MXPA98006631A - Synthesis of nucleosid acicli - Google Patents

Abstract

A method for preparing antiviral compounds of improved bioavailability of the formula (I) is described, wherein one of R1 and R2 is -C (O) CH (CH (CH3) 2) NH2 or -C (O) CH (CH ( CH 3) CH 2 CH 3) NH 2 and the other of R 1 and R 2 is alkyl C (saturated or monounsaturated C 0 -C 3, optionally substituted, and R 3 is OH or H, the method comprising: A) the mono-disacylation of a diacylated compound corresponding to the formula I where R1 and r2 are both -C (O) CH (CH (CH3) 2) NH2 or -C (O) CH (CH (CH3) CH2CH3) NH2 (optionally N protected) or R1 and R2 are both an alkyl -C (-O) C3-C21 saturated or monounsaturated, optionally substituted, and R3 is H or OH; B) acylation of the 4-hydroxy group of either side-chain or 2-hydroxymethyl side chain thus liberated with the corresponding alkyl -C (O) CH (CH (CH3) 2) NH2 or -C (O) CH (CH (CH3) CH2CH3) NH2 or -C (-O) C3-C21 saturated or monounsaturated, optionally substituted to produce a compound of the formula I; C) the deprotection if necessary. (See Formula

Description

SYNTHESIS OF AC1CLIC NUCLEOSIS DESCRIPTION OF THE INVENTION The present invention deals with antivirals and, in particular, with acyclic nucleoside derivatives useful in combating infections caused by herpes and retroviruses. The invention offers novel compounds, pharmaceutical compositions comprising these compounds, methods for the treatment and prophylaxis of infections in which these compounds participate, methods for manufacturing them and novel intermediates.

BACKGROUND OF THE INVENTION The practical utility of many of the acyclic nucleosides is restricted by their modest pharmacokinetics. In order to improve the bioavailability of acyclic nucleosides in general, different approaches based on prodrugs have been tried. These approaches include the preparation of ester derivatives, in particular, aliphatic esters, of one or more hydroxy groups in the acyclic side chain. European Patent EP 165 289 describes the promising antiherpes agent 9- [4-hydroxy- (2-hydroxymethyl) butyl] guanine, known as H2G. European patent EP 186 640 describes 6-deoxy H2G. According to European patent EP 343 133 all these compounds, in particular the R - (-) enantiomer, are also active against infections by retroviruses, such as VI H. EP 343 133 describes several of the derivatives of H2G, such as, for example, phosphonates, aliphatic esters (for example, diacetate and dipropionate) and ethers of hydroxy groups in the acyclic side chain. This patent further describes methods for preparing these derivatives which include the condensation of the acyclic side chain at the N-9 position of a characteristic 6-halogenated purine portion or, alternatively, the closing of the pyrimidine ring of a portion of imidazole or the furazano- [3,4-d] pyrimidine moiety, where the acyclic side chain is already present in the pyrimidine precursor or in the im idazole moiety, respectively. Although in the more general description of each of these methods pre-derivatives are obtained in the acyclic side chain, the individual examples also show a one-step diacylation of H2G with acetic or propynyl anhydride and DMF. Harnden, et al. , J. ed. Chem. 32, 1738 (1989) investigated an amount of short chain aliphatic esters of an acyclic 9- [4-hydroxy- (3-hydroxymethyl) butyl] guanine nucleoside, known as penciclovir, and its 6-deoxy analogue. Famciclovir, an antiviral agent for commercial use, is the diacetyl derivative of 6-deoxy penciclovir. Benjamín, et al. , Pharm. Res. 4 No. 2, 120 (1987) describes short chain aliphatic esters of 9 - [(1,3-dihydroxy-2-propoxy) -methylguanine, known as ganciclovir. The dipropionate ester is described as the preferred ester.

Lake-Bakaar, et al., Describe in Antimicrob. Agents Chemother. 33 No. 1, 110-112 (1989), diacetate and H2P dipropylate derivatives and monoacetate and diacetate derivatives of 6-deoxy H2G. It has been reported that diacetate and H2G dipropionate derivatives produce only minimal improvements in bioavailability relative to H2G. International patent application W094 / 24134, published on October 27, 1994, describes prodrugs of aliphatic esters of ganciclovir analog 6-deoxy N-7, which include esters of di-pivaioyl, di-valeroyl, mono-valeroyl, mono-oleoyl and mono-stearoyl. The international patent application W093 / 07163, published on April 15, 1993 and the international patent application W094 / 22887, published on October 13, 1994, describe nomoester derivatives of analogous nucleosides derived from monounsaturated Cie or C20 fatty acids. U.S. Patent No. 5,216,142 of June 111, 1993 also describes nomoester derivatives of long chain fatty acids of analogous nucleosides. A second attempt to provide prodrugs of acyclic nucleosides is to prepare amino acid esters of one or more of the hydroxy groups in the acyclic side chain. European patent EP 99 493 generally describes acyclovir amino acid esters and European patent application EP 308 065, published on March 22, 1989, describes the valine and isoleucine esters of acyclovir. European patent application EP 375 329, published on June 27, 1990 discloses amino acid esters derived from ganciclovir, including derivatives of di-valine, di-isoieucine, diglycine and di-alanine esters. International patent application W095 / 09855, published on April 13, 1995, discloses amino acid esters derived from penciclovir, including esters derived from mono-valine and di-valine. DE 19526163, published February 1, 1996 and US Pat. UU No. 5,543,414 of August 6, 1996 describe achiral amino acid esters of ganciclovir. European patent application EP 694 547, published on January 31, 1996 describes the mono-L-valine ester of ganciclovir and its preparation from di-valyl-ganciclovir. European patent application EP 654 473, published on May 24, 1995, discloses several bis amino acid derivatives of β-JI '^' -bishydroxymethi-cyclopropan-1'l] methylguanine. International patent application W095 / 22330, published on August 24, 1995, discloses aliphatic esters, amino acid esters and combined acetatolvalinate esters of acyclic nucleosides of 9- [3,3-dihydroxymethyl-4-hydroxy-but-1 - il] guanina. These references indicate that the bioavailability is reduced when a valine ester of the trivalin ester derivative is replaced by an acetate ester.

BRIEF DESCRIPTION OF THE INVENTION We have discovered that H2G diester derivatives that exhibit specific combinations of an amino acid ester and a fatty acid ester are capable of providing a significant improvement in oral availability relative to the parent compound (H2G). According to a first aspect of the invention, the novel compounds of Formula I are provided: where a) R, is -C (O) CH (CH (CH3) 2) NH2 or -C (O) CH (CH (CH3) CH2CH3) NH2 and R2 is a saturated C (O) C3-C21 alkyl or monounsaturated, optionally substituted or b) R, is a C (O) C3-C2 alkyl, saturated or monounsaturated, optionally substituted and R2 is -C (O) CH (CH (CH3) 2) NH2 or C (O) CH (CH (CH3) CH2CH3) NH2; and R3 is OH or H; and the pharmaceutically acceptable salts thereof. The advantageous effect on the oral bioavailability of the fatty acid compound and amino acid esters of the invention is particularly unexpected in comparison with the oral bioavailability of the corresponding fatty acid esters. Based on the results using a urine recovery test (Table 1A) or a plasma drug test (Table B) of rat H2G, none of the H2G mono- or di-fatty acid esters provide any improvement in oral bioavailability in relation to the compound of H2G origin. In fact, the di-stearate derivative provided a significantly lower bioavailability than the parent compound indicating that a stearate ester can be harmful to improve oral bioavailability of H2G. It has been reported that the conversion of one or both hydroxyls into other analogous acyclic nucleosides in the corresponding valine or di-valine esters improves bioavailability. The conversion of H2G to the corresponding mono- or di-vally ester derivatives produced similar improvements in the relative bioavailability to the main compound. Since H2G fatty acid derivatives are detrimental to the improvement of bioavailability, the finding that a combined 1-amino acid fatty acid diester derivative of H2G provides improved oral availability or comparable to that produced by the diester derivative of H2G valine, on the basis of the urine recovery and plasma drug tests, respectively, was unexpected.

Table 1A Group Ri Group R2 Bioavailability * Hydrogen Hydrogen 8% Hydrogen Stearoyl 12% Stearoyl Stearoyl 1% Valyl Hydrogen 29% Valyl Valyl 36% Valyl Stearoyl 56% * See Biological Example 1 below, where more details are given.

Table 1B Group R, Group R2 Bioavailability * Hydrogen Hydrogen 3.8% Hydrogen Stearoyl 1.9% Stearcyl Stearoyl 0% Valyl Hydrogen 31.3% Valyl Valyl 35.0% Valyl Stearoyl 29% See Biological Example 2 below, where They provide more details. The invention further provides pharmaceutical compositions which include the compounds of Formula I and the respective pharmaceutically acceptable salts together with a pharmaceutically acceptable carrier or diluent. Other aspects of the present invention include the compounds of Formula I and the respective pharmaceutically acceptable salts for the therapeutic use and use of these compounds and their salts in the preparation of a medicament for the treatment or prophylaxis of viral infections in humans or animals. The compounds of the present invention are potent antivirals, especially against infections caused by herpes, such as, for example, those caused by the Varicella zoster virus, Herpes simplex type 1 & 2, Epstein-Barr, Herpes type 6 (H HV-6) and type 8 (H HV-8). The compounds are especially effective against infections caused by the Varicella zoster virus, such as shingles in the elderly, including post-herpetic neuralgia, or chickenpox in young people when the duration and severity of the disease can be reduced by several days. Infections caused by the Epstein Sarr virus that respond to treatment with the compounds include glandular fever / infectious mononucleosis, diseases that previously lacked treatment and can produce months of scholastic disability among adolescents. The compounds of the present invention are also active for certain infections by retroviruses, especially SIV, HIV-1 and HIV-2, and against infections for which a transactivating virus is indicated.

