NO126325B - - Google Patents

Description

Process for the production of benzodiazepine derivatives.

The present invention relates to a new process for the production of new and usable benzodiazepine derivatives with the general formula:

where is hydrogen, alkyl, aryl or aralkyl, is hydrogen or lower alkyl and where rings A and/or B are unsubstituted or substituted with one or more, which may be the same or different, nitro, trifluoromethyl, halogen, alkyl and alkoxy, as the nitrogen atom in the 5-position can be in the form of the N-oxide.

The benzodiazepine derivatives with formula (I) are prepared according to the invention by reacting 2-hydrazinobenzodiazepine derivatives with the general formula: where A, B and R have the above meaning and where the nitrogen atom in the 4-position can be in the form of the N-oxide carboxylic acids of the general formula

where R 1 has the same meaning as indicated above or their reactive derivatives. By reactive derivatives of said carboxylic acids (III) are meant esters (e.g. alkyl esters such as methyl and ethyl esters or activated esters such as p-notrophenyl esters), anhydrides, halides (e.g. chlorides, bromides), amides (e.g. formamide , dimethylformamide, acetamide), orthoesters, iminoethers and amidines.

Said orthoesters have the following general formula:

where R^ has the same meaning as stated above and R^ is a lower alkyl group, e.g. methyl or ethyl.

The iminoethers have the following general formula:

where said symbols have the same meaning as stated above. The amidines have the following general formula

where R^ has the same meaning as stated above.

The carboxylic acids (III) or their reactive derivatives are usually used in amounts varying from approx. 1 to approx. 10 mol, purely practical in quantities from approx. 2 to approx. 5 moles per mole of 2-hydrazinobenzodiazepine derivative (II) present. The reaction is preferably carried out in the presence of a solvent and an acid catalyst at a temperature between approx. 0° and approx. 300°C, and the exact conditions will vary with the reagents used. Said solvent can mean methanol, ethanol, chloroform, methylene chloride, dimethylformamide and mixtures thereof. The acid catalyst can be exemplified by inorganic acids (e.g. hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, etc.), organic carboxylic acids (e.g. acetic acid, propionic acid, etc.) and organic sulfonic acids (e.g. benzenesulfonic acid, p-toluenesulfonic acid, etc). The amount of said acid catalyst is usually from about 2 to about 10 mol per mol of said 2-hydrazinobenzodiazepine derivative (II).

In this reaction, acylhydrazino compounds (IV), or their enol ether derivatives (IV) or α-aminoalkylidene (or aralkylidene) compounds (IV") with the following general formula:

where R^, Rg, Rj3 A and B have the same meaning as stated above, this included the case where the nitrogen atom in the 4-position carries an oxygen atom, - are produced as intermediates. These intermediates can be cyclized to the compounds (I) under somewhat drastic conditions. In the present method, a compound of formula (I) can be synthesized in one step without isolating the intermediates, or alternatively they can be synthesized in two steps, which include first preparing and isolating the intermediates and then ring-closing these to the desired compounds.

When you e.g. uses the amidines under mild conditions, e.g. in a solvent and at a temperature of approx. room temperature,, then the intermediates (IV") can be isolated. This intermediate can be cyclized by heating to 140° - 250°C to a compound of formula I with the evolution of ammonia. For a one-step synthesis of compounds of formula (I) 2 -hydrazinobenzodiazepine derivative (II) and amidines (III'") • react with each other at relatively high temperatures, e.g. from 140° - 250°C. This reaction can occur in the presence or in the absence of a solvent. In particular, a melting method, and then in the presence of 2-methylimidazole, gives very good results.

Also in cases where esters, amides, anhydrides and halides are used, the intermediate products, i.e. the acylhydrazino-benzodiazepine derivative (IV), can be isolated if the reaction is carried out under weak conditions, i.e. in a solvent and at room temperature. The produced and separated acylhydrazinobenzodiazepine derivatives (IV) can then be easily cyclized to the compounds (I) by heating to a temperature from 130° to 250°C. The cyclization can, if necessary, be accelerated by using a catalyst such as polyphosphoric acid. The cyclization can be carried out either in the presence or in the absence of a solvent. As a solvent, you can e.g. use pyridine, dimethylformamide, xylene or tetralin. With regard to the intermediate product with formula (IV), the above-mentioned method can also be used.

The produced benzodiazepine derivatives (I) can be isolated in the form of a free base or in the form of a suitable acid salt (e.g. a chloride, a sulphate, an acetate, etc.), by methods known per se. For example, the reaction mixture can be neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with a suitable solvent (e.g. methylene chloride, chloroform, etc.), followed by a distillation of the solvent, whereby the benzodiazepine derivatives (I) are obtained.

The structure of the benzodiazepine derivatives (I) can be determined

from X-ray analysis of 8-chloro-6-phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine.

When the benzodiazepine derivative (I) has been prepared with an oxygen atom in the 5-position (i.e. the 5N-oxide), these can, if necessary, be reduced to the corresponding benzodiazepine derivatives (I) where the nitrogen atom in the 5-position does not carry an oxygen atom . The reduction can be carried out in the usual way, e.g. by a catalytic hydrogenation and by a reduction where halogen-phosphorus compounds (e.g. phosphorus trichloride) are used. The hydrogenation is usually carried out in a suitable solvent, e.g. methanol or ethanol, around room temperature and under atmospheric pressure. A reduction using halogen-phosphorus compounds can usually be carried out by heating in a suitable solvent, e.g. chloroform or methylene chloride.

Said 2-hydrazinobenzodiazepine derivatives (II) which can be used as a starting compound for the above-mentioned ring closure reaction are new compounds, and they can be prepared by a method which includes that a 2-aminobenzodiazepine of the general formula

where the symbols have the same meaning as stated above, herein including a case where the N atom in the 4-position carries an oxygen atom), is reacted with hydrazine.

With regard to the above-mentioned 2-aminobenzodiazepine derivatives (VI), these can also have the following isomeric form:

which can also be used in the present method.

The compounds of formula (VI) can e.g. produced on

the way described in the Journal of Organic Chemistry 26, -lill,

(1961). prepared 2-amino-α-phenylbenzylidene-aminoacetonitrile derivatives a ring closure in the presence of an acid or alkali.

The reaction between the 2-aminobenzodiazepine derivative (VI) and hydrazine is preferably carried out in the presence of a suitable solvent and an acid at a suitable temperature between 0° and 150°C.

As a solvent, you can e.g. use methanol, ethanol, pyridine, dimethylformamide, a mixture of these, or aqueous mixtures of said solvents. The acids used can e.g. e.g. be inorganic acids (e.g. hydrochloric acid, sulfuric acid, phosphoric acid, etc.) as well as organic acids (e.g. acetic acid, p-toluenesulfonic acid, etc.). The acids can be added in the form of salts with amines, and from said amines you can e.g. use pyridine, trialkylamines, 2-methylimidazole, etc. It may be noted that one or both of the aforementioned hydrazines and 2-aminobenzodiazepine derivatives (VI) can be used in the form of their acid salts, and in such cases it is not always necessary to add additional acid to the reaction system. The amount of the hydrazine and the acid is usually approx. 1 to approx. 5 mol per mol of said 2-amino-benzodiazepine derivative (VI), but this ratio can be changed as desired.

The above-mentioned 2-hydrazinobenzodiazepine derivatives (II) can be subjected to a subsequent cyclization reaction with or without isolation from the reaction mixture. The isolation of the 2-hydrazinobenzodiazepine derivatives (II) can be carried out in the usual way, e.g. by adding water to the reaction mixture and extracting the whole with a suitable solvent (e.g. methylene chloride, chloroform, etc.), after which the solvent is distilled off. The 2-hydrazinobenzodiazepine derivative (II) where the nitrogen atom in the 4-position does not carry any oxygen atom can also be prepared by a method which includes that a compound with the general formula:

where R 1 means hydrogen, alkyl or aralkyl and where the other symbols have the same meaning as stated above, is reacted with hydrazine.

