RU2112765C1 - PHARMACEUTICAL COMPOSITION SHOWING ACTIVITY AGAINST VIRAL INFECTION AND 9-β--D-ARABINOFURANOSYL-2-AMINO-6-METHOXY-9H-PURINES - Google Patents

Abstract

FIELD: heterocyclic compounds, purines, pharmacy. SUBSTANCE: invention relates to 9-β--D-arabinofuranosyl-2-amino-6-methoxy-9H-purine of the formula (I)

Description

 The invention relates to certain substituted purine arabinosides and their physiologically acceptable derivatives, in particular esters and their use for the treatment of certain DNA viral diseases.

 The Varicella herpes zoster virus (BBZ) virus, which causes chickenpox and shingles, is a herpes DNA virus. Chickenpox is the main disease caused by VVZ in a host without an immune response; in general, it is a mild illness of young children, which manifests itself in the form of fever and scabies rash. Herpes zoster (shingles) is a recurrent form of the disease that occurs in adults who have previously been infected with varicella-zoster virus. The clinical symptoms of this infection are characterized by neuralgia and a vesicular skin rash, which has a unilateral and skin distribution. The spread of inflammation can lead to paralysis or convulsions and coma if meningitis subsequently develops.

 In immunocompromised patients, this virus can spread, causing serious, often fatal diseases. The cause of immunodeficiency may be medications used in the treatment of transplant patients or in the treatment of malignant neoplasms, or diseases such as AIDS that destroy the immune system, making the patient vulnerable to infections that would not otherwise be so dangerous.

 Cytomegalovirus (CMV) is another herpes virus. Infection can be acquired in childhood or in youth and in the fetus, and intrauterine infection is probably the most common form of infection, but up to 90% of congenital infections are asymptomatic during childbirth. Pre-infection of the mother during pregnancy is generally considered the highest risk for an unborn baby, while re-activation of fetal infections is generally clinically rare. Clinical effects range from death and serious illness (microcephaly, enlarged liver or spleen, jaundice, mental retardation) through the cessation of the disease to its rapid development, susceptibility to pulmonary and ear infections, to the absence of obvious effects of the disease. In young people, an infection can go undetected or manifest as a fever caused by glandular inflammation, similar to a disease resulting from close physical contact.

 Serious infections can also occur as a result of reactivation of the “dormant” virus in patients with an ineffective immune system, as described for BBZ infection. Such infections lead to higher morbidity and mortality from inflammation of the lining of the eye, inflammation of the lungs and gastrointestinal disorders.

 It was found that some purine-arabino nucleazides, described in detail below, characterized by the presence of a group substituted at the 2- and 6-positions of the purine ring, are highly active against human viral infections, in particular those caused by varicella zoster virus (BBZ) or cytomegalovirus (CMV).

 Some substituted purine-arabino nucleosides, in particular 9-β D-arabinofuranosyl-6-methoxy-9H-purine, 9-β D-arabinofuranosyl-6-pyrrolidino-9H-purine, 9-β D-arabinofuranosyl-6-methylamino 9H-purine and 9-β D-arabinofuranosyl-6-dimethylamino-9H-puri, which are described below, when used for the treatment of BBZ and DIV infections, are described previously in J. Org. Chem., Volume 27, 3274-9 (1962); Carner Treatment Rep, 60 (10) 1567-84 (1976); Tetrahedron, 40 (4), 709-13, (1984); Canada, J. Biochem., 43 (1), 1-15, (1965); J. med. Chem. 12, 498-504, (1969); J. Biol, Chem., 251 (13), 4055-61, (1976); Ann.n.J. acad., Sci, 284, 81-90, (1977); in European patent 002192; U.S. Patent Nos. 3,666,856; 4,371,613; 3,758,684.

где
R₁ - представляет галоген (например, хлор или йод), C_1-5алкоксигруппу (например, метокси или этокси); галоген-замещенный C_1-5алкокси (например, трифторэтокси); амино-группу, которая является одно- или двузамещенной C_1-5алкилом (например, метилом или этилом), C_1-5алкилом, замещенным одним или несколькими атомами фтора (например, 2-фторэтилом или 2,2,2-трифторэтилом), или C_3-6циклоалкилом (например, циклопропилом) или амино-составляющей кольца, содержащей 4 - 7 атомов углерода, и, возможно, двойной связью (например, пирролидино) и/или, кроме того, атомом азота; R₂ - представляет водород, галоген или амино; и его приемлемые с физиологической точки зрения производные для лечения или профилактики вирусных инфекций у человека, вызванных ВВЗ или ЦМВ.Thus, in accordance with a first aspect of the present invention, there is provided a compound of formula (I)

Where
R ₁ - represents halogen (for example, chlorine or iodine), a C _1-5 alkoxy group (for example, methoxy or ethoxy); halogen-substituted C _1-5 alkoxy (e.g. trifluoroethoxy); an amino group which is mono- or disubstituted with C _1-5 alkyl (e.g. methyl or ethyl), C _1-5 alkyl substituted with one or more fluorine atoms (e.g. 2-fluoroethyl or 2,2,2-trifluoroethyl) or C _3-6 cycloalkyl (e.g. cyclopropyl) or an amino moiety containing 4 to 7 carbon atoms and optionally a double bond (e.g. pyrrolidino) and / or, in addition, a nitrogen atom; R ₂ - represents hydrogen, halogen or amino; and physiologically acceptable derivatives thereof for the treatment or prophylaxis of human viral infections caused by VZV or CMV.

The invention also includes compounds of formula (I) in which R ₂ is hydrogen and R ₁ is methoxy, piperidino or pyrrolidino, and when R ₂ is amino and R ₁ is chlorine, and their pharmaceutically acceptable derivatives for use in medical therapy.

 In the above formula (I), alkyl groups (including groups in alkoxy, alkylamino or dialkylamino groups) are preferably methyl, ethyl or propyl groups.

Preferred compounds of formula (I) are those in which:
(a) R ₂ is hydrogen;
(b) R ₁ is C _1-5 alkoxy, especially methoxy; or
(c) R ₁ is C _1-5 alkylamino, especially dimethylamino; or
(d) R ₁ is halogen, especially iodine.

The following compounds are preferred compounds in accordance with the present invention due to their strong antiviral activity against BBZ or CMV,
1) 9-β-D-arabinofuranosyl-6-methylamino-9H-purine,
2) 9-β-D-arabinofuranosyl-6-dimethylamino-9H-purine,
3) 9-β-D-arabinofuranosyl-6-methoxy-9H-purine,
4) 9-β-D-arabinofuranosyl-6-ethoxy-9H-purine,
5) 9-β-D-arabinofuranosyl-6-iodine-9H-purine,
6) 9-β-D-arabinofuranosyl-6-amino-9H-iodopurine,
7) 9-β-D-arabinofuranosyl-6-pyrrolidino-9H-purine,
8) 9-β-D-arabinofuranosyl-2-chloro-6-methylamino-9H-purine,
9) 9-β-D-arabinofuranosyl-6-cyclopropylamino-9H-purine,
10) 9-β-D-arabinofuranosyl-6-ethylmethylamino-9H-purine,
11) 9-β-D-arabinofuranosyl-2-amino-6-methoxy-9H-purine,
12) 9-β-D-arabinofuranosyl-2-amino-6-n-propoxy-9H-purine.

 Of the above compounds, compounds 2, 3, and 5 are most preferred. The present invention also includes novel compounds of formula (1) and physiologically acceptable derivatives thereof, in particular compounds 4, 5, 6, 8, 9, 10, 11, and 12 listed above.

,
в которой
R₁ представляет галоген (например, хлор или йод), C_1-5алкокси-группу (например, метокси или этокси); галоген-замещенную C_1-5алкокси (например, трифторэтокси), амино-группу, которая является одно- или двузамещенной C_1-5алкокси (например, метилом или этилом), C_1-5алкилом, замещенным одним или несколькими атомами фтора (например, 2-фторэтилом или 2,2,2-трифторэтилом/или C_3-6циклоалкилом (например, циклопропилом), или амино-составляющей кольца, содержащей 4-7 атомов углерода, и, возможно, двойной связью (например, пирролидино), и/или, кроме того, атомом азота; R₂ представляет водород, галоген или амино при условии, что, когда R₂ является водородом, R₁ не является хлором, метокси, метиламино, этиламино, диметиламино, пиперидино или пиррлидино, а когда R₂ является амино, R₁ не является хлором или метиламино; и их приемлемые с физиологической точки зрения производные, отличные от 2', 3', 5'-триацетатных и трибензиловых производных соединений формулы I(а), в которой R₁ является хлором или фтором, когда R₂ является хлором, фтором, водородом или амино.In accordance with a second aspect of the present invention, novel compounds of general formula 1 (a) are provided:

,
wherein
R ₁ represents halogen (eg, chlorine or iodine), a C _1-5 alkoxy group (eg, methoxy or ethoxy); halogen-substituted C _1-5 alkoxy (e.g. trifluoroethoxy), an amino group that is a mono- or disubstituted C _1-5 alkoxy (e.g. methyl or ethyl), C _1-5 alkyl substituted with one or more fluorine atoms ( for example, 2-fluoroethyl or 2,2,2-trifluoroethyl / or C _3-6 cycloalkyl (e.g. cyclopropyl), or the amino moiety of the ring containing 4-7 carbon atoms, and possibly a double bond (e.g. pyrrolidino) and / or further nitrogen atom; R ₂ represents hydrogen, halogen or amino provided that when R ₂ is hydrogen, R ₁ is not YaV is Busy chlorine, methoxy, methylamino, ethylamino, dimethylamino, piperidino or pirrlidino, and when R ₂ is amino, R ₁ is not chlorine or methylamino; and their physiologically acceptable derivatives of view other than the 2 ', 3', 5'- triacetate and tribenzyl derivatives of the compounds of formula I (a) in which R ₁ is chloro or fluoro, when R ₂ is chloro, fluoro, hydrogen or amino.

 The invention also includes compounds of formula I (a) for use in medical therapy, in particular for the treatment of human viral infections caused by BBH or CMV.

 In accordance with another aspect of the invention, pharmaceutically acceptable derivatives of the compounds of formula (I) are provided, namely, any pharmaceutically acceptable ethers, salts, esters or salts of such esters, or any other compound which, after application to a person is able to give (directly or indirectly) a compound of formula (I), or an antiviral metabolite or residue thereof.

 Pharmaceutically acceptable esters of the aforementioned compounds of formula (I) are particularly preferred since they are able to provide high concentrations of the main compound in the patient’s plasma after dental use. In accordance with the present invention, in particular, it is proposed, as a preferred class, new compounds of pharmaceutically acceptable esters of compound 3 formed by the esterification of the 2'-, 3'- and / or 5'-hydroxy group of the arabino-sugar moiety.

 Particularly preferred derivatives of the compounds of formula (I) are the mono-dio or tri-esters of the arabino-sugar residue substituted at the 2'-, 3'- and 5'-positions of the aforementioned residue.

Such preferred esters include esters in which the non-carbonyl moiety of the ester group is selected from straight chain or branched chain alkyl (e.g. n-propyl, tertiary butyl, n-butyl), alkoxyalkyl (e.g. methoxymethyl), aralkyl ( for example benzyl), aryloxyalkyl (for example phenoxymethyl), aryl (for example phenyl) may be substituted with halogen, C _1-4 alkyl or C _1-4 alkoxy, nitro or amino; sulfonate esters such as alkylsulfonyl; or alkylarylsulfonyl (e.g. methanesulfonyl or tolylsulfonylsulfonyl); amino acid esters, e.g., β-valyl); and mono-, di- or triphosphate esters. Pharmaceutically acceptable salts of these esters include sodium, potassium, PR ₄ +, where P = H or C _1-6 alkyl, and attached acid salts. In the above ester groups, alkyl groups (including groups in the alkoxy group) contain from 1 to 12 carbon atoms, and the aryl groups are preferably phenyl.

