1,3-oxathiolan, its geometrical and optical isomers, mixtures of these isomers, the method of production thereof and pharmaceutical composition exhibiting antiviral activity

 

(57) Abstract:

The described compounds of formula

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where R1is hydrogen; R represents a purine or pyrimidine base, its analogue or a derivative thereof; Z is S, S = 0 and SO2and their pharmaceutically acceptable derivatives. It also describes the use of these compounds as antiviral agents, pharmaceutical compositions and methods for producing such compounds. 5 C. and 20 C.p. f-crystals, 3 tables.

The invention relates to new substituted cyclic derivatives of 1,3-oxathiolane having pharmacological activity, to processes for their preparation and intermediate compounds used for their production, to containing these derivatives, pharmaceutical compositions and to the use of these derivatives for the treatment of viral diseases in mammals.

Retroviral infections are a major cause of disease and it is noteworthy that the acquired immunodeficiency syndrome (AIDS). The human immunodeficiency virus (HIV) as the causative agent of AIDS, and in this regard there is an active search for compounds that have an inhibitory effect on the multiplication of HIV.

Mitsuya et al. with TCS. reports th action lymphotropic virus type 111 T-lymphocytes person, associated with lymphadenopathies virus in vitro", Proc. Natl. Acad. Sci. USA, 82, S. 7096 7100 (1985) and refers to a compound of formula (A) (3'-azido-2',3'-dideoxythymidine, commonly called AZT. This connection, as indicated, may be used for some protection AIDS carriers from cytopathogenic steps of human immunodeficiency virus (HIV).

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In the work Mitsuya with TCS. "Inhibition of the infectivity and cytopathic effect lymphotropic virus type 111 T-lymphocytes person associated with lymphadenopathies virus (HTLB-111/LAV) by using 2', 3'-dideoxynucleosides", Proc. Natl. Acad. Sci. USA, 86, pp. 1911 15( 1986) also refers to a group of 2',3'-dideoxynucleotides reflected by the formula (B),which, as indicated, have protective activity against induced HIV cytopathogenicity.

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In the work Balgarini with TCS. "A strong and selective anti-HTLV-111-LAV activity of 2',3'-dideoxycytidine-2',3'-unsubstituted derivative of 2',3'-dideoxycytidine", Biochem. Biophys. Res. Comm. 140 p. 735 742 (1986) refers to unsaturated analogue of such nucleosides (2',3'-dideoxycytidine reflected by the formula (C) as characterizing antiretroviral activity.

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In the work of Baba with TCS. "2',3'-dideoxythymidine and its 2',3'-unsaturated derivative strong invoked on 2',3'-unsubstituted analogue, represented by formula (D), 2', 3'-dideoxythymidine. This analog, as indicated, is a selective inhibitor of HIV replication.

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Analogues AZT, also known as 3'-azido-2',3'-dideoxyuridine represented by the formula (E), in which Y represents a bromine or iodine, as indicated, have inhibitory activity against leukemia, Malone mice. Cm. T. S. Lin with TCS. "Synthesis and antiviral activity of various 3'-azido, 3'-amino, 2', 3'-unsaturated and 2',3'-dimethoxy pyrimidine analogues, deoxyribonucleosides against retroviruses" J. Med. Chem. 30, page 440 41 (1987).

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And, finally, 3'-pornology 2',3'-dideoxycytidine /formula (G)/, indicated in Herdewijn with TCS. "3'-substituted analogues of 2',3'-dideoxynucleosides as potential anti-HIV (HTLV-III/LAV) agents", J. Med. Chem. 30, page 1270 1278 (1987), as have strong antiviral activity.

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Thus, the most powerful of the above anti-HIV compounds are 2',3'-dideoxynucleoside, more specifically 2',3'-dideoxycytidine (ddCyd) and 3'-azido-2',3'-dideoxythymidine (AzddThd or AZT). These connections are active and in relation to other types of retroviruses, such as leukemia virus, Malone mice. Due to growth in the case of disease is snych inhibitors HIV and substances, blocking the infectivity of HIV. Thus, the aim of the invention is the creation of the effectiveness of anti-HIV compounds with low toxicity, and the creation of an easily accessible method for the synthesis of such compounds.

We opened structurally defined class of compounds, namely 2-substituted-5-substituted-1,3-oxathiolanes for which the detected antiretroviral activity. In particular, it was found that these compounds act as non-toxic inhibitors of HIV-1 replication in T-lymphocytes extended periods of time.

Thus, in the first aspect of the invention provides a compound of formula (1)

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where R1is hydrogen; R2represents a radical selected from the formulae given at the end of the descriptions.

Expert it is clear that the compounds of formula (1) have at least two chiral center (indicated in the formula (1) asterisk ( * ), which exist in the form of two pairs of optical isomers (i.e. enantiomers) and mixtures thereof, including receices mixtures. In addition, the compounds of formula (1) can be either CIS-isomers (formula II), or TRANS-isomer (formula III) or a mixture of these isomers. Each of the CIS - and TRANS-isomers can exist is somery and mixtures thereof, including racemic mixtures, are included in the scope of the invention.

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The compounds of formula (1) preferably exist in the form of CIS-isomers.

It is also clear that if z is s 0, the compounds exist in two additional isomeric forms, represented by formulas (IIa) and (IIb), which differ from each other by the configuration of oxide oxygen atom relative to the 2,5-substituents. Compounds of the invention additionally include such isomers and mixtures thereof.

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Preferably R2represents a radical of the formula

,

where R3and R4agree to the above values.

By "pharmaceutically acceptable derivative" is meant any pharmaceutically acceptable salt, ester or salt of such a complex ester compounds of formula (1) or another compound capable of when introducing the recipient to form, directly or indirectly, a compound of formula (1) or antiviral active metabolite or residue.

For professionals it is obvious that the compounds of formula (1) can be modified with the formation of its pharmaceutically acceptable derivatives in functional groups as in the fragment base R2and hydroxymethyl is, however, of particular interest are the pharmaceutically acceptable derivatives (e.g. esters) obtained by modification of the 2-hydroxymethylene group oxathiolane cycle.

Featured esters of compounds of formula (1) include compounds in which R1substituted carboxyl function , where decarbonising part R of the ester group is selected from hydrogen, alkyl, normal or ISO-structure (for example, methyl, ethyl, n-propyl, tert-butyl, n-butyl, alkoxyalkyl (for example, methoxymethyl), aralkyl, (e.g., benzyl), aryloxyalkyl (e.g. phenoxymethyl), aryl (e.g. phenyl, possibly substituted with halogen, C1-C4-alkyl, C1-C4the alkoxy group); substituted dihydropyridine (e.g. N-methyldihydromorphine); sulphonate esters such as alkyl or aralkylamines (e.g. methanesulfonyl); sulfate esters; amino acid esters (e.g. L-poured or L-isoleucyl) and mono-, di - and trifosfatnogo ethers.

These esters also included are esters formed from polyfunctional acids, such as carboxylic acids containing more than one carboxyl, for example dicarboxylic acid of the formula HO2C(CH2)nCO2OH, where n is 1 to 10 (e.g., succinic acid) or phosphoric acid. Methods of obtaining such finddevice man" Nucleotide Analogues, page 156 159 (1989) and Busso with TCS. "Dimers of molecules that suppress the expression of HIV in vitro", AIDS Research and Human Retroviruses, 4 (6), page 449 455 (1988). In the formation of esters of these acids each acid group preferably etherification compound of formula (I) or other nucleosides, or their analogues and derivatives with the formation of esters of the formula (IV)

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where W is PO-4, SPO-3or-O-CO-(CH2)n-CO-O-, where J is the remainder oxo - or aminopyrimidine, which may be substituted by lower alkyl, or the residue of 6'-chloro or 6'-hydroxypurine, R2and Z have the values listed above.

With regard to the above-described esters, unless otherwise specified, any alkyl fragment mainly contains 1 to 16 carbon atoms, preferably 1 to 4 carbon atoms and may contain one or more double bonds. Any aryl fragment present in such esters, predominantly represents phenyl.

In particular, it may be C1-C16-alkilany ether, unsubstituted benzoyloxy ether or benzoyloxy ether, substituted by at least one halogen (bromine, chlorine, fluorine or iodine), a saturated or nemesisurvivorleon.

Pharmaceutically acceptable salts of compounds of formula (I) include salts formed with pharmaceutically acceptable organic or inorganic acids and bases. Examples of acceptable acids include hydrochloric, Hydrobromic, sulphuric, nitric, perchloro, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, p-toluensulfonate, tartaric, acetic, citric, methansulfonate, benzoic, malonic, naphthalene-2-sulphonic and benzosulfimide acid. Other acids, such as oxalic, while not pharmaceutically acceptable may be used to produce salts, used as intermediates for producing compounds of the invention and their pharmaceutically acceptable salts with acids.

Salts derived from appropriate bases include melodramatycheskye salts (e.g. sodium), salts of alkaline earth metal (e.g. magnesium), ammonium salts and salts ion NR+4(where R is C1-C4-alkyl).

In subsequent references to the compound of the invention include compounds of formula (I) and their pharmaceutically acceptable derivatives.

Specific examples of joint is Jn-1'-yl)-1,3-oxathiolane and mixtures thereof;

CIS-2-benzoyloxymethyl-5-(cytosine-1'-yl)-1,3-oxathiolan;

TRANS-2-benthological-5-(cytosine-1'-yl)-1,3-oxathiolane and mixtures thereof;

CIS-2-hydroxymethyl-5-(N'4-acetyl - cytosine-1'-yl)-1,3-oxathiolan;

TRANS-2-hydroxymethyl-5-(N'4-acetyl - Cytosar-1'-yl)-1,3-oxathiolane and mixtures thereof;

CIS-2-benzoyloxymethyl-5-(N'4-acetyl - cytosine-1'-yl)-1,3-oxathiolan;

TRANS-2-benzoyloxymethyl-5-(N'4-acetyl - cytosine-1'-yl)-1,3-oxathiolane and mixtures thereof;

CIS-2-hydroxymethyl-5-(cytosine-1-yl)-3-oxo-1,3-oxathiolan;

CIS-2-hydroxymethyl-5-(N-dimethylamino - Meilenstein-1'-yl)-1,3-oxathiolan;

bis-CIS-2-scleroxylon-5-(cytosine-1'-yl)-1,3-oxathiolan;

CIS-2-benzoyloxymethyl-5-(6'-globulin-N-9'-yl)-1,3-oxathiolan;

TRANS-2-benzoyloxymethyl-5-(6'-globulin-N-9'-yl)-1,3-oxathiolane and mixtures thereof;

CIS-2-hydroxymethyl-5(6'-hydroxypurine-N-9'-yl)-1,3-oxathiolan;

CIS-2-benzoyloxymethyl-5-(uracil-N-1'-yl)-1,3-oxathiolan;

TRANS-2-benzoyloxymethyl-5-(uracil-N-1'-yl)-1,3-oxathiolane and mixtures thereof;

CIS-2-hydroxymethyl-5-(uracil-N-1'-yl)-1,3-oxathiolan;

CIS-2-benzoyloxymethyl-5-(thymine-N-1'-yl)-1,3-oxathiolan;

TRANS-2-benzoyloxymethyl-5-(thymine-N-1'-yl)-1,3-oxathiolane and mixtures thereof;

CIS-2-hydroxymethyl-5-(thymine-N-1'-yl)-1,3-oxania.

Compounds of the invention or possess antiviral activity and/or are able to metabolize these compounds. In particular, these compounds are effective in inhibiting the replication of retroviruses, including human retroviruses such as the human immunodeficiency viruses (HIV), which causes AIDS.

Thus, as another aspect of the invention provides a compound of formula (I) or its pharmaceutically acceptable derivative intended for use as an active therapeutic agent, in particular antiviral agents, for example for the treatment of retroviral infections.

In another or alternative aspect of the invention provides a method of treating viral diseases, in particular caused by a retrovirus infections, such as HIV in a mammal, including humans, the method consists in the introduction of effective antiviral compounds of the formula (I) or its pharmaceutically acceptable derivative.

In addition, in the same or alternative aspect of the image given by the formula (I) or its farmatsevticheskii acceptable derivative for the preparation of drugs intended for the Pid States, such as AIDS related complex (ARC), persistent generalized lymphadenopathy (PGL), AIDS-related nevrologicheskie conditions (such as dementia), the state with antovic positive antibody status with HIV-positive reaction, sarcoma, Kaposi, thrombocytopenia purpura and opportunistic infections.

Compounds of the invention are also applicable to the prevention or development to clinical disease, individuals with anti-HIV antibodies or HIV-positive antigen, and also to prevent States after HIV infection.

The compounds of formula (I) or their pharmaceutically acceptable derivatives may also be used to prevent infection biological liquids such as blood or semen in vitro.

Individual compounds of the formula (I) are also applicable as intermediates in obtaining other compounds of the invention.

For professionals it is obvious that links here to apply treatment and prevention, as well as for treatment of the identified infections and symptoms.

It is also clear that the amount of the compound of the invention required for the treatment will vary not only in the Covenant and condition of the patient, and fully within the competence of the attending physician or veterinarian. Typically, however, the appropriate dosage will be the interval 1-750 mg/kg of body weight per day, for example, 3-120 mg/kg of body weight of the recipient per day, preferably 6-90 mg/kg/day, most preferably 15-60 mg/kg/day.

