DE1965894A1 - 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

New 2-hydrazine-benzodiazepine derivatives and process for their preparation Elimination from patent ....... (patent application P 19 55 349.2) The invention relates to new 2-hydrazine-benzodiazepine derivatives of the general formula where R2 is hydrogen or a lower alkyl radical and the rings A and / or B are unsubstituted or substituted by one or more substituents from the group consisting of nitro, trifluoromethyl, halogen, alkyl or alkoxy, which are identical or different, including the case that the nitrogen atom in the 4-position carries an oxygen atom, as well as the acid salts of these compounds.

The new 2-hydrazinbenæodiazepine derivatives of the general formula I can be prepared by adding 2-aminobenzodiazepines of the general formula in which the symbols have the meanings given above, including the case in which the nitrogen atom in the 4-position bears an oxygen atom, is reacted with hydrazine.

The 2-aminobenzodiazepine derivatives of the above general formula (II) can exist in the following isomeric form: This shape is also suitable for this process.

The compounds of the formula (II) can, for example, by the method which is described in "Journal of Organic Chemistry" 26, 1Xlf (1961)., or by Conversion of 2-aminobenzophenone derivatives with an alkylamine to form 2-amino-α-phenylbenzylidene alkylamine derivatives, Implementation of these derivatives with an aminoacetonitrile derivative and cyclization of the 2-amino-α-phenylbenzylideneaminoacetonitrile derivatives obtained in the presence of this an acid or in the presence of alkali.

The reaction between the 2-aminobenzodiazepine derivatives (II) and Hydrazine is preferably in the presence of a suitable solvent and a Acid carried out at a temperature between 0 and about 150 ° C. As a solvent ieiEPfe; TsEYfs tiEs%, Jio, tEy-kEE $ 3 .ui: r'f "d-wrr3-fi or Ge # ische these solvents or their aqueous mixtures. Suitable acids are for example inorganic acids (e.g. hydrochloric acid, sulfuric acid and phosphoric acid) and organic Acids (e.g. acetic acid and p-toluenesulfonic acid).

The acids can be in the form of salts with amines, e.g. pyridine, trialkylamines and 2-methylimidazole, can be added. It should be noted that the hydrazine and / or the 2-aminobenzodiazepine derivatives (II) are used in the form of their acid addition salts can be. In such a case it is not always necessary to add more acid or to add their salt with the amine to the reaction mixture. The hydrazine and the Acid are generally used in an amount of about 1 to 5 moles per mole of the 2-aminobenzodiazepine derivatives (II) is used, but these amounts can be changed as needed.

The 2-hydrazine benzodiazepine derivatives prepared in the manner described above (I) Can the subsequent ring closure reaction with or without isolation from the reaction mixture are subject to. They can be isolated by customary methods, e.g. by adding water to the reaction mixture and extracting the mixture with a suitable solvent (e.g. methylene chloride and chloroform) and then Evaporation of the solvent.

The 2-hydrazine benzodiazepine derivatives (I) in which the nitrogen atom in the 4-position has no oxygen atom can be prepared by reacting a compound of the general formula in which R4 is a hydrogen atom, an alkyl radical or an aaltyl radical and the other symbols have the meanings given above, are prepared with hydrazine.

If R4 in the general formula (III) is a hydrogen atom, the compounds can exist in the following isomeric form: This shape is also suitable for this procedure.

The compound of the formula (III) can, for example, according to the process described in "Journal of Organic Chemistry" 29, 231 (1964) is.

The alkyl radical R4 is preferably a lower alkyl radical with up to 6 carbon atoms, e.g. a methyl radical, ethyl radical, propyl radical, isopropyl radical, butyl radical, sec-butyl radical, tert-butyl radical, amyl radical or hexyl radical. The aralkyl radical for which R4 is, for example, a benzyl radical or phenylethyl radical.

The reaction is generally carried out in the presence of a solvent (e.g. methanol, ethanol and aqueous mixtures of methanol and ethanol) at approx Room temperature or optionally with heating to the boiling point of the used Solvent carried out. Das.Hydrazine is used in an amount of about 1 to 10 Moles per mole of the compound (III) are used.

The 2-hydrazine benzodiazepine derivatives prepared in this way (I) can by customary methods, for example by evaporating the solvent from the reaction mixture, are isolated.

The new compounds of the formula (I) are valuable intermediates for the production of benzodiazepines, the muscle slacking, calming and have depressant effects and are therefore valuable as muscle relaxants, anticonvulsants, Are sedatives, tranquilizers, etc.

Example 1 To a suspension of 3.4 parts of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine dihydrochloride 1.25 parts of 80% hydrazine hydrate are added to 60 parts by volume of methanol.

