Derivatives of diazepinone, mixtures of their isomers and their salts

 

(57) Abstract:

Usage: in medicine, because they possess a number of pharmacological properties. The inventive product is a derivative of diazepinone F.-ly (I), which means one of the two radicals a - g: , , , ; X is a group-CH or N, when means the residue of f-crystals (a) ; R - prosvetlenny or razbelenny alkyl with 1 to 4 carbon atoms; R1and R2the same or different and mean a hydrogen atom, or alkyl with 1 to 4 carbon atoms; R3Is H, Cl or methyl; R4and R5the same or different hydrogen atom or alkyl with 1 to 4 carbon atoms, and R5can also mean a halogen atom, m, p, -1; Oh, n is 1 or 2, mixtures of their isomers and their salts. Reagent 1: compound f-ly II. Reagent 2: compound f-crystals III. Reaction conditions: preferably in the environment of a solvent and at 40 - 100°C. 2 C. p. F.-ly, 3 tables.

The invention relates to new diazepinones having valuable properties, in particular pharmacological properties, more particularly to derivatives of diazepinone General formula

< / BR>
(I) means where one of the divalent radicals a) to d)

, R3,

where X is the group=CH or a nitrogen atom, when means the residue of formula (a);

R is unbranched or branched alkyl with 1-4 atom is a;

R3is a hydrogen atom or chlorine;

R4and R5the same or different and mean a hydrogen atom or alkyl with 1-4 carbon atoms;

m, p, -1;

n, o - 1 or 2

mixtures of their isomers and their salts.

New derivatives of diazepinone can be obtained by the following methods.

A.

The interaction of compounds of General formula

(II) where and X have the above meanings;

Y means a halogen atom or a group OR6and R6means alkyl with 1-5 carbon atoms, unsubstituted or substituted by a halogen atom, phenyl, unsubstituted or substituted by halogen atoms or nitro groups, or aralkyl with 7-15 carbon atoms, to obtain, if necessary, in situ, a compound of General formula

where R, m, n, o and p have the above meanings;

R7means a hydrogen atom, alkali metal atom or an equivalent of an alkali earth metal atom.

The reaction is carried out without solvent or preferably in the environment solvent, such as water, toluene or alcohol, for example methanol, ethanol or isopropanol, particularly preferably in the environment aprotic polar solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylforamide the boiling temperature of the reaction mixture, preferably at a temperature of 40-100aboutC. Appropriate additional use of inorganic or organic bases such as hydroxide, alcoholate or carbonate of alkali or alkaline earth metal, for example sodium hydroxide, methanolate sodium tert-butanolate potassium, sodium carbonate or potassium hydroxide, tertiary amines such as triethylamine, ethyldiethanolamine, N,N-dimethylaniline, pyridine or 4-(dimethylamino)pyridine. It is also advisable to use an excess of the compounds of General formula (III).

B.

The interaction of compounds of General formula

where X and have the listed values are obtained, if necessary, in situ, a compound of General formula

Cl(V)where R, m, n, o and p have the specified values.

The reaction is preferably carried out in inert organic solvent, for example an aromatic hydrocarbon, for example toluene or xylene, a simple ester, for example a simple diisopropyl ether, tetrahydrofuran or dioxane, a ketone, for example 3-pentanone, chlorinated aliphatic hydrocarbons, such as 1,2-dichloroethane, or in the environment of another solvent such as acetonitrile or dimethylformamide, or mixtures or what ur up to the boiling point of the reaction mixture, preferably at a temperature of 30-100aboutC.

Century

Hydrogenolysis obtained, if necessary, in situ compounds of General formula

where X, R, m, n, o and p have the above significance, and R8means a chlorine atom.

The hydrogenolysis is carried out in the presence of a catalyst based on a metal of the VIII, the side group of the Periodic system of elements, for example, palladium on animal charcoal, palladium on barium sulphate, Nickel or Raney cobalt, Raney, when the hydrogen pressure 1-300 bar and at a temperature of 0-130aboutSince, in the environment of the solvent, for example alcohol, like methanol or ethanol, a simple ether, for example dioxane or tetrahydrofuran, carboxylic acids, for example acetic acid, or a tertiary amine, such as triethylamine. In that case, if the hydrogenolysis is carried out in the absence of additional acceptors of hydrogen chloride, for example sodium bicarbonate, potassium bicarbonate, triethylamine or sodium acetate, then directly obtain the hydrochloride of the desired product, which, after removal of the catalyst can be identified easily by evaporation of the reaction solution. If in the above hydrogenolysis with hydrogen replaced with formic acid, the reaction always successfully crack the Oh acid in a medium of dimethylformamide as solvent and in the presence of palladium on coal as a catalyst, at a temperature of 70-110aboutWith, and restore the formate of triethylamine in an environment of excess triethylamine and in the presence of palladium on animal charcoal, or palladium acetate, or triarylphosphine, such as triphenylphosphine, Tris-(o-tolyl)phosphine, Tris(2,5-diisopropylphenyl)phosphine, at a temperature of 40-110aboutC.

Thus obtained base of the General formula (1) can then be transferred to the acid additive salt or obtained an acid additive salt can be converted to the free base or into another pharmacologically tolerable acid additive salt.

As already mentioned, diazepinone General formula (1) and their acid additive salts possess valuable properties, in particular they have a selective spasmolytic effects on peripheral organs, particularly the terminal ileum and urinary bladder, and due to the lack of medical and veterinary increase heart rate, inhibiting the secretion of gastric acid and separation of saliva and reduce the ability of the eye to the funds in accommodation suitable for therapy doses, which could be used for therapy cholinergic spasms and motility disorders of the gastrointestinal tract and in the region is ecologicheski increased tone of hollow organs for therapy relative incontinence, caused by the mismatch between the tone of the sphincter and tone the muscles of the bladder, for the symptomatic treatment of bronchial asthma and bronchitis by podavleniya muscarinic shares compression of the bronchi, as well as for therapy of ischemic heart disease by lowering heart rate and simultaneous podavleniya coronary spasms associated with the parasympathetic nervous system, and reduce basal coronary tone.

Favorable ratio spasmolytic action on the one hand and the unwanted actions of drugs with antiholinergicheskim effect on heart rate, width pupils, tearing, Department of saliva and the secretion of gastric acid on the other hand has a special significance for therapeutic use of substances. These experiments show that the new compounds in this respect have unexpectedly advantageous relationships.

A. the Study of functional selectivity antimuskarinovoe act occurs the action.

Substances with properties antimuskarinovoe act occurs inhibit exogenous supplied agonists or acetylcholine, which is released from Jolinar muskarinovykh funds.

Dissection of the organs in vitro.

Dissociation constants (the values of Kd) in vitro was determined on the ileum and on spontaneously beating atrium of the Guinea pig. The terminal ileum was removed and incubated in a bath containing a solution of Krebs-Henseleit. The addition of increasing amounts of methacholine caused a reduction so that you can make solid curves actions on the concentration. Then metafolin washed, added investigated the connection and left to stand for 30 min, after which the newly constituted curve based actions on the concentration of methacholine.

On the basis of the ratio of doses, i.e., the degree of offset curve effects on the concentration, determined the dissociation constant according Arunachala and Schild (see Brit. J. Pharmacol. 14, page 48, 1959).

In the isolated, spontaneously beating right atrium of metafolin depending on concentration caused a decrease in the frequency of contractions. Due to the adding means antimuskarinovoe act occurs, this effect disappeared. Dissociation constants muscarinic receptors in the Atria was determined by the method described above. Comparison of the dissociation constants for both authorities to identify

Methods in vivo.

The methods used were designed to confirm the selectivity antimuskarinovoe act occurs actions. Selected studies in vitro were investigated regarding

1. Selectivity bronchospasmolytic activity on Guinea pigs;

2. Check salivation actions in the rat;

3. Spasmolytic activity on the live Guinea pig.

1. The effect on the receptors metacholine in the bronchi, heart and bladder shot of Guinea pigs.

Method: Female and male Guinea pigs weighing 550-600 g was anestesiologi 1.4 g/kg (intraperitoneally) urethane. For injection of active substances in the jugular vein was introduced cannula. Intravenously injected 220 units/kg of heparin. Introduced canula and into the trachea, and in Guinea pigs, using the pressure pump company Braun-Melsungen performed artificial respiration, oxygen-enriched air at 80 beats per minute. One branch tracheotomies cannula was connected with hydromineral height 10 cm Volume of respiration was chosen so that during respiration maximum intratracheal pressure was reached, but not exceeded the pressure of 10 cm water. Art.

Except for a few changes actually is aemy by compression of the bronchi volume of the gas mixture, used with artificial breathing, flowing through hydromancer, were determined using tubular pneumatic tachometer type 1000 firm "Plays" connected with dierential pressure SP R. Values were recorded by the respective device. Prior experience trachea short time perikli in order to achieve the maximum degree of compression of the bronchi for calibration. Left large cervical artery entered the cannula and arterial blood pressure was determined using a pressure transducer type 4-327 I bell & do this" associated with the recording device. Heart rate was measured using the respective device, triggered arterial pulse waves.

Did the median crevoshay, and the bladder was associated with the power Converter when the voltage in the quiescent state 1,

Analyzed the active substance was injected into the jugular vein, and after 5 min after injection of acetylcholine (50 mg/kg intravenously and intraarterially) was determined by increasing the voltage in the bladder (in grams), bronchial resistance (%) and decrease in heart rate (in beats per minute). After Octavarium logarithms of the doses studied species (mol/kg) curves were based on doses. The results of the experiments are given in table. 1 represent average values of 4-6 experiments.

2. Check salivation effect on the rats.

According to the method of levy and Mulder (Arch. int. Pharmacodyn. 178, 437-445, 1969 ), anesthetized with 1.2 g/kg urethane rats - males intravenously was given increasing doses of the substance of interest. Salivation caused subcutaneous feed 2 mg/kg of pilocarpine. Saliva had soaked up carrying paper occupied her area planimetrically was determined every 5 minutes Graphically determined dose of a substance by 50% reducing the volume of discharge of saliva. The results are shown in table. 2.

3. Spasmolytic effect on Guinea pigs in situ.

Male Guinea pigs weighing 500-600 g was anestesiologi intraperitoneal submission of 1.2 g/kg urethane, and into the trachea, jugular vein and the left neck artery was injected cannula. In animals with injection pump was performed artificial respiration, oxygen-enriched air at 80 beats per minute. Performed crevoshay length of 3-4 cm, and maintains the blood circulation distal tied movable loop of the ileum length of about 15 cm Proximal part was filled with Krebs solution and ringer and intestine with the help supplied with the surrounding wall of the stomach so that when filling a glass tube with Krebs solution and ringer's Guinea pig served as a private for your body.

A glass tube filled with Krebs solution and ringer before all hypogastric region was filled. Analyzed the active substance was injected through the jugular vein and after 5 min intra-arterial supply of 20 μm/kg methacholine caused reduction. Recording podavlenie called methacholine reductions (in percent) and using the logarithm of the dose (mol/kg) analyte was curves actions on doses. The results of the experiments are given in table. 2 represent average values of 4-8 experiments.

