DE2525691A1 - NEW TRIAZOLE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

CIBA-GEIGYAG, CH-4002 Base!

Case 4-9461 / +

CIBA-GEIGY

GERMANY

New triazo derivatives and processes for their preparation

The present invention relates to new triazole derivatives and their acid addition salts, processes for the preparation of these new substances and pharmaceutical compositions containing such new substances.

The new triazole derivatives according to the invention correspond to the general formula I,

CH ₉ -N ²

(D

60988 1/1 095

in which

R-- hydrogen, lower alkyl, optionally esterified or etherified hydroxymethyl, formyl, optionally functionally modified carboxy or optionally mono- or disubstituted aminomethyl,

R ₂ lower alkyl and

Ro denotes hydrogen or lower alkyl, where R 1 and R 1 as lower alkyl can be connected directly or in the β or ^ position also via oxygen, sulfur or the imino or a lower alkylimino radical, and

the rings A and B, independently of one another, can be unsubstituted or substituted.

The subject of the invention also includes the addition salts of the triazole derivatives of the general formula I with inorganic and organic acids.

In the triazole derivatives of the general formula I, R, as lower alkyl, is e.g. ethyl, propyl, butyl, isobutyl, Pentyl, isopentyl, neopentyl (2,2-dimethylpropyl), hexyl or Isohexyl and especially methyl, as esterified hydroxymethyl e.g. lower alkanoyloxymethyl, such as formyloxymethyl, propionyloxymethyl, Butyryloxymethyl, pivaloyloxymethyl and especially acetoxymethyl, and as etherified hydroxymethyl e.g. lower alkoxymethyl, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, Sec. Butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy

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or isohexyloxy-methyl. As a functionally modified carboxy, R- is, for example, esterified carboxy, in particular lower alkoxycarbonyl, such as propoxycarbonyl, butoxycarbonyl, isobutyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl and especially methoxycarbonyl or ethoxycarbonyl; further cyano and optionally mono- or disubstituted carbamoyl. Substituents of carbamoyl groups R, as well as of aminomethyl groups R, are on the one hand mainly monovalent hydrocarbon radicals with a maximum of 10 carbon atoms, such as lower alkyl, e.g. propyl, isopropyl, butyl, isobutyl, sec.butyl, pentyl, isopentyl, neopentyl, hexyl or heptyl, and in particular Methyl or ethyl, or araliphatic hydrocarbon radicals with 7 to 10 carbon atoms, e.g. benzyl, phenethyl, α-, ο-, m- or p-methylbenzyl, 3-phenylpropyl, 2-phenylpropyl, a-methylphenethyl, 4-phenylbutyl or p-isopropylbenzyl ; and, on the other hand, two lower alkyl radicals connected to one another directly or in β- or 7-position via oxygen, sulfur, the imino radical or a lower alkylimino radical, _{analogously to the definition for R 2 and R-, which together with the adjacent nitrogen atoms, for example, the 1-aziridinyl, 1} -Azetidinyl, 1-pyrrolidinyl, piperidino, hexahydro-1H-azepin-1-yl, morpholino, thiomorpholino, 1-piperazinyl or hexahydro-1H-1,4-diazepln-1-yl group , with the last two groups in the 4-position,

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i.e. in the imino group e.g. by methyl, ethyl, propyl, isopropyl, Butyl or isobutyl, and all of the aforementioned cyclic groups on carbon atoms by ethyl, propyl or in particular methyl can be substituted.

_{The lower alkyl R 1} and the radical R 3 in the meaning of lower alkyl are, for example, propyl, isopropyl, butyl, isobutyl, sec.butyl, pentyl, isopentyl, neopentyl, hexyl or heptyl, and especially methyl or ethyl. Linked to one another in the manner defined above, R ₂ and R "together with the adjacent nitrogen atom form, for example, the cyclic groups mentioned above in connection with the meaning of R, especially 1-pyrrolidinyl, piperidino or morpholino.

As far as lower groups are mentioned above and below, these include those with a maximum of 7 carbon atoms and preferably understood at most 4 carbon atoms.

The rings A and B can each be polysubstituted per se, but ring A is preferably monosubstituted and Ring B is preferably unsubstituted or disubstituted and, above all, monosubstituted. The substituents are for example halogen up to atomic number 35, trifluoromethyl, Nitro, lower alkyl or lower alkoxy. A substituent of the ring A is preferably in the 4-position to the triazole ring, and the substituent or substituents on ring B in the two ortho positions to the carbonyl group. Halogen atoms as Substituents of rings A and B are fluorine, chlorine or bromine atoms, while lower alkyl, for example, methyl, ethyl, Propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl,

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Neopentyl, tert.pentyl, hexyl or heptyl and as e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, Pentyloxy, isopentyloxy, hexyloxy or heptyloxy come into consideration. One preferably located in the 4-position to the triazole ring The substituent of ring A is in particular one of the halogen atoms mentioned, especially chlorine, in the following nitro or Trifluoromethyl. The ring B is preferably unsubstituted or by fluorine, chlorine, bromine or trifluoromethyl in any position, but especially by fluorine or substituted by chlorine in the o-position.

The triazole derivatives of the general formula I and their addition salts with inorganic and organic Acids have valuable pharmacological properties. In particular, they are anticonvulsant, such as an of the mouse in the pentetrazole convulsive test after administration of oral doses from approx. 0.3 mg / kg, as well as in the strychnine seizure test and in the electric shock test after administration of oral doses from approx. 1 mg / kg each, for example 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- (morpholinomethyl) -IH-I, 2,4 -triazole-3-carboxamide or N, N-dimethyl-1- [2- (o-fluorobenzoyl) -4-chlorophenyl] -5- [(dimethylamino) -methyl] -lH-l ^^ - triaz is detectable. In addition, the triazole derivatives of the general formula I and their acid addition salts have also moderate central damping effectiveness. The mentioned

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and other effective qualities, which are selected by

Standard tests [cf. W. Theobald and H.A. Kunz, Pharmaceutical Research. 13_, 122 (1963) and W. Theobald et al., Arzneimittelforsch. Γ7_, 561 (1967)] can be recorded, characterize the triazole derivatives of general formula I and their pharmaceutically acceptable addition salts with inorganic and organic acids as active ingredients for anticonvulsants and psychosedativa (tranquilizers), which can be used, for example, for the treatment of epilepsy as well as states of tension and excitement. Various are also suitable Triazole derivatives of the general formula I also as intermediates for the preparation of others among these general formula covered by compounds.

The invention relates in particular to those triazole derivatives of the general formula I in which R-, R ₂ and R _{3 have} the meaning given under this formula, ring A in the 4-position to the triazole ring by halogen up to atom number 35, in particular chlorine, or by nitro or trifluoromethyl substituted, and ring B is unsubstituted or substituted in any position by halogen up to atomic number 35 or trifluoromethyl, but preferably by fluorine or chlorine in the ortho position. In the context of the general formula I - as triazole derivatives of the general formula Ia- as well as within the narrower group of compounds defined above, triazole derivatives are of particular concern with regard to their pharmacological properties

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interpretation, in which R, is a group of the partial formula I aa,

M / * ⁴ (I aa)

CN ^ ^;

in which

X denotes oxygen or two hydrogen atoms and R, and R ₁ -, as stated above with regard to the substitution of aminomethyl and carbamoyl groups R-, independently denote hydrogen or hydrocarbon radicals with at most 10 carbon atoms each, which, if lower alkyl is concerned , also among themselves directly or in ß- or 9 ^ -position via oxygen, sulfur, the imino or a lower alkylimino radical can be connected. If R _{1 and R 5 are} not hydrogen, they correspond in particular to the definition given under the formula I for R 1 ^and R 4, but preferably, independently of one another, are hydrogen or lower alkyl with at most 3 carbon atoms, such as methyl, ethyl or isopropyl, or together with the adjacent nitrogen atom morpholino, or alkylenimino with 5 to 6 ring members, such as 1-pyrrolidinyi or piperidino. In this connecting group, R2 and Ro have the meaning given under the formula I, but are preferably methyl or ethyl, or together with the adjacent nitrogen atom, morpholino or alkylenimino with 5 to 6 ring members, such as 1-pyrrolidinyl or piperidino,

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while the rings A and B are independently unsubstituted or substituted and in the latter Preferably the above-mentioned groups of substituents and especially the specifically mentioned substituents wear.

Triazole derivatives of the general formula I in which R ₁ denotes hydroxymethyl, formyl, carboxy or lower alkoxycarbonyl, while R ₂ and R ^ have the meanings given under the formula I or, preferably, the narrower meanings given above, and the rings A and B, as under the formula I indicated, but can preferably be substituted in the manner specified above, are particularly important as intermediates for the preparation of other compounds falling under the general formula I and of other pharmacologically valuable compounds. In this connection, compounds of the general formula I with a carboxy group or lower alkoxycarbonyl group R- are of particular importance as intermediates because of their ease of preparation.

The above statements also relate to the addition salts of the above., Among the general Formula I covered by triazole derivatives with inorganic and organic acids, especially the pharmaceutical ones acceptable acid addition salts.

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The new triazole derivatives of the general formula I and their acid addition salts are prepared according to the invention here by

a) a reactive ester of a compound of the general formula II,

CH ₂ -OH

(H)

in which R-. has the meaning given under formula I. and the rings A and Bj are substituted as indicated there can be, with a compound of the general formula III,

H-N

N ₁

(III)

in which R ^ and R _{3 have} the meaning given under the formula I, or reacts with an alkali metal derivative of such a compound with Ro other than hydrogen, or

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252b691

b) for the preparation of compounds of the general
Formula I, in which R ~ and R ~ are methyl, while R,
has the meaning given under formula I, a
Compound of the general formula IV,

(IV)

in which R, the meaning given under the formula I.
and the rings A and B, as indicated there, can be substituted, reacts with formaldehyde and formic acid, or

c) for the preparation of compounds of general formula I in which R has the meaning given under formula I with the exception of hydroxymethyl, while R ₂ and R ₃
have the meaning given under the formula I, a compound of the general formula V,

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252b691

CH ₂ -N

^R 3

(V)

in which

R-, R ₂ and R «have the meaning given under the formula I and the rings A and B, as indicated there, can be substituted, oxidized, or

fc.

d) for the preparation of compounds of the general formula I in which R is carboxy or lower alkoxycarbonyl, while R "and R" are those given under the formula I. Have meaning on a compound of the general formula VI,

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CO-O-R,

C-CO-O-R

(VI)

in which

R ₆ denotes lower alkyl

R _? and R "have the meaning given under the formula I and the rings A and B, as stated there, can be substituted, allows a basic medium to act,

and, if desired, a compound I obtained by a process given under a) to d) Addition salt converted with an inorganic or organic acid.

