Dimethoxydimethylsilane nucleosides, the pharmaceutical composition

 

(57) Abstract:

The proposed compounds of formula :

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where X represents H, NRR1, SR, or, or halogen; Z represents H, OR2or NRR1; R, R1and R2represent H, C1-C4is alkyl or aryl and their pharmaceutically acceptable salts. Also proposed the use of these compounds as antiviral and antitumor agents, farbkomposition based on them, and methods of obtaining the source and intermediate compounds. 3 S. and 13 C.p. table 2.

The invention relates to analogs dimethoxyaniline nucleosides. More specifically, the present invention relates to carbocyclic analogues of 2', 3'-dideoxy-2', 3'-didehydrothymidine and their use in therapy, in particular as antiviral agents.

In light of the similarities between viral and host-cell functions, it is difficult to selectively strike the virus and at the same time to leave the host cell intact. Thus there are only a few agents are effective against viruses per se and it is very difficult to find antiviral agents that have an acceptable therapeutic index, i.e. agents that have significant protivovetrovye.

One group of viruses, which recently received a major importance are retroviruses responsible for the acquired immunodeficiency syndrome (AIDS) human. These viruses had different terminology, but is now mostly referred to as the virus of human immunodeficiency (HIY'S) ; two such virus HIY-I and HIY-II reproductive isolated from patients with AIDS and related conditions, such as AIDS-related complex (ARC) and sustainable widespread lymphadenopathy.

Although a number of nucleosides is considered as useful in the treatment of conditions associated with infections HIY, only zidovudine (AZ1, Petrovir) received permanent approval for the treatment of such conditions. However, it is known that AZT is highly undesirable side effects that cause bone marrow depression, which leads to a decrease in the number of cells with subsequent severe anemia, and there is a need for effective agents that are less cytotoxic.

The applicant has discovered a new class of nucleoside analogues with antiviral activity. It is therefore proposed that the first variant of the compounds of formula (I):

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where

X denotes hydrogen, NRR1, SR, OR, and are selected from hydrogen, C1-C4of alkyl and aryl, and its pharmaceutically acceptable derivatives.

The expert will understand that the compounds of formula (I) represent the CIS-compounds, and cyclopenten - ring compounds of formula (I) contains two chiral center (shown in the formula (I) under the designation*) and their mixtures, including racemic mixtures. All such isomers and mixtures thereof, including racemic mixtures, are included in the scope of the present invention. Thus, in compounds of formula (I) or a chiral center that is attached to the base, is R-configuration, and the chiral center that is attached to the part of CH2OH, is S-configuration (hereinafter D-isomer) or a chiral center that is attached to the base, is S-configuration, and the chiral center that is attached to the part of CH2OH, is R-configuration (hereinafter L-isomer). Connections can be either a racemic mixture or mainly as a pure D-isomer.

D-isomers may be represented by formula (Ia):

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where

X and Z are as defined above values. In further reference to the compounds of formula (I) includes the compounds of formula (Ia).

You should also understand that some of the present inventions.

As used here, the term halogen refers to fluorine, chlorine, bromine, and iodine; and when X is halogen, it is preferably chlorine.

C1-C4-alkyl refers here to remotemachine or branched alkilani group, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl. Preferably, C1-C4-alkyl means methyl.

Aryl here refers to any mono - or polycyclic aromatic part and includes unsubstituted and substituted aryl (such as phenyl, tolyl, xylyl, anisyl), and unsubstituted and substituted aralkyl, including ar (C1-C4)alkyl, such as a Hairdryer(C1-C4)alkyl, for example benzyl or phenethyl.

In the compounds of formula (I), Z preferably represents amino.

In one preferred class of compounds of formula (I) X denotes OR, in particular OH.

In another preferred class of compounds of formula (I) X denotes NRR1in particular NH2or hydrogen.

Especially preferred compounds of formula (I) in which Z represents NH2and X denotes H, NH2or, especially, OH. Such compounds are particularly desirable therapeutic index in cachestoreprivate acceptable salt, ester or salt of such a complex ester compounds of formula (I) or any other compound which upon administration to the recipient is able to produce (directly or indirectly) the compounds of formula (I) or antiviral active metabolite or residue.

Preferred esters of the compounds of formula (I) include esters of carboxylic acids, in which decarbonising part of the group of ester selected from hydrogen, pravarasena or branched alkyl (e.g. methyl, ethyl, n-propyl, tert-butyl, n-butyl, alkoxyalkyl (for example, methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (e.g. phenyl, optionally substituted with halogen, C1-C4-alkyl or C1-C4-alkoxy); esters of sulfonic acids, such as alkyl or aralkylamines (for example, methanesulfonyl), amino acid esters (for example, L-poured or L-isoleucyl) and esters of mono-, di - or tri-phosphoric acid.

As for the above-mentioned esters, if not stated otherwise, any present alkyl part mainly contains from 1 to 18 carbon atoms, h is but contains a phenyl group.

Pharmaceutically acceptable salts of compounds of formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, perchloro acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-n-acid, tartaric acid, acetic acid, citric acid, methanesulfonate, formic acid, benzoic acid, malonic acid, naphthalene-2-acid and benzosulfimide. Other acids, such as oxalic acid, although not are pharmaceutically acceptable in themselves, can be used in obtaining salts useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid additive salts.

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

Specific compounds of formula (I) include: / 1,4 /-4-/6-chloro-9H-purine-9-yl/-2-cyclopentenyl-carbinol,

/ 1,4 /-4-/6-hydroxy-9H-purine-9-yl-/2-cyclopentenyl-carbinol,

/ 1,4 /-4-/6-amino-9H-purine-9-yl-/2-cyclopentenyl-carbinol,

/ 1,4 /-4-/6-mercapto-9H-purine-9-yl-/2-cyclopentenyl-carbinol,

/ 1,4 /-4-/2-amino-6-chloro-9H-purine-9-yl-/2-cyclopentenyl-carbinol,

/ 1,4 /-4-/2-amino-6-hydroxy-9H-purine-9-yl-/2-cyclopentenyl-carbinol,

/ 1,4 /-4-/2,6-diamino-9H-purine-9-yl-/2-cyclopentenyl-carbinol

in the form of racemic mixtures or simple enantiomer.

Compounds of the present invention either by themselves possess antiviral activity, or are metabolized in such compounds. In particular, these compounds effective in inhibiting replication of retroviruses, including human retroviruses such as the human immunodeficiency viruses (HIY'S) causative agents of AIDS.

Some compounds of the present invention have anti-cancer activity, in particular compounds in which a represents hydrogen.

Thus, it is proposed another variant of the present invention relative to the compounds of formula (I) or the pharmacist who retroviral infections, or as an anticancer agent.

In another or alternative embodiment, the present invention features a method of treating viral infections, particularly infection caused by a retrovirus, such as HIY, in mammals, including humans, which is administered an effective amount of the antiviral agent in the form of compounds of formula (I) or its pharmaceutically acceptable derivative.

Also available as an additional or alternative variant of the invention using the compounds of formula (I) or its pharmaceutically acceptable derivative for the manufacture of a medicinal product for the treatment of viral infections or use as anti-cancer tool.

Compounds of the present invention, having antiviral activity, are also suitable in the treatment of AIDS-related conditions such as AIDS-related complex (ARC), progressive common lymphadenopathy (PGL), AIDS-related neurological conditions (such as dementia or tropical prepares), anti-HIY antibody-positive and HIY-positive status, idiopathic multiple hemorrhagic sarcoma (angiomatosis of Kaposi) and thrombocytopenias the development of clinical disease patients which are anti-HIY antibody or HIY-antigen-positive, and in the prevention following exposure HIY.

Antiviral compounds of the formula (I) or their pharmaceutically acceptable derivatives may also be suitable for preventing virus infection of physiological fluids such as blood or semen, in vitro.

Some compounds of formula (I) are also suitable as intermediates in obtaining other compounds of the present invention.

The specialist will be clear that the reference here to the treatment involves prevention and treatment of established infections or symptoms.

It is clear that a number of compounds of the present invention required for use in treatment will vary not only depending on the type of the selected connection, but also depending on the route of administration of the medicinal product, the nature of the condition to be treated, the age and condition of the patient and will be fully in competence of the physician or veterinarian. In General, a suitable dose will be the range from approximately 1 to approximately 750 mg/kg, for example, from about 1 to 750 mg/kg body weight per day or from about 3 to 120 is the azone 15 to 60 mg/kg/day.

The desired dose may be in the form of a single dose or in the form of separate dosages, administered at appropriate intervals, for example, as two, three, four or more podosinovets a day.

Connection it is convenient to introduce in the form of uniform dose, for example, containing 10 to 1500 mg, more convenient from 20 to 1000 mg, most conveniently, 50 to 700 mg of active component on a standard drug dose.

Ideally the active ingredient should be administered to achieve peak concentrations of the active compounds in the plasma of approximately from 1 to 75 microns, preferably about 2-50 microns, most preferably about 3-30 μm. This can be achieved, for example, by intravenous injection of 0.1-5%-aqueous solution of the component of choice in physiological solution, or by oral administration in the form of a bolus containing about 1 to 100 mg/kg of the active ingredient. Desirable blood levels may be maintained by continuous infusion of obtaining from about 0.01 to 5.0 mg/kg/HR or by intermittent infusions containing about 0.4-15 mg/kg of the active component.

