The method of obtaining triazolo/4,3/ /1,4/benzodiazepines

 

(57) Abstract:

Usage: in the chemistry of heterocyclic substances, in particular in the synthesis of derivatives triazolo-[4,3-a] (1,4) benzodiazepines with PAF-antagonistic action. The inventive product is triazolo-[4,3-a](1,4)-benzodiazepines of General formula I, where X is the radical: -CH=CH -, or S; R' is lower alkyl or trifluoromethyl; R2is chlorine or fluorine; R3radical; R4- -(CH2)nWith a triple bond, or R5-O-CH2-C triple bond; R4is phenyl or mono-, di-, or tricyclic 5-7-membered heterocyclic radical containing as heteroatoms of oxygen or sulfur, and/or 1-3-nitrogen atom, is not - or substituted lower alkoxy, oxo, actigraphy or chlorine; R5is phenyl or pyridyl. Reagent 1: the corresponding (R3) - unsubstituted triazolo-[4,3-a](1,4)-diazepin. Reagent 2: Z-substituted acetylene, where Z is a radical of the formula: R4-(CH2)nor R5-O-CH2. Reaction conditions: inert solvent at a temperature from room temperature to about 100oIn the presence of palladium catalyst. table 2.

and

The invention relates to a method for producing new derivatives triazolo-[4,3-a](1,4) benzodiazepines General form is R or fluorine;

R3the radical of the formula R4-(CH2)nC or R5-O-CH2-C_C-, where n is the integer 0, 1 or 2;

R4phenyl or mono-, di-, or tricyclic 5-7-membered heterocyclic radical containing as heteroatoms 0 or S, and/or 1-3 nitrogen atom, unsubstituted or substituted lower alkoxy, oxo, actigraphy or chlorine,

R5phenyl or pyridylethyl provided that when n is 0, the radical R4must be attached through a carbon to carbon link, and that R5attached via a carbon to oxygen connection with RAG-antagonistic properties.

Known benzo - and cyanothioacetamide with RAG-antagonistic action (1).

The purpose of the invention to obtain new derivatives triazolo-[4,3-a](1,4) benzodiazepines with improved properties is achieved by the described method of production thereof, which consists in the fact that the compound of General formula II

II,

where R1and R2have the above values, and I bromine or iodine,

subjected to interaction with the compound of General formula III:

Z CCH III,

where Z is a radical of the formula R4-(CH2)nor R5-O-CH2- where R4and R5have given flax formula III is carried out in an inert solvent; preferred solvents are acetonitrile, tetrahydrofuran and dimethylformamide at a temperature ranging from room temperature to about 100oWith, depending on the nature of Y and X in the formula II, in the presence of a palladium catalyst, such as dichloride or diacetate bis(triphenylphosphine)palladium, not necessarily in the presence of catalytic amount of copper iodide (I) and excess proton acceptor, such as triethylamine.

The resulting reaction product of the formula I can be isolated by conventional methods such as chromatography or crystallization.

Educt of the formula II are known compounds or can be obtained by analogy with the published methods. This also applies to acetylene compounds of the formula III. Acetylene formula III in which n is 1, is conveniently obtained by alkylation of the corresponding heterocyclic system using bromide propargyl, following known methods. The compounds of formula III in which n is 2, can be similarly obtained by alkylation of the corresponding heterocyclic system, for example, by using 4-titolare-1-butyne.

It is noticed that when the connection of the EP instead of the racemic mixture as the starting materials.

The compounds of formula I can form salts when joining acids with strong inorganic or organic acids. Thus, they form pharmaceutically acceptable salts with the connection acids with pharmaceutically acceptable organic and inorganic acids, for example, using galoidvodorodnykh acids, such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, other inorganic acids such as sulfuric acid, phosphoric acid, perchloric acid or the like, alkyl - and monoarylamino acids, such as econsultancy acid, toluensulfonate acid, benzosulfonate acid or the like. Pharmaceutically unacceptable salts when joining acids of the compounds of formula I can be converted into pharmaceutically acceptable salts by connection of acid through normal metabolic reactions by which pharmaceutical unacceptable anion is replaced by a pharmaceutically acceptable anion, or otherwise by neutralizing pharmaceutically acceptable salt accession acids, and then the interaction of the thus obtained free base with a reagent, leading to farm as antagonists of platelet activating factor (PAF) and are therefore useful for painful conditions characterized by an excess of platelet activating factor, or the prevention and treatment of cardiovascular diseases, pulmonary diseases, immunological disorders, shocks or graft rejections.

The useful activity of compounds of the formula I can be demonstrated by the following procedures.

Quantitative analysis of binding

a) Analysis

Quantitative analysis of binding was carried out in plastic microcentrifuge tubes with a volume of 400 μl (Bachman) containing 50 µl of the oil mixture of 2 parts of Silicone AR200 (Serva) and 1 part of a Silicone fluid (Arthur H. Thom). In a test tube were added to the buffer, standards or equivalents (total volume 150 μl). Radiolabelled 3H-PAF (50 ml) then add in a test tube. The reaction begins to proceed by adding 50 μl of platelet dogs (2 x 107platelets). The tubes are sealed by caps, turning several times to mix and incubate for 10 minutes at room temperature. Platelets were separated from the incubation mixture by centrifugation for 1 min in a centrifuge of the type of the Bachman Microfuge Century, the Upper end of the microcentrifuge tubes rashidinia the l) add, and the radioactivity in the samples determined using a liquid scintillation counter type Bachman 158100 associated with the recorder of the type Tehran. Data are being processed through your home computer system. Or radioactivity determined using a liquid scintillation counter type Searle mark III, associated with the microprocessor of the Iso Data. The results are presented in tables I and II.

b) obtaining a platelet count

Blood is collected from the shot and panettiruling dogs in plastic centrifuge tubes of 50 ml volume containing 3.8% sodium citrate as anticoagulant (1 volume of citrate/9 volumes of blood). Red blood cells are removed by centrifugation for 15 minutes at 600 rpm (100-125 g) at room temperature. Aliquot part of pooled plasma, platelet-rich (SWEAT), lay to determine the number of blood corpuscles, and the remaining portion is acidified to pH 6.5 with 0.15 M citric acid. The precipitate platelets in vitro receive after a 10-minute centrifugation at 2000 rpm (1000 g) at room temperature. Washed platelets obtained by personenbezogene sediment platelets in vitro once with phosphate-saline, Supermicro above, and then personenbezogene platelets in 0.1% bovine serum albumin in phosphate-saline buffer solution (BSA-PBS). Aliquot part of washed platelets counted. Platelets are used for quantitative determinations of binding, dilute to a concentration of 2 x 107platelets (test tube 4 x 108platelets/ml). The platelet count is done using royko cell-Crete 921 (Royco Cell-Crit 921).

Test bronchostenosis induced by platelet activating factor (PAF)

Male Guinea pigs (Line Hartley weighing 400-500 g) anestesiologica of urethane (2 g/kg, intraperitoneally). The trachea of each animal kanyoro, and supply of Guinea pigs apparatus artificial respiration using a Harvard respirator for small animals-rodents (3,0 CC shock (systolic) blood volume, 40 breaths per min). Tracheal pressure recorded from canula introduced into the trachea and connected to a pressure sensor Statema.

Jugular vein onuliruetsya for input connections. Spontaneous breathing is served with succinylcholine (1.2 mg/kg, intravenously), input for 2 minutes until the internal injection of platelet activating factor (PAF). Because propanolol to infection propranolol (0.1 mg/kg, intravenous).

For intravenous test Guinea pig subjected to a one-minute pre-treatment (introduction) propranolol at a dose of 0.1 mg/kg intravenously. The test compound is introduced with a one-minute preliminary introduction to intravenous infection with PAF. Then the animal becomes infected through intravenous dose of 1 μg/kg of PAF and the change in tracheal pressure is measured.

For oral testing procedure involves a one-hour period prior administration of the test compound, administered through the oral tube for enteral feeding. Propranolol or succinylcholine and PAF are administered intravenously, and the change in tracheal pressure is measured.

The change in tracheal pressure is determined by subtracting the steady state baseline achieved after administration of succinylcholine, from a peak bronchostenosis that appear after infection with PAF. The average value is calculated for each test compound and compared to the mean value of the control animals in order to obtain the percentage of inhibition of bronchostenosis. The standard error is calculated as the standard error of the mean.

what is in this description, includes racemates and enantiomers, when one or more asymmetric carbon atoms present in the compound of formula I.

The compounds of formula I and pharmaceutically acceptable salts can be introduced using techniques well known in the field. Thus, the compound of formula I or its salt can be administered either separately or together with other medications, such as antihistamines, inhibitors neurotransmitter release, methyl-quantieme, beta-agonists (substances with affinity to the receptor) or asthma steroids, such as prednisone and prednisolone, orally, parenterale, premonicion (rectally or by inhalation, for example in the form of an aerosol, microdispensing powder or spray solution. For oral input, they can be introduced in the form of tablets or capsules, for example in a mixture with talc, starch, milk sugar or other inert ingredients, that is, with pharmaceutically acceptable carriers, or in the form of aqueous solutions, suspensions, elixirs or aqueous alcoholic solutions, for example in a mixture with sugar or other sweetening agents, flavouring agents, dyes, Z. and can be introduced in solution or in suspension, for example in the form of an aqueous solution or a solution of peanut butter or suspension with the use of inert fillers and carriers commonly used for this input method. For parenterale introduction they can be put into solution or suspension, for example in the form of an aqueous solution or a solution of peanut butter, or suspension with the use of inert fillers and carriers commonly used for this method of administration. For administration as aerosols, they can be dissolved in a suitable pharmaceutically acceptable solvent, for example ethanol or a combination of miscible solvents, or can be mixed with pharmaceutically acceptable jet fuel (propellant). Such aerosol compositions are packaged for use in a sealed vessel, fitted with an aerosol valve, suitable for releasing the liquefied composition. Preferably, the aerosol valve is a measuring valve, i.e. a valve which when exposed allocates a predetermined effective dose aerosol composition.

In practice, the dose of a compound of formula I or salt thereof which must be entered, and frequency of administration must depend on the effectiveness of the method of introduction, as well as the severity of the condition, the age of mammals, which must be cured, etc. Oral dose of the compounds of formula I or salts thereof, intended for use in practice of the invention are in the range from about 0.5 to about 1000 mg per day, preferably from about 0.5 to about 100 mg per day, preferably from about 0.5 to about 10 mg per day, either as a single dose or in divided doses.

In addition, since the compounds of formula I of the invention in which R2different from hydrogen, possess an asymmetric center, they are usually obtained in the form of racemic mixtures. It should be clear that when R6and R7are heterocyclic group which may have one or more asymmetric centers, the resulting racemates, enantiomers and diastereoisomers also form part of the present invention. The separation of such racemates on the optically active isomers can be carried out by known methods. Some racemic mixture can be subjected to precipitation in the form of eutectic and can then be separated. Chemical separation is, however, preferred. In this method, the diastereomers education is provided by the diastereomers are separated by selective crystallization or chromatography and converted into corresponding optical isomer. Thus, the invention encompasses the racemates of the compounds of formula I, as well as their optically active isomers (enantiomers).

The examples which follow illustrate the invention. All temperatures are presented in degrees Celsius, unless otherwise indicated.

Example 1

a) a Mixture of 31 g (of 0.08 mole) of 1,3-dihydro-5-(2-forfinal)-7-iodide-1,4-benzodiazepine-2(2H)-it (link G. F. Fiel and L. A. Sternbach, Swiss patent N 561706, may 1975, and N 562222, April 1975), 20 g (of 0.09 mole) of pentasulfide phosphate, 20 g of sodium bicarbonate and 300 ml of diglyme stirred and heated to 80-85oC for 3 hours. The reaction mixture is then poured onto ice, diluted with water. After stirring for 30 minutes the solid yellow reaction product is filtered off, washed with water, 2-propanol and a small amount of ether. He was sucked away dry in the funnel and additionally dried under vacuum to obtain 26 g (80%) of 1,3-dihydro-5-(2-forfinal)-7-iodide-1,4-benzodiazepine-2(2H)-thione, which is further converted as described below. A pure substance is obtained by recrystallization from a mixture of tetrahydrofuran and ethanol, it has so pl. 242-244oC.

b) To a suspension of 8 g of the above thione in 40 ml of 2-propanol in 100 ml of tetrahydrofuran is added through 20 g of silica gel, using tetrahydrofuran for elution. The filtrate is evaporated and the residue crystallized from ether to obtain 6.7 g (83%) of 5-(2-forfinal)-2-hydrazino-7-iodide-3H-1,4-benzodiazepine with so pl. 179-181oC.

C) a Mixture of 4 g of the above hydrazine powered connections, 20 ml teeterboro ether octoxynol acid, 30 ml of toluene and 4 g of silica gel was heated to boiling under reflux with stirring for 3 hours. The silica gel is filtered off and washed with ethanol. The filtrate is evaporated, and the residue is crystallized from a mixture of methylene chloride and ethyl acetate to obtain 3.9 g (92%) of 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4]-triazolo[4,3-a] (1,4)-benzod - azepine with so pl. 235-238oC.

g) a Mixture of 1.68 g (4 mmole) 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4]-triazolo -[4,3-a] (1,4)-benzodiazepine, 0.88 g (4.8 mmole) P-propargylamine, 2 ml of triethylamine, 0.36 g of triphenylphosphine, and 0.08 g of copper iodide (I) and 40 ml of dimethylformamide is stirred and Tegaserod with slow current of argon for 15 minutes. At this point add 0.12 g of palladium acetate, and the mixture is stirred under argon for 16 hours at room temperature. The reaction mixture is divided into parts between 200 ml of methylene chloride and 100 ml of a saturated aqueous solution of BIC and, at the end of the azeotrope with xylene. The crude reaction product chromatographic over 120 g of silica gel (Merck, 70-230 mesh) using 5 vol. ethanol in methylene chloride. Purified fractions of the reaction product are combined and evaporated, and the residue is crystallized from ethyl acetate to obtain 1.6 g(84%) 2-{ 3-[6-(2-forfinal)-1-methyl-4H-[1,2,4] -triazolo -[4,3-a](1,4)-benzodiazepine-8-yl]-2-PROPYNYL}-1H-isoindole-1,3(2H)-dione with so pl. 253-255oC.

Example 2.

a) 15 ml monochloride iodine (21 g) are added to a solution of 23 g (0.1 mole) of (2-AMINOPHENYL)-(2-chlorophenyl)-methanol (link E. Peeder and L. H. Sternbach, U.S. patent N 3371085, February 1968) in 500 ml of methylene chloride, cooled to -60oC. After stirring with cooling for 5 hours the cooling bath is removed and the temperature of the reaction mixture will reach the 0oC. Followed by addition of 300 ml of an aqueous solution of sodium bisulfate two-phase system is stirred for 10 minutes. The organic phase is separated, dried over sodium sulfate and evaporated. The residue is crystallized from a mixture of ether and hexane, to obtain 20 g (56%) of 2-amino-5-itfinal)-(2-chlorophenyl)methanone with so pl. 120-122oC.

b) To a solution of 52 g (0,145 mole) 2-amino-5-itfinal)-(2-chlorophenyl)methanone 300 ml chloride At 10% aqueous sodium carbonate solution (150 ml), and a two-phase system is stirred under cooling for 30 minutes. The organic layer was separated, washed with water and dried over sodium sulfate. The solution is filtered and evaporated. Crystallization of the residue from a mixture of methylene chloride and ether to give 61 g (90%) of 2-bromo-N-[2-(2-chlorobenzoyl)-4-itfinal]ndimethylacetamide with so pl. 150-152oC. a Solution of 50 g of this substance in 1 liter of methylene chloride is added to 800 ml of liquid ammonia, cooling with dry ice. After boiling under reflux for 16 hours before cooling off to allow ammonia to evaporate. The remaining solution is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is dissolved in 1 liter of ethanol, and the solution is heated to boiling point under reflux for 30 minutes after adding 15 ml of acetic acid. The crystals which separated from the cooled reaction mixture is collected to obtain 38 g (89%) of 5-(2-chlorophenyl)-1,3-dihydro-7-iodide-2H-1,4-benzodiazepine-2-it, which melts at 260-262oAfter recrystallization from a mixture of tetrahydrofuran and ethanol.

