NO162070B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE TRIAZOL (2,3-C) (1,3) BENZODIAZEPINES. - Google Patents

Abstract

1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE Compounds of the formula see diagramm : EP0129509,P18,F1 wherein R1 is hydrogen, C1 -C4 alkylthio, amino, (C1 -C4 alkanoyl-, C1 -C4 alkoxycarbonyl-, carbamoyl-, sulfamoyl-, C1 -C4 monoalkyl-, or di-C1 -C4 alkyl-carbamoyl- or -sulfamoyl-, halosulfonyl-, phenyl-C1 -C2 alkoxy-carbonyl-, C1 -C4 alkyl- or di-C1 -C4 alkyl-)amino, C1 -C4 alkoxy, (C1 -C4 alkanoyl-, C1 -C4 alkoxycarbonyl-, carbamoyl-, sulfamoyl-, mono-C1 -C4 alkyl- or di-C1 -C4 alkyl-carbamoyl- or -sulfamoyl-, halosulfonyl- or phenyl-C1 -C2 alkoxycarbonyl-) oxy, C1 -C4 alkyl, acetyl, propionyl, hydroxy, halogen, trifluoromethyl, cyano, carboxy, methoxy- or ethoxy-carbonyl, carbamoyl, mono- or di-methyl- or -ethyl-carbamoyl, hydroxy-C1 -C4 alkyl or di-C1 -C4 alkylamino-C1 -C4 alkyl ; Cn H2n is C2 -C4 alkylene separating the two nitrogen atoms by 2 or 3 carbon atoms ; R2 is hydrogen, C1 -C7 alkyl, allyl, propargyl, acetyl, propionyl, phenyl-C1 -C3 alkyl which can be substituted at the phenyl ring by halogen, C1 -C4 alkoxy or by C1 -C4 alkyl, methoxy- or ethoxy-carbonyl, phenylmethoxycarbonyl, phenylethoxycarbonyl, 2-hydroxy-(ethyl or propyl), 3-hydroxy-(propyl or butyl), 4-hydroxybutyl, C2 -C4 alkanoyl-oxy-C2 -C4 alkyl, phenoxy-C2 -C4 alkyl which can be substituted at the phenyl ring by halogen, C1 -C4 alkoxy or by C1 -C4 alkyl, or C1 -C4 alkoxy-C2 -C4 alkyl ; R3 and R4 independently represent hydrogen, C1 -C7 alkyl, C1 -C4 alkoxy, C1 -C4 alkylthio, halogen, trifluoromethyl, hydroxy, acetoxy, propionyloxy, sulfamoyl, mono- or di-C1 -C4 alkylsulfamoyl, and R5 and R6 represent hydrogen or C1 -C4 alkyl ; and N-oxides and salts thereof. 1. Claims for the Contracting State : AT A process for the manufacture of compounds of the formula see diagramm : EP0129509,P20,F2 wherein R1 is hydrogen, C1 -C4 alkylthio, amino, (C1 -C4 alkanoyl-, C1 -C4 alkoxycarbonyl-, carbamoyl-, sulfamoyl-, C1 -C4 monoalkyl-, or di-C1 -C4 alkyl-carbamoyl- or -sulfamoyl-, halosulfonyl-, phenyl-C1 -C2 alkoxy-carbonyl-, C1 -C4 alkyl- or di-C1 -C4 alkyl-)amino, C1 -C4 alkoxy, (C1 -C4 alkanoyl-, C1 -C4 alkoxycarbonyl-, carbamoyl-, sulfamoyl-, mono-C1 -C4 alkyl- or di- C1 -C4 alkyl-carbamoyl-or -sulfamoyl-, halosulfonyl- or phenyl-C1 -C2 alkoxycarbonyl-)oxy, acyloxy, C1 -C4 alkyl, acetyl, propionyl, hydroxy, halogen, trifluoromethyl, cyano, carboxy, methoxy- or ethoxy-carbonyl, carbamoyl, mono- or di-methyl- or -ethyl-carbamoyl, hydroxy- C1 -C4 alkyl or di-C1 -C4 alkylamino-C1 -C4 alkyl ; Cn H2n is C2 -C4 alkylene separating the two nitrogen atoms by 2 or 3 carbon atoms ; R2 is hydrogen, C1 -C7 alkyl, allyl, propargyl, acetyl, propionyl, phenyl-C1 -C3 alkyl which can be substituted at the phenyl ring by halogen, C1 -C4 alkoxy or by C1 -C4 alkyl, methoxy- or ethoxy-carbonyl, phenylmethoxycarbonyl, phenylethoxycarbonyl, 2-hydroxy-(ethyl or propyl), 3-hydroxy-(propyl or butyl), 4-hydroxybutyl, C2 -C4 alkanoyloxy-C2 -C4 alkyl, phenoxy-C2 -C4 alkyl which can be substituted at the phenyl ring by halogen, C1 -C4 alkoxy or by C1 -C4 alkyl, or C1 -C4 alkoxy-C2 -C4 alkyl ; R3 and R4 independently represent hydrogen, C1 -C7 alkyl, C1 -C4 alkoxy, C1 -C4 alkylthio, halogen, trifluoromethyl, hydroxy, acetoxy, propionyloxy, sulfamoyl, mono- or di- C1 -C4 alkylsulfamoyl, and R5 and R6 represent hydrogen or C1 -C4 alkyl ; and N-oxides and salts thereof, characterized in that a) a compound of the formula III see diagramm : EP0129509,P20,F3 wherein X is a group detachable together with hydrogen or with an alkali metal, and the other symbols are as defined under the formula I, is condensed with a compound of formula IV see diagramm : EP0129509,P21,F1 or with an alkali metal derivative thereof in which R2 is as defined under the formula I, or b) a compound of the formula VI see diagramm : EP0129509,P21,F2 wherein Z is oxygen, sulfur or NH, and the other symbols are as defined above, is cyclized under dehydrating, dehydrosulfurating or deaminating conditions, and, if desired, a resulting free compound is converted into a salt or a resulting salt is converted into the free compound or into another salt, and/or, if desired, a resulting mixture of isomers or racemates is resolved into the single isomers or racemates, and/or, if desired, resulting racemates are resolved into the optical antipodes.

