CH532065A - Sedative chloro-phenyl-triazolobenzodiazepines - Google Patents

Abstract

Benzodiazepines of formula (I) and the 5-N-oxides (where R1 = H or a hydrocarbon residue, e.g. (1-6C) alkyl, (7-8C) aralkyl or aryl, R2 = H or alkyl, and rings A and/or B may be substd. by one or more NO2, CF3, hal., alkyl or alkoxy), are of use as muscle relaxants, anticonvulsants, sedatives and tranquillisers, at a dose of 1-30 mg./d. (p.o.), or 0.5-10 mg/d. (parenteral). (I) are prepd. by reaction of the novel hydrazides (II) with a carboxylic acid R'CO2H (III) or its reaction deriv. Sedative chloro-phenyl-triazolobenzodiazepines.. followed by ring closure if necessary. The reaction is carried out with 1-10 mol. (III) at 0-300 degrees in the presence of an acid catalyst. (II) are prepd. from the corresp. amine, alkylthio or aralkylthio deriv. and N2H4.

Description

  

  
 



  Process for the preparation of benzodiazepine derivatives
The present invention relates to a process for the preparation of new and valuable benzodiazepine derivatives of the general formula:
EMI1.1
 wherein the radical Rl is a hydrogen atom or a hydrocarbon radical, the radical R2 is a hydrogen atom or a lower alkyl radical and the rings A and B are either unsubstituted or substituted by identical or different nitro, trifluoromethyl, halogen, alkyl or alkoxy radicals, including the case in which the nitrogen atom in the 5-position carries an oxygen atom.



   In the above general formula (I), suitable hydrocarbon radicals Ri are generally those with 1 to 8 carbon atoms, including alkyl groups of up to 6 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, amyl , Hexyl, tert-butyl, etc.), aralkyl (e.g. benzyl, phenethyl, etc.) and aryl (e.g. phenyl). The alkyl radicals represented by the radical R2 are, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, amyl, hexyl etc. The rings A and B can be unsubstituted or in any way by one or more of the the following substituents may be substituted: nitro, trifluoromethyl, halogen (ie chlorine, fluorine, bromine and iodine), alkyl, so z. Lower alkyl (e.g. methyl, ethyl, propyl, etc.) and alkoxy such as. B. lower alkoxy (e.g. methoxy, ethoxy, etc.).



   According to the invention, the benzodiazepine derivatives of the formula I are prepared by adding a compound of the general formula:
EMI1.2
 in which R is a group of the formula -NHCOR1,
EMI1.3
 where R3 is a lower alkyl radical, the other symbols are as defined above and the nitrogen atom present in the 4-position can carry an oxygen atom, subjecting it to a ring-closing reaction.



   The starting products for their part can be prepared by adding a 2-hydrazinobenzodiazepine derivative of the general formula:
EMI2.1
 wherein the symbols have the above definitions, including the case in which the nitrogen atom present in the 4-position carries an oxygen atom, with a carboxylic acid of the general formula: Rl-COOH (III) in which the radical R has the above meaning, or with a reacting reactive functional derivative thereof. Reactive derivatives of carboxylic acids of the formula III include esters (e.g. alkyl esters, e.g. methyl and ethyl esters, or activated esters, e.g. p-nitrophenyl esters), anhydrides, halides (e.g. chloride, bromide ), Amides (e.g. formamide, dimethylformamide, acetamide), orthoesters, imino ethers and amidines.



   The ortho-esters correspond to the general formula: Rl C (OR3) 3 (III) where the radical Rs has the above meaning and the radical Rc is a lower aralkyl radical, e.g. B. a methyl or ethyl radical means. The imino ethers correspond to the general formula:
EMI2.2
 wherein the symbols have the above meanings.



   The amidines correspond to the general formula:
EMI2.3
 wherein the radical Rl has the above meaning.



   In this way, the desired starting products, namely the acylhydrazino compounds of the formula IIA, their enol ether derivatives of the formula IIB or a-aminoalkylidene or a-aminoaralkylidene compounds of the formula IIC:
EMI2.4
 receive. The case in which the nitrogen atom in the 4-position carries an oxygen atom is also included.



   If the process according to the invention and the preparation of the starting materials are considered together, the compounds of the formulas IIA, IIB and IIC are at the same time intermediate products of the entire synthesis. These intermediate products can be cyclized to the compounds of the formula I under somewhat drastic conditions. The compounds of the formula I can now be synthesized in a single step without isolating the intermediates, or, on the other hand, one can work in two steps by first preparing and isolating the intermediates and then cyclizing the latter to form the compounds of the formula I.



   The preparation of the starting products (IIA, IIB and IIC) and the process according to the invention can advantageously be carried out as follows.



   The carboxylic acids of the formula III or their reactive derivatives are generally used in an amount of about 1 to about 10 moles and especially in an amount of about 2 to about 5 moles per mole of the 2-hydrazinobenzodiazepine derivative of the formula IV . The reaction is preferably carried out in the presence of a solvent and an acidic catalyst at a temperature in the range from about 0OC to about 300OC, but the conditions vary depending on the reactants used. Possible solvents are methanol, ethanol, chloroform, methylene chloride, dimethylformamide or mixtures of these solvents. The acidic catalyst can be an inorganic acid, e.g. B. hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, etc., an organic carboxylic acid, e.g. B.

  Acetic acid, propionic acid, etc., or an organic sulfonic acid, e.g. B. benzenesulfonic acid, p toluenesulfonic acid, etc., be. The amount of acid catalyst is generally between about 2 moles and about 10 moles per mole of the 2-hydrazinobenzodiazepine derivative of the formula IV.



   For example, if amidines are used under mild conditions, e.g. B. in a solvent and at about room temperature, the intermediate of formula IIC can be isolated. The intermediate of the formula IIC can be cyclized by heating to about 140 to 250 ° C. to form the compounds of the formula I and to produce ammonia. Therefore, in the one-step synthesis of the compounds of the formula I, the 2-hydrazinobenzodiazepine derivatives of the formula IV and the amidines of the formula III 'are preferably allowed to react with one another at a rather high temperature of, for example, 140 to 250 ° C. This reaction takes place either in the presence or in the absence of a solvent. In general, a melt method, particularly in the presence of 2-methylimidazole, gives good results.



   Even when using esters, amidines, anhydrines and halides, the intermediate, namely the acylhydrazinobenzodiazepine derivatives of the formula IIA or the compounds of the formula IIB, can be isolated if the reaction is carried out under mild conditions, e.g. B. is carried out in a solvent and at about room temperature. The acylhydrazinobenzodiazepine derivatives of the formula IIA thus obtained and separated can easily be cyclized to form the compounds of the formula I by heating to about 130 to 250 ° C. The cyclization can, if necessary, by using a catalyst such as. B. a polyphosphoric acid can be accelerated. This cyclization can be carried out either in the presence or in the absence of a solvent. Pyridine, dimethylformamide, xylene or tetralin can be used as solvents.

  With regard to the intermediate of the formula IIB, the information mentioned above applies in a similar manner.



   The benzodiazepine derivatives of the formula I thus obtained can be used in the form of a free base or in the form of a suitable salt, e.g. B. of the hydrochloride, sulfate, acetate, etc., isolate in a conventional manner. For example, the reaction mixture can be neutralized with a saturated aqueous sodium bicarbonate solution and treated with a suitable solvent, such as. B. methylene chloride, chloroform, etc., extract, whereupon the solvent is distilled off.



  In this way, the benzodiazepine derivatives of the formula I are obtained.



   The structure of the benzodiazepine derivatives of the formula I is determined by X-ray analysis of 8-chloro-6-phenyl-4H-s -triazolo - (4,3-a) (1,4) -benzodiazepine.



