Derivatives of 1,2,4-triazolo [1,5-a]pyrimidines, their pharmaceutically acceptable salts and stereoisomers, pharmaceutical composition and method of inhibiting seizures

 

(57) Abstract:

The invention relates to new nitrogen-containing heterocyclic compounds possessing biological activity, and more particularly to derivatives of 1,2,4-triazolo[1,5-a]pyrimidines, their pharmaceutically acceptable salts and stereoisomers, pharmaceutical compositions containing them, and method of inhibiting seizures. Describes derivatives of 1,2,4-triazolo-[1,5-a]pyrimidines of General formula I, where R1, R4and R5are hydrogen atom or alkyl with 1 to 6 carbon atoms; R2and R3are a hydrogen atom; R6, R7and R8independently from each other are hydrogen atom, halogen, cyano, alkanoyl with 1 to 6 carbon atoms, alkoxyl with 1 to 6 carbon atoms, unsubstituted or substituted by halogen, alkylthio with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, alkyl with 1 to 6 carbon atoms, unsubstituted or substituted by halogen, provided that if R1, R2, R3, R4and R8- hydrogen atoms, R5is methyl, R6and R7- hydrogen atoms, or R6- 4-chloro -, and R7is a hydrogen atom or a 2-chloro, the compound of formula I is not predstavleniya, possessing anticonvulsant activity on the basis of the compounds of formula I and a method of inhibiting seizures with the use of compounds of formula I. 3 C. and 8 C.p. f-crystals.

The invention relates to new nitrogen-containing heterocyclic compounds possessing biological activity, and more particularly to derivatives of 1,2,4-triazolo[1,5-a]pyrimidines, their pharmaceutically acceptable salts and stereoisomers, pharmaceutical compositions containing them, and method of inhibiting seizures.

Known derivatives of aryl - and aralkylamines[1,2-b]pyridazines, which have biological activity, in particular, anticonvulsant activity (see application WO-A-89/01478, published. 23.02.1989,)

Object of the invention is the expansion of the range of nitrogen-containing heterocyclic compounds with anticonvulsant activity.

The problem is solved proposed derivatives of 1,2,4 - triazolo[1,5-a]pyrimidines of General formula (I)

< / BR>
where

R1, R4and R5are hydrogen atom or alkyl with 1 to 6 carbon atoms:

R2and R3are a hydrogen atom;

R6, R7and R8independently of one another are a hydrogen atom, halo is illuminated by halogen, alkylthio with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, alkyl with 1 to 6 carbon atoms, unsubstituted or substituted by halogen,

in this case, if R1, R2, R3, R4and R8- hydrogen atoms, R5is methyl, R6and R7- hydrogen atoms, or R6- 4-chloro and R7is a hydrogen atom or a 2-chloro, the compound of formula (I) represents the racemate, and their pharmaceutically acceptable salts and stereoisomers.

The second object of the invention is a pharmaceutical composition having anticonvulsant activity, which includes the active principle on the basis of the nitrogen-containing heterocyclic compounds and pharmaceutically acceptable diluent or carrier, the distinctive feature of which is that as the active agent on the basis of the nitrogen-containing heterocyclic compounds it contains a compound of General formula (II)

< / BR>
where R'1, R'4and R'5are hydrogen atom or alkyl with 1 to 6 carbon atoms;

R'2and R'3are a hydrogen atom;

R'6, R'7and R'8independently of one another are a hydrogen atom, halo is emenim halogen, alkylthio with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, alkyl with 1-6 carbon atoms, unsubstituted or substituted by halogen,

or its pharmaceutically acceptable salt or stereoisomer in therapeutically effective amounts.

In the first group of preferred derivatives of 1,2,4-triazolo [1,5-a]pyrimidines of General formula (I) and (II) include compounds in which R1, R'1, R4, R'4, R5and R'5are hydrogen atom or alkyl with 1 to 4 carbon atoms;

R2, R'2, R3and R'3are a hydrogen atom;

R6, R'6, R7, R'7, R8, R'8- independently from each other are hydrogen atom, halogen, cyano group, alkyl with 1 to 4 carbon atoms, unsubstituted or substituted by halogen, alkoxyl with 1 to 4 carbon atoms, unsubstituted or substituted by halogen, alkanoyl with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, alkylsulfonyl with 1 to 4 carbon atoms and alkylsulfonyl with 1 to 4 carbon atoms.

The second group preferred derivatives of 1,2,4-triazolo [1,5-a]pyrimidines of General formula (I) and (II) are compounds that have

Rthe from each other are a hydrogen atom, the stands or ethyl,

R6, R'6, R7, R'7, R8and R'8independently from each other are hydrogen atom, fluorine, chlorine, bromine, cyano, trifluoromethyl, metaxylem, cryptomaterial, acetyl, methylthiourea, ethylthiourea, methylsulfinyl or methylsulfonyl.

Particularly preferred compounds of General formula (I) and (II), which are:

7-[1-(4-pertenece)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine;

7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine;

7-[1-(4-bromophenoxy)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine;

7-[1-(4-cianfrocca)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine;

7-[1-(4-triptoreline)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine;

7-[1-(4-methoxyphenoxy)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine;

7-[1-(4-triftormetilfosfinov)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine;

7-[1-(4-acetylphenol)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine;

7-{1-[4-(methylthio)phenoxy]ethyl}-1,2,4-triazole[1,5-a]-pyrimidine;

7-[1-(4-methylsulfinylphenyl)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine;

7-[1-(4-methylsulfinylphenyl)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine;

7-{1-[4-(ethylthio)phenoxy]ethyl}-1,2,4-triazole[1,5-a]-pyrimidine;

7-[1-(3-chlorophenoxy)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine;

7-[1-(2,4-diftorhinolonom)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine;

7-[1-(2-chloro-4-pertenece)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine;

7-[1-(4-chlorophenoxy)ethyl]-2-methyl-1,2,4-triazole[1,5-a]-pyrimidine;

7-(4-chlorphenoxy)-1,2,4-triazole[1,5-a]-pyrimidine;

7-[1-(4-chlorophenoxy)-1-methylethyl]-1,2,4-triazole[1,5-a]-pyrimidine;

7-[1-(4-chlorophenoxy)propyl]-1,2,4-triazole[1,5-a]-pyrimidine.

(+)-7-[1-(4-pertenece)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine,

(-)-7-[1-(4-pertenece)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine,

(+)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine,

(-)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine.

Suitable pharmaceutically acceptable salts of the compounds of General formula (I) or (II) in particular are salts with acids, including salts with inorganic acid, such as, for example, hydrochloric, Hydrobromic, uudistoodetena, nitrogen, californa and/or phosphoric acid; salts with organic acid, such as, for example, maleic, acetic, citric, fumaric. tartaric, succinic, benzoic, Panova, palmitic, mmelserna and/or dodekanisa acid; or salts with amino acids such as, for example, glutamic acid. Such salts include all pharmaceutically acceptable salts with polyvalent acids, for example, bicarbonate and/or what to use instead of the corresponding compounds of General formula (I) or (II). Such salts can be obtained by reacting the corresponding compounds of General formula (I) or (II) with a suitable acid or a suitable base of a standard technique.

Some compounds of General formula (I) or (II) may exist in different physical forms, for example, in the form of different crystalline forms, and therefore, this invention encompasses any physical, for example, crystalline, form compounds of General formula (I) or (II) and mixtures thereof.

Compounds of General formula (I) or (II) may be in the form of a solvate, for example, hydrates, and therefore, this invention covers each MES compounds of formula (I) or (II) and mixtures thereof. The degree of solvation can be non-stehiometrichesky. If the solvent is water, the hydrate may represent, e.g., hemihydrate, monohydrate or dihydrate.

Some compounds of General formula (I) or (II) may have one or more chiral centers, and exist in different optically active forms. So, for example, compounds of General formula (I) or (II) where the radicals R4and R5different, have a chiral center at the asymmetrically substituted carbon atom. If there is one chiral centre, the compounds of formula (I) or (II) the second formula (I) or (II) and mixtures thereof. Individual enantiomers may be obtained well-known specialist methods. Examples of such methods are education salts diastereoisomers or complexes of diastereoisomers, which can be divided, for example, by crystallization, the formation of derivatives or complexes of diastereoisomers, which can be divided, for example, by crystallization, gas-liquid chromatography or liquid chromatography followed by separation of the desired enantiomer of proizvodnjo, selective engagement of one enantiomer with an appropriate reagent, for example enzymatic esterification, oxidation, or restoration, followed by separation of the modified and unmodified enantiomers, gas-liquid or liquid chromatography in a chiral environment, for example, chiral media, such as silica gel, with a bound chiral ligand and/or in the presence of a chiral solvent, asymmetric synthesis of a specific enantiomer using optically active reagents, substrates, catalysts or solvents, and/or enzymatic processes, or translation of one enantiomer into the other enantiomer due to the asymmetric rearrangement.

If connected to the Mer, which can be divided into well-known specialist methods, such as chromatography or crystallization. The individual isomers any diastereoisomeric pairs can be distinguished above methods. This invention covers any diastereoisomer compounds of formula (I) or (II), and mixtures thereof.

If the active part of the compound is converted into the above-mentioned processes of separation, the additional stages of the transformation product again transferred to the active form.

Some compounds of formula (I) or (II) may exist in different tautomeric forms or as different geometric isomers, therefore, this invention encompasses any tautomer and/or geometric isomer of compounds of formula (I) or (II), and mixtures thereof.

The proposed pharmaceutical composition can be any standard form of therapeutic drug for oral, rectal, parenteral or topical application. The composition of the known techniques can be produced so that provided a controlled, i.e., either fast or extended release of active substances. As a pharmaceutically acceptable diluent or carrier offer compo is Erno 0.1 to 99 wt.% the active agent. Usually it's in the form of a dosage unit. A dosage unit of the active agent is preferably about 1 to 1000 mg.