C) a Solution of 15.7 g (0,04 mole) 5-(2-chlorophenyl)-1,3-dihydro-7-iodide-2H-1,4-benzodiazepine-2-it in 350 ml of tetrahydrofuran is cooled to -30ooC. Then add to 6.6 ml of diethyl-chlorophosphate, and the mixture is stirred at this temperature for an additional 30 minutes. After adding 3.4 g acetyl-hydrazine stirring without cooling continued for 1 hour and add 150 ml of n-butanol. The tetrahydrofuran is distilled off from the reaction mixture over a 45 minute period. The remainder is divided into parts between water and toluene. The organic phase is washed with brine, dried over sodium sulfate and evaporated down to a small volume. Precipitated crystals are collected to obtain 14 g of a crude reaction product, which is purified by chromatography over 250 g of silica gel using 5 vol. ethanol in methylene chloride. Purified fractions are collected and evaporated. Crystallization from a mixture of tetrafauna and ethanol gives 8.5 g (49% ) of 6-(2-chlorophenyl)-8-iodine-1-methyl-4H-[1,2,4] -triazolo -[4,3-a] (1,4)-benzodiazepine with so pl. 290-292oC.

g) Reaction of 6-(2-chlorophenyl)-8-iodine-1-methyl-4H-[1,2,4]-triazolo -[4,3-a] (1,4)-benzodiazepine N-propargylamine as described in example 1G, gives the target hemihydrate 2-{3-[6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]-triazolo-[4,3-a] (1,4) -benzodiazepine-8-yl] -2-PROPYNYL}-1H-isoindol-1,3-(2H)-dione, which is purified by chromatography and crystallized from a mixture of methanol and atilas g of 5-(2-forfinal)-7-iodine-2-hydrazino-7-iodide-4H-1,4-benzodiazepine (see example 1B), 5 ml teeterboro ether orthopropionate acid and 10 ml of xylene is heated to boiling under reflux for 1 hour. The solvent was partially evaporated, and the residue was diluted with hexane. Precipitated crystals are collected and recrystallized from a mixture of methanol and ethyl acetate to obtain 1,05 g (97%) of 1-ethyl-6-(2-forfinal)-8-iodide-4H-[1,2,4]-triazolo-[4,3-a](1,4) -benzodiazepine with so pl. 209-211oC.

b) a Mixture of 435 mg (1 mmole) of 1-ethyl-6-(2-forfinal)-8-iodide-4H-[1,2,4]-triazolo-[4,3-a] (1,4) -benzodiazepine, 220 mg of N-propargylamine, 80 mg of triphenylphosphine, 20 mg of copper iodide (I), 0.5 ml of triethylamine and 10 ml of dimethylformamide is stirred and Tegaserod current of argon for 10 minutes. Then add 30 mg of palladium acetate, and stirring under argon continue for 48 hours. The reaction mixture is divided into parts between methylene chloride and saturated aqueous sodium bicarbonate. The organic phase is dried and evaporated under reduced pressure, at the end of the azeotrope with xylene. The remainder chromatographic over 30 g of silica gel (Merck 70-230 mesh) using 5 vol. ethanol in methylene chloride. Crystallization of the combined purified fractions from ethyl acetate gives 0,41 g hemihydrate 2-{3-[1-ethyl-6-(2-LASS="ptx2">

Example 4.

6-(2-Chlorophenyl)-8-iodine-1-methyl-4H-[1,2,4] -triazolo-[4,3-a(1,4) -benzodiazepine subjected to interaction with 1-(2-PROPYNYL)-1H-indole-2,3-Diana (link A. Lindguist, P. Lagerstrom and R. Dahlbom //Acta pharm. Suecica, 1972, 9, 99), as described in example 3b. The crude reaction product is purified by chromatography over 40-fold amount of silica gel using 5 vol. ethanol in methylene chloride. Crystallization from ethyl acetate gives yellow crystals 1-{ 3-[6-(2-chlorophenyl)-1-methyl-4H-[1,2,4] -triazolo-[4,3-a] (1,4) -benzodiazepine-8-yl] -2-PROPYNYL} -1H-indole-2,3-dione with so pl. 210-212oC. These crystals contain according to microanalysis and the PMR spectrum of 0.25 molar quantity of ethyl acetate.

Example 5.

6-(2-Chlorophenyl)-8-iodine-1-methyl-4H-[1,2,4] -triazolo -[4,3-a](1,4)-benzodiazepine subjected to interaction with 2-(2-propylen)-1H-Benz(de) isoquinoline-1,3-(2H)-dione as described in example 3b. The crude reaction product chromatographic over 40-fold amount of silica gel using 4 about. ethanol in methylene chloride for elution. Crystallization from a mixture of methylene chloride and ether and recrystallization from a mixture of tetrahydrofuran and ethanol to give 2-{3-[6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]-triazolo-[4,3-a](1,4) -benzodiazepine-8-yl] -2-PROPYNYL}-1H-Benz(de) isoquinoline-1,3(2H)-dione in the analysis.

Acetylene component of the reaction was obtained as follows: 6.2 g (by 0.055 mole) of tert-butoxide potassium are added to a solution of 9.9 g (0.05 mole) of naphthalimide in 50 ml of dimethylformamide, cooled to -20oC. After stirring under cooling for 1 hour, add 5 ml (by 0.055 mole) of propargyl bromide in 20 ml of dimethylformamide, and the mixture is left to warm to room temperature. The mixture is then heated to 45oC for 45 minutes. After cooling, add 15 ml of glacial acetic acid, and the reaction product is precipitated by adding water. The solids are collected and recrystallized from ethyl acetate to obtain 10 g (84%) of colorless crystals of 2-(2-PROPYNYL)-1H-Benz(de) isoquinoline-1,3(2H)-dione with so pl. 235-237oC.

Example 6.

6-(2-Chlorophenyl)-8-iodine-1-methyl-4H-[1,2,4] -triazolo -[4,3-a](1,4)-benzodiazepine subjected to interaction with 1-(2-PROPYNYL)-1H-benzimidazole (link I. I. Popov, P. C. Tkachenko, A. M. Simonov //Chemistry of heterocyclic. compounds, 1973, 551), as described in example 3b. The reaction product produce by using chromatography over 40-fold amount of silica gel using 5 vol. ethanol in methylene chloride. Crystallization from ethanol gives hemihydrate 8-[3-(1H-benzimidazole-1-yl)-1-impregnated is>the. Analytical and spectroscopic data show the presence of hemihydrate.

Example 7.

The reaction of 6-(2-chlorophenyl)-8-iodine-1-methyl-4H-[1,2,4]-triazolo-[4,3-a](1,4) -benzodiazepine 3-(2-PROPYNYL)-2,3-dihydro-1,3-benzoxazol-2-one (reference A. Lindqvist, etc. //Acta pharm. Suecica, 1972, 9, 99) gives, after chromatography on a 40-fold amount of silica gel using 3 about. ethanol in methylene chloride and crystallization from ethanol in colourless crystals of hydrate 3-{ 3-[6-(2-chlorophenyl)-1-methyl-4H-[1,2,4] -triazolo-[4,3-a] (1,4) -benzodiazepine-8-yl]-2-PROPYNYL}-2,3-dihydro-1,3-benzoxazol-2-she's so square 158-160oC.

Example 8.

6-(2-Chlorophenyl)-8-iodine-1-methyl-4H-[1,2,4] -triazolo -[4,3-a](1,4)-benzodiazepine subjected to interaction with 1,3-dihydro-1-(2-PROPYNYL)-2H-indol-2-ion (link A. Lindqvist, etc. //Pharm Suecica, Acta, 1972, 9, 99), as described in example 3b. The reaction product is isolated and purified using chromatography on a 40-fold amount of silica gel using 5 vol. ethanol in methylene chloride. Crystallization from ethanol gives 1-{3-[6-(2-chlorophenyl)-1-methyl-4H-[1,2,4] -triazolo-[4,3-a](1,4) -benzodiazepine-8-yl]-2-PROPYNYL}-1,3-dihydro-2H-indol-2-he is so pl. 141-143oWith containing of 0.33 mol of ethanol and of 0.66 mole of water.

Example 9.

A mixture of 0.84 g (2 mmole) 6-(is on, 90 mg of triphenylphosphine, 20 mg modestou copper (I), 1 ml of triethylamine and 20 ml of dimethylformamide Tegaserod slow current of argon for 15 minutes. Then add 30 mg of palladium acetate, and the mixture is stirred under argon for 5 hours at room temperature. The reaction mixture is divided into parts between methylene chloride and saturated aqueous sodium bicarbonate. The organic phase is dried and evaporated, and the residue chromatographic over 40 g of silica gel using 5 vol. ethanol in methylene chloride for elution. Crystallization of the purified fractions from a mixture of methanol and ethyl acetate gives 1-{3-[6-(2-forfinal)-1-methyl-4H-[1,2,4]-triazolo-[4,3-a] (1,4) -benzodiazepine-8-yl]-2-PROPYNYL}-Benz(cd) indol-2(1H)-it is in the form of light yellow crystals with so pl. 224-226oC.

The original acetylene compound was prepared as follows: to a solution 8,46 g (5 mmole) benzo-(cd)-indole-2(1H)-she's in 100 ml of dimethylformamide type of 6.17 g (by 0.055 mole) of tert-butoxide potassium. After stirring for 10 minutes at room temperature add to 4.9 ml (by 0.055 mole) of methyl propargyl, and the mixture is stirred for 1 hour at room temperature. The reaction mixture is acidified with acetic acid and separated into parts between chloride METI isout from a mixture of tetrahydrofuran and ethanol, to obtain 8 g (77%) of 1-(2-PROPYNYL)-benzo-(cd)-indole-2(1H)-she's so square 183-186oC. the Compound is recrystallized twice for the analysis of a mixture of methylene chloride and ethyl acetate, it has so pl. 185-187oC.

Example 10.

The reaction 0,84 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4]-triazolo -[4,3-a] (1,4)-benzodiazepine from 0.53 g (2.6 mmole) of 4-(2-PROPYNYL)-2H-1,4-benzothiazin-3(4H)-it (link R. N. Prasad and K. Tietje //Can. J. Chem. 1966, 44, 1247), as described in example 9, gives, after chromatographic purification (5% ethanol in methylene chloride on silica gel and crystallization from ethyl acetate, 0.5 g (51%) of yellowish crystals of 4-{3-6-(2-forfinal)-1-methyl-4H-(1,2,4)-triazolo-[4,3-a] (1,4) -benzodiazepine-8-yl]-2-PROPYNYL}-2H-1,4-benzothiazin-3(4H)is it so pl. 203-206oC. These crystals contain according to the PMR spectrum and analysis 0,166 molar quantity of ethyl acetate.

Example 11.

4-{3-[6-(2-Forfinal)-1-methyl-4H-[1,2,4]-triazolo-[4,3-a](1,4) -benzodiazepine-8-yl]-2-PROPYNYL}-2H-1,4-benzothiazin-3(4H)-he will receive a similar way, using the reaction mix 0.84 g of 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4]-triazolo -[4,3-a](1,4)-benzodiazepine 4-(2-PROPYNYL)-2H-1,4-benzothiazin-3(4H)-one (reference A. Lindqvist, etc. //Acta Pharm Surceca, 1972, 9, 99), as described in example 9. The reaction product is isolated and PTS is impressive with so pl. 238-240oC. These crystals contain 0,166 mol of ethyl acetate according to the spectral and analytical data.

Example 12.

The reaction 0.84 g (2 mmole) 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4]-triazolo -[4,3-a] (1,4)-benzodiazepine with 0,48 g (2.6 mmole) of 3-(2-PROPYNYL)-4(3H)-hintline (link J. Maillard and other //Chimie There, 1967, 3, 202), as described in example 9, gives 0.6 g (59%) not quite white reaction product, kristallicheskogo of ethyl acetate. Crystals 3-{3-[6-(2-forfinal)-1-methyl-4H-[1,2,4] -triazolo-[4,3-a](1,4) -benzodiazepine-8-yl]-2-PROPYNYL}-4(3H)-hintline with so pl. 199-201oContain 1 mol of water and 0,166 molar quantity of ethyl acetate.

Example 13.

3-{ 3-[6-(2-Forfinal)-1-methyl-4H-[1,2,4] -triazolo-[4,3-a](1,4) -benzodiazepine-8-yl]-2-PROPYNYL}-2-methyl-4(3H)-hintline get a reaction mix 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4]-triazolo-[4,3-a] (1,4)-benzodiazepine-2-methyl-3-(2-PROPYNYL)-4(3H)-hinazolinam (link B. Danielsson, L. Rkanbern and B. Alerman //Acta Pharm. Suecia, 1969, 6, 379), as described in example 9. He was isolated from 57% yield and crystallized from ethyl acetate, so pl. 241-244oWith decomposition. The crystals contain 0,66 molar amount of water.

Example 14.

The reaction of 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4] -triazolo -[4,3-a] (1,4)-benzodiazepine with 2,3-e khromatograficheskoi cleaning, as described in example 9, and crystallization from ethyl acetate, colorless crystals 2-{3-[6-(2-forfinal)-1-methyl-4H-[1,2,4] -triazolo-[4,3-a](1,4) -benzodiazepine-8-yl] -2-PROPYNYL} -2,3-dihydro-1H-isoindole-1-she's so square 165-168oC. According to the spectral and analytical data of these crystals containing 0.5 molar amount of water and traces of ethyl acetate.

Example 15.

Racemic 2,3-dihydro-2-{ 3-[6-(2-forfinal)-1-methyl-4H-[1,2,4]-triazolo -[4,3-a](1,4)-benzodiazepine-8-yl]-2-PROPYNYL}-3-methoxy-1H-isoindole-1-he will receive as described in example 1G, by reacting 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4] -triazolo -[4,3-a](1,4)-benzodiazepine with racemic 2,3-dihydro-3-methoxy-2-(2-propyl)-1H-isoindole-1-one. The reaction product is not obtained in the crystalline state and was characterized by a spectroscope. To analyze the connection is subjected to precipitation from tetrahydrofuran by adding hexane and the resulting Amory powder is dried under vacuum. NMR (CDCl3): 2,64 (singlet, 3, CH3), 2,96 (singlet, 3 OMe), 4,1 (d, e) and 5,54 (d, e) (AB-system, J 7 Hz, CH2) and 4.2 (d, e) and 4,88 (d, e) (AB-system, J 9 Hz, CH2propinyl), 6,07 (singlet, 1, C3-H) and 6.9-8.0 (multiplet, 11, aromatic H) M. D.

Acetylene component reaction poluchat to stand at room temperature overnight. The reagent is evaporated azeotrope with toluene under reduced pressure. The residue is dissolved in 20 ml of methanol, and the solution is treated with 5 ml of triethylamine. After heating on the steam bath for 5 minutes, the mixture is evaporated, and the residue is divided into parts between methylene chloride and saturated aqueous sodium bicarbonate. The organic layer is separated, dried and evaporated. The residue is crystallized from a mixture of ether and hexane to obtain 0.8 g of racemic 2,3-dihydro-3-methoxy-2-(2-PROPYNYL)-1H-isoindole-1-it is in the form of colorless crystals with so pl. 85-87oC.

Starting material was obtained as follows: a mixture of 10 g of N-propargylamine and 2 g of sodium borohydride in 100 ml of ethanol is heated on a steam bath for 15 minutes with stirring. The resulting solution concentrated under reduced pressure to one-third volume, and the reaction product is crystallized by addition of ice and saturated sodium bicarbonate solution. Precipitated crystals of racemic 2,3-dihydro-3-methoxy-2-(2-PROPYNYL)-1H-isoindole-1-it is collected by filtration, washed with water and sucked dry. After drying under vacuum, these crystals are so pl. 157-159oC.

Example 16.

2-{ 3-[6-(2-F. the hunger as described in example 9, the reaction mix 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4]-triazolo-[4,3-a](1,4) -benzodiazepine 2-(2-PROPYNYL)-1,2,4-triazolo-[4,3-a] -pyridine-3(2H)-one. The reaction product is purified by chromatography in the usual manner and crystallized from a mixture of ethyl acetate and ethanol. Recrystallization from ethanol gives pale yellow crystals with so pl. 170-173oC. These crystals contain 0,66 molar amount of water.

