MXPA97000360A

MXPA97000360A - Dinoclyside-5, 5-pyrophosphate

Info

Publication number: MXPA97000360A
Application number: MXPA/A/1997/000360A
Authority: MX
Inventors: De Flora Antonio; Benatti Umberto; Giovine Marco
Original assignee: Benatti Umberto; De Flora Antonio; Giovine Marco; Gruppo Lepetit Spa; Universita' Degli Studi Di Genova
Priority date: 1994-07-15
Filing date: 1997-01-13
Publication date: 1998-10-15

Abstract

The present invention describes 5 ', 5'-pyrophosphates of non-naturally occurring nucleonics, selected from thymine-3'-azido-2', 3'-dideoxy-D-riboside, 5-fluorouacyl-2'-deoxy-D- riboside, uracil-3'-azido-2 ', 3'-dideoxy-D-riboside, guanine-2', 3'-dideoxy-D-riboside, hypoxanthine -2 ', 3'-dideoxy-D-riboside, cytosine- 2 ', 3'-dideoxy-D-riboside, and adenine-2', 3'-dideoxy-D-riboside, with its manufacture and use as therapeutic agents against tumors and retroviral infections including HIV infections. The compounds can be administered as the active ingredients of pharmaceutical compositions, or as pro-drugs, encapsulated in biological carriers, for example, transformed erythrocytes, to direct them towards populations of specific cells, responsible for the development of pathological disorders.

Description

DINUCLEOSID-5 *, 5 '-PIROPHOSPHATES DESCRIPTION OF THE INVENTION This invention relates to dinucleoside-5', 5'-p 1, p 2-pyrophosphates of the formula (I): x x II II A-X-P-X -? - * - * O) I I X »x *? wherein: symbols A and B each represent a 5 '-C' radical of a nucledside that does not exist naturally, selected from: thymine-3'-azido-2 ', 3'-dideoxy-D-ribsido , 5-fluorouracil-2'-deoxy-D-riboside, uracil-3'-a2ido-2,, 3'-dideoxy-D-riboside, guanine-2 ', 3'-dideoxy-D-riboside, hypoxanthine-2f , 3'-dideoxy-D-ribsido, cytosine-2 ', 3'-dideoxy-D-riboside, and adenine-2f, 3'-dideoxy-D-riboside; the symbols X each independently represent oxygen or sulfur; REF: 23520 the symbols R and R, each independently represent hydrogen or an alkyl group of 1 to 10 carbon atoms; and the addition salts of the compounds of formula (I), wherein R and / or R represent hydrogen, with bases that provide biologically acceptable cations. This invention also includes a process for the pre-paration of the dinucleoside-5 ', 5'-p1, p2-pyrophosphates of formula (I), a method for their encapsulation in biological carriers, in particular erythrocytes, to direct the compounds from above to specific sites or cell populations that are involved in the development or are responsible for pathological disorders such as tumors or viral infections, and compositions containing biological carriers, in particular erythrocytes, encapsulating the 5 'dinucleoside, 5'-p 1, p2-pyrophosphates of formula (I). Chemical modification of the erythrocyte membrane to encapsulate biologically active molecules is a powerful method for delivering target cells to the encapsulated molecule in a biologically active form. See, for example: -From Flora A. et al. "Engineered erythrocytes as carriers and bioreactors". The Year in Immunology, Basel, Karger, (1993), Vol. 7, 168-174.

/ * --- -Tonetti M. et al. "Liver targeting of autologous ery- throcytes loaded with doxorubicin". Eur. J. Cancer, (1991), Vol. 27, No. 7, 947-948. -Zocchi E. et al. "Human and murine erythrocytes as bioreactors releasing the antineoplastic drug 5-fluoro-2'-deoxyuridine". Advances in Biosciences, (1991), Vol. 81, Pergamon Press foot. 51-57. -From Flora A. et al. "Conversion of encapsulated 5-fluoro-2 '-deoxyuridine-5' -monophosphate to the antineoplastic drug 5-f luoro-2 '-deoxyuridine in human erythrocytes". Proc. Nati Acad. Sci. USA, (1988), Vol. 85, 3145-3149. -From Flora A. et al. "The technology of carrier erythrocytes: a versatile tool for diagnosis and therapy". Biotechnology in Diagnostics, Elsevier Science Publishers B.V., (1985), 223-236. Additional literature is cited in the field in the articles and publications mentioned above. In the following, description and claims, the correspondence between chemical names and commonly used acronyms will be maintained, as reported below: thymine-3 '-azido ~ 2', 3 '-dideoxy-D-riboside (AZT), adenine -2 ', 3' -dideoxy-D-riboside (DDA), 5-fluorouracil- '-deoxy-D-riboside (FDU), cytosine-2', 3'-dideoxy-D-riboside (DDC), uracil- 3'-azido ~ 2 ', 3' -dideoxy-D-riboside (AZDDU), l '"" hypoxanthin-2', 3 '-dideoxy-D-riboside (DDI), and guanine-2', 3 '- dideoxy-D-riboside (DDG). Methods for encapsulating biologically active substances, in particular, phosphorylated compounds, in transformed erythrocytes and compositions for their use, as well as methods for inducing cells derived from animals, especially erythrocytes, to selectively search for and fuse with other erythrocytes. cells, have also been described in the patent literature: Publication of Application of 0 International Patent No. 92/22306, US Patent No. 4,931,276, Patent of E.U.A. No. 4,652,449 and European Patent Application Publication No. 298280. International Patent Application Publication No. WO 91/00867 discloses 5'-diphosphohexose nucleosides which have biological activity that includes antiviral activity. A structurally related class of bridged nucleoside dimers is described in EP-A 284 405, which is reported to be active in treating AIDS and H. simplex infections. In this description and claims, the expression "5'-C 'radical of a naturally-occurring nucleoside" identifies a radical derived from a nucleoside that does not exist naturally by elimination of the hydroxy group at the 5'-position of the pentose portion. 5 The expression "the symbols X represent each independently oxygen or sulfur" means that each of the symbols X can represent an oxygen or sulfur atom, independently of the meanings assumed by the others. According to a preferred embodiment of this invention, any of all the symbols X represents oxygen, or only one or two of them represents (n) sulfur and the others represent oxygen. In the latter case, the most preferred compounds of formula (I) are those in which the symbol (s) X representing (s) sulfur is (are) that (those) directly attached to the atom (s) ( s) of phosphorus through a double bond, or that (those) that is (are) part of the XR or (y) XR portion. The term "a biologically acceptable cation" means a cation that is suitable for use in pharmaceutical practice, and that includes those cations that are not toxic to the biological carriers of the compounds of formula (I), and are compatible with the for its encapsulation in carriers. When the symbol R and / or R1 independently represents hydrogen, the compounds of formula (I) can form addition salts with bases that provide biologically acceptable cations. Such salts can be represented by the compounds of formula (I) wherein the symbol X of the portion XR and / or XR. represents (s) an oxygen and / or sulfur atom in the anionic form (ie 0 and / or S) and the symbol R and / or R represents (n) a biologically acceptable cation. The cations that are acceptable for use in pharmaceutical practice are those that are derived from alkaline or alkaline-earth metals, such as sodium, potassium and magnesium, ammonia, and aliphatic, alicyclic and aromatic amines, such as methylamine, dimethylamine , triethanolamine, piperidine, piperazine, N-methylpiperidine, N-methylpiperazine, morpholine and picoline. -'-. The biologically acceptable cations suitable for Both, the use in pharmaceutical practice and the encapsulation procedures are, for example, Na and K. The term "an alkyl group of 1 to 10 carbon atoms" identifies a linear or branched alkyl radical which optionally may contain an unsaturation and / or one or two substituents selected from hydroxy, mercapto, chloro, iodo, fluoro, bromo, amino, (C.-C,) alkylamino, di- (C, -C,) -alkylamino, (C.-C,) -alkoxy and (C , -C,) -alkylthio. Preferably, the above term identifies an alkyl radical of 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 1,1-dimethylethyl, and 2-methylpropyl, which optionally they may contain one or two substituents as defined above. A further preferred group of compounds of this invention includes those compounds of formula (I) in which of the symbols A, B and X are as specified above, and the symbols R and R, each independently represent hydrogen, or a (C.-C,) alkyl as defined above. This group of preferred compounds also includes the addition salts of the compounds of formula (I) wherein R and / or R represents (n) hydrogen, with bases that provide ogically acceptable cations, such as Na, K, and the other cations mentioned above. A more preferred group of compounds of this invention is individuated by those derivatives of formula (I) wherein symbols A and B are as specified above, all symbols X represent oxygen, and both, R and R. represent hydrogen, and its salts with ogically acceptable cations, for example Na or. Some specific examples of dinucleoside-5 ', 5'-p 1, p2-pyrophosphates of formula (I) that can illustrate this invention are specifically represented in the following Table I.