With regard to the above general formula (VII), these compounds when R^ is hydrogen can have the following isomeric form:

which can also be used in the present method.

The compound of formula (VII) can be prepared, e.g. according to the method described in Journal of Organic Chemistry 29, 231 (1961»).

The alkyl group represented by the symbol R 1 is preferably a lower alkyl group with up to 6 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, amyl, hexyl, etc. The aralkyl group represented by the symbol Rn is preferably benzyl, phenethyl, etc.

The reaction is usually carried out in the presence of a solvent (e.g. methanol, ethanol, aqueous mixtures thereof, etc.), around room temperature or under heating if necessary, up to the boiling point of the solvent used. The amount of hydrazine is usually from 1 to about 10 mol per mol of the compounds of formula (VII).

The prepared 2-hydrazinobenzodiazepine derivatives (II) can be isolated in the usual way, e.g. by evaporating the solvent from the reaction mixture.

The benzodiazepine derivatives produced according to the present invention are new compounds that show muscle relaxant, sedative and dampening effects and also have activity against convulsions, and they can consequently be used as agents for muscle relaxation, for sedative and tranquilizing purposes as well as against convulsions in general.

The benzodiazepine derivatives (I) as well as their acid salts can be administered orally or parenterally in a manner known per se, e.g. in the form of a powder, in the form of granules, tablets or injection solutions mixed with a pharmaceutically acceptable carrier or diluent.

The dose of said benzodiazepine derivatives (I) or their acid salts to be administered will depend on the type of benzo-diazepine derivative used, the nature of the disorder, etc., and will usually fall in a range from approx. 1 to approx. 30 mg by oral administration, and from approx. 0.5 to approx. 10 mg by parenteral administration for adult patients per day.

The following examples illustrate the invention. The term "part or parts" means parts by weight if nothing else is stated, and the ratio between parts and parts by volume corresponds to the ratio between grams and ml.

Example 1

To a suspension of 3.4 parts of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine dihydrochloride in 60 parts of methanol was added 1.25 parts of 80% hydrazine hydrate. The suspension was stirred for 40 minutes, diluted with water and extracted with methylene chloride. The extract was washed with water and dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue was recrystallized from a mixture of methylene chloride and benzene to give 7-chloro-2-hydrazino-5-phenyl-3H-1,3-benzodiazepine as colorless prisms. Melting point: approx. 170°C (browning), 202 - 204°C (decomposition).

Elemental analysis for C-^H-^CIN^

calculated: C 63.27, H 4.60, N 19.68

found: C 63.43, H 4.48, N 19.27.

Example 2

A suspension of 3 parts of 2-amino-7-chloro-5-(p-methoxy-phenyl)-3H-1,4-benzodiazepine in a mixture of 50 parts by volume of methanol and 0.6 parts by volume of glacial acetic acid was added dropwise while stirring to 1, 5 parts by volume 100% hydrazine hydrate. The mixture was stirred for 30 minutes and poured into ice water, followed by an extraction with chloroform. The chloroform layer was washed with water, dried over sodium sulfate, after which the chloroform was evaporated. Treatment of the residue with benzene gives 7-chloro-2-hydrazino-5-(p-methoxyphenyl)-3H-1,4-benzodiazepine as colorless crystals melting at 214 - 220°C.

Elemental analysis: C^gH-^ClN^O

calculated: C 6l.05, H 4.80, N 17.80

found: C 60.93, H 4.67, N 17.83

Example 3

A mixture of 2.35 parts of 2-amino~5-phenyl-3H-1,4-benzodiazepine, 50 parts by volume of ethanol and 1.2 parts by volume of glacial acetic acid was added to 1.5 parts by volume of 100% hydrazine hydrate, and the mixture was stirred for 1 hour at room temperature. The treatment of the mixture was in the same manner as in Example 2, which gave 2-hydrazino-5-phenyl-3H-1,4-benzodiazepine as white crystals. Recrystallization from a mixture of methylene chloride and benzene gave white crystals melting at 116 - 118°C (effervescent).

Elemental analysis: ^15^14^4*l/3 ^gHg

calculated: C 73.89, H 5.84, N 20.28

found: C 73.86, H 5.47, N 20.44

Example 4

A mixture of 9.1 parts of 2-amino-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine, 150 parts by volume of ethanol and 3.6 parts by volume of glacial acetic acid was added to 4.5 parts by volume of 100% hydrazine hydrate. The mixture was stirred for 30 minutes at room temperature and treated as described in example 1, whereby 2-hydrazino-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine was obtained as a crystalline powder. Melting point: 127°C (sintering), 133 - 135°C (effervescent).

Elementary analysis: '-'16^13^3^4

calculated: C 60.37, H 4.12, N 17.60

found: C 60.05, H 3.96, N 17.4-0

Example 5

A mixture of 2.5 parts of 2-amino-7-methyl-5-phenyl-3H-1,4-benzodiazepine, 100 parts by volume of methanol and 1.2 parts of glacial acetic acid was added to 2.5 parts of 100*fo hydrazine hydrate. The mixture was stirred for 1 hour at room temperature and treated as described in example 1, whereby 2-hydrazino-7-methyl-5-phenyl-3H-1,4-benzodiazepine was obtained as crystals. Recrystallization from a mixture of chloroform and diethyl ether gives colorless crystals with a melting point of 240 - 241°C (decomposition).

Elementary analysis: ^ iS^ l6^/\.

calculated: C 72.70, H 6.10, N 21.20

found: C 72.70, H 6.08, N 21.31

Example 6

A mixture of 26.5 parts of 2-amino-7-methoxy-5-phenyl~3H-1,4-benzodiazepine, 100 parts by volume of methanol and 1.2 parts of glacial acetic acid was added to 25 parts of 100% hydrazine hydrate. The mixture was stirred for 1 hour at room temperature and treated as described in example 1, whereby 2-hydrazino-7-methoxy-5-phenyl-3H-1,4-benzodiazepine was obtained as crystals with m.p. from 110 - 120°C.

Example 7

A mixture of 5.6 parts of 2-amino-7-nitro-5-phenyl-3H-1,4-benzodiazepine, 200 parts by volume of ethanol and 2.4 parts by volume of glacial acetic acid was added to 5 parts by volume of 80% hydrazine hydrate. The mixture was stirred for 30 minutes at room temperature and then treated as described in Example 1, whereby 2-hydrazino-7-nitro-5-phenyl-3H-1,4-benzodiazepine was obtained as a reddish, viscous, oily substance.

Example 8

A solution of 16 parts of 2-amino-7-chloro-3-isobutyl-5-phenyl-3H-1,4-benzodiazepine and 25 parts of 100% hydrazine hydrate in 400 parts by volume of methanol was added to 6 parts of glacial acetic acid while stirring and ice-cooling. The mixture was stirred at room temperature for 5 hours. Water was added, followed by an extraction with chloroform. The chloroform layer was washed with water, dried over sodium sulfate, after which the solvent was evaporated. Treatment of the residue with isopropyl gives 7-chloro-2-hydrazino-3-isobutyl-5-phenyl-3H-1,4-benzodiazepine as colorless

crystals melting at 165 - 168°C.

The manufactured product is identical to the product from example 11.