Target acetylene was prepared as follows: to a solution of 3.25 g (2.4 mmole) 1,2,4-triazolo-[4,3-a] -pyridine-3(2H)-she's in 75 ml of dimethylformamide added 3 g (2.6 mmole) of tert-butoxide potassium. After stirring under nitrogen for 15 minutes add 2.35 ml (2.6 mmole) of methyl propargyl, and stirring at room temperature continued for 1 hour. The solvent is evaporated under reduced pressure, at the end of the azeotrope with xylene. The residue is extracted with methylene chloride, and the solution is evaporated. Chromatographic purification of the residue on silica gel (5% ethanol in methylene chloride) and crystallization of the purified fractions from methanol to give 1.7 g of colorless crystals of 2-(2-PROPYNYL)-1,2,4-triazolo-[4,3-a]-pyridine-3(2H)-she's so square 126-128oC.

Example 17.

6-(2-Forfinal)-1-methyl-8-[3-(shimodate 6-(2-forfinal)-1-methyl-8-iodine-1-methyl-4H-[1,2,4]-triazolo-[4,3-a](1,4)-benzodiazepine-1-(2-PROPYNYL)-1H-indazole (link Century. P. Tkachenko, I. I. Perov, A. M. Simonov and Y. C. Medvedev //Chemistry of heterocyclic. connect. 1975, 11, 1542). Chromatographic selected reaction product is crystallized from ethyl acetate to obtain yellow crystals with so pl. 148-151oC.

Example 18.

The reaction mix 6-(2-forfinal)-1-methyl-8-iodine-1-methyl-4H-[1,2,4]-triazolo- [4,3-a] (1,4)-benzodiazepine with 1,3-dihydro-1-(2-PROPYNYL)-1H-indol-2-one (reference A. Lindqvist, etc. //Acta pharm. Suecica, 1971, 9, 99), as described in example 9, gives colorless crystals 1-1-{3-[6-(2-forfinal)-1-methyl-4H-[1,2,4]-triazolo-[4,3-a](1,4) -benzodiazepine-8-yl]-2-PROPYNYL} -1,3-dihydro-2H-indol-2-he-hydrate of ethyl acetate, which have so pl. 233-235oC.

Example 19.

Hemihydrate 1,1-dioxi 2-{ 3-[6-(2-forfinal) -1-methyl-4H-[1,2,4]-triazolo-[4,3-a] (1,4)-benzodiazepine-8-yl] -2-PROPYNYL} -1,2-benzisothiazol-3(2H)-get it in accordance with the method of example 9 by reacting 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4] -triazolo-[4,3-a](1,4)-benzo - diazepine with 1,1-dioxide of 2-(2-PROPYNYL)-1,2-benzisothiazol-3(2H)-it (link R. Granger and J. Giraux, French patent N 1273867, February 1962; S. A. 57, 7285, 1963). The reaction product is isolated and purified by chromatography, and crystallized from a mixture of methylene chloride and ethyl acetate to obtain colorless crystals with so pl. 4,3-a](1,4)-benzo - diazepine with 2-(2-PROPYNYL)-tetrahydro-1H-pyrrolo-[1,2-C] imidazole-1,3(2H)-dione, under conditions described in example 9, gives, after chromatographic purification and crystallization from ethanol not quite white crystals of hemihydrate 2-{3-[6-(2-forfinal)-1-methyl-4H-[1,2,4]-triazolo-[4,3-a] (1,4)-benzo - diazepin-8-yl] -2-PROPYNYL}-tetrahydro-1H-pyrrolo-[1,2-C]-imidazol -1,3 (2H)-dione, with so pl. 158-161oC.

Acetylene component of the reaction was obtained as follows: 1,23 g (11 mmol) of tert-butoxide potassium are added to a solution of 1.4 g (10 mmol) tetrahydro-1H-pyrrolo-[1,2-C] imidazole-1,3(2H)-dione (1-Proline-as) (link T. Suzuki, K. Igerushi, K. Hase and T. K. Tuzimura //Agr.Bid Chem, 1973, 37, 411) in 20 ml of dimethylformamide. After stirring for 10 minutes at room temperature add 1 ml (11 mmol) of methyl propargyl, and stirring under nitrogen was continued for 2 hours. The reaction mixture is acidified with acetic acid and evaporated under reduced pressure. The residue is converted into a slurry with methylene chloride and filtered. The filtrate is evaporated, and the residue chromatographic over 45 g of silica gel using 5 vol. ethanol in methylene chloride. The purified fractions are combined and evaporated to obtain 2-(2-PROPYNYL)-tetrahydro-1H-pyrrolo-[1,2-C] imidazole-1,3(2H)-dione as a colourless viscous oil. NMR (CDCl3): 1,72 (multiplet, 1, C6-N), 1,9-2, multiplet, 1, C5-N), 4,11 (double doublet, 1, J 4 Hz and 3.5, WITH7(H) to 4.23 (doublet, 2, J 1.5 Hz, CH2) memorial plaques

Example 21.

2-{3-[6-(2-forfinal)-1-methyl-4H-[1,2,4]-triazolo-[4,3-a](1,4) -benzodiazepine-8-yl]-2-PROPYNYL}-3A,4,7,7-tetrahydro-1H-imida-1,3 -(2H)-dione get the reaction of 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4]-triazolo-[4,3-a] (1,4) -benzodiazepine with N-propargyl-tetrahydropyrimido (link W. E. Hahm and A. Sokolowsica //Soc. Sci. Acta Chim. 1974, 18, 187), following the procedure described in example 1. The reaction product highlight chromatography and crystallized from ethanol to obtain colorless crystals with so pl. 259-261oC. According to the analytical data of these crystals contain 0,33 molar amount of water.

Example 22.

The reaction mix 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4]-triazolo-[4,3-a] (1,4) -benzodiazepine with 3,4-dihydro-4-methyl-1-2-PROPYNYL)-1H-1,4-benzodiazepine-2,5-dione as described in example 9, gives, after chromatography and crystallization from etilatsetata colorless crystals 1-{3-[6-(2-forfinal)-1-methyl-4H-[1,2,4] -triazolo-[4,3-a] (1,4) -benzodiazepine-8-yl-2-PROPYNYL} -2,4-dihydro-4-methylbenzamide-2,5-dione with so pl. 179-182oC. the Crystals contain according to the analytical and NMR data of 0.16 mol of etilatsetata and of 0.66 mole of water.

Required Acero-4-methyl-1H-1,4-benzodiazepine-2,5(2H)-dione (reference M. Uskokavis and W. Wenner, U.S. patent N 3261828, July, 1966), 3.4 g of barium oxide and 100 ml of dimethylformamide. After stirring at room temperature for 2 hours, the reaction mixture was divided into parts between water and methylene chloride. The organic phase is separated, washed with water, dried and evaporated. The residue is dissolved in ethyl acetate, and the reaction product is crystallized by addition of hexane to obtain 3,4-dihydro-4-methyl-1-(2-PROPYNYL)-1H-1,4-benzodiazepin-2,5(2H)-dione as colorless crystals with so pl. 148-150oC.

Example 23.

The reaction mix 6-(2-chlorophenyl)-8-iodine-1-methyl-4H-[1,2,4]-triazolo-[4,3-a] (1,4) -benzodiazepine-1-(3-pyridyloxy)-2-propyne (link J. Bruhn, J. Zcindely, H. Chmid and G. Frater //Helv Chim. Acta. 1978, 61, 2542), as described in example 1 gives, after chromatography and crystallization from a mixture of ethanol and ether, colorless crystals of 6-(2-chlorophenyl)-1-methyl-8-[3-(3-pyridyloxy)-1-PROPYNYL] -4H -[1,2,4] -triazolo-[4,3-a](1,4)-benzodiazepine with so pl. 128-130oC. These crystals contain 0,66 molar amount of water according to the analytical data.

Example 24.

6-(2-Chlorophenyl)-1-methyl-8-(3-phenoxy-1-PROPYNYL)-4H -[1,2,4]-triazolo-[4,3-a](1,4)-benzodiazepine is obtained by reaction of a combination of 6-(2-chlorophenyl)-8-iodine-1-methyl-4H-[1,2,4] -triazolo-[4,3-a](1,4) -benzo is ethyl acetate to give colorless crystals with so pl. 160-162oC.

Example 25.

a) a Solution of 54.8 g of 5-(2-chlorophenyl)-1,3-dihydro-2H-thieno-[2,3-e](1,4)-diazepin-2-she (patent of Nireland N 7203730, November 1972, Hoffman-La Roche & Comp. AH, Washell) in 350 ml of acetic acid and 350 ml of methanol is treated with 64,4 g monochloride iodine and 16.2 g of sodium acetate. The mixture is stirred for 15 minutes at room temperature. Then add a solution of 65 g of sodium bisulfite in 350 ml of water, and stirring is continued for 10 minutes. The mixture is neutralized by adding 500 ml of concentrated ammonia and 1 kg of ice. Precipitating the reaction product is filtered off and washed with water and ethanol. Recrystallization from a mixture of tetrahydrofuran and ethanol gives white crystals of 5-(2-chlorophenyl)-1,3-dihydro-7-iodide-2H-thieno-[2,3-e](1,4) -diazepin-2-she's so square 229-231oC.

b) a Mixture of 70 g of 5-(2-chlorophenyl)-1,3-dihydro-7-iodide-2H-thieno-[2,3-e](1,4) -diazepin-2-it, 43,3 g pentasulfide phosphorus, 45 g of sodium bicarbonate and 700 ml of diglyme stirred and heated to 70-80oC for 2 hours. After cooling to room temperature the mixture of water and crushed ice added, and stirring is continued for 15 minutes. Precipitated 5-(2-chlorophenyl)-1,3-dihydro-7-iodide-2H-thieno-[2,3-e] (phenyl)-1,3-dihydro-7-iodide-2H-thieno-[2,3-e](1,4) -diazepin-2-thione, 650 ml of tetrahydrofuran and 65 ml of hydrazine was stirred at room temperature for 30 minutes. The solvent is evaporated under reduced pressure, and the residue is stirred together with 275 ml of methylene chloride and 275 ml of water for 15 minutes. Precipitated crystalline substance is filtered off and washed with water and ether. The crude reaction product 5-(2-chlorophenyl)-2-hydrazino-7-iodide-2H-thieno-[2,3-e](1,4)-diazepin unite with 375 ml of ethyl acetate, 170 ml teeterboro ether octoxynol acid and a few crystals of para-toluensulfonate acid, and the mixture is heated on a steam bath for 30 minutes. The reaction product crystallizes during this process and is collected after cooling. Recrystallization from a mixture of methylene chloride and ethanol gives colorless crystals of 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo-[4,3-a](1,4)-diazepine with so pl. 254-256oC.

g) a Mixture of 0.88 g (2 mmole) of 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo-[4,3-a](1,4)-diazepine, 565 mg (2.4 mmole) of 2-(2-PROPYNYL)-1H-benzo-(de) isoquinoline-1,3(2H)-dione, 1 ml of triethylamine, 20 mg of copper iodide (I), 90 mg of triphenylphosphine and 20 ml dimethylformamide Tegaserod slow current of argon for 15 minutes. Then add 30 mg of acetate Pavia shows almost complete reaction after 5 hours. The reaction mixture is divided into parts between methylene chloride and saturated aqueous sodium bicarbonate. The organic layer is separated, dried over sodium sulfate and evaporated under reduced pressure, at the end of the azeotrope with xylene to remove residual dimethylformamide. The remainder chromatographic over 40 g of silica gel using 5 vol. ethanol in methylene chloride for elution. The purified fractions are combined and evaporated. Crystallization from a mixture of methanol and ethylacetate gives 0,58 g(53%) 2-{3-[4-(2-chlorophenyl)-9-methyl-6N-6N-thieno-[3,2-f][1,2,4] -triazolo -[4,3-e] (1,4)-diazepin-2-yl]-2-PROPYNYL}-1H-benzo-(de)-isoquinoline -1,3(2H)-dione with so pl. 188-192oC. Other crystalline modification with so pl. 252-254oWith is also present (observed).

Example 26.

1-{ 3-[4-(2-Chlorophenyl)-9-methyl-6N-thieno-[3,2-f] [1,2,4]-triazolo-[4,3-e] (1,4)-diazepin-2-yl] -2-PROPYNYL} -1H-Indo-2,3-dione receive as described in example 25g, the reaction mix (4-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f] [1,2,4]-triazolo -[4,3-e](1,4)-diazepine with 1-(2-PROPYNYL)-1H-indole-2,3-dione (reference A. Lindqvist, etc. //Acta Pharm Suecica, 1972, 9, 99). Chromatographic separation and crystallization from a mixture of methanol and ethyl acetate to give orange crystals with so pl. 185-190o

Example 27.

The reaction of 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno -[3,2-f][1,2,4]-triazolo-[4,3-e] (1,4)-diazepine with 1-(2-PROPYNYL)-benzo-(CD)-indole-2-(1H)-one as described in example 25g, gives, after chromatographic purification and slow crystallization from ethyl acetate yellow crystals with so pl. 202-205 areoC. These crystals contain according to the analytical data of 0.75 mol of water. Treatment of this product with ethanolic hydrogen chloride and the addition of ethyl acetate to give crystalline hydrochloride 1-{ 3-[4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo -[4,3-e] (1,4)-diazepin-2-yl] -2-PROPYNYL}-benzo-(CD)-indole-2(1H)-she's so square 219-222oC.

Example 28.

1-{ 3-[4-(2-Chlorophenyl)-9-methyl-6N-thieno-[3,2-f][1,2,4]-triazolo -[4,3-e] (1,4)-diazepin-2-yl] -2-PROPYNYL} -1,3-dihydro-2H-indol-2-he receives the influence of 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno -[3,2-f] [1,2,4]-triazolo-[4,3-e] (1,4)-diazepine c 1-3-dihydro-1-(2-PROPYNYL)-1,3-dihydro-2H-indol-2-one (reference A. Lindqvist, etc. //Acta Phirm Suecica, 1972, 9, 99, as described in example 25g. This reaction product is produce by using chromatography and crystallized from ethyl acetate to obtain yellow crystals with so pl. 203-206oC. These crystals contain according to NMR spectral and analytical data of 0.66 molar number of the Il-6N-thieno-[3,2-f][1,2,4] -triazolo -[4,3-a](1,4)-diazepine with 1-(2-PROPYNYL)-1H-benzimidazole (link I. I. Popov and others //Chemistry of heterocycle. compounds, 1973, 551) gives, after chromatographic separation and crystallization from a mixture of ethanol and hexane are not white crystals with so pl. 215-217oC. Crystals of 2-[3-(1H-benzimidazole-1-yl)-1-PROPYNYL] -4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f][1,2,4]-triazolo-[4,3-a] (1,4)-diazepine contain 0,66 molar amount of water that is based on analytical data.

Example 30.

2-{ 3-[4-(2-Chlorophenyl)-9-methyl-6N-thieno-[3,2-f][1,2,4]-triazolo -[4,3-a] (1,4)-diazepin-2-yl] -2-PROPYNYL} -1,2,4-triazolo-[4,3-a] -pyridine-3(2H)-he get reactions combination of 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo-(1,4) -diazepine with 2-(2-PROPYNYL)-1,2,4-triazolo-[4,3-a]-pyridine-3(2H)-one as described in example 25g. The reaction product produce by using chromatography using 7.5 to about.-hydrated ethanol in methylene chloride for elution. Crystallization from ethanol gives 0.55 g (55%) of yellow crystals with so pl. 220-223oC. According to the analytical and NMR spectral data crystals containing 0.25 molar amount of ethanol.

Example 31.

1,1-Diocese 2-{ 3-[4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f][1,2,4]-triazolo -[4,3-a] (1,4)-diazepin-2-yl]-2-PROPYNYL}-1,2-benzisothiazol-3(2H)-it is produced by interaction of 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f] [1,2,4] -CII N 1273867, February 1962), as described in example 25g. The reaction product produce by using chromatography and crystallized from ethyl acetate to obtain colorless crystals with so pl. 232-234oC.

Example 32.

The reaction mix 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f][1,2,4] -triazolo -[4,3-a](1,4)-diazepine with 1-(pyridyloxy)-2-propyne (link J. Bruhm J. Zcindely H. Sehmid and G. Frater //Helv Chim. Acta, 1978, 61-2542) under the conditions described in example 25g, gives after the usual chromatographic selection resinous substance containing 4-(2-chlorophenyl)-9-methyl-2-[3-(3-pyridyloxy)-1-PROPYNYL]-6N-thieno -[3,2-f][1,2,4]-triazolo-[4,3-a](1,4)-diazepin, which does not crystallize and therefore was characterized only by a spectroscope. NMR (CDCl3): 2,72 (singlet, 3, Me), 4,95 (singlet, 4, CH2; C6(H) to 6.8 (singlet, 1, C3-H), 7,2-7,6 (multiplet, 6, aromatic H), compared to 8.26 (multiplet, 1) and at 8.36 (broadened singlet, 1), pyridine C2and C6-H), etc.