The target dose may be given as a single dose or in separate doses, administered at appropriate intervals, for example as two, three, four or more subds daily.

The compound is usually administered in a single dosage form containing, for example 10-1500 mg, usually 20-1000 mg, more usually 50-700 mg of the active component in a unit dosage form.

Ideally the active ingredient should be entered so that the peak concentration of the active component in plasma was 1-75 microns, preferably 2-50 μm, most preferably 3-30 μm. This can be achieved, for example, intravenous injection of 0.1-5% salt solution of the active component, possibly in saline solution or the introduction of a bolus containing 0.1-110 mg/kg of the active ingredient. The target concentration in the blood can be achieved by continuous infusion to provide from 0.01 to 5 mn/kg/h or prerevenue compounds of the invention in the form of the raw chemical, however, it is recommended to give the active ingredient in the form of a pharmaceutical composition.

Thus, the invention also provides a pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable derivative in a mixture with one or more pharmaceutically acceptable carriers and, possibly, other therapeutic and/or prophylactic ingredients. The carrier(s) must be "acceptable" in the sense of compatibility with other components of the composition and not to give harm to the recipient.

Pharmaceutical compositions include compositions suitable for oral, rectal, nasal, local (including transbukkalno and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form acceptable for administration by inhalation or insufflate. The compositions can be introduced where necessary, in a separate dosage form and prepared by any well-known in pharmacy way. All methods include the stage of mixing the active compound with liquid carriers or finely powdered solid carriers, or both, followed if necessary by forming the product in a is Wallpaper discrete singular form, such as capsules, areas, tablets, each containing a specified number of the active component, powders or granules in the form of solutions, suspensions or emulsions. The active ingredient may also be present in the bolus, electuary or pasta. Tablets and capsules for oral administration may contain conventional additives, such as binders, fillers, lubricants, resolutely or wetting means. The tablets may be coated in a well-known coating methods. Oral liquid preparations may be, for example, aqueous or oily suspensions, solutions, emulsions, syrups or Alexiou or may be a dry product intended for dilution with water or other acceptable media before use. Such liquid preparations may include conventional additives, such as suspendresume tools, emulsifying agents, non-aqueous carriers (including edible oils), or preservatives.

Compounds of the invention can be also introduced in parenteral formulations (e.g., for injection, such as bolus injection or continuous infusion) may be present in unit dosage form in ampoules, pre-filled syringes, Levanevsky a suspension, solutions or emulsions in oily or aqueous media and may include ancillary tools, such as suspendida, stabilizing and/or dispersing the funds. Or the active ingredient may be a powder, prepared with aseptic allocation of sterile solid component by lyophilization of the solution followed by dilution before use acceptable carrier, e.g. sterile, containing no pyrogen water.

For local application on epidermis compounds of the invention can be in the form of ointments, creams, lotions or patches. Ointments and creams can be prepared, for example, aqueous or oily base with the addition of acceptable thickener and/or celebritysee funds. Lotions can be cooked in oil or water-based and, in addition, typically include one or more emulsifiers, stabilizers, dispersing funds, suspendida agents, thickeners or dyes.

Formulations suitable for topical use in the oral cavity include logidis containing the active ingredient in a flavor, usually sucrose, gum acacia or trigiante; tablets containing the active ingredient in enesee active component in an acceptable liquid carrier.

Pharmaceutical compositions suitable for rectal administration and containing solid carrier, most preferably have the form of candles with a single dose. Acceptable carriers include cocoa butter and other materials commonly used for this purpose, and candles is usually prepared by mixing the active compounds with the softened or melted carrier(s) followed by chilling and shaping in the form.

Formulations for vaginal introduction can be in the form of pessaries, tampons, creams, gel, paste, foam, or composition for spraying, in addition to containing the active ingredient such carriers, which are suitable for this specific purpose.

For vnutripuzarnogo the introduction of the compounds of the invention can be used in the form of a composition for injection or dispersible powder or in droplet form.

Drip form can be prepared in aqueous or non-aqueous base containing, in addition, one or more dispersing means, solubilizers funds or suspendida funds. Liquid compositions for injection can be obtained from pressurized containers.

With the introduction by inhalation the compounds of the invention typically do the ACI aerosol composition. Pressurized containers may contain acceptable propellant, such as DICHLORODIFLUOROMETHANE, Trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other acceptable gas. In the case of a pressurized aerosol single dosage can be set by using the provided valve, feed a measured amount of the mixture.

Or for administration by inhalation or insufflate compounds of the invention can be in the form of a dry powder composition, for example a powder mix of the compound and acceptable powder base such as lactose or starch. The powder composition may be a single dosage form such as a capsule or cartridge, or, for example, gelatin or bubble packs from which the powder may be introduced using an inhaler or insufflator.

If desired, the above compounds may be converted to compounds with an extended selection of the active component.

The pharmaceutical compositions of the invention may include other active ingredients such as antimicrobial agents or preservatives.

Compounds of the invention can also be used in combination with other lia may be taken together with the known antiviral agents.

Thus, another aspect of the invention provides a combination comprising the compound of formula (1) or its physiologically acceptable derivative in a mixture with other therapeutically active agent, in particular an antiviral agent.

These combinations usually are intended for use in the form of a pharmaceutical composition and thus pharmaceutical compositions comprising a combination of the above in a mixture with a pharmaceutically acceptable carrier, are another aspect of the invention.

Acceptable therapeutic tools for such combinations include acyclic nucleosides such as acyclovir, ganciclovir, interferons such as alpha-, beta - and gamma-interferon; glucuronoside inhibitors such as probenecid; inhibitors transfer nucleoside, such as dipyridamole; analogues of nucleosides, such as: 3'-azido-2', 3'-dideoxythymidine, 2', 3'-dideoxycytidine, 2', 3'-dideoxyadenosine, 2', 3'-dideoxyinosine, 2', 3'-dideoxythymidine, 2', 3'-dideoxy -2', 3'-didehydrothymidine and 2', 3'-dideoxy-2', 3'-didehydrothymidine and ribavirin, immunomodulators such as interleukin 11(IL2) and the factor, colony stimulating granulocyte macrophages (GM-CSF), retrop is, 1-deoxynojirimycin, inhibitors of the binding of HIV to CD4 receptors, such as soluble CD4, CD4 fragments and hybrid molecule CD4.

The individual components of such combinations can be entered either individually or simultaneously in separate or combined pharmaceutical formulations.

When using the compounds of formula (1) or its pharmaceutically priemlevogo derivative in combination with a second therapeutic agent, which is active against the same virus, the dose of each compound may be the same or different from the dose used in a separate connection. The required dose can be easily determined by the expert.

The compounds of formula (1) and their pharmaceutically acceptable derivatives may be synthesized by any applicable method of obtaining compounds of similar structure.

The symbols R1and R2in the following formulas above values, unless otherwise specified.

In one of the following ways (A) use the reaction of 1,3-oxathiolane formula (VIII)

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where R1represents hydrogen or protection for the hydroxyl group, and L is capable of replacing or atom with an appropriate base R2 the m or chlorine, or a radical-OR where R represents a substituted or unsubstituted, saturated or unsaturated alkyl, for example, C1-C6-alkyl, such as methyl, or R is substituted or not substituted, aliphatic or aromatic acyl, e.g. aliphatic C1-C6-acyl, such as acetyl and aromatic acyl such as benzoyl.

The compound of formula (VIII) enter into reaction with the corresponding purine or pyrimidine base of formula R2-H, (pre similarbank using cilleruelo agent, such as hexamethyldisilazane) in an acceptable solvent such as methylene chloride, in the presence of a Lewis acid such as titanium tetrachloride or tin chloride (IV) or trimethylsilyltriflate.

1,3-oxathiolan formula (VIII) can be prepared, for example, by reaction of the aldehyde of formula (VII) with mercaptoacetate formula (VI) in an acceptable organic solvent, such as toluene, in the presence of an acid catalyst such as p-toluensulfonate or a Lewis acid such as zinc chloride.

(VI) HSCH2CH(OC2H5)2; C6H5COOCH2CHO (VII)

Mercaptoacetate formula (VI) can be synthesized by known

The aldehyde of formula (VII) can be obtained by known methods. Cm. for example, E. G. Halloquist and H. Hibbert, "research in the field related to carbohydrates and polysaccharides. Part XLIV. Synthesis of isomeric bicyclic acetylenic ethers", Can. J. Research, 8, pp. 129-136 (1933).

The resulting compound of formula (1) is transformed into another compound of formula (1) by interconversion of reasons. This vzaimoprevrascheny can be carried out either simple chemical transformation (e.g. turning Aracinovo of the base cytosine) or by using, for example desoxyribonuclease. Such methods and conditions for their implementation are well known in chemistry of nucleosides.

In another method, the compounds of formula (1) can be obtained by reaction of compounds of formula (IX)

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with the compound of the formula (X)

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where P represents a protective group, followed by removal of the protective group.

The compound of formula (IX) can be synthesized by reaction of the appropriate epoxide of the formula (XI)

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with a corresponding sulfur-containing compound, such as thioacetate sodium. The compounds of formula (XI) are either known or can be synthesized by similar methods.

Many , Nucleoside analogues: chemistry, biology and medical applications", Ed. by R. T. Walker et al. Plenum Press, new York, pp. 193-223, the text of this publication is introduced here as a reference.

Obviously, the above reactions may require the use of protecting groups or can be made using the parent compounds with protected functional groups, resulting to obtain the target compound may be necessary to remove the intermediate or end-stage protective group. Protect and unprotect functional groups can be carried out using conventional means. Examples of acceptable protective for hydroxyl groups include alkyl (e.g. methyl, tert-butyl or methoxymethyl), aralkyl (for example, benzyl, diphenylmethyl or triphenylmethyl), heterocyclic groups such as tetrahydropyranyl, acyl (e.g. acetyl or benzoyl), and silyl groups such as trialkylsilyl (for example, tert-butyldimethylsilyl). Protecting the hydroxyl group can be removed by conventional methods. So, for example, alkyl, silyl, acyl and heterocyclic groups can be removed by solvolysis, for example by hydrolysis in the presence of acid or base. Kalkilya group, the ilen group, such as benzyl, can be derived, for example, by treatment with efratom BF3and acetic anhydride with the subsequent removal of the acetate groups formed at appropriate stages of the synthesis. Silyl group can be easily removed by using a source of fluoride ions, such as Tetra-n-butylammonium.

In the above methods, compounds of formula (1) as a rule, formed as a mixture of CIS - and TRANS-isomers.

These isomers can be separated, for example by acetylation, for example by treatment with acetic anhydride, followed by physical separation methods such as chromatography on silica gel and dezazetilirovanie, for example by treatment of a methanol solution of ammonia or by fractional crystallization.

Pharmaceutically acceptable salts of the compounds of the invention can be obtained as described in U.S. patent N 4383414, the description of which is introduced here by reference. For example, if you want to obtain the salt of the compounds of formula (1) with the acid, the product obtained according to any one of the above methods, can be converted into a salt by processing the obtained free base acid using conventional techniques. Pharmaceutically pryemlemost acceptable solvent, such as an ester (e.g. ethyl acetate), alcohol (e.g. methanol, ethanol or isopropanol). Salts with inorganic bases can be obtained by reaction of the free base of the compounds of formula (1) with an appropriate base such as an alkoxide (e.g. sodium methoxide), possibly in the presence of a solvent, such as alcohol (e.g. methanol). Pharmaceutically acceptable salts can also be obtained from other salts, including other pharmaceutically acceptable salts of compounds of formula (1) using conventional techniques.

The compound of formula (1) can be converted into a pharmaceutically acceptable phosphate or other ester in the reaction with fosforiliruyusciye agent such as POCl3or acceptable etherification agent such as galoyanized acid or anhydride. Ester or salt of the compounds of formula (1) can be transformed into the original connection, for example, by hydrolysis.

So, where the compound of formula (1) preferably be in the form of an individual isomer, it can be obtained either by separation of the final product or stereospecific synthesis of isomere pure starting compound or any of the usual intermediate compounds.

Split tym way. Cm. for example, stereochemistry of carbon compounds, E. L. Eliel (Macgraw hill, 1962), as well as the table separating means, S. H. Wilen.

Further, the invention is illustrated in the following examples, which in no way intended to limit. All temperatures are given in degrees Celsius.

