Triazolinone the tertiary amine compound and pharmaceutical composition

 

(57) Abstract:

The invention relates to new triazolylmethyl tertiary amine of the formula I, where A is a simple bond or lower Allenova group; B is a lower alkyl, a group (a), naphthyl, pyridyl, thienyl, thiazolyl, benzothiazolyl, hinely, benzofurazanyl or benzothiazolyl, possibly substituted with halogen or alkyl; D - ring group, (b) or benzofurazanyl; E - ring - 4H-1,2,4-triazole or 1H-1,2,4-triazolyl; R1- H, halogen, cyano-, nitro-group, CF3, lower alkyl or alkoxy; R2is hydrogen or halogen; R3- halogen, cyano-, nitro-, CF3or amino group, provided that when both R1and R2are chlorine atoms, And a is methylene. Compound I or its salt are aromatase inhibitory activity. 3 s and 5 C.p. f-crystals, 5 PL.

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and

The present invention relates to new triazolylmethyl tertiary amine compounds with inhibiting aromatase activity and are useful as medicines.

It is known that the enzyme aromatase is involved in the implementation of the last stage of the pathway of biosynthesis of estrogen in vivo. Aromatase flavoring a steroid cycle, using cachestoreprivate and treatment of various diseases, caused by estrogen as an aggravating factor.

On this basis, the previously suggested several compounds inhibiting aromatase. As a typical example we can mention imidazolyl or triazolyl or pyridylamine methyl compounds (European patent laid-open NN 236,940 and 293,978).

However, compounds provided by the present invention, are definitely different from known compounds in their structure to those that have triazolylmethyl tertiary amino group. Such compounds having triazolylmethyl tertiary amino group, have not been received to date. In particular, it was not known no effective method for direct alkylation, especially arilirovaniya, the terminal amino group triazolyl.

According to the present invention, the proposed new thiazolidinedione tertiary amine compounds which differ in structure from any previously known compounds, and the best way of obtaining them. Moreover, I found that these new compounds have high activity of inhibiting aromatase. Based on these findings and was accomplished the present invention.

According to this invention, prset a simple bond or lower alkylenes group;

In denotes a lower alkyl, a group of the formula , naphthyl, pyridyl, thienyl, thiazolyl, benzothiazolyl, hinely, benzofurazanyl or benzothiazolyl, possibly substituted by one or more halogen atoms or lower alkyl groups;

D ring is a group of the formula or benzofurazanyl;

E ring indicates 4H-1,2,4-triazole group or 1H-1,2,4-triazole group;

R1denotes a hydrogen atom, a halogen atom, a cyano, a nitro-group, trifluoromethyl, lower alkyl or lower alkoxygroup;

R2denotes a hydrogen atom or a halogen atom;

R3denotes a halogen atom, a cyano, a nitro-group, a trifluoromethyl or amino group,

provided that if both R1and R2are chlorine atoms, A represents methylene; or its pharmaceutically acceptable salt.

Preferably the compound of formula (I) or its salt, which is a group of the formula and the D ring is a group of the formula ; especially, when R2it is a hydrogen atom; even more preferably, R1was a halogen atom, a cyano or a nitro-group, and R3was a cyano or a nitro-group.

Premine]- 4H-1,2,4-triazole or its salt.

According to this invention proposed above thiazolidinedione connection tertiary amine corresponding to the General formula (I) or its salt as an aromatase inhibitor.

Provided by the present invention compounds will be hereinafter described in more detail. Used herein, the term "low" corresponds to a linear or branched carbon chain containing from 1 to 6 carbon atoms, except where otherwise indicated.

Thus, the term "lower alkyl group" includes specifically, for example, methyl group, ethyl group, through the group, isopropyl group, boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, pentelow (amylou) group, isopentyl group, neopentyl group, tert-pentelow group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropylene group, hexoloy group, isohexyl group, 1-methylpentyl group, 2 - methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3 - dimethylbutyl group, 3,3-dimethylbutyl group, 1-Ativ-methylpropyl group and 1-ethyl-2-methylpropyloxy group. Among them, preferred are methyl group, ethyl group, through the group, isopropyl group and bucilina group.

"Lower Alchemilla group" represents a linear or branched carbon chain comprising from 1 to 6 carbon atoms, including specifically, for example, methylene group, ethylene group, propylene group, tetramethylene group, 2-methyltrienolone group, 1-ethylethylene group, pentamethylene group and 1,2-diethylethylene group. Among them, preferred are a methylene group and ethylene group.

"Aryl group" in the case of a or D ring includes, for example, phenyl group, naftalina group, antarctilyne group and phenanthroline group, and

"5 - or 6 - membered heterocyclic group containing from 1 to 3 heteroatoms of oxygen, sulfur and/or nitrogen atoms in the case of a ring includes, for example, follow group, thienyl group, thiazolidine group, thiadiazolyl group, oxazolidinyl group, imidazolidinyl group, triazolyl group, pyrrolo group, pyridyloxy group, pyrimidinyl group and pyridinoline group.

"Bicyclic connected geterotsiklicheskikh group, benzoxazolyl group, pinolillo group, izohinolinove group, benzotriazolyl group and benzofurazanyl group.

Each of the above-mentioned "aryl group", "5 - or 6-membered heterocyclic group containing from 1 to 3 heteroatoms of oxygen, sulfur and/or nitrogen atoms", and "connected bicyclic heterocyclic group consisting of the above heterokonta and the benzene ring may bear one or more, preferably 1 or 2, Deputy.

As examples of substituents in the groups imply a halogen atom, a cyano, a nitro-group, triptorelin group, hydroxyl group, amino group, mono - or di-lower alkylamino, a lower alkyl group, lower CNS group, carboxyl group, lower alkoxycarbonyl group, lower alkanoyloxy group, a lower alkanoyloxy, lower alkanolamines, arilou group, Kolocep, karbamoilnuyu group, mono - or di-lower alkylaminocarbonyl group, alphagroup, lower alkylsulfonyl group, sulfamoyl group, and mono - or di-lower alkylsulfonyl group. Among them, preferred are a halogen atom, cyano, nitrogroup the group, carboxyl group, a lower alkoxycarbonyl group, and the lowest alkanolamine. More preferred are a halogen atom, cyano and nitro-group.

"Halogen atom" includes fluorine atom, chlorine atom, bromine atom and iodine atom. "Lower CNS group" include a methoxy group, ethoxypropan, propoxylate, isopropoxy, butoxypropyl, isobutoxy, sec-butoxypropyl, tert-butoxypropyl, pentyloxy(amyloxy-) group, isopentylamine, tert-pentyloxy, neopentylglycol, 2-methylbutoxy, 1,2 - DIMETHYLPROPANE, 1-ethylpropoxy and hexyloxy. Among them, preferred are a methoxy group and ethoxypropan.

"Lower alkoxycarbonyl group" includes methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, tert - butoxycarbonyl group, and ventilatsioonile group; "lower alcoolica (alkanoyloxy-) group includes acetyl (atomic charges-) group, propionyloxy (propionyloxy-) group, butyryloxy (butyryloxy-) group, valerino (valeriote-) group, and isovaleryl (isovaleraldehyde, valerianovna and isovaleraldehyde.

"Arolina group" or "kolocha includes benzoyloxy (benzoyloxy-) group, 1 - afterburning (1 niftycorners-) group, 2-afterburning (2 niftycorners-) group, tenolol (titolare-) group, pyrrolo (pyrrolone-) group, and 2-, 3 - or 4-pyridylcarbonyl (2-, 3 - or 4-pyridylcarbonyl-) group.

The value used above concepts "lower alkyl group" should be applied to the lower alkyl part of the "mono - or di-lower alkylaminocarbonyl group or mono - or di-lower alkylsulfonyl group". Typical examples of such groups are methylaminomethyl group, dimethylaminocarbonylmethyl group, diethylaminocarbonylmethyl group, propylaminoethyl group, methylsulfonyl group, dimethylsulphamoyl group, and diethylaminocoumarin group.

"Lower alkylsulfonyl group" includes methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylphenyl group, butylsulfonyl group, isobutylamino group, sec-butylsulfonyl GRU">

Provided by the present invention compounds can form salts with inorganic acids and organic acids, and these salts also have inhibiting aromatase activity as the corresponding free base. The preferred salts are, for example, imply a salt of an inorganic acid such as hydrochloride, hydrobromide, sulphates, nitrates and phosphates; and salts of organic acids such as oxalate, fumarate and tartrate.

Depending on the type of substituents in the composition of the compounds, these compounds may also form pharmaceutically acceptable salts with alkali metals or alkaline-earth metals (for example, salts of sodium, potassium, magnesium or calcium), or to form salts with organic amines, such as ammonia or triethylamine.

Depending on the type of substituents in the composition of the compounds, these compounds may contain an asymmetric carbon atom and includes all isomers such as optical isomers and diastereoisomers based on asymmetric carbon atom.

In addition, there may be instances of different hydrates, solutions and tautomers of the compounds provided by the present image is ptx2">

Provided by the present invention compounds can be obtained using various methods, based on the characteristics of their main skeleton, as well as the use of substitutes. Some typical methods are as follows.

The first method of obtaining:

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where X represents a halogen atom, arylsulfonate or lower alkylsulfonates.

Obtaining the desired compound (I) of the N-aminotriazole (II) can be carried out using the two above ways. At each stage these paths reaction is an alkylation or acylation of the amino group that may be performed in a similar manner.

More specifically, in accordance with the above reaction, is required for the reaction amount of source of lead compounds in contact with each other, for example, in the neutral reaction solvent, such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dimethoxyethane, acetone or methyl-ethyl-ketone, in the presence of a base. Acceptable as grounds are, for example, sodium hydride, sodium amide, n-butyl lithium, t-piperonyl potassium, sodium, sodium methoxide, ethoxide sodium, sodium hydroxide and potassium hydroxide. R is veloxigrup includes, for example, phenylsulfonylacetate and benzylmethylamine; lower alkylsulfonates is sulfonyloxy substituted lower alkyl group, including, for example, methylsulfonylamino. ethylsulfonyl and propylsulfonyl.

The second way get:

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where A1represents the lowest alkylenes group in which the number of methylene groups, one less than in A. the same designation used and later.

In accordance with this method, N-aminotriazol (II) result in interaction with the aldehyde compound (VII ) to obtain the corresponding Schiff bases (IX), which restores obtaining the compounds (XI) and compound (XI) alkylate or acelerou in the same way as described in the first method of obtaining with the formation of the desired product (Ia). The reaction of receipt of the Schiff's base is carried out using an azeotropic dehydrogenation or similar methods in a solvent such as methanol, ethanol or other alcohol, or benzene, or toluene, in the presence of an acidic catalyst. The recovery may be carried out using the standard method, using, for example, borohydride sodium, Oh as methanol or ethanol, or an organic solvent, such as acetic acid or water, or solvent, which is their mixture. As recovery could not allocate the resulting Schiff's base, and add a reducing agent to containing Schiff base reaction solution for exercise recovery.

The third way get:

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where R1represents aminoamides group

Y denotes a halogen atom,

IN1and D1each represents an aryl group, a 5 - or 6-membered heterocyclic group or a bicyclic connected group consisting of the above heterocycle and a benzene ring which is substituted by a nitro-group,

IN2denotes aryl group, 5 - or 6-membered heterocyclic group or a bicyclic connected group consisting of the above heterocycle and a benzene ring which is substituted by an amino group,

IN3represents an aryl group, a 5 - or 6-membered heterocyclic group or a bicyclic connected group consisting of the above heterocycle and a benzene ring which is substituted by a halogen atom. These same designations are used and later.

Thus, the compound described by the General formula (XIII) or (XVI), restore obtaining amine compounds corresponding to General formula (XIV) or (XVII), the specified amine compound is subjected to reaction Sandmeyer, resulting in the turning on of the halogen atom and the removal of the protective group, to obtain compounds corresponding to General formula (XV) or (XVIII), after which the connection lead into interaction with the compound (V) or (III) to obtain the desired compounds described by formula (Ib) or (Ic), respectively.

The reduction of compound corresponding to the formula (XIII), produced using the standard method of chemical recovery or catalytic reduction.

Suitable as a reducing agent in chemical reduction are a metal, such as tin, zinc or iron. In the case of catalytic reduction using traditional catalysts, including, for example, a platinum catalyst such as platinum or platinum oxide, palladium catalyst such as palladium black or palladium oxide, and Nickel catalyst such as Nickel of Renee.

As solvent for the reaction reset the Tyl acetate and acetic acid. Protection of the nitrogen atom in the compound corresponding to formula (XIII) or (XVI) is carried out using traditional acylamino group such as acetyl or benzoline group. The introduction of protective group can be achieved using the reaction of the compound with acetic anhydride, acetyl chloride or benzoyl chloride in the presence of a base such as sodium acetate, pyridine, picoline, lutidine, trimethylamine or triethylamine. As solvent for the reaction is suitable dichloromethane, dichloroethane, chloroform, benzene and toluene. The reaction can also be carried out in the absence of solvent.

