Triazolo[4,3-a][1,4]-benzodiazepine-and thieno[3,2-f]-[1,2,4]- triazolo[4,3-a] [1,4]benzodiazepines, in the presence of at least one asymmetric center of their enantiomers, racemates, and pharmaceutically acceptable salts accession acids, method for their production and pharmaceutical composition inhibiting platelet activating factor.

 

(57) Abstract:

The invention relates to new triazolo[4,3-a][1,4] benzodiazepine or a thieno[3,2-f][1,2,4]triazolo[4,3-a]benzodiazepines of General formula I

< / BR>
where X is-CH=CH -, or S; R1- lower alkyl or trifluoromethyl; R2is chlorine or fluorine; R3is a radical of the formula R4-(CH2)n-CC - or R5-O-CH2-CC -, where n is an integer of 0,1 or 2; s is 0 or 1; R4is phenyl or mono-, di - or tricyclic 5-7-membered heterocyclic radical containing as heteroatoms O or S and/or 1-3 nitrogen atom, unsubstituted or substituted lower alkoxy, oxo, actigraphy or chlorine; R5is phenyl or pyridyl radical, provided that when n is 0, the radical R4must be attached through a carbon to carbon link, and that R5always attached through carbon to oxygen of communication, and in the presence of at least one asymmetric center, their enantiomers and racemates and pharmaceutically-acceptable salts accession acids exhibiting the properties of antagonists of platelet activating factor (PAF) and, respectively, with angioprotective, immunological, antishock properties, and properties that prevent oloricde R3means the group - CCH. Get the compounds of formula I or their pharmaceutically-acceptable salt accession acids by the interaction of the compounds of formula II with a compound R4- Y, in which R4means specified in paragraph 1, and Y is bromine or iodine and, if necessary, to obtain the compounds of formula I, in which s is 1 and R4differs from a residue containing a basic nitrogen atom, is treated with a compound of the formula I, in which s is 0 and R4differs from a residue containing a basic nitrogen atom, nagkalat, and/or, if desired, convert the obtained compound of formula I in a pharmaceutically-acceptable salt accession acids. 3 S. and 14 C. p. F.-ly, 2 tab.

The invention relates to new compounds of General formula

< / BR>
in which: X is-CH=CH -, or S;

R1lower alkyl or trifluoromethyl;

R2chlorine or fluorine;

R3the radical of the formula R4-(CH2)n-CC - or R5-O-CH2-CC-,

where n is the integer 0, 1 or 2, s is 0 or 1;

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;5always attached through carbon to oxygen of communication, and in the presence of at least one asymmetric center of their enantiomers and racemates, and pharmaceutically-acceptable salts accession acids.

The compounds of formula I possess the properties of antagonists of platelet activating factor (PAF) and therefore are useful in disease States characterized by excessive platelet activating factor, or for the prevention and treatment of cardiovascular diseases, pulmonary diseases, immunological disorders, inflammatory diseases, dermatological disorders, shocks or graft rejections.

Structural analogues of such actions is not known. The closest analogue is the U.S. patent 4,621,083, which describes benzo - and thenationallottery with PAF-antagonistic properties. In the above-mentioned U.S. patent is not specifically disclosed no connection, substituted alkenylphenol group on a condensed benzene ring or thiophene ring.

Thus, in the above-mentioned U.S. patent discloses compounds of the same action, but structural analogues it is not disclosed. Alchemilla group R4-(CH2)n

Used in this description, the term "lower alkyl" denotes unbranched or branched saturated hydrocarbon group containing from 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, tert. -butyl, neopentyl, pentyl, heptyl and the like.

The term "lower alkoxygroup" denotes an alkyl ether group in which the alkyl group is as described above, and means, for example, methoxy, ethoxy, propoxy, pentox and the like.

The term "heterocyclic radical" denotes a monocyclic 5-, 6 - or 7-membered heterocyclic or bi - or tricyclic heterocyclic radical containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and which may be substituted, preferably mono - or disubstituted, lower alkyl, lower alkoxygroup, exography, actigraphy, chlorine. The term "heterocyclic" refers to carbocyclic residue in which one or more carbon atoms are replaced independently of one another by oxygen, nitrogen or sulfur.

Typical monoc thienyl, 2-chloranil, furyl, pyrimidinyl, oxazolyl or the like.

Typical monocyclic 5-, 6 - or 7-membered non-aromatic heterocyclic radicals are

< / BR>
and things like that.

Typical bicyclic heterocyclic radicals are

(a) 5,5-cyclic system

< / BR>
and the like;

(b) a 6.5-cyclic system

< / BR>
and the like;

(C) 6,6-cyclic system

< / BR>
< / BR>
and the like; and

(g) 6,7-cyclic system

< / BR>
and things like that.

Typical tricyclic heterocyclic radicals are 5,5,6-, 5,6,6-, 6,6,6 - 6,6,7-cyclic system

< / BR>
< / BR>
and things like that.

Used in this description and which is evident from the nomenclature and structures, structural image L is-CCH , and is-CC-.

A preferred group of compounds of formula I are compounds in which X is-CH=CH - or S, R1is lower alkyl, R2is chlorine, fluorine; R3is a radical of the formula R4-(CH2)n-CC - or R5-O-CH2-CC-,, R4is a bicyclic or tricyclic radical and R5is f is always attached through carbon to oxygen connection.

Another preferred group of compounds of formula I are compounds where R1methyl or ethyl, R2is fluorine or chlorine, R3matter, above n 1, 2, s 0.

A more preferred group of compounds of formula I are compounds where R1methyl, R2fluorine, chlorine, s 0, n 1, R4bi - or tricyclic heterocyclic radical above, and R5is phenyl or pyridyl.

The most preferred group of compounds of formula I are compounds where X is S, R1methyl, R2chlorine, s=0, R3is R4-(CH2)n-CC - n=1, and R4is

< / BR>
Preferred compounds of the invention are

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}-phenanthridine-6(5H)-he;

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;

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)-chinoline;

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]-1H-Benz[de]d]indol-2(1H)-he;

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)-he.

Other preferred compounds of the invention are

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]-1H-indole-2,3-dione;

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-indol-2-he;

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;

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;

4-(2-chlorophenyl)-2-[3-(1H-indazol-1-yl)-1-PROPYNYL] -9-methyl-6N-thieno [3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepin;

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]diazepin;

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 and

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-benzoxazin-3(4H)-he.

The subject invention are also compounds of General formula

< / BR>
in which X, R1, R2and s have the meanings specified above,relates to compounds, specified above for use as therapeutically active substances or as antagonists of the factor of activation of platelets (PAF).

The compounds of formula I and their pharmaceutically acceptable salts accession acids can be obtained in accordance with the invention by

a) interaction of the compounds of General formula

< / BR>
in which X, R1, R2and s have the meanings specified above, and Y is bromine or iodine,

with the compound of the formula

R4-(CH2)nCC-H (IIIa)

or

R5-O-CH2CC-H (IIIb)

in which R4, R5n have the meanings specified above, or

b) interaction of the compounds of General formula

< / BR>
in which X, R1, R2and s have the meanings indicated above, with a compound of General formula

R4-Y

in which R4and Y have the meanings indicated above, or

to obtain the compounds of formula I, in which s is 1 and R4does not contain a residue containing a basic nitrogen atom, is treated with a compound of the formula I, in which s is 0 and R4does not contain a residue containing a basic nitrogen atom, nagkalat, or

g) if desired, turn the compound obtained of General formula I which may be obtained, as described below in schemes of reactions I and II.

A reaction scheme I

< / BR>
in which R1, R2, R3, R4, R5, X, n and s are as described previously and Y is bromine or iodine.

Scheme I triazoline or triazolobenzodiazepine formula II in which Y is bromine or iodine, is subjected to the interaction with acetylene of the formula IIIa or IIIb with the use of a transition metal catalyst, according to methods known in this field, to obtain the corresponding compound of formula I in accordance with variant (a) of this method.

The reaction of bromine or preferably iodotope compounds of structure II with acetylene of the formula IIIa or IIIb is carried out in an inert solvent; the preferred solvents are acetonitrile, tetrahydrofuran and dimethylformamide, at a temperature ranging from room temperature to about 100oC, 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, optionally in the presence of catalytic amounts modestou copper(I) and excess proton acceptor, such as triethylamine.

The resulting connection of the reaction of the formula I can be isolated by conventional methods, for example by 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 formula IIIa and IIIb. Acetylene formula IIIa, in which n is 1, conveniently be obtained by alkylation of the corresponding heterocyclic system using bromide propargyl by known methods. The compounds of formula IIIa, in which n is 2, can be obtained by alkylation of the corresponding heterocyclic system, for example, 4-tosyloxy-1-Butina.

It is noticed that when the compound of the formula I and/or formula II has an asymmetric carbon atom, it may be convenient to use enantion the UB>1, R2, R4, Y and s are as described previously.

In reaction scheme II, a compound of formula I in which n is 0 can be obtained otherwise than stated above. The compound of formula II in which Y is bromine or iodine, is subjected to reaction in the presence of a palladium catalyst with trimethylsilylacetamide to get the appropriate reaction product of formula IV. The parameters of the reaction are essentially the same as described above for reaction scheme I. Further, the compound of formula IY desilicious by treatment with aqueous alkaline solution to obtain etinilnoy compound of formula Y. the Transformation of compounds of formula IV to the compound of the formula Y is carried out by hydrolysis, preferably by treatment with an aqueous solution of alkali metal hydroxide in miscible in water solvent, such as alcohol, tetrahydrofuran, dioxane or the like, eliminating the presence of oxygen. The temperature at which the reaction is carried out is not critical, but preferred is a temperature in the range of about from 0 to 100oC. the Resulting compound of the formula Y undergoes further reaction, kataliziruemoi palladium, arylalkenes or gonski radical, according to variant b) method.

The resulting compound of formula Ia can be isolated by known methods, for example by crystallization or chromatography.

The compounds of formula I can form salts accession acids by treatment of the compounds of the first strong inorganic or organic acids. In particular, they form pharmaceutically acceptable salt accession acids with pharmaceutically acceptable organic and inorganic acids, for example, using kaleidograph acids, such as hydrochloric acid, Hydrobromic acid, itestosterone acid, other inorganic acids such as sulfuric acid, phosphoric acid, perchloric acid or the like; alkyl - and mono-aryl-sulfonic acids, such as econsultancy acid, toluensulfonate acid, benzolsulfonat acid or the like. Pharmaceutically unacceptable salts accession acid compounds of the formula I can be converted into a pharmaceutically acceptable salt accession acid through normal metabolic reactions by which the pharmaceutically unacceptable anion is replaced by a pharmaceutically acceptable anion; or otherwise: by N. there are thus free base with a reagent, leading to a pharmaceutical acceptable salt accession acid.

