The way to obtain 1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy-5h-2, 3-benzodiazepine

 

(57) Abstract:

Usage: in medicine, as drugs acting on the nervous system. Entity: product:1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy--2,3-benzodiazepine. The output of approx. 80%., so pl. 168-169 deg. C. Reagent 1:2-acetonyl-3'-chloro-4,5-dimethoxybenzophenone. Reagent 1: 2 hydrazinehydrate. Reaction conditions: reagent ratio 1:(3-7), the lower aliphatic alcohol when 28-68 castle, in an oxygen-free environment, if necessary, in the presence of water. 3 C.p. f-crystals, 1 table.

The present invention relates to a method for producing 1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy--2,3-benzodiazepine of the formula (I)

(I)

high purity and high quality, appropriate pharmaceutical prescriptions.

1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy--2,3-benzodiazepine is a substance of high purity in that case, if according to the method of liquid chromatography high pressure total content of impurity therein is not more than 0.3 weight.

Derivatives-2,3-benzodiazepine has generally beneficial effects on the Central nervous system, such as antiaggressive, antidepressant and a narcotizing effect. According to preclinical and clinical is the author of medicinal substance (Patent specification Hungary NN 179 018 and 191 702).

A method of obtaining-2,3-benzodiazepines, and, most preferred, given both the high yield and feasibility on an industrial scale, is a method whereby 1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy--2,3-benzodiazepine of the formula (I) is produced by interaction of 2-acetonyl-3'-chloro-4,5-dimethoxybenzophenone formula (II) [hereinafter diketone of formula (II)]

(II)

at a temperature of from -20oC to 110oC 3-7 moles of hydrazine hydrate is added per one mole of the diketone. The reaction time depends on temperature and varies from 1 to 168 hours. The yield of the crude product isolated from the reaction mixture, is 80-85% and the efficiency recrystallization of the crude product from isopropanol to about 90% (Patent Hungary N 191702).

According to our research thus obtained 1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy--2,3-benzodiazepine of the formula (I) contains 3 typical impurities. Semiquantitative studies by thin layer chromatography (adsorbent: silica gel HF254the solvent for elution: a mixture of 2: 8 benzene and ethyl acetate, the definition in UV-light) show that the total amount of these impurities is about 1% of the Contaminants were razdelek spectrometry).

Determine what impurities is the following connections:

1. 1-(chlorophenyl)-4-methyl-5-hydroxy-7,8-dimethoxy--2,3-benzodiazepine of the formula (III), melting point: 181-184oC (from isopropanol).

2. 1-(3-course)-4-methyl-8-methoxy--2,3-benzodiazepine of the formula (IV), melting point: 128-129oC (from isopropanol).

3. 1-(3-chlorophenyl)-3-methyl-6,7-dimethoxyisoquinoline formula (V), melting point: 163-265oC (from absolute ethanol).

Method data liquid chromatography high pressure indicate that precrystallization 1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy--2,3-benzodiazepine of the formula (I) typically contains about 0.1-0.3 weight. 8 monomethoxy-derivative of formula (IV)

(IV)

and isoquinoline derivative of the formula (V).

(V)

5-hydroxybenzothiazole formula (III)

(III)

in the crude product, obtained according to the method described in the Patent Hungary N 191 702, it is usually possible to determine the number of 0.5-1.0 weight. however, in some cases even using the same source materials and explicitly carrying out the reaction in the same conditions, the number could suddenly be up to 2-3 weight.

The crude product containing such a large kollichestvo solvents and mixtures of solvents (such as alcohols, containing from 1 to 3 carbon atoms, acetic acid esters, aliphatic ketones, tetrahydrofuran, benzene, mixtures thereof and mixtures of these solvents formed with dimethylformamide, chlorinated hydrocarbons, water and acetic acid). According to these experiments, 5-oxibendazole impurity of formula (III) is separated almost together with 1-(3-chlorophenyl)-methyl-7,8-dimethoxy--2,3-benzodiazepines formula (I).

The product containing 2 weight. 5-oxybenzoates formula (III), clear fractionated crystallization and recrystallization from 30-fold volume of ethyl acetate (relative to the weight of the product), I get the first fraction (output 52,4%) containing 3 weight. and the second fraction (yield of 40.6 wt.), containing 0.6 weight. 5-oxybenzoates-derivative of formula (III). In order to reduce the content of 5-oxybenzoates at least below 0.5 weight. fraction 2 repeatedly subjected to fractionated crystallization. However, this stage leads to unacceptably high loss of substance.

