The method of obtaining dimethoxydimethylsilane nucleosides

 

(57) Abstract:

Usage: as antiviral agents. The inventive product: dimethoxydimethylsilane nucleoside of the General formula I:

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where X Is al, -NRR1, -SR, -OR, where R and R1- H or C1-4-alkyl; Z is H or NH2. Reagent 1: compound II, where X' is halogen, Z is the above values.

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Reagent 2: formic acid or its derivative, such as trialkylaluminium. Reaction conditions: in a medium of an organic solvent (amides, chlorinated hydrocarbons, ethers, NITRILES, excess reagent 2) at t - 25-150oC. 4 C.p. f-crystals.

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

Because of the similarity 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 reg se and it is very difficult to find Protei antiviral effect at the dose level, when the agent has acceptable toxicity or side effect profile.

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 (YIV's>); two such virus, HIV-I and HIV-II, reproductive isolated from patients suffering from AIDS, 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 HIV infections, only zidovudine (AZI, Petrovir) received permanent approval for the treatment of such conditions. However, it is known that zidovudine 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, meyssonnier hydrogen, NRR1, SR, or, or halogen, Z represents hydrogen, OR2or NRR1, R, R1and R2may be the same or different 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 cyclopentene ring of compounds of formula (I) contains two chiral center (shown in the formula (I) under the symbol *) 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 5-configuration (hereinafter D-isomer) or a chiral center that is attached to the base, is a 5-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 the future, SS is the compounds of formula (I) can exist as a number of tautomeric forms, and all such tautomers are included in the scope of the present invention.

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

C1-C4-alkyl refers here to remotemachine or branched alkilani group, for example, methyl, ethyl, n-propyl, ISO-propyl, n-butyl, sec-butyl and tert-butyl. Preferably, WITH1-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 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 represents N, NH2or especially OH. Such compounds are particularly desirable therapeutic index in necesariamente 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, aralkyl (e.g., benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (e.g. phenyl, optionally substituted with halogen, 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, in particular from 1 to 4 carbon atoms. Any arifmeticheskii acceptable salts of compounds of formula (I) include those which came 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-p-acid, tartaric acid, acetic acid, citric acid, methanesulfonate, 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 denotes a1-C4-alkyl).

In further reference to the connection in accordance with the invention include compounds of formula (I), and pharmacist who-purine-9-yl/-2-cyclopentenyl-carbinol,

/Ia, 4a/-4-/6-Hydroxy-N-purine-9-yl/-2-cyclopentenyl-carbinol,

/1,4/-4-/6-Amino-N-purine-9-yl/-2-cyclopentenyl-carbinol.

/1,4/-4-4/6-Mercapto-N-purine-9-yl/-2-cyclopentenyl-carbinol,

/1,4/-4-/2-Amino-6-chloro-N-purine-9-yl/-2-cyclopentenyl-carbinol,

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

/1,4/-4-/2,6-Diamino-N-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, either/or they are metabolization when the inhibition of the replication of retroviruses, including human retroviruses such as the human immunodeficiency viruses (HIV's), the 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 its pharmaceutically acceptable derivative for use as an active therapeutic agent, in particular as an antiviral agent, for example, in the treatment of retroviral infections, or kachestvenie viral infection, in particular infection caused by a retrovirus, such as HIV, 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 compounds, such as AIDS-related complex (ARC), progressive disseminated lymphadenopathy (PGL), AIDS-related neurological conditions (such as dementia or tropical prepares), anti-HIV antibody-positive and HIV-positive status, idiopathic multiple hemorrhagic sarcoma (angiomatosis of Kaposi) and thrombocytopenic purpura.

Antiviral compounds of the present invention is also suitable in preventing the development of clinical disease patients, Kotor">

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, and the age and condition of the patient and will be fully in competence of the physician or veterinarian. In General, a suitable dose will range from about 1 to about 750 mg/kg, for example about 1 to 750 mg/kg body weight per day, or about 3 to 120 mg/kg body weight of recipient per day, preferably in the range of 6 to 90 mg/kg, most preferably in dipascali dosages, entered at appropriate intervals, for example as two, three, four or more sub-doses per 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 active ingredient, optionally in saline, 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 invention in the form of the raw chemical, it is preferable that the active component prisutstvujuschih 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 stage of forming the product into a desired configuration.

Pharmaceutical compositions suitable for oral administration may be present in the form of discrete units such as capsules, starch wafers or tablets, each contains a set amount of active component in the form of a powder or granules; in the form of a solution, suspension or emulsion. The active component was also present which may contain conventional fillers, such as binders, 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 agents, 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 continuous infusion) and may be present in the form of uniform dosage in ampoules, pre-filled syringes or in the packaging of the medicines for multiple reception with the addition of a preserving agent. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous hydrated component can be in the form of powder, received 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. The mazes 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 Arabian gum; and liquid mouth rinse containing the active ingredient in a suitable liquid carrier.

Pharmaceutical compositions suitable for rectal administration, and the carrier is a solid, most predpochtitel 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 suspendida substances. Liquid compositions for spraying conveniently enclosed in sealed packages.