   If the benzodiazepine derivatives of the formula I are prepared in this way, the corresponding starting materials also give those compounds in which there is an oxygen atom in the 5-position, ie. H. to 5N oxides.



   The 2-hydrazinobenzodiazepine derivatives of the formula IV used as precursors for the above ring-closing reaction are also new compounds and can be prepared by adding a 2-aminobenzodiazepine of the general formula:
EMI3.1
 wherein the symbols have the above definitions, including the case in which the nitrogen atom in the 4-position carries an oxygen atom, reacts with hydrazine.



   With regard to the above general formula, the 2 aminobenzodiazepine derivatives of the formula VI can also have the following isomeric form:
EMI3.2
 This connection can also be used.



   The compounds of the formula VI can be prepared, for example, by the method described in Journal of Organic Chemistry 26, 1 1 1 1 (1 96 1). But you can also react 2 aminobenzophenone derivatives with an alkylamine in order to obtain 2-amino-a-phenylbenzylidene-alkylamine derivatives, whereupon the 2-amino-a-phenylbenzylidene-alkylamine derivatives obtained in this way are reacted with an aminoacetonitrile derivative and the 2- Amino-ct-phenylbenzylideneaminoacetonitrile derivatives cyclized in the presence of an acid or an alkali.



   The reaction between the 2-aminobenzodiazepine derivatives of the formula VI and hydrazine is preferably carried out in the presence of a suitable solvent and an acid at a suitable temperature in the range from approx. 0 to approx.



  1500C. Suitable solvents are, for example, methanol, ethanol, pyridine, dimethylformamide, mixtures thereof and their aqueous mixtures. The acids can be, for example, inorganic acids, such as. B. hydrochloric acid, sulfuric acid, phosphoric acid, etc., and organic acids, such as. B. acetic acid, p-toluenesulfonic acid, etc., use. The acids can be added in the form of salts with amines. Examples of these are pyridine, trialkylamines, 2-methylimidazole, etc. Both the hydrazine and the 2 aminobenzodiazepine derivatives of the formula VI can be used in the form of their salts with acids. In this case, it is not always necessary to add an additional amount of acid or its salt with amine to the reaction system. The amount of hydrazine and acid is generally between about 1 mole and about 5 moles per mole of 2-aminobenzodiazepine derivatives of the formula VI.

  However, this ratio can be changed if necessary.



   The 2-hydrazinobenzodiazepine derivatives of the formula IV, as they are obtained according to the above information, can then be converted into the starting products of the formula II with prior isolation or without isolation from the reaction mixture. The isolation of the 2-hydrazinobenzodiazepine derivatives of the formula IV can be done in a manner known per se, for example by adding water to the reaction mixture and by extracting the mixture with a suitable solvent, such as. B. methylene chloride, chloroform, etc., whereupon the solvent is evaporated.



   The 2-hydrazinobenzodiazepine derivatives of the formula IV in which the nitrogen atom in the 4-position does not have an oxygen atom can also be obtained by using a compound of the general formula:
EMI4.1
 wherein R4 denotes a hydrogen atom, an alkyl or aralkyl radical and the other symbols have the above definitions, reacts with hydrazine.



   With reference to the aforementioned general formula, in which the radical R4 represents a hydrogen atom, the compounds can also be present in the isomeric form. The structural formula is the following:
EMI4.2

The compounds of the formula VII can be prepared, for example, by the method as described in Journal of Organic Chemistry 29, 231 (1964).



   If the radical R4 is an alkyl radical, it is preferably a lower alkyl radical with up to 6 carbon atoms, such as. B.



  Methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert. Butyl, amyl, hexyl etc. If the radical R4 is an aralkyl radical, it is, for example, the benzyl radical, the phenethyl radical etc.



   The reaction is generally carried out in the presence of a solvent, such as. As methanol, ethanol, an aqueous mixture thereof, etc., carried out at about room temperature or, if necessary, with heating to near the boiling point of the solvent. For practical purposes, about 1 to about 10 moles of hydrazine will generally be used per mole of the compounds of the formula VII.



   The 2-hydrazinobenzodiazepine derivatives of the formula IV obtained in this way can be isolated in a manner known per se, for example by evaporating the solvent from the reaction mixture.



   The benzodiazepine derivatives of the formula I obtainable according to the invention are new compounds, are muscle relaxants, anticonvulsants and sedatives and have calming effects. They are therefore suitable as tranquillizers etc.



   Both the benzodiazepine derivatives of the formula I and their salts with acids can be administered orally or parenterally as such or in a suitable form, e.g. B. as a powder, as granules, in the form of tablets or in the form of injection solutions, in admixture with other pharmaceutically acceptable carriers or excipients. The dose of the benzodiazepine derivatives of the formula I or their salts to be administered depends on the nature of the benzodiazepine derivatives, the extent of the disease, etc. from. In general, the values are in the range from about 1 to about 30 mg for oral administration and about 0.5 to about 10 mg for parenteral administration in adult humans per day.



   The invention is illustrated by the following examples, in which, unless otherwise stated, parts are parts by weight. First, the production of the starting products is described.



   a) 1.25 parts of 80% hydrazine hydrate are added to a suspension of 3.4 parts of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine dihydrochloride in 60 parts by volume of methanol. The suspension is stirred for 40 minutes, then diluted with water and extracted with methylene chloride. The extract is washed with water and dried over anhydrous sodium sulfate, and the solvent is evaporated. The residue is recrystallized from a mixture of methylene chloride and benzene, 7-chloro-2-hydrazino-5-phenyl-3H iP-benzodiazepine being obtained in the form of colorless prisms. The melting point is around 1700C (with browning); the product decomposes at 202-204ob.



   Elemental analysis for ClsHI-CINJ:
C H N
Calculated 63.27 4.60 19.68
Found 63.43 4.48 19.27 b) To a suspension of 3 parts of 2-amino-7-chloro-5 (p-methoxyphenyl) -3H-1,4-benzodiazepine in a mixture of 50 parts by volume of methanol and 0.6 parts by volume of glacial acetic acid are added dropwise with stirring, 1.5 parts by volume of 100% hydrazine hydrate. The mixture is stirred for 30 minutes and then poured into ice water, followed by extraction with chloroform. The chloroform layer is washed with water, dried over sodium sulfate and the solvent is evaporated. Treatment of the residue with benzene gives 7-chloro-2-hydrazino-5 (p-methoxyphenyl) -3H-1,4-benzodiazepine in the form of colorless crystals with a melting point of 214 ° to 220 ° C.



   Elemental analysis for ClhHI.iCINJO:
C H N
Calculated 61.05 4.80 17.80
Found 60.93 4.67 17.83 c) To 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 Glacial acetic acid is added to 1.5 parts by volume of 100% strength hydrazine hydrate and the mixture is stirred at room temperature for 1 hour. If this mixture is treated in the same way as in Example 2, 2-hydrazino-5-phenyl-3H 1,4-benzodiazepine is obtained, which is obtained in the form of white crystals. 25 parts of 100% hydrazine hydrate are added by recrystallization from a mixture of methylene chloride and ben phenyl-3H-1,4-benzodiazepine, 500 parts by volume of methanol and 1.2 parts of glacial acetic acid.

  The mixture is stirred for 1 hour at room temperature and then treated in a similar manner to Example 1, whereby 2-hydrazino-7-methoxy-5-phenyl-3H-1,4-benzodiazepine is obtained in the form of crystals with a melting point of 110 to 1200C receives.



   g) 200 parts by volume of ethanol and 2.4 parts of glacial acetic acid are added to a mixture of 5.6 parts of 2-amino-7-nitro-5 phenyl-3H-1,4-benzodiazepine, while stirring, 5 parts by volume of 80 % hydrazine hydrate added.