Although for use in therapy, you can enter the compound of the present sabrage composition.

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

Pharmaceutical formulations include those suitable for oral, rectal, nasal, local (including transbukkalno and sublingual), vaginal and parenteral (including intramuscular and intravenous) administration or in a form suitable for administration by inhalation or insufflation. Structures, where this is appropriate, may be present in the form of a discrete dosage units and may be obtained by any methods well known in the field of pharmacy. All methods include the stage of linking the active compound with liquid carriers or finely dispersed solid carriers, or both, and, if necessary, the formation stage of the product into the desired configuration.

Pharmaceutical formulations suitable for Perera is blecki, each contains a set amount of active component in the form of powder or granules, in the form of a solution, suspension or emulsion. The active ingredient may also be present in the form of a bolus, electuary (medicinal porridge or pasta. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, oiling agents, wetting agents or disintegrator. Tablets may be coated according to methods well known in the art. Liquid preparations for oral administration can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they may be present in the form of a dry product for making together with water or other suitable carrier prior to use. Such liquid preparations may contain conventional additives, such as suspendresume ingredients: emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives.

Compounds in accordance with the present invention can also be prepared for parenteral administration (e.g. by injection, for example, the introduction of the ball or neolane syringes or in the packaging of the medicines for multiple reception with the addition of preservatives. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous carriers can contain suspendresume substances, stabilizers and/or dispersants. Alternative active ingredient may be in powder form, obtained by aseptic allocation of sterile solid or by lyophilization from solution, for making together with suitable filler, such as sterilized pyrogen-free water, before use.

For topical application to the epidermis of the compounds in accordance with the present invention can be prepared in the form of ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be prepared with an aqueous or oily base and may also contain one or more emulsifiers, stabilizers, dispersants, suspendida substances, thickeners or coloring substances.

Formulations suitable for topical application in the mouth include tablets containing the active ingredient in Corrientes basis, usually sucrose and Arabian gum) or tragakant; tablets containing the active ingredient in an inert basis such as gelatin and glycerin or sucrose and motor.

Pharmaceutical compositions suitable for rectal administration, and the carrier is a solid are most preferably presented in the form of suppositories single application. Suitable carriers include coconut oil and other substances commonly used in the art, and the suppositories may be conveniently prepared by mixing the active compounds with the softened or melted carrier (s) followed by chilling and shaping in molds.

Formulations suitable for vaginal administration, can be in the form of vaginal suppositories, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient, such carriers which are known in this field.

Intranasal injection of the compounds of the present invention can be used as a liquid composition for spraying or in the form of drops.

Drops may be formulated with an aqueous or non-aqueous base also containing one or more dispersing agents, solubilization or suspecious substances. Liquid compositions for spraying conveniently enclosed in sealed packages.

For the introduction of inhale and sealed package or other suitable means of delivery of aerosols. Sealed packages may contain suitable dispersant, such as DICHLORODIFLUOROMETHANE, Trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage can be determined by providing a valve to deliver a measured quantity of connections.

Alternative to injection therapy or insufflate connection in accordance with the present invention can take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in a dosage form such as capsules or cartridges, or, for example, gelatin or exhaust transparent packs from which the powder may be introduced using an inhaler or insufflator.

If desired, the above compositions can be used to obtain sustained release of the active component.

Pharmaceutical compositions in accordance with the present invention can also contain other active ingredients such as antimicrobial agents or preservatives.

Connected is an example of other anti-infective agents. In particular, the compounds of the present invention can be used together with known antiviral agents.

Thus, the present invention in its additional embodiment provides for a combination containing the compound of formula (I) or its physiologically acceptable derivative together with another therapeutically active substance, in particular an antiviral substance.

The above combinations may be provided for use in the form of pharmaceutical medicine, and such pharmaceutical compositions containing defined above combination, together with a pharmaceutically acceptable carrier are additional variant of the present invention.

Suitable therapeutic agents for use in such combinations include acyclic nucleosides such as acyclovir, interferon, such as interferon, renal excretion inhibitors such as probenicid, inhibitors of nucleoside transport such as dipyridamole, 2',3'-dideoxynucleoside, such as 2',3'-dideoxycytidine, 2',3'-dideoxyadenosine, 2',3'-dideoxyinosine, 2', 3'-dideoxycytidine and 2',3'-dideoxy-2',3'-didehydrothymidine, as well as immunomodulators, such as inter is ptx2">

The individual components of such combinations may be administered either sequentially or simultaneously in separate or joint pharmaceutical compositions.

When the compound of formula (I) or its pharmaceutically acceptable derivative used in combination with a second therapeutic agent active against the same virus, the dose of each compound may differ from the dose when the connection is used separately. Suitable dose will be clear to the specialist.

The compounds of formula (I) and their pharmaceutically acceptable derivatives may be obtained by any known in this field by the method of obtaining compounds of similar structure.

Suitable methods of making compounds of formula (I) and their pharmaceutically acceptable derivatives are described below; the groups X and Z have the above meanings, except in those cases where other values are given. It should be understood that the following reactions may require the use or conveniently can be adapted to the original materials having protected functional groups, and exemption from protection so you may need as an intermediate or final stage for telemedicine ways. So, for example, amino groups can be protected by a group selected from aralkyl (for example, benzyl, acyl or aryl (e.g., 2,4-dinitrophenyl); subsequent removal of the protective group carry out, if necessary, by hydrolysis or hydrogenolysis using standard conditions. Hydroxyl groups may be protected using any conventional hydroxyl protective group, for example, as described in "Protective groups in organic chemistry", Ed. T. F. W. MC Omie (Plenum Press, 1973) or "Protective groups in organic synthesis", Theodora W. Greene/La Tohu Wiley and Sons, 1981). Examples of suitable hydroxyl protective groups include groups selected from 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). Hydroxyl protective group can be derived by traditional methods. So, for example, alkyl, silyl, acyl and heterocyclic groups can be derived by solvolysis, for example by hydrolysis in acidic or basic conditions. Kalkilya group, that is H. Kalkilya groups such as benzyl, can be split by hydrogenolysis in the presence of a catalyst of a noble metal such as palladium charcoal. Silyl groups can also be derived using a source of fluoride ions, such as Tetra-n-butylammonium.

In the first process (a) compounds of formula (I) and their pharmaceutically acceptable derivatives may be obtained by reacting the compounds of formula (II)

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where

X and Z denote substituents having the formula (I), or represent protected forms, and a hydroxyl group in the grouping cyclopentanecarbonyl may be in a protective form, or its pharmaceutically acceptable derivative with a reagent selected from formic acid or its reactive derivative, followed where necessary by removal of unwanted groups entered this reagent, and/or the removal of any protective groups.

Examples of suitable derivatives of formic acid, which can be used in process (A) include orthoformiate (for example, triethylorthoformate), dialkoxybenzene (for example, diethoxymethylsilane), dicionario acid, formamide, triazine or formamidine may be conveniently derived by hydrolysis under mild conditions, for example, with inorganic acids, such as aqueous hydrochloric acid.

When using trialkylaluminium, such as triethylorthoformate, it is also a solvent for the reaction. Other solvents that may be used include amides (e.g. dimethylformamide or dimethylacetamide), chlorinated hydrocarbons (e.g. dichloromethane), ethers (e.g. tetrahydrofuran) or a nitrile (e.g. acetonitrile).

In some cases (for example, when using trialkylaluminium, such as triethylorthoformate) reaction preferably takes place in the presence of a catalyst such as a strong acid (e.g. concentrated hydrochloric acid, nitric acid or sulfuric acid). The reaction can be performed at temperatures from -25 to 150oC, for example, from 0 to 100oC, conveniently at ambient temperature.

In another process (B) compounds of formula (I) and their pharmaceutically acceptable derivatives or their protected form is subjected to reaction interconversion, in which the Deputy X, present initially, replaced by Deputy X, and/or the group Z is present symptom is CLASS="ptx2">

In one embodiment, the process (B) compounds of formula (I) in which X denotes a group RR1(where R and R1have the above meanings, can be obtained by aminating the corresponding compounds of formula (I) in which X denotes a halogen atom (e.g. chlorine). Amination can be accomplished by interaction with the reagent HNRR1(where R and R1have the above values) in a solvent such as alcohol (e.g. methanol). The reaction may be carried out at any suitable temperature and conveniently at an elevated temperature, such as temperature phlegmy, or when the use of liquid ammonia in a sealed tube at a temperature of about 50 - 80oC. Suitable conditions for the conversion of halides in the secondary and tertiary amines are also described by Harrison et. al., Compendium of Organic Sinthetic Methods, Wiley-Jntesscience, new York (1971) on pages 250 to 252.

In another embodiment of process (B) compounds of formula (I) in which X denotes a group OR (where R has the above meaning), can be obtained by substitution of the halogen atom (e.g. chlorine) corresponding anion RO-. When R denotes a hydrogen atom, the substitution reaction can be performed in water or in a mixture of water and miscible with water solvent, such Keaton), amide (e.g. dimethylformamide) or sulfoxide (e.g., dimethylsulfoxide), conveniently in the presence of acid or base. Suitable acids include organic acids such as p-toluensulfonate, and inorganic acids such as hydrochloric acid, nitric acid or sulfuric acid. Suitable bases include inorganic bases such as hydroxides or carbonates of alkali metals (for example, the hydroxide or carbonate of sodium or potassium). As the reaction solvent can also be used aqueous acid or base. The hydrolysis may conveniently be carried out at temperatures from -10 to +150oC, for example, at a temperature of phlegmy. When R represents C1-C4is alkyl or aryl, anion RO-form of the corresponding alcohol ROH with the use of inorganic bases, such as alkali metal (e.g. sodium) or an alkali metal hydride (e.g. sodium hydride). The reaction with the formation of the in situ anion can be conveniently carried out at ambient temperature.