The following esters and ethers are preferred new compounds of the present invention:
13) 9- (5-0-benzoyl-β-D-arabinofuranosyl) -6-methoxy-9H-purine,
14) 6-methoxy-9- [5-0- (4-methylphenylsulfonyl) - β-D-arabinofuranosyl] -9H-purine,
15) 6-methoxy-9- (5-0-methylsulfonyl) - β-D-arabinofuranosyl] - 9H-purine,
16) 9- [5-0- (4-methylbenzoyl) - β-D-arabinofuranosyl] -6-methoxy-9H-purine,
17) 9- [5-0- (4-chlorobenzoyl) - β-D-arabinofuranosyl] -6-methoxy-9H-purine,
18) 9- [5-0- (4-methoxybenzoyl) - β-D-arabinofuranosyl] -6-methoxy-9H-purine,
19) 6-methoxy-9- (5-0-phenylacetyl-β-D-arabinofuranosyl) -9H-purine,
20) 5-methoxy-9- (5-0-phenyloxyacetyl-β-D-arabinofuranosyl) -9H-purine,
21) 6-methoxy-9- (5-0-methoxyacetyl-β-D-arabinofuranosyl) -9H-purine,
22) 9- [5-0- (4-nitrobenzoyl) - β-D-arabinofuranosyl) -6-methoxy-9H-purine,
23) 6-methoxy-9- (5-0-pentanoyl-β-D-arabinofuranosyl) -9H-purine,
24) 9- [5-0- (4-aminobenzoyl) - β-D-arabinofuranosyl) -6-methoxy-9H-purine,
25) 6-methoxy-9- [5-0-propionyl-β-D-arabinofuranosyl) -9H-purine,
26) 9- (5-0-butanoyl-β-D-arabinofuranosyl) -6-methoxy-9H-purine,
27) 9- [5-0- (2,2dimethylpropionyl) - β-D-arabinofuranosyl) -6-methoxy-9H-purine,
28) 9- [5-0-acetyl β-D-arabinofuranosyl) -6-methoxy-9H-purine,
29) 6-methoxy-9- [5-0- (2-methylpropionyl) - β-D-arabinofuranosyl) -9H-purine,
30) 6-methoxy-9- [2-0- (2,2-dimethylpropionyl) - β-D-arabinofuranosyl) -9H-purine,
31) 6-methoxy-9 - [(2,3,5-tri-0-acetyl) - β-D-arabinofuranosyl) - 9H-purine,
32) 6-methoxy-9- (2-0-pentanoyl-β-D-arabinofuranosyl) -9H-purine,
33) 9- (2-0-butanoyl-β-D-arabinofuranosyl) -6-methoxy-9H-purine,
34) 6-methoxy-9- [2-0- (2-methylpropionyl-β-D-arabinofuranosyl] -9H-purine,
35) 9- (3-0-benzoyl-β-D-arabinofuranosyl) -6-methoxy-9H-purine,
36) 9- (2,3-anhydro-β-D-lixofuranosyl) -6-methoxypurine,
37) 6-methoxy-9 - [(2-0- (4-methoxybenzoyl)) - β-D-arabinofuranosyl] -9H- purine,
38) 6-methoxy-9 - [(2-0- (4-methylbenzoyl)) - β-D-arabinofuranosyl] -9H-purine,
39) 9- [2-0- (4-chlorobenzoyl) - β-D-arabinofuranosyl] -6-methoxy-9H-purine,
40) 6-methoxy-9- [3,5-0- (1,1,3,3-tetraisopropyl-1,3-disiloxane-1,3-diyl) - β-D-arabinofuranosyl] -9H-purine,
41) 6-methoxy-9- [2-0- (2-aminobenzoyl) - β-D-arabinofuranosyl] - 9H-purine,
42) 6-methoxy-9- [2- (4-methylbenzoyl) -3.5-0- (1,1,3,3-tetraisopropyldisiloxane-1,3-diyl) - β-D-arabinofuranosyl] -9H- purin
43) 6-methoxy-9- [2- (4-methoxybenzoyl) -3.5-0- (1,1,3,3-tetraisopropyldisiloxane-1,3-diyl) - β-D-arabinofuranosyl] -9H- purin
44) 9- [2- (4-chlorobenzoyl) -3.5-0- (1,1,3,3-tetraisopropyl disiloxane -1,3-diyl) - β-D-arabinofuranosyl] -6-methoxy-9H- purin
45) 5'-phosphate monoester 9-β-D-arabinofuranosyl-6-dimethylamine-9H-purine,
46) 6-methoxypurin arabinoside 5'-monophosphate,
47) 6-methoxypurin arabinoside 5'-triphosphate.

 Particularly preferred are compounds 16, 24 and 32.

 Purine nucleosides of the formula (I) and their derivatives are hereinafter referred to as the compounds of the invention or active ingredients.

 In accordance with another preferred aspect of the present invention, the use of a compound of the invention is provided for the manufacture of a medicament for the treatment or prophylaxis of human viral infections caused by BBH or CMV.

 In addition, in accordance with the invention, there is provided a method of treating or preventing a BBZ and CMV infection in a person, which comprises applying to the said person an effective amount of the proposed compound.

 The method described above includes inhibiting the replication of BBZ or CMV viruses in a mammalian host cell, which comprises using an effective amount to inhibit the replication of the virus of a compound of formula (I) or a pharmaceutically acceptable derivative thereof for infected cells.

 Examples of clinical diseases caused by BBZ and CMV infections that can be treated in accordance with the invention include the diseases listed above.

 The compounds of formula (I) and their pharmaceutically acceptable derivatives (hereinafter collectively referred to as active ingredients) can be used in any manner appropriate for the disease; such methods include dental, rectal methods, through the nose, local method (including buccal and under the tongue), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and epidural) methods. The preferred method may vary, for example, depending on the condition of the patient.

 For each of the above uses and indications, the amount of active ingredient required (as defined above) will depend on various factors, including the severity of the disease to be treated and compatibility with the recipient, and will depend more on the decision of the attending physician. In the general case, however, for each of these uses and indications, the corresponding effective dose will vary from 0.1 to 250 mg per kilogram of recipient body weight per day, preferably in the range from 0.1 to 100 mg per kilogram of body weight body per day, and most preferably from 1 to 20 mg per kilogram of body weight per day; the optimal dose is about 15 mg per kilogram of body weight per day (unless otherwise specified, all the weights of the active ingredient are calculated for the main compound of formula (I); for its salts and esters, these numbers should be increased proportionally). The desired dose is preferably divided into two, three, four or more sub-doses, which are applied at appropriate intervals throughout the day. Such sub-doses may be administered in unit dosage forms, for example, containing from 5 to 1000 mg, in a preferred embodiment from 20 to 500 mg, and in the most preferred embodiment, from 100 to 400 mg of active ingredient per unit dosage form.

 Although only active ingredients can be used, they are preferably used in pharmaceutical forms. Forms (compositions) in accordance with the invention contain at least one active ingredient, as defined above, together with one or more acceptable carriers thereof, as well as, possibly, other therapeutic ingredients. The carrier (s) should be "acceptable" in the sense that it must be compatible with the other ingredients of the composition and should not adversely affect the recipient.

 The above forms include those suitable for oral, rectal, nasal, topical (including buccal and under the cheek) use, vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal and epidural) use. Such forms can be made in unit dosage form and can be prepared by any well-known technique in the pharmaceutical field. Such techniques include the step of bringing the active ingredient into contact with a carrier, which includes one or more accessory ingredients. In general, such forms are obtained by uniformly and thoroughly mixing the active ingredient with liquid carriers or finely divided solid carriers, or both, and then giving the mixture the desired shape.

 Forms in accordance with the invention for dental use may take the form of discrete units such as capsules, pills or tablets, each of which contains a predetermined amount of the active ingredient; as a powder of silt granules; as a solution or suspension in an aqueous liquid or non-aqueous liquid; or as an oil in water liquid emulsion or a water in oil liquid emulsion. The active ingredient may also be in the form of a ball, medicinal porridge or paste.

 A tablet may be prepared by compression or molding, possibly using one or more accessory ingredients. Compressed tablets may be prepared by compression, using an appropriate device, the active ingredient in a free-flowing form such as powder or granules, may be mixed with a binding agent (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), a lubricant, an inert diluent, a preservative an agent, a disintegrating agent (for example, sodium starch glycollate, crosslinked povidone, crosslinked sodium carboxymethyl cellulose), a surface active or dispersing agent. Molded tablets may be made by molding in a suitable device a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be coated or provided with a groove, and may be shaped to provide a slow or controlled release of the active ingredient, using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile.

 In case of infection of the eye or other external tissues, for example the mouth and skin, the compositions are preferably used in the form of local ointments or creams containing the active ingredient in an amount of, for example, from 0.075 to 20 w / w%, in the preferred embodiment, from 0.2 to 15 w / w%, and in the most preferred embodiment, from 0.5 to 10 w / w%. If the aforementioned form is an ointment, the active ingredients can be used together with either a paraffin wax or a water miscible ointment base. Alternatively, the active ingredients can be used to make an oil-in-water cream.

 If necessary, the aqueous phase of the cream may include, for example, at least 50 w / w% polyhydric alcohol, namely, an alcohol containing two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol , glycerin and polyethylene glycol, and mixtures thereof. Local forms may optionally contain a compound that increases the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancing agents include dimethyl sulfoxide and related analogs.

 The oil phase of the emulsions in accordance with the invention can be formed from known ingredients using a known technique. Despite the fact that this phase may contain only an emulsifier (also known under another name emulsifier), in the preferred embodiment, it contains a mixture of at least one emulsifier with fat or oil, or both. In a preferred embodiment, the hydrophilic emulsifier is included with the lyophilic emulsifier, which acts as a stabilizer. In a preferred embodiment, it also includes oil and fat together. Together emulsifier (s) with or without stabilizer (s) form the so-called emulsifying wax and this wax together with oil and / or fat forms the so-called emulsifying base of the ointment, which forms the cream phase dispersed in the oil.

 Emulsifiers and emulsion stabilizers suitable for use in the form of the invention include Tween 60, Spen 80, ketostearyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.

 The choice of the appropriate oils or fats for the composition is based on the achievement of the necessary cosmetic properties, since the solubility of the active compound in most oils, such as those used in the form of pharmaceutical emulsions, is very low. Thus, the cream should preferably be a non-greasy, non-staining and rinse-off product with an appropriate consistency, which would avoid leakage from pipes or other containers. Mono- or dibasic straight chain or branched chain alkyl esters such as di-isoadipate, isoacetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palminate, butyl stearate, 2-ethyl a branched chain ester mixture known as Crodamol KAP, with the latter three being preferred esters. They can be used individually or in combination, depending on the required properties. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

 Compositions suitable for topical application to the eyes also include eye drops in which the active ingredient is dissolved or suspended in an appropriate carrier, in particular an aqueous solvent for the active ingredient. The active ingredient is preferably contained in such forms in a concentration of from 0.5 to 20%, in a preferred embodiment, from 0.5 to 10%, for example, at a concentration of about 1.5 w / w%.

 Compositions suitable for topical application in the oral cavity include lozenges containing the active ingredient on a palatable basis, generally in sugar and acacia or tragacanth; lozenges containing the active ingredient in an inert basis such as gelatin and glycerin, or sugar and acacia; an oral medicine containing the active ingredient in an appropriate liquid carrier.

 Compositions for rectal administration may be in the form of suppositories on a suitable basis containing, for example, coconut oil or salicylate.

 Compositions intended for use through the nose, in which the carrier is a solid, include coarse powder having a particle size of, for example, 20-500 microns, which is applied by rapid inhalation through the nasal cavity from a powder container that is held close to the nose. Suitable compositions in which the carrier is a liquid for use, for example, in the form of a nasal spray or nasal drops, include aqueous or oily solutions of the active ingredient.

 Forms intended for vaginal use may take the form of pessaries, tampons, creams, gels, pastes, foams or aerosols containing, along with the active ingredient in the carrier, the use of which is well known in the art.

 Formulations intended for parenteral use include aqueous and non-aqueous sterile injectable solutions, which may include antioxidants, buffering materials, bacteriostats, and dissolved substances that impart isotonic properties to the blood relative to the intended recipient; aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. These forms may take the form of a single dose or several doses, for example, hermetically sealed ampoules and vials, and may be stored under freeze-dried (lyophilized) conditions requiring the addition of only a sterile liquid carrier, for example, water for injection immediately before use. Untreated solutions and suspensions for injection can be obtained from sterile powders, granules and tablets of the type described above.

 Preferred unit dosage forms are those containing a daily dose or a unit daily sub-dose, as defined above, or corresponding proportions of an active ingredient thereof.

 It should be clear that along with the ingredients listed above, the forms of the invention may include other agents, the use of which is well known depending on the type of form, for example, agents intended for dental use, may include flavoring agents.

в которой
R₁ и R₂ уже были определены выше, с соединение формулы (III)

в которой
X представляет пиримидиновое или пуриновое основание отличное от соединения формулы (II), либо
B. взаимодействие соединения формулы (IV):

в которой
Z является замещаемой группой, а R₂ уже был определен выше, с соединением, способным ввести необходимую группу в 6-позиций; и, возможно, последующее или одновременное с этим в том случае, когда полученным в результате соединения является соединение формулы (I), превращение его в его приемлемое с фармацевтической точки зрения производное, превращение его в другое, приемлемое с фармацевтической точки зрения, производное соединения формулы (I).In accordance with the invention, there is provided a process for the preparation of a compound of formula I (a) or a pharmaceutically acceptable derivative thereof, in particular an ester thereof, comprising reacting a compound of formula (II)

wherein
R ₁ and R ₂ have already been defined above, with a compound of formula (III)

wherein
X represents a pyrimidine or purine base other than the compound of formula (II), or
B. the interaction of the compounds of formula (IV):

wherein
Z is a substituted group, and R ₂ has already been defined above, with a compound capable of introducing the desired group at 6 positions; and possibly subsequent or simultaneous in this case, when the resulting compound is a compound of formula (I), converting it into a pharmaceutically acceptable derivative thereof, converting it into another pharmaceutically acceptable derivative of a compound of formula (I).

Regarding method A, X is preferably a uracil base. This reaction can be carried out, for example, by treating the compounds of formulas II and III with an enzyme such as a phosphorylase enzyme, for example uridine phosphorylase or purine nucleoside phosphorylase, or a mixture thereof, in the preferred embodiment, in the presence of a phosphate salt at pH 5.0-9.0 and a temperature of from 15 to 90 ^o C, in a preferred embodiment, from 40 to 60 ^o C.

As for procedure B, it can be carried out in accordance with the procedure described by Reist et al. In J. Org. Chem. 27 (1962), p. 3274-3279. The corresponding substituted group is a halogen atom, for example chlorine, the reaction is preferably carried out in an organic solvent, for example absolute methanol, with an agent capable of providing the desired group at the 6-position, for example, the corresponding amine in the case where R ₁ represents an alkyl or dialkylamino group.

 Physiologically acceptable esters and salts of the compounds of formula (I) can be prepared using known techniques, for example, esters can be prepared by esterification of the basic compound with a suitable acyl halide or anhydride. Alternatively, esters can be prepared by substituting the corresponding displaceable group, for example a halide with a suitable carboxylic acid, or by breaking the corresponding anhydronucleoside of the basic compound with a suitable carboxylic acid or its salt.

 Example 1. 9-β-D-arabinofuranosyl-6-methylamino-9H-purine.

6-Thiol-9-β-D-arabinofuranosyl) 9-H-purine (Reist E.J. et al., J. Org, Chem, 27 (1962), p. 3274-3279) (0.35 mmol, 100 mg) and 5 ml of absolute methanol were combined and cooled to a temperature of -10 ^o C, while providing protection from moisture. Chlorine gas was carefully bubbled through the suspension for 2 minutes. The resulting solution was stirred for 5 minutes at a temperature of -10 ^° C., then dry nitrogen was bubbled through the solution for 15 minutes until excess chlorine was removed. To the reaction mixture was added 2 ml of a 40% aqueous solution of methylamine, which was then heated in a stainless steel autoclave at a temperature of 115 ^° C, maintained for 4.5 hours. The reactor was cooled to 0 ^° C and the contents were evaporated to dryness, providing 88% yield of the title compound. After recrystallization in water, the sample had a melting point of 201.5 - 202.5 ^o C.