According to another aspect of the present invention there is provided a method for the prophylaxis or treatment of a viral infection in humans or animals that includes the administration of an effective amount of a compound of Formula I or the respective pharmaceutically acceptable salt to humans or animals. Conveniently, the group R1 is a hydroxy or its tautomer = 0, so that the base portion of the compounds of the present invention is the guanine that occurs naturally, for example, in case the side chain is cleaved in vivo. Alternatively, R3 can be hydrogen, thus defining the most soluble 6-deoxy derivative that can be oxidized in vivo (eg, xanthine oxidase) in a guanine form. The compound of Formula I may be presented in racemic form, ie, it is a mixture of the 2R and 2S isomers. Preferably, however, the compound of Formula I has at least 70%, preferably at least 90%, of the R form, for example greater than 95%. More preferably, the compound of Formula I is an enantiomerically pure R form. Preferably, the amino acid of the Rt R2 group derives from a L-amino acid. Preferably, the fatty acid of the group R? / R2 has in total an even number of carbon atoms, especially decanoyl (C10), lauryl (Cl2), myristoyl (C, 4), palmitoyl (C16), stearoyl (Co. ) or eicosanoyl (C20). Other RT / R groups; include butyryl, hexanoyl, octanoyl or behenoyl (C22). Other useful Ri / R-2 groups include those derived from myristoleic, myristicidal, palmitoleic, palmitalaidic, n6-octadecenoic, oleic, elaidic, gandoic, erucic or brassidic acids. The monounsaturated fatty acid esters have, in general, double binding in the transconfiguration, preferably the position? -6,? -9 or? -11, depending on their length. Preferably, the RT / R2 group is derived from a fatty acid containing a saturated Cg to C17 alkyl or n: 9 monounsaturated. The saturated or unsaturated fatty acid or the R1 / R2 group can be optionally substituted with up to five substituents, similar or different, independently selected from a group consisting of hydroxy, C? -C6, alkyl, d-C ?, akoxy, C? -C6, C, -C6 alkoxy, alkyl, C, -C3 alkanoyl, amino, halo, cyano, azido, oxo, mercapto and nitro and the like. The most preferred compounds of Formula I are those in which R, is -C (O) CH (CH3) 2) NH2 or -C (O) CH (CH (CH3) CH2CH3) NH2 and R2 is -C (O) C9-C17 saturated alkyl. The term "lower alkyl" in this context refers to straight or branched chain alkyl radicals containing from 1 to 7 carbon atoms including, among others, methyl, ethyl, n-propyl, iso-propyl, n-butyl , iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like. The term "N-protecting group" in this context refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesired reactions during synthetic procedures. The most common N-protecting groups are described in Greene, "Protective Groups in Organic Synthesis" (John Wiley &Sons, New York, 1981), a document that is incorporated herein by reference. Protecting groups of N include asyl groups, for example formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, (α-chlorobutyryl, benzoyl, -chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like, sulfonyl groups, such as, for example, benzenesulfonyl, p-toluenesulfonyl, and the like, carbamate-forming groups, such as, for example, benzyloxycarbonyl, p-chlorobenzyloxycarbonite, P-methoxybenzyloxycarbonyl , p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-di methoxy benzyl oxycarbonyl, 4-methoxy-benzyloxycarbonyl, 2-n it ro-4, 5-Di methoxy ben cilaxica rboni lo, 3,4, 5-trimethoxybenzyloxycarbonyl, 1 - (p-biphenylyl) 1-methylethoxycarbonyl, a, ad im ethyl-3, 5-di methoxy benzyl oxycarbonyl, be nch id ril oxycarbonyl , t-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, alkyloxycarbonyl, 2,2,2-trieloroethoxycarboxylic acid, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, heavenpentyloxycarbonyl, adamanylloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and similar; alkyl groups, such as, for example, benzyl, triphenylmethyl, benzyloxymethyl and the like; and sil ilo groups, such as, for example, trimethylsilyl and the like. Preferred N-protecting groups include forinyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butoxycarbonyl (BOC) and benzyloxycarbonyl (Cbz). The term "activated ester derivative" in this context refers to acid halides, such as, for example, hydrochloric acids and activated esters which include, inter alia, anhydrides derived from formic acid and acetic acid, anhydrides derived from alkoxycarbonyl halides. , such as, for example, isobutyloxycarbonylchloride and the like, esters derived from N-hydroxysuccinimide, esters derived from N-hydroxyphthalimide, esters derived from N-hydroxybenzotriazole, esters derived from N-hydroxy-5-norbomeno-2,3-dicarboxamide, derived esters of 2,4,5-trichlorophenyl and the like. Preferred compounds of Formula I include: (R) -9- [2- (butyroxymethyl) -4- (L-isoleucyloxy) butyl] guanine, (R) -9- [2- (4-acetylbutyryloxymethyl) - 4- (L-Isoleucyloxy) butyl] guanine, (R) -9- [2- (hexanoyloxymethyl) -4- (L-isoleucyloxy) butyl] guanine, (R) -9- [4- (L-isoleucyloxy) - 2- (Octanoyloxymethyl) buty IJguan ina, (R) -9- [4- (L-Isoleucyloxy) -2- (decanoyloxymethyl) butyl] guanine, (R) -9- [4- (L-isoleucyloxy) -2 - (dodecanoyloxymethyl) buty] guanine, (R) -9- [4- (L-isoleucyloxy) -2- (tetradecanoyloxymethyl) butyl] guanine, (R) -9- [4- (L-isoleucyloxy) -2- (hexadecanci loxi metii) butyl] guan ina, (R) -9- [4- (L-Isoleucyloxy) -2- (octadecanoyloxymethyl) butyl] guan ina, (R) -9- [2- (eicosanoyloxymethyl) -4- (L-iso le uci loxi) bu til] guanine, (R) -9- [2- (docosanoyloxymethyl) -4- (L-isoleucyloxy) butyl] guanine, (R) -9- [4- (L-Isoleucyloxy) -2 - ((9-tetradecen oil) oxymethyl) butyl] guanine, (R) -9- [2 - ((9-hexadecenoyl) oxymethyl) -4- (L-iso le uci loxi) butyl] guanine, (R) -9- [4- (L-isoleucyloxy) -2 - ((6-octadecen oil) oxy methyl) butyl] guanine, (R) -9- [ 4- (L-Isoleucyloxy) -2 - ((9-octadecenoyl) oxymethyl) -butyl] guanine, (R) -9- [2 - ((1,1-eicosanoyl) -oxymethyl) -4- (L-isoleucyloxy) butyl] guanine, (R) -9- [2 - ((13-docosenoii) -oxymethyl) -4- (L-isoleucyloxy) butyl] guanine, (R) -2-amino-9- [2- (buti loxi m eti l) -4- (Li solé uci I oxy) buti I] purine, (R) -2-amino-9- [2- (4-acetylbutyryloxymethyl) -4- (L-isoleucyloxy) butyl] purine, (R) -2-am i no-9- [2- (hexan oxy oxy m eti) -4- (L-isole uci loxi) butyl] purine, (R) -2-amino-9- [4- (L-Isoleucyloxy) -2- (octanoyloxymethyl) butyl] purine, (R) -2-amino-9- [4- (L-isoleucyloxy) -2- (decanoyloxymethyl) butyl] purine, (R) -2-amino -9- [4- (L-Isoleucyloxy) -2- (dodecanoyloxymethyl) butyl] purine, (R) -2-am ino-9- [4- (L-isoleucyloxy) -2- (tetradecanoyloxymethyl) butyl] purine , (R) -2-amino-9- [4- (L-isoleucyloxy ) -2- (hexadecanoyloxymethyl) butyl] purine, (R) -2-amino-9- [4- (L-isoleucyloxy) -2- (octadecanoyloxymethyl) butyl] purine, (R) -2-amino-9 - [4- (L-Isoleucyloxy) -2- (eicosanailoxim eti l) b util] purine, (R) -2-ainino-9- [2- (eicosanoyloxymethyl) -4- (L-isoleucyloxy) butyl] purine, (R) -2-amino-9- [2- (docosanoyloxymethyl) -4- (L-isoleucyloxy) butyl] purine, (R) -2-amino-9- [4- (Li solé uci loxi) -2- ((9-tetradecenoyl) oxy) methyl) butylpurine, (R) -2-amino-9- [2 - ((9-hexadecenoyl) oxymethyl) -4- (L-isoleucyloxy) butylpulline, (R) -2-am -9- [4- (L-Isoleucyloxy) -2 - ((6-octadecenoyl) oxymethyl) butyl] purine, (R) -2-amino-9- [4- (L-isoleucyloxy) -2 - ((9 -octadecenoyl) oxymethyl) butylpurine, (R) -2-am ino-g- [2 - ((1,1-eicosanoyl) oxymethyl!) - 4- (L-isoleucyloxy) butyl] purine, or (R) -2 -am ino-g- [2 - ((1 3-docosenoyl) oxymethyl) -4- (L-isoleucyloxy) butylpulline, and their respective pharmaceutically acceptable salts. Other preferred compounds include: (R) -9- [2- (butyryl oxy] methyl) -4- (L-valloxy) buty] guan ina, (R) -9- [2- (4-acetylbutyryloxymethyl) ) -4- (L-valyloxy) butyl] guanine, (R) -9- [2- (hexane and loxymethyl) -4- (L-valyloxy) butyl] nonane, (R) -9- [2- (Octanyloxymethyl) -4- (L-valyloxy) butyl] guan ina, (R) -9- [2- (decanoyloxymethyl) -4- (L-valyloxy) buty] guanine, ( R) -9- [2- (can or ioxy methyl)) -4- (L-valyloxy) butyl] guanine, (R) -9- [2- (tetradecanoyloxymethyl-4- (L-valyloxy) butyl] guanine, (R) -9- [2-hexadecanoyloxymethyl) -4- (L-valyloxy) butylguanine, (R) -9- [2- (octadecane i loxi meti I) -4- (L-val i loxi) buti l] guan ina, (R) -9- 12 - (e cosan oi I oxymethyl) -4- (L- va lyloxy) butyl] guanine, (R) -9- [2- (eicosanoyloxymethyl) - 4- (L-valyloxy) butyl] guanine, (R) -9- [2- (docosanoyloxymethyl) -4- (L-valyloxy) butyl] guanine, (R) -9- [2 - ((9- tetradenoxy) oxymethyl) -4- (L-valyloxy) butyl] guanine, (R) -9- [2 - ((9-hexadecenoyl) oxymethyl) -4- (L-valyloxy) butyl] guanine, (R) -9 - [2 - ((6-octadecenoyl) oxymethyl) -4- (L-va lyoxy) butyl] guanine, (R) -9- [2 - ((9-Octadecenoyl) oxymethyl) -4- (L-valyloxy) -butyl] guanine, (R) -9- [2 - ((11-eicosanoyl) oxymethyl) -4- (L-Valyloxy) butyl] guanine, (R) -9- [2 - ((13-docosenoyl) oxymethyl) -4- (L- valyloxy) butyljguanna, (R) -2-amino-9- [2 - (buti ril oxi methyl) -4- (L-vali loxi) bu ti I] puri na, (R) -2-am? no-9- [2- (4-aceti I butiri loxi meti l) -4 - (L-valloxy) buti I] purine, (R) -2-amino-9- [2- (hexanoyloxymethyl) -4- (L-valyloxy) butyl] purine, (R) -2-amino -9- [2- (Octanyloxymethyl) -4- (L-valyloxy) butyl] purine, (R) -2-amino-9- [2- (decanoyloxymethyl) -4- (L-vallyloxy) butyl] purine , (R) -2-amino-9- [2- (dodecanoyloxymethyl) -4- (L-valyloxy) butyl] purine, (R) -2-amino-9- [2- (tetradecanoyloxymethyl) -4- (L-valyloxy) butyl] purine, (R) -2-amino-9- [2- (hexadecanoyloxymethyl) -4- (L-valyloxy) butyl] purine, (R) -2-amino-9- [ 2- (octadecanoyloxymethyl) -4- (L-va lyoxy) butyl] purine, (R) -2-amino-9- [2- (eicosanoyloxymethyl) -4- (L-va lyoxy) buti] purine , (R) -2-am ino-g- [2- (docosanoyloxymethyl) -4- (L-vali loxi) butyljp urine, (R) -2-amino-9- [2 - ((9-tetradecenoyl) oxy methyl) -4- (L-vallyloxy) butyl] purine, (R) -2-am ino-9- [2- ( (9-hexadecenoyl) oxymethyl) -4- (L-vallyloxy) butyl] purine, (R) -2-amino-g- [2 - ((6-octadecenoyl) oxymethyl) -4- (L-vali loxy) ) butyl] purine, (R) -2-amino-9- [2 - ((9-octadecenoyl) oxymethyl) -4- (L-valyloxy) -butyl] purine, (R) -2-amino-g- [ 2 - ((1,1-eicosenoyl) -oxymethyl) -4- (L-vallyloxy) tyl] purine, or (R) -2-amino-9- [2 - ((13-docosenoyl) -oxymethyl) -4- (L- vallyloxy) buti I] purine; and their respective salts acceptable in pharmaceutical terms. Other preferred compounds of Formula I include: (R) -9- [4- (butyryloxy) -2- (L-valloxymethyl) buty IJguanin a, (R) -9- [4- (4-acetylbutyryloxy) -2 - (L-valyoxymethyl) butyl] guanine a, (R) -9- [4- (hexanoyloxy) -2- (L-valyloxymethyl) butyl] guanine, (R) -9- [4- (octanoyloxy) -2- (L-valyloxymethyl) butyl] guanine, (R) -9- [4- (decanoyloxy) -2- (L-val i loxymethyl) butyl] guanine, (R) -9- [4- ( dodecanoyloxy) -2- (L-valyloxymethyl) butyl] guanine, (R) -9- [4- (tetradecanoyloxy) -2- (L-valyloxymethyl) buty] guanine, (R) -9- [4-hexadecanoiioxy) -2- (L-val i loxi methyl) buti] guani na, (R) -9- [4- (Octadecanoyloxy) -2- (L-valyloxymethyl) butyl] guanine, (R) -9- [4- (eicosanoyloxy) -2- (L-vali loxymethyl) butyl] guan ina, (R) -9- [4- (docosanoyloxy) -2- (L-valyloxymethyl) butyl ] guanine, (R) -9- [4 - ((9-tetradecenoyl) oxy) -2- (L-valyloxymethyl) butyl] guanine, (R) -9- [4 - ((9-hexadecenoyl) oxy) -2- (L-valyloxymethyl) butyl] guanine, (R) -9- [4 - ((6-Octadecenoyl) oxy) -2- (L-valyloxymethyl) butyl] guanine, (R) -9- [4 - ((9-Octadecenoyl) oxy) -2- (L-valyloxymethyl) -butyl] guanine, (R) -9- [4 - ((1 1 -eicosenoyl) oxy) -2- (L- val i I oxymethyl) butyljguan ina, (R) -9- (4 - ((13-docosenoyl) -oxi) -2- (L-val i loxi methyl) butyl] guan ina, (R) -2-amino-9- [4- (butyryloxy) -2- (L-valyoxymethyl) butyl] purine, (R) -2-amino-9- [4- (4-acetylbutyryloxy) -2- (L-valyloxymethyl) butyl] purine, (R) -2-amino-9- [4- (hexanoyloxy) -2 - (L- va lyloxy methyl) bu til] purine, (R) -2-amino-9- [4- (octanoyl oxy) -2- (L- vallyloxymethyl) butyl] purine, (R) -2-amino-9- [4- (decanoyloxy) -2- (L-valyloxymethyl) buti] purine, (R) -2-am i no-9- [4- (dodecanoyloxy) -2- (L-valyloxymethyl) buti] p urine, (R) -2-amino-9- [4- (tetradecanoyloxy) -2- (L-valyloxymethyl) butyl] purine, (R) -2-amino-9- [4- (hexadecanoyloxy) -2- (L- valilox? methyl) butyl] purine, (R) -2-am ino-9- [4- (octadecanoyloxy) -2- (L-valyloxy) l-buyl] purine, (R) -2-amino -9- [4- (eicosanoyloxy) -2- (L-va lyoxymethyl) buti Ijjpurine, (R) -2-amino-9- [4- (docosanoyloxy) -2- (L-vali I oxymethyl) butyl] purine, (R) -2-amino-9- [4 - ((9-tetradecenoyl) oxy) -2- (L-vallyloxymethyl) butyl] purine, (R) -2-am ino-9- [4 - ((9-hexadecenoyl) oxy) -2- (L-valyloxymethyl) butyl] purine , (R) -2-amino-9- [4 - ((6-octadecenoyl) oxy) -2- (L-valyloxymethyl) butyl] purine, (R) -2-amino-9- [4 - (( 9-octadecenoyl) oxy) -2- (L-vali I oxymethyl) butyl] purine, (R) -2-am ino- 9- [4- ((1,1-eicosenoyl) oxy) -2- (L- valyloxy) butyl] purine, (R) -2-amino-9- [2 - ((13-docosenoli) oxymethyl) -2- (L- va lyl oxy) butyl] purine and their respective pharmaceutically acceptable salts. The compounds of Formula I can form salts that constitute a further aspect of the present 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, glycoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylethylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camforate, undecanoate and succinate, organic sulphonic acids, such as, for example, methanesulfonate, ethanesulfonate, 2-hydroxyethane sulfonate, camphorsulfonate, 2-naphthalenesulfonate, benzenesulfonate, p-chlorobenzenesulfonate and p-toluenesulfonate, inorganic acids, such as, for example, hydrochloride acids, hydrobromide, hydroiodide, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate, phosphoric and sulphonic. The hydrochloric acid salts are convenient. The compounds of Formula I can be isolated as the hydrate.

The compounds of the present invention can be isolated in the form of crystals, preferably, homogeneous crystals, and thus, a further aspect of the invention provides the compounds of Formula I in substantially pure crystalline forms, comprising crystalline material > 70%, preferably homogeneous crystalline material > 90%, for example, homogeneous crystalline material > 95% The compounds of the present invention are especially suitable for oral administration, although they can also be administered rectally, vaginally, nasally, topically, transdermally or parenterally, for example intramuscularly, intravenously or epidurally. While the compounds can be administered alone, for example, in a capsule, in general, they are administered together with a pharmaceutically acceptable carrier or diluent. The invention encompasses methods for preparing a pharmaceutical composition comprising a compound of Formula I, or the respective salt acceptable in pharmaceutical terms, together with or associated with a pharmaceutically acceptable vehicle. The oral presentations are conveniently prepared in the form of unit doses, such as, for example, capsules or tablets, with conventional vehicles or binders, such as, for example, magnesium stearate, chalk, starch, lactose, wax, gum or gelatin. Liposomes or synthetic or natural polymers, such as H PMC or PVP, can be used to provide a sustained release formulation. Alternatively, the formulation can be presented as nasal or ocular drops, syrups, gels or creams, comprising a preparation type solution, suspension, emulsion, oil in water or water in oil in conventional vehicles, such as water, saline , ethanol, vegetable oil or glycerin, and, as optional elements, flavorings and / or preservatives and / or emulsifiers. The compounds of the present invention can be administered in daily doses generally ranging from 0.1 to 200 mg / kg / day, more preferably from 0.5 to 100 mg / kg / day, more preferably from 10 to 50 mg / day. kg / day, for example, from 10 to 25 mg / kg / day. A characteristic dose intensity for a normal adult would be 50 to 500 mg, for example 300 mg, once or twice per day in the case of herpes infections and 2 to 10 times the same dose in case of LV infections. H. As a precautionary measure common to antiviral therapies, the compounds of the present invention can be administered in combination with other antiviral agents, such as, for example, acyclovir, valciclovir, penciclovir, famciclovir, ganciclovir and their prodrugs, cidofovir, foscarnet and the like for initiations. of herpes and AZT, ddl, ddC, d4T, 3TC, foscarnet, ritonavir, indinavir, saquinavir, delaviridine, Vertex VX 478, Agouron AG 1343 and the like for indications of retroviruses. The compounds of the present invention can be prepared de novo or by esterification of the main H2G compound which is prepared, for example, by the synthesis methodology described in European patent EP 343 133, which is incorporated herein by reference. The following is a characteristic reaction scheme for preparing H2G: H2G The condensation in Step 1 is generally carried out with an alkaline catalyst, such as, for example, NaOH or Na 2 CO 3 in a solvent, such as, for example, DMF. Step 2 consists of a reduction that can be performed with LiBH / tetrahydrofuran in a solvent, such as, for example, t-BuOH. The replacement of Step 3 from a chlorine with an amino group can be carried out under pressure with ammonia. In step 4 adenosine deaminase is used which can be conveniently immobilized on a solid support. The cooling of the reaction mixture allows the non-reacted isomeric precursors to remain in solution whereby higher purity is obtained. The starting materials for the compounds of the invention in which R3 is hydrogen can be prepared as indicated in European Patent EP 186 640, the content of which is incorporated herein by reference. These initial materials can be acylated in the manner previously described for H2G, and optionally, after having protected the 2-amino purine group with a conventional N-protecting group, as defined above, in particular, BOC (t- BuO-CO-), Z (BnO-CO-) or Ph3C-.

The compounds of the present invention can be prepared from H2G as described in Schemes A and B.

A. Direct acylation method Scheme A I Scheme A describes the preparation of compounds in which Ri is a derivative of the amino acid and R2 is a derivative of the fatty acid, although the reverse scheme can be applied in the compounds in which Ri is a derivative of the fatty acid and R2 of the latter r of the amino acid. In the variant shown in Scheme A above, G is guanine or 6-deoxyguanine, PG is ungroup protecto r of optional N or hydrogen, RX is the side chain of valine or isoleucine and R2 * is the acid chain fatty H2G has been previously described as an initial material but, of course, it can be optionally protected in the position of R3 or in position 2 of the purine with N-protecting groups (not shown). The H2G (derivative) reacts in the first step with a derivative Ri of activated α-amino acid, as described above, in a solvent, such as, for example, dimethylformamide or pyridin, to obtain a monoacylated product. The N-terminus of Ri a-amino acid can be protected with BOC or N-CBZ or similar. Under controlled conditions, the first acylation can be performed so that it occurs predominantly in the 4-hydroxy side-chain group of H2G. These controlled conditions can be achieved, for example, by manipulating the reagent concentrations or the rate of addition, in particular of the acylating agent, by reducing the temperature or by selecting the solvent. The reaction can be followed by TLC to monitor the controlled conditions. After purification, the monoacylated Ri compounds are acylated in the 2-CH OH group of the side chain with the appropriate activated fatty acid derivative to obtain acylated products by procedures similar to those used in the first step of esterification. The dietheric products are subjected to a conventional deprotection treatment using, for example, trifluoroacetic acid, HC I (aq) / dioxane, or a hydrogenation in the presence of a catalyst to obtain the desired compound of Formula I. The compound can be presented in salt form according to the deprotection conditions. The acid derivative Ri / R2 activated in the various equations may include, for example, halide acid, anhydride acid, activated ester acid or acid in the presence of a coupling reagent, for example dicyclohexylcarbodiimide, where the "acid" in each case represents the amino acid R? / R2 or the fatty acid R? R ?. Representative activated acid derivatives include acid chloride, combined anhydrides derived from formic acid and acetic acid, anhydrides derived from alkoxycarbonyl halides, such as, for example, isobutyloxycarbonylchloride and the like, esters derived from N-hydroxysuccinamide, esters derived from N-hydroxyphthalimide, derived esters of N-hydroxy-5-norbornene-2,3-dicarboxamide, esters derived from 2,4,5-trichlorophenol and the like.