Example 1. Diethylacetal 2-dibenzoylacetylene

C6H5COS-CH2CH(OC2H5)2(Y)

To a solution of tert butoxide potassium (11,5 g, 0.11 mol) in DMF (100 ml) add thiobenzoic acid (17 g, 0.11 mol) and the solution is partially evaporated in vacuum, two successive portions add benzene (230 ml) and every time evaporated in vacuum. To the residual DMF solution add diethylacetal of bromoacetaldehyde (20,3 g, 0.1 mol) and the mixture is stirred for 15 h at 120oC. After cooling, the mixture is transferred into water (500 ml), the extract washed with aqueous solution of NaHCO3then water, dried and the solvent is removed in vacuum. The residue is dispersed in vacuum and get to 17.2 g of pure compound (V), so Kip. 131-133oWith/0,07 mm

1H-NMR (h/min, CDCl3): of 7.97 (d, 2H, aromatic), 7,47 (m, 2H, aromatic), 4,59 (t, 1H,-CH(OC2H5)2), 3,66 (m, 4H, 2OCH2CH3), and 3.3 (d, 2H, SCH2), of 1.23 (t, 6H, 2OCH2
(YI)

Described in the previous dibenzoylperoxide (V) (17,2 g) dissolved in 100 ml of THF, then add 6 g of NaOH in 20 ml of H2O. the Mixture is boiled in an atmosphere of N215 h, then cooled, diluted with water (200 ml) and the product extracted with ether (3200 ml). The extract is dried, the solvent is removed in vacuo and distillation of the residue in vacuum gain of 7.1 g of pure compound (VI), so Kip. 60-62oC/18 mm

1H-NMR s (h/min, CCl3): 4,51 (t, 1H, CH(OC2H5)2), 3,51 (m, 4H, 2 OCH2CH3), 2,65 (LW. d, 2H, H-CH2), and 1.54 (t, 1H,HS), of 1.23 (t, 6H, 2OCH2CH3).

Example 3. Benzyloxyacetaldehyde

C6H5COOCH2CHO (YII)

The title of the known intermediate compound synthesized previously not described on the basis of known 1-benzoylglycine. Namely 50 g latest in a mixture of 500 ml of CH2Cl2and 25 ml of H2O handle portions 80 g NaIO4(intensive mixing at room temperature). Upon completion of addition, stirring is continued for 2 hours, then add 100 g MgSO4and stirring is continued for further 30 minutes the Mixture is filtered, the filtrate is evaporated in vacuo and distillation of the residue in vacuum to obtain 26 g of pure compound (VII), so Kip. 92-94oC (0,25 Miu ), to 7.6 (m, 1H, aromatic), 7,46 (m, 2H, aromatic), 4,88 (s, 2H, -CH2CHO).

Example 4. 2-Benzoyloxymethyl-5-ethoxy-1,3-oxathiolan

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The previously described acetal of mercaptoacetate (VI) (7 g) are mixed in 100 ml of toluene with 7 g of the above benzyloxyacetaldehyde (VII), a few crystals of p-toluenesulfonic acid and the mixture is heated in an atmosphere of N2at an oil bath at 120oC. the Formed ethanol to allow Athanasia, the mixture was kept at 120oC for another 30 min, then cooled, washed with aqueous solution of NaHCO3, dried and evaporated in vacuum. Distillation of the residue in vacuum gain of 9.8 g of pure compound (XIII) in the form of a mixture of CIS - and TRANS-isomers, so Kip. 140 143oC /0.1 mm, Rfof 0.51 (hexane-EtOaC).

(ppm, CDCl3) with 8.05 (m, 2H, aromatic), EUR 7.57 (m, 1H, aromatic), the 7.43 (m, 2H, aromatic), of 5.55 (m, 2H, C2-H C5(H) 4,55 (m, 2H, C2-C6H5CO2CH2), and 3.8 (m, 1H, C5-C6H5CO2CH2), 3,76 (m, 1H, C5-OCH2CH3), 3,17 (m, 2H, C4-H2), to 1.21 (t, 3H, C5-OCH2CH3).

Example 5. CIS - and TRANS-2-Benzoyloxymethyl-5 - cytosine-1'-yl-1,3-oxathiolane

< / BR>
A mixture of 2.7 g of cytosine, 30 ml hexamethyldisilazane (HMDS) and trimethylsily is in vacuum. The remaining volatile components are removed in high vacuum (15 min), the solid residue is transferred into a 250 ml 1,2-dichloroethane and in a dry argon add 5 g of the above key intermediate compound (XIII) in 50 ml of dichloroethane, and then the 4.7 ml trimethylsilyltriflate (TMTTF). After three days of boiling in a stream of argon, the mixture is cooled and transferred to 300 ml of a saturated aqueous solution of NaHCO3. The organic layer is separated, the aqueous phase extracted with CH2Cl2(2100 ml), the combined extracts washed with water, dried and evaporated in vacuum. The residue is purified by chromatography on silica gel using as eluent CH2Cl2-CH3OH (9 1) and obtain 2.5 g of the pure mixture of CIS-/TRANS-(XIV) in the ratio of 1 to 1, as confirmed1H-NMR. The mixture is separated in the form of N-acetyl derivatives according to the methods described in the following example.

Example 6. CIS - and TRANS-isomers of 2-benzoyloxymethyl-5-(N'4- acetylcytosine-1'-yl)-1,3-oxathiolane

< / BR>
Described in the previous example, the compound (XIV) (2.5 g) in 100 ml of dry pyridine containing 0.1 g of 4 dimethylaminopyridine (DMAP), treated with acetic anhydride (7 ml) at room temperature and after 6 h the mixture is transferred into cold water, then extracted with CHspraut in vacuum, the residual oil purified by chromatography on silica gel (EtOAc-CH3OH 99 1) and obtain 1.35 g of pure TRANS- (XV) in the form more quickly washed out of the product and 1.2 g of pure CIS-(XV) in the form of slowly washed out of the product. Both described 1H-NMR spectroscopy. TRANS-(XV), so pl. 158 160o, Rfof 0.48 (EtOAc-CH3OH 95 5).

UV (CH3OH)max: 297 nm

(ppm, CDCl3): 9 (ush. 1H, C'4-H-Ac), of 8.06 (m, 2H, aromatic), 7,74 (d, 1H, C'6-H), 7,56 (m, 1H, aromatic), 7,47 (d, 1H, C'5-H), was 7.45 (m, 2H, aromatic), 6,53 (LW. d, 1H, C5(H) of 5.89 (LW. d, 1H, C2-H), 4,46 (LW. d, 2H, C2-CH2OCOC6H5), 3,66 (LW. d, 1H, C4-H), 3,32 (LW. d, 1H, C4-H in), 2.25 (s, 3H, NH-COCH3).

CIS-(XV), so pl. 150 152oS, RfOf 0.4 (EtOAc-MeOH 95: 5). For

UV (CH3OH) lmax: 297 nm.

1H-NMR (ppm, CDCl3) 9,03 (ush. 1H, NH-Ac), 8,21 (d, 1H, C'6- H ), with 8.05 (m, 2H, aromatic), 7,6 (m, 1H, aromatic), 7.5 (m, 2H, aromatic), 7,29 (d, 1H, C'5(H) 6,34 (LW. d, C5(H) 5,52 (LW. d, 1H, C2-H), 4,48 (LW. d, 2H, C2-CH2OCOC6H5), 3,66 (LW. d, 1H, C4-H), 3,24 (LW. d, 1H, C4(H) of 2.23 (s, 3H, NH-COCH3).

Example 7. CIS - and TRANS-2-hydroxymethyl-5- (cytosine-1'-yl)-1,3-oxathiolane

< / BR>
a) TRANS-(XVI). In 100 ml metalmeister removed in vacuum, and the residue is crystallized from ether and recrystallization from ethanol-ether get 1741 mg of pure product, so pl. > 220oC (decomp.), described1H and13C-NMR spectra.

1H-NMR (ppm), DMSO-d6): EUR 7.57 (d, 1H, C'6-H,7,18 (d, 2H, C'4N H2, 6,30 (LW. d, 1H, C'5- H, 5,48 (1, 1H, C2H5,18 (t, 1H, C2-CH2OH, the 5.45 (m, 3H, C2-CH2+ C4-H), 3,06 (LW. d, 1H, C4-H).

UV (CH3OH) lmax270 nm.

13C-NMR (DMSO-d6Option XL-300) (ppm):

C'2; C'3; C'5; C'6; C5; C4; C2; CH2OH

154,71; 165,7; 93,47; 140,95; 87,77; 36,14 86,80; 64,71

b) CIS-(XVI). Processing according to the aforementioned method of 375 mg of CIS-(XV) obtain 165 mg of the pure product, recrystallized from ethanol-ether, so pl. 171-173odescribed 1H and13C-NMR spectra.

1H-NMR - s (ppm, DMSO - d6): 7,8 (j, 1H, C'6(H) to 7.2 (d, 2H, C'4NH2), 6,18 (t, 1H, C5H) and 5.7 (d, 1H, C'5H) 5,14 (t, 1H, C2CH2OH), 3,71 (m, 2H, C2C H2OH), 3,4 (LW. d, 1H, C4(H) 2,99 (LW. d, 1H, C4-H).

UV (CH3OH) lmax270 nm.

13C-NMR (ppm, DMSO-d6):

C'2; C'4; SCES-2-Hydroxymethyl-5-(cytosine-1'-yl)-3-oxo-1,3-oxathiolan

< / BR>
Previously obtained isomer CIS-(XVI) (100 mg) in 30 ml ice methanol is treated with 93 mg m-chlormadinone acid. After 15-minute stirring stands a white precipitate, which was separated and washed with 10mlmethanol to obtain the pure isomer a sulfoxide. The methanol filtrate is evaporated with a vacuum, the solid residue is washed with 15 ml of ethanol-ether (1:) and then 30 ml of ether to obtain pure isomer b sulfoxide. Both isomers described1H-NMR spectra.

Isomer (XVII)a.

So pl. > 270oC (decomp.), Rf= 0,3 (CH2Cl2-MeOH 3:1). UV (CH3OH) max270 nm.

(h/ml, DMSO-D6): to 7.68 (d, 1H, C'6(H) of 7.36 (s, 2H, C4'-NH2), 6,69 (LW. d, 1H, C5- H), USD 5.76 (d, 1H, C5'- H), vs. 5.47 (t, 1H, C2CH2OH), 4,63 (LW. d, 1H, C2-H), 3,88 (m, 1H, C2-CH-OH), and 3.72 (m, 1H, C2-CH2-OH), 3,36 (LW. d, 1H, C4(H) 3,05 DV. D. 1H, C4-H).

Isomer (XVII)b.

So pl. > 220oC (decomp.), Rf0,32 (CH2Cl2-MeOH 3 1) s (h/m/ DMSO-d6) 7,76 (d, 1H, 66'- H), 7,28 (d, 2H, C4-NH2), 6,66 (LW. d, 1H,C5(H) 5,77 (d, 1H, C5'- H), the 5.45 (t, 1H, C2-CH2OH), with 4.64 (t, 1H, C2(H) of 3.77 (t, 2H, C2-CH2OH), 3,65 (LW. d, 1H, C4- H), 3,17 (LW. d, 1H,x2">

< / BR>
In 10 ml of N-dimethylformamid-dimethylacetal (DMF-dimethylacetal) suspended 300 mg of CIS-2-hydroxymethyl-5- (cytosine-1'-yl)-1,3-oxathiolane and the mixture is stirred at room temperature for about a day (18h). Volatile components are removed by evaporation under reduced pressure and recrystallization of the residue from ethanol-ether to obtain 345 mg (93%) of pure product, so pl. 162-164oC; Rf=0,56 (CH2Cl2-MeOH 4:1).

UVmax325 nm.

1E-NMR (ppm, DMSO-d6): 8,64 (1H, N=CH-N), of 8.04 (d, 1H, d, 1H, C6'-H, J=7,2 Hz), to 6.22 (t, 1H, C5-H, J=4.9 Hz), 5,97 (d, 1H, C5'-H, J=7,2 Hz), lower than the 5.37 (t,1H, -OH, J=5.8 Hz, D2O-exchange), with 5.22 (t, 1H, C2-H, J=4.4 Hz), of 3.77 (t, 2H, C2CH2OH, J=4,9 Hz), 3,5 (LW. d, 1H, C4-H, J=4.9 and 9.9 Hz), 3,17 (s, 3Hz, -CH3), 3,12 (LW, d, 1H, C4-H, J=4,2 and 11.9 Hz), 3.04 from (s, 3H,-CH3).

Example 10. Bis-CIS-2-succinylcholine-5- (cytosine-1'-yl)-1,3-oxathiolan

< / BR>
In 10 ml of dry pyridine is dissolved 284 mg of CIS-2 - hydroxymethyl-5-(N,N-dimethylaminomethylene-1'-yl)-1,3-oxathiolane and cooled in a bath with ice to 0oC. Syringe add 60 ál of succinylcholine and stirred for about a day (18 hours). The mixture is then transferred into 50 ml of a saturated solution of NaHCO3, extracted with methylene chloride (350 ml), objednavala evaporation under reduced pressure. Foamy residue is dissolved in 10 ml of CH2Cl2containing 5 ml of methanol, add 2 ml of 80% aqueous acetic acid and the mixture is stirred for about a day at room temperature. The mixture is then evaporated to dryness and the solid after purification of the residue on silica gel (CH2Cl2-MeOH 4: 1) to obtain 145 mg (54%) of pure product, so pl. > 230oC (decomp.) Rf=0,23 (CH2Cl2-MeOH 4:1).

UV (MeOH)max271 nm.

