Mono-, di - or triclinia esters of 2-amino-6-(c1- c5- alkoxy-9-(d-arabinofuranosyl)-n-purine, method for their preparation and use and pharmaceutical composition

 

(57) Abstract:

The invention relates to mono-, di - or tri-esters of 2-amino-6-(C1-C5-alkoxy)-9-( -D-arabinofuranosyl)-N-purine General formula (I)

< / BR>
where arabinofuranosyl residue substituted for 2'-, 3'- or 5'-positions, and esters formed by carboxylic acids, in which decarbonising part selected from n-propyl, tert-butyl, n-butyl, methoxymethyl, benzyl, phenoxymethyl, phenyl, methanesulfonyl and succinyl. The compounds of formula (I) is obtained by esterification of 2-amino-6-methoxy-9--D-arabinofuranosyl-N-purine in the presence of the enzyme, with available hydroxyl group is optionally protected. Also described pharmaceutical forms containing the compounds of formula (I) in an effective amount and possessing antitumor activity. 4 C. and 9 C.p. f-crystals, 2 tab.

The invention relates to anti-tumor and immunoregulatory ability of some derivatives arabinofuranosyladenine.

Reported (Blood, 61, 1983, 660; J. Clin. Invest., 74, 1984, 951 and Cancer Research, 45, 1985, 1008) that arabinofuranosylguanine (ara G) selectively inhibits the growth of T-cells compared to B-cells and has a selective cytotoxic activity against T - and he was proposed as proposed chemotherapeutic or immunodepressive tools.

In European patent application N 294 114 described inter alia compounds of formula (I)

< / BR>
where

R1represents a C1-5alkoxygroup (for example, methoxy-or amino group which is mono - or bi - substituted C1-5-alkyl (e.g., stands) and their physiologically acceptable derivatives, for the treatment or prophylaxis of viral infections in humans, caused by some herpes viruses. Pharmaceutically acceptable esters of compounds of formula (I), as claimed, are preferred because they provide high levels of compounds of formula (I) after oral administration.

Now found that compounds of the formula (I), where R1represents a C1-5-alkoxygroup, and their pharmaceutically acceptable esters are useful as anticancer agents and, in particular, are useful in the treatment of disorders of growth T-lymph cells. Thus, they are useful for the treatment of lymphocytic leukemia, malignant lymphoma, diseases of autoimmunity (e.g., rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus and type I or insulin-dependent diabetes mellitus), and as immunore represents a C1-5-alkoxygroup, or its pharmaceutically acceptable ether complex for the production of pharmaceuticals for the treatment of tumors.

In another aspect of the present invention is a method for regulating the growth of tumors in mammals which comprises introducing into the mammal an effective amount of the compounds of formula (I) in which R1represents a C1-5-alkoxygroup, or its pharmaceutically acceptable ether complex.

As R1suitable methoxy - or ethoxy, but preferred is a methoxy group.

In another aspect the invention are new pharmaceutically acceptable esters of compounds of formula (I), where R1represents a C1-5-alkoxygroup.

Pharmaceutically acceptable esters of the above compounds are practically more preferable, since they are able to provide high levels of ara G in the plasma of the recipient after oral administration.

Found that the compounds according to the invention the enzymatic into ara G in the recipient. What ara G and has limited solubility in water, making parenteral impractical, as well as providing low Biol for preferential treatment of the aforementioned disorders and diseases.

Preferred derivatives of the compounds according to the invention include mono-, di - or tizamidine esters arabinofuranose residue substituted in positions 2'-, 3'- and 5'- the specified residue.

These preferred esters include esters of carboxylic acid in which decarbonising part of ester group selected from premiani or razvetvlennnoj groups: alkyl (e.g. n-propyl, t-butyl), alkoxyalkyl (for example, methoxymethyl), Uralkaliy (e.g., benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (e.g. phenyl) optionally substituted with halogen, (C1-4-alkyl or C1-4-alkoxy, nitro or amino group; esters as sulfonates, such as alkylsulfonyl; or alkylarylsulfonate (for example, methanesulfonyl or totalsalary); esters of dicarboxylic acids (e.g., succinyl) or C1-4-alkyl esters; esters of amino acids (for example, L-felled); and esters in the form of mono-, di - or triphosphates. Pharmaceutically acceptable salts of these esters include salts of sodium, potassium, NR4where R=H or (C1-6-alkyl, halide and acid additive salt. In the above-mentioned ester groups, alkyl GRU is aetsa phenyl group.

Preferred esters of the invention include:

1) 2-amino-6-methoxy-9-(5-O-propionyl-D - arabinofuranosyl) - purine;

2) 2-amino-9-(5-O-butyryl- -D - arabinofuranosyl)-6-methoxy - purine;

3) 2-amino-6-methoxy-9-(3-O-pivaloyl - a-D-arabinofuranosyl) - purine;

4) 2-amino-6-methoxy - 9-(2-O-valeryl- -D-arabinofuranosyl) - purine;

5) 2-amino-9-(3-O - benzoyl- -D-arabinofuranosyl)-6-methoxy - purine;

6) 2-amino-6-methoxy-9-(2-O-pivaloyl - a-D-arabinofuranosyl) - purine;

7) 2-amino-9-(2-O-benzoyl- -D-arabinofuranosyl)-6-methoxy - purine;

8) 2-amino-6-methoxy-9-(5-O-valeryl- -D-arabinofuranosyl) - purine;

9) (5-O-acetyl- -D-arabinofuranosyl)-2-amino-6-methoxy - 9 - purine;

10) 2-amino-6-methoxy-9-(5-O-(4-methoxy-4-oxobutyryl)- -D-arabinofuranosyl) - purine;

11) 9-(3,5-di-O-acetyl- -D-arabinofuranosyl)-2-amino-6-methoxy - purine;

12) 9-(2,5-di-O-acetyl- -D-arabinofuranosyl)-2-amino-6-methoxy - purine;

13) 9-(2-O-acetyl- -D-arabinofuranosyl)-2-amino-6-methoxy - purine;

14) 9-(2,3,5-tri-O-acetyl- -D-arabinofuranosyl)- 2-amino-6-methoxy-N-purine;

15) 2-amino-9-(5-O-isobutyryl- -D - arabinofuranosyl)-6-methoxy-N-purine;

16) 9-(2,3-di-O-acetyl- -D-arabinofuranosyl)-2-amino-6-methoxy-9H-purine.

3,5-di-O-Acetyl ester (compound 11), 5-the preferred esters.

Compounds according to the invention are effective ara G prodrugs, effective growth inhibitor of T cells. In the invention, therefore, report the method of inhibiting the replication and/or functioning of T-cells by introducing an effective amount of the compounds of the present invention.

The effect on tumor growth using the compounds of the present invention may include the introduction of only one of the interconnects or together with other medicines as a preparatory regime designed to remove bone marrow was preceded by autologous or allogeneic bone marrow transplantation in leukemia, lymphoma, myeloma or other zlokacestvennosti, for example, in a manner analogous to the introduction of large doses of busulfan and cyclophosphamide prior to bone marrow transplantation in leukemia (G. W. Santos, Bone Marrow Transplant, 1989 Jan; 4 suppl. 1, 236-9).

Compounds of the present invention can also be used for treating the blood or bone marrow ex vivo removal of malignant cells in a manner analogous to that described for the case of 4 - oxyprogesterone (Jager A. M. al.: Yeager's, A. M. et al., N. Engl. J. Med., July 17 1986, 315 (3), 141-7).

T-cells are found in rheumatoid joints and ENES rheumatoid arthritis, and from 5 to 10% of patients with rheumatoid arthritis incapacitated due to painful swallowing joints despite a full course of treatment. The compound of the present invention can be used for the treatment of rheumatoid arthritis.

Also claim that T cells are involved in muscular dystrophy; the present invention therefore apply to the use of compounds of the present invention in the treatment of muscular dystrophy.

The compounds of formula (I), where R1represents a C1-5- alkoxygroup, and their pharmaceutically acceptable esters (which will be referred to as the active ingredients) you can enter any suitable treatment for this condition way, and suitable routes of administration are oral, nasal, local (including transbukkalno and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, vnutriobolochechnoe and epidural). It should be understood that the preferred route of administration will depend, for example, from the state of the recipient.

For each of the above disorders, diseases and indications required amount of active ingredient (as specified vienta, and will eventually be in the description of the attending physician. In General, however, for each of these uses and indications, a suitable effective dose is in the range from 0.1 to 250.0 mg per 1 kg body weight of recipient per day, preferably in the range from 0.1 to 100.0 mg per 1 kg of body weight per day and more preferably in the range of from 1 to 20 mg per 1 kg of body weight per day; the optimal dose is the dose of between 5 and 15 mg per 1 kg of body weight per day (unless otherwise provided, then all weights of active ingredient calculated based on the primary compound of formula (I), its salts and esters numbers will increase proportionally). The desired dose is preferably one, two, three, four or more padosi introduced at suitable intervals of time during the day or week. These padosi you can enter in the form of a unit dose, for example, containing 5 to 1000 mg, preferably from 20 to 500 mg and more preferably from 100 to 400 mg of active ingredient per dose form.

It should be understood that for a process that affects the function of T - cells that is required for the treatment of autoimmune diseases (e.g. rheumatoid arthritis), the size of the dose will be usually in the lower part of the dose range.

Drug compound include a form suitable for oral, nasal, local (including transbukkalno and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, vnutriobolochechnoe and epidural) administration. The dosage form may be conveniently presented in the form of single doses and can be prepared by any well-known in the field of pharmacology method. Such methods include the step of connection of the active ingredient and carrier, which consists of one or more accessory ingredients. In General, the dosage form will receive a uniform and thorough bonding of the active ingredient and liquid carriers or completely divided solid carriers, or both, and then, if necessary, shaping the product.

Dosage forms for this July, starch capsules or tablets, which contain a certain amount of the active ingredient; as a powder or granules; as solutions or suspensions in aqueous or non-aqueous solutions, or in the form of liquid emulsions of the type oil-in-water or water in oil. The active ingredients can also be present in the form of a bolus, electuaries or pastes.

The tablet can be made by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compression in a suitable device is the active ingredient found in an easily compressible form, such as powder, granules, optionally mixed with a binder (e.g. povidone, gelatin, oksipropilmetiltselljulozy), lubricant, inert diluent, preservative, dezintegriraat means (for example, sodium starch glycolate, Poperechnaya povidone, Poperechnaya sodium carboxymethyl cellulose) surface-active or dispersive means. Molded tablets can be obtained by moulding in a suitable device is a mixture of compounds in the form of a powder, moistened with an inert liquid diluent. The tablets may optionally be covered with a shell or supply of a poison when used, for example, to add oksipropilmetiltselljuloza in different proportions to obtain the desired rate of drug release.

For the treatment of external tissues e.g. mouth and skin, the dosage form preferably applied in the form of local ointment or cream containing the active ingredient in amounts of, for example, from 0,075 up to 20 wt.%, preferably from 0.2 to 15 wt.% and more preferably from 0.5 to 10 wt.%. In the case of a preparation in the form of an ointment, the active ingredient can be applied with either paraffin or miscible in water base. Alternatively, the active ingredients can be prepared on the basis of type oil-in-water.

If necessary, the aqueous phase of the cream may include, for example, at least 30 weight. % polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and a mixture thereof. Dosage forms for topical use may preferably include a compound which enhances absorption or penetration of the active ingredient through the skin or other exposed to the processing area. Examples of such compounds that enhance penetration through the skin include DIMET is known ingredients by known methods. While this phase may include only one emulsifier (or emulgent), nevertheless desirable to include a mixture of at least one emulsifier with a fat or oil, or both with the other. Preferably, the hydrophilic emulsifier is included in a composition together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferable to include oil and grease. Along with this emulsifier (emulsifying agents) together with or without stabilizer (stabilizer) forms a so-called emulsion wax, and the wax together with the oil and/or fat forms a so-called emulsion base ointment, which is the oily dispersed phase of the cream formulations.

Emergency and emulsion stabilizers suitable for use in the dosage forms of the present invention include Tween 60, Span 80, cetostearyl alcohol, ministerului alcohol, glyceryl-monostearate and sodium lauryl sulfate.