B. By protecting the Ri-hydroxy group Scheme B Deprotection Formula I where G, Ri * and R2 * have the same definition as in Scheme A. While Scheme B has been exemplified in relation to the preparation of a compound where Ri is derived from an amino acid and R2 is derived from the fatty acid ester, the Inverse scheme can be applied to the compounds where R2 derives from the amino acid and Ri from the fatty acid. This scheme depends on the regioselective protection of the side chain 4-hydroxy group of H2G with a global protection group. In Scheme B above this is represented as t-butyldiphenylsyl, however other regioselective protecting groups can be used, such as, for example, trityl, 9- (9-phenyl) xanthenyl, 1,1-bis (4-methylphenyl) - 1 '-pi renylmethyl. The resulting product is acylated in the side chain 2-hydroxymethyl group using reagents and procedures analogous to those described in Scheme A above, except that the acid derivative is the fatty acid R 1 for example, myristic acid chloride, stearic , oleic, elaic, and the like. The thus acylated compounds are subjected to the appropriate deprotection treatment to remove the side chain 4-hydroxy protecting group. This treatment can be carried out with great selectivity, according to the regioselective protection group, with reagents such as HF / pyridine and the like, and the manipulation of the reaction conditions, viz reagent concentration, addition rate, temperature and solvent etc., as mentioned previously. The free side chain 4-hydroxy group is acylated with the activated α-amino acid in a manner similar to that described in Scheme A above. As additional techniques for introducing the amino acid ester of R? / R2, as for example, in the schemes A, B, C or D of the present document we can mention the method of 2-oxa-4-aza-cycloalkane 1, 3 -dione described in the International Patent Application no. WO 94/2931 1. As additional techniques for introducing the fatty acid ester of R? / R2, for example in schemes A, B, C or D of the present, the enzymatic route described in Preparative Biotransformations 1.1 may be cited. 8 (Ed S M Roberts, J Wiley and Son, NY, 1995) with a lipase, such as SP 435 immobilized Candida antarcticus (Novo Nordisk), porcine pancreatic lipase or Candida rugosa lipase. Enzymatic acylation is especially convenient in cases where it is desired to avoid the steps of protection and deprotection of the N-terminus in the other acyl group or in the purine 2-amine. An alternative route to obtain compounds of Formula I wherein R3 is hydrogen, consists of 6-activating the corresponding guanine compound of Formula I (wherein the amino acid ester portion of R? / R2 is optionally protected with N-protecting groups, as for example, BOC) with an activating group, such as, for example, halo. The 6-purine thus activated is therefore reduced to purine, for example, with a palladium catalyst and deprotected to obtain the desired 6-deoxy-H2G di-ester. Another aspect of the invention provides a method for preparing compounds of Formula I comprising: a) optional deprotection of N termini of positions 2 and / or 6 of the purine of a compound of Formula I wherein Ri and R2 are each hydrogen; b) regioselective acylation of the compound of Formula I in the 4-hydroxy side chain group with i) a valine or isoleucine group with optional N protection, ii) a C3C2 derivative? Optionally substituted, saturated or monounsaturated COOH or iii) a regioselective protection group; (e) acylation in the side chain 2-hydroxymethyl group with i) a valine derivative or isoleucine with optional protection at the N termini or ii) an optionally substituted, saturated or monounsaturated C3C21COOH derivative; d) replacement of the regioselective protection group in R1 f if present, with i) valine derivative or isoleucine with optional protection in the N termini or ii) a C3C2 derivative? COO H optionally substituted, saturated or monounsaturated and e) deprotection of the resulting compounds as necessary. In Schemes A and B above, selective acivation is used to water the fatty acid and amino acid esters stepwise. An alternative process for the preparation of the compounds of Formula I begins with a diacrylated H2 G derivative, where both acyl groups are the same and perform a selective removal of one of the acyl groups to obtain an intermediate monoacyl. acylate with the second different acyl group in the same manner as in Schemes A and B above. Also, another aspect of the present invention provides a method for preparing a compound of Formula I, as defined, consisting of A) the mono-disaczylation of a diacylated compound of Formula I wherein Ri and R2 are both esters of Valyl or isoleucyl (with optional N protection) or Ri and Ri are both an alkyl -C (= O) C3-C2? saturated or monounsaturated, optionally substituted, and B) acylation of the side chain 4-hydroxy group or of the side chain 2-hydroxymethyl group thus liberated with the alkyl, isoleucyl or C (= O) C3-C2 alkyl group ? saturated or monounsaturated, optionally substituted, corresponding (C) deprotection, which is necessary. This alternative process offers the advantage that the preparation of the diacylated H2G derivative is simple and requires few or no purification steps. The selective removal of only one of the acyl groups of the deacylated H2G derivative can be achieved by manipulating the reaction conditions, in particular, the temperature, the rate of addition of the reagent and the choice of the base. The compounds that best adapt to this alternative synthesis are those that present the following formula: where Ri and R2 are both a valeryl ester or isoleucyl ester (with optional N protection) or an alkyl C (= O) C3-C2? saturated or monounsaturated, optionally substituted and R3 is OH or H. To facilitate synthesis in this alternative form, it is preferred that R- and R2 are initially identical and more preferably, the same amino acid ester. A diamino acid ester of such characteristics will generally have N protection during its preparation and may be used directly in this condition in the selective diacylation step. Alternatively, a di-aminoacylated H2G derivative with N-protection can be deprotected and optionally re-protected, as described above. The unprotected diaminoacyl H2G derivative comprises one of the following compounds: (R) -9- [2- (L- sun eucyloxim eti l) -4- (Li so leu cyl oxy) butyl] guanine, (R) -9- [2- (L-valyloxymethyl) -4- ( L-valyloxy) butyl 3 guanine, (R) -2-am ino-9- [4- (Li so leuci loxi) -2- (Li solé uci loxi methyl) butyl] purine and (R) -2-amino-9- [4- (L-valyloxy) -2- (L-valyloxymethyl) butyl] purine.

These non-protected diacylated H2G derivatives can be subjected directly to a selective deacylation of one of the acyclo groups (in general, the acyl of the 4 position of the side chain) followed by the enzymatic acylation of the 4-hydroxy group released as he has described before. As an alternative, the non-protected diacylated H2G derivative can be re-protected and then subject to selective deacylation, followed in turn by a conventional acylation with fatty acid ester, as described in Schemes A and B. Conveniently, said Reprotection step is performed with a different N protection group with suitable properties for the subsequent acylation. For example, it would be convenient to use a lipophilic N-protection group, such as, for example, Fmoc in the preparation of the H2G diamino acid derivative, since the lipophilic properties of the protection g roup contribute to the separation of the acylated products.

On the other hand, the lipophilic nature of the Fmoc is less useful when performing an acylation with a fatty acid, and, accordingly, it is convenient to re-protect the diacylated H2G with an alternative N-protection group, such as BOC. It is evident that the preparation of the compounds of Formula I can be initiated with the novel monoacylated intermediates of step b i), ii) or iii) in the first aspect of the invention defined above. These compounds have the following formula: where one of Ri and R2 is i) -C (O) CH (CH (CH3) 2) NH2 or -C (O) CH (CH (CH3) CH2CH3) N H2 ii) an alkyl -C (= O) C3-C2? saturated or monounsaturated, optionally substituted or iii) a regioselective protection group; the remaining Ri or R2 is hydrogen and R3 is OH or H; The following are useful compounds: (R) -9- [2-h-idroxy-methyl-4- (t-butyldiphenylsilyloxy) buty] guanine, (R) -9- [2-h id roxymethyl-4- ( trityloxy) buty] guanine, (R -9- [2-h id roxymethyl-4- (9- (9-phenyl) xanthenyloxy) butyl] guanine, (-9- [2-hydroxymethyl-4- (1,1-bis (4-methylphenii) -1'-pyrenylmethyloxy) bu iljguanine, (R -9- [2-h id roxi methyl-4- (de can oi loxi) buti I] guanine, (R -9- [2-hydroxymethyl) -4- (dodecanoyloxy) butyl] guanine, (R -9- [2-h id roxy methyl-4- (tetradecanoi loxi) butyl] guan ina, (R -9- [2-hydroxymethyl) -4- (hexadecanoyloxy) butyl] guanine, (R -9- [2-hydroxymethyl-4- (octadecanoyloxy) butyl] guanine, (R -9- [2 -hydroxyrnethyl) -4- (eicosanoyloxy) butyl] guanine, (R -9- [2-h id roxy methyl-4- (docosa non-yloxy) bu ti l] guan ina, (R -9- [4-hydroxy] 2- (decanoyloxymethyl) butyl] guanine, (R -9- [4-h-idroxy-2- (dodecanoyloxymethyl) butyl] guanine, (R -9- [4-hydroxy-2- (tetradecanoyloxymethyl) butyl] guanine, (R -9- [4-hydroxy-2- (hexadecanoyloxymethyl) butyl] guanine, (R -9- [4-h id roxy-2- (octadecane-yloxymethyl) buti] gu] nina, (R -9- [4-h] idroxy-2- (eicosanoyloxymethyl!)) butyl] guanine, (R -9- [4-hydroxy-2- (docosanoyloxymethyl) butyl] guanine, (R -9- [2-h id roxi meti I -4- (L -val i loxi) buti I] guanine, (R -9- [2-hydroxymethyl) -4- (L-isoleucilox i) butyl] guanine, (R -9- [4-hydroxy-2- (L-isoleucyloxymethyl) butyl] guanine, (R -9- [4-h-idroxy-2- (L-valyloxymethyl) butyl] guanine. (R -2-ainino-9- [2-hydroxymethyl-4- (L-valyloxy) butyl] purine, (R -2-am ¡no-9- [2-hydroxymethyl) -4- (L-isoleuci) oxi) butyl] pu bra, (R -2-am ino-9- [4-hydroxy-2- (L-isoleuci loxi methyl) buti I] puri na and (R -2-amino-9- [4- Hydroxy-2- (L-valyloxymethyl) butyl] purine.

The side chain 4-hydroxy intermediates with regioselective protection of step c) of the appearance of the first method of the present invention are also novel compounds. Useful compounds include: (R) -9- [2-decanoyloxymethyl-4- (t-buty Id ifenylsilyloxy) buty] guanine, (R) -9- [2-dodecanoyloxymethyl-4- (t-butyldiphenylisilyloxy) butyl ] guanina, (R) -9- [2-tetradecanoyloxymethyl-4- (t-butyldiphenylsilyloxy) util] guanine, (R) -9- [2-hexadecanoyloxymethyl-4- (t-butyldiphenylsilyloxy) butyl] guanine, (R) -9- [2-Octadecanoyloxymethyl-4- (t-butyldiphenylsilyloxy) butyl] guanine, (R) -9- [2-eicosanoyloxymethyl-4- (t-butyldiphenylisilyloxy) butyl] guanine, (R) -9- [2-docosanoyloxymethyl-4- (t-butyldiphenylsilyloxy) butyl] gua ni na, Scheme C shows an alternative process for the preparation of compounds of the invention of Formula I wherein R 3 is -OH.

Scheme C FORMULA 1"41 With reference to Scheme C, the malonate 1_ (R4 and R5 are lower alkyls or benzyl or the like) is alkylated by the reaction with 0.5 to 2.0 molar equivalents approximately of acetal 2 (Re and R7 are lower alkyl or benzyl and the like or R6 and R7 taken together are -CH2CH2- or -CH2CH2CH2- or -CH2CH2CH2CH2- and Xi is a separating group (eg, Cl, Br or I, or a sulfonate, such as , methanesulfonate, triflate, p-toluenesulfonate, benzenesulfonate and the like) in the presence of about 0.5 to 2.0 molar equivalents of a base (eg, potassium butoxide or sodium ethoxide or NaH or KH and the like) in a solvent inert (for example, DMF or THF or dioxane or dioxolane or N-methylpyrrolidone and the like) at a temperature of -40 ° C to 190 ° C approximately to obtain 3-alkylated malonate.

Reduction of 3 with 0.5 to 4.0 molar equivalents of about an ester in an alcohol reducing agent (eg, LiBH4 or Ca (BH4) 2 or NaBH4 or LiAIH4 and the like) in an inert solvent (eg, THF or methyl t-butyl ether or t-BuOH and the like) at a temperature of -20 ° C to about 100 ° C produces -4-diol. Enzymatic esterification of 4 by the reaction with about 1.0 to 20.0 molar equivalents of a vinyl ester 5 (R8 is a saturated or monounsaturated C3-C21 alkyl, optionally substituted) in the presence of a lipase (for example,! Passes PS-30 or lipase PPL or lipase CCL and the like) or a phospholipase (eg, phospholipase D and the like) produces the stereoisomer of ester 6. This reaction can be carried out in the absence of a solvent or in the presence of a inert solvent (for example, methyl t-butyl ether or toluene or hexane and the like). The reaction is carried out at a temperature of -20 ° C to 80 ° C approximately. The substituent alcohol of 6 becomes a leaving group (for example, a halogen or a sulfonate) as a consequence of the reaction with a halogenating agent (for example, NBS / P (Ph), or NCS / P (Ph) 3 or, POCI3 or NCS / P (Ph) 3 / Nal in acetone and the like) in an inert solvent (for example, methylene chloride or toluene or ethylacetate and the like) or as a consequence of the reaction with 0.8 molar equivalents at 2.0 molar equivalent of approximately one sulfonyl halide (per example, benzenesulfonylchloride, toluenesulfonylchloride or methanesulfonylchloride and the like) in the presence of 1.0 to 4.0 molar equivalents of about a base (eg, triethylamine or potassium carbonate or pyridine or dimethylaminopyridine or ethyldiisopropylamine and the like) in an inert solvent ( example, methylene chloride or toluene or ethylacetate or pyridine or methyl t-butyl ether and the like) at a temperature of about -25 ° C to about 100 ° C to obtain the ester 7 (X2 is a leaving halogen or sulfonate group). The reaction of 7 with 0.9 to 2.0 molar approximately equivalents of 2-amino-4-chloropurine 8 in the presence of 1.0 to 6.0 molar equivalent of about one base (eg, potassium carbonate or NaH or KH or NAOH or KOH or lithium diisopropylamide and the like) in an inert solvent (e.g., DMF or THF or acetonitrile or N-methylpirralidone or ethanol and the like) at a temperature of about -25 ° C to 140 ° C produces substituted 9-purine. Alternatively, M itsunobu coupling (for example P (Ph) 3 / diethyl azidocarboxylate) of alcohol 6 with 2-amino-4-chloropurine 8. yields 9. The reaction of 9 with 2.0 to 20 molar equivalents approximately of alcohol R9OH (R9 is an alcohol protecting group, such as, for example, benzyl and the like) in the presence of 1.0 to 6.0 molar equivalents of about a base (eg, Potassium t-butoxide or potassium carbonate or NaH or KH or lithium diisopropylamide and the like) in an inert solvent (for example, TH F or DM F and the like) at a temperature of -25 ° C to 150 ° C produces alcohol 1_0. The removal of the alcohol protection group R9 of 1_0 (for example, by hydrogenation catalyst in an inert solvent, such as, for example, ethanol or benzyl alcohol or methanol or THF and the like in the presence of a hydrogenation catalyst, such as for example, Pd / C or Pd (OH) 2 and the like) produces substituted guanine V \ _. The esterification of 1J_ by reaction with a) from 0.8 to 2.0 molar approximately equivalents of R10COOH and a coupling agent (eg, DCC / DMAP) and if more in an inert solvent (eg THF or DMF and similar) ab) from about 0.8 to 2.0 molar equivalents of an R10COOH derivative in which R10 is a C3-C2 alkyl? saturated or monounsaturated, optionally unsubstituted activated (eg, acid chloride or ester of N-hydroxysuccinimide or R? 0C (O) OC (O) R? 0 and the like) in the presence of 0 to 3.0 molar equivalent of about one base (e.g., pyridine or triethylamine or ethyldiisopropylamine or DBU or potassium carbonate and the like) in an inert solvent (e.g., methylene chloride or THF or pyridine or acetonitrile or DM F and the like) at a temperature of -25 ° C at 100 ° C produces ester 1_2. The acetal substituent of 12 is deprotected and the resulting aldehyde is first reduced by the reaction of 12. with 0.1 to 10.0 molar approximately equivalent of an acid (eg, triflic acid or HCl or acetic acid or sulfuric acid and the like ) in an inert solvent (for example, TH F / H 2 O or methylene chloride / H 2 O or ethyl acetate / H 2 O or ethanol / H 2 O or methanol / H 2 O and the like) at a temperature of -25 ° C to about 100 ° C. To the crude reaction mixture were added from about 0.1 to 10.0 molar equivalents of a base (e.g., sodium bicarbonate or potassium carbonate or triethylamine or pyridine or KOH and the like), additional inert solvent (e.g. THF and / or methylene chloride or ethylacetate or methyl t-butyl ether or isopropoanol and the like) and from 0.3 to 5.0 molar approximately equivalent to an aldehyde reducing agent (for example, sodium bromohydride RaNi / H2 and similar) at a temperature of -25 ° C to 100 ° C to produce an alcohol 1_3. The reaction of 13. with 0.8 to 3.0 molar equivalents of approximately one amino acid P? N HCH (Rn) N-protected COOH or an activated derivative thereof (Pi is a protecting group N and Rn is isopropyl or isobutyl) in an inert solvent (for example, THF or dioxane or dioxolane or DMF or methylene chloride and similar) at a temperature of 25 ° C to 100 ° C approximately produces alcohol? A_. Elimination of the N protection of ± 4 yields the compound of the invention of Formula I where R3 is -OH. As an alternative, the compound .13. can it be reacted with symmetric anhydride derived from P? N HCH (Rn) COOH (i.e. Pi N HCHÍRNJCÍOJO-CÍOJCHíRNJ N HPi) to provide i where R3 is OH. In Scheme D another alternative process for the preparation of compounds where R3 is -OH is shown.

