MXPA99007340A

MXPA99007340A - Synthesis of acyclic nucleoside derivatives

Info

Publication number: MXPA99007340A
Application number: MXPA/A/1999/007340A
Authority: MX
Inventors: Chang Soujen; Robert Leanna M; Weijiang Zhang; A Riley David; J Tien Jienheh; M Hannick Steven; Kolaczkowski Lawrence; Michael Rasmussen; R Patel Ramesh; Lakshmi Bhagavatula; Reddy Singam Pulla; d gates Bradley; Wayne Greg; Lannoye Greg; Tian Zhenping; L Lukin Kirill; A Narayanan Bikshandarkor; Morton Howard
Original assignee: Abbott Laboratories
Priority date: 1997-02-10
Filing date: 1999-08-09
Publication date: 2000-05-01

Abstract

Methods and novel intermediates for the preparation of acyclic nucleoside derivatives of formula (I) where one of R1 and R2 is an amino acid acyl group and the other of R1 and R2 is a -C(O)C3-C21 saturated or monounsaturated, optionally substituted alkyl and R3 is OH or H;or a pharmaceutically acceptable salt thereof.

Description

SYNTHESIS OF ACICLIC NUCLEOSID DERIVATIVES 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.

BACKGROUND OF THE INVENTION The practical utility of many of the acyclic nucleosides is restricted by their relatively 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 186640 describes 6-deoxy H2G. According to European patent EP 343 133 all these compounds, in particular the R - (-) enantiomer, are also active against retroviral infections, such as HIV. EP 343 133 describes several of the H2G derivatives. 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 closure of the imidazole ring of a portion of pyrimidine or furazano- [3,4-d] pyrimidine or the pyrimidine ring closure of an imidazole moiety, where the acyclic side chain is already present in the pyrimidine precursor or in the imidazole 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 propynoic anhydride and DMF. Harnden, et al., J. Med. Chem. 32, 1738 (1989) investigated a quantity of short chain aliphatic esters of an acyclic 9- [4-hydroxy- (3-hydroxymethyl) butyl] guanine nucleoside, known as penciclovir. , and its 6-deoxy analog. Famciclovir, an antiviral agent for commercial use, is the diacetyl derivative of 6-deoxy penciclovir. Benjamin, et al., Pharm. Res. 4 No. 2, 120 (1987) describe 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) derivatives diacetate and H2G dipropionate 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. The international patent application W094 / 24134, published on October 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 international patent application W094 / 22887, published on October 13, 1994, describe nomoester derivatives of analog nucleosides derived from C18 or C2o monounsaturated fatty acids. U.S. Patent No. 5,216,142 of June 1, 1993 also describes derivatives nomoesters of long chain fatty acids of nucleoside analogues. 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. The 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. The European patent application EP 375 329, published on 27 June 25, 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 U.S. Pat. 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 654473, published on May 24, 1995, discloses various bis-amino acid derivatives of 9- [1 ', 2'-bishydroxymethi) -cyclopropan-1'yl] methylguanine. The international patent application W095 / 22330, published on August 24, 1995, discloses aliphatic esters, amino acid esters and combined acetateivalinate esters of acyclic nucleosides of 9- [3,3-dihydroxymethyl-4-hydroxy-but-1-yl] guanine. 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 DRAWINGS Figure 1 illustrates H2G levels in the plasma as a > time function in cynomolgus monkeys administered with a compound of the invention or an alternative prodrug derivative derived from H2G, as further explained in Biological Example 3; and Figure 2 illustrates survival as a function of time for mice infected with Herpes simplex that were administered several doses of a compound of the invention or a prior art antiviral, as further explained in Biological Example 4.

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 (0) CH (CH (CH3) 2) NH2 or -C (0) CH (CH (CH3) CH2CH3) NH2 and R2 is a saturated C (O) C3-C21 alkyl or monounsaturated, optionally substituted or b) Ri 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; or an acceptable salt in pharmaceutical terms thereof. The advantageous effect on the oral bioavailability of The fatty acid compound and amino acid esters of the invention are 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 drug trial in the In the plasma (Table 1B) of the H2G of rats, none of the esters of mono- or di-fatty acid of H2G provides any improvement in oral bioavailability relative to the compound of H2G origin. Actually, the di-stearate derivative provided a significantly lower bioavailability than the parent compound indicating that An ester of stearate can be harmful to improve the 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 into ester derivatives of corresponding mono- or d¡-vaülo produced similar improvements in > the bioavailability relative to the main compound. Since H2G fatty acid derivatives are detrimental to the improvement of bioavailability, the finding that a combined fatty acid / amino 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 Ri 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 are provided 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 Varicella zoster viruses. Herpes simplex type 1 & 2, Epstein-Barr, Herpes type 6 (HHV-6) and type 8 (HHV-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 chicken pox 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 R3 is a hydroxy or its tautomer = O, 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 may be hydrogen, thereby defining the more 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 group R ^ R2 derives from an L-amino acid. Preferably, the fatty acid of the group R 1 / R 2 has in total an even number of carbon atoms, especially decanoyl (C 0), lauryl (C 12), myristoyl (C,), palmitoyl (C 16), stearoyl (C 18) or eicosanoyl (C2o). Other Ri / R2 groups include butyryl, hexanoyl, octanoyl or behenoyl (C22). Other useful R1 / R2 groups include those derived from myristoleic, myristicidal, palmitoleic, paimitelaidic, n6-octadecenoic, oleic, elaidic, gandoic, erucic or brassidic acids. The esters of monounsaturated fatty acids have, in general, double binding in the transconfiguration, preferably the position? -6,? -9 or? -11, according to its length. Preferably, the group R- | / R2 is derived from a fatty acid containing a saturated C9 to C17 alkyl or n: 9 monounsaturated. The saturated or unsaturated fatty acid or the Ri / R2 group can be optionally substituted with up to five substituents, similar or different, independently selected from a group consisting of hydroxy, alkyl, C -? - C6, alkoxy, CT-CT Alkoxy alkyl, C- | -C6 alkanoyl, amino, halo, cyano, azido, oxo, mercapto and nitro and the like. The most preferred compounds of Formula I are those in which R1 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 "alkanoyl" in this context refers to R20C (O) -, wherein R20 is a lower alkyl group. The term "alkoxy" in this context refers to R21O-, wherein R21 is a lower alkyl group. The term "alkoxyalkyl" in this context refers to an alkoxy group attached to a lower alkyl radical. The term "protecting group of N" or "protected with N" 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 & amp; amp;; Sons, New York, 1981), which is incorporated herein by reference Protective groups of N include acyl groups, such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl , tpfluoracetyl, tpcloroacetyl, phthalyl, o-nitrophenoxyacetyl, (a-chlorobutyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-n-trobenzoyl, and the like, sulfonyl groups, such as, for example, benzenesulfonyl, p- toluenesulfonyl, and the like, carbamate-forming groups, such as, for example, benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-n-trobenzylcarbonyl, p-bromobenzyloxycarbonyl, 3,4- d? methox? benc? lox? carbon? lo, 4-methox? -benzyloxycarbonyl, 2-n? tro-4,5-d? methox? benc? lax? carbon? lo, 3,4,5-tpmethoxybenzyloxycarbonyl, 1 - (pb? phen? l?) 1-methoxycarbonyl, a, ad? met? l-3,5-d? methox? benc? lox? carbon? lo, benchidploxycarbonyl, t-butoxycarbonyl, dnsopropylmethoxycarbonyl, isopropyloxycarbonyl, etoxic arbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-tp-chloroethoxycarbonyl, phenoxycarbonyl, 4-n-trofenoxylcarbonyl, fluorenyl-9-methoxylcarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl phenylthiocarbonyl, and the like, alkyl groups, such as, for example, benzyl, tphenylmethyl, benzyloxymethyl and the like, and sihlo groups, such as, for example, tpmethylsilyl and the like. Preferred N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t -butoxycarbonyl (BOC) and benzyloxycarbonyl (Cbz) The term protection group with O or "protection group with hydroxy" or "protection group with OH" in this context refers to a substituent, which protects the hydroxyl groups against undesirable reactions during synthetic procedures such as those N-protection groups described by Greene, "Protective Groups In Organic Synthesis", (John Wiley & Sons, New York (1981)). The protecting groups with O comprise substituted methyl esters, for example, methoxymethyl, benzyloxymethyl, 2-, ethoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, 1-butyl, benzyl and trif-enylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, for example, 2,2,2-trichloroethyl; silico ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; and esters prepared by reacting the hydroxyl group with a carboxylic acid, for example, acetate, propionate, benzoate and the like. The term "activated ester derivative" in this context refers to acid halides, such as, for example, hydrochloric acids and activated esters including, but not limited to, anhydrides derived from formic acid and acetic acid, anhydrides derived from alkoxycarbonyl halides, 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-norbonene-2,3-dicarboxamide, esters derived from 2, 4,5-trichlorophenyl, anhydrides derived from sulfonic acid (for example, anhydrides derived from p-toluenesulfonic acid and the like) and the like.

Preferred compounds of Formula I include: (R) -9- [2- (Butyryloxymethyl) -4- (L-isoleucyloxy) butyl] guanine, (R) -9- [2- (4-acetylbutyryloxymethyl) -4- ( L-isoleucyloxy) butyl] guanine, (R) -9- [2- (Hexyanoyloxymethyl) -4- (L-isoleucyloxy) butyl] guanine, (R) -9- [4- (L-Isoleucyloxy) -2- (octanoyloxymethyl) butyl] guanine, (R) -9- [4- (L-Isoleucyloxy) -2- (decanoyloxymethyl) butyl] guanine, (R) -9- [4- (L-Isoleucyloxy) -2- (dodecanoyloxymethyl) butyl] guanine, (R) -9- [4- (L-Isoleucyloxy) -2- (tetradecanoyloxymethyl) butyl] guanine, (R) -9- [4- (L-Isoleucyloxy) -2- (hexadecacyloxymethyl) butyl] guanine, (R) -9- [4- (L-Isoleucyloxy) -2- (octadecanoyloxymethyl) butyl] guanine, (R) -9- [2- (Eicosanoyloxymethyl) -4- (L-isoleucyloxy) butyl] guanine, (R) -9- [2- (docosanoyloxymethyl) -4- (L-isoleucyloxy) butyl] guanine, (R) -9- [4- (L-Isoleucyloxy) -2 - ((9-tetradecenoyl) oxymethyl) butyl] guanine, (R) -9- [2 - ((9-hexadecenoyl) oxymethyl) -4- ( L-Isoleucyloxy) butyl] guanine, (R) -9- [4- (L-isoleucyloxy) -2 - ((6-octadecenoyl) oxymethyl) butyl] guanine, (R) -9- [4- (L -isoleucyloxy) -2 - ((9-octadecenoyl) oxymethyl) -butyl] guanine, (R) -9- [2 - ((11-eicosanoyl) -oxymethyl) -4- (L-isoleucyloxy) butyl] guanine, ( R) -9- [2 - ((13-docosenoii) -oxymethyl) -4- (L-isoleucyloxy) butyl] guanine, (R) -2-amino-9- [2- (butyryloxymethyl) -4- (L -isoleucyloxy) butyl] purine, (R) -2-amino-9- [2- (4-acetylbutyryloxymethyl) -4- (L-isoleucyloxy) butyl] purine, (R) -2-amino-9- [ 2- (Hexyanoyloxymethyl) -4- (L-isoleucyloxy) 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-amino-9- [4- (L-isoleucyloxy) -2- (tetradecanoyloxymethyl) butyl] purine, (R) -2-amino-9- [4- (L-isoleucyloxy) -2- (hexadecanoyloxymethyl) butyl] pur ina, (R) -2-amino-9-t4- (L-isoleucyloxy) -2- (octadecanoyloxymethyl) butyl] purine, (R) -2-amino-9- [4- (L-isoleucyloxy) -2- (eicosanayloxymethyl) butyl] 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- (L-isoleucyloxy) -2 - ((9-tetradecenoyl) oxymethyl) butylpulline, (R) -2- amino-9- [2 - ((9-hexadecenoyl) oxymethyl) -4- (L-isoleucyloxy) butylpurine, (R) -2-amino-9- [4- (L-isoleucyloxy) -2 - ((6- octadecenoyl) oxymethyl) butylpurine, (R) -2-amino-9- [4- (L-isoleucyloxy) -2 - ((9-octadecenoyl) oxymethyl) butylpurine, (R) -2-amino-g- [ 2 - ((11-eicosanoyl) oxymethyl) -4- (L-isoleucyloxy) butylpulline, or (R) -2-amino-g- [2 - ((13-docosenoyl) oxymethyl) -4- (L-isoleucyloxy) butylglycine, or its respective salt acceptable in pharmaceutical terms. Other preferred compounds include: (R) -9- [2- (Butyryloxylmethyl) -4- (L-valyloxy) butyl] guanine, (R) -9- [2- (4-acetylbutyryloxymethyl) -4- (L-valyloxy) ) butyl] guanine, (R) -9- [2- (hexanoyloxymethyl) -4- (L-valyloxy) butyl] guanine, (R) -9- [2- (octanoyloxymethyl) -4- (L-valyloxy) butyl ] guanine, (R) -9- [2- (decanoyloxymethyl) -4- (L-valyloxy) butyl] guanine, (R) -9- [2- (dodecanoyloxymethyl)) -4- (L-valyloxy) butyI] guanine, (R) -9- [2- (tetradecanoyloxymethyl-4- (L-valyloxy) butyI] guanine, (R) -9- [2-hexadecanoyloxymethyl) -4- (L-valyloxy) buty I guanine, ( R) -9- [2- (Octadecanoyioxymethyl) -4- (L-vallyloxy) butyI] guanine, (R) -9-12- (eicosanoyloxymethyl) -4- (L-valyloxy) butyl] guanine, ( R) -9- [2- (eicosanoyloxymethyl) -4- (L-valyloxy) butyl] guanine, (R) -9- [2- (docosanoyloxymethyl) -4- (L-vayloxy) butyl] guanine, (R) -9- [2 - ((9-tetradecenoyl) 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-valyloxy) 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) butylj guanine, (R) -2-amino-9- [2- (butyryloxymethyl) -4- (L-valyloxy) butyl] purine, (R) -2-amino-9- [2- (4-acetylbutyryloxymethyl) -4- (L-valyloxy) butyl] purine, (R) -2-amino-9- [2- (hexanoyloxymethyl) -4- ( L-valyloxy) butyl] purine, (R) -2-amino-9- [2- (octanoyloxymethyl) -4- (L-vayloxy) butyl] purine, (R) -2-amino-9- [2- (decanoyloxymethyl) -4- (L-valyloxy) butyI] 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-valyloxy) butyl] purine, (R) -2-amino-9- [2- (eicosanoyloxymethyl) -4- (L-valyloxy) butyl] purine, (R) -2-amino-g- [2- (docosanoyloxymethyl) -4- (L-valyloxy) butyl] purine, (R) -2-amino-9- [2 - ((9-tetradecenoyl) oxymethyl) -4- (L-valyloxy) butyl] purine, (R) -2-amino-9- [2 - ((9- hexadecenoyl) oxymethyl) -4- (L-valyloxy) butyl] purine, (R) -2-amino-g- [2 - ((6-octadecenoyl) oxymethyl) -4- (L-valyloxy) butyl] purine.