The choice of suitable oils or fats for formulations based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely used in pharmaceutical emulsion preparin substance, in a suitable condition to avoid leakage from vials or other containers. You can use primocane or razvetvleniya, mono - or dienone alkalemia esters, such as di-Saadiyat, isolatedstore, propylene glycol fluids fatty acids, isopropylmyristate, decillia, isopropylpalmitate, butilstearat, 2-ethylhexylamine or esters of mixed or branched chain, known as Crodamol CAP, and the last three ether are preferred. They can be used alone or together depending on the desired properties. Alternatively, you can use lipids with high melting point, such as white soft paraffin and/or liquid paraffin or other mineral oils.

Dosage forms suitable for topical application in the oral cavity include tablets containing the active ingredient with a flavored basis, usually sucrose and acacia or tragakant; tablets containing the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and liquid mouth rinse containing the active ingredient in a suitable liquid carrier.

Dosage forms for rect cocoa or salicylate.

Dosage form suitable for nasal administration, in which the carrier is a solid phase include unground powder having a particle size of, for example, in the range from 20 to 500 microns which is administered by inhalation, i.e., by rapid inhalation through the nasal passage of the powder in the container, bringing close to the nose. Suitable dosage forms in which the carrier is a liquid, in the form of, for example, spray or nasal drops, include aqueous or oily solutions of the active ingredient.

Dosage forms suitable for vaginal insertion, can be presented as pessaries, tampons, creams, gels, pastes, foams or spray nozzles, containing in addition to the active ingredient such carriers as are known in the field of pharmacology, are appropriate.

Dosage forms suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostatic compounds and substances that give the form of the drug isotonic compatibility with the blood of the recipient; and aqueous and non-aqueous sterile suspensions, Clat in the form of single doses or containers, containing several doses, for example, sealed ampoules or vials, and may be stored frozen in a dry (lyophilized) condition requiring only immediately prior to use for injection add sterile liquid carrier, for example water. Unprepared injection solutions and suspensions can be obtained from sterile powders, granules and tablets having the above-described type.

A preferred single dose dosage forms are dose containing a weak dose, daily dose or unit daily paddsw, as discussed above, or an appropriate part thereof, of the active ingredient.

It should be understood that, in addition to ingredients, partially mentioned above, the dosage form according to this invention may include other means commonly used in pharmacology related to this type of dosage forms, for example, tools that are suitable for oral administration may include flavouring agents.

The invention also provides a method of obtaining a pharmaceutically acceptable esters of compounds of formula (I) in which R1represents a C1-5-alkoxygroup, including esterification the compounds of formula (I) is oxygraph esterification using Alliluyeva means, usually acylhalides or anhydride, with non-extremal temperatures from -30 to +100oC and more suitably at a temperature from -5 to +30oC, in a polar solvent, typically acetonitrile, in the presence of a base, such as triethylamine, and then by removing the protecting groups by conventional means.

Alternative esters can be obtained by enzymatic esterification, for example, using the appropriate trichlorethylene ether and subtilisin as an initiator of the reaction. The reaction is best done in solution with the basic properties, such as pyridine, non-extremal temperatures, usually between 10 and 50oC. the Reaction is terminated by filtering off the enzyme and solvent removal.

The compounds of formula (I) can be obtained by the method described in European patent application N 294114 (where R1represents a C1-5-alkoxy).

The following examples serve to illustrate obtain esters of compounds of formula (I) and dosage forms containing them.

Example 1. Enzymatic production of esters of the present invention.

a) 2-Amino-6-methoxy-9-(5-O-propionyl-D - arabinofuranosyl)-N-purine. 2-Amino-6-methoxy-9-( -D - arabinofuranose is in 40 ml of pyridine, containing 300 μl of water and 2 ml of trichloromelamine (trichloromelamine synthesized by adding 19 ml of propionitrile (Aldrich) for 30 min to 19,1 ml trichloroethanol (Aldrich) in 40 ml of pyridine at 0oC). The product was purified by washing 2 x 100 ml portions of water, 5% NaHCO3and H2O.

1H-NMR (200 MHz) CDCl3: 4,74 (s, 2H, Cl3CH2); 2,49 (q, 2H, J = 7,6 Hz, CH3CH2CO2); to 1.21 (t, 3H, J = 7,6 Hz, CH3CH2CO2).

The reaction was initiated using 0,100 g subtilisin (Corporation Sigma Chemical Co., St. Louis, MO, P-5380, lot N 38F - 0356), which was activated by dissolving 1 g of enzyme in 20 ml of 0.1 mol/l solution of potassium phosphate at pH 7.8 and liofilizirovanny to dryness. After stirring for 23 hours at 40oC the reaction was stopped by filtering off the enzyme and the solvent was removed under vacuum. The crude product was purified by chromatography on silicagel column size 4.5 x 25 cm CH2Cl2:CH3OH (9:1) as eluent. The resulting fraction was defended and liofilizirovanny from water getting from 0.76 g of the desired product as a white powder: so pl. 124oC; TLC (value for thin-layer chromatography) Rf= 0,43 (silica gel; CH2Clthe C, DMSO-d6): 7,83 (s, 1H, H8, 6,44 (s, 2H, 2-NH2); 6,14 (s, 1H, H1); of 5.75 (d, 1H, J = 4.3 Hz, 2'-OH); the 5.65 (d, 1H, J = 3.5 Hz, 3'-OH); to 4.28 (m, 2H, H2and H3); 4,08 (m, 2H, H5); of 3.95 (s, 3H, -OCH3); 3,91 (m, 1H, H4'); 2,32 (q, 2H, J = 7,6 Hz, CH2H2CO2-); a 1.01 (t, 3H, J = 7.5 Hz, H3CH2CO2-); MC (ci) 354 (M+I), 280 (M-C2H5CO2).

Analytical calculation for C14H19N5O60,46 H2O:

calculated: C 46,49; H of 5.55; N 19,36;

found: C 46,46; H 5,52; N 19,45.

b) 9-(5-O-Acetyl- -D-arabinofuranosyl)-2-amino-6-methoxy-N-purine.

2-Amino-6-methoxy-9- -D-arabinofuranosyl-N-purine (1.0 g, 3.3 mmol) suspended in 40 ml of pyridine that contained 300 μl of water and 1 ml of trichloroacetate (trichloroacetate synthesized as follows: 2,2,2-trichloroethanol (19.1 ml, 197,1 mmol) and dry pyridine (40 ml) were placed in triggerlevel with a round bottom flask equipped with a crane for puckane argon, thermometer, addition funnel, magnetic stirrer and a bath with ice (H2O). Acetylchloride (14,5 ml, 199,8 mmol) was placed in an addition funnel and added over 10 min, keeping the temperature below 25oC and stirring in argon atmosphere. The resulting product was washed with water (2 x 100 ml), 5% NaHCO3(2 x 100 ml) and H2is listed under vacuum. The average slice weight 5,18 g was a desired substance, contaminated with a small amount of acetic acid.

1H-NMR (CDCl3): to 4.73 (s, 2H, CH2O); of 2.20 (s, 3H, CH3CO); MC (Cl, CH4); m/z 197 (M+H, C4H5O237Cl3); 195 (M+H, C4H5O237Cl2); 193 (M+H, C4H5O2O35Cl237Cl); 191 (M+H, C4H5O235Cl3); 159 (195-HCl, C4H4O237Cl2); 157 (193-HCl, C4H4O237Cl35Cl); 155 (191-HCl, C4H4O235Cl2); (E1): m/z 195 (M+H); 193 (M+H); 191 (M+H); 157 (193-HCl); 155 (191-HCl).

Analysis for C4H5Cl3O2+ 0,054 mol CH3COOH: C 25,35; H 2,70; Cl 54,62.

Found: C 25,57; H 2,72; Cl 54,66.

The reaction was initiated 0,050 g subtilisin (Sigma Chemical Co., St. , Mo, P-5380, lot N 38F-0356), which was previously activated by dissolving 1 g of enzyme in 20 ml of 0.1 mol/l solution of potassium phosphate pH 7.8 and lyophilization to dryness. After stirring for 23 hours at 40oC was added to the reaction mixture an additional 50 mg of subtilisin and 2 ml of trichloroacetate. After stirring at 40oC for an additional 24 h the reaction was interrupted by otfiltrovana imageline column size 4.5 x 25 cm CH2Cl2:CH3OH (9:1) as eluent. The resulting fractions were defended and liofilizirovanny of water to obtain 0.28 g of the desired product as a white powder. TLC Rf= 0,35 (silica gel; CH2Cl2: CH3OH (9: 1)); UVmax((mmol/l)-1cm-1) at pH 7.0, 279 nm (8,8).

1H-NMR (200 MHz, DMSO-d6): 7,83 (s, 1H, H8); 6,45 (s, 2H, 2-NH2); 6,14 (d, 1H, J = 3,7 Hz, H1); of 5.75 (d, 1H, J = 4.5 Hz, 2'-OH); the 5.65 (d, 1H, J = 3,7 Hz, 3'-OH); 4.26 deaths (m, 2H, H2and H3); 4,07 (m, 2H, H5); of 3.94 (s, 3H, -OCH3); to 3.92 (m, 1H, H4); a 2.01 (s, 3H, CH3CO2-); MC (Cl) 340 (M+I); 280 (M-CH3CO2).

Analytical calculation for C14H19N5O60,52 H2O:

calculated: C 44,77; H 5,22; N 20,12;

found: C 44,79; H to 5.21; N 20,09.

The following compounds were obtained in a similar way, based on the corresponding trichlorethylene ether.

c) 2-Amino-9-(5-O-butyryl- -D-arabinofuranosyl)-6-methoxy-N-purine.

1H-NMR (200 MHz, DMSO-d6): 7,83 (s, 1H, H8); 6,46 (s, 2H, 2-NH2); 6,14 (d, 1H, J = 3,9 Hz, H1); USD 5.76 (d, 1H, J = 4.3 Hz, 2'-OH); to 5.66 (d, 1H, J = 3,7 Hz, 3'-OH); to 4.28 (m, 2H, H2and H3); 4,07 (m, 2H, H5); of 3.94 (s, 3H, -OCH3); 3,91 (m, 1H, H4); 2,28 (t, 2H, J = 7.2 Hz, CH3CH2CH2CO2-); of 1.52 (sextet, 2H, J = 7,4 G Is

d) 2-Amino-6-methoxy-9-(5-O-valeryl- -D-arabinofuranosyl)-N-purine.

1H-NMR (200 MHz, DMSO-d6): 7,83 (s, 1H, H8); 6,46 (s, 2H, 2-NH2); x 6.15 (d, 1H, J = 3,7 Hz, H1); USD 5.76 (d, 1H, J = 4,2 Hz, 2'-OH); the 5.65 (d, 1H, J = 3.5 Hz, 3'-OH); to 4.28 (m, 2H, H2' and H3'); 4,08 (m, 2H, H5); of 3.94 (s, 3H, -OCH3); to 3.92 (m, 1H, H4); to 2.29 (t, 2H, J = 7,1 Hz, CH3CH2CH2C CO2-); for 1.49 (m, 2H, CH3C CH2CH2CO2-); to 1.28 (m, 2H, CH3C CH2CH2CO2-); or 0.83 (t, 3H, J = 7.2 Hz, C CH2CH2CH2CO2-).

e) 2-Amino-6-methoxy-9-(5-O-(4-methoxy-4-oxobutyryl)- -D - arabinofuranosyl)-N-purine (as educt - trichloromethylbenzene).

1H-NMR (200 MHz, DMSO-d6): 7,83 (s, 1H, H8); 6,45 (s, 2H, 2-NH2) x 6.15 (d, 1H, J = 3,7 Hz, H1); of 5.75 (d, 1H, J = 4.3 Hz, 2'-OH); the 5.65 (d, 1H, J = 3,7 Hz, 3'-OH); to 4.28 (m, 2H, H2' and H3'); 4,08 (m, 2H, H5'); 3,95 (s, 3H, -OCH3); 3,91 (m, 1H, H4'); 3,51 (s, 3H, CH3CO(O)-): 2,56 (s, 4H, -OC(O)CH2CH2C(O)O-); MC (Cl) 412 (M+I); 280 (M-C5H7O4).

Analytical calculation for C16H21N5O80,40 H2O:

calculated: C 45,64; H 5,28; N 16,63;

found: C 45,62; H to 5.21; N 16,67.