In the future, thus obtained compound (XIV) or (XVII) is subjected to reaction Sandmeyer so that the halogen atom is introduced into the connection, and the protective group is removed from it, with the formation of compound (XV) or (XVIII). The reaction of Sandmeyer can be performed using any conventional method, for example, using copper chloride, copper bromide or copper iodide, and hydrochloric acid, Hydrobromic acid, iodomethane acid or sulfuric acid. As solvent for the reaction of acceptable water, acetone, dioxane and tetrahydrofuran. The removal of the protective group can be achieved through Kislov is received thus compound (XV) and compound (V) or (III) you can use the same path, which provides a first method of obtaining or second method of obtaining. Other ways of getting:

1. If provided by the present invention compounds contain an amino group as a substituent, they may be obtained through the recovery provided by the present invention compounds carrying the corresponding nitro-group. The reaction is a conversion of the Deputy, which you can use the same recovery path, which is described in the third method.

2. If provided by the present invention compounds contain lower alkanolamines as a substitute, they can be obtained through the interaction provided by the present invention compounds carrying the appropriate amino group with acetic anhydride or similar agent with the conventional method.

3. If provided by the present invention compounds contain benzotryazolyl group as a substituent or as D rings, they can be obtained through the recovery provided by the present invention compounds bearing an amino group (or monosubstituted the amino group) and the nitrogroup is Samadashvili restored compounds with sodium nitrite, the potassium nitrite or similar agent for ring closure with the formation of benzotryazolyl group in this connection.

Thus obtained compounds provided by the present invention can be isolated or purified using any conventional methods, for example by extraction, precipitation, fractional chromatography, fractional crystallization, recrystallization and the like methods. Salts provided by the present invention compounds can be obtained through use of the free base in a conventional salt-forming reaction to obtain the expected salt.

Provided by the present invention compounds have the ability to inhibit aromatase, which is involved in the biosynthesis of estrogen from androgen. In this regard, provided by the present invention compounds are suitable for treating diseases in which estrogen is an aggravating factor in diseases such as breast cancer, mastopathy, endometriosis, prostatomegaly, hysteromyoma, as well as cancer of the uterus.

Pharmacological effects provided by the present invention compounds were identified using transferred from the ovary of the rat. Aromatase activity was measured in accordance with the known method.

The value of the IC50showing the effect of test compounds on the inhibition of aromatase, was determined to suppress the release of3H2O from [1,2-3H] Androstenedione in ovarian microsomes of rats.

6. Inhibition of aromatase, isolated from human placenta.

Aromatase activity was measured in accordance with the known method.

Inhibitory activity of compounds was determined by suppression of the release of3H2O from [1,2-3H] Androstenedione in the microsomes of human placenta.

2. Inhibition of aromatase activity in vivo.

Females of Wister rats, weighing 60 g each, (immature) was subcutaneously injected serum gonadotropin mares (PMSG) at a concentration of 100 IU per rat. After 72 hours, the rat was used by the test compound, dissolved in 0.5 ml of 20% aqueous solution of polyethylene glycol. As control was used 20% aqueous solution of polyethylene glycol. Three hours after administration of the tested compounds rats were killed by decapitate and blood loss, remove their ovaries and using a radioimmune assay (RIA) measured the content of estradiol is soedineniya in relation to carcinoma of the breast was measured on the model caused by dimethylbenzanthracene (DMBA) cancer in female rats Sprague-Dawlay.

4. Inhibiting the production of aldosterone in vitro and in vivo.

A. Inhibiting the production of aldosterone in vitro.

Activity was measured in accordance with the known method. Inhibitory activity of test compounds was determined on the basis of suppression of production of aldosterone caused by the first generation of cultured cells of the adrenal glands in rats under the effect of the stimulation of adrenocorticotropic hormone (ACTH). The amount of aldosterone was measured using RIA.

B. Inhibiting the production of aldosterone in rats in vivo.

Inhibitory activity was measured in accordance with the known method. Inhibitory activity of test compounds was determined on the basis of suppression caused by ACTH concentration increases aldosterone in the blood of rats. The amount of aldosterone was measured using RIA.

5. Inhibition of the production of cortisol in vitro.

Inhibitory activity was measured in accordance with the known method. Inhibitory activity of test compounds was determined on the basis of the suppression of the production of cortisol, caused by the first generation of cultured cells of the adrenal glands in rats under the action of ACTH stimulation. Quantities of the Lena next.

1. Inhibition of aromatase in vitro in microsomes of human placenta.

The value of the IC50the inhibition of aromatase microsomes from human placenta ex vivo was determined in accordance with the above experimental method 1.B. the results obtained are presented in table. 1.

Control connection: connection from example 20 b. The same connection will be used below.

As can be seen from the above results, the compounds provided by the present invention, showing a significantly higher inhibition of aromatase in vitro in microsomes human placenta than the control connection.

2. Selectivity of inhibition of aromatase from the ovary of the rat in vitro and production of aldosterone in rats in vitro.

The values of the IC50the inhibition of aromatase rats in vitro and suppress the production of aldosterone in rats ex vivo was measured using the above experimental methods 1. A. and 4.A. respectively. Selectivity was determined by counting and are given in table. 2. Selectivity shows the ratio of the value of the IC50for the production of aldosterone rats to the value of the IC50for aromatase activity in rats.

As can be seen from presented nsibirwa activity in relation to the aromatase rats in vitro, than the control connection. In addition, both compounds exhibit almost the same inhibitory activity against the production of aldosterone in rats in vitro.

In this regard, the selectivity of inhibiting aromatase activity in vitro compared with the activity of inhibiting the production of aldosterone in vitro, (b/a) is equal to 6100 for compounds of example 15, while for the control connection, the corresponding value is 1700. This fact means provided by the present invention the compound has an extremely low impact on the system of production of aldosterone, and therefore is a selective inhibitor of aromatase.

Aldosterone, known as mineral corticoid, has a number of biological effects. It is shown that inhibiting the production of aldosterone leads to harmful side effects, such as lowering blood pressure and orthostatic reduction of turgor due to the reduced amount of fluid in the body, and abnormal electrolyte balance arising due to washout from the body of potassium ions. Accordingly, as provided by the present invention the compound is an inhibitor of aromatase is the production of aldosterone, assume that this connection will be more secure and will have minor side effects.

3. Inhibiting the production of aldosterone in rats in vivo.

Inhibitory activity against the production of aldosterone in rats in vivo was measured using the above experimental method 4.B. If the test connection is used for each of the five rats at a concentration of 10 mg/kg, the inhibition of the production of aldosterone was in rats 37%, which is significant when compared to control.

Meanwhile, if each of the five rats used as the experimental group used each provided by the present invention compounds of examples 10, 12 and 15 at a concentration of 100 mg/kg (10 times higher than in the previous case), inhibiting the production of aldosterone was unreliable. Statistical significance values were analyzed using one-dimensional variational analysis. The results indicate that provided by the present invention compounds are highly safe substances that have few harmful side effects in in vivo tests.

4. Inhibition of PR is of the production of cortisol, were determined using the above experimental method 5, the results are presented in table. 3.

As can be seen from the above results, it is noted that provided by the present invention compounds exhibit significantly lower activity, inhibitory products of cortisol rabbit in vitro than control connection. It is known that suppress the production of cortisol leads to various harmful side effects such as lowering the concentration of sugar in the blood, disorders of nervous system function, increased stress and increased inflammation. Accordingly, as provided by the present invention compounds exhibit weak activity, inhibitory products of cortisol, suggest that these compounds will have less harmful side effects than the control connection.

5. Inhibition of aromatase activity in vivo.

Inhibitory activity against the aromatase rats was measured using the above experimental method 2. Minimum effective dose of a compound provided by the present invention was 0.001 mg/kg

6. Anticancer activity.

Rela is to provide a suppression or regression of existing tumors with daily oral use in doses from about 0.04 to 1.0 mg/kg

7. The metabolism.

If the test rats orally used pursuant to this invention the compound of example 15 at a dose of 3 mg/kg, the maximum value (Cmax) concentrations of unchanged compound in the plasma was 2.88 mg/ml, and the time of its half-life (T1/2) was 11 hours. From these results it is clear that provided by the present invention a connection is characterized by excellent oral absorptivity, and the effect of absorbed connection lasts long. Thus, the specified connection has good performance in medicine.

If the compounds corresponding to formula (I) and their non-toxic salts or hydrates used for the above objects, these compounds usually applied orally or intraperitoneally. The number in the dose varies depending on age, body weight and condition of the patients, and also from a therapeutic effect, the route of application and time of treatment of these compounds. Typically, the number of connections in the dose range from 0.1 to 100 mg /adult/ day, preferably from 1 to 10 mg /adult/ day in the case of oral administration in a single dose or parts thereof, intended for som is a single dose, or its parts, designed for multiple doses throughout the day or for a permanent intravenous injection for 1 to 24 hours per day. As the number provided by the present invention compounds vary dose depending on various conditions, a smaller dose than the above level, in some cases could also be satisfactory.

According to this invention proposed by inhibiting aromatase pharmaceutical composition comprising an effective amount of the active ingredient and pharmaceutically acceptable carrier, characterized in that the active ingredient is triazolinone connection tertiary amine of the formula (I) or its salt.

As solid compositions intended for application of the present invention, are acceptable tablets, powder, and granules. In the solid compositions of this type are one or more active substance is mixed with at least one inert filler such as lactose, mannitol, glucose, hydroxypropyl cellulose, high-purity crystalline cellulose, starch, polyvinyl pyrrolidone and metasilicate of magnesium aluminate. A similar composition using s, for example, a lubricant such as magnesium stearate, disintegrity agent, such as calcium, glycolate cellulose, a stabilizing agent, such as lactose, and an agent that promotes dissolution, such as glutamic acid or aspartic acid. Pills and tablets may optionally be coated with a film of soluble in the stomach or soluble in the inner cavity of the substance, such as sucrose, gelatin, hydroxypropyl cellulose or phthalate-free hydroxypropylmethyl pulp.

A liquid composition intended for oral administration of the present invention includes pharmaceutically acceptable emulsion, solution, syrup or elixir, and it also contains traditional dissolving agent, such as pure water or ethanol. Furthermore, in addition to the inert solvent agent such composition may contain other auxiliary agents such as wetting agent or suspendisse agent and sweetener, odorous substance, flavor and antiseptic agent.

Injection is intended for internal use of the present invention, includes a sterilized aqueous or nonaqueous solution, suspension or emulsion. Odologies saline. Non-aqueous solution and suspension include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, Polysorbate 80, and so on, in Addition, such a composition may contain other auxiliary additives such as an antiseptic agent, a moisturizing agent, emulator, dispersing agent, stabilizing agent (e.g., lactose), contributing to the dissolution agent (for example, glutamic acid, aspartic acid) etc., the composition is sterilized, for example by not filtering through a bacteria-proof filter, by introducing into the composition of the agent, kills germs, or by means of light irradiation. In some cases, first prepare a sterile solid composition, which before use can be dissolved in sterile water or a sterile solvent intended for injection, receiving injections.

The best way to use the invention.

In the next section, the essence of the present invention will be explained in more detail using the following examples. Getting the source compounds for use in these examples is described in spravochnyiblog and 1.9 g of monohydrate p-toluensulfonate acid, and the resulting mixture was heated at reflux distilled for 4 hours under azeotropic dehydrogenation. The crystals precipitated in the sediment after cooling, the mixture was collected by filtration with quantitative getting 4-[(4-cyanobenzylidene)amino]-4H-1,2,4 - triazole.

Mass spectrometry (m/z: 198 (M++1)

Reference example 2

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2,52 g of 4-amino-1,2,4-triazole in small portions was added at room temperature to dimethylsulfoxide suspension of 1.2 g of sodium hydride. After stirring for 3 hours at room temperature was added to the mixture of 1.21 g of 4-perbenzoate in one portion and continued stirring for another one hour. To the reaction solution was added water, then was extracted with the mixture with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and removed the solvent by distillation under reduced pressure. The resulting crystals were washed with ethyl acetate to obtain 1,09 g of 4-[(4-cyanophenyl)amino]-4H-1,2,4 - triazole.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: to 6.57 (2H, d, J=9 Hz), 7,69 (2H, d, J=9 Hz), 8,83 (2H, s).

Mass spectrometry (m/z): 185 (M+).

Reference example 3

Was carried out as described in reference example 2, received the following connection:

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4-[="ptx2">

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 6,53 - 6,70 (2H, m), 8,08-8,31 (2H, m), and 8.8 (2H, s), 10,52 (1H, s).

Mass spectrometry (m/z): 205 (M+).

Reference example 4

Was carried out as described in reference example 2, received the following connection:

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1-[(4-cyanophenyl)amino]-1H-1,2,4-triazole.