TABLE I (Contioúa) B I? TABLE I (Continued) B o \ TABLE I (Continued) B 4) B2 TABLE I (Continued) B TABLE I (Continued) B TABLE I (Continued) B I TABLE I (Continued) B I TABLE I (Continued) B i TABLE I (Continued) B TABLE I (Continued) B oo TABLE I (Continued) B I TABLE I (Continued) B o TABLE I (Continued) B I TABLE I (Continued) B TABLE I (Continued) B - TABLE I (Continued) B > TABLE I (Continued) B K3 Ul TABLE I (Continued) B TABLE I (Continued) B t The dinucleoside-5e I, 5-p, p-pyrophosphates of formula (I) above, wherein at least one of A and B represent a 5'C 'radical which is derived from 5-fluorouracil-2'-deoxy-D-riboside are useful as anti-tumor therapeutics, while the dinucleoside- 5 ', 5' -p 1, p2-pyrophosphates wherein at least one of A and B represents a 5'-C 'radical of a naturally occurring non-naturally occurring nucleoside, selected from: thymine-3' -azido-2, 3'-dideoxy-D-riboside, uracil-3 '-azido-2', 3'-dideoxy-D-riboside, guanine-2 ', 3'-dideoxy-D-riboside, hypoxanthine-2', 3 '- dideoxy-D-riboside, cytosine-2 ', 3'-dideoxy-D-riboside, adenine-2', 3'-dideoxy-D-riboside, are useful as antiviral therapeutic agents, in particular, against retroviral infections, such as HIV infections. According to the properties described above, the di-nucleosides containing both types of 5'C 'radicals as defined above, can be useful in both ways, as antitumor and antiviral agents. The process for preparing the dinucleoside-5 ', 5'-p 1, p2-pyrophosphates runs according to procedures that are already described in the art. See for example: A. M. Michelson, "Synthesis of nucleotide anhydrides by anion exchange", in him. hys. Acta, (1964), 91, 1-13. According to this method, a nucleoside phosphate of the formula (II): A-X-P-XH (ID XR wherein A, X and R have the same meanings as above, it is activated on the XH group of the phosphoric acid portion by reaction with an activating agent, such as tetraphenyl pyrophosphate or diphenyl phosphochloridate, to form an activated phospho-ester of the nucleoside phosphate above. The activated phospho-ester is then reacted with a nucleoside phosphate of the formula (III): X II B-X-P-XH (? D I X * i wherein B, X and R have the same meanings as above, to form the compound of formula (I) by displacement of the activated diphenyl phosphate portion of the activated phospho-ester. Other examples of methods useful for preparing the di-nucleoside-5 ', 5'-p 1, p2-pyrophosphates of this invention can be derived from the literature cited in US 4855304, which discloses some pyrophosphates of dinucleoside and pyrophosphate homologs useful for inhibit the replication of plant viruses. In a representative embodiment of this invention, the reaction path described above is carried out essentially under the conditions described by AM Michelson, that is, the nucleoside phosphate of the formula (II) or a salt thereof, (e.g. salt of sodium, lithium, or barium) is first converted to the corresponding salt with a hindered tertiary amine base, such as tri-n-butylamine or tri-n-octylamine, or with a hindered quaternary ammonium base, such as hydroxide of methyl-tri-n-octylammonium. The transformation is usually carried out via the intermediate formation of a pyridinium salt, by elution of the nucleoside phosphate or a salt thereof (preferably the sodium salt) through an ion exchange resin (strongly cationic) in the pyridinium form. This stage has mainly the purpose of eliminating sodium or other mineral cations. The pyridinium salt is then incubated with a methanol solution containing an equimolar amount of the hindered tertiary amine base, and then dried under reduced pressure, to provide the salt with hindered tertiary amine base. The salt of the nucleoside phosphate of formula (II) is then contacted with an excess -3: (from 1.5 to 2.5 moles per mole of nucleoside phosphate) of the activating agent (for example diphenyl phosphochloridate or tetraphenyl pyrophosphate) in the presence of an excess of an acid acceptor (from 1.2 to 2 moles per mole of active agent). ) that does not interfere with the reagents, for example, a tertiary aliphatic amine (for example tri-n-butylamine) or a tertiary heterocyclic amine (for example N-methylpiperidine, N-methylpyrrolidine). The activation reaction is generally carried out at room temperature and under anhydrous conditions, using as the solvent an inert aprotic organic solvent, such as a cyclic ether (for example dioxane) or a mixture thereof. In some cases, the addition of an additional inert organic solvent of high solubility power (for example dimethyl formamide) is advisable to increase the concentration of the reagents and, therefore, the speed of the reaction, Under the conditions above, the formation of the activated phosphate ester is generally completed within 2 to 5 hours. The activated phosphate ester is then reacted with a salt of the nucleoside phosphate (III) with a hindered tertiary amine base or quaternary ammonium hydroxide such as those exemplified above, in the presence of an inert organic aprotic solvent, for example pyridine, hexamethylphosphoramide, dimethylformamide or a mixture thereof. The reaction is usually carried out at a temperature in the range between 20 ° C and 35 ° C, and is completed in a period of time of 15 to 30 hours. The crude reaction product is usually recovered by evaporating the solvent under reduced pressure, and then subjected to common purification procedures, including chromatographic methods. For example, for the purification process of those compounds of formula (I) wherein R and / or R, are (is) hydrogen, the crude product is then suspended in water and, after adjustment of the pH value to 8 with an aqueous alkali metal hydroxide, the solution is extracted with an aprotic organic solvent not miscible with water, such as diethyl ether. The aqueous phase containing the dinucleoside pyrophosphate is subjected to further purification by combining column chromatography methods (for example using a gel filtration column and water as the solvent) and HPLC methods (for example using a phase column). reversal of silica gel functionalized with linear hydrocarbons and eluting with a linear gradient of methanol in water, or a strong anion exchange resin, and eluting with a linear gradient of lithium chloride in water). The 5 ', 5' -p 1, p 2-pyrophosphate dinucleoside of the formula (I) of this invention are in general stable compounds, in particular when they are isolated in the form of salts with biologically acceptable salts, for example as sodium or potassium salts. Therefore, although when R and / or R. represent (n) hydrogen, they can be isolated and characterized in the form of free acids (eg, loading an aqueous solution of the salt onto an ion exchange resin in form H and eluting the resin with water or a mixture of methanol and water), they are preferably stored or used in the form of salts, more preferably, as salts with biologically acceptable cations. The nucleoside phosphate starting materials that do not exist naturally: X II A-X-P-XH a-x-p-xa I I XA XXl can be prepared according to standard procedures from the corresponding non-phosphorylated nucleosides Examples of such non-phosphorylated precursors, which are described in the state of the art, are the following: thymine-3'-azido-2 ', 3' -dideoxy-D-riboside (AZT), adenine-2 ', 3'-dideoxy-D-riboside (DDA), 5-f luorouracil-2' -deoxy-D-riboside (FDU), cytosine-2 ', 3 '-dideoxy-D-riboside (DDC), uracil-3' -azido-2 ', 3'-dideoxy-D-riboside (AZDDU), hypoxanthin-2', 3'-dideoxy-D-riboside (DDI), and guanine-2 ',' -dideoxy-D-riboside (DDG). See the following references: Levene, P.A., J. Biol. Chem., (1929), Vol. 83, 793; Davoli, J. et al., J. Chem. Soc. (1948), 967; Howard, G.A. et al., J. Chem. Soc. (1947), 1052; Robins, M. J. et al., J. Am. Chem. Soc. (1971), 93:20, 5277; Chu, C. K. et al., J. Org. Chem. (1989), 54, 2217; Colla L. et al., Eur. J. Med. Chem. Chim. Ther., (1985), No. 4, 295. In most cases the above precursors are also available on the market (for example from SIGMA Chemical Co., St. Louis, MO, USA). The methods for converting the non-phosphorylated precursor to the corresponding phosphorylated compound are also known from the state of the art. A typical procedure for the preparation of the nucleoside monophosphates is to contact the nucleoside with a solution of cyanoethyl phosphate in anhydrous pyridine, in the presence of a condensing agent such as dicyclohexylcarbodiimide at room temperature. The final products can be conveniently recovered and purified in the form of salts with alkaline or alkaline earth metals such as sodium, lithium or barium. In some cases, nucleoside monophosphates are commercially available (for example 5-fluoro-2 '-des-oxy-ididin-5' -raponophosphate, SIGMA Chemical Co., St. Louis, MO, USA). The compounds of formula (I) have antiviral (including anti-HIV) and / or antitumor activity, and are useful as active ingredients of pharmaceutical compositions. To confirm the anti-HIV activity of some dinucleoside-5 ', 5'-p 1', p 2 -pyrofosphates representative of this invention, in vitro tests have been carried out on a cell line transformed with HTLV-1. , MT-4, which is highly susceptible and permissive for HIV infection. The inhibition of the cytopathic effect induced by HIV was used as the end point. The procedure of this test is essentially that described by R. Pauwels et al. "Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds". Journal of Virological Methods, 20, (1988), 309-321. The following Table II shows the 50% effective concentration (IC50) and 50% cytotoxic concentration (CC50) for di- (thymine-3 '-azido-2', 3 '-dideoxy-D-ribo-been) -5 '.S'- 1, p-pyrophosphate (di-AZT-5', 5'-p1, 2-pyrophosphate). Thymine-3 '-azido-2', 3'-dideoxy-D-riboside (AZT) was taken as the control compound.

TABLE II In vitro anti-HIV activity COMPOUND IC50 CC50 pyrophosphate (Compound 1, Table 1) 0.031 > 100 AZT 0.028 70 The compounds of this invention are particularly useful as pro-drugs to be transported by erythrocytes to specific cell populations, where they can be rapidly converted in vivo to the active form. Erythrocytes offer a unique opportunity as biological carriers of drugs or pro-drugs, because: (a) they have a rather simple metabolism and, therefore, a relatively limited group of enzymes, which can interact with the drug or pro-drug encapsulated, (b) can reach all parts of the body, and can act as bioreactors for the transformation of the drug or pro-drug encapsulated in the active form according to controlled kinetics, which can be programmed on the basis of characteristics of the enzymes involved, and (c) are suitable for relatively simple modifications that can confer a site-specific direction on tissues and organs that are rich in blood cells. - cleosides are the phosphorylated derivatives In particular, it is commonly accepted that the triphosphorylated derivatives are the forms that are responsible for the inhibition of replication viral by the deoxy-nucleosides that have anti-HIV activity. However, the triphosphorylated deoxy nucleosides are not clinically useful, since they can not pass through cell membranes. Therefore, a critical factor in the effectiveness of anti-HIV deoxy nucleosides is how easily they can enter the target cell and undergo phosphorylation by cellular enzymes. Either way, it is known that nucleosides can undergo not only intracellular phosphorylation, but also other reactions can be promoted by intracellular enzymes, which transform the nucleosides into therapeutically less active, or even inactive, compounds. If the speed of these reactions has the same order as that of the phosphorylation process, then the therapeutic effectiveness of the nucleosides decreases. These considerations are particularly important, since some target cells (for example macrophages) have low levels of phosphorylating enzymes, and therefore the administration of antiviral nucleosides in the phosphorylated form to the infected cells may present remarkable advantages in terms of viral inhibition on the conventional administration route. One of the objects of this invention is to exploit the ability of dinucleoside-5 ', 5'-p 1, p2-pyrophosphates to be encapsulated in red blood cells, and to be transported specifically to target cells, in where an enzymatic pathway is available, which hydrolyzes the pyrophosphate binding, giving two nucleotides. The two nucleotides, which already contain a phosphorylated moiety, are in the appropriate chemical form to carry out the desired biological function, or to be rapidly converted into the active form of the triphosphorylated derivatives, without being substantially inactivated. Dinucleoside pyrophosphates are more suitable than the corresponding monophosphates for encapsulation technology and targeting because, once they are introduced into erythrocytes, they are more stable, and show a lower diffusion rate from the erythrocyte membrane. during the period between the encapsulation time and the site-specific release time of the prodrug. These characteristics allow more flexibility in programming the kinetics of the release of the nucleoside from its carrier.