(R) -2-amino-9- [2 - ((9-octadecenoyl) oxymethyl) -4- (L-valyloxy) -butyl] purine, (R) -2-amino-g- [2 - ((11) -eicosenoyl) -oxymethyl) -4- (L-valyoxy) butyl] purine, or (R) -2-amino-9- [2 - ((13-docosenoyl) -oxymethyl) -4- (L-valyloxy) butyl ] purine; or its respective salt acceptable in pharmaceutical terms. Other preferred compounds of Formula I include: butyryloxy) -2- (L-valyloxymethyl) butyl] guanine, -acetylbutyryloxy) -2- (L-valyloxymethyl) butyl] guanine, hexanoyloxy) -2- (L-valyloxymethyl) butyl] guanine , octanoyloxy) -2- (L-vayloxymethyl) butyl] guanine, decanoiioxy) -2- (L-valyloxymethyl) butyl] guanine, odecanoyloxy) -2- (L-valyoxymethyl) butyl] guanine, ededecanoyloxy) -2- ( L-valyloxymethyl) butyl] guanine, exadecanoyloxy) -2- (L-valyloxymethyl) butyl] guanine, octadecanoyloxy) -2- (L-valyloxymethyl) butyl] guanine, eicosanoyloxy) -2- (L-valyloxymethyl) butyl] guanine, docosanoyloxy) -2- (L-valyoxymethyl) butyl] guanine, (9-tetradecenoyl) oxy) -2- (L-valyloxymethyl) butii] guanine, (9-hexadecenoyl) oxy) -2- (L-valyloxymethyl) butyl] guanine, (6-octadecenoyl) oxy) -2- (L-valyloxymethyl) butyl] guanine, (9-octadecenoyl) oxy) -2- (L-valyloxymethyl) -butyl] guanine, (11-eicosenoyl) oxy) -2 - (L-Valyloxymethyl) butyl] guanine, (13-docosenoyl) -oxi) -2- (L-valyloxymethyl) butyl] guanine, (R) -2-amino-9-4- butyryloxy) -2- ( L-valyloxymethyl) butyl] p urina, (R) -2-amino-9,4-4-acetylbutyryloxy) -2- (L-valyloxymethyl) butyl] purine, (R) -2-amino-9-4-hexanoyloxy) -2- (L-valoyloxymethyl) butyl] purine, (R) -2-amino-9-4- octanoyloxy) -2- (L-valyloxymethyl) butyl] purine, (R) -2-amino-9-4-decanoyloxy) -2- (L-valyloxymethyl) butyl] purine, (R) -2-amino-9- 4-dodecanoyloxy) -2- (L-valyoxymethyl) butyl] purine, (R) -2-amino-9-4-tetradecanoyloxy) -2- (L-valyloxymethyl) butyl] purine, (R) -2-amino-9- 4-hexadecanoyloxy) -2- (L-valyloxymethyl) butyl] purine, (R) -2-amino-9-octadecanoyloxy) -2- (L-valyloxymethyl) -butyl] purine, (R) -2-amino-9-4-eicosane loxi) -2- (L-valoxymethyl) ) butyl] j purine, (R) -2-amino-9-4-docosanoyloxy) -2- (L-valyoxymethyl) butyl] purine, (R) -2-amino-9- 4- (9-tetradecenoyl) oxy) -2- (L-valyloxymethyl) butyl] purine, (R) -2-amino-9-4- (9-hexadecenoyl) oxy) -2- (L-Valyloxymethyl) butyl] purine, (R) -2-amino-9- (6-octadecenoyl) oxy) -2- (L-valyloxymethyl) butyl] purine, (R) -2-amino-9 4- (9-octadecenoyl) oxy) -2- (L-valyloxymethyl) butyl] purine, (R) -2-amino-9- 4- (11-eicosenoyl) oxy) -2- (L-valyloxy) butyl ] purine (R) -2-amino-9-2- (13-docosenolyl) oxymethyl) -2- (L-valoxy) butyl] purine or its respective pharmaceutically acceptable salt. The compounds of Formula I can form salts that constitute a further aspect of the present invention. Appropriate pharmaceutically acceptable salts of the compounds of Formula I include salts of organic acids, especially carboxylic acids, including but not limited to acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate. pantothenate, isethionate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate. tartrate, lactobionate, pivolate, camphorate, 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, hydrobromide, hydroiodide, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate, phosphoric and sulphonic acids. 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 pharmaceutically acceptable salt, together with or associated with a pharmaceutically acceptable carrier. 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, clay, starch, lactose, wax, gum or gelatin. Liposomes or synthetic or natural polymers, such as HPMC 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, for example, 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 typical dose intensity for a normal adult would be 50 to 500 mg, for example 300 mg, once or twice a day in the case of herpes infections and 2 to 10 times the same dose in case of HIV infections. 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. Below is a characteristic reaction scheme for preparing H2G: The condensation in Step 1 is carried out, in general, with an alkaline catalyst, as for example. NaOH or Na2CO3 in a solvent, such as DMF. Step 2 consists of a reduction that can be performed with LiBHj / 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 described below 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 Formula I Scheme A describes the preparation of compounds in which R ^ 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 R is a derivative of the fatty acid and R2 of the amino acid ester. In the variant illustrated in scheme A above, G is guanine or 6-deoxyguanine, PG is an optional N-protecting group or hydrogen, Ri * is the side chain of valine or isoleucine and R2 * is the fatty acid chain . H2G has been previously described as starting material but, of course, it can be optionally protected at the position of R3 or position 2 of the purine with N-protecting groups (not shown). The H2G (derivative) reacts in the first step with an activated R-a derivative of α-amino acid, as described below, in a solvent, such as, for example, dimethylformamide or pyridine, to obtain a monoacylated product. The N-terminus of Ri a-amino acid can be protected with BOC or N-CBZ or the like. Under controlled conditions, the first acylation can be performed so that it occurs predominantly in the side chain 4-hydroxy 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 R-monoacylated compounds are acylated in the 2-CH2OH 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 esterification step. The diethylene products are then subjected to a conventional deprotection treatment using, for example, trifluoroacetic acid, HCl (aq) / dioxane, or hydrogenation in the presence of a catalyst to obtain the desired compound of Formula I. The compound can be present in the form of salt according to the deprotection conditions. The R ^ R2 acid derivative activated in the various acylations 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 Rt / 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, esters derived from N-hydroxy-5-norbornene-2,3-dicarboxamide, esters derived from 2,4,5-trichlorophenol, sulfonic acid anhydrides (e.g. , p-toluenesulfonic acid anhydrides and the like) and the like.

B. Through the protection of the 4-side chain hydroxy group Scheme B where G, PG, R ^ * 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 is derived from the amino acid and RT of 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-butyldiphenylsilyl, however other regioselective protecting groups can be used, such as, for example, trityl, 9- (9-phenyl) xanthenyl, 1,1-bis (4-methylphenyl) -1 '-pirenilmethyl. 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 R2, for example, myristic acid chloride, stearic , oleic, elaic, and the like. The thus monoacylated 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 R1 / R2, as for example, in schemes A, B, C or D of the present document, mention may be made of the method of 2-oxa-4-aza-cycloalkane. diona described in the International Patent Application no. WO 94/29311. As additional techniques for introducing the fatty acid ester of R? / R2, for example in schemes A, B, C, D or E of the present, the enzymatic route described in Preparative Biotransformations 1.11 can 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 where R3 is hydrogen, consists of 6-activating the corresponding guanine compound of Formula I (where the amino acid ester portion of R ^ R2 is optionally protected with N-protecting groups, for example, BOC) with an activating group, such as 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 RT and R2 are each hydrogen; b) regioselective acylation of the compound of Formula I in the side chain 4-hydroxy group with i) a valine or solucin group with optional N protection, ii) an optionally substituted, saturated or monounsaturated C3C21COOH derivative or iii) a group of regioselective protection; (c) 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 R1f if present, with i) valine or isoleucine derivative with optional protection in the N termini, or ii) an optionally substituted, saturated or monounsaturated C3C2? COOH derivative and e) deprotection of the resulting compounds as necessary. In Schemes A and B above, selective acylation is used to step-add the fatty acid and amino acid esters. An alternative process for the preparation of the compounds of Formula 1 begins with a diacylated H2G derivative, where both acyl groups are the same and perform a selective removal of one of the acyl groups to obtain an intermediate monoacyl which is then acylated with the second group acyl different in the same way 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-disacylation of a diacylated compound of Formula I wherein R <; And R2 are both vaux or solucil esters (with optional N protection) or Ri and Ri are both a saturated or monounsaturated C (= O) C3-C21 alkyl, optionally substituted and B) acylation of group 4 side chain hydroxy or the side chain 2-hydroxymethyl group thus liberated with the saturated, or monounsaturated, optionally substituted, C (= O) C3-C21 alkyl, isoleucyl or alkyl group, 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: OF where Ri and R2 are both vallyl or isoleucyl (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 anative form, it is preferred that Ri 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. Anatively, an N-protected di-aminoacylated H2G derivative can be deprotected and optionally re-protected, as described below. The unprotected diaminoacyl H2G derivative comprises one of the following compounds: (R) -9- [2- (L-Isoleucyloxymethyl) -4- (L-isoleucyloxy) butyl] guanine, (R) -9- [2- (L-valyloxymethyl) -4- (L-valyloxy) butyl] guanine, (R) -2-amino-9- [4- (L-isoleucyloxy) -2- (L-isoleucyloxymethyl) butyl] purine and (R) -2-amino-9-f4- (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 acyl 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 described previously. Anatively, the non-protected diacylated H2G derivative can be re-protected and then subject to selective deacylation, followed in turn by conventional acylation with fatty acid ester, as described in Schemes A and B. Suitably, 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 di-amino acid H2G derivative, since the lipofilic properties of the protecting group 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 anative 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 the R, and R2 is i) -C (O) CH (CH (CH3) 2) NH2 or -C (0) CH (CH (CH3) CH2CH3) NH2 ii) an alkyl -C (= O) C3-C21 saturated or monounsaturated, optionally substituted or iii) a regioselective protection group; the remaining R ^ or R2 is hydrogen and R3 is OH or H; The following are useful compounds: (R) -9- [2-hydroxymethyl-4- (t-butyldiphenylsilyloxy) butyl] guanine, (R) -9- [2-hydroxymethyl-4- (trityloxy) butyl] guanine, (R) -9- [2-hydroxymethyl-4- (9- (9-phenyl) xantenyloxy) butyl] guanine, (R) -9- [2-hydroxymethyl-4- (1,1-bis (4-met ilf in ii) - 1 '-pyrenylmethyloxy) butylguanine, (R) -9- [2-hydroxymethyl-4- (decanoyloxy) butyl] guanine, (R) -9- [2-hydroxymethyl) -4- (dodecanoyloxy) butyl ] guanine, (R) -9- [2-hydroxymethyl-4- (tetradecanoyloxy) butyl] guanine, (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-hydroxymethyl-4- (docosanoyloxy !) Butyl] guanine, (R) -9- [4-hydroxy-2- (decanoyloxymethyl) butyl] guanine, (R) -9- [4-hydroxy-2- (dodecanoyloxymethyl) butyl] guanine, (R) - 9- [4-hydroxy-2- (tetradecanoyloxymethyl) butyl] guanine, (R) -9- [4-hydroxy-2- (hexadecanoyloxymethyl) butyl] guanine, (R) -9- [4-hydroxy-2- ( octadecanoyloxymethyl) butyl] guanine, (R) -9- [4-hydroxy-2- (eicosanoyloxymethyl) butyl] guanine, (R) -9- [4-hydroxy-2- (docosanoyloxymethyl) butyl] guanine, (R) -9- [2-hydroxymethyl] -4- (L-Valyloxy) butyl] guanine, (R) -9- [2-hydroxymethyl) -4- (L-isoleucyloxy) butyl] guanine, (R) -9- [4-hydroxy-2- (L-isoleucyloxymethyl) butyl] guanine, (R) -9- [4-hydroxy-2- (L-valyloxymethyl) butyl] guanine. (R) -2-ainino-9- [2-hydroxymethyl-4- (L-valyloxy) butyl] purine, (R) -2-amino-9- [2-hydroxymethyl) -4- (L-isoleucyloxy) butyl ] purine, (R) -2-amino-9- [4-hydroxy-2- (L-isoleucyloxymethyl) butyl] purine 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-butyldiphenylsilyloxy) butyl] guanine, (R) -9- [2-dodecanoyloxymethyl-4- (t-butyldiphenylsilyloxy) butyl] guanine, ( R) -9- [2-tetradecanoyloxymethyl-4- (t-butyldiphenylsilyloxy) butyl] guanine, (R) -9- [2-hexadecanoy-oxymethyl-4- (t-butyldiphenylsilyloxy) butyl] guanine, (R) -9 - [2-Octadecanoyloxymethyl-4- (t-butyldiphenylsilyloxy) butyl] guanine, (R) -9- [2-eicosanoyloxymethyl-4- (t-butyldiphenylsilyloxy) butyl] guanine, (R) -9- [2-docosanoyloxymethyl-4- (t-butyldiphenylsilyloxy) butyl] guanine, Scheme C shows an alternative process for the preparation of compounds of the invention of Formula I where R3 is -OH.