  The mixture is stirred for 30 minutes at room temperature and then treated in the same way as in Example 1. In this way, 2-hydrazino-7-nitro-5phenyl-3H-1,4-benzodiazepine is obtained in the form of a reddish, viscous, oily substance.



   h) 6 parts of glacial acetic acid are added with stirring to a solution of 16 parts of 2-amino-7-chloro-3-isobutyl-5phenyl-3H-1,4-benzodiazepine and 25 parts of 100% hydrazine hydrate in 400 parts by volume of methanol and ice cooling too. The whole mixture is then stirred for 5 hours at room temperature. The reaction mixture is then mixed with water and extracted with chloroform. The chloroform layer is washed with water, dried over sodium sulfate and the solvent is removed. Treatment of the residue with isopropyl ether gives 7-chloro-2-hydrazino-3-isobutyl-5phenyl-3H-1,4-benzodiazepine in the form of colorless crystals with a melting point of 165 to 1680C.



   The product obtained in this way is identical to the product obtainable according to section k).



   i) 5 parts by volume of 80% hydrazine hydrate are added to a solution of 2 parts of 7-chloro-2-methyl-mercapto-5phenyl-3H-1,4-benzodiazepine in 70 parts by volume of ethanol and the mixture is left stand for 3 days at room temperature. After the solvent has evaporated, a small amount of water is added to the residue, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine being obtained in the form of crystals. Crystals are obtained by recrystallization from a mixture of methylene chloride and benzene. Melting point 1750C (with browning), 205 to 2070C (with decomposition).



   The product obtained in this way is identical to the product according to section a).



   j) To 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. Parts of ethanol are added to 5 parts by volume of 80% hydrazine hydrate, whereupon the mixture is left to stand for 24 hours. After the solvent has been evaporated off under reduced pressure, the residue is diluted with water and then extracted with methylene chloride. The methylene chloride layer is dried over sodium sulfate and the solvent is evaporated. The treatment of the Rückzol leads to white crystals with a melting point of 116 to 1180C (with foaming).



   Elemental analysis for CIsHl4N4. 1/3 CsHs:
C H N
Calculated 73.89 5.84 20.28
Found 73.86 5.47 20.44 d) To 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 Parts of glacial acetic acid are added to 4.5 parts by volume of 100% hydrazine hydrate. The entire mixture is stirred for 20 minutes at room temperature and then treated in the same manner as in Example 1, the 2-hydrazino-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine in the form of a crystalline powder with a melting point 1270C (with sintering) and 133 to 135OC (with foaming).

 

   Elemental analysis for C16Hl3F3N4:
C H N
Calculated 60.37 4.12 17.60
Found 60.05 3.96 17.40 e) To a mixture of 2.5 parts of 2-amino-7-methyl-5phenyl-3H-1,4-benzodiazepine, 100 parts by volume of methanol and 1.2 parts of glacial acetic acid are added one adds 2.5 parts of 100% hydrazine hydrate. The mixture is stirred for 1 hour at room temperature and treated in a similar manner to Example 1. In this way, 2-hydrazino-7-methyl-5phenyl-3H-1,4-benzodiazepine is obtained in the form of crystals. Recrystallization from a mixture of chloroform and diethyl ether gives colorless crystals with a melting point of 240 to 2410 ° C. (with decomposition).



   Elemental analysis for Cl6Hl6N4:
C H N
Calculated 72.70 6.10 21.20
Found 72.70 6.08 21.31 f) To a mixture of 26.5 parts of 2-amino-7-methoxy-5 by means of benzene gives 7-chloro-2-hydrazino-5-phenyl-3H-1,4 -benzodiazepine.



  Recrystallization from a mixture of methylene chloride and benzene gives crystals with a melting point of 205 to 207OC (with decomposition). It is the same product as the products available under sections a) and i).



   k) 40 parts of 100% hydrazine hydrate are added to a solution of 1.6 parts of 7-chloro-3-isobutyl-2-methylmercapto-5phenyl-3H-1,4-benzodiazepine in 150 parts by volume of methanol. The mixture is refluxed for 41/2 hours and then poured into water.



  It is then extracted with chloroform. The chloroform layer is washed with water, dried over sodium sulfate and the solvent is evaporated. Treatment of the residue with diethyl ether gives 7-chloro-2-hydrazino-3-isobutyl-5phenyl-3H-1,4-benzodiazepine in the form of crystals. Recrystallization from a mixture of chloroform and n-hexane gives colorless crystals with a melting point of 168 to 1690C.



   Elemental analysis for ClsH2lCIN4:
C H N
Calculated 66.95 6.21 16.44
Found 67.21 6.19 16.70
example 1
3.6 parts of 2-methylimidazole hydrochloride and 2.25 parts by volume of 80 are added to a suspension of 8.1 parts of 2-amino-7-chloro-5phenyl-3H-1,4-benzodiazepine in 180 parts by volume of methanol % hydrazine hydrate added. The suspension is stirred for 11/2 hours at room temperature and 25 parts of ethyl orthoformate are then added. 60 parts by volume of ethanol containing 10% hydrochloric acid are added dropwise to this mixture with stirring. After stirring for an additional hour, the mixture is warmed for a short time to complete the reaction. After the solvent has evaporated, an aqueous sodium bicarbonate solution is added to the residue in order to neutralize it.

  The mixture is then extracted with methylene chloride. The methylene chloride layer is washed with water, dried over sodium sulfate and the solvent is evaporated. The residue is recrystallized from a mixture of acetone and n-hexane, 8-chloro-6-phenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine in the form of colorless flakes, Melting point 226 to 2270C.



   Elemental analysis for Cl6Hl1CIN4:
C H N
Calculated 65.20 3.76 19.01
Found 65.30 3.48 19.03
Example 2
To 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, 2 parts of concentrated sulfuric acid are added with stirring added. The mixture is stirred at room temperature for 30 minutes, after which a saturated aqueous sodium bicarbonate solution is added to neutralize the mixture. The chloroform layer is washed with water and dried over anhydrous sodium sulfate, followed by evaporation of the solvent.

  The residue is recrystallized from a mixture of acetone and n-hexane, the 8-chloro-6-phenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine in the form of colorless flakes obtained from melting point 226 to 2270C.



   The product obtained in this way is identical to the product obtainable according to Example 1.



   Example 3
7.4 parts of ethyl orthoformate and 20 parts by volume of methanol are added 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. which is saturated with hydrogen chloride. The mixture is stirred for 2 hours and then refluxed for 30 minutes.



  The solvent is distilled off under reduced pressure. An aqueous sodium bicarbonate solution is added to the residue to make the mixture alkaline, followed by extraction with chloroform. The chloroform extract is washed with water and dried over anhydrous sodium sulfate and the solvent is evaporated.



  The residue is recrystallized from ethyl acetate, whereby 8-chloro-6-phenyl-4H-s-triazolo (4,3-a) (1,4) -benzodiazepine is obtained in the form of colorless flakes with a melting point of 226 to 2270C.



   The product obtained in this way is identical to the product obtained according to Examples 1 and 2.



   Example 4
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 is left to stand overnight. The solution is diluted with water, then neutralized with an aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform extract is washed with water, dried over anhydrous sodium sulfate and the solvent is evaporated. The residue is recrystallized from a mixture of acetone and n-hexane, 8-chloro-6-phenyl-4H-s-triazolo- (4, 3-a) (1,4) -benzodiazepine being obtained in the form of colorless flakes . Melting point 226 to 227cd.



   The product obtained in this way is identical to that of Examples 1, 2 and 3.