The proposed composition is preferably given orally known for such applications pharmaceutical drugs. Preparations suitable for oral villas are tablets, pills, capsules, granules, powders, harnesses, elixirs, syrups, solutions, aqueous and oily suspensions.

Solid preparations for oral giving, for example tablets, are prepared by mixing the active principle with at least one component and/or a mixture of components, including:

inert fillers such as, for example, lactose, powdered sugar, starch, kaolin, mannitol, calcium phosphate, calcium sulfate;

dezintegriruetsja agents, such as, for example, corn starch, methylated cellulose, agar, bentonite, cellulose and wood products, alginic acid, guaran, citrus pulp, carboxymethycellulose and/or sodium lauryl sulfate;

lubricants, such as, for example, magnesium stearate, boric acid, sodium salt benzoic acid, sodium salt acetic acid, sodium chloride, latingirl, polyethylene is chose, and/or natural and/or synthetic gums such as acacia, sodium alginate, extract Gagarina, carboxymethylcellulose, methylcellulose, ethylcellulose, polyethylene glycol, waxes, microcrystalline cellulose and/or polyvinylpyrrolidone,

colorants, such as, for example, standard, pharmaceutically acceptable dyes,

sweetening and/or flavoring substances,

preservatives,

at least one pharmaceutically acceptable pair, including, for example, an acid and a carbonate and/or bicarbonate, which by boiling promote dissolution in the event of the filing of the solid drug in the water,

and other known components for the manufacture of preparations for oral villas by known methods, for example, pelletizing.

Solid preparations for oral villas can be performed so that the active principle is released within a certain time. Containing the new compounds of solid preparations for oral villas, made with the floor, depending on the active agent can be pre-emptive. Various substances, such as, for example, shellac and/or sugar, can be used as coatings or for drwily pills if necessary, can be applied by known coating techniques, for example, phthalate cellulose acetate and/or phthalate of oksipropilmetiltselljulozy.

Capsules, for example, hard or soft gelatin containing the active principle and optionally fillers, for example, oil, is prepared by known methods and, if necessary, they are coated desired known methods. The contents of the capsule are well-known techniques so that you receive prolonged release of active beginning.

Liquid preparations for oral villas, containing the proposed compounds are elixir, suspension and/or syrup, for example, aqueous suspensions containing the active principle in an aqueous medium in the presence of a non-toxic suspending agent such as, for example, carboxymethylcellulose sodium, and/or oily suspension containing the active principle in a suitable vegetable oil, such as, for example, peanut butter and/or sunflower oil. Liquid preparations for oral villas may also contain sweeteners, flavorings, preservatives and/or mixtures thereof.

The active principle can also be translated into granules and powders, optionally with additional excipients. Gran is in the media, such as, for example, water, before use. Granules and/or powders may also contain pharmaceutically acceptable dezintegriruetsja agents, such as, for example, a granular mixture consisting of acids and salts of carbonic acid or bicarbonate, which facilitates dispersion in a liquid medium.

Each of these preparations preferably contain about 1 to 1000 mg, more preferably about 5 to 500 mg of active substance.

Suitable for rectal villas form the proposed compositions are the known pharmaceutical forms, for example, suppositories, containing the cured fat, semi-synthetic glycerides, cocoa butter and/or polietilenglikoli basis.

Suitable for parenteral villas, for example, by intravenous injection, the form of the suggested songs are the known pharmaceutical forms, for example, a sterile suspension in water and/or oil medium or sterile solutions in a suitable solvent.

Compositions for local villas can contain a matrix in which the active principle dispersed in such a way that it is in contact with the skin so that the active principle could penetrate into the body of transdermal is that a therapeutically effective amount of the active agent is released over a desired period of time.

A suitable composition for transdermal application can be prepared by mixing or dispersing pharmaceutically active agent in a suitable carrier and suitable for transdermal application accelerator, such as, for example, dimethyl sulfoxide and/or propylene glycol. As the carrier can be used pharmaceutically acceptable foam, paste, ointment, lotion, cream, emulsion and/or a gel and the composition is suitable for application by spray. Means for transdermal application may also be, for example, poultices, plasters and/or impregnated dressings.

Suitable cream can be produced by incorporating the active agent in petrolatum and/or liquid paraffin, which with the use of surfactants dispersed in the aquatic environment. The ointment can be produced by mixing the active agent with mineral oil, petroleum butter and/or wax, such as, for example, paraffin or beeswax. The gel can be produced by mixing the active agent with a thickener, such as, for example, podlachian trading product Carbomer BP, in the presence of water. Transparent gel may contain a brightening agent, such as, for example, denatured application preferably contains a thickener and/or a substance for adjusting the pH, compatible with active early. Substance for adjusting the pH preferably is used in an amount sufficient to activate the thickener, if any, and stores the pH of the composition within a pharmaceutically and cosmetically acceptable limits so that the skin is not damaged. In particular, the preferred pH of the composition is equal to about 5,0 - 9,0.

If the pharmaceutical composition for topical application according to this invention is an emulsion, it may be either an emulsion of the type oil-in-water or emulsion type water in oil". In the oil phase of such emulsions contain at least one of the following components: hydrocarbon oils, waxes, natural oils, silicone oils, esters of fatty acids, fatty alcohols and/or mixtures thereof. The pharmaceutical compositions of this invention, the emulsions can be produced using an emulsifier or mixture of emulsifiers suitable for use in the emulsions of the type oil-in-water" or type "water in oil" and acceptable for use in pharmaceutical compositions intended for topical application. Suitable emulsifiers are any known special is built for local applications is not an emulsion, it is still possible to apply the emulsifier as a surfactant to enhance therapeutic activity locally appliciruemah pharmaceutical compositions.

The pharmaceutical composition of the present invention intended for topical application, can additionally contain a further component or further components known to the specialist, such as, for example: stabilizers of emulsions, including in the form of salts, anti-irritation of the skin, humectants, substances for education film, perfumes, preservatives, dyes, and/or mixtures thereof.

The proposed connection can also be given by continuous infusion or outside, for example, by intravenous infusion, or by application of the source of the active principle, is placed inside the patient's body. These internal sources are, for example, implanted capacity, which contain the subject of the infusion of the active principle. In this case, the active principle continuously released, for example by osmosis. In addition, implanted drugs can be a liquid, such as, for example, a suspension or solution in a pharmaceutically p is wow, such as, for example, salt or ester with dodecanol acid, or serving as the basis for subject infusion connections solid, for example, synthetic resin or wax. This base may be a single body containing all of the active principle, or series of bodies, each of which contains part appliciruemah active principle. The active principle must be an internal source so that a therapeutically effective amount of the active agent given during the desired period of time.

For some purposes it may be desirable that the composition contains the active principle in the form of fine particles obtained, for example, by spraying.

The proposed pharmaceutical composition may also contain other pharmacologically active agent that is compatible with the proposed connections.

The third object of the invention is a method of inhibiting seizures by giving people or animals nitrogen-containing heterocyclic compounds, which is that as the nitrogen-containing heterocyclic compounds used as a compound of General formula (I)

< / BR>
where R1, R
R6, R7and R8independently from each other are hydrogen atom, halogen, cyano-group, alkanoyl with 1 to 6 carbon atoms, alkoxyl with 1 to 6 carbon atoms, unsubstituted or substituted by halogen, alkylthio with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, alkyl with 1-6 carbon atoms, unsubstituted or substituted by halogen,

or its pharmaceutically acceptable salt or stereoisomer in a daily dose of approximately 1 to 1000 mg.

Although the exact mechanism of action of the active principle are still unknown, it is assumed that the pharmacological activity of the active principle in these conditions is based on the ability of potentiation of transmission of the neurotransmitter - aminobutyric acid and/or ability activation of potassium (K+) channels in neurons. Therefore, further abychom of the invention is described herein a method of treatment, where the active principle is a substance, potentiating transfer - aminobutyric acid and/or activator potassium channels in neurons. However, the invention is not limited to active beginning with specified here pharmacological activity.

Neobhodimosti disease, age and/or medical history of the patient, so in each case, a pharmacist, a doctor and/or veterinarian should find the suitable dosage. As a rule, new connections to give a person or animal in the amount of 1 - 1000 mg/day, preferably 5 to 500 mg/day as single dose or multiple doses, once or several times a day, if this is preferred oral giving.

The active substance may be used together with one or more known compounds of the same biological activity to achieve sinergeticheskogo effect.

The following describes possible methods of producing compounds of the above General formulas (I) and (II).

The compounds of formula (I) can be obtained by reacting the compounds of formula (III)

< / BR>
with the compound of the formula (IV)

< / BR>
where Y is a suitable removable group, such as, for example, a chlorine atom, dimethylamine or alkoxy group.

The compounds of formula (I) can be obtained by reacting the compounds of formula (V)

< / BR>
where Z means a group to delete, such as, for example, bromine atom or chlorine, with the anion of the formula (VI)

< / BR>
The compounds of formula (IV), where Y - dimethylamine, can be PU is rmula Me2NCH=NCH= NMe2Cl (Me is methyl).

The compounds of formula (V) can be obtained by reacting the compounds of formula (III) with the compound of the formula (VIII)

< / BR>
The compounds of formula (IX), where Y - dimethylamine can be obtained by reacting the compounds of formula ZCR4R5COCH2R3reagent gold.

The compounds of formula (V), where Z is halogen, can be obtained by reacting the compounds of formula (IX)

< / BR>
with a halogenation agent, such as, for example, N-bromosuccinimide.

The compounds of formula (IX) can be obtained by reacting the compounds of formula (III) with the compound of the formula (X)

< / BR>
The compounds of formula (X), where Y - dimethylamine can be obtained by reacting compounds of the formula CHR4R5COCH2R3with the above reagent gold.

The compounds of formula (IX), where R1does not mean a hydrogen atom, can be obtained by reacting the compounds of formula (XI)

< / BR>
with the compound of the formula R1CN--->O, and thus obtain an intermediate product, which is subjected to cyclization using a suitable acid catalyst.