Analysis results: calculated for C ₁₁ H ₁₃ N ₅ O ₄ :
Calculated: C, 47.0; H 5.38; N, 24.9.

 Found: C, 47.2; H 5.72; N, 25.2.

 Example 2. 9-β-D-arabinofuranosyl-6-dimethylaminopurine.

6-dimethylaminopurin (Sigma Chemical Co., St. Louis, Mo.) (6.4 mmol, 1.04 g) and uracil arabinoside (Torrens, P.F., et al. J. Med. Chem., 22 (3 ) (1979), pp. 316–319 (8 mmol, 1.96 g) were combined in 0.412 L of a 5 mM potassium phosphate solution, pH 8.0, with 0.02% potassium azide. Purified purine nucleoside phosphorylase (3260 units) was added. .) and uridine phosphorylase (810 units), and the solution was stirred at 35 ^° C. After 59 days, the reaction was lyophilized, the residue was suspended in 250 ml of water and stirred at room temperature for 1 hour. Solid materials were separated by filtration and the filtrate was stored. at tamper round 3 ^o C. After 72 h, the precipitate was collected and combined with the previous cake. This was added to 100 ml of 95% ethanol in water, heated to boil and filtered. The solvent was removed in vacuo and the residue chromatographed on BioRad P-type resin -2 in 30% n-propanol / water (v / v), once using a column measuring 7.5 • 90 cm and two more times a column of 5 • 90 cm. As a result of this procedure, 0.12 g of 6-dimethylaminopurine 9 was obtained - β-D-arabinofuranoside in the form of 0.5 hydrate.

Analysis results: calculated for C ₁₂ H ₁₇ N ₅ O ₄ • 0.5 H ₂₀ .

Calculated: C, 47.36; H 5.96; N, 23.01
Found: C, 47.23; H 5.59; N, 22.75
NMR and mass spectra are consistent with such a structure.

 Example 3. 9-β-D-arabinofuranosyl-6-methoxypurine.

6-methoxypurin (Sigma Chemical Co., St. Louis, Mo.), (6.6 mmol, 1 g) and uracil arabinoside (Torrens, P.F. et al., J. Med. Chem., 22 (3 ) (1979)) (10.1 mmol, 2.45 g) were suspended in 575 ml of 10 mM potassium phosphate, 0.04% potassium azide solution, pH 7.8, containing 10% n-propanol (v / v) about.). Purified uridine phosphorylase (560 IU) and purine nucleoside phosphorylase (10,000 IU) were added (Krenitsky, T.E. et al. Biochemistry, 20, p. 3615, 1981 and US patent No. 4381444) and the solution was mixed at a temperature of 35 ^o C. Thirty days later, the reaction was filtered. The filtrate was made alkaline to pH 10.5 with ammonium hydroxide and chromatographed on a 2.5 x 7 cm column containing Dowex-1 formate resin. The resin was eluted with 30% n-propanol / water (v / v). The fractions containing the product were combined and the solvent was removed in vacuo. The resin was dissolved in 30% n-propanol / water (v / v) and chromatographed on a Bio-Rad P-2 type column (7.5 x 90 cm). Product fractions were combined and, after lyophilization, 0.922 g of 6-methoxypurin-9-β-D-arabinofuranoside was obtained as a dihydrate.

Analysis results: calculated for C ₁₁ H ₁₄ N ₄ O ₅ • 2H ₂ O.

Calculated: C 41.51; H 5.70; N, 17.70
Found: C, 41.46; H 5.74; N, 18.13
NMR and mass spectra are consistent with such a structure.

 Example 4. 9-β-D-arabinofuranosyl-6-ethoxypurine.

6-Ethoxypurin (Sigma Chemical Co., St. Louis, MO) (3.05 mmol, 0.5 g) and uracil arabinoside (6.09 mmol, 1.48 g) were suspended in 100 ml of 10 mM potassium phosphate, 0.04% potassium azide solution at pH 7.4. Purified uridine phosphorylase (6000 moe) and purine nucleoside phosphorylase (8400 moe) were added (Krenitsky, T.E. et al., Biochemistry, 20, p. 3615, 1981 and US patent No. 4381444) and the suspension was stirred at a temperature of 35 ^o C.

 After 168 hours, another 18,000 units were added. uridine phosphorylase; and 75,600 units of purine nucleoside phosphorylase. After seven days, the reaction was filtered, and the filtrate was chromatographed on a column containing Dowex-1-hydroxide resin (2.5x8 cm). The column was eluted with 90% methanol / water (v / v). The fractions containing the product were combined and the solvent was removed in vacuo. The residue was dissolved in 30% n-propanol and water (v / v) and chromatographed on a column containing BioRad P-2 (5x90 cm). The product was eluted with 30% n-propanol / water (v / v). The product containing fractions were combined and the solvent was removed in vacuo to give 0.363 g of 6-ethoxypurin-9-β-D-arabinofuranoside, which was identified as 0.3 hydrate.

Analysis results: calculated for C ₁₂ H ₁₆ N ₄ O ₅ • 0.3 H ₂ O.

Calculated: C 47.78; H 5.55; N, 18.57
Found: C, 47.99; H 5.54; N, 18.40
NMR and mass spectra are consistent with this structure.

 Example 5. 9-β-D-arabinofuranosyl-6-iodopurine.

6-Yodpurin (Sigma Chemical Co., St. Louis, Mo.) (4 mmol, 1 g) was dissolved in 16 ml of 1,2-dimethoxyethane with heating. Fifty milliliters of a solution of uracil arabinoside (10.1 mmol) in 10 mM potassium phosphate, a 0.04% potassium azide solution, pH 7.4 were added. Purified uridine phospharylase (6800 IU) and purine nucleoside phosphorylase (12000 IU) were added and the reaction was stirred at 35 ^° C. After 21 days, an additional 4800 units of uridine phosphorylase and 20,000 units of purine nucleoside phosphorylase were added. After ninety days, the reaction was filtered, and the solvent was removed in vacuo. The residue was dissolved in 100 ml of water, heated with steam, and then filtered. The filtrate was chromatographed on a column containing XAD-2 resin (5x35 cm). This column was eluted with 2 L of water and then 2 L of ethanol. The fractions containing the product were combined and the solvent was removed in vacuo. The residue was dissolved in 30% n-propanol / water (v / v) and chromatographed on a Sephadex G-10 column (5x90 cm). This column was eluted with 30% n-propanol / water (v / v). The product containing fractions were combined and, after removal of the solvent in vacuo, 0.253 g of 6-iodopurin-9-β-D-arabinofuranoside was obtained, which was identified as 1.5 hydrate.

Analysis results: calculated for C ₁₀ H ₁₁ IN ₄ O ₄ • 1.5 H ₂ O:
Calculated: C 26.65; H 3.48; N 13.83; I 31.32
Found: C, 29.43; H 3.53; N, 13.66; J 31,20
NMR and mass spectra are consistent with such a structure.

 Example 6. 9-β-D-arabinofuranosyl-2-amino-6-iodopurine.

2-amino-6-iodopurine (Sigma Chemical, St. Louis, Mo.) (25.5 mmol, 6.75 g) and uracil arabinoside (61.9 mmol, 15.1 g) were combined in 0.31 L 10 mM potassium phosphate, pH 6.9, with 0.02% potassium azide. Purified purine nucleoside phosphorylase (17000 units) and uridine phosphorylase (2000 units) were added, and the solution was stirred at 37 ^° C. After 18 days, another 5700 units of uridine phosphorylase were added. After fifty-seven days, the reaction was filtered, and the filtrate was chromatographed on a column containing XAD-2 resin (8x11 cm). The product was eluted with a successive ethanol / water gradient (v / v) as follows: 0.35 L 10%; 1 liter of 20%; 1 l 50%; 0.2 L 95%. The fractions containing the product were combined, and ethanol was removed in vacuo. The residue was dissolved in 30% n-propanol / water (v / v) and chromatographed on a 7.6 x 90 cm column containing Bio-Rad P-2 resin. As a result, 1.1 g of 2-amino-6-iodopurin-9-β-D-arabinofuranoside was obtained as a 0.5 hydrate.

Analysis results: calculated for C ₁₀ H ₁₂ N ₅ O ₄ • 0.5 H ₂ O;
Calculated: C 29.87; H 3.26; N 17.41
Found: C, 29.86; H 3.29; N, 17.39
NMR and mass spectra confirmed this structure.

 Example 7. 9-β-D-arabinofuranosyl-6-pyrrolidinopurin.

6-Pyrrolidinopurin (Sigma Chemical K., St. Louis. MO) (2.6 mmol) 0.5 g and uracil arabinoside (5.29 mmol, 1.29 g) were suspended in 100 ml of 10 mM potassium phosphate, 0.04 % potassium azide solution at pH 7.4. Purified uridine phosphorylase (6000 IU) and purine nucleoside phosphorylase (8400 IU) were added (Krenitsky, T.A. et al., Biochemistry, 20, p. 3615 (1981) and US patent N 4381444), and the suspension was stirred at 35 ^° C. After twenty days, the reaction was filtered and the filtrate was chromatographed on a column containing Dowex-1-hydroxide resin (2.5x8 cm). The product was eluted from the column using a 90% methanol / water (v / v) mixture. The fractions containing the product were combined and the solvent was removed in vacuo. The residue was dissolved in 50 ml of 30% n-propanol and water (v / v) and chromatographed on a BioRad P-2 column (5x90 cm). The product was eluted using 30% n-propanol / water (v / v). The product containing fractions were combined and the solvent was removed in vacuo to give 0.573 g of 6-pyrrolidinopurin-9-β-D-arabinofuranoside.

Analysis results: calculated for C ₁₄ H ₁₉ N ₅ O ₄ :
Calculated: C, 52.33; H 5.96; N, 21.79
Found: C, 52.60; H 6.09; N, 21.51
NMR and mass spectra confirm the structure.

 Example 8. 9-β - D-arabinofuranosyl-2-chloro-6-methylaminopurine.

A solution of 2,6-dichloro-2 ', 3', 5'-tri-O-benzyl-9 (β-D-arabinofuranosyl) -purine (Keller, F. et al., J. Org, Chem., 32, p. 1644 (1967); Montgomery, J.E. and Hewson, C.J., J. Med. Chem 12, p. 498 (1967)) (5.92 g, 10 mmol) in benzene (35 ml of solution , 0.6 g of methylamine per 10 ml of benzene) was kept at room temperature in a sealed autoclave for 4 days. The reactor was ice-cooled, opened and the contents were filtered to remove methylamine hydrochloride. The solvent was removed in vacuo, whereby an oil was obtained which was combined with the reaction oil with the same amounts but carried out at a temperature of 125 ^° C. The total weight was 11.4 g. As a result of thin-layer chromatography (TLC), the material was a mixture of starting material, mono- and dimethylamino compounds. The oil was chromatographed on 285 g of silica gel using 30% acetone and 70% cyclohexane (volumes). The components following the starting material (TLC, silica gel, 3: 7, acetone-cyclohexane), and the solvent was removed under vacuum. Yield: 4.8 g of 2-chloro-6-methylamino-2 ', 3', 5'-thi-O-benzyl-9- (β-D-arabinofuranosyl) purine as an oil. A portion of 1.1 g of this material in 40 ml of 2-methoxyethanol was added to palladium chloride (0.87 g), which was previously reduced in a Parr apparatus. The mixture was hydrogenated at a pressure of 50 psi (3.515 kg / cm ² ) for 30 minutes in a hydrogen atmosphere, which was replaced after the first 15 minutes. The catalyst was removed by filtration through a Celite pad and washed with methanol. The filtrate was neutralized by the addition of Dowex-1 (HCO ₃ ).

 The resin was removed by filtration and washed with methanol. The filtrate was evaporated in vacuo and the residue was triturated with chloroform. The crude product was washed with hot water, dissolved in hot methanol, filtered, cooled and the solid was collected. Crystallization from boiling water gave the product as a hydrate.

Yield: 44.5 mg; melting point temperature: 224-225 ^o C.

Analysis result: calculated for C ₁₁ H ₁₄ N ₅ O ₄ CI • H ₂ O:
Calculated: C 39.58; N, 20.98; H 4.84
Found: C, 39.27; N, 20.83; H 5.16
Example 9. 9-β-D-arabinofuranosyl-6-cyclopropylaminopurine.

6-Cyclopropylaminopurine (obtained by nucleophilic substitution of a chlorine group with 6-chloropurine (Sigma Chemicals Co., St. Louis, Mo.) using cyclopropylamine in acetonitrile) (2.85 mmol, 0.5 g) and uracil arabinoside (Torrens , P.F. et al., J. Med. Chem., 22 (3) (1979), pp. 316-319) (5.71 mmol, 1.39 g) were suspended in 100 ml of 10 mM potassium phosphate, 0.04% potassium azide solution with a pH of 7.4. Purified uridine phosphorylase (6000 IU) and purine nucleoside phosphorylase (8400 IU) were added (Krenitsky et al., Biochemistry, 20, p. 3615, 1981 and US patent N 381444), and the suspension was stirred at a temperature of 35 ^o C. After 120 hours, the reaction was filtered and the filtrate was chromatographed on a column containing Dowex-1-hydroxide resin (2.5x10 cm). The column was eluted with 90% methanol / water (v / v). The fractions containing the product, the compounds, and the solvent were removed in vacuo. The residue was dissolved in 30% n-propanol and water (v / v) and chromatographed on BioRad P-2 (5x90 cm). The column was eluted with 30% n-propinol / water (v / v). The precipitate from the reaction was recrystallized from hot methanol to give 0.052 g, a compound that was identified as 6-cyclopropylaminopurin-9-β-D-arabinofuranoside monohydrate. After recrystallization, the filtrate was chromatographed on BioRad P-2 resin (5x90 cm), as described above. The product containing fractions were combined from both columns and the solvent removed in vacuo to give 0.342 g of 6-cyclopropylaminopurin-9-β-D-arabinofuranoside, which had the form of a 0.8 hydrate with 0.3 C ₃ H ₈ O .

Analysis results: calculated for C ₁₃ H ₁₇ N ₅ O ₄ • 1H ₂ O;
Calculated: C 48.00; H 5.89; N 21.53
Found: C, 48.05; H 5.89; N, 21.55
NMR and mass spectra confirm this structure.