Starting compound: 1-amino-1,2,4-triazole and 4-perbenzoate.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 6,56 (2H, d, J=9 Hz), of 7.70 (2H, d, J=9 Hz), 8,18 (1H, s), 8,82 (1H, s), 10,51 (1H, brs).

Mass spectrometry (m/z): 185 (M+).

Reference example 5 - 1

Was carried out as described in reference example 2, received the following connection:

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1-[(4-nitrophenyl)amino]-1H-1,2,4-triazole.

Starting compound: 1-amino-1,2,4-triazole and 4-ftorirovannom.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard )

: 6,59 (2H, d, J=9 Hz), 8,16 (2H, d, J=9 Hz), to 8.20 (1H, s), cent to 8.85 (1H, s), 10,80 (1H, s).

Mass spectrometry (m/z): 205 (M+).

Reference example 5 - 2

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2.28 g of sodium borohydride was gradually added to the suspension 9,85 g of 4-[(4-cyanobenzylidene)amino] -4H-1,2,4-triazole, receiving amasyali at the same temperature for 1 hour, then the solvent was removed by distillation under reduced pressure. For further vysalivaniya was added to the mixture of water and sodium chloride and was extracted with a mixture of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and removed the solvent by distillation under reduced pressure. The residue was subjected to chromatography on silicagel column, coarse crystals obtained from the eluate with a mixture of chloroform and methanol in a ratio of 15:1, washed with chloroform receipt of 4.2 g of 4- [(4-cyanobenzyl)amino]-4H-1,2,4-triazole.

Physico-chemical characteristics.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

:/ or 4.31 (2H, d, J=4 Hz), 7,29 (1H, t, J=4 Hz), 7,51 (2H, d, J=9 Hz), 7,82 (2H, d, J=9 Hz), 8,48 (2H, s).

Example 1

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A catalytic amount of Nickel Raney added to 50 ml of ethanol containing 3,74 g of 4-[N-(4-bromobenzyl)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole, and stirred the mixture for 2 hours in the presence of hydrogen gas at room temperature. After removal of the catalyst by filtration, the obtained filtrate was concentrated under reduced pressure and purify the residue by chromatography on silicagel and methanol in the ratio of 50:1.

Mass spectrometry (m/z): 344 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d, TMS internal standard)

: 4,71 (2H, s), to 4.98 (2H, br), of 6.52 (2H, d, J=9 Hz), to 6.58 (2H, d, J=9 Hz), 7,26 (2H, d, J=9 Hz), of 7.48 (2H, d, J=9 Hz), 8,73 (2H, s).

Example 2

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0.3 g of 4-[(4-cyanophenyl)amino] -4H-1,2,4-triazole obtained in reference example 2, was added in small portions to a suspension of 65 mg of sodium hydride in 5 ml of N,N-dimethylformamide at room temperature. After adding all substances the reaction mixture was stirred at 50oC for 30 minutes and then cooled. To the mixture dropwise added 5 ml of N,N-dimethylformamide containing 0.20 g of 4-perbenzoate. After the addition the reaction mixture was stirred at 100oC for 5 hours and the solvent was removed by distillation under reduced pressure. To the residue was added water, then the mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was removed by distillation. The residue was purified by chromatography on silicagel column got rough crystals from the eluate with a mixture of chloroform and methanol in a ratio of 100: 1.

These crude crystals were recrystallize from etelaat the SUB>N6).

Calculated: C(%) 67,13; H(%) 3,52; N(%) 29,35.

Found: C(%) 66,92; H(%) 3,62; N(%) 29,23.

Mass spectrometry (m/z): 286 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

:? 7.04 baby mortality (4H, d, J=9 Hz), of 7.69 (4H, d, J=9 Hz), 8,44 (2H, s).

Example 3

Was carried out as described in example 2, received the following connection:

< / BR>
4-[N-(4-cyanophenyl)-N-(4-nitrophenyl)amino]-4H-1,2, 4-triazole.

Starting compound: 4-[(4-cyanophenyl)amino] -4H-1,2,4-triazole and 4 - ftorirovannom.

Elemental analysis (for C15H10N6O2).

Calculated: C(%) 58,82; H(%) 3,29; N(%) 27,44.

Found: C(%) 58,79; H(%) Of 3.46; N(%) 27,37.

Mass spectrometry (m/z): 307 (M++1).

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: 6,98-7,16 (4H, m), 7,72 (2H, d, J=9 Hz), compared to 8.26 (2H, d, J=9 Hz), 8,46 (2H, s)

Example 4

Was carried out as described in example 2, received the following connection:

< / BR>
4-[N-( 4-cyanophenyl)-N-methylamino]-4H-1,2,4-triazole.

Starting compound: 4-[(4-cyanophenyl)amino] -4H-1,2,4-triazole and methyl iodide.

Elemental analysis (for C10H9N5).

Calculated: C(%) 60,29; H(%) 4,55; N(%) To 35.15.

3, TMS internal standard)

: to 3.36 (3H, s), 6,60 (2H, d, J=9 Hz), 7,60 (2H, d, J=9 Hz), to 8.41 (2H, s).

Example 5

Was carried out as described in example 2, received the following connection:

< / BR>
4-[N-(4-cyanophenyl )-N-propylamino]-4H-1,2,4-triazole.

Starting compound: 4-[(4-cyanophenyl)amino] -4H-1,2,4-triazole and methyl iodide.

Elemental analysis (for C12H13N5).

Calculated: C(%) 63,42; H(%) 5,77; N(%) 30,82.

Found: C(%) 63,41; H(%) Of 5.82; N(%) 30,77.

Mass spectrometry (m/z: 227 (M+), 198.

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: of 1.03 (3H, t, J=7 Hz), 1,45 to 1.76 (2H, m) to 3.67 (2H, dd, J=7 Hz, J=7 Hz), is 6.54 (2H, d, J=9 Hz), 7,56 (2H, d, J=9 Hz), with 8.33 (2H, s).

Example 6

Was carried out as described in example 2, received the following connection:

< / BR>
4-cyano-N-( 4-cyanophenyl)-N-(4H-1,2,4-triazole-4-yl )-benzamide.

Starting compound: 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole and cyanobenzoyl chloride.

Elemental analysis (for C17H10N6O).

Calculated: C(%) 64,96; H(%) Is 3.21; N(%) 26,74.

Found: C(%) 64,81; H(%) At 3.35; N(%) 26,72.

Mass spectrometry (m/z): 314 (M+).

Spectrum of nuclear magnetic resonance (CDCl3That TMS napisano in example 2, received the following connection:

< / BR>
4-[N-(4-cyanophenyl)-N-(2, 4-dinitrophenyl)amino]-4H-1,2,4-triazole.

Starting compound: 4-[(4-cyanophenyl)amino] -4H-1,2,4-triazole, 2,4-dinitrophenol.

Elemental analysis (for C14H9N7O6).

Calculated: C(%) 45,29; H(%) 2,44; N(%) 26,41.

Found: C(%) 45,25; H(%) Of 2.55; N(%) 26,40.

Mass spectrometry (m/z): 371 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: PC 6.82 (2H, d, J=9 Hz), 7,95 (1H, d, J=9 Hz), to 8.20 (2H, d, J=9 Hz), 8,71 (1H, q, J=9 Hz), of 8.95 (1H, d, J=3 Hz), of 9.21 (2H, s).

Example 8

Was carried out as described in example 2, received the following connection:

< / BR>
4-[bis(4-nitrophenyl)amino]-4H-1,2,4-triazole.

Starting compound: 4-[(4-nitrophenyl)amino] -4H-1,2,4-triazole and 4-ftorirovannom.

Elemental analysis (for C14H10N6O4).

Calculated: C(%) 51,54; H(%) To 3.09; N(%) 25,76.

Found: C(%) 51,59; H(%) 3,14; N(%) 25,80.

Mass spectrometry (m/z): 326 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6,TMS internal standard)

: 7,24 (4H, d, J=9 Hz), 8,30 (4H, d, J=9 Hz), 9.28 are (2H, s).

Example 9

< / BR>
1. Carried out in the same way as this ensol obtaining 4-[N-(4-cyanophenyl)-N- [(3-methylamino-4-nitro)phenyl]amino]-4H-1,2,4-triazole.

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: and 3.16 (3H, s), 7.23 percent (2H, d, J=8 Hz), of 7.75 (2H, d, J= 9 Hz), 7,80 (2H, s), 8,13 (2H, d, J=9 Hz), 8,87 (2H, s).

Mass spectrometry (m/z): 335 (M+).

2. 30 ml of methanol and 1 g of Nickel Raney added to 1.8 g of 4-[N-(4-cyanophenyl)- N-[(3-methylamino-4-nitro)phenyl]amino]-4H-1,2,4-triazole, obtained in the preceding paragraph 1, and the mixture was subjected to catalytic recovery in hydrogen atmosphere at normal pressure. After removal of Nickel Raney and removal of the solvent by distillation under reduced pressure to quantitatively allocated the desired 4-[[N-(4-amino-3 - methylamino)phenyl]-N-(4-cyanophenyl)amino] -4H-1,2,4-triazole. The resulting substance was dissolved in 30 ml of 6 N hydrochloric acid to the reaction mixture dropwise added to 2 ml of an aqueous solution of 0.37 g of sodium nitrite at a temperature below 5oC. After the addition the reaction mixture was stirred at a temperature below 5oC for 30 minutes, and then Podlachia aqueous solution of sodium hydroxide. The resulting mixture was extracted with ethyl acetate, the separated organic layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure. The residue was purified with panola in the ratio of 100:1. These crude crystals were recrystallize from ethyl acetate to obtain 0.17 g of 6-[N-(4-cyanophenyl)-N-(4H-1,2,4-triazole-4-yl)amino]-1-methyl - 1H-benzotriazole.

Spectrum of nuclear magnetic resonance (CDCl3+ DMSO-d6, TMS internal standard)

: of 2.81 (3H, s), of 6.75 (2H, d, J=9 Hz), was 7.36 (1H, dd, J=9 Hz, J=2 Hz), to 7.59 (1H, d, J=2 Hz), 7,63 (1H, d, J=9 Hz), 8,11 (2H, d, J=9 Hz), 8,73 (2H, s).

Mass spectrometry (m/z): 316 (M+), 220.

Example 10

< / BR>
To a suspension of 0.37 g of 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole obtained in reference example 3 in 20 ml of 2-butanone at room temperature sequentially added 0,83 g of anhydrous potassium carbonate, 1.30 grams p-nitrobenzyl bromide and a catalytic amount of sodium iodide, and then the reaction mixture is heated under reflux distilled for 2 hours. After cooling, the solvent was removed by distillation under reduced pressure, to the residue was added the required amount of water, then was extracted several times its ethyl acetate. Separated an ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure. The resulting residue was purified by chromatography on silicagel column with POM coarse crystals have recrystallize from ethanol to obtain 0.28 g of 4-[N-(4-nitrobenzyl)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole.

Elemental analysis (for C15H12N6O4).

Calculated: C(%) 52,94; H(%) 3,55; N(%) 24,70.

Found: C(%) 52,94; H(%) 3,62; N(%) 25,02.

Mass spectrometry (m/z): 340 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 5,33 (2H, S), 6,77 (2H, d, J=9 Hz), 7,66 (2H, d, J=9 Hz), to 8.20 (4H, d, J=9 Hz), 8,93 (2H, s).

Example 11

Was carried out as described in example 10, received the following connection:

< / BR>
4-[N-(4-cyanobenzyl)-N-(4-cyanophenyl)amino]-4H-1,2,4-triazole.

Starting compound: 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole and 4-cyanobenzyl bromide.

Mass spectrometry (m/z): 300 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard )

: to 4.98 (2H, s), only 6.64 (2H, d, J=9 Hz), 7,26-7,74 (6H, m), to 8.20 (2H, s).

Example 12

< / BR>
8 ml of acetonitrile was added to 0.63 g of 4-[N-(4-nitrophenyl)amino]-4H-1,2,4-triazole, of 0.82 g of 4-bromobenzyl bromide and 0.62 g of anhydrous potassium carbonate and stirred for 3 hours at room temperature. The solvent was removed by distillation under reduced pressure, and the obtained residue was added water, then was extracted with him chloroform. Selected chloroform layer was washed with water and broom chromatography on silicagel column with obtaining coarse crystals from the eluate with a mixture of chloroform and methanol in a ratio of 100:1. These crude crystals were recrystallize from acetone to obtain 0.71 g of 4-[N-(4-bromobenzyl)-N-(4-nitrophenyl) amino]-4H-1,2,4-triazole.

So pl.: 241oC.

Elemental analysis (for C15H12BrN5O2).

Calculated: C(%) 48,15; H(%) 3,23; N(%) 18,72; Br(%) 21,35.

Found: C(%) 48,21; H(%) 3,17; N(%) 18,97; Br(%) Of 21.50.

