NO142260B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE TIENOTRIAZOLODIAZEPINE DERIVATIVES - Google Patents

Description

The present invention relates to an analogous method for the production of thienotriazolodiazepine derivatives with the general formula

where and R 2 independently mean halogen, and alkyl or the group

wherein R^ and R^ independently of each other mean hydrogen or alkyl,

as well as acid addition salts thereof.

The term "alkyl" used in the description denotes as such or in combination, such as e.g. in hydroxyalky, straight-chain or branched hydrocarbon groups with 1-4 carbon atoms, such as e.g. methyl, ethyl, propyl, isopropyl, t-butyl and the like. The term "halogen" denotes the four forms bromine, chlorine, fluorine and iodine.

In a preferred class of compounds of formula I means

R₂ chlorine, R₂ preferably means fluorine and chlorine, R₂ preferably means alkyl or aminoalkyl, and methyl is particularly preferred.

A particularly preferred compound is 2-chloro-4-(o-chlorophenyl)-9-methyl-6H-thieno-[3,2-f]-s-triazolo[4,3-a]-[1,4]diazepine . Further typical representatives of the compounds of formula I are: 2-chloro-4-(o-fluorophenyl)-9-methyl-6K-thieno[3,2-f]-s-triazolo-[4,3-a] [l ,4]diazepine,

9-aminomethyl-2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo-[4,3-a] [1,4]diazepine, and 2-chloro- 4-(o-chlorophenyl)-9-dimethylaminomethyl-6H-thieno-[3,2-f]-s-triazolo[4,3-a][1,4]diazepine.

According to the invention, the thienotriazolodiazepine derivatives of formula I and their acid addition salts can be prepared by

a) cyclizes a compound of the general formula

where R-^, R2 and R^ have the meanings mentioned above, or that one, b) cyclizes a compound with the formula

where R-jy R0 and R^ have the meanings mentioned above, or that one

c) halogenates a compound of formula

where R2 and R-j have the above-mentioned meanings,

or that one

d) in the preparation of a compound of formula I, where R^

means the group

reacts a compound with formula

where Rj and R2 have the meanings mentioned above, and

X stands for a departure group,

with an amine of the formula

where R^ and R^ have the above-mentioned meanings, and

e) if desired, transfers a compound obtained in an acid addition salt.

According to a first process aspect of the present invention, compounds with the above formula I can thus be prepared by cyclizing a corresponding compound with the above formula II.

The cyclization of a compound of formula II is carried out by

per se known methods, e.g. by heating the compound of formula II. The temperature is not critical for a successful completion of this reaction, but depends on the starting product and the reaction conditions used. Thus, the reaction can be carried out in a temperature range between approx. room temperature and 300°C. The cyclization according to the invention can be carried out in the absence or presence of, and then preferably in the presence of, an inert, organic solvent. If you work in the presence of an inert organic solvent, the preferred reaction temperature is between approx. 60 and 1B0°C, whereby the reflux temperature of the reaction mixture is particularly preferred

perature. If, on the other hand, you work in the absence of a solvent, the preferred temperature range is between approx. 200°

and 260°C. As inert organic solvents, e.g. hydrocarbons such as toluene, xylene and the like, halogenated hydrocarbons such as chlorobenzene and the like, ethers such as tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and the like, amides such as hexamethylphosphoric acid triamide, dimethylformamide and the like, dimethyl sulfoxide, and especially preferred alkanols, such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, cyclohexanol and the like. The reaction time depends on the reaction temperature used as well as on the circumstance whether a solvent is used,

and is between a few minutes and 48 hours, preferably a few minutes when no solvent is used, and otherwise between 1 and 24 hours.

The compounds of formula II must and can in all cases be used

in isolated form, as they often spontaneously cyclize under the reaction conditions used for their preparation.

According to a further method aspect, one obtains compounds of the above formula I by cyclizing one corresponding compound of the above formula III. The cyclization with formula III also takes place by methods known per se. E.g. this cyclization can take place by heating the compounds of formula III in an organic medium, whereby, in order to achieve a satisfactory yield, one preferably works in the presence of acid in many cases. Thus, one can e.g. carry out the cyclization by heating under reflux compounds of formula III during several hours in a solution of aliphatic carboxylic acids, such as formic acid or acetic acid, in an alcohol, such as ethanol or n-propanol, or by heating under reflux in relatively short time (approx. 5 min. to half an hour) in an aliphatic carboxylic acid, such as acetic acid, isobutyric acid or pivalic acid.