The compounds of formula I are active antagonists of platelet activating factor (PAF) and therefore are useful in disease States characterized by excessive platelet activating factor, or for the prevention and treatment of cardiovascular diseases, pulmonary diseases, immunological disorders, shocks or graft rejections.

The activity of the compounds of formula I can be demonstrated as follows:

Quantitative analysis of binding

a) Analysis

Quantitative analysis of binding was carried out in plastic microcentrifuge tubes of Beckman 400 ál containing 50 µl of the oil mixture of 2 parts of Silicone AR200 (Serva) and 1 part of a Silicone fluid (Arthur H. Thoma). In a test tube were added to the buffer, standards or equivalents (total volume 150 μl). Then in a test tube add radiolabelled3H-PAF (50 μl). The reaction begins to occur when adding 50 μl of platelet dogs (2107platelets). Tubes clog caps are turned over several times to mix and incubate for 10 min at room temperature the and Microfuge At Beckman. The upper end of the microcentrifuge tubes separated and washed platelets from the upper end with 200 µl of 50% methanol (Paul Burdick and Jackson). Add Aquasol (NEN, 10 ml), and determine the radioactivity in the samples using liquid scintillation counter type Bachman LS 8100 associated with the recorder of the type Techran. Data are processed using a home computer system, or radioactivity determined using a liquid scintillation counter type Searl Merk III, associated with the microcompressor Iso Data. The results are presented in table. 1 and 2.

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 min at 600 rpm (100-125 g) at room temperature. Aliquot part of pooled plasma rich in platelets (PRP), leave 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 obtained after 10-mine centrifugation at 2000 rpm (1000 g) when it is once with phosphate-saline buffer solution (PBS), containing 1 mm ethylenediaminetetraacetic acid (EDTA); centrifugation as mentioned 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, diluted to a concentration of 2107platelets/empatheia tube (4103platelets/ml). The platelet count is performed 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 Guinea pigs supplied by the ventilator, using a Harvard respirator for small animals-rodents (3.0 cm3shock (systolic) blood volume, 40 breaths per mine). Tracheal pressure recorded from the cannula introduced into the trachea and connected to a pressure sensor Statema.

Jugular vein onuliruetsya to enter the compound. Spontaneous breathing is created using succinylcholine (1.2 mg anolol, as shown, increases responsiveness to bronchostenosis, all animals pre-treated for 5 min prior to injection of propranolol (0.1 mg/kg, intravenously).

For internal testing Guinea pig subjected to pre-treatment with propranolol in a dose of 0.1 mg/kg intravenously over mine before injection. The test compound is introduced for mine to intravenous infection with PAF. Then the animal becomes infected intravenous dose of 1 μg/kg of PAF and recorded the change in tracheal pressure.

For oral test prior to the introduction of the test compound, administered through the oral tube for enteral feeding, hold for 1 h before injection. Propranolol or succinylcholine and PAF are administered intravenously, and the change in tracheal pressure is logged.

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 brancote ulitity presented in table.1 and 2.

The compounds of formula I include the racemates and enantiomers, if one or more asymmetric carbon atoms present in the compound of formula I.

The compounds of formula I and their pharmaceutically acceptable salts can be introduced using techniques well known in the field. In particular, 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 for the receptor) or asthma steroids, such as prednisone and prednisolone, orally, parenterally, 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, mixed with sugar or other sweetening agents, flavouring ve is naturalnego 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, using 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 in a mixture of miscible solvents, or can be mixed with pharmaceutically acceptable active propellants. Such aerosol compositions are packaged for use in the hermetic vessel, fitted with an aerosol valve, suitable for releasing the liquefied composition. Although it is preferred that the aerosol valve was measured 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 its salts, which must be entered, and frequency of administration must depend on the effectiveness and duration of preservation activity of certain compounds of formula I or salts, which must be entered, and the method of administration, and severity of condition, age of the mammal to be treated, and the like. Oral doses of the compounds of formula lah 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, which have asymmetric centers, and are usually obtained in the form of racemic mixtures. In particular, when R4and R5are heterocyclic group, the latter may also have one or more asymmetric centers, and the resulting racemates, enantiomers and diastereomers are also part of the 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 are formed from the racemic mixture of the compounds of formula I with an optically active separating reagent. Formed 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 somersaults in degrees Celsius, if not specified otherwise.

Example 1.

a) a Mixture of 31 g (0.08 mol) of 1,3-dihydro-5-(2-forfinal)-7-iodine-1,4-benzodiazepine-2(2H)-it (see G. F. Field, and L. A. Sternbach, Swiss patents 561, 706, may 1975, 562, 222, April 1975), 20 g (0.09 mol) of pentasulfide phosphorus, and 20 g of sodium bicarbonate and 300 ml of diglyme stirred and heated to 80-85oC for 3 hours, the Reaction mixture was then poured onto ice and diluted with water. After stirring for 30 min the solid yellow reaction product is filtered off, washed with water, 2-propanol and a small amount of ether. Sucked dry in the funnel and additionally dried under vacuum to obtain 26 g (80%) of 1,3-dihydro-5-(2-forfinal)-7-iodine-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 and has so pl. 242-244oC.

b) To a suspension of 8 g of the above thione in 40 ml of 2-propanol and 100 ml of tetrahydrofuran, add 3 ml of hydrazine. After stirring for 15 min at room temperature, the reaction mixture was filtered 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%) 5-(2-�asenavage connection 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 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] -benzodiazepine with so pl. 235-238oC.

g) a Mixture of 1.68 g (4 mmol) of 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4]triazolo[4,3-a] [1,4]-benzodiazepine, 0.88 g (4.8 mmol) of N-propargylamine, 2 ml of triethylamine, 0.36 g of triphenylphosphine, 0.08 g modestou copper (I) and 40 ml of dimethylformamide is stirred and Tegaserod with slow current of argon for 15 minutes Immediately add 0.12 g of palladium acetate and the mixture is stirred under argon for 16 h at room temperature. The reaction mixture is divided into parts between 200 ml of methylene chloride and 100 ml of saturated aqueous sodium bicarbonate solution. The organic phase is separated, dried over sodium sulfate and evaporated under reduced pressure, 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. Peeled(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 mol) of (2-AMINOPHENYL)-(2-chlorophenyl)-methanol (see E. Peeder and L. H. Sternbach, U.S. patent 3,371,085, February 1968) in 500 ml of methylene chloride, cooled to -60oC. After stirring with cooling for 5 h, the cooling bath is removed and the temperature of the reaction mixture was allowed to reach 0oC. Followed by addition of 300 ml of an aqueous solution of sodium bisulfite 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-itfeel)-(2-chlorophenyl)-methanone with so pl. 120-122oC.

b) To a solution of 52 g (0,145 mol) of (2-amino-5-itfeel)-(2-chlorophenyl)-methanone in 300 ml of methylene chloride, cooled to 0oC add 15 ml of methyl bromacetyl. Slowly with stirring, 10% aqueous sodium carbonate solution (150 ml) and the biphasic system was 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-ablaut to 800 ml of liquid ammonia, cooling with dry ice. After boiling under reflux for 16 h cooling interrupt and 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 l of ethanol and the solution is heated to boiling point under reflux for 30 min after addition of 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-iodine-2H-1,4-benzodiazepine-2-it, which melts at 260-262oC after recrystallization from a mixture of tetrahydrofuran and ethanol.

C) a Solution of 15.7 g (0.04 mol) of 5-(2-chlorophenyl)-7-iodine-1,3-dihydro-2H-1,4-benzodiazepine-2-it in 350 ml of tetrahydrofuran is cooled to -30oC. Tert. -piperonyl potassium, 4.9 g (0,044 mol) is added and stirring under nitrogen was continued for 30 minutes at a temperature of from -10 to -5oC. Then add to 6.6 ml of diethylphosphate and the mixture is stirred at this temperature for an additional 30 minutes After addition of 3.4 g of acetylhydrazine stirring without cooling continued for 1 h and add 150 ml of n-butanol. The tetrahydrofuran is distilled off from the reaction mixture in more 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 tetrahydrofuran 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 1 g, 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-isoindole-1,3(2H)-dione, which is purified by chromatography and crystallized from a mixture of methanol and ethyl acetate to obtain white crystals with so pl. 248-250oC.

Example 3

a) a Mixture of 1 g of 5-(2-forfinal)-7-iodine-2-hydrazino-7-iodine-3H-1,4-benzodiazepine (see example 1B), 5 ml teeterboro ether orthobionomy acid and 10 ml of xylene is heated to boiling under reflux for 1 h the Solvent was partially evaporated and the residue 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-FPO is(2-forfinal)-8-iodine-4H-[1,2,4]triazolo[4,3-a] [1,4] benzodiazepine 220 mg of N-propargylamine, 80 mg of triphenylphosphine, 20 mg modestou copper (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-forfinal)-4H-[1,2,4] triazolo[4,3-a][1,4]-benzodiazepine-8-yl]-2-PROPYNYL]-1H-isoindole-1,3(2H)-dione with so pl. 216-219oC.

Example 4

6-(2-Chlorophenyl)-8-iodine-1-methyl-4H-[1,2,4] triazolo[4,3-a] [1,4]-benzodiazepine is subjected to interaction with 1-(2-PROPYNYL)-1H-indole-2,3-dione [see F. Lindquist, P. Lagerstrom and R. Dahlbom, Acta Pharm. Suecica, 9, 99 (1972)] 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-chlorine is actally 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 is subjected to interaction with 2-(2-PROPYNYL)-1H-benzo[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 gives 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 as colorless crystals with so pl. 213-215oC containing 0,66 molar amount of water, according to the PMR spectrum and analysis.

Acetylene component of the reaction was obtained as follows:

6.2 g (by 0.055 mol) of tert. -butoxide potassium are added to a solution of 9.9 g (0.05 mol) of naphthalimide in 50 ml of dimethylformamide, cooled to -20oC. After stirring under cooling for 1 h, add 5 ml (by 0.055 mol) of propargylamine 20 mg 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 precipitates in to the STN crystals of 2-(2-PROPYNYL)-1H-benzo[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 is subjected to interaction with 1-(2-PROPYNYL)-1H - benzimidazole [see I. I. Popov, P. C. Tkachenko, A. M. Simonov. Chemistry of heterocyclic.compounds 551, (1973)] 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-PROPYNYL] -6-(2-chlorophenyl)-1-methyl-4H-[1,2,4] triazolo[4,3-a] [1,4] -benzodiazepine as colorless crystals with so pl. 165-168oC. 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 [see A. Lindquist et al. Acta Pharm. Suecica, 9, 99 (1972)] 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] Suecica, 9, 99 (1972)] 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. 141-143oC and containing 0.33 mol of ethanol and 0.66 mol of water.