The aim of the present invention is a simple and effective way, providing 1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy-benzodiazepine of high purity and of high quality, relevant, pharmaceutical the tion, on the basis of the diketone of formula (II) and hydrazine hydrate is added, by eliminating the possibility of education in the process of impurity of formula (III) to(V) or by a significant reduction in the formation of these impurities.

in Another method effective at clearing the compounds of formula (I) containing impurities due to shortcomings in the implementation of the method of obtaining a product of high purity, on the basis of the diketone of formula (II), and/or due to the presence in the source diketone random impurities.

Method a) of this invention is based on the unexpected discovery, namely, that if the reaction of the diketone of formula (II) with a hydrogenation product to hold in the absence of oxygen, the reaction of 5-hydroxy-benzodiazepine practically not formed. It is not clear why hydrazinehydrate present in the reaction mixture in a large excess of despite the fact that he is a strong regenerating agent cannot prevent the occurrence of adverse reactions oxidation leading to the formation of 5-oxybenzoates formula (III); the formation of this compound can be completely prevented in the absence of oxygen. In addition, it was found that choosing suitable reaction conditions, such as t is ASS="ptx2">

Thus, according to one aspect of the present invention, it is proposed a way to obtain 1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy--2,3-benzodiazepine of the formula (I) with high yield and high quality, appropriate pharmaceutical assignments, interaction in an organic solvent or mixture of organic solvents at a temperature of from 15 to 85oC 1 mol of 2-acetonyl-3'-chloro-4,5-dimethoxybenzophenone formula (II) with 3-7 moles of hydrazine hydrate is added, followed by recrystallization of the crude product of an aliphatic alcohol containing 1 to 5 carbon atoms, characterized in that it comprises carrying out the reaction of 2-acetonyl-3'-chloro-4,5-dimethoxybenzophenone with hydrazinehydrate in the absence of oxygen, if necessary, in the presence of water.

The original 2-acetonyl-3'-chloro-4,5-dimethoxybenzophenone formula (II) can be obtained according to the method described in the Patent application Hungary N 194 529.

The solvent can be used monatomic or polyhydric aliphatic alcohols containing 1 to 5 carbon atoms, dimethylformamide, dimethylsulfoxide, chlorinated hydrocarbons, dioxane, does not contain peroxide, tetrahydrofuran, a mixture thereof or, in the case of rastaplivaem solvent to deoxygenate simple boiling. The reaction vessel may be deoxygenation by known methods, for example, pumping or flushing equipment with an inert gas. For this purpose it is preferable to use nitrogen or inert gas.

In accordance with a preferred embodiment of the method of this invention, the diketone of formula (II) are suspended in an aliphatic alcohol WITH1C5possibly containing water, the reaction vessel deoxygenated nitrogen or argon and added to the suspension under stirring 98-100% hydrazinehydrate. The reaction is carried out in an atmosphere of inert gas at a temperature of from 25 to 70oC. the reaction Time given the extreme temperatures of approximately 78 and 3 hours, respectively. Then, the reaction mixture may be diluted with distilled water and excess hydrazine hydrate is added to neutralize the acetic acid. The crystalline product formed during cooling, is filtered off, washed with an aqueous solution of alcohol and dried. The yield of the crude product is 85-90%

The crude product is recrystallized from 10-12-fold volume based on the weight of the product is ethanol or isopropanol. The solution, if necessary, treated with charcoal.

The method is based on the unexpected opened eticheskim ring under certain conditions behaves as a phenolic group. When implementing the method of the present invention this means that if 1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy--2,3-benzodiazepine of the formula (I), contaminated 5-oxybenzoates formula (III), dissolved in a suitable solvent and treated with alkali metal hydroxide, carbonate or alcoholate of an alkali metal, and then the compound of formula (I) is crystallized from the solution, this latter compound has a high purity and large output, while alkaline derivative compound of the formula (III), due to its better solubility, remains dissolved. Recrystallization by this method is an effective method of purification of the desired compounds of formula (I), also contaminated and isoquinolines of the formula (V).

Thus, according to an additional aspect of the present invention, it is proposed a method of purification of 1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy-benzodiazepine of the formula (I) containing an impurity of the formula (V) and/or particularly of the formula (III), characterized in that the method includes dissolving the contaminated compounds of formula (I) in a suitable solvent, processing it, preferably at the boiling temperature of the solvent, the alkali metal hydroxide, carbonate or alkoholillisia it from aliphatic alcohol, containing from 1 to 5 carbon atoms.