According to the above procedure were investigated, for example, the following connections:

A = 5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6N-pyrido- [2,3-b][1,4]benzodiazepine-6-he

B = 5,11-dihydro-8-methyl-11-[[7-methyl - 2,7-diazaspiro[4,4]non-2-yl] carbonyl]- 6N-pyrido[2,3-b][1,4]benzodiazepine-6-he

In = 5,11-dihydro-11-[[6-methyl-2,6-diazaspiro [3,4]Oct-2-yl]carbonyl]-6H-pyrido- [2,3-b][1,4]benzodiazepine-6-he

G = 5,11-dihydro-8-ethyl-11-[[6-methyl - 2,6-diazaspiro[3,4] Oct-2-yl] carbonyl]-6N-pyrido[2,3-b][1,4]benzodiazepine-6-he

D = 5,11-dihydro-8-methyl-11-[[2-methyl - 2,6-diazaspiro-yl]carbonyl] -1,4,9,10-tetrahed - romeralo[3,2-b][1,5]benzodiazepine-10-he

W = 4,9-dihydro-3-methyl-4-[[6-methyl - 2,6-diazaspiro[3,4]Oct-2-yl]-carbonyl] -10H-thieno [3,4-b][1,5]benzodiazepine-10-it C = 5,10-dihydro-5-[[7-methyl-2,7 - diazaspiro[4,4] non-2-yl] -carbonyl]-11N-dibenzo- [b,e][1,4] diazepin-11-he

And = 6,11-dihydro-11-[[7-methyl-2,7-diazaspiro [4,4]non-2-yl]carbonyl]-5H-pyrido- [2,3-b][1,5]benzodiazepine-5-he

K = 6,11-dihydro-11-[[6-methyl-2,6-diazaspiro [3,4]Oct-2-yl]-carbonyl] -5H-pyrido- [2,3-b][1,5]benzodiazepine-5-he

L = 6,11-dihydro-11-[[2-methyl-2,6-diazaspiro [3,4]Oct-6-yl]-carbonyl] -5H-pyrido- [2,3-b] [1,5] benzodiazepine-5-he as a comparative connections:

X = 5,11-dihydro-11-[(4-methyl-1-piperazinil)acetyl] -6N-pyrido[2,3-b] [1,4] benzo-diazepin-6-he (trade product of Pirenzepine, see U.S. patent N 3660380).

The findings of the experiments.

Compared with the known compound X, the new compounds of General formula (I) in smaller doses delay the action of exogenously supplied acetylcholine or methacholine on smooth muscles of the bronchi, bladder and small intestine, without changing agonistic effect on heart rate (see tab. 1 and 2). Compounds of General formula (I) not only possess selectivity relatively smooth muscles, compared with the evoked cardiac muscarinic receptors. 2).

Determined in vivo selectivity of new compounds correspond to the results of experiments in vitro. In comparison with the known compound, the new compounds have a greater affinity for the muscarinic receptors in the ileum than with cardiac muscarinic receptors (see table. 3).

The results of the experiments show that the new compounds of General formula (I) delay the action of muscarinic agonists on smooth muscles, for example, bronchi, bladder and ileum at doses that have no effect on heart rate or salivation. Comparative compound X (pirenzepine) has no selectivity, i.e., in the same dose range causes the same effects.

All compounds of General formula (I) are resistant to hydrolysis. Therefore, it is possible to prepare stable during storage solutions for parenteral use.

Obtaining new compounds is illustrated by the following examples. In case of reduction of the percentage of data always mean mass percent, if nothing else is specified.

P R I m e R 1. 5,11-Dihydro-11- [[7-methyl-2,7 - diazaspiro[4,4]non-2-yl]carbonyl]-6N-pyrido[2,3-b] [1/4] company code level (0.041 mol) of anhydrous sodium carbonate, 5 ,6 g (0.04 mol) of 2-methyl-2,7-diazepino[4,4]nonane and 100 ml of acetonitrile is stirred for 30 minutes at a temperature of 50aboutC. Then the solvent is distilled off in vacuum, the remaining viscous residue absorbed in 30 ml of water, alkalinized sodium lye and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulfate and evaporated, the residue is chromatographically purified on silica gel (35-70 mesh) using as eluent a mixture of dichloromethane complex ethyl ester acetic acid, cyclohexane, methanol and concentrated ammonia in a volume ratio 50:11:9:9:1. The remainder of elution is recrystallized from water and methanol in the ratio of 1:9. Obtain 5.9 g (48% of theory) of colourless crystals with a melting point 271-274aboutC.

WITH21H23N5O2(377,45).

Calculated, %: C 66,83; N 6,14; N 18,55.

Found, %: C 67,00; N 6.35mm; N 18,85.

P R I m m e R 2. 5,11-Dihydro-8-methyl-11-[[7-methyl-2,7-diazaspiro[4,4] non-2-yl]-carbonyl]-6N-pyrido[2/3-b][1/4] benzodiazepine-6-he

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6N-pyrido[2,3-b] [1,4] benzodiazepine-6-it 2 - methyl-2,7-diazaspiro[4,4] nonane with a 71% yield of theory. Colorless crystals with so pl. 212-214about

Calculated, %: C 67,50; N 6,44; N 17,89.

Found, %: C 67,89; N. Of 6.20; N 18,00.

P R I m e R 3. 5,11-Dihydro-8-ethyl-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]-Carbo - Nile-6N-pyrido[2,3-b][1,4]benzodiazepine-6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-ethyl-6N-PI - Rideau[2,3-b][1,4]benzodiazepine-6-it 2-methyl-2,7-diazaspiro[4,4] nonane with the release of 57% of theory. Colorless crystals with so pl. 216-217about(From acetonitrile using active charcoal).

WITH23H27N5ABOUT2(405,50).

Calculated, %: C 68,13; H Of 6.71; N 17,27.

Found, %: C, 69.30; H For 6.81; N 17,30.

P R I m e R 4. 5,11-Dihydro-9-methyl-11-[[7-methyl-2,7-diazaspiro[4,4] non-2-yl[carbonyl] -6N-pyrido[2,3-b]benzodiazepine-6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6N-pyrido[2,2-b] [1,4] benzodiazepine-6-it 2-methyl-2,7-diazaspiro[4,4] nonane with the release of 9% of theory. Colorless crystals with so pl. 253-255about(From acetonitrile).

WITH22H25N5ABOUT2(391,48).

Calculated, %: C 67,50; N 6,44; N 17,89.

Found, %: C 66,99; N 6,47; N 17,62.

P R I m e R 5. 5,11-Dihydro-11-[[7-ethyl-2,7-diazaspiro[4,4]non - 2-yl] carbonyl]-6N-pyrido[2,3-b][1,4]benzodiazepine-6-he.

Get on the same period the yield 85% of theory. Colorless crystals with a melting point of 214-215aboutC.

WITH22H25N5ABOUT2(391,48).

Calculated, %: C 67,50; N 6,44; N 17,89.

Found, %: C 67,44; N 6,70; N 18,10.

P R I m e R 6. 5,11-dihydro-11-[[7-ethyl-2,7-diazaspiro[4,4] non-2-yl] -carbonyl]-8-methyl-6N-pyrido[2/3-b][1,4]benzodiazepine-6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6N-pyrido[2,3-b] [1,4]benzodiazepine-6-it 2-ethyl-2,7-diazaspiro[4,4] nonane with yield 74% of theory. Colorless crystals with so pl. 178-180about(From acetonitrile).

WITH23H27N5ABOUT2(405,50).

Calculated, %; 68,13; N. Of 6.71; N 17,27.

Found, %: From 67.94; H 6,70; N 17,57.

P R I m e R 7. 5,11-Dihydro-11[[7-ethyl-2,7-diazaspiro [4,4]non-2-yl]-carbonyl]-9-methyl-6N-pyrido[2,3-b][1,4]benzodiazepine-6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6N - pyrido[2,3-b] [1,4]benzodiazepine-6-it 2-ethyl-2,7-diazaspiro[4,4] nonane with the release of 85% of theory. Colorless crystals with so pl. 244-246about(From acetonitrile).

WITH23H27N5ABOUT2(405,50).

Calculated, %: C 68,13; N. Of 6.71; N 17,27.

Found, %: C 67,83; N 6,92; N 17,17.

P R I m e R 8. 5,11-Dihydro-11-[[6-methyl-2,6 - diazaspiro[3,4]IMT-5,11-dihydro-6N-pyrido[2,3-b] [1,4]benzodiazepine-6-it 6-methyl-2,6-diazaspiro[3,4]octane with the release of 26% of theory. Colorless crystals with so pl. 225,5-227,0about(From acetonitrile).

WITH20H21N5ABOUT2(363,42).

Calculated, %: C 66,10; H Of 5.82; N 19,27.

Found, %: C 66,18; N. Of 5.82; N 19,17.

Source benzodiazepine can be obtained as follows.

(a) 4,4-Bis-(etoxycarbonyl)-1-methyl-2-pyrrolidinone.

The mixture 221,6 g (0.90 mol) of a compound ethyl ester 1,1,2-tantriceskovo acid, 116,3 g (0.90 mol) of 1,3,5-trimethylhexane-1,3,5-triazine and 20.6 g (0.18 mol) triperoxonane acid at a temperature of 100aboutWith is stirred for 20 hours After cooling, the mixture is diluted with 1 l of toluene and then extracted three times with 100 ml of 10% hydrochloric acid. Hydrochloric acid aqueous extracts are combined and extracted with 100 ml of ethyl acetate. The resulting organic phase are combined to shake 200 ml of saturated aqueous sodium bicarbonate solution and then washed three times with 300 ml of water, dried over sodium sulfate and evaporated in vacuum. Receive 200 g (91% of theory) of colorless oil, which was used without additional purification in the next stage.

b) 3,3-Bis-(oxymethyl)-1-methylpyrrolidine.

To a suspension of 75.0 g (1,976 mol) of lithium aluminum hydride in 1 liter of anhydrous tetrahydrofuran drops doba is that the reaction can be controlled, and tetrahydrofuran moderately boils. Then for 4 h refluxed. Allow to cool and stirring, and when the external cooling with ice water drops and consistently add 75 ml of water, 75 ml of 15% sodium lye and 215 ml of water. The resulting precipitate is filtered off by suction, again suspended in tetrahydrofuran and heated to boiling, then filtered by suction. The resulting filtrates are combined thoroughly dried over sodium sulfate and evaporated in vacuum. Get 71,4 g (75% of theory) of a colourless, viscous oil, which was used without additional purification in the next stage.

C) 3,3-Bis-(methyl bromide)-1-methylpyrrolidine.

A mixture of 28.0 g (0,193 mol) obtained in stage b) connection and 250 ml of 63% aqueous Hydrobromic acid is heated in a refractory tube at a temperature of 180aboutWith within 24 hours After cooling in vacuum evaporated to dryness, the residue, which is poorly soluble in water, absorb 400 ml of water and treated with excess potassium carbonate. The resulting suspension is exhaustively extracted with complex ethyl ester, acetic acid extracts are combined and dried over sodium sulfate. By evaporation of the solvent receive 49,0 g (94% t F 0,9 (silica gel PolyGram ZIL G/UV254, eluent: a mixture of complex ethyl ester acetic acid, methanol and concentrated ammonia in a volume ratio of 100:30:3).

g) 6-Methyl-2-[(4-were)sulfonyl]-2,6-diazaspiro[3,4]octane.