Example 33.

4-(2-Chlorophenyl)-9-methyl-2-[3-(1H-indazol-1-yl)-1-PROPYNYL] -6N-thieno -[3,2-f] [1,2,4] -triazolo-[4,3-a](1,4)-diazepin receive, as described in example 25g, the interaction of 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno -[3,2-f] [1,2,4]-triazolo-[4,3-a](1,4)-diazepin with 1-(2-PROPYNYL)-1H-ENATOM (link P. C. Tkachenko and others //Chem is MESI ethyl acetate and ether, to get not quite white crystals with so pl. 170-173oC.

Example 34.

The reaction mix 6-(2-forfinal)-8-iodine-1-methyl-4H-thieno-[3,2-f][1,2,4] -triazolo -[4,3-a](1,4)-benzodiazepine-1-(2-PROPYNYL)-N-indole (reference A. J. Hubert and H. Reiwebinger //J. Chem. Soc. 1968, p. 606), as described in example 9, gives, after chromatography and crystallization from a mixture of ethyl acetate and ether are not white crystals of 6-(2-forfinal)-8-[3-(1H-indol-1-yl)-1-PROPYNYL] -1-methyl-4H-[1,2,4] -triazolo-[4,3-a](1,4)-diazepine with so pl. 167-169oC.

Example 35.

The reaction of 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4]-triazolo-[4,3-a](1,4) -benzodiazepine with 3,7-dihydro-3,7-dimethyl-1-(2-PROPYNYL)-1H-purine-2,6-dione (reference J. W. Daly, W. L. Padgett, and M. T. Shamin //J. Med. Chem 1986, 29, 1305) gives, after chromatography and crystallization from a mixture of methylene chloride and ethanol are not white crystals 1-{3-[6-(2-forfinal)-1-methyl-4H-[1,2,4] -triazolo-[4,3-a] (1,4) -benzodiazepine-8-yl] -2-PROPYNYL}-3,7-dihydro-3,7-dimethyl-1H-purine-2,6-dione with so pl. 290-292oC. These crystals contain a 0.75 molar amount of water according to the analytical data.

Example 36.

2-{4-[6-(2-Forfinal)-1-methyl-4H-[1,2,4]-triazolo-[4,3-a](1,4) -benzodiazepine-8-yl]-3-butenyl}-1H-isoindole-1,3(2H)-dione obtained by reaction of a combination of 6-(2-forfinal)-8-iodine-1-inuggren, U. Svensson, J. H. G. Nilson, A. Erikson, A. Hartkoorn and R. Lunden //J. Med. Chem. 1975, 18, 278), as described in example 1. The reaction product produce by using chromatography and crystallized from ethanol to obtain colorless crystals with so pl. 128-130o(With foaming). These crystals contain according to the analytical and spectral data of the molar amount of ethanol.

Example 37.

4-{ 3-[4-(2-Chlorophenyl)-9-methyl-6N-thieno-[3,2-f][1,2,4]-triazolo -[4,3-a] (1,4)-diazepin-2-yl] -2-PROPYNYL}-2H-1,4-benzoxazin-3(4H)-it is produced by interaction of 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f][1,2,4]-triazolo -[4,3-a] (1,4)-diazepine with 4-(2-PROPYNYL)-2H-1,4-benzoxazin-3(4H)-one (reference A. Lindqvist, etc. //Acta Pharm Suecica, 1972, 9, 99), as described in example 25g. After chromatographic separation of the reaction product is crystallized from ethyl acetate to obtain yellow crystals with so pl. 190-192>198>C. Treatment with ethanolic hydrogen chloride gives a crystalline hydrochloride with so pl. 215-218oC.

Example 38.

1-{ 3-[4-(2-Chlorophenyl)-9-methyl-6N-thieno-[3,2-f][1,2,4] -triazolo-[4,3-a] (1,4)-diazepin-2-yl] -2-PROPYNYL}-3,7-dihydro-3,7-dimethyl-1H-purine-2,6-dione is obtained by reaction of a combination of 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo -[4,3-a] (1,4)-diazepine with 3,7-dihydro-3,7-di the functions allocate using chromatography and crystallized from ethyl acetate, to obtain yellow crystals with so pl. 277-280oC.

Example 39.

The reaction of 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f][1,2,4]-triazolo -[4,3-a] (1,4)-diazepine with 3,7-dihydro-3,7-dimethyl-1H-purine-2,6-dione (reference J. W. Daly, W. O. Padgett, and M. T. Shamin //J. Med. Chem. 1986, 29, 1305), followed by chromatographic separation and crystallization from a mixture of ethyl acetate and ethanol gives yellow crystals 7-{3-[4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo -[4,3-a](1,4)-diazepin-2-yl]-2-PROPYNYL} -3,7-dihydro-3,7-dimethyl-1H-purine-2,6-dione with so pl. 229-232oC. These crystals contain a 0.125 molar quantity of ethyl acetate according to the analytical and spectral data.

Example 40.

The reaction mix 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f][1,2,4] -triazolo-(4,3-a)(1,4)-diazepine with 2-(3-buten-1-yl)-1H-benzo-(de) isoquinoline-1,3 (2H)-Diana as described in example 25g, gives, after chromatography and crystallization from ethyl acetate pale yellow crystals 2-{4-[4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo -[4,3-a](1,4)-diazepin-2-yl] -3-butenyl} -1H-Benz(de) isoquinoline -1,3(2H)-dione with so pl. 175-179oC. There is also more vysokoglavye crystalline modification with so pl. 227-229oC.

Acetylene component reactions receive the following about what hydroxy-1-butyne (link G. and M. Egliutan C. Whiting //J. Chem. Soc. 1950, 3650) and 150 ml of dimethylformamide is heated on the steam bath with stirring for 1.5 hours. The mass of the solvent is removed under reduced pressure, and the remaining suspension is filtered. The filtrate is diluted with water, and precipitating the reaction product is collected by filtration and dissolved in methylene chloride. The solution is dried and passed over pressed silica gel, using methylene chloride for elution. Crystallization from a mixture of methylene chloride and ethanol gives (2-butynyl)-1H-Benz(de) isoquinoline-1,3(2H)-dione as colorless needles with so pl. 191-193oC.

Example 41.

4-(2-Chlorophenyl)-2-iodine-9-methyl-6N-thieno -[3,2-f][1,2,4]-triazolo-[4,3-a] (1,4)-diazepin subjected to interaction with 1-(2-PROPYNYL)-2(1H)-quinoline (reference A. Lindqvist, etc. //Acta Pharm Suecica, 1972, 9, 99), as described in example 25g. The reaction product highlight chromatographic passing the solution over 50 g of silica gel using 5 vol.-hydrated ethanol in methylene chloride, and optionally purified by repeated chromatography over 50 g of silica gel using tetrahydrofuran. Crystallization from a mixture of ethyl acetate gives not quite white crystals 1-{3-[4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f][1,2,4]-triazolo -[4,3-a] (1,4)-diazepin-2-yl]-3-PROPYNYL}-2(1H)-Chinar CLASS="ptx2">

Example 42.

A mixture of 33 g (0,075 mol) of 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo-[4,3-a](1,4)-diazepine, 21 g (0,113 mole) of 3,4-dihydro-1-(2-PROPYNYL)-2(1H)-Hinayana (link A. Lindqvist, etc. //Acta Pharm. Suecica, 1972, 9, 99), 0.75 g of triphenylphosphine, and 0.2 g of copper iodide (I), 60 ml of triethylamine and 600 ml of dimethylformamide is stirred and Tegaserod current of argon for 30 minutes. During this time 0,225 g of palladium acetate added, and the mixture is stirred at room temperature under argon for 3 days. The mixture is then poured into 2.5 l of a saturated aqueous solution of sodium bicarbonate and ice. After stirring for 15 minutes, drop the precipitate is filtered off, washed with water and sucked dry. This substance is dissolved in methylene chloride, and the solution is washed with bicarbonate solution and dried over sodium sulfate. The solvent is removed under reduced pressure, and the residue is dissolved by heating in ethyl acetate. After priming, cooling and crystallizing the reaction product is collected and recrystallized from a mixture of methanol and ethyl acetate to obtain white crystals 1-{3-[4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo -[4,3-a](1,4)-diazepin-2-yl]-2-PROPYNYL}-3,4-dihydro-2(1H)-Hinayana with so pl. 180-182oC.

oC with decomposition. These crystals contain 0,66 molar amount of water according to the analytical and spectral data.

Required propargilovyh derivative was prepared as follows: a mixture of 2 g of 2-(2-pronil)-1H-benzo-(de) isoquinoline-1,3(2H)-dione, 0.75 g of sodium borohydride in 50 ml ethanol and 50 ml of tetrahydrofuran is heated on the steam bath until then, until the dissolution. An additional portion of 0.25 g borohydride added and then the tetrahydrofuran is distilled off on a steam bath within 30 minutes. The remaining mixture is cooled, diluted with ice water, create a buffer with acetic acid and diluted with water Rast is m, sucked to dryness and dissolved in about 250 ml of methylene chloride. The solution is dried and evaporated, and the residue is converted into a slurry by using a mixture of methylene chloride and hexane. The crystals are collected and washed with ether to get to 0.67 g of 2,3-dihydro-2-hydroxy-2-(2-PROPYNYL)-1H-benzo-(de)-isoquinoline-2-it, which restores in the future as follows.

To a stirred solution of 0.6 g of the above intermediate in 6 ml triperoxonane acid in small portions add 0.3 g of sodium borohydride. After 15 minutes reaction time the mixture is divided into parts between ice, ammonium hydroxide and methylene chloride. The organic layer is separated, dried and evaporated, to obtain a crystalline residue, which chromatographic over 30 g of silica gel using 10 vol.-hydrated ethyl acetate in methylene chloride. Crystallization of the combined purified fractions from a mixture of atacamite and hexane gives colorless crystals of 2,3-dihydro-2-(2-PROPYNYL)-1H-Benz(de) isoquinoline-1-she's so square 139-140oC.

Example 44.

4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f][1,2,4]-triazolo -[4,3-a] (1,4)-diazepin subjected to interaction with 1,3-dihydro-1-methyl-3-(2-PROPYNYL)-2H-benzimidazole-2-one under the conditions described in premierepro. Crystallization of the combined homogeneous fractions from ethanol gives pale yellow crystals 1-{3-[4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo -[4,3-a](1,4)-diazepin-2-yl]-2-PROPYNYL}-1,3-dihydro-2H-benzimidazole-- 2-she's so square 188-191oC.

The desired acetylene was prepared as follows: to a solution of 2.5 g (to 16.9 mmole) of 1,3-dihydro-1-methyl-2H-benzimidazole-2-it in 25 ml of dimethylformamide added 2.1 g (18.5 mmole) of tert-butoxide potassium. After stirring under nitrogen for 15 minutes type of 2.21 g (18.5 mmole) of methyl propargyl, and the mixture is stirred at room temperature for 30 minutes. The mixture is diluted with ice water, and drop down the precipitate is filtered off, washed with water and sucked dry. The crude reaction product is passed through silica gel, using 10 vol.-hydrated ethyl acetate in methylene chloride for elution. Crystallization from a mixture of ethyl acetate and hexane gives colorless crystals of 1,3-dihydro-1-methyl-3-(2-PROPYNYL)-2H-benzimidazole-2-she's so square 110-112oC.

Example 45.

4-(2-Chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f][1,2,4]-triazolo -[4,3-a] (1,4)-diazepin subjected to interaction with racemic 2A,3,4,5-tetrahydro-2-(2-PROPYNYL-benzo-(cd)-indole-2(1H)-one under the conditions described in example 9. The product of reaction is the methylene for elution. The combined purified fractions are evaporated and the residue crystallized from a mixture of ethyl acetate and ether to obtain colorless crystals of racemic 2A-{ 3-[4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f] [1,2,4]-triazolo -[4,3-a] (1,4)-diazepin-2-yl] -2-PROPYNYL} -2A, 3,4,5-tetrahydrobenzo-(cd) -2(1H)-she's so square 215-217oC.

Required propargilovyh compound was prepared as follows: to the solution of 6,92 g (0,04 mole) of racemic 2A,3,4,5-tetrahydrobenzo-(cd)-indole-2(1H)-she's in 50 ml of dimethylformamide add 4.94 g (0,044 mole) of tert-butoxide potassium. After stirring for 15 minutes under nitrogen add 5,23 grams or 3.9 ml of methyl propargyl, and stirring is continued for 30 minutes. The mixture is diluted with water and ice, and drop down the precipitate is collected by filtration, washed with water and sucked dry. The solids dissolved in methylene chloride, and the solution is dried and evaporated. Crystallization of the residue from ethyl acetate gives the crude product of the reaction of racemic 2A,3,4,5-tetrahydro-2-(2-PROPYNYL)-benzo-(cd)-indole-2(1H)-he is so pl. 174-177oC, which is recrystallized from ethyl acetate and melts at 177-180oC.

Example 46.

4-(2-Chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f][1,2,4] -triazolo-[4,3-a] (1,4)-diazepin subjected to reaction with the reaction purified by chromatography over 60-fold amount of silica gel, using 5 vol.-hydrated ethanol in methylene chloride. The combined purified fractions do not crystallize, and viscous resin is transformed into a crystalline dichlorhydrate treatment with excess ethanolic solution of hydrogen chloride in a mixture of ethanol and ethyl acetate. Yellow crystals dichlorhydrate 2-[3-(N-carasol-9-yl)-1-PROPYNYL]-4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-a] [1,2,4]-triazolo-[4,3-a](1,4)-diazepin have so pl. 180-184oC.

Example 47.

A mixture of 44 g (0.1 mole) of 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-a] [1,2,4] -triazolo -[4,3-a](1,4)-diazepine, 28 g (0.12 moles) of 5-(2-PROPYNYL-6(5H)-phenanthridinone (link R. F. Cookson, etc. //Herterocyclic Chem. 9, 1972, 475). 1 g of triphenylphosphine, and 0.25 g of copper iodide (I), 80 ml of triethylamine and 800 ml of dimethylformamide Tegaserod slow current of argon for 30 minutes. Then add 0.3 g of palladium acetate, and the mixture is stirred under argon for 4 days at room temperature. Insoluble matter is removed by filtration through celite, and the filtrate is concentrated to approximately 400 ml under reduced pressure. This solution was poured into 2 l of saturated aqueous sodium bicarbonate solution with stirring. Drop down the precipitate is collected by filtration after 10 minutes, washed with water and sucked dry. Solid particles razdelyali layer is dried over sodium sulfate, filtered and partially evaporated. After dilution with 500 ml of ethyl acetate solution was concentrated on a steam bath with the crystallization of the reaction product. After cooling, the crystals are collected and washed with ethyl acetate and ether to obtain of 56.5 g of the reaction product. An analytical sample is recrystallized first from ethanol and then from a mixture of tetrahydrofuran and ethyl acetate, to obtain the not quite white crystals 5-{3-[4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo -[4,3-a](1,4)-diazepin-2-yl]-PROPYNYL}phenanthridine-6-(5H)-she's so square 247-249oC.

Example 48.

4-(2-Chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f][1,2,4]-triazolo -[4,3-a] (1,4)-diazepin subjected to interaction with 6-(2-PROPYNYL)-5H-dibenz-(C,e)-azepin-5,7(6N)-dione (reference J. R. Crunder etc. //J. Pharm Sci. 1973, 62, 120) under the conditions used in example 25g. The reaction product is purified by chromatography through 50-fold amount of silica gel using 5 vol.-hydrated ethanol in methylene chloride. The combined purified fractions are evaporated and the residue crystallized from a mixture of ethanol and ethyl acetate to obtain white crystals 6-{3-[4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f][1,2,4] -triazolo -[4,3-a] (1,4)-diazepin-2-yl] -PROPYNYL}-5H-dibenz-(C,e)-azepin-5,7(6N) -dione c so pl. 220-223oC. LASS="ptx2">

Example 49.

