H) 4.26 (m, 1 H) 5.14 (s, 2 H) 6. 90 (d, 2H) 7.28 (d, 2H) b) Synthesis of 4-methoxybenzyl-2- (N-CBZ-valyloxy) propionate. To a solution of 4-methoxybenzyl-2-hydroxypropionate (4.2 g, 20 mmol), N-CBZ-L-valine (5.02 g, 20 mmol) and DMAP (0.24 g, 2 mmol) and 100 ml of dichloromethane was added a DCC solution (4.54 g, 22 mmol) and the mixture was stirred overnight at room temperature. The mixture was cooled to 5 ° C and the urethane was filtered. The filtrate was evaporated and the product isolated by silica gel column chromatography. Yield: 7.9 g 1 H-NMR (CDCl 3) 0.88 (m, 6 H) 1.50 (m, 3 H) 2.26 (m, 1 H) 3.81 (s, 3 H) 4.34 (m, 1 H) 5.04-5.30 (m, 6 H) 6.88 ( d, 2H) 7.26 (m, 7H) c) Synthesis of 2- (N-CBZ-L-valyloxy) propionic acid. To a solution of 4-methoxybenzyl-2- (N-CBZ-L-valyloxy) propionate (7.8 g, 17.5 mmol) in dichloromethane (100 ml) was added trifluoroacetic acid (10 ml) and the solution was stirred for one hour at room temperature. The solution was evaporated under reduced pressure and the product was isolated by column chromatography on silica gel. Yield: 5.0g H-NMR (CDCl 3) 0.94 (m, 6H9, 1.56 (d, 3H) 2.30 (m, 1H) 4.42 (m, 1H) 5.12-5.30 (m, 4H) 7.28 (m, 5H) d) synthesis of 2,3'-dideoxy-3'-fluoro-5-O- [2- (N-CBZ-L-valyloxy) -propanoyl] guanosine. A mixture of 2 ', 3'-dideoxy-3'-fluoroguanosine (404 mg, 1.5 mmol), 2- (N-CBZ-L-valyloxy) -propionic acid (0.582 g, 1.8 mmol), DMAP (22 mg, 0.18 mmoles) and HOBT (243 mg, 1.8 mmoles) was co-evaporated twice with DMF and reduced to approximately 30 ml. DCC (412 mg, 2.0 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was filtered and the solution was evaporated under reduced pressure. 100 ml of ethyl acetate were added and the organic phase was washed twice with 5% acetic acid, with 5% sodium hydrogen carbonate and with water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel. Yield: 0.72g H-NMR (DMSO d-6) 0.92 (m, 6H) 1.40 (d, 3H) 2.10 (m, 1H) 2.50-3.6 (m, 2H) 4.03 (m, 1H) 4.20-4.44 (m , 3H) 5.04 (s, 2H) 5.12 (m, 1H) 5.44-5.58 (m, 1H) 6.18 (t, 1H) 6.42 (2, 2H) 7.36 (m, 5H) 7.70 (d, 2H) 7.92 (s) , 1H) e) Synthesis of 2,3'-dideoxy-3'-fluoro-5-O- [2- (L-valyloxy) -propanoyl] guanosine. A solution of 2,3'-dideoxy-3'-fluoro-5-O- [2- (N-CBZ-L-valyloxy) -propanoyl] guanosine (0.6 g, 1.04 mmol) in 20 ml of ethyl acetate, 10 ml of methanol and 10 ml of acetic acid was hydrogenated with black palladium (0.1 g) for two hours at room temperature and normal pressure. The filtered catalyst was washed with methanol. The solution was evaporated under reduced pressure to give the title compound as the acetate salt. Yield: 0.5 g. 1 H-NMR (DMSO d-6) 0.88 (m, 6H), 1.40 (d, 3H) 1.92 (m, 4H) 2.52-3.04 (m, 2H) 3.18 (m, 1 H) 4.18-4.42 (m, 3H ) 5.05 (m, 1H) 5.32-5.58 (m, 2H) 6.18 (m, 1H) 6.52 (s, 2H) 7.90 (s, 1H). EXAMPLE 33 2,3'-dideoxy-3'-fluoro-5'-O-3- [2,3-bis- (L-valyloxy) -1-propyloxycarbonyl] -propanoyl guanosine a) Synthesis of 4-methoxybenzyl monoster succinate To a mixture of succinic anhydride (75 g, 750 mmol) and 4-methoxybenzyl alcohol (59.1 g, 500 mmol) in 1,4-dioxane (300 ml) was added pyridine (79.1 g)., 1000 mmol) and the mixture was stirred for five hours at 80 ° C. The mixture was evaporated under reduced pressure and 600 ml of ethyl acetate and 60 ml of acetic acid were added. The organic phase was washed three times with water, dried with sodium sulfate and evaporated under