Scheme D Malonate 1 (R 4 and R 5 are lower alkyl or benzyl and the like) are alkylated with about 0.5 to 2.0 molar equivalents of ether wherein X is a leaving group (for example Cl, Br or I, or a sulfonate) , such as, for example, methane sulphonate, triflate, p-toluenesulfonate, benzenesulfonate and the like) and R12 is -CH (Ph) 2, -C (PH) 3 or -Si (t-Bu) (Me) 2 and the like ( Ph = phenyl) in the presence of 0.5 to 2.0 molar equivalents of about a base (for example potassium t-butoxide or sodium ethoxide or NaH or KH and the like) in an inert solvent (e.g., DMF or TH) F or dioxane or dioxolane or N-methyl pyrrolidinone and the like) at a temperature of about -40 ° C to 190 ° C to produce alkylated malonate 1_6. Reduction of? 6 with 0.5 to 4.0 molar approximately equivalent of an ester in an alcohol reducing agent (for example LiBH4 0 Ca (BH4) 2 0 NaBH4 or LiAIH4 and the like) in an inert solvent (e.g. THF or put t-butyl ether or ethanol or t-butanol and the like) at a temperature of -20 ° C to about 100 ° C produces diol 1_7. Enzymatic esterification of .17. by reaction with about 1.0 to 20.0 molar equivalents of a vinyl ester 5 (R8 is a C3-C21 saturated or monounsaturated alkyl, optionally substituted) in the presence of a lipase (e.g., lipase PS-30 or lipase PPL or CCL lipase and the like) or a phospholipase (eg, phospholipase D and the like) produces the desired ester stereoisomer? 8. The reaction can be carried out in the absence of a solvent or in the presence of an inert solvent (for example, methyl t-butyl ether or toluene or hexane or the like). The reaction is carried out at a temperature of -20 ° C to 80 ° C approximately. The substituent alcohol of 18. is converted to a leaving group (for example a halogen or sulfonate) by reaction with a halogenating agent (for example, N BS / P (Ph) 3 or NCS / P (Ph) 3 or POC13 or NCS / P (Ph) 3 / Nal in acetone and the like) in an inert solvent (for example methylene chloride or toluene or ethyl acetate and the like) or by reaction with 0.8 molar equivalent to 2.0 molar equivalent of about one halide of sulfonyl (eg, benzenesulfonylchloride, toluenesulfonylchloride or methane sulfonylchloride and the like) in the presence of 1.0 to 4.0 molar equivalents of about a base (eg, triethylamine or potassium carbonate or pyridine or methyl t-butyl ether and the like) ) at a temperature of -25 ° C to about 100 ° C to produce an ester? 9 (X2 is a halogen or sulphonate leaving group). The reaction of 19. with 0.9 to 2.0 molar equivalents of about 2-amino-4-chloropurine 8 in the presence of 1.0 to 6.0 molar equivalent of about one base (eg, potassium carbonate or NaH) or KH or NAOH or KOH or lithium diisopropylamide and the like) in an inert solvent (for example, DM F or TH F or acetonitrile or N-methylpyrrolidone or ethanol and the like) at a temperature of about -25 ° C to 140 ° C. produces substituted purine 20. Alternatively, the Mitsunobu coupling (eg, P (Ph) 3 / diethyl azidocarboxylate) of alcohol 18 with 2-amino-4-chloropurine 8. yields 20. The reaction of 20 with 2.0 to 20 , About 0 molar equivalents of an alcohol R9OH (R9 is an alcohol protecting group, such as, for example, benzyl and the like) in the presence of 1.0 to 6.0 molar equivalents of about one base (eg, t-butoxide) potassium or potassium carbonate or NaH or KH or lithium diisopropylamide and the like) in an inert solvent (for example, THF or DMF and the like) at a temperature of -25 ° C to 150 ° C produces alcohol 21_. The removal of the alcohol protecting group R9 from 2 _ (for example, by hydrogenation catalyst in an inert solvent (such as for example, ethanol or benzyl alcohol or methanol or THF and the like) in the presence of a hydrogenation catalyst, such as for example , Pd / C or Pd (OH) 2 and the like) produces substituted guanine 22. The esterification of 22 by reaction with a) of 0, 8 to 2 molar approximately equivalent of R10COOU of a C3-C2 alkyl? saturated or monounsaturated, optionally unsubstituted and a coupling agent (e.g., DCC / DMAP and the like) in an inert solvent (e.g., THF or DMF and the like) or b) from 0.8 to 2.0 molar equivalents approximately an activated derivative of R10-COOH (for example, the acid chloride or the ester of N-hydroxysuccimide or R? 0-C (O) = C (O) -R? o and the like) in the presence of 0 to 3.0 molar equivalents of a base (eg, pyridine or triethylamine or ethyldiisopropylamine or DBU or potassium carbonate and the like) in an inert solvent (eg, methylene chloride or THF or pyridine or acetonitrile or DMF and the like) at a temperature between -25 ° C and 100 ° C approximately produces ester 2Z_. The substituent ether of 23. is deprotected as a consequence of the reaction with a) a reducing agent (e.g., HC2H and Pd / C and the like) where R12 is -CH (Ph) 2 0 -C (Ph) 3- or b) a desilylating agent (e.g., Bu4NF and the like) where Ri2 is -Si (t-Bu) (Me) 2 and the like to produce 1_3. The alcohol 13 can be converted to 1 as shown in Scheme C. A further alternative includes an enzymatic esterification of the alcohol 4 or 1_7 with the vinyl ester CH 2 = CH-OC (O) R 0 (ie R 8 = Rio in Schemes C and D) to directly incorporate in 6 or 18 the carboxylic acid ester of the final product 1_. This makes it possible to eliminate the hydrolysis of the ester and the reesterification which involves going from 9 to 12 or 20 to 2_3. The processes of Schemes C and D are characterized by the fact that each of the hydroxyl groups of the acyclic side chain is differentiated by the use of different precursor groups or hydroxy protecting groups. This allows the selective acylation of each hydroxy group with an amino acid or fatty acid group. The above Schemes C and D have been illustrated and described in relation to the compounds wherein Ri derives from an amino acid and R2, from a fatty acid. It is evident, however, that the corresponding inverse scheme can be applied to the compounds where Ri is derived from a fatty acid and R2 from an amino acid.

DETAILED DESCRIPTION OF THE INVENTION The invention will now be described by way of example with reference to the following Examples, Comparative Examples and Attached Figures where: Figure 1 shows levels of H2G in plasma as a function of time in cynemolgus monkeys which were administered a compound of the invention or an alternative prodrug derivative of H2G, as explained in detail in Biological Example 3; and Figure 2 shows survival as a function of time for rats infected with Herpes simplex to which several doses of a compound of the invention or an anti-viral of the prior art were administered, as explained in Biological Example 4.

EXAMPLE 1 (R) -S-F2- (Estearoi loximeti l) -4- (L-valyloxy) butyl] guani na This example illustrates the application of the preparation of the Scheme A. a) (R) -9- [4- (N -tert- Bu toxi carbo ni I-L-val i loxi) -2- (hydroxymethyl) butyljguanine. H2G (5 g, 19.7 mmol) was dissolved in DM F (300 ml) under hot conditions and cooled to room temperature before adding Nt-BOC-L-valine (5.58 g, 25.7 g). mmol), DMAP (0.314 g, 2.57 mmol) and DCC (6.52 g, 31.6 mmol). The mixture was stirred at room temperature for 24 h and filtered. The product was chromatographed on silica gel, diluted with CH2Cl2 / MeOH and 2.4 g of the desired intermediate was obtained. 1 H-NMR (250 MHz, DMSO-d 6): 8.95 (d, 6H), 1.47 (s, 9H), 1.5-1.8 (m, 2H), 1.96-2, 20 (m, 2H), 3.40 (m, 2H), 3.91 (t, 1H), 4.05 (m, 2H), 4.21 (t, 2H), 4.89 (t, 1H) ), 6.6 (br s, 2H), 7.27 (d, 1H), 7.75 (s, 1H), 10.7 (br s, 1H). b) (R) -9- [4- (N -tert-Butoxycarbonyl-L-valloxy) -2- (is aro i loxi-methyl) butyl] guanine The product of step a) (185 mg, , 41 mmol) was dissolved in pyridine (5 ml), the solution was cooled with an ice bath and stearoyl chloride (179 μl, 0.531 mmol) was added. The solution was kept in the ice bath for 2 hours, then at room temperature for 1 hour. It was then evaporated and chromatographed on silica gel. It was eluted with dichloromethane-methanol and 143 mg of the desired intermediate product were obtained. (C) (R) -9- [2- (Stearoyloxymethyl) -4- (L-valyloxy) butyl] guanine. The product from step b) (138 mg, 0.192 mmol) was cooled with an ice bath and trifluoroacetic acid (5 ml) was added. The solution was kept in the ice bath for 45 minutes, then evaporated and an oil was obtained. Water (0.5 to 1 ml) was added and evaporated twice. The residue was dissolved once more in water (5 ml), filtered, dried by freezing and 148 mg of the desired compound was obtained in the form of bistrifluoroacetate salt. 1 H NMR (250 MHz, DMSCO-d 6): 0.97 (t, 3 H), 1.05 (dd, 6 H), 1.34 (br s, 28 H), 1.59 (m, 2 H), 1 , 80 (m, 2H), 2.25 (m, 1H), 2.36 (t, 2H), 2.50 (m, 1H), 3.98-4.18 (m, 5H), 4, 35 (t, 2H), 6.6 (br s, 2H), 8.0 (br s, 1H), 8.4 (br s, 3H), 10.9 (br s, 1H).

EXAMPLE 2 (R) -9- [2- (Myristoyloxyrnethyl) -4- (L-valyloxy) butyl] guanine The title compound was obtained in the form of the bistrifluoroacetate salt in a manner similar to that of Example 1 using myristoyl chloride instead of stearoyl chloride in step b). 1 H NMR (250 MHz, DMSO-d 6): 5 0.97 (t, 3H), 1.05 (dd, 6H), 1.34 (br, 20H), 1.57 (m, 2H), 1.78 (m, 2H), 2.24 ( m, 1H), 2.35 (t, 2H), 2.51 (m, 1H), 3.97- 4.20 (m, 5H), 4.36 (t, 2H), 6.8 (brs, 2H), 8.2 (br s, 1H), 8.5 (brs, 3H), 11.1 (br s, 1H).

EXAMPLE 3 (R) -9- [2- (Oleoyloxymethyl) -4- (L-valyloxy) butyl] guanine The title compound was obtained as the bistrifluoroacetyl salt in a manner similar to that of Example 1, except that in step b) oleoyl chloride was used in place of stearoyl chloride. 1 H NMR (250 MHz, DMSO-d 6): 0.96 (t, 3H), 1.05 (dd, 6H), 1.35 (br s, 20H), 1.59 (m, 2H), 1, 76 (m, 2H), 2.09 (m, 4H), 2.24 (m, 1H), 2.35 (t, 2H), 2.50 (m, 1H), 3.97-4.17 (m, 5H), 4.35 (t, 2H), 5.43 (t, 2H), 6.7 (br s, 2H), 8.0 (br s, 1H), 8, 5 (br s , 3H), 11, 1 (br s, 1H).

EXAMPLE 4 (R) -9- [2- (Butyrylaxymethyl) -4- (L-valyloxy) butyl] guanine a) (R) -9- [4- (N -tert- Butoxica rboni I-L-val i I oxy) -2-butyloxymethyl) butyl] guanine DCC (110 mg, 0.53 mmol) was dissolved in dichloromethane (10 ml) and butyric acid (82 mg, 0.93 mmol) was added. After 4 hours at room temperature the mixture was filtered and the filtrate was evaporated. The residue was dissolved in pyridine (5 ml) and (R) -9- [4- (N-tert-Butoxycarbonyl-L-valyloxy) -2-hydroxymethylbutyl] guanine (200 mg, 0.44 mmol) was added (Example 1, step a). The mixture was stirred for 120 hours at room temperature. According to the TLC the reaction was not completed and more anhydride was prepared by applying the above procedure. This anhydride was added and the mixture was stirred for a further 20 hours. The reaction mixture was evaporated and chromatographed first on silica gel and then on aluminum oxide, in both cases it was eluted with dichloromethanemethanol and 79 mg of the intermediate product was obtained. b) (R) -9- [2- (Butyryloxymethyl) -4- (L-valyloxy) butyl] guanine The intermediate from step a) was deprotected in a similar manner to that of Example 1, step 3 and obtained 84 mg of the desired compound in the form of bistrifluoroacetate salt. 1 H-NMR (250 MHz, D 2 O): d 3 0.88 (t, 3 H), 1.06 (dd, 6 H), 1.53 (m, 2 H), 1.93 (q, 2 H), 2.25 (t, 2H), 2.36 (m, 1H), 2.60 (m, 1H), 4.06 (d, 1H), 4.14-4.30 (m, 2H), 4.43 ( m, 4H), 8.99 (br s, 1H).

EXAMPLE 5 (R) -9- (2-Decanoyloxymethyl) -4- (L-valyloxy) buti!] Guanine The title compound was obtained as the bistrifluoroacetate salt in a manner similar to that of Example 1, except that in step b) decanoyl chloride was used in the escape of stearoyl chloride. NMR 'H (250 MHz, D2O): d 0.90 (m, 3H), 1.01 (d, 6H), 1.28 (br s, 12H), 1.5 (m, 2H), 1, 8 (m, 2H), 2.3 (m, 3H), 2.5 (m, 1 H), 4.0-4.4 (m, 7H), 8.1 (br s, 1H).