   Example 5
1 part by volume of concentrated sulfuric acid is added to a suspension of 2.8 parts of 7-chloro-2-hydrazino-5phenyl-3H-1,4-benzodiazepine in 40 parts by volume of formamide. The solution obtained is left to stand for 6 hours and then heated on a water bath for 30 minutes. The solution is diluted with water, neutralized with sodium carbonate and extracted with chloroform. The chloroform extract is washed with water and dried over anhydrous sodium sulfate and the solvent is evaporated. The residue is recrystallized from ethyl acetate, giving 8-chloro-6-phenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine in the form of colorless flakes. Melting point 226-2270C.



   The product obtained in this way is identical to the product according to the preceding examples.



   Example 6
A mixture of 2.8 parts of 7-chloro-2-hydrazino-5phenyl-3H-1,4-benzodiazepine, 2.4 parts of formamidine hydrochloride and 2.5 parts of 2-methylimidazole is melted at 160 ° C. for 10 minutes.



  Water is then added to the mixture, followed by extraction with methylene chloride. The methylene chloride layer is washed with water, dried over sodium sulfate and the solvent evaporated to give 8-chloro-6-phenyl-4H-s-triazolo (4,3-a) (1,4) -benzodiazepine. Recrystallization from ethyl acetate gives colorless flakes with a melting point of 226 to 2270C.



   The product thus obtained is identical to that according to the preceding examples.



   Example 7
0.6 parts of 2-methylimidazole hydrochloride and 6 parts by volume are added 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 to a 1 mole methanol solution of hydrazine hydrate. The mixture is stirred for 1/2 hour at room temperature, after which 4.8 parts of ethyl orthoacetate and 10 parts by volume of ethanol containing 10% hydrogen chloride are added. The mixture is then refluxed for 30 minutes and the solvent is evaporated. evaporates. The residue is neutralized with saturated sodium bicarbonate solution and extracted with methylene chloride. The methylene chloride extract is washed with water and dried over sodium sulfate, whereupon the solvent is evaporated.

  The residue is purified by means of silica gel column chromatography, 8-chloro-1-methyl-6-phenyl-4H-s-triazolo (4,3-a) (1,4) -benzodiazepine being obtained. Recrystallization from a mixture of acetone and n-hexane gives needles without a needles with a melting point of 225 to 226 C.



   Elemental analysis for Cl7Hl3ClN4
C H N
Calculated 66.13 4.24 18.15
Found 66.39 4.08 18.07
Example 8
10 parts of ethyl orthoacetate and 4 parts of p-toluenesulphonic acid are added to a solution of 2.84 parts of 7-chloro-2-hydrazino-5phenyl-3H-1,4-benzodiazepine in 50 parts by volume of chloroform. The solution is left to stand at room temperature for 6 hours and heated on a water bath for a certain period of time to complete the reaction. The mixture is then washed with an aqueous saturated sodium bicarbonate solution and then with water and dried over anhydrous sodium sulfate.

  After evaporation of the solvent, the residue is treated in a manner similar to Example 18, whereby 8-chloro-1-methyl-6-phenyl-4H-s-triazolo (4,3-a) (1,4) -benzodiazepine is obtained in the form of colorless needles with a melting point of 224 to 225OC.



   The product obtained in this way is identical to the product according to Example 18.



   Example 9
1 part by volume of concentrated sulfuric acid is added 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. The resulting solution is left to stand at room temperature for 1 hour, then poured into ice water, then neutralized with sodium bicarbonate and extracted with methylene chloride. The methylene chloride extract is washed with water and dried over anhydrous sodium sulfate, whereupon the solvent is evaporated. The residue is recrystallized from a mixture of acetone and n-hexane, giving 8-chloro-1-methyl-6-phenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine in the form obtained from colorless needles with a melting point of 224 to 225OC.



   The product obtained in this way is identical to that according to Examples 7 and 8.



   Example 10
2.46 parts of ethylacetoimidate hydrochloride are added to a solution of 2.84 parts of 7-chloro-2-hydrazino-5phenyl-3H-1,4-benzodiazepine in 60 parts by volume of chloroform. The mixture is stirred for 8 hours and then aqueous sodium bicarbonate is added to render the mixture neutral. The chloroform layer is separated, washed with water and dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue is recrystallized from ethyl acetate, whereby 8-chloro-1-methyl-6-phenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine is obtained in the form of colorless needles. Melting point 225 to 2260C.

 

   The product obtained in this way is identical to the product according to Examples 7, 8 and 9.



   Example 11
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 is heated to 160 ° C. for 10 minutes Brought melting. The melt is mixed with water, whereupon it is extracted with methylene chloride. The methylene chloride layer is washed with water and dried over sodium sulfate. The solvent is evaporated to give 8-chloro-methyl-6-phenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine. Recrystallization from ethyl acetate gives colorless needles with a melting point of 223 to 2250C.



   The product obtained in this way is identical to the product according to Examples 7, 8, 9 and 10.



   Example 12
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 is used for 24 Stirred for hours at room temperature. The chloroform layer is washed with water, dried over sodium sulfate and the solvent is evaporated. After treating the residue with diethyl ether, the crystals obtained are extracted with hot methanol. Evaporation of the methanol gives 2- (c: -aminoethylidene) hydrazino-7-chloro-5-phenyl-3H-1,4-benzodiazepine in the form of crystals. Recrystallization from acetone gives pale yellow needles with a melting point of 203 to 2050C (with foaming).



   Elemental analysis for Cl7Hl6CINs:
C H N
Calculated 62.67 4.95 21.50
Found 62.99 4.84 21.53
3.5 parts of 2- (a-aminoethylidene) hydrazino-7-chloro-5-phenyl-3H-1,4-benzodiazepine are heated in an oil bath for 10 minutes, whereby the product melts with foaming and finally solidifies.



  Recrystallization from ethyl acetate gives 8-chloro-1-methyl-6-phenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine in the form of colorless needles with a melting point of 225.5 to 226 , 50C.



   The product obtained in this way is identical to the product according to Examples 7 to 11.



   Example 13
0.47 parts by volume of acetic anhydride are stirred into a solution of 1.4 parts of 7-chloro-2-hydrazino-5 phenyl-3H-1,4-benzodiazepine in 30 parts by volume of chloroform. The mixture is stirred for 1 hour and washed with a saturated aqueous sodium bicarbonate solution and then with water. The chloroform layer is dried over sodium sulfate and the solvent is evaporated. Adding methanol leads to 2- (2-acetylhydrazino) -7-chloro-5phenyl-3H-1,4-benzodiazepine in the form of white crystals. Recrystallization from a mixture of chloroform and methanol gives powdery crystals with a melting point of 202 to 204 ° C. (with foaming).



   Elemental analysis for Cl7HasCIN4O:
C H N
Calculated 62.48 4.63 17.15
Found 62.38 4.44 17.23
3.3 parts of 2- (2-acetylhydrazino) -7-chloro-5 phenyl-3H-1,4-benzodiazepine are heated to 2150 ° C. for 10 minutes under slightly reduced pressure. The molten substance is recrystallized from ethyl acetate, giving 8-chloro-1-methyl-6-phenyl-4H-s-triazolo (4,3-a) (1,4) -benzodiazepine in the form of colorless needles with a melting point of 225 to 2260C.



   The product obtained in this way is identical to the product according to Examples 7 to 12.



   Example 14
A suspension of 3.3 parts of 2- (2-acetylhydrazino) -7-chloro-5-phenyl-3H-1,4-benzodiazepine, obtained as described in Example 13, in 20 parts by volume of pyridine is heated under reflux , which gradually loosens the crystals. After 2 hours the solvent is evaporated under reduced pressure. The residue is recrystallized from a mixture of acetone and n-hexane, 8-chloro-1-methyl-6-phenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine in the form obtained from colorless needles with a melting point of 224 to 225ob.