In triazole derivatives falling under the general formula I. substituents can be introduced or eliminated in the customary manner within the scope of the definition for these compounds or modify, i.e. triazole derivatives of the general formula I in the usual way in other definition

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according to the end products of the general formula I. This is how you get to compounds of the general formula I, by

e) for the preparation of compounds of the general formula I in which R, optionally denotes mono- or disubstituted carbamoyl, while R ₂ and R, which have the meaning given under the formula I, are a carboxylic acid of the general formula I falling under the general formula I e,

CO-OH

(I e)

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in which R ~ and R "are those given under the formula I. Have meaning and the rings A and B, as indicated there, can be substituted, or a reactive functional Derivative of such with a compound of the general formula VII,

H-N (VII)

in which

R, and R ₁ . independently of one another hydrogen or hydrocarbon radicals with a maximum of 10 carbon atoms each, which, if it is lower alkyl, are also linked directly or in β- or 7-position via oxygen, sulfur, the imino or a lower alkylimino radical

can mean

or with a reactive functional derivative of such a compound, or

f) for the preparation of compounds of the general formula in which R is aminomethyl or mono- or disubstituted aminomethyl, while R ₂ and R- have the meaning given under the general formula I, a reactive

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Ester of a compound of the general formula If falling under the general formula I,

CH ₂ -OH

CH ₂ -N,

(i f)

• R.

in which R ^ and R »have the meaning given under the formula I. and the rings A and B, as indicated there, may be substituted with a compound of the above given general formula VII, in which R, and R, - the have the meaning given under this formula, or reacts with an alkali metal derivative of such a compound, or

g) for the preparation of a triazole derivative of the general formula I, in which R 1 denotes hydroxymethyl, while R ₂ and Ro have the meaning given under the formula I, a compound of the general formula VIII,

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(viii)

in which

Ac means the acyl radical of an organic acid, R «and R, which have the meanings given under the formula I. and rings A and B, as indicated therein, may be substituted, solvolyzed, or

h) for the preparation of a triazole derivative of the general Formula I, in which R. is formyl, while R "and R" are the have the meaning given under the formula I, a compound of the general formula Ih,

CH ₂ -OH

(I h)

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in which R 'and R ₃ have the meaning given under formula I, and the rings A and B, as indicated there, may be substituted, oxidized, or

i) for the preparation of a triazole derivative of the general formula I, in which R ₁ denotes cyano, while R ₂ and R _{3 have} the meaning given under the formula I, a compound of the general formula I i,

(I i)

in what R _? and R _{3 have} the meaning given under the formula I and the rings A and B, as stated there, can be substituted, dehydrated, or

j) for the preparation of triazole rings of the general formula I, in which R, optionally denotes mono- or disubstituted carbamoyl, while R2 and R _{3 have} the meaning given under the formula I, a compound of the general under the general formula I

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(I j)

in which R ^ and R ~ have the meaning given under the formula I and the rings A and B, as indicated there, can be substituted with a compound of the general formula VII given above, in which R, and R ₁ - die under the formula VH have the meaning given, is reacted in the presence of an alkali metal cyanide and a selective oxidizing agent, and if desired, a triazole derivative of the general formula I obtained by one or more successive processes according to e) to j) is converted into an addition salt with an inorganic or organic base.

Suitable reactive esters of hydroxy compounds of the general formula II are suitable for process a) for example hydrohalic acid esters such as chlorides and Bromides, as well as the iodides produced from them in situ, if appropriate only immediately before the further reaction.

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Furthermore, their sulfonic acid esters also occur as reactive esters of compounds of the general formula II all lower alkanesulfonic acid esters, such as the methanesulfonic acid esters, and arenesulfonic acid esters, such as the o- and p-toluenesulfenic acid esters, the o- or ρ-nitrobenzenesulfonic acid esters or the o- or ρ-chlorobenzenesulfonic acid esters into consideration. The reactions with compounds of the general formula III are preferably carried out in the presence of an acid-binding agent carried out. As such, there can be an excess of the connection of the general formula III, or e.g. also a tertiary organic base, such as ethylrdiisopropylamine or collidine, or an inorganic basic such as potassium carbonate can be used. As a reaction medium, e.g. inert, optionally aqueous solvent, e.g. a lower alkanol such as methanol, ethanol, propanol, Isopropanol or butanol, a ketone such as acetone or methyl ethyl ketone, further e.g. dioxane, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide, or an excess of the compound of the general formula III, as such or as an aqueous or organic solution.

If the reaction component used instead of the compound of the general formula III is an alkali metal

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A derivative of such, for example a sodium, lithium or potassium derivative, is preferably used as the solvent Hydrocarbons such as benzene, toluene or xylene, ethereal liquids such as 1,2-dimethoxyethane, tetrahydrofuran or dioxane, acid amides, such as dimethylformamide or N, N, N ', N', N ", N" -hexamethyl-phosphoric acid triamide, or sulfoxides, such as Dimethyl sulfoxide. The formation of the alkali metal derivatives of compounds of the general formula III in which R ~ is different from hydrogen are preferably carried out in situ, e.g. by adding at least an equimolar amount of alkali metal hydride, such as sodium hydride, alkali metal amide, such as sodium or lithium amide, or an organic alkali metal Compound such as phenyl or butyllithium. The reaction temperatures are preferably between 0 and 120 C or the boiling point of the reaction medium used.

Some chlorides of compounds of general ■ Formula II are as intermediates in the German Offenlegungsschriften 2,159,527, 2,215,943 and 2,304,307. The manufacture of other reactive esters of compounds the general formula II can be carried out analogously.

When the diazepine ring is cleaved according to process b) by means of formaldehyde and formic acid, no

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only the amino group previously belonging to the diazepine ring is dimethylated, but any aminomethyl or monosubstituted aminomethyl R, which may be present, is also dimethylated or monomethylated. The cleavage according to the process is carried out at an elevated temperature, preferably at about 80 ° C. to the boiling point of the reaction mixture. Although not absolutely necessary according to the overall balance of the reaction, a considerable water content of the reaction mixture is advantageous, therefore both aqueous, for example 30 to 36% formaldehyde solution and hydrous, for example 85 to 95% formic acid, can be used. The formaldehyde is preferably used in a considerable excess, for example two to five times the theoretical amount per mole of starting material of the general formula IV 2 to 4 mol, and the formic acid in an even larger excess, for example two to five times the molar amount based on the Formaldehyde. Of the starting materials of the general formula IV are those with hydrogen, carboxy or lower alkoxycarbonyl R-. in German Offenlegungsschriften 2 159 527 and 2 215 943, those with lower alkyl or hydrogen as R, in German Offenlegungsschriften 2 055 889 and 2 159 527, those with optionally mono- or disubstituted

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tuted aminomethyl or with hydroxymethyl R-, in the German Offenlegungsschrift 2 234 652, and those with possibly mono- or disubstituted carbamoyl or with formyl R, in German Offenlegungsschrift 2 304 307 described. Further compounds of the general formula IV can be prepared analogously to those in the laid-open specifications mentioned above produce described.

The oxidation according to process c) takes place

added for example by means of a higher metal oxide such as chromium trioxide, for example in acetic acid or, dissolved in dilute sulfuric acid as an oxidizing solution according to Jones gradually to the solution of the starting material in acetone, at temperatures between about 0 ° and 60 ⁰ C, preferably at 20-3O ⁰ C , or furthermore with manganese dioxide,-especially in the by J. Attenburrow et al., J. Chem. Soc. 1952 , 1104 described activated form, in an inert organic solvent such as benzene or dioxane, at temperatures between room temperature and the boiling point of the reaction medium.

Starting materials of the general formula V are obtained, for example, by reducing reactive esters .of compounds of the general formula II, in particular of chlorides, with an alkali metal borohydride, such as sodium boron

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hydride, in a lower alkanol, such as methanol, or another suitable organic solvent, such as tetrahydrofuran, at low temperatures, preferably between about -20 G and O ⁰ C, and reaction of the reduction products obtained with compounds of the general formula III analogously to process a ) obtain.

In addition, starting materials of the general formula V can also be used, for example, by reducing compounds of the general formula I obtained using a suitable reduction process or catalytic hydrogenation, e.g. in the presence of Raney nickel or a noble metal catalyst, such as e.g. palladium on carbon or on an alkaline earth metal carbonate,

can choose, if per se reducible groups R, intact should be preserved. However, it is more expedient to use the oxidation according to c) together with the preceding reduction to those compounds of the general formula I which contain a group R, whose reduction is intended, but not or only with difficulty without simultaneous reduction of the carbonyl group located between rings A and B. is feasible. For example, one can use a compound of the general formula I in which R is disubstituted Carbamoyl is, by means of a complex hydride such as lithium aluminum hydride, in an ethereal solvent such as e.g. tetrahydrofuran, to a compound of the general

Reduce formula V, in which R, the corresponding disubstituted Is aminomethyl. You can also use

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analogously a compound of the general formula I, in which R 1 is lower alkoxycarbonyl, to a compound of the general formula V, in which R, hydroxymethyl is to reduce. If the reduction product is then oxidized directly, the hydroxymethyl group becomes R-. attacked in front of the hydroxymethylene group and initially, depending on the oxidizing agent used, a Formyl group or carboxyl group R-,, immediately afterwards the hydroxymethylene group is oxidized to the carbonyl group in the same operation. Because connections of the general formula I with a carboxy group R-. to others Are more easily obtainable, is primarily the oxidation of a hydroxymethyl group R, analogous to process h), e.g. by means of the above-mentioned oxidation solution according to Jones, in the same process as the oxidation of the hydroxymethylene group according to procedure c) of practical importance. On the other hand, one can also initially use an abovementioned reduction product selectively acylate the hydroxymethyl group R ^, e.g. acetylate, then carry out the oxidation according to c) and, if desired then release the hydroxymethyl group again according to method g).

The cyclization of compounds of the general formula VI according to d) takes place, for example, in a dilute aqueous or aqueous-organic alkali hydroxide solution, in particular sodium hydroxide or potassium hydroxide solution,

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as a basic medium at room temperature or moderately increased Temperatures up to the boiling point of the reaction medium. The organic solvent used is e.g. dioxane or a lower alkanol such as ethanol. If one chooses mild reaction conditions, e.g. those based on the compound of General formula VI allows a maximum of twice the molar amount of alkali metal hydroxide to act at room temperature and neutralizes the reaction mixture before working up, is obtained as

Main product a triazole derivative of the general formula I, in which R, the lower alkoxycarbonyl corresponding to the group R, - is, while under less mild conditions the corresponding carboxylic acid, i.e. the compound of the general Formula I with carboxy as R, is obtained. The cyclization can also be carried out using an aqueous-organic ammonia solution as a basic medium, e.g. in a mixture of conc. aqueous ammonia and dimethylformamide will.