For introduction by inhalation the compounds according to the present invention are conveniently delivered from insufflator, nebulizer or pressurized pack or other suitable means of delivery of aerosols. Sealed packages may contain suitable dispersant, gas. In the case of a pressurized aerosol the dosage can be determined by providing a valve to deliver a measured quantity of connections.

Alternatively, for administration by inhalation 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.

Compounds of the present invention can also be used in combination with other therapies, such as other anti-infective agents. In particular, compounds of the Sabbath.">

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 other 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 in combination with pharmaceutically acceptable carrier, amount to an 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 interleukin II /IL2/ and granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin, ampligen.

Separate Konig 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 to obtain the desired compound. Protection and exemption from the protection of functional groups can be carried out using traditional methods. So, for example, amino groups can basedowii cleavage 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. McOmie (Plenum Press, 1973) or "Protective Groups in Organic Synthesis" heodora W. Greene (Tohn 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 groups, such as triphenylmethyl can be similarly derived by solvolysis, for example by hydrolysis in acidic conditions. 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 group is P CLASS="ptx2">

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 cyclopentylamine may be in a protective form) or its pharmaceutically acceptable derivative with a reagent selected from formic acid and its reactive derivatives, 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), dichiarazione acid, formamide, S-triazine or formamidines.

Unwanted group entered formic acid or its reactive derivative can be conveniently derived by hydrolysis under mild conditions, for example, with inorganic acids, such as aqueous hydrochloric acid.

When using three are gathered together solvents, which can 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) the reaction is preferably carried out 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 a temperature of -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's, initially present, replace the other Deputy's, and/or the group Z is present initially, substitute another group Z, and, if necessary, then otscheplaut any present protective group.

In one process variant (C) the compounds of formula (I) in which X denotes a group RR1(where R and R1have the above spacealien (for example, 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, as described in Harrison et al. Compendium of Organic Sinthetic Methods Wilet-Interscience, new York (1971) on pages 250-252.

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 as alcohol (e.g. methanol or ethanol), a simple ether (e.g. dioxane or tetrahydrofuran), a ketone (e.g. acetone), amide (e.g. dimethylformamide) or sulfoxide (e.g., dimethylsulfoxide), conveniently in the presence of acid or base. Suitable Cyclostomata 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 denotes a1-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 formed 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 thiourea in a suitable solvent, such as alcohol (e.g. n-propanol), at elevated temperature (for example, temperature phlegmy), with subsequent basic hydrolysis. Suitable bases that may be used in this case include hydroxide of Molochny the Coll, so 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 J. R. Marshall, and others J. Chem.Soc. 1004 (1951). Alternatively, the 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. Naie and other J. Org.Chem. 52, 1344 (1987).

In another embodiment of process (b) compounds of formula (I) in which X denotes a halogen atom, can be obtained from the other halo-compounds of formula (I) traditional methods halide-halide exchange. Alternatively, when X denotes chlorine, the Deputy may be substituted by other halogen atoms with espelir> 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, in the work of Nucleosid. Analogs - Chemistry, Biology and Medical Application. 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, the description of which is introduced here as a reference. For example, when it is necessary to obtain an acid additive salt of the compounds of formula (I), the product of any of the above methods can be converted into a salt by treatment received free the e additive salts can be obtained by reacting the free base with a suitable acid, optionally 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) can be converted into a pharmaceutically acceptable phosphate or other ester by reacting with fosforiliruyusciye substance, such as l3or suitable esterification substance, such as halogen-anhydride or acid anhydride. Ester or salt of the compounds of formula (I) can be transformed into a related compound, for example, by hydrolysis.

The compounds of formula (II) and their salts are new compounds, and they constitute an additional distinctive feature of the present invention.

The compounds of formula (II) in which Z represents a hydrogen IOM pyrimidine of formula (III)

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(where Y denotes a halogen atom, e.g. 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 2 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, such as p-chlorophenyl, and E-denotes an anion, for example halide, such as chloride) in a solvent such as water, an organic acid such as acetic acid, or a mixture thereof, conveniently at ambient temperature, to obtain the compounds of formula (IV)

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(where Ar has the above meaning), which can be converted into the desired compound of formula (II) restore the 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-3a-acetoxy-methylcyclopentene-2-ene (Ia), 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-chlorocompounds 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 pure source materials or any suitable intermediate connections.