Example 9

A solution of 2 parts of 7-chloro-2-methylmercapto-5-phenyl-3H-1,4-benzodiazepine in 70 parts by volume of ethanol was added to 5 parts by volume of 80% hydrazine hydrate, and the mixture was left at room temperature for 3 days. After evaporation of the solvent, a small amount of water was added to the residue, whereby 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine was obtained as crystals. Recrystallization from a mixture of methylene chloride and benzene gave crystals. Melting point: 175 °C (browning), 205 - 207 °C (decomposition).

The product obtained is identical to the product from example 1.

Example 10

A solution of 2.9 parts of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione in a mixture of 2.5 parts by volume of dimethyl sulfoxide and 100 parts by volume of ethanol was added 5 parts by volume 80% hydrazine hydrate, and the mixture was left for 24 hours. After evaporation of the solvent under reduced pressure, the residue was diluted with water followed by an extraction with methylene chloride. The methylene chloride layer was dried over sodium sulfate, after which the solvent was evaporated. Treatment of the residue with benzene gave 7-chloro-2-hydrazino-5-phenyl~3H-1,4-benzodiazepine. Recrystallization from a mixture of methylene chloride and benzene gives crystals melting at 205 - 207°C (decomposition), and the product was identical to the product prepared according to examples 1 and 9.

Example 11

A solution of 1.6 parts of 7-chloro-3-isobutyl-2-methyl-mercapto-5-phenyl-3H-1,4-benzodiazepine in 150 parts by volume of methanol was added to 40 parts of 100% hydrazine hydrate. The mixture was refluxed for 4.5 hours and poured into water followed by an extraction with chloroform. The chloroform layer was washed with water, dried over sodium sulfate, after which the solvent was evaporated. Treatment of the residue with diethyl ether gave 7-chloro-2-hydrazino-3-isobutyl-5-phenyl~3H-1,4-benzodiazepine as crystals. Recrystallization from a mixture of chloroform and n-hexane gave colorless crystals melting at 168 - 169°C Elemental analysis: ^gH<g>^<C>lN^

calculated: C 66.95, H 6.21, N 16.44

found: C 67,21,. ; H 6.19, N 16.70

Example 12

To a suspension of 8.1 parts of 2-amino-7-chloro-5-phenyl~3H-1,4-benzodiazepine in 180 parts by volume of methanol was added 3>6 parts of 2-methylimidazole hydrochloride and 2.25 parts by volume of 80% hydrazine hydrate. The suspension was stirred at room temperature for 1.5 hours, after which 25 parts of ethyl orthoformate were added. 60 parts by volume of ethanol containing 10% hydrogen chloride were added dropwise to the mixture while stirring. After stirring for an additional 1 hour, the mixture was heated to complete the reaction. After evaporation of the solvent, an aqueous solution of sodium bicarbonate was added for neutralization. The mixture was then extracted with methylene chloride. The methylene chloride layer was washed with water and dried over sodium sulfate, after which the solvent was evaporated. The residue was recrystallized from a mixture of acetone and n-hexane, and 8-chloro-6-phenyl-4H-s-triazolo-[4,3-aJ[1,4]-benzodiazepine was obtained as colorless flakes. Melting point: 226 - 227°C

Elemental analysis: Ci<gH>^<d>N^

calculated: C 65.20, H 3.76, N 19.01

found: C 65.30, H 3.48, N 19.03.

Example 13

A solution of 2.8 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine and 7.4 parts of ethyl orthoformate in 80 parts by volume of chloroform was added with stirring to 2 parts of concentrated sulfuric acid. The mixture was stirred at room temperature for 30 minutes, after which a saturated aqueous sodium bicarbonate solution was added to neutralize the mixture. The chloroform layer was washed with water and dried over anhydrous sodium sulfate, after which the solvent was evaporated. The residue was recrystallized from a mixture of acetone and n-hexane, whereby 8-chloro-6-phenyl-4H-s-triazol[4,3~aH1,41-benzodiazepine was obtained as colorless flakes. Melting point: 226 - 227°C.

The product produced was identical to the product from example 12.

Example 14

To a solution of 2.85 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 100 parts by volume of methanol was added 7.4 parts of ethyl orthoformate and 20 parts by volume of methanol saturated with hydrogen chloride. The mixture was stirred for 2 hours and gently refluxed for 30 minutes. The solvent was distilled off under reduced pressure. To the residue was added a saturated aqueous sodium bicarbonate solution to make the mixture alkaline, after which the whole was extracted with chloroform. The chloroform extract was washed with water and dried over anhydrous sodium sulfate, after which the solvent was evaporated. The residue was recrystallized from ethyl acetate to give 8-chloro-6-phenyl-4-H-s-triazole-[4>3-a][1,4-1-benzodiazepine as colorless flakes. Melting point: 226 - 227°C.

The product produced was identical to the product from examples 12 and 13.

Example 15

A solution of 2.8 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 20 parts by volume of formic acid was left overnight. The solution was diluted with water, neutralized with an aqueous solution of sodium bicarbonate and extracted with chloroform. The chloroform extract was washed with water, dried over anhydrous sodium sulfate, after which the solvent was evaporated. The residue was recrystallized from a mixture of acetone and n-hexane to give 8-chloro-6-phenyl-4H-s-triazole-[4.3_a][1,41-benzodiazepine as colorless flakes. Melting point: 226 - 227°C.

The manufactured product is identical to the product from examples 12, 13 and 14.

Example 16

To a suspension of 2.8 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 40 parts by volume of formamide was added 1 part by volume of concentrated sulfuric acid. The resulting solution was allowed to stand over 6 hours and then boiled on a boiling hot bath for 3 minutes. The solution was diluted with water, neutralized with sodium bicarbonate and extracted with chloroform. The chloroform extract was washed with water and dried over anhydrous sodium sulfate, after which the solvent was evaporated. The residue was recrystallized from ethyl acetate to give 8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1»4ibenzodiazepine as colorless flakes. Melting point: 226 - 227°C.

The manufactured product is identical to the product from examples 12, 13, 14 °g 15*

Example 17

A mixture of 2.8 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, 2.4 parts of forramidine hydrochloride and 2.5 parts of 2-methyliraidazole was melted down at 160°C in 10 minutes. Water was added to the mixture, after which the whole was extracted with methylene chloride. The methylene chloride layer was washed with water, dried over sodium sulfate, . after which the solvent was evaporated. This produced 8-chloro-6-phenyl-4H-s-triazolo14,3-alt1,43benzodiazepine. Recrystallization from ethyl acetate gave colorless flakes with a m.p. at 226 - 227°C.

The manufactured product is identical to the product from examples 12, 13, 14, 15 and 16.

Example 18

To a suspension of 1.35 parts of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine in 25 parts by volume of methanol was added 0.6 parts of 2-methylimidazole hydrochloride and 6 parts by volume of a 1-mol methanol solution of hydrazine hydrate. The mixture was stirred at room temperature for 1.5 hours, after which 4.8 parts of ethyl orthoacetate and 10 parts by volume of ethanol containing 10% hydrogen chloride were added. The mixture was refluxed for 10 minutes after which the solvent was evaporated. The residue was neutralized with a saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The methylene chloride extract was washed with water and dried over sodium sulfate, after which the solvent was evaporated. The residue was purified by silica gel column chromatography, whereby 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4>3-a H1,4]benzodiazepine was obtained. Recrystallization from a mixture of acetone and n-hexane gave colorless needles. Melting point: 225 - 226°C.