Scheme C Scheme C Cont.

Formula With reference to Scheme C, malonate 1_ (R4 and R5 are lower alkyl or benzyl or the like) is alkylated by the reaction with 0.5 to 2.0 molar approximately equivalents of 2_ acetal (R6 and R7 are lower alkyl or benzyl and the like or R6 and R7 taken together are -CH2CH2- or -CH2CH2CH2- or -CH2CH2CH2CH2- and X, is a separating group (e.g., Cl, Br or I, or a sulfonate, such as, for example, methanesulfonate, triflate, p-toluenesulfonate, benzenesulfonate, and the like) in the presence of 0.5 to 2.0 molar equivalents of about a base (eg, potassium butoxide or sodium ethoxide or NaH or KH and the like) in an inert solvent ( example, DMF or THF or dioxane or dioxolane or N-methylpyrrolidone and the like) at a temperature of -40 ° C to about 190 ° C to obtain 3. alkylated malonate 3. The alkylated malonate 3. can be purified by distillation or by treating first the crude alkylated malonate with a dilute aqueous base (for example, 7% Aqueous KOH), followed by the removal of volatile impurities by distillation. The reduction of 3. with 0.5 to 4.0 molar approximately equivalent of an ester in an alcohol reducing agent (for example, LiBH4 or Ca (BH4) 2 or NaBH4 or LiAIH4 and the like) in an inert solvent (e.g. , 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 reaction with 1.0 to 20.0 molar approximately equivalent of a vinyl ester 5 (R8 is a C3-C21 saturated or monounsaturated 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 an 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 is converted to 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 ethyl acetate and the like) or as a consequence of the reaction with 0.8 molar equivalent to 2, 0 molar approximately equivalent of a sulfonyl halide (for example, benzenesulfonylchloride, toluenesulfonylchloride or methanesulfonylchloride and the like) in the presence of 1.0 to 4.0 molar equivalents of about one base (for example, triethylamine or potassium carbonate or pyridine or dimethylaminopyridine) or ethyldiisopropylamine and the like) in an inert solvent (for 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 ester 7_ ( X2 is a halogen group or salting sulfonate). 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 (for example, DMF or THF or acetonitrile or N-methylpirralidone or ethanol and the like) at a temperature of about -25 ° C to 140 ° C produces 9-substituted purine. Alternatively, the Mitsunobu coupling (for example P (Ph) 3 / d-butyl azidocarboxylate) of alcohol 6 with 2-amino-4-chloropurine 8. yields 9_. The reaction of 9_ with 2.0 to 20 molar approximately equivalents of alcohol R9OH (R9 is an alcohol protection group, such as, for example, benzyl and the like) in the presence of 1.0 to 6.0 molar equivalents of about one base ( for example, potassium t-butoxide or potassium carbonate or NaH or KH or lithium diisopropylamide and the like) in an inert solvent (e.g., THF) 0 DMF and the like) at a temperature of -25 ° C to 150 ° C produces alcohol 10. The removal of the alcohol protection group Rg 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 11. The esterification of 1 to 1 by reaction with a) from 0.8 to 2.0 molar approximately equivalent of R10COOH and a coupling agent (eg, DCC / DMAP) and the like in an inert solvent (eg, THF or DMF and the like) ) or b) from about 0.8 to 2.0 molar equivalents of an R10COOH derivative (for example, the N-hydroxysuccinimide acid chloride or ester or R10C (O) OS (0) R3o (R30 is lower alkyl, phenyl or tolyl) or R10C (O) OC (O) R10 or R10C (O) OC (O) R10a (Rioa is lower alkyl and the like) in the presence of 0 to 3.0 molar equivalents of about one base (e.g., pyridine , dimethylaminopyridine or triethylamine or ethyldiisopropylamine or N-methylmorpholine or DBU or potassium carbonate and the like) in an inert solvent (for example, methylene chloride or THF or pyridine or acetonitrile or DMF and the like) at a temperature of -25 ° C to 100 ° C produces ester 1_2, R10 is saturated or monounsaturated alkyl, optionally substituted, the acetal is deprotected, of 12 and the resulting aldehyde is first reduced by the reaction of 1_2 with 0.1 to 10.0 molar approximately equivalent of an acid (for example, triflic acid or HCl or acetic acid or sulfuric acid and the like) in an inert solvent (for example, THF / H2O or methylene chloride / H2O or ethylacetate / H2O or ethanol / H2O or methanol / H2O and the like) at a temperature of -25 ° C to 100 ° C. To the crude reaction mixture were added from 0.1 to 10.0 molar approximately equivalent of a base (eg, sodium bicarbonate or potassium carbonate or triethylamine or pyridine or KOH and the like), (additional inert solvent) (by example, 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 about equivalent of an aldehyde reducing agent (eg, sodium bromohydride RaNi / H2 or a complex of borane t-butylamine and the like) at a temperature of -25 ° C to 100 ° C to produce an alcohol 1_3. The optical purity of compound 13 can be improved through the reaction with optionally active organic sulfonic acids, such as (S) - (+) - alkane-sulfonic acid and the like. A preferred sulfonic acid for this purpose is (S) - (+) - alkane-sulfonic acid. Alternatively, the 1_2 acetal substituent can be hydrolyzed through the reaction in an inert solvent with an acidic resin (for example, Amberlyst 15 resin, Nafion NR50 resin, Dowex 50WX4-200R resin or Amberlyte 120 resin and the like) to provide the corresponding aldehyde. The aldehyde can be isolated before reduction to alcohol 1_3, as described above, or the crude aldehyde can be reduced directly in situ. The reaction of 1_3 with 0.8 to 3.0 molar equivalents approximately of an N-protected N-N-protected amino acid or an activated derivative thereof (PT is a protecting group N and Rn is isopropyl or isobutyl) in an inert solvent (e.g. , THF or dioxane or dioxolane or DMF or methylene chloride and the like) at a temperature of about 25 ° C to 100 ° C produces alcohol 14. Elimination of the N protection of 1_4 yields the compound of the invention of Formula I wherein R3 is -OH Alternatively, compound 1_3 can be reacted with symmetrical anhydride derived from PTNHC ^ R ^ COOH (ie, P1NHCH (R11) C (O) OC (O) CH (R11) NHP1) to provide 14. The anhydride can be prepared in situ or can be separately prepared before the reaction with 13.

Alternatively, 1_1_ can be prepared through hydrolysis of the ester of 9. to an alcohol (for example, through the reaction with K2CO3 in MeOH / H2O and the like), followed by the direct conversion of the chlorine group to an -OH group (for example, through the reaction with an inorganic base such as KOH or NaOH and the like in H2O with heating and the like). In another alternative method, 1-can be prepared directly through hydrolysis of the chloro-ester 9 (for example, through reaction with an inorganic base such as KOH or NaOH and the like in H2O with heating and the like). In another alternative method, it can be prepared from 9 (or from the hydroxy compound resulting from the hydrolysis of the ester at 9_) through the reaction with an inorganic base (eg, NaOH, LiOH, KOH and the like, preferably, NaOH) and trimethylamine in an aqueous solvent. In another alternative method, 1 _ can be prepared directly through hydrolysis of the 9-chloro ester (for example, through the reaction with 1-3 equivalents of a base such as sodium methoxide (and the like) in the presence of mercaptoethanol in a mixed solvent of water and methanol or dioxane (and the like) at a temperature from about 20 ° C to about reflux and the like). In another more alternative method, 1_3 can be prepared through the reaction of 9_ (where Rs = R? O) with formic acid, optionally with heating, followed by the reduction of the aldehyde to give 13. In Scheme D it is shown another alternative process for the preparation of compounds where R3 is -OH.

Scheme D Scheme D Cont.

Formula I Malonate 1 (R and R5 are a lower alkyl or benzyl and the like) is alkylated with 0.5 to 2.0 molar approximately equivalents of ether wherein X is a leaving group (for example Cl, Br or I. or a sulfonate, as for example, methane sulfonate, 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 about 0.5 to 2.0 molar equivalents of a base (eg potassium t-butoxide or sodium ethoxide or NaH or KH and the like) in an inert solvent (e.g., DMF or THF 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_. The reduction of 1_6 with 0.5 to 4.0 molar approximately equivalent of an ester in an alcohol reducing agent (for example LiBH4 or Ca (BH4) 2 or NaBH4 or LiAIH4 and the like) in an inert solvent (for example, THF) or methyl t-butyl ether or ethanol or t-butanol and the like) at a temperature of from -20 ° C to about 100 ° C produces diol 1_7_. The enzymatic esterification of 17. by the reaction with about 1.0 to 20.0 molar equivalent of a 5-vinyl ester (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 lipase CCL and the like) or a phospholipase (eg, phospholipase D and the like) produces the desired ester stereoisomer 1_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 1_8_ is converted to a leaving group (for example a halogen or sulfonate) by reaction with a halogenating agent (for example, NBS / 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 ethylacetate and the like) or by reaction with 0.8 molar equivalent to 2.0 molar equivalent of about one sulfonyl halide (for example, 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) a temperature of -25 ° C to 100 ° C approximately to produce an ester 1_9 (X2 is a halogen or sulphonate leaving group). The reaction of 1_9 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 (for example, DMF or THF or acetonitrile or N-methylpyrrolidone or ethanol and the like) at a temperature of -25 ° C to about 140 ° C produces substituted purine 20. Alternatively, the Mitsunobu coupling (eg, P (Ph) 3 / diethyl azidocarboxylate) of alcohol 1_8 with 2-amino-4-chloropurine 8. yields 20. The reaction of 20. with 2.0 to 20, 0 molar approximately equivalents of an RgOH alcohol (R9 is an alcohol protection group, such as, for example, benzyl and the like) in the presence of 1.0 to 6.0 molar equivalent of about one base (eg, potassium t-butoxide) 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 protection group R9 from 2 _ (for example, by hydrogenation catalyst in an inert solvent such as, 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., which can be esterified as described in Scheme C to provide 23 .. The substituent ether of 23. is deprotected as a consequence of the reaction with a) a reducing agent (for example, HC2H and Pd / C and the like) where R? 2 is -CH (Ph) 2 or -C (Ph) 3- or b) a desilylating agent (e.g., Bu4NF and the like) where R- | 2 is -Si ( t-Bu) (Me) 2 and the like to produce 13 .. Alcohol 13 can be converted to 1 as shown in Scheme C. Alternatively, 22. can be prepared through hydrolysis of the ester of 20. to a alcohol (for example, through reaction with K2CO3 in MeOH / H2O and the like), followed by direct conversion of the chlorine group to an -OH group (for example, through reaction with KOH in H2O with heating, and Similar). In another alternative method, 2Z2_ can be prepared directly through hydrolysis of the chloroster 20 (for example, through reaction with KOH in H 2 O with heating and the like). In another alternative method, 22. can be prepared from . (or from the hydroxy compound resulting from hydrolysis of the ester in 20.) through reaction with an inorganic base (for example, NaOH, LiOH, KOH and the like, preferably NaOH) and trimethylamine in an aqueous solvent. In another alternative method, 2 can be prepared directly through hydrolysis of the chloro ester 20. (for example, through the reaction with 1-3 equivalents of a base such as sodium methoxide (and the like) in the presence of mercaptoethanol in a mixed solvent of water and methanol or dioxane (and the like) at a temperature from about 20 ° C to about reflux and the like). In another more alternative method, 23. can be prepared through the reaction of 20. (where R8 = R? O) with formic acid, optionally with heating, followed by reduction of the aldehyde to give 23. An additional alternative includes an enzymatic esterification of alcohol 4 or 17. with the vinyl ester CH2 = CH-OC (O) R10 (i.e.