Peptization end-product, or intermediate, or the original product can be accomplished in 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 Agenets enzymatic transformation of a racemic mixture of compound 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 invention is described below with reference to the following detailed examples, in which the elemental analysis was carried out with the participation of the M-H-W Laboratories, Phoemix, AZ. Melting points were determined on the apparatus l-Temp and adjusted. The spectra of nuclear magnetic resonance were obtained on a spectrometer Teol FX 90QFT or Nicollet NT300 and were recorded in DMSO-d6. Chemical shifts are expressed in million shares of the IU4Si. IR spectra were determined as KBR pellets spectrometer IR Nicollet 50XC FT and UV spectra were determined on a spectrophotometer Wischmopp 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 (230-400 mesh mesh). All chemicals and solvents are of the purity of the reagent, if not specified otherwise. The term "active 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-cyclopentenone and barium (0.5 n, 300 ml) is heated under reflux during the night. After cooling, the mixture is neutralized with dry ice. The residue 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), placed in the flash column (4.0 x 12 cm) and elute l3-MeOH (20:1) to obtain the 2,69 g (74%) compounds

3A; melting point 130-132oC. an Analytical sample obtained by recrystallization from ethyl acetate (tOAc), melting point 134-135oC, mass spectrum (MS) (30 eV, 200oC), m/e 240 and 242 (M+and M++2), 209 (M+-31), 144 (B+), IR: 3600-2600 (OH), 1620, 1580 (C=C, C=N). Anal. (C10H13ClN4O), C, H, n

Example 2

()-(1,4)-4-(/ 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 canola with the to separate undissolved by-product (double pyrimidin-nuke). A methanol solution adsorb on silica gel (8 g), Packed in a column (4.0 x 14 cm) and elute l3-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. (C10H13ClN4) 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 Hcl (25 ml) and sodium nitrile (870 mg, 12.5 mmol) in water (10 Il). 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 at room temperature. The precipitated yellow filtered and washed with cold water until until it becomes neutral, and then dried in the air with the receipt of 3.60 g (94%) of compound 5A; melting point 229oC (decomposition). An analytical sample is obtained from media 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), 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 x 18 cm) and elute l3-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 (NH2, OH), 1620, 1580 (C=C, C=N), Anal. (C10H14ClN5) C, H, n

Example 5

()-(1,4)-4-/6-Chlorine-N-purine-9-yl/-2-cyclopentanecarbonyl (7a) X Cl, Z H

A mixture of compound 3A (1,30 g, 5.4 mmol), triethylorthoformate (30 ml) and hydrochloric acid (12 n, and 0.50 ml) is stirred overnight at room temperature. The solvent is evaporated at a temperature of 35oC in vacuum. Rastvoritel acid (30 ml) and the mixture stirred for 1 h, the mixture is then neutralized to pH 7-8 1H. the sodium hydroxide solution and adsorb on silica gel (8 g), placed in a column (4.0 x 8 cm) and elute l3-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-N-purine-9-yl/2-cyclopentylamine (8A) X is OH, Z H

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 was adjusted to pH 5-6 with acetic acid. The reaction mixture adsorb on silica gel (2 g), placed in a column (2.0 x 11 cm) and elute l3-MeOH (10:1) to give 105 mg (45%) of compound 8A. The crude product is white is recrystallized from water-methanol (3:1) to give compound 8A, melting point 248-250oC (decomposition); MS (30 eV, 300oC), m/e 232 (M+, 214 (M+-18), IR: 3600-2600 OH), 1680, 1600 (C=O, C=C, C=N), Analyt. (C11H12N4O2) C, H, N.oC. the Autoclave is sealed and heated at a temperature of 60oC for 24 h Ammonia and methanol evaporated and the residue will 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-N-purine-9-yl)-2-cyclopentanecarbonyl (10A) X SH, Z H

A mixture of compound 7a (125 mg, 0.5 mmol), thiourea (40 g, 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 again, melting point 260-262oC (decomposition), and then recrystallized from N, N-dimethylformamide to obtain the compound 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). Edilkamin (13A) Z NH2X Cl

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 (4.0 x 10 cm) and elute l3-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. (C11H12N5OCl3/4H2O) C, H, n

Example 10

()-(1,4)-4-(2-Amino-6-hydroxy-N-purine-9-yl)-2 - cyclopentanecarbonyl (14a) Z NH2Z OH

A mixture of compound 13A (266 mg, 1 mmol) and an aqueous solution of sodium hydroxide (0,33 BC) is heated under reflux for 5 h, adsorb on silica gel (2 g), placed in a column (2.0 x 7.5 cm) and elute l3-MeOH (5:1). The crude product is recrystallized from a mixture of methanol-water (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. (C11H13N5O23/4H2O) C, H, n

Example 11

()-(1,4)-4-(2,4-Diamino-N-purine-9-yl)-2-cyclopentanecarbonyl (15A) Z X NH2< / BR>
Liquid ammonia is passed into a solution of compound 13A (265 mg, 1 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 (2.0 x 10 cm) and elute l3-MeOH (15:1). The crude product is recrystallized from ethanol to obtain 196 mg (80%) of compound 15A, melting point 152-155oC. MS (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-N-purine-9-yl/-2-cyclopentanecarbonyl [/1S, 4R/-4-/2,6-Diamino-N-purine-9-yl/-2-cyclopentanemethanol]

(a) Intermediate compound 1: /1R,2S,3R,5R/-3-[6-Amino-N-purine-9-yl/] -5-[ // 1,1-dimethylethyl/- dimethylsiloxy / methyl]-1,2-cyclopentanediol

(-) Eritromicin1(12,505 g), tert-butylmethacrylate (7,8 g) and kienny the solution is diluted with ethyl acetate (500 ml), then washed with water (3 x 100 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 (DMSO-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), 0,07 (6H).