The compounds of formula III must and cannot in all cases be used in isolated form, as they often cyclize spontaneously under the reaction conditions used for their preparation. According to a further process aspect of the present invention, compounds of the above formula I can be prepared by halogenating a compound of formula IV.

The halogenation is carried out using one of those for halogenation

in the thiophene series common methods, e.g. by means of elemental chlorine, bromine or iodine, by means of sulphuryl chloride, etc., whereby the reaction conditions are primarily dependent on the type of halogenating agent used. The reaction can be carried out by chlorination using elemental chlorine, e.g. in chloroform/pyridine or nitrobenzene, and then suitably at room temperature. In a bromination using elemental bromine, the reaction is carried out e.g. in chloroform at elevated temperature, e.g. at boiling temperature and under reflux. An iodination with elemental iodine can e.g. carried out in chloroform and in the presence of mercuric oxide at room temperature. A chlorination using sulfuryl chloride can e.g. carried out in chloroform or glacial acetic acid at room or elevated temperature, e.g. at reflux temperature.

According to a further aspect of the method, the compounds of formula I, where R 1 means a group -alkyl-NC 1 ^R 4 , are obtained by reacting a compound of formula V with a compound of formula VI. The symbol X in formula V means a leaving group, preferably a halogen atom and then especially a chlorine atom or a reactive ester group, for example a methanesulphonic acid ester group.

This method aspect concerns the formation of aminoalkyl compounds, and said formation can take place with the help of

of known methods per se. E.g. one can transfer a compound according to formula V, where X means a methanesulfonic acid ester group, and react this with an amine of formula VI. The reaction takes place in a known manner, preferably in the presence of a suitable inert organic solvent, such as dimethylformamide or an alcohol such as methanol or ethanol, and at a temperature between 0° and 100°C, preferably at 0-5°C.

Compounds of formula I can, by treatment with inorganic or organic acids, be converted into corresponding salts, whereby particularly pharmaceutically usable salts are of importance. Examples of acids that form pharmaceutically usable salts are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, tartaric acid, citric acid, maleic acid, ascorbic acid, formic acid, acetic acid, succinic acid, methane-, benzene- and p-toluenesulfonic acid, etc.

The starting substances of formula II can be prepared from the corresponding thienodiazepine derivatives of the general formula

where and R2 have the above meaning.

The first step consists in a reaction of a compound of the above formula VEI" with a sulfide such as phosphorus pentasulfide, whereby a compound of the general formula is formed

where R± and R2 have the meaning indicated above.

In this reaction, an excess of sulphide is preferably used. The reaction is suitably carried out in an inert organic solvent, such as pyridine, xylene and the like, and at a temperature of approx. 40°C and up to the reflux temperature of the reaction mixture, and then preferably at the reflux temperature. A preferred solvent for this reaction is pyridine.

A compound of the above formula VIII is further reacted with an organic acid hydrazide of the general formula

where R has the above meaning,

forming a compound of the above formula II. The condensation of . ethion of the above formula VIII with an acid hydrazide of formula IX is preferably carried out in an inert organic solvent, preferably an alkanol. such as methanol,

ethanol, 1- or 2-propanol, 1- or 2-butanol and the like,

and at a temperature between approx. 6o° and 12o°C, preferably at the reflux temperature of the reaction mixture. In a preferred embodiment, the acid hydrazide is used in an excess that exceeds the theoretically necessary amount by 2 to 5 times. The reaction time depends on the reaction temperature and is between a few minutes and 48 hours, preferably between approx. one and 24 hours. The crude product thus obtained mainly consists of the desired compound of formula II and the already cyclized compound of formula I. However, due to the different solubilities of certain compounds in organic solvents, this mixture may and the like, separate. The compound of formula II can, after separation in the manner described above, be converted into the compound of formula I. According to a simple method, the mixture consisting of the compound of formulas I and II can be converted into a uniform product of formula I in the manner indicated above. The reaction of a compound of formula VIII with an acid hydrazide of formula IX takes place preferably during the flow of an inert gas, preferably nitrogen, through the reaction mixture, so that the hydrogen sulphide formed is continuously removed.