In another embodiment of process (B) compounds of formula (I) in which X denotes a group of SH can be obtained by reacting a halo-compound of the formula (I) with t the emer, the temperature phlegmy) with subsequent basic hydrolysis. Suitable bases that may be used in this case include hydroxides of alkali metals (e.g. sodium hydroxide). The reaction can be carried out in accordance with the method of G. G. Urquart and other Org. Syn. Coll., Tom. 3, S. 363, 1953, for example, by heating under reflux intermediate product using aqueous NaOH solution, for about 0.25 to 5 hours

In an additional embodiment of process (B) compounds of formula (I) in which X denotes a hydrogen atom, can be obtained by reduction of halo-compounds of formula (I), using the recovery system, which does not affect the rest of the molecule. Suitable reducing agents which can be used to perform the required reaction dehalogenase are zinc/water. The recovery of this type is described in T. R. Marshall and others J. Chem. Soc., 1004 (1951). Alternative reaction can be carried out by photolysis in a suitable solvent, such as tetrahydrofuran containing 10% triethylamine, and conveniently in the reactor Rayonet photochemical (2537A) in accordance with the method of V. Nair and others, J. Org. Chem., 52, 1344 (1987).

In another embodiment of process (B) compounds the traditional methods halide-halide exchange. Alternatively, when X is chlorine, the Deputy may be substituted by other halogen atoms by using different n-/halo/benzene-vasodilation in accordance with well known techniques.

The compounds of formula (I) in which X denotes a group SR where R denotes the group of C1-C4-alkyl or aryl, can be obtained from the corresponding thiols using standard techniques alkylation or arilirovaniya, for example, as described in U.S. patent N 438114.

The compounds of formula (I) in which Z denotes a hydroxyl group, can be conveniently obtained from the corresponding compounds of formula (I) in which Z represents NH2by interaction with nitrous acid, for example, using the method described in J. Davoll in J. Amer. Chem. Soc., 73, 3174 (1951).

Many of the reactions described above are widely described in the context of the purine nucleoside synthesis, for example, Nucleoside Analogs-Chemistry, Biology and Medical Applications, R. T. Walker and others, EDS. Plenum Press, new York (1979) S. 193 - 223, the description of which is introduced here as a reference.

Pharmaceutically acceptable salts of the compounds of the present invention can be obtained, as described in U.S. patent N 4383114, description to the Oia formula (I), product of any of the above methods can be converted into a salt by processing the obtained free base suitable acid using traditional methods. Pharmaceutically acceptable acid additive salts can be obtained by reacting the free base with a suitable acid by choice - in the presence of a suitable solvent, such as an ester (e.g. ethyl acetate) or an alcohol (e.g. methanol, ethanol or isopropanol). Inorganic basic salts can be obtained by reacting the free base with a suitable base such as alkoxide (e.g. sodium methoxide), optionally 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 (I) using conventional methods.

The compound of formula (I) may be converted into pharmaceutically acceptable phosphate or other ester by reacting with fosforiliruyusciye substance, such as POCl3or suitable esterification substance, such as galoyanized or acid anhydride. Ester or salt of the connection the I of the formula (II) and their salts are new compounds, and they are additional distinctive feature of the present invention.

The compounds of formula (II) in which Z represents hydrogen or hydroxyl, can be obtained directly from compounds 2a.

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by reacting with an excess of a pyrimidine of formula (III):

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(where

Y denotes a halogen atom, for example chlorine, and Z denotes hydrogen or a hydroxyl group) in the presence of an amine base, such as triethylamine, and in an alcohol solvent (e.g. n-butanol), conveniently at a temperature of phlegmy.

The compounds of formula (II) in which Z represents NH2can be obtained using the compounds of formula 2a by reacting with an excess of a pyrimidine of formula (IV):

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(where

Y represents the same as in the formula (III) above) under these same conditions described for preparing compounds of the formula (II) in which Z represents a hydrogen or hydroxyl group, to obtain compounds of formula (V):

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which can be diazotized using diazonium salt FRN+2E-(where Ar denotes an aromatic group, for example, p-chlorophenyl, and E-denotes an anion, for example halide, such kao at ambient temperature, obtaining the compounds of formula (VI):

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(where

Ar has the above meaning), which can be converted into the desired compound of formula (II) restoration using, for example, recovery of metal, such as zinc, in the presence of acid, for example acetic acid. It should be understood that the choice of the reducing agent depends on the nature of the group X.

Compound 2a can be obtained from the universal precursor, 1-acetylamino - 3-acetoxy-methylcyclopentene-2-ene (1a), by hydrolysis in the presence of a weak base such as a hydroxide of alkaline earth metal.

Extremely convenient synthesis of compounds of formula (I) via 6-chloromethylene formula (II) below.

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Compound 2a and compounds of the formulas (V) and (VI) are novel intermediate compounds and form a further characteristics of the present invention.

Compound 1a is a known compound described in U.S. patent N 4138562.

When the compound of formula (I) it is desirable to have a simple isomer, it can be obtained either by patsatsia the final product or stereospecific synthesis of isomerically net source or substance of any podhodyashaya can be accomplished by any suitable method, known in this field of knowledge: see, for example, "Stereochemistry of carbon compounds, E. L. Eliel (McGraw Hill, 1962) and "Table patitiri agents" written by S. H. Wilen.

One convenient method of obtaining pure chiral compounds of formula (I) is the enzymatic conversion of racemic mixtures of the compounds or its predecessor. Using this method (+) and (-) of the compounds of formula (I) can be obtained in optically pure form. Suitable enzymes include desaminase, such as adenoidectomies.

The present invention is described below with reference to the following detailed examples, in which the elemental analysis was carried out with the participation of M-H-W Laboratories, Phoenix, AZ. Melting points were determined with the apparatus of the Mel - Temp and adjusted. The spectra of nuclear magnetic resonance were obtained on a spectrometer Yed FX 90QFT or Nicollet NT300 and were recorded in DMCO-d6. Chemical shifts are expressed in million shares from Me4Si. IR spectra were determined as KBr pellets spectrometer IR Nicollet 50XC FT and UV spectra were determined on a spectrophotometer Beckmann DU-8. Mass spectra were obtained with a mass spectrometer AEI Scientific Apparatus Limited MS-30. Thin-layer chromatography (TLC) was performed on 0.25 mm layers of silica gel Merck (230-Chelny ingredient", as used in the examples means a compound of formula (I) or its pharmaceutically acceptable derivative.

Example 1. ()-( 1,4 )-4-/5-Amino-6-chloro-4-pyrimidinyl) amino-2-cyclopentanecarbonyl (3a)

A mixture of 1-acetylamino - 3-acetoxymethyl-2-ene (1a) (3.0 g, 15 mmol) and an aqueous solution of barium hydroxide (0.5 n, 300 ml) is heated under reflux during the night. After cooling, the mixture is neutralized with dry ice. The precipitate is filtered off and the aqueous solution concentrated to dryness. The residue is extracted with absolute ethanol and concentrated again to obtain compound 2a as a colorless syrup (1.6 g, 14 mmol).

To this syrup was added 5-amino-4,6-dichloropyrimidine (4.59 g, 28 mmol), triethylamine (4,2 g, 42 mmol) and n-butanol (50 ml) and the mixture heated under reflux for 24 hours of the Volatile solvents are removed, the absorb residue on silica gel (7 g), putting in the flash column (4,0 12 cm) and elute CHCl3-MeOH (20:1) to obtain the 2,69 g (74%) of compound 3a; melting point 130-132oC. an Analytical sample obtained by recrystallization from ethyl acetate (EtOAc), melting point 134-135oC, mass spectrum (MC) (30 eV, 200oC), m/e 240 and 242 (M+and M++2), 209 (M+-31), 144 (B+/2-Amino-6-chloro-4-pyrimidinyl)/amino/-2-cyclopentanecarbonyl (4a)

To 14 mmol crude compound 2a (example 1) was added 2-amino-4,6-dichloropyrimidine (3,74 g of 22.8 mmol), triethylamine (15 ml) and n-butanol (75 ml) and the mixture heated under reflux for 48 hours the Volatile solvents are removed, the residue is treated with methanol in order to separate the undissolved by-product (double pyrimidine-nucleoside). A methanol solution adsorb on silica gel (8 g), Packed in a column (4,0 14 cm) and elute CHCl3-MeOH (40:1) to give 1.52 g (42%) of crude compound 4a. The product is recrystallized from ethyl acetate to obtain compound 4a; melting point 132-134oC, MC (30 eV, 200oC), m/e 240 and 242 (M+and M++2), 209 (M+-31), 144 (B+)

IR: 3600-3000 (NH2, OH), 1620, 1580 (C=C, C=N). Anal. (C10H13Cl-N4) C, H, n

Example 3.