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

(b) an Intermediate compound 2: (4R,3a,6R,6aR)-4-[6-Amino-N-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 ethyl acetate (100 ml), then washed with water (2 x 20 ml) and brine (2 x 20 ml), dried with magnesium sulfate and evaporated to a solid yellow color, which is simple washed with diethyl ether (25 ml), then collected by filtration, further washed with simple what about the substance (3,61 g), lmax(ethanol) 240,0 nm (E1%1Cm459),1H NMR (DMSO-d6OF 8.27 (1H), 8,13 (1H), 7,33 (2N), 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: /1'R,4'S/-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. Next, the substance is washed with simple diethyl ether (10 ml), dried in vacuum, obtaining specified in the title compound (1.47 g).max(ethanol) 261,4 nm (E1%1Cm443),1H-NMR (DMSO-d6), 8,14 (1H), 8,00 (1H), 7,20 (2N), 6,12 (1H), 5,95 (1H), THE CEILING OF 5.60 (1H), 3,66 (2N), 2,96 (1H), 2,69 (1H), 1,65 (1H), 0,74 (N), 0,02 (6N).

(d) Intermediate compound 4: /1',R,4'S/-9-[4- / / / 1,1-Dimethylethyl / dimethylsiloxy / methyl / -2 - cyclonaut 80-90% m-chloroperoxybenzoic acid (1.29 g), 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 color, which, together with the substance recovered by evaporation of the filtrate, dissolved in chloroform (100 ml), then washed with saturated aqueous sodium bicarbonate (3 x 10 ml) and brine (2 x 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%1Cm248), to 300.2 nm (E1%1Cm75),1H-NMR (l3) 8,72 (1H), 8,02 (1H), 7,16 (2N), 6,21 (1H), BY 5.87 (1H), 5,72 (1H), 3,68 (2H), 3.04 FROM (1H), 2,82 (1H), 1,74 (1H), 0,89 (N), 0,06 (6N).

(e) the Intermediate compound 5: (1',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-methanol (20 ml) is treated with a solution of cyanogenmod (0.34 g) in methanol (20 ml), 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 g)max(ethanol) to 228.2 nm (E1%1Cm530), RUB 285.2 nm (E1%1Cm445),1H-NMR (l3) AND 10.20 (1H), 10,02 (1H), OF 8.37 (1H), AND 6.25 (1H), 6,01 (1H), 5,90 (1H), 3,69 (2N), WAS 3.05 (1H), 2,86 (1H), 1,73 (1H), 0,86 (N), 0,03 (6N).

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

A solution of intermediate compound 5 (1,36 g) in dimethylformamide (10 ml) was stirred at ambient temperature, then treated with triethylamine (1.2 ml). After 40 minutes add iodomethane (0.54 ml), which leads to the formation of yellow coloured solution. 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 x 20 ml) and brine (20 ml), dried in the presence of magnesium sulfate and evaporated to a solid those who toe body white simple washed with ether (10 ml), dried in vacuum to obtain 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 (1N), 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), 0,88 (N), 0,05 (6N).

(g) Intermediate compound 7: (1'R,4'S)-9-[4- / / / 1,1-dimethyl / dimethylsiloxy / methyl / -2-cyclopenten-1 - yl]-6-methoxy-amino-N-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% of scale), then subjected to column chromatography on silica (40 g, Merck 9385), elwira chloroform, then with a mixture of chloroform-ethanol, to obtain the 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%1Cm42 (6N).

(h) an Intermediate compound 8: a /1S,4R/-4-[2-Amino-6-methoxyamino-N-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, obtaining specified in the header of the product as a solid (243 mg),max(pH 6 buffer) 250,2 nm (E1%1Cm534),1NMR (DMSO-d6) OF 9.75 (1H), 7,39 (1H), 6,52 (2N), 6,10 (1H), OF 5.84 (1H), 5,27 (1H), 4,73 (1H), 3,40 (2N), AND 2.83 (1H), 2,55 (1H), 1,52 (1H).

/1S,4R/-4-[2,6-Diamino-N-purine-9-yl]-2-cyclopentanecarbonyl

Mixed, chilled on ice, a solution of intermediate compound 6 (210 mg) in water (10 ml) and tetrahydrofuran (50 ml) is treated with aluminum 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 mixture was filtered che is 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-81oC (c, 1,04, methanol);max(pH 6 buffer) 255,0 nm (E1%1Cm302), 280,8 nm (E1%1Cm381),1NMR (DMSO-d6) TO 7.61 (1H), 6,66 (2N), 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-N-purine-9-yl/-2-cyclopentenyl-carbinol

/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 in 0.01 M potassium phosphate, pH 6.0, and then stirred and heated to a temperature of 37oC. After 18.5 hours, the resulting suspension is cooled. Collected solid is recrystallized from water to obtain specified in the header of the product in the form of a solid body in white (86 mg), []D- 49oC (s, 0,5, dimethylsulfoxide), max(pH 6 buffer) 252,6 nm (E1%1Cm531),1H-NMR (DMSO-d6Tihomirov (1,4)-4-(2-Amino-6-hydroxy-N-purine-9-yl/-2-cyclopentanecarbonyl

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

Diaminoanisole (100 mg) (example 11) are dissolved in 3 ml, 0.05 M2PO4buffer (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 fractions of solid paracrystalline of water to obtain the pure product specified in the header, melting point 269-272oC []2D462,1 (c, 0.3 Meon).