The compounds of formula (IX) can be obtained by reacting Conn/SUB>C(OR11)3where R11means methyl or ethyl.

The compounds of formula (IX) can also be obtained by decarboxylation of the acid of formula (XIII)

< / BR>
using, for example, heat and/or a suitable acid catalyst.

The compounds of formula (XIII) can be obtained by hydrolysis of ester of the formula (XIV)

< / BR>
where substituent R12means unsubstituted or substituted alkyl or unsubstituted or substituted aryl.

The compounds of formula (XIV) can be obtained by reacting the compounds of formula (III) with the compound of the formula (XV)

< / BR>
The compounds of formula (XV), where Y - dimethylamine can be obtained by reacting compounds of the formula CHR4R5COCHR3CO2R12with the above reagent gold.

The compounds of formula (I) or (II) can also be obtained by combining the alcohol of formula (XVI)

< / BR>
with a phenol of the formula (XVII)

< / BR>
in the presence of contributing to the combination of substances, which are, for example, in response to Mitsunobu diethylazodicarboxylate with triphenylphosphine.

If R4and R5different, stereospetsifichno reaction Mitsunobu represents an opportunity will be obtained by reacting the alcohol of formula (XVI) with a halogenation agent, such as, for example, thionyl chloride or triphenylphosphine and bromine.

Alcohols of formula (XVI), where R5the hydrogen atom can be obtained by restoring the compounds of formula (XVIII)

< / BR>
a reducing agent, such as, for example, sodium borohydride, or with a chiral reducing agent, to obtain the individual enantiomers of the alcohol of formula (XVI).

The compounds of formula (XVIII) can be obtained by removing the protective group from compounds of formula (XIX)

< / BR>
where L1and L2mean alkoxy group or alkylthio group

or together with the carbon atom to which they are linked, represent dioxolane, dioxane, dithiolane or diciannove ring. For example, if the compound of formula (XIX) is a ditiolan or Titian, as agent for facilitating the removal of the protective group, you can use silver nitrate with N-chlorosuccinimide or cerium ammonium nitrate. If L1and L2both mean methoxy, then as a chip off the agent can use a suitable ion exchanger brand "Amberlyst" (commercial product of the firm Aldrich Chemicals).

The compounds of formula (IX), where R5the hydrogen atom can be obtained by restoring the compounds of formula (XVI formula (XX)

< / BR>
The compounds of formula (XX), where Y - dimethylamine, can be obtained by reacting the compounds of formula (XXI)

< / BR>
with the above reagent gold.

Alcohols of formula (XVI) can also be obtained by reacting the compounds of formula (V) hydroxyl ion, for example, using a suitable alkali.

In addition, the alcohols of formula (XVI) can be obtained by hydrolysis of compounds of formula (XXII)

< / BR>
where the remainder R13is unsubstituted or substituted alkyl, or unsubstituted or substituted aryl, for example, potassium carbonate. The hydrolysis can be performed under such conditions that receive separate the enantiomers of the alcohol of formula (XVI), for example, by use of the corresponding hydrolytic enzyme.

The compounds of formula (XXII) can be obtained by reacting the compounds of formula (V) with carboxylate anions of the formula R13CO2-that can be any allalou group, such as, for example, acetate or benzoate, and which can also be a chiral group, such as, for example, mandelate [PhCH(OH)CO2]. If the individual enantiomers of formula R13CO2-used for connections poorno to share, for example, by selective recrystallization, and gidrirovanii desired diastereoisomer with obtaining the individual enantiomers of the alcohol of formula (XVI).

The compounds of formula (XXII) can be obtained by reacting the compounds of formula (XVI) with a carboxylic acid of formula R13CO2H in the presence of facilitating the combination of substances, such as, for example, dicyclohexylcarbodiimide, or triphenylphosphine with diethylazodicarboxylate.

The compounds of formula (XXII) can also be obtained by reacting the compounds of formula (III) with the compound of the formula (XXIII)

< / BR>
The compounds of formula (XXIII), where Y - dimethylamine can be obtained by reacting the compounds of formula (XXIV)

< / BR>
with the above reagent gold.

The compounds of formula (XXIV) can be obtained by reacting the compounds of formula (XXV)

< / BR>
with the anion of the formula R13CO2-.

The compounds of formula (I) or (II), where R1does not mean a hydrogen atom, can also be obtained by reacting the compounds of formula (XXVI)

< / BR>
with the compound of the formula R1CN--->O, and thus obtain an intermediate product, which is subjected to cyclization using a suitable kislotno the R8selected from the group comprising alkylsulfonyl and alkylsulfonyl, can be obtained by oxidation of compounds of formula (I), where R6, R7and/or R8indicate alkylthio group, using, for example, peracetic acid or 3-chlormadinone acid.

The compounds of formula (I) can also be obtained by decarboxylation of the acid of formula (XXVII)

< / BR>
using, for example, heat and/or a suitable acid catalyst.

If R4and R5different, it represents the possibility of obtaining individual enantiomers of the compound (I).

The compounds of formula (XXVII) can be obtained by hydrogenation of ester of the formula (XXVIII)

< / BR>
where R14means unsubstituted or substituted alkyl or unsubstituted or substituted aryl.

The compounds of formula (XXVIII) can be obtained by reacting the compounds of formula (III) with the compound of the formula (XXIX)

< / BR>
The compounds of formula (XXIX) can be obtained by reacting the compounds of formula (VIII) with the compound of the formula (XXX)

< / BR>
In addition, the compounds of formula (I) or (II) can be obtained by restoring the compounds of formula (XXXI)

< / BR>
where W is a suitable UD is , for example, hydrogen, optionally in the presence of a catalyst, such as, for example, palladium.

If R4and R5different, it represents the possibility of obtaining individual enantiomers of the compound (I).

The compounds of formula (XXXI), where W is halogen, can be obtained by reacting the compounds of formula (XXXI), where W is a hydroxy group, with a halogenation agent, such as, for example, phosphorylchloride.

The compounds of formula (XXXI), where R3is a hydrogen atom, and W is a hydroxy group can be obtained by reacting the compounds of formula (III) with the compound of the formula (XXXI).

The compounds of formula (II) can be obtained in the same way as the compounds of formula (I).

The compounds of formula (I) or (II) exhibit anticonvulsant activity, which was detected using the following pharmacological experiments.

The first experiment was aimed at determining the ability of compounds of the formula (I) or (II) to the manifestation of the action of the antagonistic myoclonic seizures caused in mice by giving trading of the product (+)-bicuculline (see Buckett W. R.; J. Pharmacol.Meth.; 1981, 5; page 35 -41). The bicucullin, representing a selective receptor antagonist-aminobutyric acid (A), the PL of anti-epileptic drugs potentiating the transmission of the neurotransmitter - aminobutyric acid. Experience in the following is referred to as a "BICM".

In the experience of "BICM was used mouse-females weighing 25-30 g 2 hours before the start of the experiment mice were no longer receiving food, and only water in the desired quantity. Mice were divided into two groups, i.e. control group and experimental group. The control group was orally given a dose of 10 ml/kg of a 1% aqueous solution of methylcellulose. The experimental group was orally given suspended in the same dose solution of methylcellulose compound of formula (I) or (II) or at a dose of 100 mg/kg for the initial experience, or the presence of compounds in sufficient quantities in different doses to determine the ED50(see below). 1 hour later after giving all preparations all mice from both groups intravenously in the tail vein gave (+)-bicucullin at a dose equal to 0.55 mg/kg (+)-bicucullin at the given dose, usually in mice causes a seizure.

In the next two minutes was observed each group of mice was recorded the number of mice that have manifested seizures, and thus determined the proportion of mice in the experimental group, which prevented convulsions. The stronger anticonvulsant activity of the compounds of formula (I) in doses connection dose inhibitory seizures in 50% of mice (ED50), was calculated by regression analysis. For each dose of the formula (I) or (II) was determined by the percentage number of animals that have inhibited seizures.

The second experiment for the determination anticonvulsant activity was aimed at determining the ability of the compounds of formula (I) or (II) to the manifestation of the action of the antagonistic seizures caused in mice by maximum electroshock. Experience in the following is referred to as a "MESM".

In the experience of "MESM" used mouse-males weighing 25-30 g, which before the start of the experiment were given feed and water in the desired quantity. Mice were divided into two groups, i.e. control group and experimental group. The control group was orally given a dose of 10 ml/kg of a 1% aqueous solution of methylcellulose. The experimental group was orally given suspended in the same dose solution of methylcellulose compound of formula (I) or (II) or at a dose of 100 mg/kg for the initial experience, or the presence of compounds in sufficient quantities in different doses to determine the ED50(see below). 1 hour later after giving all preparations all mice from both groups using electrodes attached to the ears and hydrated salt concrete is the aka shock, as a rule, in mice causes a seizure.

In the next two minutes was observed each group of mice was recorded the number of mice that have manifested straightening tonic hind limb, and thus determined the proportion of mice in the experimental group, which prevented convulsions.

The stronger anticonvulsant activity of the compounds of formula (I) or (II), the higher the percentage the number obtained as a result of experience "MESM". If results obtained with different doses of the compound, dose, inhibitory seizures in 50% of mice (ED50), was calculated by regression analysis. For each dose of the formula (I) or (II) was determined by the percentage number of animals that have inhibited seizures.

Described in the following examples 1 - 25A compounds of formula (I) or (II) in at least one of the tests "BICM" and "MESM" showed anticonvulsant activity.

The invention is illustrated by the following examples which do not limit its scope. Target products in each of these examples were characterized by one or more of the following methods: elemental analysis, infrared spectroscopy, spectroscopy, nuclear magnetic PEP> Example 1.

