Derivative dipyrido-diazepine and their hydrates, having biological activity

 

(57) Abstract:

Usage: in pharmacology, in particular as biologically active substances, an inhibitory effect on reverse transcriptase of the virus HIV-1. The inventive product derivative dipyrido-diazepine and their hydrates f-ly I (see drawing), where Z is oxygen, sulfur, group NCN or-NOR9when R9-alkyl; R1hydrogen, hydroxyl, alkyl, alkenyl, alkenylacyl, alkoxy, alkanoyl, dialkylaminomethyl, alkoxyalkyl, alkylthiomethyl, benzyl; R2hydrogen, alkyl, foralkyl, cycloalkyl, cycloalkenyl, alkenyl, quinil, alkoxyalkyl, alkylthiomethyl, alkanoyl, cyano, phenyl, benzyl, alkoxybenzyl, methylsulphonyl; R3hydrogen, hydroxyl, halogen, Citro, alkyl, alkoxy, amino, mono - or dialkylamino, alkenylamine, pyrrolidin-1-yl, pyrrolin-1-yl, tetrahydropyridine-1-yl, morpholine-1-yl, piperidine-1-yl, methoxyphenylethylamine, methoxybenzylamine; R4hydrogen, halogen, alkyl, nitro, amino; R5hydrogen, hydroxyl, halogen, alkyl, alkoxy, trihalomethyl, oxyalkyl, cyano; R6hydrogen, hydroxyl, alkyl; R7hydrogen, halogen, azido, nitro, amino, alkyl; R8hydrogen, alkyl, and in all the mentioned akilah it is lower. 1 Biologicheskie properties, in particular, the derivative of dipyrido-diazepine General formula (I)

(I) where Z is oxygen, sulfur, group NCN NOR9where R9lower alkyl;

R1hydrogen, hydroxyl, lower alkyl, lower alkenyl, lower alkenylacyl, lower alkoxyl, lower alkanoyl, lower dialkylaminoalkyl, lower alkoxyalkyl, lower alkylthiomethyl, benzyl;

R2hydrogen, lower alkyl, lower foralkyl, lower cycloalkyl, lower cycloalkenyl, lower alkenyl, lower quinil, lower alkoxyalkyl, lower alkylthiomethyl, lower alkanoyl, cyano, phenyl, benzyl, lower alkoxybenzyl, methylsulphonyl;

R3hydrogen, hydroxyl, halogen, nitro, lower alkyl, lower alkoxy, amino, lower mono - or dialkylamino, lower alkynylamino, pyrrolidin-1-yl, pyrrolin-1 - yl, tetrahydropyridine-1-yl, morpholine-1-yl, piperidine-1-yl, methoxyphenylethylamine, methoxybenzylamine;

R4hydrogen, halogen, lower alkyl, nitro, amino;

R5hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy, trihalomethyl, lower oxyalkyl, cyano;

R6hydrogen, hydroxyl, lower alkyl;

R7hydrogen, halogen, azido, nitro, amino, lower alkyl;

R8hydrogen, lower alkyl; and when Z kisahcintanasil, lowest alkanoyl, phenyl, benzyl, lower alkoxybenzyl; R3, R4, R5, R6, R7and R8a hydrogen atom or one of the substituents R3, R4, R5, R6, R7and R8the lower alkyl and the other substituents are hydrogen, or one of the substituents R3, R4, R5and R7the halogen and the other substituents R6and R8hydrogen, or one of the substituents R3, R4and R7nitro, and the remaining substituents R5, R6and R8hydrogen, or one of zamestitelei R3, R5and R6is hydroxyl, and the other substituents R4, R7and R8hydrogen, or one of the substituents R3, R4and R7amino and the other substituents R5, R6and R8hydrogen, or one of the substituents R3and R5alkoxy, and the other substituents R4, R6, R7and R8hydrogen, or R5lowest oxyalkyl or cyano, and R3, R4, R6, R7and R8hydrogen, or R7azido, and R3, R4, R5, R6and R8hydrogen, or when R3, R4and R5independently of one another denote hydrogen or lower alkyl, provided that at least one of them means bodoro the/SUP> and R8mean hydrogen, and R6, R7and R8independently of one another denote hydrogen or lower alkyl, provided that at least one of them means hydrogen, or one of the substituents R6, R7and R8means butyl, and the other substituents R3, R4and R5mean hydrogen, R1does not mean hydrogen, lower alkyl, lower alkenyl, benzyl, lower alkanoyl, lower alkoxyalkyl and lower alkylthiomethyl, and their hydrates and pharmacologically tolerable salts have valuable biological properties, particularly an inhibitory effect on reverse transcriptase of the virus HIV-1, so that they can be used for prevention or treatment of AIDS.

The compounds of formula (I) can be obtained by methods analogues, such as reactions And J.

Reaction AND

Cyclization of compounds of General formula (II)

RR8(II) where R1and R3R8have the above values,

R10halogen atom,

R11group with other12in which R12has the same meaning as R2with the exception of hydrogen, or R10means a group with other12and

R11a hydrogen atom, or its salt of the alkali metal obtained, if necessary the th mixture.

Usually the reaction is carried out in an inert solvent, such as tetrahydrofuran, 1,4-dioxane, simple gikondonyabugogo ether, simple dietilaminoetilovogo ether, simple triethyleneglycoldinitrate ether, dimethylformamide, benzene or anisole. The cyclization can also be accomplished by heating compounds of General formula (II) in a dipolar aprotic solvent, preferably sulfolane or dimethyl sulfone. It is advisable to add a catalytic amount of a strong acid, such as sulfuric, hydrochloric, Hydrobromic, phosphoric or polyphosphoric acid, or methanesulfonate or p-toluenesulfonic acid. Usually the reaction is carried out at a temperature 110-220aboutC.

The compound of formula (II) may contain one or more protective groups are removed after the implementation of the response.

Reaction B

The hydrolysis of compounds of General formula (III)

(III) where R1and R3R8have the above values,

Ar nezameshchenny or substituted aryl.

The hydrolysis is carried out with the use of weak to strong acids or Lisovich acids at temperatures from -20 to +150aboutC. is Used, for example sulfuric acid, meansi using phosphoric or polyphosphoric acid, it is advisable to add a solvent, for example, benzene, toluene, phenol, anisole or veratrol.

In the case of removal of arylmethyl Lisovoy acid, for example, chloride or bromide of aluminum, it is advisable to add a solvent, for example aromatic hydrocarbons: benzene, toluene, anisole or a mixture with dichloromethane.

The compound of formula (III) may contain one or more protective groups are removed after the implementation of the response. If necessary, obtained by hydrolysis of the compound can be subjected to alkylation or acylation.

Reaction TO

The compound of General formula (IV)

(IV) where R2R8have the above significance, or its corresponding received, if necessary, in situ 5-derived alkaline or alkaline-earth metal, is subjected to the interaction with the compound of General formula (V)

R13X (V), where R13has the same meaning as R1with the exception of hydrogen, and X is the radical reactive complex ester, halogen atom, the group OSO2OR13and R13has the above value,

methysulfonylmethane or econsultancy.com or aromatic sulfonyloxy.

In the case of ethylamine, diazabicyclo - undecene or 4-(dimethylamino)pyridine, or a carbonate or bicarbonate of an alkali metal, for example sodium carbonate or potassium or sodium bicarbonate.

The translation of the compounds of General formula (IV) into the corresponding salt of the alkali or alkaline earth metal can be carried out by reacting the compounds of formula (IV) with lithium hydroxide, barium hydroxide, sodium hydroxide or potassium hydroxide, alcoholate of an alkali metal, for example, methanolate or sodium tert. -butanolato potassium, amidon alkali metal, such as Amida sodium or potassium. Preferably the reaction is carried out at elevated temperature and in an environment suitable organic solvent. In the case if the gas metallizing agent is used, the alkali metal hydride, preferably an inert organic solvent, for example tetrahydrofuran or simple Picadilly ether, and if using a hydroxide of alkali or alkaline earth metal, it is also possible to use aqueous mixture with an organic solvent, for example methanol or tetrahydrofuran.

The solution or suspension of alkali or alkaline earth derived compounds of General form is aimogasta is carried out at a temperature of -20aboutWith or at elevated temperature, up to the lower of the boiling points of the solvent and reaction medium. The substitution takes place almost exclusively on the nitrogen atom in position 5 of dehydrodimerization, even if the initial compound of the formula (IV) R2means hydrogen, with the proviso that the use of one equivalent of base and one equivalent of the compound of formula (V).

Reaction G

The compound of General formula (VI) or (VII)

(VI) or

(VII) receive, if necessary, in situ, where R1and R3R8have the above values,

M is alkali metal or group MgHal, and Hal is a chlorine atom, bromine or iodine, is subjected to the interaction with the compound of General formula (VIII)

R2X (VIII), where R2and X have the above values.

The compounds of formula (VI) and (VII) can be obtained by reacting the compounds of formula (I) in which R2means hydrogen, alkyl lithium, e.g. n-bootrom lithium or tert.-bootrom lithium, if necessary, in the presence of tetramethylethylenediamine, dialkylamino lithium (for example, diisopropylamide lithium, dicyclohexylamine lithium or isopropylcyclohexane lithium, aryl lithium (for example, phenyl lithium), Ki-the, hydride, sodium or potassium), alkali metal amide (e.g. sodium amide or potassium) or Grignard reagent (e.g., iodide Metalmania, bromide of etermine or bromide vinylmania). Requires one equivalent of a base to obtain the compounds of formula (VI), while it requires two equivalents of base to obtain the compounds of formula (VII). Suitable metallization to carry out in an inert organic solvent at a temperature from -78aboutC to the boiling point of the respective reaction mixture. If for metallization using alkyl lithium, aryl lithium, dialkylamide lithium or Grignard reagent, the solvent preferably used is a simple ether, for example tetrahydrofuran, simple, diethyl ether or dioxane, if necessary in a mixture with aliphatic or aromatic hydrocarbons, such as hexane or benzene, and the reaction can be carried out at temperatures from -20 to +80aboutC. In that case if the metallization is carried out using hydride or alkali metal amide, in addition to the above-mentioned solvents can be used Xilin, toluene, acetonitrile, dimethylformamide or dimethylsulfoxide, while in the case, if the use of aliphatic ketones, such as acetone, and a mixture of the mentioned solvents with water.

The solution or suspension of alkali compounds of the formula (VI) or (VII) can be directly i.e. not selecting the received connection, and are subjected to interaction with the compound of the formula (VIII), and the interaction is carried out at a temperature from -20aboutC to the boiling point of the reaction mixture, preferably at room temperature.

The compound of formula (VI) or (VII) may contain one or more protective groups are removed after the implementation of the response.