Description

The invention is based on the task of providing new ZNS-active compounds that have psychoactive effects, but also anti-allergic, e.g. anti-histaminic effects.

This task is solved by the invention, which relates to an analogue method for the production of psychoactive and anti-allergic triazol[2,3-c][1,3]benzodiazepine compounds.

Triazole[2,3-c][1,3]benzodiazepine compounds which can be prepared according to the invention have the formula

wherein R means hydrogen, C 1 -C 4 alkyl, halogen or C 1 -C 4 alkylmercapto, R 2 means hydrogen or C 1 -C 4 alkyl, and R means hydrogen or halogen. Of these compounds, it is also possible to prepare therapeutically usable acid addition salts.

The general definitions as they are used here, within the scope of the present invention, have the meaning indicated below.

A halogen atom is preferably fluorine or chlorine, but also bromine or iodine.

A C₁-C₁ alkyl group or such 1 the other mentioned alkylated groups are above all methyl and also ethyl, as well as n-or iso-(propyl or butyl).

A C1-C4 alkylmercapt group means, for example, ethylthio, propylthio or especially methylthio.

The aforementioned compounds of formula I form acid addition salts, preferably with therapeutically usable inorganic or also organic acids, such as e.g. with strong mineral acids, such as halogen, hydrogen acids, e.g. hydrochloric or hydrobromic acid, sulphurous, sulfuric or also nitric acid, or with organic acids, such as e.g. aliphatic or aromatic carboxylic or sulphonic acids, e.g. formic acid, acetic acid, propionic acid, succinic acid, glucolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, 4-aminosalicylic acid, pamoic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, sulfamic acid or cyclohexylsulfamic acid, or ascorbic acid.

The compounds produced according to the invention have valuable pharmacological properties, particularly psychoactive, such as e.g. neuroleptic effects, but also antiallergic, such as e.g. anti-histaminic effects. These can be demonstrated in animal experiments, preferably with mammals, such as e.g. murres, rats, guinea pigs, or monkeys as test subjects. The said compounds can be administered enterally or parenterally, preferably orally or subcutaneously, intravenously or intraperitoneally, e.g. in the form of capsules or in the form of starch-containing suspensions, resp. aqueous solutions. The dose used may be in a range of approximately between 0.1 and 50 mg/kg/day, preferably approximately 0.33 mg/kg/day, especially between 1 and 20 mg/kg/day.

The aforementioned neuroleptic properties can be demonstrated in adult rats or squirrel monkeys. The animals are trained to operate a lever, whereby they can avoid an electric shock administered on the foot. Each lever press moves the shock around 30 seconds. If the animal forgets to press the lever once in the mentioned time interval, a short (0.5 second) electric shock is delivered every 15 seconds, until the animal operates the lever again. Under control conditions, subjects press the lever at a suitably equalized rate, rarely receiving more than 5 or 6 shocks during a 25 minute (rat) to 4 hour test period. The said compounds, which are administered to the animals 30, 90 and 210 minutes before the experiment, block the established conditioned avoidance relationship. The consequences are a decrease in the avoidance reaction, and a significant increase in the shocks received by the animals. Both the number of avoidance reactions and those of the error condition (formed shocks) are recorded for assessment.

Finally, the anti-histaminic properties can be demonstrated in vitro according to Chasin et' al., J. Neurochem, 22, 1031 (1974). Homogenates of a cell-free preparation of the guinea pig cerebrum are pre-incubated with ^H-adenine, as endogenous <3>H-adenosine triphosphate is formed. The homogenates are then incubated with 50 micromolar histamine to activate the synthesis of <3>H-cyclic adenosine monophosphate. This process is carried out in the presence or absence of test compound, using concentrations between 0.01 and 100 micromoles. If the tested substance is active, the histamine activation of adenylate cyclase is inhibited. The ICsø value means the concentration at which histamine activation is inhibited around 50$.