1-H-NMR (ppm, DMSO-d6: of 7.69 (d, 2H, 2C6'-H, J=7,6 Hz), 7,28 (m, 4H, 2 NH2, 24,9 Hz, D2O-exchange), 6,24 (t, 2H, 2 C5-H, J=5.6 Hz), USD 5.76 (d, 2H, 2C5'-H, J= 7.4 Hz), 5,35 (t, 2H, 2C2-H, J=4.5 Hz), 4,37 (d, 2C2-CH2O-), 3,42 (LW. d, 2C4-H, J=5,5 and 10.9 Hz), 3,1 (LW. d, 2H, 2C4-H, J=5,6 and 11.7 Hz), and 2.6 (s, 4H, 2-CH2-C-O).

Example 11. CIS - and TRANS-2 - benzoyloxymethyl-5-(6'-globulin-N-9'-yl)-1,3-oxathiolane

< / BR>
In 50 ml of hexamethyldisilazane (HMDS) containing 50 mg (NH4)2SO4boil 1.7 g of 6-chloropurine until a clear solution is formed (1 h). Excess HMDS removed under reduced pressure, the oily residue is dried for 1 h in high vacuum and then dissolved in 100 ml of dry 1,2-dichloroethane.

In a round bottom flask of 500 ml two-evaporation with 50 ml of dried benzene 2.7 g of 2-bemowo cannula in an argon atmosphere transfer solution similarvideo 6-chloropurine in a solution of 1,3-oxathiolane. In the reaction flask add 11 ml of TMS-triflate (trimethylsilyltrifluoromethane), boiled for 5 h and cooled to room temperature. The mixture is then transferred into a 300 ml saturated sodium bicarbonate solution (solution of NaHCO3) under stirring, the organic layer separated and the aqueous phase is extracted with CH2Cl2Cl2(2100 ml). The combined organic phase washed with water, dried over MgSO4, filtered and evaporated under reduced pressure. Purification and separation of the residue on silica gel (hexane-ethyl acetate 7:3) receive 1.5 (26%) of the less polar product in the form of foam, identified as alpha-or TRANS-isomer, and 710 mg of another component, identified as beta - or CIS-isomer. The total yield of 46.1% the ratio of CIS-/TRANS-1:1,4.

the TRANS-isomer ( - -isomer): Rf=0,43 (hexane-EtOAc 1:1)

UV (MeOH)max264,7 nm

1H-NMR (CDCl3): 8,76 (c, 1H, C8'-H), 8,48 (s, 1H, C2'-H), of 8.06 (m, 2H, aromatic), 7,56 (m, 1H, aromatic), was 7.45 (m, 2H, aromatic), 6,9 (LW.d, 1H, C5- H, J=5 Hz), 5,78 DV. d, 1H, C2- H, J=6 Hz), 4,56 (m, 2H, C2-CH2OCOC6H5), 3,74 (m, 2H, C4-H).

CIS-isomer-isomer): Rf=0,35 (hexane-EtOAc 1:1)

UV (MeOH)max:264,7 nm

1H-NMR (CDCl3): 8,72 (c, 1H,5
-N, J=4,7 Hz), 5,62 (t,1H, C2-H, J=4.9 Hz), 4,69 (m, 2H, C2CH2OCOC6H5), 3,66 (m, 2H, C4-H).

Example 12. CIS-2-Hydroxymethyl-5-(6'-hydroxypurine - -9)-yl)-1,3-oxathiolane (derived inosine)

< / BR>
In 25 ml of methanol is dissolved 533 mg of CIS-2 - benzoyloxymethyl-5-(6'-globulin-N-9'-yl)-1,3-oxathiolane, to the solution was added 5 g of sodium hydroxide (NaOH) and 3 ml of water and the mixture is boiled for 5 hours Cooled to room temperature, the mixture was then diluted with 100 ml of water, neutralize the pyridinium resin and filtered. The remaining resin was washed with 100 ml of methanol, and the combined filtrate evaporated under reduced pressure. Purification of the residue on silica gel (CH2Cl2-MeOH 4: 1) obtain 183 mg (51%) of pure product, identified as a derivative of inosine, so pl. 208-210oC. Rf=0,27(EtOAc-MeOH 4:1).

UV (MeOH)max: 246 nm.

1H-NMR (hours/million, DMSO-d6): 12,42 (s, 1H, -NH, D2O-exchange), at 8.36 (s, 1H, C8'-H), 8,07 (c, 1H, C'2-1H), 6,37 (t, 1H, C5-H, J=5,1 Hz), from 5.29(t, 1H, -OH, J= 6 Hz, D2O-exchange) of 5.24 (t, 1H, C2-H, J=4.9 Hz), 3,63 (m, 4H, 2H and C4-H and 2H from CH2-OH).

Example 13. CIS - and TRANS-2 - benzoyloxymethyl-5-(uracil-N-1'-yl)-1,3-attilan

< / BR>
In 30 ml HMDS in the presence of 50 mg (NH4)2SO4boil 760 mg in the dried 1 hour in high vacuum and dissolved in 100 ml of dry 1,2-dichloroethane.

In a round bottom flask of 500 ml two-evaporation with 50 ml of dried benzene and 1.5 g 2-benzoyloxymethyl-5 - ethoxy-1,3-oxathiolane and dissolved in 150 ml of dry 1,2-dichloroethane.

Using a cannula in an argon atmosphere a solution of similarvideo uracil transferred into the solution oxathiolane add 1.5 ml TMS-triflate and the reaction mixture is boiled for 48 h in an argon atmosphere. Cooled to room temperature, the mixture is transferred into a saturated solution of NaHCO3(30 ml), the organic layer is separated, the aqueous phase is twice extracted with CH2Cl2(2100 ml). The combined organic layer washed with water (2200 ml), once with NaCl solution (ml) and dried over MgSO4.

After filtration the solvent is removed in vacuo and purification of the residue on silica gel (hexane - EtOAc 1:1) receive 594 mg (32%) of pure product.

The product is only a single spot in TLC. However,1H-NMR spectrum shows the presence of two isomers (CIS - and TRANS-) in the ratio 1:1,2, which were not separated at this stage. Rf=0,35 (hexane-EtOAc 3:7).

UV (MeOH)max261 nm.

1H-NMR (ppm, CDCl3): 8,88 (ush, s, 1H, N3'-H), with 8.05 (m, 2H, aromatic), 7,71 (d, 1H, C6'-H-Cys, J=8,2 Hz), EUR 7.57 (m, 1H, aromatic), was 7.45 (m, 3H, aromatic and N5'-H, J=8,2 Hz), to 5.57 (d, 1H, C5'-H, J=8,2 Hz), 5,46 (t, 1H, C2-H-Cys, J=3,9 Hz), to 4.73 (d,2H,-CH2O-COC6H5), of 4.45 (t, 2H, -CH2OCOC6H5), of 3.57 (m, 1H, C4-H), 3,17 (m, 1H).

Example 14. CIS-2-Hydroxymethyl-5-(uracil-N-1'-yl)-1,3-oxathiolan

< / BR>
75 methanolic solution of ammonia dissolved 300 mg of the mixture of CIS-and TRANS-2-benzoyloxymethyl-5-(uracil-N-1'-yl)-1,3-oxathiolane and the mixture is stirred for about a day at room temperature. After evaporation of the solvent to dryness, the residue is purified and separated into two isomers by chromatography on silica gel (EtOAc-MeOH 98:2).

The predominant product, isolated as a solid substance, identified as the CIS-isomer.

CIS-isomer. So pl. 162-164oC. Rf=0,57 (EtOAc-MeOH 95:5).

UV (MeOH)max261,4 nm.

1H-NMR (ppm, DMSO-d6): 11,36 (s, 1H, N3'-H), 7,88 (d, 1H, C6'-H, J= 8.1 Hz), 6,18 (t, C5-H, J=4,8 Hz), 5,62 (d, 1H, C5-H, J=8.1 Hz), 5,33 (t, 1H, C2-H, J=5.7 Hz), to 5.17 (t, 1H,-OH, D2O-exchange), and 3.72 (t, 2H, C2-CH2OH, J= 4.6 Hz), 3,41 (LW. d, 1H, C4-H, J=5.7 and 12 Hz), 3,2 (LW. d, 1H, C4-H, J=4,6 and 9.8 Hz).

Example 15. CIS-and TRANS-2-Benzoyloxymethyl-5-(thymine-N-1'-yl)-1,3-oxathiolane

< / BR>
In 50 ml of GMDS containing 50 mg (NH4)2m pressure. The residue is dried for 1 h in high vacuum and dissolved in 150 ml of 1,2-dichloroethane.

Two-evaporation with 75 ml of dried benzene 3 g 2-benzoyloxymethyl-5-ethoxy-1,3-oxathiolane and dissolved in 150 ml of dry 1,2-dichloroethane.

The solution similarvideo thymine through the cannula in an argon atmosphere transferred into the solution oxathiolane and the reaction mixture via a cannula in the atmosphere of argon injected with 3.3 ml of TMS-triflate (trimethylsilyl-triphala in 30 ml of dry 1,2-dichloroethane. The solution is boiled in an argon atmosphere for 36 h, cooled to room temperature and transferred into 30 ml of a saturated aqueous solution of NaHCO3. The organic layer is separated and the aqueous phase is twice extracted with methylene chloride (2100 ml). The combined organic phase washed twice with water (2200 ml), once with NaCl solution (1150 ml) and dried over MgSO4. The solution is filtered, the filtrate is evaporated in vacuo and chromatography of the residue on silica gel (hexane-EtOAc 1:1) to obtain 1.3 g (35%) of pure product.

The product gives only a single spot in TLC, but1H-NMR spectrum shows the presence of two isomers (CIS and TRANS) in the ratio 1:1,2. Rf=0,3 (hexane-EtOAc).

UV (MeOH) 266 nm.

1H-NMR (ppm, CDCl3): 8,6 (ush, s, N3'-H), of 8.06 (m, 2H, aromatic), to 7.59 (m, 1D, 1H, C5-H-TRANS-isomer. J= 1.3 Hz), 6,55 (LW. d, 1H, C5-H-CIS-isomer, J=5.5 Hz), 5,78 (LW. d, 1H, C2-H-TRANS, J=4.4 and 6.4 Hz), 5,46 (t, 1H, C2-H-CIS-isomer, J=4.3 Hz), 4,49 (d, 2H, C2-CH2OCOC6H5, J=4, 2 Hz), of 4.45 (m, 2H, C2-CH2OCOC6H5), to 3.58 (m, 1H, C4(H) of 3.13 (m, 1H, C4(H) of 1.93 (d, 1H, C5'-CH3-TRANS-isomer, J=1.2 Hz), 1,78 (d, 1H, C5'-CH3-CIS-isomer, J=1.2 Hz).

Example 16. Nu-2-Hydroxymethyl-5-(thymine-N-1'-yl)-1,3-oxathiolan

< / BR>
100 ml of a saturated methanolic solution of ammonia is dissolved 500 mg of the mixture of CIS - and TRANS-2-benzoyloxymethyl-5-(thymine-N-1'-yl)-1,3-oxathiolane (XXIV) and the mixture is stirred for about a day (18 h) at room temperature. After evaporation of the mixture under reduced pressure, the residue is separated on silica gel (EtOAc-MeOH 98:2).

The less polar product identified as CIS-isomer, so pl. 167-168oC. RfOf 0.66 (EtOAc-MeOH 95:5).

UV (MeOH),max266 nm

1H-NMR (ppm, DMSO-d6) 11,38 (s, 1H, N'3(H) 7,73 (d, 1H, C'-H, J 1.1 Hz), 6,16 (t, 1H, C5-H, J 5.5 Hz), 5,31 (t, 1H, C2-H, J 5,9 Hz), 5,14 (t, 1H, OH, D2O-exchange), and 3.7 (t, 2H, C2-CH2OH, J 5.1 Hz), 3,36 (LW. D. 1H, C4-H, J of 5.7 and 1.7 Hz), and 3.16 (LW. d, 1H, C4-H, J 5.5 and 11.7 Hz), a 1.75 (d, 3H, C'5- CH3, J 1.7 Hz).

Example 17. MA the CSR-1 - pyrimidinyl)-1,3-oxathiolan-2-methanol (1.0 g, 4.6 mmole) and maleic acid (506 mg, 4,36 mmole) in industrial methylated spirit (IMS 320 ml) was heated to the temperature of reflux distilled. The resulting clear solution was concentrated by distillation from 140 ml of solvent, and then cooled to 5oC. using filtering separated white crystalline solid, was filtered IMS (15 ml) and dried in vacuum at 40oC, giving CIS-5- (4-amino-1,2-dihydro-2-oxo-1-pyridiniumyl)-1,3-oxathiolan-2-methanol maleate (1.22 g), so pl. 187oC.

Found: C 41,7; H to 4.4; N, 12.1% of C8H11N3O3C4H4O4< / BR>
Calculated: C 41,7; H 4,4; N 12,2%

Example 18. Harkirat CIS-5-(4 - amino-1,2-dihydro-2-oxo-1-pyrimidinyl)-1,3-oxathiolan-2-methanol.

A solution of CIS-5-(4-amino-1,2-dihydro-2-oxo-1-pyrimidinyl) 1,3-oxathiolan-2-methanol (1.0 g, 4.6 mmole) in industrial methylated spirit (IMS 320 ml) was treated at reflux distilled solution of concentrated hydrochloric acid (160 mg, 4,36 mmole) in IMS (8 ml). The mixture then was cooled to 0oC. the Resulting white crystalline solid was separated by filtration, washed with IMS (5 ml) and dried in vacuum at 40oC, giving the hydrochloride, CIS-5- (4-amino-1,2-digu>N3O3HCl.