The solution to 51.3 g (0.3 mol) of p-toluensulfonate and 33.6 g (0.6 mol) of potassium hydroxide in 160 ml of water is added a solution of 80 g (0,295 mol) of 3,3-bis-(methyl bromide)-1-methylpyrrolidine in 4.8 l of dioxane, and the resulting mixture heated under reflux. After 17 h, and an additional 24 h each time add 10.0 g (0,0584 mol) of p-toluensulfonate and 6.7 g (0.12 mol) of potassium hydroxide dissolved in 30 ml of water, and in the end again heated under reflux for 24 hours the reaction mixture is evaporated in vacuo, the residue is distributed between water and ethyl acetate, the organic layer washed with water, dried over sodium sulfate and rotary evaporator evaporated in vacuum. The obtained residue (64,0 g) is stirred diisopropyl ether and filtered off by suction, the filtrate is recrystallized from hot cyclohexane using activated carbon. Get a 50.5 g (61% of theory) of colorless crystals with so pl. 83-85aboutC.

WITH14H20N2ABOUT d) 6-Methyl-2,6-diazaspiro[3,4]octane.

A mixture of 48.5 g (0,173 mol) of 6-methyl-2-[(4-were)sulfonyl]-2,6-diazaspiro[3,4] octane, 199 ml (approximately 0.7 mol) of about 3.5 M solution of bis-(2-methoxyethoxy)dehydroalanine sodium in toluene and 300 ml of dry toluene under stirring for 15 h, heated at a temperature of 60aboutWith and for 6 hours at a temperature of 80aboutC. after the reaction gently and with external cooling with ice water drops add 20% sodium lye until cessation of hydrogen evolution. Then separate the toluene phase, it is dried over sodium sulfate and carefully evaporated using columns in a Game at a pressure of 50 mm RT. Art. the Target connection is so Kip. 80-85aboutWith a pressure of 22 mm RT.article and is colorless, thin liquid, smelling like Amin, liquid. Yield 7.5 g (34% of theory).

P R I m e R 9. 5,11-Dihydro-8-ethyl-11-[[6-methyl-2,6 - diazaspiro[3,4] Oct-2-yl]-Carbo-Neil]-6N-pyrido [2,3-b][1,4]benzodiazepine-6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-ethyl-6N-PI - Rideau[2,3-b][1,4]benzodiazepin-6-it 6-methyl-2,6-diazaspiro[3,4] octane with the release of 47% of theory. Colorless crystals with so pl. 215-217about(From acetonitrile).

WITH22H25N5ABOUT2(391,48).

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6N - pyrido[2,3-b][1,4]benzodiazepine-6-it 6-methyl-2,6-diazaspiro[3,4] octane with the release of 34% of theory. Colorless crystals with so pl. 220-223about(From acetonitrile).

WITH21H23N5ABOUT2(377,45).

Calculated, %: C 66,83; N 6,14; N 18,55.

Found, %: C 66,59; N 6,12; N 18,41.

P R I m e R 11. 5,11-Dihydro-9-methyl-11-[[6-methyl-2,6-diazaspiro [3,4] Oct-2-yl]-carbonyl]-6N-pyrido[2,3-b][1,4]benzodiaz-pin 6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6N-pyrido[2,3-b] [1,4] benzodiazepine-6-it 6-methyl-2,6-diazaspiro[3,4] octane with the release of 41% of theory. Colorless crystals with so pl. 242-245about(After two recrystallization from acetonitrile).

WITH21H23N5ABOUT2(377,45).

Calculated, %: C 66,83; N 6,14; N 18,55.

Found, %: C 66,57; N 6,23; N 18,41.

P R I m e R 12. 5,11-Dihydro-11-[[2 methyl-2,6-diazaspiro[3,4]Oct-6-yl] carbonyl]-6N-pyrido[2,3-b][1,4]benzodiazepine-6-he

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6N-pyrido-[2,3-b][1,4]benzodiazepine-6-it 2-methyl-2,6-diazaspiro[3,4]octane. The output 46% of theory. Colorless crystals with so pl. 273-275about(From acetonitrile).

is of 5.89; N 18,90.

Source benzodiazepine can be obtained, for example, as follows.

(a) 4,4-Bis-(etoxycarbonyl)-1-(phenylmethyl)-2-pyrrolidinone.

Get analogously to example 12A) from complex teeterboro ether 1,1,2-tantriceskovo acid and 1,3,5-Tris-(phenylmethyl)-hexahydro-1,3,5-triazine in the presence of triperoxonane acid. Yield 90% of theory. Colorless, viscous oil, which was used without additional purification in the next stage.

b) 3,3-Bis-(oxymethyl)-1-(phenylmethyl)-pyrrolidine.

Get analogously to example 12B) of 4,4-bis-(etoxycarbonyl)-1-(phenylmethyl)-2-pyrrolidinone and lithium aluminum hydride. Yield 78% of theory. Colorless, particularly viscous oil, which when stored at room temperature for about a week fully crystallized and which is used without additional purification in the next stage.

C) 3,3-Bis-(methyl bromide)-1-(phenylmethyl)-pyrrolidin-hydrobromide.

A mixture of 22.0 g (0.1 mol) of 3,3-bis-(oxymethyl)-1-(phenylmethyl)-pyrrolidine and 130 ml of 63% aqueous Hydrobromic acid is heated in a refractory tube at a temperature of 180aboutWith within 24 hours After cooling in vacuum evaporated to dryness, the crystalline residue premesis is 82% of theory) of colourless crystals with a melting point 222-225aboutC.

WITH13H17Br2N.NVG (428,0).

Calculated, %: 36,48; N 4,24; Br 56,01; N Is 3.27.

Found, %; 36,56; N 4,10; Br 55,73; N To 3.02.

g) 6-(Phenylmethyl)-2-[(4-were)sulfonyl]-2,6-diazaspiro[3,4]octane.

Get analogously to example 12g) of the hydrobromide 3,3-bis-(methyl bromide)-1-(phenylmethyl)-pyrrolidine potassium hydroxide and p-toluensulfonate. Yield 60% of theory. The resulting crystalline substance directly used in the next stage without recrystallization or other purification.

e) 6-(Phenylmethyl)-2,6-diazaspiro[3,4]octane.

Get analogously to example d) of 6-(phenylmethyl)-2-[(4-were)sulfo - Neil]-2,6-diazaspiro[3,4]octane and bis-(2-methoxyethoxy)-dehydroalanine sodium. Exit 41% of theory. Colorless liquid with so Kip. 161-170aboutC at a pressure of 18 mm RT.article and RFof 0.25 (silica gel PolyGram ZIL G/UV254, eluent: a mixture of dichloromethane, methanol, cyclohexane and concentrated aqueous ammonia in a volume ratio 68:15:15:2).

e) 2-Methyl-6-(phenylmethyl)-2,6-diazaspiro[3,4]octane.

10.8 g (0,0534 mol) 6-(phenylmethyl)-2,6-diazaspiro[3,4]octane are dissolved in 300 ml of ethanol, diluted with 5 ml (approximately 0,062 mol) of 37% aqueous formalin solution and in techmesh hydronaut at room temperature for 5 h at a hydrogen pressure of 4 bar. The catalyst is filtered off, the filtrate is evaporated in vacuo and the resulting residue purified by high speed liquid column chromatography on silica gel using as eluent a mixture of dichloromethane, methanol, cyclohexane and concentrated aqueous ammonia in a volume ratio of 68: 15:15:2. By evaporation of suitable fractions obtain the desired compound in the form of a viscous, colorless oil. Output: 6,1 g (53% of theory). RFof 0.54 (silica gel PolyGram ZIL G/UV254, eluent: a mixture of dichloromethane, methanol, cyclohexane and concentrated aqueous ammonia in a volume ratio 68:15:15:2).

W) 2-Methyl-2,6-diazaspiro[3,4]octane.

To a solution of 6.1 g (0,0282 mol) of 2-methyl-6-(phenylmethyl)-2,6-diazaspiro[3,4]octane in 60 ml of ethanol is added 4.0 g of 10% palladium on animal coal as a catalyst, then hydronaut at room temperature for 5 h at a hydrogen pressure of 5 bar. Filtered, the filtrate evaporated under reduced pressure (100 mm RT.CT.) and as the remainder receive a colorless oil with RF0,1.

P R I m e R 15. 5,11-Dihydro-9-Methyl-11-[[2-methyl - 2,6-diazaspiro-[3,4] ] Oct-6-yl] -carbonyl] -6N-pyrido [2,3-b][1,4]benzodiazepine-6-he. Get analogously to example 1 from 11-(chlarkers the Colorless crystals with so pl. 284-285about(From acetonitrile).

WITH21H23N5ABOUT2(377,45).

Calculated, %: C 66,83; N 6,14; N 18,55.

Found, %: C 67,08; H 6,12; N 18,85.

P R I m e R 16. 5,11-Dihydro-11-[[6-ethyl-2,6-diazaspiro[3,4] Oct-2-yl] -carbonyl]-8-methyl-6N-pyrido[2,3-b][1,4]benzodiazepine-6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6N-pyrido-[2,3-b] [1,4]benzodiazepine-6-it 6-ethyl-2,6-diazaspiro[3,4]octane. Exit 27% of theory. Colorless crystals with so pl. 216-217about(From acetonitrile).

WITH22H25N5ABOUT2(391,48).

Calculated, %: C 67,50; N 6,44; N 17,89.

Found, %: C 67,39; N. Of 6.20; N 17,60.

Source benzodiazepine can be obtained as follows.

a) 4-Cyan-4-(etoxycarbonyl)-1-ethyl-2-pyrrolidinone.

Get analogously to example 8A) from diethyl ether complex 2-sanantano acid and 1,3,5-triethylhexyl-1,3,5-triazine in the presence of triperoxonane acid. Yield 89% of theory. Colorless oil as the crude product used in the next stage without purification.

b) 3-(Aminomethyl)-3-(oxymethyl)-1-ethylpyrrolidin.

Get analogously to example 8b) of 4-cyan-4-(etoxycarbonyl)-1-ethyl-2-feast of the KAHL PolyGram ZIL G/UV254, eluent: a mixture of complex ethyl ester acetic acid, methanol, cyclohexane and concentrated aqueous ammonia in a volume ratio 68:15:15:2).

C) 3-(Aminomethyl)-3-(methyl bromide)-1-ethylpyrrolidin-dihydrobromide.

Get analogously to example 8b) of 3-(aminomethyl)-3-(oxymethyl)-1-acylpyrrole - DIN and 63% aqueous Hydrobromic acid. Yield 94% of theory. Raw, brownish salt directly, i.e. without purification, is used for the subsequent cyclization.

d) 3-Ethyl-2,6-diazaspiro[3,4]octane.

The solution 149,4 g (to 0.39 mol) 3-(aminomethyl)-3-(methyl bromide)-1-ethylpyrrolidin in 2 l of dioxane gently stirred with a mixture of 130 g (3.25 mol) of sodium hydroxide and 120 ml of water and then stirring for 8 h heated under reflux. After chilling filtered, the aqueous phase of the filtrate is separated and removed from the organic phase under slightly reduced pressure (100 mm RT.CT.) by distillation to remove the solvent. From the residue by distillation in a vacuum created by water-jet pump, get to 15.8 g (29% of theory) of colorless oil, so boiling 83-87aboutC at a pressure of 20 mm RT.article.