Starting materials of the general formula VI are obtained, for example, by converting the e.g. in German Laid-open documents 2,159,527, 2,215,943 and 2,304,307 analogous compounds described as intermediates which contain a halogen atom, in particular a chlorine atom, instead

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the disubstituted amino group, with a compound of the general formula III given above, in which R ₂ and R ^ have the meaning defined there, or with an alkali metal derivative thereof, analogously to process a) for the preparation of the triazole derivatives of the general formula I. Here if necessary, avoid the simultaneous occurrence in reactions with primary or secondary amines of the general formula III with lower radicals R ₁ and R 3 by choosing mild reaction conditions and / or only a small excess of such amines or by using secondary amines in the form of their alkali metal derivatives aminolysis of the carboxylic acid ester groups.

To carry out the process e), for example, a carboxylic acid of the general formula I e with a Compound of the general formula VII in the presence of a carbodiimide, such as dicyclohexyl-carbodiimide, in one inert solvents such as tetrahydrofuran, reacted.

You can also use a carboxylic acid of the general formula I e with a lower alkyl isocyanate or isothiocyanate - as reactive functional derivative of a compound of general formula VII - let react and heat the immediate reaction product until the development of Carbon dioxide or carbon oxysulphide stops.

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Suitable reactive functional derivatives of carboxylic acids of the general formula I e are for example their lower alkyl esters, some of which are already associated with compounds of the general formula VII Room temperature or, if necessary, with warming and, if necessary, in a closed vessel, depending on the reactivity or the boiling point of the compound of the general formula VII used can be reacted. As a reaction medium can here, for example, a lower alkanol, such as methanol or Ethanol, or another inert organic solvent, such as tetrahydrofuran or dioxane, if necessary serve together with an excess of the compound of the general formula VII to be converted.

Further suitable reactive functional derivatives of carboxylic acids of the general formula I e are their halides, especially the chlorides, especially in the form of their hydrohalides, such as the hydrochlorides. These

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are preferably prepared immediately before the further reaction with the compounds of the general formula VII from the corresponding free carboxylic acids and suitable acid halides, such as thionyl chloride, oxalyl chloride or phosphorus tribromide, and reacted further without purification. The carboxylic acid halides or their hydrohalides are preferably used with compounds of the general formula VII in the presence of at least equivalent or at least twice the equivalent amount of an acid-binding agent, for example a strong tertiary organic base such as triethylamine, N-ethyl-diisopropylamine, pyridine or s-collidine, which in excess can also serve as a reaction medium, or a corresponding excess the compound to be reacted of general formula VII in the presence or absence of an inert organic solvent such as dioxane, tetrahydrofuran, benzene or dimethylformamide, at temperature doors between about 0 ⁰ C and 100 ⁰ C or boiling point of the Reakti onsmediums, if this is lower, implemented. _{Mixed anhydrides of carboxylic acids of the general formula I e},} in particular those obtainable, for example, by reacting alkali metal salts of such carboxylic acids with chloroformic acid esters, preferably chloroformic acid lower alkyl esters, can also be obtained under analogous reaction conditions

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mixed anhydrides with carbonic acid half-esters, with compounds of the general formula VII.

As another reactive functional

Derivatives of carboxylic acids of the general formula Ie come, for example, reactive esters such as p-nitrophenyl ester and Cyanine thy Ie st he, considering those with connections of general Formula VII can be reacted in inert organic solvents, if necessary with heating. Among the same Conditions are set for the 1-imidazolides of the carboxylic acids of the general formula Ie with compounds of the general Formula VII around.

As reactive functional derivatives of compounds of the general formula VII, the Called lower alkyl isocyanates and isothiocyanates, which differ from compounds of the general formula VII with a hydrogen derive atom as Rr. The reactions of the same with carboxylic acids of the general formula I e can be carried out in an or Absence of an inert organic solvent with a sufficiently high boiling point or range, e.g. in toluene or in Xylene or a xylene mixture. As further reactive functional derivatives of compounds of the General formula VII with a hydrogen atom as Rr are also, for example, those obtained by reacting these compounds with Tri- (lower alkyl) silyl chlorides, such as trimethylsilyl chloride, available in inert anhydrous organic solvents

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Mention should be made of N-tri- (lower alkyl) silyl derivatives. Their implementation with reactive functional derivatives of the carboxylic acids of the general formula Ie in inert organic solvents leads to N-tri- (lower alkyl) silyl derivatives of carboxamides falling under the general formula I, from which Decomposition with water or lower alkanols releases the desired carboxamides.

As functional derivatives of those compounds of the general formula VII in which neither R nor R are hydrogen means, their N-chlorocarbonyl derivatives come, for example Consideration. These are salted with salts, e.g. alkali metal! of carboxylic acids of the general formula I e in the presence or absence of inert organic solvents, such as e.g. Toluene or dimethylformamide, reacted and the reaction mixtures heated until the equimolar amount of carbon dioxide is off the primarily formed carboxylic acid-carbamic acid anhydrides is released. "Also of compounds of the general formula VII with .von hydrogen radicals R, and R ^ For example, sulfurous acid monoalkyl ester monoamides can be derived, which in the reaction with carboxylic acids of the general Formula Ie in organic solvents, e.g. in pyridine, dioxane or dimethylformamide or in benzene, the

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desired, falling under the general formula I. Deliver Garboxamide.

Suitable reactive esters of compounds of the general formula I f are, for example, their Sulfonic acid esters, especially lower alkanesulfonic acid esters, such as the methanesulfonic acid esters, and arenesulfenic acid esters, such as the o- and p-toluenesulfonic acid esters, the o- or p-nitrobenzenesulfonic acid esters or the o- or ρ-chlorobenzenesulfonic acid esters. Next come as reactive esters of compounds of the general formula I f also their hydrohalic acid esters, in particular chlorides and Bromides as well as the iodides prepared in situ from such, into consideration. The implementations with compounds of the general Formula VII or their alkali metal derivatives can be carried out entirely analogously to process a).

The compounds of the general formula I f can be prepared by various processes according to the invention, for example by process b), if R ₂ and R _{3 are to be} methyl, and especially by process g), and by methods known per se into reactive esters convict. Another production option for the organic compounds also comprised by the general formula VIII of the starting materials for process g)

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Sulphonic acid ester is given below.

In the starting materials of the general formula VIII for process g), the acyl radical Ac is preferably the Acyl radical of a carboxylic acid, a carbonic acid half ester or an organic sulfonic acid. As an acyl residue of a carboxylic acid Ac is e.g. lower alkanoyl, such as formyl, propionyl, butyryl, Isobutyryl, valeryl or pivaloyl and especially acetyl, further for example halogenated lower alkanoyl, such as trifluoroacetyl or trichloroacetyl, or arene carbonyl, such as benzoyl, p-chlorobenzoyl or p-nitrobenzoyl. As the acyl radical of a carbonic acid half-ester, Ac is e.g. methoxycarbonyl, ethoxycarbonyl, Propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, Phenoxycarbonyl or benzyloxycarbonyl, and as an acyl radical an organic sulphonic acid e.g. lower alkylsulphonyl, such as methylsulfonyl, or arylsulfonyl, such as phenylsulfonyl, o- or p-tolylsulfonyl, o- or ρ-nitrophenylsulfonyl or o- or ρ-chlorophenylsulfonyl. The solvolysis of the compounds of the general formula VIII according to g) can by methods known per se in a basic or acidic medium, for example in lower alkanolic or lower alkanolic aqueous solutions Alkali hydroxide solutions at room temperature to the boiling point of the reaction mixture, or with aqueous or aqueous

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organic mineral acids, e.g. in dilute hydrochloric acid, the optionally a water-miscible organic solvent, such as dioxane, tetrahydrofuran, methanol or Ethanol, is added, take place at the same temperatures.

The starting materials of the general formula VIII are obtained, for example, starting from compounds of the general formula Formula I, in which R 1 is lower alkoxycarbonyl, by simultaneous reduction of this group to the hydroxymethyl group and the carbonyl group between the rings A and B to the hydroxymethylene group by means of a complex Hydrides such as lithium aluminum hydride in an ethereal solvent such as tetrahydrofuran at temperatures by about 0 C to room temperature, followed by partial acylation of the hydroxymethyl group according to known methods Methods and finally oxidation of the hydroxymethylene group to the carbonyl group analogous to the aforementioned process c) for Preparation of the compounds of the general formula I.

For the oxidation of triazole derivatives of the general formula I h to give triazole derivatives of the general Formula I with formyl as R, used according to method h) mild, selective oxidizing agents, such as dimethyl sulfoxide, optionally in the presence of a water-binding agent such as dicyclohexylcarbodiimide and

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Phosphoric acid, at room temperature or moderately elevated temperatures up to about 100 ° C., or manganese dioxide, which is preferably produced according to J. Attenburrow et al., J. Chem. Soc. 1952 , 1104 is activated, in an inert organic solvent at temperatures between about 50 C and the boiling point of the solvent, for example in boiling benzene. In addition, chromium trioxide, for example dissolved in dilute sulfuric acid, can also be used as the oxidizing agent as the Jones oxidizing solution, this oxidizing solution being added gradually to the solution of the starting material in acetone, preferably at 0 ° C. to room temperature. The starting materials of the general formula Ie are prepared, for example, by the aforementioned process g) or, if R2 and R ~ are methyl, also by process b).

The dehydration of the triazole derivatives of the general Formula I i according to process i) can be prepared by methods known per se at room temperature or elevated temperatures can be carried out up to approx. 180 ° C. For example, a carboxamide of the general formula I i is allowed to be an organic one or inorganic acid halide, in particular a sulfonic acid halide, such as ρ-toluenesulfonyl chloride or methanesulfonyl chloride, or a halide of an acid of the trivalent or pentavalent type Phosphorus such as phosphorus oxychloride or a

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S-acidic anhydride, especially the anhydride of an inorganic one Oxygen acid, such as phosphorus pentoxide, in an inert organic Solvent such as dimethylformamide or xylene act. The sulfonic acid halides, such as p-toluenesulfonyl chloride, is preferably used in an equimolar amount or in a moderate excess, optionally together with one

somewhat larger excess of an acid-binding agent, in particular a tertiary organic base such as pyridine. For example, dehydration can take place at room temperature or, if necessary, slightly elevated temperatures by means of approx. 1.5 times the molar amount of ρ-toluenesulfonyl chloride and approx. 2-bis 3 times the molar amount of pyridine can be carried out in dimethylformamide. As another example of a dehydrating agent triphenylphosphine is mentioned, for example in a halogenated hydrocarbon such as carbon tetrachloride, can be reacted with a carboxamide of the general formula I i. The starting materials of the general Formula I i can be prepared by some of the aforementioned processes, in particular by process e).