The acid hydrazides of formula IX are known compounds and can

easily produced analogously to the production of the known ones

the connections, e.g. by heating an ester of the formula R3~C00-alkyl with hydrazine hydrate to reflux, e.g. in methanol.

The compounds of formula VII are also known compounds, or can easily be prepared analogously to the preparation of known compounds. Thus, they can e.g. is obtained from correspondingly substituted aminoaroyl-thiophene derivatives by reaction with an α-halocarboxylic acid halide, such as chloroacetyl chloride, treatment of the obtained compound with ammonia and then cyclization.

According to a further embodiment, compounds of formula II can also be prepared from compounds of the general formula

where R 1 and R 2 have the meanings given above,

by reaction with a carboxylic acid of the formula R-^-COOH, where R3 has the above meaning, or with a reactive derivative thereof. Suitable reactive derivatives of the above"carboxylic acids are, for example, esters, anhydrides, halides, amides, iminoethers, amidines and orthoesters, whereby the orthoester is particularly preferred. Examples of such orthoesters are orthoacetic acid trimethyl ester, orthoacetic acid triethyl ester, orthopropionic acid triethyl ester, orthobutyric acid triethyl ester and the like .

The reaction of a compound of formula X with a carboxylic acid or a reactive derivative preferably takes place in the presence of an inert, organic solvent and an acidic catalyst. such as halogen hydrogen acids, e.g. hydrochloric acid, p-toluenesulfonic acid and the like. Suitable solvents are alkanols, such as methanol, ethanol and the like, ethers, such as tetrahydrofuran, diethyl ether and the like, dimethylsulfoxide, dimethylformamide and the like. The temperature is not critical for a successful implementation of this reaction step, but one preferably works at higher temperatures, i.e. between approx. 3o°C and the reflux temperature of the reaction mixture, and then especially at the reflux temperature.

According to a further embodiment, compounds of formula II can also be prepared from compounds of the general formula

■ formula

where and R2 have the above meaning,

by reaction with an acid hydrazide of formula IX. The reaction takes place in an inert organic solvent, such as alkanols, e.g. ethanol, propanol, butanol and the like, dimethylformamide, ether, such as diglyme or methoxyethanol and the like, and in the presence of a strong base, such as amines, f .ex. tertiary amines, such as triethylamine, methylpiperidine and the like, and at higher temperatures, preferably at the reflux temperature of the reaction mixture.

Compounds of the above formula XI can be easily prepared from corresponding compounds of formula VII by reacting the compound of formula VII with an alkylamine in the presence of a Lewis acid, such as titanium tetrachloride.

The compounds of formula X can be prepared from the corresponding compounds of formula XI by reacting a compound of formula XI in a manner known per se with nitric acid to form a corresponding N-nitroso compound. By reacting this N-nitroso compound with hydrazine, the desired compound of formula X is obtained. Compounds of formula X can also be obtained by reacting a compound of formula VIII with hydrazine.

The production of the starting products with formula III is summarized in the following reaction core.

The 2-amino-3-benzoylthiophene derivative of formula XII is transferred by treatment with an orthoester of formula R3-C(Oalkyl)^ into a compound of formula XIII. The reaction is carried out respectively in the presence of an inert organic solvent, such as benzene, toluene and the like, and an acidic catalyst, such as hydrochloric acid, sulfuric acid, acetic acid, propionic acid and benzenesulfonic acid, p-toluenesulfonic acid and the like. The temperature is not critical, but you usually work at temperatures between approx. 5o° - 16o°C,

whereby, however, higher or lower temperatures can also be used. Suitable solvents are hydrocarbons, such as benzene or toluene and the like, or an excess of the orthoester used as a reaction component.

The thus obtained compound of formula XIII is then reacted with hydrazine, which is preferably used as hydrazine hydrate, in an inert organic solvent. suitable solvents are particularly alkanols, such as methanol, ethanol, 1-propanol, 2-propanol and the like. The reaction is carried out at temperatures between 0°C and the reflux temperature of the reaction mixture, preferably between approx. lo°C and approx. 3o°C. The reaction can be accelerated by adding an acid catalyst

such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. The raw product thus obtained is then reacted with an α-haloic acid halide, such as chloroacetyl chloride, bromoacetyl bromide and the like, in an inert organic solvent under ice-cooling or at temperatures below the solvent's boiling point, and a compound with the formula is obtained. Chloroform is suitable as a solvent, methylene chloride, ether, dimethylformamide, pyridine, acetic acid, monochloroacetic acid or mixtures of such a solvent with water. When using a neutral solvent, the reaction is preferably carried out in the presence of an acid acceptor, such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, pyridine, triethylamine, imidazole, 2-methylimidazole and the like.