P R I m e R 17. 5,11-Dihydro-11-[[6-ethyl-2,6-diazaspiro [3,4]Oct-2-yl] -carbonyl]-6N-pyrido[2,3-b][1,4]enzodiazepin-6-it 6-ethyl-2,6-diazaspiro[3,4]octane with the release of 15% of theory. Colorless crystals with so pl. 221-223about(From acetonitrile).

WITH21H23N5ABOUT2(377,45).

Calculated, %: C 66,83; H 6,14; N 18,55.

Found, %: C 66,77; N 6,32; N 18,32.

P R I m e R 18. 5,11-Dihydro-11-[[6-ethyl-2,6-diazaspiro [3,4]Oct-2-yl] -carbonyl]-9-methyl-6N-pyrido[2,3-b][1,4]benzodiazepine-6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl[2,3-b] [1,4]benzodiazepine-6-it 6-ethyl-2,6-diazaspiro[3,4]octane with the release of 26% of theory. Colorless crystals with so pl. 169-171about(From acetonitrile).

WITH22H25N5ABOUT2(391,48).

Calculated, %: C 67,50; N 6,44. N 17,89.

Found, %: C 67,46; N 6,09; N 17,49.

P R I m e R 19. 5,11-Dihydro-11-[[6-propyl-2,6-diazaspiro[3,4]Oct-2-yl] -carbonyl]-6N-pyrido[ 2,3-b][1,4]benzodiazepine-6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6N-pyrido-[2,3-b][1,4]benzodiazepine-6-it 6-propyl-2,6-diazaspiro[3,4]octane to yield 74% of theory. Colorless crystals with so pl. 208-209about(From acetonitrile).

WITH22H25N5ABOUT2(391,48).

Calculated, %: 67; N 6,44; N 17,89.

Found, %: C 67,40; N To 6.39; N 17,60.

Source benzodiazepine can be obtained as follows.

b) 3-(Aminomethyl)-3-(oxymethyl)-1-propylpyrrolidine.

Get analogously to example 8b) of 4-cyan-4-(etoxycarbonyl)-1-propyl-2-feast - of religion and lithium aluminum hydride to yield 28% of theory. Colorless viscous oil, used without further purification in the next stage.

C) Dihydrobromide 3-(aminomethyl)-3-(methyl bromide)-1-propylpyrrolidine.

Get analogously to example 8b) of 3-(aminomethyl)-3-(oxymethyl)-1-propeller-tolidine and 63% aqueous Hydrobromic acid with a yield of 91% of theory. Brown salt used without purification in the next stage.

g) 6-Propyl-2,6-diazaspiro[3,4]octane.

Analogously to example 16 d) 3-(aminomethyl)-3-(methyl bromide)-1-propylpyrrolidine subjected to interaction with sodium hydroxide, water and dioxane. Obtained after processing of the crude product with a value of RF0.5 (silica gel PolyGram ZIL G/UV254, eluent: a mixture of dichloromethane, methanol, cyclohexane, concentrated aqueous ammonia in a volume ratio of 68:20:10:5) purify by chromatography on a column of Ni - rolein the above compound is obtained in yield of 47% of theory.

P R I m e R 20. 5,11-Dihydro-8-methyl-11-[[6-propyl-2,6-diazaspiro[3,4] Oct-2-yl]-ka - ronil]-6N-pyrido[2,3-b][1,4]benzodiaz - pin 6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6N-pyrido-[2,3-b][1,4]benzodiazepine-6-it 6-propyl-2,6-diazaspiro[3,4] octane to yield 60% of theory. Colorless crystals with so pl. 219-221about(From acetonitrile).

WITH23H27N5ABOUT2(405,50).

Calculated, %: C 68,13; N. Of 6.71; N 17,27.

Found, %: C 68,02; N 6,74; N 17,00.

P R I m e R 21. 5,11-Dihydro-8-ethyl-11-[[6-ethyl-2,6-diazaspiro[3,4] Oct-2-yl]-carbonyl] -6N-pyrido-[2,3-b][1,4]benzodiazepine-6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-ethyl-6N-PI - Rideau[2,3-b] [1,4] benzodiazepine-6-it 6-ethyl-2,6-diazaspiro[3,4] octane with the release of 12% of theory. Colorless crystals with so pl. 190-191about(From acetonitrile) and RF(silica gel PolyGram ZIL G/UV254, eluent: a mixture of dichloromethane, ethyl acetate, methanol, cyclohexane and concentrated ammonia in a volume ratio 62:16,7:10:10:3).

WITH23H27N5ABOUT2(405,50).

Calculated, %: C 68,13; N. Of 6.71; N 17,27.

Found, %: C 67,92; N 6,64; N 17,44.

P R I m e R 22. 5,11-Dihydro-9-methyl-11-[[6-propyl - 2,6-diazaspiro[3,4] Oct--5,11-dihydro-9 - methyl-6N-pyrido[2,3-b] [1,4]benzodiazepine-6-it 6-propyl-2,6-diazaspiro[3,4] octane with the release of 39% of theory. Colorless crystals with so pl. 183-184about(From acetonitrile) and RFof 0.51 (silica gel PolyGram ZIL G/UV254, eluent: a mixture of dichloromethane, ethyl acetate, methanol, cyclohexane and concentrated aqueous ammonia in a volume ratio 63,5:13:11:11:1,5).

WITH23H27N5ABOUT2(405,50).

Calculated, %: C 68,13; N. Of 6.71; N 17,27.

Found, %: C 68,00; N. Of 6.52; N 17,10.

P R I m e R 23. 5,11-Dihydro-8-ethyl-11-[[6-propyl-2,6 - diazaspiro[3,4] Oct-2-yl]-carbonyl]-6N-pyrido[2.3-b][1,4]benzodiaz-pin 6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-ethyl - 6N-pyrido[2,3-b] [1,4] benzodiazepine-6-it 6-propyl-2,6-diazaspiro[3,4] octane with yield 55% of theory. Colorless crystals with so pl. 170-172about(From acetonitrile) and RFof 0.52 (silica gel PolyGram ZIL G/UV254, eluent: a mixture of dichloromethane, ethyl acetate, methanol, cyclohexane and concentrated aqueous ammonia in a volume ratio 63,5:13:11:11:1,5).

WITH24H29N5O2(419,53).

Calculated, %: C 68,71; N 6,97; N 16,69.

Found, %: C 68,90; N 7,18; N 16,72.

P R I m e R 24. 5,11-Dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4]-Oct-2-yl] -carbonyl]-6N-pyrido[2,3-b][1,4]benzodiazepine-6-he .

Get similar primaverii. Colorless crystals with so pl. 251-254about(From dioxane) and RFof 0.3 (silica gel PolyGram ZIL G/UV254, eluent: a mixture of dichloromethane, ethyl acetate, methanol, cyclohexane and concentrated aqueous ammonia in a volume ratio 63,5:13:11:11:1,5).

WITH21H23N5O2(377,45).

Calculated, %: C 66,83; N 6,14; N 18,55.

Found, %: C 66,61; N. Of 6.20; N Is 18.40.

Source benzodiazepine can be obtained, for example, as follows.

a) 2-Acetyl-6-(phenylmethyl)-2,6-diazaspiro[3,4]octane.

In the solution of 70.8 g (0.35 mol) of 6-(phenylmethyl)-2,6-diazaspiro[3,4]octane in 300 ml of ethanol with vigorous stirring add drops of 37.7 ml (0.4 mol) of acetanhydride, and then the resulting mixture was heated under reflux for 3 hours Evaporated in vacuum, alkalinized 20% aqueous sodium lye and exhaustively extracted with simple diethyl ether. The combined ether extracts dried over caustic liquor, the solvent is removed and the residue is distilled in a medium vacuum. Get the desired compound as a colourless oil so Kip. 155-168aboutWith pressure 0,035 mm RT.article The output of 69.3 g (81% of theory).

b) 2-Ethyl-6-(phenylmethyl)-2,6-diazaspiro[3,4]octane.

Get analogian. The desired compound obtained as a colorless oil so Kip. 91-93aboutC at a pressure of 0.2 mm RT.article and RF0.6 (silica gel PolyGram ZIL G/UV254, eluent: a mixture of dichloromethane, methanol, cyclohexane and concentrated aqueous ammonia in a volume ratio of 68:15:15:2). Yield 73% of theory.

a) 2-Ethyl-2,6-diazaspiro[3,4]octane.

Get analogously to example I) by catalytic hydrogenation of 2-ethyl-6-(phenyl-methyl)-2,6-diazaspiro[3,4] OK-tan in the presence of 10% palladium on coal. Get the desired compound as a colourless oil with RFto 0.45 (silica gel PolyGram ZIL G/UV254, eluent: a mixture of dichloromethane, methanol, cyclohexane, ethyl acetate and concentrated aqueous ammonia in a volume ratio 62:10:10:16,7:1,3). Yield 96% of theory.

P R I m e R 25. 5,11-Dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4]Oct-6-yl] -carbonyl]-8-methyl-6N-pyrido[2,3-b][1,4]benzodiazep in 6 he.

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6N-pyrido[2,3-b] [1,4] benzodiazepine-6-it 2-ethyl-2,6-diazaspiro[3,4] octane to yield 61% of theory. Colorless crystals with so pl. 213-215about(From acetonitrile).

WITH22H25N5ABOUT2(391,48).

Calculated, %: C 67,50; N 6,44; N 17,89.

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6N-pyrido-[2,3-b] [1,4]benzodiazepine-6-it 2-ethyl-2,6-diazaspiro[3,4] octane to yield 56% of theory. Colorless crystals with so pl. 251-253about(From acetonitrile).

WITH22H25N5ABOUT2(391,48).

Calculated,%: C 67,50; N 6,44; N 17,89.

Found, %: C 67,32; N. Of 6.49; N 18,31.

P R I m e R 27. 5,11-Dihydro-11-[[6-(2-methylpropyl)-2,6-diazaspiro[3,4] Oct-2-yl]- carbonyl]-6N-pyrido-[2,3-b][1,4]benzodiazepine-6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6N-pyrido- [2,3-b] [1,4] benzodiazepine-6-it 6-(2-methylpropyl-2,6-diazaspiro[3,4] octane with the release of 48% of theory. Colorless crystals with so pl. 199-201about(From acetonitrile) and RFof 0.48 (silica gel PolyGram ZIL G/UV254, eluent: a mixture of dichloromethane, ethyl acetate, methanol, cyclohexane and concentrated ammonia in a volume ratio 63,5:13:11:11:1,5).

WITH23H27N5ABOUT2(405,50).

Calculated, %: C 68,13; N. Of 6.71; N 17,27.

Found, %: C 67,96; N 6,84; N 17,47.

Source benzodiazepine can be obtained as follows.

a) 4-Cyan-4-(etoxycarbonyl)-1-(2-methylpropyl)-2-pyrrolidinone.

Get analogously to example 8A) from the CA yield 74% of theory. Colorless oil c RFto 0.8 (silica gel PolyGram ZIL G/UV254, eluent: a mixture of ethyl acetate and petroleum ether in a volume ratio 1:1).

b) 3-(Aminomethyl)-3-(oxymethyl)-1-(2-methylpropyl)-pyrrolidin.