An additional advantage of dinucleoside-5 ', 5'-p 1, p 2 -pyrofosphates is that it is possible to combine, through the pyrophosphate bond, different pairs of nucleosides that show a complementary or synergistic action, and having both nucleosides introduced in the carriers, delivered to the specific target cells, and released in the respective active forms, simultaneously, during each of such steps. Typical target cells for encapsulated dinucleoside-5 ', 5'-p 1, p2-pyrophosphates are macrophages, or the hepatic and splenic body districts. Methods for directing encapsulated erythrocytes to the reticuloenothelial system have been described for example by Zocchi E. et al., In "Hepatic or splenic targeting of carrier erythrocytes: A murine model", Biotechnology and Applied Biochemistry (1987), _9, 423 -434, and in the article by Tonetti M. et al., Mentioned above. These methods allow the target cell or body districts to recognize the biological carriers, and interact with them to trigger the release of the site-specific and controlled pharmacokinetic drug. The encapsulation of antitumor drug and pro-drugs in suitable biological carriers such as erythrocytes, has been proposed as a useful means to achieve a selective direction to an organ, for the slow release of therapeutic agents with positive effects on both, therapeutic responses and toxicity (Zocchi, E. et al., In Proc. Nati, Acad. Sci. USA (1989) Vol. 86, 2040-2044). An example of encapsulation of the pro-drug 5-fluorouracil-2'-deoxy-D-riboside-5'-monophosphate in erythrocytes (see: From Flora A. et al., Proc. Nati. Acad. Sci., USA, (1988), Vol. 85, 3145-3149) shows that to achieve a pharmacokinetically useful control of the release of the active non-phosphorylated drug, a co-encapsulation of equimolar amounts of other nucleoside triphosphates is required. The co-entrapment of other nucleotides may involve problems of biological compatibility, and of interaction between the selected nucleoside pro-drug and the nucleoside triphosphate that accompanies it. One of the advantages provided by this invention consists in the possibility of preparing pro-drugs of 5-fluorouracil that do not require the co-trapping of other nucleoside triphosphates to achieve the appropriate pharmacokinetic control. A representative example of the pro-drugs of this invention, which shows useful pharmacokinetic characteristics, is a 5 ', 5'-pyrophosphate dinucleoside consisting of two units of 5-fluorouracil-2'-deoxy-D-riboside linked through of a pyrophosphate linkage [di- (5-fluorouracil-2'-deoxy-D-riboside) -5 ', 5'-p1, p2-pyrophosphate], which shows a lower de-phosphorylation rate with respect to the respective monophosphate. A typical example of encapsulation of a representative 5 ', 5'-p 1, p2-pyrophosphate dinucleoside of this invention in human red blood cells was performed with di-AZT-5', 5'-p 1, p2-pyrophosphate by the method of hypotonic dialysis and isotonic release (De Flora A. et al., Proc. Nati, Acad. Sci. USA, (1988), Vol. 85, 3145-3149). A two-step procedure was used, consisting of a first dialysis of the washed and packed erythrocytes (80% hematocrit) against 70 volumes of hemolyzing buffer (5 mM Na + HPO, supplemented with 4 mM MgCl », pH 7.2, 26 mOsm) for 35 minutes at 4 ° C under a gentle rotation.

This step was followed by the addition of 10-15 mM of di-AZT-5, 5 '-p1, p2-pyrophosphate within the dialysis bag, and additional dialysis for 15 minutes under the same conditions. The erythrocytes were then closed again by dialyzing them for 40 minutes at 4 ° C against phosphate-buffered saline solution, pH 7.4, supplemented with 10 mM glucose and adenosine, 310 mOsra. The loaded erythrocytes were then washed extensively with ice-cold aqueous NaCl (0.9% w / w) and incubated at 37 ° C in autologous plasma at 10% hematocrit. The concentration of dinucleoside pyrophosphate and its metabolites in plasma and red blood cells was determined at successive time intervals, using the following method. Aliquots of 1 ml of the incubation mixture were extracted at different times. After separation of the erythrocytes from the plasma, the two fractions were extracted separately. 100 microliters of red blood cells (CSR or RBC) packed in 100 microliters of water were added, then 68 raicroliters of 3.7 M perchloric acid were added under vigorous agitation. The sample was centrifuged, and 140 microliters of the supernatant was neutralized with 30 microliters of 3 M potassium carbonate. The sample was then centrifuged, to remove the precipitate formed. 150 microliters of the plasma fractions were treated with 50 microliters of 3.7 M APC and 120 microliters of the supernatant were neutralized with 27 microliters of 3 M potassium carbonate, and centrifuged. 5 microliters of each extraction were injected into an HP 1090 instrument (Hewlett-Packard, Palo Alto, CA) equipped with a column with a particle size of 3 microns of 4.6 x 60 mm HP 0DS Hypersil. The solvent program was a linear gradient that started in 100% buffer solution A (KH ^ PO, 0.1 M with 5 mM tert-butylammonium hydroxide (TBA), pH 4.9) and increased up to 100% buffer B (H2P04 0.1 M with 5 mM TBA, in 40% methanol (v / v) in water, pH 4.9) in 30 minutes; 100% buffer B was maintained until 50 minutes. The flow rate was 0.4 ml / minute, and the eluted compounds were monitored with a spectrophotometric detector set at 265 nm. The retention times for the various compounds were (in minutes): AZT, 17; AZT-monophosphate, 21; di-AZT-pyrophosphate, 33. The following Tables III and IV report the results of the determinations described above. TABLE III Concentration of di-AZT-5 ', 5'-p 1, p2-pyrophosphate and its metabolites in human red blood cells, expressed as J-imols / ml Time Di-AZT-pyro-AZT-mono-AZT (hours ) phosphate phosphate 0 3.9 0.04 2 4.1 0.09 6 2.9 0.65 0.60 24 1.8 0.93 0.10 TABLE IV 1 2 Concentration of di-AZT-5 ', 5' -p, p-pyrophosphate and its metabolites in human plasma, expressed in nmol / ml Time Di-AZT-AZT-mono-AZT (hours) pyrophosphate phosphate 0 4.49 21.94 4.6 2 3.75 28.21 14.42 6 5.2"24.68 62.43 24 5.34 67.11 355.78 The data above show that the concentration of di-AZT-5 ', 5' -p1, p2-pyrophosphate in human red blood cells reaches a value that It is compatible with the therapeutic requirements according to current practice, and the drug is released from the erythrocytes at a very low speed.The characteristics described above make the erythrocytes obtained by engineering, which contain an effective anti-HIV quantity. of dinucleoside phosphate pro-drug, particularly useful for therapeutic purposes It is in fact known that human erythrocytes can be modified appropriately to encapsulate nucleoside drugs, and to impart specific properties of direction to an object. and that such modifications do not alter the physiological behavior of the erythrocytes, apart from the selective characteristics of direction to an objective (International Patent Application Publication No. WO 92/22306) 1"~ The estimate of the concentration of the Drosophosphate pyrophosphate in erythrocytes, which corresponds to the therapeutic effectiveness when directed to cells infected with HIV, such as macrophages, is made on the basis of the data reported by BL Robbins et al., in Antimi- Crobial Agents and Chemotherapy, Vol. 38, No. 1, (1994), 115-121. In fact, these authors show that in patients infected with HIV who are under effective treatment with AZT, the intracellular concentration of triphosphate or AZT in peripheral blood mononuclear cells (CMSPs) is in the range of 5%. x 10 moles / 10 cells to 9 x 10 moles / 10 cells. These values are clearly overcome when at least one erythrocyte containing dinucleoside pyrophosphate in the concentration value indicated in Table III (corresponding to about 2 x 10 moles / 10 cells at 4 x 10 moles / 10 cells) / is captured by a PBMC (for example, a monocyte or a macrophage). As described above, the dinucleoside-5 ', 5'-0 P 1? P 2-pyrophosphates of this invention can be used as active ingredients of pharmaceutical compositions, for an oral or parenteral route of administration, or they can be used as drugs active or pro-drugs encapsulated in biological carriers, directed to specific districts of the body (for example liver / spleen) and / or cell populations (for example monocytes / macrophages). 1 2 When dinucleoside-5 ', 5'-p, p-pyrophosphates are used as active ingredients of pharmaceutical compositions for oral or parenteral administration, the com positions generally comprise a therapeutically effective amount of dinucleoside pyrophosphate and a carrier and / or inert diluent. For example, in liquid pharmaceutical compositions for oral administration, water, preferably sterilized water, may be used as a carrier and / or diluent. Solid pharmaceutical compositions for oral administration may contain binders, disintegrating agents and lubricants. As an example, gelatin binders, tragacanth gum or microcrystalline cellulose can be used as binders, as disintegrating agents can be used as alginic acid or corn starch.; Magnesium or calcium stearate can be used as lubricants. Certain solid forms, such as capsules, may contain a liquid carrier, for example, a fatty oil. For parenteral administration forms, a preferred carrier and / or diluent may be physiological saline or phosphate buffered saline. Liquid pharmaceutical compositions for both oral and parenteral administration may also include other compatible components, such as solvents, preservatives, and / or adjuvants, for example: polyethylene glycols, propylene glycols, or glycerin as solvents, methyl parabens as an annealing agents. ibacteria, ascorbic acid or sodium bisulfite as antioxidants, ethylenediaminetetraacetic acid as a chelating agent, acetates, citrates or phosphates as buffering agents. In addition, other active ingredients can be incorporated, which do not impair the desired effect of the dinucleoside pyrophosphates in the pharmaceutical formulations. Oral or parenteral pharmaceutical compositions in general should be capable of providing serum concentrations in patients in the range of 0.1 to 3.0 uM. In any case, it is possible to apply doses outside this range, it being understood that the daily dosage must be adjusted according to the type and severity of the disease, the condition of the patient to be treated, and the specific dinucleoside pyrophosphate used . Tablets, pills, cams, troches and the like can be used, such as solid dosage forms for oral administration, while solutions, suspensions, elixirs and syrups are preferably used as liquid dosage forms. Parenteral formulations usually consist of solutions for subcutaneous injections or for intravenous administration. The unit dosage forms can generally contain from 10 to 500 mg of dinucleoside-5 ', 5' - "'" p1, p2-pyrophosphate, this indication being purely exemplary, and is not in any way limiting the scope of the invention. When the dinucleoside-5 ', 5'-p, p-pyrophosphates of this invention are used as drugs or pro-drugs encapsulated in suitable biological carriers, pharmaceutical compositions containing such dinucleoside pyrophosphates preferably comprise transformed erythrocytes. The surface of the transformed erythrocytes is modified to be specifically recognized by the cells of the organism in which the dinucleoside pyrophosphates contained in the erythrocytes are to be integrated. For example, a typical way of achieving specific recognition by cells harboring human or animal pathogenic RNA viruses is described in European Patent Application Publication No. 517986, and is essentially based on binding proteins of the surface and / or transmembrane proteins of the erythrocytes, before or after the encapsulation of the dinucleoside pyrophosphates, specific antibodies that can be recognized by phagocytes (for example lymphocytes, monocytes or macrophages) that successively surround the red cells . According to a preferred embodiment, the erythrocytes, after being charged with the dinucleoside-5 ', 5'-p1, p2-pyrophosphates, are treated first, with a reversible grouping agent of the proteins of the surface or transmembrane, then, with a cross-linking agent that covalently binds, and finally, incubated in autologous plasma to bind the IgG molecules. These erythrocytes are recognized by human macrophages through their receptors, and then phagocytosed in a ratio of about 1 erythrocyte per macrophage. The following experiments describe in detail the targeting of erythrocytes loaded with di-AZT-pyrophosphate to human macrophages. Human erythrocytes subjected to the process of loading with di-AZT-pyrophosphate described above were then modified to increase their recognition by macrophages. The process is described in detail in EP-A-517986. The erythrocytes loaded with di-AZT-pyrophosphate were found to show close to 1, 500 IgG molecules / cell, and were phagocytosed more efficiently than untreated erythrocytes, as shown in Table V. The number of bound IgG / cell was determined by incubation of 50 ul of RBC with 100 ul of 5 mM HEPES. in PBS, pH 7.4, containing 4% (w / v) of bovine serum albumin and 0.1 mCi of protein A with radioactive iodine (specific activity 30 mCi / mg of protein). The samples were incubated for 30 minutes at room temperature, and then washed four times, and read to determine the bound radioactivity in a gamma-counter Beckman 5500. Phagocytosis of the erythrocytes loaded with drug was determined in vitro as described in the article by M. Magnani et al. "Targeting viral antiretro nucleo-side analogues in phosphory lated form to macrophages: in vitro and in vivo studies", (1992) Proc. Nati Acad. Sci. USA, 89: 6477-6481. TABLE V Recognition of erythrocytes loaded with di-AZT-pyrophosphate by macrophages Loaded with Charge with di-AZT-di-AZT-pyro pyrophosphate plus Native phosphate ZnCl2 / BS 3 Bound IgG 20-40 20-40 OE 1,500 (molecules / cell) Phagocytosis (erythrocytes / macrophage) 0.1-0.2 0.1-0.2 > 1 (1-1.2) Di-AZT-pyrophosphate in macrophages N.D. N.D. 3 pmoles / 10 cells N.D .: not detectable The amount of di-AZT-pyrophosphate supplied by the erythrocytes carrying to the macrophages, and their stability in the macrophages was also evaluated. Human erythrocytes were loaded with di-AZT-pyrophosphate in a concentration of 0.4 umoles / ral of RBC and then modified to increase their recognition by macrophages as above. The modified erythrocytes were added to macrophages in a ratio of 100 RBC per macrophage, and the phagocytosis was for 24 hours. Uninserted RBCs were then extensively washed (three times) with RPMI 1640 medium, and washed once with 0.9% (w / v) ammonium chloride. Extracts were prepared with perchloric acid from the macrophages at time 0 and at 24, 48 or 72 hours after the phagocytosis of the RBC, and were neutralized with K ^ CO-. The extracts were then neutralized and processed for solid phase extraction of the MR di-AZT-pyrophosphate, using columns of Isolute C18 (from International Sorbent Technology, Mid-Glamorgan, UK) according to the manufacturer's instructions, and using methanol as the eluent. The extracts were analyzed by HPLC as described above. The results on the stability of di-AZT-pyrophosphate in human macrophages are shown in Figure 1. An assay of the antiviral activity of erythrocytes loaded with di-AZT-pyrophosphate was also performed on macrophages derived from infected feline monocytes. with feline immunodeficiency virus (FIV). Macrophages derived from feline raonocites were cultured as reported for macrophages derived from human monocytes by M. Magnani et al. "Targeting antiretroviral nucleoside analogues in phosphorylated form to macrophages: in vitro and in vivo studies", (1992) Proc. Nati Acad. Sci.