Elemental analysis: C^<H>^<CI>N^

calculated: C 66.13, H 4.24, N 18.15

found: C 66.39, H 4.08, N 18.07

Example 19

A solution of 2.84 parts of 7~chloro-2-hydrazino-5-phenyl-. 3H-1,4-benzodiazepine in 50 parts by volume of chloroform was added to 10 parts of ethyl orthoacetate and 4 parts of p-toluenesulfonic acid. The mixture was left at room temperature for 6 hours and heated on a water bath to complete the reaction. The mixture was washed with saturated aqueous sodium bicarbonate solution, then with water and then dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was treated in the manner described in Example 18, whereby 8-chloro-1-methyl-6-phenyl-4H-s-triazolo {4,3_a][1>4]benzo-

diazepine as colorless needles. Melting point: 224 - 225°C.

The manufactured product is identical to the product from example 18.

Example 20.

To a suspension of 2.84 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 50 parts by volume of acetic anhydride was added 1 part by volume of concentrated sulfuric acid. The resulting solution was left at room temperature for 1 hour, poured into ice water, neutralized with sodium bicarbonate and extracted with methylene chloride. The methylene chloride extract was washed with water and dried over anhydrous sodium sulfate, after which the solvent was evaporated. The residue was recrystallized from a mixture of acetone and n-hexane to give 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3_a3 £1,4]benzodiazepine as colorless needles. Melting point: 224 - 225°C.

The manufactured product is identical to the product from examples 18 and 19.

Example 21

To a solution of 2.84 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 60 parts by volume of chloroform was added 2.46 parts of ethyl acetoimidate hydrochloride. The mixture was stirred for 8 hours, after which aqueous sodium bicarbonate solution was added for neutralization. The chloroform layer was separated, washed with water and dried over anhydrous sodium sulfate, after which the solvent was evaporated. The residue was recrystallized from ethyl acetate to give 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3_αHl,4]benzodiazepine as colorless needles. Melting point: 225 - 226°C.

The product produced is identical to the product from examples 18, 19 and 20.

Example 22

A mixture of 2.8 parts of 7~chloro-2-hydrazino-5-phenyl~3H-1,4-benzodiazepine, 2.8 parts of acetamidine hydrochloride and 2.5 parts of 2-methylimidazole was melted while heating at 160°C for 10 minutes. Water was added to the mixture, after which the whole was extracted with methylene chloride. The methylene chloride layer was washed with water and dried over sodium sulfate. The solvent was evaporated to give 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-al[1,4]benzodiazepine. Recrystallization from ethyl acetate gave colorless needles of m.p. of 223 - 225°G.

The manufactured product is identical to the product from examples 18, 19, 20 and 21.

Example 21

A mixture of 2.8 parts of 7-chloro-2-hydrazino-5-phenyl~3H-1,4-benzodiazepine, 2.8 parts of acetamidine hydrochloride, 2.5 parts of 2-methylimidazole and 100 parts by volume of chloroform was stirred at room temperature for 24 hours. The chloroform layer was washed with water, dried over sodium sulfate, after which the solvent was evaporated. After treatment of the residue with diethyl ether, the resulting crystals were subjected to extraction with hot methanol. The evaporation of methanol gives 2-(α-aminoethylidene)-hydrazino-7-chloro-5-phenyl-3H-1,4-benzodiazepine as crystals. Recrystallization from acetone gives pale yellow needles with m.p. from 203 - 205°C (effervescent).

Elemental analysis: C<->^<y>H^gClN^\

calculated: C 62.67, H 4.95, N 21.50

found.: C 62.99, H 4.84, N 21.53

Example 24

3) 5 parts of 2-(oc-aminoethylidene)-hydrazino-7-chloro-5-phenyl-3H-1,4-benzodiazepine prepared in example 23 were heated in an oil bath for 10 minutes at 200°C whereby a, strong foam formation and the whole thing was then cooled. Recrystallization from ethyl acetate gives 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3~a]thi,4]benzodiazepine as colorless needles, m.p. 225.5 - 226.5°C.

The manufactured product is identical to the product from examples 18, 19, 20, 21 and 22.

Example 25

A solution of 1.4 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in JO parts by volume of chloroform was added with 0.47 parts by volume of acetic anhydride while stirring. The mixture was then stirred for 1 hour, then washed with a saturated aqueous solution of sodium bicarbonate and then with water. The chloroform layer was dried over sodium sulfate, after which the solvent was evaporated. Addition of methanol gives 2-(2-acetylhydrazino)-7-chloro-5-phenyl-3^-1>4-benzodiazepine as white crystals. Recrystallization from a mixture of chloroform and methanol gives powdery crystals with a melting point of 202 - 204°C (effervescent). Elemental analysis: C-jyH-^CIN^O

calculated: C 62.48, H 4.63, N 17.15

found: C 62.38, H 4.44, N 17.23

Example 26

3.3 parts of 2-(2-acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine prepared as described in Example 25 were heated for 10 minutes at 215°C under slightly reduced pressure. The molten material was recrystallized from ethyl acetate to give 8-chloro-1-methyl-6-phenyl-4-H-s-triazolo[4,3_αHl,41benzodiazepine as colorless needles with a m.p. at 225 - 226°C.

The product produced is identical to the product from examples 18, 19, 20, 21, 22 and 24.

Example 27

A suspension of 3.3 parts of 2-(2-acetylhydrazino)-7-chloro-5-phenyl-4H-1,4-benzodiazepine prepared as described in Example 25)

in 20 parts by volume of pyridine was refluxed, whereby the crystals were gradually dissolved. After two hours, the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixture of acetone and n-hexane to give 8-chloro-1-methyl-6-phenyl-4H-s-triazolo4>3~a^"

[1,43benzodiazepine as colorless needles, m.p. 224 - 225°C.

The product produced is identical to the product from examples 18, 19, 20, 21, 22, 24 and 26.

Example 28

A mixture of 1.4 parts of 7"chloro-2-hydrazino-5~phenyl-3H-1,4-benzodiazepine prepared as described in example 1, 50 parts by volume of ethanol and 4 parts by volume of ethyl orthopropionate was added to 0.5 parts by volume of concentrated sulfuric acid. The mixture was stirred for 10 minutes at room temperature and then treated as described in example 14", whereby 8-chloro-1-ethyl-6-phenyl-4H-s-triazolo-[4>J-a.] [1,4lbenzodiazepine as crystals.

Recrystallization from acetone gives colorless prisms with a melting point of 229 - 230°C.

Elemental analysis: C^gH-^ClN^

calculated: C 66.97, H 4.68, N 17.36

found: C 67.18, H 4.48, N 17.53

Example 29

A solution of 1.4 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine prepared as described in example 1, in 30 parts by volume of chloroform was added with stirring to 0.65 parts by volume of propionic anhydride. The mixture was stirred for 1 hour, washed with a saturated aqueous solution of sodium bicarbonate, then with water, after which the whole was dried over sodium sulfate. After evaporation of chloroform, methanol was added, whereby .7-chloro-5-ferryyl-2-(2-propionylhydrazino)-3H-1,4-benzodiazepine was precipitated as crystals. Recrystallization from a mixture of chloroform and methanol gives colorless prisms with a melting point of 186 - 187°C (effervescent).

Elemental analysis: C-^qH-^CIN^O

calculated: C 63.43» H 5.03, N 16.44

found: C 63.54, H 4.88, N 16.70

Example 30

Under slightly reduced pressure, 3>4 parts of 7-chloro-5-phenyl-2-(2-propionylhydrazino)-3H-1,4-benzodiazepine were prepared as described in example 29" for 15 minutes held at 195°C The melted substance was recrystallized from acetone to give 8-chloro-1-ethyl-6-phenyl-4H-s-triazolo[4»3_aH1»4]benzodiazepine as colorless prisms with a m.p. at 229 - 230°C.

The manufactured product is identical to the product from example 28.