1.12 g of 4-terfenol serves to stir a suspension of 0.48 g of sodium hydride in 35 ml of dry 1,2-dimethoxyethane. The mixture is stirred at room temperature for 30 minutes, then added dropwise a solution of 2.27 g of 7-(1-bromacil)-1,2,4-triazole [1,5-a]pyrimidine is obtained analogous to example 6 with a reception in 85 ml of dry 1,2-dimethoxyethane. The mixture is stirred at room temperature for 24 hours. Sodium bromide is removed from the mixture by filtration. The solvent is evaporated from the filtrate and the residue is dissolved in dichloromethane and successively washed with 200 ml of 5% aqueous solution of sodium hydroxide and water. The organic phase is dried over magnesium sulfate. The solvent is evaporated, thus obtain the crude product, which was purified by column chromatography on silica gel using as eluent a mixture of petroleum ether and ethyl acetate in the ratio 6:4, followed by recrystallization from a mixture of ethyl acetate and hexane. Gain of 1.03 g of 7-[1-(4-pertenece)ethyl] - 1,2,4-triazole[1,5-a]-pyrimidine with a melting point of 106 - 108oC.

ED50this connection in the above experience BICM": 13.9 mg/kg

ED50this connection in the above experience "MESM": 21,4 mg/kg

A solution of 9.80 g of 4-(4-chlorophenoxy)-1-(dimethylamino)-1-penten-3-one in 50 ml of glacial acetic acid added to mixed solution of 3.25 g of 3-amino-1,2,4-triazole in 50 ml of glacial acetic acid. The mixture is heated for 5 hours under reflux, then cooled to room temperature. The mixture is poured into 300 ml ice water and extracted with toluene. The extracts are successively washed with 10% aqueous sodium bicarbonate solution and water, dried over non-aqueous magnesium sulfate, the solvent was evaporated under reduced pressure. The remainder using cold diethyl ether pounded into powder, the resulting solid is collected by filtration and recrystallized from a mixture of ethyl acetate and petroleum ether with a boiling within 40 - 60oC, you get a 6,91 g of 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazole[1,5-a]pyrimidine with a melting point of 111 - 112oC.

ED50this connection in the above experience "B3.

A solution of 1.73 g of 4-bromophenol in dry 1,2-dimethoxyethane slowly served in stir a suspension of 0.48 g of sodium hydride in 35 ml of dry 1,2-dimethoxyethane. The mixture is stirred for 30 minutes, then added dropwise a solution of 2.27 g of 7-(1-bromacil)-1,2,4-triazole [1,5-a]pyrimidine is obtained analogous to example 6 with a reception in 85 ml of dry 1,2-dimethoxyethane. The reaction mixture was stirred at room temperature for 1.5 hours. Sodium bromide is removed from the mixture by filtration. The solvent is evaporated from the mixture, and the residue is dissolved in dichloromethane and successively washed with 200 ml of 5% aqueous solution of sodium hydroxide and water. The organic phase is dried over magnesium sulfate. The solvent is evaporated, thus obtain the crude product, which was purified by column chromatography on silica gel using as eluent a mixture of ethyl acetate and petroleum ether in the ratio of 4:6, followed by recrystallization from a mixture of ethyl acetate and hexane. Obtain 2.28 g of 7-[1-(4-bromophenoxy)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine with a melting point of 121 - 124oC.

ED50this connection in the above experience BICM": 18,9 mg/kg

ED50this connection in the above experience "MESM": 73,7 mg/kg of the requested suspension of 0.48 g of sodium hydride in 35 ml of dry 1,2-dimethoxyethane. The mixture is stirred for 30 minutes, then added dropwise a solution of 2.27 g of 7-(1-bromacil)-1,2,4-triazole [1,5-a]pyrimidine is obtained analogous to example 6 with a reception in 85 ml of dry 1,2-dimethoxyethane. The reaction mixture was stirred at room temperature overnight. Sodium bromide is removed from the mixture by filtration. The solvent is evaporated from the mixture, and the residue is dissolved in dichloromethane and successively washed with 200 ml of 5% aqueous solution of sodium hydroxide and water. The organic phase is dried over magnesium sulfate. The solvent is evaporated, thus obtain the crude product, which was purified by column chromatography on silica gel using as eluent a mixture of ethyl acetate and petroleum ether in the ratio 6:4, followed by recrystallization from ethyl acetate. Obtain 1.07 g of 7-[1-(4-cianfrocca)ethyl] -1,2,4-triazole[1,5-a] -pyrimidine with a melting point of 163 - 164oC.

Percentage number of experimental mice, which experience "MESM" not manifested seizures, at the dosage of this compound, 100 mg/kg, was 60%.

Example 5.

of 1.62 g of 4-triptoreline serves to stir a suspension of 0.48 g of sodium hydride in 35 ml of dry 1,2-dimethoxyethane. The mixture peremeshivajutsa[1,5-a]pyrimidine, obtained analogous to example 6 with a reception in 85 ml of dry 1,2-dimethoxyethane. The mixture is stirred at room temperature for 24 hours. Sodium bromide is removed from the mixture by filtration. The solvent is evaporated from the filtrate and the residue is dissolved in dichloromethane and successively washed with 200 ml of 5% aqueous solution of sodium hydroxide and water. The organic phase is dried over magnesium sulfate. The solvent is evaporated, thus obtain the crude product, which was purified by column chromatography on silica gel using as eluent a mixture of petroleum ether and ethyl acetate in the ratio 6:4, followed by recrystallization from hexane. Obtain 1.1 g of 7-[1-(4-triptoreline)ethyl]-1,2,4 - triazole[1,5-a]-pyrimidine with a melting point of 100 - 102oC.

ED50this connection in the above experience BICM": 29,8 mg/kg

ED50this connection in the above experience "MESM": 52.1 mg/kg

Example 6.

The mixture 11,74 r 3-amino-1,2,4-thiazole and 16.5 r 1-chloro-1-penten-3-one in 225 ml of acetic acid is heated under reflux for 45 minutes. The reaction mixture is cooled, poured on ice and extracted with dichloromethane. The organic phase is dried and the solvent evaporated 4-triazole[1,5-a]pyrimidine, 12.63 g of N-bromosuccinimide, 0.3 g of dibenzoylperoxide and 270 ml of carbon tetrachloride for 5 hours with stirring is heated under reflux. The mixture is filtered and the solvent evaporated from the filtrate, thus obtain the crude product, which was purified by recrystallization from carbon tetrachloride. Obtain 10.8 g of 7-(1-bromacil)-1,2,4-triazole [1,5-a]pyrimidine.

A solution of 1.24 g of 4-methoxyphenol in dry 1,2-dimethoxyethane slowly served in stir a suspension of 0.48 g of sodium hydride in 35 ml of dry 1,2-dimethoxyethane. The mixture is stirred for 30 minutes, then added dropwise a solution of 2.27 r 7-(1-bromacil)-1,2,4-triazole [1,5-a]pyrimidine in 85 ml of dry 1,2-dimethoxyethane. The reaction mixture was stirred at room temperature overnight, filtered, and the solvent evaporated from the filtrate under reduced pressure. The residue is purified by flash chromatography using as eluent a mixture of ethyl acetate and petroleum ether, followed by recrystallization from a mixture of ethyl acetate and hexane. Get 1,67 g of 7-[1-(4-methoxyphenoxy)ethyl] -1,2,4-triazole[1,5-a]- pyrimidine with a melting point of 112 - 114oC.

ED50this connection in the above experience BICM": 93,3 mg/kg

Example 7.

g of sodium hydride in 35 ml of dry 1,2-dimethoxyethane. The mixture is stirred for 30 minutes, then added dropwise a solution of 2.27 g of 7-(1-bromacil)-1,2,4 - triazole[1,5-a]pyrimidine is obtained analogous to example 6 with a reception in 85 ml of dry 1,2-dimethoxyethane. The reaction mixture was stirred at room temperature for 4 hours. Sodium bromide is removed from the mixture by filtration. The solvent is evaporated from the mixture and the residue is dissolved in dichloromethane and successively washed with 200 ml of 5% aqueous solution of sodium hydroxide and water. The organic phase is dried over magnesium sulfate. The solvent is evaporated, thus obtain the crude product, which was purified by column chromatography on silica gel using as eluent a mixture of petroleum ether and ethyl acetate in the ratio 6:4, followed by recrystallization from a mixture of ethyl acetate and hexane. Get 2,69 g of 7-[1-(4-triftormetilfosfinov)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine with a melting point of 91 to 93oC.

ED50this connection in the above experience BICM": 11.4 mg/kg

ED50this connection in the above experience "MESM": 52,8 mg/kg

Example 8.

A solution of 1.36 g of 4-oxazolidinone in dry 1,2-dimethoxyethane slowly served in stir a suspension of 0.48 g of the guide is jut a solution of 2.27 g of 7-(1-bromacil)-1,2,4 - triazole[1,5-a]pyrimidine, obtained analogous to example 6 with a reception in 85 ml of dry 1,2-dimethoxyethane. The mixture is stirred at room temperature for 24 hours. Sodium bromide is removed from the mixture by filtration. The solvent is evaporated from the mixture and the residue is dissolved in dichloromethane and successively washed with 200 ml of 5% aqueous solution of sodium hydroxide and water. The solvent is evaporated, thus obtain the crude product, which will recrystallised of ethyl acetate. Obtain 0.87 g of 7-[1-(4-acetylphenol)ethyl]-1,2,4-triazole[1,5-a]- pyrimidine with a melting point of 136 to 138oC.

ED50this connection in the above experience BICM": 105,8 mg/kg

Example 9.