Used to carry out reactions And G of the initial compounds known from the literature, or they can be purchased or obtained by well-known from the literature reactions.

Reaction D

The compound of General formula (I) in which Z means oxygen is subjected to interaction with sulfurous agent, such as 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide, bis(tricyclohexyltin)sulfide, bis(tri-n-botillo)sulfide, bis(triphenylamine)sulfide, bis(trimethylsilyl)sulfide or phosphorus Penta - sulfide. The reaction is carried out in inert inert organic solvent such as carbon disulfide, benzene or true, to the boiling point of the reaction mixture and preferably in an anhydrous environment. In that case, if you use the above sulfides of tin or silila, preferably acarnania carried out in the presence of Lisovoy acid, such as trichloride boron.

In the presence of other carbonyl group in the compound of formula (I), for example compounds in which Z means oxygen, require the protection of ketocarone appropriate group prior to sulfonation, and by removing the protective group after the reaction receive the desired connection. Similarly, if R2means, for example, the lowest alkanoyl, it is necessary that the sulfonation was carried out prior to the acylation of the nitrogen in position 11.

Reaction E

The compound of formula (IX)

(IX) in which R2R8have the above values,

subjected to interaction with cyanamide.

The reaction is carried out in the presence of a base, e.g. potassium carbonate, sodium carbonate, triethylamine or diisopropylethylamine, in an inert solvent, such as methylene chloride, 1,4-dioxane, tetrahydrofuran, simple, diethyl ether, chloroform or dimethylformamide, with those who in which R2R8have the above meanings, is subjected to the interaction with suitable alkoxyamino (0-alkylhydroxylamines) or its salt (e.g. the hydrochloride of methoxylamine). The reaction is carried out in similar reactions conditions.

The compounds of formula (I) can in a known manner to translate their non-toxic, pharmacologically-tolerated acid additive salts, for example, by dissolving the compounds of formula (I) in a suitable solvent and oxidation of the solution by one (or more) of the molar equivalents of the desired acid.

As inorganic and organic acids, with which the compound of formula (I) can be converted to non-toxic pharmacologically-tolerated acid additive salts include the following: hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonate etc. of the Compounds of formula (I) usually form an acid additive salt with one molar equivalent of acid.

Deriving dipyrido-diazepine General formula (I) is illustrated by the following examples.

P R I m e R 1. 5,11-Dihydro-6N-dipyrido[3,2-b:2',3'-e]diazepin-6-he

a) 2-Chloro-N-(2-chloro-3-pyridinyl)-3-pyridi the Noah funnel serves 215 g (1,672 mol) 3-amino-2-chloropyridine, dissolved in a mixture of 400 ml of dioxane and 500 ml of cyclohexane and 130 ml of pyridine. Add a solution 299,2 g (1.7 mol) their acid chloride of 2-chloro-3-pyridine - carboxylic acid in 200 ml of dioxane with a speed that enables you to control intense reaction. Then the reaction mixture is allowed to cool to room temperature, and the crystalline precipitate is filtered and washed first with cyclohexane and then with a simple ether.

Dark brown compound is dissolved in 5 l of 3% aqueous solution of sodium hydroxide. The resulting solution is treated with animal charcoal, filtered by suction, and the filtrate is acidified by adding 50% aqueous acetic acid. The precipitate is collected by filtration and thoroughly washed with water. After drying in a stream of nitrogen at room temperature over night get almost colorless compound with a melting point 156-159aboutWith sufficiently pure for use in the next stage. Output: 376,0 g (84% of theory).

b) N-(2-Chloro-3-pyridinyl)-2-{ [(4-methoxyphenyl)methyl]amino}-3-pyridinecarboxylic - MFA

of 13.4 g (0.05 mol) obtained in stage a) compounds dissolved in 20 ml of xylene and the resulting solution added 13.8 g (0.1 mol) of p-methoxybenzylamine. Then the obtained mixture is heated the raffia on napolnennoi silica gel (particle size of 0.2-0.5 mm) column using as eluent a mixture of dichloromethane and ethyl acetate in a volume ratio of 10:1. After evaporation and recrystallization from acetonitrile gain of 17.2 g (93% of theory) of colourless crystals with a melting point of 122-124aboutC.

in) 5,11-Dihydro-11-[(4-methoxyphenyl)methyl] -6N-dipyrido[3,2-b:2',3'-e] [1,4] Diaz EPIN

16.7 g (0,0453 mol) obtained in the previous phase compounds are dissolved in 150 ml of absolute dioxane and the resulting solution was added 6.7 g (0.14 mol) of a 50% dispersion of sodium hydride in mineral oil. Then the mixture in a stream of nitrogen heated under reflux until, while thin-film chromatographia no longer find the original connection. Excess sodium hydride is decomposed by careful addition of 10 ml of a mixture of methanol and tetrahydrofuran in a volume ratio of 50:50. The reaction mixture was neutralized by adding acetic acid, and then evaporated in vacuum. The residue is purified by chromatography on filled with silica gel (particle size of 0.2-0.5 mm) column, using as eluent first mixture of dichloromethane and ethyl acetate in a volume ratio of 10:1 and then a mixture of dichloromethane and ethyl acetate in a volume ratio of 1:1. The appropriate fractions are evaporated, resulting in a gain of crystalline compound, which is recrystallized from acetonitrile and 2-prop the second melting 213-215aboutC.

g) 5,11-Dihydro-6N-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-he

10.0 g (0.3 mol) obtained in stage C) compounds dissolved in 50 ml triperoxonane acid, and the mixture is slightly heated. Then the reaction mixture is stirred at a temperature of 60aboutWith in an hour. Then using thin-layer chromatography no longer find the original connection. The mixture is evaporated in vacuo and to the residue add 0,5% aqueous ammonia, stirred thoroughly and filtered by suction. The crude compound is recrystallized from 150 ml of dimethyl sulfoxide and obtain 4.8 g (75% of theory) of 5,11-dihydro-6N-dipyrido[3,2-b: 2', 3'-e] [1, 4]diazepin-6-it is in the form of colorless crystals with a melting point above 340aboutC.

P R I m m e R 2. 5,11-Dihydro-11-propyl-6N-dipyrido[3,2-b:2',3'-e][1,4] diazepin-6 - he

a) N-(2-Chloro-3-pyridinyl)-2-(propylamino)-3-pyridinecarboxamide

of 26.8 g (0.1 mol) of 2-chloro-N-(2-chloro-3-pyridinyl)-3-pyridinecarboxamide dissolved in 200 ml of dioxane. To the resulting solution was added with 21.4 g (0,362 mol) of Propylamine. Then the mixture at a temperature of 150aboutC for 6 h and stirred in an autoclave of stainless steel. The reaction mixture is evaporated in vacuo, the residue is purified by chromatography on full silikatiniu 10:1, and then a mixture of dichloromethane, cyclohexane and ethyl acetate in a volume ratio of 1:2:1. By evaporation receive high-viscosity resin, suitable for use in the next stage.

b) 5,11-Dihydro-11-propyl-6N-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-he

As described in example 1B) method from the obtained in the previous phase of the product and sodium hydride as a result of recrystallization from acetonitrile get 5,11-dihydro-11-propyl-6N-dipyri - up[3,2-b:2',3'-e][1,4] diazepin-6-he with a melting point of 184-186aboutC. Yield: 74% of theory.

P R I m e R 3. 5,11-Dihydro-5-methyl-11-propyl-6N-dipyrido[3,2-b:2',3'-e] [1,4]dia - zipin-6-he

a) 2-Chloro-N-(2-chloro-3-pyridinyl)-N-methyl-3-pyridinecarboxamide

In chetyrehosnuju round bottom flask with reflux condenser, mechanical stirrer, thermometer and addition funnel serves 268,1 g (1.0 mol) of 2-chloro-N-(2-chloro-3-pyridinyl)-3-pyridinecarboxamide-Yes, 260 ml of 50% aqueous sodium hydroxide solution, 1500 ml of toluene and 8.0 g (0,0352 mol) of the chloride of benzyltriethylammonium. Under stirring for about 3 h drops add a solution of 134 ml (178,5 g 1,415 mol) dimethylsulfate in 1 l of toluene, and the temperature rises to 50-60aboutC. after adding dimethylsulfate continue Paramecium 1 l of water. The layers separated, the aqueous phase is shaken out three times with 300 ml of toluene. The organic layers are combined and washed first with 300 ml of water, followed by 300 ml of 1% aqueous acetic acid and in the end 300 ml of water. Combined organic extracts dried over sodium sulfate and the solvent is removed by distillation at elevated pressure. The residue is purified by chromatography on filled with silica gel (particle size of 0.2-0.5 mm) column using as eluent first of toluene and then a mixture of ethyl acetate, cyclohexane and tetrahydrofuran in a volume ratio 1:9:10. Obtained by evaporation of the appropriate fractions, the product precrystallization from a mixture of acetonitrile and simple tert. butyl ether in a volume ratio of 1:1. Get 232.5 m g (82,5% of theory) of 2-chloro-N-(2-chloro-3-pyridinyl)-N-methyl-3-pyridinecarboxamide with a melting point 98-101aboutSince, well soluble in dichloromethane.

b) N-(2-Chloro-3-pyridinyl)-N-methyl-2-(propylamino)-3-pyridinecarboxamide

According analogous to example 2A) method from the obtained in the previous phase of the product and Propylamine get N-(2-chloro-3-pyridinyl)-N-methyl-2-(cuts)-3-pyrenecarboxaldehyde. Yield: 91% of theory.

in) 5,11-Dihydro-5-methyl-11-propyl-6N-dipyrido[3,2-instead of dioxane and only equimolar amount of sodium hydride, from the obtained at the previous stage of the product get 5,11-dihydro-5-methyl-11-propyl-6N-dipyrido[3,2-b:2',3'-e][1,4]di-azepin-6-it is in the form of a viscous oil. Yield: 75% of theory.

P R I m e R 4. 5,11-Diethyl-5,11-dihydro-6N-dipyrido[3,2-b:2',3'-e][1,4] diazepin-6-he

6.4 g (0.03 mol) of 5,11-dihydro-6N-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-she dissolved in 100 ml of absolute dimethylformamide. To the resulting solution was added 3.4 g (0,071 mol) of a 50% dispersai herida of sodium in mineral oil. In atmsophere nitrogen mixture is stirred at a temperature of 50-70aboutWith in an hour. After hydrogen evolution, the mixture is cooled to 30aboutC and for 15 min add drops of 10.9 g (0.07 mol) iodine ethyl. Then for the completion of the exothermic reaction the reaction mixture is heated at a temperature of 80-90aboutWith in an hour. The solvent is removed by distillation under reduced pressure. To the residue water is added, and the resulting suspension is exhaustively extracted with dichloromethane. The resulting normal processing of the compound is recrystallized from 150 ml of isooctane. Obtain 5.7 g (71% of theory) of 5,11-diethyl-5,11-dihydro-6N-dipyrido[3,2-b: 2',3'-e][1,4]diazepin-6-one with a melting point of 102-103aboutC.