reduced pressure. The product was recrystallized from toluene. Yield: 104 g. 1 H-NMR (DMSO d-6) 2.48 (m, 4 H) 3.72 (s, 3 H) 5.00 (s, 2 H) 6.90 (d, 2 H) 7.28 (d, 2 H) b) Synthesis of 2,3-dihydroxy ester propyl succinic acid, 4-methoxybenzyl ester. To a solution of glycerol (23. Og, 250 mmol), monoester of 4-methylbenzyl succinate (5.96 g, 25 mmol) and DMAP (0.36 g, 3 mmol) in DMF (200 ml) was added DCC (6.2 g, 30 mmol) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and 150 ml of dichloromethane were added. The mixture was filtered and the solution was washed twice with water. The organic phase was extracted twice with dichloromethane and the combined organic phases were dried with sodium sulfate. The solution was evaporated under reduced pressure and the product was isolated by column chromatography on silica gel. Yield: 3.0 g 1 H-NMR (CDCl 3) 2.65 (m, 4 H) 3.61 (m, 2 H) 3.80 (s, 3 H) 3.90 (m, 1 H) 4.18 (m, 2 H) 5.05 (s, 2 H) 6.89 (d, 2H) 7.26 (d, 2H) c) Synthesis of 2,3-ib / 's- (N-CBz-L-valoyloxy) propyl ester of succinic acid, 4-methoxybenzyl ester. To a stirred solution of 2,3-dihydroxy-propyl ester of succinic acid, 4-methoxybenzyl ester (2.9 g, 9.28 mmol), N-CBZ-L-valine (5.03 g, 20 mol) and DMAP (0.244 g, 2 mmol) in dichloromethane (60 ml) was added DCC (4.5 g, 22 mmol) and the mixture was stirred overnight at room temperature. The mixture was filtered and the solution was evaporated under reduced pressure. The product was isolated by column chromatography on silica gel. Yield: 2.5 g 1 H-NMR (CDCl 3) 0.90 (m, 12 H) 2.16 (m, 2 H) 2.62 (m, 4 H) 3.80 (s, 3 H) 4.32 (m, 4 H) 5.05-5.52 (m, 9 H) 6.89 ( d, 2H) 7.30 (m, 12H) d) Synthesis of ester 2,3- £ >; / s- (N-CBZ-L-valyloxy) propyl of succinic acid. To a solution of the above intermediate (2.3 g, 2.95 mol) in dichloromethane (25 ml) was added trifluoroacetic acid (2.5 ml) and the solution was stirred for two hours at room temperature. The solution was evaporated under reduced pressure and the product was isolated by column chromatography on silica gel. Yield: 1.8 g 1 H-NMR (CDCl 3) 0.92 (m, 12 H) 2.12 (m, 2 H 9 2.64 (m, 4 H) 4.32 (m, 4 H) 5.10 (s, 4 H) 5.22-5.50 (m, 3 H) 7.34 (m , 10H) e) Synthesis of 2,3'-dideoxy-3'-fluoro-5'-O-. { 3- [2,3-j / s- (N-CBZ-L-valyloxy) -1-propyloxycarbonyl] propanoyl} guanosine A mixture of 2 ', 3'-dideoxy-3'-fluoroguanosine (0.5838 g, 2 mmole), HOBT (0.327 g, 2.42 mmole), DMAP (29.3 mg, 0.24 mmole) and succinic acid 2,3-bis (N -CBZ-L-valyloxy) -l-propyl ester (1.6 g, 2.42 mol) was co-evaporated twice with DMF and reduced to approximately 50 ml. DCC (0.536 g, 2.5 mmol) was added and the mixture was stirred for 72 hours at room temperature. The mixture was filtered and the solution was evaporated under reduced pressure. 100 ml of ethyl acetate were added and the organic phase was washed twice with 5% acetic acid, 5% sodium hydrogen carbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel. Yield: 0.65g. 1 H NMR (DMSO-d 6) 0.88 (m, 12 H) 2.08 (m, 2 H) 2.58-3.04 (m, 6 H) 3.92 (m, 2 H) 4.10-4.46 (m, 7 H) 5.00 (s, 4 H) 5.22 ( m, 1H) 5.32-5.56 (m, 1H) 6.17 (m, 1 H) 6.50 (s, 2H) 7.32 (m, 10H) 7.70 (d, 2H) 7.92 (s, 2H) f) Synthesis of 2.3 '-dideoxy-3'-fluoro-5'-O-. { 3- [2,3-o / s- (L-valyloxy) -1-propyloxycarbonyl] -propanoyl} guanosine A solution of the immediately preceding intermediate (0.57 g, 0.626 mmol) in 20 ml of ethyl acetate, 10 ml of methanol