The compounds produced according to the invention can consequently be used as neuroleptics and as antihistamine preparations, e.g. in the treatment and handling of psychotic phenomena such as e.g. aggression, agitation, schizophrenia and/or allergic conditions in mammals, including humans. They can also be used as an intermediate for the production of other valuable products, especially pharmacologically active preparations.

Preferred compounds produced according to the invention are those of formula I, in which R 1 means hydrogen, methyl, ethyl, chlorine or methylmercapto, R 2 means hydrogen or methyl, and R 3 means hydrogen or chlorine, as well as their therapeutically applicable acid addition salts.

In particular, as representatives of the compounds produced according to the invention, the compound in the following example 1, namely 2-methyl-5-(4-methyl-1-piperazinyl)-11H-1,2,4-triazole [2,3-c] [ 1 , 3]benzodiazepine maleate , against the antipsychotic properties. The compound decreases the avoidance responses (increase in error ratio) in rats and baboons at an orally administered total dose of about 1.0 mg/kg or lower.

Furthermore, it should also be mentioned that the compound according to the following example 1, at effective antipsychotic doses, also excels in that it is essentially free of extrapyramidal side effects such as e.g. dyskinesias and dystonias in cynomolgus monkeys.

The antihistaminic action is particularly evident by 2-methyl-5-(4-methyl-1-piperazinyl)-11H-1,2,4-triazol[2,3-c][1,3]benzodiazepine maleate (the compound from example 1) . This compound inhibits the histamine activation of adenylate cyclase with an IC50 of approximately 3 x 10_<6>M.

The compounds according to the invention are produced according to methods known per se, e.g. by that

a) a compound with formula

in which X means a group cleavable together with hydrogen or an alkali metal, and the second symbol has the meaning given under formula I, is condensed with a compound of formula

or an alkali metal derivative thereof, of which Rg has the meaning given under formula I, or

b) a compound of formula

wherein Z means oxygen, sulfur or =N-H, and the others

symbols have the aforementioned meanings, are cyclized during elimination of water, hydrogen sulphide or ammonia, and a compound in which Rg means benzyloxycarbonyl, is transferred by hydrolysis to a compound in which Rg means hydrogen, and if desired, in a compound in which R2 means hydrogen, by reaction with haloformic acid C 1 -C 4 -alkyl ester and reduction of the acyl derivative with complex light metal hydride, is transferred to a compound in which R 1 means -C 4 -alkyl; and/or a formed compound is transferred to a salt.

The concentration according to method variant a) preferably takes place in an excess of the used compound of formula IV, or with an equivalent amount of the in situ produced alkali metal compound thereof, when X as a cleavable group means a compound of formula III, preferably methylthiol. Depending on the meaning of X, the reaction takes place at temperatures between 0 and 150°C, preferably in a suitable solvent, such as e.g. lower alkanol, for example amyl alcohol, dimethylformamide, hexamethylene phosphoramide or toluene. Said condensation of a compound of formula III with a compound of formula IV can, however, also be carried out in the presence of an acid, for example a halogen-hydrogen acid which e.g. hydrogen chloride (hydrochloric acid).

The new 11H-1,2,4-triazol[2,3-c][1,3]benzodiazepine starting materials of formula III are prepared according to ring closure methods known per se. Compounds of formula are preferably condensed

in which R} and R3 have the meanings mentioned under formula I, with reactive carboxylic acid derivatives such as e.g. phosgene, thiophosgene, 1,1-carbonyldiimidazole, cyanogen bromide or chloroformic acid phenyl ester.

Starting compounds of formula V are preferably prepared by reduction of the correspondingly different substituted 5-(o-nitrobenzyl)-1,2,4-triazoles by reduction which in turn are preferably prepared from the correspondingly substituted o-nitrobenzylnitriles and derived lower alkyliminoethers with the hydrazides of formula R ^-CONHNHg, in which R]^ has the meaning indicated above for the compounds of formula I, according to known methods analogous to those mentioned in the examples. The cyclization according to method variant b) is preferably carried out at a temperature between 0 and 120°C with a reaction agent such as phosphorus halides and/or oxyhalides, which e.g. phosphorus pentachloride or phosphorus oxychloride, or cyanohalides, such as cyanobromine, with or without crown ether catalysts, e.g. 18-crown-6-ether, in the presence or absence of basic catalysts, such as e.g. triethylamine or potassium carbonate, preferably in an inert solvent, e.g. acetonitrile or toluene.

The starting substances with formula VI can, if they are new, be obtained by methods known per se. For example, the starting substances of formula VI can be prepared starting from their (tautomeric) precursor compounds of formula III, in which X means hydroxy. These compounds are condensed with compounds of formula IV in the presence or absence of other bases, e.g. the above, preferably in inert solvents such as methylene chloride or toluene at temperatures between 0° and 15°C, advantageously between 10° and 50°C. The ring opening is preferably carried out at lower temperatures to prevent side reactions of the possibly present reactive functional groups Rj to R4.