For this reaction can be any solvent or any mixture of solvents suitable for recrystallization benzodiazepine of formula (I) and inert relative to the used alkali metal hydroxide, carbonate or alcoholate of an alkali metal, meaning that it can be obtained the solution of these alkaline compounds in the indicated solvent with a concentration of not less than 0,005 mol/l, Preferably as a solvent to use a linear or branched one - or polyhydric aliphatic alcohols containing from 1 to 5 carbon atoms, or mixtures thereof. It is not necessary to use anhydrous solvents, however, increasing the water content of the cleaning efficiency is reduced. (A significant improvement in quality can be achieved using recrystallization even solvent containing 10% water).

As the hydroxides and carbonates of alkali metals can be used easily available compounds of sodium or potassium. As an alcoholate of an alkali metal is preferable to use a sodium alcoholate or potassium derived from linear or branched alcohols containing 1 to 4 atoms ugley limit the amount of alkaline compounds, used in the reaction is limited by the solubility of these compounds in this solvent, however, on 1 mol of 5-oxybenzenesulfonate impurity of formula (III) you must use at least 1 mol of alkali compounds. (The use of alkaline compounds in more than 35 moles of benefits does not).

According to a preferred variant of the purification method of this invention, from 5 to 30 moles of alkali metal hydroxide, carbonate or alcoholate of an alkali metal per 1 mol of 5-oxybenzoates add to 12-fold volume of isopropanol or to 18-fold the volume of tert-butanol based on the weight of the compounds of formula (I) containing from 1 to 3 weight. 5-oxibutinina, solution, thus obtained, heated to boiling and dissolve in it untreated benzodiazepine of formula (I), which must be cleaned. From the thus obtained solution is crystallized by cooling the compound of formula (I), the product is filtered, washed successively with isopropanol or tert-butanol and distilled water until neutral and dried. Thus, the content of impurities in the compound of formula (I) is reduced by approximately one order of magnitude, and the output of the target product when you elisavet of the 12-fold volume of isopropanol or more preferably, ethanol. This recrystallization may be carried out with the output from 94 to 97% According to the method of liquid chromatography high pressure, the thus obtained product contains no more than 0.3% of impurities, mainly 5-oxybenzoates formula (III) and 8 monomethoxy-derivative of formula (IV).

According to this invention, these methods allow to obtain 1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy--2,3-benzodiazepine, containing not more than 0.3% of impurity. This result is achieved by simple methods, i.e., by conducting the reaction in the absence of oxygen and the selection of the appropriate temperature. These techniques, although they greatly improve the quality of the product, they do not lead to losses of output in comparison with the known methods, and even make it possible to stabilize the output at a high level. The cleaning method in accordance with this invention is a simple and effective method of purification of 1-(3-chlorophenyl)-4-methoxy-7,8-dimethoxy-benzodiazepine contaminated for any reason, and particularly those containing 5-oxybenzoates formula (III).

Both methods are in accordance with this invention are economically feasible in industrial Margaritescu use.

This product, thus obtained, can be converted into a pharmaceutical composition, preferably after micronisation, ensuring the formation of particles with an average size of less than 25 microns.

The following examples illustrate the proposed method and do not limit the scope of the claims of this invention.

Example 1

1,(3-chlorophenyl)-methyl-7,8-dimethoxy--2,3-benzodiazepine

20,0 g (to 0.060 mole) 2-acetonyl-3'-chloro-4,5-dimethoxybenzophenone (II) are added to 70 ml of isopropanol and removed from flask air, blowing it with nitrogen. Then within 1-2 minutes add the insufficient 18,0 ml (0,368 mole) of 98-100% hydrazine hydrate is added, then the reaction mixture was stirred in nitrogen atmosphere at 28-32oC for 78 hours. The mixture is cooled to 20oC, diluted with 70 ml of distilled water, and then add to it and 17.1 ml of glacial acetic acid. Crystalline product stands out from the orange-red solution for 1-2 minutes. This suspension of crystals was stirred at 0-5oC for 4 hours, filtered, washed with a mixture of isopropanol and water (1:1) and dried at 40oC. Thus receive 17,85 g of the crude product with a melting point 168,5-170ooC. the isolated product is filtered, washed with isopropanol with a temperature of 0-5oC and dried at 40oC. Thus receive 16,1 g (yield 80.2% in the calculation of the diketone of formula (II) of the desired compound in the form of white crystals, which according to the method of liquid chromatography high pressure does not contain impurities in measurable quantities. This product is suitable for pharmaceutical use, or in this form, or if necessary after micronisation, leading to the formation of particles with an average size of less than 25 microns.

Melting point: 168-169oC.