Get analogously to example 8b) of 4-cyan-4-(etoxycarbonyl)-1-(2-methylpropyl)- 2-pyrrolidinone by reduction with lithium aluminum hydride. Exit 35% of theory. Colorless oil c RFof 0.26 (silica gel PolyGram ZIL G/UV254, eluent: a mixture of dichloromethane, methanol, cyclohexane and concentrated aqueous ammonia in a volume ratio 68:15:15:2).

C) Dihydrobromide 3-(aminomethyl)-3-(methyl bromide)-1-(2-methylpropyl)-pyrroline.

Get analogously to example 8b) of 3-(aminomethyl)-3-oxymethyl-1-(2-methylprop-saws)pyrrolidine and 63% aqueous Hydrobromic acid. Caricabatteria salt used without purification in the subsequent stages.

g) 6-(2-Methylpropyl)-2,6-diazaspiro[3,4]octane.

Get analogously to example 19g) from dihydrobromide 3-(aminomethyl)-3-(methyl bromide)-1-(2-methylpropyl)-pyrrolidine and caustic soda in the presence of water and dioxane to yield 63% of theory. Colorless oil with RFto 0.45 (silica gel PolyGram ZIL G/UV254, eluent: a mixture of dichloromethane, methane 5,11-Dihydro-8-methyl-11-[[6-(2-methylpropyl) -2,6-diazaspiro[3,4]Oct-2-yl]Carboni[1,4]benzodiazepine-6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6N-pyrido[2,3-b] [1,4] benzodiazepine-6 - it 6-(2-methylpropyl)-2,6-diazaspiro[3,4] -octane to yield 52% of theory. Colorless crystals with so pl. 186-188about(From acetonitrile).

WITH24H29N5ABOUT2(419,53).

Calculated, %: C 68,71; N 6,97; N 16,69.

Found, %: C 68,67; N. Of 6.99; N 16,47.

P R I m e R 29. 5,11-D hydro-9-methyl-11-[[6-(2-methylpropyl)- 2,6-diazaspiro[3,4]Oct-2-yl]carbonisation-6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6N-pyrido[2,3-b] [1,4] benzodiazepine-6-it 6-(2-methylpropyl)-2,6-diazaspiro[3,4] octane with the release of 24% of theory. Colorless crystals with so pl. 163-165about(From acetonitrile).

WITH24H29N5ABOUT2(419,53).

Calculated, %: C 68,71; N 6,97; N 16,69.

Found, %: C 68,62; N 6,72; N 16,67.

P R I m e R 30. 6,11-Dihydro-11-[[7-methyl-2,7 - diazaspiro[4,4]non-2-yl] carbonyl]-5H-pyrido[2,3-b][1,4]benzodiazepine-6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido- [2,3-b][1,5]benzodiazepine-5-on and 2-methyl-2,7-diazaspiro[4,4]nonane with yield 84% of theory. Colorless crystals with so pl. 212-214about(From acetonitrile).

WITH21H23N

P R I m e R 31. 6/11-Dihydro-11-[[7-ethyl-2,7 - diazaspiro[4,4]non-2-yl] -carbonyl]-5H-pyrido[2,3-b][1/5] benzodiazepine-6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido-[2,3-b][1,5]benzodiazepine-5-on and 2-ethyl-2,7-diazaspiro[4,4]nonane with yield 68% of theory. Colorless crystals with so pl. 151,0-152,5about(From acetonitrile).

WITH22H25N5ABOUT2(391,48).

Calculated, %: C 67,50; N 6,44; N 17,89.

Found, %: C 67,65; N 6,55; N 18,04.

P R I m e R 32. 6,11-Dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]Oct-2-yl] -carbonyl]-5H-pyrido-[2,3-b][1,5]benzodiazepine-6-he .

Get analogously to example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido-[2,3-b] [1,5]benzodiazepine-5-on and 6-methyl-2,6-diazaspiro[3,4]octane with 38% of theory. Colorless crystals with so pl. 239-241about(From acetonitrile).

WITH20H21N5ABOUT2(363,42).

Calculated, %: C 66,10; N. Of 5.82; N 19,27.

Found, %: C 65,99; N 5,77; N 19,17.

P R I m e R 33. 6,11-Dihydro-11-[[2-methyl-2,6 - diazaspiro[3,4]Oct-6-yl] -carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepine-6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido-[2,3-b] [1,5]benzodiazepine-5-on and 2-methyl-2,6-diazaspiro[3,4]octane to yield 50% of theory. Bescot is="ptx2">

Calculated, %: C 66,10, N Of 5.82; N 19,27.

Found, %: C 65,88; N Between 6.08; N 19,00.

P R I m er 34. 6,11-Dihydro-11-[[6-ethyl-2,6 - diazaspiro[3,4]Oct-2-yl] -carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepine-6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido-[2,3-b][1,5]benzodiazepine-5-on and 6-ethyl-2,6-diazaspiro[3,4]octane with the release of 10% of theory. Colorless crystals with so pl. 196-200about(From acetonitrile) and RFof 0.62 (silica gel PolyGram ZIL G/UV254, eluent: a mixture of dichloromethane, ethyl acetate, methanol, cyclohexane and concentrated aqueous ammonia in a volume ratio 62:16,7:10:10:1,3).

WITH21H23N5ABOUT2(377,45).

Calculated, %: C 66,83; N 6,14; N 18,55.

Found, %: C 66,26; H 6,11; N 18,14.

P R I m e R 35. 6,11-Dihydro-11-[[6-propyl-2,6 - diazaspiro[3,4]Oct-2-yl]-carbonyl]-5H-pyrido-[2,3-b][1,5]benzodiazepine-6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido-[2,3-b] [1,5]benzodiazepine-5-on and 6-propyl-2,6-diazaspiro[3,4]octane in 51% yield of theory. Colorless crystals with so pl. 195-197about(From acetonitrile) and a value of RF0,58 (obtained under the conditions of example 46).

WITH22H25N5ABOUT2(391,48).

Calculated, %: C 67,50; N 6,44; N nil]-5H-pyrido[2,3-b][1,5]benzodiazepine-6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido-[2,3-b] [1,5]-benzodiazepine-5-on and 2-ethyl-2,6-diazaspiro[3,4]octane in an environment of tetrahydrofuran. Yield 61% of theory. Colorless crystals with so pl. 186-189about(From acetonitrile) and RFof 0.32 (silica gel PolyGram ZIL G/UV254, eluent: a mixture of dichloromethane, ethyl acetate, methanol, cyclohexane and concentrated aqueous ammonia in a volume ratio 63,5:13:11:11:1,5).

WITH21H23N5ABOUT2(377,45).

Calculated, %: C 66,83; N 6,14; N 18,55.

Found, %: C 67,00; N 6,17; N 18,73.

P R I m e R 37. 6,11-Dihydro-11-[[6-(2-methylpropyl)- 2,6-diazaspiro[3,4]-Oct-2-yl]carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepine-5-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido [2,3-b] [1,5] benzodiazepine-5-on and 6-(2-methylpropyl)-2,6-diazaspiro[3,4] octane to yield 60% of theory. Colorless crystals with so pl. 187-189about(From acetonitrile).

WITH23H27N5ABOUT2(405,50).

Calculated, %: C 68,13; N. Of 6.71; N 17,27.

Found, %: C 67,95; N 6,77; N 17,47.

P R I m e R 38. 5,10-Dihydro-5-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl] -carbonyl]-11N - dibenzo[b,e][1,4]diazepin-11-he.

Get analogously to example 1 from 5-(chlorocarbonate with so pl. 190about(From acetonitrile).

WITH22H24N4ABOUT2(376,46).

Calculated, %: C 70,19; N To 6.43; N 14,88.

Found, %: C 70,14; N To 6.43; N 14,86.

P R I m e R 39. 4,9-Dihydro-3-methyl-4-[[7-methyl-2,7 - diazaspiro[4,4]non-2-yl]carbonyl]-10H-thieno[3,4-b][1,5]benzodiazepine-6-he.

Get analogously to example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H - thieno[3,4-b][1,5]benzodiazepine-10-she and 2-methyl-2,7-diazepino[4,4] nonane in an environment dichloromethane. Yield: 44% of theory. Colorless crystals with so pl. 213-214about(From acetonitrile).

WITH21H24N4O2S (396,51).

Calculated, %: C 63,61; N 6,10; N 14,13; S 8,09.

Found, %: C 63,30; N Is 6.19; N 14,21; S 7,94.

P R I m e R 40. 4,9-Dihydro-4-[[7-ethyl-2,7-diazaspiro[4,4]non-2-yl] carbonyl]-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepine-10-he.

Get analogously to example 51 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H - thieno[3,4-b][1,5]benzodiazepine-10-she and 2-ethyl-2,7-diazaspiro[4,4] nonane with yield 65% of theory. Colorless crystals with so pl. 215-216about(From acetonitrile).

WITH22H26N4ABOUT2S (410,54).

Calculated, %: 64,36; N 6,38; N 13,65; S 7,81.

Found, %: C 64,28; N 6,33; N 13,87; S To $ 7.91.

P R I m e R 41. 4,9-Dihydro-3-methyl-4-[[6-methyl - 2,6-Diderot-3-methyl-10H - thieno[3,4-b][1,5]benzodiazepine-10-she and 6-methyl-2,6-diazaspiro[3,4] octane with the release of 52% of theory. Colorless crystals with so pl. 200-203about(From acetonitrile).

WITH20H22N4ABOUT2S (382,49).

Calculated, %: C 62,80; N 5,80; N 14,65; S Scored 8.38.

Found, %: C 62,51; N. Of 5.68; N 14,67; S 8,40.

P R I m e R 42. 4,9-Dihydro-3-methyl-4-[[2-methyl - 2,6-diazaspiro[3,4] Oct-6-yl]-carbonyl]-10H-thieno[3/4-b][1,5]benzodiazepine-6 - he.

Get analogously to example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H - thieno[3,4-b][1,5]benzodiazepine-10-she and 2-methyl-2,6-diazaspiro[3,4] octane with the release of 28% of theory. Colorless crystals with so pl. 135-137about(From acetonitrile).

WITH20H22N4ABOUT2S (382,49).

Calculated, %: C 62,80; N 5,80; N 14,65; S Scored 8.38.

Found, %: C 62,62; H Of 5.81; N 14,70; S 8,54.

P R I m e R 43. 4,9-Dihydro-4-[[6-ethyl-2,6-diazaspiro[3,4]Oct-2-yl] carbonyl]-3-methyl - 10H-thieno[3,4-b][1,5]benzodiazepine-10-he.

Get analogously to example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H - thieno[3,4-b][1,5]benzodiazepine-10-she and 6-ethyl-2,6-diazaspiro[3,4] octane with 30% yield of theory. Colorless crystals with so pl. 208-210about(From acetonitrile).

WITH21H24N4ABOUT2S (396,51).

Calculated, %: C 63,61; N 6,10; N 14,13; S 8,09.

Found, %: C 63,35; N. Of 6.25; N 14,32; S 8,19.

P R I m e R 44. 4,9-Digit analogously to example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H - thieno[3,4-b] [1,5] benzodiazepine-10-she and 6-propyl-2,6-diazaspiro[3,4] octane with the release of 44% of theory. Colorless crystals with so pl. 180-181about(From acetonitrile) and RFof 0.54 (silica gel PolyGram ZIL G/UV254, eluent: a mixture of dichloromethane, ethyl acetate, methanol, cyclohexane and concentrated ammonia in a volume ratio 63,5:13:11:11:1,5).