In another way, starting material f is of formula VI, in which R 2 means lower alkoxycarbonyl or benzyloxycarbonyl, can be prepared by condensation of compounds of formula V with a compound of formula VII,

wherein Y' means halocarbonyl, halothiocarbonyl or cyan, preferably in an inert solvent, as already indicated above, at temperatures between 0° and 150°C, in the presence

or absence of a basic catalyst, such as triethylamine or potassium carbonate.

The starting compounds of formula VII are preferably obtained from compounds of formula IV, in which Rg has the meaning given under formula VII, or from the corresponding N-trimethylsilyl derivatives by reaction with phosgene, thiophosgene or cyanogen bromide, in an inert solvent such as e.g. diethyl ether, methylene chloride or diethoxyethane, at temperatures between -70°C and +50°C. The reaction can be carried out in the presence or absence of a basic catalyst, for example triethylamine or potassium carbonate.

The compounds of formula I in which R 2 means C 1 -C 2 -alkyl, for example methyl, can be prepared as follows: initially, compounds in which hydrogen means are transferred by reaction with haloformic acid lower alkyl esters, e.g. chloroformic acid ethyl esters, to compounds of formula I, in which R 2 means -(^-Alkoxycarbonyl. These acyl derivatives are then reduced with simple or complex light metal hydrides, for example with lithium aluminum hydride, sodium tri-tert.-butoxy aluminum hydride or sodium bis-(2-methoxyethoxy)-aluminum hydride.

Finally, the compounds according to the invention can be obtained in the form of free bases or as salts. A formed, free base can be transferred to the corresponding acid addition salt, preferably to therapeutically used acid addition salts. Acids that give therapeutically useful acid addition salts are e.g.

the previously mentioned inorganic acids or organic acids.

Due to the narrow relationship between the new compounds in free form and in the form of their salts, in the foregoing and the following, free compounds and salts also possibly mean the corresponding salts, resp. free connections.

The invention will be explained in more detail with the help of some examples.

EXAMPLE 1

A mixture of 6.94 g of 1-{o-[5-methyl-3-(1,2,4-triazolyl)methyl]

-phenylcarbamoyl}-4-methylpiperazine, 52 ml of phosphorus oxide chloride and 4.65 g of phosphorus pentachloride are stirred at room temperature for 5 hours and then evaporated to dryness. The residue is suspended in 1,125 ml of methylene chloride, the mixture is cooled to 0°C and then 15.5 ml of triethylamine is added dropwise. The mixture is then stirred at room temperature for 30 minutes and washed with cold water. The aqueous layer is washed with methylene chloride and the combined organic layers are washed with water, dried over magnesium sulfate, decolorized with activated charcoal and evaporated. The residue is chromatographed with 50 g of silica gel, whereby methylene chloride-methanol-ammonium hydroxide (450:50:1) is used as eluent, whereby 2-methyl-5-(4-methyl-1-piperazinyl)-11H-1,2 ,4-triazole(2,3-c)(1,3)-benzodiazepine.

A solution of 2-methyl-5-(4-methyl-1-piperazinyl)-11H-1,2,4-triazolo(2,3-c)(1,3)benzodiazepine in isopropanol is treated with a solution of an equimolar amount of maleic acid in isopropanol, whereby 2-methyl-5-(4-methyl-1-piperazinyl)-11H-1,2,4-triazolo (2,3-c)(1,3)-benzodiazepine is treated in isopropanol, whereby obtained 2,methyl-5-(4-methyl-1-piperazinyl)-11H-1,2,4-triazolo(2,3-c)

(1,3)benzodiazepine mono-maleate, with a melting point of 206-208°C. This compound is a salt of a compound of formula I,

where R, and R0= CH,, R0-R,= H and C H_ = CH„CH„.

1^2 3 36 3 n 2n 22

The starting material is produced as follows:

2,250 ml of absolute ethanol and 1,500 g of o-nitrophenylactonitrile are filled in advance in a 22 liter bottle. This suspension is cooled to 5-10°C and chlorine hydrogen gas is introduced into the mixture for 2.5 hours. The reaction mixture is stirred overnight at 10°C under a nitrogen atmosphere. It is then diluted with 16,000 ml of diethyl ether and stirred for 1 hour. The solid is separated by filtration, washed 4 times with 1,000 ml diethyl ether and dried (5 ml Hg/40°C), thereby obtaining 2-(o-nitrophenyl)-ac8ci..duau hydrochloride with a melting point of 122-123° C (cleavage).

To a solution of 4.1 g of ethyl-2-(o-nitrophenyl)-acetoxyliclac hydrochloride in 40 ml of ethanol is added at room temperature and over a period of 10 minutes a solution of sodium ethoxide, which is formed by dissolving 0.38 g sodium in 40

ml of ethanol. The mixture is stirred for 10 minutes and filtered. The filtrate is added with 1.29 g of acetylhydraziu, the mixture is stirred at room temperature for 2 hours, the solid is filtered off and washed with ethanol, thereby obtaining N-acecyl-o-nitrophenylacetamidrazone with a melting point of 195-197°C.

A mixture of 1.29 g of N-aeethyl-o-nitrophenyl acecar.iiurazori and

20 ml of ethanol are boiled for 60 hours at reflux and then evaporated to dryness. The oily residue is crystallized from ether, thereby obtaining 5-methyl-3-(o-nitrobenzyl)-1, 2, 4-trizole with a melting point of 119-123 °C.