Example 2. Chemical synthesis of esters of the present invention.

a(i) 2-Amino-9-(2,5-di-O-t is (10 g, 34 mmol) was added in a 500 ml round bottom flask and dried by co-evaporation with pyridine (2 x 50 ml). Added imidazole (11 g, 74 mmol). The flask was purged with argon and closed by a partition. Was added dry dimethylformamide (DMF, 40 ml) and the solution stirred at room temperature for 18 hours Thin layer chromatography on silicagel column with acetone : CHCl3(1:10) showed that remained about 20% of the original substance (Rf= 0.05) and that there are three strong features Rfwhen to 0.18, 0.41 and 0.75 in. Added additional tert-butyldimethylsilyloxy (1.0 g, 6.6 mmol), the mixture was continued to stir for 24 hours of Subsequent thin-layer chromatography in the same solvent showed that all starting material was consumed.

Then under reduced pressure to remove DMF, the residue was separated between ethyl acetate (350 ml) and H2O (100 ml and 3 x 50 ml). The ethyl acetate (100 ml) was back extracted aqueous layers, the combined organic layers were dried (MgSO4), filtered and concentrated. The crude product was purified on silicagel flash column (5 x 25 cm) were suirable step-by-step gradient of acetone in CHCl3(from 1:20 to 1:2). Three of the obtained fractions corresponded to the three characteristics, n'doye phase, identified as 2,5-dailyliving substance: so pl. 180-182oC (uncorrected); UVmax(95% EtOH): 248 nm and 280,8 nm; MC (E1): m/z 468 (C19H34N5O5Si2); 450 (C19H32N5O4Si2); 336 (C13H18N5O4Si); 322 (C14H24N5O2Si); 264 (C10H14N5O2Si); 222 (C8H8N5O3); 208 (C8H10N5O2); 194 (C7H8N5O2); 166 (C6H8N5O); 133 (C6H17OSi); 115 (C6H15Si); 57 (C4H9).

1H-NMR (CDCl3): 7,87 (s, 1H, H-8); of 6.29 (d, 1H, H-1', J = 4.6 Hz); 4,82 (br s, 2H, NH2); 4,39-4,34 (m, 2H, H-2' and 3'); 4,07 (s, 3H, -OCH3); 3,94-3,82 (m, 3H, H-4' and 5'); 2.40 a (br s, 1H, 3'-OH); of 0.91 (s, 9H, (CH3)3CSi); of 0.71 (s, 9H, (CH3)3CSi); and 0.09 (s, 6H, (CH3)2Si); -0,02 (s, 3H, (CH3Si); -0,24 (s, 3H, (CH3Si).

Analytical calculation for C23H43N5O5Si2:

calculated: C 52,54; H 8,24; N 13,32;

found: C 52,28; H 8,20; N 13,17.

a(ii) 2-Amino-9-(2,5-di-O-tert-butyldimethylsilyl-3-O-pivaloyl - a-D-arabinofuranosyl)-6-methoxy-N-purine.

2-Amino-9-[(2,5-di-O-tert-butyldimethylsilyl)- -D-arabinofuranosyl] - 6-methoxy-N-purine (2.5 g, 3.8 mmol) was weighed in prokalenny the om and closed by a partition. To the reaction mixture was added dry acetonitrile (50 ml), triethylamine (8.0 ml) and Pavlinovich anhydride (3 ml, of 14.8 mmol). After 158 h the reaction mixture was concentrated, the residue was mixed with ethyl acetate (250 ml) and was extracted with water (3 x 50 ml). The ethyl acetate was dried (MgSO4), filtered and concentrated to obtain 3.8 g of a yellow oil, 300 g of this substance was purified on chromatotron (Chromatotron, Harrison Scientific), equipped with a 4-mm silicagel rotor, aliremove using a mixture of acetone:CHCl3(1 : 10). The product was isolated in the form of a transparent resin (0,176 g).

MC (E1): m/z 609 (C28H51N5O6Si2); 594 (C27H48N5O5Si2); 552 (C24H42N5O6Si2); 450 (C19H32N5O4Si2); 322 (C14H24N5O2Si); 314 (C16H30O4Si); 194 (C7H8N5O2); 166 (C6H8N5O); 57 (C4H9).

1H-NMR (CDCl3): to 7.93 (s, 1H, H-8); and 6.25 (d, 1H, H-1', J = 3.8 Hz); 5,28 (d, 1H, H-3', J = 2.2 Hz); of 5.05 (3 br, 2H, NH2); 4,30 (dd, 1H, H-2', J2',3'= 1,8 Hz); 4,10 (s, 3H, -OCH3); Android 4.04 (dt, 1H, H-4', J = 2.5 Hz, J = 5,9 Hz); 3,19 (d, 2H, H-5', J = 5.5 Hz); of 1.27 (s, 9H, -OCOC(CH3)3); to 0.75 (s, 9H, CSi(CH3)3); and 0.09 (s, 6H, -Si(CH3)2); 0,02 (s, 3H, Si(CH3)); -033>< / BR>
calculated: C 55,19; H 8,49; N TO 10.62;

found: C 55,32; H 8,61; N 10,53.

b) 2-Amino-6-methoxy-9-(3-O-pivaloyl - a-D - arabinofuranosyl)-N-purine.

2-Amino-6-methoxy-9-[(3-O-pivaloyl-2,5-di-O-tert - butyl-demetevler)- -D-arabinofuranosyl] -N-purine (2.1 g, 3.4 mmol) was taken with THF (40 ml) and cooled in a bath with ice to 5oC. was Added H2O (2 ml) and then tetrabutylammonium fluoride (TBAF) in a 1 mol/l solution in THF (10 ml, 10 mmol/l). After exposure for 2 h in 5oC was added an additional 10 ml of TBAF. After 2 h the reaction mixture was further treated with 5 ml of TBAF and continued to stir for a further 18 hours and Then the reaction mixture was diluted with CHCl3(40 ml) and passed through a layer of silica gel (230-400 mesh grit size 5 x 5 cm) with a solution of 1 : 1 acetone : CHCl3(500 ml). The filtrate was concentrated and added to silicagel column (230-400 mesh grit size 5 x 18 cm). The column was suirable using a step gradient of acetone with CHCl3(from 1 : 10 to 1 : 1, acetone : CHCl3). From the column received two major fractions corresponding to the substances with Rf= 0.74 and 0.50 in ratio acetone : CHCl3equal to 1 : 1. A substance with a lower value of Rfwas isolated as a white powder with a weight of 0.77 g (53%) and, as p is
( ): pH 7,00: 278,9 nm (8700) and 247,7 nm (8900); 0,1 HCl solution: 287,0 (8600) and 243,7 (6800); 0.1 N. NaOH solution: 279,2 (8900) and 247,7 (8200); MC (E1): m/z 381 (M, C16H23N5O6); 366 (C15H20N5O6); 296 (C11H14N5O5); 280 (C11H14N5O4); 250 (C10H12N5O3); 232 (C10H10N5O2); 208 (C8H10N5O2); 194 (C7H8N5O2); 165 (C6H7N5O); 136 (C5H4N4O); 85 (C5H9O).

IR (KBr): 1733,6, 1594,7 cm-1.

1H-NMR (Me2SO-d6): of 7.95 (s, 1H, H-2); of 6.45 (br s, 2H, NH2); 6,10 (d, 1H, H-1', J = 4.3 Hz); 6,10 (d, 1H, 2'-OH, J = 5.5 Hz); 5,16-5,10 (m, 2H, H-3' and 5'-OH); 4,23-4,20 (m, 1H, H-2'): of 3.94 (s, 3H, Pur-OCH3); 3,90-3,86 (m, 1H, H-4'); 3,67-of 3.60 (m, 2H, 5'); of 1.18 (s, 9H, C(CH3)3).

Analytical calculation for C16H23N5O60,40 CHCl3:

calculated: C 45,90; H 5,50; N 16,32;

found: C 45,72; H 5,43; N 16,04.

c(i) 2-Amino-9-(3,5-di-O-tert-butyldimethylsilyl- -D - arabinofuranosyl)-6-methoxy-N-purine.

2-Amino-9-( -D - arabinofuranosyl)-6-methoxy-N-purine (10 g, 34 mmol) was added in a 500 ml round bottom flask and dried by co-evaporation with pyridine (2 x 50 ml). Added imidazole (11 g, 160 mmol) and then chloromethylphosphonate (DMF), 40 ml) and the solution stirred at room temperature for 18 hours Thin layer chromatography on silica gel with acetone : CHCl3(1 : 10) showed that remained about 20% of the original substance (Rf= 0.05), and three strong features Rfmanifested in 0,18; of 0.14 and 0.75. Added additional chloride tert-butyldimethylsilyl (1.0 g, 6.6 mmol) and continued to stir for 24 hours of Subsequent thin-layer chromatography in the same solvent showed that all starting material was consumed.

Then DMF was removed under reduced pressure, the residue was separated between ethyl acetate (350 ml) and water (100 ml and 3 x 50 ml). The aqueous layers back was extracted with ethyl acetate (100 ml), the combined organic layers were dried (MgSO4), filtered and concentrated. The crude product was purified on silicagel flash column (5 x 25 cm), eluruumi step-by-step gradient of acetone in CHCl3(from 1 : 20 to 1 : 2). Three of the fractions obtained were consistent with the three features observed by thin layer chromatography. Fraction with Rf= 0,41 gave 8.0 g (45%) of the white matter in the solid phase, identified as the product 3,5-distillirovanna: so pl. 88-90oC (uncorrected); UVmax(95% EtOH): 247,1 nm and 28068 (C19H34N5O5Si2); 336 (C13H18N5O4Si); 301 (C13H25O4Si2); 261 (C11H11N5O3); 231 (C10H9N5O2); 208 (C8H10N5O2); 194 (C7H8N5O2); 165 (C6H7N5O); 133 (C6H17OSi); 115 (C6H15Si); 57 (C4H9).

1H-NMR (CDCl3) 8,01 (s, 1H, H-8); 6,16 (d, 1H, H-1', J = 3.1 Hz); 5,08 (br. s, 1H, 2'-OH); 4,84 (br. s, 2H, NH2); or 4.31 (t, 1H, H-3', J = 1.8 Hz); 4,16 is 4.13 (m, 1H, H-2'); of 4.05 (s, 3H, -OCH3); as 4.02-to 3.99 (m, 1H, H-4'); 3,94 (dd, 1H, H-5', J4',5'= 3,7 Hz, J5',5"= to 11.0 Hz); 3,79 (dd, 1H, H-5", J4',5'= 2.7 Hz, J5',5"= to 11.0 Hz); of 0.94 (s, 9H, (CH3)3CSi); of 0.93 (s, 9H, (CH3)3CSi); 0,17 (s, 3H, CH3Si) of 0.14 (s, 3H, CH3CSi); to 0.12 (s, 6H, (CH3)2Si).

Analytical calculation for C23H43N5O5Si2:

calculated: C 52,54; H 8,24; N 13,32;

found: C 52,32; H 8,24; N 13,25.

c(ii)2-Amino-9-(3,5-di-O-tert-butyldimethylsilyl-2-O-valeryl- -D-arabinofuranosyl)-6-methoxy-N-purine.

2-Amino-9-[(3,5-di-O-tert-butyldimethylsilyl)- -D - arabinofuranosyl]-6-methoxy-N-purine (1.3 g, 2.5 mmol) was weighed in burnt dried 250 ml round bottom flask. Was added 4-N, N-dimethylaminopyridine (0.05 g, 0.4 to moml), the solution was cooled in a bath of ice. Was added to the reaction mixture valeric anhydride (0.6 ml, 3.0 mmol). After 18 h at 0.5oC the reaction mixture was concentrated and the residue was taken up with hexane : ethyl acetate (1 : 1) (200 ml) and was extracted with water (3 x 50 ml). The organic layer was dried (MgSO4), filtered and concentrated to obtain 1.7 g of a yellow oil. 270 mg of this substance was purified on chromatotron (Chromatotron, Harrison Scientific), equipped with a 2-mm silicagel rotor. The rotor was suirable a mixture of acetone : CHCl3(1 : 10). Resulting from chromatotron the product was a white substance in the solid phase (0.21 g, 0.34 mmol), pl. 105-107oC (uncorrected); MC (E1); 609 (C28H51N5O6Si2); 594 (C27H48N5O6Si2); 552 (C24H42N5O6Si2); 420 (C18H28N5O5Si); 292 (C13H18N5O3); 261 (C12H15N5O2); 231 (C10H9N5O2); 194 (C7H8N5O2); 166 (C6H8N5O); 159 (C7H25O2Si); 57 (C4H9).