Example 9

A mixture of 0.84 g (2 mmol) 6-(2-chlorophenyl)-8-iodine-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine, 0.5 g (2.4 mmol) of 1-(2-PROPYNYL) -benzo[cd] indol-2(1H)-she, 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 h 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. The remainder chromatographic on 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]-benzo[cd]-Indosat as follows.

To a solution 8,46 g (5 mmol) benzo[cd] indol-2(1H)-she's in 100 ml of dimethylformamide type of 6.17 g (by 0.055 mol) of tert.-butoxide potassium. After stirring for 10 min at room temperature add to 4.9 ml (by 0.055 mol) of methyl propargyl and the mixture is stirred for 1 h at room temperature. The reaction mixture is acidified with acetic acid and separated into parts between methylene chloride and saturated aqueous sodium bicarbonate. The organic layer is dried and evaporated and the residue crystallized from a mixture of tetrahydrofuran and ethanol to obtain 8 g (77%) of 1-(2-PROPYNYL)-benzo[cd] indol-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, and it has so pl. 185-187oC.

Example 10

The reaction 0.84 g of 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4]triazolo [4,3-a] [1,4] -benzodiazepine from 0.53 g (2.6 mmol) of 4-(2-PROPYNYL)-2H-1,4-benzothiazin-3(4H)-it [see R. N. Prasad and K. Tietje, Can.J.Chem.44, 1247 (1966)] 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 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 is racette.

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-benzoxazin-3(4H)-he will receive a similar way, using the reaction of 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-benzoxazin-3(4H)-one [see A. Lindquist et. al, Acta Pharm. Suecica, 9, 99 (1972)] as described in example 9. The reaction product is isolated and purified using chromatography and crystallized from ethyl acetate to obtain 0.55 g (56%) of light yellow crystals 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 mmol) 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4] triazolo[4,3-a] [1,4]-benzodiazepine with 0,48 g (2.6 mmol) of 3-(2-PROPYNYL)-4(3H)-hintlian [see J. Maillard et al. Chimie There, 3, 202 (1967)] 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)-hintlian with so pl. 199-201oC contains 1 mol of water and 0,166 mol 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 obtained by reaction of 6-(2-forfinal) is B. Akerman, Acta Pharm. Suecica, 6, 379, (1969)] as described in example 9. He was isolated from 57% yield and recrystallized from ethyl acetate, so pl. 241-244oC with decomposition. The crystals contain 0.66 mol 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-2,3-dihydro-2-(2-PROPYNYL)-1H-isoindole-1-one [see I. J. Neumeyer, U. V. Mayer, J. A. Richman, F. J. Rosenberg, and D. G. Teiger, J. Med. Chem. 10, 615 (1967)] gives, after chromatographic purification 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 contain 0.5 mol 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-PROPYNYL)-1H-isoindole-1-one. The reaction product is not obtained in the crystalline state and was characterized by a spectroscope. For analysis soedinenijam under vacuum. NMR (CDCL3):of 2.64 (s, 3, CH3); 2,96 (s, 3, OMe); to 4.1 (d, 1) and 5,54 (d, 1); (AB system, J=7 Hz, CH2); 4,2 (d,1) and 4,88 (d, 1) (AB-system, J= 9 Hz, CH2propinyl); 6,07 (s, 1, C3-H); from 6.9 to 8.0 (m, 11, aromatic H) M. D.

Acetylene component of the reaction was obtained as follows.

A solution of 2 g of 2,3-dihydro-3-hydroxy-2-(2-PROPYNYL)-1H-isoindole-1-she's in 20 ml of chloride tiomila leave 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 min, 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 min with stirring. The resulting solution concentrated PR is astora sodium bicarbonate. Precipitated crystals of racemic 2,3-dihydro-3-hydroxy-2-(2-PROPYNYL)-1H-isoindole-1-it is separated 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-Forfinal)-1-methyl-4H-[1,2,4] triazolo[4,3-a] [1,4]- benzodiazepine-8-yl] -2-PROPYNYL] -1,2,4-triazolo[4,3-a]-pyridine-3(2H)- he will receive, as described in example 9, reaction of 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 mol of water.

The target product was obtained as follows.

To a solution of 3.25 g (2.4 mmol) of 1,2,4-triazolo[4,3-a]-pyridine-3(2H)-she's in 75 ml of dimethylformamide added 3 g (2.6 mmol) of tert.-butoxide potassium. After stirring under nitrogen for 15 min add 2.35 ml (2.6 mmol) of methyl propargyl and stirring at room temperature continued for 1 h the Solvent is evaporated under reduced pressure, at the end of the azeotrope with xylene. The remainder extragroup in methylene chloride and crystallization of purified fractions from methanol yields 1.7 g of colorless crystals of 2-(2-propenal)-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-(1H-indazol-1-yl)-1-PROPYNYL] -4H-[1,2,4] triazolo[4,3-a] [1,4] -benzodiazepine receive, as described in example 9, by reacting 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4]triazolo[4,3-a] [1,4] -benzodiazepine-1-(2-PROPYNYL)-1H-indazole [see P. C. Tkachenko, I. I. Popov, A. M. Simonov and Y. C., Medvedev, Chemistry, heterocyclic. connect. 11, 1542 (1975)] Chromatographic selected reaction product is crystallized from ethyl acetate to obtain yellow crystals with so pl. 148-151oC.

Example 18

The reaction of 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4]triazolo[4,3-a] [1,4]-benzodiazepine with 1,3-dihydro-1-(2-PROPYNYL)-2H-indol-2-one [see A. Lindquist et.al, Acta Pharm. Suecica, 9, 99 (1972)] as described in example 9, 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]-1,3-dihydro-2H-indol-2-it is a hydrate of ethyl acetate, which have so pl. 233-235oC.

Example 19

Hemihydrate 1,1-diocese 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]-benzodiazepine with 1,1-dioxide of 2-(2-PROPYNYL)-1,2-benzisothiazol-3(2H)-ografia and crystallized from a mixture of methylene chloride and ethyl acetate, to obtain colorless crystals with so pl. 238-240oC.

Example 20

The reaction of 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4]triazolo[4,3-a] [1,4]-benzodiazepine-2 - (2-PROPYNYL)-tetrahydro-1H-pyrrolo[1,2-c] imidazole-1,3(2H)-dione, under the 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]-benzodiazepine-8-yl] -2-PROPYNYL] -tetrahydro-1H-pyrrolo-[1,2-c] imidazole-1,3(2H)-dione with so pl. 158-161oC.

Acetylene component of the reaction was obtained as follows:

of 1.23 g (11 mmol) of tert.-butoxide potassium added to a solution of 1.4 g (10 mmol) tetrahydro-1H-pyrrolo-[1,2-c] imidazole-1,3(2H)-dione (L-prolegomenon) [see T. Suzuki, K. Igarashi, K. Hase and T. K. Tuzimura, Agr. Biol. Chem. 37, 411 (1973)] in 20 ml of dimethylformamide. After stirring for 10 min at room temperature was added 1 ml (11 mmol) of methyl propargyl and stirring under nitrogen was continued for 2 hours, the Reaction mixture was acidified with acetic acid and evaporated under reduced pressure. The residue is dissolved in methylene chloride and filtered. The filtrate is evaporated and the residue chromatographic over 45 g of silica gel using 5 vol. ethanol chloride matile,3(2H)-dione as a colourless viscous oil.

NMR (CDCl3): 1,72 (m, 1, C6-H); 1,9-2,4 (m, 3, C6-H); 2,22 (t, 1, J=1.5 Hz, acetylenic H); 3,24 (m, 1, C5-H); 3,70 (m, 1, C5-H); 4,11 (dd, 1, J=4 Hz and 3.5, Si-H); to 4.23 (d, 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-isoindole-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 [see W. E. Hahn, A. Sokolowska, Soc. Sci. Lodz. Acta Chim. 18, 187 (1974)] 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 mol of water.

Example 22

The reaction of 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 ethyl acetate, 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-4-methyl-1H-1,4 - benzodiazepine-2,5-dione with so pl. 179-182oC. the Crystals contain according to the analytical and NMR data of 0.16 mol of ethyl acetate and 0.66 mol of water.

Neobhodimy mmol) of 3,4-dihydro-4-methyl-1H-1,4-benzodiazepine-2,5-dione (see M. Uskokavic and W. Wenner, U.S. patent 3,261,828, July 1966) 3.4 barium oxide and 100 ml of dimethylformamide. After stirring at room temperature for 2 h, 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-benzodiazepine-2,5(2H)-dione as colorless crystals with so pl. 148-150oC.

Example 23

The reaction of 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4]triazolo[4,3-a] [1,4]-benzodiazepine-1-(3-pyridyloxy)-2-propyne [see J. Bruhn, J. Zsindely, H. Schmid, and G. Frater, Helv. Chim. Acta, 61, 2542 (1978)] 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 mol 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 6-(2-forfinal)-8 - iodine-1-methyl-4H-[1,2,4] triazolo[4,3-a][1,4]-benzodiazepine-1-phenoxy-2-propyne, as described in>C.

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 (the Netherlands patent 7,205,730, November 1972, Hoffmann-La Roche & Comp. AG, Basel) 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 min 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-iodine-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-iodine-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 h After cooling to room temperature the mixture of water and crushed ice is added and stirring is continued for 15 minutes precipitated 5-(2-chlorophenyl)-1,3-dihydro-7-iodine-2H - thieno-[2,3-e] [1,4]-diazepin-2-he collected filter is,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 of 5-(2-chlorophenyl)-2-hydrazino-7-iodine-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 paratoluenesulfonyl 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 mmol) 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 mmol) of 2-(2-PROPYNYL)-1H-benzo[oe]-isoquinoline-1,3(2H)-dione, 1 ml of triethylamine, 20 mg modestou copper (I), 90 mg of triphenylphosphine and 20 ml of dimethylformamide Tegaserod slow current of argon for 15 minutes Then add 30 mg of palladium acetate and the mixture peices completion of the reaction after 5 o'clock 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 ethyl acetate gives 0,58 g(53%) 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] -1H-benzo[oe] -isoquinoline-1,3(2H)-dione with so pl. 188-192oC. There is also another crystal modification with so pl. 252-254oC.