USA, 89: 6477-6481. The erythrocytes loaded with di-AZT-pi-rhophosphate were added for 15 hours, in a ratio of 100 CSRs per macrophage. The di-AZT-pyrophosphate content of the erythrocytes loaded with the drug was 0.4 jimoles / ml of CSRs. The non-ingested erythrocytes were removed with intensive washes. As a control, macrophage cultures were treated with "uncharged" erythrocytes (ie erythrocytes subjected to the same procedure but without the addition of di-AZT-pyrophosphate) The macrophage cultures that received RBCs loaded with di-AZT-pyrophosphate, RBCs "not loaded" or without addition, were infected with 330 di / well of feline inununodeficiency virus (Pisa M-2) as described in the article by M. Sendinelli et al. "Feline immunodeficiency virus: and inte-resting model for AIDS studies and an important cat pathogen ", (1995), Clin. Microbiol., rev 8: 87-112 Cell cultures were extensively washed (six times) to remove any viral particles associated with macrophages? hours later The cell cultures were then maintained at 37 ° C, and 5% C02 for three days, and then their total DNA was isolated.The DNA isolation of the macrophages was obtained by standard techniques, which included lysis of the cells with urea 8 M, 0.3 M NaCl, 10 mM Tris HCL, pH 7.5, for 60 minutes at 37 ° C. The extraction was done with phenol-chloroform-isoamyl alcohol (25: 24: 1 v / v / v) and the preci-pitation of the DNA was made with ethanol. The pro-viral DNA analysis of FIV was performed by amplification of 498 base pairs of the viral gag p24 gene in two stages. For the first amplification step, the following primers were used: 5'-GGCATATCCTATTCAAACAG-3 '(sense) (SEQ ID No: l) which corresponds to nucleotides 1025-1044 in the viral sequence, and 5'-CCTATATTTTACGTTGAGAA-3 '(antisense) (SEQ ID No: 2) corresponding to nucleotides 1680-1699. For the second amplification stage, the first ones used were: 5'-TATGGTTTACTGCCTTCTCT-3 '(sense) (SEQ ID No: 3), corresponding to nucleotides 1141-1160 in the viral sequence and 5 * -GAATTCGGTCTTTCATGGGA-3 '(antisense) (SEQ ID No: 4) corresponding to nucleotides 1619-1638. The PCR, performed in a Perkin-elmer thermocycler, was done in a final volume of 50 ul, which contained 168 ng of genomic DNA, 50 mM of KCl, 10 mM of Tris HCL, pH 8.3, 1.5 mM of gCl2, 0.005% of Tween-20, 0.005% of NP-40, 0.001% of gelatin, 150 nM of each of the former, and 5 U of Replitherm DNA polymerase (Epicenter Technologies, Madison, Wisconsin, USA). The reaction mixture containing the first pair of first, was subjected to 40 cycles of denaturation at 94 ° C for 1 minute, cancellation at 50 ° C for 1 minute, and extension at 72 ° C for 2 minutes, followed by an extension final at 72 ° C for 15 minutes. Then, 10 ul of this amplified mixture was re-amplified with the second '"* pair of first, using exactly the same conditions The PCR products were analyzed by electrophoresis on a 1.5% agarose gel, transferred on nylon membrane and hybridized with a 498 pbase probe of the p24 gag gene cloned in a TA-cloning plasmid (Invitrogen Corporation, San Diego, California, USA) As an internal control the feline hexokinase gene was amplified with the following primers: 5 '- ACATGGAGTGGGGGGCCTTTGG-3 '(sense) (SEQ ID No: 5) corresponding to nucleotide 2198-2219, and 5'-GTTGCGGACGATTTCACCCAGG-3' (antisense) (SEQ ID No: 6) corresponding to nucleotide 2328-2349 in the cDNA Type I human hexokinase was detected with a FIV hexokinase probe, the results are shown in Figure 2. An additional assay of antiviral activity of the erythrocytes loaded with di-AZT-pyrophosphate was performed on murine macrophages inf. ected with the murine immunodeficiency virus. Murine macrophages were obtained from the peritoneal cavity of C57BL / 6 mice, and were cultured as described in the article by Rossi et al. "Inhibition of murine retrovirus-induced immunodeficiency disease by dideoxycytidine and dideoxycytidine 5 '-triphosphate", (1993), J. AIDS, 6: 1179-1186. The erythrocytes loaded with di-AZT-pyrophosphate and the infection were made as described for FIV, with the following modifications: the feline immunodeficiency virus (LP-BM5) was prepared as a cell-free supernatant from SC cells -1, according to standard procedures (DE Yetter et al. "Functional T-lymphocytes are required for a murine retrovirus induced immunodeficiency disease (MAIDS)", (1987), J. Exp. Med. 165: 1737-1742. The PCR analysis of the viral DNA was carried out according to the following procedure: The following oligonucleotide primers were used for the amplification of the defective virus genome (BM5d): 5'-primer, 5 '-AACCTTCCTCCTCTGCCA-3' (sense), corresponding to nucleotides 1456-1473 in the viral sequence and 3'-primer, 5'-ACCACCTCCTGGGCTTTC-3 '(antisense) which corresponds to nucleotides 1579-1596 of the BM5d genome.A second pair of oligonucleotide primer used for the amplification n of a G6PD gene of 203 base pairs of a mouse. This amplification served as an internal control (endogenous standard) for the evaluation of the relational integration of BM5d in the mouse genome. The first nucleotides for this amplification were the 5'-primer, 5 '-TGTTCTTCAACCCCGAGGAT-3' (sense) and 3 '-first, 5' -AAGACGTCCAGGATGAGGTGATC-3 '(antisense). The first four used in the present are described in the article by G. Brandi et al. "Efficacy and to-xicity of long-term administration of 2 ', 3' -dideoxycytidine in the LP-BM5 murine induced immunodeficiency model", (1995), Antiviral Chemistry and Chemotherapy, 6, 153-161. PCR, performed in a Perkin-Elmer thermocycler, was done in a final volume of 25 ul, which contained 0.229 ug of genomic DNA, which corresponded to about 114,000 cells, 50 mM KCl, 10 mM Tris-HCl, pH 8.3, 1 mM MgCl2 >; 0.05% Tween-20, 0.005% NP-40, 0.001% gelatin, 150 uM each of the four deoxyribonucleoside triphosphates, 20 pmol each, and 2.5 U Replitherm DNA polymerase (Epicenter Technologies, Madison, Wisconsin , USA). The reaction mixtures were subjected to 37 cycles of denaturation at 95 ° C for 30 seconds, cancellation at 58 ° C for 30 seconds, and extension at 72 ° C for 30 seconds, followed by final extension at 72 ° C for 10 minutes. The PCR products were analyzed by electrophoresis on 2.5% agarose gel, transferred on nylon membrane and hybridized with either the D30 probe labeled with 32 P or with G6PD. The labeling of the DNA probes was made with the primer random DNA labeling of Bio-Rad (Bi-Rad Laboratories, Hercules, California, USA). The results are shown in Figure 3. The pharmaceutical compositions containing modified erythrocytes enclosing the dinucleotide pyrophosphates of this invention are generally presented in the form of isotonic solutions, such as isotonic saline or glucose solutions. , for injectable use, or in a form to be used for the extemporaneous preparation of injectable solutions for intraperitoneal administration or intravenous. These pharmaceutical compositions generally contain an amount of erythrocytes that preferably ranges from 2 to 8 ml, and a total amount of dinucleoside-5 ', 5'-p 1, p 2-pyrophosphate ranging from about 0.5 to 10 mM. The dosage at which the encapsulated dinucleoside pyrophosphates of this invention can be administered is in the range of from about 0.5 to about 80 ug of dinucleoside pyrophosphates per kilogram of patient's body weight, it being understood that these values are given as an indication, which is not proposed to constitute a limitation of the scope of the invention. - • - - Description of the Figures Figure 1 shows the stability of di-AZT-pyrophosphate in human raaphophages 0 Figure 2 shows the antiviral activity of erythrocytes loaded with di-AZT-pyrophosphate against macrophages derived from feline monocytes infected with FIV (Pisa M-2), measured by proviral DNA analysis of FIV in macrophages.5 Figure 3 shows the antiviral activity of erythrocytes loaded with di-AZT-pyrophosphate against murine macrophages infected with immunodeficiency virus murine (LP-BM5), measured by DNA analysis of the defective virus genome (BM5d) EXAMPLE 1 Preparation of hypoxanthine-2 ', 3'-dideoxy-D-riboside-5'-monophosphate 100 mg (0.4 mmol) was added ) of hypoxanthine-2 ', 3' -dideoxy-D-riboside at 0.11 ml (1.2 mmol) of phosphorus oxychloride in 1 ml of triethyl phosphate, and the mixture was stirred for 2 hours at -5 ° C. it was extracted four times with 10 ml of diethyl ether cooled in ice , then, it was centrifuged at 2000 rpm for 5 minutes at 0 ° C. After the ethyl ether was removed, the residue was suspended in 5 ral of water at 0 ° C. and immediately neutralized with cold 1N NaOH. The mixture was kept on an ice bath for 10 minutes, and the pH value was adjusted to 7. After drying under vacuum, the residue was dissolved in 25 ml of methanol. The solution was applied to a column containing 35 g of silica gel suspended in ethyl ether. The pure title compound was obtained by eluting the column as follows (flow rate 3 ml / minute): 150 ml of ethyl ether, 150 ml of a mixture of ethyl ether: methanol 60:40 (v / v), to remove the impurities, and finally about 300 ml of methanol, to elute the purified product.