Calculated: C and 36.2; H 4,55; N, 15.8% OF

Example 19. CIS - and TRANS-2 - benzoyloxymethyl-5-(5'-azacytosine-N-1'-yl)-1,3-oxathiolane

< / BR>
5-azacytosine (2:0 g) was heated under reflux in HMDS (50 ml) containing a catalytic amount (NH4)2SO4(50 mg) up until the solution became clear. The mixture is evaporated to dryness. The residue was dried in high vacuum for 1 h and dissolved in dry dichloromethane (100 ml).

2-benzoyloxymethyl-5-ethoxy-1,3-oxathiolan was dried by a double-joint evaporation with benzene (250 ml) in a 500-ml flask with a round bottom and was dissolved in dry dichloromethane (150 ml).

Sililirovany a solution of 5-azacytosine transferred into the solution oxathiolane through a cannula in an argon atmosphere followed by the addition of a solution trimethylsilyltrifluoromethane (TMS-triflate, 3.5 ml) in dichloromethane (20 ml). The mixture was heated under reflux for 24 h, cooled to room temperature and poured into saturated aqueous solution of NaHCO3(300 ml). The organic phase was collected. The aqueous phase was extracted with methylene chloride (2100 ml). The combined extracts were washed with water (2200 ml), once with NaCl solution (100 ml) and dried sulfate magnicent using EtOAc-MeOH (95:5). Received 1.6 g (34%) of pure solid product, which was found only one spot on TLC, but1H-NMR spectrum showed the presence of CIS - and TRANS-isomers in the ratio 1:1,2.

1H-NMR (CDCl3) (ppm):

to 8.41 (s, 1H, C6-H, CIS-isomer),

compared to 8.26 (s, 1H, C6TRANS-isomer),

to 7.95 (m, aromatic.),

rate of 7.54 (m, aromatic.),

6,36 (DD, 1H, C5-H TRANS-isomer, J 1.9 and 5.0 Hz),

of 6.17 (t, 1H, C5-H CIS-isomer),

equal to 6.05 (t, 1H, C2-H TRANS-isomer),

of 5.53 (t, 1H, C2-H CIS-isomer),

and 4.68 (m, 2H, C2CH2OCOC6H5CIS-isomer),

was 4.42 (m, 2H, C2OCOC6H5TRANS-isomer),

of 3.54 (m, 2H, C1-H CIS and TRANS),

to 3.36 (m, 2H, C4-H CIS and TRANS).

Example 20. CIS - and TRANS-2-hydroxymethyl-5- (5'-azacytosine-N-1'-ml)-1,3-oxathiolane

< / BR>
The mixture of CIS - and TRANS-2 - benzoyloxymethyl-5-(5'-azacytosine-N-1'-yl)-1,3-oxathiolane (505 mg) was dissolved in methanolic ammonia (100 ml) and stirred at room temperature for 18 hours the Solution is evaporated to dryness. The residue was treated twice with diethyl ether (250 ml) and decantation. The solid residue was precrystallization in methanol and the crystals were collected by filtration. The product was identified as the pure CIS-isomer.

CIS-is,62 (c, 1H, C6-H,

7,53 (CL, 2H,-NH2)

6,12 (DD, 1H, C5(H)

of 5.40 (t, 1H, -OH),

5,20 (t, 1H, C2-H, J=3,9 Hz),

of 3.75 (m, 2H, C2-CH2OH),

of 3.45 (DD, 1H, C4-H, J=5.3 Hz),

of 3.25 (DD, 1H, C4-H, J=3.5 Hz),

Another product was obtained as foamy substance and identified as TRANS-isomer.

TRANS-isomer:

1H-NMR(DMSO-d6): s (ppm):

8,25 (c, 1H, C6(H)

7,58 (CL, 2H,-NH2)

of 6.29 (DD, 1H, C5H, J=3.1 and 4.9 Hz),

the 5.65 (t, 1H, C2-H, J=5,2 Hz),

5,44 (SHS, 1H, -OH),

to 3.49 (m, 3H, 2H, C2-CH2OH and 1H from C4(H)

3,24 (m, 1H, C4-H).

Example 21. CIS - and TRANS-2-benzoyloxymethyl-5- (8'-Azadegan-N-9'-yl)-1,3-oxathiolane and CIS - and TRANS-2-benzoyloxymethyl-5-(8'-azadani-N-8'-yl)-1,3-oxathiolane

< / BR>
A suspension of 8-asadena (1,00 g 7,348 mm) and ammonium sulfate (30 mg) in HMDS (30 ml) was heated overnight (16 h). The clear solution was concentrated under reduced pressure. The white solid residue was dried in high vacuum for 2 h, was dissolved in freshly distilled 1,2-dichloroethane (30 ml) and transferred to an argon atmosphere via cannula into a solution of 2-benzoyloxy - methyl-5-methylcarbonate-1,3 oxathiolane (1,461 g, 4,90 mm) in anhydrous 1,2-dichloroethane (50 ml). Then it is time to relax is 2 days then cooled to room temperature and poured into saturated aqueous solution of NaHCO3(100 ml). The organic phase was separated, and the aqueous phase was extracted with methylene chloride (350 ml). The combined organic extracts washed with brine (50 ml), dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, elwira CH2Cl2:MeOH (98: 2), resulting in a received 0,875 g (49,6%) light yellow solid, which was discovered only a single spot on TLC, but1H-NMR spectrum showed the presence of two N-9'-isomers, CIS - and TRANS-2-benzoyloxymethyl-5-(8'-azadani-N-9'-yl)-1,3-oxathiolan.

N-9'-regioisomers:

UV:max(EtOH):280,19 nm;

1H-NMR (SDCl3: (ppm):

8,50 (c, 1H, C2H, CIS-isomer),

8,46 (c, 1H, C2H, TRANS-isomer),

8,03 (m, 4H, aromatic.),

EUR 7.57 (m, 2H, aromatic.),

7,44 (m, 4H, aromatic.),

was 7.08 (DD, 1H, C5-H, J=2,97 and 6.14 Hz, TRANS-isomer),

of 6.73 (DD, 1H, C5-H, J=of 5.53 and 6,53 Hz, CIS-isomer),

6,64 (CL, 4H,-NH2)

of 5.89 (DD, 1H, C2-H, J=4,15 and 5,59 Hz, TRANS-isomer,

5,72 (t, 1H, C2-H, J=lower than the 5.37 Hz, CIS-isomer),

with 4.64 (t, 2H, C2CH2OCOC6H5C 5,76, CIS-isomer),

Android 4.04 (DD, 1H, C4H, J 3,14 and 11,81 Hz, TRANS-isomer),

with 3.79 (DD, 1H, C4H, J 6,14 and 11.6 Hz, CIS-isomer),

3,61 (DD, 1H, C4H, J 5,52 11.45 Hz, TRANS-isomer).

Another product was obtained as a yellow oily product (0,313 g, 17.7 percent ) and identified as two N-8'-regioner, CIS - and TRANS-2-benzoyloxymethyl-5-(8'-azadani-N-8'-yl)-1,3-oxathiolan.

N-8'-regioisomers:

UV: lmax(EtOH): 295 nm,

1H-NMR (CDCl3): (ppm):

of 8.50 (s, 1H, C2-H, CIS-isomer),

8,46 (s, 1H, C2-H, TRANS-isomer),

8,03 (m, 4H, aromatic.),

EUR 7.57 (m, 2H, aromatic.),

7,44 (m, 4H, aromatic.),

? 7.04 baby mortality (DD, 1H, C5-H, J 2,97 and 6.14 Hz, TRANS-isomer),

of 6.73 (DD, 1H, C5-H, J of 5.53 and 6,53 Hz, CIS-isomer),

6,64 (Shir. C. 4H, -NH2)

of 5.89 (DD, 1H, C2H, J 4,15 and 5,59 Hz, TRANS-isomer),

5,72 (t, 1H, C2-H, J lower than the 5.37 Hz, CIS-isomer),

with 4.64 (t, 2H, C2CH2OCOC6H5, J 5,76 Hz, CIS-isomer),

4,60 (DD, 2H, C2CH2OCOC6H5, J 5,32 Hz, TRANS-isomer),

4,37 (DD, 1H, C4H, J 6,33 and 11,42 Hz, CIS-isomer),

Android 4.04 (DD, 1H, C4H, J 3,14 and 11,81 Hz, TRANS-isomer),

with 3.79 (DD, 1H, C4H, J 3,14 and 11.6 Hz, CIS-isomer),

3,61 (DD, 1H, C4H, J 5,52 11.45 Hz, TRANS-isomer).

Example 22. CIS - and TRANS-2 - hydroxymethyl-5-(8'-Aslanov (0,285 g, 0,7908 mm) in methanol ammonia (50 ml), stirred for 1 day at room temperature. This mixture was concentrated under reduced pressure and the solid residue was purified using flash chromatography on silica gel, elwira gradient MeOH (1% to 6%) in CH2Cl2, resulting in the received 0,079 g of the CIS isomer and 0,084 g of the TRANS isomer as white solids. The total yield was 81%

CIS-isomer:

So pl. 203 204oC UV:max(MeOH) 278 nm,

Rf: 0,31 (CH2Cl2:MeOH 9:1),

1H-NMR (DSMO-d6) (ppm):

8,54 (Shir.with. 1H, -NH2)

with 8.33 (s, 1H, C2(H)

8,20 (Shir.with. 1H, -NH2)

of 7.69 (t, 1H, C5-H, J of 6.68 Hz),

of 5.34 (t, 1H, C2-H, J of 5.53 Hz),

with 5.22 (t, 1H, -OH, J 5,74 Hz),

of 4.05 (DD, 1H, C4-H, J 6,93 and 11,05 Hz),

3,63 (m, 2H, C2-CH2OH),

to 3.50 (DD, 1H, C4-H, J 5,44 and 11,32 Hz),

13C-NMR (DMSO-d6): s (ppm): 157,153; 156,119; 149,049; 126,631; 87,674; 85,339; 64,137; 32,846.

TRANS-isomer:

So pl. >213 214oC UV: lmax(MeOH): 278 nm,

Rf: 0,24 (CH2Cl2:MeOH 9:1)

1H-NMR (DMSO-d6) (ppm):

8,53 (Shir.with. 1H, -NH2)

8,33 (C. 1H, C2(H)

8,18 (Shir.with. 1H, -NH2)

7,01 (DD, 1H, C5-H, J 3,24 and is 6.54 Hz),

to 5.35 (t, 1H, C2-H, J EQUAL TO 4.97),

of 5.55 (t, 1H, -OH, J 6,05),

< / BR>
A solution of CIS - and TRANS-2 - benzoyloxymethyl-5-(8'-azadani-N-8'-yl)-1,3-oxathiolane (0,300 g, 0,8324 mm) in methanol ammonia (50 ml) stirred for 30 h at room temperature. The mixture was concentrated under reduced pressure and the solid residue was purified using flash chromatography on silica gel, using as eluent a gradient of MeOH (2% to 6%) in CH2Cl, resulting in a received 0,037 g cisisomer, 0,058 g transisomer, and 0,095 g of a mixture of isomers in the form of a pale yellow solid product. Hollow output was 90%

CIS-isomer: so pl. 182 183oC, Rf: 0,44 (CH2Cl2- MeOH 9:1),

UV:max(MeOH) 296 nm,

1H-NMR (DMSO-d6): (ppm):

scored 8.38 (Shir. S. 1H, NH2)

8,30 (s, 1H, C'2H),

8,17 (Shir.with. 1H, NH2)

6,77 (DD, 1H, C5-H, J 4,12 and 5,28 Hz), 5,41 (t, 1H, C2-H, J 6,04 Hz),

of 5.17 (t, 1H, -OH, J 5,77 Hz),

to 3.92 (DD, 1H, C4-H, J 4,15 and 12,05 Hz),

3,70 (m, 3H, C4-H, and C2CH2OH),

TRANS-isomer: so pl. 206 207oC, Rf: 0,38 (CH2Cl2MeOH 9:1),

UV: lmax.(MeOH): 196 nm,

1H-NMR (DMSO-d6): (ppm):

scored 8.38 (Shir.with. 1H, NH2)

8,30 (s, 1H, C2(H)

8,16 (Shir.with. 1H, -NH2)

? 7.04 baby mortality (DD, 1H, C5-H, J 1.92 and 5,76 (Hz)

5,46 (t, 1H, C2-H, J 5,01 Hz),

of 5.24 (t, 1H, -OH, C 5,77 Hz),
the Rance-2 - benzoyloxymethyl-5-(8'-azaguanine-9'-yl)-1,3-oxathiolan

< / BR>
8-azaguanine (1.0 g, to 6.58 mm) was subjected to perselisihan by heating under reflux with 1,1,1,

3,3,3-hexamethyldisilazane (HMDS, 50 ml) in the presence of catalytic amounts of ammonium sulfate (50 mg) overnight (16 h). The clear solution is evaporated to dryness under reduced pressure. The residue was dried in high vacuum for 1 h and dissolved in anhydrous 1,2-dichloroethane (100 ml).