WITH22H26N4O2S (410,54).

Calculated, %: 64,36; N 6,38; N 13,65; S 7,81.

Found, %: C 64,26; N 6.35mm; N 13,64; S 7,71.

P R I m e R 45. 4,9-Dihydro-4-[[2-ethyl-2,6-diazaspiro[3,4] Oct-6-yl]-carbonyl]-3-methyl - 10H-thieno[3,4-b][1,5]benzodiazepine-10-he.

Get analogously to example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H - thieno[3,4-b][1,5]benzodiazepine-10-she and 2-ethyl-2,6-diazaspiro[3,4] octane. Yield: 61% of theory. Colorless crystals with so pl. 216-217about(From acetonitrile) and with a value of RF0,47 (obtained as indicated in example 56).

WITH21H24N4ABOUT2S (396,51).

Calculated, %: C 63,61; N 6,10; N 14,13; S 8,09.

Found, %: C 63,51; N 6,10; N 14,27; S 8,08.

P R I m e R 46. 4,9-Dihydro-3-methyl-4-[[6-(2-methylpropyl) -2,6-diazaspiro[3,4]-Oct-2-yl]carbonyl]-10H-thieno[3/4-b][1,5]benzodiazepine-6-he.

Get analogously to example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H - thieno[3,4-b][1,5]benzodiazepine-10-she and 6-(2-methylpropyl)-2,6-diatas the SUB>H28N4ABOUT2S (424,56).

Calculated, %: C 65,07; N. Of 6.65; N 13,20; S 7,55.

Found, %: C 65,07; N Is 6.61; N 13,30; S 7,42.

P R I m e R 47. 3-Chloro-1-methyl-4-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl] -carbonyl] -1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepine-10-he.

Get analogously to example 1 from 3-chloro-4-(chlorocarbonyl)-1-methyl-1,4,9,10-the - dragedreperen[3,2-b][1,5]benzodiazepine- -10-she and 2-methyl-2,7-diazaspiro[4,4] nonane. Yield 80% of theory. Colorless crystals with so pl. 205-206about(From acetonitrile).

WITH21H24lN5O2(413,92).

Calculated, %: C 60,94; H Of 5.84; Cl To 8.57; N 16,92.

Found, %: C 61,13; N 5,66; CL 8,78; N 17,20.

P R I m e R 48. 1-Methyl-4-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5] benzodiazepine-10-he.

3.5 g (8,46 mol) 3-chloro - a-methyl-4-[[7-methyl-2,7-diazaspiro [4,4]non-2-yl] carbonyl] -1,4,9,10-tetrahydropyrrolo[3/4-b] [1,5]benzodiazepine-6-it is dissolved in 350 ml of hot ethanol, and after adding 3 g of palladium (20%) on the animal angle hydronaut at a temperature of 40aboutC and a hydrogen pressure of 50 bar for 2 hours is Filtered off from the catalyst, the filtrate is concentrated in vacuo, the crystalline hydrochloride is absorbed in 20 ml of water, the resulting solution was alkalinized hydroxide is evaporated, and the obtained residue is recrystallized from n-propanol. Yield 1.1 g (34% of theory). Colorless crystals with so pl. 223-225aboutC.

WITH21H25N5ABOUT2(379,47).

Calculated, %: C 66,47; N 6,64; N 18,46.

Found, %: C 66,43; H 6,84; N 18,44.

P R I m e R 49. 3-Chloro-1-methyl-4-[[6-propyl - 2,6-diazaspiro[3,4]Oct-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo [3/4-b][1,5]benzodiazepine-10-he.

Get analogously to example 1 from 3-chloro-4-(chlorocarbonyl)-1-methyl-1,4,9,10-tet - rahydropyranyl[3,2-b] [1,5]benzodiazepine-10-she and 6-propyl-2,6-diazaspiro[3,4] octane. Exit 51% of theory. Colorless crystals with so pl. 164-165about(From acetonitrile).

WITH22H26ClN5O2(427,94).

Calculated, %: C 61,75; H 6,12; Cl Of 8.28; N 16,37.

Found, %: C 61,48; N 5,99; Cl 8,42; N 16,37.

P R I m e R 50. 3-Chloro-1-methyl-4-[[6-(2-methylpropyl)-2,6-diazaspiro[3,4] -Oct-2-yl] - carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepine-10-he.

Get analogously to example 1 from 3-chloro-4-(chlorocarbonyl)-1-methyl-1,4,9,10-tet - rahydropyranyl[3,2-b][1,5]benzodiazepine-10-she and 6-(2-methylpropyl)-2,6-diazaspiro[3,4] octane. Exit 23% of theory. Colorless crystals with so pl. 163-165about(From acetonitrile).

WITH23H28lN5ABOUT2(441,96).

Get analogously to example 1 from 3-chloro-4-(chlorocarbonyl)-1-methyl-1,4,9,10-the-dragedreperen[3,2-b] [1,5] benzo diazi 6-methyl-2,6-diazaspiro[3,4] octane. Yield 61% of theory. Colorless crystals with melting point 215-217about(From acetonitrile) and RFof 0.7 (silica gel PolyGram ZIL G/UV254, eluent: a mixture of dichloromethane, methanol, cyclohexane and concentrated aqueous ammonia in a volume ratio 68:15:15:2).

WITH20H22ClN5O2(399,88).

Calculated, %: 60,07; N 5,55; Cl 8,87; N 17,51.

Found, %: C 60,13; N 5,39; Cl 9,02; N 17,64.

P R I m e R 52. 5,11-Dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]Oct-2-yl] -carbonyl]-6N-pyrido[2,3-b][1,4]benzodiazepine-6-he.

In a mixture of 22.5 ml of 20% solution of phosgene in toluene, 100 ml of acetonitrile and of 4.75 g (0.045 mol) of anhydrous sodium carbonate in a topical cooling with ice add drops are 5.36 g (0,0425 mol) of 6-methyl-2,6-diazaspiro[3,4]octane. Stirred at room temperature for 60 min, then the reaction mixture are added 9.0 g (0,0428 mol) of 5,11-dihydro-6N-pyrido[2,3-b] [1,4] benzodiazepine-6-she and refluxed for 4 hours, the Hot mixture is filtered, the precipitate washed thoroughly three times with 10 ml of hot acetonitrile and the combined filtrates in vacuo Shuman wand. The resulting set of crystals and mother liquor is served on a suction filter, the obtained crystals are recrystallized from acetonitrile, resulting in a gain of colorless crystals with so pl. 225,5-227,0aboutWith identical obtained according to example 12 of the connection.

The output of 5.4 g (35% of theory).

Similarly receive the following connections:

()-5,11-Dihydro-11-[[7-methyl-2,7-diazaspiro[4,4] non-2-yl]carbonyl] -6N - pyrido[2,3-b][1,4]benzodiazepine-6-it has a melting point 272-274about(From acetonitrile), 5,11-Dihydro-8-methyl-11-[[7-methyl-2,7-diazaspiro[4,4] non-2-yl] carbonyl]-6N-PI Rideau[2,3-b][1,4]benzodiazepine-6-it has a melting point 212-214about(From acetonitrile),

5,11-Dihydro-8-ethyl-11-[[6-methyl-2,6 - diazaspiro[3,4]Oct-2-yl]carbonyl] -6N-pyrido[2,3-b] [1,4]benzodiazepine-6-he is so pl. 215-217about(From acetonitrile), 5,11-Dihydro-8-methyl-11-[[2-methyl - 2,6-diazaspiro[3,4]Oct-6-yl]carbonyl] -6N-pyrido[2,3-b] [1,4] benzodiazepine-6-o n with a melting point 184,0-184,5about(From acetonitrile).

P R I m e R 53. 5,11-Dihydro-11-[[6-methyl-2,6-diazaspiro[3,4] Oct-2-yl] -carbonyl]-6N-pyrido[2,3-b][1,4]benzodiazepine-6-he.

To a suspension of 2.6 g(9.50 mmol) of 11-(chlorocarbonyl)-5,11-dihydro-6N-pyrido[2,3-b] [1,4] benzodiazepine-6-she's in 30 ml of dimethylformamide at comb 10 ml of dimethylformamide. The solution, which is initially transparent, within a few minutes it becomes muddy. Stirred at room temperature for 30 min, then the colorless solid is filtered off by suction and washed thoroughly three times 3 ml of ice-cold ethanol. The obtained colorless monohydrochloride desired compounds dissolved in 10 ml of water, alkalinized with saturated aqueous potassium carbonate solution until an alkaline reaction, and then filtered. The obtained solid is washed thoroughly with water, then dried in a vacuum drying Cabinet at a temperature of 50aboutWith over propeciacom of Diaspora.Recrystallized from acetonitrile and again dried in vacuum. Get 2,35 g (68% of theory) of colourless crystals with a melting point 225,5-227,0aboutWith identical obtained according to example 12 of the connection.

P R I m e R 54. 1-Methyl-4-[[7-methyl-2,7-diazaspiro[4,4] non-2-yl]-carbonyl]-1,4,9,10-tetrahydropyrrolo [3/2-b][1,5]benzodiazepine-10-he.

as 4.02 g (9,71 mmol) 3-chloro-1-methyl-4-[[7-methyl-2,7-diazaspiro[4,4] non-2-yl] carbonyl] -1,4,9,10-tetrahydropyrrolo[3,2-b] [1,5]Ben zodiazepine-10-she dissolved in a mixture of 5 ml of 85% formic acid and 25 ml of dimethylformamide and after adding 0.5 g of 10%aqueous palladium on active coal is heated obratnye another 6 h and after adding another 4,0 ml of formic acid and 0.8 g of 10% palladium on coal again heated under reflux for 8 hours The hot mixture is filtered, the filtrate evaporated in vacuo, and the residue purified by chromatography on a column (silica gel, eluent: a mixture of dichloromethane complex ethyl ester acetic acid, methanol and concentrated ammonia in a volume ratio of 3.5:1,5:0,46:0,06). The output of 1.14 g (31% of theory) of colorless crystals with so pl. 223-225aboutWith (n-propanol), is identical with that obtained according to example 60 compound.

P R I m e R 55. 1-Methyl-4-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3/2-b][1,5]benzodiazepine-10-he.

The mixture 4,14 g (0.01 mol) 3-chloro-4-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl] carbonyl]-1,4,9,10-tetrahydropyrrolo [3/2-b][1,5]benzodiazepine-10-he. zodiazepine-10-she, and 83.3 mg (0.001 mol) of a mixture of Tris-(o-tolyl)phosphine and palladium acetate in the ratio of 2:1 as the catalyst, 2,025 g (0,044 mol) of formic acid and 5,77 g (0,057 mol) of triethylamine in 200 ml of tetrahydrofuran at a temperature of 100aboutC for 40 h heated in nitrogen atmosphere in an autoclave. The mixture is filtered and evaporated in vacuo, the residue is alkalinized by adding sodium liquor and exhaustively extracted with dichloromethane. The organic phase is dried and evaporated and purified by chromatography on a column according to example 66. Obtain 1.44 g (38% of theory) of the funeral.