4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f][1,2,4] -triazolo-[4,3-a] (1,4)-diazepin subjected to reaction with racemic 2A,3,4,5-tetrahydro-2-methyl-1-(2-PROPYNYL)-benzo-(c, d)-indole-2(1H)-one under the conditions used in example 25g. The reaction product is purified by chromatography through 50-fold amount of silica gel using 5 vol. ethanol in methylene chloride for elution. The combined purified fractions are evaporated to obtain a resinous substance which is not crystallized, but gives crystalline dichlorhydrate handling excess ethanolic solution of hydrogen chloride and ethyl acetate. These crystals contain 0,33 molar amount of ethanol according to the spectral and analytical data. Pale yellow crystals dichlorhydrate 1-{ 3-[4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f][1,2,4]-triazolo -[4,3-a] (1,4)-diazepin-2-yl]-PROPYNYL}-2A,3,4,5-tetrahydro-2a-methylbenz -(c,d)-indole-2(1H)-she has so pl. 175-178oC.

Source propargilovyh substance synthesized as follows: to the solution of 6,92 g (0,04 mole) of racemic 2A,3,4,5-tetrahydrobenzo-(cd)-indole-2(1H)-she's in 50 ml of dimethylformamide add 4.94 g (0,0 mole) of tert-butoxide potassium. After stirring for 15 minutes under nitrogen add 6,24 g or 2,75 ml (0,044 stragiht methylene chloride. The extracts are dried over sodium sulfate and evaporated. The remainder chromatographic through silica gel, using 10 vol.-hydrated ethyl acetate in methylene chloride. The combined purified fractions are evaporated and the residue crystallized from ether to obtain 3.2 g of colorless racemic 2A, 3,4,5-tetrahydro-2A-methylbenz-(cd)-indole-2(1H)-she's so square 148-150oC.

This substance, 2.5 g (13.3 mmole), was dissolved in 20 ml of dimethylformamide. The solution is treated with 1.65 g (14.7 mmole) of tert-butoxide potassium and stirred under nitrogen for 15 minutes. Then add a 1.75 g of methyl propargyl (1.31 ml, 14 mmole) and stirring at room temperature continued for 30 minutes. The reaction mixture is diluted with ice and saturated sodium bicarbonate solution. Drop down the precipitate is collected by filtration, and the solids washed with water and sucked dry. It is dissolved in methylene chloride and the dried solution is filtered through a thick layer of silica gel. The filtrate is evaporated, and the residue is crystallized from ethyl acetate and hexane (mixture) to obtain colorless crystals of racemic 2A,3,4,5-tetrahydro-2-methyl-1-(2-PROPYNYL)-benzo-(c,d)-indole-2(1H)-she's so square 127-130oC.

Example 50.

4-(2-Chlorophenyl)-2-iodine-the data in example 25g. The reaction product is purified by chromatography through 50-fold amount of silica gel using 5 vol.-hydrated ethanol in methylene chloride. The evaporated purified fractions give a remainder of a viscous oil which does not crystallize, but gives crystalline dichlorhydrate handling excess ethanolic solution of hydrogen chloride and ethyl acetate. Pale yellow crystals dichlorhydrate 4-(2-chlorophenyl)-2-iodine-9-methyl-2-[3-(phenoxy)-1-PROPYNYL] -6N-thieno-[3,2-f][1,2,4]-triazolo-[4,3-a](1,4)-diazepine melt with foaming when 148-151oAnd analysis are hydrate.

Example 54.

A mixture of 0.88 g of 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f][1,2,4]-triazolo -[4,3-a] (1,4)-diazepine, 0.65 g of 3-methyl-1-(2-PROPYNYL)-2,4(1H, 3H)-chineselanguage (link Acta Pharm. Suecica, 1965, 2, 167), 90 mg of triphenylphosphine, 20 mg of copper iodide (I), 2 ml of triethylamine and 50 ml of dimethylformamide Tegaserod with argon for 10 minutes. Then add 30 mg of palladium acetate, and the mixture is heated up to 90-95oC within 30 minutes with stirring under argon. The temperature of the support at 90-95oC for 15 minutes, and the weight of dimethylformamide is evaporated PR reduced pressure. The remainder is divided into parts between methylene chloride and water solution bicarbon graperoot through 30 g of silica gel, using a mixture of tetrahydrofuran and hexane in a ratio of 4:1 for elution. The combined purified fractions are evaporated and the obtained resin is crystallized from ethanol to obtain colorless crystals 1-{3-[4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo -[4,3-a](1,4)-diazepin-2-yl]-2-PROPYNYL} -3-methyl-2,4(1H, 3H)-hinzelin - dione with so pl. 167-170oC. These crystals contain 0.5 molar quantity of water according to the analytical and spectral data.

Example 52.

4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f][1,2,4] -triazolo-[4,3-a] (1,4)-diazepin subjected to reaction with 5-(2-PROPYNYL)-5H-dibenz-(b,e)-azepine-6,11-dione, under the conditions described in example 25g. The reaction product is purified by chromatography through 50-fold amount of silica gel using a mixture of tetrahydrofuran and hexane in a ratio of 4:1 for elution. The resin remaining after evaporation of the combined purified fractions crystallized from ethyl acetate to obtain colorless crystals 5-{3-[4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo -[4,3-a](1,4)-diazepin-2-yl]-2-PROPYNYL} -5H-dibenz-(b, e)-azepine-6,11-dione with so pl. 245-247oC. These crystals contain 0,33 molar quantity of ethyl acetate according to the analytical and spectral data.

And what of dimethylformamide add 2.5 g of tert-butoxide potassium. After stirring under nitrogen for 30 minutes, add 2 ml of methyl propargyl, and stirring is continued for 1 hour at room temperature. The reaction mixture is acidified with acetic acid and diluted with water. Drop down the precipitate is filtered off and sucked dry. The solids dissolved in methylene chloride. The solution is dried and evaporated, and the residue chromatographic over 120 g of silica gel, using methylene chloride. The combined purified fractions containing the reaction product, is evaporated, and the residue is crystallized from a mixture of ether and hexane to obtain colorless crystals of 5-(2-PROPYNYL)-5H-dibenz-(b,e)-azepine-6,11-dione with so pl. 117-118oC.

Example 53.

4-(2-Chlorophenyl)-2-iodine-9-methyl-6N-[3,2-f] [1,2,4] -triazolo -[4,3-a] (1,4)-diazepin subjected to reaction with 6-chloro-4-(2-PROPYNYL)-2H-1,4-benzoxazin-3(4H)-one (reference P. Rao and others //Judian J. Chem. 1985, 24, 1120), as described in example 25g, but the duration of the reaction is increased to 72 hours. The reaction product produce by using chromatography through 100-fold amount of silica gel (Merck, 230-400 mesh mesh) using 10 vol. ethanol in methylene chloride. Crystallization of the residue obtained after evaporation of the combined purified fractions from ethylacetate} -2H-1,4-benzoxazin-3(4H)-she's so square 202-205 areoC.

Example 54.

4-(2-Chlorophenyl)-2-iodine-9-methyl-6N-[3,2-f] [1,2,4] -triazolo -[4,3-a] (1,4)-diazepin subjected to reaction with 1,4-di-hydro-1-(2-PROPYNYL)-3,1-benzoxazin-2-one under the conditions described in example 25g. The reaction product produce by using chromatography through 50-fold amount of silica gel using 5 vol.-hydrated ethanol in methylene chloride, and optionally purified by re-chromatography through 30-fold amount of silica gel using a mixture of tetrahydrofuran and hexane in a ratio of 4:1 for elution. Purified fractions are evaporated and the residue crystallized from a mixture of methanol and ethyl acetate to obtain white crystals 1-{3-[4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo -[4,3-a](1,4)-diazepin-2-yl]-2-PROPYNYL}-2H-3,1-benzoxazin-2-she's so square 173-176oC. These crystals contain 0,33 molar quantity of water, according to the analytical data.

Necessary acetylene synthesized as follows: to a solution of 4.7 g (31 mmole) of 1,4-dihydro-3,1-benzoxazin-2-she's in 30 ml of dimethylformamide added to 3.9 g (34,6 mmole) of tert-butoxide potassium. After stirring for 15 minutes under nitrogen was added 4.1 g or 3.1 ml of methyl propargyl, and stirring at room temperature continued in the precipitate of the reaction product is filtered off, washed with water and sucked dry. The residue is dissolved in methylene chloride, and the solution is passed through a dense layer of silica gel. The filtrate is evaporated, and the residue crystallized from methanol to obtain colorless crystals of 1,4-dihydro-3,1-benzoxazin-2-she's so square 123-125oC.

Example 55.

4-(2-Chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f][1,2,4] -triazolo-[4,3-a] (1,4)-diazepin subjected to reaction with 2-ethynylpyridine under the conditions used in example 25g. The reaction product produce by using chromatography through 50-fold amount of silica gel using 5 vol.-hydrated ethanol in methylene chloride. Fractions homogeneous according to TLC, combined and evaporated. Crystallization of the residue from ethyl acetate and recrystallization from a mixture of tetrahydrofuran and methanol to give white crystals of 4-(2-chlorophenyl)-9-methyl-2-[2-(2-pyridinyl)-ethinyl] -6N-thieno -[3,2-f][1,2,4]-triazolo-[4,3-a](1,4)-diazepine with so pl. 153 to 155oC.

Example 56.

4-(2-Chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f][1,2,4] -triazolo-[4,3-a] (1,4)-diazepin subjected to reaction with 2-(2-PROPYNYL)-1(2H)-skinline under the conditions described in example 25g. The reaction product produce by using chromatography through 50-fold amount of silica gel using a mixture of thetragic crystallized from a mixture of ethanol and ethyl acetate, to obtain colorless crystals 2-{3-[4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo -[4,3-a](1,4)-diazepin-2-yl]-2-PROPYNYL}-1(2H)-athinaikon with so pl. 148-150oC. These crystals contain according to the analytical data of 0.66 molar amount of water.

Necessary acetylene was obtained as follows: a solution of 1 g (7 mmole) isocurvature in 40 ml of dimethylformamide is treated with 0,86 g (7.7 mmole) of tert-butoxide potassium. After stirring under nitrogen for 30 minutes, add 0.7 ml of methyl propargyl, and stirring at room temperature continued for 1 hour. The reaction mixture is acidified with acetic acid and diluted with water. Precipitating the reaction product is filtered off, washed with water and sucked dry. The residue is purified by chromatography through 30 g of silica gel using 5 vol.-hydrated ethanol in methylene chloride and crystallized from ether to obtain colorless crystals of 2-(2-PROPYNYL)-1(2H)-athinaikon with so pl. 104-105oC.

Example 57.

4-(2-Chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f][1,2,4]-triazolo -[4,3-a] (1,4)-diazepin subjected to reaction with 1,3-dihydro-1-phenyl-3-(2-PROPYNYL)-2H-benzimidazole-2-one under the conditions used in example 25g. The reaction product is isolated C. the untreated fractions are combined and evaporated, and the residue is crystallized from a mixture of methanol and ethyl acetate and recrystallized from methanol to obtain white crystals 1-{ 3-[4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo -[4,3-a] (1,4)-diazepin-2-yl)-2-PROPYNYL} -1,3-dihydro-3-phenyl-2H-benzimidazole-2-she's so square 176-179oC. These crystals contain 0,66 mole of water according to the analytical data.

Required propargilovyh derivative synthesized as follows: to a solution of 3 g (14.2 mmole) of 1,3-dihydro-1-phenyl-2H-benzimidazole-2-she's in 30 ml of dimethylformamide type of 1.76 g (15.7 mmole) of tert-butoxide potassium, and the mixture is stirred under nitrogen for 15 minutes. Then add a 1.4 ml (15 mmole) of methyl propargyl, and stirring is continued for 30 minutes at room temperature and 15 minutes on the steam bath. The reaction product is precipitated by dilution with saturated aqueous sodium bicarbonate, it is filtered off, washed with water, sucked dry, dissolved in methylene chloride, and the solution is passed through a dense layer of silica gel, using methylene chloride. The filtrate is evaporated, and the residue is crystallized from a mixture of methylene chloride and ethyl acetate to obtain colorless crystallographer)-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo -[4,3-a] (1,4)-diazepin subjected to reaction with 6,8-dichloro-3,4-dihydro-1-(2-PROPYNYL)-2(1H)-Hinayana under conditions used in the example 25g. The reaction product is purified using chromatographie after 50-fold amount of silica gel using a mixture of tetrahydrofuran and hexane in a ratio of 4:1. Fractions homogeneous according to TLC, combined and evaporated. The residue is crystallized from ethyl acetate to obtain colorless crystals 1-{3-[4-(2-chlorophenyl) -9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo-[4,3-a](1,4) -diazepin-2-yl]-PROPYNYL}-6,8-dichloro-3,4-dihydro-2(1H)-Hinayana with so pl. 163-165oC.

Required propargilovyh derivative was prepared as follows: a mixture of 1.5 g of 6,8-dichloro-3,4-dihydro-2(1H)-Hinayana, 1.3 g of barium oxide, 40 ml of dimethylformamide and 0.8 ml of methyl propargyl heated on the steam bath for 4 minutes and stirred for an additional hour without heating. The reaction product is precipitated by addition of ice and water, it is collected by filtration. The solids dissolved in methylene chloride, and the solution is dried and evaporated. The residue is crystallized from a mixture of ether and hexane to obtain colorless crystals of 6,8-dichloro-3,4-dihydro-2(1H)-Hinayana with so pl. 92-95oC.

Starting material was obtained as follows: a solution of 6 g of 3,4-dihydro-2(1H)-Hinayana in 50 ml of formic acid and 50 ml concentrated is for 30 minutes. Chlorine is injected within 5 minutes, and stirring in the cold continued for 2 hours. Then Smeg poured on ice, alkalinized with ammonium hydroxide and extracted with methylene chloride. The extracts are dried and evaporated, and the residue chromatographic through 300 g of silica gel using 8.-hydrated ethyl acetate in methylene chloride. Crystallization of the combined purified fractions from ether gives colorless crystals of 6,8-dichloro-3,4-dihydro-2(1H)-Hinayana with so pl. 145-146oC.

Example 59.

4-(2-Chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f][1,2,4] -triazolo-[4,3-a] (1,4)-diazepin subjected to reaction with 3,4-dihydro-2-(2-PROPYNYL)-1(2H)-athinaikon (link W. Schueider etc. //Arch. Pharm. 1958, 291, 561) under the conditions described in example 25g. The reaction product produce by using chromatography through 50-fold amount of silica gel using a mixture of tetrahydrofuran and hexane in a ratio of 4:1 for elution. The purified fractions are combined and evaporated, and the residue is crystallized from ethyl acetate to obtain colorless crystals 2-{3-[4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f] [1,2,4]-triazolo -[4,3-a](1,4)-diazepin-2-yl]-PROPYNYL}-3,4-dihydro-2(1H)-athinaikon with so pl. 164-166oC.

Example 60.

4-(2-Chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f][x, used in the example 25g. The reaction product produce by using chromatography through 50-fold amount of silica gel using 4 about. ethanol in methylene chloride. Good fractions are combined and evaporated, and the residue is crystallized from ethyl acetate to policity colorless crystals 4-{ 3-[4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f] [1,2,4]-triazolo -[4,3-a] (1,4)-diazepin-2-yl] -PROPYNYL}-7-fluoro-2H-1,4-benzoxazin -3(4H)-she's so square 215-217oC.

Propargilovyh compound was prepared as follows: a mixture of 1.7 g of 7-fluoro-2,4-dihydro-1,4-benzoxazin-3-one, 2 g of barium oxide, 1.3 ml of methyl propargyl and 40 ml of dimethylformamide is heated on a steam bath for 4 minutes. The cooled reaction mixture is diluted with water, and drop in precipitate the reaction product is collected by filtration. The drop down is dissolved in methylene chloride and the solution washed with water, dried and evaporated. The residue is crystallized from a mixture of ether and hexane to obtain colorless crystals of 7-fluoro-4-(2-PROPYNYL)-2H-1,4-benzoxazin-3(4H)-she's so square 98-100oC.

Example 61.

4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo -[4,3-a] (1,4)-diazepin subjected to reaction with 1,2,3,4-tetrahydro-9-(2-PROPYNYL)-carbazole under the conditions used in example 25g.ethanol in methylene chloride for elution. The residue obtained after evaporation of the combined purified fractions containing the reaction product, crystallized from ethanol to obtain colorless crystals of 4-(2-chlorophenyl)-2-[3-(1,2,3,4-tetrahydro-N-carbazole-9-yl)-1-PROPYNYL] -9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo-[4,3-a] (1,4)-diazepin with so pl. 164-166oC. These crystals contain 0,66 molar amount of ethanol according to the analytical and spectral data.