2-benzoyloxymethyl-5-methylcarbonate-1,3-oxathiolan (1,96 g, to 6.58 mm) was drained by double distillation with benzene (250 ml) in a 500-ml flask with a round bottom, and was dissolved in anhydrous 1,2-dichloroethane (150 ml).

The solution similarvideo 8-azaguanine was introduced via cannula into a solution oxathiolane in an argon atmosphere followed by the addition of TMS-Triflate (1.3 ml, to 6.58 mm). The reaction mixture was heated under reflux in an argon atmosphere for 5 h, cooled to room temperature, and poured into saturated aqueous solution of NaHCO3(100 ml). The organic layer was collected. The aqueous phase was extracted with CH2Cl2(3100 ml). The combined organic layer was washed with water (2100 ml), once with NaCl solution (100 ml) and was dried with magnesium sulfate. After filtration the solvent was removed by viparita the KTA in the form of a mixture of CIS - and TRANS-isomers in the ratio of 1:1.

Rf:0,40 (CH2Cl2:MeOH 95:5)

1H-NMR (DMSO-d6): (ppm):

11,06 (sh.with. 1H, NH),

a 7.92 (m, 2H, aromatic.),

7,66 (m, 1H, aromatic.),

at 7.55 (m, 2H, aromatic),

7,05 (sh.with. 2H, NH2-),

6,74 (DD, 1H, H-5, TRANS-isomer, J 3 and 6 Hz),

of 6.45 (t, 1H, H-5, CIS-isomer, J 6 Hz),

of 5.68 (m, 1H, H-2),

4,55 (m, 2H, CH2OBr),

the 3.65 (m, 2, H-4).

Example 25. CIS - and TRANS-2-hydroxymethyl-5- (8'-azagury-9'-yl)-1,3-oxathiolan

< / BR>
A solution of CIS - and TRANS-2-benzoyloxymethyl-5- (8'-azaguanine-9'-yl)-1,3-oxathiolane (350 mg) in methanol (100 ml) was cooled to 0oC in an ice bath and ammonia gas was barbirolli through the solution for 15 minutes the Reaction mixture was stirred at room temperature overnight (16 h). The solution is evaporated to dryness. The residue was purified, and the two isomers were partially separated on silica gel, elwira CH2Cl2MeOH 9 1, resulting in a net target product, which was identified as the CIS-isomer (30 mg).

CIS-isomer:

So pl. >260oC (Razlog.)

Rf0,26 (CH2Cl2MeOH 9 1),

UV:max(pH 14) 278 nm,

1H-NMR (DMSO-d6) (ppm):

11,08 (sh.with. 1H, NH-), 7,05 (sh.with. 2H, NH2)

6,33 (DD, 1H, C2-H, J 6 and 7 Hz),

of 5.26 (t, 1H, C2-H, J 6 Hz),

of 5.17 (t, 1H, OH - J 6 g of The O-d6) s (ppm):

155,81; 155,46; 151,79; 124,35; 86,73; 84,94; 64,22 and 32,42.

Other fractions were combined and concentrated to dryness. The residue was purified using ghvd (liquid chromatography high pressure), resulting in a received 72 mg transisomer.

TRANS-isomer:

So pl. 220 222oC (Razlog.):

UV: lmax(rH 14): 280 nm.

1H-NMR (DMSO-d6): (ppm):

11,0 (sh.with. 1H, -NH),

7,06 (sh.with. 2H, -NH2)

to 6.67 (DD, 1H, C5-H, J 3 and 7 Hz),

5,28 (t, 1H, C2-H, J 5 Hz),

5,20 (sh.T. 1H, -OH, J 6 Hz),

of 3.78 (DD, 1H, 1H, C4-H, J 3 and 12 Hz),

to 3.67 (m, 1H, C4-H and 2H,-CH2OH),

13C-NMR (DMSO-d6): σ(ppm):

155,8; 155,6; 151,4; 124,3; 86,7, 86,4; 63,6; 34,4.

Example 26. CIS - and TRANS-2-benzoyloxymethyl-5- (3'-carboethoxy-1',2'-4'-triazole-1'-yl)-1,3 oxathiolan

< / BR>
3 carboethoxy-1,2,4-triazole (400 mg, and 2.83 mmole) was heated in a vessel under reflux in HMDS (1,1,1,3,3,3-hexamethyldisilazane, 20 ml) containing a catalytic amount of ammonium sulfate (20 mg) for 2 hours a Clear solution was evaporated until dry under reduced pressure, and the residue was dissolved in dry dichloroethane (50 ml). A solution of 2-benzoyloxymethyl-5-acetoxy-1,3-oxathiolane (1.2 g, 4,20 mmole) in dry dichloroethane (100 ml) was added to bilirubinemia solution trimethylsilyltrifluoromethane (TMSOTf) (5 ml).

The reaction mixture was heated in a vessel under reflux in an argon atmosphere for 2 h, cooled to room temperature and poured into saturated sodium bicarbonate solution (100 ml). The organic layer was collected. After this aqueous solution was extracted with methylene chloride (2 times 50 ml).

The combined organic phase was washed with water (2 times 100 ml), dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure. The residue was purified on silica gel using mixtures of hexane with ethyl acetate at a ratio of 1 to 1 as eluent, resulting in a received desired product (800 mg) with a yield of 77% as a mixture of CIS - and TRANS-isomers in a ratio of 3 to 2.

An NMR spectrum on1H (300 MHz, CDCl3) was as follows: value in millions of shares amounted to 8.57 (singlet, 1H, H'-5, CIS-isomer), 8,43 (singlet, 1H, H'-5, transisomer), 8,04 (multiplet, 4H, benzene ring, CIS - and TRANS-isomers), EUR 7.57 (multiplet, 2H, benzene ring, CIS - and TRANS-isomers), 7,47 (multiplet, 4H, benzene ring, CIS - and TRANS-isomers), 6,57 (doublet of doublet, 1H, H-5, TRANS-isomer, J of 1.6 and 4.8 Hz), 6,37 (doublet of doublet, 1H, H-5, CIS-isomer, J 3.2 and 7.8 Hz), 5,79 (doublet of doublet, 1H, H-2, transisomer, J 4 and 6.1 Hz), 5,63 (doublet of doublet, 1H, 6H5and 4H of COO(C2H5), CIS - and TRANS-isomers), 3,65 (multiplet, 4H, H-4, CIS - and TRANS-isomers) and 1.43 (triplet, 6H, COO(C2H5), CIS - and TRANS-isomers).

Example 27. CIS - and TRANS-2 - hydroxymethyl-5-(3'-carboxamide-1',2',4'-triazole-1'-yl)-1,3-oxathiolan

< / BR>
The mixture of CIS - and TRANS-isomers of 2 - benzoyloxymethyl-5-(3'-carboethoxy-1',2', 4'-triazole-1'-yl)-1,3 oxathiolane (800 mg, 2,2-mmole) was dissolved in methanolic ammonia (80 ml). The solution was stirred in a sealed flask at room temperature for 4 days. The solvent was removed by evaporation under reduced pressure, and the oily residue was filled with simple ether (3 times 30 ml). The residue was purified on silica gel using mixtures of ethyl acetate with methanol in the ratio of 95:5 as eluent, resulting in pure solid form received both CIS - and TRANS-isomer.

CIS-isomer. Melting point 119-120oC. an NMR Spectrum on1H (300 MHz, dimethylsulfoxide-d6): the value in cent to 8.85 ppm (singlet, 1H, C5'-H), 7,81 (broad singlet, 1H, CONH2-, D2O (able to communicate)), to 7.59 (broad singlet, 1H, (able to communicate)), 6,38 (triplet, 1H, C5-H), 5,27 (triplet, 2H, C2-H and OH), 3,56 (multiplet, 4H, C4-H and C6: the value of s in ppm 8,83 (singlet, 1H, C5'-H), 7,87 (broad singlet, 1H, CONH2-, D2O (able to communicate)), the 7.65 (broad singlet, 1H, CONH2-, D2O (able to communicate)), 6,69 (doublet of doublet, 1H, C5-H, J=3 and 4.2 Hz), 5,43 (triplet, 1H, C2-H, J=5,1 Hz), 5,23 (triplet, 1H, OH, D2O (able to communicate)), 3,60 (multiplet, 4H, C4-H and C2-CH2OH).

Example 28, CIS - and TRANS-2 - benzoyloxymethyl-5-(2'-amino-6'-globulin-9'-yl)-1,3-oxathiolan

< / BR>
6-chloro-2-aminopurine (3,96 g, 23,35 mmole) was heated in a vessel under reflux in HMDS (1,1,1,3,3,3-hexamethyldisilazane, 100 ml) containing a catalytic amount of ammonium sulfate (20 mg) overnight (16 h). The clear solution was evaporated to dryness under reduced pressure, and the residue was dissolved in dichloroethane (60 ml). The solution was added to a mixture of 2-benzoyloxymethyl-5-acetoxy-1,3-oxathiolane (5,98 g, 21,33 mmole) in dry dichloroethane (30 ml) with molecular sieves 4 (2 g), then added trimethylsilyltrifluoromethane (TMS - triflate of 4.1 ml). The reaction mixture was heated in a vessel under reflux in an argon atmosphere for 10 h and drank in a saturated aqueous solution of sodium bicarbonate (100 ml). The organic layer was collected. An aqueous solution of the ZAT is), was dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure. The residue was purified on silica gel using a mixture of hexane and ethyl acetate at a ratio of 1:1 as eluent, resulting received the required cisisomer (2 g, 24%) and TRANS - isomer (3,10 g, 37,38%) with a total yield of 61%

CIS-isomer. Melting point 137-138oC. the Value of Rfwas 0,29 (a mixture of hexane with ethyl acetate at a ratio of 1:1).

An NMR spectrum on1H (300 MHz, CDCI3): the value in ppm was 8,11 (singlet, 1H, C'8(H) 8,02 (multiplet, 2H, benzene ring), 7,55 (multiplet, 1H, benzene ring), 7,44 (multiplet, 2H, benzene ring), 6,38 (triplet, 1H, C5-H, J=5,2 Hz), the ceiling of 5.60 (doublet of doublet, 1H, C2-H, J= 4.2 and 5.4 Hz), 5,32 (broad singlet, 2H, NH2), 4,66 (multiplet, 2H, -CH2OC(C6H5)), to 3.58 (Multiplet, 2H, C4-H).

The TRANS-isomer. The melting point was 152-153oC. the Value of Rfwas 0,29 (a mixture of hexane with ethyl acetate at a ratio of 1:1).

An NMR spectrum on1H (300 MHz, CDCl3): the value of s in ppm was 8,15 (singlet, 1H, C'8(H) 8,02 (multiplet, 2H, benzene ring), 7,56 (multiplet, 1H, benzene ring), the 7.43 (m>H, J 4.1 and 6.0 Hz), 5,50 (broad singlet, 2H, NH2), 4,57 (multiplet, 2H, -CH2OC(C6H5)), 3,66 (doublet of doublet, 1H, C4-H, J 5.3 and 12.0 Hz) and 3,55 (doublet of doublet, 1H, C4-H, J 2.8 and 12 Hz).

Example 29. CIS-2-hydroxymethyl-5-(guanine-9'-yl)-1,3-oxathiolan

< / BR>
To 10% of the resultant aqueous methanol solution of CIS-2 - benzoyloxymethyl-5-(2'-amino-6'-globulin-9'-yl)-1,3-oxathiolane (200 mg, 0.73 mmole) was added in one portion sodium hydroxide (3 g, 75 mmol). The reaction mixture was heated in a vessel under reflux for 16 h, then cooled to room temperature, and the solvents were removed under reduced pressure. The residue was again dissolved in water (100 ml), the solution was neutralized pyridinium resin and filtered. The filtrate was evaporated to dryness under reduced pressure, and the residue was purified high-performance liquid chromatography on a column of reversed phase, resulting received the named compound (146 mg) with a yield of 74%

The melting temperature exceeded 258oC (decomposition).

The value of Rfwas 0,54 (a mixture of ethyl acetate with methanol at a ratio of 4:1).

Ultraviolet spectrum: the value ofmax(in water) was 254 and 275 (wavelength region) nm.

8'-H), 7,00 (broad singlet, 2H, NH2), 6,15 (triplet, 1H, C5-H, J=5.6 Hz), 5,50 (wide line, 1H, HE), 5,22 (triplet, 1H, C2-H, J=4,7 Hz), 3,62 (multiplet, 4H, C4-H and C2-CH2OH).

An NMR spectrum on13C (75,46 MHz, dimethylsulfoxide-d6): the value of s in ppm was 162,25 157,79, 151,72, 134,33, 117,18, 85,52, 85,22, 64,18 and 34,81.

Example 30. CIS-2-hydroxymethyl-5- (2'-6'-diaminopurine-9'-yl)-1,3-oxathiolan

< / BR>
Ammonia propulsively through a solution of CIS-2 - benzoyloxymethyl-5-(2'-amino-6 globulin-9'-yl)1,3-oxathiolane (185 mg, of 0.64 mmole) in ethanol (25 ml) at 0oC for 20 minutes the Solution was placed in a steel bomb and heated at 110oC for 16 hours the Bomb was cooled to room temperature and then was released. The solvents were removed under reduced pressure, and the residue was purified on silica gel using mixtures of ethyl acetate with methanol at a ratio of 9:1 as eluent, as a result received the desired product (125 mg) with a yield of 73%

The melting point was 120-122oC (decomposition). The value of Rfamounted to 0.48 (a mixture of ethyl acetate with methanol at a ratio of 4:1).