()-( 1,4 )-4-[/2-Amino-6-chloro-5-/4-chlorophenyl/azo-4-pyrimidinyl-amino] -2-cyclopentanecarbonyl (5a)

A cold solution of diazepamas salt is obtained from p-Chloroaniline (1.47 g, 11.5 mmol) in 3h. a solution of HCI (25 ml) and sodium nitrile (870 mg, 12.5 mmol) in water (10 ml). This solution is added to a mixture of compound 4a (2,40 g, 10 mmol), acetic acid (50 ml), water (50 ml) and three-hydrate of sodium acetate (20 g). The reaction mixture was stirred over night Fri neutral, then air-dried with the receipt of 3.60 g (94%) of compound 5a; melting point 229oC (decomposition). An analytical sample is obtained from a mixture of acetone-methanol (1:2) melting point 241 to 243oC (decomposition). MC (30 eV, 260oC), m/e 378 and 380 (M+and M++2), 282 (B+)

IR: 3600-3000 (NH2, OH), 1620, 1580 (C=C, C=N). Anal. (C16H16Cl2N6O) C, H, n

Example 4.

()-( 1,4 )-4-[/2,5-Diamino-6-chloro-4-pyrimidinyl/amino] -2-cyclopentanecarbonyl (6a)

A mixture of compound 5a (379 mg, 1 mmol), zinc powder (0.65 g, 10 mmol) in acetic acid (0,32 ml), water (15 ml) and ethanol (15 ml) is heated under reflux under nitrogen for 3 hours, the Zinc is removed and the solvent evaporated. The absorb residue on silica gel (2 g), placed in a column (2,0 18 cm) and elute CHCl3-MeOH (15:1). Get yellowish-green syrup. Further purification of the methanol-simple ether leads to the production of compound 6a in the form of crystals of yellowish-green color, 170 mg (66%), melting point 168-170oC, MC (30 eV, 220oC), m/e 225 and 257 (M+and M++2), 224 (M+-31), 159 (B+)

IR: 3600-3000 (NH2OH), 1620, 1580 (C=C, C=N). Anal. (C10H14ClN5) C, H, n

Example 5

()-( 1,4 )-4-/6-Chloro-8H-purine-9-yl/-2-C is one of the acid (12 n, 0,50 ml) is stirred overnight at room temperature. The solvent is evaporated at a temperature of 35oC in vacuum. To the residue was added a 0.5 n solution (aqueous) hydrochloric acid (30 ml) and the mixture stirred for 1 h, then the mixture is neutralized to pH 7-8 1 N. solution of sodium hydroxide and adsorb on silica gel (8 g), placed in a column (4,0 8 cm) and elute CHCl3-MeOH (20:1) to obtain white crystals of compound 7a, 1.12 g (82%). The crude product is recrystallized from ethyl acetate to obtain compound 7a, melting point 108-110oC, MC (30 eV, 200oC), m/e 250 and 252 (M+and M++2), 219 (M+-31), 154 (B+)

IR: 3600-2800 (OH), 1600 (C=C, C=N). Anal. (C11H11ClN4O) C, H, n

Example 6.

()-( 1,4 )-4-/6-Hydroxy-9H-purine-Il/-2-cyclopentanecarbonyl (8a)

A mixture of compound (7a) (251 mg, 1 mmol) and an aqueous solution of sodium hydroxide (0.2 n, 10 ml) is heated under reflux for 3 hours After cooling, the reaction mixture is adjusted to pH 5-6 with acetic acid. The reaction mixture adsorb on silica gel (2 g), placed in a column (2,0 11 cm) and elute CHCl3-MeOH (10:1) to give 105 mg (45%) of compound 8a. The crude product is white color prakrits (30 eV, 300oC), m/e 232 (M+), 214 (M+-18), 136 (B+)

IR: 3600-2600 (OH), 1680, 1600 (C=O, C=C, C=N). Anal. (C11H12N4O2) C, H, n

Example 7

()-/ 1,4 - /-4-/-6-Amino-8H-purine-9-yl/-2-cyclopentanecarbonyl (9a)

Liquid ammonia is passed into the autoclave containing a solution of compound 7a (250 mg, 1 mmol) in methanol ( 5 ml) at a temperature of -80oC. the Autoclave is sealed and heated at a temperature of 60oC for 24 h Ammonia and methanol evaporated and the residue recrystallized from water to obtain off-white crystals of compound 9a, 187 mg (81%), melting point 198-200oC. MS (30 eV, 210oC), m/e 231 (M+), 213(M+-18), 135 (B+).

IR: 3600-2600 (NH2, OH), 1700, 1600 (C=C, C=N). Anal. (C11H13N5O) C, H, n

Example 8

()-( 1,4 ) -4-(6-Mercapto-9H-purine-9-yl)-2-cyclopentanecarbonyl (10a)

A mixture of compound 7a (125 mg, 0.5 mmol), thiourea (40 mg, 0.64 mmol) and n-propanol (5 ml) is heated under reflux for 2 hours After cooling, the precipitates are filtered, washed with n-propanol and dissolved in sodium hydroxide (1 n solution, 5 ml). The solution is brought to pH 5 using for this purpose acetic acid. The crude compound 10a (90 mg, 73%) was isolated by their connection 10a, melting point 263-265oC (decomposition). MS (30 eV, 290oC): m/e 248 (M+), 230 (M+-18), 152 (B+)

IR: 3600-3200 (OH), 3100, 2400 (SH), 1600 (C=C, C=N). Anal. (C11H12N4OS) C, H, n

Example 9.

()-( 1,4 ) -4-(2-Amino-6-chloro-9H-purine-9-yl)-2-cyclopentanecarbonyl (13a).

A mixture of compound 6a (1,41 g, 5.5 mmol), triethylorthoformate (30 ml) and hydrochloric acid (12 n, 1,40 ml) is stirred over night. The suspension is dried in vacuum. Add diluted hydrochloric acid (0.5 n, 40 ml) and the mixture is subjected to interaction at room temperature for 1 h the Mixture was neutralized to pH 8 with 1 n sodium hydroxide solution and adsorb on silica gel (7.5 g), placed in a column (4,010 cm) and elute CHCl3-MeOH (20: 1) to give off-white crystals of compounds 13a, 1.18 g (80%). The crude product is recrystallized from ethanol to obtain compounds 13a, melting point 145-147oC. MC (30 eV, 220oC): m/e 265 and 267 (M+and M++2), 235 (M+-30), 169 (B+)

IR: 3600-2600 (NH2, OH), 1620, 1580 (C=C, C=N). Anal. (C11H12-N5OCl3/4 H2O)C, H, n

Example 10.

()-( 1,4 ) -4-(2-Amino-6-hydroxy-9H-purine-9-yl)-2-cyclopentanecarbonyl (14a).< the refrigerator for 5 h, absorb on silica gel (2 g), placed in a column (2,07,5 cm) and elute CHCl3-MEOH (5:1). The crude product is recrystallized from a mixture of methanol-water (1: 4) to give white crystals of compound 14a, 152 mg (61%), melting point 254-256oC (decomposition). MC (30 eV, 200oC): m/e 247 (M+), 217 (M+-30), 151 (B+)

IR: 3600-2600 (NH2, OH), 1700, 1600 (C=O, C=C, C=N), Anal. (C11H13N5O23/4 H2O) C, H, n

Example 11

()-( 1,4 ) -4-(2,6-Diamino-9H-purine-9-yl)-2-cyclopentylamine (15A).

Liquid ammonia is passed into a solution of compound 13a (265 mg, mmol) in methanol (10 ml) at a temperature of -80oC in the autoclave. The autoclave is sealed and heated at a temperature of 75oC for 48 hours the Ammonia and methanol evaporated. The absorb residue on silica gel (2 g), placed in a column (2,010 cm) and elute CHCl3-MeOH (15:1). The crude product is recrystallized from ethanol to obtain 196 mg (80%) of compound 15A, melting point 152-155oC. MC (30 eV, 200oC), m/e 246 (M+), 229 (M+-17), 216 (M+-30), 150 (B+)

IR: 3600-3000 (NH2, OH), 1700, 1650, 1600 (C= O, C=C, C=N). Anal. (C11H14N6O) C, H, n

Example 12.

(1S, 4R)-4-(2,6-Diamino-9H-purine-9-yl/-2-5R/-3-[6-Amino-9H-purine-9-yl/]-5-[/1,1-dimethylethyl/- dimethylsiloxy/methyl]-1,2-cyclopentanediol

(-) Eritromicin1(12,505 g), tert-butyldimethylsilyloxy (7,8 g) and imidazole (12,96 g) in dry dimethylformamide (85 ml) was stirred at ambient temperature for 2.5 hours the resulting solution was diluted with ethyl acetate (500 ml) then washed with water (3100 ml) and brine (50 ml), resulting in vykristallizovyvalas white solid. This body is collected by filtration, washed with ethyl acetate, then dried in vacuum to obtain specified in the connection header (to 3.92 g).

1H NMR (DMCO-d6) 8,15 (8,09 1H), 7,19 (2H), 5,0 (1H), 4.72 IN (1H), 4,69 (1H), 4,36 (1H), 3,85 (1H), TO 3.67 (2H), 2,23 (1H), IS 2.09 (1H), 1,79 (1H), 0,89 (9H), OF 0.07 (6H).