A mixture of 1.67 g of 5-methyl-3-(o-nitrobenzyl)-1,2,4-triazole, 42 mg of 10% palladium on activated carbon and 15 ml of ethanol is hydrated for 4 hours at a pressure of 3 atmospheres, filtered, decolourised, evaporated to a smaller volume and diluted with ether, whereby 3-(o-aminobenzyl)-5-methyl-1,2,4-trizole with a melting point of 143-145°C is obtained.

A mixture of 12.87 g of 3-(o-aminobenzyl)-5-methyl-1,2,4-triazole, 11.21 g of 1,1'-carbonyldiimidazole and 470 ml of methylene chloride is stirred for 5 days at room temperature and then filtered . The filtrates are washed with water, dried over magnesium sulfate, decolorized and evaporated. The residue is recrystallized from tetrahydrofuran, whereby 2-methyl-11H-1,2,4-triazol-(2,3-c)(1,3)benzodiazepine-5-(6H)-one with a melting point of 245-247° is obtained C,

i.e. the starting material of formula III, where X= OH, R^-R^=

H, R, = CH0 and C H~ = CH„CH„.

1 3 ^ n 2n 2 2

A mixture of 7.23 g of 2-methyl-11H-1,2,4-triazol(2,3-c)(1,3)-benzodiazepine-5(6H)-one, 5.45 g of N-methylpiperazine and 76 ml methylene chloride is boiled for 48 hours at reflux and evaporated to dryness. The residue is chromatographed with silica gel using

mixture of methylene chloride-methanol-ammonium hydroxide (150:50:1)

as eluent. 1-[o-(5-methyl-3(1,2,4-triazolyl)methyl]-phenylcarbamoyl-4-methylpiperazine is obtained as foamy material, mass spectrum M+/e= 314, this compound is the intermediate of formula VI, in which C Hn = CH„CH~, R-, and R„= CH-., R-.-R,= H

n2n 2 2 1^ 2 3 36

and Z = 0.

EXAMPLE 2

In a similar way as according to the method in example 1, the following compounds of formula I are prepared, in which R 1 means methyl.

The starting materials of formula VI, in which R0 means methyl, for the above-mentioned compounds 1 to 5 are the following:

The starting materials of formula III, in which X means OH, the above-mentioned compounds of 1 to 5 of formula I are the following:

Starting materials for compound 1:

a) N-propionyl-o-nitrof enylaceta.aidrazone, melting point 184.5-186.5°C. b) 5-ethyl-3-(o-nitrobenzyl)-1,2,4-triazole, melting point 100-103°C. c) 5-ethyl-3-(o-aminobenzyl)-1,2,4-triazole, melting point 148.5-151.5°C.

)

Starting materials for compound 2_:

a) N-formyl-o-nitrof enylacataniidrazone, melting point 149-151°C, starting from formyl hydrazide.

b) 3-(o-nitrobenzyl)-1,2,4-triazole, melting point 123-125°C.

c) To a solution of 9.64 g 3-(o-nitrobenzyl)-1,2,4-triazole in 150 ml tetrahydrofuran, 220 ml of a 1.3 M

aqueous solution of titanium trichloride and the mixture is stirred at room temperature for 24 hours. The mixture is cooled in an ice-water bath and concentrated ammonium hydroxide is added dropwise, until the pH of the solution is 8. The solution is further diluted with water and extracted four times with methylene chloride. The combined extracts are decolorized with activated charcoal, dried over magnesium sulfate, evaporated to a smaller volume and diluted with ether, whereby 3-(o-aminobenzyl)-1,2,4-triazole with a melting point of 134-136°C is obtained.

Starting materials fpr_ connection 3_:

a) N-formyl-p-chloro-o-nitrophenylacetanidrazone, melting point 173-175°C (decomposition). b) 3-(p-chloro-o-nitrobenzyl)-1,2,4-triazole, melting point 180-185°C. c) 3-(p-chloro-o-aminobenzyl)-1,2,4-triazole, melting point 149-152°C.

Starting material r for connection_4:

a) A solution of sodium ethoxide, which has been prepared by dissolving 0.22 g of sodium in 11 ml of ethanol, is added dropwise at 0°C to a solution of 2.36 g of ethyl-o-nitrophenylacetiaidate in 23 ml of ethanol. The mixture is stirred for 30 minutes, filtered and 1 g of ethyl hydrazinocarbonate is added to the filtrate. The mixture is stirred at room temperature for 60 hours, evaporated to a smaller volume and filtered, whereby N-ethoxycarbonyl-o-nitrophenyl-acGtaaidrazone is obtained, melting point 183-185°C. b) A mixture of 1 g of N-ethoxycarbonyl-o-nitrophenylacetaiuid- •■ razone and 10 ml of amyl alcohol is boiled overnight at reflux,

is cooled and filtered, thereby obtaining 5-hydroxy-3-(o-nitrobenzyl)-1,2,4-triazole with a melting point of 210-212.5°C.

c) A mixture of 1 g of 5-hydroxy-3-(o-nitrobenzyl)-1,2,4-triazole, 10 ml of phosphorus oxychloride and 1.8 g of phosphorus pentachloride

stirred first at 70°C for 11 hours and then at room temperature over the end of the week and then evaporated to dryness. The residue is dissolved in water, the solution is made basic with 10% aqueous potassium carbonate and then extracted with ethyl acetate for approx. c. The shaken extracts are dried over magnesium sulfate, decolorized with activated charcoal and evaporated to dryness.