For process j), the alkali metal cyanide used is, for example, potassium cyanide and especially sodium cyanide. Under selective oxidizing agents are to be understood as those which under the reaction conditions the aldehyde group of the starting material of formula I j do not attack, however, the hydroxy

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able to oxidize the methylene group of the intermediate cyanohydrin to the carbonyl group. A suitable oxidizing agent is manganese dioxide, especially in the method described by J. Attenburrow et al., J. Chem. Soc. 1952, 1104, described active form. The reactions with manganese dioxide are preferably carried out in isopropanol or in another, lower secondary alkanol to which a further organic solvent which is inert under the reaction conditions, preferably one with good dissolving power for the starting materials of the general formula Ij, such as dioxane, can be added, in the cold, for example between -10 C and +10 C, preferably around 0 C, carried out. Based on the compound of the general formula I j, for example, a considerable excess of the compound of the general formula VII, as well as of alkali metal cyanide, is used, e.g. about 5 times the molar amount of the latter and an even larger excess, e.g. about 20 times the molar amount of manganese dioxide, with a reaction time of 2 to 6, preferably about 4 hours. The triazole derivatives of the general formula I j used as starting materials are prepared, for example, by the aforementioned process h) or further by the process c) using compounds of the general formula V in which R 1 is a hydroxymethyl group.

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The present invention also relates to such modifications of the processes mentioned under a) to j) and their preliminary stages, in which a process is discontinued at any stage or in which one of one starts at some stage as an intermediate compound and carries out the missing steps or a starting material under the reaction conditions or optionally used in the form of a salt, If the required starting materials are optically active, both the racemates and the isolated antipodes, or in the presence of diastereomerism either mixtures of racemates or certain racemates or likewise isolated antipodes are used. Such starting materials can optionally also be in the form of salts be used. Such reactions are preferably used for carrying out the reactions according to the invention Starting materials which lead to the groups of end materials particularly mentioned at the beginning.

Depending on the process conditions and starting materials, the starting materials are obtained in free form or in the form of their acid addition salts likewise included in the invention, or optionally also than hydrates of the latter. The acid addition salts of the new compounds of general formula I can be used in

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be converted into the free bases in a manner known per se, e.g. with basic agents, such as alkalis or ion exchangers, on the other hand, those obtained by the process according to the invention can be used Compounds of general formula I if desired in the usual way in their addition salts with inorganic or organic acids are converted. For example a solution of a compound of the general formula I in an organic solvent is mixed with the salt component desired acid. Organic solvents are preferably chosen for the reaction in which the The resulting salt is sparingly soluble, so that it can be separated off by filtration. Such solvents tel are e.g. ethyl acetate, methanol, ether, acetone, methyl ethyl ketone, Acetone-ether, acetone-ethanol, methanol-ether, or ethanol-ether.

For use as drugs, pharmaceutically acceptable acid addition salts can be substituted for free bases are used, i.e. salts with acids whose anions cannot be used at the dosages in question are toxic. It is also advantageous if the salts to be used as medicinal substances can be readily crystallized and are not or only slightly hygroscopic. For salt formation

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with compounds of the general formula I, for example, the Hydrochloric acid, hydrobromic acid, sulfuric acid, Phosphoric acid, methar sulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, acetic acid, lactic acid, Succinic acid, fumaric acid, maleic acid, malic acid, v? Anic acid, citric acid, benzoic acid, salicylic acid, Phenylacetic acid, mandelic acid and emboxylic acid can be used.

Depending on the choice of starting materials and working methods, the new compounds can act as optical antipodes or racemates or, if they contain at least two asymmetric carbon atoms, also as mixtures of isomers (Mixtures of racemates) are present. Isomer mixtures (racemic mixtures) obtained can be due to the physico-chemical Differences between the components in a known manner in the two stereoisomeric (diastereomeric) pure racemates be separated, for example by chromatography and / or fractional crystallization.

Obtained racemates can be by known methods, for example by Uracrystallization from a optically active solvent, with the help of microorganisms or by reacting with one, with the racematic Compound Salt-forming optically active acid

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and separation of the salts thus obtained, for example on the basis of their different solubilities, into the Diastereomers that make up the antipodes by acting suitable means can be released, decompose. Optically active acids which are particularly common are e.g. the D- and L-forms of tartaric acid, di-o-toluyltartaric acid, Malic acid, mandelic acid, camphorsulfonic acid or quinic acid. It is advantageous to isolate the more effective of the two antipodes.

The new active ingredients are administered orally, rectally or parenterally. The dosage depends on the Application x '/ise, the species, the age and the individual condition. The daily doses of the free bases or pharmaceutically acceptable salts thereof range between 0.1 mg / kg and 3 mg / kg for warm-blooded animals. Suitable unit dosage forms, such as dragees, tablets, Suppositories or ampoules preferably contain 0.5-50 mg of an active ingredient according to the invention.

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Unit dosage forms for oral use contain preferably between 0.5-50% of an active ingredient Compound of the general formula I or a pharmaceutical acceptable salt of such. To produce them, the active ingredient is combined, for example, with solid, powdery ones Carriers such as lactose, sucrose, sorbitol, mannitol; Starches, such as potato starch, corn starch or amylopectin, furthermore laminaria powder or citrus pulp powder, cellulose derivatives or gelatin, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols, tablets or coated tablets. the Dragee cores are coated, for example, with concentrated sugar solutions, which e.g. still contain Arabic gum, talc and / or titanium dioxide, or with a varnish that is in volatile organic solvents or solvents mixed s is solved. Dyes can be added to these coatings can be added, e.g. to identify different doses of active ingredients.

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Other suitable oral unit forms are Süeckkapseln made of gelatine as well as v / oak, closed capsules made of gelatin and a plasticizer such as glycerin. The Steok capsules contain the active ingredient preferably as granules, e.g. mixed with fillers such as corn starch, and / or Lubricants, such as talc or magnesium stearate, and optionally stabilizers, such as sodium metabisulphite (Na ^ SpO, -) or Ascorbic acid. In soft capsules, the active ingredient is preferably in suitable liquids, such as liquid P ο Iy "a thy 1 en glycols, dissolved or suspended, it also being possible for stabilizers to be added.

As unit dose forms for rectal use, suppositories, for example, come into consideration, which consist of a combination an active ingredient with a suppository base. Natural ones, for example, are suitable as a suppository base or synthetic trig ^ 'ceride, paraffinic hydrocarbons, PolyMethylene glycols or higher alkanols. Gelatin rectal capsules made from a combination are also suitable of the active ingredient with a base material. Liquid triglycerides, polyethylene glycols, for example, are suitable as a base or paraffinic hydrocarbons.

Ampoules for parenteral, especially intramuscular Administration preferably contain a water-soluble salt of an active ingredient in a concentration of preferably

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0.2-5%, if necessary together with suitable stabilizers and buffer substances, in aqueous solution.

The following regulations are intended to detail the manufacture of tablets, coated tablets, suppositories and ampoules explain:

a) 50.0 g of l- [2- (o-chlorobenzoyl) -4-chlorophenyl] -

5- (morpholinomethyl) -lH-l, 2,4-triazole-3-carboxamide are mixed with 500 g of lactose and 292 g of potato starch mixed, the mixture moistened with an alcoholic solution of 8 g of gelatin and granulated through a sieve. After drying, mix 60 g of potato starch, 60 g of talc, 10 g of magnesium stearate and 20 g of highly dispersed silicon dioxide and presses the mixture into 10,000 tablets, each weighing 105.0 mg and containing 5.0 mg of active ingredient, which, if desired, can be provided with partial notches for finer adjustment of the dosage.

b) 2.50 g of N, N-dimethyl-1- [2- (o-fluorobenzoyl) -4-chlorophenyl] -5 - [(dimethylamine) methyl] -lH-l, 2,4-triazole-3- carboxamide are mixed well with 16 g of corn starch and 6 g of highly dispersed silicon dioxide. The mixture is made with a Solution of 2 g of stearic acid, 6 g of ethyl cellulose and 6 g of stearin in about 70 ml of isopropyl alcohol and moistened through a sieve III (Ph.HeIv. V) granulated. The granulate is approx. Dried for 14 hours and then beaten through sieve III-IIIa.

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Then it is made with 16 g of corn starch, 16 g of talc and 2 g of magnesium stearate mixed and pressed into 1000 dragee cores. These are made with a concentrated syrup of 2 g Lacca, 7.5 g of gum arabic, 0.15 g of colorant, 2 g of highly dispersed silicon dioxide, 25 g of talc and 53.35 g of sugar and coated dried. The coated tablets each weigh 162.5 mg and each contain 2.5 mg of active ingredient.

c) 10.0 g of l- [2- (o-chlorobenzoyl) -4-

chlorophenyl] -5- (morpholinomethyl) -IH-I, 2,4-triazole-3-carboxamide and 1990 g finely grated suppository base (e.g. cocoa butter) are mixed thoroughly and then melted. The melt, which is kept homogeneous by stirring, becomes 1000 suppositories poured from 2 g. They each contain 10 mg of active ingredient.

d) A solution of 5.0 g of 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -3,5-bis - [(dimethylamino) methyl] -1H-1,2,4-triazole dihydrochloride 1000 ampoules in one liter of water are filled and sterilized. Each ampoule contains 5 mg of active ingredient as a 0.5% solution.

The following examples explain the preparation of the new compounds of general formula I and of previously unknown starting materials, but are not intended to limit the scope of the invention in any way. The temperatures are given in degrees Celsius.

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example 1

A mixture of 8.8 g (0.018 mol) of 1- (2-benzoyl-4-chlorophenyl) -5- (iodomethyl) -IH-I, 2,4-triazole-3-carboxylic acid methyl ester and 3.5 ml (0.040 mol) of morpholine in 175 ml of methanol is stirred for 6 hours at 40 °. Then you steam the reaction mixture in a vacuum, the residue is treated with water and extracted twice with methylene chloride. the The organic phase is washed three times with water and once with saturated sodium chloride solution and dried over sodium sulfate and evaporate them in a vacuum. The residue is rubbed with ether, the reaction product being obtained in crystalline form. After filtering off with suction and drying in vacuo, methyl 1- (2-benzoyl-4-chlorophenyl) -5- (morpholinomethyl) -IH-1, 2,4-triazole-3-carboxylate is obtained from m.p. 165-170.