Example 10.9-β-D-arabinofuranosyl-6-ethyl / methyl / aminopurine
6-Ethyl (methyl) aminopurine was obtained by nucleophilic substitution of a chlorine group with 6-horrorpurine (Sigma Camels, St. Louis, Mo.) using 6-ethyl (methyl) amine in acetonitrile. 6-ethyl (methyl) aminopurine (2.8 mmol, 0.5 g) and uracil arabinoside (5.6 mmol, 1.38 g) were suspended in 575 ml of 10 mM potassium phosphate, 0.04% potassium azide solution , pH 7.4, containing 10% n-propanol (v / v). Purified uridine phosphorylase (6000 IU) and purine nucleoside phosphorylase (8400 IU) were added. (Krenitsky et al., Biochemistry, 20, p. 3615, 1981 and US patent N 4381444), and the solution was stirred at 37 ^o C. After nineteen days, the solution was filtered and the filtrate was chromatographed on a 2.5x13 cm column containing Dowex resin -1-hydroxide. The resin was eluted with 90% methanol / water (v / v). The fractions containing the product were combined and the solvent was removed in vacuo. The residue was dissolved in 30% n-propanol / water (v / v) and chromatographed on a BioRad P-2 column (7.5 x 90 cm). The product fractions were combined and, after lyophilization, 0.680 g of 6-ethyl (methyl) aminopuri-9-β-D-arabinofuranoside was obtained.

Analysis results: calculated for C ₁₃ H ₁₉ N ₅ O ₄ :
Calculated: C 50.48; H 6.19; N, 22.64
Found: C, 50.36; H 6.25; N, 22.52
NMR and mass spectra are consistent with such a structure.

 Example 11. 9-β-D-arabinofuranosyl-2-amino-6-methoxypurine.

2-amino-6-methoxypurine (obtained by nucleophilic substitution of a chlorine group with 2-amino-6-chloropurine (Sigma Chemicals, St. Louis, MR) using methanol with sodium hydride in tetrahydrofuran (6.4 mmol, 1, 05 g) was combined with a 35 ml solution of uracil arabinoside (7.04 mmol, 1.75 g) in 10 mM potassium phosphate and 7% n-propanol (v / v). The pH was adjusted to 6.75. purine nucleoside phosphorylase (18000 units) and uridine phosphorylase (1020 units), and the solution was incubated at a temperature of 37 ^o C. After 26 days, the reaction was filtered and the filtrate was subjected to chromatography aphii on a Duoex-1-formate resin column (2x7 cm) after adjusting the pH to 10.5 using concentrated ammonium hydroxide The column was eluted using a 7% n-propanol / water (v / v) mixture and fractions containing the product was combined and the solvent was removed in vacuo. The residue was extracted with 25 ml of water and the filtrate was separated from the solid material by centrifugation. The upper layer, after standing at ambient temperature, gave crystals of 2-amino-6-methoxy-9-β-D-arabinofuranoside, which gave after drying under vacuum 0.327 g of product .

Analysis results: calculated for C ₁₁ H ₁₅ N ₅ O ₅ :
Calculated: C 44.44; H 5.09; N, 23.56
Found: C, 44.49; H 5.13; N, 23.52
NMR and mass spectra confirmed this structure.

Example 12.9-β-D-arabinofuranosyl-6-n-propoxypurine
6-n-Propoxypurin (5.6 mmol, 1 g, Sigma Chemicals, St. Louis, Mo.) was combined with 545 ml of a solution of uracil arabinoside (10.1 mmol) in 10 mM potassium phosphate and 7% n-propanol (v / v). Purified uridine phosphorylase (680 IU) and purine nucleoside phosphorylase (12000 IU) were added, and the reaction was stirred at 35 ^° C. The reaction was filtered after 59 days and the filtrate was stored at 3 ^° C for 20 hours. The resulting precipitate was collected by centrifugation, dissolved in 30% n-propanol / water (v / v) and chromatographed on a Dowex-1-formate column (2.5x5 cm) after the pH was 10.5 sec. using a concentrated solution of ammonium hydroxide. The column was eluted with 30% n-propanol / water (v / v) and the fractions containing the product were combined and the solvent was removed in vacuo. The residue was dissolved in n-propanol and chromatographed on a column containing BioRad P-2 (5x90 cm). The column was eluted with 30% n-propanol / water (v / v). The product containing fractions were combined and, after removal of the solvent under vacuum, the residue was dissolved in water and chromatographed on a column containing BioRad P-2 (5x90 cm). The column was eluted with water. The product containing fractions were combined and, after lyophilization, 0.758 g of 6-n-propoxypurin-9-β-D-arabinofuranoside was obtained in the form of a monohydrate.

Analysis data: calculated for C ₁₃ H ₁₈ N ₄ O ₅ • 1.0 H ₂ O:
Calculated: C 47.56; H 6.14; N 17.06
Found: C, 47.63; H 6.13; N, 17.11
NMR and mass spectra are consistent with this structure.

 Example 13. 9- (5-O-benzoyl-β-D-arabinofuranosyl) -6-methoxy-9H-purine.

The 9- (β-D-arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (0.283 g, 1.0 mmol) was dissolved in anhydrous dimethylacetamide (5.0 ml), rapidly cooled to 4 ^° C. and benzoyl chloride was added. (0.155 g, 1.1 mmol). The mixture was stirred for 24 hours under argon, then allowed to slowly warm to room temperature. Then, an additional 1.1 equivalents of benzoyl chloride was added at room temperature and stirring was continued for another 24 hours. The reaction was quickly quenched by pouring on 50 ml ice-water, extracted with CHCI ₃ (3x30 ml) and the organic extracts dried (magnesium sulfate ) The evaporation residue was purified by flash chromatography on silica gel (25.0 g, 2.5 x 15 cm) with a successive gradient from CHCI ₃ to CHCI ₃ : acetone / 1: 1. Fractions containing product with R _f = 0.21 (silica gel , CHCl ₃ : acetone (1: 1)) were combined, whereby 92 mg of the target compound were obtained: melting point: 202-204 ^° C.

Analysis results: calculated for C ₁₈ H ₁₈ N ₄ O ₆ :
Calculated: C 55.96; H 4.70; N 14.50
Found: C, 56.04; H 4.74; N, 14.40
NMR and mass spectra confirm the above structure.

 Example 14 6-Methoxy-9- [5-0- (4-methylphenylsulfonyl) - β-D-arabinofuranosyl] -9H-purine.

4-Toluenesulfonyl chloride (0.312 g, 1.63 mmol) immediately after recrystallization and 9-β-D-arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (0.308 g, 1.09 mmol) were suspended in anhydrous acetonitrile (25 ml), cooled to 3 ^° C. in an ice bath, and pyridine (5.0 ml) was added to dissolve the nucleoside. The solution was stirred under argon at 3 ^° C. for 1 hour. Then it was kept at -15 ^° C. for 42 hours. The reaction was quickly stopped by the addition of 5% NaHCO ₃ (3 ml), evaporated to approximately 10 ml, then again evaporated with 95% ethanol. The residue was absorbed on a minimal amount of silica gel and added to the silica gel column for flash chromatography (25.0 g 2.5x15 cm) in CH ₂ Cl ₂ : MeOH (15: 1). As a result of elution with such a solvent (450 ml), then CH ₂ Cl ₂ : MeOH (10: 1, 550 ml) gave three UV-absorbing materials. Fractions containing material with R _f = 0.42 (silica gel, CH ₂ Cl ₂ : MeOH (10: 1) were collected and then purified on three consecutive silica gel plates for preparative chromatography, the first using CH ₂ Cl ₂ : MeOH (10: 1) and acetone: CH ₂ Cl ₂ (1: 1) on the following two plates to obtain 88 mg of the target material in the form of a transparent glass: melting point: 177-181 ^o C.

Analysis results: calculated for C ₁₈ H ₂₀ N ₄ O ₇ S • 0.15H ₂ O:
Calculated: C 49.23; H 4.66; N, 12.76
Found: C, 49.28; H 4.71; N, 12.71
NMR and mass spectra are consistent with such a structure.

 Example 15. 6-Methoxy-9- (5-0-methylsulfonyl-β-D-arabinofuranosyl) -9H-purine.

The 9-β-D-arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (0.600 g, 2.13 mmol) was suspended in dry acetonitrile (40 ml) and anhydrous pyridine (8 ml) was added. The flask was cooled to -3 ^° C in an ice-salt bath and methane sulfonyl chloride (0.16 ml, 2.13 mmol) was added. After 25 minutes, the solution was rapidly cooled with water (3 ml) and concentrated to a volume of 10 ml, then evaporated several times with several additions of ethanol, keeping the temperature in the region below 38 ^o C for the whole time. Residual pyridine was removed by vacuum pump. The residue was applied to a flash chromatography silica gel column (25.0 g, 2.5 x 15 cm), equilibrated in CH ₂ Cl ₂ : MeON (15: 1). This column was first eluted with 150 ml of this solvent, and then with CH ₂ Cl ₂ : MeOH (10: 1, 450 ml). Fractions containing material with R _f = 0.34 (silica gel, CH ₂ Cl ₂ : MeOH (10: 1) gave 0.448 g of product (57%) as a white foam: melting point: 177 - 181 ^o C (decomposition .).

Analysis results: calculated for C ₁₂ H ₁₆ N ₄ O ₇ Si • 0.5H ₂ O:
Calculated: C 39.02; H 4.64; N 15.17
Found: C, 39.02; H 4.66; N 15.08
NMR and mass spectra confirm this structure.

 Example 16. 9- [5-0- (4-Methylbenzoyl-β-D-arabinofuranosyl] -6-methoxy-9H-purine.

The 9- (β-D-arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (0.283 g, 1.0 mmol) was suspended in anhydrous acetonitrile (10.0 ml), pyridine (2.3 ml) was added to to obtain complete dissolution, then 4-methyl-benzoyl chloride (0.170 g, 1.1 mmol) was added. The mixture was stirred at room temperature for 24 hours under argon, the reaction was quickly stopped by the addition of isopropanol (5 ml) and evaporated to dryness, and then again evaporated with ethanol (2 x 20 ml). Next, the residue was purified using flash chromatography on silica gel (25.0 g 2.5 x 15 cm) using a sequential gradient from CHCl ₃ to CHCl ₃ : acetone, 1: 1. Fractions containing the product with R _f = 0.41 (silica gel, CHCl ₃ : acetone (1: 1)) were combined, whereby 132 mg of the target compound was obtained. Melting point: 127-128 ^o C.

Analysis results: calculated for C ₁₉ H ₂₀ N ₄ O ₆ • 0.5 H ₂ O:
Calculated: C 55.74; H 5.17; N 13.69
Found: C, 55.48; H 5.36; N 13.64
NMR and mass spectra confirmed the above structure.

Example 17. 9- [5-0- (4-Chlorobenzoyl) - β-D-arabinofuranosyl] -6-methoxy-9H-purine
9-β-D-Arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (0.283 g, 1.0 mmol) was suspended in anhydrous acetonitrile (10.0 ml), then pyridine (2.3 ml) was added to get complete dissolution, and 4-chloro-benzoyl chloride (0.193 g, 1.1 mmol). The mixture was stirred at room temperature for 24 hours under argon, the reaction was quickly stopped by the addition of isopropanol (5 ml) and evaporated to dryness, then evaporated again with ethanol (2x10 ml). The residue was further purified by flash chromatography on silica gel (25.0 g, 2.5 x 15 cm) using a sequential gradient of CHCl ₃ to CHCl ₃ : acetone (1: 1). Fractions containing the product with R _f = 0.37 (silica gel, CHCl ₃ : acetone (1: 1)) were combined, whereby 105 mg of the target compound was obtained: melting point: 122-124 ^° C.

Analysis results: calculated for C ₁₈ H ₁₇ ClN ₄ O ₆ • 0.5 H ₂ O;
Calculated: C, 50.30; H 4.22; N 13.04
Found: C, 50.20; H 4.28; N, 12.94.

 NMR and mass spectra confirmed the above structure.

Example 18. 9- [5-0- (4-methoxybenzoyl) - β - D-arabinofuranosyl] -6-methoxy-9H-purine
The 9- (β-D-arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (0.283 g, 1.0 mmol) was suspended in anhydrous acetonitrile (10.0 ml), pyridine (2.3 ml) was added to complete dissolution, then 4-methoxybenzoyl chloride (1.1 mmol) was added. The mixture was stirred at room temperature for 24 hours under argon and the reaction was quickly stopped by the addition of isopropanol (5 ml) and evaporated to dryness, then evaporated again with ethanol (2x10 ml). The residue was then purified using flash chromatography on silica gel (25.0 g, 2.5 x 15 cm) using serial from CHCl ₃ to CHCl ₃ : acetone (1: 1). Fractions containing the product with R _f = 0.30 (silica gel, CHCl ₃ : acetone (1: 1)) were combined to obtain 110 mg of the target compound: melting point: 195-197 ^o C.

Analysis results: calculated for C ₁₉ H ₂₀ N ₄ O ₇ • 0.25 H ₂ O.

Calculated: C, 52.22; H 4.91; N 13.31
Found: C, 54.22; H 4.94; N 13.30
NMR and mass spectra were consistent with such a structure.

Example 19. 6-methoxy-9- (5-0-phenylacetal-β - D-arabinofuranosyl) -9H-purine
The 9- (β-D-arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (0.300 g, 1.06 mmol) was suspended in acetonitrile (25 ml), then anhydrous pyridine (5 ml) was added. The solution was cooled to 3 ^° C. in an ice bath and phenyl acetate chloride (0.20 ml, 1.5 mmol) was added. After stirring at 3 ^° C for one hour, the solution was cooled to -15 ^° C and held at this temperature for 40 hours. The reaction was quickly stopped by the addition of 5% NaHCO ₃ (3 ml), concentrated to 10 ml, and then evaporated at adding several times ethanol. The residue was taken up in a mixture of CH ₂ Cl ₂ : MeOH (15: 1) and applied to a flash chromatography silica gel column (25.0 g, 2.5 x 15 cm) located in the same solvent, 500 ml of the same solvent was eluted, then with a mixture (15: 1) CH ₂ Cl ₂ : methanol (15: 1, 500 ml). Fractions with R _f = 0.38 (silica gel, 10: 1, CH ₂ Cl ₂ : methanol) gave 0.128 g of crude product with impurities having higher R _f . As a result of subsequent purification by preparative thin layer chromatography using CH ₂ Cl ₂ : MeOH (10: 1), and then using a second plate using a mixture of acetone: CH ₂ Cl ₂ (1: 1), 0.102 g of the expected product is obtained in the form white foam: melting point: 74-75 ^o C.

