Heterocyclic derivative and drug

 

(57) Abstract:

Usage: in medicine. A pharmaceutical composition comprising a compound of the following General formula:

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or its salt, where R1- thienyl, pyridyl, aryl; R2is hydrogen, alkyl, phenyl; R3and R4independently represent hydrogen or alkyl, or R3and R4taken together with the adjacent N atom represent a 6-membered heterocycle; And - alkylen C2-C6; W is a direct bond, 0, S, or (CH2)nwhere n = 1 or 2; X, Y and Z may be the same or different and each represents CH (which may be substituted by alkyl), or N, however, excluded the case in which X, Y and Z are both CH. The connection according to the invention exhibits an excellent inhibitory activity of neuronal death and may be used as therapeutic drugs for cerebrovascular diseases. 2 C. and 15 C.p. f-crystals, 1 table.

The invention relates to a heterocyclic derivative, which can be used as a medicine.

The prior art.

Vascular diseases represent such States, presleya, head injury or subarachnoid hemorrhage. As with cerebrovascular diseases blood flow to the brain is interrupted or reduced, and the brain becomes chemisorbant, nerve cells are damaged. Even if you managed to avoid the death of the patient, he or she will suffer the consequences of neuronal death caused by this damage. A therapeutic agent for cerebrovascular diseases can be divided into tools that act against cerebral infarction, hemorrhage, etc., and the funds that inhibit the specified death of neurons.

Recently it became known that after brain tissue comes in ischemic condition, even if the ischemia is transient and full recovery of regional blood flow immediately restores normal energy metabolism and neuronal activity, the end result will be the loss of nerve cells. Such pathological changes in the nerve cells that typically are found mainly in the hippocampus appear 3-4 days after ischemia and are therefore called delayed death of neurons. Moreover, even in cerebral areas not subjected to reperfusion, there C is miraut for continuing ischemia. This neuronal cell death could prevent, and the consequences of cerebrovascular disease, occurring after ischemia, can be prevented.

It is known that the amplifier cerebral metabolism, propentofylline is effective against delayed neuronal death, but partly because of its side effects it is not quite satisfactory drug.

With the aim of developing therapeutic drugs in this area, there have been many studies of the relationship of inhibitors of excitatory amino acids. This is based on the concept of prevention of ischemic neuronal death by inhibiting excessive excitation of neurons, occurring after brain ischemia. It is well known that glutamina acid or glutamate is an excitatory amino acid. As inhibitors, excitatory amino acid, now known to many antagonists of glutamate, which could specifically block receptors of this amino acid, and compounds that inhibit the release of glutamate. The glutamate receptors are divided into N-methyl-D-aspartate (hereinafter referred to as NMDA) receptors and receptors, other than the above is what for example, about YM-90K know that he is an antagonist of non-NMDA receptors. As inhibitors selection of glutamate known 2,4-diamino-5-(2,3,5-trichlorophenyl)-pyrimidine and 2,4-diamino-5-(2-chlorophenyl) pyrimidine [EP-A-459830; 6th SCI-RSC Medical Chemistry Symposium, Sept. 8-11, 1991].

Meanwhile, in WO 92/04333 described that derived phenylpyrimidine has improved activity in disorders of the functions of learning and memory and finds application in dementia. Although dementia can be affected various nervous system, it is known that lesions of the cholinergic nervous system, which plays an important role in teaching and learning, is especially dangerous. Derived phenylpyrimidine described in WO 92/04333, acts on the cholinergic nervous system and activates the residual nerve cells, which reduces the manifestation of defects in the function of learning and memory. This superior effect on the function of learning and memory is completely different from the steps consisting in the inhibition of the onset of effects of cerebrovascular diseases by inhibition of neuronal death.

In addition to the above compounds, at the present time there have been reports of a number of derivatives of pyrimidine. For example, in Japanese Examined Publication S48-21949 raskrscu activity (sedative effect, hypotension and vasodilatation). Moreover, in CA 100: 209733u and CA 106: 13483r reported that 4-[2-(N, N-dimethylamino)ethyloxy] -6-methyl (or phenyl)-2 - phenylpyrimidine and 4-[2-(N,N-dimethylamino)-ethylthio] -6-methyl (or phenyl)-2-phenylpyrimidine, respectively, have the ability to enhance the action of bleomycin (phleomycin). In addition, in J. Med. Chem. 31(6), 1231-40 (1983) it is reported that derivatives of 2-(2 - dimethylamino)ethylthio-4-methyl (or unsubstituted)-6-phenyl (or aromatic heterocyclyl) pyrimidine and derivatives of 2-[2-(N,N - dimethylamino)ethoxy]-4-thienyl-pyrimidine enhance the effect of bleomycin (bieomycin).

The aim of the present invention to provide a pharmaceutical composition having inhibitory effect on neuronal loss, and a new heterocyclic compound which is an active ingredient of the specified composition.

In order to achieve the above objectives, the present invention was synthesized and subjected to screening a series of compounds. In the process, they found that the compound of the following General formula I has a protective activity against neuronal death, which is completely different from the improved action in disorders of the functions of learning and memory, has low toxicity, and what you want to make against neuronal death, in particular, when the acute phase of cerebrovascular disorders, and thus, can be used in the treatment of cerebrovascular disorder and inhibiting the onset of its effects.

The present invention in another aspect relates to pharmaceutical compositions comprising a compound of the following General formula I

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or its salt or its MES as the active ingredient,

where R1- thienyl, pyridyl, aryl group which may be substituted by 1-3 identical or different substituents selected from the group comprising hydroxy, halogen;

R2is hydrogen, alkyl, phenyl which may be substituted, the said phenyl may be substituted by 1-3 identical or different substituents selected from the group comprising halogen, alkyl;

R3and R4may be the same or different and each represents hydrogen, alkyl, or R3and R4taken together with the adjacent N atom represent a 6-membered heterocycle, which can in addition to the N atom can contain as a ring member N, and may be substituted by one or more substituents selected from the group comprising alkyl, hydroxy, aryl, and pyridyl;

X, Y and Z may be the same or different and each represents CH, CR (where R is alkyl) or N, however, excluded the case when X, Y and Z are both CH.

In another aspect, the present invention relates to a compound of General formula Ia

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and salts thereof, including a solvate,

where R11- R14, A', E', W', X', Y' and Z' correspond to R1, R2, R3, R4, A, E, W, X, Y, and Z, respectively, in formula I, provided that the following compounds are excluded:

(a) compound, in which A' is alkalinous group of 2-3 carbon atoms, X'= Y' - N when Z' is CH or X'=Z' - N when Y' is CH, W' is a simple link, E' is O, R11is phenyl which may be substituted by hydroxy, alkoxy, trifluoromethyl or halogen, R12represents methyl, trifluoromethyl or tert-butyl;

(b) a compound in which A' is alkalinous group of 2 carbon atoms, X'= Y' - N when Z' is CH, W' represents -(CH2)2-, E' is O, R11is phenyl, and R12is stands;

(C) a compound in which A' is alkalinous group of 2 carbon atoms; ring G is a pyrimidine, W' is a simple link, E' is S, and R12is sadomania formula I has a protective activity against neuronal death in the brain (neuronal cell death), which is quite different from giving an improvement in the disorder of the function of learning and memory activity known phenyl-pyrimidine derivative (WO 92/04333), which is structurally similar to the compound according to the invention, or from - sympatholytic activity piperazine derivative described in JP Examined Publication S48-21949.

The structural characteristics of the compounds Ia are as follows: (1) the connection far in its structure from the known therapeutic agents for cerebrovascular diseases, which are based on either activity type activity of antagonists of glutama or activity, inhibiting the release of glutamate, and (2) the connection is different from the derived phenylpyrimidine described in 92/04333, the number of carbon atoms constituting alkylenes chain.

As used in the present description, the term "alkyl" denotes a linear or branched alkyl group comprising 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl or isohexyl. Particularly preferred is an alkyl group of 1-4 carbon atoms.

Aryl refers to a group and the

The Halogens include chlorine, fluorine, bromine and iodine.

Alkoxy is preferably a linear or branched group of from 1-6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentylamine, n-hexyloxy or etexilate.

Alkylene represented by a symbol And may be linear or branched. To use the compound as a therapeutic drug in cerebrovascular disease And is preferably alkalinous group of 3-6 carbon atoms and more preferably a group of 4-6 carbon atoms. With regard to chemical compounds, A' is preferably alkalinous group of 4-6 carbon atoms, E preferably represents O, W preferably represents a simple bond, X, Y and Z preferably such that X=Z - N when Y is CH, or Z - N if X=Y - CH (the first combination is particularly preferred), R1preferably represents halogen-substituted phenyl, in particular forfinal, R2preferably is alkyl or halogenation, more preferably alkyl, especially preferred is methyl.

Predpochtitelnei is a group piperidino.

The connection, which is particularly preferred in the sense that the slow death of neurons can be inhibited regardless of whether you entered it before ischemia of the brain or after it, is a compound of formula Ib

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where A21is alkylenes group of 4-6 carbon atoms;

E21represents O;

W2is a direct link;

X21=Z21- N if Y21- CH or X21=Y21- CH if Z21N;

R21represents a halogen-substituted phenyl;

R22is alkyl or halogenated.

R23and R24taken together with the adjacent N atom represent piperidine.