Example 26

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]-1H-indole-2,3-dione receive as described in example 25 g, 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 1-(2-PROPYNYL)-1H-indole-2,3-dione [see A. Lindquist et al, Acta Pharm. Suecica, 9, 99 (1972)] Chromatographic separation and crystallization from a mixture of methanol and ethyl acetate gives orange crystals with so pl. 185-190oC with foaming at 130-140oC. These crystals with the R>
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 1-(2-PROPYNYL)-benzo[cd] indol-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 adding ethyl acetate to give crystalline hydrochloride 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]-benzo[cd] indol-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-a] [1,4] -diazepin-2-yl] -2-PROPYNYL] -1,3-dihydro-2H-indol-2-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 1,3-dihydro-1-(2-PROPYNYL)-2H-indol-2-one [link A. Lindquist et al, Acta Pharm. Suecica, 9, 99 (1972)] 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 mol of water and traces of ethyl acetate.

Example 29

The reactions. Popov and other Chemistry of heterocyclic compounds, 551 (1973)] 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 mol of water, which shows 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)-it is produced by 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 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 of these crystals containing 0.25 mol 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] triazolo[4,3-a] [1,4] -diazepine with 1,1-Dionisio 2-(2-PRG. 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 of 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno[3,2-f] [1,2,4] triazolo[4,3-a] [1,4]-diazepine with 1-(3-pyridyloxy)-2-propyne [see J. Bruhn, J. Zsindely, H. Schmid, and G. Frater, Helv. Chim. Acta, 61, 2542 (1978)] 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): of 2.72 (s, 3,CH3); 4,95 (s, 4, CH2; C6-H); at 6.8 (s, 1, C3-H); 7,2-7,6 (m, 6, aromatic H); compared to 8.26 (m, 1) and at 8.36 (broadened s, 1), pyridine2and C6Mr. M. D.

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]diazepine with 1-(2-PROPYNYL)-1H-indazole [see P. C. Tkachenko and other Chemistry of heterocyclic compounds, 1542 (1975)] the reaction Product is isolated and purified using chromatography and the crystal is example 34

The reaction of 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4]triazolo[4,3-a] [1,4]-benzodiazepine-1-(2-PROPYNYL)-1H-indole [see A. J. Hubert and H. Reimlinger, J. Chem. Soc. c.606 (1968)] 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]-benzodiazepine 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 [see J. W. Daly, W. L. Padgett, and M. T. Shamin, J. Med. Chem. 29, 1305 (1986)] 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 0.75 mol 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 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4] triazolo[4,3-a] [1,4]-benzodiazepine-2 - (3-buten-1-yl)-1H-isoindole-1,3(2H)-dione [see K. J. Hoffmann, P. Steuberg, C. Ljunggren, V., Svensson, J. L. G. Nilsson, A. Erikson, A. Hartkoorn and R. Lunden, J. Med. Chem. 18, 278 (1975)] ecolocal colorless crystals with so pl. 128-130oC (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 [see A. Lindquist et al, Acta Pharm. Suecica, 9, 99 (1972)] as described in example 25g. After chromatographic separation of the reaction product is crystallized from ethyl acetate to obtain yellow crystals with so pl. 190-192oC. 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 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-1-(2-PROPYNYL)-1H-purine-2,6-dione [see J. W. Daly, W. L. Padgett, and M. T. Shamin, J. Med. Chem. 29, 1305 (1986)] as described in example 25g. The reaction product produce by using chromatography and crystallized from ethyl acetate to obtain yellow crystals with so pl. 277-280o, 7-dihydro-3,7-dimethyl-7-(2-PROPYNYL)-1H-purine-2,6-dione [see J. W. Daly, W. L. Padgett, and M. T. Shamin, J. Med. Chem. 29, 1305 (1986)], 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]-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione with so pl. 229-232oC. These crystals contain 0.125 mol of ethyl acetate according to the analytical and spectral data.

Example 40

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 2-(3-buten-1-yl)-1H-benzo[de] isoquinoline-1,3(2H)-dione as described in example 25g, gives, after chromatography and crystallization from ethyl acetate light 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 of the reaction was obtained as follows.

A mixture of 6 g (0.03 mol) 1H-Benz[de]isoquinoline-1,3(2H)-dione, 4 g (0,0355 mol) of tert. -butoxide potassium, 9 g (0.04 mol) of 4-tosyloxy-1-butyne [see G. Eglinton and M. C. Whiting, J. Chem. Soc. 3650 (1950)] and 150 ml of dimethylformamide is heated on the steam bath with stirring for 1.5 hours the Weight of the solvent of si to precipitate the reaction product is collected by filtration and dissolved in methylene chloride. The solution is dried and passed over pressed silicagel using methylene chloride for elution. Crystallization from a mixture of methylene chloride and ethanol gives 2-(3-buten-1-yl)-1H-benzo[de] isoquinoline-1,3(2H)-dione as colorless needles with so pl. 191-193oC.

Example 41

a) a Mixture 2,52 g of 6-(2-forfinal)-8-iodine-1-methyl-4H-{1,2,4]triazolo [4,3-a] [1,4] -benzodiazepine, 270 mg of triphenylphosphine, 60 mg modestou copper (I), 1.5 ml of triethylamine and 60 ml of dimethylformamide is stirred and Tegaserod slow current of argon for 10 min Trimethylsilylacetamide 1.2 ml then add to the mixture and degassing continued for 2 minutes At this time, add 90 mg of palladium acetate and the mixture is stirred under argon for 4 h at room temperature. The reaction mixture rasclaat between methylene chloride and saturated sodium bicarbonate solution. The organic layer is washed with water, dried and evaporated, at the end of the azeotrope with xylene. The remainder chromatographic over 60 g of silica gel (Merck, 70-230 mesh) using 5 vol.-hydrated ethanol in methylene chloride for elution. Crystallization of the combined purified fractions from a mixture of ethyl acetate and hexane gives 2,05 g (86%) of colorless crystals of 6-(2-forfinal)-1-methyl-8-[(trimethylsilyl)-1-methyl-8-[(trimethylsilyl)- ethinyl] -4H-[1,2,4] triazolo[4,3-a] [1,4]-benzodiazepine in 50 ml of ethanol was added 1 ml of 10N sodium hydroxide solution. The mixture is stirred under argon at room temperature for 1 h, and then divided into parts between methylene chloride and saturated aqueous sodium bicarbonate. The organic phase is separated, dried and evaporated. The residue is filtered over soft padding of silica gel using 5% ethanol in methylene chloride for elution. The filtrate is evaporated and the residue crystallized from a mixture of ethyl acetate and hexane to obtain colorless crystals of 8-ethinyl-6-(2-forfinal)-1-methyl-4H-[1,2,4] triazolo[4,3-a][1,4]-benzodiazepine with so pl. 258-260oC.

C) a Mixture of 316 mg (1 mmol) of 8-ethinyl-6-(2-forfinal)-1-methyl-4H-[1,2,4] triazolo[4,3-a] [1,4] -benzodiazepine, 200 mg (1.25 mmol) of 5-bromopyrimidine, 45 mg of triphenylphosphine, 10 mg modestou copper (I), 0.5 ml of triethylamine and 10 ml of dimethylformamide is stirred and Tegaserod for 10 min slow flow of argon. Then add 15 mg of palladium acetate and stirring under argon continue for 24 hours the Reaction mixture rasclaat between aqueous sodium bicarbonate solution and methylene chloride. The organic layer is washed with water, dried and evaporated, at the end of the azeotrope with xylene. The remainder chromatographic over 20 g of silica gel (Merck, 70-230 mesh) using 5% ethanol you get is not quite white crystals of 6-(2-forfinal)-1-methyl-8-[(5-pyrimidinyl)-ethinyl]-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine with so pl. 143-146oC.

Example 42

and in this way obtain 6-(2-chlorophenyl)-1-methyl-8-[(trimethylsilyl)-ethinyl] -4H-[1,2,4] triazolo[4,3-a][1,4]-benzodiazepine, using the reaction of 6-(2-chlorophenyl)-8-iodine-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4] -benzodiazepine with trimethylsilylacetamide as described in example 41A. The reaction product produce by using chromatography and crystallized from a mixture of ethyl acetate and hexane to obtain colorless crystals with so pl. 243-245oC.

b) 6-(2-Chlorophenyl)-8-ethinyl-1-methyl-4H-[1,2,4] triazolo[4,3-a] [1,4]-benzodiazepine receive, as described in example 41B, the processing of 6-(2-chlorophenyl)-1-methyl-8-[(trimethylsilyl)-ethinyl]-4H-[1,2,4]triazolo[4,3-a][1,4] -benzodiazepine sodium hydroxide in ethanol. The reaction product is crystallized from ethanol to obtain colorless crystals with so pl. 304-306oC.

C) 6-(2-Chlorophenyl)-1-methyl-8-(2-titilating)-4H-[1,2,4]triazolo[4,3-a] [1,4] -benzodiazepine receive, as described in example 41C, the reaction of 6-(2-chlorophenyl)-8-ethinyl-1-methyl-4H-[1,2,4] triazolo[4,3-a] [1,4]-benzodiazepine 2-iodophenol. The reaction product is isolated and purified using chromatography and crystallized from ethyl acetate to obtain crystals with so pl. 160-163oC. These crystals contain according to the analytical and the-iodine-9-methyl-6N-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]-diazepine c trimethylsilylacetamide, as described in example 41A, gives, after chromatographic separation and crystallization from ethyl acetate and hexane are not white crystals of 4-(2-chlorophenyl)-9-methyl-2-[(trimethylsilyl)-ethinyl] -6N-thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]-diazepine c so pl. 135-138oC.

b) Processing 4-(2-chlorophenyl)-9-methyl-2-[(trimethylsilyl)-ethinyl]-6N-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]-diazepine sodium hydroxide in ethanol yields after chromatographic purification and crystallization from a mixture of methanol and ethyl acetate, colorless crystals of 4-(2-chlorophenyl)-2-ethinyl-9-methyl-6N-thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepine c so pl. 232-233oC.

C) a Mixture of 0.34 g of 4-(2-chlorophenyl)-2-ethinyl-9-methyl-6N-thieno[3,2-f] [1,2,4] triazolo[4,3-a] [1,4] -diazepine, 45 mg of triphenylphosphine, 10 mg modestou copper (I), 1 ml of triethylamine, 0,38 g 1-iodonaphthalene and 10 ml of dimethylformamide Tegaserod for 10 min slow flow of argon. After adding 15 mg of palladium acetate, the mixture is stirred under argon for 2 h at room temperature. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and ice. Drop down the precipitate is filtered off, washed with water and dissolved in methylene chloride. The solution is dried and evaporated, and the residue chromatographic on 15 g of silica gel, the mandate and the residue crystallized from a mixture of ethyl acetate and hexane, to get not quite white crystals of 4-(2 - chlorophenyl)-2-[(1-naphthyl)-ethinyl]-9-methyl-6N-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]-diazepine with so pl. 197-199oC.