Mass spectrometry (m/z): 374 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

:/ 5,12 (2H, s), 6,79 (2H, d, J=9 Hz), 7,29 (2H, d, J=9 Hz), 7,54 (4H,d, J=9 Hz), 8,19 (2H, d, J=9 Hz), 8,84 (2H, s)

Example 13

Was carried out as described in example 10, received the following connection:

< / BR>
4-[N-(4-methylbenzyl)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole.

Starting compound: 4-[(4-nitrophenyl)amino] -4H-1,2,4-triazole and 4-methylbenzyl bromide.

Elemental analysis (for C16H15N5O2).

Calculated: C(%) 62,13; H(%) 4,89; N(%) 22,64.

Found: C(%) 61,87; H(%) 5,00; N(%) 22,43.

Mass spectrometry (m/z): 309 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: of 2.34 (3H, s), the 4.90 (2H, s), of 6.68 (2H, d, J=6 Hz), was 7.08 (2H, d, J=8 Hz), 7,16 (2H, d, J=8 Hz), 8,10 (2H, s), 8,19 (2H, d, J=6 Hz)

Example 14

Carried out in the same way as described the azole.

Starting compound: 4-[(4-nitrophenyl)amino] -4H-1,2,4-triazole and p-methoxybenzyl chloride.

Elemental analysis (for C16H15N5O3).

Calculated: C(%) 59,07; H(%) 4,65; N(%) 21,53.

Found: C(%) 59,05; H(%) Br4.61; N(%) 21,50.

Mass spectrometry (m/z): 325 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: to 3.73 (3H, s), 5,04 (2H, s), 6,76-6,92 (4H, m) 7,22 (2H, d, J=9 Hz), 8,19 (2H, d, J=9 Hz), the rate of 8.75 (2H, s).

Example 15

< / BR>
40 ml of acetonitrile was added to a 3.15 g of 4-[N-(4-cyanophenyl)amino]-4H-1,2,4-triazole, of 4.25 g of 4-bromobenzyl bromide and to 3.52 g of anhydrous potassium carbonate and stirred the mixture for 3 hours at room temperature. The solvent was removed by distillation under reduced pressure, and the obtained residue was added water, then was extracted with him chloroform. Selected chloroform layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was removed by distillation. The residue was purified by chromatography on silicagel column with obtaining coarse crystals from the eluate with a mixture of chloroform and methanol in a ratio of 100: 1. These crude crystals were recrystallize from ethanol to obtain to 3.92 g of 4-[N-(4-bro is16H12BrN5).

Calculated: C(%) 54,26; H(%) 3,41; N(%) 19,77; Br(%) 22,56.

Found: (C) 53,96; (H) 3,48; (N) Of 19.72; (Br) 22,65.

Mass spectrometry (m/z): 354 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: of 5.06 (2H, s), of 6.75 (2H, d, J=9 Hz), 7,27 (2H, d, J=9 Hz), 7,53 (2H, d, J=9 Hz), of 7.75 (2H, d, J=9 Hz), 8,81 (2H, s).

Example 16

Was carried out as described in example 10, received the following connection:

< / BR>
4-[N-(4-nitrophenyl)-N-(4-thiazolyl )amino]-4H-1,2,4-triazole.

Starting compound: 4-[(4-nitrophenyl)amino] -4H-1,2,4-triazole and 4-(chloromethyl )thiazole.

Elemental analysis (for C12H10N6O2S).

Calculated: C(%) 47,68; H(%) Of 3.33; N(%) 27,80; S(%) 10,61.

Found: C(%) 47,51; H(%) Of 3.45; N(%) 27,75; S(%) 10,45.

Mass spectrometry (m/z): 302 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6. TMS internal standard)

: : 5,28 (2H, s), 6,77 (2H, d, J=9 Hz), to 7.77 (1H, brs), 8,17 (2H, d, J= 9 Hz), 8,80 (2H, s), 9,12 (1H, brs).

Example 17

Was carried out as described in example 10, received the following connection:

< / BR>
4-[N-(4-terbisil)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole/

Starting compound: 4-[(4-nitrophenyl)amino] -4H-1,2,4-triazole and p-terbisil b is%) 3,86; N(%) TO 22.35; F(%) 6,06.

Found: C(%) 57,44; H(%) 3,98; N(%) 22,37; F(%) 5,85.

Mass spectrometry (m/z): 313 (M+).

Spectrum of nuclear magnetic resonance (DMSO-D6, TMS internal standard)

: 5,12 (2H, s), for 6.81 (2H, d, J=9 Hz), 7,05-7,46 (4H, m), to 8.20 (2H, d, J=9 Hz), 8,81 (2H, s).

Example 18

Was carried out as described in example 10, received the following connection:

< / BR>
4-[N-(4-chlorbenzyl)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole.

Starting compound: 4-[(4-nitrophenyl)amino] -4H-1,2, 4-triazole and p-Chlorobenzyl bromide.

Elemental analysis (for C15H12ClN5O2).

Calculated: C(%) 54,64; H(%) To 3.67; N(%) 21,24; Cl(%) Of 10.75.

Found: C(%) 54,59; H(%) Of 3.85; N(%) 21,13; Cl Of 10.72.

Mass spectrometry (m/z): 329 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard )

:/ 5,14 (2H, s), 6,79 (2H, d, J=9 Hz), was 7.36 (2H, d, J=9 Hz), 7,40 (2H, d, J=9 Hz), to 8.20 (2H, d, J=9 Hz), 8,84 (2H, s).

Example 19

Was carried out as described in example 10, received the following connection:

< / BR>
4-[N-(4-iodobenzyl)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole.

Starting compound: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and p-iodobenzyl chloride.

Elemental analysis (for C15H12IN5SS="ptx2">

Mass spectrometry (m/z): 422 (M++1).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 5,10 (2H, s), is 6.78 (2H, d, J=9 Hz), 7,14 (2H, d, J=9 Hz), of 7.70 (2H, d, J=9 Hz), 8,19 (2H, d, J=9 Hz), 8,84 (2H, s).

Example 20

Was carried out as described in example 10, received the following connection:

< / BR>
2-[[N-(4-nitrophenyl)-N-(4H-1,2,4-triazole-4-yl)amino]methyl]quinoline.

Starting compound: 4-[(4-nitrophenyl)amino] -4H-1,2,4-triazole and 2-(chloromethyl) quinoline.

Elemental analysis (for C18H14N6O2)

Calculated: C(%) 62,42; H(%) 4,07; N(%) 24,26.

Found: C(%) 62,42; H(%) 4,22; N(%) 24,30.

Mass spectrometry (m/z): 347 (M++1).

Spectrum of nuclear magnetic resonance (DMSO-d, TMS internal standard )

: 5,52 (2H, s), 6,70 (2H, d, J=8 Hz), to 7.61 (1H, t, J=6 Hz), to 7.67 (1H, d, J= 7 Hz), 7,76 (1H, t, J=6 Hz), 7,98-8,03 (2H, m), 8,42 (1H, d, J=7 Hz), remaining 9.08 (2H, s).

Example 21

Was carried out as described in example 10, received the following connection:

< / BR>
4-[N-(4-nitrophenyl)-N-(4-pyridylmethyl)amino] -4H-1,2,4-triazole starting compound: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and 4-picolyl chloride.

Elemental analysis (for C14H12N6O2).

Calculated: C(%) 56,75; H(%) 4,08; N(%) 28,36.

Example 22

Was carried out as described in example 10, received the following connection:

< / BR>
4-[N-(4-cyanophenyl)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole.

Starting compound: 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole and 4-nitrobenzyl bromide.

Elemental analysis (for C16H12N6O2).

Calculated: C(%) 60,00; H(%) Of 3.78; N(%) 26,24.

Found: C(%) 59,75; H(%) 3,71; N(%) 26,28.

Mass spectrometry (m/z): 320 (M+).

Spectrum of nuclear magnetic resonance (DMSO-D6, TMS internal standard )

: 5,27 (2H, s), 6,74 (2H, d, J=9 Hz), the 7.65 (2H, d, J=9 Hz), to 7.77 (2H, d, J=9 Hz), to 8.20 (2H, d, J=9 Hz), of 8.90 (2H, s).

Example 23

Was carried out as described in example 10, received the following connection:

< / BR>
4-[N-(4-cyanobenzyl)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole.

Starting compound: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and 4-cyanobenzyl bromide.

Elemental analysis (for C16H12N6O2).

Calculated,%: C 60,00; H Of 3.78; N 26,24.

Found,%: C 59,94; H 3,98; N 26,21.

Mass spectrometry (m/z): 320 (M+, EI).

Range Aden, d, J=9 Hz), to 8.20 (2H, d, J=9 Hz), 8,91 (2H, s).

Example 24

Was carried out as described in example 10, received the following connection:

< / BR>
4-[N-(4-nitrophenyl)-N-[(4-trifluoromethyl)benzyl]amino]-4H-1,2, 4-triazole.

Starting compound: 4-[(4-nitrophenyl)amino] -4H-1,2,4 - triazole and 4-(trifluoromethyl)benzyl bromide.

Elemental analysis (for C16H12F3N5O2).

Calculated: C(%) 52,90; H(%) Of 3.33; N(%) 19,28; F(%) 15,69.

Found: C(%) 52,88; H(%) To 3.36; N(%) 19,38; F(%) 15,60.

Mass spectrometry (m/z): 363 (M+).

Spectrum of nuclear magnetic resonance (DMSO-D6, TMS internal standard )

:/ at 5.27 (2H, s), is 6.78 (2H, d, J=7 Hz), to 7.59 (2H, d, J=8 Hz), 7,72 (2H, d, J=8 Hz), 8,21 (2H, d, J=7 Hz), 8,91 (2H, s)

Example 25

Was carried out as described in example 10, received the following connection:

< / BR>
1-[N-(4-nitrobenzyl)-N-(4-nitrophenyl]amino]-1H-1,2,4-triazole.

Starting compound: 1-[(4-nitrophenyl)amino]-1H-1,2,4-triazole and p-nitrobenzyl bromide.

Elemental analysis (for C15H12N6O4).

Calculated: C(%) 52,94; H(%) 3,55; N(%) 24,70.

Found: C(%) 52,66; H(%) 3,74; N(%) 24,62.

Mass spectrometry (m/z): 340 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d
Was carried out as described in example 10, received the following connection:

< / BR>
1-[N-(4-bromobenzyl)-N-(4-nitrophenyl)amino]-1H-1,2,4-triazole.

Starting compound: 1-[(4-nitrophenyl)amino] -1H-1,2,4-triazole and p-bromobenzyl bromide.

Elemental analysis (for C15H12BrN5O2).

Calculated: C(%) 48,15; H(%) 3,23; N(%) 18,72; Br(%) 21,35.

Found: C(%) 48,00; H(%) Of 3.31; N(%) 18,72; Br(%) 21,42.

Mass spectrometry (m/z): 374 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 5,10 (2H, s), 6,76 (2H, d, J=9 Hz), 7,33 (2H, d, J=9 Hz), 7,54 (2H, d, J=9 Hz), 8,17 (2H, d, J=9 Hz), to 8.20 (1H, s), 8,72 (1H, s).

Example 27

Was carried out as described in example 10, received the following connection:

< / BR>
1-[N-(4-cyanophenyl)-N-(4-nitrobenzoyl]amino]-1H-1,2,4-triazole.

Starting compound: 1-[(4-cyanophenyl)amino]-1H-1,2,4-triazole and p-nitrobenzyl bromide.

Elemental analysis (for C16H12N6O2).

Calculated: (%) 60,00; H(%) Of 3.78; N(%) 26,24.

Found: C(%) 60,02; H(%) 3,91; N(%) 26,21.

Mass spectrometry (m/z): 320 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: 5,04 (2H, s), to 6.67 (2H, d, J=9 Hz), 7,54 (2H, d, J=imere 2, received the following connection:

< / BR>
1-[bis-(4-nitrophenyl)amino]-4H-1,2,4-triazole.

Starting compound: 1-[(4-nitrophenyl)amino] -4H-1,2,4-triazole and p - nitrofurant.

Elemental analysis (for C14H10N6O4).

Calculated,%: C 51,54; H 3,09; N 25,76.

Found,%: C 51,39; H 3,43; N 25,36.

Mass spectrometry (m/z): 326 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d , TMS internal standard)

: 7,22 (4H, d, J=9 Hz), of 8.28 (4H, d, J=9 Hz), of 8.37 (1H, s), 9,24 (1H, s).

Reference example 6

< / BR>
2,8 ml of acetic anhydride was added to 15 ml of pyridine solution containing 0.62 g of 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole, at room temperature, and stirred the mixture for about 2 hours. After completion of the reaction the solvent was removed by distillation under reduced pressure, and the obtained residue was added the required amount of an aqueous solution of sodium bicarbonate, after which the residue was extracted several times with ethyl acetate. An ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography on power and methanol in the ratio of 100: 1.