Analysis results: calculated for C ₁₉ H ₂₀ N ₄ O ₆ • 0.1 H ₂ O;
Calculated: C 56.74; H 5.06; N 13.93
Found: C, 56.74; H 5.11; N 13.90
NMR and mass spectra are consistent with the above structure.

Example 20. 6-methoxy-9- (5-O-phenyloxyacetyl-β-D-arabinofuranosyl) -9H-purine
The 9- (β-D-arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (0.322 g, 1.14 mmol) was suspended in dry acetonitrile (25 ml), then anhydrous pyridine (5 ml) was added. The solution was cooled to 3 ^° C. in an ice bath and phenoxyacetyl chloride (0.24 ml, 1.7 mmol) was added. After stirring for two hours at a temperature of 3 ^° C., the reaction was quickly terminated with a 5% NaHCO ₃ solution (2 ml), concentrated to a volume of 10 ml and evaporated after several additions of ethanol. The residue was subjected to flash chromatography on silica gel (25.0 g, 2.5 x 15 cm) in a mixture of CH ₂ Cl ₂ : methanol (15: 1). Elution with 400 ml of this solvent followed by 10: 1 CH ₂ Cl ₂ : methanol (500 ml) and 9: 1 CH ₂ Cl ₂ : methanol (200 ml) gave 0.213 g of crude product. This material was subjected to recrystallization from methanol, after which 0.101 g (20%) of a white crystalline material was obtained: melting point 193 - 195 ^° C.

Analysis results: calculated for C ₁₉ H ₂₀ H ₄ O ₇ • 0.05 H ₂ O.

Calculated: C 54.69; H 4.85; N 13.43
Found: C, 54.69; H 4.89; N 13.40
NMR and mass spectra are confirmed by the above structure.

Example 21. 6-methoxy-9- (5-O-phenyloxyacetyl-β-D-arabinofuranosyl) -9H-purine
The 9- (β-D-arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (0.300 g, 1.06 mmol) was suspended in acetonitrile (25 ml), and then anhydrous pyridine (5 ml) was added. The solution was cooled to -3 ^° C in an ice-salt bath and methoxyacetyl chloride (0.10 ml, 1.1 mmol) was added. After stirring in an ice-salt bath for two hours, the reaction was stopped with 5% NaHCO ₃ (2 ml), the volume was concentrated to 10 ml, and then evaporated after several additions of ethanol. The residue was applied to silica gel column for operational chromatography (25.0 g, 2.5 x 15 cm) contained in a 10: 1 mixture of CH ₂ Cl ₂ : MeOH. As a result of elution with 500 ml of this solvent, then with a 9: 1 mixture of CH ₂ Cl ₂ : MeOH (300 ml), 0.086 g of crude product was obtained. This material was subjected to recrystallization from MeOH and water, after which 0.035 g (9.3%) of white crystals were obtained: melting point: 137 - 139 ^° C.

Analysis results: calculated for C ₁₄ H ₁₈ H ₄ O ₇ • 0.5 H ₂ O.

Calculated: C 46.28; H 5.27; N, 15.42
Found: C, 46.33; H 5.27; N 15.37
NMR and mass spectra are confirmed by the above structure.

Example 22.9- [5-O- (4-Nitrobenzoyl) - β-D-arabinofuranosyl] -6-methoxy-9H-purine
The 9- (β-D-arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (0.283 g, 1.0 mmol) was suspended in anhydrous acetonitrile (10.0 ml), pyridine (2.3 ml) was added to complete dissolution, then 4-nitro-benzoyl chloride (0.205 g, 1.1 mmol). The mixture was stirred at room temperature for 24 hours under argon, the reaction was quickly terminated by the addition of isopropanol (5 ml) and evaporated to dryness, then evaporated two more times with ethanol (2 x 10 ml). The residue was then purified by flash chromatography on silica gel (25.0 g, 2.5 x 15 cm) and a sequential gradient of CHCl ₃ to CHCl ₃ : acetone (1: 1). Fractions containing the product with R _f = 0.37 (silica gel, CHCl ₃ : acetone (1: 1)) were combined, resulting in 105 mg of the target compound, melting point 202 - 203 ^o C.

Analysis results: calculated for C ₁₈ H ₁₇ H ₅ O ₈ ;
Calculated: C, 50.12; H 3.97; N, 16.24
Found: C, 50.21; H 4.02; N, 16.16
NMR and mass spectra confirm the above structure.

Example 23. 6-Methoxy-9- (5-O-pentanoyl-β-D-arabinofuranosyl) -9H-purine
The 9- (β-D-arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (0.852 g, 3.01 mmol) was suspended in dry acetonitrile (75 ml) and dry pyridine (15 ml) was added. The solution was cooled in an ice / water bath and pentanoyl chloride (0.4 ml, 3.31 mmol) was added. The reaction was quickly stopped after two hours by the addition of 3 ml of methanol and evaporated to a clear viscous oil. The residue was purified using flash chromatography on silica gel and a sequential gradient of CHCl ₃ to CHCl ₃ : MeOH (9: 1). The product with a yield of 330 mg contained impurities of the corresponding 2'-ester (see Example 32) and unknown material with a lower R _f . The residue is then purified by reverse phase preparative liquid chromatography (high performance) (HPLC) (Alltech C ₁₈ , 10 mm x 25 mm, part size 10 μm 70% H ₂ O: 30% CH ₃ CN, 4.0 ml / min), preparing a solution of 10 mg / ml in the same solvent with an injection volume of 1.0 ml. The residue was again evaporated with acetone, resulting in 260 mg of a white brittle foam (24%): melting point: 85 - 95 ^o C.

Analysis results: calculated for C ₁₆ H ₂₂ H ₄ O ₆ • 0.05 (CH ₃ ) ₂ CO • 0.55 H ₂ O:
Calculated: C 51.16; H 6.22; N 14.78
Found: C, 50.98; H 6.03; N, 14.63
NMR and mass spectra confirm the above structure.

Example 24. 9- [5-O- (4-Aminobenzoyl-β-D-arabinofuranosyl)] - 6-methoxy-9H-purine
9- [5-O- (4-Nitrobenzoyl) - β-D-arabinofuranosyl] -6-methoxy-9H-purine from Example 22 (0.350 g, 0.81 mmol) was suspended in ethanol (100.0 ml) and added 10% palladium on carbon (0.100 ml). After alternately pumping and filling the system with hydrogen, the reaction was shaken at a Parr installation under a pressure of 50 psi (3.515 kg / cm ² ) for three hours. The mixture was then filtered through Celite and the filtrate was evaporated to dryness. The evaporation residue was suspended in methanol and filtered to obtain the target compound as a white solid (0.285 g, 88%): melting point: 198-200 ^° C.

Analysis results: calculated for C ₁₈ H ₁₉ H ₅ O ₆ • 0.3 H ₂ O:
Calculated: C 53.15; H 4.86; N, 17.22
Found: C, 52.96; H 4.64; N 17.07
NMR and mass spectra confirm the above structure.

Example 25. 6-Methoxy-9- (5-O-propionyl-β-D-arabinofuranosyl) -9H-purine
The 9- (β-D-Arabinofuranosyl) -6-methoxy-9H-purine from Example 22 (0.847 g, 3.0 mmol) was suspended in anhydrous acetonitrile (30.0 ml) and pyridine (9 ml) was added to effect complete dissolution. After cooling to 5 ^° C., propionyl chloride (0.305 g 3.3 mmol) was added and the mixture was stirred overnight under argon while heating to 13 ^° C. After termination of the reaction with isopropanol (5 ml) and evaporation to dryness, additional evaporation with ethanol (2 • 10 ml), the residue was purified using flash chromatography on silica gel (25.0 g, 2.5 • 15 cm) and a successive gradient from ChCl ₃ to CHCl ₃ : acetone (1: 1). Fractions containing the product with R _f = 0.38 (silica gel, CHCl ₃ : acetone (1: 1) were combined and this material was again purified using silica gel chromatography under medium pressure (tandem columns, 1.5 • 25.0 cm and 1.5 • 100.0 cm; CHCl ₃ : acetone (3: 1), resulting in 0.114 g of the target compound as a white solid: melting point: 62-64 ^o C.

Analysis results: calculated for C ₁₄ H ₁₈ N ₄ O ₆ • 0.5 CH ₃ OH:
Calculated: C, 50.68; H 5.76; N, 15.25
Found: C, 50.72; H 5.80; N, 15.28
NMR and mass spectra confirm the above structure.

Example 26. 9- (5-0-Butanoyl-β-D-arabinofuranosyl) -6-methoxy-9H-purine
The 9-β-D-Arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (0.874 g, 3.0 mmol) was suspended in anhydrous acetonitrile (30.0 ml) and pyridine (9.0 ml) was added to effect complete dissolution. After cooling to 5 ^° C., butyryl chloride (0.352 g, 3.3 mmol) was added and the mixture was stirred overnight under argon while heating to 13 ^° C. After termination of the reaction with isopropanol (5 ml) and evaporation to dryness, subsequent evaporation with ethanol (2 • 10 ml), the residue was purified using flash chromatography on silica gel (25.0 g, 2.5 • 15 cm) and a successive gradient from CHCl ₃ to CHCl ₃ : acetone (1: 1). The fractions containing the product with R _f = 0.38 (silica gel, CHCl ₃ : acetone (1: 1) were combined. This material was purified again using chromatography under medium pressure on silica gel (tandem columns, 1.5 • 25, 0 cm and 1.5 • 100.0 cm; CHCl ₃ : acetone (2: 1), whereby 267 mg of the target compound was obtained as a white solid: melting point 108-110 ^o C.

Analysis results for C ₁₅ H ₂₀ N ₄ O ₆ :
Calculated: C 51.13; H 5.72; N 15.90
Found: C, 51.21; H 5.73; N, 15.81
NMR and mass spectrum confirmed the indicated structure.

 Example 27

9- [5-0- (2,2-Dimethylpropionyl) - β-D-arabinofuranosyl] -6-methoxy-9H-purine
The 9- (β-D-arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (0.850 g, 3.01 mmol) was suspended in dry acetonitrile (75 ml) and pyridine (15 ml) was added. The solution was cooled to 3 ^° C. in an ice bath and 2,2-dimethyl propionyl chloride (0.41 ml, 3.3 mmol) was added. After stirring at 3 ^° C. for six hours, the reaction was quickly stopped using MeOH (2 ml), concentrated to a volume of 10 ml, and then evaporated several times after several additions of ethanol. The residue was applied to a flash chromatography column on silica gel (20.0 g, 2.5 x 12.0 cm) placed in CH ₂ Cl ₂ : MeOH (10: 1). Elution with 300 ml of this solvent gave 0.464 g of starting material and 0.553 g of crude product. As a result of another purification using operational chromatography (silica, 2.5 • 10.0 cm), eluting with a gradient from CH ₂ Cl ₂ to MeOH in CH ₂ Cl ₂ (1: 9), 0.419 g (38%) was obtained clear glass: melting point: 73-76 ^o C.

Analysis results for C ₁₆ H ₂₂ N ₄ O ₆ • 0.5 H ₂ O.

Calculated: C 51.19; H 6.18; N 14.93
Found: C, 51.43; H 6.06; N 14.91
NMR and mass spectrum are consistent with the above structure.

Example 28. 9- (5-0-Acetyl-β-D-arabinofuranosyl) -6-methoxy-9H-purine
9- (β-D-arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (0.850 g, 3.01 mmol) was suspended in dry acetonitrile (75 ml), then anhydrous pyridine (15 ml) was added. The solution was cooled to 3 ^° C. in an ice bath and acetyl chloride (0.24 ml, 3.4 mmol) was added. After stirring in an ice / salt bath for half an hour, the reaction was interrupted with methanol (2 ml), concentrated to a volume of 10 ml, then evaporated several times after several additions of ethanol. The residue was purified using flash chromatography on silica gel (25.0 g, 2.5 x 15 cm), eluting with a mixture of CH ₂ Cl ₂ : MeOH (10: 1, 300 ml) to give 0.710 g of crude product. The second column (25.0 g, 2.5 • 15 cm) after elution with a mixture of CH ₂ Cl ₂ : MeOH (15: 1) gave 0.610 g of clear glass, which nevertheless contained a small amount of impurities with higher R _f . Subsequent purification of the product using preparative thin layer chromatography using CH ₂ Cl ₂ : MeOH (9: 1), then by loading flat layers onto a flash chromatography column (20.0 g, 2.5 x 12 cm) in CH ₂ Cl ₂ , the desired product was obtained in the form of a white foam (0.308 g, 31%): melting point: 64-67 ^° C.

Analysis results for C ₁₃ H ₁₆ N ₄ O ₆ • 0.5 H ₂ O:
Calculated: C 46.85; H 5.14; N 16.81
Found: C, 47.04; H 5.12; N 16.72
NMR and mass spectra were in agreement with the structure.

 Example 29 6-Methoxy-9 [5-O- (2-methylpropionyl) - β-D-arabinofuranosyl] -9H-purine.