The suspension is stirred for 40 minutes, diluted with water and with Extracted methylene chloride. The extract is washed with water and dried over anhydrous Sodium sulfate; dried, whereupon the solvent is evaporated. The residue is recrystallized from a mixture of methylene chloride: and benzene, whereby 7-chloro-2-hydrazine-5-phenyl-3H-1,4-benzodiazepine is obtained in the form of colorless prisms. Melting point about 170 ° C (browning); 202 to 204 ° C (dec.) Elemental analysis: a H N Calculated for C15H13ClN4 65.27 4X60 19.68 Found 63.43 4.48 19.27 Example 2 To a suspension of 3 parts of 2-amino-7-chloro-5- (pmethoxyphenyl) -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 given with stirring 1.5 parts by volume of 100% hydrazine hydrate. The mixture becomes 30 Stirred for minutes and poured into ice water, whereupon it is extracted with chloroform, The chloroform layer is washed with water and dried over sodium sulfate. The solvent is evaporated. Treating the residue with benzene becomes 7-chloro-2-hydrazine-5- (p-methoxyphenyl) -3H-1,4-benzodiazepine in the form of colorless Crystals from the melting point 214 to 220 ° C obtained.

Elemental analysis: CHN Calculated for C16H15ClN4O 61.05 4.80 17.80 Found 60.93 4.67 17.83 Example 3 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 of glacial acetic acid become 1.5 parts by volume 100% Given hydrazine hydrate. The mixture is stirred for 1 hour at room temperature. By Treatment of the mixture in the manner described in Example 2 gives 2-hydrazine-5-phenyl-3H-1,4-benzodiazepine obtained in the form of white crystals. By recrystallization from a mixture of methylene chloride and benzene become white crystals with a melting point of 116 to 1180C (with foaming).

Elemental analysis: C H N Calculated for C15H14N4.1 / 3 C6H6 73.89 5.84 20.28 Found 73.86 5.47 20.44 Example 4 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 of glacial acetic acid become 4.5 parts by volume 100% Given hydrazine hydrate. The mixture is stirred for 30 minutes at room temperature and worked up in the manner described in Example 1, with 2-itydrazine-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine as a crystalline powder with a melting point of 12700 (sintering) or 133 to 13500 (below Foaming) is obtained.

Elemental Analysis: C H N Calculated for C16H13F3NX 60.37 4.12 17.60 Found 60.06 3.96 17.40 Example 5 To a mixture of 2.5 parts 2-Amino-7 methyl-5 phenyl-3H-1,4-benzodiazepine, 100 parts by volume of methanol and 1,2 Parts of glacial acetic acid are added to 2.5 parts of 100% hydrazine hydrate. The mixture will Stirred for 1 hour at room temperature and in the manner described in Example 1 worked up. Here, 2-hydrazine-7-methyl-5-phenyl-3H-1,4-benzodiazepine in Preserved form of crystals. By recrystallization from a mixture of chloroform and diethyl ether become colorless crystals with a melting point of 240 to 24100 (decomp.) obtain.

Elemental Analysis: C H N Calculated for C16H16N4 72.70 6.10 21.20 Found 72.70 6.08 21.31 Example 6 To a mixture of 26.5 parts of 2-amino-7-methoxy-5-phenyl-3H-1,4-benzodiazepine, 500 parts by volume of methanol and 1.2 parts of glacial acetic acid are 25 parts of 100% hydrazine hydrate given. The mixture is stirred for 1 hour at room temperature and on that in example 1 treated manner, wherein 2-hydrazine-7-methoxy-5-phentyl-3H-1,4-benzodiazepine is obtained in the form of crystals melting at 110 to 120 ° C.

Example 7 To a mixture of 5.6 parts of 2-amino-7-nitro-5-phenyl-311-1,4-benzodiazepine, 200 parts by volume of ethanol and 2.4 parts by volume of glacial acetic acid become 5 parts by volume with stirring 80% hydrazine hydrate given. The mixture is stirred at room temperature for 30 minutes and worked up in the manner described in Example 1, using 2-hydrazine-7-nitro-5-phenyl-3H-1,4-benzodiazepine is obtained as a reddish, viscous oily substance.

Example 8 To a solution of 16 parts 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 become 6 parts Glacial acetic acid added while stirring and ice cooling. The mixture is then Stirred for 5 hours at room temperature, after adding water to the reaction mixture is extracted with chloroform. The chloroform layer is washed with water and dried over sodium sulfate. The solvent is evaporated. Through treatment of the back.

Isopropyl ether becomes 7-chloro-2-hydrazine-3, isobutyl-5-phenyl-3H-1,4-benzodiazepine obtained in the form of colorless crystals with a melting point of 165 to 16800. This The product is identical to the product produced according to Example 11, Example 9 To a solution of 2 parts of 7-chloro-2-methylmercapto-5-phenyl-3H-1,4-benzodiazepine 5 parts by volume of 80% hydrazine hydrate are added to 70 parts by volume of ethanol. That The mixture is left to stand for 3 days at room temperature. To.