As a particularly preferred representatives of the above compounds here you can specify 4-(4-forfinal)-2-methyl-6-(4-piperidinyloxy)pyrimidine, 4-(4-forfinal)-2-methyl-6-(1-methyl-4-piperidinyloxy)pyrimidine, 4-(4-forfinal)-2-methyl-6-(5-piperidinyloxy)pyrimidine, 4-(4-forfinal)-2-methyl-6-(6-piperidinyloxy)pyrimidine, 2-(4-forfinal)-4-methyl-6-(4-piperidinyloxy)pyrimidine, 4-(4-forfinal)-2-methyl-6-(3-piperidinyloxy)pyridine and 4-(4-forfinal)-2-methyl-6-(5-piperidinyloxy)pyridine, including their salts.

Solwly of compound I, included in the scope of the invention includes salts with mineral acids such as chloromethane acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid and Hydrobromic acid, and salts with organic acids such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid, toluensulfonate acid, naphthalenesulfonate acid and camphorsulfonic acid.

The compound of formula I according to the present invention can be obtained, for example, in the following ways:

Method A.

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In the above reaction scheme, R1- R4And, E, X, Y, Z and W described above. Q is halogen, preferably chlorine.

Compound Ia according to the invention can be synthesized by reacting the halide II with compound III in the presence of a base in an inert towards the reaction solvent. The solvent for the reaction, which can be used include aprotic polar solvents such as N,N-dimethylformamide (DMF), aromatic hydrocarbons, is such as tetrahydrofuran, dimethoxyethane, diethyl ether, dioxane and dimethyl ether of diethylene glycol, and including mixtures of such solvents. The base, which can be used include sodium hydride, sodium amide, tert-piperonyl potassium, utility and the like. This reaction is conducted usually at 0-140oC and preferably at 10-110oC. depending on the types of reactants, solvent and base, usually is suitable reaction time average of 2-24 hours. The preferred ratio of compound III and the specified grounds are usually 1-1,2 mol/mol of compound (II)

Method B.

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In the above reaction scheme, R1- R4, A, E, X, Y, Z, W and Q above.

The compound of formula Ia can be synthesized by reacting compound IV with halide V in the presence of a base in a solvent inert to the reaction, when 0-80oC. the Solvent that can be used for carrying out the reaction include aprotic polar solvents such as acetonitrile, dimethyl sulfoxide and N,N-dimethylformamide (DMF), alcohols, such as methanol, ethanol and isopropyl alcohol, ethers such as tetrahydrofuran, dimethoxyethane, diethyl ether and dioxane, slimy such Quaid and chloroform, aromatic hydrocarbons, such as benzene, toluene and xylene, and mixtures of such solvents. The base, which can be used include sodium hydride, potassium carbonate, sodium hydroxide, potassium hydroxide, silver carbonate, and the like. Depending on the types of reagents, base and solvent, the reaction time may usually be varied from 2 to 10 hours. The preferred ratio of halide V and the specified grounds are usually 1-1,2 mol/mol of compound IV.

Method C.

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In the above reaction scheme, R1- R4And, E, X, Y, Z, W and Q are indicated previously.

The compound of formula Ia can be synthesized by reacting the halide VI with an amine VII in the presence of a base in a solvent inert to the reaction. The solvent that can be used for carrying out the reaction include aprotic polar solvents such as acetonitrile, dimethylsulfoxide, N,N-dimethylformamide (DMF) and acetone, ethers, such as tetrahydrofuran, dimethoxyethane, diethyl ether and dioxane, aromatic hydrocarbons such as benzene, toluene, xylene, etc. and mixtures of such solvents. The base, which can be used include salts of alkaline metal is such that the base can be used amine VII in excess. Depending on the types of reagents used, the base and the solvent, the reaction time may usually be varied from 2 to 20 hours. The preferred ratio of compound VII is usually 1-3 mol/mol of compound VI. The preferred ratio of the base is usually 1-1,2 mol/mol of compound VI.

Method d (a Compound in which a represents alkylenes group of 3-10 carbon atoms and which has a hydroxy group, oxo or alkoxy in-position to NR3R4).

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In the above reaction scheme, R1- R4, E, W, X, Y, Z and Q above. A1is alkylenes group of 1-8 carbon atoms which may be substituted.

Connection Id according to the invention having a hydroxyl group at the position NR3R4can be synthesized by carrying out reaction according to the method using epoxysilane VIa instead of halogen VI. This reaction proceeds in the absence of base. The ratio of amine varies depending on its type, but it usually equimolar or excessive in relation to the connection VIa.

By oxidation of the above connection Id in a solvent inert to the reaction (for example, DMSO/CC potassium, known, essentially, a way can be obtained compound containing an oxo group in the above position.

The cream also through the interaction of a connection Id with alkylhalogenide in the presence of a base such as sodium hydride or utility in a solvent inert to the reaction, can be obtained compound having in the same position alkoxygroup.

Method E. (Compound of formula I in which W is O or S).

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In the above reaction scheme, R1- R4, A, E, X, Y, Z and Q above. Wa- O or S.

Compound Ic in which W is O or S, which relates to the compounds according to the invention can be synthesized by reacting compound VIII with a compound III in the presence of a base in a solvent inert to the reaction. The solvent that can be used for carrying out the reaction include aprotic polar solvents such as N,N-dimethylformamide (DMF), ethers such as tetrahydrofuran, dimethoxyethane, diethyl ether and dioxane, and mixtures of such solvents. The base, which can be used include sodium hydride, sodium amide, tert-piperonyl potassium, utility and the like.

Reuseware and solvent, the reaction is completed usually within 2-24 hours Used the ratio of compounds VIII and compound III are preferably equimolar. The preferred ratio of the base is usually 1-1,2 mol/mol of compound VIII.

If the target compound is compound I, having the amino group or hydroxyl group, it can be obtained by carrying out, as necessary, prior protection of the source connection of the leaving group, the reaction according to any one of the above methods a to E removal of the protective group by known methods. The group, which can be used to protect the amino group includes, but is not limited to, benzyl, benzyloxy-carbonyl, TRIFLUOROACETYL and tert-butoxycarbonyl. The group, which can be used to protect the hydroxyl group includes, but is not limited to, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, tetrahydropyranyl, tert-butyl, benzyl, trimethylsilyl and tert-butyldimethylsilyl. As an illustration, the connection according to the invention having a phenolic hydroxyl group, can be obtained by use of source materials, in advance protected by benzyl, and after the reaction of removing the protective group of the catalytic Vasto in the solvent at 0-80oC. the Solvent which can be used include alcohols such as methanol, ethanol, etc., water, carboxylic acids, such as acetic acid and so on , esters such as ethyl acetate, and ethers such as dioxane and tetrahydrofuran. The catalyst, which can be used include palladium on carbon, palladium black, platinum oxide and the like. Depending on the species used source of the compound, catalyst and solvent, the preferred reaction time is usually from 30 minutes to 48 hours

Starting compound II and IV can be obtained in a known manner [WO 92/04333] as will be described later in reference examples.

The original compound VI can be obtained according to the following reaction scheme:

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In the above reaction scheme, R1, R2And, E, X, Y, Z, W and Q above.

Compound VI can be synthesized by reacting compound IX with a halide X in the presence of a base in a solvent inert to the reaction. The solvent that can be used for carrying out the reaction include aprotic polar solvents such as acetonitrile, dimethyl sulfoxide and N,N-dimethylformamide (DMF), a simple e as benzene, toluene and xylene, and mixtures of such solvents. The base, which can be used include silver carbonate, potassium carbonate, sodium carbonate, sodium hydride, sodium hydroxide and potassium hydroxide. The reaction is carried out at 20-160oC, preferably 70-120oC. depending on the types of reagents used, the base and the solvent, the reaction time may appropriately be 5-60 including the Preferred ratio of the halide X is usually 1-4 mol/mol of compound IX. The preferred ratio of the base is 0.5 to 1.2 mol/mol of compound IX

Source epoxysilane VIa can be obtained according to the following reaction scheme.

(Stage 1).

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(Stage 2).

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In the above reaction scheme, R1, R2, A1E, X, Y, Z, W and Q are defined as previously indicated.

(Stage 1). Compound XII may be synthesized by reacting compound IV with halide XI in the presence of a base in a solvent inert to the reaction. This reaction can be carried out in the same conditions as the above method of obtaining VI. The preferred ratio of halide XI is usually 1-3 mol/mol of compound IV.

(The bed in the solvent, inert to the reaction. The solvent that can be used for the reaction includes halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform, ethers, such as tetrahydrofuran, dimethoxyethane, diethyl ether and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, and mixtures of such solvents. The oxidant, which can be used includes, but is not limited to, organic nagkalat, such as natantia acid, m-chlormadinone acid, peracetic acid and monoatomically acid; hydrogen peroxide; tert-butylhydroperoxide. The amount of oxidizing agent varies depending on its type, but is preferably 1-2 mol/mol of compound XII. This reaction is carried out at 0-50oC, preferably 10-30oC. depending on the species used source of the compound and the oxidizing agent and solvent, the reaction time may usually be varied from 2 to 24 hours

The original compound VIII can be obtained in accordance with the following reaction scheme:

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In the reaction scheme R1-R2X, Y, Z, Waand Q are defined as previously indicated.

Compound VIII can be synthesized by the reaction. This reaction can be carried out in the same conditions as the above reaction receiving Ia.

The preferred ratio of compound XIV is 2-2,5 mol/mol of halide XIII.