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-(2-PROPYNYL)-2(1H)-henryanum [see A. Lindquist et al, Acta Pharm. Suecica, 9, 99 (1972)] as described in example 25g. The reaction product highlight chromatographic passing the solution over 50 g of silica gel using 5 vol. 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 and methanol gives 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] -2(1H)-Hinayana with so pl. 162 to 165 of theoC. These crystals contain according to the analytical data of 0.5 molar quantity of water.

Example 45

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 mol) of 3,4-dihydro-1-(2-PROPYNYL)-2(1H)-Hinayana [see A. Lindquist et al, Acta Pharm. Suecica, 9, 99 (1972)] 0.75 g of triphenylphosphine, and 0.2 g modestou copper (I), 60 ml of triethylamine and 600 ml of dimethylformamide is stirred and Tegaserod current of argon for 3M for 3 days. The mixture is then poured into a 2.5 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 and cooling the crystalline 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.

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 interaction with 2,3-dihydro-2-(2-PROPYNYL)-1H-Benz[de] -isoquinoline-1-one under the conditions described in example 25g. The reaction product produce by using chromatography over 40-fold amount of silica gel using tetrahydrofuran for elution. The fractions containing the above compound are pooled and re-chromatographic over 30-fold amount of silica gel using 5 vol. ethanol, velocity yellowish 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]-2,3-dihydro-1H-Benz[de]-isoquinoline-1-she's so square 205-210oC with decomposition. These crystals contain 0.66 mol of water according to the analytical and spectral data.

Required propargilovyh derivative obtained as follows.

A mixture of 2 g of 2-(2-PROPYNYL)-1H-benzo[de] isoquinoline-1,3(2H)-dione, 0.75 g sodium borohydride, 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 of borohydride is added and the tetrahydrofuran is distilled off on a steam bath within 30 minutes Remaining mixture is cooled, diluted with ice water, create a buffer with acetic acid and diluted with aqueous sodium bicarbonate solution. Precipitating the reaction product is filtered off after stirring on ice, 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-3-hydroxy-2-(2-PROPYNYL)-1H-Benz[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 dobavljaee 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. ethyl acetate in methylene chloride. Crystallization of the combined purified fractions from a mixture of ethyl acetate and hexane gives colorless crystals of 2,3-dihydro-2-(2-PROPYNYL)-1H-Benz[de] -isoquinoline-1-she's so square 139-140oC.

Example 47

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 example 25g. The reaction product produce by using chromatography over 50-fold amount of silica gel using tetrahydrofuran. Crystallization of the combined homogeneous fractions from ethanol gives light 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-3-methyl-2H-benzimidazole-2-she's so square 188-191oC.

The desired acetylene was obtained as follows.

To a solution of 2.5 g (to 16.9 mmol) of 1,3-dihydro-1-methyl-2H-benzimidazole-2-it in 25 ml of dimethylformamide added 2.1 g (18.5 mmol) of tert.-butoxide potassium. After stirring under nitrogen for 15 min type of 2.21 g (18.5 mmol) bravado and drop the precipitate is filtered off, washed with water and sucked dry. The crude reaction product is passed through silica gel, using 10 vol. 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)-1H - benzimidazole-2-she's so square 110-112oC.

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 racemic 2A,3,4,5-tetrahydro-2-[(2-PROPYNYL)-benzo[cd] indol-2(1H)-one under the conditions described in example 9. The reaction product produce by using chromatography over 50-fold amount of silica gel using 5 vol.-aqueous ethanol in methylene chloride for elution. The combined purified fractions 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]-indole-2(1H)-she's so square 215-217oC.

Required propargilovyh compound was obtained as follows.

To a solution 6,92 g (0.04 mol) of racemic 2A,3,4,5-tetrahydrobenzo[cd] -indol-(1H)2-she's in 50 ml of dimethylformamide add 4.94 g (0,044 mol) of tert.-butoxide calitalian within 30 minutes The mixture is diluted with water and ice and drop 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 reaction product is racemic 2A,3,4,5-tetrahydro-2-(2-PROPYNYL)-benzo[cd] indol-2(1H)-he is so pl. 174-177oC, which is recrystallized from ethyl acetate at 177-180oC.

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 5-(2-PROPYNYL)-5H-carbazole [see J. L. Dumont et al. Bull. Soc Chim. Fr. 1197 (1967)] under the conditions described in example 25g. The reaction product is purified by chromatography over 60-fold amount of silica gel using 5 vol. ethanol in methylene chloride. The combined purified fractions do not crystallize and viscous resin is converted to the crystalline dichlorhydrate treatment with excess ethanolic solution of hydrogen chloride in a mixture of ethanol and ethyl acetate. Yellow crystals dichlorhydrate 2-[3-(N-carbazole-9-yl)-1-PROPYNYL] -4-(2-chlorophenyl)-9-methyl-6N-thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]-diazepine have so pl. 180-184oC.

Example 50

A mixture of 44 g (0.1 mol) of 4-(2-chlorophenyl)-2-iodine-9-methyl-6N-thieno [3,2-f] [1,2,4] triazolo[4,3 the fin, 0.25 g modestou copper (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 Nam at room temperature. Insoluble matter is removed by filtration through the zeolite and the filtrate 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 min and washed with water and sucked dry. Solid particles are divided into parts between 2 liters of methylene chloride containing 5 vol. ethanol, and sodium bicarbonate solution. The organic 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-Ieno[3,2-f][1,2,4]triazolo[4,3-a][1,4] -diazepin subjected to interaction with 6-(2-PROPYNYL)-5H-dibenz[c,e]-azepine-5,7(6N)-dione [see J. R. Grunder et al. J. Pharm. Sci.62, 1204 (1973)] 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. The combined purified fractions 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]-2-PROPYNYL]-5H-dibenz[c,e]-azepine-5,7(6N)-dione with so pl. 220-223oC. These crystals contain 0,166 molar quantity of ethyl acetate according to the spectral and analytical 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 racemic 2A,3,4,5-tetrahydro-2-methyl-1-(2-PROPYNYL)-benzo[cd] indol-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 lorgeril)-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-tetrahydro-2A-methylbenz[cd]-indole-2(1H)-she's so square 175-178oC.

Source propargilovyh substance synthesized as follows.

To a solution 6,92 g (0.04 mol) of racemic 2A,3,4,5-tetrahydrobenzo[cd] -indole-2(1H)-she's in 50 ml of dimethylformamide add 4,94 GSH storage capacity (0.044 mol) of tert. -butoxide potassium. After stirring for 15 min under nitrogen add 6,24 g or 2,75 ml storage capacity (0.044 mol) iodotope bromide and stirring is continued for 30 minutes After dilution with water and ice mixture is extracted with methylene chloride. The extracts are dried over sodium sulfate and evaporated. The remainder chromatographic through silica gel, using 10 vol. ethyl acetate in methylene chloride. The combined purified fractions 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 mmol), dissolved in 20 ml of dimethylformamide. The solution is treated with 1.65 g (14.7 mmol) of tert.-butoxide potassium and stirred under nitrogen for 15 minutes Then add to 1.75 g of methyl propargyl (1.31 ml, 14 mmol) and stirring at room temperature continued for 30 minutes, the Reaction mixture was diluted with layaout 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 crystallized from ethyl acetate and hexane (mixture) to obtain colorless crystals of racemic 2A,3,4,5-tetrahydro-2-methyl-1-(2-PROPYNYL)-benzo[cd] indol-2(1H)-she's so square 127-130oC.

Example 53

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-phenoxy-1-propyne under the conditions described in example 25g. The reaction product is purified by chromatography through 50-fold amount of silica gel using 5 vol. ethanol in methylene chloride. The evaporated purified fractions give a remainder of a viscous oil which does not crystallize, but gives a crystalline dihydrochloride handling excess ethanolic solution of hydrogen chloride and ethyl acetate. Pale yellow crystals of the dihydrochloride of 4-(2-chlorophenyl)-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 148-151oC and 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 [see B. Danielsson et al. Acta Pharm. Suecica 2, is using argon for 10 minutes Then add 30 mg of palladium acetate and the mixture is heated up to 90-95oC for 30 min with stirring under argon. The temperature of the support at 90-95oC for 15 min and the dimethylformamide is evaporated under reduced pressure. The remainder rasclaat methylene chloride and aqueous sodium bicarbonate solution. The organic layer is dried and evaporated, at the end of the azeotrope with xylene. The remainder chromatographic 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 resulting 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)-chineselanguage with so pl. 167-170oC. These crystals contain 0.5 mol of water according to the analytical and spectral data.

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 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 the ratio of the I of 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 mol of ethyl acetate according to the analytical and spectral data.

The original acetylene substance obtained as follows.

To a suspension of 4.5 g of 5H-dibenz[b,e]-azepine-6,11-dione in 50 ml of dimethylformamide, add 2.5 g of tert.-butoxide potassium. After stirring under nitrogen for 30 min add 2 ml of methyl propargyl and stirring is continued for 1 h 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 crystallized from a mixture of ether and hexane to obtain colorless crystals of 6-(2-PROPYNYL)-5H-dibenz[b,e]-azepine-6,11-dione with so pl. 117-118oC.

Example 56

4-(2-Chlorophenyl)-2-iodine-9-methyl-6N-thieno[3,2-f] [1,2,4] triazolo [4,3-a] [1,4] -diazepin PV example 25g, but the duration of the reaction is increased to 72 hours the reaction Product is 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 ethyl acetate gives colorless crystals of 6-chloro-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)-she's so square 202-205 areoC.

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 1,4-dihydro-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. 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. The purified fraction is 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-it th acetylene synthesized as follows.

To a solution of 4.7 g (31 mmol) of 1,4-dihydro-3,1-benzoxazin-2-she's in 30 ml of dimethylformamide added to 3.9 g (34.6 mmol) of tert.-butoxide potassium. After stirring for 15 min under nitrogen was added 4.1 g or 3.1 ml of methyl propargyl and stirring at room temperature continued for 30 minutes, the Reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and precipitating 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-1-(2-PROPYNYL)-3,1-benzoxazin-2-she's so square 123-125oC.

Example 58

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. 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 gives not white 55oC.

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 2-(2-PROPYNYL)-1(2H)-athinaikon 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. Fractions, purified according to TLC, combined and evaporated, and the residue is 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 mol of water.

Necessary acetylene was obtained as follows.