R8 = R10 in Schemes C and D) to incorporate directly into 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 1_2 or 20. to 23 .. The processes of Schemes C and D are characterized by the fact that each of the hydroxyl groups of the side chain Acyclic is differentiated by the use of different precursor groups or hydroxy protection 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 R ,, derives from a fatty acid and R2 from an amino acid.

Scheme E Another method for preparing the compounds of the formula _ \ is shown in Scheme E. Enzymatic esterification of 4 (see Scheme C) through the reaction with from about 1.0 to about 20.0 molar equivalents of a vinyl ester 24. (R10 is saturated or monounsaturated C3-C2 alkyl, optionally substituted) in the presence of a lipase (e.g., Lipase PS-30 or Lipase PPL or Lipase CCL and the like) or a phospholipase (e.g., phospholipase D and the like) provides the desired stereoisomer of the ester 25. This reaction can be carried out in the absence of the solvent or in the presence of an inert solvent (for example, methyl t-butyl ether or toluene or hexane and the like). The reaction is carried out at a temperature from about -20 ° C to about 80 ° C. The alcohol substituent 25. is converted to a leaving group (e.g., a halogen or a sulfonate) through reaction with a halogenating agent (e.g., NBS / P (Ph) 3 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 ethyl acetate and the like) or through the reaction with from about 0.8 molar equivalents to about 2.0 molar equivalents of a sulfonyl halide (for example, benzenesulfonyl chloride, toluenesulfonyl chloride, methanesulfonyl chloride, and the like) in the presence of about 1.0 to about 4.0 molar equivalents of a base (e.g., triethylamine or potassium carbonate or pyridine) or dimethylaminopyridine or ethyldiisopropylamine and the like) in an inert solvent (for example, methylene chloride or toluene or ethyl acetate or pyridine or methyl t-butyl ether and the like) at a temperature of about -25 ° C. at about 100 ° C to provide 26. (X2 is a leaving group of halogen or sulfonate). The acetal substituent 26. is hydrolyzed to the aldehyde 27. by reacting 26. with an acid (for example, trifluoroacetic acid, triflic acid or HCl or acetic acid or sulfuric acid and the like) in an inert solvent (for example, THF / H2O 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 from about -25 ° C to about 100 ° C. To the aldehyde 27_ in an inert solvent (for example, THF and / or methylene chloride or ethyl acetate or methyl t-butyl ether or isopropanol and the like) an aldehyde is added to the alcohol reducing agent (eg, sodium borohydride or RaNi / H2 or a complex of t-butylamine borane t) at a temperature of about -25 ° C to about 100 ° C to provide the corresponding alcohol. The reaction of the resulting alcohol with from about 0.8 to about 3.0 molar equivalents of N-protected amino acid, PiNHCHIRONCOOH or an activated derivative thereof (P, is a protecting group with N and Rn is isopropyl or isobutyl) in an inert solvent (per example, THF or dioxane or dioxolane or DMF or methylene chloride and the like) at a temperature of about 25 ° C to about 100 ° C provides the ester 28 .. Alternatively, the alcohol can be reacted with the symmetric anhydride derived from PTNHCÍRT COOH (ie, P1NHCH (R11) C (O) OC (O) CH (R11) NHP1) to provide 28. The reaction of 28. with purine 29. in the presence of a base (e.g., K2C03 and the like) in an inert solvent (eg, DMF and the like) provides 30. Purine 29. is prepared from 6-chloro-2-amino purine through the reaction with R9OH in an inert solvent (eg, toluene or THF) and the like) in the presence of a base (e.g., NaH or KH and simila beef). The substituted purine 30. is deprotected to provide the compound of the Formula L 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 mice infected with Herpes simplex given several doses of a compound of the invention or an antiviral of the prior art, as explained in Biological Example 4.

EXAMPLE 1 (R) -9- [2- (Stearoyloxymethyl) -4- (L-valyloxy) butyl] guanine This example illustrates the application of the preparation of the Scheme A. a) (R) -9- [4- (N-tert-Butoxycarbonyl-L-valyloxy) -2- (hydroxymethyl) butylguanine. H2G (5 g, 19.7 mmol) was dissolved in DMF (300 ml) under hot conditions and cooled to room temperature before adding Nt-BOC-L-valine (5.58 g, 25.7 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): d 0.95 (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-valyloxy) -2- (stearoxyloxymethyl) butyl] guanine The product of step a) (185 mg, 0.41 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): δ 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): d 0.97 (t, 3 H), 1.05 (dd, 6 H), 1.34 (br s, 20 H), 1.57 (m, 2 H), 1.78 (m, 2 H), 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 instead of stearoyl chloride. 1 H-NMR (250 MHz, DMSO-d 6): d 0.96 (t, 3 H), 1.05 (dd, 6 H), 1.35 (br s, 20 H), 1.59 (m, 2 H), 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-Butoxycarbonyl-L-valyloxy) -2-butyryloxymethyl) butyl] guanine DCC (110 mg) was dissolved, 0.53 mmol) 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-varyloxy) -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 84 were obtained. mg of the desired compound in the form of bistrifluoroacetate salt. 1 H-NMR (250 MHz, D 2 O): d 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) 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 instead of stearoyl chloride. 1 H-NMR (250 MHz, D 2 O): d 0.90 (m, 3 H), 1.01 (d, 6 H), 1.28 (br s, 12 H), 1.5 (m, 2 H), 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- [2-Docosanoyloxymethyl-4- (L-valyloxy) butyl] guanine The compound of the title was obtained as the bistrifluoroacetate salt in a manner similar to that of Example 1, but in step b) the DMAP / DCC conditions of Example 1 step a) were used together with docosanoic acid instead of Nt-Boc. L-valine and a mixture of DMF and dichloromethane as solvent. 1 H NMR (250 MHz, DMSO-d 6): δ 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, 1H), 2.35 (t, 2H), 2.50 (m, 1H), 3.97- 4.17 (m, 4.35 ( t, 2H), 6.7 (br s, 2H), 8.1 (br s, 1H), 8.4 (br s, 3H), 11.0 (br s, 1H).

EXAMPLE 7 R-9- [4- (L-lsoleucyloxy) -2- (stearoyloxyrnethyl) butyl] guanine This example illustrates the application of Preparatory Scheme B. a) (R) -9- [2-hydroxymethyl 4- (t-butyldiphenylsilyloxy) butyl] guanine H2G (2g, 8 mmol) was coevaporated with dry DMF twice and then suspended in dry DMF (120 ml) and pyridine ( 1 ml). To the suspension was added t-butyldiphenylchlorosilane drops (2.1 ml, 8.2 mmol) in dichloromethane (20 ml) at 0 ° C for a period of 30 minutes. The reaction mixture was transformed into a clear solution when the dropwise addition was complete. The reaction was continued at 0 ° C for two hours and kept at 4 ° C overnight. Methanol (5 ml) was added to the reaction. 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 and evaporated in vacuo. The product was isolated by silica gel column chromatography using a methanol / dichloromethane system by 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) butl] 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 (0.29 ml) was added 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 silica gel column chromatography by gradually increasing the MEOH, and was eluted with 3.5% MEOH in CH2Cl2. (Yield 2.7 g). c) (R) -9 - [(4-Hydroxy-2- (stearoyloxymethyl) butylguanine) (R) -9- [2- (Stearoyloxymethyl) -4- (t-butyldiphenylsilyloxy) butyljguanine (2.7 g, 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 was monitored by TLC.The reaction reached 80% about conversion, more HF-pyridine (075 ml). 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) was added and evaporated again. The product was isolated by column chromatography on silica gel. (Yield 1.26 g). d) (R) -9- [4- (N-BOC-L-isoleucyloxy) -2- (stearoyloxyethyl) 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) were 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-d 6 + 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, solucin), 1.68 (m, 2H), 1.48 (m, 4H), 1.68 (m, 28H), 0.81 (m, 9H).

EXAMPLE 8 (R) -9- [2- (Decanoyloxymethyl) -4- (L-isoleucyloxy) 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-d 6): 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-lysolucyloxy) -2- (myristoyloxymethyl) butyl] guanine The title compound was obtained as a bistrifluoroacetyl salt in a similar manner to that of Example 1 except that in step a) N-BOC-L-isoleucine was used in place of N-BOC-valine) and myristoyl chloride in step b). 1 H NMR (DMSO-d 6): d 10.99 (s, 1 H), 8.34 (br s, 3 H) 8, 1 5 (s, 1 H), 6.67 (br s, 2 H), 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 DCC / DMAP conditions of Example 1, step a) together with 4-acetylbutyric acid instead of Nt- Boc-L-valine. 1 H-NMR (250 MHz, DMSO-d 6): 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) butl] 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-valyloxy) butyl) purine This example shows the deoxygenation of the group R- |. a) (R) -2-Amino-9- (2-stearoyloxymethyl-4- (N-tert-butoxycarbonyl-L-valyloxy) but yl) -6-chloro purine: To a solution of (R) -9- ( 2-Stearoyloxymethyl-4- (N-tert-butoxycarbonyl-L-valyloxy) butyl) guanine from step 2 of Example 1 (646 mg, 0.9 mmol) in acetonitrile was 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 v / v) they 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 m g. 1 H-NMR (CDCl 3): d 8.69 (s, 1 H, H-6), 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 (m, 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-stearoyloxymethyl-4- (L-vayloxy) 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. 1H-NMR (DMSO-d6): d 8.78 (s, 1H, H-6), 8.32 (br, 3H), 8.29 (s, 1H, 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) butylguanine a) Preparation of ethyl 4,4-diethoxy-2-ethoxycarbonyl butyrate Potassium tert-butoxide (141.8g, 1.11 equiv.) 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 (CDCL3) d 1.19 (t, 6H), 1.28 (t, 6H), 2.22 (dd, 2H), 3.49 (m, 2H), 3.51 (t, 1H) , 3.65 (m, 2H) 4.20 (qd, 4H), 4.54 (t, 1 H). b) Preparation of 4,4-diethoxy-2- (hydroxymethyl) -butanol LBBH4 (purchased solution, 2M in THF, 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. they were 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 a rate such 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 combined washings with brine 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 brine 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, 6 H), 1.73 (dd, 2 H), 1.92 (m, 1 H), 2.67 (bs, 2 H), 3.52 (m, 2 H) , 3.69 (m, 2H), 3.72 (m, 4H), 4.62 (t, 1 H).