P R I m e R 5. 5,11-Dihydro-5-ethyl-6N-dipyrido example 1B), however, using as solvent a simple diethylethylenediamine ether instead of xylene, by recrystallization from a simple dietilaminoetilovogo ether of 2-chloro-N-(2-chloro-3-pyridinyl)-3-pyridinecarboxamide and benzylamine get N-(2-chloro-3-pyridinyl)-2-[(phenylmethyl)AMI - but] -3-pyridinecarboxamide with a melting point of 95 to 97aboutC. Yield: 72% of theory.

b) 5,11-Dihydro-11-(phenylmethyl)-6N-dipyrido[3,2-b: 2',3'-e][1,4]diazepin-6-he

Analogously to example 1B), but using as solvent a simple diethylethylenediamine ether instead of dioxane by recrystallization from 1-propanol obtained from the previous stage (a) connection and hydrate sodium get 5,11-dihydro-11-(phenylmethyl)-6N-dipyrido[3,2-b: 2',3'-e][1,4] diazepin-6-he melting point 212-213aboutC. Yield: 61% of theory.

in) 5,11-Dihydro-5-ethyl-11-(phenylmethyl)-6N-dipyrido[3,2-b:2',3'-e][1,4] Diaz - pin 6-he

Analgine example 3A) after recrystallization from a mixture of twala and acetonitrile in a volume ratio 1:1 mixture of dichloromethane and methanol in a volume ratio of 99: 1 obtained from the previous stage) connection and Gitelson - veil receive 5,11-dihydro-5-ethyl-11-(phenylmethyl)-6N-dipyrido[3,2-b: 2', 3'-e][1,4]-diazepin-6-he point of plvl is illogical to example 1G), however, using the autoclave instead of the open reactor and heating the reaction mixture at a temperature of 120aboutC for 10 h, by recrystallization from a mixture of isooctane and ethyl acetate in a volume ratio of 1: 1 obtained from the previous stage) connection receive 5,11-dihydro-5-ethyl-6N-dipyrido[3,2-b: 2', 3'-e] [1,4]diazepin-6-he with a melting point of 161-163aboutC. Yield: 57% of theory.

P R I m e R 6. 5,11-Dihydro-5-methyl-6N-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-he

a) N-(2-Chloro-3-pyridinyl)-N-methyl-2-[(phenylmethyl)amino]-3-pyridinecarboxylic-MFA.

Analogously to example 1B) after recrystallization from simple tert. butyl ether and mixtures of dichloromethane and ethyl acetate in a volume ratio of 3: 1 from 2-chloro-N-(2-chloro-3-pyridinyl(-N-methyl-3-pyridinecarboxamide and benzylamine get N-(2-chloro-3-pyridinyl)-N-methyl-2-[(phenylmethyl)amino]-3-pyridinecarboxylic-MFA with a melting point of 114-116aboutC. Yield: 87% of theory.

b) 5,11-Dihydro-5-methyl-11-(phenylmethyl)-6N-dipyrido[3,2-b:2',3'-e][1,4] Diaz - pin 6-he

Analogously to example 3b) after recrystallization from acetonitrile obtained in the previous phase and the connection Malchut 5,11-dihydro-5-methyl-11-(phenylmethyl)-6N-dipyrido[3,2-b: 2', 3'-e] [1,4] dia-see n-6-he melting point 198-199aboutaboutWith over 2 hours of Hot mixture while stirring served on crushed ice. Then the reaction mixture is slightly alkalinized by addition of an aqueous ammonia and exhaustively extracted with dichloromethane. The combined organic layers dried over sodium sulfate and evaporated in vacuum. The residue is subjected to chromatography on silica gel using as eluent a mixture of dichloromethane and ethyl acetate in a volume ratio of 1:1. Obtained by evaporation of the appropriate fractions, the product is recrystallized from acetonitrile and get to 21.6 g (40% of theory) of colourless crystals with a melting point 236-237aboutC.

P R I m e R 7. 5,11-Dihyro-6N-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-he

3.8 g (0,0126 mol) obtained according to example 5B) of the product was dissolved in 20 ml triperoxonane acid, and the mixture is slightly heated. Then the reaction mixture is heated under reflux for 8 hours then by thin-layer chromatography no longer find the original connection. The mixture is evaporated in vacuo, the obtained residue is thoroughly stirred with 0.5% aqueous ammonia and then filtered by suction. The crude product so filtered by suction. The filter residue is recrystallized from hot dimethylsulfate - sid and receive 1.2 g (45% of theory) of colourless crystals with a melting point above 30aboutWith identical target product of example 1G).

P R I m e R 8. 5,11-Dihydro-11-ethyl-5-methyl-6N-dipyrido[3,2-b:2',3'-e] [1,4]dia-zipin-6-he

a) 2-Chloro-N-(2-chloro-3-pyridinyl)-3-pyridinecarboxamide

Analogously to example 1A) are obtained 2-chloro-N-(2-chloro-3-pyridinyl)-N-methyl-3-PI - linecarboxylic. The purified product is obtained by cooling the reaction mixture to room temperature and desantirovaniya the supernatant liquid from the precipitate. The solid is dissolved in methylene chloride, the solution washed with water, dried over anhydrous sodium sulfate, and the solvent is removed in vacuum. The solid is then washed with ethyl acetate and dried, resulting in a gain of 7.24 g (84% of theory) of the compound, prirodno for use in the next stage.

b) N-(2-Chloro-3-pyridinyl)-2-{[(4-methoxyphenyl)methyl]amino}-3-pyridinecarboxylic - MFA

Analogously to example 1B) receive N-(2-chloro-3-pyridinyl)-2-{[(4-methoxyphenyl)IU - Tyl] amino} -3-pyridinecarboxamide. The purified product is obtained by removal of solvent in vacuo, water added to the residue and extraction of methylenchloride the brown butter, which is treated with 10 ml of a simple ester. Obtained in the form of crystals of the compound was filtered and washed first with a simple ether and then hexane. Get 78.0 g (91% of theory) of the desired product in the form of a white powder with a melting point 121-122aboutC.

in) 5,11-Dihydro-11-[(4-methoxyphenyl)methyl] -6N-dipyrido[3,2-b:2',3'-e] [1,4] diazepin-6-he

To a solution of 3.69 g (0,010 mol) of N-(2-chloro-3-pyridinyl)-2-{[(4-methoxyphenyl)methyl] amino}-3-pyridinecarboxamide in 100 ml of dimethylformamide added 1.44 g of a 50% dispersion of sodium hydride in mineral oil. After hydrogen evolution, the mixture is heated at a temperature of 110aboutC for 16 h, then heated under reflux for 8 hours, After cooling the mixture the excess sodium hydride is decomposed slow dobavleniem ice. The mixture is then diluted with water, extracted with simple ether and dried. Crystallized precipitate was filtered and washed with simple ether and receive 1,60 g (50% of theory) of 5,11-dihydro-11-[(4-methoxyphenyl)methyl] -6N-dipyrido[3,2-b:2',3' e] [1,4]diazepin-6-it is in the form of a white powder with a melting point 209-210aboutC.

g) 5,11-Dihydro-11-[(4-methoxyphenyl)methyl]-5-methyl-6N-dipyrido[3,2-b:2', 3'-e][1,4]diazepin-6-he

10.0 g (0,030 mol) of 5,11-dihydro-11-[(4-methoxyphenyl)methyl]-6N-d is m oil and 100 ml of dimethylformamide. The resulting mixture was stirred at room temperature for 30 min, then heated for 30 min at a temperature of 50aboutC. After cooling, add drops 8,51 g (to 0.060 mol) iodotope bromide in 190 ml of dimethylformamide, and the reaction mixture was stirred at room temperature overnight. Excess sodium hydride is decomposed by careful addition of ice. Then add water, extracted with simple ether, dried over anhydrous sodium sulfate and concentrated. Obtain 10.3 g (99% of theory) of 5,11-dihydro-11-[(4-methoxyphenyl)methyl]-5-methyl-6N-dipyrido[3,2-b:2', 3'-e][1,4]diazepin-6-it is in the form of a yellowish oil, suitable for use in the next stage.

d) 5,11-Dihydro-5-methyl-6N-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-he

To 10.3 g (0,030 mol) of 5,11-dihydro-11-[(4-methoxyphenyl)methyl]-5-metil-6N-dipyri - up[3,2-b: 2',3'-e][1,4]diazepin-6-it add 50 ml triperoxonane acid, and the mixture was stirred at room temperature for one hour. Acid is removed in vacuo, and the residue within the hour, mixed with 0.5% ammonium. The solid is filtered and dried, yielding 6,70 g (98% of theory) of pure 5,11-dihydro-5-methyl-6N-dipyrido[3,2-b:2',3'-e][1,4]dia-zipin-6-the melting point 230-232aboutC.

e) 5,11-Dihydro-11-ethyl-5-mutiliation-6-it in 100 ml of dimethylformamide added to 2.00 g of a 50% dispersion of sodium hydride in mineral oil. After hydrogen evolution, the mixture is heated at a temperature of 50aboutC for 30 min, then cooled to room temperature. Then for 15 min add drops 7,80 g of pure iodine ethyl, and the resulting mixture was stirred at room temperature overnight. Excess sodium hydride is decomposed by careful addition of ice and then water. Extracted with simple ether, dried over anhydrous sodium sulfate and evaporated. Obtain 4.5 g (70% of theory) of 5,11-dihydro-11-ethyl-5-methyl-6N-dipyrido[3,2-b: 2',3'- e][1,4]diazepin-6-one with a melting point of 130-132aboutC.

P R I m e R 9. 5,11-Dihydro-11-ethyl-5-methyl-6N-dipyrido[3,2-b:2',3'-e] [1,4]dia-zipin-6-tion

A mixture of 2.66 g (0.01 mol) of 5,11-dihydro-11-ethyl-5-methyl-6N-dipyrido[3,2-b: 2', 3'-e] [1,4] diazepin-6-she and 2.1 (0,005 mol) of reagent Lawesson (2,4-bis-(4-methoxyphenyl)1,3-dithia-2,4-diphosphate-2,4-disulfide) in 50 ml of toluene is heated under reflux for 2.5 hours and Then the solvent is evaporated in vacuo and to the residue water is added. Extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuum. Purify by chromatography on napolnennoi silica gel column using as eluent first of methylene chloride, then a mixture of ethyl acetate and hexanamide[3,2-b:2',3'-e][1,4]diazepin-6-- thione as a yellow powder, which is recrystallized from 10% mixture of hexane and ethyl acetate. Obtain 1.1 g of the desired product as yellow needles with a melting point 157-158aboutC.