1H-NMR (CDCl3): a 7.92 (s, 1H, H-8); to 6.39 (d, 1H, H-1', J = 5.7 Hz); 5,33 (t, 1H, H-2', J = 5.7 Hz); 4,84 (br. s, 2H, NH2); 4,60 (t, 1H, H-3', J = 5.7 Hz); of 4.05 (s, 3H, OCH3); 3,93 to 3.8(s, (H-SiC(CH3)3); to 0.89 (s, 9H, -SiC(C3)3); 0,76 (t, 3H, -CH3, J = 7,0 Hz); 0,11 (s, 3H, Si(CH3)); and 0.09 (s, 3H, -Si(CH3)); and 0.09 (s, 3H, -Si(CH3)); and 0.08 (s, 3H, -Si(CH3)).

Analytical calculation for C28H51N5O6Si2:

calculated: C 55,14; H 8,43; N 11,48;

found: C 55,09; H 8,45; N 11,46.

c(iii) 2-Amino-6-methoxy-9-(2-O-valeryl- -D - arabinofuranosyl)-N-purine.

2-Amino-9-(3,5-di-O-tert-butyldimethylsilyl-2-O-valeryl- -D - arabinofuranosyl)-6-methoxy-N-purine (1.4 g, 2.3 mmol) was taken with tetrahydrofuran (THF, 40 ml) and cooled in a bath with ice to 5oC. was Added acetic acid (0.06 ml, 10 mmol) and then tetrabutylammonium fluoride (TBAF) in a 1 mol/l solution in THF (10 ml, 10 mmol). After soaking in 5oC for 18 h, the reaction mixture was diluted with CHCl3(40 ml) and passed through a layer of silica gel (230-400 mesh grit size 5 x 5 cm) with 1 : 1 acetone : CHCl3(500 ml). The filtrate was concentrated and purified on chromatotron, equipped with a 4-mm rotor, and suirable using pure ethyl acetate. From the column was obtained pure product as a white foam in number to 0.72 g (78%) after drying and, as has been shown, it represented the desired derivative of 2'-O-Valerie: so pl. 83-86oC (Neispravan (E1): m/z 381 (C16H23N5O6); 351 (C15H21N5O5); 292 (C13H18N5O3); 279 (C11H13N5O4); 217 (C10H11O5);

194 (C7H8N5O2); 165 (C6H7N5O); 135 (C5H5N4); 85 (C5H9O); IR (KBr) 1745,2; 1613,3 and 1588,7 cm-1.

1H-NMR (Me2SO-d6): to 7.93 (s, 1H, H-2); 6,46 (br. s, 2H, NHH2); of 6.26 (d, 1H, H-1', J - 5,9 Hz); 5,79 (d, 1H, 3'-OH, J = 5,1 Hz); 5,23 (t, 1H, H-2', J = 5.8 Hz); 5,02 (t, 1H, 5'-OH, J = 5.6 Hz); 4,36 (ddd, 1H, H-3', J3',3'-OH= 5,1 Hz, J2',3'= 5.7 Hz, J3',4'= 5.8 Hz); 3,93 (s, 3H, Pur-OC ); 3,83-of 3.78 (m, 1H, H-4'); 3,68-3,61 (m, 2H, H-5'); 2,09 (dt, 1H, C(O)CH2, J = 7.5 Hz, J = 15 Hz); of 1.93 (dt, 1H, C(O)CH2, J = 7.5 Hz, J = 15 Hz); 1.30 and of 0.90 (m, 4H, -CH2CH2-); to 0.65 (t, 3H, -CH3, J = 7 Hz).

Analytical calculation for C16H23N5O60,15 C5H10O3:

calculated: C 50,41; H 6,22; N 17,29;

found: C 55,41; H 6,59; N 17,40.

d) (i) 2-Amino-9-(3-O-benzoyl-2,5-di-O-tert-butyldimethylsilyl- -D-arabinofuranosyl)-6-methoxy-N-purine.

2-Amino-9-[(2,5-di-tert-butyldimethylsilyl)- -D-arabinofuranosyl]-6-methoxy-N-purine (1.5 g, 2.9 mmol) was weighed in burnt dried 250 ml round bottom flask. Was added 4-N,N-dimethylaminopyridine (0.05 g, 0.4 mmol), the flask was purged l) and betamerica (0,77 g, 3.4 mmol). After exposure for 5 h at ambient temperature the reaction mixture was concentrated, the residue was taken up with ethyl acetate (250 ml) and was extracted with water (2 x 50 ml). The ethyl acetate was dried (MgSO4), filtered and concentrated to obtain 3.8 g of a yellow oil. 270 mg portion of this substance was purified on chromatotron (Harrison Scientific), equipped with a 4-mm silicagel rotor. The rotor was suirable a mixture of acetone : CHCl3(1 : 10). Resulting from chromatotron substance represented a white solid phase (0.18 g, 0.29 mmol), pl. 73-75oC (uncorrected); MC (E1): m/z 630 (C30H48N5O6Si2); 614 (C29H44N5O6Si2); 572 (C26H44N5O6Si2); 451 (C19H33N5O4Si2); 194 (C7H8N5O2); 179 (C6H5N5O2); 166 (C6H8N5O);

105 (C7H5).

1H-NMR (CDCl3); 8,12-8,07 (m, 2H, Ar-H); a 7.92 (s, 1H, H-8); 7,63 was 7.45 (m, 3H, Ar-H); 6,33 (d, 1H, H-1', J = 3,7 Hz); 5,46 (t, 1H, H-3', J = 1.8 Hz); 4,79 (br. s, 2H, NH2); was 4.42 (dd, 1H, H-2', J1'2'= 3,7 Hz and J2'3'= 1.7 Hz); 4,30-4,20 (m, 1H, H-4'); 4,07 (s, 3H, -OCH3); 3,99-3,95 (m, 2H, H-5'); to 0.89 (s, 9H, -SiC(CH3)3); 0,76 (s, 9H, -SiC(CH3)3); and 0.09 (s, 6H, -Si(CH3)2); 0,03 (s, 3H, -Si(CH3<
calculated: C 57,20; H 7,52; N 11,12;

found: C 57,08; H to 7.59; N 11,05.

d) (ii) 2-Amino-9-(3-O-benzoyl- -D-arabinofuranosyl)-6-methoxy-N-purine.

2-Amino-9-[(3-O-benzoyl-2,5-di-O-tert-butyldimethylsilyl)- -D-arabinofuranosyl] -6-methoxy-N-purine (1.97 g, 2.6 mmol) was combined with tetrahydrofuran (THF, 40 ml) and cooled in a bath with ice to 5oC. was Added acetic acid (0.6 ml, 10 mmol) and then tetrabutylammonium fluoride (TBAF) in a 1 mol/l solution in THF (10 ml, 10 mmol). After exposure for 18 h in 5oC the reaction mixture was diluted with CHCl3(40 ml) and passed through a layer of silica gel (230-400 mesh grit size 5 x 5 cm) with acetone : CHCl3(500 ml). The filtrate was concentrated to a white solid phase, which was adsorbing 10 g of silica gel and added to silicagel column (230-400 mesh grit size 5 x 18 cm). The column was suirable a mixture of acetone : CHCl3(1 : 2). Pure product obtained from the column corresponded to the substance with Rf= 0,56 in acetone : CHCl3(1 : 1). This substance after drying consisted of 0.77 g (1.9 mmol) of white powder and, as has been shown, was required derivative of 3'-O-benzoyl: so pl. 155-157oC (uncorrected); UVmax( ): pH 7,00: 278,3 nm (10100), 235,2 nm (18800); 0,1 HCl solution: 278,1 (91000),5O5); 250 (C10H12N5O3); 232 (C10H10N5O2); 20 (C8H10N5O2); 194 (C7H8N5O2); 179 (C7H7N4O2); 165 (C6H7N5O); 136 (C5H4N5); 122 (C7H5O2); 105 (C7H5O); IR (KBr): 1714,6; 1611,8 and 1591,7 cm-1.

1H-NMR (Me2SO-d6); of 8.06 (s, 1H, H-2); 8,02-of 8.00 (m, 2H, Ar-h); 7,71 (t, 1H, Ar-h, J = 7,3 Hz); EUR 7.57 (t, 2H, Ar-H, J = 7.4 Hz); 6,45 (br. s, 2H, NH2); of 6.20 (d, 1H, H-1', J = 4.3 Hz); 6,12 (d, 1H, 2'-OH, J = 5.5 Hz); 5,41 (t, 1H, H-3', J = 2,9 Hz); 5,20 (t, 1H, 5'-OH, J = 5.5 Hz); 4,43-4,37 (m, 1H, H-2'); 4,17-4,11 (m, 1H, H-4'); of 3.95 (s, 3H, Pur-OC ); 3,79-and 3.72 (m, 2H, 5').

Analytical calculation for C18H19N5O60,60 C3H6O 0,05 CHCl3:

calculated: C 53,92; H 5,16; N 15,84;

found: C 53,81; H 5,10; N 15,76.

e(i) 2-Amino-9-(3,5-di-O-tert-butyldimethylsilyl-2-O-pivaloyl - a-D - arabinofuranosyl)-6-methoxy-N-purine.

2-Amino-9-(3,5-di-O-tert-butyldimethylsilyl- -D-arabinofuranosyl)-6-methoxy-N-purine (1.3 g, 2.5 mmol) was weighed in burnt dried 250-ml round bottom flask. Was added 4-N,N-dimethylaminopyridine (0.05 g, 0.4 mmol), the flask was purged with argon and closed by a partition. To the reaction mixture was added with stirring at room temp the mixture was concentrated, the residue was taken up with ethyl acetate (250 ml) and was extracted with water (3 x 50 ml). The ethyl acetate was collected, dried (MgSO4), filtered and concentrated to obtain 2.0 g of a yellow oil. a 250 mg portion of this substance was purified on chromatotron (Harrison Scientific), equipped with a 2-mm silicagel rotor, suirable using acetone: CHCl3(1:10). Resulting from chromatotron product was a transparent resin (0,176 g); MC (E1): m/z 609 (C28H51N5O6Si2); 594 (C27H48N5O6Si2); 552 (C24H42N5O6Si2); 420 (C18H28N5O5Si); 292 (C13H18N5O3); 261 (C12H15N5O2); 231 (C10H9N5O2); 194 (C7H8N5O2); 166 (C6H8N5O); 159 (C7H15O2Si); 57 (C49).

1H-NMR (CDCl3): 7,89 (s, 1H, H-8); 6,40 (d, 1H, H-1', J = 5,9 Hz); and 5.30 (t, 1H, H-2', J = 6.0 Hz); 4,85 (br. s, 2H, NHH2Y); the 4.65 (t, 1H, H-3', J = 6.0 Hz); Android 4.04 (s, 3H, OCH3); 3,95-of 3.85 (m, 1H, H-4' and H-5'); to 0.92 (s, 9H, OCOC(CH3)3); to 0.89 (s, 9H, SiC(CH3)3); to 0.88 (s, 9H, SiC(CH3)3); 0,13 (s, 3H, SiCH3); 0,11 (s, 3H, SiCH3); and 0.08 (s, 3H, SiCH3); of 0.07 (s, 3H, SiCH3).

Analytical calculation for C28H51N5O6Si

2-Amino-6-methoxy-9-(3,5-O-di-tert-butyldimethylsilyl-2-O-pivaloyl - a-D-arabinofuranosyl)-N-purine (1.3 g, 2.0 mmol) were taken with tetrahydrofuran (THF, 40 ml) and cooled in a bath with ice to 5oC. was Added acetic acid (0.06 mmol) and then tetrabutylammonium fluoride in a 1 mol/l solution in THF (10 ml, 10 mmol). After soaking for 24 h in 5oC the reaction mixture was diluted with CHCl3(40 ml) and passed through a layer of silica gel (grain size 230-240, size 5 x 5 cm) with 1:1 acetone: CHCl3(500 ml). The filtrate was concentrated and directed in silicagel column (230-400 mesh grit size 5 x 18 cm), was suirable with acetone:CHCl3(1:2, 1.5 l) and then with acetone: CHCl3(1:1, 1.5 l). Pure product obtained from the column was a white powder weighing 0,76 g (100%) after drying and, as has been shown, was a desired derivative of 2'-O-pivaloyl: so pl. 83-85oC (uncorrected); UVmax( ): pH 7,00: 279,7 nm (8100), 247,9 nm (8800); 0,1 HCl solution: 286,6 (7300), 244,7 (6200); 0,1 N. NaOH solution: 279,7 (8000), 248,8 (7900); MC (E1): m/z 250 (C10H12N5O3); 232 (C10H10N5O2); 217 (C10H17N5); 208 (C8H10N5O2); 194 (C7H8N5O2); 165 (C6H7N5O); 135 (C;

1H-NMR (Me2SO-d6): of 7.97 (s, 1H, h-2); 6,47 (br. s, 2H, NH2); of 6.26 (d, 1H, H-1', J = 5,9 Hz); 5,79 (d, 1H, 3'-OH, J = 5.3 Hz); 5,23 (dd, 1H, H-2', J1',2'= 5,9 Hz, J2',3'= 5,2 Hz); 5,06 (5,1 H, 5'-OH, J = 5.5 Hz); 4,37 (ddd, 1H, H-3', J3',3'-OHwith 5.3 Hz, J2',3'= 5,2 Hz, J3',4'= 6,9 Hz); to 3.92 (s, 3H, Pur-OC ); 3,84-with 3.79 (m, 1H, H-4'); 3,68-3,62 (m, 2H, H-5').