A solution of 1 g (7 mmol) isocurvature in 40 ml of dimethylformamide is treated with 0,86 g (7.7 mol) of tert.-butoxide potassium. After stirring under nitrogen for 30 min add 0.7 ml of methyl propargyl and stirring at room temperature continued for 1 h, the Reaction mixture was 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 ether, to obtain colorless crystals of 2-(2 - PROPYNYL)-1(2H)-athinaikon with so pl. 104-105oC.

Example 60

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 produce by using chromatography through 50-fold amount of silica gel using 5 vol. ethanol in methylene chloride. The purified 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 mol of water according to the analytical data.

Required propargilovyh derivative synthesized as follows.

To a solution of 3 g (of 14.2 mmol) of 1,3-dihydro-3-phenyl-2H-benzimidazole-2-she's in 30 ml of dimethylformamide type of 1.76 g (15.7 mmol) of tert.-butoxide potassium and the mixture is stirred under nitrogen for 15 minutes Then added to 1.4 ml (15 mmol) of methyl propargyl and stirring is continued for 30 min at controcorrente sodium and filtered, washed with water and sucked dry. It is 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 crystallized from a mixture of methylene chloride and ethyl acetate to obtain colorless crystals of 1,3-dihydro-1-phenyl-3-(2-PROPYNYL)-2H-benzimidazole-2-she's so square 145-147oC.

Example 61

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 6,8-dichloro-3,4-dihydro-1-(2-PROPYNYL)-2(1H)-Hinayana under the conditions used 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. 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]-2-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 bundok adding ice and water and 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-1-(2-PROPYNYL)-2(1H)-Hinayana, 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 of concentrated hydrochloric acid is added to 75 ml of 1,2-dichloroethane, which was saturated with chlorine. The mixture is stirred on ice for 30 minutes Chlorine injected for 5 min and stirring in the cold continued for 2 hours the mixture is Then 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 about 8. 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 62

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 [see W. Schneider et al. Arch. Pharm. 291, 561 (1958)] under the conditions described in example 25g. the ü 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]-2-PROPYNYL]-3,4-dihydro-1(2H)-athinaikon with so pl. 164-166oC.

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 7-fluoro-4-(2-PROPYNYL)-2H-1,4-benzoxazin-3(4H)-one under the conditions used in 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 obtain 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] -2-PROPYNYL] -7-fluoro-2H-1,4-benzoxazin-3(4H)-she's so square 215-217oC.

Propargilovyh compound was obtained 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 45 minutes the Cooled reaction mixture is diluted with water and precipitating the reaction product is collected by filtration. Drop-down sediment is 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 64

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 1,2,3,4-tetrahydro-9-(2-PROPYNYL)-N-carbazole under the conditions used in example 25g. The reaction product produce by using chromatography through 50-fold amount of silica gel using 8 about. 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]-diazepine with so pl. 164-166oC. These crystals contain 0.66 mol 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 45 min under nitrogen, add a 3.9 grams or 2.9 ml (33 mmol) of methyl propargyl and stirring is continued for 30 min at room temperature ether. The extract is 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 to obtain colorless crystals 1,2,3,4-tetrahydro-9-(2-PROPYNYL)-N-carbazole with so pl. 74-76oC.

Example 65

A mixture of 0.88 g (2 mmol) 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 mmol) of 10-(2 - PROPYNYL)-9(10H)-acridinone [see A. R. Katritzky et al. J.Org. Chem. 50, 852 (1985)] 80 mg of triphenylphosphine, 20 mg modestou copper (I), 5.6 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 heated to 80-90oC for 30 minutes the reaction Product is precipitated by adding saturated aqueous sodium bicarbonate solution and 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. ethanol in methylene chloride for elution. The combined purified fractions evaporated and the residue crystallized from ethanol, inil] -9(10H)-acridinone with so pl. 175-180oC with foaming. These crystals contain a mole of water.

Example 66

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 in example 25g, but in the end the reaction mixture is heated for 5 min at 90-95oC. 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. 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)-2-iodine-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, 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 h, 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 is, operasie 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 67

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 phenylacetylene under the conditions described in example 25g. The reaction product produce by using chromatography through 50-fold amount of silica gel using 5 vol. ethanol in methylene chloride for elution. The combined purified fractions evaporated and the residue crystallized from ethyl acetate to obtain 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. 215-217oC.

Example 68

A mixture of 0.84 g (2 mmol) 6-(2-forfinal)-8-iodine-1-methyl-4H-[1,2,4] triazolo[4,3-a] [1,4] -benzodiazepine of 0.48 g (2.6 mmol) of 3,4-dihydro-1-(2-PROPYNYL)-2(1H)-Hinayana, 80 mg of triphenylphosphine, 20 mg modestou copper (I), 1.5 ml of triethylamine and 50 ml of dimethylformamide Tegaserod with argon for 10 minutes Then add a 25 mg acetate palladium and stirring is continued for 18 hours the Solvent is evaporated under reduced pressure and the residue is divided into parts between chloride mitilineos chromatographic through 50 g of silica gel, using about 5. 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. 236-239oC.

Example 69

6-(2-Forfinal)-8-iodine-1-methyl-4H-[1,2,4] triazolo[4,3-a] [1,4]- benzodiazepine is subjected to reaction with 4-phenyl-1-Butina under the conditions used in example 3b. The reaction product produce by using chromatography with 40-fold amount of silica gel using 5 vol. ethanol in methylene chloride for elution. The combined purified fractions 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 70

a) a Mixture of 5 g of 5-(2-forfinal)-2-hydrazino-7-iodine-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 ward off the methylene chloride. Then add 100 ml of toluene and nahrawan is or 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-iodine-4H-[1,2,4]triazolo[4,3-a][1,4] -benzodiazepine with so pl. 202-204oC.

b) a Mixture of 0.94 g (2 mmol) 6-(2-forfinal)-8-iodine-1-(trifluoromethyl)- 4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine, 0.55 g (3 mmol) of N - propargylamine, 80 mg of triphenylphosphine, 20 mg modestou copper (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. ethanol in methylene chloride. United good fraction is evaporated and the residue 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 71

a) a Solution of 2.9 g (13 IMO is) petaluridae phosphorus and the mixture is stirred for 30 min at -30oC. Then add a solution to 3.41 g (10 mmol) of 2-(2 - perbenzoic)-4-iodoaniline in 50 ml of methylene chloride and stirring is continued for 15 min at 0 to 10oC. After addition of 10% aqueous sodium carbonate solution of a two-phase mixture is stirred at this temperature for 30 minutes Then 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 of complex benzyl ether (S)-[2-[2-(2-perbenzoic)-4-itfeel] -amino]-1-methyl-2-oxoethylidene acid so pl. 159-161oC; []D= - 10,35(c 0,985 in CH2Cl2).

b) a Mixture of 11 g of benzyl ether (S)-[2-[2-(2-perbenzoic)-4-itfeel]-amino] -1-methyl-2-oxoethylidene acid and 30 ml of acetic acid containing 30% hydrogen bromide, stirred at room temperature for 3 hours, the Reaction mixture rasclaat 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, sod the AI and balance rasclaat methylene chloride and 10% aqueous solution of sodium carbonate. The organic phase is dried and evaporated and the residue crystallized from ethyl acetate and recrystallized from a mixture of methylene chloride and ethyl acetate 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= + 100,79(0,9891 in CH2Cl2).

C) a Solution of 2 g (5,07 mmol) of (S)-5-(2-forfinal)-1,3-dihydro-7-iodine-3-methyl-2H-1,4-benzodiazepine-2-it in 60 ml of tetrahydrofuran is cooled to 30oC and add 0,57 g (5.7 mmol) of tert.-butoxide potassium. The mixture is stirred under nitrogen for 30 min, while the temperature allow to rise to 5oC. Then add of 1.03 g (6.5 mmol) of diethylphosphate and stirring is continued for 30 minutes without cooling. After addition of 0.54 g (7.2 mmol) acetylhydrazide the mixture is stirred for additional 30 min at room temperature. Then add 75 ml of butanol and tetrahydrofuran is 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. canakci, from a mixture of ethyl acetate and hexane gives colorless crystals of (S)-6-(2-forfinal)-8-iodine-1,4-dimethyl-4H-[1,2,4] triazolo[4,3-a] [1,4]-benzodiazepine with so pl. 142-145oC; []D= + 50,38(c 0,9964 in CH2Cl2).

g) (S)-6-(2-forfinal)-8-iodine-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 with 50-fold amount of silica gel using 5 vol. ethanol in methylene chloride for elution. The combined purified fractions evaporated and the residue crystallized very slowly from a mixture of ethanol and ether to obtain colorless crystals (S)-1-[3-[6-(2-forfinal)-1,4-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. 155-160owith foaming. These crystals contain ethanol and water according to the analytical and spectral data. []D= + 87,5(c 1,0091 in CH2Cl2).

Example 72

a) a Solution of 29 g of N-benzyloxycarbonyl-L-alanine in 100 ml of tetrahydrofuran is cooled to -40oC. Then add 27 g petaluridae phosphorus and stirring continued for 30 min at -30oC. Add rastvori 0-10oC. Then it rasclaat with 300 ml of 10% aqueous sodium carbonate solution and two-phase mixture was stirred at 0 to 10oWith within 30 minutes After dilution with ether, the organic layer was separated, washed with an aqueous solution of sodium carbonate, dried and evaporated. The residue is crystallized from ethanol with the help of the seed. The seed is obtained by chromatography was carried out with 2 g of the sample through 60 g of silica gel using 10 vol. 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 of benzyl ether (S)-[2-[3-(2-chlorobenzoyl)-2-thienyl] -amino] -1-methyl-2-oxoethylidene acid so pl. 133-135oC; []D= - 26,92(c 0,9546 in CH2Cl2).

b) a Solution of 22 g of benzyl ether (S)-[2-[3-(2-chlorobenzoyl)-2-thienyl]-amino] -1-methyl-2-oxoethylidene acid in 75 ml of acetic acid containing 30% hydrogen bromide, leave to stand at room temperature for 3 hours, the Reaction mixture was 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 extragere 66 g of silica gel, the mixture is stirred and heated to boiling under reflux for 3 h with the Department of the resulting environment. The silica gel is filtered off and washed well with methanol. The filtrate is evaporated and the residue passed through 200 g of silica gel using a mixture of ethyl acetate and methylene chloride in the ratio of 1:1 for elution. The reaction product is crystallized from a mixture of methylene chloride and hexane, 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. 200-203o; []D= - 0,4(c 1,0185 in CH2Cl2).