The solution 2,80 g of 4-(methylthio)phenol in dry 1,2-dimethoxyethane slowly served in a mixed suspension of 0.87 g of sodium hydride in 50 ml of dry 1,2-dimethoxyethane. The reaction mixture is stirred for 30 minutes, then added dropwise a solution of 4.54 g of 7-(1-bromacil)-1,2,4-triazole[1,5-a]- pyrimidine is obtained analogous to example 6 with a reception in 150 ml of dry 1,2-dimethoxyethane. The mixture is stirred at room temperature overnight. Sodium bromide is removed from the mixture by filtration. The solvent is evaporated from the mixture and the residue is dissolved in dichloromethane and Polekhina magnesium. The solvent is evaporated, thus obtain the crude product, which was purified by column chromatography on silica gel using as eluent a mixture of ethyl acetate and petroleum ether in the ratio of 4:6, followed by recrystallization from a mixture of ethyl acetate and hexane. Get 3,66 g of 7-{1-[4-(methylthio)phenoxy]ethyl}- 1,2,4-triazole[1,5-a]-pyrimidine with a melting point of 84 - 86oC.

Percentage number of experimental mice, which experience "MESM" not manifested seizures, at the dosage of this compound, 50 mg/kg, was 50%.

Example 10.

The solution to 0.63 g of 3-chlormadinone acid in 30 ml dichloromethane dropwise at a temperature of -78oC served in a mixed solution of 0.89 g of 7-{1-[4-(methylthio)phenoxy]ethyl}-1,2,4-triazole[1,5-a]-pyrimidine is obtained analogous to example 9 with a reception in 30 ml of dichloromethane. The reaction mixture is stirred at a temperature of -78oC for 2 hours, washed with 10% aqueous sodium bicarbonate solution and water. The organic phase is dried and the solvent evaporated under reduced pressure. The residue is purified by flash chromatography using as eluent a mixture of dichloromethane and ethanol in a ratio of 95: 5, followed by recrystallization from a mixture of etenia 89 - 102oC.

Percentage number of experimental mice, which experience BICM" not manifested seizures, at the dosage of this compound, 100 mg/kg, was 60%.

Example 11.

A solution of 2.13 g of 3-chlormadinone acid in 50 ml dichloromethane dropwise at room temperature served in a mixed solution of 1.2 g of 7-{1-[4-(methylthio)phenoxy]ethyl}-1,2,4-triazole[1,5-a]-pyrimidine is obtained analogous to example 9 with a reception in 70 ml of dichloromethane. The reaction mixture is stirred for 3 hours, washed with 10% aqueous sodium bicarbonate solution and water. The organic phase is dried and the solvent evaporated under reduced pressure. The residue is purified by flash chromatography using ethyl acetate as eluent, followed by recrystallization from ethanol. Get to 0.72 g of 7-[1-(4-methylsulfinylphenyl)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine with a melting point of 163 - 164oC.

Percentage number of experimental mice, which experience BICM" not manifested seizures, at the dosage of this compound, 100 mg/kg, was 60%.

Example 12.

A solution of 1.54 g of 4-(ethylthio)phenol in dry 1,2-dimethoxyethane slowly served in stir a suspension of 0.48 g of sodium hydride in 35 ml bromacil)-1,2,4 - triazole[1,5-a]pyrimidine, obtained analogous to example 6 with a reception in 85 ml of dry 1,2-dimethoxyethane. The mixture is stirred at room temperature overnight. Sodium bromide is removed from the mixture by filtration. The solvent is evaporated from the mixture and the residue is dissolved in dichloromethane and successively washed with 200 ml of 5% aqueous solution of sodium hydroxide and water. The organic phase is dried over magnesium sulfate. The solvent is evaporated, thus obtain the crude product, which was purified by column chromatography on silica gel using as eluent a mixture of diethyl ether and ethyl acetate in the ratio 6:4, followed by recrystallization from a mixture of ethyl acetate with hexane. Obtain 2.28 g of 7-{1-[4-(ethylthio)phenoxy]ethyl}- 1,2,4-triazole[1,5-a]-pyrimidine with a melting point of 65 - 67oC.

ED50this connection in the above experience BICM": 48,9 mg/kg

Example 13.

A solution of 1.28 g of 3-chlorophenol in dry 1,2-dimethoxyethane slowly served in stir a suspension of 0.48 g of sodium hydride in 35 ml of dry 1,2-dimethoxyethane. The mixture is stirred for 30 minutes, then added dropwise a solution of 2.27 g of 7-(1-bromacil)-1,2,4-triazole [1,5-a]pyrimidine is obtained analogous to example 6 with a reception in 85 ml of dry 1,2-Eitel under reduced pressure evaporated from the mixture. The residue is purified by flash chromatography using as eluent a mixture of ethyl acetate and petroleum ether. Get 2,11 g of 7-[1-(3-chloro-phenoxy)ethyl]-1,2,4 - triazole[1,5-a]-pyrimidine with a melting point of 124 -126oC.

Percentage number of experimental mice, which experience BICM" not manifested seizures, at the dosage of this compound, 100 mg/kg, was 78%.

Percentage number of experimental mice, which experience "MESM" not manifested seizures, at the dosage of this compound, 100 mg/kg, was 60%.

Example 14.

A solution of 1.30 g of 2,4-differenoe in dry 1,2-dimethoxyethane slowly served in stir a suspension of 0.48 g of sodium hydride in 35 ml of dry 1,2-dimethoxyethane. The mixture is stirred for 30 minutes, then added dropwise a solution of 2.27 g of 7-(1-bromacil)-1,2,4 - triazole[1,5-a]pyrimidine is obtained analogous to example 6 with a reception in 85 ml of dry 1,2-dimethoxyethane. The reaction mixture was stirred at room temperature overnight. Sodium bromide is removed from the mixture by filtration. The solvent is evaporated from the mixture and the residue is dissolved in dichloromethane and successively washed with 200 ml of 5% aqueous solution of sodium hydroxide and water. The solvent of the label as eluent a mixture of dichloromethane and ethanol in a ratio of 97:3, followed by recrystallization from a mixture of ethyl acetate and hexane. Obtain 1.8 g of 7-[1- (2,4-divergence)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine with a melting point of 96 - 97oC.

ED50this connection in the above experience BICM": 37.5 mg/kg

Example 15.

A mixture of 4.66 g of 3-(2,4-dichlorophenoxy)-2-butanone and of 2.38 g of N,N-dimethylformamide-dimethylacetal in the atmosphere of argon in a bath of oil heated at a temperature of 120oC for 11 hours. The resulting methanol is removed under reduced pressure and the residue using n-hexane grind him to powder. The solid is collected by filtration and washed with cold diethyl ether. Get 4,07 g of 4-(2,4-dichlorophenoxy)-1-(dimethylamino)-1-penten-C-it.

A solution of 2.9 g of 4-(2,4-dichlorophenoxy)-1-(dimethylamino)-1-penten-3-one in 25 ml of glacial acetic acid added to mixed solution of 0.93 g of 3-amino-1,2,4-triazole in 25 ml of glacial acetic acid. The mixture is heated for 5 hours under reflux, then cooled to room temperature. The mixture is poured into 200 ml ice water and extracted with toluene. The extracts are successively washed with 10% aqueous sodium bicarbonate solution and water, dried over non-aqueous magnesium sulfate, rastvoritelyami the solid is collected by filtration and recrystallized from a mixture of ethyl acetate and petroleum ether with a boiling within 40 - 60oC. thus receive 2,02 g of 7-[1-(2,4-dichlorophenoxy)ethyl]-1,2,4-triazole[1,5-a]pyrimidine with a melting point of 137 to 138oC.

ED50this connection in the above experience BICM": 39,7 mg/kg

ED50this connection in the above experience "MESM": 109,7 mg/kg

Example 16

A solution of 1.22 g of 3,4-dichlorophenol in dry 1,2-dimethoxyethane slowly served in stir a suspension of 0.33 g of sodium hydride in 30 ml of dry 1,2-dimethoxyethane. The mixture is stirred for 30 minutes, then added dropwise a solution of 1.68 g of 7-(1-bromacil)-1,2,4 - triazole[1,5-a]pyrimidine is obtained analogous to example 6 with a reception in 60 ml of dry 1,2-dimethoxyethane. The reaction mixture was stirred at room temperature overnight. Sodium bromide is removed from the mixture by filtration. The solvent is evaporated from the mixture and the residue is dissolved in dichloromethane and successively washed with 200 ml of 5% aqueous solution of sodium hydroxide and water. The organic phase is dried over magnesium sulfate. The solvent is evaporated, thus obtain the crude product, which was purified by column chromatography on silica gel using as eluent a mixture of ethyl acetate and petroleum ether in the ratio of 4:6, with subsequent recr the ina with a melting point of 146 - 149oC.

Percentage number of experimental mice, which experience BICM" not manifested seizures, at the dosage of this compound, 100 mg/kg, was 50%.

Example 17.

A mixture of 0.65 g of 2-chloro-4-terfenol and 210 mg of sodium hydride in 15 ml of dry 1,2-dimethoxyethane stirred at room temperature for 30 minutes. A solution of 1 g of 7-(1-bromacil)-1,2,4-triazole[1,5-a]- pyrimidine is obtained analogous to example 6 with a reception in 35 ml of 1,2 - dimethoxyethane dropwise served in the above stir the mixture. The mixture is stirred at room temperature for 21 hours, filtered and the solvent under reduced pressure evaporated from the filtrate. The residue is dissolved in dichloromethane, washed sequentially with 5% aqueous solution of sodium hydroxide and water, dried over non-aqueous magnesium sulfate and the solvent is removed under reduced pressure. The solid residue purified by flash chromatography on silica gel using as eluent a mixture of ethyl acetate and petroleum ether in the ratio 1:1, followed by recrystallization from a mixture of ethyl acetate and hexane. Get 0,99 g of 7-[1-(2-chloro-4-pertenece)-ethyl]-1,2,4-triazole[1,5-a]-pyrimidine with a melting point of 89 - 91oC.

Percentage Choi 100 mg/kg, was 50%.

ED50this connection in the above experience "MESM": 66,0 mg/kg

Example 18.