(C) Preparation of (2R) -2-acetoxymethyl-4,4-diethoxy-butanol 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 (2/1 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 In a 100 mL flask with round neck and base, equipped with a magnetic stirring bar and a separator in N2, the crude product of Example 14 step c) (4.629, 19 mmol) dry CH2Cl2 (20 mL) and Et3N (5.62 mL, 40 mmol) was charged. To this solution was added tosyl chloride (4.76 g, 25 mmol). The resulting mixture was stirred at room temperature for 4 hours. H 2 O (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 H2O and the aqueous layer was separated. To the organic layer was added 75 ml of a 5% aqueous solution of KH2PO4. 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 (CDCU) 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), brine (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 = Benzyl) 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 brine, dried over Na2SO4, 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) d 1.22 (m, 6H); 1.55 (2H); 2.18 (m, IH); 3.15 (m, 1H); 3.40 (m, 1H); 3.51 (m, 2H); 3.70 (m, 2H); 4.25 (m, 2H); 4.63 (t, 1H); 4.90 (bs, 2H); 5.25 (m, 1H); 5.58 (s, 2H); 7.35 (m, 3H); 7.51 (m, 2H); 7.72 (s, 1H), 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 was charged into a 100 mL round-neck flask and neck. , 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 H2 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 CH3CN (2 mL) and MTBE (35 mL) were added. 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 1.16 (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 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 mmol) dissolved in CH 2 Cl 2 (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) 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 Na2SO4, 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, 1H); 3.45 (m, 1H); 3.60 (m, 2H); 4.08 (m, 2H); 4.60 (m, 1H); 6.0 (bs, 2 H); 7.53 (s, 1H). 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 THF (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- [4- (N-tert-butyloxysarbonyl-L-valyloxy) -2- (stearoyloxymethyl) butyl] guanine (R) -9- [2- (stearoyloxymethyl) -4- (t-) butyldiphenylsilyloxy) butyl] guanine (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 taken up in 2 liters of CH 2 Cl 2 and washed with 2 L of solutions 1/2 of saturated sodium bicarbonate and brine. 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- [2- (Stearoyloxymethyl) -4- (L-valyloxy) butyl] guanine a) (R) -9- [2-Hydroxymethyl) -4- (t-butyldiphenylsilyloxymethyl) 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.NH OAc (0.05 M) at 1.5 ml / mini UV detection at 254 nm)). 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, 1113 mol) was charged in a Buchi evaporator of 50 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 mícron); 60:40 acetonitrile -ac. NH4OAc (0.05 M) at 1.5 ml / min UV detection at 254 nm)). 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-Hydroxy-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 mol) 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 container 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 20j5 ° 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-Valyloxy) -2- (stearoyloxymethyl) butyl] guanine A solution of the product of Example 16, step d), (77 g) in warm (2.3 L) ethanol (40 ° C) was charged 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-Valyloxymethyl) -4- (stearoxy) butyl] guanine a) (R) -9- [2-Hydroxymethyl-4- (stearoyloxy) butyl] guanine. 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 (chlorofort: methanol 15: 1) yielded the pure title compound as a white solid. 1 H NMR (DMSO-de) 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-de) 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 (Cl '); 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, 0.654 mmol), 4-dimethylaminopyridine (25 mg, 0.205 mmol) and N, N-dimethylformamide (15 ml) dry they added and the mixture was stirred for 4 h at 50 ° C under N2. The solvent was evaporated in vacuo 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) d 0.85-1.0 (m, 9H) 18-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) C1'-CH2, 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) 13 C NMR (CHCl 3) d: 13, 9 (C 1 8); 17,511 8.9 (2 Val CH 3); 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 (C1') 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- (stearoyloxy) butyl] guanine. Refrigerated 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 maintained at room temperature for 1 hour, evaporated to obtain a small volume and was repeatedly eluted with dioxane until a white amorphous powder was obtained. The yield of the title compound, obtained as the trifluoroacetate salt, was quantitative. 1 H NMR (DMSO-de) d: 0.87 (t, 3H) 18-CH 3, 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) guaH8; , 37 (br s, 3 H) NH 3 +, 10.73 (br s, 1 H) guaNH. 13 C NMR (DMSO-d 6) 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 (C1 '); 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- [2-hydroxymethyl-4-stearoyloxy) butyl] guanine H2G (7.60 g, 30 mmol) was heated to a dry DMF solution (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- [2-stearoyloxymethyl-4- (L-valyloxy) butyl] 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 (117.5 ml). To this solution was added water (HPLC grade, 103.5 ml), and the mixture was allowed to cool to 35-40 ° C. The mixture was then 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 under vacuum at room temperature to obtain the title compound as white crystalline powder (19.43 g, 97%), mpt 169-170 ° C.

EXAMPLE 20 9-R- (4-Hydroxy-2- (L-valyloxymethyl) butyl) guanine a) To a solution of 9-R- (4- (tert-butyldiphenylsilyloxy) -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 mg). , 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 aqueous sodium hydrogen carbonate solution was poured out and extracted with dichloromethane. The organic phase was evaporated, purified by column chromatography on silica gel and 950 mg of the protected N-monoaminoacyl 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 of 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-isoleucyloxy) 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-dimethylamino pyridine (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 with silica gel yielding 1.25 g of protected N-monoaminoacyl intermediate. NMR-1H (DMSO-d6): d 10.56 (s, IH), 7.62 (s, 1H), 6.43 (s, 2H), 4.75 (t, 1H), 4.15- 3.80 (m, 5H), 3.25 (m, 2H) 2.05 (m, 1H), 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 unprotected monoaminoacyl product of the title was obtained in a quantitative yield. 1 H-NMR (DMSO-d 6 + 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, 1H), 1.83 (m, 1H), 1.61 (m, 2H), 1.15 (m, H), 0.77 (d, 3H), 0.71 (t, 3H) ).

EXAMPLE 22 . { R) -9- [2-Hydroxymethyl-4- (L-val i loxi) butyl] guaní na The product of Example 1, step a) was deprotected with trifluoroacetic acid in the same manner as in Example 1, step c). NMR-'H (250 MHZ, DMSO-d6): 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-Valyloxymethyl) -4- (valyloxy) butyl] guanine a) (R) -9- [4- (N-Boc-L-valyloxy) -2- (N-Boc-L-varyloxymethyl) 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, the title compound was obtained. 1 H NMR (250 MHz, CHCl 3) d: 0.95 (M. 12H), 1.42 (br, 18H), 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 as the tris-trifluoroacetate salt of the intermediate of Example 20 step a) by means of a deprotection technique similar to that of Example 1 step c). 1 H NMR (250 MHz, D 2 O): d 1.0 (M, 12H), 1.89 (m, 2H), 2.29 (m, 2H), 2.62 (m, 1H), 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- (is aroyloxymethyl) 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) butyl] 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-benzyloxycarbonyl-L-valyloxy) -2- (hydroxymethyl) butyl] guanine Dry H 2 G (252 mg, 1 mmol), 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-benzyloxycarbonyl-L-valyloxy) -2- (stearyloxymethyl) butylguanine 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 from step a) (243 mg, 1 mmol) and 4-dimethylaminopyridine (20 mg) in dry pyridine (5 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-valyloxy) 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 through 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 Example 16.

EXAMPLE 27 Alternative preparation of (R) -9- (4-hydroxy-2- (L-valyloxymethyl) -butyl] guanine. (R) -9- (4- (L-valyloxy) -2- (L-valyloxymethyl) was dissolved. -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 HPLC 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, 1 H) 1.73 (m, 2H), 1.03 (dd, 6H).

EXAMPLE 28 Alternative preparation of (R) -9- (2-hydroxymethyl-4- (L-valyloxy) -butyl) guanine. HPLC separation from the reaction solution of Example 27 yielded the title compound in 29.2% yield. NMR-1H (DMSO-d6): 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 30 Alternative preparation of (R) -9 - [(2-stearoyloxymethyl-4- (L-valyloxy) butyl) guanine. a) Preparation of (R) -2-amino-6-chloro-9- [4,4-diethoxy-2- (hydroxymethyl) butyl] purine. The product of Example 14, step e) (200 g) was dissolved in methanol (670 ml) and 20% aqueous K2CO3 was added. The mixture was stirred at 25 ± 5 ° C for 30 minutes. The reaction mixture was then cooled to 0-5 ° C for about 20 minutes, when a precipitate formed. Water (500 ml) was added and the suspension was mixed at 5 ± 5 ° C for 15 minutes. The resulting solid was isolated through filtration and its filter cake was washed with water (100 ml) and dried under vacuum at 20 ° C to provide the desired product as a pale yellow powder (81 g). 300 MHz RMN -H, (DMSO-d6) d 1.04 (m, 6H); 1.36 (m, 1H); 1.55 (m, 1H); 2.10 (m, 1H); 3.40 (m, 6H); 4.06 (m, 2H); 4.48 (t, 1H); 4.78 (t, 1H); 6.93 (br s, 2H); 8.10 (s, 1H). b) Preparation of (R) -9- [4,4-diethoxy-2- (hydroxymethyl) butyl] guanine.

To the product of Example 30 step a) (22.5 kg, 65.4 moles) was added an aqueous solution of KOH (prepared by dissolving 12.9 kg of KOH in 225 kg of water). This mixture was refluxed for 16 hours. The reaction was cooled to room temperature and filtered in a large reactor equipped with a standardized pH electrode at a pH of 7-10. The filtered solution was cooled to 5 ° C and the product was precipitated through the slow addition of a dilute acetic acid solution (prepared by mixing glacial acetic acid (12.6 kg, 210 moles) with 75 kg of water and cooled mix at 5 ° C) until the pH was between 7.5 and 9.0 (objective 8.5). The resulting suspension was filtered immediately and the filter cake was recharged back to the reactor. The reactor was charged with 225 kg of distilled water. The mixture was heated at or above 50 ° C for 30 minutes, then at 15 ± 10 ° C and stirred for 30 minutes. The resulting precipitate was filtered through vacuum filtration, rinsed with 50 kg of distilled water and dried in a vacuum oven at no more than 45 ° C for no more than 8 hours to provide the desired product as a solid. cinnamon colour. c) Preparation of anhydride mixed with stearoyl-pivaloyl A 22.4 kg of stearic acid (78.7 moles) in 156.4 kg of toluene was added with 8.2 kg of triethylamine (81.0 moles). The internal temperature of the resulting suspension was reduced to -5 ° C, then 9.52 kg of pivaloyl chloride (79.0 moles) was added slowly maintaining an internal temperature of no more than 5 ° C: The suspension was stirred for 2 hours at 5 ° C, then warmed to 20 ° C and stirred for 4 hours. The precipitate of triethylammonium hydrochloride was filtered and washed with 36.6 kg, 35.5 kg and 37.9 kg of toluene. The filtrate was concentrated to no more than 60 ° C internal temperature and 61.1 kg of heptane were added, followed by cooling the suspension to -15 to -10 ° C. After 4 hours of stirring, the resulting solid was collected by vacuum filtration, blow-dried for 1 hour with nitrogen and dried in a vacuum oven at room temperature for 1.5 hours to provide the desired product as white crystals ( 18.9 kg). An additional load of 2.7 kg of the desired product was obtained by concentrating the mother liquors under vacuum and adding 41.1 kg of heptane. The resulting suspension was cooled to -15 to -10 ° C for 4 hours, filtered, dried by blowing with nitrogen for 1 hour and the product dried in a vacuum oven at room temperature. d) Preparation of (R) -9- [4,4dietoxy-2- (stearoyloxymethyl) butyl] guanine. The product of Example 30 step b) (3.9 kg, 11.9 moles), the product of Example 30 step c) (5.2 kg, 13.6 moles) and 300 g of 4-dimethylaminopyridine (2.4 moles) were combined in 103.3 kg of THF at room temperature. After mixing for 16 hours, water (3 kg) was added. After mixing for 45 minutes, the solution was distilled at no more than 45 ° C internal temperature. Ethyl acetate (62.9 kg) was charged and the solution distilled again at no more than 45 ° C internal temperature. Then acetone (56 kg) was added and the suspension was heated to reflux (56 ° C) for 15 minutes. The resulting clear solution was cooled to room temperature (not more than 15 ° C / hour). After 4 hours at room temperature, the resulting precipitate was filtered and rinsed with acetone (17 kg). The mother liquors were concentrated under vacuum at no more than 45 ° C. Ethyl acetate (260 kg) and water (72.1 kg) were charged. The biphasic mixture was stirred and then allowed to settle. The organic phase was separated and distilled. Ethyl acetate (200 kg) was added and the solution distilled again. Acetone (101 kg) was charged, the solution was heated to reflux (56 ° C) for 15 minutes and then the solution was cooled to room temperature (no more than 15 ° C / hour) and the precipitate was filtered. The product was washed with acetone (19 kg, 15 kg and 15 kg), dried by blowing with nitrogen for 1 hour and then dried under vacuum at no more than 40 ° C for about 6 hours to produce the desired product (3 , 1 kg). e) Preparation of (R) -9- [4-hydroxy-2- (stearoyloxymethyl) butyl] guanine. The product of Example 30 step d) (3.0 kg) was formed into a suspension in THF (46 liters) at 20 ° C. A solution of trifluoromethanesulfonic acid (2.25 kg) in 2.25 kg of water (prepared by slowly adding the acid to the cold water) was added and the reaction mixture was stirred at 22 ° C for 2 hours. The reaction mixture was cooled to 15 ° C and quenched with a solution of NaHCO3 (1.5 kg) in water (5.3 kg). A complex of borane t-butylamine (powder, 340 g) was added in four portions and then the reaction temperature was increased to 35 ° C and stirred for 12 hours. The reaction mixture was added to a solution of 320 g of concentrated HCl (37% aqueous) in 115 kg of tap water at 5 ° C. This mixture was stirred for 30 minutes and the resulting precipitate was filtered and washed with acetonitrile (15 kg). The solids were re-precipitated once or twice from acetone (35 kg). Final precipitation was achieved by dissolving the product in THF (24 kg) at 65 ° C, adding water (1.3 kg), cooling to 30 ° C and then adding methylene chloride (105 kg). The resulting suspension was cooled to 10 ° C and the precipitate was filtered to provide the desired product. f) Preparation of (R) -9- [4- (N-benzyloxycarbonyl-L-valyloxy) -2- (stearoyloxymethyl) butyl] guanine. A solution of dicyclohexylcarbodiimide (1500 g, 7.27 mole) in THF (7 liters) was added to a reactor containing a mixture of N-carbobenzyloxy-L-valine (3630 g, 14.5 mole) in THF (20 ml. ). The resulting mixture was stirred at 20 ± 5 ° C for 1-2 hours. The product of Example 30 step e) (2500 g, 4.81 mol) and 4-dimethylaminopyridine (59 g, 0.48 mol) were charged to a second reactor. To this second reactor, the THF mixture was filtered from the first reactor, followed by a THF rinse (15 liters). The resulting mixture was stirred at 20 ± 5 ° C for 1-3 hours. Water (600 ml) was added and the solution was concentrated under vacuum at no more than 45 ° C. The residual oil was taken up in ethyl acetate (14 liters) and filtered. The filtrate was washed successively with 10% sodium bicarbonate (2 x 14 liters) and 10% brine (14 liters). The organic phase was concentrated under vacuum and the residue was dissolved in methanol (10 kg) at 50-60 ° C. The warm solution was gradually added to a mixture of acetonitrile (30 kg) and water (13 kg) at room temperature. The mixture was stirred 1 hour at 15 ° C, then filtered to isolate the crude product, which was dried at 40 ° C under vacuum to provide the desired product as a white solid (3.9 kg). g) Preparation of (R) -9 - [(2-stearoyloxymethyl) -4- (L-valyloxy) butyl] guanine. A hydrogenation reactor was charged with 10% Pd-C (400 g) and the product of Example 30 step f) (2.4 kg). Absolute ethanol (52 liters) was added and the mixture was heated to 40 ° C and hydrogenated at 30-40 psi for 3-5 hours. At the end of the reaction, the catalyst was removed by filtration through diatomaceous earth and the filter cake rinsed very well with ethanol (30 liters). The combined filtrates were concentrated under vacuum at no more than 60 ° C to leave a solid white residue. This was dissolved in isopropanol (15 liters) and isopropyl acetate (60 liters) at reflux and then allowed to cool to room temperature for 4 hours. After cooling for 3 hours at 1510 ° C, the precipitate was isolated by filtration, washed with isopropyl acetate (6 liters) and dried under vacuum at 40 ° C to provide the desired product as a white powder (864). g).