The raw material is produced as follows:

a) A solution of 112.2 g (0.299 mol) of 1- (2-benzoyl-4-chlorophenyl) -5- (chloromethyl) -IH-I, 2,4-triazole-3-carboxylic acid in 1120 ml of methanol is mixed with 224 ml of a 6-n. Solution of hydrogen chloride in methanol and 21 hours under Boiled under reflux. 800 ml of methanol are then distilled off at normal pressure and the concentrated solution is left

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Stand at room temperature for 18 hours. The product that has crystallized out is filtered off with suction and washed with cold methanol and hexane washed. After drying in vacuo, the 1- (2-benzoyl-4-chlorophenyl) -5- (chloromethyl) -lH-1,2,4-triazole ~ 3- methyl carboxylate of m.p. 132-134.

b) A solution of 51.6 g (0.132 mol) of 1- (2-benzoyl-4-chlorophenyl) -5- (chloromethyl) -IH-I, 2,4-triazole-3-carboxylic acid methyl ester and 29.8 g (0.198 mol) of sodium iodide in 1000 ml of acetone is refluxed for 45 minutes. The reaction mixture is then evaporated in vacuo. Water is added to the residue and extracted twice with Methylene chloride. The organic phase is washed once with dilute aqueous sodium bisulfite solution and twice with saturated sodium chloride solution, dry it over sodium sulfate and evaporate them in a vacuum. The residue is rubbed with ether, the reaction product crystallizing out. After viewing and drying in vacuo, the is obtained 1- (2-Benzoyl-4-chlorophenyl) -5- (iodomethyl) -IH-I, 2,4-triazole-3-carboxylic acid methyl ester from m.p. 139-142.

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Example 2

A mixture of 24 ", 0 g (0.050 mol) of 1- (2-benzoyl-4-chlorophenyl) -5- (iodomethyl) -IH-1, 2,4-triazole-3-carboxylic acid methyl ester [See Example 1 a) and b)] and 20.5 ml of 33% ethanolic dirnethylamine solution in 480 ml of methanol is 2 Stirred for hours at room temperature. Then you steam them Reaction solution in vacuo, the residue is treated with water and extracted twice with methylene chloride. The organic phase it is washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporates them to dryness in a vacuum. The amorphous residue is dissolved in 150 ml of ether. Crystallizes on standing the reaction product from. It is suction filtered and washed with ether. After drying, the 1- (2-benzoyl-4-chlorophenyl) -5- [ (dimethylamino) methyl] -lH-1,2,4-triazole-3-carboxylic acid methyl ester from m.p. 118-121.

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Hi

Example 3

To the solution of 6.0 g (0.0203 mol) of 6-phenyl-8-chloro-4H-s-triazolo [l, 5-a] [l, 4] benzodiazepine (see German Offenlegungsschrift No. 2 159 527) in 27 ml of 857o-iger Formic acid is added to 13.7 ml of 36% aqueous formaldehyde solution and heat the mixture to 100 for 2 hours while stirring. The reaction solution is then allowed to cool to room temperature, pour it on ice water and add conc. Sodium hydroxide solution until the pH reaches 11. The unusual one The crude product is taken up in ether. The organic phase is washed twice with water and once with saturated water Sodium chloride solution, dry it over sodium sulfate and evaporate it in vacuo. The residue is dissolved in 100 ml Ethyl acetate and add essential hydrochloric acid solution until the pH value reaches 3. . The hydrochloride precipitates in crystalline form. It is suction filtered after 2 hours and washed with ether and hexane 1- (2-Benzoyl-4-chlorophenyl) -5 - [(dimethylamino) methyl] -IH-I, 2,4-triazole hydrochloride is obtained from m.p. 182-185 ° with decomposition.

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Example 4

3.4 g (0.001 mol) of 6-phenyl-8-chloro-4H-s-triazolo [l, 5-a] [l, 4] benzodiazepine-2-carboxylic acid (see German Offenlegungsschriften No. 2,159,527 and 2,215,943) are mixed with 13.5 ml of 857% formic acid and 6.7 ml of 36% aqueous formaldehyde solution. The reaction mixture is then heated to 100 for 2 hours with stirring, the Starting product clearly goes into solution. After cooling down, conc. Sodium hydroxide solution until the pH value reaches 5, and the mixture is evaporated to dryness in vacuo. The residue is for total drying three times with a mixture of Toluene-methanol (1: 1) evaporated in vacuo at 60. The residue is digested three times with warm methylene chloride. The organic phase is evaporated in vacuo and the residue is dissolved in 300 ml of ethyl acetate. The cloudy solution becomes with Treated charcoal and filtered through Hyflo. The clear filtrate becomes Congo acidic with a solution of hydrogen chloride displaced in ether. The precipitated crystals are suction filtered and washed with ethyl acetate and ether. 1- (2-Benzoyl-4-chlorophenyl) -5 - [(dimethylamino) methyl] -IH-I, 2,4-triazole-3-carboxylic acid hydrochloride is obtained from m.p. 160-165 with decomposition.

In an analogous way one obtains

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from 3.25 g (0.001 mol) of 6-phenyl-8-chloro-4H-s-triazolo [l, 5-al [1,4] benzodiazepine-2-methanol 1- (2-benzoyl-4-chlorophenyl) -5- [(dimethylamino) methyl] -lH-l ^^ - triazole-S-methanol hydrochloride;

from 3.43 (0.001 mol) 6- (o-fluorophenyl) -8-chloro-4H-s-triazolo [1,5-a] [1,4] benzodiazepine-2-methanol the 1-f2- (o- Fluorobenzoyl) 4-chlorophenyl] -5 - [(dimethylamino) methyl] -lH-l, 2,4-triazole-3-methanol hydrochloride, and

from 3.59 g (0.001 mol) 6- (o-chlorophenyl) -8-chloro-4H-s-triazolo [1,5-a] [1,4] benzodiazepine-2-methanol the 1- [2- ( o-chlorobenzoyl) -4-chlorophenyl] -5-Ϊ (dimethylamino) -methyl] -lH-l ^^ - triazole-S-methanol-hydrochloride.

The production of the starting materials is described in German Offenlegungsschrift 2,234,652.

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Example 5

To the solution of 19.2 g (0.050 mol) of N, N-dimethyl-6- (o-fluorophenyl) -8-chloro-4H-s-triazolo [1,5-a] [1,4] benzodiazepine-2 -carboxamide (see German Offenlegungsschrift No. 2 304 307) in 68 ml of 85% formic acid is added 35 ml 367% aqueous formaldehyde solution and heat the mixture to 100 for 2 hours while stirring. The reaction solution is then cooled to room temperature, pour it onto ice water and add conc. Add sodium hydroxide solution until the pH is 11 achieved. The precipitated crude product is taken up in methylene chloride. The methylene chloride solution is washed twice with water and once with saturated sodium chloride solution, dry it over sodium sulfate and evaporate it in a vacuum. The residue is recrystallized from isopropanol and, after drying in vacuo, N, N-dimethyl-1- [2- (ofluorobenzoyl) -4-chlorophenyl] -5 - [(dimethylamino) -methyl] -IH-1,2 is obtained , 4-triazole-3-carboxamide from m.p. 140-142.

In an analogous way one obtains

from 20.6 g of N, N-diethyl-6- (o-fluorophenyl) -8-chloro-4H-s-triazolo [1,5-a] [1,4] benzodiazepine-2-carboxamide the N, N-diethyl-1- [2- (o-fluorobenzoyl) -4-chlorophenyl] -5 - [(dimethylamine) methyl] -IH-1,2,4-triazole-3-carboxamide;

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from 20.0 g of N, N-dimethyl-6- (o-chlorophenyl) -8-chloro-4H-striazolo [l, 5-a] [l, 4] benzodiazepine-2-carboxamide the N, N-dimethyl-1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- [(dime thy! Amino) methyl] -lH-l ^^ -

from 21.4 g of N, N-diethyl-6- (o-chlorophenyl) -8-chloro-4H-s-triazolo [1,5-a] [l, 4] benzodiazepine-2-carboxamide the Ν, Ν-diethyl-l- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- [(dimethylamino) methyl] -IH-1,2,4-triazole-3-carboxamide;

from 18.3 g of N, N-dimethyl-6-phenyl-8-chloro-4H-s-triazolo [l, 5-a] [l, 4] benzodiazepine-2-carboxamide the Ν, Ν-dimethyl-l- (2-benzoyl-4-chlorophenyl) -5- [ (dime thy lamino) methyl] -1H-1,2,4-triazole-3-carboxamide;

from 19.7 g of N, N-diethyl-6-phenyl-8-chloro-4H-s-triazolo [l, 5-a] [1,4] benzodiazepine-2-carboxamide the N, N-diethyl-1- (2-benzoyl-4 ~ chlorophenyl) -5- [(dimethylamino) methyl] -lH-l ^^ - triazole-S-carboxamide;

from 20.0 g of N, N-dimethyl-6-phenyl-8- (trifluoromethyl) -4H-s-tri-azolo [1,5-a] [1,4] benzodiazepine-2-carboxamide the N, N-dimethyl-1- (2-benzoyl-a, a, a -trifluoro-p-tolyl) -5 - [(dimethylamine) -methyl] -1H-1,2,4-triazole-3-carboxamide ;

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from 18.8 g of N, N-dimethyl-6-phenyl-8-nitro-4H-s-triazolo [l, 5-a] [1,4] benzodiazepine-2-carboxamide the Ν, Ν-dimethyl-l- (2-benzoyl-4-nitrophenyl) -5 - [(dimethylamino) methyl] -IH-I, 2,4-triazole-3-carboxamide;

from 19.7 g of N, N-dimethyl-6- (o-fluorophenyl) -8-nitro-4H-s-triazolo [1,5-a] [1,4] benzodiazepine-2-carboxamide the N, N-dimethyl-1- [2- (o-fluorobenzoyl) -4-nitrophenyl] -5 - [(dimethylamino) methyl] 1H-1,2,4-triazole-3-carboxamide;

from 16.9 g of 6-phenyl-8-chloro-4H-s-triazolo [l, 5-a] [l, 4] benzodiazepine-2-carboxamide 1- (2-Benzoyl-4-chlorophenyl) -5 - [(dimethylamino) methyl] -IH-I, 2,4-1

from 18.6 g of 6- (o-chlorophenyl) -8-chloro-4H-s-triazolo [l, 5-a] [1,4] benzodiazepine-2-carboxamide l- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5 - [(dimethylamino) methyl] -IH-I, 2,4-triazole-3-carboxamide;

from 17.8 g of 6- (o-fluorophenyl) -8-chloro-4H-s-triazolo [l, 5-a] [1,4] benzodiazepine-2-carboxamide the l- [2- (o-fluorobenzoyl) -4-chlorophenyl] -5- [(dimethylamino) -methyl] -lH-l ^^ -

from 18.5 g of N-methyl-6- (o-fluorophenyl) -8-chloro-4H-s-triazolo [1,5-a] [1,4] benzodiazepine-2-carboxamide N-methyl-1- [2- (ofluorobenzoyl) -4-chlorophenyl] -5 - [(dimethylamino) methyl] -IH-1, 2,4-triazole-3-carboxamide;