The residue is chromatographed with 50 g of silica gel using methylene chloride-acstau (1:1) as eluent, whereby 5-chloro-3-(o-nitrobenzyl)-1,2,4-triazole is obtained, melting point 160-163°C .

d) To a solution of 6.27 g of 5-chloro-3-(o-nitrobenzyl)-1,2,4-triazole in 146 ml of tetrahydrofuran is added at 0°C with stirring

146 ml of 20% aqueous solution of titanium trichloride. The mixture is stirred at room temperature overnight, made basic with concentrated ammonium hydroxide and extracted 3 times with methylene chloride. The shaken extracts are dried, evaporated and the residue crystallized from diethyl ether, whereby 3-(o-aminobenzyl)-5-chloro-1,2,4-triazole with a melting point of 162-165°C is obtained.

e) A mixture of 0.35 g of 3-(o-aminobenzyl)-5-chloro-1,2,4-triazole, 9 ml of methylene chloride and 0.284 g of 1,1'-carbonyldiimdazole

stirred overnight at room temperature. The mixture is evaporated to a smaller volume and diluted with diethyl ether, thereby obtaining 1-{o-[5-chloro-3-(1,2,4-triazolyl)methyl]-phenylcarbamoyl}-imidazole with a melting point of 165-167°C .

f) A mixture of 0.324 g of 1-{o-[5-chloro-3-(1,2,4-triazolyl)-methyl]-phenylcarbamoyl}-imidazole, 3 ml of methylene chloride and 0.11 g

N-methylpiperazine is stirred overnight at room temperature. The mixture is washed with water, dried over magnesium sulfate and evaporated, thereby obtaining 1-{o-[5-chloro-3-(1,2,4-triazolyl)-methyl]-phenylcarbamoyl}-4-methylpiperazine with a melting point of 190-195° C (starting material 4/a).

Starting materials for compound 5:

a) A solution of sodium ethoxide (prepared by dissolving 0.38 g of sodium in 40 ml of ethanol) is added dropwise at 0°C to a solution of 4.1 g of ethyl-2-(o-nitrophenyl)aoethimidate in 40 ml of ethanol. After stirring at room temperature for 30 minutes, the solids are filtered off, the filtrate is evaporated to a volume of approximately 10 ml and diluted with 20 ml of dimethyl sulphoxide. 1.52 g of thiosemicarbazide is added to the solution formed and the mixture is stirred for 2 days at room temperature. The solvent is evaporated in vacuo, the residue treated with water and ethyl acetate; the aqueous layer is further extracted with ethyl acetate and the shaken organic extracts are washed with water, dried over magnesium sulfate, evaporated to a smaller volume and diluted with diethyl ether, thereby obtaining N-(aminothiocarbonyl)-o-nitrophenyl-acetanidrazone with a melting point of 172-174 °C. b) A mixture of 1 g of N-(aminothiocarbonyl)-o-nitrophenylacetamidrazone and 10 ml of amyl alcohol is boiled for 6 hours at reflux, evaporated to a smaller volume and diluted with diethyl ether, thereby obtaining 5-mercapto-3-(o- nitrobenzyl)-1,2,4-triazole with a melting point of 239-241°C. c) To a suspension of 0.61 g of sodium hydroxide in 50 ml of tetrahydrofuran, 5 g of mercapto-3-(o-nitro-benzyl)-1,2,4-triazole are added in portions while stirring at room temperature over a period of 30 minutes. The mixture is stirred for 2 hours, 1.51 ml of methyl iodide is added at once, the mixture is stirred overnight at room temperature and then evaporated to dryness in vacuo. The remainder is treated with water and methylene chloride,

the aqueous layer is further extracted with methylene chloride,

the shaken organic extracts are dried over magnesium sulfate, evaporated to a smaller volume and diluted with diethyl ether, thereby obtaining 5-methyl-mercapto-3-(o-nitrobenzyl)-1,2,4-triazole with a melting point of 120-132°C .

d) To a solution of 2 g of 5-methylmercapto-3-(o-nitrobenzyl)-1,2,4-triazole in 45 ml of tetrahydrofuran, add dropwise 44 ml

20% aqueous titanium trichloride at 0°C. The mixture is stirred at room temperature overnight, diluted with water, cooled to 0°C, made basic with ammonium hydroxide and extracted three times with methylene chloride. The organic extracts are dried, evaporated and the residue crystallized from toluene, whereby 3-(o-aminobenzyl)-5-methylmercapto-1,2,4-triazole with a melting point of 99-102°C is obtained.

e) A mixture of 7 g of 3-(o-aminoenzyl)-5-methylmercapto-1,2,4-triazole, 5.26 g of 1,1'-carbonyldiimidazole and 179 ml of methylene chloride

heated overnight at reflux. The largest part of the solvent is then evaporated in vacuo, the solid formed is filtered off and washed with a small amount of methylene chloride, whereby 2-methylmercapto-11H-1,2,4-triazole(2,3-c)(1,3)benzodiazepine is obtained -5 (6H)-one with a melting point of 250-252°C (starting material 5/b).