The 9- (β-D-arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (0.500 g, 1.77 mmol) was suspended in dry acetonitrile (25 ml), anhydrous pyridine (5 ml) was added. The solution was cooled to 3 ^° C. in an ice bath and isobutyryl chloride (0.21 ml, 2.0 mmol) was added. After stirring at 3 ^° C. for three hours, the reaction was quickly terminated with MeOH (2 ml), concentrated to a volume of 10 ml, and then evaporated several times after several additions of ethanol. The residue was applied to a flash chromatography column on silica gel (25.0 g, 2.5 x 15 cm) placed in CH ₂ Cl ₂ : MeOH (10: 1). After elution with 300 ml of this solvent, 0.167 g of starting material and 0.221 g of crude product were obtained. As a result of subsequent purification using preparative current-layer chromatography with CH ₂ Cl ₂ : MeOH (9: 1), subsequent loading of flat layers onto a column for operational chromatography on silica gel (16.0 g, 2.5 • 10 cm), placed in CH ₂ Cl ₂ , the column was eluted with a gradient of MeOH in CH ₂ Cl ₂ , whereby 0.127 g of clear glass (20%) was obtained: melting point 68-71 ^° C.

Analysis results: for C ₁₅ H ₂₀ N ₄ O ₆ • 0.25 H ₁ O: 0.05 MeOH.

Calculated: C, 50.43; H 5.82; N 15.63
Found: C, 50.49; H 5.83; N 15.62
NMR mass spectra confirmed the indicated structure.

 Example 30. 6-Methoxy-9- [2-0- (2,2-dimethylpropionyl) - β-D-arabinofuranosyl] -9H-purine.

9- (β-D-arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (298.5 mg, 1.06 mmol), 4-dimethylaminopyridine (1 mg, 10 μmol), acetonitrile (20 ml) and pyridine (5 ml) was added to a three-neck round-bottom flask equipped with a thermometer, an argon supply valve, a magnetic stirrer, a refrigerator and a jacket. Trimethylacetic anhydride (0.22 ml, 1.06 mmol) was added and the solution was heated to a temperature of 40 ^° C. for 26 hours. The reaction was quickly stopped at that time by adding 2 ml of water and evaporated to a clear oil. The residue was purified by flash chromatography on silica gel using a gradient sequence from CHCl ₃ to CHCl ₃ : MeOH (9: 1). This material was further purified using preparative thin layer chromatography and CHCl ₃ : MeOH (9: 1), and then evaporated with carbon trichloride and acetone, whereby 90 ml of a white brittle foam was obtained.

Analysis results for C ₁₆ H ₂₂ N ₄ O ₆ • 0.05 (CH ₃ ) ₂ CO - 0.45 CCl ₄ .

Calculated: C 45.47; H 5.13; N, 12.78
Found: C, 45.67; H 5.27; N, 12.67
NMR and mass spectra confirm the above structure
Example 31. 6-Methoxy-9- [2,3,5-tri-O-acetyl) - β-D-arabinofuranosyl] -9H-purine.

9- (β-D-arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (1.009 g, 3.57 mmol), 4-mimethylaminopyridine (0.0098 g, 80 μmol), triethylamine (0.59 ml, 4.2 mmol) and anhydrous acetonitrile (52 ml) were added to a three-neck round-bottom flask equipped with a thermometer, argon inlet, magnetic stir bar and dry ice / acetone bath. After the white solution was cooled to a temperature of −20 ^° C., acetic anhydride (2.5 ml, 25.4 mmol) was added. The solution instantly became transparent. After 5 min, the reaction was stopped by the addition of MeOH (5 ml) and evaporated to a clear viscous oil. As a result of processing using flash chromatography on silica gel with a gradient of CHCl ₃ and MeOH, the product was obtained as a clear, viscous oil. By dissolving this material in a minimum amount of acetone, diluting with water and lyophilization, 1.03 g (71%) of the product was isolated in the form of a white powder.

Analysis results for C ₁₇ H ₂₀ N ₄ O ₈ :
Calculated: C 50.00; H 4.94; N 13.72
Found: C, 49.80; H 5.09; N 13.50
NMR and mass spectra confirmed the above structure.

Example 32. 6-Methoxy-9- (2-0-pentanoyl-β-D-arabinofuranosyl] -9H-purine
Method 1

9- (β-D-arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (283 mg, 1.0 mmol), acetonitrile (20 ml) and pyridine (5 ml) were added to a round-necked three-necked flask equipped with thermometer, argon valve and magnetic stirrer. Valerian anhydride (0.2 ml, 1.0 mmol) was added and the solution was stirred at 20 ^° C. for three hours. The reaction was quickly terminated with water (2 ml) and evaporated to a clear oil, then purified using flash chromatography on silica and a gradient sequence from CHCl ₃ to CHCl ₃ : MeOH (9: 1). The result was 110 kg of 2'-ester with impurities of 5'-ester (see Example 23), material with a lower R _f . This material was further purified by preparative thin-layer chromatography on silica with CHCl ₃ : MeOH (9: 1) and coevaporation with acetone, whereby 70 mg of 2'-ester was obtained in the form of a clear glass.

Analysis results for C ₁₆ H ₂₂ N ₄ O ₆ • 0.5 (CH ₃ ) ₂ CO.

Calculated: C 53.16; H 6.37; N 14.17
Found: C, 52.89; H 6.37; N 13.96
NMR and mass spectra are consistent with this structure.

 Method 2

5-Methoxy-9- [3,5-0- (1,1,3,3-tetraisopropyldisiloxane-1,3-diyl) - β-D-arabinofuranosyl] -9H-purine from Example 40 (2.5 g, 4.8 mmol) was added to a 250 ml round-bottom flask along with 4-dimethylaminopyridine (0.06 g, 0.47 mmol). Dry acetonitrile (30 ml) and triethylamine (2.65 ml) were added, and acetonitrile (20 ml) and pentanoic anhydride (1.13 ml, 5.7 mmol) were charged through a funnel for continuous supply. The reaction mixture was cooled to 3 ^° C. in an ice bath under an argon stream. The pentanoic anhydride solution was slowly added over 2 hours. Then the reaction mixture was treated with methanol (10 ml), concentrated under reduced pressure. The residue was taken up in CHCl ₃ (200 ml) and extracted with water (2 x 50 ml). The combined aqueous layers were again extracted with CHCl ₃ (25 ml) and the combined organic layers were dried (magnesium sulfate), filtered and concentrated to give 3.44 g of crude product.

The crude 6-methoxy-9- [2-0-pentanoyl-3,5-O- (1,1,3,3-tetraisopropyl disiloxane-1,3-diyl) - β-D-arabinofuranosyl] -9H-purine was dissolved in tetrahydrofuran (120 ml) and water (3 ml). The solution was cooled to 3 ^° C in an ice bath and a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (6.0 ml) was added. After 1.5 hours, a saturated solution of ammonium chloride (2 ml) was added and the reaction mixture was directly passed to a silica gel purification column (5.0 x 8.0 cm) in chloroform. The column was eluted with chloroform (200 ml), then with a 1: 1 mixture of acetone: chloroform (400 ml) and all fractions containing the product were combined and concentrated. Final purification was carried out on a flash chromatography column on silica gel (5.0 x 15 cm), eluting with a successive gradient of acetone in CHCl ₃ , whereby 1.17 g (67%) of a clear, sticky glass with pentanoic acid impurities was obtained:
Analysis results for C ₁₆ H ₂₂ N ₄ O ₆ • 0.2 C ₅ H ₁₀ O ₂ .

Calculated: C 52.79; H 6.25; N, 14.48
Found: C, 52.97; H 6.38; N 14.60
Example 33. 9- (2-O-Butanoyl-β-D-arabinofuranosyl) -6-methoxy-9H-purine
9- (β-D-arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (283 mg, 1.0 mmol), acetonitrile (20 ml) and dry pyridine (5 ml) were added to a three-neck round-bottom flask, equipped with a thermometer, an argon inlet, a magnetic stirrer, and cooled to a temperature of 4 ^° C. Oil anhydride (170 L, 1.0 mmol) was added and the solution was stirred at 5 ^° C for 6 hours in an argon atmosphere. To this element, the reaction was stopped by adding 2 ml of water and evaporated to a clear oil. The reaction mixture was purified by flash chromatography using a sequential gradient of CHCl ₃ to 1: 1 CHCl ₃ : acetone. This material was further purified by preparative thin-layer chromatography on silica gel using a 9: 1 mixture of CHCl ₃ : MeOH to give 90 mg of 2'-ester as a clear oil.

Analysis results for C ₁₅ H ₂₀ H ₄ O ₆ • 0.3 H ₂ O:
Calculated: C 50.36; H 5.80; N 15.66
Found: C, 50.36; H 5.81; N 15.66
NMR and mass spectra corresponded to the above structure.

 Example 34. 6-Methoxy-9- [2-O- (2-methylpropionyl) - β-D-arabinofuranosyl] -9H-purine.

9- (β-D-arabinofuranosyl] -9H-purine from Example 3 (290.0 mg, 1.03 mmol), acetonitrile (20 ml) and pyridine (5 ml) were added to a round-necked three-necked flask equipped with a thermometer, with argon inlet, a magnetic stirrer, a refrigerator, and a jacket, isobutyric anhydride (170 L, 1.0 mmol) was added, and the solution was heated with a jacket to a temperature of 30 ^° C for four hours. The residue was purified by flash chromatography on silica gel using successively minute gradient from CHCl ₃ to CHCl _3: MeOH (9: 1). The fractions containing product with R _f = 0,54 (silica gel, CHCl _3: MeOH, 20: 1) and further purified by preparative thin layer chromatography on silica gel with CHCl ₃ : MeOH (9: 1), 90.0 mg of 2'-ester was obtained as a clear glass.

Analysis results for C ₁₅ H ₂₀ N ₄ O ₆ • 0.1 C ₃ H ₆ O.

Calculated: C 51.31; H 5.80; N 15.64
Found: C, 51.41; H 5.81; N, 15.72
NMR and mass spectra confirmed the above structure.

 Example 35. 9- (3-O-Benzoyl-β-D-arabinofuranosyl) -6-methoxy-9H-purine.

9- (2,3-Anhydro-β-D-lycosphuranosyl) -6-methoxy-9H-purine (for preparation see Example 36) (0.264 g, 1.0 mmol) was dissolved in anhydrous ethanol (20.0 ml ), heated to reflux, and ammonium benzoate (0.209 g, 1.5 mmol) was added in an argon atmosphere. An additional 1.5 mmol of ammonium benzoate was added after 24 and 35 hours. The reaction was evaporated to dryness after 48 hours with reflux. The evaporation residue was purified using flash chromatography on silica gel (25.0 g, 21.5 x 15 cm) and a mixture of CHCl ₃ : acetone (3: 1). Fractions containing the product with R _f = 0.52 (silica gel, CHCl ₃ : acetone (1: 1) were combined, resulting in 138 mg of the target compound. Melting point: 180 - 182 ^o C.

Analysis results for C ₁₈ H ₁₈ N ₄ O ₆ :
Calculated: C 55.96; H 4.70; N 14.50
Found: C, 55.90; H 4.71; N, 14.44
NMR and mass spectra confirmed the above structure.

 Example 36. 9- (2,3-Anhydro-β-D-lixofuranosyl) -6-methoxypurine.

Triphenylphosphine (5.902 g, 22.5 mmol) was dissolved in 1,4-dioxane (138 ml) and heated to a temperature of 70 ^° C. 9- (β-D-arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (4.234 g, 15.0 mmol), the mixture was stirred for 10 minutes and diethyl azodicarboxylate (3.919 g, 22.5 mmol) in 1,4-dioxane (50 ml) was added dropwise over 10 minutes. The reaction was stirred at a temperature of 70 ^o C for 1 h, cooled to room temperature and evaporated to a highly viscous brown oil. This material was purified by flash chromatography on silica gel (188.0 g, 5.0 x 21.0 cm), eluting with a mixture of CHCl ₃ : acetone (5: 1, 3.6 L) and CHCl ₃ : acetone (3: 1 2.0 L). Fractions containing material with R _f = 0.24 (silica, CHCl ₃ : acetone, 1: 1) were combined and evaporated to dryness. The residue was further purified using flash chromatography on silica (250.0 g, 6.0 • 28.0 cm), eluting with E OAc to give 2.452 g (62%) of the target compound as a white foam: temperature melting point 144 - 145.5 ^o C.

Analysis results for C ₁₁ H ₁₂ H ₄ O ₄ • 0.25 H ₃ H ₆ O • 0.05 CHCl ₃ :
Calculated: C 49.78; H 4.80; N, 19.68
Found: C, 49.80; H 4.95; N 19.87
NMR and mass spectra confirmed the indicated structure.

 Example 37. 6-Methoxy-9 - [(2-O- (4-methoxybenzoyl)) - β-D-arabinofuranosyl] -9H-purine.

6-Methoxy-9- [2- (4-methoxybenzoyl) -3,5-O- (1,1,3,3-tetraisopropyldisiloxane-1,3-diyl) - β-D-arabinofuranosyl] -9H-purine ( for the preparation see Example 43 below) (0.86 g, 1.3 mmol) was dissolved in THF (40 ml) and water (1 ml) was added. The solution was cooled to 3 ^° C. and a 1.0 M solution of tetrabutylammonium fluoride in THF (6.3 ml) was added. After 30 minutes, an additional 5 ml of water was added, the reaction was reduced by half, and passed directly through a flash chromatography silica gel column (25.0 g, 2.5 x 15 cm) located in CH ₂ Cl ₂ . The column was eluted with CH ₂ Cl ₂ (200 ml), then with a mixture of CH ₂ Cl ₂ : MeOH (20: 1, 400 ml) and all fractions containing material with R _f = 0.20 / silica gel, CH ₂ Cl ₂ : MeOH / 20: 1 //, were combined, whereby 0.570 g of a white foam was obtained. Final purification was carried out on a column for operational chromatography on silica gel / 5.0 • 15 cm /, located in CHCl ₃ . After elution with a successive gradient of acetone in chloroform, 0.325 g (60%) of the product was obtained as a white foam: melting point 71–75 ^° C.

Analysis results calculated for C ₁₉ H ₂₀ H ₄ O ₇ • 0.3 CHCl ₃ • 0.25 C ₃ H ₆ O:
Calculated: C 51.60; H 4.71; N 12.00
Found: C, 51.56; H 4.70; N 11.95
NMR and mass spectra of agreement with the indicated structure.

 Example 38. 6-Methoxy-9 - [(2-O- (4-methylbenzoyl)) - β-D-arabinofuranosyl] -9H-purine.