Compound I according to the present invention can be processed by nagkalat known, essentially, a way of obtaining oxide.

In the case when some representatives of the compounds according to the invention contain an asymmetric carbon, the respective optical isomers and racemic mixtures are also within the scope of the invention. Thus, the racemic compound, synthesized by any of the above methods can be divided into optical isomers by standard methods of separation of optical isomers using its basicity, i.e. using a chiral acid (such as tartaric acid, dibenzoyltartaric acid, almond acid, 10-camphorsulfonic acid), or optical isomers can be, respectively, synthesized by using optically active compounds obtained in advance (for example, 1,2-epoxypropane), as the starting material.

Compound I according to the present invention can be converted to the above is the link I in ethanol solution of hydrogen chloride.

Among the compounds I according to the present invention, any compound containing a carboxyl group can be converted into an appropriate salt by known process. Here salt includes alkali metal salts such as sodium salt and potassium salt, and salts of alkaline-earth metals such as calcium salt. For example, salt of compound I according to the invention with the alkaline metal can be obtained by adding one equivalent of sodium hydroxide, potassium hydroxide or the like for containing the carboxyl group of the compound I according to the invention, preferably in an alcohol solvent. Salt of compound I according to the invention with alkaline-earth metal can be obtained by dissolving the above-mentioned salts with alkali metal, for example, water, methanol or ethanol or mixtures thereof, and adding one equivalent, such as calcium chloride.

MES (including hydrate) of compound I or its salt according to the invention is also included in the scope of the present invention. MES can usually be obtained by recrystallization of the compound from the matching of a suitable solvent or mixed solvent containing the corresponding races is lisali of compound I of the water-containing alcohol.

Compound I according to the present invention may be crystalline polymorphism. Polymorphic forms in such cases are also included in the scope of the invention.

Thus obtained target compound I can be isolated and purified in the form of a free base or as an acid additive salt is known, essentially, methods such as concentration, determination of pH, phase transfer, solvent extraction, crystallization, fractional distillation and chromatography.

The connection according to the present invention can be used as therapeutic drugs for cerebrovascular disease or as a drug for the inhibition of the onset of effects of cerebrovascular diseases.

When used as a drug compound according to the present invention can be administered to animals, including humans, either in the form of the actual connection, as it is or as a pharmaceutical composition containing, for example, from 0.01 to 99.5%, preferably 0.5 to 90% of the compound in pharmaceutically acceptable, non-toxic, inert carrier.

As the carrier may apply is DSTV for the formulation. The pharmaceutical composition is preferably introduced in the form of standard dosage. The pharmaceutical composition according to the present invention can be administered orally, parenterally (e.g. intravenously), locally (e.g., percutaneous) or rectally. Of course, the form of dosage for the respective routes of administration must be different. Especially preferred is intravenous or oral administration.

The dosage of therapeutic drugs against cerebrovascular disease set taking into account the patient's age, body weight and other factors, routes of administration, nature and severity of the disease, and so on, But the daily dose in oral administration for adults can usually be changed from 0.1 mg to 1 g per patient, and preferably from 1 mg to 300 mg per patient. In the case of intravenous administration the usual daily dose is 0.01 mg to 100 mg per patient and preferably 0.1 to 30 mg per patient. In some cases it may be enough to lower dosage levels, while in other cases, you might need a higher dose. The above dosage may preferably be entered in the x forms a standard dosage, such as no powders, powders, tablets, coated tablets, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets, etc.

No powders can be produced by grinding into a powder of the active substance until finely ground form. Powders can be obtained by grinding into a powder of the active substance to powdered form and mix it with crushed similarly pharmaceutical carrier, for example, with food carbohydrate, such as starch or mannitol. If necessary, can be added in corrigent, preservative, dispersant, colorant, odorant, etc.

Capsules can be made by filling in the shells of capsules, such as gelatin shell of the capsule, these fine no powders or powders, or granules, are described below for tablets. Before the operation of filling with powders can be mixed grease or fluidizing agent, such as colloidal silicon dioxide, talc, magnesium stearate, calcium stearate or solid polyethylene glycol. Can be expected to improve the effectiveness of a drug after oral administration in the case of adding baking powder or solubili with a low degree of substitution, sodium salt croscarmellose, sodium salt of carboxymethyl amylum, calcium carbonate or sodium carbonate.

Soft capsules can be obtained by suspension of these fine powders in vegetable oil, polyethylene glycol, glycerin or a surface-active substance and conclusions of the suspension in gelatin shell. Tablets can be obtained by adding excipients to these powders, granulation or clumping of the mixture, add baking powder and/or lubricants and crushing of the entire composition. Powdery mixture can be obtained by mixing the above fine powders with the specified diluent or base. In those cases, when necessary, can be added binder (for example, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl-methylcellulose, gelatin, polyvinyl pyrrolidone, polyvinyl alcohol and so on), the moderator of dissolution (e.g., paraffin), agent for re-absorption (for example, Quaternary salts) and the adsorbent (for example, bentonite, kaolin, dicalcium phosphate and so on). Powdery mixture can be processed into granules by wetting her binder such as syrup, krahmalosushilnye mixture, drying this mixture and rubbing. Instead of granulation such powders can be compressed powders using a tablet press machines and to break up the formed lumps of semi-finished product to obtain granules. The resulting granules can be protected from clumping with each other by adding lubricants, such as stearic acid, a salt of stearic acid, talc or mineral oil. Greased so the mixture is then pressed. The resulting tablets without coating can be covered with the composition, giving the film coating, or composition, giving the sugar coating.

The connection according to the invention can be mixed with granular inert carrier, and the mixture can be directly pressed without having to resort to the above process of granulation or clumping. Can also be applied to a transparent or translucent protective covering consisting, for example, from the hermetic coating of shellac, sugar or polymeric coating, or a coating of polishing wax. Other oral compositions, such as mortar, syrup and elixir can also be produced in a standard dosage forms, each containing determined by dissolving the compounds in a suitable flavored water while elixirs can be made using non-toxic alcoholic media. A suspension can be obtained by dispersing the compounds in a non-toxic carriers. In those cases, when necessary, can also be added soljubilizatory and emulsifying agents (e.g. ethoxylated isostearoyl alcohol, ester (polyoxyethylene) sorbitan, and so on), preservatives and flavorings (for example, peppermint oil, saccharin, and so on).

If necessary, the composition with the standard dosage for oral administration may be microcapsulated. This composition can be coated or encased in a polymer, wax or other matrix to provide a prolonged action or long allocation dosage dosage forms.

Parenteral administration can be carried out using liquid forms the standard dosage for subcutaneous, intramuscular or intravenous injection, for example, solutions and suspensions. Such a standard dosage forms can be obtained by suspension or dissolution of a predetermined number of compounds according to the invention is suitable for injection of non-toxic liquid carrier, such as water n the particular injection can be added non-toxic salt or salt solution. In addition, can also be added stabilizers, preservatives, emulsifiers, etc.

Rectal administration can be carried out using suppositories manufactured by dissolution or suspension of the compound in a low-melting water-soluble or water-insoluble solid carrier, such as polyethylene glycol, cocoa butter, semi-synthetic oil (e.g., Witerspol), the highest ether (for example, ministervalletta) or their mixture.

The toxicity of the compounds according to the invention is extremely low, as will be described below.

The following reference examples and examples of the preparation of the compounds according to the invention, and examples of tests using some of the representative compounds according to the invention are intended to further illustrate the present invention.

Reference example 1. 4-(4-Forfinal)-6-hydroxy-2-methylpyrimidin.

(Stage 1). To 1.3 l of dry tetrahydrofuran (THF) was added 162 g of 60% sodium hydride (NaH) and 342 g of diethylmalonate. To this mixture was added dropwise a solution of 200 g of p-fortetienne in 440 ml of anhydrous THF for about 1 h under reflux, then within 6 who was alitwala of concentrated hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate (MgSO4) and was evaporated. The residue was distilled under reduced pressure to obtain 291 g of ethyl(3-(4-forfinal)-3 - oxopropionate) as a pale yellow oil.

Tpl.145-150oC (5 mm RT.article or 667 PA).

(Stage 2). A mixture of 145 g of ethyl (3-(4-forfinal)-3-oxo - propionate), and 97.8 g of the hydrochloride of acetamidine, 191 g of powdered potassium carbonate and 1,16 l of ethanol was stirred at 60-70oC for 16 hours the reaction mixture was filtered to remove nerastvorim part, and the filtrate was evaporated. To the residue was added water and the resulting product was neutralized with acetic acid. Emitted when the crystals were collected by filtration, washed with water and dried to obtain 88,7 g specified in the title compound as white crystals. TPL290-292oC (decomp.).

In the same way as described above, were synthesized the following compounds: 4-(2-chlorophenyl)-6-hydroxy-2-methylpyrimidine, 4-(2,4-dichlorophenyl)-6-hydroxy-2-methylpyrimidin, TPL271-274oC; 2,5-dimethyl-4-(4-forfinal)-6-hydroxypyrimidine, TPL242-243oC; 4-(4-forfinal)-6-hydroxy-5-methylpyrimidin, TPL228 - 229oC.

pyrimidine was added 63 ml of phosphorus oxychloride and the mixture was heated under reflux 5 for 1 hours The reaction mixture was cooled, poured into ice water and neutralized 28% aqueous ammonia and released when the crystals were collected by filtration. The crystals were washed with water and dried to obtain 21 g specified in the connection header.