The compound of formula XIV is then treated with ammonia or hexamethylenetetramine, whereby the compound of formula III obtained is cyclized without isolation to the corresponding compound

compound of formula I. The compound of formula III needs

namely no isolation before the cyclization, i.e. the ring closure of the compound of formula I can be carried out in the reaction mixture in which the compound of formula III is prepared without isolating this or interrupting the reaction. One can e.g. added a compound of formula XIV to alcoholic ammonia, such as ethanol-containing or methanol-containing ammonia, or dissolve the compound of formula XIV in an inert organic solvent and treat with liquid ammonia or hexamethyltetramine, whereby a compound of formula III is obtained. Suitable solvents for this reaction are methylene chloride, carbon tetrachloride, ether, such as tetrahydrofuran or dioxane, dimethylsulfoxide, dimethylformamide, alkanols, such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol and the like. The obtained compound of formula III, and then either in crude or purified state, can be cyclized to form a compound of formula I in the manner described above.

The compounds of formula V used for method d) can be prepared analogously to method a). They can also be prepared from corresponding 9-hydroxyalkyl compounds, which again can be obtained analogously to method a), e.g. can one transfer

re such a 9-hydroxyalkyl compound in the corresponding methanesulfonic acid ester.

The compounds of formula I and their pharmaceutically usable acid addition salts are valuable drugs, and can e.g. are used as anticonvulsants, sedatives, muscle relaxants, sedatives and anxiolytics.

The compounds of formula I as well as their pharmaceutically usable acid addition salts can be processed according to generally known methods for pharmaceutical preparations, e.g. for tablets, dragées, suppositories, capsules, solutions, suspensions, emulsions, etc. Besides usual pharmacologically indifferent carriers, such as e.g. milk sugar, starch, talc, magnesium stearate, water, vegetable oils, polyalkylene glycols,

and the like, these preparations may also contain preservatives,

stabilising, wetting or emulsifying agents, salts for changing the osmotic pressure, puffs or further other therapeutically valuable substances. If necessary, the aforementioned preparation forms can be sterilized or undergo other normal working operations in the pharmaceutical industry.

A suitable pharmaceutical dosage unit may contain 1 to 50 mg of a compound according to the present invention. Suitable daily doses for oral administration to mammals are in the range of approx. 0.1 mg/kg to approx. 30 mg/kg, and with parenteral administration to mammals, a suitable daily dose amounts to approx. 0.1 mg/kg to approx. 10 mg/kg. However, these dosages should only be considered as examples, and the dosages must in each case be adapted to individual needs.

The following examples illustrate the invention, and all temperatures are given in degrees Celsius.

EXAMPLE 1

2.5 g of 2-(2-acetylhydrazino)-7-chloro-5-(o-chlorophenyl)-3H-thieno-[2,3-e]-1,4-diazepine are heated under reduced pressure (water-jet vacuum) in an oil bath (250°) for 5 - 7 minutes until gas evolution is more visible. The product formed is finely pulverized in a pulverizing bowl and boiled with a total of 400 ml of ethyl acetate. After removal of the solvent, the precipitated crude product is recrystallized in ethanol with activated charcoal, whereby 2-chloro-4-(o-chlorophenyl)-9-methyl-6H-thieno-[3,2-f]-s-triazolo-[4 ,3-a][l,4]diazepine in the form of cream-colored crystals with m.p. 205 - 206°.

The starting material can be produced as follows:

3.1 g (0.01 mol) of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-thieno[2,3-e][1,4]-diazepin-2-one is heated with 2.45 g of P2S5

in 100 ml abs. pyridine for 30 minutes at reflux, whereby dried nitrogen is passed through the solution. The solution is divided over a 35 cm long, soyle (0 3.5 cm) filled with 100 g of silica gel [(0.05 to 0.2 mm) (Merck)J. The separation continues by thin-layer chromatography (eluent: benzene/ethanol 9:2).