and 10 ml of acetic acid was hydrogenated with black palladium (0.1 g) for two hours at room temperature and normal pressure. The catalyst was filtered and washed with methanol. The solution was evaporated under reduced pressure and the product was isolated by column chromatography on silica gel. The product was dissolved in dichloromethane and 1M hydrogen chloride in ether (1.1 ml) was added. The mixture was evaporated under reduced pressure and dried in vacuo to give the title compound as the dihydrochloride salt. Yield: 0.37 g. 1 H-NMR (DMSO d-6) 0.92 (m, 12H) 2.12 (m, 2H) 2.58-3.04 (m, 6H) 3. 75 (m, 2H) 4.16-4.50 (m, 7H) 5.19-5.60 (m, 2H) 6.18 (m, 1H) 6.79 (s, 2H) 7.92 (s, 1H) EXAMPLE 34 2,3-dihydrochloride salt -dideoxy-3'-fluoro-5'-OM, 3-¿> / s- (L-valyloxy) -2-propyloxycarbonyl propanoyl guanosine a) Synthesis of 1,3-dibromo-2-propyl ester, 4-methoxybenzyl succinic acid ester To a solution of 1,3-dibromopropane-2-olo ( 21.8 g, 100 mmol) 4-methoxybenzyl ester of succinic acid (28.6 g, 120 mmol) and DMAP (1.22 g, 10 mmol) in dichloromethane (400 ml) was added DCC (24.8 g, 120 mmol) in portions to approximately 10 ° C. The mixture was stirred overnight at room temperature and cooled to about 5 ° C. The mixture was filtered and the solution was evaporated under reduced pressure. 600 ml of ethyl acetate were added and the organic phase was washed twice with 5% acetic acid, % sodium hydrogen carbonate and water. The solution was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel. Performance: 34. 8 g. 1 H NMR (CDCl 3) 2.69 (m, 4 H) 3.57 (m, 4 H) 3.81 (s, 3 H) 5.07 (s, 2 H) . 14 (m, 1H) 6.88 (d, 2H) 7.26 (d, 2H) b) Synthesis of ester 1,3- /? / S- (N-CBZ-L-valyloxy) -2-propyl succinic acid , 4-methoxybenzyl ester. To a solution of N-CBZ-L-valine (58.5 g, 232.8 mmol) in dry DMF (300 mL) was added potassium tert-butoxide (24.68 g, 220 mmol) and the mixture was stirred for one hour at room temperature. ambient. A solution of 1,3-dibromo-2-propyl ester of succinic acid, 4-methoxybenzyl ester (34 g, 77.6 mmol) in dry DMF (50 ml) was added and the mixture was stirred for eighteen hours at 60 ° C. . The potassium bromide was filtered and the solution evaporated under reduced pressure. 500 ml of ethyl acetate were added and the organic phase was washed twice with 5% sodium hydrogen carbonate and with water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel. Yield: 45 g. 1 H-NMR (CDCl 3) 0.90 (m, 12 H) 2.16 (m, 2 H) 2.61 (m, 4 H) 3.80 (s, 3 H) 4.12-4.42 (m, 6 H) 5.02 (s, 2 H) 5.10 (s, 4 H) 5.43 (m, 3H) 6.88 (d, 2H) 7.32 (m, 12H) c) Synthesis of 1,3-jb / s- (N-CBZ-L-valoxy) -2-propyl ester of succinic acid. To a cooled solution of the immediately preceding intermediate (44.5 g, 57.1 mmoles) in dichloromethane (500 ml) was added trifluoroacetic acid (50 ml) between 5 ° C and 10 ° C and the solution was stirred for two hours at 10 ° C. . The solution was evaporated under reduced pressure and twice co-evaporated with toluene. 