Analytical calculation for C16H23N5O60,40 CHCl3:

calculated: C 45,90; H 5,50; N 16,32;

found: C 46,03; H 5,69; N 16,03.

f(i) 2-Amino-9-(2-O-benzoyl-3,5-di-O-tert-butyldimethylsilyl- - D-arabinofuranosyl)-6-methoxy-N-purine.

2-Amino-9-[(3,5-di-O-tert-butyldimethylsilyl)- -D-arabinofuranosyl] - 6-methoxy-N-purine (1.3 g, 2.5 mmol) was weighed in burnt dried 250-ml round bottom flask. Was added 4-N,N-dimethylaminopyridine (0.05 g, 0.4 mmol) and benzhydryl (of 0.67 g, 3.0 mmol), the flask was purged with argon and closed by a partition. Then added dry acetonitrile (30 ml) and triethylamine (5.0 ml), the mixture is stirred at room temperature. After 18 h the reaction mixture was concentrated, the residue is stirred with ethyl acetate (250 ml) and was extracted with water (3 x 50 ml). The ethyl acetate was dried (MgSO4), filtered and concentrated to obtain 1,76 g yellow oil. a 250 mg portion of this substance was purified on chromator is, which of hromatron the product was a white solid phase (0.21 g): so pl. 129-131oC (uncorrected); MC (E1): m/z 629 (C30H47N5O6Si2); 572 (C26H47N5O6Si2); 440 (C20H22N5O5Si); 312 (C15H14N5O3); 261 (C11H25O3Si2); 231 (C9H19O3Si2); 194 (C7H8N5O2); 166 (C6H8N5O); 105 (C7H5O).

1H-NMR (CDCl3): 8,07 (s, 1H, H-8); to 7.67 (dd, 2H, Ar-H, J = 1.0 Hz, J = 8,2 Hz); 7,50 (tt, 1H, Ar-H, J = 2.0 Hz, J = 8.0 Hz); 7,30 (t, 2H, Ar-H, J = 7.5 Hz); 6.48 in (d, 1H, H-1', J = 5.5 Hz); 5,63 (t, 1H, H-2', J = 5.5 Hz); 4,74 (t, 1H, H-3', J = 5.6 Hz); and 4.68 (br. s, 2H, NH2); 3,98 (s, 3H, -OCH3); 4,00-of 3.80 (m, 3H, H-4' and H-5'); to 0.92 (s, 9H, -SiC(CH3)3); to 0.88 (s, 9H, -SiC(CH3)3); to 0.12 (s, 3H, -Si(CH3)); and 0.09 (s, 3H, -Si(CH3)); and 0.08 (s, 3H, -Si(CH3)); to 0.06 (s, 3H, -Si(CH3)).

Analytical calculation for C30H47N5O6Si2:

calculated: C 57,20; H 7,52; N 11,12;

found: C 57,42; H EUR 7.57; N 11,12.

f(ii) 2-Amino-9-(2-O-benzoyl- -D-arabinofuranosyl)-6 - methoxy-N-purine.

2-Amino-9-[(2-O-benzoyl-3,5-di-O-tert-butyldimethylsilyl)- -D-arabinofuranosyl] -6-methoxy-N-purine (1.26 g, 2.0 mmol) stirred in tetrahydrofuran (THF, 40 ml) and cooled in a bath with ice to 5oC. was Added acetic acid (0.06 ml, 10 mmol h at 5oC the reaction mixture was diluted with CHCl3(40 ml) and passed through a layer of silicagel (230-400 mesh grit size 5 x 5 cm) with 1 : 1 acetone : CHCl3(500 ml). The filtrate was concentrated and directed in silicagel column (230-400 mesh grit size 5 x 18 cm). The column was suirable a mixture of acetone : CHCl3(1 : 2, 1 l) and then acetone : CHCl3(1 : 1, 1.5 l). Pure product obtained from the column corresponded to the substance with Rf= 0.33 in acetone : CHCl3(1 : 1). After drying, this substance was a white powder weighing 0.74 g (90%) and, as has been shown, was required derivative of 2'-O-benzoyl: so pl. 82-84oC (uncorrected); UVmax( ): pH 7,00: 279, 1 nm (8600); 237,5 nm (17800); 0,1 HCl solution: 277,8 (10000), 245 (sh) (10800); 0.1 N. NaOH solution: 286,1 (7600), 236,4 (17000). MC (E1): m/z (M, C18H19N5O6); 371 (C17H17N5O5); 312 (C15H14N5O3); 279 (C11H13N5O4); 237 (C12H13O5); 220 (C12H12N4); 208 (C8H10N5O2); 194 (C7H8N5O2); 165 (C6H7N5O); 135 (C5H5N5); 105 (C7H5O). IR (KBr): 1725,3; 1613,6 and 1588,9 cm-1.

1H-NMR (Me2SO-d6): of 8.04 (s, 1H, H-2); 7,70-EUR 7.57 (m, 3H, AC); 4,51 (allowed Quartet, 1H, H-3', J3',3'-OH = 4,9 Hz, J2',3'= 5.6 Hz, J3',4'= 5,1 Hz); a 3.87 (s, 3H, Pur-OC ); 3,94-a 3.83 (m, 1H, H-4'); of 3.77-3,66 (m, 2H, H-5').

Analytical calculation for C18H19N5O60,20 C3H6O 0,50 CHCl3:

calculated: C 48,53; H to 4.41; N 14,82;

found: C 48,68; H of 4.54; N 14,96.

g(i) 2-Amino-9-(5-O-tert-butyldimethylsilyl- -D - arabinofuranosyl)-6-methoxy-N-purine.

9-(-D-arabinofuranosyl)-2-amino - 6-methoxy-9-purine (2.0 g, 6.7 mmol) was added to a 500 ml round bottom flask and dried by co-evaporation with pyridine (2 x 50 ml). Added chloride tert-butyldimethylsilyl (1.2 g, 8 mmol), the flask was purged with argon and was clogging partition. Was added via syringe and needle dry acetonitrile (20 ml) and dry pyridine (20 ml). The solution is stirred at room temperature for 24 h Thin-layer chromatography on silica gel with methanol : CHCl3(1 : 10) showed that all starting material (Rf= 0,05) was spent and that formed one high peak Rf(Rf= 0,31). The reaction mixture was treated with ethanol (2 ml) and concentrated under reduced pressure. The yellow residue was purified on silicagel column (230-400 mesh grit size 5 x 18 cm) with methanol : CHCl3(1 :UP>oC (uncorrected): MC (E1): m/z 412 (M+H, C17H30N5O5Si); 396 (C16H26N5O5Si); 354 (C13H20N5O5Si); 208 (C8H10N5O2); 194 (C7H8N5O2); 178 (C7H8N5O);

166 (C6H8N5O); 165 (C6H7N5O); 135 (C5H5N5); 57 (C4H9).

1H-NMR (Me2SO-d6), 300 MHz): 7,88 (s, 1H, H-8); of 6.49 (br. s, 2H, NH2); 6,14 (d, 1H, H-1', J = 4,7 Hz); 5,67 (d, 1H, 2'- or 3'OH, J = 5.0 Hz); to 5.57 (d, 1H, 2' - or 3'OH, J = 4.4 Hz); 4,15-4.09 to (m, 2H, H-2' and 3'); 3,98 (s, 3H, -OCH3); a 3.87 is 3.76 (m, 3H, H-4' and 5'); of 0.90 (s, 9H (CH3)3CSi); of 0.07 (s, 6H, (CH3)2Si);

Analytical calculation for C17H29N5O5Si2:

calculated: C 49,62; H 7,10; N 17,02;

found: C 49,36; H 7,06; N 16.88 in.

g(ii) 9-(2,3-di-O-Acetyl-5-O-tert-butyldimethylsilyl- -D - arabinofuranosyl)-2-amino-6-methoxy-N-purine.

2-Amino-9-(5-O-tert - butyldimethylsilyl- -D-arabinofuranosyl)-6-methoxy-N - purine (1.5 g, 3.5 mmol) was weighed in burnt dried 100-ml round-bottom flask equipped with razmeshivatelyami. Added anhydrous acetonitrile (25 ml) and then triethylamine (5 ml). Was added 4-N,N-dimethylaminopyridine (0.05 g, 0.4 mmol), the flask was purged with argon and closed the military distillation). The reaction mixture was stirred at ambient temperature (20oC) and examined by thin-layer chromatography on silica gel with methanol:CHCl3(1 : 20). After 18 h all starting material (Rf= 0,34) was consumed and formed a strong peak product (Rf= 0,77).

The reaction mixture was concentrated, the residue was mixed with ethyl acetate (250 ml) and was extracted with water (3 x 50 ml). The organic layer was dried with MgSO4(anhydrous), filtered and concentrated to obtain 1.7 g of a yellow oil. 210-mg portion of this substance was purified on chromatotron (Harrison Scientific), equipped with a 2-mm silicagel rotor. The rotor was suirable using a mixture of acetone : CHCl3(1 : 10). After drying was obtained pure product in the form of a solid phase (0.16 g; 0.33 mmol), pl. 58-60oC (uncorrected). MC (E1): m/z 497 (C21H35N5O7Si); 438 (C17H24N5O7Si); 396 (C15H22N5O6Si); 378 (C15H20N5O5Si); 336 (C13H18N5O4Si); 318 (C13H16N5O3Si); 273 (C11H18O6Si); 250 (C10H12N5O3); 208 (C8H10N5O2); 194 (C7H8N5O2); 165 (C6H7N5<(m, 2H, H-2' and 3'); 4,85 (br. s, 2H, NH2); of 4.05 (s, 3H, -OCH3); 4,04-4,00 (m, 1H, H-4'); 3,94-3,91 (m, 2H, H-5'); a 2.12 (s, 3H, C(O)CH3); of 1.85 (s, 3H, C(O)CH3); to 0.92 (s, 9H, SiC(CH3)3); to 0.10 (s, 6H, Si(CH3)2).

Analytical calculation for C21H33N5O7Si:

calculated: C 50,89; H of 6.71; N 14,13;

found: C 50,70; H of 6.75; N 13,91.

g(iii) 9-(2,3-di-O-Acetyl- -D-arabinofuranosyl)-2-amino-6-methoxy-N-purine.

The intermediate connection sililirovanie 9-(2,3-di-O-acetyl-5-O-tert-butyldimethylsilyl- -D-arabinofuranosyl)-2-amino-6-methoxy-N-purine (1.4 g, 2.9 mmol) were taken together with THF (40 ml) and cooled in a bath with ice to 5oC. was Added acetic acid (0.25 ml), 16 mmol) and then tetrabutylammonium fluoride in a 1 mol/l solution in THF (9 ml, 9 mmol). After exposure for 28 h at 5oC thin-layer chromatography with acetone : CHCl3(1 : 1) showed that starting material was consumed (Rf= 0.77) and formed one low peak Rf(Rf= 0,32). Thin-layer chromatography with methanol : CHCl3(1 : 10) showed the presence of one particular when Rf= 0,41.

The reaction mixture was passed through a layer of silica gel (230-400 mesh grit, size 3 x 5 cm) with acetone : CHCl3(1 : 1,500 ml). The filtrate was concentrated the config product (0.95 g) was contaminated with tetrabutylammonium hydroxide. The product was purified on chromatotron with a 4-mm rotor with the same solvent gave pure product weight 0,877 g (2.3 mmol). so pl. 100 - 102oC (uncorrected); UVmax( ): pH 7,00: 279 nm (8200), 247,3 nm (9800); 0,1 HCl solution: 286,7 (8500), 242,5 (6100); 0,1 N. NaOH solution: 279,3 (8200), 248,9 (7700); MC (E1): m/z 381 (C15H19N5O7); 322 (C13H14N5O5); 292 (C12H12N5O4); 194 (C7H8N5O2); 165 (C6H7N5O);

135 (C5H5N5); 43 (C2H3O).