Example 2

1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy--2,3-benzodiazepine of 20.0 g (to 0.060 mole) 2-acetonyl-3'-chloro-4,5-dimethoxybenzophenone (II) is added in portions to 100 ml of a mixture of methanol and water (9:1) and removed from flask air, blowing with argon. Then under weak stirring, for 1-2 minutes to 17.6 ml (0,363 mole) of 98-100% hydrazine hydrate is added, after which the reaction mixture is boiled (68oC) in argon atmosphere for 3 hours. The mixture is cooled to 20oC and add it to 16.5 ml of glacial acetic acid. The suspension of the crystals thus obtained, diluted with 80 ml of distilled water and stirred at 0-5oC1:1) and dried at 40oC. are Thus obtained 18.0 g of the crude product, melting point 166-169oC. This product is dissolved in 216 ml of boiling absolute ethanol, the solution is treated with charcoal, washed with ethyl alcohol to a temperature of 0-5oC and dried at 40oC. Thus get to 15.4 g of the desired compound yield of 78.1 weight. in the calculation of the diketone of formula (II), which according to the method of liquid chromatography high pressure does not contain any impurities.

Melting point: 168-169oC.

Example 3

1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy--2,3-benzodiazepine.

Get on the methodology described in example 2, except that the crude product is recrystallized from 216 ml of isopropanol. So get 16,43 g of 1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy--2,3-benzodiazepine, output 83.1% of per diketone of formula 11. According to the method of liquid chromatography high pressure product contains 0.12 weight. monomethoxy-derivative of formula (IV).

Melting point: 168-170oC.

Example 4

Purification of 1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy--2,3-benzodiazepine, containing a mixture of 50.0 grams (0.15 mole) of 1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy--2,3-benzo is enzodiazepine formula (III), dissolved in 600 ml of isopropanol containing potassium hydroxide in the amount of 0.39 g/100 ml At the end of dissolving the mixture is cooled to 0-5oC and enable at the same temperature to crystallize within 4 hours. The crystals formed is filtered off, washed until neutral with isopropanol with a temperature of 0-5oC and distilled water, and then dried to constant weight at 40oC. Thus receive 47,6 g of the desired product, which is recrystallized from 12-fold volume of isopropanol. The output of 46.2 g (92.4 per cent). According to the method of liquid chromatography high pressure this product contains 0.20 weight. 5-oxibutinina impurity of formula (III).

Melting point: 168-169oC.

Example 5

Purification of 1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy--2,3-benzodiazepine, containing a mixture of 0.15 g (1.3 mmole) of potassium tert-butylate is added to 90 ml of tert-butanol, the mixture is heated to boiling and dissolve in it 5.0 g (15 mmol) of 1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy--2,3-benzodiazepine of the formula (I), containing according to the method of liquid chromatography high pressure

1.5 weight. (0.22 mmole) of the impurity 5-oxybenzoates formula (III). Then the solution is cooled to 25-27oC and give the prob is and washed until neutral reaction of tert-butanol with a temperature of 25-27oC and distilled water, after which the crystals are dried to constant weight at 40oC. are Thus obtained 4.4 g of white crystalline substance, which is recrystallized from 12-fold volume of ethanol (based on the weight of the substance) and receive (84%) of the desired compound according to the method of liquid chromatography high pressure of 0.12 weight. impurity - 5-oxybenzoates formula (III).

Melting point: 167-167,5oC.

Example 6

Purification of 1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy--2,3-benzodiazepine containing an admixture of 0.5 g (5.0 mmol) of ateleta sodium are dissolved in 70 ml of isopropanol, the solution is heated to boiling and add 5.0 g (15 mmol) of 1-(3-chloranil)-4-methyl-7,8-dimethoxy--2,3-benzodiazepine of the formula (I), containing according to the method of liquid chromatography high pressure 1.5 weight. impurity 5-oxybenzoates formula (III). After dissolution, the reaction mixture is cooled to 0-5oC and stirred at this temperature for 4 hours. The crystals formed is filtered off, washed until neutral with isopropanol with a temperature of 0-5oC and distilled water, then dried to constant weight at a temperature of 40oC. Tanypodinae (calculated on the weight of the product) and obtain 4.3 g (85,0%) of the desired product, containing according to the method of liquid chromatography high-pressure - 0.22 weight. impurity 5-oxybenzoates formula (III).

Melting point: 167,5-168,5oC.

Example 7

Analysis of possible impurities 1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy--2,3-benzodiazepine.

Impurities present in the compound of formula (I), divided by liquid chromatography high pressure using a column of Nucleosil C1810 ám (4 x 250 mm) with mobile phase composed of a mixture of acetonitrile and 0.1 M acetate buffer (pH 4), 60 to 40. Detection is carried out at 230 nm using UV detector. Chromatogram recorded on a recording integrator.