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

The leachate as a result of receiving 1S, 4R-isomer (example 14a) are combined and evaporated to dryness. Unchanged diamino-the source material was separated on a flash column of silica gel using 10% methanol/chloroform. Diamino-compound is dissolved in 0.05 M2PO4buffer, pH 7.4 (15 ml), and 800 units of adenosine-deaminase of probable is 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 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 (c, 0.3 Meon).

Example 15

//1,4/-4-/2-Amino-6-hydroxy-N-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 is concentrated to obtain solid white. The solid product is washed with a mixture of Meon-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

but-6-methoxyamino-N-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 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, 420 and 40 mg). The two largest fractions separately crystallized from isopropanol. The filtrates combined with smaller column fraction and subjected to preparative thin-layer chromatography (Merck 5717), showing three times in a mixture of chloroform:methanol (10:1). Plate elute with ethyl acetate and a mixture of ethyl acetate-ethanol (1:1) obtaining solid brown (45 mg). The solid body is subjected to column chromatography on silica (2.7 g, Merck 7734) in chloroform and elute with mixtures of chloroform-methanol-triethylamine to obtain gum (17 mg) After a failed Krista dried by freezing to produce specified in the connection header 15 mg1H-NMR (DMSO-d6) OF 1.62 (1H), 2.63 IN (1H), 2,89 (1H), 3,45 (2N), TO 4.73 (1H), 5,48 (1H), 5,91 (1H), 6,14 (1H), 6,50 (2N), 7,98 (1N), TO 8.57 (1H). Mass spectrum: [MH]+232.

1. The method of obtaining dimethoxydimethylsilane nucleosides of General formula I

< / BR>
where X is hydrogen, halogen, a group of the formula

-NRR', -SR or-OR,

where R and R' is hydrogen or C1C4-alkyl;

Z is hydrogen or-NH2,

characterized in that the compound of General formula II

< / BR>
where X' is halogen;

Z has the value

subjected to interaction with formic acid or its reactive derivative and, if necessary, make the target product of the General formula I, where X is a halogen, the compound of General formula I where X is hydrogen, a group-NRR', -SR and-OR, where R and R' have the specified values.

2. The method according to p. 1, characterized in that, as the reactive derivative of formic acid use trialkylaluminium.

3. The method according to p. 1, wherein Z is NH2.

4. The method according to p. 1, characterized in that the compound of General formula I are selected from(1, 4)- 4-(6-chlorine-N-purine-9-yl)-2-cyclopentanecarbonyl, (1, 4)-4-(6-hydroaxe-N-purine-9-yl)-2-cyclopentanecarbonyl, (1, 3)-4-(6-amino-N-purine-9-yl)-2-cyclopentanecarbonyl, (1, 4)-4-(2-amino-6-chloro-N-purine-yl)-2-cyclopentanecarbonyl, (1, 4)-4-(2-amino-N-purine-9-yl)-2-cyclopentanecarbonyl.

5. The method according to p. 1, characterized in that the compound of formula I is a(1, 4)-4-(2-amino-6-hydroxy-N-purine-9-yl)-2-cyclopentanecarbonyl.

 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of xanthine of the formula (I): possessing inhibitory effect on activity of phosphoenolpyruvate carboxykinase. In compound of the formula (I) R1 is chosen from group consisting of lower alkenyl, lower alkynyl, lower alkenyl substituted with halogen atom, phenyl and phenyl substituted with one or two substitutes chosen independently from group comprising halogen atom, hydroxy-group, lower alkoxy-group, nitro-group, amino-group or 5- or 6-membered aromatic heterocyclic ring comprising 1, 2, 3 or 4 nitrogen atoms added to phenyl by ring carbon atom; R2 is chosen from group comprising unsubstituted lower alkyl, lower alkyl substituted with lower alkoxy-group or hydroxy-group, lower alkenyl, phenyl, -(CH2)n-unsubstituted lower cycloalkyl and -(CH2)n-lower cycloalkyl substituted with at least one substitute chosen from group comprising carboxy-group, lower alkyl, carboxy-lower alkyl and lower alkyl substituted with hydroxy-group, -(CH2)n-C(O)Rb wherein Rb is chosen from group comprising hydroxyl, lower alkoxy-group, hydrogen atom, benzyl, lower alkyl and -NHRb wherein Rb is chosen from group comprising lower alkoxy-group, -NHRc wherein Rc is chosen from group comprising hydrogen atom, benzyl, lower alkyl and -NHRd wherein Rd is chosen from group comprising hydrogen atom and carboxy-lower alkyl; -(CH2)n-unsubstituted aromatic 5-membered heterocyclic ring comprising one oxygen or sulfur atom, -(CH2)-aromatic 5-membered heterocyclic ring comprising one oxygen or sulfur atom wherein ring is substituted with carboxylic acid residue, -(CH2)n-unsubstituted aromatic 5-membered heterocyclic ring comprising 1, 2 or 3 nitrogen atoms, -(CH)n-nonaromatic 5- or 6-membered heterocyclic ring comprising at least one oxygen atom and two nitrogen atoms or not comprising nitrogen atoms wherein nonaromatic heterocyclic ring has no substitutes or comprises one ring carbon atom as carbonyl, and wherein R3 means: and others. Also, invention relates to pharmaceutically acceptable salts of compounds, pharmaceutical composition based on thereof, using and inhibition of activity of PEPCK.