TPL95-98oC.

In the same way as described above, were synthesized the following compounds: 4-chloro-6-(2-chlorophenyl)-2-methylpyrimidin, TPL88-90oC; 4-chloro-6-(2,4-dichlorophenyl)-2-methylpyrimidin, TPL104-105oC; 4-chloro-2,5-dimethyl-6-(4-forfinal)pyrimidine, TPL110-113oC; 4-chloro-6-(2-forfinal)-5-methylpyrimidin, TPL88-90oC.

Reference example 3. 4-(4-Chloroethoxy)-2-(4 - forfinal)-6-methylpyridin.

A mixture of 2.5 g of 2-(4-forfinal)-4-hydroxy-6-methylpyridine, and 3.16 g of 1-bromo-4-chlorobutane, 1.7 g of silver carbonate and 100 ml of toluene was heated under reflux for 40 hours the reaction mixture was filtered to remove nerastvorim part, and the filtrate was evaporated. The residue was purified using column chromatography on silica gel to obtain 1.45 g specified in the connection header.

TPL59-61oC.

Reference example 4. 4-(4-Forfinal)-2-hydroxy-6 - meilani acid was heated under reflux for 20 hours The reaction mixture was cooled, poured into an ox with ice, podslushivaet using aqueous potassium carbonate solution and neutralized with acetic acid. Emitted when the crystals were collected by filtration, washed with isopropyl ether and dried to obtain 2.65 g of pale yellow crystals. TPL265-268oC.

Reference example 5. 4,6-bis(4-Pertenece)-2 - methylpyrimidin,

In a mixture of solvents consisting of 13 ml of THF and 2.7 ml of DMF was dissolved 448 mg of 4-terfenol and while stirring the solution at room temperature was added in small portions 160 mg of 60% NaH. The mixture was further stirred at the same temperature for 30 minutes Then added 326 mg of 4,6-dichloro-2-methylpyrimidine and the mixture was stirred further at room temperature for 12 hours the reaction mixture was poured into ice water and was extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4and evaporated under reduced pressure. The remainder, 700 mg, was purified using column chromatography on silica gel (WakogelTMC-200, n-hexane - ethyl acetate = 9: 1) and recrystallized from n-hexane to obtain 461 mg of white crystals. TPL93-97oC.

Similarly, the 34-136oC.

Reference example 6. 4-(4, 5-Epoxidations)-6- (4-forfinal)-2-methylpyrimidin.

(Stage 1). A mixture of 2 g of 4-(4-forfinal)-6-hydroxy-2-methylpyrimidine obtained in reference example 1, 2.8 g of 5-bromo-1 - pentene, 1.5 g of silver carbonate and 80 ml of toluene was heated under reflux for 22 hours the reaction mixture was filtered to remove nerastvorim part, and the filtrate was evaporated. The residue was purified using column chromatography on silica gel to obtain 370 mg of 4-(4-forfinal)-2-methyl-6-(4 - pentenyl)pyrimidine as white crystals. TPLof 44.5 and 45.5oC.

(Stage 2). In 5 ml of methylene chloride was dissolved 350 mg of 4-(4 - forfinal)-2-methyl-6-(4-pentenyl)pyrimidine. To this solution in a bath of a mixture of ice water was added under stirring 217 mg, 70% chloroperbenzoic acid. Then the mixture was stirred at room temperature for 18 h thus Obtained reaction mixture was evaporated and to the residue was added n-hexane and ethyl acetate. The mixture is washed four times with an aqueous solution of sodium bicarbonate, and then washed with water, dried over MgSO4and was evaporated. The residue was purified using column chromatography on silica gel to obtain 160 mg okasankaar-4-methyl-6-phenyl-1,3,5-triazine.

(Stage 1). To 50 g of 2,4,6-trichloro-1,3,5-triazine was added 300 ml of anhydrous tetrahydrofuran, and with stirring the mixture at room temperature for approximately 30 min was added dropwise 150 ml of 2 M solution of phenylmagnesium in tetrahydrofuran. After completion of adding dropwise, the mixture was stirred at room temperature for 1 h and then evaporated. To the residue was added ice water and the resulting product was extracted with ether. The extract was washed with water, dried over MgSO4and was evaporated. The resulting mass of crystals was recrystallized from isopropyl alcohol to obtain 21.1 g of 2,4-dichloro-6-phenyl - 1,3,5-triazine as pale yellow crystals.

(Stage 2). In 85 ml of anhydrous tetrahydrofuran was dissolved 17 g of 2,4-dichloro-6-phenyl-1,3,5-triazine. To this solution in a bath of ice water in the space of about 30 minutes was added dropwise 135 ml of 1 M solution methylacrylamide in tetrahydrofuran. After completion of adding dropwise, the mixture was stirred at room temperature for 2 hours the reaction mixture was poured into ice water and was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4and was evaporated. The residue was purified by colons.

Reference example 8. 2-Benzyloxyphenyl-4-hydroxy-6 - methylpyrimidin.

(Stage 1). In 200 ml of methanol added 23 g of 4-benzyloxybenzoate and barbotirovany gaseous hydrogen chloride through the suspension in a bath of a mixture of ice water for about 1 hour then the mixture was stirred at room temperature for 2 h and then at room temperature for 1.5 hours To the obtained reaction mixture was added ether and released when the crystals were collected by filtration to obtain 28 g of white crystals. These crystals are suspended in 200 ml of methanol and the bath of a mixture of ice water was barbotirovany through the suspension of gaseous ammonia for about 1 hour Then the mixture was stirred at room temperature for 15 h the reaction mixture was evaporated and to the residue was added ethyl acetate. Emitted when the crystals were collected by filtration and dried to obtain a 21.6 g of the hydrochloride of 4-benzyloxybenzaldehyde in the form of white crystals.

(Stage 2). A mixture of 12 g of the hydrochloride of 4-benzyloxy-benzamidine, 6.3 g of ethylacetoacetate, of 13.9 g of potassium carbonate and 144 ml of ethanol was heated under reflux for 24 hours the reaction mixture was filtered to UDA is ovali acetic acid. Emitted when the crystals were collected by filtration, washed with water and dried to obtain 12.0 g specified in the title compound as white crystals.

Example 1. The hydrochloride of 4-(4-forfinal)-2-methyl-6-(5 - piperidinyloxy)pyrimidine.

To a mixture of solvents consisting of 155 ml of anhydrous THF and 33 ml of anhydrous DMF, was added 3,59 g of 60% sodium hydride (NaH) and stirring the mixture at room temperature, was added 7,06 g 5-piperidino-1-pentanol. The mixture was further stirred for 10 minutes Then added 10 g of 4-chloro-6-(4 - forfinal)-2-methylpyrimidine and the mixture was stirred at room temperature for 20 hours the reaction mixture was poured into ice water and was extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4and was evaporated. The residue was purified using column chromatography on silica gel (WakogelTMC-200, chloroform containing 1% methanol) to give a pale yellow oil. This oil was dissolved in methanol and the pH of the solution was brought to 5 with the aid of 1H. HCl and the solution was evaporated.

To the residue was added ether and released when the crystals were collected by filtration. The resulting mass of crystals was recrystallized and the>C.

Elemental analysis for C21H28FN3O HCl:

Calculated (%): 64,03; H 7,42; N 10,67.

Found (%): 63,82; H 7,39; N 10,70.

Crystals of type II:

TPL182-184oC.

Elemental analysis for C21H28FN3O HCl:

Calculated (%): C 64,03; H 7,42; N 10,67.

Found (%): C 63,80; H 7,38; N A 10.74.

In the same manner as in example 1, were synthesized the following compounds.

Example 2. The hydrochloride of 4-(4-forfinal)-2-methyl-6-(4-piperidino - butoxy)pyrimidine.

TPL174-176oC.

Elemental analysis for C20H26FN3O HCl:

Calculated (%): C 63,23; H 7,16; N 11,06.

Found (%): C 62,83; H Of 7.23; N Br11.01.

Example 3. The hydrochloride of 4-(4-forfinal)-2-methyl-6-(6 - piperidinyloxy)pyrimidine.

TPLto 190.5-192oC.

Elemental analysis for C22H30FN3O HCl:

Calculated (%): 64,77; H 7,66; N 10,30.

Found (%): C 64,49; H 7,66; N 10,48.

Example 4. Hydrochloride of 2-(4-forfinal)-4-methyl-6-(4 - piperidinyloxy)pyrimidine.

TPL168-172oC.

Elemental analysis for C20H26FN3O HCl:

Calculated (%): C 63,23; H 6,90; N 11,06.

Found (%): C 63,10;>/P>TPL184-185oC.

Elemental analysis for C21H28FN3O HCl:

Calculated (%): C 64,03; H 7,42; N 10,67.

Found (%): C 63,80; H 7,52; N Or 10.60.

Example 6. The hydrochloride of 4-(2-chlorophenyl)-2-methyl-6-(4 - piperidinyloxy)pyrimidine.

TPL147-149oC.

Elemental analysis for C20H26ClN3O HCl:

Calculated (%): 60,01; H 6,87; N Or 10.60.

Found (%): C 60,43; H 7,05; N 10,80.

Example 7. The hydrochloride of 4-(2,4-dichlorophenyl)-2-methyl-6-(4 - piperidinyloxy)pyrimidine.

TPL144-146oC.