When the solvent is evaporated, a small amount of water becomes the residue given, taking 7-chloro-2-hydrazine-5-phenyl-3H-1,4-benzodiazepine in the form of crystals is obtained. By recrystallization from a mixture of methylene chloride and Benzene produces crystals with a melting point of 175 ° C (browning) and 205 to 207 ° C (decomp.) obtain.

This product is identical to the product made according to Example 1 identical.

Example 10 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 of ethanol 5 tree parts of 80% hydrazine hydrate are given. The mixture will last 24 hours ditched. After evaporation of the solvent under reduced pressure is the residue is diluted with water, whereupon with methylene chloride extracted will. The methylene chloride layer is dried over sodium sulfate and the solvent evaporated.

Treatment of the residue with benzene gives 7-chloro-2-hydrazine-5-phenyl-3H-1,4-benzodiazepine obtain. Recrystallization from a mixture of methylene chloride and benzene gives crystals with a melting point of 205 to 2070C (Zers0). This product is identical with the product prepared according to Examples 1 and 9.

Example 11 To a solution of 1.6 parts of 7-chloro-3-isobutyl-2-methylmercapto-5-phenyl-3H-1,4-benzodiazepine 40 parts of 100 hydrazine hydrate are added to 150 parts by volume of methanol. The mixture is refluxed for 4.5 hours and poured into water, whereupon with chloroform is extracted0 The chloroform layer is washed with water and over sodium sulfate dried, whereupon the solvent is evaporated. By treating the residue 7-chloro-2-hydrazine-3-isobutyl-5-phenyl-3H-1,4-benzodiazepine is obtained with diethyl ether obtained in the form of crystals.

By recrystallization from a mixture of chloroform and n-hexane colorless crystals with a melting point of 168 to 169 ° C. are obtained.

Elemental analysis: o H N Calculated for C19H21ClN4 66.95 6.21 16.44 Found 67.21 6.19 16.70 Example 12 To a suspension of 4.3 parts of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine-4N-oxide In 400 parts by volume of methanol, 12.5 parts by volume are 100% hydrazine hydrate and 10 Parts by volume of methanol which is saturated with hydrogen chloride are added. The mixture is refluxed for 10 minutes and the resulting solution to half of the the original volume. The concentrate is poured into 500 parts by volume of water and the obtained oily substance is extracted with chloroform. The chloroform layer will dried over sodium sulfate and evaporated. By treating the residue with diethyl ether is 7-chloro-2-hydrazine-5-phenyl-3H-1,4-benzodiazepi-4N-oxide as pale yellow powdery crystals with a melting point of 262-263 ° C were obtained.

Elemental analysis: C H N Calculated for C15H13ClN4O: 59.90 4.36 18.63 Found: 60.05 4.13 18.41 Example 13 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 2.5 parts by volume of 100% hydrazine hydrate and 1.8 Volumes of acetic acid given, the 'mixture is light for some time on the water bath warmed, forming a solution, and stirred for about 20 minutes at room temperature.

The precipitated crystals are separated and washed with ethanol and then washed with diethyl ether, with 2-hydrazine-7-nitro-5-phenyl-3H-1,4-benzodiazepine-4N-oxide in the form of yellow pins with a melting point of 176 ° C (sintering) and 2260C (decomp.) Elemental analysis: C H N Calculated for C15H13N5O3: 57.87 4.21 22.50 Found: 57.98 4.01 22.26

Claims (2)

P atent claims 1) Compounds of the general formula where R2 is hydrogen or a lower alkyl radical and the rings A and / or B are unsubstituted or substituted by one or more substituents from the group consisting of nitro, trifluoromethyl, halogen, alkyl or alkoxy, which are identical or different9, including the case that the nitrogen atom in the 4-position carries an oxygen atom, as well as the acid salts of these compounds. 2) Process for the preparation of compounds of the general formula where R2 is hydrogen or a lower alkyl radical and the rings A and / or B are optionally substituted by one or more substituents from the group consisting of nitro, trifluoromethyl, halogen, alkyl or alkoxy, which can be identical or different, including the case, that the nitrogen atom in the 4-position bears an oxygen atom, characterized in that there are compounds of the general formula in which R2 has the abovementioned meaning and the rings A and / or 13 are substituted in the manner indicated above, reacted with hydrazine or compounds of the general formula where R2 has the abovementioned meaning, the rings A and / or B can be substituted as indicated above and R4 denotes hydrogen, alkyl or a sinen aralkyl radical, is reacted with hydrazine.