Example 31

A mixture of 2.85 parts of 7~chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, 50 parts by volume of chloroform and 2 parts by volume of triethylamine was gradually added under ice-cooling to a solution of 1.6 parts of enantyl chloride in 20 diethyl ether by volume. The mixture was then stirred for an extended period of time to complete the reaction. After evaporation of the solvent under reduced pressure, the residue was treated with methanol, whereby 7-chloro-2-(2-enantylhydrazino)-5-phenyl-3H-1,4-benzodiazepine was obtained as crystals. Recrystallization from a mixture of dimethylformamide and water gives colorless needles melting at 205 - 206°C (effervescent).

Elementary analysis<see:> C^ R^ GWqO

calculated: C 66.57, H 6.35, N 14.12

found: C 66.43. H 6.24, N 14.29

Example 32

A mixture of 1.98 parts of 7-chloro-2-(2-enantylhydrazino)-5-phenyl-3H-1,4-benzodiazepine and JO parts of polyphosphoric acid was kept at 170 - 180°C for 2 hours. To the mixture was then added 200 parts by volume of ice water, and the resulting solution was neutralized with concentrated aqueous ammonia under ice-cooling, after which the mixture was extracted with chloroform. The chloroform layer was washed with water, dried over sodium sulfate, after which the solvent was evaporated. The residue was recrystallized from aqueous acetone to give 8-chloro-1-hexyl-6-phenyl-4-H-s-triazolo-[4, 3-a J [1>4 ]-benzodiazepine as colorless plates melting at 75 - 78°C (sintering). Elemental analysis: <C>^H^ClN^.SH<g>O,

calculated: C 63.68, H 6.56, N 13.50

found: C 63.71, H 6.15, N 13.60

The produced product was further dried under reduced pressure, whereby a compound containing a quarter of H^O was obtained, and this sintered at 6l - 63°C

Example 33

A suspension of 4 parts of 7-chloro-2-(2-enantylhydrazino)-5-phenyl-3H-1,4-benzodiazepine prepared as described in example 31" in 20 parts by volume of pyridine was refluxed for approx. 3 hours. After evaporation of the pyridine, water was added to the residue, whereby 8-chloro-1-hexyl-6-phenyl-4H-s-triazolo-[4> 3~ al[1> 41-benzodiazepine was precipitated as crystals. Recrystallization from aqueous acetone gives colorless flakes that melt at 75 - 78°C (sintering).

The manufactured product is identical to the product from example 32.

Example 34

To a solution of 1.4 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, prepared as described in Example 1, in 25 parts by volume of tetrahydrofuran was added 0.62 parts by volume of benzoyl chloride, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with a saturated aqueous solution of sodium bicarbonate. The resulting white precipitate was separated, washed with water and then with methanol, and then dried to give 2-(2-benzoyl-hydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine as crystals. Recrystallization from a mixture of chloroform and methanol gives white needles melting at 207 - 208°C (effervescent).

Elemental analysis<see:><CggH>^yClN^O

calculated: C 67.95, H 4.41, N 14.41

found: C 67.87, H 4.20, N 14.49

Example 35

A mixture of 38.8 parts of 2-(2-benzoylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine, prepared as described in Example 34. and 400 parts of polyphosphoric acid were kept at 150°C for 1.5 hours. The mixture was treated as described in example 32, whereby 8-chloro-1,6-diphenyl-4H-s~triazolo-[4,3-a][1,4]-benzodiazepine was obtained as crystals. Recrystallization from ethyl acetate gives colorless needles melting at 191 - 192°C.

Elemental analysis: C22H-L^C1N^

calculated: C 71.25, H 4.08, N 15.11

found: C 71.11, H 4.10, N 14.98

Example 36

Under slightly reduced pressure, 3.9 parts of 2-(2-benzoyl-hydrazino)-7-chloro-5-phenyl-3H'-1,4-benzodiazepine were prepared as described in Example 34, melted down at 215°C during 15 minutes until all foaming had stopped. Recrystallization of the molten substance from ethyl acetate gives 8-chloro-1,6-diphenyl-4H-s-triazolo-[4,3-a]-[1,4]-benzodiazepine as colorless needles melting at 193 - 194° C.

The manufactured product is identical to that from example 35.

Example 37

A solution of 1.4 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine and 1.8 parts of ethyl benzimidate hydrochloride in JO parts by volume of chloroform was stirred at room temperature for 24 hours and then washed with water . The chloroform layer was dried over sodium sulfate, after which the solvent was evaporated. Treatment of the residue with diethyl ether gives 8-chloro-1,6-diphenyl-4H-s-triazolo-[.4,J-a]11,41-benzodiazepine as crystals. Recrystallization from a mixture of ethyl acetate and n-hexane gives colorless needles melting at 192 - 193»5°C.

The manufactured product is identical to the product from examples 35 and 3&.

Example 38

As described in Example Jl, a solution of 0.85 parts of phenylacetyl chloride in 10 parts by volume of diethyl ether was added to a mixture of 1.4 parts of 7~chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, 1 part by volume of triethylamine and 25 parts by volume chloroform. The mixture was stirred for 45 minutes, whereby 7-chloro-2-(2-phenylacetylhydrazino)-5-phenyl-3H-1,4-benzodiazepine precipitated as crystals. Recrystallization from a mixture of dimethylformamide and water gives colorless, fine prisms melting at 220 - 221°C (effervescent).

Elementary analysis: Ggrjtt^ ClNqO

calculated: C 68.57, H 4.75, N 13.91

found: C 68.72, H 4.79, N 13.71

Example 39

A mixture of 4 parts of 7-chloro-2-(2-phenylacetylhydrazino)-5-phenyl-3H-1,4-benzodiazepine, prepared as described in example 38, and 50 parts of polyphosphoric acid was held for 2 hours at 180°C. The mixture was then treated as described in examples J2 and 35, whereby 1-benzyl-7-chloro-6-phenyl-4H-s-triazolo[4,3~aJ II,4]-benzodiazepine was precipitated. Recrystallization from ethyl acetate gives colorless prisms melting at 190 - 192°C.

Elemental analysis: CgoH-^yClN^

calculated: C 71.78, H 4.45, W 14.56"

found: C 72.07, H 4.34, N 14.74

Recrystallization from methanol gives colorless needles melting at 101 - 103°C (effervescent).

Elementary analysis:> C^H-^CIN^. GH^OH

calculated: C 69.14, H 5.08, N 13.44

found: C 69.31, H 5.02, N 13.59

Example 40

4 parts of 7-chloro-2-(2-phenylacetylhydrazino)-5-phenyl-3H-1,4-benzodiazepine T prepared as described in example 38, were melted down under slightly reduced pressure while heating at 230°C for 10 minutes until foaming stopped up. Recrystallization of the melted substance from ethyl acetate gives 1-benzyl-8-chloro-6-phenyl-4H-s-triazolo[4,3~a]thi,4]-benzodiazepine as colorless prisms melting at 191 - 192°C.

The manufactured product is identical to the product from example 39-

Example 41

To a suspension of 1.6 parts of 7-chloro-2-hydrazino-5-(p-methoxyphenyl)-3H-1,4-benzodiazepine, prepared as described in Example 2, in 50 parts by volume of ethanol was added J, 0 parts of ethyl orthoformate and 0.5 parts by volume of concentrated sulfuric acid were then added dropwise while stirring. The mixture was stirred for a certain period of time and then neutralized with an aqueous solution of sodium bicarbonate, after which the solvent was evaporated. Water was added to the residue, whereby 8-chloro-6-(p-methoxyphenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine was precipitated as crystals. Recrystallization from acetone and then from ethyl acetate gives pale yellow flakes which melt at 216 - 217°C. Elemental analysis: C-^H-j^ClN^O

calculated: C 62.87, H 4.03, N 17.25

found: C 62.98, H 3.95, N 17.57

Example 42

A mixture of 2.1 parts of 7-chloro-2-hydrazino-5-(p-methoxyphenyl)-4H-1,4-benzodiazepine, prepared as described in Example 2, 4.33 parts of ethyl orthoacetate and 60 parts by volume of ethanol was added dropwise 0.75 parts by volume of concentrated sulfuric acid. The mixture was stirred for approx. 15 minutes. After the reaction was complete, the mixture was neutralized with a saturated aqueous sodium bicarbonate solution to precipitate 8-chloro-1-methyl-6-(p-methoxyphenyl)-4H-s-triazolo[4>3_aHl,4]benzodiazepine as crystals. Recrystallization from a mixture of methanol and chloroform gives colorless needles melting at 268 - 269°G.