EXAMPLE 31 Alternative Preparation of (R) -9 - [(2-stearoyloxymethyl) -4- (L-valyloxy) buti I] guanine a) Preparation of (2R) -4,4-diethoxy-2-stearoyloxymethyl-butanol.

Vinyl stearate (17.76 g, 0.057 moles) was charged to a 100 ml round base flask with a magnetic stir bar. The flask was immersed with agitation in a bath at 35 ° C. The product of Example 14 step b) (10.0 g, 0.052 moles) and Lipase Amano PS-30 (0.20 g) were added and stirred for 4 hours at 35 ° C. The reaction was diluted with hexane (260 mL) and MTBE (115 mL) and filtered through Celite. The filtrate was washed twice with water (100 ml), dried with Na2SO and concentrated to provide the desired product (26.21 g) as a clear oil which formed a wet solid upon standing at room temperature. b) Preparation of (2R) -4,4-diethoxy-2-stearoyloxymethyl-butyl Toluenesulfonate TsO OC (0) (CH2) 16CH3 EtO ~ ^ OEt The product of Example 31, step a) (26.21 g, 0.057 mol) was dissolved in methylene chloride (75 ml) and charged to a 250 ml three neck flask equipped with a magnetic stir bar, a condenser , an N2 input and a thermosensitive probe. Triethylamine (14.4 g) was added followed by p-toluenesulfonyl chloride (16.3 g). The flask was purged with N2 and heated to reflux (46 ° C). The reaction was stirred at reflux for 6 hours. The reaction was cooled to room temperature. Water (10 ml) was added and the reaction was stirred vigorously for 16 hours. The reaction mixture was emptied into a 1 liter separatory funnel containing ethyl acetate (350 ml). The organic layer was separated and washed with 7% aqueous sodium bicarbonate (w / w) (100 ml). The organic layer was then washed with 23% aqueous sodium chloride / w / w) (100 ml). The organic layer was dried with Na2SO4 and filtered. The solution was concentrated to give the desired product (29.4 g) as an oil that formed a wet solid when cooled to room temperature, c) Preparation of (3S) -3-stearoyloxymethyl-4-toluenesulfonyloxy-butyraldehyde.

TsO 0C (0) (CH2) 16CH3 V o The product from Example 31 step b) (29.38 g, analyzed at 23.12 g, 0.037 mol) was dissolved in THF (90 ml) and charged to a 250 ml round bottom flask, equipped with a magnetic stirring bar and a thermosensitive probe. Water (38 ml) was charged and cooled to 10 ° C. Trifluoroacetic acid (55 ml) was emptied and the mixture was stirred for 25 minutes. The reaction mixture was emptied into a 2 liter separatory funnel containing a 20% K2CO3 (w / w) solution (690 g), ice (600 g, and ethyl acetate (500 ml). The aqueous layer was extracted a second time with ethyl acetate (500 ml) The combined organic extracts were washed with a 23% NaCl (w / w) solution The organic layer was separated, dried with Na 2 SO 4 The solution was concentrated to 21.5 g of an oil, dissolved in heptane (150 ml) and stirred slowly (crystals formed after 10 minutes) .The suspension was stirred for 15 hours at room temperature. filtered and washed with environmental heptane (20 ml) The desired product was obtained as white crystals, which were dried at a constant weight of 12.3 g. d) Preparation of (2S) -4-N-carbonylbenzyloxy-L-valinyloxy-2-stearoyloxymethyl-butyl toluensulfonate Ts H2) 16CH3 The product of Example 31 step c) (11.91 g, 0.022) was charged to a 250 ml shake bottle. THF (120 ml) and RaNi (17.8 g) were added. The reaction was pressurized to 4 atm., With H2. The reaction was shaken for 1.5 hours. The reaction was filtered and washed with 20 ml of THF. The filtrate was diluted with 100 ml of CH 2 Cl 2, dried with Na 2 SO 4, filtered and washed with 25 ml of CH 2 Cl 2. The filtrate was charged to a 500 ml 3 neck flask equipped with a magnetic stir bar and an N2 inlet. N-Cbz-L-valine (13.88 g, 0.055 mole), 1,3-dicyclohexylcarbodiimide (11.37 g, 0.055 mole) and 4-dimethylaminopipdine (0.40 g, 0.003 mole) were added and the reaction was stirred for 1 hour. The reaction mixture became heterogeneous after several minutes. The reaction was filtered and washed with CH2Cl2 (50 mL). The filtrate was diluted with ethyl acetate (600 ml) and washed twice with a 7% NaHCO3 (w / w) solution (100 ml). The organic layer was then washed twice with a 5% solution of KH 2 PO 4 (w / w) (100 ml). The organic layer was washed with a 7% NaHCO3 (w / w) solution (100 ml), then dried with MgSO4 and filtered. The solution was concentrated to 19.46 g of oily solids. The solid was dissolved in 30 ml of 8: 2 hexanes: ethyl acetate and chromatographed in two portions. Each half was chromatographed on a 40M Flash siliceous gel cartridge (90 g of 32-63 μm, 60A 4.0 cm x 15.0 cm silica) and eluted with 8: 2 hexanes: ethyl acetate at 25 ml / min. , 25 ml fractions were collected. The fractions were analyzed through TLC. Fractions 10-22 contained the crude product in the first operation and fractions 9-26 contained the crude product in the second operation. The fractions were combined and concentrated to provide the desired product as a clear viscous oil (12.58 g). e) Preparation of 6-benzyloxy-2-amino-purine.

Sodium hydride 60% in mineral oil (2.36 g, 0.059 mole) was charged to a 3-neck 500 ml flask equipped with magnetic stirring, thermosensitive probe, condenser and N2 inlet. Toluene (250 ml) was added. Benzyl alcohol (50 ml) was added portionwise for 30 minutes. After the addition of the benzyl alcohol, the reaction was stirred for 10 minutes. Then 6-chloro-2-aminopurine (5.00 g, 0.029 mole) was added and the reaction mixture was heated to reflux (115 ° C) for 4.5 hours. The reaction mixture was filtered hot through a thick glass frit funnel and 11.65 g of wet off-white solids were obtained. The wet solids were titrated with CH2Cl2 (100 ml) and water (100 ml). After 10 minutes of stirring, the solids dissolved. The aqueous layer was separated and the pH was reduced to 9 for 3 minutes with 6M HCl. A solid white precipitate formed. The suspension was filtered, washed with water (50 ml), and dried (under vacuum at 50 ° C) at a constant weight to provide the desired product as white crystals 85.15 g). f) Preparation of (R) -9 - [(2-stearoyloxymethyl) -4- (N-benzyloxycarbonyl-L-valyloxy) butyl] guanine.

The product of Example 3 step e) (2.40 g, 0.0099 mole) was charged to a 100 ml round base flask equipped with magnetic stirring and an N2 inlet. DMF (6 ml) and potassium carbonate (6.27 g) were added. The mixture was stirred at room temperature for 30 minutes. The product from Example 31 step d) (7.02 g, 0.0091 mol) was dissolved in DMF (21 ml) and added to the mixture. The flask was immersed in an oil bath at 70 ° C and stirred for 24 hours. The reaction was cooled to room temperature and evacuated to a 500 ml separatory funnel containing ethyl acetate (135 ml) and a 5% solution of KH 2 SO 4 (w / w) (135 ml). The upper organic layer was maintained and washed with a 7% NaHCO3 (w / w) solution (100 ml). The organic layer was dried over MgSO4 and filtered. The solution was concentrated to 9.79 oily solids. This was titrated in 50 ml of 1 1 hexanes: ethyl acetate, filtered and concentrated to 9.10 g of the yellow oil. The oil was dissolved in 20 ml of 1/1 hexanes: ethyl acetate and chromatographed over a 40M silica gel cartridge (90 g of 32-63 μm, silica of 60 A, 4.0 cm x 15.0 cm) eluted with 6: 4 hexanes: ethyl acetate at 25 ml / min. 25 ml fractions were collected. The fractions were analyzed through TLC. Fractions 27-92 contained the crude product through TLC. The pure fractions were combined and concentrated to yield the desired product as an oil (2.95 g). g) Preparation of (R) -9 - [(2-steroyloxymethyl) -4- [L-valyloxy) butyl] guanine.

H? N U (CH2), sCH3 The product of Example 31 step f) (2.63 g, 0.0031 mol) s was dissolved in ethanol (50 ml) and charged to a 500 ml round base flask. A suspension of 10% Pd / C (0.5 g) in ethanol (20 ml) was formed and added to the flask. The reaction was stirred under H2 (1 atm., From a balloon) for 1.5 hours. The suspension was briefly heated to dissolve any solids, filtered and washed with hot ethanol (50 ml). The filtrate was concentrated to give 1752 g of white solid. The solid was dissolved in isopropyl alcohol (10 ml) and isopropyl acetate (42 ml) at 70 ° C. The solution was cooled to 15 ° C for 2 hours and stirred at 15 ° C for 12 hours. The solution was cooled to 0 ° C for 30 minutes and stirred for 1 hour. The suspension was filtered and washed with isopropyl acetate (10 ml). The solid was dried under vacuum at 50 ° C to provide the desired product (0.882 g). The mother liquors were concentrated to give 0.55 g of a white solid, which was dissolved in isopropyl alcohol (3 ml) and isopropyl acetate (16 ml) at 75 ° C. The solution was cooled to 15 ° C for 2 hours, then filtered and dried as above to provide 0.181 g of the desired product.