400 ml of ethanol was added and the mixture was stirred for 30 minutes at 40 ° C. The mixture was cooled and the by-product was filtered. The solution was evaporated under reduced pressure and the product was isolated by column chromatography on silica gel. Yield: 33g 1H-NMR (DMSO-d6) 0.88 (m, 12H) 2.04 (m, 2H) 2.46 (m, 4H) 3.94-4.40 (m, 6H) 5.02 (s, 4H) 5.18 (m, 1H) 7.31 (m, 10H) 7.74 (d, 2H) d) Synthesis of 2,3'-dideoxy-3'-fluoro-5'-O-. { 3- [1, 3-or / s- (N-CBZ-L-valyl oxy) -2-propyl oxycarbonyl] propanoyl} guanosine A mixture of 2 ', 3'-dideoxy-3'-fluoroguanosine (17.8 g, 66 mmol), HOBT (10.64 g, 78.8 mmol), succinic acid 1,3-α / s- (N-CBZ-L-valyloxy) ) -2-propyl ester (52 g, 78.8 mmol) and DMAP (0.96 g, 7.88 mmol) was co-evaporated twice with DMF and reduced to approximately 500 ml. DCC (17.3 g, 84 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was heated for six hours at 60 ° C and then cooled to approximately 10 ° C. The mixture was filtered and the solution reduced under reduced pressure. 1200 ml of ethyl acetate were added and the organic phase was washed twice with 5% acetic acid, 5% sodium hydrogen carbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel. Yield: 42 g. 1 H-NMR (DMSO-d 6) 0.90 (m, 12H) 2.02 (m, 2H) 2.5-3.02 (m, 6H) 3.94 (m, 2H) 4.22 (m, 7H) 5.02 (s, 4H) 5.18 (m, 1H) 5.22-5.50 (m, 1H) 6.16 (m, 1H) 6.50 (s, 2H) 7.32 (m, 10H), 7.72 (d, 2H) 7.92 (s, 1H) e) Synthesis of 2,3'-dideoxy-3'-fluorohydrochloride salt 5'-O-. { 3- [1, 3-b / s- (L-valyloxy) -2-propyloxycarbonyl] -propanoyl} guanosine A solution of 2,3'-dideoxy-3'-fluoro-5'-O-. { 3- [1, 3-b / s- (N-CBZ-L-valyloxy) -2-propyloxycarbonyl] propanoyl} guanosine (5.0, 5.9 mmoles) in 75 ml of ethyl acetate and 75 ml of methanol was hydrogenated with palladium on activated charcoal 10% Pd (1 g) for one hour at room temperature and normal pressure. The catalyst was filtered and washed with methanol. The solution was evaporated under reduced pressure. The product was dissolved in dichloromethane with a 1M hydrogen chloride solution in ether (6ml) added while cooling. The mixture was evaporated under reduced pressure. Yield: 3.5 g 1H-NMR (DMSO d-6) 0.94 (m, 12H) 2.18 (m, 2H) 2.5-3.04 (m, 6H) 4.20-4.54 (m, 7H) 5.24 (m, 1?) 5.34- 5.64 (m, 1H) 6.22 (m, 1H) 6.92 (s, 2H) 8.30 (s, 1H) 8.62 (s, 6H) EXAMPLE 35 Alternative synthesis of 2,3'-d-deoxy-3'-fluoro-5'-O-p, 3-¿> / s- (L-valyloxy) -2-propyl oxi ca bonillo ropanoilguanosina a) Synthesis of 1, 3-dibromo-2-propyl ester of succinic acid, 1,2-dimethyl ester. To a solution of 1,3-dibromopropane-2-olo (10.9 g, 50 mmol), 1,1-dimethylethyl ester of succinic acid (J. Org Chem 59 (1994 4864) (10.45 g, 60 mmol) and DMAP (0.61 g, 5 mmol) in dichloromethane (180 mL) was added DCC (12.4 g, 60 mmol) in portions at approximately 10 ° C. The mixture was stirred overnight at room temperature and cooled to approximately 5 °. C. The mixture was filtered and the solution was evaporated under reduced pressure, 250 ml of ethyl acetate were added and the organic phase was washed twice with 5% citric acid, 5% sodium hydrogen carbonate and water. dried with sodium sulfate and evaporated under reduced pressure.The product was distilled in vacuo. (Bp 0.5 135-140 ° C) Yield: 16.8 g 1 H-NMR (CDCl 3) 1-45 (s, 9 H) 2.8 (m, 4H) 3.61 (m, 4H) 5.15 (m, 1H) b) Ester synthesis of 1, 3- £ > / s- (N-CBZ-L-valyloxy) -2-propyl succinic acid, ester of 1,2-diethyl leti lo. To a solution of N-CBZ-L-valine (18.85 g, 75 mmol) in dry DMF (100 mL) was added potassium tert-butoxide (7.85 g, 70 mmol) and the mixture was stirred for one hour at room temperature. ambient. A solution of 1,3-dibromo-2-propyl ester of succinic acid, 1,1-dimethylethyl ester (9.35 g, 25 mmol) in dry DMF (20 mL) was added and the mixture was stirred for eighteen hours at 60 ° C. The potassium bromide was filtered and the solution evaporated under reduced pressure. 