C) a Mixture of 7.7 g (of 26.5 mmol) of (S)-5-(2-chlorophenyl)-1,3-dihydro - 3-methyl-2H-thieno-[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 (of 26.5 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-iodine-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-Gloria and 40-50 ml diglyme stirred under nitrogen at 80-90owithin 6 hours Add water and ice and the mixture is stirred for 15 minutes, the Solids filtered off, washed with water and sucked dry. The resulting tion additionally dried under vacuum at 50oWith, 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 min 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 the steam bath for 30 min 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 a rotation angle indicating a full racemization.

d) Racemic 4-(2-chlorophenyl)-2-iodine-6,9-dimethyl-6N-thieno[3,2-f] [Primera 25g. The reaction product produce by using chromatography through 50-fold amount of silica gel using 5 vol. ethanol in methylene chloride. The reaction product is crystallized from ethanol to obtain yellow 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. 182-186oWith foaming. These crystals contain according to the analytical data, molar quantities of water.

Example 73

A mixture of 1.1 g (2 mmol) 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 and 0.68 g of meta-chlormadinone acid in 100 ml of methylene chloride is left to stand at room temperature for 20 hours the Solution was washed with 10% aqueous solution of sodium carbonate, dried and evaporated. The residue is crystallized from a mixture of methanol and ethyl acetate to obtain 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]-2-PROPYNYL]-6(5H)-phenanthridinone with so pl. 260-270oWith decomposition.

Example 74

A mixture of 0.7 g 5-[3-[4-(2-chlorophenyl)-9-methyl-6N-thieno [3,2-f][1,2,4]triazolo[4,3-a] [1,4] -diazepin-5-oxide-2-yl]-2-PROPYNYL] 6(5H)- phenanthridinone, 25 ml of anhydride UKS the nom pressure and the residue chromatographic through 30 g of silica gel, using about 3. ethanol in methylene chloride for elution. Purified fractions containing 5-[3-[6-atomic charges-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, combined and evaporated. The rest is not crystallized and characterized only by a spectroscope.

NMR (CDCl3): a 2.36 (s, 3, OAc); in 2.68 (s,3, 9-Me); 5,43 (s, 2, -CH2-); 6,78 (s, 2, C6-H and thienyl-N); a 7.2 to 8.6 (m, 12, aromatic H) M. D.

Example 75

A solution of 0.25 g of 5-[3-[6-atomic charges-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 in 30 ml of warm methanol is treated with 2 ml of 3N sodium hydroxide solution. After 15 min the reaction mixture was 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 remainder chromatographic through 25 g of silica gel (Merck, 230-400 mesh mesh) using 5 vol. ethanol in methylene chloride for elution. After elution certain amount reclassified racemic 4-(2-chlorophenyl)-4,5-dihydro-9-methyl - 2-[3-(5,6-dihydro-6-oxo-5-phenanthridine)-1-PROPYNYL]-6N-thieno[3,2-f] [1,2,4] triazolo[4,3-a] [1,4] -diazepin-6-she's so square 225-230o(From a mixture of methods[4,3-a] [1,4]-diazepin-2-yl] -2-PROPYNYL] -6(5H)-phenanthridinone, combined and evaporated. The residue is crystallized from a mixture of methanol and ethyl acetate to obtain colorless crystals with so pl. 255-258oC.

Example 76

6-(2-Forfinal)-8-iodine-1-methyl-4H-[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 [see H. Meyer et al. Helv. Chim. Acta, 67, 650 (1963)] under the conditions described in example 25g. The reaction product produce by using chromatography with 50-fold amount of silica gel using 5 vol. 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-2H-1-benzopyran-6-ol with so pl. 265-267oC.

Example 77

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 2-ethinyl-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-I under the conditions described in example 25g. The reaction product produce by using chromatography through 50-fold amount of silica gel using 5 vol. ethanol in methylene chloride. Unite the Alla 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. 155-160oWith foaming. These crystals contain 1.5 mol of water, which follows from the analytical and spectral data.

Example 78

a) a Solution of 0.8 g of tert.-butoxide of potassium in 20 ml of tetrahydrofuran and 15 ml of tert. -butanol and 0.6 ml of triethylphosphite cooled to -30oWith stirring under argon. A solution of 0.8 g of 6-(2-forfinal)-8-iodine-1 - methyl-4H-[1,2,4]triazolo[4,3-a] [1,4] -benzodiazepine in 5 ml of dimethylformamide is added and stirring is continued for 1 h at a temperature of from -20 to -10oC. while stirring the mixture allow oxygen 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 crystallized from a mixture of methylene chloride and ethyl acetate and recrystallized from ethanol to obtain colorless crystals of racemic 6-(2-forfinal)-4-hydroxy-8-iodine-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine with so pl. 258-260oC.

b) a Mixture of 0,435 g (1 mmol) of racemic 6-(2-forfinal)-4-hydroxy-8-iodine-1-methyl-4H-[1,2,4] triazolo[4,3-a] [1,4]-benzodiazepine, 3 ml of chloride tiomila and 20 ml chlorestol who's headed the remainder was dissolved in 20 ml of methanol and the solution was treated with 3 ml of triethylamine. After heating on the steam bath for 5 min, 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 evaporated and the residue crystallized from ethyl acetate to obtain colorless crystals of racemic 6-(2 - forfinal)-8-iodine-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 and get so pl. 243-244oC.

C) Racemic 6-(2-forfinal)-8-iodine-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. ethanol in methylene chloride for elution. The combined purified fractions 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-4H- [1,2,4] triazolo[4,3-a] [1,4]-benzodiazepine-8-yl]-2-PROPYNYL]-3,4 - dihydro-2(1H)-Hinayana with so pl. 155-160oC. These crystals contain 0.33 mol of water.

Example 79
<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. ethanol in methylene chloride. The purified fractions are combined and evaporated and the residue 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 80

Racemic 6-(2-forfinal)-4-hydroxy-8-iodine-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 over 50-fold amount of silica gel using 5 vol. ethanol in methylene chloride. United good fraction is evaporated and the residue 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. 253-255oWith decomposition. These crystals contain molar equivalents of water.

Example 81

4-(2-Chlorophenyl)-2-iodine-9-methyl-6N-thieno-[3,2-f] [1,2,4] triazolo [4,3-a] [1,4] -diazepin bedproduct reaction allocate using chromatography with 50-fold amount of silica gel, using about 5. ethanol in methylene chloride for elution. United good fraction is evaporated and the residue is converted into the crystalline dihydrochloride by treatment with excess ethanolic solution of hydrogen chloride in a mixture of ethanol and ethyl acetate. Light yellow crystals of the dihydrochloride 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] -cyclopentane-1,3'-(3H)-indole-2(1'H)-she has so pl. 173-176oWith foaming and contain 2 mol of water and 0.66 mol 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 mmol) of Spiro-[cyclopentane-1,3'-(3H)-indole]-2'-(1'H)-it [see R. J. Owellen, J. Org. Chem.39, 69 (1974)] in 10 ml of dimethylformamide type of 0.37 g (3.3 mmol) of tert.-butoxide potassium. The mixture is stirred for 15 min and add 0.3 ml of methyl propargyl and stirring is continued for 30 minutes, the Reaction mixture rasclaat between xylene and saturated sodium bicarbonate solution. The organic phase is dried and evaporated and the residue chromatographic with 20 g of silica gel using methylene chloride for elution. The combined purified fractions evaporated lapenta-1,3'-(3H)-indole] -2'- (1'H)-she's so square 109-111oC.

Example 82

A mixture of 0.5 g (1 mmol) 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 and 0.34 (2 mmol) of meta-chlormadinone acid in 30 ml of methylene chloride is left to stand at room temperature overnight. Then it was washed with 10% aqueous solution of sodium carbonate, dried and evaporated. The residue is purified by chromatography through 20 g of silica gel (230-400 mesh mesh) using 5 vol. ethanol in methylene chloride. The combined purified fractions evaporated and the residue crystallized from ethyl acetate and recrystallized from a mixture of ethyl acetate and methanol 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-5-oxide-2-yl] -2-PROPYNYL]-3,4-dihydro-2(1H)-Hinayana with so pl. 225-230oWith decomposition. These crystals contain according to the spectral and analytical data 0,166 mol of ethyl acetate.

Example 83

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 g of meta-chlormadinone acid. After stirring at room temperature in the dark for 18 h the mixture was washed with 10% wodniok crystallized from a mixture of tetrahydrofuran, methanol and ethyl acetate to obtain 3.3 g of crude reaction product. It is cleaned by passing through a dense layer of silica gel, using 10 vol. methanol in methylene chloride. The eluate is evaporated and the residue 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] -diazepin-5-oxide with so pl. 280-283oWith decomposition.

b) the reaction Product of example 73 is obtained by reaction 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, 5-(2-PROPYNYL)-6(5H)-phenanthridinone using the conditions described in example 25g.

Example 84

a) 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 a 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. ethanol in methylene chloride for elution. The combined purified fractions evaporated and the reaction product is crystallized from ethyl acetate and recrystallized from a mixture of tetrahydrofuran, methanol and ethyl acetate to obtain best the ina 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 3N sodium hydroxide solution and 10 ml of water. After standing at room temperature for 30 min the solution is acidified with acetic acid and rasclaat 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][1,4]-diazepin-6-ol with so pl. 240-243oC (decomp).

C) the reaction Product of example 75 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]-diazepin-6-ol with 5-(2-PROPYNYL)-6(5H)-phenanthridinone under the conditions described in example 25g.

Example 85

a) a Solution of 23 g of (2-AMINOPHENYL)(4-chlorophenyl)-methanol 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 stopped by adding a solution of sodium bisulfite in water. After peremeci MESI toluene and hexane, to obtain yellow crystals of (2-amino-5-itfeel)(4-chlorophenyl)-methanone with so pl. 137-139oC.

b) To a solution of 18 g (2-amino-5-itfeel)(4-chlorophenyl)-methanone in 250 ml of methylene chloride add 5 ml of methyl bromacetyl and the mixture is stirred together with melkorazdroblennym 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 bromacetyl-derived. 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 is washed with water, dried and evaporated. The residue is dissolved in 300 ml of ethanol and heated to boiling under reflux for 30 min 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-iodine-2H-1,4-benzodiazepine-2-she's so square 246-248oC.

C) a Mixture of 12 g of 5-(4-chlorophenyl)-1,3-dihydro-7-iodine-2H-1,4-benzodiazepine-2-it, 8 g of pentasulfide phospho what I add water and melkorazdroblennyh 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-iodine-2H-1,4-benzodiazepine-2-tion, which melts at 260-262oC.