Mass spectrometry (m/z: 247 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: to 2.13 (3H, s), 7,49 (2H, d, J=9 Hz), of 8.28 (2H, d, J=9 Hz), charged 8.52 (2H, s).

Reference example 7

< / BR>
The required amount of 10% of the coal palladium was added to 15 ml matalavage solution containing of 0.38 g of 4-[N-acetyl-N-(4-nitrophenyl)amino] -4H-1,2,4-triazole, and the resulting mixture was subjected to catalytic recovery in the presence of gaseous hydrogen at room temperature for about 40 minutes. After completion of the reaction the catalyst was removed by filtration and the resulting filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silicagel column to obtain 0.33 g of 4-[N-acetyl-N-(4-AMINOPHENYL)amino]-4H-1,2,4-triazole from the eluate with a mixture of chloroform and methanol in the ratio of 50:1.

Mass spectrometry (m/z: 217 (M+).

Spectrum of nuclear magnetic resonance (CDC3, TMS internal standard)

: of 1.97 (3H, s), of 5.53 (2H, br), to 6.58 (2H, d, J=9 Hz), 7,35 (2H, d, J=9 Hz), 8,88 (2H, s).

Reference example 8

< / BR>
1 ml of 47% hydrochloric acid containing 0.32 g of 4-[N - acetyl-N-(4-AMINOPHENYL)amino] -4H-1,2,4-triazole, cooled to rampolokeng the mixture was stirred for about 20 minutes at the same temperature. Further, this mixture was poured into a pre-prepared cold aqueous solution containing 0.55 g of copper bromide and 1 ml of 47% bromide acid, and the mixture was stirred for approximately 20 hours at room temperature. The reaction mixture was neutralized with an aqueous solution of sodium bicarbonate, after which it was extracted several times with ethyl acetate. Formed an ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain coarse crystals, which were washed with ether emitting 0.28 g of 4-[N - acetyl-N-(4-bromophenyl)amino]-4H-1,2,4-triazole.

Mass spectrometry (m/z): 281 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

:/ a 2.00 (3H, s), 7,74 (4H, m), 9,06 (2H, s).

Reference example 9

< / BR>
5 ml of 4 N hydrochloric acid was added to 0.22 g of 4-[N-acetyl-N-(4 - bromophenyl)amino]-4H-1,2,4-triazole, and the resulting mixture was stirred at a temperature of 90oC for 40 minutes. After cooling the neutralized solution with an aqueous solution of sodium carbonate, and then was extracted several times its ethyl acetate. Formed an ethyl acetate layer was washed with water and so is I. The obtained residue was purified by chromatography on silicagel column with the release of 0.18 g of 4-[(4-bromophenyl)amino] -4H - 1,2,4-triazole from the eluate with a mixture of chloroform and methanol in the ratio of 50:1.

Mass spectrometry (m/z): 239 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 6,45 (2H, d, J=9 Hz), 7,41 (2H, d, J=9 Hz), 8,77 (2H, s), 9,62 (1H, s).

Reference example 10

< / BR>
26,70 g of tert-butoxide potassium dissolved in 100 ml of anhydrous dimethyl sulfoxide, was added to the mixture of 20.00 g of 4-amino-4H-1,2,4-triazole, and then stirred the mixture for 2 hours at room temperature. Then for a time span of 20 minutes a solution dropwise added 50 ml of anhydrous dimethyl sulfoxide containing 11,00 g 5-perbendaharaan, then stirred the mixture for 15 minutes. The reaction mixture was poured into 500 ml of water and 500 g of ice, and then washed with 200 ml of ethyl acetate. In the future, using 1 N hydrochloric acid brought the pH to 7.0, which led to the selection of crystals. The obtained crystals were collected by filtration, and the remaining mother liquor was extracted with ethyl acetate. An ethyl acetate layer was washed with water and saturated aqueous chlorine is under reduced pressure, and the thus obtained crude crystals were recrystallize from ethanol. Selected crystals were combined with the previously formed crystals with getting 12,49 g [(4H - 1,2,4-triazole-4-yl)amino]benzofurazan.

Mass spectrometry (m/z): 202 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 6,09 (1H, dd, J=2 Hz, 1 Hz), 7,29 (1H, dd, J=10 Hz, 2 Hz), 8,17 (1H, dd, J=10 Hz, 1 Hz), 8,89 (2H, s), 10,46 (1H, brs)

Reference example 11

< / BR>
to 6.67 g of tert-butoxide potassium dissolved in 36 ml of anhydrous dimethyl sulfoxide, was added to the mixture of 5.00 g of 4-amino-4H-1,2,4-triazole, and then stirred the mixture for 15 minutes at room temperature. In the future, in a time interval of 10 minutes in a solution dropwise added 9 ml of anhydrous dimethyl sulfoxide containing of 3.23 g of 2-perbenzoate, then stirred the mixture for another 15 minutes. The reaction mixture was poured into 90 ml of water and 90 g of ice, and then with 1 N hydrochloric acid brought the pH to 5.7. Precipitated precipitated crystals were collected by filtration and dried to obtain 2.64 g of 4-[(2 - cyanophenyl)amino]-4H-1,2,4-triazole.

Mass spectrometry (m/z): 185 (M+).

Range nuclear magnitno 10,14 (1H, s).

Example 29

< / BR>
0.3 g of 4-[(4-cyanophenyl)amino] -4H-1,2,4-triazole was added in small portions to a suspension of 0.12 g of sodium hydride in 6 ml of N,N-dimethylformamide at room temperature. After adding all substances, the reaction mixture was stirred for 30 minutes at 50oC, and then cooled. When cooled mixture was added 0,42 g 5-perbendaharaan, and then stirred the reaction mixture for 1 hour at 100oC. the Solvent was removed by distillation under reduced pressure, the obtained residue was added water and then was extracted with a mixture of chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The residue was purified by chromatography on silicagel column with obtaining coarse crystals from the eluate with a mixture of chloroform and methanol in a ratio of 200:1. These crude crystals were recrystallize from ethyl acetate emitting 0.17 g of 5-[N-(4-cyanophenyl)-N-(4H-1,2,4-triazole-4-yl)amino]benzofurazan.

Elemental analysis (for C15H9N7O).

Calculated: (%) 59,40; H(%) 2,99; N(%) 32,33.

Found: C(%) 59,43; H(%) 3,01; N(%) 32,38.

Spectrum of nuclear magnetic resonance (CBR> Was carried out as described in example 29, received the following connection:

< / BR>
4-[N-(4-nitrophenyl)-N-(5-nitropyridine-2-yl]amino]-1 H-1,2,4-triazole.

Starting compound: 4-[(4-nitrophenyl)amino] -4H-1,2,4-triazole and 2-bromo-5-nitropyridine.

Elemental analysis (for C13H9N7O4).

Calculated: C(%) 47,71; H(%) 2,77; N(%) 29,96.

Found: C(%) To 47.46; H(%) 2,90; N(%) 30,04.

Mass spectrometry (m/z): 327 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 6,77 (1H, d, J=9 Hz), 7,74 (2H, d, J=9 Hz), scored 8.38 (2H, d, J=9 Hz), 8,53 (1H, d, J=9 Hz), 9,13 (1H, s), a 9.25 (2H, s).

Example 31

< / BR>
40 ml of acetonitrile was added to 500 mg of 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole, of 0.42 ml of 4-terbisil bromide and 746 mg of potassium carbonate and stirred the mixture for 2 hours at room temperature. The solvent was removed by distillation under reduced pressure, the obtained residue was added water, and then extracted it with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The residue was subjected to chromatography on silicagel column with obtaining coarse crystals from the eluate with a mixture of chloroform is cyanophenyl)-N-(4-terbisil)amino]-4H-1,2,4-triazole.

Elemental analysis (for C16H12N5F).

Calculated: C(%) 65,52; H(%) 4,12; N(%) 23,88; F(%) 6.48 In.

Found: C(%) 65,53; H(%) 4,16; N(%) 23,93; F(%) To 6.43.

Mass spectrometry (m/z): 293 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: of 5.05 (2H, s), 6,77 (2H, d, J=9 Hz),? 7.04 baby mortality-7,44 (4H, m), 7,76 (2H, d, J=9 Hz), 8,78 (2H, s).

Example 32

Was carried out as described in example 31, received the following connection:

< / BR>
4-[N-(4-chlorbenzyl)-N-(4-cyanophenyl)amino]-4H-1,2,4-triazole.

Starting compound: 4-[(4-cyanophenyl)amino] -4H-1,2,4-triazole and 4-Chlorobenzyl bromide.

Elemental analysis (for C16H12N5Cl).

Calculated: C(%) 62,04; H(%) 3,90; N(%) 22,61; Cl(%) Of 11.45.

Found: C(%) 61,97; H(%) 4,10; N(%) 22,59; Cl(%) Of 11.26.

Mass spectrometry (m/z): 309 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

:/ 5,07 (2H, s), of 6.75 (2H, d, J=9 Hz), 7,37 (4H, s), 7,76 (2H, d, J=9 Hz), 8,80 (2H, s).

Example 33

Was carried out as described in example 31, received the following connection:

< / BR>
4-[N-(4-cyanophenyl)-N-(4-iodobenzyl)amino]-1H-1,2,4-triazole.

Starting compound: 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole and 4-iodobenzyl chlorine is(%) 31,63.

Found: C(%) 47,76; H(%) 3,05; N(%) 17,46; I(%) 31,51.

Mass spectrometry (m/z): 401 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: to 5.03 (2H, s), 6,74 (2H, d, J=9 Hz), 7,13 (2H, d, J=8 Hz), to 7.68 (2H, d, J=8 Hz), 7,76 (2H, d, J=9 Hz), 8,81 (2H, s).

Example 34

Was carried out as described in example 31, received the following connection:

< / BR>
4-[N-(4-cyanophenyl )-N-[(4-trifluoromethyl)benzyl]amino]-4H-1,2,4-triazole.

Starting compound: 4-[(4-cyanophenyl)amino] -4H-1,2,4-triazole and 4-(trifluoromethyl)benzyl bromide.

Elemental analysis (for C17H12N5F3).

Calculated: C(%) 59,48; H(%) 3,52; N(%) 20,40; F(%) 16,60.

Found: C(%) 59,40; H(%) 3,59; N(%) 20,41; F(%) 16,48.

Mass spectrometry (m/z): 343 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 5,20 (2H, s), of 6.75 (2H, d,J=9 Hz), 7,58 (2H, d, J=8 Hz), 7,71 (2H, d, J=8 Hz), to 7.77 (2H, d, J=9 Hz), 8,88 (2H, s).

Example 35

Was carried out as described in example 31, received the following connection:

< / BR>
4-[N-[(5-chlorothiophene-2-yl)methyl]-N-(4-nitrophenyl)amino]-1H-1,2,4-triazole.

Starting compound: 4-[(4-nitrophenyl)amino] -4H-1,2,4-triazole and 2-chloro-5-(chloromethyl)thiophene.

Elemental analysis Found: C(%) 46,30; H(%) To 3.02; N(%) 20,78; Cl(%) 10,69; S(%) 9,48.

Mass spectrometry (m/z): 335 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: and 5.30 (2H, s), 6,74-7,02 (4H, m), to 8.20 (2H, d, J=10 Hz), 8,81 (2H, s).

Example 36

Was carried out as described in example 31, received the following connection.

< / BR>
4-[N-(4-nitrophenyl)-N-(thienylmethyl)amino]-1H-1,2,4-triazole.

Starting compound: 4-[(4-nitrophenyl)amino] -4H-1,2,4-triazole and 2-(chloromethyl)thiophene.

Elemental analysis (for C13H11N5O2S).

Calculated: C(%) 51,82; H(%) 3,68; N(%) 23,24; S(%) At 10.64.

Found: C(%) 51,94; H(%) And 3.72; N(%) 23,10; S(%) Or 10.60.

Mass spectrometry (m/z): 301 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: to 5.35 (2H, s), 6,80-7,02 (4H, m), 7,54 (1H, d, J=5 Hz), to 8.20 (2H, d, J=10 Hz), a total of 8.74 (2H, s).

Example 37

Was carried out as described in example 31, received the following connection:

< / BR>
4-[N-(4-bromophenyl)-N-(4-cyanobenzyl)amino] -1H-1,2,4-triazole. Starting compound: 4-[(4-bromophenyl)amino]-4H-1,2,4-triazole and a-bromo - p-tolunitrile.

Elemental analysis (for C16H12N5Br).

Calculated: C(%) 54,26; H(%) 3,41; N(%) 19,77; Br(%) 22,56.

Neid is gitogo resonance (DMSO-d6, TMS internal standard)

: 5,07 (2H, s), of 6.66 (2H, d,J=10 Hz), 7,45-of 7.90 (6H, m), 8,84 (2H, s).

Example 38

Was carried out as described in example 31, received the following connection:

< / BR>
4-[N-(4-bromophenyl)-N-(4-nitrobenzyl)amino]-1H-1,2,4-triazole.