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from 19.3 g of N-methyl-6- (o-chlorophenyl) -8-chloro-4H-s-triazolo [1,5-a] [lj4] benzodiazepine-2-carboxamide the N-methyl-1- [2- (ochlorbenzoyl) -4-chlorophenyl] -5- [(dimethylamine)) methyl] -IH-1,2 ^ -triazole-β-carboxamide;

from 19.2 g of N-ethyl-6- (o-fluorophenyl) -8-chloro-4H-s-triazolo [1,5-a] [l, 4] benzodiazepine-2-carboxamide N-ethyl-1- [2- (o-fluorobenzoyl) 4-chlorophenyl] -5 - [(dimethylamino) methyl] -1H-1,2,4-triazole-3-carboxamide;

from 19.9 g of N-isopropyl-6- (o-fluorophenyl) -8-chloro-4H-s-triazolo [1,5-a] [1,4] benzodiazepine-2-carboxamide N-isopropyl-1- [2- (o-fluorobenzoyl) -4-chlorophenyl] -5 - [(dimethylamino) methyl] -IH- 1,2,4-triazole-3-carboxamide;

from 21.3 g of 4- [[6- (o-fluorophenyl) -8-chloro-4H-s-triazolo [1,5-a] [1,4] benzodiazepin-2-yl] carbonyl] morpholine 4 - [[1- [2- (o-fluorobenzoyl) -4-chlorophenyl] -5 - [(dimethylamino) methyl] -IH-1 , 2,4-triazol-3-yl] carbonyl] morpholine;

from 20.5 g of l - [[6- (o-fluorophenyl) -8-chloro-4H-s-triazolo [l, 5-a] [1,4] benzodiazepin-2-yl] carbonyl] pyrrolidine 1- [[1- [2- (o-Fluorobenzoyl) -4-chlorophenyl] -5 - [(dimethylamino) methyl] -IH-1,2,4-triazol-3-yl] carbonyl] pyrrolidine;

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from 21.2 g of l - [[6- (o-fluorophenyl) -8-chloro-4H-s-triazolo [l, 5-a] [l, 4] benzodiazepin-2-yl] carbonyl] piperidine 1- [[1- [2- (o-Fluorobenzoyl) -4-chlorophenyl] -5 - [(dimethylamino) methyl] -IH-1,2,4-triazol-3-yl] carbonyl] piperidine;

from 23.8 g (0.050 mol) l - [[6- (o-fluorophenyl) -8-chloro-4H-S-triazolo [1,5-a] [1,4] benzodiazepin-2-yl] carbonyl] -4-methylpiperazine hydrochloride released base the l - [[l- [2- (o-fluorobenzoyl) -4-chlorophenyl] -5 - [(dimethylamino) methyl] -IH-1,2,4-triazol-3-yl] carbonyl] -4-methylpiperazine and its dihydrochloride.

The starting materials used are described in German Offenlegungsschrift No. 2 304 307.

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Example 6

To the solution of 4.30 g (0.010 mol) of 2 - [(methylamino) methyl] -6- (o-chlorophenyl) -8-chloro-4H-s-triazolo [1,5-a] [l, 4] benzodiazepine fumarate (2: l) (see German Offenlegungsschrift 2 234 652) released base in 13.5 ml (approx. 0.25 mol) of 85% formic acid is added 8.35 ml (approx. 0.10 mol) 36% aqueous formaldehyde solution and heats the mixture

with stirring for 2 hours to 100. The reaction solution is then cooled to room temperature, pour it onto ice water and add conc. Add sodium hydroxide solution until the pH is 11 achieved. The precipitated crude product is taken up in ether. The organic phase is washed twice with water and once with saturated sodium chloride solution, dry it over sodium sulfate and evaporate it in a vacuum. The oily residue is dissolved in 100 ml of ethanol and adds ethereal hydrogen chloride solution, until the pH value reaches 2. The ethanol is then completely distilled off in vacuo and the residue is treated with ethyl acetate. The resulting crystalline product is suction filtered and washed with ethyl acetate and ether. After drying in vacuo, 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -3,5-bis [(dimethylamino) methyl is obtained 1 -IH-1,2,4-triazole dihydrochloride of m.p. 100-105 with decomposition.

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In an analogous way one obtains

from 4.30 g (0.010 mol) of 2-1 (methylamino) methyl] -6- (o-fluorophenyl) -8-chloro-bK- s-triazolo [l, 5-a] [l, 4] benzodiazepine hydrochloride dihydrate released base, the 1- [2- (o-fluorobenzoyl) -4-chlorophenyl] -3,5-bis - [(dimethylamino) methyl] -1H-1, 2,4-triazole and its dihydrochloride.

Likewise, but if desired under Reduction in the amount of 36% formaldehyde solution 5.85 ml (approx. 0.07 mol) are obtained

from 3.52 g (0.010 mol) of 2 - [(dimethylamino) methyl] -6-phenyl-8-chloro-4H-s-triazolo [1,5-a] [1,4] benzodiazepine 1- (2-Benzoyl-4-chlorophenyl) -3,5-bis - [(dimethylamino) methyl] -1H-1,2,4-triazole and its dihydrochloride;

from 3.92 g (0.010 mol) of 2- (piperidinomethyl) -6-phenyl-8-chloro-4H-s-triazolo [1,5-a] [1,4] benzodiazepine 1- (2-Benzoyl-4-chlorophenyl) -3- (piperidinomethyl) -5 - [(dimethylamino) -methyl] - 1H-l, 2,4-triazole and its dihydrochloride;

from 3.78 g (0.010 mol) of 2 - [(1-pyrrolidinyl) methyl] -6-phenyl-8-chloro-4H-s-triazolo [1,5-a] [1,4] benzodiazepine 1- (2-Benzoyl-4-chlorophenyl) -3 - [(1-pyrrolidinyl) methyl] -5 - [(dimethylamino) methyl] -IH-1, 2,4-triazole and its dihydrochloride;

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from 3.94 g (0.010 mol) of 2- (morpholinomethyl) -6-phenyl-8-chloro-4H-s-triazolo [1,5-a] [1,4-benzodiazepine 1- (2-Benzoyl-4-chlorophenyl) -3- (morpholinomethyl) -5 - [(dimethylamino) methyl] ■ 1H-l, 2,4-triazole and its dihydrochloride;

from 4.07 g (0.010 mol) of 2 - [(4-methyl-l-piperazinyl) methyl] -6-phenyl-8-chloro-4H-s-triazolo [l, 5-a] [l, 4] benzodiazepine the 1- (2-Benzoyl-4-chlorophenyl) -3 - [(4-methyl-1-piperazinyl) methyl] -5 - [(dimethylamino) methyl] -IH-1, 2,4-triazole and its trihydrochloride.

The starting materials used are described in German Offenlegungsschrift 2 234 652.

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Example 7

7.6 g (0.017 mol) of 1- (2-benzoyl-4-chlorophenyl) -5- (morpholinomethyl) «. 1H-1 ^ j ^ -triazole-S-carboxylic acid methyl ester (see Example 1) with 340 ml of methanol and 69 ml of conc. Poured over aqueous ammonia solution. One warms up the mixture with stirring for 4 hours to 40, the starting material slowly going into solution. The reaction mixture is then left to stand at room temperature for 18 hours and evaporated then a vacuum. Water is added to the residue and the mixture is extracted twice with methylene chloride. The organic phase one washes twice with ice cold 1-n. Sodium bicarbonate solution, once with water and once with saturated sodium chloride solution, dry them over sodium sulfate and evaporate them to dryness in a vacuum. The residue is crystallized from isopropanol and after drying in vacuo, the 1- (2-benzoyl-4-chlorophenyl) -5- (morpholinomethyl) -IH-1,2,4-triazole-3-carboxamide is obtained from m.p. 146-149.

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Example 8

17.5 g (0.044 mol) 1- (2-benzoyl-4-chlorophenyl) -5- [ (dimethylamine)) -methyl] -lH-l ^^ - triazole-S-carbonsMuremethylester (see Example 2) with 850 ml of methanol and 175 ml of conc. Pour aqueous ammonia solution over it. The reaction solution is stirred for 7 hours at room temperature and then evaporated to dryness in vacuo. Add to the residue Water and extracted twice with methylene chloride. The organic phase is washed twice with water and once with saturated sodium chloride solution, dry it over sodium sulfate and evaporate them to dryness in a vacuum. The residue is dissolved in 300 ml of ethyl acetate and ethereal added Hydrogen chloride solution is added until the pH value reaches 2. The crystalline product is filtered off with suction and washed with ethyl acetate and ether. After drying in vacuo, one obtains 1- (2-Benzoyl-4-chlorophenyl) -5 - [(dimethylamino) methyl] -1H-1,2,4-triazole-3-carboxamide hydrochloride of m.p. 250-255 ° with decomposition.

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Example 9

9.00 g (0.018 mol) of crude 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- (morpholinomethyl) -IH-I, 2,4-triazole-3-carboxylic acid hydrochloride are refluxed with 90 ml of thionyl chloride for 90 minutes. The clear solution will be at 40 evaporated in vacuo and the residue for total removal of the thionyl chloride again in 100 ml of abs. toluene dissolved and evaporated again.

The obtained crude acid chloride hydrochloride is with 90 ml conc. Poured over aqueous ammonia solution and stirred for 18 hours at room temperature. Then you cool it Reaction mixture with ice water for 2 hours, the precipitated crude product is filtered off and washed well with cold water after. This is obtained after recrystallization from isopropanol 1- [2- (o-Chlorobenzoyl) -4-chlorophenyl] -5- (morpholinomethyl) -1H-1,2,4-triazole-3-carboxamide from m.p. 165-167 °.

The raw material is produced as follows:

a) A mixture of 9.3 g (0.0226 mol) of 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- (chloromethyl) -lH-1,2,4-triazole-3-carboxylic acid (see German Offenlegungsschrift No. 2 159 527, page 32) and 9.5 g (0.11 mol) of morpholine in 100 ml of ethanol is mixed with 0.10 g of sodium iodide and 2 hours under

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Boiled under reflux. The reaction mixture is then evaporated in a vacuum, toast the residue in water and add 2-n. Hydrochloric acid up to the Congo acid reaction. The unusual one The hydrochloride of the reaction product is extracted with twice ICX) ml of methylene chloride. The organic extracts result after washing with saturated sodium chloride solution, drying the 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- (morpholinomethyl) -1H-1,2,4-triazole-3-carboxylic acid hydrochloride over sodium sulfate and evaporation as amorphous yellow foam, which is used directly for the next stage.