   The product obtained in this way is identical to the product according to Examples 7 to 13.



   Example 15
To a mixture of 1.4 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, obtained according to the information in section a), 50 parts by volume of ethanol and 4 parts by volume of ethyl orthopropionate is added to 5.0 parts by volume of concentrated sulfuric acid. The mixture is stirred for 30 minutes at room temperature and then treated in the same manner as in Example 14, 8-chloro-1-ethyl-6-phenyl-4H-s-triazolo- (4,3-a) (1 , 4) -benzodiazepine in the form of crystals. Recrystallization from acetone leads to colorless prisms with a melting point of 229 to 2300C.



   Elemental analysis for ClsHlsCIN4:
C H N
Calculated 66.97 4.68 17.36
Found 67.18 4.48 17.53
Example 16
To a solution of 1.4 parts of 7-chloro-2-hydrazino-5phenyl-3H-1,4-benzodiazepine, obtained according to the information in section a) in 30 parts by volume of chloroform, 0.65 parts by volume of chloroform are added with stirring. - Add parts of propionic anhydride. The mixture is stirred for 1 hour, then washed with a saturated aqueous sodium bicarbonate solution and then with water and finally dried over sodium sulfate. After evaporation of the chloroform, methanol is added to the residue, 7-chloro-5-phenyl-2- (2-propionylhydrazino) 3H-1,4-benzodiazepine being obtained in the form of crystals.

  Recrystallization from a mixture of chloroform and methanol gives colorless prisms with a melting point of 186 to 1870C (with foaming).



   Elemental analysis for ClsHl7CIN4O:
C H N
Calculated 63.43 5.03 16.44
Found 63.54 4.88 16.70
3.4 parts of 7-chloro-5-phenyl-2- (2-propionylhydrazino) 3H-1,4-benzodiazepine are heated to 1950 ° C. for 15 minutes under slightly reduced pressure. The molten substance is recrystallized from acetone, 8-chloro-1-ethyl-6-phenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine in the form of colorless prisms with a melting point of 229 up to 230 C.



   The product obtained in this way is identical to the product according to Example 15.



   Example 17
A solution of 1.6 parts of enanthyl chloride is added to 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 gradually add in 20 parts by volume of diethyl ether while cooling with ice.



  The mixture is stirred for a period of time to stop the reaction. After evaporating the solvent under reduced pressure, the residue is treated with methanol to give 7-chloro-2- (2-enanthylhydrazino) -5-phenyl-3H-1,4-benzodiazepine in the form of crystals. Recrystallization from a mixture of dimethylformamide and water gives colorless needles with a melting point of 205 to 2060 ° C. (with foaming).



   Elemental analysis for C22H2sCIN4O:
C H N
Calculated 66.57 6.35 14.12
Found 66.43 6.24 14.29
A mixture of 1.98 parts of 7-chloro-2- (2-enanthylhydrazino) -5phenyl-3H-1,4-benzodiazepine and 30 parts of polyphosphoric acid is heated to 170 to 180 ° C. for 2 hours. The mixture is then admixed with 200 parts by volume of ice water and the resulting solution is neutralized with concentrated aqueous ammonia while cooling with ice and then extracted with chloroform. The chloroform layer is washed with water, dried over sodium sulfate and the solvent is evaporated.

  The residue is recrystallized from aqueous acetone, giving 8-chloro-hexyl-6-phenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine in the form of colorless plates with a melting point of 75 to 78oC (under sintering).



   Elemental analysis for Cz7Hz3C1N4.2HO:
C H N
Calculated 63.68 6.56 13.50
Found 63.71 6.15 13.60
The product thus obtained is further dried under reduced pressure to obtain the compound which contains 1 / 4H2O and sinters at 61 to 63OC.



   Example 18
A suspension of 4 parts of 7-chloro-2- (2-enanthylhydrazino) -5-phenyl-3H-1 4-benzodiazepine in 20 parts by volume of pyridine is refluxed for about 3 hours. After the pyridine has evaporated, water is added to the residue, 8-chloro-1-hexyl-6-phenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine being obtained in the form of crystals obtained, which is recrystallized from aqueous acetone. In this way, colorless flakes with a melting point of 75 to 85OC (with sintering) are obtained.



   The product obtained in this way is identical to the product according to Example 17.

 

   Example 19
To a solution of 1.4 parts of 7-chloro-2-hydrazino 5-phenyl-3H-1,4-benzodiazepine obtained according to the information in section a), in 25 parts by volume of tetrahydrofuran is added 0.62 parts by volume Benzoyl chloride is added and the mixture is stirred at room temperature for 2 hours to complete the reaction. The reaction mixture is neutralized with an aqueous saturated sodium bicarbonate solution. The white precipitate obtained is separated off, washed with water and then with methanol and dried. In this way, 2- (2-benzoylhydrazino) -7-chloro-5-phenyl-3H-1,4-benzodiazepine is obtained in the form of crystals. Recrystallization from a mixture of chloroform and methanol gives white needles with a melting point of 207 to 2080C (with foaming).



   Elemental analysis for Cn2HClN4O:
C H N
Calculated 67.95 4.41 14.41
Found 67.87 4.20 14.49
A mixture of 38.8 parts of 2- (2-benzoylhydrazino) -7-chloro-5-phenyl-3H-1 .4-benzodiazepine and 400 parts of polyphosphoric acid is heated to 150 ° C. for 12 hours. The mixture is treated in a similar manner to Example 32 to give 8-chloro-1,6-diphenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine in the form of crystals.



   Colorless needles with a melting point of 191 ° to 1920 ° C. are obtained by recrystallization from ethyl acetate.



   Elemental analysis for C22HlsCIN:
C H N
Calculated 71.25 4.08 15.11
Found 71.11 4.10 14.98 Example 20
Under slightly reduced pressure, 3.9 parts of 2- (2-benzoylhydrazino) -7-chloro-5-phenyl-3H-1,4-benzodiazepine, obtained according to the information in Example 19, are obtained with heating to 2150 ° C. for about 15 minutes melted until foaming stopped. By recrystallizing the molten substance from ethyl acetate, 8-chloro-1,6-diphenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine is obtained in the form of colorless needles with a melting point of 193 to 1940 ° C.



   The product obtained in this way is identical to the product according to Example 19.



   Example 21
A solution of 1.4 parts of 7-chloro-2-hydrazino 5-phenyl-3H-1, 4-benzodiazepine and 1.8 parts of ethylbenzimidate hydrochloride in 30 parts by volume of chloroform is stirred for 24 hours at room temperature and then with water washed. The chloroform layer is dried over sodium sulfate and the solvent is evaporated. By treating the residue with diethyl ether, the 8-chloro-1, 6-diphenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine is obtained in the form of crystals, which are obtained from a mixture of Recrystallized ethyl acetate and n-hexane. In this way, colorless needles with a melting point of 192 ° to 1930 ° C. are obtained.



   The product obtained in this way is identical to the product according to Examples 19 and 20.



   Example 22
In a similar manner to Example 17, a solution of 0.85 parts of phenylacetyl chloride in 10 parts by volume of diethyl ether of 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 of chloroform are added. The whole mixture is stirred for 45 hours, whereby 7-chloro-2- (2-phenylacetylhydrazino) -5-phenyl-3H-1,4-benzodiazepine is obtained in the form of crystals. Recrystallization from a mixture of dimethylformamide and water gives colorless, fine prisms with a melting point of 220 to 2210 ° C. (with foaming).