EXAMPLE 32 Preparation of ethyl 4,4-diethoxy-2-ethoxycarbonyl butyrate To a suspension of sodium ethoxide (20 g, 0.294 mole) in dimethylformamide (68 g) was added diethyl malonate (49 g, 0.306 mole) for 13 minutes). After the addition was complete, the mixture was heated to 110 ° C and bromoacaraldehyde diethyl acetal (40 g, 0.203 mol) was added for 1 hour and 45 minutes. After completing the addition, the mixture was heated at 110 ° C for 7 hours. The reaction mixture was cooled to room temperature and methyl t-butyl ether (160 ml) and water (100 g) were added and the mixture was stirred for 15 minutes. The organic layer was separated and treated with a 7% aqueous potassium hydroxide solution (155 g). The layers were separated and the organic layer was washed with water (100 g) and then with brine (60 g). The organic layer was concentrated to give the desired crude product. The crude product was heated under housing vacuum (approximately 45 mm Hg) at 160-170 ° C (bath temperature) to distill the volatile impurities providing 43.6 g of the desired product.

EXAMPLE 33 Alternative Preparation of (R) -9- [4,4-diethoxy-2- (hydroxymethyl) butyl] guanine.

To a one-neck flask of 100 ml was added the product of Example 30 a) (5, 0.0145 moles), followed by the addition of a solution of KOH (2.05 g, 0.0445 moles) in water (20 ml). The mixture was stirred at reflux for 16-20 hours. Then, the reaction mixture (reflux) was adjusted to a pH of 7.0 through the addition of acetic acid. The reaction mixture was then cooled to room temperature and stirred for 30 minutes. The resulting precipitate was collected by filtration and washed with water (5 ml). The resulting solid was dried overnight at not more than 50 ° C to provide 4.45 g of the desired product.

EXAMPLE 34 Alternative Preparation of (R) -9- [4-hydroxy-2- (stearoyloxy-methyl) butyl] guanine as the (S) - (+) - alkane-sulfonic acid salt The product of Example 14 i) (13.0 g) and (1 S) - (+) -1 O-camphorsulfonic acid (5.85 g) was placed in a 250 ml round bottom flask. Heptane (50 ml) was added and the mixture was stirred for 15 minutes. Then tetrahydrofuran (THF, 50 ml) was added and the mixture was stirred for 5 hours. The resulting precipitate was collected through filtration and washed with heptane (100 ml). The resulting solid was dried under vacuum at 45 ° C to provide the desired product (11.3 g). HPLC analysis of the product indicated 98.76% e.e.

EXAMPLE 35 Preparation of: A 50 ml round base flask was charged with the product of Example 14 h) (1.0 g, 1.7 mmol), THF (20 ml), H20 (1 ml) and Amberlyst resin 15 (1.0 g). The solution was then heated at 65 ° C for 3 hours. The solution was then filtered hot and the resin was washed with THF (2 x 10 ml). The solvent was then stirred under vacuum to give the desired product (0.74 g, 84%).

EXAMPLE 36 Alternative Preparation of (R) -9- [4-hydroxy-2- (stearoyloxy-methyl) butyl] guanine.

A 100 ml round base flask was charged with the product of Example 14 h) (2.45 g, 4.14 mmol), THF (25 ml), H 2 O (1 ml) and Amberlyst 15 resin (2.5 g). ). The solution was then heated at 65 ° C for 3 hours. The solution was then filtered hot and the resin was washed with THF (2 x 15 ml). The crude anhydride solution was cooled to room temperature and a solution of borane t-butylamine complex (0.3 g, 3.45 mmol), in THF / H 2 O (1/1 20 ml), was added dropwise to the aldehyde solution. The solution was stirred at room temperature for 1.5 hours and the reaction was then quenched through the addition of H2O (100 ml). After stirring at room temperature for an additional 30 minutes, the precipitate was isolated through filtration and dried to give 1.00 g (47%) of the desired product.

EXAMPLE 37 Alternative Preparation of (R) -9- [4- (N-benzyloxycarbonyl-L-valloxy) -2- (stearoyloxymethyl) butyl] guanine. a) N-carbobenzyloxy-L-valine anhydride A solution of dicyclohexylcarbodiimide (5 kg, 24 moles) in acetonitrile (17.5 kg) was added to a reactor containing a solution of N-carbobenzyloxy-L-valine (12.5) kg, 50 moles) in acetonitrile (200 kg). The mixture was stirred at 5 +/- 5 ° C for 6 hours and the resulting solid was filtered. The filtrate was concentrated under vacuum at no more than 45 ° C and the residue was dissolved in toluene (50 kg) at 40 ° C. Heptane (50 kg) was added and the mixture was cooled to 15 +/- 5 ° C. the precipitate was filtered and dried to give 10.2 kg of the desired product. b) (R) -9- [4- (N-benzyloxycarbonyl-L-valyloxy) -2- (stearoyloxymethyl) butylguanine. A mixture of (R) - (- [4-hydroxy-2- (stearoyloxymethyl) butyl] guanine (5.2 kg, 10 moles), N-Cbz-L-valine anhydride (6.3 kg, 13 moles), 4-dimethylaminopyridine (60 g, 0.5 mol) and tetrahydrofuran (67 kg) was stirred for 2-4 hours at 25 +/- 5 ° C. Water (2 kg) was added and the mixture was concentrated under vacuum at no more than 45 ° C. The residue was dissolved in ethyl acetate (58 kg) and extracted with 10% aqueous sodium bicarbonate (2 x 50 kg) and water (1 x 50 kg) The ethyl acetate solution was concentrated under vacuum and the residue was dissolved in methanol (20 kg) at 50 +/- 5 ° C. The solution was cooled to 20 +/- 5 ° C and diluted with acetonitrile (50 kg) and water (3 kg). filtered and dried under vacuum to give the desired product (5.3 kg).

EXAMPLE 38 Alternative Preparation of (R) -9- [4,4-diethoxy-2- (stearoyloxy-methyl) butyl] guanine. To a stirred solution of stearic acid (1.05 g) and N-methylmorphoiin (0.62 g) in THF (13 ml) at 0-4 ° C was added a solution of p-tosyl chloride (0.67 g) in THF (2 ml) at -3 to -4 ° C. The mixture was stirred at room temperature for 3 hours. The product of Example 14 g) (1.0 g) and 4-dimethylaminopyridine (75 mg) were added and the suspension was stirred at room temperature for 5 days and quenched with 135 ml of water. The mixture was stirred overnight and the precipitate was filtered and washed with water. The wet filter cake was dried under vacuum (40 ° C) to give the desired product (1.3 g) as a light yellow powder.

EXAMPLE 39 Alternative Preparation of (R) -9- [4,4-diethoxy-2- (hydroxymethyl) butyl] guanine. The product of Example 30 a) (10.0 g, 29.1 mmol) was added to a solution of sodium hydroxide (2.33 g, 5.82 mmol) in water (200 ml). A solution of trimethylamine (6.61 ml of a 40% by weight solution in water, 43.6 mmol) was charged to the suspension. The heterogeneous mixture was stirred at room temperature. The reaction was diluted with water (50 ml) and then extracted with ethyl acetate (200 ml). The water layer was charged with a saturated solution of ammonium sulfate (300 ml). The mixture was stirred at room temperature for 30 hours and the resulting precipitate was filtered. The filter cake was washed with ethyl acetate (100 ml). The product was dried in a vacuum oven (high housing vacuum, 45 ° C) overnight to provide the desired product (7.88 g).

EXAMPLE OF FORMULATION A Tablet Formulation The following ingredients were filtered with a 0.15 mm sieve and dried and mixed with 10 g of (R) -9- [2- (stearoyloxymethyl) -4- (L-valyloxy) butyl] guanine 40 g of lactose 49 g crystalline cellulose 1 g magnesium stearate A tabletting machine was used to compress the mixture into tablets of 250 mg of active ingredient. 14 EXAMPLE OF FORMULATION 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 (Methocell 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 oil of peanuts 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 0.1 mmol / kg of the prodrug dissolved in an aqueous vehicle was obtained (Example 4, , Comparative Example 1 - 3, 5), peanut 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. H2G was analyzed in the urine using Stahl's HPLC / UV test; Óberg, Antimicrob Agents Chemother. 36 No 2, 339-342 (1992), with the following modifications: upon thawing the samples were diluted 16 1: 100 aq. dist. H2O and filtered with an amicon filter and centrifuged 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 NH4PO4, 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. The bioavailability was calculated as the recovery of H2G measured in each animal and the average was obtained in at least three animals and was expressed as a percentage of the recovery of average H2G in urine during 24 hours of a group of four heavy rats individually injected ivjugularis with 0.1 mmol / kg of H2G in Ringer's regulating 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 Examples 21 and 23. 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. Comparative examples 5 & 8 (Val / Ac H2G) were prepared in the same manner as Example 4 using acetic anhydride with the relevant H2G monovaline. Comparative Example 6 (Ala / stearoyl H2G) was prepared in a similar manner to Example 6 using Nt-Boc-L-alanine in step 4. Comparative Example 7 (Gly / decanoyl) was prepared in a similar manner to Example 5 but was used the intermediate product from step 1 made with Nt-Boc-L-glycine. The preparation of Comparative Examples 9 and 10 are shown in Examples 24 and 25 respectively. The results appear in Table 2 below: Table 2 Ri R Compound: Bioavailability Comparative example 1 Hydrogen hydrogen hydrogen 8% Comparative example 2 Hydrogen gas 29% Comparative example 3 Valyl ilo valil 36% Example 1 Valyl stearoyl 56% Comparative example 4 Stearoyl ether 1% Example 2 Valyl Myristoylous 57% Exemplar 3 Valyl Oleoyl 51% Exemplary 4 Valyl Butyryl 45% Comparative Example 5 Valid Acetyl 11% Exemplary 5 Valyl Decanoic 48% Exemplary 6 Valyl Docosanoyl 48% Exemplary 7 Iso Leucii stearoyl 53% Example 8 iso leuci decanoyl 57% Example 9 iso leucii miristoil 49% Sample 10 value 4-acetylbutyryl 52% Example 11 value dodecanoil 46% Example 12 value palmitoyl 58% Example 17 stearoyl 52% valilo Comparative Example 6 alanyl stearoyl 23% Comparative example 7 decanyl glyclic 25% Comparative example 8 acetyl valyl 7% Comparative example 9 hydrogen stearoyl 12% Comparative example 10 stearoyl 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 the night before the administration but had 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 of 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 the initiation and reconstitution, the plasma concentrations were determined by reverse phase HPLC 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 of 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.o. 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 at 1000 times the LD50 either with the formulation composed of the existing anti-herpes agent acyclovir in place (21 and 83 mg / kg in 2% propylene glycol in sterile water as vehicle, three times per 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

1. - A process for the preparation of a compound of the formula: wherein R10 is saturated or monounsaturated C3-C21 alkyl, optionally substituted and Rn is isopropyl or isobutyl, which comprises: a) deprotecting the acetal of the compound of the formula: where R6 and R? they are lower alkyl or benzyl, or R6 and R7 taken together with -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-, and R10 is as defined above; b) reducing the aldehyde substituent of the product of step a) to provide the alcohol of the formula: where R-i is as defined above; and c) reacting the product of step b) with Pi HCHIRONOH or an activated derivative thereof or with P1NHCH (R11) C (O) -OC (O) CH (R11) NHP1, wherein Rn is as defined above and Pi is a protecting group of N.

2. The process according to claim 1, further comprising N-deprotecting the product of step c).

3. The process according to claim 1, wherein R6 and 7 are -CH3 or -CH2CH3 or R6 and R7 taken together are -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2-, R10 is C9-C19 alkyl and P-, is t-butyloxycarbonyl or benzyloxycarbonyl.

4. The process according to claim 1, wherein R6 and R7 are -CH2CH3, Ri0 is - (CH2) 16CH3 and P- is t-butyloxycarbonyl or benzyloxycarbonyl.

5. The process according to claim 1, wherein the acetal is deprotected through the reaction with an acid or an acid resin.

6. The process according to claim 1, wherein the aldehyde substituent of the product of step a) is reduced with a borane t-butylamine complex.

7. A process for purifying a compound of the formula: OH wherein R10 is saturated or monounsaturated, optionally substituted C3-C21 alkyl, which comprises reacting with a chiral organic sulfonic acid.

8. The process according to claim 7, wherein R-io is - (CH2) 16CH3 and the sulfonic acid is (S) - (+) - alkane-sulfonic acid.

9. A process for the preparation of a compound of the formula: wherein R6 and 7 are lower alkyl or benzyl or R6 and R7 taken together are -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2 and R10 is C3-C21 alkyl saturated or monounsaturated, optionally substituted, which comprises reacting a compound of the formula: wherein R6 and R7 are as defined above with R10COOH or an activated derivative thereof.

10. The process according to claim 9, wherein the activated derivative of R10COOH is R10C (O) OS (O) 2R3o, wherein R30 is lower alkyl, phenyl or tolyl or R? 0C (O) OC (O ) R? 0 or R10C (O) OC (O) R? 0a. wherein R10a is lower alkyl and wherein R10 is - (CH2) 16CH3.