EXAMPLE 3

To a solution of 6.25 g of 2-methyl-5-cyanothio-11H-1,2,4-triazole-(2,3-c)(1,3)benzodiazepine in 7.3 ml of hexamethylphosphoric

amide is added dropwise at 0°C to 4.94 g of N-methylpiperazine over a period of 5 minutes. The mixture is stirred at room temperature for 4 hours, poured into water and extracted with ethyl acetate. The organic extracts are washed with water, dried over magnesium sulfate and evaporated to dryness, thereby obtaining 2-methyl-5-(4-methyl-1-piperazinyl)-11H-1,2,4-triazole(2,3-c)

(1,3)benzodiazepine with a melting point of 185-187°C. This material is treated with an equivalent amount of maleic acid to give 2-methyl-5-(4-methyl-1-piperazinyl)-11H-1,2,4-triazole (2,3-c)(1,3)benzodiazepine monomaleate according to example 1.

The starting material is produced as follows:

To a solution of 5.41 g of thiophosgene in 30 ml of methylene chloride, a solution of 7.5 g of 5-methyl-3-(o-amino-benzyl)-1,2,4-triazole and 8, 07 g of triethylamine in 285 ml of methylene chloride over a period of 45 minutes. The mixture is stirred at room temperature overnight, washed first with 10% aqueous potassium bicarbonate and then with water, dried over magnesium sulfate, decolorized with activated charcoal and evaporated to dryness,

whereby 5-methyl-3-(o-isothiocyanatobenzyl)-1,2,4-triazole is obtained,

IR 2080 cm<_1>.

To a suspension of 0.91 g of sodium hydride in 27 ml of tetrahydrofuran, a solution of 8.74 g of 5-methyl-3-(o-isothiocyanatobenzyl)-1,2,4-triazole in 60 ml tetrahydrofuran. The mixture is stirred for 2 hours at room temperature. A solution of 4.02 g of cyanogen bromide in 35 ml of tetrahydrofuran is added dropwise to the resulting suspension at 0°C over a period of 15 minutes. The mixture is stirred for 1h hours at 0°C, poured into water and then extracted three times with ethyl acetate. oe organic extracts are dried over magnesium sulfate, decolorized with activated charcoal and evaporated, whereby 2-methyl-5-cyanothio-11H-1,2,4-triazole(2,3-c)(1,3)benzodiazepine is obtained,

IR 2 150 cm<-1.>

EXAMPLE 4

To a solution of 1.0 g of 2-methyl-5-(4-ethoxycarbonyl-1-piperazinyl)-11H-1,2,4-triazole(2,3-c)(1,3)benzodiazepine in 10 ml of dry tetrahydrofuran, 500 mg of lithium aluminum hydride is added at once and the mixture is then refluxed under a nitrogen atmosphere for 24 hours. The mixture is cooled to 0°C, the excess of lithium aluminum hydride is cleaved with ethyl acetate, the mixture is then poured into water and extracted with ethyl acetate. The extracts are dried and evaporated, whereby after purification 2-methyl-5-(4-methyl-1-piperazinyl)-11H-1,2,4-triazole(2,3-c)(1,3) benzodiazepine according to example 1 is obtained .

The starting material is obtained according to the indications in example 3 by condensation of 2-methyl-5-cyanothio-11H-1,2,4-triazole (2,3-c)(1,3)benzodiazepine with N-carboketoxypiperazine.

EXAMPLE 5

To a solution of 200 mg of 2-methyl-5-(4-benzyloxycarbonyl-1-1-piperazinyl)-11H-1,2,4-triazole(2,3-c)(1,3)benzodiazepine in 0.6 ml of acetic acid 0.70 ml of a 2N solution of hydrobromic acid in acetic acid is added. The mixture is heated for 2 hours at 100°C and then stirred at room temperature overnight. The work-up gives 2-methyl-5-(4H-1-piperazinyl)-1H-1,2,4-triazole(2,3-c)(1,3)benzodiazepine.

The starting material is prepared in a similar manner to the starting material in Example 4 by replacing 1-ethoxycarbonylpiperazine with the equivalent amount of 1-benzyloxycarbonylpiperazine.

EXAMPLE 6

A mixture of 300 mg of 5-(4H-1-piperazinyl)-11H-1,2,4-triazole (2,3-c)(1,3)benzodiazepine, 0.5 g of potassium carbonate, 1 molar equivalent of methyl iodide and 2 ml acetone is stirred overnight at room temperature and then evaporated. The residue is added with water and the mixture is extracted with methylene chloride. The extracts are dried over magnesium sulfate, evaporated and the residue is purified, whereby 2-methyl-5-(4-methyl-1-piperazinyl)-11H-1,2,4-triazole(2,3-c) is obtained

(1,3)benzodiazepine according to example 1.