P R I m e R 56. 5,11-Dihydro-8,9-dimethyl-11-[[6-methyl-2,6-diazaspiro[3,4]Oct-2-yl]-carbonyl]-6N-pyrido [2/3-b][1,4]benzodiazepine-6-he.

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8,9-dimethyl-6N-pyrido[2,3-b] [1,4] benzodiazepine-6-it 6-methyl-2,6-diazaspiro[3,4]octane. Exit 59% of theory. Colorless crystals with so pl. 247-249oC.

WITH22H25N5ABOUT2(391,48).

Calculated, %: C 67,50; N 6,44; N 17,89.

Found, %: C 67,25; N. Of 6.52; N 18,10.

P R I m e R 57. Hydrochloride 5,11-dihydro-8,9-dimethyl-4-[[2-ethyl-2,6-diazaspiro- [3,4]-Oct-6-yl]carbonyl]-6N-pyrido[2,3-b][1,4]- benzodiazepine-6-it.

3,01 g (0,00998 mol) of 11-(chlorocarbonyl)-5,11-dihydro-8,9-dimethyl-6N-pyrido[2,3-b] [1,4]benzodiazepine-6-she, 1.4 g (0,00998 mol) 2-ethyl-2,6-diazaspiro[3,4] octane and 100 ml of anhydrous acetonitrile, stirring, heated at a temperature of 60aboutC for 2 hours Released after cooling, a colorless, crystalline precipitate is filtered by suction and recrystallized from dry boiling ethanol.

Yield 2.3 g (52% of theory) of colorless crystals with so pl. 268-270aboutC.

WITH23H27N5O2.HCl (441,97).

Calculated, %: C 62,51; N 6,39; Cl 8,02; N 15,85.

Found, %: C 62,38; H 6,34; Cl 8,16; N 15,61.

Get analogously to example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8,9 - dimethyl-6N-pyrido[2,3-b] [1,4] benzodiazepine-6-it 2-methyl-2,6-diazaspiro[3,4]octane. Yield 30% of theory. Colorless crystals with so pl. 292-294aboutC.

WITH22H25N5ABOUT2(391,48).

Calculated, %: C 67,50; N 6,44; N 17,89.

Found, %: C 66,91; N To 6.39; N 17,71.

P R I m e R 59. 1-methyl-4-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-1,4,9,10-tetrahydro pyrrolo[3,2-b][1,5]benzodia-pin-10-he.

The mixture 10,235 g (0,033 mol) 3-chloro-4-(chlorocarbonyl)-1-methyl-1,4,9,10 - tetrahydropyrrolo[3,2-b] [1,5] benzodiazepine 10-he/ 4.3 g level (0.041 mol) of anhydrous sodium carbonate, 5,61 g (0.04 mol) of 2-methyl-2,7-diazaspiro[4,4] nonane and 100 ml of acetonitrile is stirred for 30 minutes at a temperature of 50aboutC. Then the solvent is distilled off in vacuum, the remaining viscous residue absorb in 400 ml of ethanol and after addition of 5 g of palladium on animal corner (20% ) hydronaut at a pressure of 50 bar and a temperature of 40aboutWith before the end of the hydrogen absorption. Filtered from the catalyst, the filtrate is concentrated under vacuum, the remaining residue is alkalinized sodium lye and extracted with dichloromethane. The combined extracts dried over sodium sulfate and evaporated, the residue paracrystal is identical with that obtained according to example 48 with the product.

P R I m e R 60. 5,11-Dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl] carbonyl - 6N-pyrido[2,3-b][1,4]benzodiazepin-6-he.

The mixture 3,763 g (0.01 mol) of 5,11-dihydro-11-[(4-nitrophenoxy)carbonyl]-6-pyrido -[2,3-b] [1,4] benzodiazepine-6-she, 1.3 g (0.012 mol) of anhydrous sodium carbonate, 1.7 g (0.012 mol) of 2-methyl-2,7-diazaspiro[4,4]nonane and 100 ml of acetonitrile is boiled for 10 hours under reflux. The solvent is then distilled off in vacuo, the remaining viscous residue is processed and purified analogously to example 1. Receive 1.5 g (40% of theory) of colorless crystals with so pl. 271-274aboutC. the Product is identical with the obtained analogously to example 1 product.

P R I m e R 61. 5,11-Dihydro-11-[[6-methyl-2,6-diazaspiro[3,4] Oct-2-yl] -carbonyl]-6N-pyrido[2,3-b][1,4]benzodiazepine-6-he.

To a solution of 1.2 g (9,51 mmol) 6-methyl-2,6-diazaspiro[3,4]octane in 50 ml of anhydrous dimethylformamide add to 0.23 g (9,58 mmol) of sodium hydride and stirred at room temperature until the evolution of hydrogen. After adding portions of 2.6 g (9.50 mmol) of 11-(chlorocarbonyl)-5,11-dihydro-6N-pyrido[2,3-b] [1,4] be-enzodiazepin-6-it is stirred for further 30 min at room temperature, then the mixture under vacuum to remove the solvent, the residue suspended in WEEE 50aboutAnd then recrystallized from hot acetonitrile. Obtain 2.5 g (72% of theory) of colorless crystals with so pl. 224-226aboutC. the Product is identical with the obtained analogously to example 12 product.

P R I m e R 62. 5,11-Dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl-carbonyl]-6N-pyrido[2,3-b][1,4]benzodiazepine-6-he.

When an external ice cooling a mixture of 22.5 ml of 20% solution of phosgene and toluene, 100 ml of acetonitrile and of 4.75 g (0.045 mol) of anhydrous sodium carbonate, add drops 5,96 g (0,0425 mol) of 2-methyl-2,7-diazaspiro-[4,4] nonane. Stirred for 60 min at room temperature, to the reaction solution was added 9.0 g (0,0428 mol) of 5,11-dihydro-6N-pyrido[2,3-b] [1,4]benzodi - azepine-6-it and then refluxed for 4 hours of Boiling, the mixture is filtered, the precipitate is thoroughly washed 3 times, each time 10 ml of hot acetonitrile, and United combined filtrates in vacuo. The remaining residue is processed and purified analogously to example 1.

1. Derivatives of diazepinone General formula

< / BR>
where

< / BR>
one of the divalent radicals a - g

< / BR>
R3< / BR>
S

< / BR>
X - band =CH or nitrogen, when

< / BR>
- the residue of formula (a),

R - neasured or C1-C4-alkyl;

R3is hydrogen or chlorine; R4and R5the same or different, is hydrogen or C1-C4-alkyl;

m, p=1;

n, o=1 or 2

or mixtures of their isomers, or their salts.

2. Derivatives of diazepinone under item 1, the mixture of their isomers and their physiologically tolerated acid additive salts with pharmacological activity.

1. Derivatives of diazepinone General formula

< / BR>
where

< / BR>
one of the divalent radicals a - g

< / BR>
R3< / BR>
S

< / BR>
X - band =CH or nitrogen, when

< / BR>
- the residue of formula (a),

R is unbranched or branched C1-C4-alkyl;

R1and R2the same or different, is hydrogen or C1-C4-alkyl;

R3is hydrogen or chlorine; R4and R5the same or different, is hydrogen or C1-C4-alkyl;

m, p=1;

n, o=1 or 2

or mixtures of their isomers, or their salts.

2. Derivatives of diazepinone under item 1, the mixture of their isomers and their physiologically tolerated acid additive salts with pharmacological activity.

 

Same patents:

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2-(1-methyl-2-(3,4-fullero[60]pyrrolidinyl)phenol of the formula (1): Method involves interaction of fullerene[60] with 2-[(dimethylamino)methyl]phenol of the general formula: (R-CH2-N(CH3)2) wherein R means in taken in the mole ratio C60 : R-CH2-N-(CH3)2 = 0.01:(0.01-0.011) in the presence of Cp2TiCl2 as catalyst taken in the amount 15-25 mole% relatively to fullerene[60] in argon atmosphere, in toluene medium as a solvent, at temperature 140-160°C for 2-4 h. Method provides preparing the novel compound with the yield 78-86%. Compound of the formula (1) can be used as a chelating agent, sorbent and biologically active substance.

EFFECT: improved method of synthesis.

1 tbl, 1 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to novel substituted derivatives of cyclohexane of the formula (I): wherein U means a free electron pair; V means a simple bond, -CH2-, -CH=CH-, -CH=CH-CH2-O-, -C≡C-; W means -COO, -CSO or -SO2; m and n mean independently of one another numbers from 0 to 4; m + n = 0-7; A1 means hydrogen atom (H), lower alkyl, hydroxy-(lower)-alkyl or lower alkenyl; A2 means pyrrolyl, pyrimidinyl, optionally substituted (lower)-alkyl or lower alkyl optionally substituted with R2; or A1 and A2 are bound to form ring; -A1-A2- means lower alkylene optionally substituted with R2 wherein one group -CH2- in -A1-A2- can be optionally replaced for -NR3 or oxygen atom (O); A3, A4, A5, A6, A7 and A8 mean H; R9 means H, lower alkyl; R10 means (lower)-alkyl, phenyl wherein phenyl can be substituted with 1-3 substitutes chosen independently from the group comprising halogen atom, -CF3, (lower)-alkyl; p means 0, 1; R2 means H; R3 means H, lower alkyl, and their pharmaceutically acceptable salts. Compounds of the formula (I) possess the inhibitory effect on activity of enzyme oxidosqualene lanosterol cyclase and can be used in pharmaceutical composition. Also, method relates to a method for treatment and/or prophylaxis of hyperlipemia, artheriosclerosis, hypercholesterolemia and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

27 cl, 9 sch, 10 tbl, 43 ex

FIELD: organic chemistry of natural compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): , wherein each R1, R2 and R3 means independently hydrogen atom or (C1-C4)-alkyl; R4 means (C1-C12)-alkyl optionally comprising from one to three substitutes chosen from group including hydroxy-group, (C1-C12)-alkoxycarbonyl, carbamoyl, (C2-C7)-alkenyl, (C6-C10)-aryl optionally comprising from one to three substitutes chosen from group including halogen atom, (C1-C12)-alkyl, (C1-C12)-alkoxy-, hydroxy-, (C1-C12)-alkylcarbonylamino-group, (C6-C10)-aryl-(C1-C12)-alkyl wherein aryl group comprises optionally from one to three substitutes chosen from group comprising halogen atom, (C1-C12)-alkyl, (C1-C12)-alkoxy-group, heterocyclyl-(C1-C12)-alkyl; R5 means hydroxy-, (C3-C7)-cycloalkylamino-group optionally substituted with phenyl, (C6-C10)-arylamino-, (C6-C10)-aryl-(C1-C4)-alkylamino-group optionally comprising from one to three substitutes chosen from group comprising sulfamoyl, (C1-C12)-alkyl, (C1-C12)-alkoxy-, hydroxy-group, heterocyclyl or benzyl, (C1-C4)-alkoxy-, benzhydrazino-group, heterocyclyl optionally comprising from one to three substitutes chosen from group including benzyl, benzhydryl, heterocyclylamino-group wherein heterocyclyl means saturated, unsaturated or aromatic monovalent cyclic radical comprising from 1 to 3 heteroatoms chosen from nitrogen (N), oxygen (O) and sulfur (S) atoms, or to their combination; n means a whole number 0, 1 or 2. Compounds of the formula (I) elicit anti-proliferative activity that allows their using in pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

30 cl, 1 tbl, 69 ex

FIELD: organic chemistry, chemical technology, biochemistry, medicine.