The yield of the total process was 85%. The EM spectrum, recorded with a Hewlett-Packard 5989A instrument, shows a molecular ion at m / z of 315.2, which corresponds to the ion [M-l] of the title compound. EXAMPLE 2 Preparation of thymine-3 '-azido-2', 3'-dideoxy-D-riboside-5'-monophosphate 240 mg (1 mmol) of thymine-3 '-azido-2', 3'-dideoxy was dissolved -D-riboside (AZT) in 2 ml of a solution of 1 M cyanoethyl phosphate in pyridine, and dried under vacuum at 30 ° C. The residue was suspended in 19 ml of anhydrous pyridine, and then dried under vacuum at 30 ° C, twice. After the addition of 9.6 ml of anhydrous pyridine and 1.15 g of dicyclohexylcarbodiimide, the mixture was stirred for 48 hours at 25 ° C. Then, 2.8 ml of water was added, and the solution was stirred for an additional 30 minutes at 25 ° C. ° C, and finally dried under vacuum at 30 ° C. The residue was suspended in 9.6 ml of water, filtered and washed again on the filter with 9.6 ml of water. Then, 19.6 ml of 1 N NaOH was added to the combined filtrates, and the mixture was heated under reflux for 40 minutes. The solution was cooled to 25 ° C, and eluted through a column filled with 15 g of Dowex 50 (H) ion exchange resin, to remove the sodium cation. The pH of the eluate was adjusted to 7.5 with a saturated solution of Ba (0H) ?, to precipitate the phosphate anion. After centrifugation, the supernatant was reduced to a small volume (30 ml) under vacuum, at 30 ° C, and centrifuged again, to remove residual inorganic phosphate. A double volume of ethanol was added to the mixture at 4 ° C, to precipitate the barium salt of the title compound. The precipitate was finally washed with acetone and ethyl ether, and dried under a gentle stream of nitrogen. The barium salt of the title compound was suspended in 5 ml of water, and mixed with 2 g of Dowex MR 50 (H +) ion exchanger resin. The mixture was then applied to a column containing 2 g of Dowex MR 50 (H +) ion exchange resin. The column was eluted with 30 ml of a methanol: water mixture 1: 1 (v / v), and the eluate was finally neutralized with 1 N NaOH, and the solution containing the sodium salt of AZT-5 '-raonophosphate was lyophilized then, giving the sodium salt of the title product in a 70% yield. The EM spectrum, recorded with a Hewlett-Packard 5989A instrument, shows a molecular ion in m / z 346.50 which corresponds to the ion [M-l] of the title compound.

EXAMPLE 3 Preparation of thymine-3 '-azido-2', 3'-dideoxy-D-riboside, 1 2 hypoxanthine-2 ', 3'-dideoxy-D-riboside-5', 5'-p, p-pyrophosphate a) Hypoxanthine-2 ', 3'-dideoxy-D-riboside-5'-monophosphate activation: 50 mg (0.016 mmol) of hypoxanthine-2', 3 '-dideoxy-D-riboside-5' -monophosphate were dissolved in a mixture of 2 ml of water and 1 ral of methanol, and the solution was then eluted through 1 g of Dowex ™ ion exchange resin. 50W-X8 (pyridinium form). The column was washed with 20 ml of 50 aqueous methanol, and the solution was dried in vacuo. The residue was suspended in a solution of 0.22 ml of tris-n-octylamine in 1.6 ml of methanol and then stirred for 30 minutes, and finally dried under vacuum at 30 ° C. The resulting residue was suspended in 1 ml of N, N-dimethylformamide, and dried under vacuum at 30 ° C. This procedure was repeated three times. The resulting product was added to a solution of 2.24 ml of dioxane, 0.096 ral of diphenyl chlorophosphate and 0.137 ml of tris-butylamine, and the mixture was stirred for 3 hours at 25 ° C. It was then dried on a rotary evaporator, and 16 ml of diethyl ether was added to the residue under vigorous stirring. The mixture was kept on ice for 30 minutes, and then centrifuged at 1000 rpm for 5 minutes. The ethyl ether was removed, and the residue was dissolved in 0.96 ml of dioxane, and dried under vacuum at room temperature, and the product was used as such in step c) below, b) Trifloilamium salt of AZT -5'-monophosphate 120 mg (0.35 mmoles) of sodium salt of AZT-5 '-monophos were dissolved in 2 ml of water and 2 ml of methanol, and the solution was eluted through 1 g of intercam resin. Dowex MR 50W-X8 ionic acid (pyridinium form), with 20 ml of 50% aqueous methanol, and dried on a rotary evaporator.