The solution was 1.58 g of 4-(4-chlorophenoxy)-1-(dimethylamino)-1-penten-3-one, obtained similar to example 2, 5 ml glacial acetic acid added to mixed solution of 0.62 g of 3-amino-5-methyl - 1,2,4-triazole in 10 ml of glacial acetic acid. The mixture is heated for 2.5 hours under reflux, then cooled to room temperature. The mixture is poured into 50 ml ice water and extracted with toluene. The extracts are successively washed with 10% aqueous sodium bicarbonate solution and water, dried over non-aqueous magnesium sulfate, the solvent was evaporated under reduced pressure. The remainder using cold diethyl ether pounded into powder, the resulting solid is collected by filtration and recrystallized from a mixture of ethyl acetate and petroleum ether with a boiling within 40 - 60oC, you get a 1.13 g of 7-[1-(4-chlorophenoxy)ethyl]- 2-methyl-1,2,4-triazole[1,5-a]pyrimidine with a melting point of 138oC.

ED50this connection in the above experience BICM": 78,2 mg/kg

ED50this connection in the above experience "MESM": to 107.7 mg/kg

Example 1 is ten-3-one, 6.5 g of 3-amino-1,2,4-triazole and glacial acetic acid for 1.5 hours, heated under reflux. The reaction mixture is poured on ice and extracted with dichloromethane. The organic phase is dried over magnesium sulfate, and the solvent evaporated to obtain a solid substance. The crude product is purified by flash chromatography using as eluent a mixture of dichloromethane and ethanol in a ratio of 97:3, followed by recrystallization from carbon tetrachloride. Get 10,15 g of 7-chloromethyl - 1,2,4-triazole[1,5-a]pyrimidine.

of 2.18 g of 4-chlorophenol, of 0.92 g of sodium methylate and 150 ml of dry methanol under stirring for 1 hour, heated under reflux. The solvent is removed under reduced pressure. 2.8 g of 7-chloromethyl-1,2,4-triazole-[1,5-a]pyrimidine and 170 ml of dry 1,2 - dimethoxyethane served in the crude reaction mixture. The mixture is heated with stirring under reflux for 10 hours. The solvent is evaporated under reduced pressure and the crude product purified by flash chromatography using ethyl acetate as eluent, followed by recrystallization from ethyl acetate. Obtain 0.26 g of 7-(4-chlorphenoxy)-1,2,4-triazole[1,5-a]pyrimidine with a melting point of 193 - 194oC.

Percentage Choi 100 mg/kg, was 70%.

Example 20.

27,2 g non-aqueous aluminium chloride is served in a mixed solution of 23.4 g of 2-methylpropionamide in 100 ml dry trichloromethane, while the reaction mixture was externally cooled to a temperature of 0 to 15oC. for 1 hour through the mixture, which is maintained at a temperature of 24 -26oC, serves 20 g chlorethane, after which stirring is continued for another 40 minutes. The reaction mixture is poured on ice, the organic phase is separated, dried over magnesium sulfate and distilled under reduced pressure to obtain 23 g of 1,1-dichloro-4-methyl-3-pentanone as a colorless liquid.

of 12.53 g of 1,1-dichloro-4-methyl-3-pentanone mixed with 6,23 g of sodium bicarbonate and 30 ml of water. The mixture is heated under reflux for 4 hours, cooled and extracted with trichloromethane. The organic phase is dried over magnesium sulfate and distilled under reduced pressure. You get to 5.93 g of 1-chloro - 4-methyl-1-penten-3-one as a colorless liquid.

A mixture of 5.83 g of 1-chloro-4-methyl-1-penten-3-it, of 3.69 g of 3-amino-1,2,4 - triazole and glacial acetic acid for 1.5 hours, heated under reflux. The reaction mixture is poured on ice and extracted with dichloromethane. Organic fatalist from petroleum ether with a boiling within 100 - 140oC. thus receive 4,18 g of 7-(1-methylethyl)-1,2,4-triazole[1,5-a]pyrimidine.

The mixture 4,18 g of 7-(1-methylethyl)-1,2,4-triazole[1,5-a]pyrimidine, 4.59 g of N-bromo-succinimide and 70 mg dibenzoylperoxide in 105 ml of carbon tetrachloride with stirring for 11 hours and heated under reflux. The mixture is filtered and the solvent removed from the filtrate to obtain 2,94 g of 7-(1-bromo-1-methylethyl)-1,2,4-triazole[1,5-a]pyrimidine.

The mixture 2,95 g of 7-(1-bromo-1-methylethyl)-1,2,4-triazole[1,5-a]pyrimidine is obtained analogously to the above described reception, 1.56 g of 4-chlorophenol, 1 g of sodium bicarbonate, 5 mg of acetylacetone Nickel d 80 ml dry toluene under stirring for 7 days is heated under reflux. The solvent is evaporated and the crude product purified by flash chromatography using as eluent a mixture of toluene and ethyl acetate in the ratio of 5:1, followed by recrystallization from n-hexane. Get to 0.67 g of 7-[1-(4-chlorophenoxy)-1-methylethyl]-1,2,4 - triazole[1,5-a]pyrimidine with a melting point of 132 - 135oC.

ED50this connection in the above experience "MESM": 45.0 mg/kg

Example 21.

A solution of 10 g of 3-chloro-2-pentanone in 50 l of acetone dropwise serving stir in a mixture of 11 g of 4-chlorophenol, 20 g of bicarbona the s ' fridge. The mixture is filtered washed with acetone, and the acetone evaporated under reduced pressure. The residue is dissolved in 150 ml diethyl ether and the ethereal mixture was successively washed with 300 ml of 10% aqueous solution of sodium hydroxide and 300 ml of water. The mixture is dried over magnesium sulfate. The solvent is evaporated and the residue is distilled under reduced pressure. You get 10,96 g 3-(4-chlorophenoxy)-2-pentanone.

The solution 10,96 3-(4-chlorophenoxy)-2-pentanone and 6 g of N,N - dimethylformamide-dematiaceous in the atmosphere of argon in a bath of oil heated at a temperature of 120oC for 24 hours. Produced during the reaction, the methanol is removed under reduced pressure and the residual oil as 12,71 g of 4-(4-chlorophenoxy)-1-(dimethylamino)-1-HEXEN-3-it is directly used in the next stage.

The solution 12,67 g of 4-(4-chlorophenoxy)-1-(dimethylamino)-1-HEXEN-3-one in 75 ml of glacial acetic acid added to mixed solution of 3.78 g of 3-amino-1,2,4-triazole in 75 ml of glacial acetic acid. The solution for 2 hours, heated under reflux, after which the mixture is poured into 200 ml of water and extracted with toluene. The organic phase is successively washed with 10% aqueous sodium bicarbonate solution and water, dried over non-aqueous sulfate Eaut in powder, the resulting solid is collected by filtration and recrystallized from a mixture of ethyl acetate and hexane, thus receive of 4.54 g of 7-[1-(4-chlorphen-oksipropil)]-1,2,4 - triazole[1,5-a]pyrimidine with a melting point of 108 - 109oC.

ED50this connection in the above experience BICM": 38,6 mg/kg

ED50this connection in the above experience "MESM": 79,4 mg/kg

Example 22.

30 g of racemic 7-[1-(4-pertenece)ethyl]-1,2,4-triazole [1,5-a]-pyrimidine is obtained similar to example 1 reception, separated into individual enantiomers by high-performance liquid chromatography on a column of type Chiralcel OD inner dimensions of 50 cm x 10 cm, using as eluent a mixture of isohexane and isopropanol in a ratio of 1:1. At the same time as the first elyuirovaniya faction get(+)-7-[1-(4-pertenece)ethyl] -1,2,4-triazole[1,5-a]-pyrimidine with an optical purity higher than 99% and a specific rotation []rDt= +116,5 (C = 1; methanol). Yield: 10 g of product with a melting point of 100 - 102oC.

ED50this connection in the above experience BICM": 48,3 mg/kg

ED50this connection in the above experience "MESM": 56,9 mg/kg

Example 23.

rDt= -118,1oC (C = 1; methanol). Yield: 9.5 g of product with a melting point of 100 - 102oC.

ED50this connection in the above experience BICM": 12,7 mg/kg

ED50this connection in the above experience "MESM": 79,8 mg/kg

Example 24.

5 g of racemic 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-thiazol[1,5-a]- pyrimidine is obtained analogous to example 2 reception, separated into individual enantiomers by high-performance liquid chromatography on a column of type Chiralcel OD inner dimensions of 50 cm x 10 cm, using as eluent a mixture of isohexane and isopropanol in a ratio of 1:1. At the same time as the first elyuirovaniya faction get(+)-7-[1-(4-chlorophenoxy)ethyl] -1,2,4-triazole[1,5-a]-pyrimidine with an optical purity higher than 99% and a specific rotation []rDt= +133,7o. Yield: 1.8 g of product with a melting point of 98 - 99oC.

ED50this connection in the above experience BICM": 28,1 mg/kg

ED50this connection in the above experience "MESM": 80,8 mg/kg

In the following examples 24A and 246 are illustrated further methods of obtaining(+)-7-[1 -(4--a]-pyrimidine, obtained analogous to example 6 reception, 32,8 g (R)-almond acid, 30 ml of triethylamine and 500 ml of dioxane are mixed and heated on the steam bath for 2.5 hours. The mixture is cooled and the solvent evaporated under reduced pressure. The solid residue is dissolved in 400 ml ethyl acetate and washed with 300 ml of water. Water wash liquid is extracted with 200 ml of ethyl acetate, and the organic layer is successively washed with 200 ml of water, 10 ml of triethylamine, 100 ml of water and 100 ml brine. The organic layer is dried over magnesium sulfate is heated in the presence of active charcoal, filtered and the solvent evaporated from the filtrate. It is 10.75 g of a mixture of two diastereoisomers: (R) complex ethyl ester (+)-1-(1,2,4-triazole[1,5-a] -pyrimidine-7-yl)-almond acid and (R) complex ethyl ester (-)-1-(1,2,4-triazole[1,5-a] -pyrimidine-7 - yl)-almond acid.