P R I m e R 10. 5,11-Dihydro-11-ethyl-2-methyl-4-trifluoromethyl-6N-dipyrido[3,2 - b:2',3'-e][1,4]diazepin-6-he

a) 3-Cyano-2-hydroxy-6-methyl-4-(trifluoromethyl)pyridine

A solution of 14.0 g of cyanoacetamide in 80 ml of ethanol is heated to 50aboutWith, then add 14 g of piperidine and 25 g of triflluoroacetylacetone. The resulting mixture is stirred at a temperature of 70aboutC for 30 min, then stirred at room temperature overnight. The mixture is concentrated in vacuo and diluted with 100 ml of water. With stirring, carefully add 15 ml of concentrated chlorotoluron acid and after 15 minutes the precipitate is filtered and dried in vacuum over night. Obtain 27.8 g of the desired cyano.

b) 3-Aminocarbonyl-2-chloro-6-methyl-4-(trifluoromethyl)pyridine

A mixture of 35 ml of phosphorous oxychloride and 9.8 g obtained predidushei stage cyano heated under reflux for 5 hours To a cooled mixture gently add 400 ml of ice water. Extravert with methylene chloride, washed with saturated sodium bicarbonate and dried over anhydrous sulfate acid and heated at a temperature of 140aboutFor 20 minutes the Cooled mixture is carefully poured onto 600 ml of ice, the precipitate is filtered, washed with ice water and dried, resulting in a gain of 7.6 g of the desired amide. The filtrate is extracted with 200 ml ethyl acetate, dried over magnesium sulfate, filtered and concentrated, resulting in receive 1.7 g of the desired product.

C) 3-Amino-2-chloro-6-methyl-4-(trifluoromethyl)pyridine

To a solution of 6.6 g of sodium hydroxide in 60 ml of water at a temperature of 5aboutWith added 9.3 g of bromine. When obtaining a clear solution is quickly added 9.2 grams 3-aminocarbonyl-2-chloro-6-methyl-4-(trifluoromethyl)Piri - DIN, with the temperature kept below 5aboutC. the resulting mixture was stirred to dissolve 3-(aminocarbonyl)-pyridine (less than 30 min). The mixture is then heated at a temperature of 75aboutC for 30 minutes After cooling to room temperature, 3-aminopyridazine extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated. Obtain 4.9 g of the desired compound.

g) 2-Chloro-N-(2-chloro-6-methyl-4-trifluoromethyl-3-pyridinyl)-3-pyridinecarboxylic - MFA.

To a chilled at a temperature of -78aboutTo a solution of 2.1 g of 3-amino-2-chloro-6-methyl-4-(trifluoromethyl)pyridine in 10 ml of tetrahydrofuran for 3 min cap the min, then for 1 min add 0.9 g of 2-chloronicotinamide in 3 ml of tetrahydrofuran. After 5 min again add 3 ml of Diisopropylamine lithium and 0.5 g of acid chloride in 1 ml of tetrahydrofuran. The resulting mixture was stirred for 10 minutes, then add 100 ml of water. Share 30 ml of ethyl acetate, then the organic phase is extracted with water and the combined aqueous phase is extracted with methylene chloride, dried over magnesium sulfate, filtered and evaporated, resulting in obtain crude compound which was washed with a small amount of ethyl acetate and dried, yielding 1.3 g of the desired compound.

d) N-(2-Chloro-6-methyl-4-trifluoromethyl-3-pyridinyl)-2-ethylamino-3-pyridinyl - boxlid

To a suspension of 1.3 g of 2-chloro-N-(2-chloro-6-methyl-4-trifluoromethyl-3-pyridinyl)-3-Piri-dicarboxamide in 5 ml of xylene added 0.4 g of ethylamine. The resulting mixture is heated in the chamber under pressure at a temperature of 160aboutC for 30 minutes, the Cooled mixture is diluted with ethyl acetate, washed, dried and concentrated. In the chromatography filled with silica gel column using as eluent a mixture of ethyl acetate and hexane in a ratio of 1: 1 gain 0.5 g of the desired compound.

e) 5,11-Dihydro-11-ethyl-2-idini)-2-ethylamino-3-PI - enecarboxylate in 3 ml of pyridine is added to 0.2 g of a 50% dispersion of sodium hydride in oil. The mixture is heated to a temperature of 150about, Then cooled and concentrated in vacuum. Then, to the residue water is added, extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The compound obtained purified by chromatography on filled with silica gel column using as eluent first of methylene chloride and then the mixture of metilenhloride and methanol. After condensation in vacuum, the residue is recrystallized from hexanol and obtain 0.09 g of target compound with a melting point of 150-151aboutC.

P R I m e R 11. 5,11-Dihydro-11-ethyl-4-methyl-6N-dipyrido[3,2-b:2',3'-e] [1,4]-dia - zipin-6-he

a) 2-Chloro-4-methyl-3-nitropyridine

A mixture of 25 g of 2-hydroxy-4-methyl-3-nitropyridine, 12.5 g of pentachloride phosphorus and 62 ml of phosphorus oxychloride is heated under reflux for 2 hours, After cooling the mixture was poured on crushed ice to sediment. Extracted with methylene chloride, dried over sodium sulfate and concentrated, resulting in a gain of brown oil, which was washed with hot hexane. By thickening waucoma obtain 16.2 g of the desired compound with a melting point 45-47aboutC.

b) 3-Amino-2-chloro-4-methylpyridin

16.2 g of 2-chloro-4-methyl-3-nitropyridine add to 470 PR 160 g of dihydrate of tin chloride in 200 ml of concentrated hydrochloric acid and the resulting mixture was stirred at room temperature overnight. The mixture is then diluted with water to 1 l and cooled slowly add 10 N sodium hydroxide to dissolve the hydrochloride tin, available in the form of a white precipitate. Extracted with methylene chloride, dried over sodium sulfate and concentrated, resulting in a gain of 12.8 g of almost pure 3-amino-2-chloro-4-methylpyridine as a yellow oil, which solidifies when left to stand, and which can be used in the next stage.

a) 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide

Analogously to example 1A) carboxamid get from 12.8 g of 3-amino-2-chloro-4-methylpyridine, to 15.8 g of 2-chloronicotinamide and 7.1 g of pyridine, 30 ml of cyclohexane and 60 ml of dioxane. After removal of solvent the product is dissolved in methylene chloride, washed with water and dried over sodium sulfate. Again remove the solvent, the residue is washed with ethyl acetate and obtain 1.2 g of the desired compound with a melting point 193-194aboutC.

g) N-(2-Chloro-4-methyl-3-pyridinyl)-2-ethylamino-3-pyridinecarboxamide

To the suspension to 21.0 g of 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide - Yes in 150 ml of xylene in a steel autoclave add 12.7 g of ethylamine. Mix in oil van is heated at a temperature of 165aboutC for 6 h, then stirred PR is t simple ether, dried over sodium sulfate and concentrated, and the resulting oil is dissolved in ethyl acetate and then with hexane, and the precipitate formed. The solid is filtered and dried, yielding 16.5 g of the desired compound with a melting point of 122-124aboutC.

d) 5,11-Dihydro-11-ethyl-4-methyl-6N-dipyrido[3,2-b: 2',3'-e][1,4]-diazepin-6-he

To a solution of 16.0 g obtained at the previous stage N-(2-chloro-4-methyl-3-pyridinyl)-2-ethylamino-3-pyridinecarboxamide in 200 ml of dimethylformamide added 7.9 g of a 50% suspension of sodium hydride and stirred for 30 minutes the mixture is Then heated under reflux for 2 h, cooled and carefully treated with crushed ice. The solvent is removed in vacuo and to the residue water is added. Extracted with simple ether, dried over sodium sulfate and concentrated. The residue is boiled with a mixture of ethyl acetate and cyclohexane at a ratio of 1:1 and filtered, resulting in a gain of 4.1 g of almost pure compounds. 2.0 g of this compound further purified by recrystallization from dichloroethane, and obtain 1.0 g of pure 5,11-dihydro-11-ethyl-4-methyl-6N-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-the melting point 212-214aboutC.

P R I m e R 12. 11-Cyclopropyl-5,11-dihydro-4-methyl-6N-dipyrido[3,2-b: 2',3'-e is Evoe connection, having a melting point 247-249aboutC.

P R I m e p 13. 11-Cyclopropyl-5,11-dihydro-5-hydroxy-4-methyl-6N-dipyrido-[3, 2-b:2',3'-e][1,4]diazepin-6-he

To a mixture of 0.5 g of 11-cyclopropyl-5,11-dihydro-4-methyl-6N-dipyrido[3,2-b:2', 3'-e] [1,4] diazepin-6-she (example 12) in 25 ml of tetrahydrofuran, add 0.12 g of a 50% dispersion of sodium hydride in mineral oil. The reaction mixture was stirred at room temperature for one hour, then cooled to 0aboutWith and add 0.9 g oxopiperidine(pyridine)hexane-tiltspeed. The reaction mixture is left to stand to reach room temperature and stirred over night. Add water to the mixture and the solvents removed in vacuo. Extracted with warm ethyl acetate, concentrated in vacuo and purified by chromatography on napolnennoi silica gel column, using as eluent ethyl acetate. Obtain 0.05 g of pure 11-cyclopropyl-5,11-dihydro-5-hydroxy-4-methyl-6N-dipyrido[3,2-b: 2', 3'-e] [1, 4] diazepin-6-the melting point 239-241aboutC. Yield: 9.5% of theory.

P R I m e R 14. 5,11-Dihyro-11-ethyl-2-methoxy-5-methyl-6N-dipyrido[3,2-b: 2',3'-e][1,4]-diazep in 6-he

a) 3-Amino-2-bromo-6-methoxypyridine

To a solution of 2.5 g of 5-amino-2-methoxypyridine in 15 ml acetic acid is added 1.6 g acetatului to a solution of 10 g of sodium hydroxide in 100 ml of water. Extracted with 50 ml ethyl acetate, dried over anhydrous magnesium sulfate and concentrated in vacuum. The resulting product was then purified by chromatography on filled with silica gel column, using kachestve eluent mixture of ethyl acetate and hexane in a ratio of 4:1. Obtain 2.7 g of the desired compound, suitable for use in the next stage.

b) N-(2-Bromo-6-methoxy-3-pyridinyl)-2-chloro-3-pyridinecarboxamide

To a solution of 2.7 g of 3-amino-2-bromo-6-methoxypyridine in 20 ml of methylene chloride and 1 ml of pyridine added 2.2 g of 2-giornico - thionyl chloride, and the mixture was stirred for 20 minutes the mixture is Then diluted with 100 ml of methylene chloride, washed with 100 ml of water, dried over anhydrous magnesium sulfate and concentrated. Semi-solid residue is saturated with hexane, filtered and dried, resulting in a gain of 4.1 g of the target product, suitable for use in the next stage.