EXAMPLE 7

5 100 ml of amyl alcohol and 918.35 g of N-methylpiperazine are filled in advance in a 12 liter three-necked flask, which is equipped with a "Dean-Stark adapter. The solution is stirred under a nitrogen atmosphere, whereby 989 ml of ION ethanolic hydrogen chloride solution

ning is quickly added. The reaction mixture is heated at reflux and the distillate is collected in the Dean-Stark adapter.

When the temperature of the reaction mixture reaches 131°C, the Dean-Stark adapter is removed and an additional amount of 918.35 g of N-methylpiperidine followed by 1112.6 g of 2-methyl-5-methylthio-11H-1,2,4- triazole(2,3-c)(1,3)benzodiazepine is added. The mixture is refluxed under a nitrogen atmosphere for 20 hours. Amyl alcohol is then removed under reduced pressure at a water bath temperature of 80°C. The viscous, residual oil is dissolved in 10,000 ml of methylene chloride, washed three times with 4,000 ml of 4N sodium hydroxide and six times with 4,000 ml of water. The methylene chloride solution is then washed three times with 2,000 ml of 6N hydrochloric acid. The aqueous solution is washed twice with 2,000 ml of methylene chloride, decolorized with activated charcoal and filtered. The aqueous filtrate is adjusted with 1,500 ml of an aqueous ammonium hydroxide solution at a pH of 9-10.

The separated oil is extracted three times with 4,000 ml of ethylene chloride, the extracts are dried over 1,000 g of sodium sulfate and the solvent is removed, thereby obtaining 2-methyl-5-(4-methyl-1-piperazinyl)-11H-1,2,4 -triazole(2,3-c)(1,3)benzodiazepine according to example 1. The treatment with an equimolar amount of maleic acid in isopropanol gives 2-methyl-5-(4-methyl-1-piperazinyl)-11H-1 ,2,4-triazole(2,3-c)(1,3)benzodiazepine mono-maleate according to Example 1, melting point 206-208°C.

The starting material is produced as follows:

To a suspension of 0.91 g of sodium hydride in 27 ml of tetrahydrofuran, a solution of 8.74 g of 5-methyl-3-(o-isothiocyanatobenzyl)-1,2,4-triazole in 60 ml is added dropwise over a period of 20 minutes tetrahydrofuran. The mixture is stirred for 2 hours at room temperature. A solution of 5.4 g of methyl iodide in 75 ml of tetrahydrofuran is added dropwise to the resulting suspension at 0°C over a period of 15 minutes. The mixture is stirred at room temperature for 1 hour, then poured into water and extracted three times with methylene chloride. The organic extracts are dried over magnesium sulfate, decolorized with activated charcoal and evaporated, whereby 2-methyl-5-methylthio-11H-1,2,4-triazole(2,3-c)(1,3)benzodiazepine is obtained. 2-Methyl-5-methylthio-11H-1,2,4-triazole(2,3-c)(1,3)benzodiazepine is also obtained as follows: A suspension of 8 g of 5-methyl-3-(o-isothiocyanatobenzyl) )-1,2,4-triazole in 100 ml of toluene is boiled overnight at reflux and cooled to room temperature, whereby 2-methyl-11H-1,2,4-triazole-(2,3-c)(1,3 )benzodiazepine-5(6H)-thione. A treatment with methyl iodide as described above gives 2-methyl-5-methylthio-11H-1,2,4-triazole(2,3-c)(1,3)benzodiazepine.

Claims (2)

1. Analogous process for the preparation of psychoactive and antiallergic triazole[2,3-c][1,3]benzodiazepine compounds of formula in which R1 means hydrogen, C1-C4-alkyl, halogen or C1-C4-alkylmercapto, R2 means hydrogen or C1-C4-alkyl, and R3 means hydrogen or halogen, and acid addition salts of these compounds, characterized in that a) a compound of formula: in which X means a group cleavable together with hydrogen or an alkali metal, and the other symbols have the meanings given under formula I, is condensed with a compound of formula IV or an alkali metal derivative thereof, in which R2 has the meaning given under formula I, or b) a compound of formula in which Z represents oxygen, sulfur or =N-H, and the other symbols have the above-mentioned meanings, is cyclized with the elimination of water, sulfur, hydrogen or ammonia, and a compound in which R 2 is benzyloxycarbonyl is transferred by means of hydrolysis to a compound in which R 2 is hydrogen , and if desired in a compound in which R~ means hydrogen, by reaction with haloformic acid C^-C^-alkyl ester and reduction of the acyl derivative with complex light metal hydride, is transferred to a compound in which means C^-C^-alkyl; and/or a formed compound is transferred to a salt. 2. Method according to claim 1 for the production of 2-methyl-5-(4-methyl-1-piperazinyl)-11H-1,2,4-triazol[2,3-c][1,3]benzodiazepine and its therapeutically usable salts , characterized in that corresponding starting materials are used.