1. J. Am. Chem. Society, 1983, 105, S. 4049-4055.

(b) an Intermediate compound 2: (4R, 3a, 6R, 6aR)-4-[6-Amino-9H-purine-9-yl] -6-[/1,1-dimethylethyl/- dimethylsiloxy/methyl]-3a,5,6,6A-tetrahydro-4H-cyclopent-1,3 - dioxol-2-tion.

Stirred suspension of intermediate 1 (of 3.45 g) in dry dimethylformamide (56 ml) is treated with 1,1'-thiocarbonyldiimidazole (3.3 grams), receiving a yellow solution. Through 15,5 h at ambient temperature the resulting solution was combined with the solution remaining from a previously conducted experiment (6% scale), and the solvent is removed by evaporation. The residual oil was diluted with atilas is solid yellow, that simple washed with diethyl ether (25 ml), then collected by filtration, further washed with simple ether (25 ml) and dried in vacuum to obtain specified in the title compound as a pale cream solid (3,61 g).

max(ethanol) 240,0 nm ( E1%1Cm) 459).1H NMR (DMCO-d6) OF 8.27 (1H), 8,13 (1H), 7,33 (2H), OF 5.81 (1H), LOWER THAN THE 5.37 (1H), 5,28 (1H), 3,78 (2H), 2,60 (1H), 2,28 (2H), OF 0.90 (9H), AND 0.09 (6H).

(c) the Intermediate compound 3:/I R, 4'6/-9-[4-///1,1- Dimethylsiloxy/methyl/-2-cyclopenten-1-yl]-9H-purine-6-amine

A solution of intermediate compound 2 (3.57 g) in dry tetrahydrofuran (25 ml) is treated with a solution of 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine (4.94 g) in dry tetrahydrofuran (10 ml), then stirred at ambient temperature for to 8.25 hours the Solvent is removed by evaporation. The residual oil combine with oil, obtained from the previous experiment (40% scale), then subjected to column chromatography on silica (200 g, MERCK 7734), elute with chloroform, then with a mixture of chloroform-ethanol, getting a solid white color. This substance is washed with simple diethyl ether (10 ml), dried in vacuum, obtaining specified in the title compound (1.47 g).

max(etno), 3,66 (2H), 2,96 (1H), 2,69 (1H), 1,65 (1H), 0,74 (9H), OF 0.02 (6H).

(d) Intermediate compound 4: /1', R 4' S/-9[4-///1, 1-Dimethylethyl/dimethylsiloxy/methyl/-2-cyclopenten-1-yl]-9H-purine - 6-amine, 1-oxide

A solution of intermediate compound 3 (1,37 g) in chloroform (30 ml) is treated with 80-90% m-chloroperoxybenzoic acid (1,29), then stirred at ambient temperature for 3 hours the Solvent is removed by evaporation and the residual gum is dissolved in ethyl acetate (10 ml). Appears solid white, which (together with the substance), recovered by evaporation of the filtrate, dissolved in chloroform (100 ml), then washed with saturated aqueous sodium bicarbonate (3 10 ml) and saline solution ( 2 10 ml). Water washing is subjected to back extraction with chloroform (50 ml). The combined organic solutions are dried in the presence of magnesium sulfate, then evaporated to a solid which was washed with simple diethyl ether (25 ml), then collected by filtration. The white solid is then washed with simple ether (10 ml), dried in vacuum, obtaining the result specified in the header connection (1,16 g).

max(ethanol) 235,4 nm E1%1Cm1324), 263,2 nm E1%1Cm<2 (1H), 3,68 (2H), 3.04 FROM (1H), 2,82 (1H), 1,74 (1H) TO 0.89 (9H), IS 0.06 (6H).

(e) the Intermediate compound 5: (I', R 4' S)-7-[4-,///1,1-dimethylethyl/dimethylsiloxy/methyl/-2-cyclopenten-1-yl] -2-imino-1,2-dihydro [1,2,4] oxadiazole [3,2-i]-9H-purine-bromohydrin

Mixed, chilled on ice, the suspension of intermediate compound 4 (1.08 g) in methanol (20 ml) is treated with a solution of cyanogenmod (0.34 g) in methanol (20 ml) was added within 5 min After 15 min, the suspension is heated to ambient temperature, obtaining the solution. After 90 min the solvent is removed by evaporation. The residue is washed simple diethyl ether (25 ml), collected by filtration. The solid is washed then a simple ether (25 ml) and dried in vacuum to obtain specified in the connection header (1,37)

max(ethanol) to 228.2 nm ( E1%1Cm530), RUB 285.2 nm ( E1%1Cm445),

1H-NMR (CDCl3) AND 10.20 (1H), 10,02 (1H), OF 8.37 (1H), AND 6.25 (1H), 6,01 (1H), 5,90 (1H), 3,69 (2H), 3,05 (1H), 2,86 (1H), 1,73 (1H), 0,86 (9H), 0.03 IN (6H).

(f) the Intermediate compound 6: (I', R, 4'S)-9-[4-///1,1-dimethylethyl/dimethylsiloxy/methyl/-2-cyclopenten-1-yl] -6-cyanoimino-1,6-dihydro-1-methoxy-9H-purine

A solution of intermediate compound 5 (1,36 g) in dimethylformamide (10 ml) was stirred at ambient temperature, then about the yellow color. After 3 h 45 min the solvent is removed by evaporation. The residue is distributed between ethyl acetate (100 ml) and water (20 ml). The organic solution was washed with water (2 20 ml) and brine (20 ml), dried in the presence of magnesium sulfate and evaporated to a solid. This solid was washed with simple diethyl ether (25 ml), then collected by filtration. Then this solid white color simple washed with ether (10 ml), dried in vacuum, obtaining specified in the connection header (0,865 g),

max(ethanol) 227,2 nm ( E1%1Cm449), 287,0 nm ( E1%1Cm544),

1H-NMR 8,23 (1H), OF 7.96 (1H), 6,24 (1H), TO 5.85 (1H), THE 5.65 (1H), IS 4.21 (3H), 3,66 (2H), 3.04 FROM (1H), 2,77 (1H), 1,68 (1H), FROM 0.88 (9H), OF 0.05 (6H).

(g) Intermediate compound 7: (1', R, 4'S)-9-[4-///1, 1-dimethylethyl/dimethylsiloxy/methyl/-2-cyclopenten-1-yl-6-methoxy-amino-9H-purine-2-amine.

A solution of intermediate compound 6 (802 mg) and 1,8-diazabicyclo [5,4,0] undec-7-ene (0.45 ml) in ethanol (80 ml) is stirred and heated under reflux. The heating is stopped after 9 h and the solution is kept at ambient temperature overnight. The solvent is removed by evaporation. The residual oil is combined with that obtained from the previous experiment (4% scale), and then ethanol to obtain foam. This foam proscout simple diethyl ether (10 ml) and the resulting solid collected by filtration. The solid is then washed with simple ether (5 ml), dried under vacuum, resulting in obtaining specified in the header of the compound (594 mg),

max(ethanol) 282,2 nm ( E1%1Cm409),

1H-NMR (DMCO-d6) 9,76 (1H),7,32,(1H), 6,53 (2H), BETWEEN 6.08 (1H), 5,26 (1H), AND 3.72 (3H), 3,61 (2H), 2,90 (1H), 2,50 (1H) OF 1.52 (1H), OR 0.83 (9H), OF 0.02(6H).

(h) an Intermediate compound 8: a /1S 4 R/-4-[2-amino-6-methoxyamino-9H-purine-9-yl]-2-cyclopenten-methanol

A solution of intermediate compound 7 (356 mg) in tetrahydrofuran (35 ml) was stirred at ambient temperature, then treated with tetrabutylammonium (1.0 M solution in tetrahydrofuran, 1.4 ml). After 90 min the reaction mixture was cooled, water (1 ml), then the solvent removed by evaporation. The residual oil is subjected to column chromatography on silica (20 g, Merck 7734), elute with chloroform, then with a mixture of chloroform-ethanol to obtain specified in the header of the product as a solid (243 mg),

max(pH 6 buffer) 250,2 nm ( E1%1Cm) 534),

1H-NMR (DMCO-d6) OF 9.75 (1H), 7,39 (1H), 6,52 (2H), 6,10 (1H), OF 5.84 (1H), 5,27 (1H), 4,73 (1H), 3,40 (2H), AND 2.83 (1H), 2,55 (1H), 1,52 (1H).

/1S 4P/-4-[2,6-Diamino-9H-poorya 6 (210 mg) in water (10 ml) and tetrahydrofuran (50 ml) is treated with amalgam (aluminum (237 mg) and 0.5% aqueous solution of a chloride of mercury), added in small portions over 15 minutes 40 minutes the stirred mixture is heated to ambient temperature. After 15 min the resulting mixture was filtered through diatomaceous earth to remove insoluble substances. They are washed with a mixture of water : tetrahydrofuran (1:5, 60 ml). The combined filtrates evaporated. The residue is subjected to column chromatography on silica (10 g, Merck 9385), elute with a mixture of chloroform-ethanol to obtain specified in the header of the product in the form of foam (159 mg),

[]D-81o(with the 1.04, methanol);

max(pH 6 buffer) 255,0 nm ( E1%1Cm) 302), 280,8 nm ( E1%1Cm) 381)

1H-NMR (DMCO-d6) TO 7.61 (1H), 6,66 (2H), 6,10 (1H), BY 5.87 (1H), USD 5.76 (2H), 5,38 (1H), AMOUNTS TO 4.76 (1H), OF 3.45 (2H), 2,87 (1H), 2,60 (1H), 1,60 (1H).