EXAMPLE 6 (R) -9-r2-Docosanoyloxymethyl-4- (L-valyloxy) butyl] guanine The title compound was obtained as the bistrifluoroacetate salt in a manner similar to that of Example 1, but in step b) the conditions of DMAP / DCC of Example 1 step a) were used together with docosaenoic acid instead of Nt-Boc -L-valine and a mixture of DMF and dichloromethane as solvent. 1 H NMR (250 MHz, DMSO-d 6): d 0.97 (t, 3H), 1.05 (dd, 6H), 1.34 (br s, 36 H), 1.58 (m, 2H) , 1.77 (m, 2H), 2.24 (m, 1 H), 2.35 (t, 2H), 2.50 (m, 1 H), 3.97- 4, 17 (m, 4 , 35 (t, 2H), 6.7 (br s, 2H), 8, 1 (br s, 1 H), 8.4 (br s, 3 H), 1 1, 0 (br s, 1 H) .

EXAMPLE 7 R-9- [4- (L-lsoleucyloxy) -2-festearoyloxirnethyl) butyl] guanine This example illustrates the application of Preparative Scheme B, a) (R) -9- [2-hydroxymethyl 4- (t-butyldiphenylsilyloxy) butyl] guanine H2G (2g, 8 mmol) was coevaporated with dry DM F twice and then suspended in dry DMF (120 ml) and pyridine (1 ml) .T-butyldiphenylchlorosilane (2.1 ml, 8.2 mmol) in dichloromethane (20 ml) at 0 ° C was added to the suspension for a period of time. The reaction mixture was transformed into a clear solution when the dropwise addition was completed.The reaction was continued at 0 ° C for two hours and kept at 4 ° C overnight Methanol (5 ml) was added After 20 minutes at room temperature, the reaction mixture was evaporated leaving a small volume, poured into an aqueous solution of sodium hydrogen carbonate and extracted with dichloromethane twice, the organic phase was dried over sodium sulfate. Sodium and evaporated in vacuo The product was isolated by column chromatography with silica gel using a methanol / dichloromethane system gradually increasing the concentration of MEOH. The product was eluted with 7% MEOH in CH 2 Cl 2 and 1.89 g was obtained. b) (R) -9- [2- (Stearoyloxymethyl) -4- (t-butyldiphenylsilyloxy) butyl] guanine (R) -9- [2-Hydroxymethyl-4- (t-butyldiphenylsilyloxy) butyl] guanine (2.31) g, 5 mmol) was coevaporated with dry pyridine twice and dissolved in pyridine (20 ml). Stearoyl chloride (1.86 ml, 5.5 mmol, titre grade) in dichloromethane (2 ml) at -5 ° C was slowly added to the solution. The reaction was maintained at the same temperature for 1 hour and then at 5 ° C for 2 hours. The reaction was monitored by TLC. More stearoyl chloride was added (0, 29 ml) at -5 ° C because the reaction was not completed. After 30 minutes at 5 ° C, methanol (3 ml) was added and the reaction mixture was stirred for 20 min. It was then poured into an aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic phase was dried and the product was purified by column chromatography with silica gel gradually increasing the MEOH, and eluting with 3.5% MEOH in CH 2 Cl 2 - (yield 2.7 g). c) (R) -9 - [(4-Hydroxy-2- (stearoyloxymethyl) butyl] guanine (R) -9- [2- (Stearoyloxymethyl) -4- (t-butyldiphenylsilyloxy) butyljguanine (2.7 g) was dissolved 3.56 mmol) in dry THF (30 ml) and HF-pyridine (1.5 ml) was added to the solution, the reaction was maintained at 4 ° C overnight and monitored by TLC. about 80% conversion, more HF-pyridine (0.75 ml) was added, after 4 hours, the TCL indicated that the initial material disappeared, the reaction mixture was concentrated in vacuo without raising the temperature and more pyridine (5 ml) and evaporated again The product was isolated by column chromatography on silica gel (yield 1.26 g) d) (R) -9- [4- (N- BOC- L- iso leucyloxy) -2- (stearoyl oxy-methyl I) butyl] guanine (R) -9- [4-Hydroxy-2- (stearoyloxymethyl) butyl] guanine (135 mg, 0.26 mmol) and N-BOC-L Isoleucine (180 mg, 0.78 mmol) was coevaporated with dry DMF twice and dissolved in the same solvent (3.5 ml). To the solution were added 1,3-dicyclohexylcarbodiimide (160 mg, 0.78 mmol) and 4-dimethylaminopyridine (4.8 mg, 0.039 mmol). After 18 hours of reaction, the reaction mixture was filtered with Celite and treated in a conventional manner. The product was isolated by column chromatography on silica gel, eluted at 5% MEOH in CH 2 Cl 2. (Yield 160 mg) e) (R) -9- [4- (L-lsoleucyloxy) -2- (stearoyloxymethyl) -butyl] guanine (R) -9- [4- (N-BOC-L-isoleucyloxy) - 2- (stearoyloxymethyl) butyl] guanine (150 mg, 0.205 mmol) from step d) was treated with trifluoroacetic acid (3 ml) at 0 ° C for 20 min. The solution was evaporated in vacuo. The residue was coevaporated with toluene twice and kept under vacuum for several hours. The residue was dissolved in MEOH (2 ml), evaporated and the trifluoroacetate salt was obtained as a glaze product (Yield 191 mg). 1 H NMR (DMSO-dβ + D 2 O): d 8.35 (s, 1H, base), 4.21 (t, 2H, H-4), 4.10 (d, 2H) 3.96 (d, 2H ), 3.90 (d, 1H, isoleucine), 2.48 (m, 1H, H-2), 2.15 (2H, stearoyl), 1.85 (m, 1H, isoleucine), 1.68 ( m, 2H), 1.48 (m, 4H), 1.68 (m, 28H), 0.81 (m, 9H).

EXAMPLE 8 (R) -9- [2- (Decanoyl oxyme i I) -4- (L-isofeucyloxy) butyl] guanine The title compound was obtained as the bistrifluoroacetyl salt in a manner similar to that of Example 7 except that in step b) decanoyl chloride was used in place of stearoyl chloride. 1 H NMR (DMSO-dβ): d 11.1 (s, IH, NH), 8.35 (s, br, 3H), 8.28 (s, 1H, base), 6.75 (s, 2H, NH,), 4.23 (t, 2H), 4.07 (d, 2H), 4.05 (m, 3H), 2.4 (m, 1H), 2.21 (t, 2H), 1.83 (m, 1H), 1.66 (m, 2H), 1.45 (m, 2H), 1.39 (m, 2H) , 1.22 (s, 12H), 0.84 (m, 9H).

EXAMPLE 9 (R) -9- [4- (L-lsoleucyloxy) -2- (myristoyloxymethyl) butyl] guanine The title compound was obtained as the bistrifluoroacetyl salt in a manner similar to that of Example 1 except that in step a) N-BOC-L-isoleucine was used instead of N-BOC-valine) and miristoil in step b). 1 H NMR (DMSO-dβ): d 1.99 (s, 1H), 8.34 (br s, 3H) 8, 1 5 (s, 1H), 6.67 (br s, 2H), 4, 23 (t, 2H), 4.05 (d, 2H), 3.97 (m, 3H), 2.48 (m, 1H), 2.20 (t, 2H), 1.85 (m, 1H) ), 1.65 (m, 2H), 1.41 (m, 4H), 1.23 (s, 20H), 0.85 (m, 9H).

EXAMPLE 10 (R) -9- [2- (4-Acetylbutyryloxymethyl-4- (L-valyloxy) butyl] guanine The title compound was obtained as the bistrifluoroacetate salt in a manner similar to that of Example 1 but using in step b) the conditions of DCCIDMAP of Example 1, step a) together with 4-acetylbutyric acid instead of Nt-Boc. L-valine. NMR? (250 MHz, DMSO-d6): d 1.05 (dd, 6H), 1.77 (m, 4H), 2.19 (s, 3H), 2.24 (m, 1H), 2.36 ( t, 2H), 2.44-2.60 (m, 3H), 3.95-4.20 (m, 5H), 4.36 (m, 2H), 6.8 (br s, 2H), 8.3 (br s, 1 H), 8.5 (br s, 3 H), 11, 1 (br s, 1 H).

EXAMPLE 11 (R) -9- [2-Dodecanoyloxymethyl-4- (L-valyloxy) butyl] guanine The title compound was obtained as the bistrifluoroacetate salt in a manner similar to that of Example 1 except that in step b) decanoyl chloride was used in place of stearoyl chloride.

EXAMPLE 12 (R) -9- [2-Palmitoyloxymethyl-4- (L-valyloxy) butyl] guanine The title compound was obtained as the bistrifluoroacetate salt in a manner similar to that of Example 1 with the proviso that in step b) palmitoyl chloride was used in place of stearoyl chloride. 1 H NMR (250 MHz, DMSO-d 6): δ 0.97 (t, 3H), 1.05 (m, 6H), 1.35 (br s, 24H), 1.58 (m, 2H), 1 , 78 (m, 2H), 2.25 (m, 1H), 2.35 (t, 2H), 2.51 (m, 1 H), 3.97-4.18 (m, 5H), 4.35 (t, 2H), 6.7 (br s, 2H), 8.1 (br s, 1 H), 8.5 (br s, 3 H), 1.0 (br s, 1 H).

EXAMPLE 13 (R) -2-Amino-9- (2-stearoyloxymethyl-4- (L-vayloxy) butyl) purine This example shows the deoxygenation of the group R ?. a) (R) -2-Amino-9- (2-stearoyloxymethyl-4- (N-tert-butoxycarbonyl-L-valyloxy) bu ti I) -6-cl or rop urin: To a solution of (R ) -9- (2-Stearoyloxymethyl-4- (N-tert-butoxycarbonyl-L-vayloxy) butyl) guanine from step 2 of Example 1 (646 mg, 0.9 mmol) in acetonitrile were added tetramethylammonium chloride (427 mg , 2.7 mmol), N, N-diethylaniline (0.716 ml, 4.5 mmol) and phosphorus oxychloride (0.417 mL, 4.5 mmol). The reaction was maintained under reflux conditions and evolution was monitored by TLC. After 3 hours the reaction mixture was evaporated in vacuo and the residue was dissolved in dichloromethane, then an aqueous solution of cold sodium hydrogen was poured. The organic phase was evaporated and purified by column chromatography on silica gel. Yield: 251 mg. 1 H NMR (CDCl 3): d 7.76 (1 H, H-8), 5.43 (br, 2 H, NH 2), 4.45-4.00 (m, 7H), 2.53 (m, 1 H), 2.28 (t 2H), 2.12 (m, 1H), 1.75 (m, 2H), 1.59 (m, 2H), 1.43 (9H), 1.25 (m, 28H), 0.96 (d, 3H), 0.87 (m, 6H). b) (R) -2-Amino-9- (2-stearoyloxymethyl-4- (N-tert-butoxycarbonyl-L-valyloxy) butyl) purine: To the solution of (R) -2-amino-9- (2 -stearoyloxymethyl-4- (N-tert-butoxycarbonyl-L-valyloxy) butyl) -6-chloropurine (240 mg, 0.33 mmol) in methanol / ethyl acetate (6 ml, 3: 1 VN) were added ammonium formate (105 mg, 1.65 mmol) and 10% palladium on carbon (15 mg). The reaction was maintained under reflux conditions for 1 hour and ammonium formate (70 mg) was added again. After one more hour the TLC indicated that the reaction was completed and the mixture was filtered with Celite and washed intensively with ethanol. The filtrate was evaporated and purified on a column of silica gel. Yield: 193 mg. 1 H-NMR (CDCl 3): d 8.69 (s, 1 H, H-ß), 7.74 (s, 1 H, H-8), 5.18 (br, s, 2 H, NH 2), 4, 45-4.01 (m, 7H), 2.55 (m, 1H), 2.28 (t, 2H), 2.10 (ra, 1H), 1.75 (m, 2H), 1.60 (m, 2H), 1.43 (s, 9H), 1.25 (s, 28H), 0.96 (d, 3H), 0.87 (m, 6H). (R) -2-Amino-9- (2-stearoxy! Oxy) methyl-4- (L-valyloxy) butyl) purine: (R) -2-Amino-9- (2-Stearoyloxymethyl-4- (N-tert-butoxycarbonyl-L-valyloxy) butyl) purine (180 mg, 0.26 mmol) was treated with trifluoroacetic acid (5 ml) at 0 ° C for 40 min. It was then evaporated in vacuo and coevaporated successively with toluene and methanol. The residue was dried by freezing overnight and 195 mg of the desired compound were obtained. 1 H-NMR (DMSO-d 6): d 8.78 (s, 1 H, H-ß), 8.32 (br, 3 H), 8.29 (s, 1 H, H-8), 4.27 (t, 2H), 4.13 (d, 2H), 3.98 (t, 2H, 2H), 3.89 (m, 1H), 2.47 (m, 1H), 2.18 (m, 3H), 1.43 (m, 2H), 1.23 (28H), 0.93 (m, 6H), 0.85 (t, 3H).

EXAMPLE 14 Alternative preparation of (R) -9-r4-Hydroxy-2- (stearoyloxymethyl) butu-guanine a) Preparation of ethyl 4,4-diethoxy-2-ethoxycarbonyl butyrate Potassium tert-butoxide (1 41, 8 g, 1.1 mole) was dissolved in dry DMF (1 L). Diethyl malonate (266 mL, 1.54 equiv.) Was added for 5 minutes. Bromoacetaldehyde diethylacetal (172 mL, 1.14 mol) was added over 5 minutes. The mixture was heated to a temperature of 120 ° C (internal temperature) and stirred at 120 ° C for 5 hours. The mixture was allowed to cool to room temperature, poured into water (5 L), and extracted with methyl tert-butyl ether (MTBE, 3 x 600 mL). The organic solution was dried over MgSO 4, filtered, concentrated and distilled (0.5 mm, 95-140 ° C) and the desired diester (244 g, 78%) was obtained as a colorless oil. H-NMR (CDCl 3) d 1, 19 (t, 6H), 1, 28 (t, 6H), 2.22 (dd, 2H), 3.49 (m, 2H), 3.51 (t, 1 H) ), 3.65 (m, 2 H) 4.20 (qd, 4H), 4.54 (t, 1 H). b) Preparation of 4,4-diethoxy-2- (hydroxymethyl) -butanol LBH4 (purchased solution, 2M in TH F, 22.5 mL) and the product of Example 14 step a) (5 g in 15 mL of THF, 18.1 mmol) were combined and heated to 60 ° C and stirred at 60 ° C for 4 hours. The reaction mixture was allowed to cool to room temperature and the reaction vessel was placed in a cold water bath. Then triethanolamine (5.97 ml, 1 equiv.) Was added at such a rate that the temperature of the reaction was maintained between 20-25 ° C. Water with salt (17.5mL) was added at a rate such that the gas evolution was controlled and the mixture was stirred for 45 minutes at room temperature. The layers were separated, the organic layer was washed with water with salt (2 x 15 mL). The washings combined with water and salt were extracted with MTBE (methyl tert-butyl ether, 3 x 20 mL). The combined organic extracts were evaporated and the residue was dissolved in MTBE (50 mL) and washed with water with salt (25 mL). The water and salt layer was extracted with MTBE (3 x 25 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to obtain the desired oil (3.36 g, 15.5 mmol, 97%) as a colorless oil. 1 H NMR (CDCl 3) d 1, 22 (t, 6H), 1.73 (dd, 2H), 1.92 (m, 1 H), 2.67 (bs, 2H), 3.52 (m, 2H), 3.69 (m, 2H), 3.72 (m, 4H), 4.62 (t, 1 H).