6-Methoxy-9 - [(2-O- (4-methylbenzyl) -3,5-O- (1,1,3,3-tetraisopropyl disiloxane-1,3-diyl) - β-D-arabinofuranosyl] - 9H-purine (for preparation see Example 42) (0.85 g, 1.3 mmol) was dissolved in THF (40 ml) and water (1 ml). The solution was cooled to 3 ^° C. and a 1.0 M solution was added. tetrabutylammonium fluoride in THF (5.0 ml) An additional 5 ml of water was added after 30 min, the reaction volume was reduced by half and passed directly through a flash chromatography silica gel column (20.0 g, 2.5 x 12 cm) in CH ₂ Cl _2. The column was eluted with CH ₂ Cl ₂ (200 mL), then mixtures th CH ₂ Cl _2: MeOH (15: 1, 400ml) and all fractions containing material with R _f = 0,20 (silica, CH ₂ Cl _2: MeOH (20: 1)) were combined crude product was applied. onto a second flash chromatography silica gel column (25.0 g, 2.5 x 18 cm) in acetone: CH ₂ Cl ₂ (1: 1), eluting with the same solvent, 0.633 g of product was obtained, which was then subjected to purification using preparative thin layer chromatography (silica, acetone: CH ₂ Cl ₂ (1: 1)) and operational chromatography (25.0 g, 2.5 • 15 cm). The column was eluted with a sequence of acetone gradients in CHCl ₃ , whereby 0.243 g (47%) of clear glass was obtained: melting point 69 - 73 ^° C.

Analysis results calculated for C ₁₉ H ₂₀ N ₄ O ₆ • 0.4 CH ₃ H ₆ O • 0.25 CHCl ₃ :
Calculated: C 54.17; H 5.03; N, 12.36
Found: C, 54.00; H 5.08; N, 12.30
NMR and mass spectrum confirmed the above structure.

 Example 39. 9- [2-O- (4-Chlorobenzoyl) - β-D-arabinofuranosyl] -6-methoxy-9H-purine.

9- [2- (4-chlorobenzoyl) -3,5-O- (1,1,3,3-tetraisopropyldisiloxane-1,3-diyl) - β-D-arabinofuranosyl] -6-methoxy-9H-purine ( for the preparation see Example 44 below) (1.07 g, 1.7 mmol) was dissolved in THF (40 ml) and water (1 ml). The solution was cooled to 3 ^° C. and a 1.0 M solution of tetrabutyl ammonium fluoride in THF (5.0 ml) was added. After 30 minutes, another 5 ml of water was added and the reaction mixture was passed directly through a flash chromatography silica gel column (20.0 g, 2.5 x 12 cm) located in CH ₂ Cl ₂ . This column was eluted with CH ₂ Cl ₂ (200 ml), then with a mixture of CH ₂ Cl ₂ : MeOH (20: 1, 400 ml) and all fractions containing material with R _f = 0.20 (silica, CH ₂ Cl ₂ : MeOH (20: 1)), combined. The crude product was applied to a flash chromatography silica gel column (30.0 g, 2.5 x 18 cm) located in acetone: CHCl ₃ (1: 1). After elution with the same solvent, 0.269 g of product was obtained, which was further purified using preparative thin layer chromatography (silica, acetone: CHCl ₃ (2: 3)) and flash chromatography (25.0 g, 2.5 x 15 cm). The column was eluted with a sequence of acetone gradients in CHCl ₃ . An analytical sample was obtained by transferring the product to anhydrous ether and precipitating with petroleum ether (40-60 ^° C) and lyophilizing the precipitate, whereby 0.082 g (12%) of white powder was obtained: melting point: 76 - 81 ^° C.

The results of the analysis calculated for C ₁₈ H ₁₇ N ₄ O ₆ Cl • 1.20 H ₂ O • 0.35 C ₃ H ₆ O:
Calculated: C 49.45; H 4.68; N, 12.11
Found: C, 49.78; H 4.38; N 11.88
NMR and mass spectra confirm the above structure.

Example 40 6-Methoxy-9- [3,5-O- (1,2,3,3-tetraisopropyl-1,3-disiloxane-1,3-diyl) - β-D-arabinofuranosyl] -9H-purine
9- (β-D-arabinofuranosyl) -6-methoxy-9-H-purine from Example 3 (1.0 g, 3.54 mmol) and imidazole (0.965 g, 14.2 mmol) were dissolved in dry dimethylformamide (10 ml) and the solution was cooled to a temperature of 3 ^° C. Then, 1,3-dichloro-1,1,3,3-tetraisopropyl disiloxane (1.35 ml, 3.90 mmol) was added and the mixture was stirred under argon for three hours . Then the reaction was stopped by adding water (1 ml) and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (150 ml) and water (50 ml), and the ethyl acetate layer was dried (ammonium sulfate), filtered and concentrated. The crude product was transferred into ethyl acetate and purified by flash chromatography on silica gel (25.0 g, 2.5 x 15 cm) in ethyl acetate. From the fraction with R _f = 0.70 (silica, ethyl acetate), 1.48 g (80%) of the expected material are obtained in the form of a white solid.

UV _max : EtOH: 248.4 nm.

 NMR and mass spectra confirmed the above structure.

 Example 41. 6-Methoxy-9- [2-O- (2-aminobenzoyl) - β-D-arabinofuranosyl] -9H-purine.

9- (β-D-arabinofuranosyl) -6-methoxy-9H-purine from Example 3 (0.283 g, 1.0 mmol), acetonitrile (15 ml), n-carboxyanthranyl anhydride (0.189 g, 1.1 mmol) and sodium bicarbonate (84 mg, 1.0 mmol) was added to a three-necked round-bottomed flask equipped with a thermometer, an argon inlet, a magnetic stirrer, a refrigerator and a heating jacket. The suspension was refluxed for 3.5 hours, and then a second equivalent of p-carboxyanthranilic anhydride was added. After refluxing for another one hour, the reaction was cooled to room temperature, filtered and the filtrate was evaporated to a foamy glass. The residue was purified using flash chromatography on silica gel and a successive gradient of CHCl ₃ to 9: 1 mixture of CHCl ₃ : MeOH. The result was 53.1 mg of complex 2'-ester in the form of brittle glass: the temperature of the melting point 91-93 ^o C.

Analysis results calculated for C ₁₈ H ₁₉ N ₅ O ₅ • 0.3 H ₂ O • 0.2 CH ₄ O:
Calculated: C 52.90; H 4.98; N 16.95
Found: C, 53.23; H 4.98; N, 17.21
NMR and mass spectra are consistent with the above structure.

Example 42. 6-Methoxy-9 [2-0- (4-methylbenzoyl) -3.5-0- (1,1,3,3-tetraisopropyldisiloxane-1,3-diyl) - β-D-arabinofuranosyl] - 9H-purine
6-Methoxy-9-3,5-0- (1,1,3,3-tetraisopropyl disiloxane-1,3-diyl) - β-D-arabinofuranosyl] -9H-purine from Example 40 (1.0 g 1, 9 mmol) was added to a 100 ml three-necked round-bottom flask with 4-dimethylaminopyridine (0.02 g, 0.16 mmol), acetonitrile (25 ml) and triethylamine (0.4 ml) and the solution was cooled in an ice bath to a temperature of 3 ^o C for 5 minutes Toluene chloride (0.30 ml, 2.3 mmol) was added and the mixture was stirred for three hours at 3 ^° C. Then an additional amount of triethylamine (0.5 ml) and toluene chloride (0.5 ml) were added, and the mixture was heated to room temperature. After seven hours, the mixture was treated with methanol (2 ml), concentrated under reduced pressure, and the residue was applied to a flash chromatography silica gel column (2.5 x 15 cm) in CH ₂ Cl ₂ . The column was eluted with a mixture of CH ₂ Cl ₂ : MeOH (10: 1, 400 ml), whereby 0.90 g (74%) of the expected product was obtained:
Analysis calculated for C ₃₁ H ₄₆ N ₄ O ₇ Si ₂ :
Calculated: C 57.92; H 7.21; N 8.71
Found: C, 57.69; H 7.43; N, 8.40
NMR and mass spectrum confirm the above structure.

Example 43. 6-Methoxy-9- [2-0- (4-methylbenzoyl) -3.5-2 (1,1,3,3-tetraisopropyldisiloxane-1,3-diyl) - β-D-arabinofuranosyl] - 9H-purine
6-methoxy-9- [3,5-0- (1,1,3,3-tetraisopropyldisiloxane-1,3-diyl) - β-D-arabinofuranosyl] -9H-purine from Example 40 (1.0 g, 1.9 mmol) was added to a 100 ml round bottom flask with 4-dimethylaminopyridine (0.02 g, 0.16 mmol), acetonitrile (25 ml) and triethylamine (0.4 ml), then anisoyl chloride (0 35 ml, 2.5 mmol). After four hours at room temperature, the reaction mixture was treated with methanol (2 ml) and concentrated under reduced pressure. The residue was applied to a flash chromatography silica gel column (25.0 g, 2.5 x 15 cm) in CH ₂ Cl ₂ : MeOH (20: 1). As a result, the same solvent was eluted to obtain 0.930 g (74%) of the expected product:
Analysis calculated for C ₃₁ H ₄₆ N ₄ O ₈ Si ₂ • 0.35 H ₂ O:
Calculated: C 55.97; H 7.08; N, 8.42
Found: C, 56.02; H 7.01; N, 8.32
Example 44. 9- [2-0- (4-Chlorobenzoyl) -3,5-O- (1,1,3,3-tetraisopropyldisiloxane-1,3-diyl) - β-D-arabinofuranosyl] -6-methoxy -9H-purine.

6-Methoxy-9- [3,5-O- (1,1,3,3-tetraisopropyldisiloxane-1,3-diyl) - β-D-arabinofuranosyl] -9H-purine from Example 40 (1.0 g, 1.9 mmol) was added to a 250 ml round bottom flask with 4-dimethylaminopyridine (0.02 g, 0.16 mmol), acetonitrile (25 ml) and triethylamine (0.4 ml) and the solution was cooled in an ice bath at a temperature 3 ^o C for 5 minutes 4-Chlorobenzoyl chloride (0.31 ml, 2.5 mmol) was added and the reaction mixture was removed from the ice bath. After standing for eight hours at room temperature, the solution was treated with MeOH (3 ml) and concentrated under reduced pressure. The residue was taken up in CH ₂ Cl ₂ and applied to a flash chromatography silica gel column (25.0 g, 2.5 x 15 cm) in the same solvent. The column was eluted with CH ₂ Cl ₂ (200 ml), then with a mixture of CH ₂ Cl ₂ : MeOH (20: 1, 400 ml), whereby 1.05 g (82%) of product was obtained, the uniformity of which was confirmed using a thin layer chromatography (silica CH ₂ Cl ₂ : MeOH (20: 1, R _f = 0.44):
Analysis calculated for C ₃₀ H ₄₃ N ₄ O ₇ ClSi ₂ :
Calculated: C 54.32; H 6.53; N, 8.45
Found: C, 54.48; H 6.72; N, 8.28
Example 45. 5'-Monophosphate ester of 9-β-D-arabinofuranosyl-6-dimethylamine-9H-purine.

 9'-β-D-arabinofuranosyl-6-dimethylamine-9H-purine 5'-monophosphate ester was synthesized by transferring the terminal phosphate group of 5'-adenosine triphosphate (ATP) to the 5'-OH-group 9-β-D- arabinofuranosyl-6-dimethylamine-9H-purine catalyzed by thymidine kinase (TK) isolated from zoster virus (BBZ) varicella virus (Fife, Molecular Pharmac, 21, p. 432, 1982).

In 0.5 ml of 0.02 M Tris-hydroxymethyl / aminomethyl-HCl buffer, pH 7.5, 50 nmol of 9-β-D-arabinofuranosyl-6-dimethylamine-9H-purine, 55 nmol of ATP (Sigma Chemicals, St. Louis, MO), 55 nmol MgCl ₂ and 0.005 i.e. TK VVZ. The solution was incubated at a temperature of 21 ^° C. for 2.5 hours, and then filtered through a Centricon 10 filter) (10 K molecular weight cut-off membrane obtained from Amicon Inc., Denver, MA) to remove the protein. The product was analyzed for the absorption range in ultraviolet light using anion exchange thin layer chromatography, which varied with R _f common to monophosphate.

 Example 46. Arabinoside 5'-monophosphate-6-methoxypurine.

Nucleoside, 6-methoxypurin arabinoside, 1.5 g (4.9 mmol) was dissolved in 15 ml of triethyl phosphate and 4.8 ml of triethylamine. This solution was cooled to -10 ^° C. 0.91 ml of phosphate oxychloride was added with stirring. After 10 minutes, an additional amount (0.3 ml) of phosphorus oxychloride was added. After another 10 min, the reaction was interrupted by the addition of 100 ml of ice-cold 0.5 M solution of triethylamine in water. All of the above reagents were obtained from Aldrich.

 The components of the final reaction mixture were separated by ion exchange chromatography on OAE-Sephadex (Pharmacy). The components were eluted with a gradient of 50 mM-1M ammonium bicarbonate. 6'-methoxypurin arabinoside 5'-monophosphate comprised only about 10% of the material eluted from the column. To remove inorganic orthophosphates from the compound, ion-exchange chromatography on BioRad AG-1X8 resin with a gradual gradient of 100 mM-750 mM ammonium bicarbonate was used. The fractions containing this compound were evaporated once in vacuo to remove excess ammonium bicarbonate, then lyophilized.

 6-Methoxy arabinoside 5'-monophosphate was obtained in 3% yield (0.14 mmol, 50 mg). The UV spectrum (max 250 nm and min 221 nm at pH 7) and the base / phosphate ratio (1.00 / 1.08) were in agreement with the structure of the compound. It can be cleaved into a nucleoside using alkaline phosphatase and 5'-nucleotidase.

 Example 47. 6-Methoxypurin arabinoside 5'-triphosphate.