Example 13

/1S, 4R/-4-/2-Amino-6-hydroxy-9H-purine-9-yl-/- 2-cyclopentanecarbonyl

/1', R, 4'S/-2-Amino-1,9-dihydro-9-[4-hydroxymethyl-2-cyclopenten-1-yl]- 6H-purine-6-he

A cloudy solution specified in the header of example 12 compound (144 mg) in 0.1 M, pH 6 buffer (10 ml) (28.4 g of dinatriumfosfaatti in 2 l of water, brought by orthophosphoric acid) is treated with a solution of adenosine-deaminase (0.5 ml, 778 units) in a 50% mixture of glycerol and 0.01 M potassium phosphate, pH 6,0, then stirred and heated to a temperature of 37 what rucenim specified in the header of the product in the form of a solid body in white (86 mg),

[]D-49o(s, 0,5, dimethylsulfoxide),

max(pH 6 buffer) 252,6 nm E1%1Cm) 531),

1H-NMR (DMCO-d6) OR 10.60 (1H), 7,60 (1H), 6,47 (2H), 6,10 (1H), 5,86 (1H), 5,33 (1H), 4.72 IN (1H), OF 3.45 (2H), 2,59 (1H), 1,58 (1H).

Example 14

Obtaining enantiomers ( 1,4 )-4-(2-Amino-6-hydroxy-9H-purine - 9-yl/-2-cyclopentanecarbonyl

(a) /1S, 4R/-4-/2-Amino-6-hydroxy-9H-purine-9-yl/-2-cyclopentenyl-carbinol

Diaminoanisole (100 g) (example 11) are dissolved in 3 ml of 0.05 M K2PO4buffer (pH 7,4) with heating (50oC). The solution is cooled to room temperature and 40 units of adenosine-deaminase (Sigma, Type VI, calf intestinal mucosa) was added to the solution, which was incubated for three days at room temperature, after which the formed precipitate is removed by filtration, thus obtaining 18,2 mg Filtrate concentrated to 1.5 ml and cooled within 2 days. When filtering receive an additional amount (to 26.8 mg) of the solid. Two factions solid is recrystallized from water to obtain the pure product specified in the header, melting point 269-272oC []2D4-62,1 (s, 0,3 MeOH).

(b) /1R, 4S/-4-/2-Amino-6-hydroxy-9H-purine-9-yl/-2-cyclopentenyl-carbinol

The filtrates in resultantes on a flash column of silica gel, using a 10% mixture of methanol/chloroform. Diamino-compound is dissolved in 0.05 M K2PO4buffer, pH 7,4 (15 ml), and 800 units of adenosine-deaminase added to the solution, which is incubated at a temperature of 37oC for 96 h Thin-layer chromatography notes the presence of some amount of unreacted product. The solution is heated in boiling water for 3 min and filtered in order to remove denatured protein. Then add another 800 units of adenosine-deaminase and the process is repeated. Deproteinizirovanny the solution is evaporated to dryness and the product is crystallized from water. Specified in the title compound in the form of solid white collected by filtration from water, the melting point 265-270oC.

[]2D4+ 61,1 (s, 0,3 MeOH).

Example 15

//-/ 1,4 /-4-/2-Amino-6-hydroxy-9H-purine-9-yl/-2-cyclopentanecarboxylate

To a suspension of the product of example 10 (130 mg, 0.50 mmol) and 4-dimethylaminopyridine (5 mg, 0.04 mmol) in a mixture of acetonitrile (6 ml) and triethylamine (and 0.09 ml, 0.66 mmol) was added acetic anhydride (0.06 ml, 0.6 mmol). The mixture is stirred at room temperature for 3 hours, Methanol (1 ml) was added to cool the reaction mixture. The solution of Conti of product are collected and concentrated to obtain solid white. The solid product is washed with a mixture of MeOH-AcOEt: exit 123 ml (85%). Further purification of the methanol results specified in the connection header in the form of needle-like crystals, melting point 237 - 239oC. Anal. (C13H15N5O3) C, H, n

Example 16

/1S,4R/-4-[2-Amino-9H-purine-9-yl]-2-cyclopentanecarbonyl

Mixed, chilled on ice, a solution of (1S,4R/-4-[2-amino-6-methoxyamino-9H-purine-9-yl] -2-cyclopenten-methanol (intermediate compound 8, example 12) (1,202 g) in tetrahydrofuran (250 ml) and water (50 ml) is treated with aluminum amalgam (aluminium (1,761 g) and 0.5% aqueous solution of a chloride of mercury), added in small portions over 1 h 47 min 35 min the stirred mixture is heated to ambient temperature. After 16 h 50 min add more an amalgam of aluminum (235 mg of aluminum) within 14 minutes After 4 h 10 min the resulting mixture was filtered through diatomaceous earth to remove insoluble body that was washed with a mixture of tetrahydrofuran : water (5: 1, 300 ml). The combined filtrates evaporated to a yellow foam. The foam is subjected to column chromatography on silica (33,8 g, Merck 7734) in chloroform and elute with a mixture of chloroform-ethanol to obtain several fractions (578 mg of the small column fraction and subjected to preparative thin-layer chromatography (Merck 5717), exercising three times in a mixture of chloroform : methanol (10 : 1). Plate elute the mixture ethylacetate (1 : 1) to obtain solid brown (45 mg). The solid body is subjected to column chromatography on silica (2,7, Merck 7734) in chloroform and elute with mixtures of chloroform-methanol-triethylamine to obtain gum (17 mg). After unsuccessful crystallization from isopropanol and treatment with charcoal in methanol aqueous solution recovered substance is dried by freezing to produce specified in the header connection - 15 mg.

1H-NMR (DMCO-d6) OF 1.62 (1H), 2.63 IN (1H), 2,89 (1H), 3,45 (2H): TO 4.73 (1H), 5,48 (1H), 5,91 (1H), 6,14 (1H), 6,50 (2H), 7,98 (1H), TO 8.57 (1H).

Mass spectrum: [MH]+232.

Example 17

Tablets drugs

A. the Following product is obtained by wet granulation of the ingredients with a solution of povidone in water, drying and sieving followed by the addition of magnesium stearate and pressed (mg-tablet):

(a) Active ingredient 250

(b) Lactose B. P. (British Pharmacopia - British Pharmacopoeia) - 210

(C) Povidone B. P. - 15

(g) Sodium salt of carboxymethyl amylum - 20

(d) magnesium Stearate - 5 - 500

B. the Following product is obtained by direct pressing, use a type of lactose for p the>(d) magnesium Stearate - 5 - 500

C. (Preparation with controlled release). The product is obtained by wet granulation of the following ingredients with a solution of povidone in water, drying and sieving, followed by the addition of magnesium stearate and pressed (mg/tablet):

(a) Active ingredient: 500

(b) Hypromellose (Methocel k4m Premium) - 112

(C) Lactose B. P. - 53

(d) Povidone B. P. - 28

(d) magnesium Stearate - 7 - 700

Example 18

Capsulated drug

Encapsulated drug is produced by mixing the following ingredients and filling hard gelatin capsules consisting of two parts, (mg/tablet):

Active ingredient - 125

Lactose is 72.5

Avicel - 50

Magnesium stearate - 2,5 - 500

Example 19

The preparation for injection

Active ingredient - 0,200 g

0.1 M Solution of sodium hydroxide to a pH of about 11

Sterile water up to 10 ml

The active ingredient is suspended in water, which can be warm, and using sodium hydroxide pH adjusted to approximately 11. The portion is then brought to the desired volume and filtered through a sterile membrane filter into a sterile glass vial of 10 ml, sealed sterile tube and poverty fat B. P. - 1770 - 2020

One-fifth of solid fat melt in the bath, equipped with panagrolaimus shirt at a temperature not above 45oC. the Active ingredient is sifted through a sieve (200 μm), add to the melted base and mix until you get a smooth dispersion using a high-performance mixer. Leave the mixture at 45oC, is added to the suspension remaining portion of the solid fat and stirred to obtain a homogeneous mixture. While continuing the stirring, the entire suspension is passed through a stainless steel sieve (250 μm) and allowed to cool to 40oC. When the temperature of the mixture from 38 to 40oC suitable plastic mold with a volume of 2 ml fill 2,02 g of the mixture and allow to cool to room temperature.

Example 21

Antiviral activity

(A) Analysis on enti-HIY

The compounds of formula (I) were subjected to screening for enti-HIY activity in the National cancer Institute on the research instrument the study of cancer, Frederick, Frederick MD (FCPF). Next describe modern operating screening methods used in the FCPF. The Protocol consists of three sections:

(I) obtaining infected cells and their distribution on the test plates;

(Edora Templ analysis.

Cm. the work of D. A. Scudiero with TCS. "A new simplified analysis of letrozole for cell growth and susceptibility to the drug culture." Cancer Res. 48 3827 (1988).