A mixture of two diastereoisomers received the above method, is subjected to fractionated crystallization using ethyl acetate as solvent. Get two fractions: the first fraction as 2.8 g of the less polar diastereoisomer, and the second fraction as of 3.3 g of the more polar diastereoisomer.

0.7 g of the less polar diastereoisomer obtained within 2 hours. The solution was diluted with 100 ml of water and during the night continuously extracted with dichloromethane. The extracts are dried over magnesium sulfate and the solvent evaporated to obtain 0.27 g of (+)-1-(1,2,4-triazole[1,5-a]-pyrimidine-7-yl)ethanol.

A mixture of 0.27 g of (+)-1-(1,2,4-triazole[1,5-a]-pyrimidine-7-yl)ethanol, 0.29 grams of diethylazodicarboxylate, of 0.44 g of triphenylphosphine and 0.22 g of 4-chlorophenol in 40 ml of dry tetrahydrofuran was stirred at room temperature for 2 days. Add 0.15 g of diethylazodicarboxylate and 0.22 g of triphenylphosphine and the solution is stirred overnight before the end of the reaction. The solvent is removed under reduced pressure and the residue is dissolved in 100 ml of ethyl acetate. The resulting solution was sequentially washed with 40 ml of 1 m solution of sodium hydroxide and 20 ml of brine. The solvent is evaporated. The residue is purified by flash chromatography on silica gel using as eluent a mixture of triethylamine and ethyl acetate in the ratio of 1:100. Obtain 0.33 g(+)-7-[1-(4-chlorphenoxy)-ethyl]-1,2,4-triazole- [1,5-a]pyrimidine.

Example 24B.

A mixture of 10.6 g of 3-chlorobutane, 15.0 g of benzoic acid, 30 ml of triethylamine and 100 ml of acetonitrile is heated under reflux for 1.5 hours. The mixture is cooled and filtered to remove acadiau in ethyl acetate and washed with water. The organic extracts are dried over magnesium sulfate, filtered over active charcoal, and the solvent is removed from the filtrate under reduced pressure. Obtain 16.7 g of 3-benzoyloxymethyl-2-she as a yellow oil, which was used in the next stage without further purification.

A mixture of 15.5 g of 3-benzoyloxymethyl-2-she and 14.4 g of dimethylformamide-dimethylacetal for 2.5 hours heated on the steam bath. The solvent is removed from the mixture under reduced pressure. In the remainder Strahovanie serves petroleum ether with a boiling within 60 - 80oC. the Ether layer is separated from the insoluble red oil. When Strahovanie in oil serves more petroleum ether and excess ether is removed under reduced pressure. You get a reddish-brown oil, which, when allowed to stand over night, partially crystallizes. Add petroleum ether, and the solid is collected by filtration and washed with petroleum ether. Thus obtain 5.6 g of 4-benzoyloxy-1-dimethylamino-1-penten-3-one. The obtained solid substance use in the next stage without further purification.

A mixture of 1.78 g of aminotriazole and 5.0 g of 4-benzoyloxy-1-dimethylamino - 1-penten-Z-she's in 25 ml of acetic acid is heated with the ATA sodium and extracted with 200 ml of ethyl acetate. The organic extracts are dried over magnesium sulfate, filtered and the solvent removed from the filtrate under reduced pressure. To the solid residue is added diethyl ether. The solid residue is collected by filtration to obtain 3.8 g of 1-(1,2,4-triazole-[1,5-a] pyrimidine-7-yl)ethyl-benzoate as a pale brown solid.

A mixture of 1 g of 1-(1,2,4-triazole-[1,5-a] pyrimidine-7-yl)ethyl benzoate, 2 g of potassium carbonate, 25 ml of methanol and 20 ml of water is stirred at room temperature for 1.5 hours. Methanol is removed from the mixture under reduced pressure, after which the mixture was diluted with 20 ml of brine and night continuously extracted with dichloromethane. The extracts are dried over magnesium sulfate and the solvent evaporated under reduced pressure to obtain 0.39 g of 1-(1,2,4-triazole-[1,5-a]pyrimidine-7-yl)ethanol.

A solution of 1 g (1,2,4-triazole-[1,5-a]pyrimidine-7-yl)ethanol obtained similarly to the above-described reception in 30 ml of dichloromethane for 30 minutes, dropwise served in a solution of 0.5 ml of thionyl chloride in 50 ml dichloromethane, which is heated under reflux and heating continued for another 2 hours. Add another 0.5 ml of thionyl chloride, and heating continued overnight. Dichloromethane is removed by distillation of the Tria, water wash liquid is extracted with 20 ml dichloromethane. Dichloromethane solutions are combined washed with 40 ml brine, dried over magnesium sulfate, and the solvent evaporated. Thus obtain 1.0 g of 7-(1-chloroethyl)-1,2,4-triazole-[1,5-a] pyrimidine as a light brown solid. 3,81 ml of triethylamine are served in a mixture of 4.16 g (R)-almond acid in 50 ml of dry acetonitrile, dried over molecular sieve hole size equal to 4A. After 5 minutes the mixture is fed from 0.90 g of 7-(1-chloroethyl)-1,2,4-triazole-[1,5-a]pyrimidine. The mixture during the night heated under reflux and the solvent evaporated under reduced pressure at a temperature of 60oC. the Residue is extracted with 100 ml ethyl acetate and 50 ml of water. An ethyl acetate layer washed sequentially with a mixture of 20 ml of water and 3 ml of 1 m sodium bicarbonate solution and 20 ml of brine. The solution is dried over magnesium sulfate and the solvent is removed under reduced pressure at a temperature of 60oC. this gain of 1.33 g of a mixture of two diastereoisomers: (R) complex ethyl ester (+)-1-(1,2,4-triazole[1,5-a] -pyrimidine-7-yl)-almond acid and (R) complex ethyl ester (-)-1-(1,2,4-triazole[1,5-a] -pyrimidine-7-yl)- almond acid. Less polar diastereoisomer can be distinguished by frcsi)ethyl]- 1,2,4-triazole[1,5-a]-pyrimidine (after (+)-1-(1,2,4-triazole[1,5-a]- pyrimidine-7-yl)ethanol as an intermediate product).

Example 25.

From racemic 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazole [1,5-a]-pyrimidine by high-performance liquid chromatography technique similar to that described in example 24 as a second elyuirovaniya faction allocate 1.9 grams(-)-7-[1-(4-chlorophenoxy)ethyl]- 1,2,4-triazole[1,5-a]-pyrimidine. Optical purity higher than 98%; specific rotation []rDt-132,6o; the melting point of 99 - 100oC.

ED50this connection in the above experience BICM": 9,4 mg/kg

ED50this connection in the above experience "MESM": 77,2 mg/kg

In the following example 25A illustrates a further method of obtaining(-)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazole[1,5-a]-pyrimidine.

Example 25A.

A solution of 10.75 g of a mixture of two diastereoisomers (R) esters (+) and (-) 1-(1,2,4-triazole[1,5-a] -pyrimidine-7-yl)-almond acid obtained analogous to example 24A or 24B reception, ethyl acetate is subjected to fractional crystallization to obtain two fractions: 2.8 g of the less polar diastereoisomer as a first fraction and 3.3 g of the more polar diastereoisomer as the second fraction. 0.7 g of the more polar diastereoisomer from the second fraction of 1.61 g of potassium carbonate, 10 years and within 2 hours continuously extracted with dichloromethane. The extracts are dried over magnesium sulfate and the solvent evaporated to obtain 0.28 g of (-)-1-(1,2,4 - triazole[1,5-a]-pyrimidine-7-yl)ethanol.

A mixture of 0.27 g of (-)-1-(1,2,4-triazole[1,5-a]-pyrimidine-7-yl)ethanol of 0.44 g of diethylazodicarboxylate, of 0.68 g of triphenylphosphine and 0.22 g of 4-chlorophenol in 20 ml of dry tetrahydrofuran leave to stand over night at room temperature until completion of the reaction. The solvent is removed under reduced pressure and the residue is dissolved in 100 ml of ethyl acetate. The solution is successively washed with 40 ml of 1 m solution of sodium hydroxide and 20 ml of brine and the solvent evaporated. The residue is purified by flash chromatography on silica gel using as eluent a mixture of triethylamine and ethyl acetate in the ratio of 1:100. Obtain 0.26 g(-)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4 - triazole-[1,5-a]-pyrimidine.

Example 26

A.

20 g of racemic 7-[1-(4-triftormetilfosfinov)ethyl]-1,2,4-triazolo [1,5-a] pyrimidine separated into the enantiomers by HPLC on silica gel type chiracel column with internal dimensions 50 x 10 cm, using as eluent a mixture of isohexane and ethanol in the ratio of 9 : 1. As a first fraction receive(+)-7-[1-(4- triftormetilfosfinov)ethyl] -1,2,4-Tricolore dissolved in diethyl ether, and the resulting solution is saturated with gaseous hydrogen chloride. You get 9,46 g of the hydrochloride(+)-7-[1-(4-triftormetilfosfinov)ethyl] -1,2,4 - triazolo[1,5-a]pyrimidine with so pl. 156-158oC. []2D2: +70,6o(c=1,03; CH3OH).

B.

The above-mentioned liquid chromatography is obtained as the second fraction(-)-7-[1-(4-triftormetilfosfinov)ethyl] - 1,2,4-triazolo[1,5-a] pyrimidine with 98% optical purity. The free base is an orange oil, which was dissolved in diethyl ether and the resulting solution is saturated with gaseous hydrogen chloride. Thus obtain 7.2 g of the hydrochloride(-)-7-[1-(4-triftormetilfosfinov)ethyl]-1,2,4-triazolo [1,5-a]pyrimidine with so pl. 156 - 158oC []2D2: 73,9o(C=1,0; CH3OH).

Examples of pharmaceutical compositions.

Example A.