Propargilovyh compound synthesized as follows: to a solution of 5 g (30 mmol) of 1,2,3,4-tetrahydro-N-carbazole in 50 ml of dimethylformamide added 3.6 g (33 mmol) of tert-butoxide potassium. After stirring for 4 minutes under nitrogen is added to 3.9 g, or 2.9 ml (33 mmol) of methyl propargyl, and stirring is continued for 30 minutes at room temperature, and then 45 minutes on the steam bath. The cooled reaction mixture is diluted with water, and the reaction product is extracted with ether. The extracts are washed with water, dried over sodium sulfate and evaporated. The residue is passed through a tightly Packed layer of silica gel, using a mixture of methylene chloride and hexane in a ratio of 1: 1. The fractions containing the least polar reaction product are pooled and evaporated. The residue is crystallized from hexane the Example 62.

The mixture 0,88 (2 mmole) of 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo -[4,3-a] (1,4)-diazepine, 0.6 g (2.6 mmole) of 10-(2-PROPYNYL)-9(10H)-acridinone (link A. R. Katritzky, etc. //J. Org. Chem. 1985, 50, 852), 80 mg of triphenylphosphine, 20 mg of copper iodide (I), 5.6 ml of triethylamine and 50 ml of dimethylformamide Tegaserod with argon for 10 minutes. Then add 26 mg of palladium acetate, and the mixture is heated to 80-90oC for 30 minutes. The reaction product is precipitated by adding saturated aqueous sodium bicarbonate solution, and it is collected by filtration. The solids dissolved in methylene chloride, and the solution is dried and evaporated. The remainder chromatographic through 50 g of silica gel using 5 vol.-hydrated ethanol in methylene chloride for elution. The combined purified fractions are evaporated and the residue crystallized from ethanol to obtain yellow crystals 10-{3-[4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo -[4,3-a](1,4)-diazepin-2-yl] -2-PROPYNYL} -9(10H)-acridinone with so pl. 175-180oC with foaming. These crystals contain the molar amount of water.

Example 63.

4-(2-Chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f][1,2,4]-triazolo -[4,3-a] (1,4)-diazepin subjected to reaction with 3,8-dichloro-5-(2-PROPYNYL)-6(5H)-phenanthridinone under the conditions used Aut using chromatography through 50-fold amount of silica gel, using a mixture of tetrahydrofuran and hexane in a ratio of 4:1 for elution. Crystallization of the combined purified fractions from a mixture of tetrahydrofuran and ethyl acetate gives colorless crystals of 3,8-dichloro-5-{3-[4-(2-chlorophenyl)-9-methyl-6N-thieno-[3,2-f] [1,2,4] -triazolo-[4,3-a](1,4)-diazepin-2-yl]-2-PROPYNYL}-6(5H)-phenanthridinone with so pl. 218-220oC.

Propargilovyh derivative used for this experience, was obtained as follows: a mixture of 5 g (19 mmol) of 3,8-dichloro-6(5H)-phenanthridinone, 3.2 g (21 mmol) of barium oxide and 1.9 ml (21 mmol) of methyl propargyl in 40 ml of dimethylformamide is heated on a steam bath for 1 hour. After cooling, the reaction product are planted in the precipitate by addition of water, filtered and washed with water. It is dissolved in methylene chloride, and the solution is dried and evaporated. The remainder chromatographic through 150 g of silica gel using 10 vol. th hexane in methylene chloride. The fractions containing the reaction product are pooled and evaporated. The solid residue is recrystallized from ethanol to obtain colorless crystals of 3,8-dichloro-5-(2-PROPYNYL)-6(5H)-phenanthridinone with so pl. 248-250oC.

Example 64.

4-(2-Chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f][1,2,4]-triazolo -[4,3-a] (1,4)-diazepin, for example, is adopted through a 50-fold amount of silica gel, using 5 vol.-hydrated ethanol in methylene chloride for elution. The combined purified fractions are evaporated and the residue crystallized from ethyl acetate to obtain colorless crystals of 4-(2-chlorophenyl)-9-methyl-2-(phenylethynyl)-6N-thieno-[3,2-f][1,2,4] -triazolo-[4,3-a] (1,4)-diazepin with so pl. 215-217oC.

Example 65.

A mixture of 0.84 g (2 mmole) 6-(2-chlorophenyl)-8-iodine-9-methyl-4H-[1,2,4[-triazolo-[4,3-a](1,4) -benzodiazepine of 0.48 g (2.6 mmole) of 3,4-dihydro-1-(2-PROPYNYL)-2(1H)-Hinayana, 80 mg of triphenylphosphine, 20 mg of copper iodide (I), 1.5 ml of triethylamine and 50 ml of dimethylformamide Tegaserod with argon for 10 minutes. Then add 25 mg of palladium acetate, and stirring is continued for 18 hours. The solvent is evaporated under reduced pressure, and the residue is divided into parts between methylene chloride and saturated aqueous sodium bicarbonate. The organic layer is separated, dried and evaporated, and the residue chromatographic through 50 g of silica gel using 5 vol.-hydrated ethanol in methylene chloride for elution. Crystallization of the combined purified fractions from ethyl acetate gives colorless crystals 1-{3-[6-(2-forfinal)-1-methyl-4H-[1,2,4] -triazolo-[4,3-a] (1,4) -benzodiazepine-8-yl]-2-PROPYNYL}-3,4-dihydro-2(1H)-Hinayana with so pl. 236-239otry the reaction with 4-phenyl-1-Butina under conditions used in example 3b. The reaction product produce by using chromatography through 40-fold amount of silica gel using 5 vol.-hydrated ethanol in methylene chloride for elution. The combined purified fractions are evaporated and the residue crystallized from ethyl acetate cooled with dry ice, and recrystallized from a mixture of ethyl acetate, ether and hexane to obtain colorless crystals of 6-(2-forfinal)-1-methyl-8-(4-phenyl-1-butenyl)-4H-[1,2,4]-triazolo -[4,3-a](1,4)-benzodiazepine with so pl. 125-128oC.

Example 67.

A mixture of 5 g of 5-(2-forfinal)-2-hydrazino-7-iodide-3H-1,4-benzodiazepine, 20 ml triperoxonane acid, 5 ml of anhydride triperoxonane acid and 100 ml of methylene chloride is heated on a steam bath under a stream of nitrogen, to repel methylene chloride. Then add 100 ml of toluene, and heated on the steam bath continued for 30 minutes. The mixture is divided into parts between methylene chloride and saturated aqueous sodium bicarbonate. The organic phase is separated, dried and evaporated. The residue is crystallized from ether and recrystallized from ethanol to obtain colorless crystals of 6-(2-forfinal)-1-(trifluoromethyl)-8-iodide-4H-[1,2,4] -triazolo -[4,3-a](1,4)-benzodiazepine with so pl. 202-204oSleep 0.55 g (3 mmole) of N-propargylamine, 80 mg of triphenylphosphine, 20 mg of copper iodide (I), 0.6 ml of triethylamine and 50 ml of dimethylformamide Tegaserod with argon for 10 minutes. Then add 25 mg of palladium acetate, and the mixture is stirred for 3 days at room temperature. The reaction product is precipitated by dilution with sodium bicarbonate solution and collected by filtration. It is dissolved in methylene chloride, and the solution is washed with bicarbonate solution, dried and evaporated. The remainder chromatographic through 40 g of silica gel using 5 vol.-hydrated ethanol in methylene chloride. United good fraction is evaporated, and the residue is crystallized from ethyl acetate to obtain colorless crystals 2-{ 3-[6-(2-forfinal)-1-(trifluoromethyl)-4H-[1,2,4]-triazolo -[4,3-a](1,4)-benzodiazepine-8-yl]-2-PROPYNYL}-1H-isoindole-1,3-(2H)-dione with so pl. 204-206oC.

Example 68.

a) a Solution of 2.9 g (13 mmol) of N-benzyloxycarbonyl-1-alanine in 15 ml of tetrahydrofuran is cooled to -40oC. Then added 2.7 g (13 mmol) petaluridae phosphorus, and the mixture is stirred for 30 minutes at -30oC. the Solution is 3.41 g (10 mmol) of 2(2-perbenzoic)-4-iodoaniline in 50 ml of methylene chloride added, and stirring is continued for 15 minutes at 0 to 10the temperature for 30 minutes. Then it is extracted with ether. The extracts washed with sodium carbonate solution and water, dried and evaporated. The residue is passed through a dense layer of silica gel with methylene chloride. The filtrate is evaporated, and the residue crystallized from ethanol to obtain colorless crystals (S)-{2-[2-(2-perbenzoic)-4-iodophenyl] -amino}-1-methyl-2-acetylcarnosine acid phenylmethylene of ester with so pl. 159-161oC. ()D= -10,35o(c 0,985 in CH2Cl2).

b) a Mixture of 11 g phenylmethylene ether (S)-{2-[2-(2-perbenzoic)-4-iodophenyl] -amino} -1-methyl-2-oxyethyl-carbamino acid and 30 ml of acetic acid containing 30% hydrogen bromide, stirred at room temperature for 3 hours. The reaction mixture is divided into parts between water and alkalinized by addition of ice and ammonia. Precipitated substance is extracted with methylene chloride, and the extracts dried and evaporated. The residue is heated in 50 ml of ethanol containing 5 ml of acetic acid on a steam bath for 15 minutes. The solvent is evaporated under reduced pressure, and the residue is divided into parts between methylene chloride and 10% aqueous solution of sodium carbonate. The organic phase is dried and evaporated, and the OS is advised to obtain colorless crystals of (S)-5-(2-forfinal)-1,3-dihydro-7-iodine-3-methyl-2H-1,4-benzodiazepine-2-she's so square 223-225oC; ()D= +100,79o(0,9891 in CH2Cl2).

C) a Solution of 2 g (5,07 mmole) of (S)-5-(2-forfinal)-1,3-dihydro-7-iodide-3-methyl-2H-1,4-benzodiazepine-2-it in 60 ml of tetrahydrofuran is cooled to -30oC, and add 0,57 (5.7 mmole) of tert-butoxide potassium. The mixture perelivajutsa under nitrogen for 30 minutes while the temperature allow to rise to 5oC. Then add of 1.03 g (6.5 mmole) of diethylphosphate, and stirring is continued for 30 minutes without cooling. After addition of 0.54 g (7.2 mmole) acetylhydrazide the mixture is stirred for an additional 30 minutes at room temperature. Then add 75 ml of butanol, and the tetrahydrofuran is distilled off. Add a few drops of acetic acid, and parts of butanol is also distilled off. The reaction mixture is evaporated under reduced pressure, and the residue is divided into parts between methylene chloride and saturated aqueous sodium bicarbonate. The organic layer is separated, dried and evaporated, and the residue chromatographic through silica gel, using 5 vol. hydrated ethanol in methylene chloride for elution. Crystallization of substances obtained from the combined purified fractions from a mixture of ethyl acetate and hexane gives colorless crystals of (S)-6SUP> (0,9964 in CH2Cl2).

g) (S)-6-(2-forfinal)-8-iodide-1,4-dimethyl-4H-[1,2,4] -triazolo -[4,3-a] (1,4)-benzodiazepine is subjected to reaction with 3,4-dihydro-1-(2-PROPYNYL)-2(1H)-Hinayana under the conditions used in example 68. The reaction product produce by using chromatography through 50-fold amount of silica gel using 5 vol.-hydrated ethanol in methylene chloride for elution. The combined purified fractions are evaporated and the residue crystallized very slowly from a mixture of ethanol and ether to obtain colorless crystals (S)-1-{3-[6-(2-forfinal)-1-dimethyl-4H-[1,2,4] -triazolo-(4,3-a)(1,4) -benzodiazepine-8-yl] -2-PROPYNYL} -3,4-dihydro-2(1H)-Hinayana with so pl. 155 to 169oC with foaming. These crystals contain ethanol and water according to the analytical and spectral data. ()D= +87,5o(1,0091 in CH2Cl2).

Example 69.

a) a Solution of 29 g of N-benzyloxycarbonyl-L-alanine in 100 ml of tetrahydrofuran cooled to -40oC. Then add 27 g petaluridae phosphorus, and stirring is continued for 30 minutes at -30oC. a Solution of 23.7 g (0.1 mole) 2-amino-3-(2-chlorobenzoyl)-thiophene in 400 ml of methylene chloride added, and the mixture is stirred for 15 minutes at 0 to 10oC. It rasclaat with 300 ml of 10%-no dilution with ether, the organic layer is separated, washed with an aqueous solution of sodium carbonate, dried and evaporated. The residue obtained by chromatography of 2 g of the sample through 60 g of silica gel using 10 vol.-hydrated ethyl acetate in methylene chloride for elution. Purified fractions give crystals from a mixture of ether and hexane, which is recrystallized from ethanol to obtain colorless crystals phenylmethylene ether (S)-{2-[3-(2-chlorophenyl)-2-thienyl]-amino}-1-methyl-2-oxoethylidene - howl acid so pl. 133-135oC; ()D= -26,92o(0,9546 in CH2Cl2).

b) a Solution of 22 g phenylmethylene ether (S)-{2-[3-(2-chlorobenzoyl)-2-thienyl] -amino} -1-methyl-2-oxoethylidene new acid in 75 ml of acetic acid containing 30% hydrogen bromide, leave to stand at room temperature for 3 hours. The reaction mixture is divided into parts between water and ether. The aqueous phase is washed with ether and alkalinized by addition of ice and ammonium hydroxide. Precipitated substance is extracted with methylene chloride. The extracts are dried and evaporated, and the residue is dissolved and heated to boiling under reflux for 3 hours with the Department of produced water. The silica gel is filtered off and washed well with methanol. The filtrate is evaporated,1:1 for elution. The reaction product is crystallized from a mixture of methylene chloride and recrystallized from ether for analysis, to obtain (S)-5-(2-chlorophenyl)-1,3-dihydro-3-methyl-2H-thieno-[2,3-e] (1,4) -diazepin-2-he is so pl. 200-203oC; ()D= -0,4o(1,0185 in CH2Cl2).

C) a Mixture of 7.7 g (26 mmol) (5)-5-(2-chlorophenyl)-1,3-dihydro-3-methyl-[2,3-e] (1,4)-diazepin-2-it, 60 ml of methanol, 60 ml of acetic acid, 8,61 (53 mmol) monochloride iodine and 2.17 g (26 mmol) of sodium acetate was stirred at ordinary temperature for 15 minutes. A solution of 9 g of sodium bisulfite in water added to lower the amount of excess reagent. The reaction mixture was alkalinized by addition of ice and ammonium hydroxide. Precipitated substance is collected, washed with water and sucked dry. It is recrystallized from a mixture of methanol and ethyl acetate to obtain colorless crystals of (S)-5-(2-chlorophenyl)-1,3-dihydro-7-iodide-3-methyl-2H-thieno[2,3-e](1,4) -diazepin-2-she's so square 235-237oC.

g) a Mixture of 2.08 g (5 mmol) of (S)-5-(2-chlorophenyl)-1,3-dihydro-7-iodide-3-methyl-2H-thieno[2,3-e] (1,4) -diazepin-2-it, 1,25 g pentasulfide phosphorus, 1.3 g of sodium bicarbonate and 40-50 ml diglyme stirred under nitrogen at 80-90oC for 6 hours. Add water and ice, and the mixture premesis is n optionally dried under vacuum at 50oC, to obtain 2.6 g of crude substance, which is further subjected to reaction as follows.

Raw tion mixed with 1.3 ml of anhydrous hydrazine in 30 ml of tetrahydrofuran for 30 minutes at room temperature. The solvent is evaporated under reduced pressure, and the residue is stirred with 15 ml water and 15 ml of methylene chloride. Crystalline hydrazine powered derivative is collected by filtration, washed with water and ether and added to 13 ml of ethyl acetate and 6.5 ml teeterboro ether octoxynol acid. This mixture is heated on a steam bath for 30 minutes, and the resulting crystals filtered off after cooling. The reaction product is recrystallized from a mixture of methylene chloride and methanol to obtain colorless crystals of racemic 4-(2-chlorophenyl)-2-iodine-6,9-dimethyl-6N-thieno-[3,2-f] [1,2,4]-triazolo -[4,3-a](1,4)-diazepine with so pl. 262 to 264oC. These crystals do not have rotation, showing that there is a complete racemization.

d) Racemic 4-(2-chlorophenyl)-2-iodine-6,9-dimethyl-6N-thieno-[3,2-f] [1,2,4] -triazolo-[4,3-a] (1,4)-diazepin subjected to reaction with 5-(2-PROPYNYL)-6(5H)-phenanthridinone under the conditions described in example 25g. The reaction product produce by using chromatography through 50 times the amount to get yellowish crystals of racemic 5-{ 3-[4-(2-chlorophenyl)-6,9-dimethyl-6N-thieno-[3,2-f] [1,2,4] -triazolo -[4,3-a] (1,4)-diazepin-2-yl] -2-PROPYNYL} -6(5H)-phenanthridinone with so pl. 182-186oC with foaming. These crystals contain according to the analytical data, molar quantities of water.