   Elemental analysis for C2H: qCIN4O:
C H N
Calculated 68.57 4.75 13.91
Found 68.72 4.79 13.71
A mixture of 4 parts of 7-chloro-2- (2-phenyl-acetylhydrazino) 5-phenyl-3H-1,4-benzodiazepine and 50 parts of polyphosphoric acid is heated to 180 ° C. for 2 hours. The mixture is treated in a manner similar to Examples 32 and 35 to give 1-benzyl-8-chloro-6-phenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine . Recrystallization from ethyl acetate gives colorless, columnar crystals with a melting point of 190 ° to 1920 ° C.



   Elemental analysis for C23Ha-ClN4:
C H N
Calculated 71.78 4.45 14.56
Found 72.07 4.34 14.74
Recrystallization from methanol gives colorless needles with a melting point of 101 to 103 ° C. (with foaming).



   Elemental analysis for C23Hl ClN.CH0OH:
C H N
Calculated 69.14 5.08 13.44
Found 69.31 5.02 13.59
Example 23
4 parts of 7-chloro-2- (2-phenylacetylhydrazino) -5-phenyl-3H-1,4-benzodiazepine, obtained according to the information in Example 22, are heated to 230 ° C. for 10 minutes and under slightly reduced pressure up to Stop foaming melted. Recrystallization of the molten substance from ethyl acetate gives 1-benzyl-8-chloro-6-phenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine in the form of colorless prisms with a melting point of 191 bis lS20C.



   The product obtained in this way is identical to the product according to Example 22.



   Example 24
To a suspension of 1.6 parts of 7-chloro-2-hydrazino 5- (p-methoxyphenyl) -3H-1,4-benzodiazepine, obtained according to the information in section b), in 50 parts by volume of ethanol are added 3, 0 parts of ethyl orthoformate are added, whereupon 0.5 parts by volume of concentrated sulfuric acid are stirred in dropwise. The entire mixture is stirred for a certain period of time and then neutralized with an aqueous sodium bicarbonate solution and the solvent is evaporated. Water is then added to the residue, giving 8-chloro-6- (p-methoxyphenyl) -4H-s-triazolo (4,3-a) (1,4) -benzodiazepine in the form of crystals. Recrystallization from acetone and then from ethyl acetate gives pale yellow flakes with a melting point of 216 to 2170C.



   Elemental analysis for Cl7Hl3CIN4O:
C H N
Calculated 62.87 4.03 17.25
Found 62.98 3.95 17.57
Example 25
To a mixture of 2.1 parts of 7-chloro-2-hydrazino 5- (p-methoxyphenyl) -3H-1,4-benzodiazepine, obtained according to the information in section b), 4.33 parts of ethyl orthoacetate and 60 vol . Parts of ethanol are added dropwise 0.75 parts by volume of concentrated sulfuric acid.



  The mixture is stirred for about 15 minutes. After the reaction has ended, the reaction mixture is neutralized with a saturated aqueous sodium bicarbonate solution, 8-chloro-1-methyl-6- (p-methoxyphenyl) 4-Hs-triazolo- (4,3-a) (1,4) -benzodiazepine being added in the form of crystals. Recrystallization from a mixture of methanol and chloroform gives colorless needles with a melting point of 268 to 2690C.



   Elemental analysis for ClsH1sCIN4O:
C H N
Calculated 63.81 4.46 16.54
Found 63.76 4.31 16.58
Example 26
To a mixture of 1 part of 2-hydrazino-5-phenyl-3H1,4-benzodiazepine, obtained according to the information in section c), 2 parts by volume of ethyl orthoformate and 20 parts by volume of ethanol are added 0.44 parts by volume . Parts of concentrated sulfuric acid are added dropwise while cooling with ice. The mixture is stirred for 30 minutes at room temperature and then neutralized with a saturated aqueous sodium bicarbonate solution. The oily substance obtained is extracted with methylene chloride. The methylene chloride layer is washed with water, dried over sodium sulfate, and the solvent is evaporated to give 6-phenyl-4H-s-triazolo- (4,3) (1,4) -benzodiazepine in the form of crystals.

  Recrystallization gives colorless needles from a mixture of acetone and n-hexane with a melting point of 195 to 196 C.



   Elemental analysis for Cl6Hl2N4:
C H N
Calculated 73.83 4.65 21.53
Found 73.71 4.37 21.21
The compound can be obtained in the form of polymorphic columnar crystals having a melting point of 201 to 202OC by recrystallization from the same solvent. The elemental analysis agrees with the calculated value for C16H12N4.



   Example 27
The procedure is the same as in Example 26, but using 4 parts by volume of ethyl orthoacetate instead of ethyl orthoformate, using 1-methyl-6-phenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine. Recrystallization from a mixture of methanol and ethyl acetate gives colorless prisms with a melting point of 226 to 2270C.

 

   Elemental analysis for C17HIJNJ:
C H N
Calculated 74.43 5.14 20.43
Found 74.70 5.17 20.41
Example 28
To a mixture of 3.2 parts of 2-hydrazino-5-phenyl-7-trifluoromethyl-3H-1, 4-benzodiazepine, obtained according to the information in section d), 8.5 parts of ethyl orthoformate and 50 parts by volume of chloroform are added 7.6 parts of p-toluenesulfonic acid are added dropwise at a temperature of less than 10 ° C. The mixture is stirred at room temperature for 2½ hours. After the reaction has ended, the reaction mixture is neutralized with a saturated aqueous sodium bicarbonate solution. The chloroform layer is separated, washed with water and dried over sodium sulfate.

  Evaporation of the solvent gives 6-phenyl-8-trifluoromethyl-4H-s-triazolo (4,3-a) (1,4) -benzodiazepine in the form of crystals. The crystals are dissolved in ethanol and the insoluble material is removed by filtration. The filtrate is concentrated and recrystallized from ethyl acetate, giving colorless flakes with a melting point of 258 to 260 ° C.



   Elemental analysis for C17HllF3NS:
C H N
Calculated 62.19 3.38 17.07
Found 61.99 3.46 16.89
Example 29
To a mixture of 9.5 parts of 2-hydrazino-5-phenyl-2-trifluoromethyl-3H-1,4-benzodiazepine.



  obtained according to the information in section d), 29 parts of ethyl orthoacetate and 150 parts by volume of chloroform are added dropwise 23 parts of p-toluenesulfonic acid with stirring and while cooling with ice below 10 ° C., whereupon the mixture is stirred for 7 hours at room temperature. After the reaction has ended, the reaction mixture is neutralized with a saturated aqueous sodium bicarbonate solution and the chloroform layer is separated off, washed with water and dried over sodium sulfate.

  After the solvent has evaporated, the residue is treated with a mixture of benzene and isopropyl ether, 1 -methyl-6-phenyl-8-trifluoromethyl-4H-s-triazolo- (4,3-a) (1,1) - benzodiazepine in the form of crystals which contain benzene resulting from the crystallization. Recrystallization from a mixture of benzene and n-hexane gives colorless needles with a melting point of 129 to 1300C (with sintering), or 133-1340C (with foaming).



   Elemental analysis for ClRHo.F3N4. '/ R CH:
C H N
Calculated 65.21 4.10 15.21
Found 65.26 4.20 14.81
Recrystallization from aqueous acetone leads to colorless needles which contain 1 fifth of H2O and which melt at 112 to 113 ° C (with sintering).



   Elemental analysis for ClsHl RF3N4. I / 5 HO:
C H N
Calculated 62.49 3.90 16.20
Found 62.53 4.08 16.42
Example 30
To a mixture of 5.3 parts of 2-hydrazino-7-methyl 5-phenyl-3H-1,4-benzodiazepine, obtained according to the information in section e), 14.8 parts of ethyl orthoformate and 150 parts by volume of ethanol 4 parts of concentrated sulfuric acid are added dropwise while cooling with ice. The entire mixture is stirred for about 30 minutes and then neutralized with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform. The chloroform layer is washed with water and dried over sodium sulfate.