Elemental analysis for C20H25ClN3O HCl:

Calculated (%): C 55,76; H Between 6.08; N 9,75.

Found (%): C 55,40; H 6,21; N 9,74.

Example 8. The hydrochloride of 4-(4-forfinal)-2-methyl-6- [4-(4-phenylpiperidine)butoxy)]pyrimidine.

TPL169-171oC.

Elemental analysis for C26H30FN3O HCl:

Calculated (%): C 68,48; H 6,85; N Of 9.21.

Found (%): C 68,20; H 7,01; N 9,27.

Example 9. Hydrochloride of 2-(4-forfinal)-4-methyl-6-[4-(4 - phenylpiperidine)butoxy)]pyrimidine.

TPL148-153oC.

Elemental analysis for C26H30FN3O HCl:

Calculated (%): C 68,48; H 6,85; N Of 9.21.

Neid is A.

After carrying out reaction according to the same method described in example 1, indicated in the title compound was obtained by use of a solution of maleic acid in ethanol.

TPL218oC (decomp.).

Elemental analysis for C25H29FN4O C4H4O4:

Calculated (%): C 64,91; H 6,20; N 10,44.

Found (%): C 64,93; H 6,24; N 10,32.

In the same manner as in example 1 or 11, were synthesized the following compounds.

Example 11. Maleate 2-(4-forfinal)-4-methyl-6-[4-(4-phenylpiperazine) butoxy]pyrimidine.

TPL155-156oC.

Elemental analysis for C25H29FN4O C4H4O4:

Calculated (%): 64,91; H 6,20; N 10,44.

Found (%): C 64,81; H 6,29; N 10,48.

Example 12. The hydrochloride of 2,4-bis-(4-forfinal)-6-(4-piperidinyloxy) pyrimidine.

TPL207-208,5oC.

Elemental analysis for C25H27F2N3O HCl:

Calculated (%): C 65,28; H 6,14; N 9,14.

Found (%): C 65,05; H Of 6.26; N Remaining 9.08.

Example 13. The hydrochloride of 2,4-bis-(4-forfinal)-6- (4-piperidinyloxy)pyrimidine.

TPL196-198,5oC.

Elemental analysis for C25H27 the measures 14. The hydrochloride of 4-(4-hydroxyphenyl)-2-methyl-6-[4-(4-phenyl - piperidino)butoxy)]pyrimidine.

Using 4-(4-phenylpiperidine)-1-butanol and 6-(4 - benzyloxyphenyl)-4-chloro-2-methylpyrimidin, but otherwise followed the method of reference example 25, which is given below, with the receipt specified in the connection header. TPL182-183oC.

Elemental analysis for C26H31N3O2HCl:

Calculated (%): C 68,78; H 7,10; N 9,26.

Found (%): C 68,58; H Of 6.96; N 8,99.

Example 15. Hydrochloride of 2-(4-forfinal)-4-(4 - piperidinyloxy)-6-methylpyridine.

A mixture of 1.45 g of 4-(4-chloroethoxy)-2-(4-forfinal)-6 - methylpyridine obtained in reference example 3, 1.26 g of piperidine and 12 ml of DMF was stirred at 100oC for 1.5 h the reaction mixture was cooled, poured into ice water and was extracted with ethyl acetate. The organic layer was washed several times with an aqueous solution of sodium chloride, dried over MgSO4and then was evaporated. The residue was purified using column chromatography on silica gel to obtain 1.2 g of the target compound in the form of oil. This oil was dissolved in methanol and the pH of the solution was brought to 5 with a 3.5 ml of 1N. HCl and the solution was evaporated. To the precipitate was added ether and the resulting cu obtaining 1,02 g specified in the title compound as white crystals. TPL164-166oC.

Elemental analysis for C21H27FN2O HCl:

Calculated (%): C 66,57; H 7,45; N 7,39.

Found (%): C 66,21; H 7,45; N 7,09.

In the same manner as in example 15, were synthesized the following compounds.

Example 16. The hydrochloride of 4-(4-forfinal)-2-methyl-6- (3-piperidinyloxy)pyridine.

TPL135oC.

Elemental analysis for C20H25FN2O HCl:

Calculated (%): C 65,83; H 7,18; N 7,68.

Found (%): C 65,40; H 7,24; N 7,44.

Example 17. The hydrochloride of 4-(4-forfinal)-2-methyl-6- (4-piperidinyloxy)pyridine.

TPL148,5-150,5oC.

Elemental analysis for C21H27FN2O HCl:

Calculated (%): C 66,57; H 7,45; N 7,39.

Found (%): C 66,54; H EUR 7.57; N 7,41.

Example 18. The hydrochloride of 4-(4-forfinal)-2-methyl-6- (5-piperidinyloxy)pyridine.

TPL138-140oC.

Elemental analysis for C22H29FN2O HCl:

Calculated (%): C 67,25; H Of 7.70; N 7,13.

Found (%): C 67,00; H Of 7.68; N 6,95.

Example 19. The hydrochloride of 2,4-bis-(4-forfinal)-6-(4 - piperidinyloxy)pyridine.

TPL219-220,5oC.

Elemental analysis for C26H28Fhydrochloride 2,4-bis-(4-forfinal)-6- (5-piperidinyloxy)pyridine.

TPL165-166,5oC.

Elemental analysis for C27H30F2N2O HCl:

Calculated (%): C 68,56; H Is 6.61; N Of 5.92.

Found (%): C 68,57; H 6,74; N 5,99.

In the same manner as in example 1 was synthesized by following the link.

Example 21. The hydrochloride of 4-(4-forfinal)-2-methyl-6- (1-methyl-4-piperidinyloxy) pyrimidine.

TPL146oC.

Elemental analysis for C21H28FN3O HCl:

Calculated (%): C 64,03; H 7,42; N 10,67.

Found (%): C 63,90; H 7,44; N 10,42.

Example 22. The hydrochloride of 4-(4-forfinal)-6-[5-(4-hydroxypiperidine) pentyloxy)]-2-methylpyrimidine.

A mixture of 4 g of 4-(4-forfinal)-6-hydroxy-2-methylpyrimidine obtained in reference example 1, 13.5 g of 1,5-dibromethane, 2,97 g of silver carbonate and 160 ml of toluene was heated under reflux for 50 hours. The reaction mixture was filtered to remove the insoluble portion, and the filtrate was evaporated. The residue was purified using column chromatography on silica gel to obtain 2.6 g of colorless oil. To 800 mg of this oil was added 275 mg of 4-hydroxypiperidine and 468 mg of potassium carbonate and 8 ml of acetonitrile, and the mixture was stirred at room temperature for the Wali aqueous solution of sodium chloride, dried over MgSO4and was evaporated. The residue was purified using column chromatography on silica gel to obtain 600 mg of oil. This oil was dissolved in methanol and the pH of the solution was brought to 5 by means of 1.61 ml of 1N. HCl and the solution was evaporated. To the precipitate was added isopropyl ether and the crystals formed were collected by filtration and recrystallized from a mixture of acetonitrile-isopropyl ether to obtain 559 mg specified in the title compound as white crystals.

TPL167-169,5oC.

Elemental analysis for C21H28FN3O2HCl:

Calculated (%): C 61,53; H 7,13; N Of 10.25.

Found (%): C 61,42; H To 7.09; N 10,47.

Example 23. The hydrochloride of 4 -(4-forfinal)-6-(4 - hydroxy-5-piperidinyloxy)-2-methylpyrimidine.

A mixture of 160 mg of 4-(4,5-epoxidations)-6-(4-forfinal)-2 - methylpyrimidine obtained in reference example 6, 140 mg of piperidine and 3 ml of acetonitrile was stirred at 80oC for 20 h the reaction mixture was cooled and then poured into a mixture of ice water and was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, dried over MgSO4and was evaporated. The residue was purified using column chromatography on a silica compound and the solution was evaporated. To the precipitate was added isopropyl ether and the resulting crystalline mass was collected by filtration and recrystallized from acetonitrile to obtain 121 mg specified in the title compound as white crystals. TPL149-150,5oC.

Elemental analysis for C21H28FN3O2HCl:

Calculated (%): C 61,53; H 7,13; N Of 10.25.

Found (%): C 61,36; H 7,06; N Of 10.25.

In the same manner as in example 1, were synthesized the following compounds.

Example 24. Hydrochloride 4-[5-(N,N-diethylamino) pentyloxy]-6-(4-forfinal)-2-methylpyrimidine.

TPL134,5 to 136.5oC.

Elemental analysis for C20H28FN3O HCl 1/4 H2O:

Calculated (%): 62,17; H Of 7.69; N 10,87.

Found (%): C 62,15; H Of 7.68; N 10,84.

Example 25 Hydrochloride of 2-methyl-4-(5-piperidinomethyl)-6-(2-thienyl)pyrimidine.

TPL192.5 kg-194,0oC.

Elemental analysis for C19H27N3OS HCl:

Calculated (%): C 59,75; H 7,39; N 11,00.

Found (%): C 59,35; H 7,32; N 10,98.

Example 26. Hydrochloride of 2-methyl-4-(5 - piperidinomethyl)-6-(pyridin-4-yl)pyrimidine.

TPL178,5-179,5oC.

Elemental analysis for CTimer 27. The hydrochloride of 4-(4-forfinal)-6-methyl-2- (5-piperidinyloxy)pyrimidine.