C) N-(2-Bromo-6-methoxy-3-pyridinyl)-2-chloro-N-methyl-3-pyridinecarboxamide

To 10 ml of dimethyl sulfoxide dobavlaut 0.3 g of a 50% dispersion of sodium hydride in mineral oil and heated to 50aboutC. After cooling to room temperature, add 2.0 g of N-(2-bromo-6-methoxy-3-pyridinyl)-2-chloro-3-pyridinyl-oxamide, and the resulting solution perambalur 10 ml of water and then 100 ml of ethyl acetate. The organic phase is washed four times with 100 ml of water, dried over anhydrous magnesium sulfate, concentrated and purified by chromatography on filled with silica gel column, using as eluent first methylene chloride and then the mixture of methylene chloride and ethanol in a ratio of 98:2. Gain of 1.9 g of the desired compound, suitable for use in the next stage.

g) N-(2-Bromo-6-methoxy-3-pyridinyl)-2-ethylamino-N-methyl-3-pyridinecarboxamide

To a solution of 1.9 g of N-(2-bromo-6-methoxy-3-pyridinyl)-2-chloro-N-methyl-3-pyridinyl - oxamide in 5 ml of xylene added 0.7 g of ethylamine. The mixture was fed into the autoclave is closed and heated at a temperature of 150aboutC for 4 h Then the solution was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, showauto and purified by chromatography on napolnennoi silica gel column (eluent mixture of ethyl acetate and hexane in a ratio of 1:4). Obtain 1.5 g of the desired compound, suitable for use in the next stage.

d) 5,11-Dihydro-11-ethyl-2-methoxy-5-methyl-6N-dipyrido[3,2-b: 2', 3'-e] [1,4]dia-ze pin

To a solution of 1.4 g of N-(2-bromo-6-methoxy-3-pyridinyl)-2-ethylamino-N-methyl-3-Piri-dicarboxamide in 20 ml of xylene added 0.9 g of a 50% dispersion of sodium hydride in m and add methanol, dilute with ethyl acetate and washed with water. The organic phase is dried over anhydrous magnesium sulfate, concentrated and purified by chromatography on filled with silica gel column, using as eluent a mixture of ethyl acetate and hexane in a ratio of 1:4. Get quite a pure compound, which is recrystallized twice from a mixture of ethyl acetate and hexane and obtain 0.52 g of pure 5,11-dihydro-11-ethyl-2-methoxy-5-methyl-6N - dipyrido[3,2-b:2',3'-e] [1,4]diazepin-6-the melting point 116-118aboutC.

P R I m e R 15. 5,11-Dihydro-11-ethyl-2-(N-pyrrolidino)-6N-dipyrido[3,2-b:2',3'-e] [1,4]diazepin-6-he

a) 5,11-Dihydro-11-ethyl-2-hydroxy-5-methyl-6N-dipyrido[3,2-b:2',3'-e][1,4] diazepin - 6-he

To a solution of 0.3 g of 5,11-dihydro-11-ethyl-2-methoxy-5-methyl-6N-dipyrido[3,2-b:2,'3'-e][1,4]diazep in-6-it in 2 ml of acetic acid, add 2 ml of 48% Hydrobromic acid, and the resulting mixture is quickly heated and refluxed for 5 minutes To the reaction mixture add 10 ml of 10% sodium hydroxide and the product extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated. Get solid, which is recrystallized from ethyl acetate, resulting in a gain of 0.08 g of the desired compound with a melting point of 215-thiepin-6-he

To a solution of 0.2 g of 5,11-dihydro-11-ethyl-2-hydroxy-5-methyl-6N-dipyrido[3,2-b: 2', 3'- e] [1,4] diazepin-6-she's in 4 ml of methylene chloride under nitrogen atmosphere add 0.2 ml of diisopropylethylamine and then 0.2 ml of anhydride triftormetilfullerenov acid. The resulting mixture is stirred for one hour, then diluted with 20 ml of methylene chloride and washed with water. The organic phase is dried over anhydrous magnesium sulfate and concentrated. In the chromatography filled with silica gel column using as eluent a mixture of ethyl acetate and hexane in a ratio of 1:3 get quite a pure compound, suitable for use in the next stage.

in) 5,11-Dihydro-11-ethyl-5-methyl-2-(N-pyrrolidino)-6N-dipyrido-[3,2-b:2', 3'-e]-[ 1,4]diazepin-6-he

0.25 g 5,11-dihydro-11-ethyl-5-methyl-2-triftormetilfullerenov-6N-DP - Rideau[3,2-b:2',3'-e][1,4]diazepin-6-she dissolved in 1 ml of pyridine and heated under reflux for 30 minutes, the Cooled solution is diluted with ethyl acetate, washed with water, and the organic phase is dried over anhydrous magnesium sulfate and concentrated. The obtained oily residue vykristallizovyvalas from a mixture of ethyl acetate and hexane and gain of 0.11 g of 5,11-dihydro-11-ethyl-5-methyl-2-N-(pyrrolidin)-6N-dipyrido[3,2-b: 2', 3'-e][14]on the pyrido[3,2-b:2',3'-e][1,4]diazep in 6-he

a) 2-Methoxy-4-methyl-5-nitropyridine

To a solution 19,0 g of 2-chloro-4-methyl-5-nitropyridine in 100 ml of methanol type of 26.1 g of sodium methylate, and the resulting mixture heated under reflux for 12 hours After cooling, the mixture was poured into 1 l of water and extracted with ethyl acetate and washed with water. The organic phase is dried over anhydrous magnesium sulfate and concentrated, and the obtained residue is dissolved in hot simple ether and filtered. By recrystallization from a simple ether obtain 10.2 g of the desired compound, suitable for use in the next stage.

b) 5-Amino-2-methoxy-4-methylpyridin

To a solution of 5.1 g of 2-methoxy-4-methyl-5-nitropyridine in 40 ml acetic acid is slowly added 41 g of dihydrate of tin chloride and 40 ml of concentrated hydrochloric acid, keeping the temperature below 35aboutC. the resulting mixture was stirred at room temperature for 2 h, then allowed to stand in the refrigerator over night. The solid is collected, solid and supernatant separately alkalinized by adding 20% sodium hydroxide solution. Extrahiert chloroform, the combined, dried over anhydrous magnesium sulfate and concentrated. The result:" >

C) 3-Amino-2-bromo-6-methoxy-4-methylpyridin

To a mixture of 3.9 g of 5-amino-2-methoxy-4-methylpyridine in 25 ml of acetic acid and 4.0 g of sodium acetate added 4.8 g of bromine. The resulting mixture was stirred for 20 min, then added to a solution of 15 g of hydroxy sodium in 200 ml of water. Extravert chloroform, dried over anhydrous magnesium sulfate, concentrated and purified by chromatography on filled with silica gel column, using as eluent a mixture of methylene chloride and ethyl acetate in the ratio from 19: 1 to 4:1 resulting in a gain of 4.5 g of compound suitable for use in the next stage.

g) N-(2-Bromo-6-methoxy-4-methyl-3-peridinin)-2-chloro-3-pyridinecarboxamide

To a solution of 4.5 g of 3-amino-2-bromo-6-methoxy-4-methylpyridine in methylene chloride add 3.5 g of 2-chloronicotinamide. The resulting mixture was stirred at room temperature overnight and grind with the simple diisopropyl ether. The solid precipitate is filtered, obtain 6.0 g of the desired compound, suitable for use in the next stage.

d) N-(2-Bromo-6-methoxy-4-methyl-3-pyridinyl)-2-ethylamino-3-pyridylcarbonyl - amide

A mixture of 2.1 g of N-(2-bromo-6-methoxy-4-methyl-3-pyridinyl)-2-chloro-3-pyridinio-kamida, 10 ml of dioxane and 0.5 g antiatom, washed with water, and the organic phase is dried over anhydrous magnesium sulfate and concentrated. The compound obtained purified by chromatography on filled with silica gel column using as eluent a mixture of methylene chloride and ethyl acetate in a ratio of 99:1 and vykristallizovyvalas simple diisopropyl ether. Obtain 0.95 g of the desired compound.

e) 5,11-Dihydro-11-ethyl-2-methoxy-4-methyl-6N-dipyrido[3,2-b: 2', 3'-e] [1,4]dia-ze pin

To a solution of 0.54 g of N-(2-bromo-6-methoxy-4-methyl-3-pyridinyl)-2-ethylamino-3-Piri - dicarboxamide in 4 ml of pyridine added 0.14 g of a 50% dispersion of sodium hydride in mineral oil. The resulting mixture is heated with reverse holodilniki for 1.5 hours, the Cooled mixture is diluted with ethyl acetate, washed with water, and the organic phase is dried over anhydrous magnesium sulfate and concentrated. The residue is washed simple diisopropyl ether and hot ethyl acetate and then vykristallizovyvalas from ethanol, resulting in a gain of 0.2 g of 5,11-dihyro-11 - ethyl-2-methoxy-4-methyl-6N-dipyrido[3,2-b:2', 3'-e][1,4]diazepin-6-the melting point 249-251aboutC.

Similar to the above method of getting brought to the table. 1 connection examples 17-122.