  After evaporation of the solvent, the residue is treated with n-hexane to give 8-methyl-6-phenyl-4H-s-triazolo (4,3-a) (1,4) -benzodiazepine in the form of crystals. Recrystallization from ethyl acetate gives pale yellow prisms with a melting point of 177 to 178 (C.



   Elemental analysis for CI-HIJNI:
C H N
Calculated 74.43 5.14 20.43
Found 74.30 5.15 20.14
Example 31
The procedure is as in Example 30, but instead of ethyl orthoformate, 16.2 parts of ethyl orthoacetate are used. In this way, 1,8-dimethyl-6-phenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine is obtained in the form of crystals, which are recrystallized from ethyl acetate. In this way, colorless needles with a melting point of 211 to 211'5'C are obtained.



   Elemental analysis for ClsHléN4:
C H N
Calculated 74.97 5.59 19.43
Found 74.93 5.42 19.73
Example 32
To a mixture of 2.8 parts of 2-hydrazino-7-methoxy 5-phenyl-3H-1,4-benzodiazepine, obtained according to the information in section f), 7.4 parts of ethyl orthoformate and 100 parts by volume of ethanol 2 parts of concentrated sulfuric acid are added while stirring and while cooling with ice. The mixture is stirred for about 45 minutes at room temperature in order to stop the reaction.



  After evaporating the solvent under reduced pressure, the residue is neutralized with a saturated aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The chloroform layer is 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) (1,4-benzodiazepine in the form of crystals. Recrystallization from ethyl acetate gives pale yellow melting point prisms 209 to 2100C.



   Elemental analysis for C17HIJNJO:
C H N
Calculated 70.33 4.86 19.30
Found 70.23 4.93 19.15
Example 33
The procedure is exactly as in Example 32, but 8 parts of ethyl orthoacetate are used instead of ethyl orthoformate, 1 -methyl-8-methoxy-6-phenyl-4H-s-triazolo (4,3-a) (1, 4) Benzodiazepine in the form of crystals. Recrystallization from ethyl acetate leads to pale yellow prisms with a melting point of 196 to 197 C.



   Elemental analysis for ClsHl6N4O:
C H N
Calculated 71.03 5.30 18.41
Found 71.16 5.44 18.21
Example 34 2-hydrazino-7-nitro -5-phenyl-3H- 1 4-benzodiazepine, obtained from 5.6 parts of 2-amino-7-nitro-5-phenyl-3H-1,4-benzodiazepine in a similar manner, as described in section g) is dissolved in a mixture of 20 parts by volume of ethyl orthoformate and 100 parts by volume of chloroform, whereupon 10 parts of p-toluenesulfonic acid are added.



  The entire mixture is left to stand for 1 hour at room temperature with occasional shaking. After the reaction has ended, the solution is washed with a saturated aqueous sodium bicarbonate solution and then with water and then dried over sodium sulfate.



  After evaporation of the solvent, the residue is treated with ethyl acetate to give 8-nitro-6-phenyl-4H-s-triazolo (4,3-a) (1,4) -benzodiazepine in the form of crystals. Recrystallization from tetrahydrofuran gives pale yellow needles with a melting point of 271 to 272 C.



   Elemental analysis for C16KllN502:
C H N
Calculated 62.94 3.63 22.94
Found 63.07 3.75 23.39
Example 35
The procedure is as in Example 34, but using 20 parts by volume of ethyl orthoacetate instead of ethyl orthoformate. That way you get
1-Methyl-8-nitro-6-phenyl-4H-s-triazolo (4,3-a) (1,4) -benzodiazepine in the form of yellow crystals. Recrystallization from acetone produces yellow prisms with a melting point of 227 to 229oC.



   Elemental analysis for Cl7Hl3NsO2:
C H N
Calculated 63.94 4.10 21.93
Found 64.11 4.00 21.69
Example 36
To a mixture of 1.7 parts of 7-chloro-2-hydrazino-3-isobutyl-5-phenyl-3H-1,4-benzodiazepine, obtained according to the information in sections h) and k), 3.7 parts of triethyl orthoformate and 40 parts by volume of ethanol, 1 part of concentrated sulfuric acid is added while stirring and while cooling with ice. The mixture is stirred for about 20 minutes at room temperature. After the reaction has ended, the mixture is neutralized with sodium bicarbonate and then extracted with chloroform. The chloroform layer is washed with water and dried over sodium sulfate.

  After evaporation of the solvent, the residue is treated with n-hexane, whereby 8-chloro-4-isobutyl-6-phenyl-4H-s-triazolo (4,3-a) (1,4) -benzodiazepine in the form of pale yellow crystals. Recrystallization from a mixture of benzene and n-hexane gives colorless needles with a melting point of 140.5 to 141.50 ° C.



   Elemental analysis for C20HIsCIN4:
C H N
Calculated 68.47 5.46 15.97
Found 68.56 5.30 16.11
1) To a suspension of 14.3 parts of 2-amino-7-chloro-5-phenyl3H-1,4-benzodiazepine-4N-oxide in 400 parts by volume of methanol are added 12.5 parts by volume
100% hydrazine hydrate and 10 parts by volume of methanol, saturated with hydrogen chloride, are added. The mixture is during
Heated under reflux for 10 minutes and the resulting solution concentrated to half of the initial volume. The concentrate is poured into 500 parts by volume of water and the resulting oily substance is extracted with chloroform. The chloroform layer is dried over sodium sulfate and evaporated.

  By treating the residue with diethyl ether, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine-4N-oxide is obtained in the form of pale yellow, powdery crystals with a melting point of 262 to 2630C.



  The crystals thus obtained are recrystallized from chloroform, whereby colorless crystals with a melting point of 268 to 2690 ° C. (with decomposition) are obtained.



   The product obtained in this way is identical to the product according to Examples 37 and 38.



   Example 40
To a suspension of 3 parts of 7-chloro-2-hydrazino-5-phenyl 3H-1, 4-benzodiazepine-4N-oxide, obtained according to the information in Section 1), and 8 parts of ethyl orthoacetate in 100 parts by volume Ethanol is added dropwise to 1.1 parts by volume of concentrated sulfuric acid.



  The entire mixture is stirred for about 15 minutes at room temperature and the solvent is then evaporated. The residue is neutralized with saturated aqueous sodium bicarbonate solution, 8-chloro-1-methyl-6-phenyl-4H-s-triazolo- (4,3-a) (14) -benzodiazepine-5N-oxide being obtained in the form of crystals receives.



   Recrystallization from a mixture of methanol and diethyl ether gives colorless needles with a melting point of 272 to 273C (with decomposition).



   Elemental analysis for CI-H17CINIO:
C H N
Calculated 62.87 4.03 17.25
Found 63.04 4.04 17.26
Example 41
2.5 parts of ethyl acetoimidate hydrochloride are added to a solution of 3 parts of 7-chloro-2-hydrazino-5-phenyl3H-1,4-benzodiazepine-4N-oxide in 100 parts by volume of ethanol. The mixture is refluxed for about 30 minutes, after which the solvent is evaporated. The residue is neutralized with a saturated aqueous sodium bicarbonate solution, with 8-chloro-1-methyl-6-phenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine-5N-oxide in the form obtained from crystals. Recrystallization from a mixture of methanol and diethyl ether gives colorless needles with a melting point of 268 to 2690 ° C. (with decomposition).



   The product obtained in this way is identical to the product according to Example 40.



   Example 42
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 is brought to melt with heating to 175 ° C. for 10 minutes . After cooling, the mixture is treated with water and extracted with chloroform.