Using 4-(4-forfinal)-2-hydroxy-6-methylpyrimidin obtained in reference example 4, but otherwise used the method of example 22 to obtain specified in the connection header. TPL173.5 metric-175,0oC.

Elemental analysis for C21H28FN3O HCl:

Calculated (%): C 64,03; H 7,42; N 10,67.

Found (%): C 63,85; H Of 7.48; N 10,82.

In the same manner as in example 27, were synthesized the following compounds.

Example 28. The hydrochloride of 4-(4-forfinal)-6-methyl-2- (5-piperidinomethyl)pyrimidine.

TPL156-158oC.

Elemental analysis for C21H28FN3S HCl 1/4H2O:

Calculated (%): C 60,85; H 7,17; N 10,14.

Found (%): C 60,80; H 7,05; N 10,02.

In the same manner as in example 1 was synthesized by following the link.

Example 29. The hydrochloride of 4-(4-forfinal)-2-methyl-6-(3-piperidinophenyl)pyrimidine.

TPL192-194oC.

Elemental analysis for C19H24FN3S HCl 1/4H2O:

Calculated (%): 59,05; H 6,59; N 10,87.

Found (%): C 58,96; H Is 6.54; N 10,79.

Example 30. The hydrochloride of 4 -(4-forfinal)-6-methyl-2-(who was jiroveci 51 mg of 60% NaH. While this suspension was stirred at room temperature, was added 218 mg 5-piperidino-1-pentanol and the mixture was stirred at room temperature for 30 minutes and Then thereto was added 400 mg of 2,4-bis-(4-pertenece)-2-methylpyrimidine obtained in reference example 5, and the mixture was stirred at room temperature for 18 hours the reaction mixture was poured into ice water and was extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4and evaporated under reduced pressure. As a result of this received 600 mg of oily residue. This oil was purified using column chromatography on silica gel [WakogelTMC-200, chloroform ---> chloroform-methanol (25:1)] to obtain 200 mg of a light yellow oil. 190 mg of this oil was dissolved in methanol and the pH of the solution was brought to 5 by using 0.5 ml of 1N. HCl and the solution was evaporated under reduced pressure. To the residue was added ether and the resulting crystals were collected by filtration. The resulting crystalline mass was washed with ether and recrystallized from acetone to obtain 137 mg specified in the title compound as white crystals.

TPL164-165oC.

Elemental analysis 10,26.

Example 31. The hydrochloride of 4-(4-forfinally)-2-methyl-6-(5-piperidinyloxy)pyrimidine.

Using 4,6-bis(4-forfinally)-2-methylpyrimidin obtained in the same manner as in reference example 5, but otherwise used the method of example 30 with obtaining specified in the title compound as light yellow crystals. TPL127-131oC (recrystallization from a mixture of acetone/ether).

Elemental analysis for C21H28FN3OS HCl 1/2H2O:

Calculated (%): C 57,98; H 6,72; N 9,66.

Found (%): C 58,03; H 6,86; N 9,62.

In the same manner as in example 1, were synthesized the following compounds.

Example 32. The hydrochloride of 4-(4-terbisil)-2-methyl-6- (5-piperidinyloxy)pyrimidine.

TPL109-115oC.

Elemental analysis for C22H30FN3O HCl H2O:

Calculated (%): C 62,03; H 7,81; N 9,86.

Found (%): C 62,30; H 8,10; N 9,94.

Example 33. Hydrochloride of 2-methyl-4-phenethyl-6-(5 - piperidinyloxy)pyrimidine.

TPL128-130oC.

Elemental analysis for C23H33N3O HCl 1/2H2O:

Calculated (%): C 66,89; H 8,54; N 10,17.

Found (%): C 66,83; H 8,35; N 10,17.

Example 34. Gidropony analysis for C21H28FN3O HCl:

Calculated (%): C 64,03; H 7,42; N 10,67.

Found (%): C 63,86; H 7,30; N 10,61.

Example 35. The hydrochloride of 4-(4-forfinal)-5-methyl-6-(4-piperidinyloxy)pyrimidine.

TPL146-149oC.

Elemental analysis for C20H26FN3O HCl:

Calculated (%): C 63,23; H 7,16; N 11,06.

Found (%): C 63,01; H 7,10; N 11,08.

Example 36. Hydrochloride of 2-methyl-4-phenyl-6-(4 - piperidinyloxy)-1,3,5-triazine.

TPL177-178oC.

Elemental analysis for C19H26N4O HCl:

Calculated (%): C 62,88; H 7,50; N 15,44.

Found (%): C 62,55; H Of 7.68; N 15,28.

Example 37. Hydrochloride of 2-methyl-4-phenyl-6-(3-piperidinyloxy)- 1,3,5-triazine.

TPL175-178oC.

Elemental analysis for C18H24N4O HCl:

Calculated (%): C 61,97; H 7,22; N 16,06.

Found (%): C 61,87; H 7,41; N 16,14.

Example 38. Maleate 2-(4-chlorophenyl)-4-methyl-6-(3-piperidinyloxy)- 1,3,5-triazine.

TPL125-128oC.

Elemental analysis for C18H23ClN4O C4H4O41/4H2O:

Calculated (%): C 56,53; H To 5.93; N 11,99.

Found (%): C 56,22; N 6,07; N 12,01.

Example 39. Hydrochloride 2-Manny analysis for C24H28N4O HCl 1/2H2O:

Calculated (%): C 66,58; H Of 6.75; N 12,94.

Found (%): C 66,56; H 7,15; N 13,30.

Example 40. Hydrochloride of 2-methyl-4-(2-naphthyl)-6-(4-piperidinyloxy) pyrimidine.

TPL174-175oC.

Elemental analysis for C24H29N3O HCl:

Calculated (%): C 69,97; H 7,34; N 10,20.

Found (%): C 69,80; H 7,20; N Of 10.21.

Examples of preparing compounds of formula I are presented below. In cases where methods are not particularly described, followed the method of example 1.

Reference example 9. The hydrochloride of 4-(4-forfinal)-2 - methyl-6-(2-piperidinoethyl)-pyrimidine.

TPL198-199oC.

Elemental analysis for C18H22FN3O HCl:

Calculated (%): C 61,45; H 6,59; N 11,94.

Found (%): C 61,23; H Is 6.78; N 11,74.

Reference example 10. The hydrochloride of 4-(4-forfinal)-2-methyl-6-(3-piperidinyloxy)pyrimidine.

TPL195,5-197oC.

Elemental analysis for C19H24FN3O HCl:

Calculated (%): C 62,37; H 6,89; N 11,48.

Found (%): C 62,00; H 7,03; N 11,13

Reference example 11. Hydrochloride of 2-(4-forfinal)-4 - methyl-6-(2-piperidinoethyl)pyrimidine.

TPL216-218oC.

E is 1,10; H IS 6.78; N 11,63.

Reference example 12. Hydrochloride of 2-(4-forfinal)-4-methyl-6- (3-piperidinyloxy)pyrimidine.

TPL205-206,5oC.

Elemental analysis for C19H24FN3O HCl:

Calculated (%): C 62,37; H 6,89; N 11,48.

Found (%): C 62,01; H 6,99; N 11,47.

Reference example 13. Hydrochloride of 2-(4-chlorophenyl)-4-methyl-6- (3-piperidinyloxy)pyrimidine.

TPL212-214oC.

Elemental analysis for C19H24ClN3O HCl:

Calculated (%): C 59,69; H 6,59; N 10,99.

Found (%): C 59,23; H 6,53; N 10,80.

Reference example 14. The hydrochloride of 4-(4-forfinal)-2 - methyl-6-[2-(4-phenylpiperidine)ethoxy]pyrimidine.

TPL184-186oC.

Elemental analysis for C24H26FN3O HCl:

Calculated (%): C 67,36; H 6,36; N 9,82.

Found (%): C 67,10; H Of 6.73; N 9,78.

Reference example 15. The hydrochloride of 4-(4-forfinal)-2-methyl-6-[3-(4-phenylpiperidine)propoxy]pyrimidine.

TPL169-171oC.

Elemental analysis for C25H28FN3O HCl:

Calculated (%): C 68,09; H 6,40; N At 9.53.

Found (%): C 67,80; H 6,60; N 9,31.

Reference example 16. Hydrochloride of 2-(4-forfinal)-4 - methyl-6-[2-(4-phenylpiperidine the SUB>3
O HCl:

Calculated (%): C 67,36; H 6,36; N 9,82.

Found (%): C 67,01; H Of 6.49; N Being 9.61.

Reference example 17. Hydrochloride of 2-(4-forfinal)- 4-methyl-6-[3-(4-phenylpiperidine)propoxy]pyrimidine.

TPL195-198oC.

Elemental analysis for C25H28FN3O HCl:

Calculated (%): C 67,94; H Is 6.61; N 9,51.

Found (%): C 67,82; H 6,50; N 9,49.

Reference example 18. Hydrochloride of 2-(4-chlorophenyl)-4 - methyl-6- [2-(4-phenylpiperidine)ethoxy]pyrimidine.

TPL208,5-210oC.

Elemental analysis for C24H26ClN3O HCl:

Calculated (%): C 64,86; H 6,12; N 9,46.

Found (%): C 64,62; H 6,10; N 9,42.

Reference example 19. Hydrochloride of 2-(4-forfinal)-4-[3-[4-(4-forfinal)-1,2,3,6-tetrahydropyridine-1-yl] propoxy]-6-methylpyrimidine.