P R I m e R 123. The hemihydrate 8-smeshannuyu mixture at 8.60 g (0,054 mol) of 2-chloro-3-nitropyridine, lower than the 5.37 g (0.12 mol) of ethylamine and 10 ml of xylene is heated in an autoclave at a temperature of 100aboutC for 3 hours After cooling, the solvent is removed in vacuo and to the residue water is added. Extravert with methylene chloride, dried over sodium sulfate and concentrated in vacuum. Obtain 10.0 g of the desired compound as a yellow oil suitable for use in the next stage.

b) 3-Amino-2-ethylaminomethyl

Analogously to example 11b) and 9.1 g of 2-ethylamino-3-nitropyridine obtain 6.5 g of the above stated connection.

a) 2-Chloro-N-(2-ethylamino-3-pyridinyl)-5-nitro-3-pyridinecarboxamide

A solution of 2.21 g of 2-chloro-5-nitronicotinic (obtained that nitrous 2-oxycodonebuy acid followed by 2-chloro-5-nitronicotinic acid, which is then treated with thionyl chloride) in 10 ml of tetrahydrofuran for 15 min added slowly to a cooled and stir will smesni of 1.34 g of 3-amino-2-Ethylenediamine, 1.29 g of diisopropylethylamine and 40 ml of tetrahydrofuran. The resulting mixture was stirred at room temperature overnight, then concentrated in vacuo. By treatment with methylene chloride obtain 2.30 g of the desired compound in the form of sediment suitable for use in the next stage. g 2-chloro-N-(2-ethylamino-3-pyridinyl)-5-nitro-3-pyridinecarboxamide - Yes in 25 ml of xylene is heated under reflux for 4 hours After condensation in a vacuum the residue is purified by chromatography on filled with silica gel column, using as eluent 50% mixture of ethyl acetate and hexane. Get 0,93 g of the desired compound.

d) 5,11-Dihydro-11-ethyl-5-methyl-8-nitro-6N-dipyrido[3,2-b:2',3'-e][1,4] diazepin 6-he

0,72 g of the above compound having a melting point 148-149aboutTo get analogously to example 8D) from 0,93 g of 5,11-dihydro-11-ethyl-8-nitro-6N-dipyrido[3,2 - b:2',3'-e][1,4]-6-.

(e) Hemihydrate 8-amino-5,11-dihydro-11-ethyl-5-methyl-6N-dipyrido[3,2-b:2', 3'-e] [1,4]diazepin-6-it

Analogously to example 11b) of 0.23 g of 5,11-dihydro-11-ethyl-5-methyl-8-nitro-6N-DP - Rideau[3,2-b:2',3'-e][1,4]diazepin-6-it is after recrystallization from a mixture of 1,2-dichloroethane and hexane get to 0.060 g of the target compound as a yellow-brown powder having a melting point 193-194aboutC.

P R I m e R 124. 6 Cyanoimino-5,11-dihyro-11-ethyl-2,5-dimethyl-6N-dipyrido- [3,2 - b:2',3'-e][1,4]diazepin

A mixture of 0.25 g (0,63 mmol) of 5,11-dihydro-11-ethyl-6-methanesulfonamido-2,4-di - methyl-6N-dipyrido[3,2-b: 2', 3'-e] [1,4]dia-zepine, 0,034 g (0.8 mmol) of cyanamide, 5 ml of 1,4-dioxane and 0.11 g (0.8 mmol) of potassium carbonate is heated at room temperature for 10 days. The mixture is then concentrated in vacuum, the mod is th a mixture of ethyl acetate and methylene chloride. Get 0.025 g of target compound with a melting point 230-233aboutC.

P R I m e R 125. 5,11-Dihydro-11-ethyl-6-methoxyimino-2,4-dimethyl-6N-dipyrido- [3,2-b:2',3'-e][1,4]diazepin

a) 5,11-Dihydro-11-ethyl-6-methanesulfonamido-2,4-dimethyl-6N-dipyrido- [3,2-b:2',3'-e][1,4]diazepin

To a solution of 0,314 g (1.2 mmol) of 5,11-dihydro-11-ethyl-2,4-dimethyl-6N-dipyrido [3,2-b:2',3'-e][1,4]diazepin-6-she's in 15 ml of methylene chloride containing 0.25 ml (14 mmol) of diisopropylethylamine add to 0.24 ml (14 mmol) of anhydride triftormetilfullerenov acid. The resulting mixture in an atmosphere of argon is heated under reflux for 3 hours Then add ethyl acetate (about 200 ml) and the solution washed three times with water and four times with brine. Dried over magnesium sulfate, then the solution is concentrated in vacuo, and the residue is dried in high vacuum for 2 hours, the Residue is dissolved in 20 ml of methylene chloride, add to 0.23 g (14 mol) of cyanide of tetraethylammonium. The resulting solution was stirred at room temperature overnight, then the reaction mixture was concentrated in vacuum. The residue is dissolved in 100 ml of ethyl acetate and the solution washed with water and saline solution. The solution is then dried over magnesium sulfate and concentrated in vacuum. The residue is subjected to chromatography on semicrystalline of heptane and get 0,033 g of the desired compound as red crystals with a melting point of 154-155aboutC.

b) 5,11-Dihyro-11-ethyl-6-methoxyimino-2,4-dimethyl-6N-dipyrido-[3,2-b:2', 3'-e] [1,4]diazepin

A solution of 0.3 g (0.75 mmol) of 5,11-dihydro-11-ethyl-6-methanesulfonamido-2,4-di - methyl-6N-dipyrido[3,2-b: 2',3'-e][1,4]dia-zepine, 0.15 g (1.8 mmol) of the hydrochloride of methoxylamine and 0.3 g (2 mmol) of diisopropylethylamine in methylene chloride was stirred at room temperature for 4 days. The organic phase is washed with water, dried and filtered. Then the solution is concentrated in vacuo, and the residue is subjected to chromatography on silica gel using as eluent 20% mixture of ethyl acetate and hexane. Obtain 0.7 g of the desired product with a melting point 164-166aboutC.

P R I m e R 126. 5,11-Dihydro-6N-11-cyclopropyl-4-methyl-dipyrido[3,2-b: 2',3'- e][1,4]diazepin-6-tion

A mixture of 5.0 g (18,77 mmol) of 5,11-dihydro-6N-11-cyclopropyl-4-methyl-dipyrido[3,2 - b: 2',3'-e][1,4]diazepin-6-she and 3.8 g (9,40 mmol) of dimeric p-methoxyphenylacetyl-sulfide (agent Lawesson) in 100 ml of toluene is heated under reflux for 2.5 hours the Solution is cooled to room temperature and left to stand over night. The toluene is removed by distillation, and the residue is subjected to chromatography on filled with silica gel column (eluent mixture of methylene chloride and ethyl acetate with the recrystallization of the simple mixture of ethyl ether and simple petroleum ether get a bright yellow solid, which is dried in high vacuum at a temperature of 80aboutC for 12 hours Yield: 1.7 g (32,0% of theory), so pl. 189-194aboutC.

As already mentioned, the compounds of formula (I) possess an inhibitory effect on reverse transcriptase of the virus HIV-1. From the experiments conducted with these compounds, it is known that they inhibit the activity of HIV reverse transcriptase-dependent RNA polymerase.

Experience with the use of reverse transcriptase inhibitors

Theory of experience.

Among the enzymes responsible human immunodeficiency virus IV-1, reverse transcriptase (1), so named because it transcribers copy of the DNA with the RNA matrix. Its activity may be quantified as part of the experience (2) using the enzyme without cells, based on the observation of the ability of reverse transcriptase to use synthetic matrix [poly r(C) with oligo d(G)] for reverse transcriptase radionational amenable to acid deposition admonitio DNA, and3N-dGT is used as a substrate.

Materials:

a) isolation of the enzyme

Reverse transcriptase from strain LAV of human immunodeficiency virus IV-1 (1) is secreted from strain JM109 bacteria (3), exprimarea the ri 37aboutC and 225 rpm) (5) overnight culture, which for positive selection serves 100 μg/ml of ampicillin (5), inoculant when diluted 1:40 in the M9 medium containing 10 μg/ml thiamine, 0.5% esamination and 50 μg/ml ampicillin. The culture is incubated at a temperature of 37aboutC at 225 rpm until reaching an optical density of 0.3-0.4 at 540. At this point add repressing inhibitor isopropyl- -D-thiogalactopyranoside in the amount of 0.5 mmol and continue to incubate in techenie 2 h, then concentrated and the residue re-suspended in 50 mmol Tris-buffer containing 0.6 mmol etilendiamintetrauksusnoy acid and the 0.375 mol of sodium chloride and the addition of lysozyme in the amount of 1 ml per ml of digested for 30 min on ice. Cells dissolve submission of 0.2% surfactant NP-40, and then served in 1 M sodium chloride.

After removal of undesirable insoluble components by centrifugation of the precipitated protein by adding 3 volumes of saturated aqueous ammonium sulfate, then concentrated and the residue re-suspended in reverse transcriptase buffer (50 mmol Tris, pH 7.5, 1 mmol ethylendiaminetetraacetic acid, 5 mol DTT (1,4-dimercapto-2,3-butanediol), 0.1% of the surface of the.

b) the Composition of the initial reaction mixture Components table of Contents

components 1 M Tris (pH 7.4), 100 mmol of 1 M DTT 40 mmol of 1 M sodium chloride 120 mmol of 1% surfactant NP-40 0.1% of 1 M magnesium chloride 4 mmol [poly r(C)/oligo d(G)] (5:1) 2 µg/ml3H-dGTP (8 μm) 0.6 µmol

Implementation experience.

Aliquots of the reaction mixture is kept at -20aboutC. the Mixture is stable, and every time to use it defrost. In a well-known experiment (6) with the use of enzyme use microtitre plates with 96 cavities. 50 mmol Tris (pH 7.4), medium (solvent for dilution of the compounds under study), or the compounds in the media serves in microtitre plate with 96 holes (10 µl per hole, 3 holes of the analyzed connection). Defrost reverse transcriptase of HIV, dilute it 50 mmol Tris (pH 7.4), so that 15 ál of diluted enzyme Saderat 0,001 unit (1 unit is that amount of enzyme that converts 1 µmol of substrate per minute at a temperature of 25aboutC), and served 15 µl in each recess. Add 20 μl of 0.12-0.5 M ethylendiaminetetraacetic acid to the first three recesses microtitre plate. Ethylenediaminetetraacetate acid is an ionic mixture add in all the cavities and allowed to incubated at room temperature for one hour. Experience complete by precipitation of DNA in each recess in the 50 ál 10% triperoxonane acid with 1% sodium pyrophosphate. Microcitrus the plate is incubated at a temperature of 4aboutC for 15 min, and the precipitate is fixed on glass fiber paper 30 (firm Schleicher Schuell) using a semi-automated apparatus Skatron. Then the filters are washed with 5% trichloroacetic acid and 1% sodium pyrophosphate, washed with 70% aqueous ethanol, dried, and fed into tubes for scintillation (6). To each tube serves 2 ml scintillation means; counting is carried out in the counter beta-particles Beckman.

The percentage inhibition was calculated by the following equation:

CPM the number of counts per minute

The results of the experiment are given in table. 2.

Not described in literature connections similar structures, which have the same inhibitory effect on reverse transcriptase of the virus HIV-1, which allows to use them for prevention or treatment of AIDS and diseases associated with infection by the HIV virus.