Then, 0.49 ml of tri-n-octylamine and 3.5 ml of methanol were added to the residual product, and the mixture was stirred for 30 minutes, and finally dried under vacuum at 30 ° C. The residue was suspended again in 1.75 ml of N, N-dimethylformamide, and 2 was dried under reduced pressure (0.0068 kg / cm, 5 mmHg) to ° C. This procedure was repeated three times, to provide a product that was used as such in the successive step c). c) Reaction The hypoxanthine-2 ', 3'-dideoxy-D-riboside-5'-activated monophosphate from step a) was dissolved in 0.9 ml of anhydrous pyridine, and the mixture was added to the tritium salt. n-octyl-araonio of AZT-5 '-monophosphate of stage b). After this, 0.16 ml of hexamethylphosphoramide was added to the mixture, which was then dried on a rotary evaporator. After the addition of 0.2 ml of anhydrous pyridine, the mixture was stirred for 24 hours at 25 ° C. The residue was suspended in 5 ml of water, adjusting the pH value to 8 with 1 N NaOH, and the solution was extracted three times with 5 ml of diethyl ether. The aqueous layer, which contained the title product above, was separated, and the product was purified according to the following step d). d) Purification 0.5 ml aliquots of the aqueous solution resulting from step c) were applied to a Sephadex MR G10 column (55 x 1.3 cm), and eluted with water, at a flow rate of 0.25 ml. minute. Fractions containing the title compound were further purified using a CLAR apparatus equipped with a reverse phase column (C18 uBondapack MR, particle size 10 um). The solvent program was a linear gradient of methanol in water, from 0 to 30% (v / v), at a flow rate of 1.5 ml / minute, in 30 minutes. Under these conditions, the title compound above shows a retention time (R) of about 7 minutes. The fractions that showed an R at the above value were combined, loaded onto 2 grams of an ion exchange MR + resin (Dowex 50W-X8, form H), and eluted with 20 ml of water. The eluate was lyophilized, giving the title product above, with a yield of 35%. The MS spectrum, recorded with a Hew-1 lett-Packard 5989A instrument, shows a molecular ion at m / z of 644, which corresponds to the ion [M-l] of the title compound. The ultraviolet absorption spectrum in a phosphate buffer solution of pH 4.9, 40% (v / v) methanol in water, exhibits a maximum absorption at 252 nm, with a shoulder at 270 nm. EXAMPLE 4 Preparation of di- (thymine-3 '-azido-2', 3'-dideoxy-D-ribosi- "" do) -5 ', 5'-p 1, p2-pyrophosphate 10 a) Activation of AZT- 5'-monophosphate 100 mg (0.26 mmoles) of sodium salt and AZT-5 '-monophosphate were dissolved in a mixture of 30 ml of water and 2 ml of ethanol, and the solution was eluted through 1 g of water. - MR Dowex ion exchange 50W-X8 (pyridinium form), with 20 ml of 50% aqueous methanol, and then dried under vacuum at room temperature. The residue was suspended in a mixture of 0.45 ml of tri-n-octylamine and 3.2 ml of methanol, and stirred for 30 minutes at 25 ° C, then dried under vacuum at room temperature. The residue was dissolved in 2 ml , N-dimethylformamide, and dried under reduced pressure 2 (0.0068 kg / cm, 5 mmHg). The procedure was repeated three times. After this, 4.48 ml of dioxane, 0.2 ml of diphenyl chlorophosphate and 0.27 ml of tri-n-butylamine were added to the residue and, after stirring for 3 hours at 25 ° C, the mixture was dried under reduced pressure. (0.0068 kg / cm, 5 mmHg) at 30 ° C. Then, 16 ml of hexane was added to the residue under vigorous stirring, and the mixture was kept on ice for 30 minutes before centrifugation at 1000 rpm for 5 minutes. The residue was dissolved in 2.0 ml of dioxane, and dried under vacuum. The recovered product was used as such in step c) in succession, b) Tri-n-octyloramonium salt of AZT-5 '-raponophosphate 100 mg (0.26 mmol) of sodium salt of AZT-5' -monophosphate was dissolved in a mixture of 3 ml of water and 2 ml of 0% aqueous methanol, and the solution was loaded onto a column containing 1 g of Dowex MR 50W-X8 ion exchange resin (pyridinium form), and eluted with 20 ml of 50% aqueous methanol. The eluate was dried under vacuum. Then, 0.45 ml of tri-n-octylamine and 3.2 ml of methanol were added to the residue, and the mixture was stirred for 30 minutes at 25 ° C, and finally, it was dried under vacuum at room temperature. The residue was suspended in 2 ml of, -dimethylforraamide, and dried under reduced pressure (0.0068 kg / cm, 5 mmHg). This procedure was repeated three times, giving a product that was used as such in step c) below, c) Reaction The activated AZT-5 '-monophosphate from step a), was dissolved in 1.8 ml of anhydrous pyridine, and the solution was added to the tri-n-octyloramonium salt of AZT-5 '-raonophosphate from step b), together with 0.32 ml of hexamethylphosphatidamide.

After drying under vacuum at room temperature, 0.4 ml of anhydrous pyridine was added to the residue, and the mixture was stirred for 24 hours at 25 ° C. After drying under vacuum at room temperature, the residue was suspended in 6 ml of water and, after adjusting the pH value to 8 with 1N NaOH, the mixture was extracted three times with 6 ml of diethyl ether. The aqueous layer, which contained the title product above, was separated by centrifugation, and the product was recovered and purified according to the following step d). d) Purification The aqueous solution resulting from step c) above was purified using a reverse phase HPLC column. Aliquots of 1 ml of the aqueous solution were applied to a column of Bio-sil ™ C18 HL 9) -10 (Biorad) (250 x 10 mm), particle size 10 μm), and eluted with a linear step gradient of ethanol in water, as described below:% (v / v) Ethanol Time (minutes) 3 0 '3 7' 5 10 * 15 15 '100 16' 100 25 'The title compound above was eluted with an R 11 minutes. The fractions that showed an R at the above value were combined, loaded onto 2 g of an MR resin + ion exchange (Dowex, 50W-X8, form H) and eluted with 30 ml of a methanol mixture : water 50:50 (v / v). The eluate was lyophilized, giving the title product above, with a yield of 35%. The EM spectrum recorded with a Hew-lett-Packard 5989A instrument shows a molecular ion at m / z 675.9 which corresponds to the ion [M-l] of the above title compound. The ultraviolet absorption spectrum in a phosphate buffer solution of pH 4.9, 40% (v / v) methanol in water, exhibits a maximum absorption at 265 nm. The NMR spectrum of H, recorded at 200 MHz, in the temperature range from 20 ° C to 30 ° C on a Varian Gemini spectrometer at D20, shows the most significant chemical shifts to: (6 ppm): 1.639 (-CH -,), 2,225 (-0-CH2), 3,943 (width 1 '-CH and 2'-CH2), 4,275 (3'-CH), 5,955 (4'-CH), 7,439 (aromatic proton 6-CH). EXAMPLE 5 Preparation of 5-fluorouracil-2'-deoxy-D-riboside, thymine-1 2 3 '-azido-2', 3'-dideoxy-D-riboside-5 ', 5'-p, p-pyrophosphate a Activation of AZT-5 '-monophosphate 70 mg (0.182 mmol) of sodium salt of AZT-5' -monophosphate was activated, following the same procedure described above under Example 4, step a), and the product was used as such in the next step c). b) Tri-n-octylammonium salt of 5-f luorouracil-2'-deoxy-D-riboside-5'-monophosphate 100 mg (0.27 mmol) of sodium salt of 5-fluorouracil-2'-deoxy D-riboside-5'-monophosphate was transformed into the corresponding tri-n-octylammonium salt following the same procedure described under Example 4, step b), and the product was used as such in the next step c). c) Reaction AZT-5'-activated monophosphate from step a) was dissolved in 1 ml of anhydrous pyridine, and the solution was added to the sodium salt of 5-fluorouracil-2'-deoxy-D-riboside -5 '-monophosphate from step b), together with 0.2 ml of hexamethyl-phosphotriamide. After drying under vacuum, 0.2 ml of anhydrous pyridine was added to the residue, and the mixture was stirred at room temperature for 24 hours. After evaporation of the solvent in a rotary evaporator at 30 ° C, the residue was suspended in 5.3 ml of water and, after adjusting the pH value to 8 by adding 1 N NaOH, the mixture was extracted three times with 5 ml of water. ethyl ether. The aqueous layer, which contained the title product above, was separated, and the product was recovered and purified according to the following step d) d) Purification: The aqueous solution resulting from step c) was applied to a column containing 2 g of Dowex MR 1-X8 ion exchange resin (Cl- form), which was previously conditioned with 5 mM HCl, the flow rate was 0.4 ml / minute. washed with 10 ml of 5 mM HCl, then a linear gradient of LiCl from 0 to 600 mM in 5 mM HCl was applied, at a flow rate of 0.5 ml / rainuto. Fractions containing the title product were collected and pooled, and the pH value was adjusted to 6.5 by adding 1M LiCl. The solution was then concentrated to a volume of 4 ml on a rotary evaporator at 30 ° C. The concentrated solution was further purified by HPLC, using a column. of Reverse Phase CLAR (uBondapack MR C18, 250 x 10. rare, particle size 10 um) eluting with water, at a flow rate of 4 ml / minute, and injections of 500 ul.

The recovered fractions were lyophilized, yielding 25 mg of the title product as the lithium salt. This product was converted, with practically quantitative yield, into the free acid compound of the title, following the same procedure described in the last part of step d) of Example 4. The EM spectrum recorded with a Hew-lett instrument -Packard 5989A, shows a molecular ion at m / z 653, which corresponds to the ion [Ml] of the title compound. EXAMPLE 6 Preparation of di- (5-fluorouracil-2 '-deoxy-D-riboside) -5', 5 '-p 1, p 2-pyrophosphate a) Activation of 5-fluorouracil-2' -deoxy-D-riboside - 5'-monophosphate: 100 mg (0.27 mmol) of sodium salt of 5-fluorouracil-2'-deoxy-D-riboside-5'-monophosphate was activated, following the same procedure described under Example 4, step to). b) Tri-n-octylammonium salt of 5-f luorouracil-2'-deoxy-D-riboside-5'-araponophosphate 100 mg (0.27 mol) of sodium salt of 5-fluorouracil-2'-deoxy D-riboside-5'-monophosphate was transformed to the corresponding tri-n-octylammonium salt, following the same procedure described under Example 4, step b), and the product was used as such in the next step c). c) Reaction: The sodium salt of activated 5-fluorouracil-2 '-deoxy-D-riboside-5'-monophosphate from step a) was dissolved in 1 ml of anhydrous pyridine, and the solution was added to the salt of tri-n-octylammonium 5-fluorouracil-2'-deoxy-D-riboside-5'-monophosphate from step b), together with 0.2 ml of hexamethyl phosphotriamide. After drying under vacuum, 0.2 ml of anhydrous pyridine was added to the residue, and the mixture was stirred at room temperature for 24 hours. After evaporation of the solvent in a rotary evaporator at 30 ° C, the residue was suspended in 6 ml of water and, after adjusting the pH value to 8 by adding 1 N NaOH, the mixture was extracted three times with 6 ml of diethyl ether. The aqueous layer, which contained the title product above, was separated, and the product was recovered and purified according to the following step d). d) Purification: The aqueous solution resulting from step c) was applied to a column containing 2 g of Dowex MR 1-X8 ion exchange resin (Cl - form), which was previously conditioned with 5 mM HCl. The flow rate was 0.4 ml / minute. The column was washed with 10 ml of 5 mM HCl, and then a linear LiCl gradient from 0 to 600 mM in 5 mM HCl was applied at a flow rate of 0.4 ml / minute. The fractions containing the above title product were collected and pooled, and the pH was adjusted to 6.5 by the addition of 1M LiCl. The solution was then concentrated to a volume of 2 ml on a rotary evaporator at 30 ° C, then the compound was precipitated by adding a double volume of a mixture of ethanol: acetone 1: 4 (v / v), on ice. The precipitated compound was finally washed with acetone and ether, and dried with a gentle stream of nitrogen, yielding the lithium salt of the title compound above, which was converted to the free acid following the same procedure described in the last part of step d) of Example 3. Yield: 30%. The MS spectrum, recorded with a Hewlett-Packard 5989A instrument, shows a molecular ion at m / z 633, which corresponds to the ion [M-l] of the title compound. The ultraviolet absorption spectrum in a phosphate buffer solution of pH 4.9, 40% (v / v) methanol in water, exhibits an absorption maximum at 269 nm.