I. Infection and distribution of ATH8 cells on microtitration trays

Cells to be infected (normal lymphoblastoid line, which expresses CD4), were placed in a 50 ml conical centrifuge tubes and within 1 h was treated with 1-2 mg/ml polybrene at 37oC. Then the cells for 8 min was centrifuged at a rotation speed of 1200 rpm Virus HIY, diluted in the ratio 1:10 medium (RMRI-1640, 10% human serum or 15% calf serum fetal - FCS) in the presence of 1-2 and antibiotics) was added to the system to ensure MOI of approximately 0.001. To the control cells not containing virus was added only environment. Assuming the titer of infectious virus equal to 10-4that is MOI of 0.001, represents 8 infective viral particles per 10,000 cells. Approximately 500000 cells /tube were exposed to 400 µl of virus diluent. The resulting mixture was incubated for 1 h at 37oC in the atmosphere: the air - CO2. Infected or uninfected cells were diluted to a value of 1 to 10-4(the uninfected cells (100 μl) was divided into respective recesses microtitration plate with a V-shaped bottom, contains 96 of the recess. Each dilution of the compounds tested infected cells, and the experiments were duplicated. Uninfected cells were investigated for their sensitivity to medications in a single recess for each dilution connection. Experiments with control cells, both infected and uninfected, repeated three times. Deepening B2-G2 served as controls for reagent, they were placed only environment. Plates were incubated at 37oC in the atmosphere: the air - CO2before pressure medications.

II. Dilution and add medications

Plates for dilution (microtitration plate with a flat bottom, with 96 holes) during the night was treated with phosphate buffer solution (PBS) or medium containing at least 1% FCS or 1% human serum (depending on the environment used in the test), starting from the day prior to analysis. Used the method of "blocking" to limit adsorption of drugs on microtitration plate during the dilution process. The cavities were completely filled with blocking solution was stood at room temperature in a humidified chamber under the hood.

The process rasagiline plates were prepared by shaking a blocking solution and blot dry with sterile gauze. Then all the cavities in each plate was filled with 225 µl of the medium using the Cetus for the treatment of liquids. Then 25 ál of each of the compounds diluted in a ratio of 1:20, had to manually add in the number And blocked and filled with thinner plates. On the plate was the solvent added four connections, which is enough for two test plates. Then these four compounds were subjected to 10-fold serial dilution from row A to H using system Cetusa. At this point, the initial dilution of each compound in A row was 1:200. Plates with dilutions were stored on ice until use.

Using a multichannel pipette with 6 micromechanically 100 µl of each dilution of the drug was transferred to the test plate, which already contained 100 μl of medium and cells. The final dilution in the test plate was started with a value of 1:400 (deepening B4-G4). This dilution (up to 0.25% DMCO) prevents negative impact DMCO on cell growth. To nesteriak medicines infected and uninfected cells (deepening B3-G3) and control reagents (B2-G2) was added only environment. The remaining two connections then ne is Ki incubated at 37oC in an atmosphere of air - CO2within 7-14 DN or up lizirovania viral controls according to macroscopic definitions.

III. Quantification of viral cytopathogenicity and activity drugs

A. Materials

1. A solution of 2,3-bis/2-methoxy-4-nitro-5-sulfophenyl/-5-/(phenylamino)carbonyl/-2H-tetrazole hydroxy, (HTT) is a solution with a concentration of 1 mg/ml in medium containing no FCS. The solution was stored at 4oC. was Prepared weekly.

2. The main solution methosulphate phenazine (PMS). This solution can be prepared in advance and stored frozen until use at -20oC. the Concentration of Pb in such a solution may be to 15.5 mg/ml

B. Analysis of tetrazole in the algae (MGA)

1. Preparation: solution Templ-PMS-Templ-PMS was prepared directly before adding it to the recesses of the plate with the culture.

The main PMS solution was diluted to 1:100 (0,153 mg/ml). Diluted PMS was added to each ml Templ to a final concentration of PMS 0.02 mm. 50 ál liquity mixture Templ-PMS was added to each of the respective recesses and the plate incubated for 4 h at 37oC. plates were removed caps and replaced them with sticky scoparius what turai and determined the absorption at a wavelength of 450 nm.

IV. Results

The obtained data are presented in the form of a graph of the dependence of interest number of test cells relative to uninfected cells (%) for both infected and uninfected cells by increasing concentrations of the test compounds. These charts allow you to calculate the effective concentration (EC50against infected cells, the inhibitory concentration (IC50)) relative to normal cells and therapeutic index (TI50).

Inhibitory concentration against HIY defined as described above for compounds of examples 7, 9, 10, 11 and 14b, are presented in table. 1 (µg/ml) and in table. 2.

therapeutic index was calculated by dividing the IC50on EC50.

In this screening compounds of examples 5 and 8 also exhibit antiviral activity.

An earlier analysis conducted with the compound of example 10 in the southern research Institute, gave values of TI50equal to 200, when culturing cells MT-2 in the presence of H9/HIIV-IIIB.

(B) Activity against the virus heads Felina

Antivirus screened for activity against FeIV-JAIDS conducted on the plates is, which was supplemented with 10% thermodesulfovibrio serum fetal calf (FBS). Twenty hours before the test plates were seeded with cells 81C with a concentration of 5 103CL /deepening. On the day of analysis the cells were pre-treated for 30 min at 37oC DEAE-dextran (25 mg/ml) in 0.1 ml of balanced salt solution Hanks. The solution was removed and then in each recess was added 0.1 ml of a vegetative medium containing 32 TCID50FIY-FAIDS, or 0.1 ml only plant environment. The virus was allowed to adsorb for one hour and then added 0.1 ml of the test or positive control compounds (2', 3'-dideoxycytidine; ddc), or plant environment. Plates were incubated at 37oC. On day 4 after infection, the cells were fed fresh vegetable medium containing the compound. The culture medium was completely exchanged and replaced with fresh medium containing the compound on the 7th day after infection. On the 10th day after infection the cells were fixed with formalin, stained with 0.1% solution of the dye Komachi Brilliant blue R-25o and observed under the microscope at the CPE and drug cytotoxicity.

The compound of example 14a mattered ED50about 1.9 μg/ml.

5class. to deepen in the total volume of 2.5 ml EMEM containing 5% thermodesulfovibrio FBS. Twenty hours after vysielanie cells the medium was poured in each recess was added 2.5 ml DEAE (25 μg/ml in phosphate buffer solution). Cultures were incubated for 1 h at 37oC, followed by DEAE-dextranase the solution was decanted and the cell layers were immediately rinsed with 2.5 ml of medium (without virus or drugs). The control culture on the medication received 2.5 ml of the medium containing the drug without virus. Virus-infected control cultures received 0.5 ml of the appropriate dilution of the fallopian CAS-BR-M with the aim of producing counted plaques plus 2.0 ml of medium. To test samples were added to 0.5 ml of the appropriate virus dilution and 2.0 ml of medium drug dilution. Felt six concentrations of the test compounds diluted semi-log serial dilutions. Tested three concentrations of positive control drugs ddc. In each analysis included three grooves for each concentration of the test compounds, and 6 viruses and 6 control cell cultures. On day 3 polyvisol inoculation toxicity of drugs in relation to the cells is determined as being a medicine. The remaining test subjects and the control culture was irradiated with light from a UV lamp for 20 s, and to each culture were added to cells XC (5 of 105CL /deepening 2.5 EMEM containing 10% thermodesulfovibrio FBS). On day 3 after irradiation, the cultures were fixed with formalin and stained with crystal violet. Plaques were counted using analytical microscope.

Antiviral activity in reducing the number of CAS-BR-M plaques expressed decrease in the average number of plaques counted in treated with medication, the virus-infected cultures compared with the average number of plaques counted in untreated infected cultures (percentage of control). The compound of example 14a mattered ED50about 1.1 μg/ml.

(D) Activity against retrovirus SAIDS (SRY-2). Simiana

Antiviral screening against the virus SAIDS (M/Washington) carried out analysis on the inhibition of syncytium cells Reggie. The drug was diluted in complete medium Iscove and then 100 ál of each dilution was added into corresponding indentations in the plate with 96 holes. Then in each recess was added to actively growing cells Reggie 5 103CL in 50 ml of complete medium Iscove. Then domowego control medications used DDS. Plates were incubated at 37oC in humidified atmosphere containing 5% CO2. On day 7 after infection were calculated syncytium. The toxicity of the drugs was determined by comparing the number of living cells in uninfected treated with medication sample with the viability of uninfected, untreated control. The compound of example 14a is set to ED502.8 mg/ml

(E) Activity against the virus Vishnu, Maadi

Antiviral activity against virus strain Vishnu, Maadi (VMV) WL C-1 was determined by measuring the decrease of virus-specific immunohistochemical staining. Monolayers of cells harodnogo roots sheep infected VMV and loaded serial dilutions of the tested compounds. After incubation for five days monolayers additionally incubated in the presence of virus-specific antisera conjugated with peroxidase of logevity seaside (HRP). Then spent the incubation of the monolayers in the presence of a chromogenic substrate for HRP, stem areas of viral replication. Counted the number of such discrete foci and expected concentration of the test compound required to reduce by up to 50% of the corresponding number in control CLASS="ptx2">

Example 22. Cytotoxic activity

Compounds of examples 7a, 9a and 10a defined in example 17, showed cytotoxic activity when tested against cell cultures of leukemia P388 mouse according to the analysis described by R. C. Loquita and R. Vince in J. Med. Chem. 16, 1396 (1973). The obtained values of the ED50(ág/ml) were:

Connection 5 - 12

The compound 7 - 40

The compound 8 - 3

Additional examples

Example 23

(22R)- 16,17-butylidenedioxy-21 kapalicarsi - 6,9-debtor-11-hydraexpress-4-ene-3,20-dione

To a solution of (22R)- 16,17-butylidenedioxy - 6,9-debtor- , 21-dihydroxypregna-4-ene-3,20-dione (60 mg) in 4 ml of methylene chloride was added capillary (35 mg) and 4-dimethylaminopyridine (30 mg). The reaction mixture was stirred at room temperature for 45 minutes After evaporation the residue was purified by chromatography on a column with Merk Keselgel 60 using a mixture of heptane: ethyl acetate 1: 1 as mobile phase. The obtained product was purified by chromatography on a column of Sephadex LH-20 (inner diameter - 852,5 cm) using as mobile phase chloroform. Fraction 280-315 ml was collected and evaporated, the residue was besieged from a mixture of methylene chloride:petroleum ether, receiving 28 mg of (22R)- 16,17-butylidenedioxy-21 kapalicarsi-6,9-debtor-11-GI is SUP>o
C (c+0,216; CH2CL2); the molecular weight of 594 (expect to. 594.7). Purity: 98.7% (HPLC analysis).