In the event of contaminants that last significantly longer, the division is interrupted. The solvent is removed in vacuo, whereby 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-thione crystallizes out in the form of yellow crystals with m.p. 223 - 225° immediately. For further use, the product is not further purified.

3.3 g (0.01 mol) 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-thieno| 2,3-e]-1,4-diazepin-2-thione is heated under a nitrogen atmosphere with 2.5 g of acetic acid hydride and 150 ml of n-butanol for 30 minutes to reflux. The solvent is removed in vacuo, 200 ml of ethyl acetate is added to the residue and shaken out three times with 200 ml of H2O each time. The precipitated solid is sucked off and combined with the ethyl acetate phase. After concentrating the solution to 50 ml, the product is allowed to crystallize. It is then suctioned off and recrystallized again in ethyl acetate and activated carbon, whereby 2-(2-acetylhydrazino)-7-chloro-5-(o-chlorophenyl)-3H-thieno[2,3-e]-1,4- diazepine in the form of orange crystals with m.p. 211 - 213°.

EXAMPLE 2

6.8 g of 2-(2-acetylhydrazino)-7-chloro-5-(o-fluorophenyl)-3H~thieno-[2,3-e][1,4]-diazepine are refluxed in 300 ml abs. xylene 9 hours. After cooling, the precipitated contaminants are sucked off. The solvent is then evaporated under reduced pressure and the product is recrystallized in ethyl acetate and activated charcoal. One obtains 2-chloro-4-(o-fluorophenyl)-9-methyl-6H-thieno[3,2-f]-s-triazolo-[4,Sa][1,4]-diazepine with m.p. 187 - 189°. The starting material is obtained as follows;

10 g of 7-chloro-5-(o-fluorophenyl)-1,3-dihydro-2H-thieno-[2,3-e][1,4]-diazepin-2-one are dissolved in 150 ml of diethylene glycol dimethyl ether at 55° C and stirred with a mixture of 15 g of finely grated phosphorus pentasulphide and 10 g of sodium bicarbonate for 40 minutes. The solvent is distilled off and the residue is digested with water, sucked off and dried. The 7-chloro-5-(o-fluorophenyl)-1,3-dihydro-2H-thieno-[2,3-e]-1,4-diazepin-2-thione obtained is boiled in 200 ml of methanol

with 15 g of acetylhydrazine for 30 minutes. On cooling, 2-(2-acetylhydrazino)-7-chloro-5-(o-fluorophenyl)-3H-thieno[2,3-e]-1,4-diazepine precipitates. The methanol is distilled off and the residue is distributed between methylene chloride and water. Thereby, additional product is precipitated. The solvent is evaporated under reduced pressure and further product is obtained from the residue by digestion in methanol. The obtained 2-(2-acetylhydrazino)-7-chloro-5-(o-fluorophenyl)-3H-thieno[2,3-e]-1,4-diazepine shows a melting point of 207 - 209°.

EXAMPLE 3

0.75 g of 2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a]-[1,4]-diazepine-9-methanol is dissolved in 25 ml abs. chloroform and 0.7 g of triethylamine and 0.6 g of methane sulphochloride are added. The mixture is stirred for 2.5 hours at 25°, then washed twice with water and twice with saturated sodium chloride solution, dried over sodium sulphate and evaporated. The oily methanesulfonic acid ester of 2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f)-s-triazole-[4,3-a][1,4]-diazepine-9-methanol is dissolved in 10 ml DMF and the solution is added dropwise at 0-5° to a solution of 1 ml liquid ammonia in 5 ml DMF. It is stirred for 2 hours at room temperature and the reaction mixture is distributed between saturated sodium chloride solution and methylene chloride. The organic phase is dried and evaporated and the residue is recrystallized in ethanol. Mon

9-amino-methyl-2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazole-[4,3-a]-[1,4)-diazepine with m.p. . 190-192°.

The starting material can be prepared as follows:

1.1 g of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2K-thieno-[2,3-e]-1,4-diazepin-2-thione is refluxed with 1.5 g of glycolic acid -zid in abs. butanol 8 hours. The solvent is then distilled off and the residue is recrystallized in ethyl acetate by treatment with activated charcoal. 2-Chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazol[4,3-a][1,4]diazepine-9-methanol is obtained with m.p. 219 - 221°.