A mixture of 4 g of 5-(4-chlorophenyl)-1,3-dihydro-7-iodine-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 the mixture is filtered through a thick layer of silica gel (10 g), using tetrahydrofuran for elution. The filtrate is evaporated and the residue crystallized from ether. Recrystallization of this substance from a mixture of tetrahydrofuran and ethanol gives colorless crystals of 5-(4-chlorophenyl)-2-hydrazino-7-iodine-3H-1,4-benzodiazepine with so pl. 250-252oC.

d) a Mixture of 2.8 g of 5-(4-chlorophenyl)-2-hydrazino-7-iodine-3H-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)-8-iodine-1-methyl-4H-[1,2,4]-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 produce by using chromatography through 50-fold amount of silica gel using 20 about. hexane in tetrahydrofuran for elution. Crystallization of the combined purified fractions from ethyl acetate and recrystallization from the same solvent gives 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 mol of water according to the analytical data.

Example 86

a) a Mixture of 3.4 g of 5-(4-chlorophenyl)-2-hydrazino-7-iodine-3H-1,4-benzodiazepine, 75 ml of methylene chloride, 5 ml of anhydride triperoxonane acid and 15 ml triperoxonane acid is heated under nitrogen on a steam bath to remove methylene chloride for about 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. The fractions containing the reaction product are pooled and evaporated. Crystallization from ethyl acetate gives bescot"ptx2">

b) 6-(4-Chlorophenyl)-1-trifluoromethyl-8-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 Product reaction allocate 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 pooled and evaporated and the residue 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 according to the analytical data.

An example of a

Suspension (for oral use), g:

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] -1H-Benz[d, e] -isoquinoline-1,3(2H)-dione (Microfin)(Compound A) 5,0

Oxypropylated-cellulose 8,0

Polysorbate 80 0,5

Distilled water Amount was adjusted to 100.0 ml

The method of cooking

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

Example B

Capsule mg/capsule

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] -1H-Benz[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 Until complete dissolution

Magnesium stearate and 0.25

The total weight 150,00 mg

The method of cooking

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 capsules.

The example IN

Tablet mg/tablet

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] -1H-Benz[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 for separation 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 D

Aerosol suspension, 0.5 mg/ready-to-use

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] -1H-Benz[d, e] -isoquinoline-1,3(2H)-dione (Microfin)(Compound A) 120,00 mg

Trioleate sorbitol 40,00 mg

Trichloronitromethane 1.80m

DICHLORODIFLUOROMETHANE 10,20 ml

The method of cooking

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 a vessel under pressure to fill DICHLORODIFLUOROMETHANE.

Example D

1% solution for topical use, g:

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] -1H-Benz[d, e] -isoquinoline-1,3(2H)-dione (Microfin)(Compound A) 1,0

The polyethylene glycol 400 is about as long until dissolved.

1. Triazolo[4,3-a] [1,4]-benzodiazepine and thieno[3,2-f] -[1,2,4]-triazolo[4,3-a][1,4]-benzodiazepines General formula I

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

R1lower alkyl or trifluoromethyl;

R2chlorine or fluorine;

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

s is 0 or 1;

R4phenyl 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 pyridyl, provided that when n is 0, R4must be attached through a carbon to carbon link and R5always attached through carbon to oxygen of communication, and in the presence of at least one asymmetric center, their enantiomers and racemates,

and pharmaceutically acceptable salts accession acids.

2. Connection on p. 1, where HSN is CH or S, R1lower alkyl, R2chlorine, fluorine, R3the radical of the formula R4-(CH2)n-CC - or R5-O-CH2CC - where n is 0, 1 or 2, s is 0, R4bi - or tricyclic heterocyclic radical and R5is phenyl when usloviya through a carbon to oxygen connection.

3. Connection on p. 1, where R1methyl or ethyl, R2chlorine or fluorine, R3matter specified in paragraph 1, n 1, 2, s 0.

4. Connection on p. 1, where R1methyl, R2fluorine, chlorine, s 0, n 1, R4bi - or tricyclic, heterocyclic radical, specified in paragraph 1, R5phenyl or pyridyl.

5. Connection PP. 1 and 2, where X is sulfur, R1methyl, R2- chlorine, s 0, R2R4-(CH2)n-CC- , n is 1 and R4is

< / BR>
6. Connection on p. 1, characterized in that it is 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-phenanthridine-6(5H)-he.

7. Connection on p. 1, characterized in that it is 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.

8. Connection on p. 1, characterized in that it is 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)-chinoline.

9. Connection on p. 1, characterized in that it is 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]-1H-Benz[de]isoquinoline-1,3-(2H)-dione.

10. Connection on p. 1, characterized in that ol-2(1H)-he.

11. Connection on p. 1, characterized in that it is 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)-he.

12. Connection on p. 1, characterized in that it is 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] -1H-indole-2,3-dione, 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-indol-2-it, 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, 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)-she 4-(2-chlorophenyl)-2-[3-(1H-indazol-1-yl)-1-PROPYNYL] -9 - methyl-6N-thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin-[3-(1H-benzimidazol-1-yl)-1-PROPYNYL] -4-(2-chlorophenyl) -9-methyl-6N-thieno[3,2-f] [1,2,4] triazolo[4,3-a] [1,4] diazepin, 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 and 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-benzoxazin-3(4H)-he.

13. Compounds of General formula

< / BR>
where X, R1, R2and s have the meanings specified in paragraph 1.

14. Join organisations on one of the PP. 1 12 active as antagonists of platelet activating factor and respectively having angioprotective, immunological and antishock properties, and properties that prevent rejection of transplanted organs.

16. Method of preparing compounds according to one of paragraphs. 1 12 and their pharmaceutically acceptable salts accession acids, characterized in that conduct the interaction of compounds of General formula

< / BR>
where X, R1, R2and s have the meanings specified in paragraph 1, with the compound of General formula

R4Y

where R4has the meaning specified in paragraph 1;

Y is bromine or iodine,

and, if necessary, to obtain the compounds of formula I, in which s 1 and R4differs from a residue containing a basic nitrogen atom, is treated with a compound of the formula I, in which s is 0 and R4differs from a residue containing a basic nitrogen atom, the above acid, and/or, if desired, convert the compound obtained of General formula I in a pharmaceutically acceptable salt accession acids.

17. The pharmaceutical composition inhibiting platelet activating factor, containing the active ingredient and pharmaceutically acceptable carrier, wherein Q2">

Priority signs:

03.08.88 when R1trifluoromethyl, s 1;

18.12.87 all other values radicals.

 

Same patents:

The invention relates to a method for producing new derivatives triazolo-[4,3-a](1,4) benzodiazepines General formula I:

I,

where X is-CH=CH -, or S;

R1lower alkyl or trifluoromethyl;

R2chlorine 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

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 new substituted pyrazolylborate, and to their use as herbicide compositions

The invention relates to compounds of formula (I) listed in the description, where R1represents a hydrogen atom or unsubstituted or substituted alkyl group; and A represents the number of cyclic or acyclic nitrogen containing groups

The invention relates to the production of Riboflavin (vitamin B2)

The invention relates to 6-oxo-asiminoaei compounds, namely to new derivatives of 6-oxo-3,4,5,6-tetrahydro-1H-azepino [5,4,3-cd] indole with, if necessary, in the 3rd or 4th position of the skeleton of the ring substituted aminoalkyl balance, and their acid salts of accession, and to pharmaceutical preparations containing these compounds, process for the preparation of these compounds and intermediates for their production

Hypotensive agent // 2084225

The invention relates to new derivatives of diazepinone having valuable properties, in particular derivatives of diazepinone General formula (I)

< / BR>
where B is one of the divalent residues and) g)

< / BR>
and

X, l, m, n and R1R7have the following meanings:

X Gruppen or, if B denotes the divalent residue (a), a nitrogen atom,

l integer 1, 2 or 3,

m is an integer 1 or 2,

n is an integer of 1 to 4,

R1a hydrogen atom or an unbranched or branched alkyl with 1 to 6 carbon atoms,

R2a hydrogen atom, an unbranched or branched alkyl with 1 to 8 carbon atoms, unbranched or branched alkenyl with 4 to 6 carbon atoms, cycloalkyl with 3 to 7 carbon atoms, unsubstituted or substituted by alkyl with 1 to 3 carbon atoms, substituted, phenyl, unsubstituted or substituted by one or two methyl groups or methoxypropane or one halogen atom, or phenylalkyl with 1 to 3 carbon atoms in the alkyl part, unsubstituted or substituted at the fragrance stands or methoxy group or a halogen atom,

R3and R4the same or the difference is,

R5a hydrogen atom or a chlorine or methyl,

R6and R7the same or different and denote hydrogen atoms or alkali with 1 to 3 carbon atoms, and, in addition, R7may also indicate a halogen atom,

mixtures of their isomers or their individual isomers and their salts, mainly their physiologically tolerated acid additive salts, in particular with pharmacological action

The invention relates to medicine, namely, neurology

The invention relates to organic chemistry, specifically to new biologically active compounds derived from polyunsaturated fatty acids, hydroxypregnenolone fatty acids and prostaglandins of General formula I:

< / BR>
where R the rest prostaglandin formula:

< / BR>
where one of the two groups at C-9 atom (R1or R2) a hydrogen atom, and the other hydroxyl (R2or R1or R1and R2together form a keto or hydroxyimino; and where one of the two groups at C-11 of the atom (R3or R4) a hydrogen atom, and the other hydroxyl (R4or R3or R3and R4together form a keto or hydroxyisopropyl; provided that R3and R4do not form a keto or hydroxyisopropyl when R1and R2together form a keto or hydroxyimino; and where one of the two groups at C-15 atom (R5or6) a hydrogen atom, and the other (R6or R5) hydroxyl or fluorine atom; the symbolrepresents a single or a CIS-double bond; or R is the residue of a prostaglandin of the formula:

represents a single or double bond, provided that R7or R8do not form a hydroxyl, when the C-10 and C-11 atoms connected by a double bond, or provided that if7or R8hydroxyl, C-12 and C-13 atoms are connected by the TRANS-double bond; and where one of the two groups at C-15 atom (R9or R10) a hydrogen atom, and the other (R10or R9) hydroxyl;

or R the rest of the prostaglandin type I formula:

< / BR>
where the group Q at C-5 of the atom the atom is iodine or bromine, the symbolrepresents a single or double bond, provided that Q is bromine or iodine, when the C-5 and C-6 atoms connected by a double bond;

or R residue of the unsaturated fatty acids of the formula:

< / BR>
where a 0 6, f 1 6, 1 7, provided that the total carbon chain length from 18 to 22 carbon atoms;

or R residue hydroxy acid of the formula:

< / BR>
where m 1 7 x 0 4, k 0 4, n is 0 to 3, provided that the total carbon chain length from 18 to 22 carbon atoms, and str is

The invention relates to gastroenterology
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