Example 24. (22R)-16,17-butylidenedioxy-21 caprylate-6,9-debtor-11-hydroxypregn-4-ene-3,20-dione.

The solution capillaria (75 mg) in 2 ml of dioxane drop added to a solution of (22R)- 16,17-butylidenedioxy - 6,9-debtor - 11 , 21-dihydroxypregna-4-gene-3,20-dione (60 mg) in 4 ml of pyridine. The reaction mixture was stirred at room temperature overnight and treated as in example 1. The crude product was purified by chromatography on a column of Sephadex LH-20 (inner diameter 892,5 cm) using a mixture of heptane:chloroform:ethanol, 20: 20: 1 as mobile phase. Fraction 245-315 ml was collected and evaporated, the residue was besieged from a mixture of methylene chloride: petroleum ether, receiving 58 mg of (22R)- 16,17-butenedioic-21 caprylate - 6,9-debtor - 11-getcoverage-4-ene-3,20-dione. Melting point 168-171oC.

[]2D5= +93,7o(c+0.302; CH2Cl2); the molecular weight of 622 (expect to. 622,8). Purity: 94.1% (HPLC analysis).

Example 25.

(22R)- 16,17-butylidenedioxy-21 caprylate - 6,9-debtor - 11-hydroxypregn-4-ene-3,20-dione

To a solution of (22R)- 16,17-butylidenedioxy - 6,9-debtor - 11 , 21-dihydroxypregna-4-ene-3,20-diene (60 mg) in 4 ml methylisatoic temperature for 30 min and processed as in example 28. After chromatography on a column with Merk Keselgel 60 product was purified by chromatography on a column of Sephadex LH-20 (inner diameter - 852,5 cm) using as mobile phase chloroform. Fraction 300-345 ml was collected and evaporated, the residue was besieged from a mixture of methylene chloride:petroleum ether, receiving 20 mg of (22R)- 16,17-butylidenedioxy-21 caprylate - 6,9-debtor - 11-hydroxypregn-4-ene-3,20-dione. Melting point 148-160oC.

[]2D5= +107,3o(c+0.232; CH2Cl2); the molecular weight of 566 (expect to. 566,7). Purity: 99,3% (HPLC analysis).

Example 26.

(22R)- 16,17-butylidenedioxy-21 butyryloxy - 6,9-debtor - 11-hydroxypregn-4-ene-3,20-dione

The solution butyrylcholine (170 mg) in 5 ml of dioxane drop added to a solution of (22R)- 16,17-butylidenedioxy - 6,9-debtor - 11 , 21-dihydroxypregna-4-ene-3,20-dione (150 mg) in 10 ml of pyridine. The reaction mixture was stirred at room temperature overnight and treated as in example 1. The crude product was purified by chromatography on a column of Sephadex LH-20 (inner diameter 706,3 cm) using chloroform as mobile phase. Fraction 1440-1740 ml was collected and evaporated, then purified on a column of Sephadex LH-20 (inner diameter 706,3 cm) using a mixture of heptane:chloroform:ethanol, 20:20:1 in alany ether, getting 118 mg of (22R)- 16,17-butylidenedioxy-21 butyryloxy - 6,9-debtor - 11-hydroxypregn-4-ene-3,20-dione. Melting point 208-216oC.

[]2D5= +to 114.4o(c+216; CH2Cl2); molecular weight 538 (expect to. 538,6). Purity: 99.4 per cent (HPLC analysis).

Example 27 (schemes I and II).

Synthesis of (hydroxymethyl) cyclopentyl-derived formulas BA-11a and (hydroxymethyl) cyclopentyl-derivatives of formula 6b-11b on the precursor CIS-(4-acetamidocinnamic-2-enyl)acetate (1A) perform in accordance with schemes I and II (see end of text). Compound 1A hydrolyzing aqueous barium hydroxide to obtain amerosport 2A. The condensation of 2A from 2-amino-4,6-dichloropyrimidine leads to the corresponding pyridinylamino 3A. 5-[(Para-chlorophenyl)azo]pyrimidine 4A was produced using the chloride vapor-chlorobenzothiazole. Shealy and Clayton, J. Pharm. Sci., 62, 1482 (1973). Restore 4A zinc and acetic acid leads to the production of pyrimidine 5A, which is then transformed into a 9-substituted 2-amino-6-globulin 6A through education cyclic compound with triethyl-ortho-formate. 2-Amino-6-globulin 6A in turn carbocyclic 2', 3'-didehydro-2',3'-dideoxyinosine similar 7a boiling with obataining analogue 8A.

The formation of cyclic compounds (cyclization reaction) 5A with sodium nitrite and acetic acid leads to the production of (+)-(CIS)-4-(5-amino-7-chloro-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl] -2-cyclopentylamine (9a) with a good yield. Basic hydrolysis of 9 with sodium hydroxide leads to the production of 8-Aza-analogue 10A - carbocyclic 2',3'-didehydro-2',3'-dideoxyinosine, whereas treatment with liquid ammonia leads to the corresponding 2,6-diaminopurine-analog 11a.

2', 3'-saturated derivative gain in accordance with scheme II. Catalytic reduction of 1A results in correspondingly substituted cyclopentane precursor 1b. The remaining stages of the synthesis of compounds of series b similar to the stages of the synthesis of compounds of series A.

1. Dimethoxydimethylsilane nucleosides of General formula I

< / BR>
where X - NRR1, SR, OR2H or halogen atom;

Z is a hydrogen atom or NH2;

R, R1, R2the same or different, is a hydrogen atom, a C1- C4-alkyl,

or their pharmaceutically acceptable derivatives.

2. The compound of formula I under item 1 or its pharmaceutically acceptable salt.

3. The compound of formula I under item 1 or 2, LASS="ptx2">

5. The compound according to any one of paragraphs.1 to 4, wherein X is a chlorine atom, NH2, SH or OH.

6. The compound according to any one of paragraphs.1 to 5, wherein X is OH.

7. The compound according to any one of paragraphs.1 to 5, characterized in that the X - NH2.

8. The compound according to any one of paragraphs.1 to 7, selected from among

(1A,4A)-4-(6-chloro-N-purine-9-yl)-2-cyclopentanecarbonyl;

(1A,4A)-4-(6-hydroxy-N-purine-9-yl)-2-cyclopentanecarbonyl;

(1A,4A)-4-(6-amino-N-purine-9-yl)-2-cyclopentanecarbonyl;

(1A,4A)-4-(6-mercapto-N-purine-9-yl)-2-cyclopentanecarbonyl;

(1A,4A)-4-(2,6-diamino-N-purine-9-yl)-2-cyclopentanecarbonyl;

(1A,4A)-4-(2-amino-6-chloro-N-purine-9-yl)-2-cyclopentanecarbonyl;

(1A,4A)-4-(2-amino-N-purine-9-yl)-2-cyclopentanecarbonyl;

9. (1A,4A)-4-(2-amino-6-hydroxy-N-purine-9-yl)-2-cyclopentanecarbonyl.

10. The compound according to any one of paragraphs.1 to 9, mostly in the form of racemic mixtures.

11. The compound according to any one of paragraphs.1 to 9, mostly in the form of optically active isomers.

12. The compound according to any one of paragraphs.1 to 9, mostly in the form of isomer.

13. 1-Monophosphate ester compound according to any one of paragraphs.1 - 12.

14. The compound of General formula I according to any one of paragraphs.1 - 13 or its pharmaceutically five antiviral activity, comprising an active ingredient and pharmaceutically acceptable additives, characterized in that the active substance it contains a compound of General formula I according to any one of paragraphs.1 - 14 or its pharmaceutically acceptable derivatives in effective amounts.

16. Dimethoxydimethylsilane nucleosides of General formula II

< / BR>
where X - NRR1, SR, OR2the halogen atom; where R, R1, R2have the values listed in paragraph 1;

Y - OH-group may secure;

Z - NH2,

or their pharmaceutically acceptable derivatives.

Priorities for items:

20.01.88 - PP.3, 4, 8, and 9;

07.09.88 - PP.1 - 16;

05.12.88 - PP.1 - 16.

 

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