The following table shows the relative retention time and relative intensity of the signal of the potential impurities of the compounds of formula (I), measured at 230 nm and is attributed to the peak of the main product (1).

1. The way to obtain 1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy-5H - 2,3-benzodiazepine of the formula

< / BR>
including the interaction of 1 mole of 2-acetonyl-3-chloro-4,5-dimethoxybenzophenone formula

< / BR>
3 7 moles of hydrazine hydrate is added in the medium aliphatic alcohol containing 1 to 5 carbon atoms, at a temperature of 28 68oWith kind characterized in that the process is carried out in an oxygen-free environment and, if necessary, in the presence of water.

2. The method according to p. 1, characterized in that aliphatic alcohol use methyl or isopropyl alcohol.

3. The method according to PP. 1 and 2, characterized in that the process is carried out in an atmosphere of nitrogen or argon.

4. The method according to PP. 1 and 2, characterized in that the solvent a mixture of methanol with water in the ratio of 9 to 1.

 

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17 cl, 496 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with general formula I, where R1 represents -(CHR')q-aryl or -(CHR')q-thiophen, which are unsubstituted or mono-, di- or tri-substituted with (inferior)alkyl, (inferior)alkoxy, CF3 or haloid, or represents (inferior)alkyl, (inferior)alkenyl, -(CH2)n-Si(CH3)3, -(CH2)n-O-(inferior)alkyl, -(CH2)n-S- (inferior)alkyl, -(CH2)q-cycloalkyl, -(CH2)n-[CH(OH)]m-(CF2)p-CHqF(3-q), or represents -(CH2)n-CR2-CF3, where two radicals R together with a carbon atom form a cycloalkyl ring; R' represents hydrogen or (inferior)alkyl; n is 1, 2 or 3; m is 0 or 1; p is 0, 1,2, 3, 4, 5 or 6; q is 0, 1, 2 or 3; R2 represents hydrogen or (inferior)alkyl; R3 represents hydrogen, (inferior)alkyl, CH2F, aryl, optionally mono-, di- or tri-substituted with a haloid, or represents -(CH2)nNR5R6, where R5 and R6 independently represent hydrogen or (inferior)alkyl; R4 represents one of the following groups a) or b), where R7 represents inferior)alkyl or -(CH2)ncycloalkyl; R8 and R9 independently represent hydrogen, (inferior)alkyl, -(CH2)n-cycloalkyl or -C(O)-phenyl. The invention also relates to pharmaceutically used acid addition salts of these compounds, optically pure enantiomers, racemates or diastereomeric mixtures, as well as compounds with general formula I-1, and medicinal agent.

EFFECT: obtaining new biologically active compounds, designed for inhibiting γ-secretase.

16 cl, 83 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 2,3-benzo-5,7-disubstituted-1,4-cycloheptadiazines of general formula , where 1) R1=2-thienyl; R2=trifluoromethyl; 2) R1-R2=1,3-(5,5-dimethyl)cyclohexyl; 3) R1=R2=methyl, which can be used as extraction agents for non-ferrous and platinum-group metals, as well as in medicine. The method of involves reaction of ortho-phenylenediamine and the corresponding 1,3-diketone in molar ratio of components equal to 1:1 and while heating to temperature from 50°C to 80°C for 1-3 hours in dry benzol or without the benzol, and in the absence of a condensing agent.

EFFECT: wider field of use.

1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new benzodiazepine compounds of general formula , wherein each R1, R2, R3 and R4 independently represent hydrogen or alkyl, or R2 and R3 together represent lower alkylene; A1 is lower alkylene optionally substituted by hydroxy; and R5 is a fragment of formula , wherein each R6 and R7 independently represents hydrogen, lower alkyl, cycloalkyl, phenyl, furyl, thienyl, pyrazolyl, etc.; each XA and XB independently represents a bond, lower alkylene, -CO-, -SO2- etc., a pharmaceutical composition containing them, and using the above compound as the pharmaceutical composition or for preparing the same.

EFFECT: new compounds may be used for preventing and treating cardiac arrhythmia.

8 cl, 1047 ex, 78 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to method of obtaining compounds of formula , where each of R1, R2, R3 and R4, which can be similar or different, represents hydrogen atom or lower alkyl group, including removal of protective group (R5) from formula compound, where R5 represents benzyl group, which can be substituted by reduction in presence of reducing agent of catalytic hydrogenation. Invention also relates to intermediate compound of formula (2) or , as well as to method of its obtaining.

EFFECT: industrially efficient, simple and effective method of obtaining basic intermediate product for production of therapeutic anti-arrhythmia means is developed.

6 cl, 44 ex

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