Example 70.

6-(2-Forfinal)-8-iodine-1-methyl-[1,2,4]-triazolo-[4,3-a](1,4) -benzodiazepine is subjected to reaction with racemic 2-ethinyl-3,4-dihydro-2,5,7,8-tetramethyl-2H-2-benzopyran-6-I (reference H. Meyer and others //Helv. Chim. Acta, 1963, 67, 650) under the conditions described in example 25g. The reaction product produce by using chromatography through 50-fold amount of silica gel using 5 vol. hydrated ethanol in methylene chloride. Purified fractions containing the reaction product are pooled and evaporated. The residue is crystallized from a mixture of ethanol and ethyl acetate to obtain colorless crystals of racemic 2-{[6-(2-forfinal)-1-methyl-4H-[1,2,4] -triazolo)-[4,3-a](1,4) -benzodiazepine-8-yl]-ethinyl} -3,4-dihydro-2,5,7,8-tetramethyl-benzodi - RAS-6-ol with so pl. 266-267oC.

Example 71.

4-(2-Chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f][1,2,4]-triazolo -[4,3-a] (1,4)-benzodiazepine is subjected to reaction with racemic 2-ethinyl-3,4-dihydro-2,5,7,8-tetramethyl-2H-benzopyran-1-benzopyran-6-I under the conditions described in example 25, the reaction Product produce by using chromatography through 50-fold amount of silica gel using 5 vol.-hydrated ethanol chloride is to be colourless crystals of racemic 2-{[4-(2-chlorophenyl)-9-methyl-6N-thieno -[3,2-f] [1,2,4] -triazolo-[4,3-a](1,4)-diazepin-2-yl] -ethinyl} -3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with so pl. 155-160oC with foaming. These crystals contain a 1.5 molar amount of water that follows from analytical and spectral data.

Example 72.

a) a Solution of 0.8 g of tertbutoxide of potassium in 20 ml of tetrahydrofuran and 15 ml of tert-butanol and 0.6 ml of triethylphosphite cooled to -30oC with stirring under argon. A solution of 0.8 g of 6-(2-forfinal)-8-iodine-1-methyl-4-[1,2,4]-triazolo-4,3-a](1,4) -benzodiazepine in 5 ml of dimethylformamide added, and stirring is continued for 1 hour at a temperature of from -20 to -10oC. a Current of oxygen is introduced at a time when the mixture is stirred for an additional hour at this temperature. The reaction mixture is acidified by adding acetic acid and separated into parts between sodium carbonate solution and methylene chloride, containing about 10. of ethanol. The organic layer is dried and evaporated, and the residue is crystallized from a mixture of methylene chloride and ethyl acetate and recrystallized from ethanol to obtain colorless crystals of racemic 6-(2-forfinal)-8-iodine-1-methyl-4-[1,2,4] -triazolo-[4,3-a](1,4) -benzodiazepine with so pl. 258-260oC.

b) a Mixture of 0,435 g (1 mmole) of racemic 6-(2-forfinal)-8-iodine-1-methyl-4-[1,2,4]-triazolo-[4,3-a](1,4) -benzodiazepine 3 ml floristeria under reduced pressure the residue is dissolved in 20 ml of methanol, and the solution is treated with 3 ml of triethylamine. After heating on the steam bath for 5 minutes, the mixture is evaporated to dryness, and the residue is divided into parts between methylene chloride and aqueous sodium bicarbonate solution. The organic layer is dried, and the residue is crystallized from ethyl acetate to obtain colorless crystals of racemic 6-(2-forfinal)-8-iodide-4-methoxy-1-methyl-4H-[1,2,4] -triazolo -[4,3-a] (1,4)-benzodiazepine with so pl. 240-242oC. an Analytical sample recrystallized from a mixture of methanol and ethyl acetate, it has so pl. 243-244oC.

C) Racemic 6-(2-forfinal)-8-iodide-4-methoxy-1-methyl-4H-[1,2,4] -triazolo -[4,3-a] (1,4)-benzodiazepine is subjected to reaction with 3,4-dihydro-1-(2-PROPYNYL)-2(1H)-Hinayana under the conditions used in example 25g. The reaction product produce by using chromatography through 50-fold amount of silica gel using 5 vol.-hydrated ethanol in methylene chloride for elution. The combined purified fractions are evaporated and the residue crystallized from a mixture of ethyl acetate and ether to obtain colorless crystals of racemic 1-{ 3-[6-(2-forfinal)-4-methoxy-1-methyl-4-[1,2,4] -triazolo -[4,3-a](1,4)-benzodiazepine-8-yl] -2-PROPYNYL} -3,4-dihydro-2(1H) -Hinayana with so pl. 155-160oC. These crystals soda is iatola -[4,3-a] (1,4)-benzodiazepine is subjected to reaction with 3,4-dihydro-1-(2-PROPYNYL)-2(1H)-Hinayana under conditions used in the example 25g. The reaction product is purified by chromatography through 50-fold amount of silica gel using 5 vol.-hydrated ethanol in methylene chloride. The purified fractions are combined and evaporated, and the residue is crystallized from ethyl acetate to obtain colorless crystals 1-{ 3-[6-(2-forfinal)-1-(trifluoromethyl)-4H-[1,2,4] -triazolo -[4,3-a] (1,4)-benzodiazepine-8-yl])-2-PROPYNYL}-3,4-dihydro -2(1H)-Hinayana with so pl. 193-196oC.

Example 74.

Racemic 6-(2-forfinal)-4-hydroxy-8-iodine-1-methyl-4-[1,2,4] -triazolo -[4,3-a] (1,4)-benzodiazepine is subjected to reaction with 3,4-dihydro-1-(2-PROPYNYL)-2(1H)-Hinayana under the conditions used in example 25g. The reaction product produce by using chromatography through 50-fold amount of silica gel using 5 vol.-hydrated ethanol in methylene chloride. United good fraction is evaporated, and the residue is crystallized from a mixture of methanol and ethyl acetate to obtain colorless crystals of racemic 1-{3-[6-(2-forfinal)-4-hydroxy-1-methyl-4H-[1,2,4] -triazolo -[4,3-a](1,4)-benzodiazepine-8-yl]-2-PROPYNYL} -3,4-dihydro-2(1H) -Hinayana with so pl. 253-255oC with decomposition. These crystals contain molar equivalents of water.

Example 75.

4-(2-Chlorophenyl)-2-iodine-9-methyl-6N-[3,2-f] [1,2,4] -triaza the x, described in example 25g. The reaction product produce by using chromatography through 50-fold amount of silica gel using 5 vol.-hydrated ethanol in methylene chloride for elution. United good fraction is evaporated, and the residue is converted into crystalline dichlorhydrate by treatment with excess ethanolic solution of hydrogen chloride in a mixture of ethanol and ethyl acetate. Light yellow crystals dichlorhydrate 1-{ 3-[4-(2-forfinal)-9-methyl-6N-thieno-[3,2 f] [1,2,4]-triazolo -[4,3-a] (1,4)-diazepin-2-yl] -2-PROPYNYL} alcohol(cyclopentane -1,3'(3H)-indole)-2(1 N)-she has so pl. 173-176oc with foaming and contain two molar equivalents of water and 0,66 molar equivalents of ethanol according to the analytical and spectral data.

Source propargilovyh derivative used in this experiment, was obtained as follows: to a solution of 0.56 g (3 mmole) of the alcohol(cyclopentane -1,3'(3H)-indole)-2(1 N)-it (link R. J. Owelen //J. Org. Chem. 1974, 39, 69) 10 moles of dimethylformamide type of 0.37 g (3.3 mmole) of tert-butoxide potassium. The mixture is stirred for 15 minutes, and add 0.3 ml of methyl propargyl, and stirring is continued for 30 minutes. The reaction mixture then share a part between xylene and saturated sodium bicarbonate solution. The PR is th methylene for elution. The combined purified fractions are evaporated and the residue crystallized from a mixture of ether and hexane to obtain colorless crystals of 1'-(2-PROPYNYL)alcohol(cyclopentane-1,3'(3H)-indole)-2(1 N)-she's so square 109-111oC.

Example 76.

a) To a solution of 4.4 g of 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2 f] [1,2,4] -triazolo -[4,3-a] (1,4)-diazepine in 200 ml of methylene chloride added 3,4-metacompetencies acid. After stirring at room temperature in the dark for 18 hours the mixture was washed with 10% aqueous solution of sodium carbonate. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue is crystallized from a mixture of tetrahydrofuran, methanol and ethyl acetate to obtain of 8.3 g of crude reaction product. It is cleaned by passing through a dense layer of silica gel, using 10 vol.-hydrated methanol in methylene chloride. The eluate is evaporated, and the residue is crystallized from a mixture of tetrahydrofuran and methanol to obtain white crystals of 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2 f] [1,2,4] -triazolo -[4,3-a] (1,4)-diazepine-5-oxide with so pl. 280-283oC with decomposition.

(b) the Product obtained by reaction of a combination of 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2 f] [1,2,4] -triazolo -[4,3-a](1,4)-diazepine-5-oxide, 5-(2 a Mixture of 1 g of 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2 f][1,2,4]-triazolo -[4,3-a](1,4)-diazepin-5-oxide, 25 ml of pyridine and 15 ml of acetic anhydride is heated on the steam bath for 4 hours. The mixture is evaporated under reduced pressure, at the end of the azeotrope with xylene. The remainder chromatographic through 25 g of silica gel using 5 vol.-hydrated ethanol in methylene chloride for elution. The combined purified fractions are evaporated and the reaction product is crystallized from ethyl acetate and recrystallized from a mixture of tetrahydrofuran, methanol and ethyl acetate to obtain colorless crystals of racemic 6-atomic charges-4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2 f][1,2,4] -triazolo-[4,3-a](1,4)-diazepine with so pl. 248-250oC.

b) To a solution of 0.3 g of racemic 6-atomic charges-4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno -[3,2 f][1,2,4]-triazolo-[4,3-a](1,4)-diazepine in 30 ml of methanol was added 1 ml of 3 n sodium hydroxide solution and 10 ml of water. After standing at room temperature for 30 minutes, the solution is acidified with acetic acid and separated into parts between methylene chloride and aqueous sodium bicarbonate solution. The organic phase is separated, dried and evaporated. The residue is crystallized from a mixture of methanol and ethyl acetate to obtain colorless crystals of racemic 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2 f] [1,2,4] -triazolo -[4,3-a](1,though 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2 f] [1,2,4] -triazolo -[4,3-a](1,4)-diazepin-6-ol with 5-(2-PROPYNYL)-6(5H)-phenanthridinone provided described in example 25g.

Example 78.

a) a Solution of 23 g of (2-AMINOPHENYL)-(4-chlorophenyl)-methanone in 500 ml of methylene chloride is cooled to -50oC. Then add 21 grams or 15 ml monochloride iodine, and the mixture is stirred in the cold for 4 hours. Then she is allowed to warm to 0oC, and the reaction is terminated by pouring the solution of sodium bisulfite in water. After stirring for 10 minutes the organic layer is separated, dried and evaporated. The reaction product is crystallized from a mixture of toluene and hexane to obtain yellow crystals of (2-amino-5-itfinal)-(4-chlorophenyl)-methanone with so pl. 137-139oC.

b) To a solution of 18 g (2-amino-5-itfinal)-(4-chlorophenyl)-methanone in 250 ml of methylene chloride add 5 ml of methyl bromacetyl, and the mixture is stirred with finely crushed ice for 15 minutes. The organic layer was separated, washed with sodium bicarbonate solution, dried and evaporated. The residue is crystallized from a mixture of methylene chloride and ether to obtain 18 g bromoacetophenone. This substance is dissolved in 200 ml of methylene chloride and added dropwise to 300 ml of liquid ammonia. The ammonia gradually allow to evaporate overnight, and the remaining methylene chloride by pravilnikom within 30 minutes after adding 10 ml of acetic acid. The solvent was partially evaporated and the reaction product is crystallized by cooling. Recrystallization from a mixture of methylene chloride and ethanol gives colorless crystals of 5-(4-chlorophenyl)-1.3-dihydro-7-iodide-2H-benzodiazepine-2-she's so square 246-248oC.

C) a Mixture of 12 g of 5-(4-chlorophenyl)-1.3-dihydro-7-iodide-2H-1,4-benzodiazepine-2-it, 8 g of pentasulfide phosphorus, 8 g of sodium bicarbonate and 100 ml of diglyme stirred and heated to 80-85oC for 3 hours. After cooling, add water and finely crushed ice, and stirring is continued for 10 minutes. Precipitating the reaction product is collected by filtration and washed with water, 2-propanol and ether. For analysis it is recrystallized from a mixture of tetrahydrofuran and ethanol to obtain 5-(4-chlorophenyl)-1.3-dihydro-7-iodide-2H-1,4-benzodiazepine-2-tion, which melts at 260-262oC.

g) a Mixture of 4 g of 5-(4-chlorophenyl)-1.3-dihydro-7-iodide-2H-1,4-benzodiazepine-2-thione, 50 ml of tetrahydrofuran, 20 ml of 2-propanol and 1.5 ml of hydrazine was stirred at room temperature for 30 minutes. This mixture is filtered through a thick layer of silica gel (10 g), using tetrahydrofuran for elution. The filtrate is evaporated, and the residue substances from a mixture of tetrahydrofuran and ethanol on the Mixture of 2.8 g of 5-(4-chlorophenyl)-1.3-dihydro-7-iodide-2H-1,4-benzodiazepine 40 ml of xylene and 10 ml teeterboro ether octoxynol acid is heated to boiling under reflux for 1.5 hours. The crystals, which are extracted from the cooled reaction mixture, is filtered off and recrystallized from a mixture of tetrahydrofuran and ethanol to obtain colorless crystals of 6-(4-chlorophenyl)-4-iodine-methyl-4H-[1,2,4]-triazolo-[4,3-a] (1,4) -benzodiazepine with so pl. 258-360oC.

a) 6-(4-Chlorophenyl)-4-iodine-methyl-4H-[1,2,4] -triazolo-[4,3-a](1,4) -benzodiazepine is subjected to reaction with 3,4-dihydro-2-(2-PROPYNYL)-2(1H)-Hinayana under the conditions used in example 25g. The reaction product produce by using chromatography through 50-fold amount of silica gel using 20 vol.-tion in hexane tetrahydrofuran for elution. Crystallization of the combined purified fractions from ethyl acetate and recrystallization from the same solvent to give colorless crystals 1-{3-[6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]-triazolo-[4,3-a](1,4) -benzodiazepine-8-yl]2-PROPYNYL}-3,4-dihydro-2(1H)-Hinayana with so pl. 215-217oC. These crystals contain 0,33 molar amount of water according to the analytical data.

Example 79.

a) a Mixture of 5-(4-chlorophenyl)-2-hydrazino-7-iodide-3H-benzodiazepine, 75 ml of methylene chloride, 5 ml of anhydride Treaty methylene within approximately 30 minutes. Then add 100 ml of toluene, and heated on the steam bath continued for 30 minutes. The cooled mixture was washed with saturated aqueous sodium bicarbonate, dried and evaporated. The remainder chromatographic through 200 g of silica gel using 10 vol. ethyl acetate in methylene chloride for elution. Crystallization from ethyl acetate gives colorless crystals of 6-(4-chlorophenyl)-1-trifluoromethyl-8-iodide-4H-[1,2,4] -triazolo-[4,3-a](1,4) -benzodiazepine with so pl. 243-245oC.