Tablet composition (in weight. part): 10 active principle, 190 lactose, 22 corn starch, 10-vinylpyrrolidone and 3 stearate prepared as follows.

The active principle, lactose and a portion of the corn starch are crushed, mixed and the resulting mixture granularit with a solution of polyvinylpyrrolidone in ocemuw the mixture is served in tablet press machine with the to obtain tablets each containing 10 mg of active principle.

Example B.

Tablets are prepared in the same manner as described in example A. Then on the pill known techniques applied coating consisting of a solution of 20% phthalate cellulose acetate and 3% diethylphthalate in a mixture of ethanol and dichloromethane in the ratio of 1:1 by volume) as solvent.

Example Century.

In the preparation of capsules 10 weight. parts of the active agent and 240 weight. parts of lactose pulverize and mix. The resulting mixture is loaded into capsules of hard gelatin so that each capsule contains 10 mg of active principle.

Example,

In the preparation of capsules 50 weight. parts of the active principle, 300 weight. parts of lactose and 3 weight. part of stearate pulverize and mix. The resulting mixture is loaded into capsules of hard gelatin so that each capsule contains 50 mg of active principle.

Example D.

In the preparation of suppository 100 weight.parts active start fire in the 1300 weight.parts of a mixture of synthetic triglycerides, and the resulting mixture was transferred to suppositories, each containing 100 mg of the asset is up in basis consisting of 9,9 g white soft paraffin by homogenization before the active principle evenly distributed. 10 g ointment load in amber jars with nevertime covers.

1. Derivatives of 1,2,4-triazolo[1,5-a]pyrimidines of General formula I

where R1, R4and R5are hydrogen atom or alkyl with 1 to 6 carbon atoms;

R2and R3are a hydrogen atom;

R6, R7and R8independently from each other are hydrogen atom, halogen, cyano, alkanoyl with 1 to 6 carbon atoms, alkoxyl with 1 to 6 carbon atoms, unsubstituted or substituted by halogen, alkylthio with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, alkyl with 1 to 6 carbon atoms, unsubstituted or substituted by halogen,

in this case, if R1, R2, R3, R4and R8- hydrogen atoms, R5is methyl, R6and R7hydrogen atoms, or R6- 4-chloro and R7is a hydrogen atom or a 2-chloro, the compound of formula I is not a racemate,

and their pharmaceutically acceptable salts and stereoisomers.

2. Derivatives of 1,2,4-triazolo[1,5-a]pyrimidines of General formula I on p. 1, where R1, R4and is kind; R6, R7and R8independently from each other are hydrogen atom, halogen, cyano, alkyl with 1 to 4 carbon atoms, unsubstituted or substituted by halogen, alkoxyl with 1 to 4 carbon atoms, unsubstituted or substituted by halogen, alkanoyl with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, alkylsulfonyl with 1 to 4 carbon atoms and alkylsulfonyl with 1 to 4 carbon atoms.

3. Derivatives of 1,2,4-triazolo[1,5-a]pyrimidines of General formula I under item 1 or 2, where R1is a hydrogen atom or stands; R4and R5independently of one another are a hydrogen atom, stands or ethyl; R6, R7and R8independently from each other are hydrogen atom, fluorine, chlorine, bromine, cyano, trifluoromethyl, metaxylem, cryptomaterial, acetyl, methylthiourea, ethylthiourea, methylsulfinyl or methylsulfonyl.

4. Derivatives of 1,2,4-triazolo[1,5-a]pyrimidines of General formula I according to any one of the preceding paragraphs, selected from the group including:

7-[1-(4-pertenece)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-bromophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-cianfrocca)ethyl]-1,2,4-the XI)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-triftormetilfosfinov)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-acetylphenol)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-{1-[4-(methylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-methylsulfinylphenyl)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-methysulfonylmethane)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-{1-[4-(ethylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(3-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(2,4-divergence)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(2,4-dichlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(3,4-dichlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(2-chloro-4-pertenece)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-chlorophenoxy)ethyl]-2-methyl-1,2,4-triazolo[1,5-a]pyrimidine;

7-(4-chlorphenoxy)-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-chlorophenoxy)-1-methylethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;

7-[1-(4-chlorophenoxy)propyl]-1,2,4-triazolo[1,5-a]-pyrimidine.

5. Derivatives of 1,2,4-triazolo[1,5-a]pyrimidines of General formula I according to any one of the preceding paragraphs, selected from the group including:

(+)-7-[1-(4-pertenece)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

(-)-7-[1-(4-pertenece)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

(+)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]feast is bladaya anticonvulsant activity, which includes the active principle on the basis of the nitrogen-containing heterocyclic compounds and pharmaceutically acceptable diluent or carrier, characterized in that the active principle on the basis of the nitrogen-containing heterocyclic compounds it contains a compound of General formula II

< / BR>
where R'1, R'4and R'5are hydrogen atom or alkyl with 1 to 6 carbon atoms;

R'2and R'3are a hydrogen atom;

R'6, R'7and R'8independently from each other are hydrogen atom, halogen, cyano, alkanoyl with 1 to 6 carbon atoms, alkoxyl with 1 to 6 carbon atoms, unsubstituted or substituted by halogen, alkylthio with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, alkyl with 1 to 6 carbon atoms, unsubstituted or substituted by halogen,

or its pharmaceutically acceptable salt or stereoisomer in therapeutically effective amounts.

7. The pharmaceutical composition according to p. 6, characterized in that the active principle on the basis of the nitrogen-containing heterocyclic compounds it contains a compound of General formula II, where R'1, R'4and R'5JW is;

R'6, R'7and R'8independently from each other are hydrogen atom, halogen, cyano, alkyl with 1 to 4 carbon atoms, unsubstituted or substituted by halogen, alkoxyl with 1 to 4 carbon atoms, unsubstituted or substituted by halogen, alkylthio with 1 to 4 carbon atoms, unsubstituted or substituted by halogen, alkanoyl with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, alkylsulfonyl with 1 to 4 carbon atoms and alkylsulfonyl with 1 to 4 carbon atoms.

8. The pharmaceutical composition under item 6 or 7, characterized in that the active principle on the basis of the nitrogen-containing heterocyclic compounds it contains a compound of General formula II, where R'1is a hydrogen atom or stands; R'4and R'5independently of one another are a hydrogen atom, stands or ethyl; R'6, R'7and R'8independently from each other are hydrogen atom, fluorine, chlorine, bromine, cyano, trifluoromethyl, metaxylem, cryptomaterial, acetyl, methylthiourea, ethylthiourea, methylsulfinyl or methylsulfonyl.

9. The pharmaceutical composition according to any one of paragraphs.6 to 8, characterized in that the active principle on the basis of azusagawa:

7-[1-(4-pertenece)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-bromophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-cianfrocca)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-triptoreline)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-methoxyphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-triftormetilfosfinov)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-acetylphenol)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-{1-[4-(methylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-methylsulfinylphenyl)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-methylsulfinylphenyl)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-{1-[4-(ethylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(3-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(2,4-divergence)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(2,4-dichlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(3,4-dichlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(2-chloro-4-pertenece)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-chlorophenoxy)ethyl]-2-methyl-1,2,4-triazolo[1,5-a]pyrimidine;

7-(4-chlorphenoxy)-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-chlorophenoxy)-1-methylethyl]-1,2,4-triazolo[1,5-a]pyrimidine;

7-[1-(4-chlorine is ecaudata fact, as active principle on the basis of the nitrogen-containing heterocyclic compounds it contains a compound of General formula II, selected from the group including:

(+)-7-[1-(4-pertenece)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;

(-)-7-[1-(4-pertenece)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;

(+)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;

(-)-7-[1-(4-pertenece)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine.

11. Method of inhibiting seizures by giving people or animals nitrogen-containing heterocyclic compounds, characterized in that as the nitrogen-containing heterocyclic compounds used as a compound of General formula I

< / BR>
where R1, R4and R5are hydrogen atom or alkyl with 1 to 6 carbon atoms;

R2and R3are a hydrogen atom;

R6, R7and R8independently from each other are hydrogen atom, halogen, cyano, alkanoyl with 1 to 6 carbon atoms, alkoxyl with 1 to 6 carbon atoms, unsubstituted or substituted by halogen, alkylthio with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, alkyl with 1 to 6 carbon atoms, unsubstituted or substituted by halogen, Il the

 

Same patents:

The invention relates to compounds and their pharmaceutically acceptable salts, having the ability to inhibit matrix metalloprotease, in particular interstitial collagenase, and therefore suitable for the treatment of painful conditions in mammals, facilitated by the inhibition of such matrix metalloprotease

The invention relates to a new protected bicyclic to amidines formula I, where a is chosen from the group

-CR1R2-CR3R4-CR5R6-; -CR1R2-CR3R4-CR5R6-CR7R8< / BR>
or

-CR1R2-CR3R4-CR5R6-CR7R8-CR9R10,

where the substituents in And respectively numbered, starting from a nitrogen atom;

In choosing from the group of CR11R12-CR13R14-, -CR11R12-CR15R16-CR17R18-CR13R14;

R1and R14respectively independently of one another denote hydrogen, C1-C4-alkyl;

R15-R18respectively independently of one another denote hydrogen, C1-C4-alkyl, or at least one of R15-R18means amino, C1-C4-alkylamino-, or substituted amino group or C1-C4-alkylaminocarbonyl C1-C4-alkyl;

and the way they are received

The invention relates to fungicidal compositions, a new derivative of triazolopyrimidine, method of production thereof and method of combating fungi

The invention relates to a derivative triazolopyridine and their salts, method of production thereof, intermediates and pharmaceuticals

The invention relates to a derived benzazepine with condensed nitrogen-containing aromatic 5-membered cycle, represented by formula I

The invention relates to new derivatives of triazole, exhibiting insecticidal and acaricidal activity

The invention relates to substituted derivative asalaam, which is an effective anti-Helicobacter tools that can be used as monotherapy for eradication of Helicobacter pylori and related species
Up!