Elemental analysis: C^gH^ClN^O

calculated: C 63.81, H 4.46, N 16.54

found: C 63.76, H 4.31, N 16.58

Example 43

A mixture of 1 part of 2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, prepared as in example 3, 2 parts by volume of ethyl orthoformate and 20 parts by volume of ethanol, was added dropwise under ice cooling to 0.44 parts by volume of concentrated sulfuric acid. The mixture was stirred at room temperature for 30 minutes and then neutralized with saturated aqueous sodium bicarbonate solution. The resulting oily substance was extracted with methylene chloride. The methylene chloride layer was washed with water, dried over sodium sulfate, after which the solvent was evaporated to give 6-phenyl-4H-s-triazolo[4,3-a]£l>4lbenzodiazepine as crystals. Recrystallization from a mixture of acetone and n-hexane gives colorless needles melting at 195 - 196°C. Elementary analysis: ^16^12^4

calculated: C 73.83. H 4.65, N 21.53

found: C 73/71, H 4.37. N 21,21

The compound can be obtained as polymorphous prisms which melt at 201 - 202°C upon recrystallization from the same solvent, and the elemental analytical data of said compound coincide with the calculated values for C^gH^N^.

Example 4- 4- Using the same method as in example 43, except that 4 parts by volume of ethyl orthoacetate were used instead of ethyl orthoformate, gave 1-methyl-6-phenyl-4H-s-triazolo[4, 3_aHl, 43benzodiazepine. Recrystallization from a mixture of methanol and ethyl acetate gave colorless prisms melting at 226-227°C.

Elementary analysis: ^17^14^4

calculated: C 74.43, H 5.14, N 20.43

found: C 74.70, H 5.17, N 20.41

Example 45

A mixture of 3.2 parts of 2-hydrazino-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine, prepared as described-in Example 4,

8.5 parts of ethyl orthoformate and 50 parts by volume of chloroform were added dropwise to 7.6 parts of p-toluenesulfonic acid at a temperature below 10°C. The mixture was then stirred at room temperature for 2.5 hours. After the reaction was complete, the mixture was neutralized with a saturated aqueous solution of sodium bicarbonate. The chloroform layer was separated, washed with water and dried over sodium sulfate. Evaporation of the solvent gives 6-phenyl-8-trifluoromethyl-4H-s-triazolo[4, 3~ a1-[ 1,4]benzodiazepine as crystals. The crystals were dissolved in ethanol and the insoluble substances removed by filtration. The filtrate was concentrated and recrystallized from ethyl acetate, whereby colorless flakes were obtained. Melting point: 258 - 260°C.

Elementary analysis: ^17^1<1>^3^4

calculated: C 62.19, H 3.38, N 17.07

found: C 61.99, H 3.46, N 16.89.

Example 46

A mixture of 9.5 parts of 2-hydrazino-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine, prepared as described in Example 4,

29 parts of ethyl orthoacetate and 150 parts by volume of chloroform were added dropwise to 23 parts of p-toluenesulfonic acid under ice cooling, after which the mixture was left at room temperature for 7 hours. After the reaction was complete, the mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, after which the chloroform layer was separated, washed with water and dried over sodium sulfate.■ After evaporation of the solvent, the residue was treated with a mixture of benzene and isopropyl ether to give precipitated 1-methyl-6-phenyl-8-trifluoromethyl-4H-s-triazolo[4,3_aH1,43benzodiazepine as crystals containing crystallization benzene. Recrystallization from a mixture of benzene and n-hexane gives colorless needles melting at 129 - 130°G (sintering), 133 - 134°C (effervescent).

Elemental analysis: C-^<g>H^F^N^.l/SCgHg

calculated: C 65.21 , H 4.10, N 15.21

found: C 65.26, H 4.20, N 14.8l

Recrystallization from aqueous acetone gives colorless needles which melt at 112 - 113°C (sintering) and contain 1/5 mol water of crystal.

Elemental analysis : <-!i8^13F3N4' ^/5H20

calculated: C 62.49, H 3.90, N 16.20

found: C 62.53, H 4.08, N 16.42

Example 47

A mixture of 5.3 parts of 2-hydrazino-7-methyl-5-phenyl~3H-1,4-benzodiazepine, prepared as described in Example 5, 14.8 parts of ethyl orthoformate and 150 parts by volume of ethanol was added dropwise to 4 parts of concentrated sulfuric acid under ice cooling. The mixture was stirred for 10 minutes and then neutralized with a saturated aqueous solution of sodium bicarbonate, after which the whole was extracted with chloroform. The chloroform layer was washed with water and dried over sodium sulfate. After evaporation of the solvent, the residue was treated with n-hexane, whereby 8-methyl-6-phenyl-4H-s-triazolo-t4,3_aHl,4]benzodiazepine was precipitated as crystals. Recrystallization from ethyl acetate gives pale yellow prisms melting at 177 - 178°C. Elementary analysis: ^17^14^4

calculated: C 74.43/ H 5.H, -N 20.43

found: C 74.30, H 5.15, N 20.14

Example 48

The procedure from example 47 was repeated, except that 16.2 parts of ethyl orthoacetate were used instead of ethyl orthoformate, whereby 1,8-dimethyl-6-phenyl-4H-s-triazolo[4,3-a]-[1, 43-benzodiazepine as crystals. Recrystallization from ethyl acetate gives colorless needles melting at 211 - 211.5°C.

Elementary analysis: ^18^16^4

calculated: C 74.97, H 5.59, N 19.43

found: C 74.93. H 5.42, N 19.73

Example 49

A mixture of 2.8 parts of 2-hydrazino-7-methoxy-5-phenyl-3H-1,3-benzodiazepine, prepared as described in Example 6, 7.4 parts of ethyl orthoformate and 100 parts by volume of ethanol was added to 2 parts of concentrated sulfuric acid with stirring and ice-cooling. The mixture was stirred at room temperature for 45 minutes to complete the reaction. After evaporation of the solvent under reduced pressure, the residue was neutralized with a saturated aqueous solution of sodium bicarbonate, after which the whole was extracted with chloroform. The chloroform layer was washed with water and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gives 8-methoxy-6-phenyl-4H-s-triazolo [4, 3-a Hl , 4]benzodiazepine as crystals. Recrystallization from ethyl acetate gives pale yellow prisms, m.p. 209 - 210°C. Elemental analysis: C-^H<->^<N>^O

calculated: C 70.33, H 4.86, N 19.30

found: C 70.23, H 4.93, N 19.15

Example 50

The procedure from Example 49 was repeated, except that 8 parts of ethyl orthoacetate were used instead of ethyl orthoformate, whereby 1-methyl-8-methoxy-6-phenyl-4H-s-triazolo-[4,3~aHl,43benzodiazepine was produced as crystals . Recrystallization from ethyl acetate gives pale yellow prisms, m.p. 196 - 197 C. Elemental analysis: C]_8Hl6N4^

calculated: C'71.03, H 5.30, N 18.41

found: C 71.16, H 5.44, N 18.21

Example 51

2-hydrazino-7-nitro-5-phenyl-3H-1,4-benzodiazepine, prepared from 5.6 parts of 2-amino-7-nitro-5-phenyl-3H-1,4-benzodiazepine as described in Example 7 , was dissolved in a mixture of 20 parts by volume of ethyl orthoformate and 100 parts by volume of chloroform, after which 10 parts of p-toluenesulfonic acid were added. The mixture was left at room temperature for 1 hour with shaking. After the reaction was complete, the solution was washed with a saturated aqueous solution of sodium bicarbonate, then with water, after which the whole was dried over sodium sulfate. After evaporation of the solvent, the residue was treated with ethyl acetate, whereby 8-nitro-6-phenyl-4H-s-triazolo[4,3-a][1.4h benzodiazepine was precipitated as crystals. Recrystallization from tetrahydrofuran gives pale yellow needles, m.p. 271 - 272°C.