1. Derivative dipyrido-diazepine General formula I

< / BR>
where Z is oxygen, sulfur, group NCN and-NOR9where R9lower alkyl;

R1hydrogen, hydroxyl, lower alkyl, lower alkenyl, n is ISSI alkylthiomethyl, benzyl;

R2hydrogen, lower alkyl, lower foralkyl, lower cycloalkyl, lower cycloalkenyl, lower alkenyl, lower quinil, lower alkoxyalkyl, lower alkylthiomethyl, lower alkanoyl, cyano, phenyl, benzyl, lower alkoxybenzyl, methylsulphonyl;

R3hydrogen, hydroxyl, halogen, nitro, lower alkyl, lower alkoxy, amino, lower mono - or dialkylamino, lower alkynylamino, pyrrolidin-1-yl, pyrrolin-1-yl, tetrahydropyridine-1-yl, morpholine-1-yl, piperidine-1-yl, methoxyphenylethylamine, methoxybenzylamine;

R4hydrogen, halogen, lower alkyl, nitro, amino;

R5hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy, trihalomethyl, lower oxyalkyl, cyano;

R6hydrogen, hydroxyl, lower alkyl;

R7hydrogen, halogen, azido, nitro, amino, lower alkyl;

R8hydrogen, lower alkyl;

moreover, if Z is oxygen or sulfur, R2hydrogen, lower alkyl, lower alkenyl, lower quinil, lower alkoxyalkyl, lower alkylthiomethyl, lower alkanoyl, phenyl, benzyl, lower alkoxybenzyl, R3, R4, R5, R6, R7and R8hydrogen, or one of the substituents R3, R4, R5, R6, R7and R8the lower and the other substituents R6and R8hydrogen, or one of the substituents R3, R4and R7means nitro, and the remaining substituents R5, R6and R8hydrogen, or one of the substituents R3, R5and R6hydroxyl, and the other substituents R4, R7and R8hydrogen, or one of the substituents R3, R4and R7amino and the other substituents R5, R6and R8hydrogen, or one of the substituents R3and R5- alkoxy, and the other substituents R4, R6, R7and R8is hydrogen, or R5lowest oxyalkyl or cyano, and R3, R4, R6, R7and R8hydrogen, or R7azido, and R3, R4, R5, R6and R8hydrogen, or when R3, R4and R5independently from each other hydrogen or lower alkyl, provided that at least one of them means hydrogen, or one of the substituents R3, R4and R5butyl, and the other substituents R6, R7and R8hydrogen, or R6, R7and R8independently from each other hydrogen or lower alkyl, provided that at least one of them means hydrogen, or one of the substituents R6, R7and R8butyl, and ostalnoe, benzyl, lower alkanoyl, lower alkoxyalkyl, lower alkylthiomethyl and lower alkoxy,

and their hydrates, possessing biological activity.

2. Derivative dipyrido-diazepine General formula I on p. 1 and their hydrates, which have an inhibitory effect on reverse transcriptase of the virus HIV-1.

Priority signs:

17.11.89 when Z is oxygen, sulfur, group NCN and-NOR9where R9lower alkyl, R1hydrogen, lower alkyl, lower alkenyl, lower alkanoyl, benzoyl, R2lower alkyl, lower foralkyl, lower cycloalkyl, lower alkenyl, lower quinil, lower alkoxyalkyl, lower alkylthiomethyl, phenyl, benzyl, lower alkoxybenzyl, R3hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino, lower mono - or dialkylamino, lower alkynylamino, R4hydrogen, halogen, lower alkyl, nitro, amino, R5hydrogen, halogen, lower alkyl, lower alkoxyl, trihalomethyl, lower oxyalkyl, cyano, R6hydrogen, lower alkyl, R7hydrogen, amino, lower alkyl, R8hydrogen, lower alkyl;

06.09.90 when R1hydroxyl, lower alkenylacyl, lower alkoxyl, lower dialkylaminoalkyl, lower alkoxyalkyl, lower alkylthiomethyl, benzyl, R2lowest alkanoyl, is benzylmethylamine, methoxybenzylamine, R5hydroxyl, R6is hydroxyl, R7halogen, azido, nitro; 19.10.90 when R2is cyano;

16.11.90 when R2lowest cycloalkenyl, methylsulphonyl, if Z is oxygen or sulfur, R2hydrogen, lower alkyl, lower alkenyl, lower quinil, lower alkoxyalkyl, lower alkylthiomethyl, lower alkanoyl, phenyl, benzyl, lower alkoxybenzyl, R3, R4, R5, R6, R7and R8hydrogen, or one of the substituents R3, R4, R5, R6, R7and R8the lower alkyl and the other substituents are hydrogen, or one of the substituents R3, R4, R5and R7is halogen and the other substituents R6and R8hydrogen, or one of the substituents R3, R4and R7nitro, and the remaining substituents R5, R6and R8hydrogen, or one of the substituents R3, R5and R6hydroxyl, and the other substituents R4, R7and R8hydrogen, or one of the substituents R3, R4and R7amino and the other substituents R5, R6and R8hydrogen, or one of the substituents R3and R5alkoxy, and the other substituents R4, R6, R7and R8hydrogen, or R5nissl>, R4, R5, R6and R8hydrogen, or when R3, R4and R5independently from each other hydrogen or lower alkyl, provided that at least one of them means hydrogen, or one of the substituents R3, R4and R5- butyl, and the other substituents R6, R7and R8hydrogen, or R6, R7and R8independently from each other hydrogen or lower alkyl, provided that at least one of them means hydrogen, or one of the substituents R6, R7and R8butyl, and the other substituents R3, R4and R5hydrogen, R1cannot be hydrogen, lower alkyl, lower alkenyl, benzyl, lower alkanoyl, lower alkoxyalkyl, lower alkylthiomethyl and lower alkoxy.

 

Same patents:

The invention relates to medicine and can be used to treat conditions involving increased adhesion - aggregation of platelets and for preservation of platelet-rich plasma

- aminoacyl)-5,10-dihydro-11h-dibenzo[b, e] [1,4]- diazepin-11-ons or their salts, possess antiarrhythmic activity" target="_blank">

The invention relates to the field of chemistry, particularly to the new series of compounds - 5-(-aminoacyl)-5,10-dihydro-11N - dibenzo [b,e]-[1,4]-diazepin-11-Onam General formula

where R1is a hydrogen atom or chlorine;

R2is a hydrogen atom or a C1-C2-alkyl;

R3- C1-C2-alkyl or cyclohexyl, or R2and R3together with the nitrogen atom can be morpholinyl or N-methylpiperazine balance; provided that, if R2is a hydrogen atom, R3can be1-C3-alkyl or cyclohexyl,

n=3-6;

m = 0-1; X=Cl or Br

- aminopropionic)-5h-dibenz[b, f] azepine with antiarrhythmic activity" target="_blank">

The invention relates to new chemical compounds of a number of dibenz (b, f) azepine, namely 3-carbalkoxy-5- (-aminopropionic)-5H-dibenz (b, f) azepine General formula

where (a) X=-CH2-CH2-, R1=R2=CH3, R3=H, n=1;

b) X=-CH2-CH2-, R1=CH3, R2=CH2CH2OH, R3=H, n=1;

C) X=-CH2-CH2-, R1=C2H5, R2=R3=H, n=1;

g) X=-CH2-CH2-, R1=C2H5, R2=CH3, R3=H, n=0 or 1;

d) X=-CH2-CH2-, R1=R2=C2H5, R3=H, n=1;

e) X=-CH2-CH2-, R1=C2H5, R2=H-C3H7, R3=H, n=1;

W) X=-CH2-CH2-, R1=C2H5, R2=R3=CH3n=1;

C) X=-CH2-CH2-, R1=R2=R3=C2H5n=1;

and) X=-CH2-CH2-, R1=C2H5, R2and R3together = -(CH2)2O(CH2)2-, n=1;

K) X=-CH2-CH2-, R1=ISO-C3H7, R2=CH3, R3=H, n=0;

l) X=-CH2-CH2-5, R2=CH3, R3=H, n=0;

n) X=-CH=CH-, R1=R2=C2H5, R3=H, n=1,

that possess antiarrhythmic effect and can find application in medicine

The invention relates to medicine, namely to obstetrics

The invention relates to new biologically active pyridyl - or pyrimidinediamine derivative of piperazine or 1,4-disallocation, or their pharmacologically active acid additive salts with psychotropic action
The invention relates to medicine, namely to psychiatry

The invention relates to new derivatives of benzodiazepine, specifically tricyclic compounds of General formula Iwhere RI- phenyl, possibly substituted by fluorine,

X - CH2or CHR3where R3- C1-C4alkyl, and R2- 2-indolocarbazole; phenyl (lower) alkanoyl, which can be substituted by amino or lower alkanolamine; or R2- phenylcarbamoyl, which may be substituted with halogen or lower alkoxygroup, or their pharmaceutically acceptable salts

FIELD: veterinary science.

SUBSTANCE: a sow should be twice injected with oxytocin and, additionally, intramuscularly about 2-4 h after afterbirth detachment one should introduce clathroprostin at the dosage of 1 ml. The innovation suggested is very efficient in preventing metritis-mastitis-agalactia and endometritis in sows, as well.

EFFECT: higher efficiency of prophylaxis.

1 ex, 1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 1 tbl, 30 ex

FIELD: medicine, cardiology.

SUBSTANCE: patient with stenocardia should be introduced with efficient quantity of omapathrylate or its pharmaceutically acceptable salt either separately or in combination with another pharmaceutically active agent. Another pharmaceutically active substance could be represented by organic nitrate, beta-adrenergistic blocking agent, blocking agent of calcium supply or antithrombocytic preparation. It is suggested to apply omapathrylate or its pharmaceutically acceptable salt to prepare medicinal preparations for treating and/or decreasing stenocardial symptoms.

EFFECT: higher efficiency.