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Example 10 W

Analogously to example 7 one obtains

starting from 7.3 g (approx. 0.017 mol) of crude 1- (2-benzoyl-4-chlorophenyl) -5 - [(1-pyrrolidinyl) methyl] -IH-

1,2 ^ -triazole-S-carboxylic acid methyl ester the amorphous 1- (2-Benzoy1-4-chlorophenyl) -5-I (1-pyrrolidinyl) -methyl] -IH-I, 2,4-triazol-3- carboxamide, its hydrochloride, prepared with an ethereal solution of hydrogen chloride in ethyl acetate, after recrystallization from isopropanol melts at 236 ° (with decomposition), and

starting from 7.5 g (approx. 0.017 mol) crude

1- (2-Benzoyl-4-chlorophenyl) -5- (piperidinomethyl) -IH-I, 2,4-triazole-3-carboxylic acid methyl ester the crude 1- (2-benzoyl-4-chlorophenyl) -5- (piperidinomethyl) -IH-1,2 ^ -triazole-S-carboxamide, its hydrochloride prepared analogously after recrystallization from isopropanol at 255-260 ° (with decomposition) melts.

The raw materials are produced as follows:

a) Analogously to Example 1, using 2.9 g (0.041 mol) of pyrrolidine or 3.0 g (0.041 mol) Piperidine instead of morpholine the crude 1- (2-benzoyl-4-chlorophenyl) -5 - [(l-pyrrolidinyl) methyl] -lH-l, 2,4-triazole- 3-carboxylic acid methyl ester or the crude 1- (2-benzoyl-4-chlorophenyl) -5- (piperidinomethyl) -IH-1, 2 ^ -tria acid me thyle s ter.

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7.0 g (0.0165 mol) of crude ethyl 1- (2-benzoyl-4-nitrophenyl) -5-1 (dimethylamino) methyl] -IH-1,2 ^ -triazole-S-carboxylate (see below) with 200 ml of ethanol and 20 ml of conc. Pour over aqueous ammonia solution. You leave that Stand the reaction mixture for 3 days at room temperature and then evaporate it in vacuo. To the residue are added water and extracted twice with ethyl acetate. The organic phase one washes twice with cold 1-n. Sodium bicarbonate solution and twice with saturated sodium chloride solution, dry them over sodium sulfate and evaporated them to dryness in vacuo a. The residue is dissolved in ethyl acetate-isopropanol (5: 1) and the solution is chromatographed on a column of 150 g silica gel. Ethyl acetate-isopropanol (5: 1) is used as the eluent. The factions which the desired Containing product are combined and evaporated. The residue is recrystallized from ethanol and obtained after drying in vacuo the 1- (2-benzoyl-4-nitrophenyl) -5- [(dimethylamino) methyl] -IH-1,2 ^ -triazole-S-carboxamide vom M.p. 187-190 °.

In an analogous manner, using 7.3 g (0.0165 mol) of crude 1- [2- (o-fluorobenzoyl) -4-nitrophenyl] -5- [(dimethylamino) -methyl] -lH-1,2 ^ -triazole-S-carboxylic acid ethyl ester (see below) the 1-12- (o-fluorobenzoyl) -4-nitrophenyl] -5-1 (dimethylamino) -methyl] -IH-1, 2 ^ -triazole-S-carboxamide.

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The raw materials are produced as follows:

To the solution of 7.55 g (0.020 mol) of 6-phenyl-8-nitro-4H-s-triazolo [1,5-a] [1,4] benzodiazepine-2-carboxylic acid ethyl ester (see German Offenlegungsschrift No. 2 304 307) 6 ml (0.072 mol) of 36% formic acid are added to 50 ml of 85% formic acid aqueous formaldehyde solution and the mixture is heated to 100 ° for 2 hours. The reaction solution is then poured on 200 ml of ice water and separates a yellow, undissolved by-product by filtration over purified diatomaceous earth. Sodium carbonate is added to the filtrate while cooling with ice until the pH value is 9, and twice with ethyl acetate extracted. The organic phase is washed twice with water and once with saturated sodium chloride solution, dry them over sodium sulfate and evaporate them in a vacuum. The residue contains the 1- (2-benzoyl-4-nitrophenyl) -5 - [(dimethylamino) -methyl] -IH-I, 2 ^ -triazole-ß-carboxylic acid ethyl ester as a viscous oil that is used directly for ammonolysis;

Analogously, starting from 7.91 g (0.020 mol) of 6- (o-fluorophenyl) -8-nitro-AH-s-triazolo 11,5-aIH, 4] benzodiazepine-2-carboxylic acid, described in the same patent application, is obtained ethyl ester 1- [2- (o-fluorobenzoyl) -4-nitrophenyl) -5-I (dimethylamino) -methyl] -lH-1,2 ^ -
ethyl ester.

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Example 12 fa

A mixture of 3.75 g (0.01 mol) of 1- (2-benzoyl-4-chlorophenyl) -5- (chloromethyl) -1H-1,2,4-triazole-3-carboxamide * and 0.15 g of sodium iodide in 70 ml of methanol are mixed with 4.0 ml of 33% ethanolic dimethylamine solution and under Stir boiled under reflux for 4 hours. The reaction mixture is then evaporated in vacuo. To the residue there add water and saturated sodium carbonate solution until the pH value 10 is reached, and extracted twice with ethyl acetate. The organic phase is washed twice with water and washed once with saturated sodium chloride solution, dried over magnesium sulfate and filtered. Add to the filtrate ethereal hydrogen chloride solution is added until the pH value is 3 is reached. The product which precipitates out in crystalline form is filtered off with suction and washed with ethyl acetate and ether. After this Drying in vacuo gives the 1- (2-benzoyl-4-chlorophenyl) -5- I (dimethylamine) -methyl} -lH-l, 2,4-triazole-3-carboxamide-hydro chloride with a melting point of 250 ° with decomposition.

The raw material is produced as follows:

a) To the suspension of 6.0 g (0.015 mol) of methyl 1- (2-benzoyl-4-chlorophenyl) -5- (chlorraethyl) -lH-1,2,4-triazole-3-carboxylate 30 ml of conc. in 220 ml of methanol are added dropwise within 5 minutes. aqueous ammonia solution at 30 ° with stirring. After 4 hours a clear reaction solution forms and a short time later a crystalline product begins fail. The mixture is stirred for a further hour at room temperature

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and one hour at 0-5 °. The crystals formed are then filtered off and recrystallized from 50 ml of methanol. That Product is suction filtered and washed with methanol and hexane. After drying in vacuo, the 1- (2-benzoyl-4-chlorophenyl) -5- is obtained (ChlorinethyI) -IH-1,2,4-triazole-3-carboxamide of melting point 128-130 °.

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Example 13 g *

A geraisch of 38.7 g (0.075 mol) 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- (iodomethyl) -lH-l, 2,4-triazol-3- " carboxylic acid methyl ester and 13.1 g (0.150 mol) morpholine in 750 ml of methanol is stirred at 40 ° for 8 hours. On that the reaction mixture is evaporated in vacuo, added; the Residue with water and extracted twice with methylene chloride. The organic phase is washed three times with water and twice with saturated sodium chloride solution, dry it over sodium sulfate and evaporate it in a vacuum. The residue it is rubbed with ether, the reaction product being obtained in crystalline form. After suction filtration and drying in vacuo 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- (morpholinomethyl) -IH-1,2 is obtained ^ -triazole-S-carboxylic acid methyl ester from m.p. 141-143 °.

In an analogous way one obtains

using 10.7 g (0.15 mol) of pyrrolidine ■ the 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5 - [(1-pyrrolidinyl) methyl] -lH ~ 1.2, 4-triazole-3-carboxylic acid methyl ester,

1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- (piperidinomethyl ·) -IH-1,2 using 12.8 g (0.15 mol) of piperidine ^ -triazole-S-carboxylic acid methyl ester, and

1- [2- (o-chlorobenzoyl) -4-chlorophenyl) -5 ~ [(diethylamuno) methyl] -lH-1,2 using 11.0 g (0.15 mol) of diethylamine ^ -triazole-S-carboxylic acid methyl ester.

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The methyl 1- [2- (o-chlorobenzoyl) -4-chlorophenyl) -5- (iodomethyl) -1H-1,2,4-triazole-3-carboxylate required as starting material is made as follows:

a) A solution of 133.0 g (0.30 mol) of 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- (chloromethyl) -IH-I, 2,4-triazole-3-carboxylic acid (crystallized with an equimolar amount of methanol, see German Offenlegungsschrift No. 2 159 527, page 32) in 1400 ml of methanol is mixed with 270 ml of a 6-n. Solution of hydrogen chloride in methanol and 18 hours under Boiled under reflux. The reaction mixture is then evaporated in vacuo, the residue is mixed with water and extracted twice with methylene chloride. The organic phase is washed once with saturated potassium bicarbonate solution, twice with water and once with saturated sodium chloride solution, dry it over sodium sulfate and evaporate it in the Vacuum a. The residue is recrystallized from 1 liter of methanol. After drying, the methyl 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- (chloromethyl) -IH-I, 2,4-triazole-3-carboxylate is obtained of m.p. 130-132 °.

b) A solution of 106.2 g (0.250 mol) 1 - ^ - (o-

benzoyl ^ -chlorophenyU-S- (chloromethyl) -lH-1,2,4-triazole-3-carboxylic acid methyl ester and 56.2 g (0.375 mol) of sodium iodide in 2200 ml of acetone is refluxed for 40 minutes.

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The reaction mixture is then evaporated in vacuo. Water is added to the residue and extracted twice with Methylene chloride. The organic phase is washed twice with dilute aqueous sodium bisulfite solution and twice with saturated sodium chloride solution, it dries over Sodium sulfate and evaporated them in vacuo. The residue is dissolved in the minimum amount of methylene chloride and added slowly adding 400 ml of ether with stirring, the reaction product crystallizing out. After sucking off and drying in The 1 ~ [2- (o-chlorobenzoyl) -4-chlorophenyl] -5 · (iodomethyl) -lH-1,2 ^ -triazole-S-carboxylic acid methyl ester is obtained in vacuo M.p. 125-128 °.

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Example 14

A mixture of 12.90 g (0.025 mol) 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- (iodomethyl) -IH-I, 2,4-triazole-

3-carboxylic acid methyl ester [cf. Example 13 b)] and 11 ml 33% ethanolic dimethylamine solution in 250 ml of methanol is stirred for 7 hours at room temperature, then the reaction solution is evaporated in vacuo, added the residue with water and extracted twice with methylene chloride. The organic phase is washed twice with water and once with saturated sodium chloride solution, dry it over sodium sulfate and evaporate it to dryness in vacuo a. The amorphous residue is dissolved in 130 ml of ether. The reaction product crystallizes out on standing. It is suction filtered and washed with ether. After drying, methyl 1- [2- (o-chlorobenzoyl) -4-chlorophenyl) -5 - [(dimethylamino) methyl] -IH-1,4-triazole-3-carboxylate is obtained from m.p. 131-134 °.