LIST OF SEQUENCES (1) GENERAL INFORMATION: (i) APPLICANT: (A) NAME: GRUPPO LEPETIT S. p. to. (B) ADDRESS: Via R. Lepetit 34 (C) CITY: GERENZANO (VA) (E) COUNTRY: ITALY (F) POSTAL CODE (ZIP): 1-21040 (ii) TITLE OF THE INVENTION: DINUCLEOSIDO-5 ', 5 * - PIROPHOSPHATES (iii) NUMBER OF SEQUENCES: 6 (iv) LEGIBLE FORMAT IN COMPUTER: (A) TYPE OF MEDIUM: Diskette (B) COMPUTER: Compatible with IBM PC (C) OPERATING SYSTEM: PC-DOS / MS-DOS (D) SOFTWARE: Patentln Relay # 1.0, Version # 1.30 (EPO) (2) INFORMATION FOR SEQ ID NO: 1: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 20 base pairs (B) TYPE: acid nucleic (C) TYPE OF HEBRA: individual (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: other nucleic acid (A) DESCRIPTION: / desc - "Synthetic oligonucleotide" l * '* (iv) ANTI-SENSE: NO ( xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1: GGCATATCCT ATTCAAACAG 20 (2) INFORMATION FOR SEQ ID NO: 2: 5 (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: acid nucleic (C) TYPE OF HEBRA: individual (D) TOPOLOGÍ A: linear 0 (ii) TYPE OF MOLECULE: other nucleic acid (A) DESCRIPTION: / desc - "Synthetic oligonucleotide" (iv) ANTI-SENSE: NO (xi) DESCRIPTION OF SEQUENCE: SEQ ID NO: 2: CCTATATTTT ACGTTGAGAA 20 5 (2) INFORMATION FOR SEQ ID NO: 3: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: individual 0 (D) TOPOLOGY : linear (ii) TYPE OF MOLECULE: other nucleic acid (A) DESCRIPTION: / desc - "synthetic oligonucleotide" (iv) ANTI-SENSE: YES (xi) DESCRIPTION OF SEQUENCE: SEQ ID NO: 3: 5 TATGGTTTAC TGCCTTCTCT 20 (2) INFORMATION FOR SEQ ID NO: 4: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: individual (D) TOPOLOGY: linear ( ii) TYPE OF MOLECULE: other nucleic acid (A) DESCRIPTION: / desc = "Synthetic oligonucleotide" (iv) ANTI-SENSE: YES (xi) DESCRIPTION OF SEQUENCE: SEQ ID NO: 4: GAATTCGGTC TTTCATGGGA 20 (2) INFORMATION FOR SEQ ID NO: 5: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: individual (D) TOPOLOGY: linear ( ii) TYPE OF MOLECULE: other nucleic acid (A) DESCRIPTION: / desc - "Synthetic oligonucleotide" (iv) ANTI-SENSE: NO (xi) DESCRIPTION OF SEQUENCE: SEQ ID NO: 5: ACATGGAGTG GGGGGCCTTT GG 22 (2) INFORMATION FOR SEQ ID NO: 6: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: individual (D) TOPOLOGY: linear ( ii) TYPE OF molecule: other nucleic acid (A) DESCRIPTION: / desc = "Synthetic oligonucleotide" (iv) ANTI-SENSE: YES (xi) DESCRIPTION OF SEQUENCE: SEQ ID NO: 6: GTTGCGGACG ATTTCACCCA GG 22 It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims

CLAIMS 1 2 A 5 ', 5' -p, p-pyrophosphate dinucleoside of the formula (I) A-.?-p-?-p-X-B (I) XR XRi characterized in that: the symbols A and B each independently represent a 5'C 'radical of a naturally occurring non-naturally occurring nucleoside, selected from: thymine-3' -azido-2 ', 3'-dideoxy-D-riboside, -fluorouracil-2'-deoxy-D-riboside, uracil-3 '-azido-2t, 3'-dideoxy-D-riboside, guanine-2', 3'-dideoxy-D-riboside, hypoxanthine-2 ', 3 '-dideoxy-D-riboside, cytosine-2', 3'-dideoxy-D-riboside, and adenine-2 ', 3'-dideoxy-D-riboside; the symbols X each independently represent oxygen or sulfur; the symbols R and R, each independently represent hydrogen or an alkyl group of 1 to 10 carbon atoms, which optionally may contain an unsaturation and / or one or two substituents selected from hydroxy, mercapto, chloro, iodo, fluoro, bromo , amino, (C.C.) alkylamino, di- (C.C.) alkylamino, (C, -C,) alkoxy and (C.C.) alkylthio; and the addition salts of the compounds of formula (I) wherein R and / or R, represent hydrogen, with bases that provide biologically acceptable cations. 2. A dinucleoside according to claim 1, characterized in that the symbol A represents a 5'-C 'radical of a non-naturally occurring nucleoside, selected from: thymine-3' -azido-2 ', 3'-dideoxy- D-riboside, 5-fluorouracil-2'-deoxy-D-riboside, hypoxanthin-2 ', 3'-dideoxy-D-riboside, adenine-2', 3'-dideoxy-D-riboside, cytosine-2 ', 3'-dideoxy-D-riboside, uracil-3'-azido-2 ', 3'-dideoxy-D-riboside and guanine-2', 3'-dideoxy-D-riboside; symbol B represents a 5'C 'radical of a non-naturally occurring nucleoside selected from: thymine-3' -azido-2 ', 3'-dideoxy-D-riboside, adenine-2', 3'-dideoxy -D-riboside, 5-fluorouracil-2 '-deso iD-riboside, cytosine-2', 3'-dideoxy-D-riboside, hypoxanthine-2 ', 3'-dideoxy-D-riboside, 10-uracil-3 '-azido-2', 3'-dideoxy-D-riboside, and guanine-2 ', 3'-dideoxy-D-riboside; one or two of the X symbols selected from those that are directly linked through a double bond to the phosphor atom (s) and those that are part of the XR and XR portions. represents (s) oxygen or sulfur, and each of the other symbols X represents oxygen; the symbols R and R, each independently represent hydrogen or an alkyl radical of 1 to 4 carbon atoms; and the addition salts of the compounds wherein R and / or R represent hydrogen, with bases that provide biologically acceptable cations, preferably sodium and potassium cations. 3. A compound according to claim 2, characterized in that all the symbols X represent oxygen, R and R. both represent hydrogen, and their salts with biologically acceptable cations, preferably Na or K 4. A compound according to claim 2 , characterized in that each of the symbols A and B represents a 5'C 'radical of a nucleoside that does not exist naturally in the following combinations:

1) A: thymine-3' -azido-2 ', 3 '-dideoxy-D-riboside B: thymine-3'-azido-2', 3'-dideoxy-D-riboside

2) A: 5-f luorouracil-2 '-deoxy-D-riboside B: adenine-2', 3'-dideoxy-D-riboside

3) A: 5-f luorouracil-2 '-deoxy-D-riboside B : 5-fluorouracil-2 '-deoxy-D-riboside

4) A: 5-fluorouracil-2' -deoxy-D-riboside B: cytosine-2 ', 3' -dideoxy-D-riboside

5) A: 5- fluorouracil-2 '-deoxy-D-riboside B: thymine-3'-azido-2', 3'-dideoxy-D-riboside

6) A: 5-f luorouracil-2 '-deoxy-D-riboside B: hypoxanthine-2', 3'-dideoxy-D-riboside

7) A: thymine-3 '-azido-2', 3'-dideoxy -D-riboside B: hypoxanthine-2 ', 3' -dideoxy-D-riboside

8) A: thymine-3 '-azido-2', 3'-dideoxy-D-riboside B: cytosine-2 ', 3' -dideoxy-D-riboside

9) A: thymine-3 '-azido-2', 3'-dideoxy-D-riboside B: adenine-2 ', 3'-dideoxy-D-riboside

10) A: adenine-2 ', 3' -dideoxy-D-riboside B: adenine-2 ', 3'-dideoxy-D-riboside

11) A: hypoxanthine-2 ', 3'-dideoxy-D-riboside B: adenine-2', 3'-dideoxy-D-riboside

12) A: hypoxanthine-2 ', 3'-dideoxy-D-riboside B: hypoxanthine-2 ', 3'-dideoxy-D-riboside

13) A: hypoxanthine-2', 3'-dideoxy-D-riboside B: cytosine-2 ', 3' - dideoxy-D-riboside

14) A: cytosine-2 ', 3' -dideoxy-D-riboside B: cytosine-2 ', 3'-dideoxy-D-riboside