300 ml of ethyl acetate were added and the organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel. Yield: 14 g 1 H-NMR (CDCl 3) 0.90 (m, 12 H) 1.42 (s, 9 H) 2.14 (m, 2 H) 2.52 (m, 4 H) 4.32 (m, 6 H) 5.10 (s, 4 H) 5.32 (m, 3H) 7.26 (m, 10H) c) Monoester synthesis of 1, 3- £ > / s- (N-CBZ-L-valyloxy) -2-propyl succinate. To a solution of 1,3-bis- (N-CBZ-L-varyloxy) -2-propyl ester of succinic acid, 1,1-dimethylethyl ester (13 g, 18.18 mmol) in dichloromethane (100 ml) was added. he added trifluoroacetic acid (20 ml) and the solution was stirred for six hours at room temperature. The solution was evaporated under reduced pressure. 200 ml of ethyl acetate were added and the organic phase was washed with 5% sodium hydrogen carbonate and water. The solution was evaporated under reduced pressure. Yield: 11.7 g. 1 H-NMR (DMSO-d 6) 0.88 (m, 12 H) 2.04 (m, 2 H) 2.46 (m, 4 H) 3.94-4.40 (m, 6 H) 5.02 (s, 4 H) 5.18 (m, 1 H) 7.32 (m, 10H) 7.74 (d, 2H) d) Synthesis of 2,3'-dideoxy-3'-fluoro-5'-O-3- [1,3- or s- (L-valyloxy) -2-propyloxycarbonyljpropanoyl guanosine The intermediate step of step c) was esterified in FLG as shown in step 35 step d) and the N-protected groups on the vallyl portions were removed by conventional techniques, as shown in Example 35 step e) in Example 29 step e). BIOLOGICAL EXAMPLE 1 Pharmacokinetics The confirmation that the orally administered prodrugs of the invention release FLG in vivo is obtained from a rat model that is recognized as a useful model for analyzing the pharmacokinetic parameters of nucleoside analogs. The oral compositions are administered in a pharmaceutical carrier comprising propylene glycol, or in the case of more soluble compounds such as those of Example 26, or Example 34, in water, to rapidly duplicate the animals in a dose corresponding to 0.1 mmol / kg. For comparison, a group of rats was dosed iv with 0.01 mmol / kg. of the metabolite of 2 ', 3'-didexoxy-3'-fluoroguanosine. The serum levels of the metabolite were then monitored in rered serum at individual animal intervals 0.5 to 12 hours after administration (5 minutes to 6 hours for FLG). The metabolite was analyzed with HPLC with UV detection at 254 nm, in a manner analogous to Stahle and others, 1994, J. Pharm. Biomed. Anal. 13, 369-376. A CLAR system can be based on a 0.05M ammonium-dihydrogen phosphate buffer solution, with 12% 2-propanol solvent, regulated at pH 4.5 or 30 mM sodium dihydrogen phosphate buffer with 2% solvent acetonitrile regulated at pH 7.0. the column can be a particle size of 5 μm of 100 x 2.1 mm BASC18 with a C18 cover column of 7 μm or a 5 μm column Zorbax SB-CN C18 150x4.6 mm. The binding of pro tein of the compounds of the invention is negligible since the metabolite and ultrafiltration through Amicon or Microcon 30 filters are useful for serum samples. Advantageously, the main peak is subjected to additional column chromatography to improve the aid in resolution of FLG on low weight serum components. IV levels were multiplied by a factor of ten in order to obtain AUC values for comparison with oral values. The absolute oral bioavailability is determined as the ratio between ° "00AUCiv and ° -00AUCorai Table 1 'Calculated. ** Value of literature The compounds of the invention thus provide significantly improved oral bioavailability