11. A process for the purification of a compound of the formula: wherein R4 and R5 are lower alkyl or benzyl and R6 and R are lower alkyl or benzyl or R6 and R7 taken together are -CH2CH2-, or -CH2CH2CH2- or -CH2CH2CH2CH2-, which comprises the compound with a dilute aqueous base.

12. A process for the preparation of a compound of the formula: wherein R6 and R are lower alkyl or benzyl or R6 and R? taken together are -CH2CH2-, or -CH2CH2CH2- or -CH2CH2CH2CH2-, which comprises reacting a compound of the formula: wherein R6 and R7 are as defined above and R8 is C3-C2 alkyl? saturated or monounsaturated, optionally substituted with an inorganic base.

13. The process according to claim 12, wherein the inorganic base is KOH or NaOH.

14. A process for the preparation of a compound of the formula: wherein R6 and R7 are lower alkyl or benzyl or R6 and R7 taken together are -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-, and R8 is saturated or monounsaturated, optionally substituted C3-C21 alkyl, which comprises reacting a compound of the formula: wherein R6 and R7 are as defined above with CH2 = CH-OC (O) R8, wherein R8 is as defined above, in the presence of a lipase.

15. The process according to claim 14, wherein R6 and R7 are -CH3 or -CH2CH3 or R6 and R taken together are -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-, and R8 is - (CH2) 16CH3 .

16. The process according to claim 14, wherein R6 and R7 are -CH2CH3 and R8 is - (CH2) 6CH3.

17. A process for the preparation of a compound of the formula: wherein R6 and R7 are lower alkyl or benzyl or R6 and R7 taken together are -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2- and R8 is C3-C2 alkyl? saturated or monounsaturated, optionally substituted and X2 is a leaving group, comprising: a) reacting a compound of the formula: wherein R6 and R7 are as defined above with CH2 = CH-OC (O) R8, wherein R8 it is as defined above, in the presence of a lipase to provide an ester of the formula: wherein R6, R7 and R8 are as defined above; and b) converting the hydroxy group of the product from step a) to a leaving group.

18. The process according to claim 17, wherein R6 and R7 are -CH3 or -CH2CH3 or R6 and R7 taken together are -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2- and, R8 is - (CH2) 16CH3 and X2 is a halogen or a sulfonate leaving group.

19. The process according to claim 17, wherein R6 and R7 are -CH2CH3 and R8 is - (CH2) 16CH3 and X2 is tosylate.

20.- A compound of the formula: wherein R6 and R are lower alkyl or benzyl or R6 and R7 taken together are -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2- and R8 is saturated or monounsaturated C1-C21 alkyl, optionally substituted.

21. The compound according to claim 20, wherein R6 and R7 are -CH3 or -CH2CH3 or R6 and R7 taken together are -CH2CH2-? -CH2CH2CH2- or -CH2CH2CH2CH2- and R8 is CH3.

22. The compound according to claim 20, wherein R6 and R7 are -CH2CH3 and R8 is CH3.

23. The compound according to claim 20, wherein R6 and R7 are -CH3 or -CH2CH3 or R6 and R7 taken together are -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2- and R8 is - (CH2)? ECH3.

24. The compound according to claim 20, wherein R6 and R are -CH2CH3 and R8 is - (CH2) 16CH3.

25.- A compound of the formula: wherein R6 and R7 are lower alkyl or benzyl or R6 and R7 taken together are -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2- and R9 is H or an alcohol protecting group.

26. The compound according to claim 25, wherein R6 and R7 are -CH3 or -CH2CH3 or R6 and R7 taken together are -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2- and R9 is benzyl.

27. The compound according to claim 26, wherein R6 and R7 are -CH2CH3 and R9 is benzyl.

28.- A compound of the formula: wherein R6 and R7 are lower alkyl or benzyl or R6 and R7 taken together are -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2- and R10 is C3-C2 alkyl? saturated or monounsaturated, optionally substituted.

29. The compound according to claim 28, wherein R6 and R7 are -CH3 or -CH2CH3 or R6 and R7 taken together are -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2- and R10 is - (CH2) 16CH3.

30. The compound according to claim 28, wherein R6 and R7 are -CH2CH3 and Rio is - (CH2) 16CH3.

31.- A compound of the formula: wherein R6 and R7 are lower alkyl or benzyl or R6 and R7 taken together are -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-, and R8 is saturated or monounsaturated C3-C21 alkyl, optionally substituted.

32. The process according to claim 31, wherein R6 and R are -CH3 or -CH2CH3 or R6 and R7 taken together are -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-, and R8 is - (CH2) 16CH3 .

33. The process according to claim 31, wherein R6 and R7 are -CH2CH3 and R8 is - (CH2) 16CH3.

34.- A compound of the formula: wherein R6 and R7 are lower alkyl or benzyl or R6 and R7 taken together are -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2- and R8 is C3-C2 alkyl? saturated or monounsaturated, optionally substituted and X2 is a leaving group.

35.- The process according to claim 34, wherein R6 and R? are -CH3 or -CH2CH3 or R6 and R7 taken together are -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2- and, R8 is - (CH2) 16CH3 and X2 is a halogen or a sulfonate leaving group.

36. The process according to claim 34, wherein R6 and R7 are -CH2CH3 and R8 is - (CH2) 16CH3 and X2 is tosylate.

37.- A process for the preparation of a compound of the formula: wherein R10 is saturated or monounsaturated C3-C21 alkyl, optionally substituted, and Rn is isopropyl or isobutyl, which comprises: a) deprotecting the ether substituent of the compound of the formula: wherein R12 is -CH (Ph) 2, -C (Ph) 3 or -Si (t-Bu) (CH3) 2, wherein Ph is phenyl and R10 is as defined above to provide the alcohol of the formula: wherein R10 is as defined above; and b) reacting the product of step b) with PICHOHIR COOH or an activated derivative thereof or with P1NHCH (R11) C (O) -OC (O) CH (R11) NHP1, wherein Rn is as defined above and P - is a protecting group of N.

38.- The process according to claim 37, which further comprises N-deprotecting the product of step b).

39.- The process according to claim 37, wherein R 2 is as defined herein, R 10 is C 9 -C 19 alkyl and P-, is t-butyloxycarbonyl or benzyloxycarbonyl.

40. The process according to claim 37, wherein R12 is as defined herein, R10 is - (CH2) 16CH3 and P, is t-butyloxycarbonyl or benzyloxycarbonyl.

41.- A process for the preparation of a compound of the formula 'HO' OC (0) R8 R120 wherein R8 is saturated or monounsaturated C3-C21 alkyl, optionally substituted, and R? 2 is -CH (Ph) 2, -C (Ph) 3 or -Si (t-Bu) (CH3) 2, in where Ph is phenyl, which comprises reacting a compound of the formula: wherein R12 is as defined above with CH2 = CH-OC (O) R8, wherein R8 is as defined above, in the presence of a lipase.

42. The process according to claim 41, wherein R12 is as defined above, and R8 is - (CH2)? 6CH3.

43.- A process for the preparation of a compound of the formula: -OC (0) R8 R120 wherein R8 is saturated or monounsaturated C3-C21 alkyl, optionally substituted, R12 is -CH (Ph) 2, -C (Ph) 3 or -Si (t-Bu) (CH3). wherein Ph is phenyl. and X2 is a leaving group, comprising: a) reacting a compound of the formula: wherein R12 is as defined above with CH2 = CH-OC (O) R8, wherein R8 is as defined above, in the presence of a lipase to provide an ester of the formula: HO '-OC (0) R6 R120 wherein R8 and R12 are as defined above; and b) converting a hydroxyl group from the product of step a) to a leaving group.

44. The process according to claim 43, wherein R8 is - (CH2) 16CH3 and R12 is as defined herein, and X2 is a halogen or a sulfonate leaving group.

45. The process according to claim 43, wherein R8 is - (CH2) 16CH3 and R12 is as defined herein and X2 is tosylate.

46.- A compound of the formula: wherein R8 is saturated or monounsaturated alkyl, optionally substituted, and R12 is -CH (Ph) 2, -C (Ph) 3 or -Si (t-Bu) (CH3) 2, wherein Ph is phenyl.

47. The compound according to claim 46, wherein R8 is CH3 and R12 is as defined herein.

48. The compound according to claim 46, wherein R8 is - (CH2) 16CH3 and R12 is as defined herein.

49.- A compound of the formula: wherein R9 is H or an alcohol protecting group and R12 is -CH (Ph) 2, -C (Ph) 3 or -Si (t-Bu) (CH3) 2, wherein Ph is phenyl.

50.- The compound according to claim 49, wherein R9 is benzyl and R? 2 is as defined herein.

51.- A compound of the formula: wherein Rio is saturated or monounsaturated C3-C21 alkyl, optionally substituted, and R 2 is -CH (Ph) 2, -C (Ph) 3 or -Si (t-Bu) (CH 3) 2, wherein Ph is phenyl.

52. The compound according to claim 51, wherein Rio is - (CH2) 16CH3 and R? 2 is as defined herein.

53.- A compound of the formula: wherein R8 is saturated or monounsaturated d-C21 alkyl, optionally substituted, and R12 is -CH (Ph) 2, -C (Ph) 3 or -Si (t- Bu) (CH3) 2, wherein Ph is phenyl .

54. The compound according to claim 53, wherein R8 is CH3 and R12 is as defined herein.

55. The compound according to claim 53, wherein R8 is - (CH2)? 6CH3 and R12 is as defined herein.

56.- A compound of the formula: wherein R8 is saturated or monounsaturated d-C21 alkyl, optionally substituted, and R12 is -CH (Ph) 2, -C (Ph) 3 or -S? (t-Bu) (CH3) 2, wherein Ph is phenyl and X2 is a leaving group.

57.- The compound according to claim 56, wherein R8 is CH3, R12 is as defined herein and X2 is a halogen or a sulfonate leaving group.

58.- The process according to claim 56, wherein R8 is CH3, R12 is as defined herein and X2 is tosylate.

59. The compound according to claim 56, wherein R8 is - (CH2) 16CH3, R2 is as defined herein and X2 is a halogen or a sulphonate leaving group.

60. The compound according to claim 56, wherein R8 is - (CH2) 16CH3, R12 is as defined herein and X2 is tosylate.

61. - A method for the preparation of a compound of the formula I: 2 wherein a) Ri 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) Ri is a C (O) C3-C2 alkyl, saturated or monounsaturated, optionally substituted and R2 is -C (O) CH (CH (CH3) 2) NH2 or C (0) CH (CH (CH3) CH2CH3) NH2; and R3 is OH or H; the method comprises: a) converting Q2 to a compound of the formula: wherein Q is a first protecting group, Q2 is H, Q3 is optionally protected OH or a leaving group, and Q4 is H or OQ ,, to a second protecting group or an alkyl derivative -C (O) C3-C21, saturated or monounsaturated, optionally substituted; b) converting Q3 to an N-9 guanine derivative; c) replacing said second protecting group, if present, with a derivative -C (O) CH (CH (CH3) 2) NH2, a derivative -C (O) CH (CH (CH3) CH2CH3) NH2 or an alkyl derivative -C (O) C3-C21, saturated or monounsaturated, optionally substituted; d) convert, if necessary, Q4 to hydrogen; and e) convert Q ^ to a derivative -C (O) CH (CH (CH3) 2) NH2, a derivative -C (O) CH (CH (CH3) CH2CH3) NH2 or an alkyl derivative -C (O) C3- C2? Saturated or monounsaturated, optionally substituted. 62.- A process for the preparation of a compound of the formula: wherein R10 is C3-C2 alkyl? saturated or monounsaturated, optionally substituted and R is isopropyl or isobutyl, which comprises reacting a compound of the formula: wherein R9 is an alcohol protecting group with a compound of the formula: wherein X2 is a halogen or sulphonate leaving group and P-i is a protecting group of N and R10 and Rn are as defined above. 63.- The process according to claim 62, wherein R9 is benzyl, R10 is - (CH2) 16CH3 and X2 is p-toluenesulfonyloxy, 64.- A compound of the formula: 10 wherein X2 is a halogen or sulphonate leaving group, P-, is a protecting group of N, R10 is saturated or monounsaturated C3-C21 alkyl, optionally substituted and Rn is isopropyl or isobutyl. The compound according to claim 64, wherein X2 is p-toluenesulfonyloxy and R10 is - (CH2) 16CH3. 66. The compound according to claim 63, wherein X2 is p-toluenesulfonyloxy, R? 0 is - (CH2)? 6CH3, R ,, is isopropyl and P-i is benzyloxycarbonyl. 67.- A compound of the formula: • OC (O) R10 CHO wherein X2 is a halogen or a leaving group of sulfonate and R10 is C3-C2 alkyl? saturated or monounsaturated, optionally substituted. The compound according to claim 67, wherein X 2 is p-toluenesulfonyloxy and R 0 is - (CH 2) 16 CH 3.