TPL197,5-199,5oC.

Elemental analysis for C25H25F2N3O HCl:

Calculated (%): C 65,57; H 5,72; N 9,18.

Found (%): C 65,30; H Of 5.68; N 9,12.

Reference example 20. Hydrochloride of 2-(4-forfinal)-4-methyl-6-[3-(4-phenyl-1,2,3,6-tetrahydropyridine-1-yl) propoxy]pyrimidine.

TPL197-199oC.

Elemental analysis for C25H26FN3O HCl:

Calculated (%): C 68, [4-(4-forfinal)piperidino]propoxy]-6-methylpyrimidine.

TPL186-187oC.

Elemental analysis for C25H27F2N3O HCl:

Calculated (%): C 65,28; H 6,14; N 9,14.

Found (%): C 64,90; H 6,23; N 8,90.

Reference example 22. Hydrochloride of 2-(4-forfinal)-4-methyl-6-[3-[4-(pyridine-4 - yl)piperidino]propoxy]pyrimidine.

TPL186-187oC.

Elemental analysis for C24H27FN4O HCl:

Calculated (%): C 65,08; H 6,37; N 12,65.

Found (%): C 64,80; H 6,46; N 12,35.

Reference example 23. Maleate 4-(4-forfinal)-2-methyl-6- [3-(4-phenylpiperazine) propoxy]pyrimidine.

TPL158-159oC.

Elemental analysis for C24H27FN4O C4H4O4:

Calculated (%): C 64,36; H 5,98; N Of 10.72.

Found (%): C 64,02; H To 5.93; N Or 10.60.

Reference example 24. Maleate 2-(4-forfinal)-4 - methyl-6-[3-(4-phenylpiperazine)propoxy]pyrimidine.

TPL174-175oC.

Elemental analysis for C24H27FN4O C4H4O4:

Calculated (%): 64,36; H 5,98; N Of 10.72.

Found (%): C 64,62; H 6,01; N 10,79.

Reference example 25. Hydrochloride of 2-(4 - hydroxyphenyl)-4-methyl-6-(3-piperidinyloxy)pyrimidine.

To a mixture of solvents, the status is in the mixture was stirred at room temperature to it was added 461 mg 3 piperidino-1 - propanol, followed by a 10-minute mixing. To this reaction mixture was added 1 g of 2-(4-benzyloxyphenyl)-4-chloro-6 - methylpyrimidine obtained in reference example 8, and the mixture was stirred at room temperature for 48 hours the reaction mixture was poured into ice water and was extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4and was evaporated. The residue was purified using column chromatography on silica gel (WakogelTMS-200; chloroform) to obtain 1.08 g of pale yellow oil. This oil was dissolved in methanol and subjected to catalytic recovery in the presence of 5% palladium on carbon (Pd/C) at atmospheric pressure and temperature. The resulting reaction mixture was filtered and the filtrate was evaporated. The residue was dissolved in methanol and the pH of the solution was brought to 5 with 1 N. HCl and the solution was evaporated. To the residue was added ether and collecting the resulting crystals. The resulting crystalline mass was recrystallized from methanol to obtain 572 mg specified in the title compound as white crystals.

TPL248-249oC.

Elemental analysis for C19H25N

Reference example 26. The hydrochloride of 4-(4-hydroxyphenyl)- 2-methyl-6-(2-piperidinoethyl)pyrimidine.

TPL301oC.

Elemental analysis for C18H23N3O2HCl:

Calculated (%): C 61,80; H 6,91; N 12,01.

Found (%): C 61,50; H 6,83; N, 11.87 Per.

Reference example 27. The hydrochloride of 4-(4 - hydroxyphenyl)-2-methyl-6-(3-piperidinyloxy)pyrimidine.

TPL234-235oC.

Elemental analysis for C19H25N3O2HCl:

Calculated (%): C 62,71; H 7,20; N 11,55.

Found (%): C 62,45; H 7,24; N 11,51.

Reference example 28. The hydrochloride of 4-(4 - hydroxyphenyl)-2-methyl-6-[2-(4-phenylpiperidine)ethoxy]pyrimidine

TPL185oC (decomp.).

Elemental analysis for C24H27N3O2HCl:

Calculated (%): C 67,67; H 6,63; N 9,86.

Found (%): C 67,30; H To 6.58; N 9,72.

Reference example 29. Hydrochloride of 2-(4-hydroxyphenyl)-4-methyl-6-[3-(4-phenylpiperidine)propoxy]pyrimidine.

TPL229-230,5oC.

Elemental analysis for C25H29N3O2HCl:

Calculated (%): C 68,25; H 6,87; N Of 9.55.

Found (%): C 67,91; H 7,01; N For 9.64.

Reference example 30. Maleate 4-(4-hydroxyphenyl)-2 - methyl is I C24H28N4O2C4H4O4:

Calculated (%): 64,60; H 6,20; N 10,76.

Found (%): C 64,20; H 6,47; N 10,36.

Reference example 31. Hydrochloride of 2-(4 - hydroxyphenyl)-4-methyl-6-[3-(4-phenylpiperazine)propoxy]pyrimidine.

TPL253-254oC.

Elemental analysis for C24H28N4O2HCl:

Calculated (%): C 65,37; H 6,63; N 12,71.

Found (%): C 64,98; H Of 6.73; N Of 12.33.

Reference example 32. The hydrochloride of 4-(4-forfinal) -2-methyl-6-[2-[4-(2-methoxyphenyl)-piperazine derivatives]ethoxy]pyrimidine.

TPL193,0-194,5oC.

Elemental analysis for C24H27FN4O2HCl:

Calculated (%): C 62,81; H X 6.15; N 12,21.

Found (%): C 62,68; H 6,18; N 12,34.

Reference example 33. The hydrochloride of 4-(4-forfinal)-2 - methyl-6-[2-(4-phenylpiperazine)ethoxy]pyrimidine.

TPL201-204oC.

Elemental analysis for C23H25FN4O HCl:

Calculated (%): C 64,40; H 6,11; N 13,06.

Found (%): C 64,21; H 6,10; N 13,26.

Example of structure 1.

Injection of 1 ml can be obtained in the usual manner according to the following recipe, mg:

The connection according to the invention (example 1) - 1

Chloride IO can be obtained in the usual manner according to the following recipe, mg:

The connection according to the invention (example 2) - 1

Glucose - 48

Sodium dihydrophosphate - 1,25

Phosphate sodium - 0,18

Water for injection, ml To 1

Example of compound 3.

Injection of 1 ml can be obtained in the usual manner according to the following recipe, mg:

The connection according to the invention (example 4) - 1

Sorbitol - 48

Benzyl alcohol - 20

Sodium dihydrophosphate - 2,5

Phosphate sodium - 0,36

Water for injection, ml To 1

Example of compound 4.

Tablet weight of 120 mg can be obtained in the usual manner according to the following recipe, mg:

The connection according to the invention (example 3) - 3

Lactose - 58

Corn starch - 30

Crystalline cellulose - 20

Hydroxypropylcellulose - 7

Magnesium stearate - 2

The test example 1. Inhibiting delayed death of neurons (SGN) activity in gerbils.

The protective effect of the compounds against delayed neuronal death was confirmed by the experiment using gerbils. This test is most widely used for all relevant evaluations in vivo and, reportedly, it can be expected that any drug in the clinical application for the treatment of a person (GENDAI-IRYO, 24, 129-133 (1992). Neurology 1987, 37, 1281-1287).

The experimental part.

Male gerbils weighing 60-80 g was anestesiologi sodium intraperitoneally with pentobarbital in the amount of 35 mg/kg and placed in the supine position. After he cut the skin in the neck area, allocated on each side of the common carotid artery and put a bead around each artery. Both ends of each suture was introduced into a polyethylene tube and during suturing the incisions tube was fixed on the skin of the neck by means of a seam protruding from another end of the tube. The next day the animal without anesthesia gently pulled both ends of the seam and the carotid artery, which under the action of the weld took the shape of a loop, forced to enter into a bent position in the tube, to thereby pinch the carotid artery. After loading in the form of temporary ischemia duration of 5 minutes due to occlusion (overlapping of blood flow) to the common carotid arteries on both sides of perfusion in the arteries restored. After 7 days, the brain was dissected and fixed. Part located around the hippocampus were prepared and stained by Nissle crazylove purple and located in the subregion of the hippocampal CA-1 pyramidal cells were subjected to microscopic LASS="ptx2">

Criteria for assessing the degree of neuronal death in subregions of the hippocampal CA-1.

Degeneration and loss of pyramidal cells - Score

The death of 0-10% (close to normal) - 0

The death of 10-25% - 1

The death of 25-50% - 2

The death of 50-75% - 3

Death 75-100% - 4

The test drug was dissolved in saline and injected intraperitoneally at the same time, when he carried out the recovery of perfusion after the 5-minute load in the form of temporary ischemia. The results are presented in the table.

From the above results it is obvious that the connection according to the invention significantly inhibits the death of neurons in a model of temporary ischemia in gerbils. Moreover, oral administration of the compound according to the invention inhibits delayed neuronal loss. In addition, even if the compound of example 1 is administered in a single dose after 1-2 h after ischemia, it exerts a protective activity against delayed neuronal death.

These results show that the compound according to the invention not only can be used to prevent the occurrence of effects of cerebrovascular disease, but also as therapeutic drugs for the Church the rats occlude the middle cerebral artery.