15) A: adenine-2', 3'-dideoxy -D-riboside B: cytosine-2 ', 3' -dideoxy-D-riboside

16) A: uracil-3 '-azido-2', 3'-dideoxy-D-riboside B: uracil-3'-azido- 2 ', 3' -dideoxy-D-riboside

17) A: guanine-2 ', 3'-dideoxy-D-riboside B: guanine-2', 3'-dideoxy-D-riboside

18) A: thymine-3 '-azido-2', 3 '-dideoxy-D-riboside B: uracil-3' -azido-2 ', 3'-dideoxy-D-riboside

19) A: uracil-3' -azido-2 ', 3 '-dideoxy-D-riboside B: hypoxanthine-2', 3'-dideoxy-D-riboside

20) A: thymine-3 '-azido-2', 3'-dideoxy-D-riboside B: guanine-2 ' , 3 '-dideoxy-D-riboside and

21) A: uracil-3 '-azido-2', 3'-dideoxy-D-riboside B: guanine-2 ', 3'-dideoxy-D-riboside; each of the symbols X represents oxygen; each of the symbols R and R represents hydrogen; and their addition salts with bases that provide biologically acceptable cations, preferably sodium or potassium cations. 5. A compound according to claim 4, characterized in that: i) A represents a 5'-C 'radical of a non-naturally occurring nucleoside, which is thymine-3' -azido-2 ', 3'-dideoxy -D-riboside, and B represents a 5 '-C' radical of a non-naturally occurring nucleoside, which is hypoxanthine-2 ', 3'-dideoxy-D-riboside; or ii) each of the symbols A and B represents a 5'C 'radical of a nucleoside which does not exist neturally, which is thymine-3' -azido-2 ', 3'-dideoxy-D-riboside or iii) A represents a 5'C 'radical of a non-naturally occurring nucleoside, which is 5-f luorouracil-2'-deoxy-D-riboside, and B represents a 5'-C' radical of a nucleoside which does not exist naturally, which is thymine-3 '-azido- 2', 3'-dideoxy-D-riboside; or iv) each of the symbols A and B represents a 5'-C 'radical of a non-naturally occurring nucleoside, which is 5-fluorouracil-2'-deoxy-D-ribophore; each of the symbols X represents oxygen; each of the symbols R and R. represents hydrogen; s sodium and potassium salts. 6. A compound according to claim 5, characterized in that: each of the symbols A and B represents a 5'-C 'radical of a non-naturally occurring nucleoside, which is thymine-3' -azido-2 ' , 3'-dideoxy-D-riboside; each of the symbols X represents oxygen; each of the symbols R and R. represents hydrogen; and the sodium and potassium salts thereof. 7. A compound according to any of claims 1 to 6, characterized in that it is to be used as a medicament. 8. A compound according to any of claims 1 to 4, characterized in that at least one of the symbols A and B represents a 5'-C 'radical of a non-naturally occurring nucleoside, selected from: thymine-3'- azido-2 ', 3' -dideoxy-D-riboside, uracil-3 '-azido-2', 3'-dideoxy-D-riboside, guanine-2 ', 3'-dideoxy-D-riboside, hypoxanthine-2 ', 3' -dideoxy-D-riboside, cytosine-2 ', 3'-dideoxy-D-riboside, and adenine-2', 3'-dideoxy-D-riboside, to be used as an antiviral agent, in particular against retroviral infections such as feline and murine immunodeficiency virus infections and HIV infections. 9. The compound according to claim 6, characterized in that it is to be used as an anti-viral agent, in particular against retroviral infections, such as infections or feline and murine immunodeficiency viruses and HIV infections. 10. A compound according to any of claims 1 to 4, characterized in that at least one of the symbols A and B represents a 5'-C 'radical of a non-naturally occurring nucleoside, which is 5-fluorouracil- 2'-deoxy-D-riboside, to be used as an antitumor agent. 11. The use of any of the compounds according to claim 5, letters i), ii) and iii), the use is characterized in that it is for the manufacture of an anti-HIV agent. 12. The use of the compound according to claim 6, characterized in that it is for the manufacture of an anti-HIV agent. 13. The use of any of the compounds according to claim 5, letters iii) and iv), the use is characterized in that it is for the manufacture of an antitumor agent. 14. A pharmaceutical composition, characterized in that it contains a 5 ', 5' -p 1, p 2-pyrophosphate dinucleoside of the formula (I): X II A-X-P-X-P-X-B? XR XRi wherein: the symbols A and B, each independently, represent a 5'C 'radical of a nucleoside that does not exist naturally, selected from: thymine-3'-azido-2', 3'-dideoxy-D- riboside, 5-fluorouracil-2 '-deoxy-D-riboside, uracil-3' -azido-2 ', 3'-dideoxy-D-riboside, guanine-2', 3'-dideoxy-D-riboside, hypoxanthine- 2 ', 3' -dideoxy-D-riboside, cytosine-2 ', 3'-dideoxy-D-riboside, and adenine-2', 3'-dideoxy-D-riboside; the symbols X each independently represent oxygen or sulfur; the symbols R and R. each independently represent hydrogen or an alkyl group of 1 to 10 carbon atoms; and the addition salts of the compounds of formula (I) wherein RyoR represents hydrogen, with bases that provide biologically acceptable cations. 15. The use of a compound according to any of claims 1 to 6, for the manufacture of a therapeutic agent against tumors and / or viral infections, the use is characterized in that the compound is encapsulated in a biological carrier. 16. The use according to claim 15, characterized in that the biological carrier is a transformed erythrocyte. 17. A composition characterized in that it comprises transformed erythrocytes containing a dinucleoside-5 ', 5'-p 1, p2-pyrophosphate of the formula (I): X X XR XXl wherein: the symbols A and B, each independently, represent a 5'C 'radical of a non-naturally occurring nucleoside, selected from: thymine-3'-azido-2', 3 '-dideso iD-riboside, 5-fluorouracil-2 '-deoxy-D-riboside, uracil-3' -azido-2 ', 3'-dideoxy-D-riboside, guanine-2', 3'-dideoxy-D-riboside, hypoxanthine-2 ' , 3'-dideoxy-D-riboside, cytosine-2 ', 3'-dideoxy-D-riboside, and adenine-2', 3'-dideoxy-D-riboside; the symbols X each independently, represent oxygen or sulfur; the symbols R and R, each independently, represent hydrogen or an alkyl group of 1 to 10 carbon atoms; and the addition salts of the compounds of formula (I) wherein R and / or R, represent hydrogen, with bases that provide biologically acceptable cations. 18. A process for preparing a 5 ', 5' -p 1, p2-pyrophosphate dinucleoside of the formula (I): X X II II A-X-P-X-P-X-B I I XR XR? wherein: symbols A and B, each independently, represent a 5 '-C' radical of a non-naturally occurring nucleoside, selected from: thymine-3 '-azido-2', 3'-dideoxy-D-riboside , 5-fluorouracil-2 '-deoxy-D-riboside, uracil-3' -azido-2 ', 3'-dideoxy-D-riboside, guanine-2', 3'-dideoxy-D-riboside, hypoxanthine-2 ', 3' -dideoxy-D-riboside, cytosine-2 ', 3'-dideoxy-D-riboside, and adenine-2', 3'-dideoxy-D-riboside; the symbols X each independently represent oxygen or sulfur; the symbols R and R., each independently, represent hydrogen or an alkyl group of 1 to 10 carbon atoms; and the addition salts of the compounds of formula (I) wherein R and / or R, represent hydrogen, with bases that provide biologically acceptable cations, the process is characterized in that it comprises activating the XH group of a nucleoside phosphate of the formula (II): A-X-P-XH (ID XR wherein A, X and R have the same meanings as above, to form an activated phospho-ester, and reacting such activated phospho-ester with a salt of a nucleoside phosphate of the formula (III): X II B -? - P-XH I? D XRl wherein B, X and R have the same meanings as above, with a hindered tertiary amine base. 19. A process according to claim 18, characterized in that the XH group of the nucleoside phosphate of the formula (II) is activated by reaction with tetraphenyl pyrophosphate or diphenyl phosphochloridate. 20. A process according to any of claims 18 and 19, characterized in that the salt of the nucleoside phosphate of the formula (III) with a hindered tertiary amine base, is a salt with tri-n-butylamine, tri-n -octylamine or methyl-tri-n-octylammonium hydroxide. 21. A process according to any of claims 18, 19 and 20, characterized in that the reaction between the activated nucleoside phosphate of the formula (II) and the salt of a nucleoside phosphate of the formula (III) with a hindered tertiary amine, is carried out in the presence of an excess of an acid acceptor, which does not interfere with the reactants, preferably a tertiary aliphatic amine or a tertiary heterocyclic amine.

22. A process according to any of claims 18, 19, 20 and 21, characterized in that the reaction between the. activated nucleoside phosphate of formula (II) and the nucleoside phosphate salt of formula (III) are 5 is carried out at room temperature, in the presence of an inert organic solvent, preferably dioxane, optionally in the presence of an additional inert organic solvent of high solubility power, preferably dimethylformamide. 23. A method for encapsulating a 5 ', 5'-p1, p2-pyrophosphate dinucleoside according to any of claims 1 to 6 in erythrocytes, characterized in that the erythrocytes are: (i) dialysed in a hemolyzing buffer solution (ii) placed in contact with the dinucleoside 1 2 15 do-5 ', 5'-p-p-pyrophosphate under the same dialysis conditions, (iii) re-closed dialyzing against a phosphate-saline solution which is hypertonic with respect to the lysate, and (iv) extensively washing the red cells closed. 24. A composition of transformed erythrocytes containing a 5 ', 5' -p1, p2-pyrophosphate dinucleoside according to any of claims 1 to 6, further characterized in that the surface of the transformed erythrocyte is modified to be specifically recognized by the cells that host the human or animal pathogenic retroviruses. 25. A method for preparing a composition according to claim 24, characterized in that erythrocytes containing the dinucleoside-5 ', 5'-p1, p2-pyro-phosphate are first treated (i) with a bulking agent Reversible surface or transmembrane proteins, then (ii) with a crosslinking agent that covalently binds and, finally, (iii) are incubated in autologous plasma, to bind the IgG molecules.