  The chloroform layer is washed with water and dried over sodium sulfate. After evaporation of the solvent, methanol is added to the residue, whereby
8-chloro-methyl-6-phenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine-SN-oxide is obtained in the form of crystals. By recrystallization
Elemental analysis for ClsHl3CIN4O:
C H N
Calculated 59.90 4.36 18.63
Found 60.05 4.13 18.41
Example 37
To a solution of 3 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1, 4-benzodiazepine-4N-oxide obtained according to the information in Section 1), 7.4 in 60 parts by volume of chloroform are added Parts of ethyl orthoformate and then 1.1 parts by volume of concentrated sulfuric acid dropwise.



  The entire mixture is stirred for about 20 minutes and then neutralized using saturated aqueous sodium bicarbonate solution. The chloroform layer is washed and dried over sodium sulfate. Evaporation of the solvent leaves 8-chloro-6-phenyl-4H-s-triazolo (4,3-a) (1,4) -benzodiazepine-5N-oxide in the form of crystals. Recrystallization from a mixture of methanol and chloroform (mixing ratio 1: 1 parts by volume) gives colorless needles with a melting point of 267 to 2680 ° C. (with decomposition).



   Elemental analysis for Cl6HllCIN4O:
C H N
Calculated 61.74 3.57 18.03
Found 61.87 3.26 17.92
Example 38
1.1 parts by volume of concentrated sulfuric acid are added dropwise to a mixture of 3 parts of 7-chloro-2-hydrazino-5-phenyl 3H-1, 4-benzodiazepine-4N-oxide and 20 parts by volume of formamide, and the mixture is stirred whole mixture for 4 hours. When the reaction has ended, the mixture is neutralized with a saturated aqueous sodium carbonate solution. The crystals obtained, consisting of 8-chloro-6-phenyl-4H-triazolo (4,3-a) (1,4) -benzodiazepine-5N-oxide, are separated off by filtration and recrystallized from chloroform. In this way, colorless needles with a melting point of 267 to 2690C (with decomposition) are obtained.



   The product obtained in this way is identical to the product according to Example 37.



   Example 39
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 is left to stand overnight at room temperature, whereupon the solvent is added distilled off. Neutralization with saturated aqueous sodium bicarbonate solution gives 8-chloro-6-phenyl-4H-s-triazolo (4,3-a) (1,4) -benzodiazepine-5N-oxide.



  Methanol leads to colorless needles with a melting point of 268 to 270oC (with decomposition).



   The product obtained in this way is identical to the product according to Examples 40 and 41.



   Example 43
To 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 are added 0.5 Parts by volume of acetic anhydride are added with stirring. The entire mixture is stirred for about 1 hour, after which water is added. In this way, 2- (2-acetylhydrazino) -7-chloro-5-phenyl-3H-1,4-benzodiazepine-4N-oxide is obtained in the form of crystals. Recrystallization from a mixture of dimethylformamide and water produces fine needles with a melting point of 256 to 2580C (with decomposition).



   Elemental analysis for Cl7HlsCIN402:
C H N
Calculated 59.56 4.41 16.35
Found 59.38 4.55 16.30
A mixture of 3 parts of 2- (2-acetylhydrazino) -7-chloro-5-phenyl-3H-1, 4-benzodiazepine-4N-oxide and 30 parts by volume of pyridine is refluxed for 4 hours, whereupon the pyridine is added evaporated under reduced pressure. The residue is recrystallized from methanol, with 8 - chloro-1-methyl-6-phenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine-SN-oxide in the form of needles from Melting point 272 to 274 C (with decomposition).



   The product obtained in this way is identical to the product according to Examples 40 to 42.



   Example 44
To a suspension of 3 parts of 7-chloro-2-hydrazino-5-phenyl 3H-1, 4-benzodiazepine-4N-oxide, obtained according to the information in Section 1), and 8.8 parts of ethyl orthopropionate in 100 vol. Parts of ethanol are added dropwise to 1.1 parts by volume of concentrated sulfuric acid.



  The whole mixture is stirred for 20 minutes and the solvent is evaporated. The residue is neutralized with a saturated aqueous sodium bicarbonate solution, whereby the 8-chloro-1-ethyl-6-phenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine-SN-oxide crystallizes out. Recrystallization from methanol gives colorless flakes with a melting point of 273 to 275C (with decomposition).



   Elemental analysis for ClsHlsCIN4O:
C H N
Calculated 63.81 4.46 16.54
Found 63.60 4.20 16.34 m) 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 are added 2.5 parts by volume of 100% hydrazine hydrate and 1.8 parts by volume of acetic acid are added. The entire mixture is warmed gently on a water bath for a short time to obtain a solution which is stirred for about 20 minutes. The precipitated crystals are collected and washed with methanol and then with diethyl ether, 2-hydrazino-7-nitro-5-phenyl 3H-1,4-benzodiazepine-4N-oxide in the form of yellow needles with a melting point of 176 ° C (with sintering) or 2260C (with decomposition).



   Elemental analysis for ClsHl3NsO3:
C H N
Calculated 57.87 4.21 22.50
Found 57.98 4.01 22.26
Example 45
To a suspension of 1.55 parts of 2-hydrazino-7-nitro-5-phenyl-3H-1, 4-benzodiazepine-4N-oxide obtained according to the information in section m), in 100 parts by volume of ethanol are added 3, 7 parts of ethyl orthoformate and then 0.6 parts by volume of concentrated sulfuric acid are added, causing the solid substance to dissolve and yellow crystals to form. After stirring for 30 minutes, the mixture is neutralized with a saturated aqueous sodium bicarbonate solution. The crystals are collected and washed with water, then with ethanol and finally with diethyl ether, 8-nitro-6-phenyl-4H-s-triazolo- (4,3-a) (1,4) -benzodiazepine-SN- oxide in the form of yellow crystals.

  Recrystallization from an aqueous dimethylformamide solution gives yellow crystals with a melting point of 274 to 2750 ° C. (with decomposition).



   Elemental analysis for Cl6HllNsO3:
C H N
Calculated 59.81 3.45 21.80
Found 59.58 3.48 21.56

 

Claims (1)

PATENT CLAIM Process for the preparation of benzodiazepine derivatives of the general formula: EMI16.1 wherein the radical Rl is a hydrogen atom or a hydrocarbon radical and the radical R is a hydrogen atom or a lower alkyl radical and the rings A and B are either unsubstituted or substituted by identical or different nitro, trifluoromethyl, halogen, alkyl or alkoxy radicals, including that case in which the nitrogen atom present in the 5 position bears an oxygen atom, characterized in that a compound of the general formula: : EMI16.2 in which R is a group of the formula -NHCORl, EMI16.3 where Rs is a lower alkyl radical, the other symbols are as defined above and the nitrogen atom present in the 4-position can carry an oxygen atom, subjecting it to a ring-closing reaction. SUBCLAIMS 1. The method according to claim, characterized in that the ring closure reaction is effected by heating the starting product by itself or in a solvent. 2. The method according to claim and dependent claim 1, characterized in that pyridine, dimethylformamide, xylene or tetralin is used as the solvent. 3. The method according to dependent claim 1 or 2, characterized in that the ring closure of an acylhydrazinobenzodiazepine or a corresponding enol ether derivative of the formula II in which R denotes the group -NHCORI or -N = C (Rl) OR is carried out by heating to 130 to 250C . A. The method according to dependent claim 3, characterized in that the ring closure reaction by heating in the presence of a catalyst, such as. B. polyphosphoric acid is accelerated. 5. The method according to claim and dependent claim 1, characterized in that the ring closure of an a-aminoalkylidene or a-aminoaralkylidenhydrazinobenzodiaze- pins of the formula II, in which R is the group -N = C (R) NH2, by heating to 140 to 250tC is carried out.