Starting compound: 4-[(4-bromophenyl)amino]-4H-1,2,4-triazole and 4 - nitrobenzyl bromide.

Elemental analysis (for C15H12N5O2Br).

Calculated: C(%) 48,15; H(%) 3,23; N(%) 18,72; Br 21,35.

Found: C(%) 48,08; H(%) 3,39; N(%) 18,66; Br(%) 21,19.

Mass spectrometry (m/z): 374 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

:/ to 5.13 (2H, s), of 6.68 (2H, d,J=9 Hz), 7,51 (2H, d, J=9 Hz), the 7.65 (2H, d, J=9 Hz), 8,19 (2H, d, J=9 Hz), 8,88 (2H, s).

Example 39

Was carried out as described in example 31, received the following connection:

< / BR>
4-[N-benzyl-N-(4-cyanophenyl)amino]-4H-1,2,4-triazole.

Starting compound: 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole and benzyl bromide.

Elemental analysis (for C16H13N5).

Calculated: C(%) 69,80; H(%) Value Of 4.76; N(%) 25,44.

Found: C(%) 69,66; H(%) 4,84; N(%) 25,43.

Mass spectrometry (m/z): 275 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d/BR> Was carried out as described in example 31, received the following connection:

< / BR>
4-[N-benzyl-N-(4-nitrophenyl)amino]-1H-1,2,4-triazole

Starting compound: 4-[(4-nitrobenzyl)amino]-4H-1,2,4-triazole and benzyl bromide.

Elemental analysis (for C15H13N5O2).

Calculated: C(%) 61,01; H(%) Of 4.44; N(%) 23,72.

Found: C(%) 60,68; H(%) Of 4.49; N(%) 25,67.

Mass spectrometry (m/z): 295 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 5,13 (2H, s), 6,79 (2H, d, J=9 Hz), 7,33 (5H, s), to 8.20 (2H, d, J=9 Hz), 8,83 (2H, s).

Example 41

Was carried out as described in example 31, received the following connection:

< / BR>
5-[[N-(4-cyanophenyl)-N-(4H-1,2,4-triazole-4-yl)amino]methyl]benzofurazan.

Starting compound: 4-[(4-cyanophenyl)amino] -4H-1,2,4-triazole and 5-bromomethylphosphonate.

Elemental analysis (for C16H11N7O).

Calculated: C(%) 60,56; H(%) 3,49; N(%) 30,90.

Found: C(%) 60,36; H(%) To 4.41; N(%) 31,05.

Mass spectrometry (m/z): 317 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 5,27 (2H, s), of 6.75 (2H, d, J=9 Hz), to 7.61 (1H, d, J=9 Hz), 7,78 (2H, d, J=9 Hz, 8,02 (1H, s), 8,08 (1H, d, J=9 Hz), 8,99 (2H, s).

Starting compound: 4-[(4 - nitrophenyl)amino] -4H-1,2,4-triazole and 5-bromomethylphosphonate.

Elemental analysis (for C15H11N7O3).

Calculated: C(%) 53,41; H(%) 3,29; N(%) 29,07.

Found: C(%) 53,27; H(%) 3,38; N(%) 29,08.

Mass spectrometry (m/z: 337 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 5,33 (2H, s), is 6.78 (2H, d, J=7 Hz), to 7.61 (1H, d, J=9 Hz), of 8.04 (1H, s), of 8.09 (1H, d, J=9 Hz), 8,21 (2H, d, J=7 Hz), 9,03 (2H, s).

Example 43

Was carried out as described in example 31, received the following connection:

< / BR>
4-[N-(4-cyanophenyl)-N-(3,4-dichlorobenzyl)amino]-4H-1,2,4-triazole.

Starting compound: 4-[(4-cyanophenyl)amino] -4H-1,2,4-triazole and 3,4-dichlorobenzyl chloride.

Elemental analysis (for C16H11Cl2N5).

Calculated: C(%) 55,83; H(%) 3,22; N(%) 20,35; Cl(%) 20,60.

Found: C(%) 55,98; H(%) With 3.27; N(%) 20,48; Cl(%) 20,46.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 5,09 (2H, s), 6,74 (2H, d, J=9 Hz), 7,31 (2H, dd, J=9 Hz, J=2 Hz), 7,60 (1H, d, J=9 Hz), 7,63 (1H, d, J=2 Hz), to 7.77 (2H, d, J=9 Hz), 8,86 (2H, s).

Example 44

Was carried out as described in example 31, received the following connection:

< / BR>
4-[N-(4-cyanophenyl)-N-1-Iodate)nitrobenzene.

Elemental analysis (for C17H14N6O2).

Calculated: C(%) 61,07; H(%) 4,22; N(%) 25,14.

Found: C(%) 60,92; H(%) 4,27; N(%) 25,11.

Mass spectrometry (m/z): 334 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

:/ to 1.48 (3H, d, J=7 Hz), 5,88 (1H, q, J=7 Hz), of 6.66 (2H, d, J=9 Hz), to 7.68 (2H, d, J=9 Hz), 7,74 (2H, d, J=9 Hz), to 8.20 (2H, d, J=9 Hz), 8,77 (2H, s).

Example 45

Was carried out as described in example 31, received the following connection:

< / BR>
4-[[N-(4-cyanophenyl)-N-[2-(4-nitrophenyl)ethyl]amino]-4H-1,2,4-triazole.

Starting compound: 4-[(4-cyanophenyl)amino] -4H-1,2,4 - triazole and 4-nitrophenacyl bromide.

Elemental analysis (for C17H14N6O2).

Calculated: C(%) 61,07; H(%) 4,22; N(%) 25,14.

Found: C(%) 61,01; H(%) 4.26 Deaths, N(%) 25,14.

Mass spectrometry (m/z): 334 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: to 2.99 (2H, t, J=7 Hz), 4,18 (2H, t, J=7 Hz, of 6.26 (2H, d, J=9 Hz), to 7.61 (2H, d, J=9 Hz), 7,72 (2H, d, J=9 Hz), 8,17 (2H, d, J=9 Hz), 8,88 (2H, s).

Example 46

Was carried out as described in example 31, received the following connection:

< / BR>
4-[N-(2-bromobenzyl)-N-(4-cyanophenyl)amino]-1H-1,2,4-triazole.

The UIS C16H12BrN5).

Calculated: C(%) 54,26; H(%) 3,41; N(%) 19,77; Br(%) 22,56.

Found: C(%) 54,10; H(%) Of 3.32; N(%) 19,85; Br(%) 22,72.

Mass spectrometry (m/z): 353 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 5,14 (2H, s), of 6.75 (2H, d, J=9 Hz), 7,27 was 7.36 (3H, m), the 7.65 (1H, d, J=7 Hz), 7,78 (2H, d, J=9 Hz), 8,80 (2H, s).

Example 47

Was carried out as described in example 31, received the following connection:

< / BR>
4-[N-(3-bromobenzyl)-N-(4-cyanophenyl)amino]-1H-1,2,4-triazole.

Starting compound: 4-[(cyanophenyl)amino] -4H-1,2,4-triazole and 3-bromobenzyl bromide.

Elemental analysis (for C16H12BrN5).

Calculated: C(%) 54,26; H(%) 3,41; N(%) 19,77; Br(%) 22,56.

Found: 54.16 per 3,29 19,89 22,59.

Mass spectrometry (m/z): 353 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 5,09 (2H, s), of 6.75 (2H, d, J=9 Hz), 7,27-7,34 (2H, m), to 7.50 (1H, d, J=7 Hz), 7,56 (1H, s), to 7.77 (2H, d, J=9 Hz), 8,86 (2H, s).

Example 48

Was carried out as described in example 31, received the following connection:

< / BR>
5-[N-(4-nitrobenzyl)-N-(4H-1,2,4-triazole-4-yl)amino] benzofurazan.

Starting compound: 5-[(4H-1,2,4-triazole-4 - yl)amino] benzofurazan and 4-nitroben,41; H(%) 3,29; N(%) 29,07.

Found: C(%) 53,13; H(%) Of 3.28; N(%) 29,10.

Mass spectrometry (m/z: 337 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: of 5.29 (2H, s),? 7.04 baby mortality (1H, dd, J=10 Hz, 2 Hz), to 7.15 (1H, d, J=2 Hz), 7,69 (2H, d, J=9 Hz), with 8.05 (1H, d, J=10 Hz), 8,21 (2H, d, J=9 Hz), of 8.92 (2H, s).

Example 49

Was carried out as described in example 31, received the following connection:

< / BR>
5-[N-(4-bromobenzyl)-N-(4H-1,2,4-triazole-4-yl)amino] benzofurazan.

Source connection:

5-[(4H-1,2,4-triazole-4-yl)amino]benzofurazan and 4-bromobenzyl bromide.

Elemental analysis (for C15H11BrN6O).

Calculated: C(%) 48,54; H(%) 2,99; N(%) 22,64; Br(%) 21,53.

Found: C(%) 48,36; H(%) 3,03; N(%) 22,71; Br(%) 21,67.

Mass spectrometry (m/z): 370 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 5,07 (2H, s), 7,02 (1H, dd, J=10 Hz, 2 Hz), 7,18 (1H, d, J=2 Hz), 7,31 (2H, d, J=8 Hz), 7,54 (2H, d, J=8 Hz), 8,03 (1H, d, J=10 Hz), 8,83 (2H, s).

Example 50

Was carried out as described in example 31, received the following connection:

< / BR>
4-[N-(4-bromobenzyl)-N-(2-cyanophenyl)amino]-4H-1,2,4-triazole.

Starting compound: 4-[(2-cyanophenyl)amino] -4H-1,2,4-triazole and 4-bromobenzyl bromide.

Found: C(%) To 54.19; H(%) 3,41; N(%) 19,90; Br(%) Are 22.42.

Mass spectrometry (m/z): 355 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

:/ to 4.92 (2H, s), 7,37 (2H, d, J=9 Hz), 7,40-7,53 (2H, m), 7,54 (2H, d, J=9 Hz), 7,75-7,79 (1H, m), 7,89 (1H, d, J=8 Hz), 8,86 (2H, s).

Example 51

Was carried out as described in example 31, received the following connection:

< / BR>
4-[[N-(4-bromonaphthalene-1-yl)methyl] -N-(4-nitrophenyl)amino] -4H-1,2,4-triazole.

Starting compound: 4-[(4 - nitrophenyl)amino] -4H-1,2,4-triazole and 4-dibromo-1-methylnaphthalene.

Elemental analysis (for C19H14N5BrO2).

Calculated: C(%) 53,79; H(%) Of 3.33; N(%) 16,51; Br(%) 18,83.

Found: C(%) 53,77; H(%) 3,38; N(%) 16,46; Br(%) 18,87.

Mass spectrometry (m/z): 425 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 5,61 (2H, s), make 6.90 (2H, d, J=9 Hz), 7,35 (1H, d, J=8 Hz), 7.68 per-7,83 (3H, m), 8,09-8,29 (4H, m), 8,64 (2H, s).

Example 52

Was carried out as described in example 31, received the following connection:

< / BR>
1-[N-(4-bromobenzyl)-N-(4-cyanophenyl)amino]-1H-1,2,4-triazole.

Starting compound: 1-[(4-cyanophenyl)amino] -1H-1,2,4 - triazole and 4-bromobenzyl bromide.

Physico-chemical characteristics of the 77; Br(%) 22,56.

Found: C(%) 54,30; H(%) Of 3.43; N(%) 19,84; Br(%) 22,75.

Mass spectrometry (m/z): 353 (M+-1).

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: to 4.87 (2H, s), 6,69 (2H, d, J=9 Hz), 7,14 (2H, d, J=9 Hz), 7,47 (2H, d, J=9 Hz), EUR 7.57 (2H, d, J=9 Hz), 7,87 (1H, s), 8,03 (1H, s).

Reference example 12

< / BR>
3,36 g of tert-butoxide potassium added to 15 ml of anhydrous dimethyl sulfoxide and stirred the mixture for 30 minutes at room temperature. Then to the solution was added 2,52 g of 4 - amino-4H-1,2,4-triazole. After the reaction mixture was stirred for 15 minutes at room temperature, thereto was added 1.64 g of 4-fermentatively and stirred the mixture for a further 30 minutes at room temperature. To the reaction mixture was added ice water, and then neutralized the mixture of diluted hydrochloric acid. Precipitated precipitated crystals were collected by filtering from the receipt of 1.93 g of 4-[(4 - triptoreline)amino]-4H-1,2,4-triazole.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 6,62 (2H, d, J=8 Hz), 7,60 (2H, d, J=8 Hz), 8,82 (2H, s), 10,06 (1H, br)

Example 53

< / BR>
In a 0.23 g of 4-[(4-triptoreline)amino]-4H-1,2,4-triazole, and 0.28 ml of 4-bromobenzyl bromide is in at room temperature. The solvent was removed by distillation, was added to the obtained residue, water, and then extracted it with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography on silicagel column with obtaining coarse crystals from the eluate with chloroform. Selected coarse crystals have recrystallize from a solvent composed of a mixture of ethyl acetate and ether to obtain 0,22 g of 4-[N-(4-bromobenzyl)-N-(4-triptoreline)amino]-4H-1,2,4 - triazole.