EXAMPLE 4

500 mg 2-[3,5-bis(aminomethyl)-4H-1,2,4-triazol-4-yl]-5-chloro-3-thienyl-o-chlorophenylketone dihydrochloride (m.p./decomposition point from 230° C) is dissolved in 10 ml of water and made alkaline with 1 N caustic soda and the water phase is extracted with methylene chloride.

After drying over sodium sulphate and evaporation of the organic phase, the residue is heated for 30 minutes in 5 ml of absolute alcohol at reflux. After evaporation, the crude base is chromatographed on alumina. 9-(aminomethyl)-2-chloro-4-(o-chlorophenyl)-6H-thienol-[3,2-f]-s-triazolo(4,3-a)[1,4]-diazepine which is eluted with chloroform and is crystallized from acetic acid has m.p. 167-168°C. A sample recrystallized from acetic acid and low-boiling petroleum ether melts at 170.5 - 171°C. The monohydrochloride has a melting point/decomposition point of 198-200°C.

EXAMPLE 5

0.95 g (0.0034 mol) of 5-(o-chlorophenyl)-1H-thieno[2,3-e][1,4]-diaze-pin-2(3H)-one is dissolved in 25 ml of diethylene glycol dimethyl ether at 80°C. A finely grated mixture of 1.6 g of phosphorus pentasulphide and 1 g of sodium bicarbonate is added to the solution, during which the reaction mixture foams strongly. After the addition is complete, stir for a further 50 minutes at 80°C. The solvent is evaporated to 10 ml and made up with 120 ml of water. The precipitated product is suctioned off, washed with water and dried at room temperature. 1.05 g of 5-(o-chlorophenyl)-1H-thieno[2,3-e][1,4]-diazepine-2(3H)-thione are obtained. This product is resolved

in 50 ml glacial acetic acid and 20 ml methanol and heated for 1 hour at 50°C

with 2 g of acethydrazide-dimethylammonium chloride. After evaporation of the solvent, the oil is mixed with 150 ml of 5% sodium bicarbonate

solution and extracted in portions with a total of 150 ml of methylene

chloride. The solvent is removed after drying over sodium sulfate.

The oil obtained is boiled in 70 ml of glacial acetic acid for 1 hour at reflux. The solvent is evaporated and the residue is distributed between 100 ml of sodium bicarbonate solution and 100 ml of methylene chloride. After evaporation of the organic phase, the 4-(o-chlorophenyl)-9-dimethyl-aminomethyl-4H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]- diazepine out with 100 ml of ethyl acetate, filter hot from the impurity and evaporate to 20 ml. The precipitated product is recrystallized from ethyl acetate.

You get 0.42 g of product with m.p. 210-212°C

0.2 g of this product is dissolved in 30 ml of absolute chloroform, mixed

treated with 0.2 ml of absolute pyridine and cooled to -5°C. In this solu-

dry chlorine gas is introduced slowly. After 3 hours, no more starting material can be detected. After evaporation of the solvent

, the mixture is purified by column chromatography (silica gel,

eluent ethanol). "an obtains 2-chloro-4-(o-chlorophenyl)-9-dimethylaminomethyl-4H-thieno[3,2-f]-s-triazolo[4,3-a]-[1,4]-diazepine with mp 203 - 205°C.

Claims (1)

1. Analogous method for the preparation of thienotriazolodiazepine derivatives of the general formula where and R 2 independently of each other mean halogen and R 1 alkyl or the group whereby R 2 and R 1 , independently of each other mean hydrogen or alkyl, as well as acid addition salts thereof, characterized in that one a) cyclizes a compound with the general formula where R^, R2 and R^ have the aforementioned meaning, or that one, b) cyclizes a compound of formula where R 1 , R 2 and R 3 have the aforementioned meaning, or that one c) halogenates a compound of formula where R2 and R^ have the aforementioned meaning, or that one d) when preparing a compound of formula I where R-. means the group reacts with a compound of formula where and R2 have the aforementioned meaning and X stands for a leaving group, with an amine of formula where and R^_ have the aforementioned meaning, and e) if desired, transfer an obtained compound into an acid addition salt • 2. Method according to claim 1, characterized by using starting materials, where ^ and means chlorine and n3 methyl or aminomethyl .