(C) Preparation of (2R) -2-acetoxirnethyl-4,4-diethoxybutanoi HO 'OAc EtO OEt The product of Example 14 step b) (3.84 g, 20 mmol) was charged into a 10 ml flask with round neck and base, then vinyl acetate (2.6 g, 30 mmol) and finally lipase were added. PS 30 (69 mg, purchased from Amano, Lombard, Illinois). The mixture was allowed to stir at room temperature for 16 hours. The evolution of the reaction was monitored by TLC (21 1 hexane-EtOAc; with Ce 2 (SO 4), and carbonized on a hot plate: rf of diol is 0.1, monoacetate is 0.3, bis acetate is 0.75 ). The reaction mixture was diluted with CH2Cl2 and filtered with a 5 micron filter. The filter was washed with additional CH2Cl2. The filtrate was concentrated in vacuo and the desired product was obtained. d) Preparation of (2S) -2-acetoxymethyl-4,4-diethoxybutyl toluenesulfonate TsO OAc EtO OEt Into a 100 mL flask with a round neck and base equipped with a magnetic stir bar and a separator in N2 was charged the crude product of Example 14 step c) (4.62 9, 1 9 mmol) dry CH2CI (20 mL) and Et 3 N (5.62 mL, 40 mmol). To this solution was added tosyl chloride (4.76 9, 25 mmol). The resulting mixture was stirred at room temperature for 4 hours. H 0 (0.27 g, 15 mmol) was charged and stirred vigorously for 4 hours. The reaction mixture was diluted with 80 mL EtOAc and 50 mL H20 and the aqueous layer was separated. To the organic layer was added 75 ml of a 5% aqueous solution of KH2PO. After mixing and separating the layers. the aqueous layer was removed. The organic layer was washed with 50 mL of saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo to a constant weight of 7.40 g of the desired compound. 1 H NMR (CDCl 3) d 1.17 (t, 6H); 1.62 (m, 2H); 1.94 (s, 3H); 2.19 (m, 1H); 2.45 (s, 3H); 3.42 (m, 2H); 3.6 (m, 2H); 4.03 (m, 4H); 4.51 (t, 1H); 7.36 (d, 2H); 7.79 (d, 2H). e) Preparation of The product of Example 14 step d) (3.88 g, 10 mmol), anhydrous DMF (20 mL), 2-amino-4-chloro-purine (2.125 g) was charged into a 50 mL flask with a round neck and base. , 12.5 mmol) and K2CO3 (4.83 g). The resulting suspension was stirred at 40 ° C under a layer of N2 for 20 hours. The mixture was concentrated to remove most of the DMF in a rotary evaporator. The residue was diluted with EtOAc (50 mL) and H20 (50 mL). The reaction mixture was transferred to a separatory funnel, shaken and the aqueous layer separated. The aqueous layer was extracted with EtOAc (25 mL). The organic layers were combined and washed with 5% KH2PO4 (75 mL). The organic layer was separated and washed with H20 (75 mL), water and salt (75 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain 3.95 g of the crude product. The crude product was suspended with 40 mL of methyl-t-butyl ether. This mixture was stirred overnight at 4 ° C and the mixture was filtered. The filtrate was concentrated and 3.35 g of the product was obtained as an oil (containing 2.6 g of the desired compound based on HPLC analysis). 300 MHz 1 H NMR (CDCl 3) d 1.19 (m, 6H); 1.69 (2H); 1.79 (s, 1H); 2.03 (s, 3H); 2.52 (m, 1H); 3.48 (m, 2H); 3.62 (m, 2H); 4.04 (m, 2H); 4.16 (m, 2H); 4.61 (t, 1 H); 5.12 (bs, 2H); 7.81 (s, 1 H). f) Preparation of (Bn = Bencil) In a 500 mL flask with a round neck and base, benzyl alcohol (136 mL) was charged, cooled to 0 ° C, followed by the gradual addition of KO-t-Bu (36 g, 321 mmol). . The temperature was allowed to reach 40 ° C and the mixture was stirred for 20 minutes. To this mixture was added at a temperature of 0 ° C, the crude product of Example 14 step e) (24.7 g, 64.2 mmol) was dissolved in 25 mL anhydrous THF and benzyl alcohol (30 mL). A temperature of 8 ° C was allowed to slowly reach for 2 hours. The reaction mixture was poured into 500 mL of ice and extracted with 500 mL MTBE. The organic layer was washed with 250 mL of water and salt, dried over Na 2 SO 4, filtered and concentrated in vacuo and 193 g of a benzyl alcohol solution of the desired compound were obtained. HPLC analysis indicated that the solution contained 25.96 g of the desired compound. 300 MHz 1 H NMR (CDCl 3) 6 1.22 (m, 6H); 1.55 (2H); 2, 18 (m, IH); 3.15 (m, 1 H); 3.40 (m, 1 H); 3.51 (m, 2H); 3.70 (m, 2H); 4.25 (m, 2H); 4.63 (t, 1 H); 4, 90 (bs, 2H); 5.25 (m, 1 H); 5.58 (s, 2H); 7.35 (m, 3H); 7.51 (m, 2H); 7.72 (s, 1 H), MS (M + H) + = 416 (Cl). g) Preparation of The crude product of Example 14 step f) (9.65 g of the benzyl alcohol solution, containing 1.30 g, 3.13 mmol of the product of Example 14, step f) dissolved in absolute ETOH (20 mL). Then, 0.45 g of 10% Pd / C in suspension in 5 mL of absolute ETOH was added. The reaction vessel was evacuated and charged with H three times with a balloon of H2. The reaction vessel was pressurized with 1 atm. The H2 and the reaction mixture were stirred overnight. The reaction mixture was filtered with diatomaceous earth to remove the Pd / C The volatile elements were removed in vacuo. The residue was mixed with 25 mL of isopropyl acetate and concentrated in vacuo. The residue was diluted with EtOAc (10 mL) and the desired product was added, heated under reflux conditions, then added CH3CN (2 mL) and MTBE (35 mL). The mixture was stirred for 30 minutes. The precipitate was filtered and dried at a constant weight of 600 mg of the desired product. 300 MHz 1 H NMR (d 6 -DMSO) d 1.1 6 (m, 6H); 1.45 (m, 1H); 1.61 (m, 1H); 2.16 (m, 1H); 3.45 (m, 2H); 3.40 (m, 1H); 3.62 (m, 2H); 4.02 (m, 2H); 4.53 (t, 1 H); 4.85 (t, 1 H); 6.55 (bs, 1 H); 7.75 (s, 1H), MS = (M + H) + = 416 (Cl). h) Preparation of OEt The product of Example 14 step g) (0.650 g, 2.0 mmol), pyridine (4 mL) and CH2Cl2 (2 mL), DMAP (10 mg) was charged into a 25 mL round neck flask with a round base. . The mixture was cooled to -5 ° C and dissolved and the stearoyl chloride (790 mg, 2.6 mmoi) dissolved in CH 2 Cl (0.5 mL) was added for 5 minutes. The resulting mixture was stirred 16 hours at -5 ° C. ETOH (0.138 g, 3.0 mmol) was added and the mixture was stirred for an additional hour. The reaction mixture was concentrated in vacuo. Toluene (30 mL) was added to the residue and the mixture was concentrated in vacuo. Toluene (30 mL) was added to the residue and the mixture was concentrated in vacuo. 1% KH2PO4 (25 mL) was added to the residue and this mixture was extracted with CH2Cl2 (60 mL). The organic layer was separated and dried over Na 2 SO 4, filtered and concentrated in vacuo to a constant weight of 1.65 g. The crude product was chromatographed on 40 g of SiO2, eluted with 95/5 CH2CI2-ETOH, in a yield of 367 mg of the desired compound. 300 MHz 1 H NMR (CDCl 3) d 0.89 (t, 3H); 1.26 (m, 30H); 1.65 (m, 3H); 2.32 (m, 1 H); 3.45 (m, 1 H); 3.60 (m, 2H); 4.08 (m, 2H); 4.60 (m, 1 H); 6, 0 (bs, 2 H); 7.53 (s, 1 H). i) Preparation of The product of Example 14 was loaded in a 25 mL round neck and base flask, step h) (0.234 g, 0.394 mmol) was dissolved in TH F (1.7 mL). To this solution was added triflic acid (0.108 g) in H20 (180 mg). The mixture was stirred overnight at room temperature. To the reaction mixture was added a solution of saturated NaHCO3 (10 mL), THF (5 mL), CH2CI2 (2 mL) and NaBH4 (0.10 g). This mixture was stirred for 30 minutes. A 5% solution of KH2PO4 (30 mL) was added to the reaction mixture. This mixture was extracted with 2 x 15 ml of CH2Cl2. The organic layers were combined and dried over Na2SO4, filtered and concentrated in vacuo to a constant weight of 207 mg. This material was recrystallized from EtOAc (8 mL) and CH3CN (0.5 mL) and 173 mg of the desired compound was obtained. 300 MHz 1 H NMR (d 6 -DMSO) d 0.82 (t, 3H); 1.19 (m, 30H); 1.41 (m, 4H); 2.1 9 (t, 2H); 2.32 (m, 1H); 3.40 (m, 2H); 3.9 (m, 4H); 4.49 (m, 1H); 6.4 (bs, 2H); 7.61 (m, 1.5H); 9.55 (m, 0.5H).

EXAMPLE 15 Alternative preparation of (R) -9-r4- (N-tert-butyloxysarbonyl-L-valyloxy) -2- (stearoyloxymethyl) butylguanine (R) -9- [2- (stearoyloxymethyl) -4- (t-butyldiphenylsilyloxy) butyl ] guanina (45g) and THF (950 ml) were combined in a 2L vessel. Then Boc-L-valine (3.22 g, 0.25 eq) was added, followed by tetrabutylammonium fluoride (IM in THF, 89.05 mL) for 10 minutes. The clear reaction mixture was stirred at room temperature for 2 hours and 50 minutes and the evolution of the reaction was monitored by TLC (90/10 CH2Cl2 / MeOH). Boc-L-valine (35.43 g, 2.75 eq), DCC (36.67 g, 2.75 eq) and dimethylaminopyridine (1.1 g, 0.15 eq) were added to the reaction mixture. THF (25 ml). The reaction mixture was stirred at room temperature for 24 hours. DCU was filtered and washed with CH2Cl2. The filtrate was concentrated and the residue was extracted into 2 liters of CH 2 Cl 2 and washed with 2 L of solutions 1/2 of saturated sodium bicarbonate and water with salt. After the drying and evaporation steps, 100 g of the crude product were obtained. The material was purified by silica chromatography (6000 ml of silica) with 3% MeOH / CH 2 Cl 2 in 5% MeOH / CH 2 Cl 2 to obtain 38.22 mg of the desired compound.

EXAMPLE 16 Alternative preparation of (R) -9-r2- (stea roil oxy methyl) -4- (L-vallyloxy) butylguanine a) (R) -9- [2-Hydroxymethyl) - 4- (t-butyldiphenyl) Mi! oxymethyl!) butyl] guanine H2G (450.0 g, 1.78 mol) and N, N-dimethylformamide (6.4 kg) were charged to a Bucchi evaporator and the mixture was heated to dissolve the solid. The solution was concentrated to dry under vacuum conditions at a temperature not higher than 90 ° C. The resulting powder was transferred to a 22 liter vessel equipped with a stirrer and funnel and a thermosensitive probe. N. N-dimethylformamide (1.7 kg) was added followed by pyridine (3.53 kg). The resulting suspension was cooled to -10 ° C under nitrogen and stirred at -5 + 5 ° C while adding t-butylchlorodiphenylsilane (684 g, 2.49 mol) per drop. The resulting mixture was stirred at -5 + 5 ° C until the reaction was complete (monitored by TLC (10: 1 methylene chloride / methanol) and HPLC (4.6 x 250 mm Zorbax RxC8 (5 micron); 40 acetonitrile -ac N H4OAc (0.05 M) at 1.5 ml / mini UV detection at 254 n)). Water (16 kg) was added and the mixture was stirred for 30 minutes to precipitate the product, then the mixture was cooled to 0 ° C for 30 minutes. The solid was isolated by filtration and the cake of the product was washed with cold water, dried with air and the crude product was obtained as an off-white solid. The crude solid was extracted into pyridine (3 kg) and concentrated in vacuo at 60 ° C to remove the water. The dried solid residue was suspended with methanol (10 kg) at 60 ° C for 1-2 hours and filtered while hot. The filtrate was concentrated in vacuo and the solid residue was refluxed with isopropyl acetate (7 kg) for 30 minutes. The mixture was cooled to 20 ° C and filtered. The filter cake was dried under vacuum at 50 ° C to yield the title compound as a white solid (555 g). b) (R) -9- [2- (Stearoyloxymethyl) -4- (t-butyldiphenylsilyloxy) butyl] guanine The product of Example 16, step a) (555 g, 1, 113 mol) was charged to an evaporator of 50 g. liters. Pyridine (2.7 kg) was added per drop to dissolve the solid and the mixture was distilled until dried under vacuum at 60 ° C. The residue was separated into fresh pyridine (2.7 kg) and transferred to a 22 liter vessel equipped with stirrer, funnel and thermosensitive probe. The solution was cooled to -5 ° C under nitrogen. A solution of stearoyl chloride (440 g, 1.45 mol) in methylene chloride (1.5 kg) was added in order to keep the temperature below 0 ° C. 4- (N, N-dimethylamino) pyridine (15 g, 0.12 mol) was added and the mixture was stirred at -5 - 0 ° C for 2-4 hours until complete conversion (as monitored with TLC (10: 1 methylene chloride / methanol) and HPLC (4.6 x 250 mm Zorbax RxC8 (5 micron), 60:40 acetonitrile -ac NH4OAc (0.05 M) at 1.5 ml / mini UV detection at 254 n) ). At the end of the reaction, acetonitrile (8.7 kg) was added and the mixture was stirred for not less than 15 minutes in order to precipitate the product. The suspension was cooled to 0 ° C for 2 hours and the solid was isolated by filtration and the filter cake was washed with acetonitrile (2 kg). The desired product was obtained as a white solid (775 g). c) (R) -9- [4-H-idroxy-2- (stearoyloxymethyl) butyl] guanine A solution of the product of Example 16, step b) (765 9, 0.29 mol) in tetrahydrofuran (10 kg) was prepared in a reactor. A solution of tetra (n-butyl) ammonium fluoride in tetrahydrofuran (1.7 kg of 1 M solution, 1.7 mole) was added and the resulting clear solution was stirred at 20 ± 5 ° C for 4 hours. Water (32 kg) was added and the resulting suspension was stirred for 1 hour and cooled to 0 ° C for 30 minutes. The precipitate was isolated by filtration and the filter cake was washed successively with water (10 kg) and acetonitrile (5 kg). After drying under vacuum at 25 ° C, 702 g of the crude product were obtained. The crude product was dissolved under reflux conditions in THF (4.2 kg) and water (160 g), then cooled to 40 ° C and treated with methylene chloride (14.5 kg). The mixture was allowed to cool to 25 ± 5 ° C for 1 hour, then cooled to 5 ± 5 ° C for 1 hour to complete the precipitation. The whitish powder was isolated by filtration and dried under vacuum at 40 ° C and the desired product was obtained (416 g). d) (R) -9- [4- (N-Cbz-L-valyloxy) -2- (stearoyloxymethyl) butyl] guanine To a solution of N-Cbz-L-valine (169 g, 0.67 mol) in dry THF (750 ml) was prepared in a 2 liter vessel equipped with a mechanical stirrer, a thermometer and an additional funnel. To a solution of dicyclohexylcarbodiimide (69.3 g, 0.34 mol) in THF (250 ml) was added over 5 minutes and the resulting suspension was stirred at 20 + 5 ° C for 2 hours. The suspension was filtered and the filter cake was washed with THF (300 ml). The filtrate and the washing were loaded in a 3 liter vessel equipped with stirrer and thermometer. The product of Example 16, step c) (116 g, 0.22 mol) was added as a solid, rinsed with THF (250 ml). 4- (N, N-dimethylamino) pyridine (2.73 g, 0.022 mol) was added and the white suspension was stirred at 20 ± 5 ° C. In a period of 15 minutes, the solids were dissolved and the reaction was completed in 1 hour (as determined by HPLC: 4.6 x 250 mm Zorbax RxC8 column; 85:15 acetonitrile - 0.2% ac. HC104 to 1 ml / min, UV detection at 254 nm, elution of the initial material occurred at 4.1 min and that of the product at 5.9 min.). The reaction was stopped as a result of the addition of water (5 ml) and the solution was concentrated in vacuo to yield a light yellow semi-solid. It was separated in methanol (1.5 liters) and heated under reflux conditions for 30 minutes. The solution was cooled to 25 ° C and the precipitate was removed by filtration. The filtrate was concentrated in vacuo and a pale yellow viscous oil was obtained. Acetonitrile (1 L) was added and the resulting white suspension was stirred at 20 ± 5 ° C for 90 minutes. The crude solid product was isolated by filtration, washed with acetonitrile (2 x 100 ml), dried with air overnight and the desired product was obtained as a waxy, waxy solid (122 g). It was purified by crystallization from ethyl acetate (500 ml), dried under vacuum at 30 ° C and the desired product was obtained as a white waxy solid (104 g). e) (R) -9- [4- (L-Valxyloxy) -2- (stearoxyloxymethyl) butyl] guan i na A solution of the product of Example 16, step d), (77 g) in ethanol ( 2, 3 L) warm (40 ° C) was loaded in a hydrogenation reactor with 5% Pd-C (15.4 g). The mixture was stirred at 40 ° C under 40 psi hydrogen for 4 hours, evacuated and hydrogenated for 4-10 hours more. The catalyst was removed by filtration, the filtrate was concentrated in vacuo and a white solid was obtained. This was stirred with ethanol (385 ml) at 25 ° C for 1 hour, then cooled to 0 ° C and filtered. The filter cake was dried with air, then under vacuum at 35 ° C to yield the title compound as a white powder (46 g).