Ultraviolet spectrum: the value ofmax(in water) was 256 and 280 nm.

An NMR spectrum, ,86 (broad singlet 2H, -NH2), a triplet, 1H, C5-H, J= 5,2 Hz), 5,90 (wide line, 3H, NH2), of 5.40 (triplet, 1H, OH), 5,22 (triplet, 1H, C2(H) 3,62 (multiplet, 4H, C4-H and C2-CH2OH).

An NMR spectrum on13C (75,46 MHz, dimethylsulfoxide-d6): the value of s in ppm was 160,70, 156,44, 151,65, 135,91, 113,07, 85,47, 85,39, 63,83 and 34,92.

TRANS-2-hydroxymethyl-5-(2',6'-diaminopurine-9'-yl)-1,3-oxathiolan

< / BR>
Ammonia policewala through a solution of CIS-2 - benzoyloxymethyl-5-(2'-amino-6'-globulin-9'-yl)1,3-oxathiolane (200 mg, to 0.69 mmole) in ethanol (25 ml) at 0oC for 20 minutes the Solution was placed in a steel bomb and heated at 110oC for 16 hours the Bomb was cooled to room temperature and was released. The solution was removed under reduced pressure, and the residue was purified on silica gel using mixtures of ethyl acetate and methanol at a ratio of 9:1 as eluent, resulting in the required product (136 mg, yield 72%).

The melting temperature exceeded 220oC (decomposition). The value of Rfwas 0,40 (a mixture of ethyl acetate with methanol at a ratio of 4:1).

The ultraviolet spectrum of the value ofmax(in water) was 256 and 280 nm.

An NMR spectrum on1 is litharge, 2H, -NH2), of 6.49 (doublet of doublet, 1H, C5-H, J=3.0 and 5.4 Hz), 5,88 (wide line, 2H, NH2), 5,32 (triplet, 1H, C2-H, J= 4,7 Hz), to 5.21 (triplet, 1H, OH), 3,62 (multiplet, 4H, C4-H and C2-CH2OH).

An NMR spectrum on 13C (75,46 MHz, dimethylsulfoxide-d6): the value of s in ppm 160,90, 156,64, 151,81, 135,27, 113,35, 86,00, 85,31, 64,50 and 35,23.

Example 31. CIS - and TRANS-2-benzoyloxymethyl-5-(N4'-acetyl - 5'-fertilizin-1'-yl)-1,3-oxathiolan

< / BR>
5-ferritin (4,30 g, 33.3 mmol), hexamethyldisilazane (25 ml) and ammonium sulfate (120 mg) was boiled under reflux until dissolution of cytosine (3 h) and then boiled for 2 hours of Hexamethyldisilazane evaporated in vacuo and to the residue was added toluene (100 ml) for co-evaporation of the solvents. The resulting solution of bis(trimethylsilyl)-fertilizin in dichloromethane (40 ml) was added in an argon atmosphere to a solution of 2-benzoyloxymethyl-5 - acetoxy-1,3-oxathiolane (8,537 g, 30.3 mmol) in dry dichloromethane (100 ml) and molecular sieves (4 2 g), pre-cooled to 0oC and was kept in an argon atmosphere for 20 minutes

To this mixture was added (triptorelin-sulfonyl)hydroxy trimethylsilane (6 ml, 31 mmol) at 0oC and the resulting solution stirred carbonate sodium and stirred at room temperature for 2 hours The filtrate was twice shaken with 300 ml of saline solution and one with distilled water. The organic layer was dried over magnesium sulfate, filtered and evaporated until dry. This gave the crude derivative of 5-Perlstein (10.1 g). RfOf 0.57 (EtOAc:MeOH 9:1).

This residue was subjected to acetylation in the next step without further purification. The crude substance was dissolved in dry dichloromethane (120 ml) in an argon atmosphere in a 500-ml round-bottom flask. To the solution was added triethylamine (1,27 ml, to 91.1 mmol) and dimethylaminopyridine (0.9 mmol). Then the flask was immersed in an ice bath for 1 h at create an atmosphere of argon. In cooling the flask was injected acetic anhydride (4.3 ml, 45 mmol), purified over sodium acetate. The mixture was stirred overnight and then carefully decantation in Erlenmeyer flask containing a saturated solution of sodium bicarbonate. Then the obtained product was washed with distilled water, followed by brine. Methylenchloride portion was dried and evaporated in high vacuum until dry, forming acetylated mixture in the form of a colorless foam having after drying the weight of 9.6, Flash chromatography of this substance when used in the>

TRANS-isomer: Rf: 0,65 in a mixture of ethyl acetate: methanol 9:1

U. F. (MeOH) Lambda Maxim. 309 nm.

1H-NMR (mil.D. in CDCl3)

8,77 (ush. 1H, C'4-NH-Ac)

of 8.06 (m, 2H; flavor)

of 7.70 (d, 1H; C'6-H, J6, F=6.3 Hz)

a 7.62 (m, 1H; flavor)

7,49 (m, 2H;flavor)

6,51 (DD, 1H; C5H)

5,91 (DD, 1H; C2-H)

4,48 (DD, 2H; C2-CH2OCOC6H5)

3,66 (DD, 1H; C4-H)

3,44 (DD, 1H; C4-H)

of 2.56 (s, 3H; NH-COCH3)

CIS-isomer: Rf: 0,58 in acetic acid ethyl ester / methanol 9:1

U. F. (MeOH) Lambdamax309 nm

1H-NMR s (mil.D. in CDCl3)

8,72 (ush. 1H; C'4-NH-Ac)

of 8.06 (m, 2H; aromatic.)

7,87 (d, 1H; C'6-H, I6, F=6.2 Hz)

of 7.60 (m, 1H; flavor)

7,49 (m, 1H; aromatic.)

6,32 (DD, 1H; C5-H)

vs. 5.47 (DD, 1H; C2-H)

to 4.73 (DD, 2H; C2CH2OCOC6H5)

3,62 (DD, 1H; C4-H)

3,19 (DD, 1H; C4-H)

to 2.55 (s, 3H; H-COCH3)

Example 32. CIS - and TRANS-hydroxymethyl-5-(5'-fertilizin-1'-yl)- 1,3-oxathiolan

< / BR>
1.0 g (2.54 mmol) of TRANS-2-benzoyloxymethyl-5- (N'4-acetyl-5'-fluoro-cytosine-1'-yl)-1,3-oxathiolane was stirred in 25 ml of methanolic ammonia solution at 0oC for 1 h and then overnight at room temperature. A mixture of you who stylizowane in absolute ethanol, forming 484 mg (1,95 mmol, 77%) of the desired product, TRANS (LII): so pl. 219-221oC; Rf0.21 in the mixture eteltetet: methanol (9:1), which was identified using 1H,13C-NMR and U. F. Lambdamax(H2O) 280,9 nm.

1.2 g (3,05 mmol) of CIS-2-benzoyloxymethyl-5-(N4'-acetyl-5'-fluoro-cytosine-1'-yl)-1,3-oxathiolane was stirred in 30 ml of methanolic ammonia solution at 0oC for 1 h and then overnight at room temperature. The mixture is evaporated under reduced pressure. The residue was twice washed (h ml) with anhydrous ether. The solid residue was recrystallized in absolute ethanol with the formation of 655 mg (2,64 mmol. 87%) of pure product, CIS- (LII): so pl. 204-206oC; Rf=0.21 in a mixture of ethyl acetate-methanol (9:1). The desired compound was identified using 1H,13C-NMR and U. F. Lambdamax(H2O) 280,9 nm.

TRANS-isomer:

1H-NMR (mil.d in DMSO-d6):

the 7.85 (d, 1H; C6'-H, J=7,01 H2)

7,83 (d, 2H; C-NH2)

6,30 (DD, 1H; C5-H)

the ceiling of 5.60 (t, 1H; C2-H)

by 5.18 (t, 1H; C2-CH2-OH)

to 3.49 (m, 3H; C2-CH2-OH+ C4H )

3,17 (DD, 1H; C4H

13C-NMR (DMSO-d6( Varian XL-300) s in mil.D.

< / BR>
CIS-isomer

1H-NMR (mi is R>
5,43 (t, 1H; C2-CH2-OH)

5,19 (t, 1H; C2- H)

of 3.77 (m, 2H; C2-CH2OH)

the 3.35 (DD, 1H; C4- H )

of 3.12 (DD, 1H; C4- H )

13C NMR (DISO-d6)

< / BR>
Example 33. Chiral BASH separation of enantiomers (+) - CIS-2-hydroxymethyl-5-(5'-fertilizin-1'-yl)-1,3-oxathiolane.

Racemic products of example 35 can be separated using chiral HPLC under the following conditions:

Column: Astec Cyclobond I acetylated - cyclodextrin, 4,6 250 mm

Eluent: 0.1% triethylamine in water containing 0.1% acetonitrile at pH 7.3 (isocratic mode)

Speed: 1 ml/min

(-) and (+) enantiomers were suirable with a retention time of 492 and 538, respectively. Chiral HPLC separates racemic CIS-isomer on it, mainly pure enantiomers. Mostly pure (-)-enantiomeric mixture contains less than 1% of (+)-enantiomer. Mostly pure (+)-enantiomer contains less than 2% (-) enantiomer.

Antiviral activity

To determine the inhibitory properties of individual compounds of the invention were tested in vitro. The results are shown in table. 1 and 2. Indicated concentration (µg/ml) in the incubation media correspond to the concentrations that have the of Avani lady Davis (Montreal) and other Dr. Mar K. A. Wainberg against HIV-1 infection according to the method similar to the method of H. Mitsuya and S. Broder, "Inhibition of the in vitro infectivity and cytopathic effect T-lymphotropic virus type III human/virus lympadenopathy (HTLV III/LAV) by 2', 3' - dideoxynucleoside", Proc. Natl. Acad. Sci. USA, 83, pp. 1911-15 (1986). Protection cell lines from infection carry out their staining with monoclonal antibodies to viral proteins in the usual way (PL.1). In all experiments, the comparison is conducted with the drug AZT as a control. To confirm the results of the drug action is detected by measuring the activity of reverse transcriptase () in monocytic human cells lines V 937 in the test in the usual way using titiraupenga of timeinterest (CTF) (table.2). And, finally, identify acceptable mode of action of drugs on cell viability measurement is well known cytolytic action of HIV-1 on the cell line MT-4 (PL.2).

Toxicity

No toxic effect is not observed in the above tests.

Were also carried out tests to determine antiviral activity for a number of compounds of the present invention. For the study of antiviral activity as control patita B, was carried out basically as described by E. Mathes and other Antimicrob. Agents. Cnamotherap. 34 (10), 1986 1990 (1990).

Antiviral activity against virus HTV-1 was determined on cells MT-4. The cell suspension (approximately 106cells/ml) in RPM1 1640 medium growth was infected by a strain RF virus HIV 1 at M. O. 1. 10-3infected units/cell. The suspension was thermostatically for 90 min at room temperature. Compound was serially diluted with a tenfold decrease from 100 μg/ml to 0.01 μg/ml (final concentration in two 96-cell micromicrofarad cups), 20 μl of the infected cell suspension was thermostatically in each cell cups. Then the Cup was thermostatically at 37oC for 7 days. After incubation in whole cells was added 10 μl of 3-(4,50 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) at 20 mg/ml and cups were thermostatically another 90 min at 37oC.

Then there was added 150 μl of 10% (by volume) alcohol solution Triton X-100 and the cells re-suspendibility. After 15 min stay cups at room temperature and their contents were analyzed on a Multiskan MC with a recording device at 405 nm. Conversion of yellow MMT in his formisano prervannyj cells. The values of optical density for cytotoxic control samples and for cells treated with antiviral substances, Viceroyalty graphically and calculated dose of the compounds required to inhibit the conversion of MTT 50% relative to untreated uninfected control samples. In this way can be defined as the 50% cytotoxic dose, CD 50%) and 50% anti-virus dose (ID 50%).

The results are presented in table. 3.

Example formulations 1

Tablets formulations

A. the Following composition is obtained by wet granulation of the ingredients with an aqueous solution of povidone, drying, sieving and subsequent addition of magnesium stearate and compression. mg/tablet

(a) Active ingredient 250

(b) Lactose VP 210

(c) Povidone C. R. 15

(d) Glycolate natricinae 20

(e) magnesium Stearate 5 500

B. the Following composition is obtained by direct pressing; lactose refers to the type designed for direct compression. mg/tablet

The active ingredient 250

Lactose 145

Avicel 100

Magnesium stearate 5 500

C. (extended Composition). This composition obtained by wet granulation of the ingredients (below) cation. mg/tablet

(a) Active component 500

(b) Hypromellose (Methocel CM premium) 112

(c) Lactose C. R. 53

(d) Povidone C. R. 25

(e) magnesium Stearate 5 700

Example formulation 2

A capsulated composition

A capsulated composition obtained by mixing the following and filling the mixture of hard gelatin capsules consisting of two parts.

mg/capsule

Active component 125

Lactose 72,5

Avicel 50

Magnesium stearate 2,5 250

Example formulation 3

The composition for injection

The active ingredient 0.2 g

The sodium hydroxide solution; 0,1 MgS To pH 11

Sterile water sufficient To 10 ml

The active ingredient is suspended in a quantity of water (which can be heated) and the addition of sodium hydroxide solution establish a pH of about 11. The resulting mixture is then brought to the required volume and filtered through a sterilized membrane filter into a sterile glass vials of 10 ml, which clog sterile lids seal.