EFFECT: improved method of synthesis, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

32 cl, 1 tbl, 125 ex

FIELD: medicine.

SUBSTANCE: invention relates to a benzylammonium and cyclohexylammonium salt of [3-methyl-1-n-propyl-7-(1,1-dioxothietanyl-3)xanthinyl-8-thio]acetic acid of formula Ia,b, where B+=H3N+-CH2 (la), H3N+) (Ib).

EFFECT: novel compounds which can be used in medicine as proaggregant agents are obtained and described.

4 cl, 1 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to cyclohexylammonium salt of [3-methyl-1-n-propyl-7-(1-oxothietanyl-3)xanthinyl-8-thio]acetic acid of formula .

EFFECT: what is prepared and described is a new compound which can find application in medicine as an antiaggregation and anticoagulation agent.

3 cl, 2 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: co-crystals possess firstly the anti-inflammatory, antipyretic and analgesic action and are applicable to produce pharmaceutical preparations. The co-crystal of diflunisal and theophylline has an endothermal peak from 183 to 195°C according to the measured data by differential scanning calorimetry and peaks at 2θ(°) 5.2, 10.3, 11.9, 18.18, 23.5, 26.4 according to the measured data of X-ray powder diffraction, while the co-crystalline form of diclofenac and theophylline has an endothermal peak from 186 to 198°C according to the measured data by differential scanning calorimetry and peaks at 2θ(°) 7.6, 12.2, 16.7, 17.4, 20.1, 27.0 according to the measured data of X-ray powder diffraction. The co-crystals can be presented in the solid phase and in the solution.

EFFECT: co-crystal enables increasing water-solubility for diflunisal and for diclofenac as compared to the unformulated solubility.

12 dwg, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula V-A or their pharmaceutically acceptable salts possessing the properties of PI3-kinase (phosphatidylinositol-3-kinase) activity inhibitors. The compounds can find application for treating diseases and conditions associated with PI3-kinase activity, particularly in a T-cell, B-cell, mastocyte, dendritic cell, or neutrophil. This disease represents one or more diseases specified in cancer, a bone disorder, inflammatory disease, immune disease, respiratory disease or thrombosis. Cancer represents leukaemia or lymphoma, or cancer is specified in acute myeloid leukaemia, chronic lymphocytic leukaemia and multiple myeloma, where lymphoma represents non-Hodgkin lymphoma; an inflammatory or immune disorder is asthma, allergy, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, systemic lupus erythematosus, or graft-versus-host disease. The compound of formula V-A, or its pharmaceutically acceptable salt, or a composition can be used in a combination with rapamycin. In formula V-A:

B represents a group of formula

wherein Wc represents phenyl, 6-merous heterocyclyl with one heteroatom specified in oxygen or nitrogen, or C3-C6cycloalkyl; q is equal to 0 or 1; R1 represents hydrogen, C1-C4alkyl or halogeno; R2 represents halogeno or C1-C4alkyl optionally substituted by halogeno; R3 represents halogeno; R9 represents hydrogen or C1-C4alkyl.

EFFECT: producing the new compounds for treating the diseases or conditions associated with PI3-kinase activity.

62 cl, 19 dwg, 6 tbl, 55 ex

FIELD: organic chemistry, heterocyclic compounds, biochemistry.

SUBSTANCE: invention relates to new compounds - purine derivatives of the general formula (I): in free form or salt wherein X means oxygen or sulfur atom or group NR5; R1 means alkyl, alkenyl, cycloalkyl, benzocycloalkyl, cycloalkylalkyl or aralkyl group that can be substituted optionally with hydroxy-, carboxy-group or alkoxycarbonyl; or if X means NR5 then R1 can mean alternatively heterocyclic group taken among benzylpiperidyl or the formula: ; or group of the formula (II): ; R2 means hydrogen atom, alkyl or alkoxy-group; R3 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, alkoxycarbonyl, -N(R9)R10, (C1-C4)-alkylene-SO2N(R11)R12 or -CON(R13)R14; or if two substitutes R2 and R3 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-10 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen and sulfur atom; R4 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, -SO2N(R11)R12, -N(R9)R10 or -CON(R13)R14; or if two substitutes R3 and R4 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen or sulfur atom; R5 means hydrogen atom or alkyl; R6, R7 and R8 mean hydrogen atom, or one of these radicals means -SO2NH2, -N(CH3)COCH3, -CONH2 and two others mean hydrogen atom; R9 means hydrogen atom or alkyl; R10 means hydrogen atom, -COR15 wherein R15 means alkyl, alkoxy-group; or R9 and R10 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R11 means hydrogen atom or alkyl; R12 means hydrogen atom, alkyl, hydroxyalkyl, carboxyalkyl or alkoxycarbonylalkyl; or R11 and R12 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R13 and R14 each and independently of one another means hydrogen atom or alkyl with exception of 2-(para-n-butylanilino)-6-methoxypurine, 2-(para-n-butylanilino)-6-(methylthio)purine, 2,6-di-(phenylamino)-purine, 2,6-di-(para-tolylamino)-purine and 2-(para-tolylamino)-6-(phenylamino)-purine.