The protective effect of the compounds according to the invention from the formation of cerebral infarction was confirmed on the model of blockage of the middle cerebral artery in rats. This model of regional ischemia of the brain, performed on animals, which is similar to the formation of cerebral infarction in humans, and it is known that this model is also applicable as a therapeutic model (Cerebral Apoplexy Experiment Handbook, 91-97, 1990, published ICP). It can be expected that any medicinal product, which in this test system is manifested protective activity of formation of cerebral infarction, will be effective in clinical use for the treatment of the person.

The experimental part.

Male SD rats aged 7-8 weeks were anestesiologi intraperitoneally with ketamine hydrochloride in the amount of 120-150 mg/kg and placed the head in the supine position, intermediate between the prone and side lying on the operating table. Skin linearly cut in the middle between the outer auditory hole and the external angle of the palpebral fissure on the leading edge of the temporal muscle to the zygomatic bone. Using electric dental drill, drilled a small hole in the middle between the mouth hole and orbital hole and rassekh the performance communications nerves (olfactory thread) was subjected to electric coagulation and cut inside the olfactory filaments, using a bipolar electrode, and the incision was sutured. Two days after surgery, animals were decapitated and the brain was dissected. Then prepared the frontal sections of the brain at intervals of 2 mm from the Rostral part of the olfactory bulb. Using saline solution (2%) chloride 2,3,5-triphenyltetrazolium (IDT) connection, which in itself is colourless, but under the action of the enzyme is converted to the red dye in living tissues, the sections were stained at 37oC for 30 minutes Then frontal sections were photographed using a processor for image processing, we measured the area that have experienced a heart attack. Counted the percentage of the area of infarction in the anterior cut at 6 mm from the tail to the front of the coracoid patterns, i.e. at the level of the striatum, relative to the total area of the tissue section and the total area of a heart attack on 5 frontal slices prepared at intervals of 2 mm from the front of the coracoid patterns, and counted the percentage of the total area of infarction in relation to the total area of all slices. As the test compound was intravenously injected compound of example 1 after occlusion of the middle cerebral artery. As a result, the connection according etemii brain.

The test example 3. Activity by inhibition of convulsions induced by N-methyl-aspartate.

Mice were injected intraperitoneally a dose of N-methyl-D-aspartate (NMDA) and watched followed by convulsions and death within a period of 30 min after injection. Test compounds used compounds of examples 1 and 2, reference examples 10 and 12, and each of them was injected intraperitoneally 30 min before the introduction of N-methyl-D-aspartate. The result was that the connection according to the invention, taken at the rate of 20 mg/kg, does not slow down caused by N-methyl-D-aspartate convulsions. These results suggest that the compound according to the present invention does not act on the NMDA receptor.

The test example 4. Study of acute toxicity.

Used male SD rats (Sic: SD, Japan SLC). Rats were purchased at the age of 7 weeks, and animals were quarantined week duration and acclimatization, used groups of 6 animals. The amount of dose was 5 ml/kg for intraperitoneal administration and 10 ml/kg for intravenous administration. Based on the result of preliminary experiment, the dosage was set in such a way as to enable the mortality rate to the via 0.22 micron bacterial filter. As test compounds, the compounds of examples 1 - 4, 16, 18, 21, and reference example 10 were, respectively, introduced intraperitoneally and observed mortality of animals during the day and for the General condition within 7 days after injection. The result was not found significant changes in the General condition of the animals. In this regard, the values of LD50compounds according to example 1 with intraperitoneal and intravenous injection was 65,8 and 22.8 mg/kg, respectively.

Industrial applicability.

As determined by the results of the above tests, the compound of the present invention exhibits excellent protective activity against neuronal death, regardless of whether it is introduced simultaneously with the onset of ischemia or infarction of the brain or introduces several hours after the attack. Moreover, the toxicity of the component is low. Therefore, the connection according to the invention is very useful as an inhibitor of neuronal death in the acute phase of cerebrovascular disease. In addition, the compound useful as therapeutic drugs for cerebrovascular diseases such as cerebral infarction, vnutrinosovyh, inhibiting consequences of the occurrence of cerebrovascular diseases (e.g., neurotic symptoms such as dyskinesia and convulsions, and mental symptoms, such as emotional and intellectual disorders), protecting thus the brain.

1. Pharmaceutical composition for the treatment of cerebrovascular disorders, inhibition of delayed neuronal death and suppression effects of cerebrovascular disorders, characterized in that as the active ingredient it contains an effective amount of the compounds of General formula I

< / BR>
where R1- thienyl, pyridyl, aryl group which may be substituted by 1 to 3 identical or different substituents selected from the group comprising hydroxy, halogen;

R2is hydrogen, alkyl, phenyl which may be substituted by 1 to 3 identical or different substituents selected from the group comprising halogen, alkyl;

R3and R4may be the same or different and represent hydrogen, alkyl, or R3and R4together with the adjacent nitrogen atom represent a 6-membered heterocycle, which in addition to the nitrogen atom can contain as a ring member nitrogen and kotoryj and pyridyl;

A - alkylen C2- C6;

E is O or S;

W is a simple bond, O, S, or (CH2)nwhere n = 1 or 2;

X, Y and Z may be the same or different and each represents CH, C-R, where R is alkyl, or N, with X, Y and Z cannot simultaneously be CH;

or its salt, or solvate, or salt.

2. The composition according to p. 1, where R1- halogen-substituted phenyl; R2is alkyl or halogenated; R3and R4together with the nitrogen atom represent piperidine; a - alkylen C3- C6; E is O or S; W is a simple bond; X and Z represent nitrogen, Y is CH, or Z is nitrogen, when X and Y are CH.

3. Company p. 1, where R3and R4together with the nitrogen atom - piperidino; a - alkylen C4- C6; E is O; W is a simple bond; X and Z is nitrogen, Y is CH, or Z is nitrogen, when X and Y are CH.

4. The composition according to PP.1-3, where the compound is selected from the group comprising 4-(4-forfinal)-2-methyl-6-(4-piperidinyloxy)pyrimidine, 4-(4-forfinal)-2-methyl-6-(5-piperidinyloxy)pyrimidine, 4-(4-forfinal)-2-methyl-6-(6-piperidinyloxy)pyrimidine, 4-(4-forfinal)-2-methyl-6-(1-methyl-4-piperidinyloxy)pyrimidine, 2-(4-forfinal)-4-methyl-6-(4-piperidinyloxy)pyrimidine, 4-(4-forfinal)-2-methyl-6-(3-piperidineacetate on PP.1 - 4, which is the inhibitor of neuronal death.

6. The composition according to PP.1 to 4, which is the inhibitor effects of cerebrovascular disorders.

7. Heterocyclic compound of General formula I

< / BR>
where R1- R4, E, W, X, Y and Z indicated in paragraph 1;

A - alkylen4- C6.

8. Connection on p. 7, where R1- R3and R4together with the nitrogen atom of the piperazine derivatives, which may be unsubstituted or substituted by alkyl or aryl.

9. Connection on p. 7 General formula Ia

< / BR>
where R11- R14, A', W', E', X', Y', Z' are the same values that are specified for R1- R4, A, E, W, X, Y, Z in paragraph 1,

or its salt, or MES, excluding compounds

in which A' - alkylen2- C3;

X' = Y' - N at Z' = CH, or X' = Z' - N when Y' = CH;

W' - a simple link;

E' - O;

R11is phenyl which may be substituted by hydroxy group, alkoxy, trifluoromethyl or halogen;

R12is methyl or tert-butyl;

compounds in which A' - alkylen2;

X' = Y' - N when Z' is CH;

W' - (CH2)2-;

E' - O;

R11is phenyl;

R12is methyl;

compounds in which A' - alkylen2;

X' = Y' - N;

Z' IS CH;

W' - simple SV is predstavljaet a N and the other is CH, or its salt, or MES.

11. Connection on p. 9, where X', Y' or Z' represents N, or its salt, or MES.

12. Connection on p. 9, where W' is O, S, or -(CH2)n- where n = 1 or 2, or its salt, or MES.

13. Connection on p. 9, where E' - S, or its salt, or MES.

14. Connection on p. 9, where A' is alkylene2- C6or its salt, or MES.

15. Connection on p. 9, where R13and R14together with the nitrogen atom represent piperidine and A' - alkylen2- C6.

16. Connection on p. 7 General formula Ib

< / BR>
where A21- alkylen4- C6;

E21- O;

W2- simple connection;

X21= Z21- N if Y21- CH or X21= Z21- CH if Z21N;

R21- halogen-substituted phenyl;

R22is alkyl or halogenated;

R23and R24together with the nitrogen piperidino.

17. Connection on p. 7, selected from the group comprising 4-(4-forfinal)-2-methyl-6-(4-piperidinyloxy)pyrimidine, 4-(4-forfinal)-2-methyl-6-(1-methyl-4-piperidinyloxy)pyrimidine, 4-(4-forfinal)-2-methyl-6-(5-piperidinyloxy)pyrimidine, 4-(4-forfinal)-2-methyl-6-(6-piperidinyloxy)pyrimidine, 2-(4 is arvanil)-2-methyl-6-(5-piperidinyloxy)pyridine, or their salts.

 

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< / BR>
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The invention relates to medicine

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

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wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex

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wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

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3 tbl, 6 dwg, 4 ex

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EFFECT: valuable medicinal properties of agent.

16 cl, 3 tbl

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