'Elementary analysis: C^gH^N^<Og>

calculated: C 62.94, H 3.63, N 22.94

found: C 63.07, H 3.75, N 23.39

Example 52

The same procedure as in example $1 was repeated,

except that 20 parts by volume of ethyl orthoacetate were used instead of the ethyl orthoformate, whereby 1-methyl-8-nitro-6-phenyl-4-H-s-triazolo [4-,3-a 1 ti,41-benzodiazepine was produced as yellow crystals. Recrystallization from acetone gives yellow prisms, m.p. 227 - 229°C. Elementary analysis: ^ if^ i^^ z

calculated: C 63.94, H 4.10, N 21.93

found: C 64.11, H 4.00, N 21.69

Example 53

A mixture of 1.7 parts of 7-chloro-2-hydrazino-3-isobutyl-5-phenyl-3H-1,4-benzodiazepine, prepared as described in example 8, as well as 3.7 parts of triethyl orthoformate and 40 parts by volume of ethanol was added 1 part concentrated sulfuric acid while stirring and ice-cooling. The mixture was stirred for approx. 20 minutes at room temperature. After the reaction was complete, the mixture was neutralized with sodium bicarbonate, after which the mixture was extracted with chloroform. The chloroform layer was washed with water and dried over sodium sulfate. After evaporation of the solvent, the residue was treated with n-hexane, whereby 5-chloro-4-isobutyl-6-phenyl-4H-s-triazolo[4,3-a]thi,4]-benzodiazepine was produced as pale yellow crystals . Recrystallization from a mixture of benzene and n-hexane gives colorless needles melting at 140.5 - 141.5°c

Elementary analysis: C^ qE^ GW^

calculated: G 68.47, H 5.46, N 15.97

found: C 68.56, H 5.30, N 16.11

Example 54

To a suspension of 14.3 parts of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine 4N-oxide in 400 parts by volume of methanol was added 12.5 parts by volume of 100% hydrazine hydrate and 10 parts by volume of methanol saturated with hydrogen chloride. The mixture was refluxed for 10 minutes and the resulting solution concentrated to half the original volume. The concentrate was poured into 500 parts by volume of water and the resulting oily substance extracted with chloroform. The chloroform layer was dried over sodium sulfate and evaporated. Treatment of the residue with diethyl ether gives 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine-4N-oxide as pale yellow powdery crystals, m.p. 262 - 263°C.

Elemental analysis: C^H^CIN^O

calculated: C 59.90, H 4.36, N 18.63

found: C 60.05, H 4.13, N 18.41

Example 55

To a solution of 3 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine-4N-oxide, prepared as described in Example 54, in 20 parts by volume of chloroform was added 7.4 parts of ethyl orthoformate, and then dropwise 1.1 parts concentrated sulfuric acid. The mixture was stirred for approx.

20 minutes and then neutralized with a saturated aqueous sodium bicarbonate solution. The chloroform layer was washed and dried over sodium sulfate. Evaporation of the solvent gives 8-chloro-6-phenyl-4H-s-triazolo[4,3_αHl,4]-benzodiazepine-5N-oxide as crystals. Recrystallization from a mixture of methanol and chloroform (1 : 1 by volume) gives colorless needles, m.p. 267 - 268°C (decomposition). Elemental analysis: C-LgH-^ClN^O

calculated: C 61.74, H 3.57, N 18.03

found: C 61.87, H 3.26, N 17.92

Example 56

A mixture of 3 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine-4N-oxide, 20 parts by volume of formamide was added dropwise with 1.1 parts by volume of concentrated sulfuric acid and the whole mixture was stirred for 4 hours. After the reaction was complete, the mixture was neutralized with a saturated aqueous solution of sodium bicarbonate. The resulting crystals of 8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1>4]-benzodiazepine-5N-oxide were separated by filtration and recrystallized from chloroform to give colorless needles which melted at 267

- 269°C (decomposition).

The manufactured product is identical to the product from example 55"

Example 57

A solution of 3 parts of 7~chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine-4N-oxide in 20 parts by volume of 99$ formic acid was left overnight at room temperature, after which the solvent was distilled off. Neutralization with a saturated aqueous sodium bicarbonate solution gives 8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,43-benzodiazepine~5N-oxide as crystals. Recrystallization from chloroform gives colorless crystals, m.p. 268 - 269°C (decomposition).

The product produced is identical to the product from examples 55 °g 5&.

Example 58

A suspension of 3 parts of 7-chloro-2-hydrazino-5-phenyl~3H-1,4-benzodiazepine-4N-oxide, prepared as described in example 54, as well as 8 parts of ethyl orthoacetate in 100 parts by volume of ethanol was added dropwise to 1,1 parts by volume of concentrated sulfuric acid. The mixture was stirred for 15 minutes at room temperature, after which the solvent was evaporated. The residue was neutralized with a saturated, aqueous sodium bicarbonate solution, whereby 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3_a3[1,41benzodiazepine-5N-oxide was precipitated as crystals. Recrystallization from a mixture of methanol and diethyl ether gives colorless needles, m.p. 272 - 273°G (decomposition).

Elemental analysis: C-^H^CIN^O

calculated: C 62.87, H 4.03, N 17.25 found: C 63.04, H 4.04, N 17.26

Example 59

To a solution of 3 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine-4N-oxide in 100 parts by volume of ethanol was added 2.5 parts of ethylacetoimidate hydrochloride. The mixture was refluxed for approx. 30 minutes, after which the solvent was evaporated. The residue was neutralized with a saturated aqueous solution of sodium bicarbonate, whereby 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a]-1,4]-benzodiazepine-5N- oxide as crystals'. Recrystallization from a mixture of methanol and diethyl ether gives colorless needles melting at 268 - 269°C (decomposition).

The manufactured product is identical to the product from example 58.

Example 60

A mixture of 3 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine-4N-oxide, 4 parts of acetamidine hydrochloride and 5 parts of 2-methylimidazole was melted down at 175°C for 10 minutes. After cooling, water was added and the whole was extracted with chloroform. The chloroform layer was washed with water and dried over sodium sulfate. Evaporation of the solvent followed by an addition of methanol gave 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-0-1[1,4]-benzodiazepine-5N-oxide as crystals. Recrystallization from methanol gives colorless needles, which melt at 268 - 270°C (decomposition).

The manufactured product is identical to the product from examples 58 and 59-

Example 6l

A mixture of 1.5 parts of 7-chloro-2-hydrazino-5-phenyl-3H"-1,4-benzodiazepine-4N-oxide, 50 parts by volume of tetrahydrofuran and 1 part by volume of triethylamine was added with 0.5 parts by volume of acetic anhydride while stirring. The mixture was stirred for 1 hour, then water was added, whereby 2-(2-acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine-4N-oxide precipitated as crystals.Recrystallization from a mixture of dimethylformamide and water gives very fine needles which melt at 256 - 258°C (decomposition).