6-(4-Chlorophenyl)-1-trifluoromethyl-4-iodine-4H-[1,2,4] -triazolo-[4,3-a] (1,4) -benzodiazepine is subjected to reaction with 3,4-dihydro-1-(2-PROPYNYL)-2(1H)-Hinayana under the conditions used in example 25g, but increasing the duration of response up to 48 hours. The reaction product produce by using chromatography through 50-fold amount of silica gel using methylene chloride and ethyl acetate in the ratio of 1:1. Purified fractions containing the reaction product, are combined and evaporated, and the residue is crystallized from a mixture of ethyl acetate and hexane to obtain white crystals 1-{3-[6-(4-chlorophenyl)-1-trifluoromethyl-4H-[1,2,4]-triazolo-[4,3-a](1,4) -benzodiazepine-8-yl]-2-PROPYNYL} -3,4-dihydro-2(1H)-Hinayana with so pl. 220-222oC. These crystals contain 0.5 molar quantity of water Soleil-6N-[4,2-f] [1,2,4] -triazolo-[4,3-a](1,4) -diazepin-2-yl]-2-PROPYNYL}-1H-benzo(d,e)-isoquinoline-1,3(2H)-dione (Microfin) (compound A) 50 g

Oksipropilmetiltselljuloza 8.0 g

Polysorbate 80 0.5 g

Distilled water (quantity brought to a) to 100.0 ml

Technique

1. Add connection And to the solution of Polysorbate 80 and dispersing.

2. In distilled water to prepare a solution of oksipropilmetiltselljulozy.

3. Mix substances from stages 1 and 2, then add distilled water to bring to 100 ml

Example B.

Capsule prescription composition mg/capsule

2-{ 3-[4-(2-chlorophenyl)-9-methyl-6N-[3,2-f] [1,2,4] -triazolo-[4,3-a](1,4) -diazepin-2-yl]-2-PROPYNYL}-1H-benzo(d,e)-isoquinoline-1,3(2H)-dione (Microfin) (compound A) 50,00

Polyvinylpyrrolidone K-90 0,50

Polysorbate 80 0,25

Microcrystalline cellulose to 99.00

Distilled water for the complete dissolution

Magnesium stearate and 0.25

The total weight 150,00 mg

Technique

1. To the connection And add a sufficient quantity of an aqueous solution of polyvinylpyrrolidone K-90 and Polysorbate 80.

2. Crushed to the consistency, dried and sieved through a sieve of 40 mesh.

3. Add microcrystalline cellulose and magnesium stearate are then mixed and filled into capsules.

Example Century.

Tablet prescription the NC(d,e)-isoquinoline-1,3(2H)-dione (Microfin) (compound A) 50,00

Polyvinylpyrrolidone (cleared) of 14.25

Polyvinylpyrrolidone K-90 0,50

Microcrystalline cellulose 35,00

Starch glycolate, sodium 10,00

Distilled water sufficient to dissolve

Magnesium stearate and 0.25

The total weight 110,00

Technique

1. Prepare a mixture of compounds And starch glycolate, sodium and polyvinylpyrrolidone, then add a sufficient quantity of an aqueous solution of polyvinylpyrrolidone K-90.

2. Pulverize until the consistency, dried and sifted through a sieve of 40 mesh.

3. Add microcrystalline cellulose and magnesium stearate are then mixed and pressed into tablets.

Example,

Aerosol suspension, 0.5 mg/actuation

2-{ 3-[4-(2-chlorophenyl)-9-methyl-6N-[3,2-f] [1,2,4] -triazolo-[4,3-a](1,4) -diazepin-2-yl]-2-PROPYNYL}-1H-benzo(d,e)-isoquinoline-1,3(2H)-dione (Microfin) (compound A) 120,00 mg

Trioleate sorbitol 40,00 mg

Crypteroniaceae 1.80m

DICHLORODIFLUOROMETHANE 10,20 ml

Technique

1. To the connection And add a solution of trioleate sorbitol and trichloronitromethane.

2. Homogenize and add a suspension in an aluminum vessel.

3. Screw 50 is microlitres measuring valve in Soso application

2-{ 3-[4-(2-chlorophenyl)-9-methyl-6N-[3,2-f] [1,2,4] -triazolo-[4,3-a](1,4) -diazepin-2-yl]-2-PROPYNYL}-1H-benzo(d,e)-isoquinoline-1,3(2H)-dione (Microfin) (compound A) 1.0 g

The polyethylene glycol 400 99,0 g

Technique

1. Add connection And the polyethylene glycol 400 and mix well until until dissolved.

A method of producing a triazole (4,3-a) (1,4)benzodiazepines General formula

< / BR>
where X is a radical-CH CH or S;

R1lower alkyl and trifluoromethyl;

R2chlorine or fluorine;

R3the radical of the formula

R4-(CH2)n-CC - or R5-O-CH2-CCH,

where n is an integer of 0, 1 or 2; R4is phenyl or mono-, di - or tricyclic 5-7-membered heterocyclic radical containing as heteroatoms O or S and/or 1 to 3 nitrogen atom, unsubstituted or substituted lower alkoxy, oxo, actigraphy or chlorine;

R5phenyl or pyridylethyl,

provided that when n is 0, the radical R4must be attached through a carbon to carbon and that R5always attached through carbon to oxygen connection, characterized in that the compound of General formula

< / BR>
where R1and R2have the specified values;

J bromine or iodine,

put vzaimodeistvie2where R4and R5have the specified values.

 

Same patents:

The invention relates to new azetidinone derived isothiazol-pyridone: 2,3,4,9-tetrahydroindazole[5,4-b]China - in-3,4-dione, 2,3,4,9-tetrahydrothieno [5,4-b] [1,8]-naphthiridine-3,4-dione, 1,2,8,9-tetrahydro-7H-isothiazol-[4',5',5,6]pyrido [1,2,3-de]benzoxazine-7,8-dione and its salts

The invention relates to compounds of formula I:

< / BR>
in which Z is hydrogen, halogen or lower alkyl;

R1is lower alkyl, cycloalkyl or aryl; and

R2is lower alkyl or cycloalkyl;

which are used to mitigate various dysfunctions of memory, which are characterized by a cholinergic deficit such as disease Alzheimer and as analgesic agents

The invention relates to the field of organic chemistry and relates to a method of obtaining new derivatives of imidazole

The invention relates to new derivatives carbapenem General formula

where a is a pyrolidine ring;

R1represents a hydrogen atom or methyl;

R2represents a hydrogen atom;

R3represents a hydrogen atom or ion with a negative charge Q represents a group of the formula (I)

-(CH2)pZ+where p is zero or an integer 1 or 2;

Z+means pyridyl, pyrrolidinyl or genocidal, each substituted with one or two1-C4-alkyl groups, and contains a Quaternary nitrogen atom, or a group of formula (2)

-(CH2)p-R6where p is an integer 2;

Ra, Rband Rceach is1-C4-alkyl, or Q and R2together with the nitrogen atom to which they are attached, form a group of formula (3)

-Nwhere m and n are each 2 or 3

R6and R7each represents alkyl with 1-4 carbon atoms or alkyl with 1-4 carbon atoms, substituted Deputy selected from the group comprising hydroxy-, carboxy-, карбам�at2/19962/007.dwl/2059639-7t.gif" ALIGN="ABSMIDDLE">where Rd, Reand Rdeach means hydrogen or C1-C4-alkyl;

R6is1-C4-alkyl, or their salts or esters

The invention relates to new triazine derivative or triazolone series, namely: to heterocyclic compounds of General formula

(I) where R1represents a hydrogen atom, l is 0 or 1; ring a represents hexahydropyridine, tetrahydropyrrole, hexahydroazepin, dihydrothiazolo, tetrahydrooxazolo, tetrahydrothiophene or dihydropyridines; Y represents a substituted lower alkyl or aryl, or unsubstituted alkylenes group containing from 1 to 3 carbon atoms; Q represents a group of the formula

N(II) where R2represents a hydrogen atom, a hydroxyl group or aryl group which may be substituted with halogen; R5represents a hydrogen atom; and R3and R4can have the same or different values, each represents a hydrogen atom, halogen atom or morpholinyl, or Q represents a group of the formula

N(III) where Ar1and Ar2may have about the Ohm halogen or alkyl group, or their acid additive salt

The invention relates to novel 3,5-dihydroimidazo[2,1-b] hinzelin-2 (1H)-it is a derivative of the formula I

O

(I) where R is a hydrogen atom, a C1-6-alkyl, phenyl, possibly substituted by 1-3 substituents, independently from each other selected from halogen atoms, hydroxy - C1-6-alkyloxy-FROM1-6is an alkyl or triptorelin groups, pyridinyl, or thienyl, unsubstituted or substituted with halogen or1-6by alkyl;

R1the atom of hydrogen or C1-6-alkyl;

R2a hydrogen atom, a C1-6-alkyl, hydroxy-C1-6alkyl or phenyl, or R1and R2together can form WITH1-5-alcander;

X is the radical of the formula

0 (a)

N-O-R3(b) or

SN-R4(c);

R3a hydrogen atom, three (C1-6-alkyl)-silyl or1-6-alkyl which may be substituted by COOH, SOOS1-4-alkyl, СОNR5R6or SOON2-CONR7R8;

R4COOH, COOC1-4-alkyl, СОNR5R6, COOCH2CONR7R8or1-6-alkyl which may be substituted by COOH, SOOS1-4-alkyl, CONR5R6or COOCH2CONR7R8;

RIS-C1-4-alkyl, C1-4-algological - Nile-C1-4-alkyl;

R6a hydrogen atom, a C1-5-alkyl, hydroxy-C1-4-alkyl or C3-7-cycloalkyl, or R5and R6together with the nitrogen atom to which they are bound, can form pyrrolidinyl, morpholinyl or piperazinil, which can be substituted at the nitrogen atom WITH1-4-alkyl or hydroxy-C1-4-alkyl;

R7and R8independently from each other mean a hydrogen atom, a C1-4-alkyl or hydroxy-C1-4-alkyl, and their pharmaceutically acceptable salts and stereoisomers

The invention relates to new derivatives of glutamic acid with any abscopal valuable properties on the enzyme, using folic acid and its metabolites as substrates and finds application in medicine, as well as the way they are received

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

wherein R1, R2 and R3 have above given values; R6 is a group RR9N-; R7 is a group R10R11N-; each among R8, R, R10 and R11 means independently of one another hydrogen atom or (C1-C6)-alkyl in inert organic solvent being optionally with the presence of a base with compound of the formula (IV) ,

(IVa)

or (IVb) ,

wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

9 cl, 12 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: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a new derivative of bicyclic heteroaromatic compound of the general formula (I) or its pharmaceutically acceptable salt eliciting agonistic activity with respect to luteinizing hormone (LH). Compounds can be used for preparing medicinal agents for control ability for conception. In compounds of the general formula (I) R1 represents R7 wherein R7 represents (C6-C10)-aryl optionally substituted with halogen atom at ortho- and/or meta-position; NHR8, OR8 wherein R8 means (C1-C8)-alkyl that can be substituted with halogen atom, (C1-C8)-alkylcarbonyl, (C1-C8)-alkylcarbonyloxy-group, phenyl, (C6-C10)-arylcarbonylamino-group, 5-methyl-2-phenylimidazol-4-yl, (C6)-heterocycloalkyl wherein 1-2 heteroatoms are taken among nitrogen and oxygen atoms, ethyloxycarbonylmethylthio-(C1-C4)-alkoxy-group, amino-group, (C6-C7)-heteroaryl; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R2 represents (C1-C8)-alkyl or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R3 represents (C1-C8)-alkyl possibly substituted with (C6-C14)-aryl possibly substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, mono- or tri-(C6-C10)-cycloalkyl, (C6-C10)-aryl, (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; (C5-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; (C3-C8)-cycloalkyl, (C2-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; X represents sulfur atom (S) or N(R4); Y represents nitrogen atom (N); R4 represents (C1-C8)-alkyl, phenyl-(C1-C8)-alkyl; or X represents sulfur atom (S), and Y represents CH; Z represents NH2 or OH; A represents sulfur (S), oxygen atom (O) or a bond. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable properties of compounds and composition.

14 cl, 1 tbl, 119 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to improved synthesis method of pyrlindone hydrochloride having formula (I) 1. Method features intramolecular cyclization of 6-methyl-1-(2-chloroethyl-imino)-1,2,3,4-tetrahydrocarbazole hydrochloride of formula IV 2 at 80°-140°C with alkali agent in presence of phase transfer catalyst to provide 1,2,5,6-tetrahydro-8-methyl-pyrazine[3,2,1-j,k]-4H-carbazole of formula VI 3 followed by reduction at 80°-120°C. Method of present invention makes in possible to produce compound of formula I with yield nearly 70 % and purity more than 99 %.

EFFECT: method of high yield with reduced amount of alkali agent and phase transfer catalyst.

7 cl, 2 ex

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, pharmaceutical composition.

SUBSTANCE: compounds satisfying the formula I 1 are disclosed, wherein each R1 and R2 independently to one another are H, OH, OA or Hal; or R1 and R2 together are -O-CH2-O- or -O-CH2-CH2-O-; R3 and R4 are A-group; X - group monosubstituted with R8, R5 or R7; R5 is linear or branched C1-C10-alkylene, wherein one or two CH2-groups may be substituted with oxygen atom; R7 is phenyl or phenylmethyl; R8 is COOH, COOA, CONH2, CONHA, CON(A)2 or CN; F is C1-C6-alkyl; and Hal is F, Cl, Br, or I, as well as physiologically acceptable salts or solvates thereof. Methods for production of claimed compounds (I) and pharmaceutical composition containing the same also are disclosed. Said compounds and pharmaceutical composition have activity as phosphodiesterase V inhibitors and are useful in treatment of cardiovascular diseases and potency disorders.

EFFECT: pharmaceutically applicable compounds and compositions.

7 cl, 16 ex

FIELD: organic chemistry, medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to a pyrrolopyridazine derivative of the following formula: wherein R1 represents (C3-C7)-cycloalkyl-(C1-C6)-alkyl group that can be substituted optionally with (C1-C6)-alkyl group; R2 represents (C1-C6)-alkyl group; R3 represents hydroxymethyl group, (C2-C6)-aliphatic acyloxymethyl group, (C6-C10)-arylcarbonyloxymethyl group, (C1-C6)-alkoxycarbonyloxymethyl group, formyl group, carboxyl group, (C1-C6)-alkoxycarbonyl group or (C6-C10)-aryloxycarbonyl group; R4 represents (C6-C10)-aryl group that can be substituted optionally with substitutes taken among the group consisting of (C1-C6)-alkyl groups, halogen-(C1-C6)-alkyl groups, (C1-C6)-alkoxy-groups, halogen-(C1-C6)-alkoxy-groups and halogen atoms; A represents imino-group, oxygen or sulfur atom, or its pharmaceutically acceptable salt. Pyrrolopyridazine derivatives elicit inhibitory activity with respect to gastric juice secretion and protective activity with respect to stomach mucosa and can be useful as a curative agent for prophylaxis or treatment of ulcer disease. Except for, invention relates to a pharmaceutical composition based on compounds of the invention and to a method for prophylaxis and treatment of ulcer disease.

EFFECT: valuable medicinal properties of compound.

25 cl, 1 tbl, 11 ex

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

SUBSTANCE: invention describes bicyclical nitrogen-containing heterocycles of the general formula (I): , wherein R1 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, pyridyl, naphthyl, furyl-(C1-C4)-alkyl, phenyl optionally substituted with di-(C1-C7)-alkylamino-(C1-C7)-group, halogen atom, (C1-C7)-alkoxy-group or hydroxy-(C1-C7)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group, amino-(C1-C7)-alkyl, amino-group or di-(C1-C7)-alkylamino-(C1-C7)-alkoxy-group; R2 means (C1-C7)-alkyl, (C3-C7)-cycloalkyl, furyl-(C1-C4)-alkyl, pyridyl or its N-oxide; phenyl optionally substituted with halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, hydroxy-group or trifluoromethyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group; R3 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, (C3-C7)-cycloalkenyl, pyridyl-(C1-C4)-alkyl, naphthyl, phenyl optionally substituted with phthalimido-(C1-C4)-alkyl, amino-(C1-C7)-alkyl, hydroxy-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, morpholino-(C1-C4)-alkyl or piperazinyl-(C1-C4)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxycarbonyl or carboxy-group. Also, invention relates to pharmaceutically acceptable salts of compounds of the formula (I) as a base with acids or pharmaceutically acceptable salts of compounds of the formula (I) as acid with bases, and pharmaceutical composition based on thereof. Compounds described above show inhibitory activity with respect to tyrosine kinase and can be used in treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular diseases, for treatment of asthma, disorders in the central nervous system or complications associated with diabetes mellitus, or for prophylaxis against transplant rejection after surgery transplantation.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 tbl, 92 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

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

26 cl, 1 tbl, 119 ex

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