relative to the metabolite of 2 ', 3'-dideoxy-3'-fluoroguanosine. notably, the compounds are released into the blood in a relatively sustained manner, rather than in an immediate peak. This means that the effective units of the active metabolite are available in the blood for many hours a day attending a dose. Additionally, a sustained release avoids the acute toxicity problems observed in the compounds with a faster release rate. Although rats are recognized as a good model to deduce the bioavailability of human nucleoside analogues, species, independent bioavailability of a compound of the invention (Example 334) was confirmed at = 11.5 kg. of male and female beagle dogs orally administered with 0.05 mmol / kg. (38 mg / kg.) Of the compound in water or iv 0.05 mmol / kg. (1.35 mg / kg.) Of the metabolite in water. The recovery of plasma and the previous analysis. Male Dog 12 hours of absolute bioavailability 51% Female Dog 12 hours of absolute bioavailability 74% BIOLOGICAL EXAMPLE 2 Antiviral-Retrovirus Activity As demonstrated by the methodology of Biological Example 1, the release compounds of the invention, in vivo, the metabolite 2 ', 3'-dideoxy, 3'-fluoroguanosine. The in vitro measurement of the antiviral activity of this metabolite could reflect the activity of the factor of the compounds of the invention. In the XTT dye uptake analysis of Koshida and other Antimicrob Agents Chemother. 33 778-780, 1989) using the MT4 cells, the metabolite measured in Biological Example 1 above showed the following in vitro activities against retroviruses: Table 2 * Concentration of the metabolite that induces 50% inhibition of retroviral replication.

Therefore, it will be apparent that administration of the compounds of the invention induces potent antiviral activities against retroviruses HIV-1, HIV-2 and SIV. It should also be noted from the results of HIV-12441 AZTr and TIBOr that the antiviral activity of the compounds of the invention does not show cross-resistance against HIV strains that become resistant with other HIV agents such as AZT of the analog of nucleoside or in TIBO reverse transcriptase inhibitor without nucleoside. BIOLOGICAL EXAMPLE 3 Antiviral-HBV Activity The activity of antivirals on ducks with hepatitis B virus (DHBV) in ducks is a recognized animal model for the validation of hepatitis B activity in vivo in humans. The metabolite activity in vivo measured in Biological Example 2 above has been analyzed in the DHBV model described by Sherker et al. (1989) Gastroenterology 91, pp. 818-824. The results are described in Figures 1 and 2. In the 4 short control ducks were treated with phosphate buffered saline (PBS) and 4 ducks with 5 mg / kg. / day of the active metabolite. The ducks were two days old when they were inoculated with DHBV and 18 days of age when the treatment started. The metabolite PBS (controls) were given intraperitoneally for 10 days as injections twice a day, at 8 a.m. and 4 p.m. The treatment was finished in 33 days and the animals were followed 5 weeks after the end of the treatment. The efficacy of the treatment was followed by the hybridization of spot spots of DHBV DNA in serum using a radioactive probe and the amount of DHBV was measured as the amount of radioactive hybridized. Figure 1 shows the amount of DHBV DNA in serum at different time points before, during and after treatment.