16 cl, 2 dwg, 2 ex, 8 tbl

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of pyridothienodiazepine. Invention describes derivatives of pyridothienodiazepine of the general formula (I):

as a racemate or in form of enantiomers or diastereomers, or their mixture wherein R1 represents hydrogen atom or radical of the formula: R'1-NH-C(Y)- wherein R' represents phenyl radical optionally substituted with one or more similar or different substitutes taken among lower alkyl, lower alkoxy-group, lower alkylthio-group, lower alkoxycarbonyl, lower alkylsulfonyl, halogen atom, trifluoromethyl, trifluoromethyloxy-group, hydroxy-, nitro-, cyano-group, phenyl, phenoxy-group, cycloalkyl or heterocycloalkyl; R2 represents lower alkyl, trifluoromethyl or phenyl radical optionally substituted with one or more similar or different substitutes taken among hydroxy-group, halogen atom, lower alkyl or lower alkoxy-group; X and Y represent independently oxygen (O) or sulfur (S) atom; R3a represents hydrogen atom, lower alkyl, hydroxy-group or radical of the formula -OC(O)R'3a wherein R'3a represents alkyl radical comprising from 1 to 10 carbon atoms optionally substituted with radical of the formula: NR''3aR'''3a wherein NR''3a and R'''3a represent independently hydrogen atom, lower alkyl, phenyl, lower phenylalkyl, alkylcarbonyl or alkoxycarbonyl; R3b represents hydrogen atom or lower alkyl radical; R4 represents radical of the formula: -(CH2)n-CHR'4R''4 wherein n represents a whole number 0, 1, 2, 3, 4, 5 or 6; R'4 and R''4 represent independently hydrogen atom, lower alkyl, cycloalkyl, lower cycloalkylalkyl, phenyl, pyridyl, phenylcarbonyl or adamantyl wherein indicated radicals are substituted optionally with one or more similar or different substitutes taken among hydroxy-group, halogen atom, trifluoromethyl, lower alkyl or lower alkoxy-group; A----B represents -C=N- or -C-N(R5)- wherein R5 represents hydrogen atom, amino-radical, lower alkylamino-group, di-(lower alkyl)-amino-group, cycloalkyl, heterocycloalkyl, guanidyl optionally substituted with nitro- or cyano-group, phenyl optionally substituted with one or more similar or different substitutes taken among alkyl or alkoxyalkyl wherein indicated alkyl or alkoxyalkyl are substituted optionally with oxy- or amino-group; indolyl or radical of the formula: -NH-C(O)-(CH2)c-NH-C(O)(CH2)d-NH2; p represents a whole number 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; c and d represent independently a whole number 0, 1, 2 or 3; or salts of these compounds. Also, invention describes methods for preparing compounds of the general formula (I), pharmaceutical composition based on compounds of the general formula (I) eliciting activity to inhibit binding somatostatin-14 and an intermediate compound of the formula (2) given in the invention description. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

17 cl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: medicine.

SUBSTANCE: method involves administering typical tricyclic antidepressants combined with selective reverse serotonin capture inhibitors. Anxious version of subpsychotic level depressive syndrome of endogenous genesis being treated, intravenous drop-by-drop infusion of 2.-4.0 ml of 1% amitriptiline solution per 200 ml of physiologic saline is applied in 12-14 procedures combined with selective reverse serotonin capture inhibitor given per os, Zoloft is per os administered as the inhibitor at a dose of 50-100 mg. Then, supporting Zoloft therapy is applied at a dose of 100 mg during 3 months. Atypic version of depressive syndrome of subpsychotic level and endogenous genesis is treated with intravenous drop-by-drop infusion of 1.25% Melipramine solution at a dose of 2.0-4.0 ml per 200 ml of power supply source in 12-14 infusions combined with a reverse serotonin capture inhibitor. Paxyl is taken at a peroral dose of 40-60 mg as the inhibitor. Then, supporting Paxyl therapy is applied at a dose of 40-60 mg during 3 months.

EFFECT: enhanced effectiveness of treatment; reduced risk of complications; accelerated depressive syndrome relief.

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to novel pyrasolbenzodiazepines of formula I 1 (in formula R1 is hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, -CONR8R9, -NR10R11, NHCOR12, NHSO2R13; each R2 and R4 independently of one another are hydrogen, halogen, -NO2, -CF3; R3 is hydpegen, C3-C8-cycloalkyl, aryl, in particular C6-C10-aromatic group having 1 or 2 rings, 5-10-membered heteroaryl, having 1 or 2 rings and1-3 heteroatoms, selected from N, O, and S, -COOR7, CN, C2-C6-alkenyl, -CONR8R9 or C1-C6-alkyl optionally substituted with OR9-group, F or aryl as mentioned above; R5 is C1-C6-alkyl; R7 is hydrogen or C1-C6-alkyl; each independently of one another are hydrogen or C1-C6-alkyl optionally substituted with hydroxyl or NH2, or alternatively R8 and R9 together form morpholino group; each R10,R11 and R12 independently of one another are hydrogen or C1-C6-alkyl; R13 is C1-C6-alkyl optionally substituted with halogen or -NR14R15; each R14 and R15 independently of one another are hydrogen or C1-C6-alkyl optionally substituted with halogen; or alternatively -NR14R15 is morpholino group) or pharmaceutically acceptable salts thereof, as well as to certain pyrasolbenzodiazepine derivatives, thiolactam intermediates for production of compound (I) and pharmaceutical compositions containing the same. Compound and pharmaceutical composition of present invention are cycline-dependent kinase (CDK2) inhibitors and antiproliferation agents used in treatment or controlling disorders associated with cell proliferation, in particular breast, colon, lung and/or prostate tumors.

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: biochemistry.

SUBSTANCE: invention relates to method for production of synthetic chlorophyll (Chl) or bacteriochlorophyll (Bchl) derivatives of general formula I , wherein X is O;. Claimed method includes interaction under anaerobic conditions of Chl, Bchl derivatives containing COOCH3-group in C-132-position and COOR3-group in C-172-position in presence of tetraethyl orthotitanate. Further compounds of formula I wherein R1 and R2 are different radicals are obtained in aproton solvent such as peroxide-free tetrahydrofurane and dimethyl formamide, and compounds of formula I wherein R1 and R2 are the same ones are produced by using R1OH as a solvent. Derivatives of present invention are useful as stabilizers, linkage/spacer for binding another acceptable molecules to Chl/Bchl macrocycle.

EFFECT: simplified method for production of various chlorophyll or bacteriochlorophyll derivatives.

13 cl, 3 ex, 2 tbl, 8 dwg

FIELD: animals science.

SUBSTANCE: the present innovation deals with intramuscular injection of sodium salt preparation cloprostenol 30-45 min before placing at the dosage of 750 mcg/animal. The method provides increased reproductive function, enhances sexual reflex, increases the volume of ejaculate, concentration, activity and quality of spermatozoa.

EFFECT: higher efficiency of breeding.

2 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new substance eliciting an antiviral and antibacterial activity that is based on derivatives of 2,8-dithioxo-1H-pyrano[2,3-d;6,5-d']dipyrimidine and their 10-aza-analogues. This substance comprises derivative of indicated group of the general formula: A1*M: wherein X is taken among the group: oxygen atom (O), NH, N-alkyl; R1 is taken among the group: hydrogen atom (H), OH, chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, NH-Ar, N-(alkyl)2, SH, S-alkyl; R2 is taken among the group: unsubstituted or substituted phenyl, naphthyl, thienyl; R3 is taken among the group: hydrogen atom (H), chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, S-dihydroxypyrimidinyl; M is absent or taken among the group: cation Na, K, Li, ammonium or any other pharmacologically acceptable cation; or complex of pharmacologically acceptable cation (see above) with anion of one of derivatives of A1 (variants R1-R3 are given above). Invention provides preparing new compounds eliciting an antiviral and antibacterial activity.

EFFECT: valuable medicinal properties of substance.

17 cl, 7 tbl, 16 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes a compound of the general formula (I) or (II) wherein R1 represents hydrogen atom; R2 is taken among the group consisting of aryl and heteroaryl; R3 is taken among the group consisting of halogen atom, nitro-, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, trifluoromethyl, trifluoromethoxy-group, -NH2, -NH-(C1-C6)-alkyl and -N-(C1-C6)-alkyl)2; b is a whole number from 0 to 4; R4 is taken independently among the group consisting of halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkoxycarbonyl, phenyl (wherein phenyl group can be substituted optionally with one-three substitutes taken independently among RD), phenylsulfonyl, heteroaryl (wherein heteroaryl can be substituted optionally with one-three substitutes taken independently among RD), heterocycloalkyl, -NH2, -NHRA, -N-(RA)2,

wherein each RD is taken independently among halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C4)-alkyl, (C1-C4)-alkylthio, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylcarbonyl, trifluoromethyl, trifluoromethoxy-group, -NH2. -NHRA, -N-(RA)2, -C(O)N(RA)2, -SO2N(RA)2, acetylamino-, nitro-, cyano-group, formyl, (C1-C6)-alkylsulfonyl, carboxy-(C1-C6)-alkyl and aralkyl; c = 0; a means a whole number from 0 to 1; Y is taken among the group consisting of a residue -(C1-C)-alkyl, -C(O)-, -(C2-C6)-alkenyl)-carbonyl, -carbonyl-(C1-C6)-alkyl)-, -C(S)-, -C(O)NH-(C1-C6)_alkyl), -C(O)-(C3-C7)-cycloalkyl)- and (C3-C7)-cycloalkyl)-C(O)-; represents phenyl;

is taken among the group consisting of phenyl, heteroaryl and cycloalkyl under condition that when R1 represents hydrogen atom, R3 represents hydrogen atom, b = 0, c = 1, Y represents -CH2-, represents phenyl and represents phenyl then R2 is not trimethoxyphenyl, and its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition designated for inhibition of activity of phosphodiesterase comprising a pharmaceutically acceptable vehicle and compound by cl. 1, method for preparing pharmaceutical composition, methods for treatment of sexual dysfunction by using compound by cl. 1 or pharmaceutical composition, method for increasing the concentration of cGMP in penis tissue and method for treatment of state when inhibition of activity of phosphodiesterase shows the favorable effect. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

17 cl, 7 tbl, 98 ex

FIELD: organic chemistry, chemical technology, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel derivative of variolin B of the general formula (I) or their pharmaceutically acceptable salts possessing antitumor activity. In the general formula (I) radical R1 means aromatic group representing aromatic group representing phenyl optionally substituted with nitro-group, amino-group or alkyl-substituted amino-group, or aromatic group represents 5-6-membered heterocycle with two nitrogen atoms or sulfur atom as heteroatoms optionally substituted with (C1-C12)-alkyl, -OH, unsubstituted amino-group or amino-group substituted with (C1-C4)-acyl, phenyl-(C1-C4)-alkyl wherein phenyl group can be substituted with -OR1, or (C1-C12)-alkylthio-group, (C1-C12)-alkyl- or phenylsulfonyl, (C1-C12)-alkyl- or phenylsulfinyl or -OR1 wherein R1 is chosen from (C1-C12)-alkyl or phenyl; R2 represents hydrogen atom; R3 represents oxo-group when a dotted line is between nitrogen atom to which R2 is bound and carbon atom to which R3 is absent, or R2 is absent when R3 represents optionally protected amino-group wherein a substitute is chosen from (C1-C4)-acyl, phenylsulfonyl and (C1-C4)-alkylphenylsulfonyl when a dotted line forms a double bond between nitrogen atom to which R2 is bound and carbon atom to which R2 is bound; R4 represent hydrogen atom. Also, invention relates to a method for synthesis of compounds of the invention and to intermediate substances for their realization. Also, invention relates to a pharmaceutical composition based on variolin B derivatives.

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

22 cl, 5 sch, 1 tbl, 50 ex

Up!