Elemental analysis: C^yH^ClN^Og

calculated: C 59.56, H 4.41, N 16.35

found: C 59.38, H 4.55, N 16.30

Example 62

A mixture of 3.4 parts of 2-(2-acetylhydrazino)~7-chloro-5-phenyl-3H-1,4-benzodiazepine-4N-oxide, prepared as described in example 6l, as well as JO parts by volume of pyridine was refluxed in 4 hours, after which the pyridine was evaporated under reduced pressure. The residue was recrystallized from methanol, whereby 8-chloro-1-methyl-6-phenyl-4H-s-triazolo-[4,3_a][1,4]-benzodiazepine-5N-oxide was precipitated as needles, m.p. . 272 - 274°C (decomposition).

The manufactured product is identical to the product from examples 58, 59 °S 60.

Example 63

A suspension of 3 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine-4N-oxide, prepared as described in Example 54, and 8.8 parts of ethyl orthopropionate in 100 parts by volume of ethanol was added dropwise 1.1 parts by volume of concentrated sulfuric acid. The mixture was stirred for 20 minutes, after which the solvent was evaporated. The residue was neutralized with a saturated aqueous solution of sodium bicarbonate, whereby 8-chloro-1-ethyl-6-phenyl-4H-s-triazolo[4,3-a]-[1-,43-benzodiazepine-5N was precipitated -oxide. Recrystallization from methanol gives colorless flakes that melt at 273 - 274° C (decomposition). Elemental analysis: C-^gH^ClN^O

calculated: C 63.81, H 4.46, N 16.54

found: C 63.60, H' 4.20, N 16.34

Example 64

To a mixture of 3 parts of 2-amino-7-nitro-5-phenyl-3H-1,4-benzodiazepine-4N-oxide and 100 parts by volume of ethanol was added 2.5 parts by volume of 100% hydrazine hydrate and 1.8 parts by volume of acetic acid. The mixture was slightly heated in a water bath, after which the whole was stirred at room temperature for approx. 20 minutes. The precipitated crystals were collected and washed with ethanol and then with diethyl ether, whereby 2-hydrazino-7-nitro-5-phenyl~3H-1,4-benzodiazepine-4N-oxide was obtained as yellow crystals, m.p. 176°C (sintering), 226°C (decomposition). Elementary analysis: '-'15^13^5^3

calculated: C 57.87, H 4.21, N 22.50

found: C 57.98, H 4.01, N 22.26

Example 65

To a suspension of 1.55 parts of 2-hydrazino-7-nitro-5-phenyl-3H-1,4-benzodiazepine-4N-oxide, prepared as described in Example 64, in 100 parts by volume of ethanol was added 3.7 parts of ethyl orthoformate, and then 0.6 parts by volume of concentrated sulfuric acid. The solid material dissolved, after which yellow crystals were precipitated. After stirring for 10 minutes, the mixture was neutralized with a saturated aqueous solution of sodium bicarbonate. The crystals were collected and washed with water, ethanol and then with diethyl ether, whereby 8-nitro-6-phenyl-4H-s-triazolo£4,3_aHl,4^-benzodiazepine-5N-oxide was obtained as yellow crystals. Recrystallization from aqueous dimethylformamide gives yellow crystals melting at 274 - 275°c (decomposition).

Elementary Analysis<:> '-'16^11^5^3

calculated: C 59.8l, H 3.45, N 21.80

found: G 59.58, H 3.48, N 21.56

Example 66

A mixture of 3.1 parts of 8-chloro-6-phenyl-4H-s-triazolo-[4»3-αHl,43-benzodiazepine-5N-oxide, prepared as described in Examples 55, 5^ and 57, 200 parts by volume chloroform and 5.3 volumes of phosphorus trichloride were refluxed for 1 hour. After evaporation of the solvent, a saturated aqueous sodium bicarbonate solution was added to the residue, after which the whole was extracted with chloroform. The chloroform layer was washed with water and dried over sodium sulfate. Evaporation of the solvent gives 8-chloro-6-phenyl-4H-s-triazolo-[4,3-αH1,43-benzodiazepine as crystals. Recrystallization from ethyl acetate gives colorless flakes that melt at 223.5 - 224.5°C

The manufactured product is identical to the product from examples 12, 13, 14, 15, 16 and 17.

Example 67

200 parts by volume of methanol were added to 3>1 parts of 8-chloro-6-phenyl-4H-s-triazolo[4>3_a][1,4]benzodiazepine-5N-oxide and 1 part by volume of Raney nickel. The mixture was subjected to catalytic hydrogenation. After absorption of 1 mole equivalent of hydrogen, the catalyst was removed by filtration, and the filtrate was concentrated to dryness. Recrystallization of the residue from ethyl acetate gives 8-chloro-6-phenyl-4H-s-triazolo[4,3-a3 ti,4^benzodiazepine as colorless flakes, melting point 222 - 223°C.

The manufactured product is identical to the product from example 66.

Example 68

A mixture of 3 > 4 parts of 8-chloro-1-ethyl-6-phenyl-4H-s-triazolo[4,3_a3 ti,43-benzodiazepine-5N-oxide, prepared as described in Example 63, 200 parts by volume of chloroform and 5 .3 parts by volume of phosphorus trichloride was refluxed for 1.5 hours, after which the solvent was evaporated. The residue was neutralized with a saturated aqueous solution of sodium bicarbonate and then extracted with chloroform. The chloroform layer was washed with water and dried over sodium sulfate. After evaporation of the solvent, the residue was treated with a mixture of acetone and petroleum ether, whereby 8-chloro-1-ethyl-6-phenyl-4H-s-triazolo[4j3-a3ti,43-benzodiazepine was precipitated as crystals. Recrystallization from acetone gives colorless granules that melt at 229 - 230°C.

The manufactured product is identical to the product from examples 28 and 30"

Example 69

To a suspension of 3>2 parts of 8-nitro-6-phenyl-4H-s-triazolo-[4,3_a^tl,4l-benzodiazepine-5N-oxide in 600 parts by volume of chloroform was added 20 parts by volume of phosphorus trichloride. The mixture was refluxed for 16 hours, after which the solvent was evaporated. The residue was neutralized with a saturated aqueous solution of sodium bicarbonate, and then extracted with chloroform. The chloroform layer was washed with water, dried over sodium sulfate. After evaporation of the solvent, the residue was treated with ethanol to give 8-nitro-6-phenyl-4H-s-triazolo4,3-a3t1,4^benzodiazepine as crystals. Recrystallization

from tetrahydrofuran gives pale yellow needles, mp 266° - 267°C.

The manufactured product is identical to the product from ex-

pole 51.

Claims (1)

Process for the preparation of benzodiazepine derivatives with the general formula: where R1 is hydrogen, alkyl, aryl or aralkyl, R2 is hydrogen or lower alkyl and where rings A and/or B are unsubstituted or substituted with one or more, which may be the same or different, nitro, trifluoromethyl, halogen, alkyl and alkoxy, as the nitrogen atom in the 5-position can be in the form of the N-oxide, characterized in that a compound with the formula: where A, B and R^ have the meaning given above and where nitrogen the atom at the 4-position can be in the form of the N-oxide, react with a carboxylic acid with the formula: Rx - COOH where R 1 has the above meaning, or a reactive derivative hence, through the formation of an intermediate with the formula: where R is -NHCOR^ where R^ is lower alkyl and where A, B and R2 have the above-mentioned meaning, the nitrogen atom in the 4-position can be in the form of the N-oxide, which compound can be separated if desired.