As can be seen in Figure 1, the amount of DHBV in serum during treatment with PBS (control, solid line) is not described. The animals gave the metabolite measured in Biological Example 2 (broken line) which shows a dramatic decrease in the amount of DHBV in the serum during the first 10 days of treatment, so that the rest of the treatment the DNA level of DHBV was followed for the limit of detection at this dose of 5 mg / kg. day. Repeated experiments at doses of 30 and 30 mg / kg. day and with congenitally infected ducks (not shown) also produced similar results, ie a dramatic lack of DHBV DNA serum under threshold detection. Even at lower doses of 0.3 mg / kg / day, the metabolite caused considerable inhibition of DHBV in vivo. After completion of treatment, virus reappeared in the serum, as shown in Figure 1. Reappearance of HBV after a short time of end treatment with conventional antivirals animals were easily observed in humans and chronic hepatitis B infection. As observed in Figure 2, the weight of the ducks increased in the same way as in the control animals (treated with PBS). The increase in weight from approximately 270 g to around 800 g observed during the treatment period is so long that the toxic effects, if present, could easily be seen as a change in the rate of development. Similar development curves were also observed for ducks receiving the regimen of doses less than 30 mg / kg / day. Therefore, this metabolite was clearly non-toxic. As the compounds of the invention were hydrolysed in vivo to give this metabolite. As 2 above, and an identical nature established in Example and therefore easily metabolized fatty acid, therefore, they conclude that the toxicity problem can be expected from the administration of the compounds of the invention. The absence of acute toxicity (short term) of the compounds of the invention, when administered orally, was established in Biological Example 2 above. EXAMPLE OF FORMULATION 1 Formulation of tablets. The following ingredients were sieved through a sieve of 0.15 mm and a colorant mixed 10 g 2 ', 3'-dideoxy-3'-fluoro-5'-O-3- [1,3-bis (L-valyloxy) -2- propyl oxycarbonyl propanoyl] guanosine 40 g lactose 49 g crystalline cellulose 1 g magnesium stearate A tabletting machine is used to compress the mixture for tablets containing 250 μg of the active ingredient. FORMULATION EXAMPLE 2 Enteric Coated Tablets The tablets of the Formulation of Example 1 were spray coated onto a tablet coated with a solution comprising 120 g ethyl cellulose 30 g propylene glycol 10 g sorbitan monooleate ad 1000 ml aq. dist. EXAMPLE OF FORMULATION 3 Controlled Release Formulation 50g 2,, 3'didexosi-3'-fluoro-5'-O- [5- (L-valoyloxymethyl) -6-stearoyloxyhexanoyl] guanosine 12g hydroxypropylmethylcellulose (Methocell K15) 4.5g lactose dry mix and granulate with an aqueous povidone paste. Magnesium stearate (0.5 g) was added and the mixture was compressed in a machine to make tablets in 13 mm diameter tablets containing 500 mg of active agent. FORMULATION EXAMPLE 4 Soft capsules 250 g 2 ', 3'didexosi-3'-fluoro-5'-O- [5- (L-valyloxymethyl) -6-stearoyloxyhexanoi I] guanosine 100g lecithin 100g arachis oil The compound of the invention It was dispersed in lecithin and arachis oil and filled into soft gelatin capsules.

Claims (20)

1. CLAIMS 1. A compound of the formula I R- \ L1 L2-0-nuc R, wherein nuc is the nucleoside residue bound through its simple hydroxy group on the cyclic or acyclic haride portion, wherein Ri is hydroxy, amino or carboxy; optionally having the esterification / amide bond therein; fatty acid or optionally substituted, saturated or unsaturated C4-C22 alcohol, or an aliphatic L-amino acid; R2 is the residue of an aliphatic L-amino acid; L1 is a trifunctional ligating group; L2 is absent or is a difunctional ligature group; and pharmaceutically acceptable salts thereof.