Example recipe 4

Candles mg/candle

The active ingredient 250

Tallow 1770 2020

One-fifth of hard fat is melted in to the 200 μm and with stirring to the molten base with the help of a mixer with a high shear strain up to the time of formation of equal variance. When the temperature of the mixture 45oC add the rest of the solid fat and stirred until the formation of homogeneous mixture. The resulting suspension is entirely passed through a stainless steel sieve of 250 μm and with continuous stirring, cooled to 40oC. At 38-40oC the mixture in an amount 2,02 g populate the corresponding plastic shapes in 2 ml of the resulting candle is allowed to cool to room temperature.

1. 1,3-Oxathiolan General formula I

< / BR>
its geometrical and optical isomers, mixtures of these isomers

where R1hydrogen;

R2radical selected from

< / BR>
where R3hydrogen;

R4hydrogen, C1WITH6-alkyl or fluorine;

R5hydrogen or C1WITH6-alkyl;

R6carbarnoyl or thiocarbamoyl;

X and Y independently hydrogen, bromine, chlorine, fluorine, iodine, amino group or hydroxyl group;

Z is S, SO or SO2,

and its pharmaceutically acceptable salts or esters.

2. Connection on p. 1, characterized in that it exists in the form of its CIS-isomer.

3. Connection under item 1 or 2, characterized in that Z s

4. The compound according to any one of paragraphs. 1 to 3, characterized in that R2- radical General is op.

5. Connection on p. 1, characterized in that it is selected from CIS-2-hydroxymethyl-5-(cytosine-1'-yl)-1,3-oxathiolane, TRANS-2-hydroxymethyl-5-(cytosine-1'-yl)-1,3-oxathiolane and mixtures thereof, CIS-2-benzoyloxymethyl-5-(cytosine-1'-yl)-1,3-oxathiolane, TRANS-2-benzoyloxymethyl-5-(cytosine-1'-yl)-1,3-oxathiolane and mixtures thereof, CIS-2-hydroxymethyl-5-(N4-acetyl-cytosin'-yl)-1,3-oxathiolane, TRANS-2-hydroxymethyl-5-(acetyl-cytosine-1'-yl)-1,3-oxathiolane and mixtures thereof, CIS-2-benzoyloxymethyl-5-(acetyl-cytosine-1'-yl)-1,3-oxathiolane, TRANS-2-benzoyloxymethyl-5-(acetyl-cytosine-1'-yl)-1,3-oxathiolane and mixtures thereof, and CIS-2-hydroxymethyl-5-(cytosine-1'-yl)-3-oxo-1,3-oxathiolane, CIS-2-hydroxymethyl-5-(N-dimethylamino-Meilenstein-1'- yl)-1,3-oxathiolane, bis-CIS-2-succinylcholine-5-(cytosine-1'-yl)-1,3 - oxathiolane, CIS-2-benzoyloxymethyl-5-(6'-globulin-N-9'-yl)-1,3-oxathiolane, TRANS-2 - benzoyloxymethyl-5-(6'-globulin-N-9'- yl)-1,3-oxathiolane and mixtures thereof, CIS-2-hydroxymethyl-5-(6'-hydroxypurine-N-9'-yl)- 1,3-oxathiolane, CIS-2-benzoyloxymethyl-5-(uracil-N-1'-yl)-1,3-oxathiolane, TRANS-2-benzoyloxymethyl-5-(uracil-N-1'-yl)-1,3-oxathiolane and their sostiene, TRANS-2-benzoyloxymethyl-5-(thymine-N-1'-yl)-1,3-oxathiolane and mixtures thereof, CIS-2-hydroxymethyl-5-(thymine-N-1'-yl)-1,3-oxathiolane, CIS-2-hydroxymethyl-5-(5'-fertilizin-1'-yl)-1,3-oxathiolane and its pharmaceutically acceptable derivatives.

6. Connection on p. 1 possessing antiviral activity.

7. CIS-2-hydroxymethyl-5-(cytosine-1'-yl)-1,3-oxathiolan and its pharmaceutically acceptable derivatives, exhibiting antiviral activity.

8. CIS-2-hydroxymethyl-5-(5'-fertilizin-1'-yl)-1,3-oxathiolan and its pharmaceutically acceptable derivatives, exhibiting antiviral activity.

9. 1,3-Oxathiolan in accordance with any of paragraphs. 1 8 in the form of a single optical isomer.

10. 1,3-Oxathiolan in accordance with any of paragraphs. 1 8 in the form of racemic mixtures.

11. The pharmaceutical composition exhibiting antiviral activity comprising an active ingredient and excipient, characterized in that as the active ingredient contains an effective amount of 1,3-oxathiolane according to any one of paragraphs. 1 10 or its pharmaceutically acceptable derivative.

12. 1,3-Oxathiolan General formula VIII

< / BR>
its geometric S, SO or SO2;

L alkoxycarbonyl group, iodine, bromine, chlorine or-or SIG, where R is an aliphatic or aromatic acyl group.

13. The ether derivative of 1,3-oxathiolane under item 1, the geometric and optical isomers or mixtures of such isomers of General formula IV

< / BR>
where W PO-4, SPO-3or-O-CO-(CH2)n-CO-O-, where n is 1 or 2;

R2and Z have the above meanings;

J the remainder of the oxo - or aminopyrimidine, which may be substituted by lower alkyl, or the remainder of the 6'-chloro - or 6'- hydroxypurine.

14. 1,3-Oxathiolan on p. 13, wherein J is a

< / BR>
where R2and Z have the specified values.

15. The method of receiving oxathiolane formula I

< / BR>
their geometrical or optical isomers, or mixtures thereof, or their pharmaceutically acceptable salts and esters,

where R1hydrogen

R2and Z have values under item 1,

characterized in that carry out the reaction of the compound of formula VIII

< / BR>
where R1hydrogen or hydroxylamine group;

Z has the values specified in paragraph 1;

L capable of substituting atom or group,

with a core group R2N, and, if necessary, on the PP; (ii) the conversion of compounds of formula I or its salts in its pharmaceutically acceptable salt.

16. The method according to p. 15, wherein the group L is selected from alkoxycarbonyl, iodine, bromine, chlorine or-or SIG, where R is substituted or unsubstituted, saturated or unsaturated alkyl group or a substituted or unsubstituted aliphatic or aromatic acyl group.

17. The method according to under item 15, characterized in that the compound of formula VIII is subjected to interaction with the corresponding sillavan, purine or pyrimidine base in a suitable solvent in the presence of a Lewis acid such as titanium tetrachloride or tin chloride, or trimethylsilyltriflate.

l8. The method of receiving oxathiolanes in the form of their geometric or optical isomers or mixtures thereof of the formula I, or their pharmaceutically acceptable salts or esters, wherein interact the compounds of formula IX

< / BR>
with the compound of the formula X

< / BR>
where P is a protective group,

and if necessary, the compound obtained is subjected to one or two further reactions, including (i) removing any protective groups, (ii) the conversion of compounds of formula I or its salts in its pharmaceutically what IP-isomer.

20. The method according to PP. 15 to 19, characterized in that Z s

21. The method according to any of paragraphs. 15 to 20, characterized in that R2radical of General formula

< / BR>
where R3hydrogen or saturated WITH a1WITH6-alkyl;

R4hydrogen, saturated WITH1WITH6-alkyl or fluorine.

22. The method according to any of paragraphs. 15 to 21, characterized in that the compound of formula I is selected from CIS-2-hydroxymethyl-5-(cytosine-1'-yl)-1,3-oxathiolane, TRANS-2-hydroxymethyl-5-(cytosine-1'-yl)-1,3-oxathiolane and mixtures thereof, CIS-2-benzoyloxymethyl-5-(cytosine-1'-yl)-1,3-oxathiolane, TRANS-2-benzoyloxymethyl-5-(cytosine-1'-yl)-1,3-oxathiolane and mixtures thereof, CIS-2-hydroxymethyl-5-(N4-acetyl-cytosine-1'-yl)-1,3-oxathiolane, TRANS-2-hydroxymethyl-5- (acetyl-cytosine-1-yl)-1,3-oxathiolane and mixtures thereof, CIS-2-benzoyloxymethyl-5-(acetyl-cytosine-1'-yl)-1,3-oxathiolane, TRANS-2-benzoyloxymethyl-5-(N-acetyl-cytosine-1'-yl)-1,3 - oxathiolane and mixtures thereof, CIS-2-hydroxymethyl-5-(cytosine-1-yl)-3-oxo-1,3-oxathiolane, CIS-2-hydroxymethyl-5-(N-dimethylamino-methylene-cytosine-1'-yl)-1,3-oxathiolane, bis-CIS-2-succinylcholine-5-(cytosine-1'-yl)-1,3 - oxathiolane, CIS-2-benzoyloxymethyl-5-(6'-j-N-9'-yl)-oximeter-5-(6'-hydroxypurine-N-9'-yl)-1,3-oxathiolane, CIS-2-benzoyloxymethyl-5-(uracil-N-1'-yl)-1,3-oxathiolane, TRANS-2-benzoyloxymethyl-5-(uracil-N-1'-yl)-1,3-oxathiolane and mixtures thereof, CIS-2-hydroxymethyl-5-(uracil-N-1'-yl)-1,3-oxathiolane, CIS-2-benzoyloxymethyl-5-(thymine-N-1'-yl)-1,3-oxathiolane, TRANS-2-benzoyloxymethyl-5-(thymine-N-1'-yl)-1,3-oxathiolane and mixtures thereof, CIS-2-hydroxymethyl-5-(thymine-N-1'-yl)-1,3-oxathiolane, and their pharmaceutically acceptable derivatives.

23. The method according to any of paragraphs. 15 to 21, characterized in that the compound of formula I is CIS-2-hydroxymethyl-5- (cytosine-1'-yl)-1,3-oxathiolan and its pharmaceutically acceptable derivatives.

24. The method according to any of paragraphs. 15 to 23, characterized in that the connection get in the form of a single optical isomer.

25. The method according to any of paragraphs. 15 to 23, characterized in that the compound obtained as racemic mixtures.

 

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FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

, where R1 represents -CO-Ra, -SO2-Rb, or aryl optionally substituted by lower alkoxy, wherein Ra represents cycloalkyl, cycloalkyl(lower)alkyl, cycloalkyloxy, aryl, aryloxy, aryl(lower)alkyl, aryl(lower)alkoxy, aryloxy(lower)alkyl, aryl-S-(lower)alkyl, aryl(lower)alkenyl, provided that aryl group can be optionally substituted by halogen, lower alkyl, hydroxy, nitro, cyano, lower alkoxy, phenyl, CF3, cyano(lower)alkyl, lower alkyl-C(O)NH, lower alkyl-CO, and lower alkyl-S; heteroaryl, heteroaryl(lower)alkyl, or heteroaryl(lower)alkoxy, provided that heteroaryl group is 5- or 6-membered ring or bicyclic aromatic group constituted by two 5- or 6-membered rings including 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur and that heteroaryl group can be optionally substituted by lower alkoxy; Rb represents aryl, aryl(lower)alkyl, or heteroaryl, aryl group optionally substituted by halogen, cyano, or lower alkyl-C(O)NH; R2 and R3 represent hydrogen atoms; R4 representshydrogen or lower alkyl; R5 represents hydrogen, lower alkyl, cycloalkyl, benzodioxyl, or aryl optionally substituted by lower alkyl, halogen, lower alkoxy, hydroxy, or (lower)alkyl-C(O)O; n is 1 or 2; and pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable esters thereof. Invention also provides a pharmaceutical composition exhibiting inhibitory activity with regard to cysteine proteases of the cathepsin family, which composition comprises compound of formula I, pharmaceutically acceptable recipient, and/or adjuvant.

EFFECT: increased choice of cysteine protease inhibitors.

34 cl, 1 tbl, 13 ex

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15 cl, 7 tbl, 56 ex

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EFFECT: higher efficiency of prophylaxis.

1 cl, 1 ex, 4 tbl

FIELD: medicine, natural compounds.

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2 ex

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21 cl, 1 dwg, 1 tbl, 6 ex

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EFFECT: improved preparing methods, valuable medicinal properties of compounds.

22 cl, 1 tbl, 2 sch, 78 ex

FIELD: medicine.

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9 cl, 11 dwg, 6 ex, 2 tbl

FIELD: pharmaceutical chemistry.

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136 cl, 448 ex

FIELD: organic chemistry, pharmacology.

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EFFECT: new compounds with value bioactive effect.

31 cl, 2 tbl, 32 ex

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EFFECT: improved preparing methods.

27 cl, 3 dwg, 16 ex

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