EFFECT: valuable biochemical properties of compounds.

11 cl, 4 tbl, 221 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel purine derivatives of general formula I in free form or in form of a pharmaceutically acceptable salt which have A2A agonist properties. In formula I , R1 denotes a N-bonded 5-6-member heterocyclic group containing 1-4 nitrogen atoms in the ring, which can be optionally substituted with oxo, phenyl or C1-8-alkyl, optionally substituted with hydroxy; R2 is hydrogen or C1-C8-alkyl, optionally substituted with hydroxy or 1-2 phenyls possibly substituted with hydroxy or C1-C8-alkoxy; R3 is C2-C8-alkynyl or C1-C8-alkoxycarbonyl, or R3 is amino substituted with C3-C8-cycloalkyl, optionally substituted with amino, hydroxy, benzyloxy or NH-C(=O)-NH-R6, or R3 is amino substituted with R4, -R4-benzyl or C5-C10-mono- or bicarbocyclic group, optionally substituted with hydroxy or C1-C8-alkoxycarbonyl, or R3 is aminocarbonyl optionally substituted with R5, or R3 is C1-C8-alkylamino optionally substituted with hydroxy, R5, NH-C(=O)-C1-C8-alkyl, -MH-SO2-C1-C8-alkyl, -NH-C(=O)-NH-R6 or phenyl, optionally substituted with phenyloxy, or R3 is a N-bonded 5-member heterocyclic group containing 1 nitrogen atom in the ring which may optionally be substituted with amino, C1-C8-alkylamino, di(C1-C8-alkyl)amino and other groups.

EFFECT: compounds can be useful in treating conditions mediated by activation of the adenosine A2A receptor, especially inflammatory or obstructive respiratory tract diseases.

9 cl, 5 tbl, 161 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula I in free form or in form of pharmaceutically acceptable salt, which possess properties of adenosine receptor A2A agonists. In formula I , R1 represents (C1-C8)alkylcarbonyl, (C3-C8)cycloalkylcarbonyl, -SO2(C1-C8)alkyl, phenyl(C1-C4)alkylcarbonyl or -(C=O)-C(=O)-NH(C1-C8)alkyl, optionally substituted with R4; R2 represents H or (C1-C8)alkyl, optionally substituted with (C6-C10)aryl; R3 represents halogen or(C2-C8)alkinyl, or R3 stands for aminogroup, optionally substituted with (C3-C8)cycloalkyl, optionally substituted with amino, or R3 represents (C1-C8)alkylaminogroup, optionally substituted with hydroxy, phenyl or R5, or R3 stands for R6, optionally substituted with amino or -NH-C(=O)-NH-R7, or R3 stands for -NH-R6, optionally substituted with -NH-C(=O)-NH-R7, or R3 stands for (C1-C8)alkylaminocarbonyl, optionally substituted with. -NH-C(=O)-NH-R8; R4, R5 and R6 represent independently 5- or 6-member heterocyclic ring, which contains one-two N ring heteroatoms, optionally substituted with amino or (C1-C8)alkyl; and R7 and R8 represent independently 5- or 6-member heterocyclic ring, which contains one-two ring heteroatoms selected from N and S, and is optionally substitutedf with halogen, (C1-C8)alkylsulfonyl or 5- or 6-member aromatic heterocyclic ring, which contains one N ring heteroatom. Invention also relates to pharmaceutical composition and to application of said compounds for treatment of states, mediated by activation of adenosine receptor A2A.

EFFECT: obtaining composition, which possesses properties of adenosine receptor A2A agonists.

10 cl, 3 tbl, 80 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing abacavir of formula (I) or pharmaceutically acceptable salt thereof, involving reaction of a compound of formula (II), (I) (II), where R denotes H or (C1-C4)-alkyl radical with an inorganic base such as an alkali metal hydroxide in a mixture of (C1-C6)-alcohol and water; and extraction of abacavir of formula (I) in form of a free base or in form of a pharmaceutically acceptable salt by treating said free base with a corresponding acid.

EFFECT: method ensures high degree of conversion without racemation, enables to minimise formation of impurities and considerably shortens reaction time.

19 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: nucleic base (e.g. uracil, cytosine, adenine, guanine, hypoxanthine, xanthine or similar) reacts with perfluoroalkyl halide in the presence of sulphoxide, peroxide and an iron compound to obtain a perfluoroalkyl-substituted nucleic base.

EFFECT: high cost effectiveness as an intermediate compound for producing medicinal agents.