2. 2. A compound according to claim 1, wherein nuc is acyclovir, ddl, (didanosine), ddC (zalcitabine), d4T (stavudine), FTC, lamivudine (3TC), 1592U89 (4- [2-amino-6 - (cyclopropylamine) -9H-purin-9-yl] -2-cyclopentene-1-methanol), AZT (zidovudine, DAPD (D-2,6-diaminopurine dioxolane) or F-ddA
3. 3. A compound according to claim 1, wherein O-nuc is derived from 2 ', 3'-dideoxy-3'-fluoroguanosine (FLG).
4. 4. A compound according to claim 1, wherein Ri defines a hydroxyl group or an esterified hydroxy function.
5. 5. A compound according to claim 4, wherein the RT ester is derived from an unsubstituted, unsaturated fatty acid having a total of 4 to 22 carbon atoms, preferably from 10 to 20.
6. 6. A compound of according to claim 5, wherein the Ri ester is derived from a monounsaturated fatty acid, preferably from the n-3 or n-6 series having a total of 10 to 22 carbon atoms, preferably from 16 to 20.
7. A compound according to claim 1, wherein R2 is derived from L-alanine, L-leucine, L-isoleucine and preferably L-valine and is esterified in a hydroxyl function on the ligation.
8. 8. A compound according to claim 7, wherein both Ri and R2 comprise the same L-amino acid.
9. 9. A compound according to claim 1, wherein Li comprises a glycerol derivative.
10. 10. A compound according to claim 1, wherein L2 comprises a dicarboxylic acid derivative.
11. 11. A compound according to claim 10, wherein the dicarboxylic acid derivative comprises oxalyl, malonyl, succinyl, glutaryl or adipyl, preferably succinyl.
12. 12. A compound according to claim 11, wherein Ri and R2 are L-valyl or L-isoleucyl.
13. 13. A compound according to claim 12, denotes 2 ', 3, -dideoxy-3'-fluoro-5'-O-3- [2,3-bis- (L-valyloxy) -1-propyloxycarbonyl] - propanoyl guanosine or 2 ', 3'-dideoxy-3'-fluoro-5'-O-3- [1, 3-bis- (L-valyloxy) -2-propyloxycarbonyl] -propanoyl guanosine or a pharmaceutically acceptable salt thereof .
14. 14. A compound according to claim 12, denotes salt of 2 ', 3'-dideoxy-3'-fluoro-5'-O-3- [1, 3-bis- (L-valyloxy) - hydrochloride salt. 2-propyloxycarbonyl] -propanol guanosine.
15. 15. A compound according to claim 1, wherein Li comprises the structure of the formula lia: lia wherein A and A 'define a respective ester ligation between a hydroxy on the ligation and the carboxy on Ri or R2 or an ester ligation between a carboxy on the ligation and the hydroxy on Rt as a fatty alcohol, or a bond of amide between an amine on the ligation and a carboxy on Ri or R2, or an amide bond between a carboxy on the ligation an amine on Ri or R2, or one of A and A 'are as defined and the other is hydroxy, amino or carboxy in the case that Ri by itself, is a free hydroxy, amino or carboxy group: Rx is H or C1-C3 alkyl, T is a ligation, -O- or -NH-; Alk is absent, optionally substituted C 2 -C 4 alkyl or C 2 -C 4 alkenyl as described above; and m and n are independently 0, 1 or 2.
16. 16. A compound according to claim 14, wherein A and A 'define ester ligatures in the carboxy functions of R1 and R2; Rx is H m and n are 1 and Alk is methylene or m is 1, n is 0 and Alk is absent, methylene or ethylene.
17. 17. A compound according to claim 16, wherein R1 is hydroxy or an L-amino acid residue esterified in the hydroxy.
18. 18. A compound according to claim 17, wherein both R- and R2 are the same L-amino acid residue.
19. 19. A pharmaceutical composition comprising the compounds as defined in any of claims 1 to 18 and a pharmaceutically acceptable carrier or diluent thereof.
20. 20. A compound or salt according to any of claims 1 to 18, for use in therapy, preferably in the manufacture of a medicament for the treatment or prophylaxis of HBV or retroviral infections.