Elemental analysis (for C16H12N4BrF3).

Calculated: C(%) 48.38 Per; H(%) 3,05; N(%) 14,11; Br(%) 20,12; F(%) 14,35.

Found: C(%) 48,46; H(%) 3.04 From; N(%) 14,06; Br(%) 20,36; F(%) 14,12.

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: a 4.86 (2H, s), 6,74 (2H, d, J=9 Hz), 7,13 (2H, d, J= Hz), 7,49 (2H, d, J=9 Hz), EUR 7.57 (2H, d, J=9 Hz), by 8.22 (2H, s).

In the same way as described in example 53, received the following connections.

Example 54

< / BR>
4-[N-(4-cyanophenyl)-N-(4-methoxycarbonylbenzyl)amino]-4H-1,2,4-triazole.

Starting compound: 4-[N-(4-cyanophenyl)amino]-4H-1,2,4-triazole and methyl 4-bromoethylene.

"ptx2">

Found: C(%) 64,77; H(%) Of 4.54; N(%) 21,07.

Mass spectrometry (m/z): 333 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: a-3.84 (3H, s), is 5.18 (2H, s), 6,74 (2H, d, J=9 Hz), 7,49 (2H, d, J=9 Hz), 7,76 (2H, d, J=9 Hz), to $ 7.91 (2H, d, J=9 Hz), 8,84 (2H, s).

Example 55

< / BR>
4-[N-(4-methoxycarbonylbenzyl)-N-(4-nitrophenyl)amino]-4H-1, 2,4-triazole.

Starting compound: 4-[N-(4-nitrophenyl)amino]-4H-1,2,4-triazole and methyl 4-bromoethylene.

Elemental analysis (for C17H15N5O4).

Calculated: C(%) 57,79; H(%) 4,28; N(%) Received 19.82.

Found: C(%) 57,60; H(%) 4.26 Deaths, N(%) 19,86.

Mass spectrometry (m/z): 353 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

:/ of 3.85 (3H, s), a 5.25 (2H, s), 6,79 (2H, d, J=9 Hz), 7,51 (2H, d, J=8 Hz), to 7.93 (2H, d, J=8 Hz), to 8.20 (2H, d, J=9 Hz), 8,88 (2H, s).

Example 56

< / BR>
1-methyl-6-[[N-(4-nitrophenyl)-N-(4H-1,2,4-triazole-4 - yl)amino] methyl] -1H-benzotriazol.

Starting compound: 4-[N-(4 - nitrophenyl)amino]-4H-1,2,4-triazole and 6-chloromethyl-1-methyl-1H - benzotriazol.

Elemental analysis (for C16H14N8O2).

Calculated: C(%) 54,85; H(%) Is 4.03; N(%) 31,98.

Found: C(%) 54,83; H(%) Of 4.05; N(%) 32,21.

Mass Spectro)

: 4,28 (3H, s), of 5.34 (2H, s), PC 6.82 (2H, d, J=9 Hz), 7,37 (2H, dd, J=9 Hz, 2 Hz), to 7.84 (1H, d, J=2 Hz), 8,00 (2H, d, J=9 Hz), 8,21 (2H, d, J=9 Hz), 8,91 (2H, s).

Example 57

< / BR>
2-methyl-5-[[N-(4-nitrophenyl)-N-(4H-1,2,4-triazole-4-yl)amino] methyl] -1H-benzotriazol.

Starting compound: 4-[N-(4-nitrophenyl)amino] -4H-1,2,4-triazole and 5-chloromethyl-2-methyl-2H-benzotriazol.

Elemental analysis (for C16H14N8O2).

Calculated: C(%) 54,85; H(%) Is 4.03; N(%) 31,98.

Found: C(%) 54,68; H(%) Was 4.02; N(%) 32,08.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 4,74 (3H, s), 5,28 (2H, s), at 6.84 (2H, d, J=9 Hz), 7,42 (2H, dd, J=9 Hz, 2 Hz), to 7.84 (1H, d, J=2 Hz), 7,89 (2H, d, J=9 Hz), 8,21 (2H, d, J=9 Hz), 8,84 (2H, s).

Example 58

< / BR>
1-methyl-5-[[N-(4-nitrophenyl)-N-(4H-1,2,4-triazole-4-yl)amino] methyl] -1H-benzotriazol.

Starting compound: 4-[N-(4 - nitrophenyl)amino]-4H-1,2,4-triazole and 5-chloromethyl-1-methyl-1H - benzotriazol.

Elemental analysis (for C16H14N8O2).

Calculated: C(%) 54,85; H(%) Is 4.03; N(%) 31,98.

Found: C(%) 54,77; H(%) Of 4.05; N(%) 32,08.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 4,30 (3H, s), and 5.30 (2H, s), 6,85 (2H, d, J=9 Hz), 7,54 (2H, dd, J=9 Hz, 2 Hz), to 7.84 (1H, d, J=9 Hz), 7,98 (1H, d, J=2 Hz), 8,21 (2H, d, J=9 Hz), 8,84 (2H, s).

Mass spectrometry (m/z): 352 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 5,31 (2H, s), for 6.81 (2H, d, J=9 Hz), 7,52 (1H, dd, J=9 Hz, J=2 Hz), of 8.06 (1H, d, J=9 Hz), 8,17 (1H, d, J=2 Hz), 8,21 (2H, d, J=9 Hz), 8,89 (2H, s), 9,40 (1H, s).

Example 60

< / BR>
4-[N-[(2-bromothiazole-5-yl)methyl]-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole.

Starting compound: 4-(4-nitrophenyl)amino-4H-1,2,4-triazole and 2-bromo-5-(methyl bromide)thiazole.

Elemental analysis (for C12H7N6O2BrS).

Calculated: C(%) 37,81; H(%) Of 2.38; N(%) 22,05; S(%) To 8.41; Br(%) 20,96.

Found: C(%) 37,64; H(%) 2,35; N(%) 21,96; S(%) 8,29; Br(%) 20,71.

Mass spectrometry (m/z): 379 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 5,42 (2H, s), 6,83 (2H, d, J=10 Hz), to 7.61 (1H, s), 8,21 (2H, d, J=10 Hz), 8,88 (2H, s).

Example 61

< / BR>
4-[N-[(2-bromothiazole-5-yl)methyl]-N-(cyanophenyl)amino-4H-1,2,4-triazole.

Starting compound: 4-(4-cyanophenyl)amino-4H-1,2,4 - triazole and 2-bromo-5-(methyl bromide)thiazole.

Elemental analysis (for C13H9N6SBr).

Calculated: C(%) 43,23; H(%) Of 2.51; N(%) 23,27; Br(%) 22,12; S(%) 8,88.

Found: C(%) 43,08; H(%) 2,41; N(%) 23,27; Br(%) 22,27; S(%) 8,75.

Mass spectrometry (m/z): 362 (M+).

Example 62

< / BR>
of 0.28 ml of acetic anhydride at room temperature was added to 10 ml of a pyridine solution containing 0.35 g of 4-[N-(4-AMINOPHENYL)- N-(4-bromobenzyl)amino]-4H-1,2,4-triazole and stirred the mixture for 20 minutes. After the reaction, the solvent was removed by distillation under reduced pressure, and the obtained residue was added the required amount of an aqueous solution of acid sodium carbonate, after which it was extracted the residue with ethyl acetate. An ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography on silicagel column to obtain 0.33 g of 4-[N-(4-acetylaminophenol)-N-(4-bromobenzyl)amino]-4H-1,2,4-triazole from the eluate with a mixture of chloroform and methanol in the ratio of 50:1.

Elemental analysis (for C17H16N5OBr).

Calculated: C(%) 52,86; H(%) 4,18; N(%) 18,13.

Found: C(%) 52,85; H(%) 4,22; N(%) 18,24.

Mass spectrometry (m/z): 387 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: a 2.01 (3H, s), a 4.86 (2H, s), is 6.78 (2H, d, J=9.0 Hz), 7,27 (2H, d, J= 8.6 Hz), 7,51 (4H, d, J=9.0 Hz), orciani added to N, N-dimethylformamide suspension containing 0.04 g of sodium hydride. The resulting mixture was stirred for 30 minutes at room temperature, added 0.15 g of 4-peritrabecular and the mixture was stirred for 15 minutes at 100oC. the Solvent was removed by distillation under reduced pressure, and the obtained residue was added water, then was extracted with him chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. Thus obtained crystals were recrystallize from a solvent composed of a mixture of ethyl acetate and ether, to obtain 280 mg of 4-[N-(4-nitrobenzyl)-N-(4 - triptoreline)amino]-4H-1,2,4-triazole.

Elemental analysis (for C15H10N5F3O2).

Calculated: C(%) 51,58; H(%) 2,89; N(%) 20,05; F(%) 16,32.

Found: C(%) 51,58; H(%) 2,84; N(%) 20,11; F(%) 16,22.

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: make 6.90 (2H, d, J=9 Hz), 7,24 (2H, d, J=8 Hz), 7,72 (2H, d, J=8 Hz), by 8.22 (2H, d, J=9 Hz), of 8.47 (2H, s).

In the same way as described in example 53, received the following connections.

Example 64

< / BR>
1 -[N-(4-cyanobenzyl)-N-(4-cyanophenyl)amino]-1H-1, 2,">

Elemental analysis (for C17H12N6).

Calculated: C(%) 67,99; H(%) Is 4.03; N(%) 27,98.

Found: C(%) 67,94; H(%) 4,17; N(%) 27,99.

Mass spectrometry (m/z): 300 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: is 5.18 (2H, s), 6,70 (2H, d, J=9 Hz), to 7.61 (2H, d, J=9 Hz), of 7.75 (2H, d, J=9 Hz), 7,82 (2H, d, J=9 Hz), 8,19 (1H, s), 8,77 (1H, s).

Example 65

< / BR>
1-[N-(4-cyanophenyl)-N-(4-methoxybenzyl)amino]-1H-1,2,4 - triazole.

Starting compound: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4 - triazole and 4-methoxybenzyl chloride.

Elemental analysis (for C17H15N5O).

Calculated: C(%) 66,87; H(%) Of 4.95; N(%) 22,94.

Found: C(%) 66,88; H(%) 5,09; N(%) 22,92.

Mass spectrometry (m/z): 305 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: and 3.72 (3H, s), is 4.93 (2H, s), 6,77 (2H, d, J=9 Hz), 6,85 (2H, d, J=9 Hz), 7.23 percent (2H, d, J=9 Hz), 7,74 (2H, d, J=9 Hz), 8,15 (1H, s), 8,53 (1H, s).

Example 66

< / BR>
1-[N-(4-chlorbenzyl)-N-(4-cyanophenyl)amino]-1H-1,2,4-triazole.

Starting compound: 1-[N-(4-cyanophenyl)amino] -1H-1,2,4-triazole and 4 - chlorbenzyl chloride.

Elemental analysis (for C16H12N5Cl).

Calculated: C(%) 62,04; H(%) 3,90; N(%) 22,61; Cl(%) Of 11.45.

Example 67

< / BR>
1-[N-(2-bromobenzyl)-N-(4-cyanophenyl)amino]-1H-1,2,4 - triazole.

Starting compound: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4 - triazole and 2-bromobenzyl bromide.

Elemental analysis (for C16H12N5Br).

Calculated: C(%) 54,25; H(%) 3,41; N(%) 19,56; Br(%) 22,56.

Found: C(%) 54,05; H(%) Of 3.42; N(%) 19,78; Br(%) Cushion 22.66.

Mass spectrometry (m/z): 353 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

:/ at 5.10 (2H, s), 6,76 (2H, d, J=9 Hz), 7.24 to 7,34 (3H, s), 7,66 (1H, dd, J=9 Hz, 8 Hz), 7,71 (2H, d, J=9 Hz), 8,17 (1H, s), 8,56 (1H, s).

Example 68

< / BR>
1-[N-(3-bromobenzyl)-N-(4-cyanophenyl)amino]-1H-1,2,4-triazole

Starting compound: 1-[N-(4-cyanophenyl)amino] -1H-1,2,4-triazole and 3-bromobenzyl bromide.

Elemental analysis (for C16H12N5Br).

Calculated: C(%) 54,25; H(%) 3,41; N(%) 19,77; Br(%) 22,56.

Found: C(%) 54,08; H(%) 3,41; N(%) 19,78; Br(%) 22,64.

Mass spectrometry (m/z): 353 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 5,07 (2H, s), 6,72 (2H, d, J=9 Hz), 7,29 (1H, t, J=8 Hz), 7,38 (1H, d, J= 8 Hz), 7,49 (1H, d, J=8 Hz), to 7.61 (1H, s), of 7.75 (2H, d, J=9 Hz), 8,1 is inane: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and benzyl bromide.