15 cl, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing abacavir of formula (I) or salts or solvates thereof. Abacavir has strong HIV-1 and HIV-2 selective inhibitor activity and can be used in treating patients infected with HIV. The method involves i) closing the ring in a compound of formula (IV) by first reacting said compound (IV) with an anhydrous hydrochloric acid solution in (C1-C6)-alcohol, preferably isopropanol, and then with tri(C1-C4)-alkylorthoformate in anhydrous conditions to obtain a compound of formula (III), ii) reaction of the compound of formula (III) with cyclopropylamine to obtain a compound of formula (II) and iii) hydrolysis of the compound of formula (II) to obtain abacavir (I) or salt thereof. R1 denotes a (C1-C4)-alkyl radical, preferably isopropyl.

EFFECT: obtaining an end product with higher output and higher quality.

12 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new purine derivatives of formula (I) and to their pharmaceutically acceptable salts exhibiting the properties of adenosine receptor A2A agonists. The compounds can find application for preparing a drug for treating an inflammatory or obstructive respiratory disease. In formula

,

R1, R2 and R3 are those as specified in the patent claim.

EFFECT: preparing new purine derivatives of formula (I) or their pharmaceutically acceptable salts showing the properties of adenosine receptor A2A agonists.

8 cl, 2 tbl, 264 ex

Compounds // 2461559

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new purine derivatives possessing the properties of an inhibitor of the enzyme CDK specified in CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 and CDK9. In formula (I): R1 and R2 each independently represents H, C1-6alkyl or C1-6halogenalkyl; R3 and R4 each independently represents H, C1-6-alkyl or C1-6-halogenalkyl; R5 represents C1-6-alkyl or C3-12-cycloalkyl, or C3-12-cycloalkyl-C1-6-alkyl each of which may be optionally substituted by one or more OH groups; R6 represents wherein Y represents N, X and Z represents CR9; R7, R8 and R9 optionally represent H, alkyl or C1-6-halogenalkyl; wherein at least one of R7 , R8 and R9 is other than H. The invention also refers to a pharmaceutical composition containing said compounds, using the compounds for treating alopecia, stroke, a proliferative disease, such as cancer, leukaemia, glomerulonephritis, rheumatoid arthritis, psoriasis, viral diseases, such as a disease caused by human cytomegalovirus, type 1 herpex simplex virus, type 1 human immunodeficiency virus, a neurodegenerative disease, a CNS disease, such as Alzheimer's disease.

EFFECT: preparing new purine derivatives possessing the properties of the inhibitor of the enzyme CDK.

30 cl, 8 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel purinyl derivatives of formula or , a stereoisomer thereof or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, where n equals 0, 1, 2 or 3; X is O, S or NR', where R' is hydrogen or methyl; Y is cycloalkyl, phenyl, benzo[1,3]dioxolyl or pyridyl, where the cycloalkyl, phenyl, benzo[1,3]dioxolyl and pyridyl are possibly substituted with one substitute selected from a group consisting of halogen, trifluoromethyl, cyano, nitro and amine; R1 is hydrogen, alkyl or alkoxy-alkyl; and Het is a pyrazolyl group which is substituted twice or more with substitutes selected from a group consisting of alkyl, hydroxy-alkyl, halogen, trifluoromethyl, alkoxy-carbonyl and phenyl. The invention also relates to pharmaceutical compositions which are useful for treating or relieving symptoms of diseases and disorders associated with activity of potassium channels.

EFFECT: novel compounds which can be used as potassium channel modulators are obtained and described.

12 cl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel N-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-(5-isopropoxy-1H-pyarazol-3-yl)-3H-imidazo[4,5-b]pyridine-5-amine or pharmaceutically acceptable salt thereof, having inhibiting activity with respect to Trk (tropomyosin-related kinase). The compounds can be used as a medicinal agent for treating cancer. The invention also relates to use of said compound of pharmaceutically acceptable salt thereof to produce a medicinal agent for treating cancer in a warm-blooded animal and a pharmaceutical composition containing said compound or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, a solvent or an inert filler.

EFFECT: high efficiency of using the compound.

4 cl, 26 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel purinyl derivatives of formula or , a stereoisomer thereof or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, where n equals 0, 1, 2 or 3; X is O, S or NR', where R' is hydrogen or methyl; Y is cycloalkyl, phenyl, benzo[1,3]dioxolyl or pyridyl, where the cycloalkyl, phenyl, benzo[1,3]dioxolyl and pyridyl are possibly substituted with one substitute selected from a group consisting of halogen, trifluoromethyl, cyano, nitro and amine; R1 is hydrogen, alkyl or alkoxy-alkyl; and Het is a pyrazolyl group which is substituted twice or more with substitutes selected from a group consisting of alkyl, hydroxy-alkyl, halogen, trifluoromethyl, alkoxy-carbonyl and phenyl. The invention also relates to pharmaceutical compositions which are useful for treating or relieving symptoms of diseases and disorders associated with activity of potassium channels.

EFFECT: novel compounds which can be used as potassium channel modulators are obtained and described.

12 cl, 16 ex

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