SUBSTANCE: invention relates to novel isoquinoline compounds of the general formula (I): wherein R1 represents hydrogen atom, halogen atom or alkyl; Y is absent or represents alkylene chain comprising from 1 to 8 carbon atoms wherein arbitrary carbon atom can comprise hydroxyl group as a substitute; R represents the following formula (II): wherein X represents -CH or nitrogen atom under condition that if Y absent in the formula (I) then X must represent -CH; W represents -CH or nitrogen atom under condition that if X represents -CH then W must represents nitrogen atom; s represents a whole number from 1 to 3; t represents a whole number from 1 to 3; if R3 represents hydrogen atom or alkyl then R2 represents hydrogen atom, alkyl, hydroxyl group or hydroxyalkyl, and R2' represents hydroxyl group or hydroxyalkyl, and if R3 represents hydroxyalkyl then R2 and R2' represent hydrogen atom. Also, invention relates to their optically active forms, pharmaceutically acceptable salts, aqueous adducts, hydrates and solvates. Compounds of the formula (I) elicit inhibitory effect on activity of poly-(ADP-ribose)-polymerase and can be used in prophylaxis of diseases associated with cerebral infarction.

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

40 cl, 4 tbl, 55 ex

FIELD: medicine, biochemistry.

SUBSTANCE: invention describes compounds that inhibit function of NS3-protease encoded by hepatitis C virus.

EFFECT: valuable medicinal properties of inhibitors.

6 cl, 2 tbl, 472 ex

FIELD: medicine; pharmacology.

SUBSTANCE: present group of inventions is referred to biologically active compounds characterised by the formula (I), their pharmaceutically acceptable salts, solvates and stereoisomers, the pharmaceutical compositions containing specified compounds, method of obtaining, the intermediate compounds used for obtaining of compounds of the formula (I), and methods of treatment of the painful conditions mediated by muscarine receptors with use of specified compounds where R4 represents hydrogen; R5 is chosen from C1-6alkyl, C3-6cycloalkyl and -CH2-R8; where the alkyle group is unessentially replaced by or 1-5 fluorine-substituents; R8 is chosen from C3-6cycloalkyl or phenyl; a, b and with are 0; d is 1; e is 8 or 9.

EFFECT: obtaining of new biologically active compounds for treatment of some diseases.

10 cl, 27 ex, 15 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

or

or to their pharmaceutically acceptable salts, where ring A, R2, R3, R4 and X are as defined in the description. The disclosed compounds are useful as 11βHSD1 inhibitor. The invention also relates to a pharmaceutical composition, an agent for treating or preventing pathology related to glucocorticoids, a 11βHSD1 inhibitor containing the disclosed compound or its pharmaceutically acceptable salt, and use of the disclosed compounds.

EFFECT: compounds are highly effective.

40 cl, 48 tbl, 191 ex

FIELD: chemistry.

SUBSTANCE: invention refers to novel compound with inhibition effect on FAAH enzyme, corresponding to the general formula (I) where variables m, n, X, R1 and R2, R3, R4 and Y variables take values provided in the claim; to method of compound obtainment, and to compound application in therapy, and to pharmaceutical composition including compound of the formula (I).

EFFECT: improved method.

12 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to enantioselective synthesis of intermediate compounds, specifically (-)-trans-(1-methyl-3-(2,4,6-trimethoxyphenyl) pyrrolidin-2-yl)methanol of formula A ; involving steps on which (-)-trans-1-methyl-5-oxo-3-(2,4,6-trimethoxyphenyl)pyrrolidin-2-carboxylic acid of formula E is treated with a reducing agent in a solvent. These compounds are used in synthesis of the (+)-trans enantiomer of pyrrolidines substituted with flavones, having formula 1 , or salts thereof which are cycline-dependant kinase inhibitors and can be used to treat proliferative disorders such as cancer.

EFFECT: method allows efficient large-scale synthesis of the compound by excluding the racemate splitting technique.

15 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: novel compounds have general formula (1), or salts thereof:

, where R10 is cyclohexyl optionally substituted with a substitute selected from group A1, or cyclohexenyl optionally substituted with a substitute selected from group A1, R30, R31 and R32 denote hydrogen, R40 denotes C1-10alkyl optionally substituted with a substitute selected from group D1, n equals 0 or 1, X1 denotes nitrogen, and R20, R21, R22 and R23 independently denote hydrogen, except when R20, R21, R22 and R23 all denote hydrogen, C1-6 alkylthio optionally substituted with a substitute selected from group F1, C2-6 alkoxycarbonyl, C1-6 alkyl substituted with a substitute selected from group W1, C1-6 alkyl substituted with a substitute selected from group K1, C1-6 alkoxy substituted with a substitute selected from group W1, a 5-6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or S atoms, substituted with a substitute selected from W1, a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or S atoms, substituted with a substitute selected from group V1, pyridyl substituted with a substitute selected from group W1, phenyl,optionally substituted with a substitute selected from group W1, C2-7 alkenyl, optionally substituted with a substitute selected from group W1, C2-7 alkynyl optionally substituted with a substitute selected from group W1, a 3-6-member cycloalkyl optionally substituted with a substitute selected from group W1, a 5-6-member cyclalkenyl optionally substituted with a substitute selected from group W1, NR1XR2X, -CO-R1X, -CO-NR1XR2X, -NR1X-CO-R2X, -SO2-R3X or -O-SO2-R3X,where R1X is hydrogen or a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N and O atoms, R2X is a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or O atoms, and R3X is C1-6 alkyl optionally substituted with a substitute selected from group F1; or R21 and R22 together form a ring selected from group Z1, where group A1 consists of C1-6 alkyl, group D1 consists of cyclopropyl and tetrahydropyranyl, group F1 consists of a halogen, group W consists of hydroxyl, C2-7 alkoxyalkyl, phenoxy, C2-7 alkoxycarbonyl, -NR6XR7X and -CO-NR6XR7X, where R6X and R7X independently denote hydrogen or C1-6 alkyl, group V1 consists of oxo (=O) and ethylenedioxy(-O-CH2CH2-O-), where ethylenedioxy is allowable only if a compound of two rings with one common atom forms together with a substituted 6-member heterocyclic group, group K1 consists of a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or O atoms, group U1 consists of carboxyl, C1-6 alkoxy, phenyl and CO-NR8XR9X, where R8X and R9X denote hydrogen, and group Z1 consists of

, where R1Z denotes C1-6 alkyl or benzyl. The invention also pertains to a medicinal agent, a cell adhesion or cell infiltration inhibitor, as well as to therapeutic or prophylactic agents.

EFFECT: obtaining novel biologically active compounds having cell adhesion or cell infiltration inhibiting activity.

20 cl, 147 ex, 3 tbl

FIELD: organic chemistry, medicine, hormones, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that act as agonists of peptide hormone vasopressin. Invention describes the compound of the general formula (1) or its pharmaceutically acceptable salt wherein V represents a covalent bond or NH; X is taken among CH2, oxygen atom (O) and N-alkyl; Z represents sulfur atom (S) or -CH=CH-; R1 and R2 are taken independently among hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom and alkyl; R3 is taken among hydroxyl group (OH), O-alkyl and NR4R5 wherein each R4 and R5 represents independently hydrogen atom (H) or alkyl, or both represent -(CH2)q-; p = 0, 1, 2, 3 or 4; q = 4 or 5. Also, invention describes a pharmaceutical composition eliciting agonistic activity with respect to V2-receptors, a method for treatment of enuresis, nicturia and diabetes insipidus, method for control of enuresis and a method for treatment of enuresis and a method for treatment of diseases associated with damage in blood coagulability. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 31 ex

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

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

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

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new substituted 7-sulfonyl-benzo[b][1,4]diazepines of the general formula (1) , their pharmaceutically acceptable salts, N-oxides or hydrates that elicit properties of a protein kinase inhibitor that can be used in pharmaceutical industry. In compounds of the general formula (1) R1 and R2 represent independently of one another hydrogen atom, inert substitute, optionally substituted carboxymethyl group, optionally substituted carbamoylmethyl group; R3 and R4 represent independently of one another hydrogen atom or inert substituted, or R3 and R4 in common with carbon atom to which they are bound form optionally substituted (C3-C7)-cycloalkyl, optionally substituted (C4-C7)-heterocyclyl or optionally substituted ethylene group; R5 represents optionally substituted amino-group or optionally substituted azaheterocyclyl. Also, invention relates to sulfochlorides of the general formula (2) that are used for preparing compound of the formula (1), and to methods for preparing compounds of general formulae (1) and (2). Also, invention relates to a pharmaceutical composition in form of tablets, capsules or injection formulations placed into pharmaceutically acceptable package, and to the focused library for the search of biologically active compound-leaders.

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

7 cl, 2 sch, 1 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of dihydrobenzo[b][1,4]diazepine-2-one. Invention describes derivatives of dihydrobenzo[b][1,4]diazepine-2-one of the general formula (I): wherein X means a simple bond or ethynediyl group wherein if X means a simple bond then R1 means cyano-group, halogen atom, lower alkyl, (C1-C3)-cycloalkyl, (lower)-alkoxyl, fluoro-(lower)-alkyl or it means pyrrole-1-yl that may be free or substituted with 1-3 substitutes taken among the group consisting of fluorine, chlorine atom, cyano-group, -(CH2)1-4-hydroxyl group, fluoro-(lower)-alkyl, lower alkyl, -(CH2)n-(lower)-alkoxyl, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'', hydroxy-(lower)-alkoxyl and -(CH2)n-COR'R'', or it means free phenyl or phenyl substituted with one or two substitutes taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, fluoro-(lower)-alkoxyl and cyano-group; if X means ethynediyl group then R1 means free phenyl or phenyl substituted with 1-3 substituted taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (C3-C6)-cycloalkyl, (lower)-alkoxyl and fluoro-(lower)-alkoxyl; R2 means -NR'R'', fluoro-(lower)-alkoxyl or 3-oxopiperazin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl wherein their rings are substituted optionally with R''; R' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl or 2-(lower)-alkoxy-(lower)-alkyl; R'' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl, 2-(lower)-alkoxy-(lower)-alkyl, -(CH2)2-4-di-(lower)-alkylamino-group, -(CH2)2-4-morpholinyl, -(CH2)2-4-pyrrolidinyl, -(CH2)2-4-piperidinyl or 3-hydroxy-(lower)-alkyl; Y means -CH= or =N-; R3 means halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, cyano-group, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'' or it means optionally substituted 5-membered aromatic heterocycle that can be substituted with halogen atom, fluoro-(lower)-alkyl, fluoro-(lower)-alkoxyl, cyano-group, -(CH2)n-NR'R'', -(CH2)n-C(O)OR'', -(CH2)n-C(O)NR'R'', -(CH2)n-SO2NR'R'', -(CH2)n-C(NH2)=NR'', hydroxyl, (lower)-alkoxyl, (lower)-alkylthio-group or lower alkyl that is optionally substituted with fluorine atom, hydroxyl, (lower)-alkoxyl, cyano-group or carbamoyloxy-group; n means 0, 1, 2, 3 or 4, and their pharmaceutically acceptable additive salts. Also, invention describes a medicinal agent as antagonist of mGlu receptors of group II based on compounds of the formula (I). Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

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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