1H-NMR (Me2SO-d6, 200 MHz): 8,00 (s, 1H, H-8); of 6.52 (br. s, 2H, NH2); 6,30 (d, 1H, H-1', J = 4.6 Hz); 5,43 to 5.35 (m, 2H, H-2' and 3'); 5,11 (t, 1H, 5'-OH, J = 5.8 Hz); Android 4.04 (dd, 1H, H-4', J = 4.5 Hz, J = 8.6 Hz); of 3.94 (s, 3H, Pur-OCH3); 3,71-3,62 (m, 2H, H-5'); is 2.09 (s, 3H, C(O)CH3); of 1.80 (s, 3H, C(O)CH3); IR (KBr) 1748,4, 1613,1 and 1588,5 cm-1.

Analytical calculation for C15H19N5O70,40 CHCl3:

calculated: C 43,11; H 4,56; N 16,32;

found: C 43,16; H 4,69; N 16,21.

h(i) 2-Amino-9-(2,3,5-tri-O-tert-butyldimethylsilyl- -D - arabinofuranosyl)-6-methoxy-N-purine.

2-Amino-9-( -D-arabinofuranosyl)-6-methoxy-9-purine (10 g, 34 mmol) was added to a 500 ml round bottom flask and dried by co-evaporation with pyridine (2 x 50 ml). Added imidazole (arapkoy. Using a syringe and needle was added dry dimethylformamide (DMF) (40 ml). The solution is stirred at room temperature for 18 hours Thin layer chromatography on silica gel with acetone : CHCl3(1 : 10) showed that about 20% of the original substance left (Rf= 0.05) and three high peak Rfformed with the values of 0.18, 0.41 and 0.75 in. So added additional chloride tetramethylpiperidine (1.0 g, 6.6 mmol) and continued to stir for 24 hours of Subsequent thin-layer chromatography in the same solvent showed that all starting material was consumed. Then DMF was removed under reduced pressure and the residue was separated between ethyl acetate (350 ml) and water (100 ml and 3 x 50 ml). The aqueous layers back was extracted with ethyl acetate (100 ml), the combined organic layers were dried (MgSO4), filtered and concentrated. The crude product was purified on silicagel flash column (5 x 25 cm) and suirable step-by-step gradient of acetone in CHCl3in a ratio of from 1 : 20 to 1 : 2. Three fractions obtained corresponded to the three features observed by thin layer chromatography. Fraction Rf= 0,75 gave 4.0 g (6.2 mmol, 19%) of a white solid identified as the product UB>N5O5Si3); 582 (C25H48N5O5Si3); 450 (C19H32N4O4Si2); 322 (C14H24N5O2Si); 222 (C8H8N5O3); 194 (C7H8N5O2); 166 (C6H8N5O); 133 (C6H17OSi); 115 (C6H15Si); 57 (C4H9).

1H-NMR (CDCl3, 200 MHz): of 7.82 (s, 1H, H-8); 6,30 (d, 1H, H-1', J = 3.5 Hz); 4,82 (br. s, 2H, NH2); or 4.31 (m, 1H, H-3'); 4,10 (dd, 1H, H-2', J1',2'= 3.5 Hz and J2',3'= 1.7 Hz); 4,06 (s, 3H, -OCH3); 4,00-3,90 (m, 1H, H-4'); 3,84-of 3.80 (m, 2H, H-5'); of 0.93 (s, 9H, (CH3)3CSi); of 0.90 (s, 9H, (CH3)3CSi); of 0.75 (s, 9H, (CH3)3CSi); of 0.14 (s, 6H, (CH3)2Si) of 0.07 (s, 3H, (CH3Si); 0,06 (s, 3H, (CH3Si); -0,09 (s, 3H, (CH3Si); -0,38 (s, 3H, (CH3Si).

Analytical calculation for C29H57N5O5Si3:

calculated: C 54,42; H 8,98; N 10,94;

found: C 54,36; H 8,86; N 10,87.

h(ii) 2-Amino-9-(2,3-di-O-tert-butyldimethylsilyl- -D - arabinofuranosyl)-6-methoxy-N-purine.

2-Amino-9-(2,3,5-di-O-tert-butyldimethylsilyl- -D-arabinofuranosyl)-6-methoxy-9-purine (2.0 g, 3.1 mmol) was added in a 250 ml round bottom flask and was treated with 80% aqueous solution of acetic acid. The solution was heated at 50oC for 20 hours Tanksley is 0.59) and left only the product (Rf= 0,19). The reaction mixture was concentrated using a rotary evaporator, several times adding water (5 ml) to remove last traces of acetic acid, and then placed in a vacuum pump for 2 hours, the Residue was purified on silicagel column (size 5 x 18 cm, grit 230 - 400) with methanol : CHCl3(1 : 30) as eluent. From containing fraction of the product obtained 1.2 g (2.3 mmol) of a white solid identified as a derivative of 2,3-distillirovanna: so pl. 93 - 95oC (uncorrected). MC (E1): m/z 526 (C23H44N5O5Si2); 510 (C22H40N5O5Si2); 468 (C19H34N5O5Si2); 322 (C14H23N5O5Si); 306 (C13H20N5O2Si); 264 (C10H14N5O2Si); 208 (C8H10N5O2); 194 (C7H8N5O2); 166 (C6H8N5O);

116 (C6H15Si); 57 (C4H9).

1H-NMR (CDCl3, 200 MHz) of 7.82 (s, 1H, H-8); 6,45 (br. s, 2H, NH2); 6,14 (d, 1H, H-1', J = 4,1 Hz); 4,99 (t, 1H, 5'-OH, J = 4.0 Hz); the 4.29 (t, 1H, H-3', J = 2,9 Hz); 4,22 (t, 1H, H-2', J = 4.5 Hz); 3,93 (s, 3H, -OCH3); 3,82 is 3.76 (m, 1H, H-4'); 3,62 - to 3.58 (m, 2H, H-5'); to 0.89 (s, 9H, (CH3)3SCi); 0,64 (s, 9H, (CH3)3CSi); of 0.13 (s, 6H, (CH3)2Si); -0,06 i2:

calculated: C 52,54; H 8,24; N 13,32;

found: C 52,37; H 8,29; N 13,22.

h(iii) 2-Amino-9-(2,3-di-O-tert-butyldimethylsilyl-5-O-isobutyryl- -D-arabinofuranosyl)-6-methoxy-N-purine.

2-Amino-9-(2,3-di-O-tert-butyldimethylsilyl- -D-arabinofuranosyl)-6-methoxy-9-purine (1.3 g, 2.5 mmol) was weighed in burnt dried 250-ml round bottom flask. Was added 4-N,N-dimethylaminopyridine (0.05 g, 0.4 mmol), the flask was purged with argon and closed by a partition. Added dry acetonitrile (25 ml) and triethylamine (5 ml). The flask was cooled in a bath of ice and added to the reaction mixture isobutyryloxy anhydride (0.5 ml, 3.0 mmol). The reaction mixture was left to slowly warm to ambient temperature (20oC). After 22 h the reaction mixture was analyzed by thin layer chromatography on silica gel with methanol : CHCl3(1 : 20). No educt (Rf= 0,27) do not have, and formed one strong feature of the product (Rf= 0,63).

The reaction mixture was concentrated, the residue is stirred in ethyl acetate (250 ml) and was extracted with water (3 x 50 ml). The ethyl acetate layer was dried with MgSO4(anhydrous), filtered and concentrated to obtain 1.5 g of a yellow oil. 200-mg portion of this is using acetone : CHCl3(1 : 10) to give after drying 0.16 g (0.27 mmol) of the white matter in the solid phase; so pl. 56 - 58oC (uncorrected); MC (E1): m/z 596 (C27H49N5O6Si2); 538 (C23H40N5O6Si2); 322 (C14H24N5O2Si); 318 (C13H24O5Si2); 264 (C10H16N5O2Si); 194 (C7H8N5O2); 166 (C6H8N5O);

115 (C6H15Si).

1H-NMR (CDCl3, 200 MHz): to 7.84 (s, 1H, H-8); 6,34 (d, 1H, H-1', J = 3.3 Hz); 4,87 (br. s, 2H, NH2); 4,39 - 4,27 (m, 2H, H2' and 3'); 4,20 - 4,10 (m, 3H, H-4' and 5'); 4,06 (s, 3H, -OCH3); 2,58 (septet, 1H, OC(O)C (CH3)2, J = 7,0 Hz); 1,17 (dd, 6H, OC(O)CH(CH3)2, J = 7,0 Hz, J = 1.9 Hz); of 0.94 (s, 9H, -SiC(CH3)3); of 0.77 (s, 9H, -SiC(CH3)3); to 0.15 (s, 3H, -Si(CH3)); 0,13 (s, 3H, -Si(CH3)); and 0.09 (s, 3H, -Si(CH3)); to 0.39 (s, 3H, -Si(CH3)).

Analytical calculation for C27H49N5O6Si20,10 CHCl3:

calculated: C 53,59; H 8,15; N 11,47;

found: C 53,58; H 8,23; N 11,40.

h(iv) 2-Amino-9-(5-O-isobutyryl- -D-arabinofuranosyl)-6 - methoxy-N-purine.

The intermediate connection sililirovanie 2-amino-9- (2,3-di-O-tert-butyldimethylsilyl-5-O-isobutyryl- -D - arabinofuranosyl)-6-methoxy-9-purine (1.2 g, 2.1 mmol) rateshistoric tetrabutylammonium 1 mmol/l solution in THF (6 ml, 6 mmol). After aging for 70 hours at 0 to 5oC, thin-layer chromatography in a mixture of acetone : CHCl3(1 : 1) showed that there was no original substance remained (Rf= 0,91), and formed one new weak feature of Rf= 0,17.

The reaction mixture was passed through a layer of silica gel (grain size 230 - 400, 2 x 8 cm) with 1 : 1 acetone : CH2Cl2(1.1 l). The filtrate was concentrated to obtain a light Golden balance. This residue was purified on chromatotron, equipped with a 4-mm rotor with acetone : CH2Cl2(1 : 1) as eluent. The obtained white substance in the solid phase (of 0.67 g), which was contaminated with tetrabutylammonium hydroxide, which is defined using the1H-NMR. Repeated cleaning with the same solvent system gave the product (0,57 g), which still contained a small amount of tetrabutylammonium hydroxide. Final purification on a 4-mm rotor chromatotron with pure ethyl acetate gave, after drying of 0.44 g (1.2 mmol) of pure product, so pl. 113 - 115oC (uncorrected); UVmax( ): pH 7.0: 278,9 nm (7800) and 247,6 nm (8300); 0,1 HCl solution: 287,5 (7000) and 242,8 (5700); 0.1 N. NaOH solution: 279,0 (7600) and 248,5 (7100); MC (E1): m/z 208 (C8H10N5O2); 194 (C7H8N5O2); 178 (C1H-NMR (300 MHz, Me2SO-d6): to 7.84 (s, 1H, H-8); 6,48 (br. s, 2H, NH2); 6,16 (d, 1H, H-1', J = 4.0 Hz); 5,77 (d, 1H, 2' or 3'-OH, J = 4.6 Hz); of 5.68 (d, 1H, 2' or 3'-OH, J = 3,9 Hz); 4,35-to 4.23 (m, 2H, H-2' and 3'); 4,11 - 4.09 to (m, 2H, H-5'); of 3.96 (s, 3H, Pur-OC ); 3,95 - to 3.92 (m, 1H, H-4'); 2,55 (septet, 1H-C(O)C (CH3)2, J = 7,0 Hz); 0,08 (dd, 6H, -C(O)CH(C )2, J = 7,0 Hz, J = 1.8 Hz); IR (KBr): 1734,3, 1616,0 and 1592,5 cm-1.

Analytical calculation for C15H21N5O60,20 C4H8O2:

calculated: C 49,29; H of 5.92; N 18,19;

found: C 49,09; H 5,97; N 18,16.

i) 9-(2,3,5-tri-O-Acetyl- -D-arabinofuranosyl)-2-amino-6 - methoxy-N-purine.