The 5'-monophosphate of 6-methoxypurin arabinoside from Example 46 (36 mg, 93 mmol) was dissolved in 2 ml of hexamethylphosphoramide. Carbonyldiimidazole (82 mg, 506 μmol) was added and the mixture was stirred for 2 hours at room temperature. Methanol (0.032 ml, 800 μmol) was added and the mixture was stirred for 20 minutes. Tributylammonium pyrophosphate (220 mg, 470 μmol from Sigma) was added, which was previously dissolved with 1.5 ml of hexamethylphosphoride, and the mixture was stirred for 18 hours at room temperature. The reaction was stopped by the addition of 50 ml of water. All of the above reagents were obtained from Aldrich, unless otherwise indicated. 5'-triphosphate was purified using ion exchange chromatography on QAE Sephadex (Pharmacy), eluting with a successive gradient of 50 mM-800 mM ammonium bicarbonate. Fractions containing compounds were evaporated once in vacuo to remove excess ammonium bicarbonate, then redissolved in water and kept frozen at a temperature of -20 ^o C.

 6'-methixipurin arabinoside 5'-triphosphate was obtained in 60% yield (57 μmol, 30 mg). The UV spectrum (max 250 nm and min 223 nm at pH 7) and the base / phosphate ratio (1.00 / 3.10) were in agreement with the structure of the compound. It can be cleaved into nucleoside using alkaline phosphatase and monophosphate using phosphodiesterase 1.

 Example 48. 6-Dimethylamino-9 - [(2-0-valeryl) - β-D-arabinosyl] - 9H-purine.

6-Dimethylaminopurin arabinoside (0.501 g, 1.67 mmol) was dissolved in 20 ml of pyridine and 20 ml of DMF. The temperature of the solution was adjusted to 4 ^° C. and valerianic anhydride (0.43 ml, 2.17 mmol, Aldrich Chemical Co., Milwaukee, VI) dissolved in 5 ml of pyridine and 5 ml of DMF was slowly added. The temperature of the solution was maintained at 40 ^° C. and after 2 hours, the solvent was removed in vacuo. The residue was processed on a silica gel column for operational chromatography, 4.8 • 20 cm using 150 ml of each of the following mixtures of dichloromethane: methanol (v / v): 100: 0, 98: 2, 96: 4, 94: 6, 92 : 8, 90:10. Fractions containing the product were collected and, after lyophilization, 0.195 g of 6-dimethylamino-9- (2-0-valeryl-β-D-arabinosyl) -9H-purine was obtained: TLC R _f = 0.55 (silica gel, 9: 1 ( dichloromethane: methanol).

Analysis for C ₁₇ H ₂₅ N ₅ O ₅ • 0.5 H ₂ O:
Calculated: C 52.57; H 6.75; N 18.03
Found: C, 52.61; H 6.77; N 17,99
NMR and mass spectra are consistent with the above structure.

 Example 49. 6-Dimethylamino-9- (2,3,5-triacetyl-β-D-arabinosyl) -9H-purine.

6-Dimethylaminopurine arabinoside (3.00 g, 10.0 mmol) was dissolved in 20 ml of acetonitrile and equilibrated at 4 ^° C. with 45 ml of pyridine. Acetyl chloride (2.85 ml, 40.08 mmol, Aldrich Chemical Co., Milwaukee, VI) in 7 ml of acetonitrile was added dropwise to the reaction mixture. After 5 hours, the solvent was removed in vacuo at a temperature below 45 ^° C, and the residual material was treated with a high vacuum pump for 24 hours. The dried residue was further processed using flash chromatography on a silica gel column, 4.8 x 25 cm, using a 9: 1 mixture ( dichloromethane / methanol). The fractions containing the product were collected and, after lyophilization, 0.445 g of 6-dimethylamino-9- (2,3,5-triacetyl-β-D-arabinosyl) -9-purine was obtained: TLC R _f = 0.61 (silica gel, 9: 1 (dichloromethane methanol)).

Analysis calculated for C ₁₈ H ₂₃ N ₅ O ₇ :
Calculated: C 51.30; H 5.50; N 16.62
Found: C, 51.40; H 5.55; N, 16.54
NMR and mass spectra confirm the above structure.

Example 50. Compositions in the form of tablets
Compositions A and B were obtained (see Table 1) by wet granulating the ingredients with a povidone solution, then magnesium stearate was added and the mixture was pressed.

 Tablets were prepared from the indicated ingredients (C) by wet granulation and subsequent compression. In an alternative preparation, Povidone B.F. can be replaced with Polyvylpyrrolidone.

 The following compositions D and E were obtained by direct compression of the mixed ingredients. The lactose in composition E is of direct compression type (Dairy Crest - Zeparox).

Composition D (mg / capsule)
Active ingredient - 250
Pre-gelatinized starch NF15 - 150
Total - 400
Composition E mg / capsule
Active ingredient - 250
Lactose - 150
Avicel - 100
Total - 500
Composition F (for controlled release of the composition).

The composition was obtained by wet granulating the ingredients (see below) with a solution of povidone, and then magnesium stearate was added and a mg / tablet was pressed:
(a) Active ingredient - 500
(b) Hydroxypropyl methylcellulose (Metocel K4M Premium) - 112
(c) Lactose B.F. - 53
(d) Povidone B.F. - 28
(e) Magnesium Stearate - 7
Total - 700
The release of the drug takes place within about 6-8 hours and ends after 12 hours
Example 51. Compositions in the form of capsules.

 Composition A.

 A capsule composition was prepared by displacing the ingredients from composition 1 in Example 50 and filling it with a two-part hard gelatin capsule mixture. Composition B was prepared similarly.

Composition B (mg / capsule)
(a) Active ingredient - 250
(b) Lactose B.F. - 143
(c) Sodium glycolate starch - 25
(d) Magnesium Stearate - 2
Total - 420
Composition C (mg / capsule)
(a) Active ingredient - 250
(b) Macrogol 4000 B.F. - 350
Total - 600
Capsules were prepared by melting Macrogol 4000 BF, dispersing the active ingredient in the melt and filling the melt in hard gelatin capsules in two parts.

Composition 1 (mg / capsule)
Active ingredient - 250
Licitin - 100
Peanut Butter - 100
Total - 450
Capsules were prepared by dispersing the active ingredient in lecithin and peanut butter and filling the dispersion with soft, elastic gelatin capsules.

 Composition E (Regulation release).

 The following controlled release capsule composition was prepared by extruding ingredients a, b, and c using an extruder, then pellets were prepared from the resulting material and dried. The dried beads were then coated with a release control shell (d), which was placed in a two-piece hard gelatin capsule (mg / capsule).

(a) Active ingredient - 250
(c) Microcrystalline cellulose - 125
(c) Lactose B.F. - 125
(d) Ethyl cellulose - 13
Total - 513
Example 52. Ophthalmic solution
Active ingredient - 0.5
Sodium chloride, analytical grade - 0.9
Thiomersal - 0.001 g
Purified Water - Up to 100 ml
pH is ensured at the level of - 7.5
Example 53 Composition for injection
Active ingredient - 0,200 g
Sterile, pyrogen-free phosphate buffer (pH 9.0) - Up to 10 ml
The active ingredient was dissolved in most of the phosphate buffer (35-40 ^° C), then adjusted to the required volume and filtered through a sterile microporous filter in a 10 ml amber glass vial (type 1), which was closed with a sterile stopper and a sealed lid.

Example 54. Intramuscular injection
Active ingredient - 0.20 g
Benzyl alcohol - 0.10 g
Glycofurol 75 - 1.45 g
Water for injection - Up to 3.00 ml
The active ingredient was dissolved in glycofurol. Then benzyl alcohol was added and dissolution was carried out, then water was added to 3 ml. The mixture was then filtered through a sterile microporous filter and hermetically sealed in sterile 3 ml amber glass vials (type 1).

Example 55. Syrup suspension
Active ingredient 0.25 g
Sorbitol solution - 1.50 g
Glycerin - 2.00 g
Dispersible cellulose - 0.075 g
Sodium benzoate - 0.005 g
Flavoring substance, Peach 17.42.3169 - 0.0125 ml
Purified water to a volume of 5.00 ml
Sodium benzoate was dissolved in a portion of purified water and a sorbitol solution was added. The active ingredient was added and dispersed. A thickening agent (dispersible cellulose) was dispersed in glycerin. Both of these dispersions were mixed and brought to the required volume using purified water. More thickening was provided, if necessary, by an increase in the slice of the suspension.

Example 56. Suppository (mg / suppository)
Active ingredient (63 microns) - 250
Refractory fat. B.F. (Witepsol X15-Dynamite Nobel) - 1700
Total - 1950
The active ingredient was used in the form of a powder in which at least 90% of the particles have a diameter of 63 μm or less.

One fifth of Witepsol X15 was melted in a cup equipped with a jacket through which steam was passed at a maximum temperature of 45 ^° C. The active ingredient was sieved through a sieve with a hole diameter of 200 μm and added to the molten base with stirring using a silverson equipped with a cutting head until a uniform dispersion was obtained. Maintaining the temperature of the mixture at 45 ^° C., the remaining Witepsol X15 was added to the suspension, and a uniform mixture was obtained by stirring. The suspension was completely passed through a stainless steel sieve with a hole diameter of 200 μm with continuous stirring, allowing the mixture to cool to 40 ^° C. At a temperature of 38 to 40 ^° C. 2.02 g of the mixture was filled in suitable plastic molds. Further, the suppositories were allowed to cool to room temperature.

Example 57. Pessaries (mg / pessary)
Active ingredient 63 μm - 250
Anhydrous Dextrose - 380
Potato Starch - 363
Magnesium Stearate - 7
Total - 1000
The above ingredients were directly mixed and pessaries were obtained by direct compression of the resulting mixture.

Example 58 Antiviral toxicity and bioavailability test. Determination of antiviral activity against the Baricella-Zoster virus
The inhibitory effect of the compounds on BB3 replication (Oka strain) was studied using the ELISA procedure (Berkowitz, F.E., and Levin, M.J. (1985), Antimicrob. Agents and Chemother, which was modified as follows: Infection was started in the presence of drug at the end of the third day of incubation of the drug and the virus with uninfected cells (human diploid fibroblasts, strain MR G-5), 96-well plates were centrifuged for 5 min at a speed of 200 g to precipitate cells before fixation of glutaraldehyde. In the modified ELISA, anti-human 1 gG conjugated with alkaline phosphatase was used as the second antibody. The rate of breakdown of para-nitrophenyl phosphate by dissecting alkaline phosphatase was determined using the procedure described in (Tadepally, S.M., Quinn, R.P. and Averett, D. R. 1986, Antimicrob, Agents and Chemother, 29 pp. 93-98) Uninfected cells were used to obtain “pure” reaction rates, which were subtracted from the rates obtained in the presence of the virus. This assay is suitable for detecting viral progeny in cultures that were initially infected with 15 to 3600 infectious particles per well.

 A study of growth inhibition of uninfected mammalian cells.

 The ability of the proposed compounds to inhibit the growth of D98 cells (human) and α-cells (mice) was measured by determining the number of cells that are obtained after three days of contacting a standard number of cells with different concentrations of the compound (Rideut, J. L., Krenitzky, T.E. ., Koshalka, G.W., Cohn, N.K., Chao, E.I., Elion, G.B., Latter. V.S. and Williams, R.B., (1982) J. Med Chem., 25, pp. 1040-1044). Then this number of cells was compared with the number obtained in the experiment without compound. Cell counting was carried out either by spectrophotometric determination of the amount of living strain made up of cells. Comparable results were obtained using both procedures.

 Data analysis.

The concentration of the compound, resulting in 50% of the control values (IC50), was calculated either by direct interpolation from graphite log of the concentration of the compounds relative to the percentage of the control value, or using a computer program that analyzes in accordance with the same algorithm. In these calculations, data were used in the range from 20 to 80% of the control (see table. 2)
Analysis and data on bioavailability.

 Two Long Evans rats received a dose of the compound using a tube inserted into the stomach from Example 3 10 mg / kg or molar equivalents of the compounds from Examples 16, 24 and 32. Animals were placed in metabolic cells and urine was collected in periods from 0 to 24 h and from 24 to 48 hours after dosing. Urine was analyzed by reverse phase high performance liquid chromatography. The results are expressed in% of the dose excreted from the urine within 48 hours, as for the compound of example 3.

Example -% Dose
3 - 4.9 / 2.5
16 - 11.7
24 - 7.9
32 - 15.9k

Claims (9)

1. A pharmaceutical composition exhibiting activity against human viral infection caused by varicella eoster virus (VZV), comprising a purine derivative and pharmaceutically acceptable target additives, characterized in that it contains an effective amount of a compound of general formula 1 as a purine derivative

where R ₁ represents a methoxy group,
R ₂ is hydrogen or an amino group,
or its pharmaceutically acceptable salts, ethers or esters, or salts of these esters.  2. 9-β-D-arabinofuranosyl-2-amino-6-methoxy-9H-purine or a physiologically acceptable derivative thereof.  3. 9-β-D-arabinofuranosyl-2-amino-6-methoxy-9H-purine according to claim 2.  4. A pharmaceutically acceptable ester of a compound of formula 1, selected from the group: 9- (5-0- (4-methylbenzoyl) β-D-arabinofuranosyl) -6-methoxy-9H-purine, 9- (5-0- (4 -aminobenzoyl) -β- D-arabinofuranosyl) -6-methoxy-9H-purine or 6-methoxy-9 (2-0-pentanoyl-β- -D-arabinofuranosyl) -9H-purine.  5. The pharmaceutical composition according to claim 1, characterized in that as a purine derivative it contains an effective amount of 9-β-D-arabinofuranosyl-2-amino-6-methoxy-9H-purine or its salt, its ester or ether, or salts of said ester with a pharmaceutically acceptable carrier.  6. The pharmaceutical composition according to claim 5, characterized in that, as a purine derivative, it contains an effective amount of 9-β-D-arabinofuranosyl-2-amino-6-methoxy-9H-purine.  7. The pharmaceutical composition according to claim 5 or 6, characterized in that the amount of the purine derivative is 5-1000 mg per unit dose.  8. The pharmaceutical composition according to claims 5, 6 or 7, characterized in that it is made in the form for oral administration.  9. The pharmaceutical composition of claim 8, characterized in that it is in the form of capsules, cachets or tablets.

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