Elemental analysis (for C16H13N5).

Calculated: C(%) 69,80; H(%) Value Of 4.76; N(%) 25,44.

Found: C(%) 69,72; H(%) To 4.81; N(%) 25,41.

Mass spectrometry (m/z): 275 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: to 5.03 (2H, s), of 6.75 (2H, d, J=9 Hz), 7,28 and 7.36 (5H, m), of 7.75 (2H, d, J=9 Hz), to 8.62 (1H, s).

Example 70

< / BR>
1-[N-(4-terbisil)-N-(4-cyanophenyl)amino]-1H-1,2,4-triazole.

Starting compound: 1-[N-(4-cyanophenyl)amino] -1H-1,2,4-triazole and 4-terbisil bromide.

Elemental analysis (for C16H12N5F).

Calculated: C(%) 65,52; H(%) 4,12; N(%) 23,88; F(%) 6.48 In.

Found: C(%) 65,60; H(%) To 4.23; N(%) 23,83; F(%) 6,47.

Mass spectrometry (m/z): 293 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 5,02 (2H, s), 6,76 (2H, d, J=9 Hz), 7.03 is-7,47 (4H, m), of 7.75 (2H, d, J=9 Hz), 8,15 (1H, s), at 8.60 (1H, s).

Example 71

< / BR>
1-[N-(4-cyanobenzyl)-N-(4-iodobenzyl)amino]-1H-1, 2,4-triazole.

Starting compound: 1-[N-(4-cyanophenyl)amino] -1H-1,2,4-triazole and 4-iodobenzyl chloride.

Elemental analysis (for C16H12N5I).

Calculated: C(%) 47,90; H(%) 3,01; N(%) 17,46; I(%) 31,63.

Found: C(%) 47,62; H(%) 3,00; N(%) 17,50; I(%) 31,71.

Example 72

< / BR>
1-[N-(4-cyanophenyl)-N-(4-methylbenzyl)amino]-1H-1,2,4-triazole.

Starting compound: 1-[N-(4-cyanophenyl)amino] -1H-1,2,4-triazole and a-bromo-p-xylene.

Elemental analysis (for C17H15N5).

Calculated: C(%) 70,57; H(%) 5,23; N(%) 24,20.

Found: C(%) 70,46; H(%) 5,28; N(%) 24,12.

Mass spectrometry (m/z): 289 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: 2,32 (3H, s), is 4.85 (2H, s), of 6.71 (2H, d, J=9 Hz), 7,11 (4H, s), 7,56 (2H, d, J=7 Hz), 7,80 (1H, s), 8,01 (1H, s).

Example 73

< / BR>
5-[[N-(4-cyanophenyl)-N-(1H-1,2,4-triazole-1-yl)amino] methyl] - benzofurazan.

Starting compound: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 4-bromomethylphosphonate.

Elemental analysis (for C16H11N7O).

Calculated: C(%) 60,56; H(%) 3,49; N(%) 30,90.

Found: C(%) 60,51; H(%) Of 3.53; N(%) 30,88.

Mass spectrometry (m/z): 317 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

:/ of 5.26 (2H, s), of 6.75 (2H, d, J=9 Hz), to 7.68 (1H, d, J=9 Hz), to 7.77 (2H, d, J=9 Hz), 8,03 (1H, s), 8,08 (1H, d, J=9 Hz, by 8.22 (1H, s), 8,89 (1H, s).

Example 74

< / BR>
5-[[N-(4-nitrophenyl)-N-(1H-1l and 5-bromomethylphosphonate.

Elemental analysis (for C15H11N7O3).

Calculated: C(%) 53,41; H(%) 3,29; N(%) 29,07.

Found: C(%) 53,29; H(%) Of 3.32; N(%) 29,16.

Mass spectrometry (m/z: 337 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6,, TMS internal standard)

: 5,33 (2H, s), is 6.78 (2H, d, J=9 Hz), of 7.70 (1H, d, J=9 Hz), 8,07 (1H, s), 8,10 (1H, d, J=9 Hz), to 8.20 (2H, d, J=9 Hz), compared to 8.26 (1H, s), of 8.95 (1H, s).

Example 75

< / BR>
5-[N-(4-triazolylmethyl)-N-(4H-1,2,4-triazole-4-yl)amino] benzofurazan.

Starting compound: 5-[N-(4H-1,2,4-triazole-4-yl)amino] benzofurazan and 4-chloromethylthiazole.

Elemental analysis (for C10H9N7OS).

Calculated: C(%) 48,15; H(%) 3,03; N(%) 32.76ˆ; S(%) 10,71.

Found: C(%) 48,05; H(%) 3,05; N(%) 32,72; S(%) Or 10.60.

Mass spectrometry (m/z): 299 (M+).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: of 5.26 (2H, s),? 7.04 baby mortality-7,06 (2H, m), of 7.75 (1H, s), 8,01 (1H, d, J=9 Hz), 8,77 (2H, s), 9,11 (1H, s).

The composition for oral administration:

The core tablets - Content (mg)

The compound of example 15 - 1,0

Lactose - 76,4

Corn starch - 19,3

Hydroxypropylcellulose - 3,0

Magnesium stearate - 0,3

Total - 100

Shell tablet

Hydroxypropyl meth In the amount of - 105

Obtaining tablets 1 mg

7 g of the compound from example 15 and 534,8 g of lactose were mixed in a polyethylene bag. The mixture was mixed and grind in dosing mill (produced by Hosakawa Micron Co. ). 541,8 g chopped mixture and 135,1 g of corn starch were mixed until a homogeneous mass with the use of equipment (produced by Ohkawara Manufacturing Co.), carrying out the granulation liquid and coated shell. For granulating this mixture is sprayed 210 g of a 10% aqueous solution of hydroxypropylcellulose. After drying the resulting granules are rubbed through a 20-mesh sieve, were added 2.1 g of magnesium stearate. Using a rotary machine that produces tablets (manufactured by Hata Ironworks Co.), as well as using mortar 6,5 MMF,8R of these granules have formed a tablet weighing 100 mg of equipment, intended to cover the membrane (manufactured by Freund Industrial Co.), tablets sprinkled 350 g of liquid, forming a membrane and containing a 20.3 g hydroxypropylmethylcellulose, 2.8 g of polyethylene glycol 6000, 11.2 g of titanium dioxide and 0.7 g of talc, to obtain film-coated tablets containing 5 mg of the shell on the tablet.

1. Triazolinone the tertiary amine compound of General formula I

< / BR>
in which A performance is/BR>< / BR>
naphthyl, pyridyl, thienyl, thiazolyl, benzothiazolyl, hinely, benzofurazanyl or benzothiazolyl, possibly substituted by one or more halogen atoms or lower alkyl groups;

D-ring is a group of the formula

< / BR>
or benzofurazanyl;

E ring indicates 4H-1,2,4-triazole group or 1H-1,2,4-triazole group;

R1denotes a hydrogen atom, a halogen atom, a cyano, a nitro-group, trifluoromethyl, lower alkyl or lower alkoxygroup;

R2denotes a hydrogen atom or a halogen atom;

R3denotes a halogen atom, a cyano, a nitro-group, a trifluoromethyl or amino, provided that when both R1and R2are chlorine atoms, A represents a methylene,

or its pharmaceutically acceptable salt.

2. The compound or its salt under item 1, characterized in that B represents a group of the formula

< / BR>
and D-ring is a group of the formula

< / BR>
3. The compound or its salt under item 2, wherein R2is a hydrogen atom.

4. The compound or its salt under item 3, wherein R1is a halogen atom, a cyano or a nitro-group, and R3allabou 4-[N-(4-bromobenzyl)-N-(4-cyanophenyl)amino]-4H-1,2,4-triazole or its salt.

6. Connection on p. 1, characterized in that it is a 4-[N-(4-bromobenzyl)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole or its salt.

7. Triazolinone the tertiary amine compound of General formula I

< / BR>
in which A represents a simple bond or lower alkylenes group;

B denotes a lower alkyl, a group of the formula

< / BR>
naphthyl, pyridyl, thienyl, thiazolyl, benzothiazolyl, hinely, benzofurazanyl or benzothiazolyl, possibly substituted by one or more halogen atoms or lower alkyl groups;

D-ring is a group of the formula

< / BR>
or benzofurazanyl,

E-ring denotes 4H-1,2,4-triazole group or 1H-1,2,4-triazole group;

R1denotes a hydrogen atom, a halogen atom, a cyano, a nitro-group, trifluoromethyl, lower alkyl or lower alkoxygroup;

R2denotes a hydrogen atom or a halogen atom;

R3denotes a halogen atom, a cyano, a nitro-group, a trifluoromethyl or amino, provided that when both R1and R2are chlorine atoms, A represents a methylene,

or its salt as an aromatase inhibitor.

8. Inhibiting aromatase pharmaceutically media characterized in that the active ingredient is triazolyl-substituted tertiary amine compound of the formula I or its salt under item 1.

Priority points and features:

02.09.91 - PP.4 to 6 and PP.1 - 3, 7 - 8, except for the signs of PCP.1, 7 and 8: D - benzofurazanyl group; A lower Allenova group; B - naphthyl, thienyl or benzofurazanyl, and group B may be substituted by one or more halogen atoms; R1is hydrogen; R2- halogen, provided that when both R1and R2are chlorine atoms, A is methylene; p. 2: A - lowest Allenova group; R1is hydrogen; R2- halogen, and provided that if both R1and R2are chlorine atoms, A is methylene; under item 3: A - lowest Allenova group; R1- hydrogen, which have priority from 02.12.91.

 

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(C1-C6)-alkyl-(C3-C7)-alkylamino and pyrrolidin-I-yl group; Raand Rbis a hydrogen atom or (C1-C3)-alkyl; n is an integer from 1 to 4; their enantiomers, racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to heterocyclic amines of formula I:

,

in which

X represents-CH2-group or-S-group;

B denotes a group selected from a number containing-CO -, - CH2OCO-, -CH2OCS-, -CH2NHCO - CH2NHCS-group;

D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-(C1C6) alkylamino, mono- (C3-C7)-alkynylamino, mono-(C3-C7)-quinil-amino group and pyrrolidin-1-yl group;

The is a simple carbon-carbon bond or a group of the formula: -CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, (C1-C3)alkyl, or taken together with the carbon atom to which they are attached, form a (C3-C6) cycloalkyl;

A is selected from the group comprising (a) carboxyl group optionally esterified (C1-C4) Ukrspirt the crystals: -CОNHRgOH, where Rcand Rdidentical or different, represent a hydrogen atom, (C1-C6) alkyl, benzyl, pyridin-2-yl, or taken together with the nitrogen atom to which they are bound, form piperidino, morpholino-, 4-thiomorpholine-, 4,5-diazepino, 4-(C1-C4)alkylpiperazine; Rfis a tolyl; Rgis a (C1-C4) alkyl;

(b) (C1-C3) alkyl;

(c) the group-NRcRdwhere Rcand Rddefined above,

(d) a cyano, if "y" does not mean a simple carbon-carbon bond

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to new biologically active chemical compounds, derived pyrazine formula I listed in the description, which is obtained by the interaction of the previously obtained through collaboration pyrazinamide with Amida sodium in liquid ammonia Na-salt pyrazin-2-carboxamide and 6-methyl-5-uracil sulfochloride in liquid ammonia

The invention relates to the derivatives of pyrazine formula I, where R1- H or C1-8-alkyl, R2- C1-8-alkyl, unsubstituted or substituted C1-4-alkoxyl, hydroxyl, fenoxaprop, which in turn is one - or multi-substituted C1-4-alkyl, C1-4-alkoxyl, alkoxyalkyl or cyano, aminowhere R3- H or C1-4-alkyl, R4-phenyl, repeatedly substituted C1-4-alkyl, a substituted amino group dichlorobenzenesulfonyl, C1-4-alkyl, unsubstituted or substituted residues selected from the group of hydroxyl, fenoxaprop, in turn multiply substituted by halogen or alkoxyalkyl, carbonylation formula II, where X is oxygen or-NH-, piperidinyl, N-substituted C1-8-alkyl, and phenyl unsubstituted or substituted C1-4-alkoxyl, amidinopropane formulawhere R5is phenyl, substituted by halogen or C1-4-alkyl, and a group of the formula III, where R1- H, or R1and R2together with the nitrogen atom to which they are bound, form a pieperazinove ring, unsubstituted or substituted in position 4 by a group IV, V,-alkyl, or alkoxyalkyl, and-naftussya, and if R1- H, R2does not mean alkyl, benzyl, fluorine - or chlorbenzyl, phenethyl, hydroxyethyl or HOCH2- (CHOH)4- CH2or if R1- C1-3-alkyl, R2does not mean C1-4-alkyl, and an acid additive salt
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