2-Amino-9-( - -arabinofuranosyl)-2-amino-6-methoxy-9-purine (2.5 g, 8.4 mmol) was added in a 250 ml round bottom flask and dried by co-evaporation with pyridine (2 x 25 ml). The residue was dried in vacuum pump for 2 hours was Added 4-N,N-dimethylaminopyridine (0.10 g, 0.8 mmol), then the flask was purged with argon and closed by a partition. Added dry acetonitrile (50 ml), then triethylamine (8.5 ml) and acetic anhydride (2.6 ml, 27.7 mmol). The solution is stirred at room temperature for 3 hours Thin layer chromatography on silica gel with acetone: CHCl3(1:10) showed that all starting material (Rf= 0,05) were reacted and formed one high is I. The residue was separated between ethyl acetate (300 ml) and 5% NaCO3(50 ml). The organic layer was washed with water (2 x 50 ml), the combined aqueous layers back was extracted with ethyl acetate (100 ml). Finally the combined organic extracts were dried (MgSO4), filtered and concentrated. The crude product was purified on silicagel column (5 x 18 cm) eluruumi a mixture of acetone : CHCl3with the ratio of 1:1. After drying, the product was received in the form of a white solid weight to 3.38 g (7,98 mmol). This substance was recrystallized from ethyl acetate and heptane to obtain after drying of 2.97 g (7.0 mmol); so pl. 178-180oC (uncorrected), UVmax( ): pH 7,00: 279,5 nm (8500), 247,6 nm (9100); 0,1 HCl solution: 287,2 (7600), 244,4 (6700); 0,1 N. NaOH solution: 278,9 (8900), 249,0 (8300); MC (E1): m/z 424 (M+H, C17H22N5O8); 380 (C15H18N5O7); 364 (C15H18N5O5); 259 (C11H15O7); 194 (C7H8N5O2); 166 (C6H8N5O); 165 (C6H7N5O); 149 (C5H3N5O); 139 (C7H7O3); 42 (C2H2O).

1H-NMR (Me2SO-d6, 200 MHz): a 7.92 (s, 1H, H-8); is 6.54 (br, s, 2H, NH2); 6,35 (d, 1H, H-1', J = 4.6 Hz); 5,46-of 5.40 (m, 2H, H-2' and 3'); to 4.41-4,20 (m, 3H, H-4' and 5'); 3,9 UB>17
H21N5O8:

calculated: C 48,23; H 5,00; N 16,54;

found: C 48,32; H is 4.93; N 16,24.

j) 9-(3,5-di-O-Acetyl- -D-arabinofuranosyl)-2-amino-6-methoxy-N-purine.

2-Amino-9-(2,3,5-tri-O-acetyl)- - -arabinofuranosyl)- 6-methoxy-9-purine (2.0 g, 4,72 mmol) was added in a 250 ml round bottom flask with sodium acetate (1.2 g, of 14.2 mmol) and chloride oxyamine (0,98 g of 14.2 mmol). The flask was purged with argon, supplied razmeshivatelyami and partition. Added dry pyridine (25 ml), the solution stirred at room temperature for 7 hours Thin layer chromatography on silica gel with acetone:CHCl3(1 : 10) showed that the starting material (Rf= 0,68) reacted and formed one small peak with Rf= 0,47. The reaction mixture was treated with acetone (20 ml) and then concentrated to dryness, again stirred with acetone (100 ml) and concentrated. The residue was mixed with acetone (100 ml) and filtered. The precipitate was washed with acetone, the filtrate was concentrated to a yellow oil. The crude product was purified on silicagel column (5 x 18 cm), eluruumi a mixture of acetone : CH2Cl2(1 : 1). The product after drying was obtained in the form of a white substance in the solid phase weight of 1.46 g (a 3.83 mmol).1H-NMR spectroscopy showed that the emission of dichloromethane and heptane, and first vykristallizovyvalas 2,5-diacetate. 3,5-diacetate was obtained as white crystals weighing coefficient was 0.796 g (of 2.08 mmol) after two precrystallization: so pl. 109 - 110oC (uncorrected); UVmax( ): pH 7,00: 278,9 nm (8 400), 247,9 nm (9 000); 0,1 HCl solution: 286,9 (8 300), 244,5 (7 300); 0,1 N. NaOH solution: 279,0 (8 500), 247,6 (8 000); MC (E1): m/z 381 (M+H, C15H19N5O7); 383 (C13H16N5O6); 194 (C7H8N5O2); 166 (C6H8N5O);

165 (C6H7N5O); 135 (C5H5N5); 43 (C2H3O).

1H-NMR (Me2SO-d6, 200 MHz): 7,89 (s, 1H, H-8); 6,50 (br. s, 2H, NH2); 6,18 (d, 1H, H-1', J = 4,9 Hz); 6,14 (d, 1H, 2'-OH, J = 4,1 Hz); 5,10 (t, 1H, H-3', J = 2.7 Hz); 4,42 - to 4.23 (m, 3H, H-2' and 5'); 4,16 - 4,08 (m, 1H, H-4'); 3,95 (s, 3H, Pur-OC ); 2,10 (s, 3H, C(O)CH3); a 2.01 (s, 3H, C(O)CH3).

Analytical calculation for C15H19N5O70,10 CH2Cl2:

calculated: C 46,52; H 4,96; N 17,96;

found: C 46,31; H 5,13; N 17,70.

k) 9-(2,5-di-O-Acetyl- -D-arabinofuranosyl)-2-amino-6-methoxy - N-purine.

2-Amino-9-(2,3,5-tri-O-acetyl)- - -arabinofuranosyl)-6-methoxy-9-purine (2.0 g, 4,72 mmol) was added in a 250 ml round bottom flask with sodium acetate (1.2 g, of 14.2 mmol) and chloride oxyamine (0,98 g of 14.2 mmol). The flask was purged with Argos temperature for 7 hours Thin layer chromatography on silica gel in acetone : CHCl3(1 : 1) showed that the starting material (Rf= 0,68) reacted and formed one small peak with Rf= 0,47. The reaction mixture was treated with acetone (20 ml), concentrated to dryness, again mixed with acetone (100 ml) and concentrated. The residue was mixed with acetone (100 ml) and filtered. The precipitate was washed with acetone, the filtrate was concentrated to obtain a yellow oil. The crude product was purified on silicagel column (5 x 18 cm), eluruumi a mixture of acetone : CH2Cl2(1 : 1). The product was obtained after drying in the form of a white substance in the solid phase weight of 1.46 g (a 3.83 mmol).1H-NMR spectroscopy showed that the substance was a mixture of 3,5-diacetate and 2,5-diacetate. These two products were separated using recrystallization from dichloromethane and heptane emitting first 2,5-diacetate. 2,5-Diacetate was obtained as white crystals weighing 0,256 g (0.67 mmol) after two precrystallization: so pl. 210 - 212oC (uncorrected), UVmax( ) : pH 7.0: 279,2 nm (8 200), 248,3 nm (8 700); 0,1 HCl solution: 287,1 (7 800), 244,3 (6 200); 0,1 N. NaOH solution: 278,7 (8 600), 248,7 (7 900); MC (M1): m/z 381 ( M+H, C15H19N5O7); 338 (C13H16N5O6); 250 (C10/SUB>N5O); 165 (C6H7N5O); 157 (C7H9O4); 139 (C7H7O7); 135 (C5H5N5); 43 (C2H3O).

1H-NMR (Me2SO-d6, 200 MHz): 7,89 (s, 1H, H-8); 6,51 (br. s, 2H, NH2); 6,32 (d, 1H, H-1', J = 5.7 Hz); 5,98 (d, 1H, 3'-OH, J = 3,9 Hz); by 5.18 (t, 1H, H-2', J = 2.7 Hz); of 4.44 - 4,22 (m, 3H, H-3' and 5'); 4,07 - of 3.97 (m, 1H, H-4'); of 3.94 (s, 3H, Pur-OC ); 2,02 (s, 3H, C(O)CH3); of 1.78 (s, 3H, C(O)CH3).

Analytical calculation for C15H19N5O70,40 CH2Cl20,05 C7H16:

calculated: C 45,01; H 4,94; N 16,66;

found: C 44,92; H to 4.92; N 16,51.

1(i) 9-(2-O-Acetyl-3,5-di-O-tert-butyldimethylsilyl- -D-arabinofuranosyl)-2-amino-6-methoxy-N-purine.

2-Amino-9-(3,5-di-O-tert-butyldimethylsilyl- -D-arabinofuranosyl)- 6-methoxy-N-purine (0.5 g, 0.95 mmol) was weighed in burnt dried 100-ml round bottom flask. Was added 4-N,N-dimethylaminopyridine (0.01 g, 0.09 mmol), the flask was purged with argon and closed by a partition. Added dry acetonitrile (25 ml) and triethylamine (5.0 ml), the solution was cooled in a bath of ice. Using a syringe and needle to the solution was added acetic anhydride (of 0.11 ml, 1.1 mmol). The reaction mixture was analyzed by thin layer chromatography on silica gel with acetone : CHCl3(1 : 10). After in what was balsa one large peak (Rfor = 0.51). The reaction mixture was concentrated, the residue is stirred in ethyl acetate (75 ml) and was extracted with NaHCO (25 ml) and then water (2 x 25 ml). The organic layer was dried with MgSO4(anhydrous), filtered and concentrated to obtain a light yellow oil. The residue was purified on silicagel column (12.5 x 14 cm, grit 230 - 400) eluruumi a mixture of acetone : CHCl3(1 : 4). Pure product was isolated as a white substance in the solid phase (of 0.58 g, 1.0 mmol); so pl. 74 - 76oC (uncorrected); MC (E1): m/z 568 (C25H46N5O6Si2); 552 (C24H42N5O6Si2); 510 (C21H36N5O6Si2); 378 (C15H20N5O5Si): 261 (C11H25O3Si2); 250 (C10H12N5O3); 194 (C7H8N5O2); 166 (C6H8N5O).

1H-NMR (CDCl3, 200 MHz): to 7.95 (s, 1H, H-8); 6,38 (d, 1H, H-1', J = 5.6 Hz); 5,33 (t, 1H, H-2', J = 5.7 Hz); 4,85 (br. s, 2H, NH2); 4,58 (t, 1H, H-3', J = 5.8 Hz); of 4.05 (s, 3H, -OCH3); 3,94 - of 3.80 (m, 3H, H-4' and H-5'); 1,78 (s, 1H, C(O)CH3); of 0.93 (s, 9H, -SiC(CH3)3); to 0.89 (s, 9H, -SiC(CH3)3); of 0.11 to 0.08 (m, 12H, -Si(CH3)).

Analytical calculation for C25H45N5O6Si2:

calculated: C 52,88; H 7,99; N S="ptx2">

Siciliano intermediate compound 2-amino-9-[(2-O-acetyl - 3,5-di-O-tert-butyldimethylsilyl)- -D-arabinofuranosyl]-6 - methoxy-9-purine (0,46 g, 0.8 mmol) was weighed in RBF, equipped with razmeshivaem device and a rubber septum. Added fluoride of tetraethylammonium (0,48 g, 3,24 mmol), and then a THF solution (40 ml) and acetic acid (of 0.18 ml, 3.2 mmol). The solution was cooled in a bath with ice to 0 - 5oC. After exposure for 48 h at 0 to 5oC thin-layer chromatography in acetone : CHCl3(1 : 10) showed that starting material was consumed (Rf= 0,37), formed one of the main low peak Rf= 0,07. The reaction mixture was sent directly to silicagel column (grit 230 - 400, size 5 x 12 cm) and suirable a mixture of acetone : CHCl3(1 : 10, 300 ml) and then acetone : CHCl3(5 : 4, 900 ml). Pure product from the column was obtained after drying in the form of a white substance in the solid phase (0.21 g, to 0.63 mmol) and as was shown, it was the desired 2'-O-acetyl derivative; so pl. 66 - 68oC (uncorrected); UVmax( ): pH 7,00: 279,0 nm (8100), 247,9 nm (8400); 0,1 HCl solution: 286,4 (8500), 243,4 (7000); 0,1 N. NaOH solution: 278,8 (8700), 246,7 (8600); MC (E1): m/z 339 (M, C13N17N5O6); 296 (C11H14N5O); 166 (C6H7N5O).1H-NMR (Me2SO-d6, 200 MHz): 7,94 (s, 1H, H-2) of 6.49 (br. s, 2H, NH2); 6,27 (d, 1H, H-1', J = 5.5 Hz); of 5.82 (d, 1H, 3'-OH, J = 5,1 Hz); by 5.18 (t, 1H, H-2', J = 5.3 Hz); 5,02 (t, 1H, 5'-OH, J = 5.6 Hz); 4,33 (ddd, 1H, H-3', J3',3'-OH= 5,1 Hz, J2',3'= 5.3 Hz, J3',4'= 5.8 Hz); of 3.94 (s, 3H, Pur-OC); 3,85 - with 3.79 (m, 1H, H-4'); 3,68 - of 3.60 (m, 2H, H-5'); to 1.76 (s, 3H, C(O)CH3).