EXAMPLE 17 (R) -9- [2- (L-Va lyoxymethyl) -4- (stearoxyloxy) butyl] guan i na a) (R) -9- [2-H id roxi meti 1-4- (this ring i I oxy) butyl] guaní na. H2G (506 mg, 2.0 mmol) was dissolved in dry N, N-dimethylformamide (40 mL) with pyridine (400 mg, 5.06 mmol) and 4-dimethylaminopyridine (60 mg, 0.49 mmol). Stearoyl chloride (1500 mg, 4.95 mmol) was added and the mixture was kept overnight at room temperature. Most of the solvent was evaporated in vacuo, the residue was stirred with 70 ml of ethyl acetate and 70 ml of water and the solid was filtered, washed with ethyl acetate and water and dried to obtain 680 mg of the crude product. Column chromatography with silica gel (chloroform: methanol 15: 1) afforded the pure title compound as a white solid. H-NMR (DMSO-dβ) d: 0.86 (t, 3H); 1.25 (s, 28H); 1.51 (qui, 2H); 1.62 (m, 2H); 2.06 (m, 1H); 2.23 (t, 2H); 3.34 (d, 2H); 3.96 (ABX, 2H); 4.07 (dd, 2H); 6.30 (br s, 2H); 7.62 (s, 1H); 10.45 (s, 1H). 13 C NMR (DMSO-dβ) d: 13.8 (C18); 22.0 (C17); 24.4 (C3); 27.7 (C3 '); 28.4-28.8 (C4-6, C15); 28.9 (C7-14); 31.2 (C16); 33.5 (C2); 38.0 (C2 '); 44.0 (CI '); 60.6161.8 (C4 \ C2"), 116.5 (guaC5), 137.7 (guaC7), 151.4 (guaC4), 153.5 (guaC2), 156.7 (guaC6), 172.7 (COO) b) (R) -9- [2- (N-Boc-L-valyloxymethyl) -4- (stearoyloxy) butyl] guanine.

A mixture of N-Boc-L-valine (528 mg, 2.1 mmol) and N, N'-dicyclohexyl carbodiimide (250 mg, 1.21 mg) in dichloromethane (20 ml) was stirred overnight at room temperature , dicyclohexylurea was filtered and extracted with a small volume of dichloromethane and the filtrate was evaporated in vacuo to obtain a small volume. (R) -9- [2-Hydroxymethyl-4- (stearoyloxy) butyl] guanine (340 mg; 0.644 mmol), 4-dimethylaminopyridine (25 mg, 0.205 mmol) and dry N, N-dimethylformamide (15 ml) were added and the mixture was stirred for 4 h at 50 ° C under N- The solvent was evaporated under vacuum to obtain a small volume Column chromatography with silica gel and then with aluminum oxide (ethyl acetate: methanol: water 15: 2: 1 as eluent) yielded 185 mg (39%) of the pure title compound as a white solid. 1 H NMR (CHCl 3) 3: 0.85-1.0 (m, 9H) I 8 -CH 3, CH (CH 3) 2; 1.25 (s, 28H) 4-17-CH2; 1.44 (s, 9H) t-Bu; 1.60 (qui, 2H) 3-CH2; 1.74 (qua, 2H) 3'-CH2; 2.14 (m, 1H) 2'-CH; 2.29 (t, 2H) 2-CH2; 2.41 (m, 1H) CH (CH3) 2; 4.1-4.3 (m, 6H) CI'-CHz. C2"-CH2, C4-CH2; 5.4 (d, 1H) aCH; 6.6 (br s, 2H) guaNH2; 7.73 (s, 1 H) guaH8; 12.4 (br s). 13C (CHCl3) d: 13, 9 (C 1 8); 17.511 8.9 (2 Val CH3); 22.4 (C 17); 24.7 (C3); 28.1 (C3 '); 28.9-29.3 (C4-6, C15); 29.4 (C7-14); 30.7 (Val ßC); 31.7 (C16); 34.0 (C2); 35.9 (C2 '); 43.9 (CV); 58.7 (Val aC); 61.4 / 63.6 (C4 \ C2"), 79.9 (CMe3), 116.4 (guaC5), 137.9 (guaC7), 151.7 (guaC4), 153.7 (guaC2), 155 7 (CONH) 158.8 (guaC6) 172.1 (CHCOO) 173.5 (CH2COO) e) (R) -9- [2- (L-Valyloxymethyl) -4- (stea roxi loxi) bu til] guani na, chilled trifluoroacetic acid (2.0 g) was added to (R) -9- [2- (N-Boc-L-valyloxymethyl) -4- (stearoyloxy) butyl] guanine (180 mg, 0.25 mmol) and the solution was kept at room temperature for 1 hour, evaporated to obtain a small volume and lyophilized several times with dioxane until a white amorphous powder was obtained. as the trifluoroacetate salt, it was quantitative.1 H NMR (DMSO-d6) d: 0.87 (t, 3H) 18-CH3, 0.98 (dd, 6H) CH (CH3) 2; 1.25 (s, 28H ) 4-17-CH2, 1.50 (qui, 2H) 3-CH2, 1.68 (qua, 2H) 3'-CH2, 2.1 9 (m, 1 H) 2'CH, 2.26 ( t, 2H) 2-CH2; 2.40 (m, 1H) CH (CH3) 2; 3.9-4.25 (m, 7H) C1'-CH2, C2"CH2, C4-CH2, aCH; 6.5 (br s, 2H) guaNH2; 7.79 (s, 1 H) gua H8; 8.37 (br s, 3H) NH3 +; 10.73 (br s, 1 H) guaNH. 13 C NMR (DMSO-dβ) d: 14.2 (C18); 17.9 / 18.3 (2 Val CH3); 22.3 (C17); 24.6 (C3); 27.7 (C3 '); 28.7-29.1 (C4-6, C15); 29.2 (C7-14); 29.5 (Val ßC); 31.5 (C16); 33.7 (C2); 35.0 (C2 '); 44.1 (CV); 57.6 (Val aC); 61.6 / 65.2 (C4 \ C2"), 116.1 (guaC5), 116.3 (qua, J290Hz, CF3), 137.9 (guaC7), 151.5 (guaC4), 154.0 ( guaC2), 156.7 (guaC6), 158.3 (qua, J15Hz, CF3COO) 169.1 (CHCOO), 173.1 (CH2COO).

EXAMPLE 18 Alternative preparation of (R) -9-r2-hydroxymethyl-4-stearoyloxy) butylguanine H2G (7.60 g, 30 mmol) was heated to a solution in dry DMF (200 ml). The solution was filtered to remove the solid impurities, cooled to 20 ° C (crystallized H2G) and stirred at that temperature during the addition of pyridine (9.0 g, 114 mmol), 4-dimethylaminopyridine (0.46 g, 3.75 mmol), then stearoyl chloride (20.0 g, 66 mmol) was added slowly. Stirring was continued at room temperature overnight. Most of the solvent was evaporated in vacuo, the residue was stirred with 200 ml ethyl acetate and 200 ml water and the solid was filtered, washed with ethyl acetate and water, dried and the crude product was obtained. As an alternative to recrystallization, the crude product was briefly heated to boiling with 100 ml of ethyl acetate: methanol: water (15: 2: 1) and the suspension was slowly cooled to 30 ° C and filtered until it remained most of the 2"isomer in solution (the crystallization of the 2" isomer should occur at a lower temperature). The extraction procedure was repeated once more and 6.57 g (42%) of almost isomer-free product were obtained after vacuum drying.

EXAMPLE 19 Preparation of crystalline (R) -9-r2-stearoyloxymethyl-4- (L-valyloxy) buty guanine The product of Example 16, step e) (20.07 g, 32.5 mmol) was dissolved in absolute ethanol (400 ml. ) by heating, filtered and diluted with ethanol (17.7 ml). To this solution was added water (H PLC grade, 103.5 ml), and the mixture was allowed to cool to 35-40 ° C. After the mixture was cooled, water (HPLC grade, 931, 5 ml) was added at a constant rate for 16 hours and stirred efficiently. After adding all the water, stirring was continued for 4 hours at room temperature. The resulting precipitate was filtered with paper and dried in vacuo at room temperature to obtain the title compound as a white crystalline powder (1 9.43 g, 97%), mpt 169-170 ° C.

EXAMPLE 20 9-R-f4-Hydroxy-2- (L-valyloxymethyl) butyl) guanine a) To a solution of 9-R- (4- (tert-butyldifen ilsi li lox) -2- (hydroxymethyl) butyl) guanine ( 695 mg, 1.5 mmol) in DMF (30 ml) were added N-Boc-L-Valine (488 mg, 2.25 mmol), 4-dimethylamino pyridine (30 mg, 0.25 mmol) and DCC (556). mg, 2.7 mmol). After 16 hours, the reaction was recharged with N-Boc-L-valine (244 mg) and DCC (278 mg) and maintained for an additional 5 hours. The reaction mixture was filtered with Celite and an aqueous solution of sadistic hydrogen carbonate was poured out and extracted with dichloromethane. The organic phase evaporated, purified by silica gel column chromatography and 950 mg of the protected monoaminoacyl N intermediate was obtained. b) The above intermediate (520 mg, 0.78 mmol) was dissolved in THF (15 ml). To the solution was added hydrogen fluoride in pyridine (70% / 30%, 0.34 ml). After two days, the solution was evaporated and coevaporated with toluene. Purification by silica gel column chromatography afforded 311 mg of the protected monoaminoacyl compound. 1 H NMR (DMSO-d 6): d 10.41 (s, 1H), 7.59 (1H), 6.26 (br s, 2H), 4.32 (t, 1H), 3.95 (m , 5H), 3.46 (m, 2H), 2.41 (m, 1H), 2.06 (m, 1H), 1.45 (m, 2H), 1.39 (s, 9H), 0 90 (d, 6H). c) The product from step b) (95 mg, 0.21 mmol) was treated with a mixture of trifluoroacetic acid (4 ml) and dichloromethane (6 ml) for 1 hour. The solution was evaporated, dried by freezing and 125 mg of the unprotected monoaminoacyl product was obtained. 1 H NMR (D 2 O): d 8.88 (s, 1 H), 4.32 (m, 4 H), 3.96 (d, 1 H), 3.68 (m, 2 H), 2.63 (m, 1H), 2.22 (m, 1H), 1.73 (M, 2H), 1.00 (m, 6H).

EXAMPLE 21 (R) -9-, 2-Hydroxymethyl-4- (L-isocyloxy) butyl) guanine a) To a solution of (R) -9- (2-hydroxymethyl-4-hydroxybutyl) guanine (2.53 g, 10 mmol) in DMF (250 ml) were added N-Boc-L-isoleucine (2.77 g). g, 12 mmol), 4-dimethylaminopyridine (61 mg, 0.6 mmol) and DCC (3.7 g, 18 mmol). After 16 hours of reaction at 0 ° C, N-Boc-L-isoleucine (1.3 g) and DCC (1.8 g) were reloaded and the reaction was maintained at room temperature overnight. The reaction mixture was filtered with Celite and the filtrate was evaporated and purified by column chromatography on silica gel yielding 1.25 g of protected N-monoaminoacyl intermediate. 1 H-NMR (DMSO-d 6): d 10.56 (s, IH), 7.62 (s, 1 H), 6.43 (s, 2H), 4.75 (t, 1 H), 4 , 15-3.80 (m, 5H), 3.25 (m, 2H) 2.05 (m, 1 H), 1.80-1 -05 (m, 14H), 0.88 (m, 6H) ). b) The intermediate from step a) (100 mg, 0.21 mmol) was treated with trifluoroacetic acid (3 m) for 30 min at 0 ° C. The solution was evaporated, dried by freezing and the monoaminoacyl product not protected from the title with a quantitative yield. 1 H NMR (DMSO-dβ + D 2 O): d 8.72 (s, 1 H), 4.15 (m, 4 H), 3.90 (d, 1 H), 3.42 (m, 2 H) , 2.09 (m, 1 H), 1.83 (m, 1 H), 1.61 (m, 2H), 1.15 (m, H), 0.77 (d, 3H), 0, 71 (t, 3H).

EXAMPLE 22 (R) -9- [2-H id roxi meti l-4- (L-valyloxy) butiI] guanine The product of Example 1, step a) was deprotected with trifluoroacetic acid in the same manner as in Example 1, step c). 1 H-NMR (250 MHz, DMSO-d 6): d 1.04 (dd, 6H), 1.55-1.88 (m, 2H), 2.21 (m, 2H), 3.48 (m, 2H), 4.00 (m, 1H), 4.13 (m, 2H), 4.34 (t, 2H), 6.9 (br s, 2H), 8.21 (s, 1H), 8 , 5 (br s, 3H), 11, 1 (br s, 1H).

EXAMPLE 23 (R) -9- [2- (L-ValMoxymethyl) -4- (goes I loxi) buti l] guan i na a) (R) -9- [4- (N-Boc-L-valyloxy) -2- (N-Boc-L-valyloxymethyl) butyl] guanine. By applying the technique described in Example 1, step a), but using 2.7 eqs, 0.28 eqs, and 3.2 eqs of N-Boc-L-valine, DMAP, and DCC, respectively, obtained the title compound. 1 H NMR (250 MHz, CHCl 3) d: 0.95 (M, 12 H), 1.42 (br s, 18 H), 1.8 (m, 2H), 2.14 (m, 2H), 2.47 (m, 1H), 4.0-4.4 (m, 8H), 6.5 (br s, 2H), 7.67 (s, 1H). b) (R) -9- [4- (L-Valyloxy) -2- (L-valyloxymethyl) butyl] guanine The title compound was obtained in the form of the tris-trifluoroacetate salt of the intermediate of Example 20 step a) by a deprotection technique similar to that of Example 1 step c). 1 H-NMR (250 MHz, D 2 O): d 1.0 (M, 12 H), 1.89 (m, 2 H), 2.29 (m, 2 H), 2.62 (m, 1 H), 4.02 ( dd, 2H), 4.38 (m, 6H), 4.89 (br s, ca, 10H), 8.98 (s, 1H).

EXAMPLE 24 (R) -9- [4-hydroxy-2- (stearyloxymethyl) butyl] guanine The title compound was prepared according to steps a) to c) of Example 7. 1 H NMR (250 MHz, DMSO-d 6): d 10.52 (s, 1 H), 7.62 (s, 1 H), 6.39 (s, 2H), 4.50 (t, 1H), 3.93 (m, 4H), 3.42 (m, 2H), 2.45 (m, 1H), 2.23 (t, 2H) , 1.48 (M, 4H), 1.22 (s, 28H), 0.89 (t, 3H).

EXAMPLE 25 (R) -9- [2-Hydroxymethyl-4- (stearoyloxy) buty!] Guanine.