Analytical calculation for C13H17N5O60,40 CHCl30,25 C3H6O:

calculated: C 44,36; H 4,99; N 18,54;

found: C 44,38; H 5,27; N 18,28.

m (i) 2-Amino-9-(2,3,5-tri-O-acetyl- -D-arabinofuranosyl)-6-methoxy-N-purine.

2-Amino-4-( -D-arabinofuranosyl)-6-methoxy-N-purine (1.5 g, of 5.05 mmol), triethylamine (of 3.06 g, 30.3 mmol) and acetic anhydride (to 2.06 g, a 20.2 mmol) stirred for 3 h at room temperature in 15 ml of dry DMF under nitrogen atmosphere. Then the solution was diluted with ethyl acetate (100 ml), the organic phase is washed with 2 x 100 ml portions of 10% NaHCO3. The solvent was removed by evaporation rotation, receiving 2,05 g (96%) of oil which was crystallized after maturation throughout the night: thin layer chromatography (silica gel) with chloroform : methanol (90 : 10) Rf= 0,63.

1H-NMR (DMSO): to 1.86 (s, 3H, OAc); to 2.06 (s, 3H, OAc); 2,12 (s, 3H, OAc); of 3.97 (s, 3H, OCH3); to 4.2 to 4.5 (m, 3H, C-4' and C-5'); 5,4 - 5,5 (m,idofuranose)-6-methoxy - N-purine.

A mixture of 2-amino-9-(2,3,5-tri-O-acetyl- -D-arabinofuranosyl)-6-methoxy-9-purine (10.0 g, 23.6 mmol), anhydrous sodium acetate (19,4 g, 236 mmol) and chloride oxyamine (16.4 g, 236 mmol) stirred for 17 h in 200 ml of pyridine at ambient temperature. Then the solution was diluted with 50 ml of acetone, most of the solvent was removed by evaporation rotation. The remaining sediment in the form of oil was purified using flash chromatography on a column (size h cm, grit 230 - 400) using CHCl3: acetone (1 : 1) as eluent. The appropriate fractions were concentrated using rotary evaporation, leaving a resinous semi-solid substance. Semi-solid substance liofilizirovanny of 100 ml of water, getting a white powder; so square 138 - 140oC (uncorrected); thin layer chromatography (silica gel) with chloroform : methanol (90 : 10) Rf= 0,27.

1H-NMR (DMSO): 2,03 (s, 3H, OAc); of 3.97 (s, 3H, OCH3); 4,1 - 4,4 (m, 5H, C-2', C-3', C-4' and C-5'); 5,69 (d, J = 3,4 Hz, 1H, OH); 5,78 (d, J = 4,2 Hz, 1H, OH); 6,17 (d, J = 3.6 Hz, 1H, C-1'H); 6.48 in (broad s, 2H, NH2and 7,86 (s, 1H, C-8H).

Analytical calculation for C13H17N5O6H2O:

calculated: C 43,70; H are 5.36; N 19,60;

found: C 43,70; H of 5.34; N 19,52.

Dosage forms, tablets. Forms And the rata magnesium and compression mg/tablet:

Form AND

(a) Active ingredient 250

(b) Lactose C. R. - 210

(c) Povidone C. R. - 15

(d) Glycolate sodium-starch - 20

(e) magnesium Stearate - 5 - 500

(a) Active ingredient 250

(b) Lactose C. R. - 26

(c) Povidone C. R. - 9

(d) Glycolate sodium-starch - 12

(e) magnesium Stearate - 3 - 300

Form

(a) Active ingredient 250

(b) Lactose C. R. - 150

(c) Avicel PH 101 - 60

(d) Povidone C. R. - 15

(e) Glycolate sodium-starch - 20

(f) magnesium Stearate - 5 - 500

(a) Active ingredient 250

(b) Lactose C. R. - -

(c) Avicel PH 101 - 26

(d) Povidone C. R. - 9

(e) Glycolate sodium-starch - 12 - 300

Form

(a) Active ingredient - 100

(b) Lactose C. R. - 200

(c) Povidone C. R. - 50

(d) Glycolate sodium-starch - 5

(e) magnesium Stearate - 4 - 359

Tablets produced from the above ingredients by wet granulation followed by compression. In the alternative receiving povidone C. R. can be replaced by polyvinylpyrrolidone.

The following forms D and E receive the direct compression of the mixed ingredients. Lactose in the form of E - type direct compression (Dairy Crest - "Zeparox"), mg/capsule:

Form D

Active ingredient: 250

Pre is - 00 - 500

Form F (dosage form with the property controlled release means). Form prepared by wet granulation gradients (discussed above) with a solution of povidone followed by the addition of magnesium stearate and compression ratio, mg/tablet:

(a) Active ingredient: 500

(b) Hypromellose (Methocel K4M Premium) - 112

(c) Lactose C. R. - 53

(d) Povidone C. R. - 28

(e) magnesium Stearate - 7 - 700

The drug release occurs within a time of about 6 to 8 hours and is completed in 12 hours

Dosage forms as capsules, mg/capsule

Form AND

Dosage forms as capsules are prepared by mixing the ingredients of the form D, described above, and filling them two piece hard gelatin capsules. The form In (infra) are obtained in a similar way.

Form

(a) Active ingredient 250

(b) Lactose C. R. - 143

(c) Glycolate sodium-starch - 25

(d) magnesium Stearate - 2 - 420

Form

(a) Active ingredient 250

(b) Macrogol 4000 C. P. - 350 - 600

Capsules are produced by melting of macrogol 4000 C. P., dispersion of the active ingredient in the melt and filling the melt of the two parts of the solid Gelati is 50

Capsules are produced by dispersing the active ingredient in the lecithin and peanut oil and infusions of the variance in soft, elastic gelatin capsules.

Form E (capsule with properties of a controlled release drug). These capsules with controlled release of funds obtained by extrusion of the ingredients (a), (b) and (c) using an extruder, followed by spheronization extruded ingredients and drying. The dried beads are then coated membrane (d) with the property controlled release means and place them in a two-part hard gelatin capsule mg/capsule:

(a) Active ingredient 250

(b) Microcrystalline cellulose - 125

(c) Lactose C. R. - 125

(d) Ethylcellulose - 13 - 513

Ophthalmic solution,

The active ingredient is 0.5

Sodium chloride, analytical purity - 0,9

Thiomersal - 0,001

Purified water, ml - 100

Choose the value of pH To 7.5

Dosage form for injection, g

Active ingredient - 0,200

Sterile non-flammable phosphate buffer solution (pH of 7.2), ml - 10

The active ingredient is dissolved in most of the phosphate buffer solution (35 - 40oC), then subarticle (type I) and sealed with sterile closures and stigma.

Intramuscular injection, g

Active ingredient - 0,20

Benzyl alcohol - 0,10

Glucotrol 75 - 1,45

Water for injection, q.s., ml - Up to 3.00

The active ingredient is dissolved in glucotrole. Then add benzyl alcohol, dissolve and add water to 3 ml of the Mixture was then filtered through a sterile Millipore filter and sealed in sterile 3-ml vials of amber glass (type I).

Syrups, g

Active ingredient - 0,25

Solution of sorbitol - 1,50

Glycerol - 2,00

Dispersed cellulose - 0,075

Sodium benzoate - 0,005

Corrigent, peach 17.42.3169, ml of 0.0125

Purified water, q.s., ml - Up to 5.00

Sodium benzoate is dissolved in a portion of purified water and add a solution of sorbitol. Add the active ingredient and is dispersed. In glycerol dispersed seal (dispersed cellulose). The two dispersions are mixed and brought to the desired volume with purified water. Further condensation of reach if necessary, by additional dispersion of the suspension.

Suppository, mg/supposely:

Active ingredient (63 μm)*- 250

Hard fat, BP (Witeposol H15-Dynamit Nobel) - 1700

- 1950

One-fifth of Witeposol H15 is melted in to the rez 200-µm sieve and added to the molten base with mixing, using screening with cutting until a smooth dispersion. Maintaining the temperature of the mixture 45oC, is added to the remaining suspension Witeposol H25 and stir to obtain a homogeneous mixture. The entire suspension is passed through a 250 μm screen of stainless steel, with constant stirring is allowed to cool to 45oC. At a temperature of from 38 to 40oC 2,02 g of the mixture is placed in a suitable plastic melt. Suppositories allowed to cool to room temperature.

The pessary, mg/pessary:

Active ingredient (63 μm)*- 250

Anhydrate-dextrose - 380

Potato starch - 363

Magnesium stearate - 7 - 1000

*The active ingredient used in the form of powder, 90% of the particles of which have a diameter of 63 μm or less.

The above ingredients directly mixed, and pessaries prepared by direct compression of the resulting mixture.

Selective inhibition of growth of T cells. Compounds according to the invention were tested for inhibition of growth of T cells (Molt 4) than In cells (IM9) method (Averett, D., Jounal of Virological Methods, 23, (1989), 263 - 276).

2-Amino-6-methoxy-9-( -D-arabinofuranosyl)-N-purine (compound I) selectively inhibits the growth of T-cells is m ara G (table.1).

Biological value ara Ara G. G and compounds according to the invention is administered orally in a special monkey (Cynomolgus monkey), which before that were isolated at 8 o'clock Each connection gave two monkeys. The magnitude of the dose was 94 nmol/kg, which is equivalent to 27 mg/kg ara G. blood Samples were taken within 24 h urine was collected during the same 24 h concentrations of ara G in extracts of plasma and urine were determined using liquid chromatography high-pressure reversed-phase.

The solubility and biological value of ara G are given in table.2.

1. Mono-, di - or triclinia esters of 2-amino-6-(C1- C5-alkoxy)-9-(- D-arabinofuranosyl)-9H-purine General formula I

< / BR>
where arabinofuranosyl residue substituted for 2'-, 3'- or 5'-positions, and esters formed by carboxylic acids, in which decarbonising part selected from n-propyl, tert-butyl, n-butyl, methoxymethyl, benzyl, phenoxymethyl, phenyl, methanesulfonyl and succinyl.

2. Connection on p. 1, selected from the group consisting of 2-amino-6-methoxy-9-(5'-O-acetyl--D-arabinofuranosyl)-9H-purine; 2-amino-6-methoxy-9-(2', 3'-di-O-acetyl--D-arabinofuranosyl)-9H-purine; 2-amino-6-methoxy-9-(3', 5'-di-O-diacetyl-D-arabinofuranosyl)-9H-purine; 2-amino-what Rin.

3. Connection on p. 2, which is 2-amino-6-methoxy-9-(5'-O-acetyl -- D-arabinofuranosyl)-9H-purine.

4. The method of obtaining the ester purine derivative of General formula I on PP. 1 to 3, characterized in that conduct the esterification of 2-amino-6-methoxy-9--D-arabinofuranosyl-9H-purine.

5. The method according to p. 4, characterized in that the esterification is carried out in the presence of the enzyme.

6. The method according to p. 4, where the hydroxyl group in 2-amino-6-methoxy-9--D-arabinofuranosyl-9H-purine, if necessary, protect before esterification.

7. Pharmaceutical composition having antitumor activity, comprising the active ingredient in an effective amount and a pharmaceutically acceptable carrier, wherein the active ingredient is a purine derivative of General formula (I).

8. The composition according to p. 7, intended for oral administration in unit dosage form.

9. The composition according to p. 8, wherein the single dosage form is a capsule, porridge or tablet.

10. The composition according to p. 8 or 9, where the unit dosage form has a mass of 5 to 1000 mg.

11. The use of 2-amino-6-methoxy-9--D-arabinofuranosyl-9H-purine as is. the label on p. 11, where the tumor disease is T-cell lymphoproliferative disease.

13. Application under item 12, where T-cell lymphoproliferative disease is leukemia or malignant lymphoma.

 

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< / BR>
where R is C1-C4-alkyl, does not necessarily substituted by one or more groups, or R is:

< / BR>
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