The title compound was prepared by the procedure of Example 17, step a) 1H-NMR (DMSO-d6): d 0.86 (t, 3H); 1.25 (s, 28H); 1.51 (qui, 2H); 1.62 (m, 2H); 2.06 (m, 1H); 2.23 (t, 2H); 3.34 (d, 2H); 3.96 (ABX, 2H); 4.07 (dd, 2H); 6.30 (br s, 2H); 7.62 (s, 1H); 10.45 (s, 1H).

EXAMPLE 26 Alternative preparation of (R) -9- [2-stearoyloxymethyl) -4- (L-valyloxy) butyl] guanine a) (R) -9- [4- (N-benzyloxic rbo or I-L-val i I oxy) -2- (idroxy methyl) buti] guanine Dry H2G (252 mg, 1 mmol) was dissolved, 4-dimethylaminopyridine (122 mg, 1 mmol) and N Cbz-L-valine p-nitrophenyl ester (408 mg, 1.1 mmol) in dry dimethyl formamide (16 mL). After stirring at 23 ° C for 30 hours, the organic solvent was removed, the residue was carefully chromatographed (silica, 2% -7% methanol / methylene chloride) and the desired product was obtained as a white solid (151 mg , 31%). b) (R) -9- [4- (N-benzyloxy carbo or I-L-valloxy) -2- (stearyloxymethyl I) butyl] guanine To a solution of stearoyl chloride (394 mg, 1.3 mmol) in dry methylene chloride (2 ml) was slowly added dropwise under nitrogen to a solution of the product of step a) (243 mg, 1 mmol) and 4-dimethylaminopyridine (20 mg) in dry pyridine ( 8 ml) at -5 ° C. The reaction mixture was stirred at that temperature for 12 hours. Methanol (5 ml) was added and the reaction was stirred for 1 hour. After removing the solvent, the residue was triturated with acetonitrile and chromatographed (silica, 0-5% methanol / methylene chloride) and the desired product was obtained (542 mg, 72%). c) (R) -9- [2-stearoyloxymethyl) -4- (L-va! -loxy) butyl] guanine The product from step b) (490 mg, 1 mmol) was dissolved in methanol (30 ml) and 5% Pd / C (100 mg) was added. A balloon filled with hydrogen was placed on the reaction vessel. After 6 hours at 23 ° C, TLC indicated the absence of initial material. The reaction mixture was filtered with a 0.45 micron nylon membrane to remove the catalyst and the solvent was removed to obtain the desired product as an identical white solid (350 mg, 99%) (analytical and spectrum data). ) to Examples 16.

EXAMPLE 27 Alternative preparation of (R) -9- (4-hydroxy-2- (L-vayloxymethyl) -butyl] guanine. (R) -9- (4-2- (L-valyloxy) -2- (L-) was dissolved. Valyloxymethyl) -butyl) guanine (100 mg, 0.126 mmol) from Example 23 step b) in an aqueous 0.1 N NAOH solution (6.3 mL, 0.63 mmol) at room temperature. At intervals, an aliquot was taken and neutralized with 0.5 N of trifluoroacetic acid. The aliquots were evaporated and analyzed by H PLC to monitor the evolution of the reaction. After four hours, a solution of trifluoroacetic acid (1.26 ml, 0.63 mmol) was added to the solution and the reaction mixture was evaporated. The desired product was purified with HPLC, (YMC, 50 x 4.6 mm, gradient 0.1% TFA + 0-50% 0.1% TFA in acetonitrile in 20 minutes, UV detection at 254 nm). Yield: 13.6% 1H-NMR (D2O): d 8.81 (s, 1H), 4.36 (m, 4H), 4.01 (d, 1H), 3.74 (m, 2H), 2.64 (m, 1H), 2.25 (m, 1H) 1.73 (m, 2H), 1.03 (dd, 6H).

EXAMPLE 28 Alternative preparation of (R) -9- (2-hydroxymethyl-1 (L-valyloxy) -butyl) guanine. HPLC separation from the reaction solution of Example 27 yielded the title compound in 29.2% yield. NMR-1H (DMSO-dβ): d 8.38 (s, 3H), 8.26 (s, 1H), 6.83 (br s, 2H), 4.23 (m, 2H), 4.06 (m, 2H), 3.91 (m, 1H), 3.40 (m, 2H), 2.19 (m, 2H), 1.8-1.40 (m, 2H), 0.95 ( dd, 6H).

EXAMPLE 29 (R) -9- [2-Stearoyloxymethyl) -4- (L-valyloxy) butyl] guanine monohydrochloride. The product of Example 16, step d) (360 mg, 0.479 mmol) was dissolved in a mixture of methanol (10 ml) and acetate and ethyl (10 ml). To this solution was added 10% Pd / C (100 mg) and 1N HCl (520 microliters). The reaction mixture was stirred at room temperature for two hours under 1 atm of H2. The reaction mixture was filtered, the solvent in the filtrate was evaporated and 300 mg of the desired product was obtained as a crystalline solid.

EXAMPLE OF FORMULATION A Tablet Formulation The following ingredients were filtered with a 0.1 mm sieve and dried and mixed with 1.0 g of (R) -9- [2- (stearoyloxymethyl) -4- (L-valyloxy) butyl] guanine. g of lactose 49 g of crystalline cellulose 1 g of magnesium stearate A tabletting machine was used to compress the mixture into tablets of 250 mg of active ingredient.

EXAMPLE OF FORMU LATION B Enteric coated tablets The tablets of Formulation Example A are spray coated with a coating composed of 120 g of ethyl cellulose 30 g of propylene glycol 10 g of sorbitan monooleate 1000 ml of distilled water.

EXAMPLE OF FORMULATION C Controlled release formulation 50 g of (R) -9- [2- (stearoyloxymethyl) -4- (L-valyloxy) butyl] guanine 12 g of hydroxypropylmethylcellulose (Metocell K15) 4.5 g of lactose were dried and mixed and granulated with an aqueous povidone paste. Magnesium stearate (0.5 g) was added and the mixture was pressed into a 13 mm diameter tablet machine containing 500 mg of active agent.

EXAMPLE OF FORMULATION D Soft capsules 250 g of (R) -9- [2- (stearoyloxymethyl) -4- (L-valyloxy) butyl] guanine 100 g of lecithin 100 g of peanut oil The compound of the invention was dispersed in lecithin and peanut oil and filled with soft gelatin capsules.

BIOLOGICAL EXAMPLE 1 Test of bioavailability in rats The bioavailability of the compounds of the invention was compared with the main compound H2G and other H2G derivatives in rats. The compounds of the invention and the comparative compounds were administered orally (via a catheter in the stomach) in multiples of three individually weighed animals and 0 were obtained., 1 mmol / kg of the prodrug dissolved in an aqueous vehicle (Example 4, 5, Comparative Example 1 - 3, 5), man oil (Comparative Example 4, 9, 10) or propylene glycol (Example 1 - 3, 6 - 12, Comparative Example 6, 7) according to the solubility of the ingredient of the test compound. The animals were fasted for the previous 5 hours and approximately 17 hours after administration in metabolic cages. The urine was collected during the 24 hours following the administration and was frozen until the moment in which the analysis was performed. The H2G was analyzed in the urine using the HPLC / UV test of Stahie & amp; amp;; Óberg, Antimicrob Agents Chemother. 36 No 2, 339-342 (1992), with the following modifications: when thawing the samples were diluted 1: 100 aq. dist. H2O and filtered with an amicon filter and cenuged at 3000 rpm for 10 minutes. 30 μl sample duplicates were chromatographed on an HPLC column; Zorbax SB-C18; 75 x 4.6 mm; 3.5 micron; Mobile phase 0.05M N H4PO4, 3-4% methanol, pH 3.3-3.5; 0.5 ml / min 254 nm, retention time for H2G in 4% MeOH and pH 3.33, -12.5 min. Bioavailability was calculated as the recovery of measured H2G in each animal and the average was obtained in at least three animals and expressed as a percentage of the average H2G recovery in urine for 24 hours from a group of four heavy rats s individually injected respectively i. v.jugularis with 0.1 mmol / kg of H2G in Ringer's buffer vehicle and analyzed as indicated above. Comparative Example 1 (H2G) was made from the same batch that was used for preparation of Examples 1 to 12. The preparation of Comparative Example 2 (monoVal-H2G) and 3 (diVal-H2G) are shown in the Examples 21 and 23. The comparative example 4 (distearoyl H2G) was prepared by di-esterification of unprotected H2G under esterification conditions comparable to those of step 2 of Example 1. The common examples 5 & 8 (Val / Ac H2G) were prepared in the same way as Example 4 using acetic anhydride with the relevant H2G monovaline. Comparative Example 6 (Ala / stearoyl H2G) was prepared similarly to Example 6 using N-t-Boc-L-alanine in step 4. Comparative Example 7 (Gly / decanoyl) was prepared in a similar manner to Example but the intermediate product of step 1 made with N-t-Boc-L-glycine was used. The preparation of Comparative Examples 9 and 1 0 are shown in Examples 24 and 25 respectively.

Table 2 Compound 1 R2 Bioavailability Comparative example 1 hydrogen hydrogen 8% Comparative example 2 val ilo hydrogen 29% Comparative example 3 valyl val ilo 36% Example 1 valilo estearoilo 56% Common example 4 estearoi lo stearoyl 1% Example 2 valilo miristoilo 57% Example 3 Valyl oleoyl 51% Example 4 Valyl butyryl 45% Example com ponent 5 valyl acetyl 1 1% Example 5 48% decanoylvalentyl Example 6 48% docosanoyl vally Example 7 isoleucyl or stearoyl 53% Example 8 isoleucyl or decanoyl 57% Example 9 isoleucyl 0-myristoyl 49% Example 1 0 Valyl 4-acetylbutyryl 52% Example 1 1 Valdo dodecanoyl 46% Example 12 Valyl Palmitoyl 58% Example 17 Estearoi Valilo 52% Common example 6 alanyl stearoyl 23% Example: 7 decanoyl glycine 25% Example com acetive 8 acetyl valyl 7% Compound example 9 hydrogen stearoyl 12% Compound example 1 0 stearoyl ilo hydrogen 7% Comparison of the bioavailability of the compounds of the present invention with the comparative examples indicate that the special combination of the fatty acids in R? / R2 With the amino acids in R? / R2 produces a significantly greater bioavailability than the diamino acid ester or corresponding fatty diacid ester. For example, in this model, the compound of Example 1 shows a 55% bioavailability greater than that of the corresponding divalin ester of Comparative Example 3. The compound of Example 4 shows an availability 25% greater than that of the corresponding divalin ester. . It is also evident that, for example, in Comparative Examples 5, 6 and 7 that only the specified fatty acid of this invention in combination with the specified amino acids produces these unexpected increases in pharmacokinetic parameters.

BIOLOGICAL EXAMPLE 2 Plasma concentration in rats A plasma concentration test was performed on male rats derived from Sprague Dawley. The animals were fasted during the night prior to administration but did not have free access to water. Each of the compounds evaluated was prepared as a solution / suspension in propylene glycol with a concentration corresponding to 10 mg H2G / ml and shaken at room temperature for eight hours. Groups of rats (at least 4 rats per group) received an oral dose of 10 mg / kg (1 ml / kg) of each of the compounds; the dose was administered by gastric intubation. At certain times after the dose (0.25, 0.5, 1, 1, 5, 2, 4, 6, 9, 12, 15 and 24 hours after dose administration), blood samples were taken heparinized (0.4 ml / sample) tail vein tail each animal. The blood samples were immediately cooled in an ice bath. Within two hours of collection, the plasma was separated from the red cells by centrifugation and frozen until the time of analysis. The components of interest were separated from the plasma proteins with precipitation with acetonitrile. After lyophilisation and reconstitution, plasma concentrations were determined by reverse phase H PLC with fluorescent detection. The oral intake of H2G and other test compounds was determined by comparing the H2G area in the curve derived from the oral dose compared with that obtained from the intravenous dose of 10 mg / kg H2G, administered to a group of separate rats. The results are shown in Table 1 B above.

BIOLOGICAL EXAMPLE 3 Bioavailability in monkeys. The compounds of Example 1 and Comparative Example 3 (see Biological Example 1) were administered p. or. by gastric intubation to cynomolgus monkeys. The solutions were composed of: Example 1 150 mg were dissolved in 6.0 ml propylene glycol, corresponding to 25 mg / kg or 0.0295 mmol / kg. Comparative Example 3 164 mg were dissolved in 7.0 ml water, corresponding to 23.4 mg / kg or 0.0295 mmol / kg. Blood samples were taken at 30 min, 1, 2, 3, 4, 6, 10 and 24 hours. The plasma was separated by centrifugation at 2500 rpm and the samples were inactivated at 54 ° C for 20 minutes before freezing and frozen until analyzed. Plasma H2G levels were monitored by the HPLC / UV assay of Example 30 above. Figure 1 indicates the recovery of H2G in plasma as a function of time. While it is not possible to draw meaningful conclusions in statistical terms from the single-animal trials, apparently the animal to which the compound of the invention was administered experienced greater and more rapid exposure to H2G than the animal that received the alternative prodrug of H2G BIOLOGICAL EXAMPLE 4 Antiviral activity Mice infected with Herpes simplex virus-1 (HSV-1) were used as model animals to determine the efficacy of the antiviral agents in vivo. The mice were inoculated intraperitoneally and administered HSV-1 1000 times the LD5o either with the formulation composed of an anti-herpes agent acyclovir existing in place (21 and 83 mg / kg in 2% propylene glycol in sterile water as a vehicle, three times day, po) or the compound of Example 29 (21 and 83 mg / kg in 2% propylene glycol in sterile water as vehicle, three times per day, po) for 5 consecutive days counted from 5 hours after inoculation. The animals were evaluated daily to verify the deaths. The results are shown in Figure 2 which represents the survival rate as a function of time. In the legend, the compound of the invention is identified as Ex. 29 and acyclovir is identified as ACV. The percentage of mice surviving infection with HSV-1 was significantly higher after a given dose of the compound of the invention relative to an equivalent dose of acyclovir. The information presented is illustrative and is not intended to limit the scope of the invention. Changes and variations apparent to those skilled in the art are considered within the scope and nature of the invention defined by the appended claims.

Claims (3)

REIVIND ICATIONS
1. A method for the preparation of a compound of the formula wherein: a) Ri is -C (O) CH (CH (CH3) 2) NH2 or -C (O) CH (CH (CH3) CH2CH3) N H2 and R2 is an alkyl -C (O) C3-C2 ? saturated or monounsaturated, optionally substituted; or b) Ri is an alkyl -C (0) C3-C2? saturated or monounsaturated, optionally substituted and R2 is ~ C (O) CH (CH (CH3) 2) N H2 or -C (O) CH (CH (CH3) CH2CH3) N H2; and R3 is OH or H, the method comprising: A) the mono-disacylation of a diacylated compound corresponding to Formula I wherein Ri and R2 are both -C (O) CH (CH (CH3) 2) N H2 or -C (O) CH (CH (CH3) CH2CH3) N H2 (optionally N protected) or Ri and R2 are both an alkyl -C (= O) C3-C2? saturated or monounsaturated, optionally substituted; and R3 is H or OH, B) acylation of the side chain 4-hydroxy group or side chain 2-hydroxymethyl thus liberated with the corresponding alkyl -C (O) CH (CH (CH3) 2) NH2 or -C (O ) CH (CH (CH3) CH2CH3) N H2 or -C (= O) C3-C? saturated or monounsaturated, optionally substituted to produce a compound of formula I; and C) the deprotection if necessary. 2. A method according to claim 1, wherein Ri and R2 each comprise -C (O) CH (CH (CH3) 2) N H2 or -C (O) CH (CH (CH3) CH2CH3) NH2 . 3. A compound of Formula I I: OR, wherein one of Ri and R2 is: i) -C (O) CH (CH (CH3) 2) NH2 or -C (O) CH (CH (CH3) CH2CH3) NH2, optionally N protected, ii) an alkyl- C (= O) C3-C2? saturated or monounsaturated, optionally substituted, or iii) a regioselective protection group; and the other of Ri and R2 is hydrogen; or both Ri and R2 are i) or both are ii) as defined above. 4. A compound according to claim 3, wherein both Ri and R2 are -C (O) CH (CH (CH3)
2. 2) N H2 or -C (O) CH (CH (CH
3. 3) CH2CH3) N H2 .