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- η

Example 15

28.5 g (0.06 mol) of 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- (morpholinomethyl) -IH-1,2 ^ -triazole-S-carboxylic acid methyl ester are concentrated with 730 ml of methanol and 290 ml. Pour over aqueous ammonia solution. One warms up the mixture with stirring for 4 hours at 40 °, the starting material slowly goes into solution. The reaction mixture is then left to stand at room temperature for 18 hours it then evaporates in a vacuum. Water is added to the residue and the mixture is extracted twice with ethyl acetate. the combined organic extracts with ice and so much 2-n. Acid solution shaken until the pH 3 is. The hydrochloride obtained in crystalline form is washed with water and ethyl acetate. From the filtrate the acidic aqueous layer is separated off and combined with the filter material. Now add 5-n. Caustic soda, until the pH value 9 is reached, and the precipitated base dissolves in methylene chloride. The methylene chloride solution it is washed once with water and twice with saturated sodium chloride solution and dried over sodium sulfate and evaporate them in a vacuum. The residue is dissolved in a methylene chloride / isopropanol mixture and the evaporated Methylene chloride from normal pressure and cools to room temperature. The crystalline reaction product is filtered off with suction and washed with isopropanol and ether. After drying in vacuo, the 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- (morpholinomethyl) -IH-1,4-triazole-3-carboxamide obtained melts at 165-167 °.

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In an analogous way one obtains

from 27.6 g (0.06 mol) of 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5 - [(1-pyrrolidinyl) -methylI-1H-l, 2,4-triazol-3 methyl carboxylate 1- [2- (o-chlorobenzoyl) -4-chlorophenyl 1-5 - [(1-pyrrolidinyl) methyl] -1 H -1,22 -triazole-S-carbo amide,

from 28.4 g (0.06 mol) of 1- [2- (o-chlorobenzoyl) -4-. chlorophenyl) -5- (piperidinomethyl) -IH-I, 2,4-triazole-3-carboxylic acid methyl ester 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- (piperidinomethyl) -IH-I, 2 ^ -triazole-S-carboxamide, and

from 27.7 g (0.06 mol) of 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5 - [(diethylamino) methyl] -IH-1, 2,4-triazole-3-carboxylic acid methyl ester 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5 - [(diethylamino) methyl] -lH-1,2,4-triazole-3-carboxy amide.

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Example 16

Analogously to Example 15, using a solution of 20 g (approx. 0.65 mol) of methylamine in 120 ml of methanol
instead of the ammonia solution, the N-methyl-1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- (jnorpholinomethyl) -IH-1,2 ^ -triazole-ß-carboxamide,

and likewise based on the amounts of the three other methyl esters mentioned in the example

the N-methyl-1- [2- (o -chlorobenzoyl) -4-chlorophenyl] -5-I (1-pyrrolidinyl) methyl] -IH-1,2 ^ -triazole-S-carboxamide,

N-methyl-1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- (piperidinomethyl) -lH-l, 2,4-triazole-3-carboxamide, and

the N-methyl-1- (2- (o -chlorobenzoyl) -4-chlorophenyl [-5 - [(diethylamino) methyl] -IH-1,2,4-triazole-3-carboxamide.

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8.66 g (0.020 mol) of 1- [2- (o-chlorobenzoyl) -4-chlorophenyl) -5 - [(dimethylamino) methyl] -IH-I, 2,4-triazole-3-carboxylic acid methyl ester are concentrated with 400 ml of methanol and 80 ml. Pour over aqueous ammonia solution. The reaction solution is stirred for 16 hours at room temperature and then evaporated to dryness in vacuo. To the arrears water is added and the mixture is extracted twice with methylene chloride. The organic phase is washed twice with ice-cold 1-n. Sodium hydroxide solution and then extracted twice with 2-n. Hydrochloric acid solution. The aqueous, hydrochloric acid solutions are added one with ice and so much 5-n. Sodium hydroxide solution until the pH value 10 is reached. The precipitated base is dissolved in methylene chloride recorded. The organic phase is washed twice with water and once with saturated sodium chloride solution, dry them over sodium sulfate and evaporate them to dryness. The amorphous residue is with ether rubbed, whereby the reaction product precipitates in crystalline form. It is suction filtered and washed with ether. After this Drying gives the 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5 - [(dimethylamino) methyl] -IH-1,4-triazole-3-carboxamide from m.p. 177-180 °.

In an analogous manner, using 6.5 g (0.21 mol) of methylamine in 40 ml of methanol instead of the conc. aqueous ammonia solution N-methyl-1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5 - [(dimethylamino) -methyl1-IH-1, 2,4-triazole -3-carboxamide.

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Example 18

A mixture of 8.0 g (0.015 mol) of 1- [2- (o-chlorobenzpyl) -4-chlorophenyl] -5- (iodomethyl) -lH-1,2,4-triazole-3-carboxylic acid methyl ester [cf. . Example 13 b)] and 3.3 ml
1-methyl-piperazine in 160 ml of methanol is stirred at 40 ° for 16 hours. The reaction solution is then evaporated in
A vacuum, the residue is treated with water and extracted twice with methylene chloride. The organic PIwse is washed twice with ice water and then extracted twice with
2-n. Hydrochloric acid solution. The aqueous, hydrochloric acid extracts are mixed with ice and so much 5-n. Sodium hydroxide solution until the pH value 10 is reached. The failed base is stored in
Aether added. The organic phase is washed twice with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness in vacuo.
The methyl 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5 - [(4-methy1-1-piperazinyl) methyl] -IH-1,4-triazole-3-carboxylate is obtained as solidified Foam.

The above crude product is concentrated with 280 ml of methanol and 56 ml. Pour aqueous ammonia solution over it. One stirs the reaction solution for about 15 hours at room temperature and it then evaporates in a vacuum. Water is added to the residue and the mixture is extracted twice with methylene chloride. The organic Extracts are washed twice with ice-cold 1-n.

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Sodium hydroxide solution, twice with water and once with saturated sodium chloride solution, dries it over sodium sulfate and evaporates them to dryness in a vacuum. The residue crystallizes one from isopropanol. After drying, the 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5 - [(4-methyl-I-piperaziny1) -methyl] -lH-l, 2,4-triazole-3- carboxamide from m.p. 167-169 °.

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A solution of 4.22 g (0.01 mol) 1- [2- (a-Hydroxybenzyl) -4-chlorophenyl] -5-1 (dimethylamino) methyl] -IH-1, 2,4-triazole-3 -carboxamide hydrochloride in 800 ml of acetone is added dropwise with 2.50 ml (corresponding to 0.0067 mol chromium trioxide) Oxidation solution according to Jones (preparation of 250 ml by dissolving 66.8 g chromium trioxide in 57.5 ml conc. Sulfuric acid and adding 250 ml of water). Gradually taking on a grline color The reaction mixture is stirred for 18 hours at room temperature and then concentrated to 100 ml in vacuo. Now one gives Ice and saturated sodium carbonate solution are added until the pH value is reached, and the mixture is extracted twice with ethyl acetate. The organic. Phase is washed twice with water and once with saturated sodium chloride solution and dried over magnesium sulfate. The drying agent is filtered off and ethereal hydrogen chloride solution is added to the filtrate until the pH value 3 is reached. The hydrochloride which precipitates in crystalline form is filtered off with suction and washed with ethyl acetate and ether. To drying in vacuo gives 1- (2-benzoyl-4-chlorophenyl) -5-ί (dimethylamino) methyl] -lH-1,2,4-triazole-S-carboxamide hydrochloride of melting point 250 ° (with decomposition).

The raw material is produced as follows:

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a) To the solution of 5.6 g (0.015 mol) of 1- (2-benzoyl-4-chlorophenyl) -5- (chlorinethyl) -IH-1,2,4-triazole-3-carboxanide Ivglo Example Ia)] in 250 ml of tetrahydrofuran and 25 ml of methanol are: with stirring at 0 ° all at once 0.57 g (0.015 mol) of sodium borohydride and then stirring is continued for one hour at room temperature. 1-n is then slowly added dropwise while cooling with ice water. Sa Iz acid I'd solution until the pH of the reaction mixture 4 is reached. The resulting mixture is evaporated to dryness in vacuo. Water is added to the residue and the mixture is extracted twice with ethyl acetate. The organic phase is washed once with saturated potassium bicarbonate solution, twice with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The amorphous 1- [2- (α-hydroxybenzyl) -4-chlorophenyl] -5- (chloromethyl) -IH-1,2,4-triazole-3-carboxamide, which is used directly in the next stage, is obtained. The compound has an Rf value of 0.61 on the silica gel plate in the ethyl acetate-methanol system (95: 5).

b) A solution of 5.6 g (approx. 0.015 mol) of 1- [2- (a-hydroxybenzyl) -4-chlorophenyl] -5- (chloromethyl) -1H-1,2,4-triazole-3-carboxamide and 0.225 g of sodium iodide in 80 ml of methanol is mixed with 6.8 ml of 33% ethanolic dimethylamine solution and refluxed with stirring for 5 hours. The reaction mixture is then evaporated in vacuo. To the arrears

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water and saturated sodium carbonate solution are added until the pH value is 10 and the mixture is extracted twice with ethyl acetate. The organic phase is washed with water and then extracted three times with 1-n. Acid solution. Sodium carbonate is added to the aqueous, hydrochloric acid extracts until the pH value is 10. The precipitated base is taken up in ether, the ether solution is washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo, the amorphous 1- [2- (a-hydroxybenzyl) -4-chlorophenyl ] -5 - [(dimethylamino) methyl] -1H-1,2,4-triazole-3-carboxamide is obtained. This is converted into the crystalline hydrochloride as follows: The crude base is dissolved in ethyl acetate and an ethereal hydrogen chloride solution is added until the pH value is 4. The precipitated hydrochloride is filtered off with suction and washed with ethyl acetate and ether. After drying in vacuo, the 1- [2- (a-hydroxybenzyl) -4-chlorophenyl] -5 - [(dimethylamino) methyl] -IH-1, 2,4-triazole-3-carboxamide hydrochloride is obtained from M.p. 155-157 ° (with decomposition)

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Example 20

The crude [1- [2- (a-hydroxybenzyl) -4-chlorophenyl] -5-ί (dimethylamino) methyl] -IK-1,2,4-triazol-3-yl obtained according to b) [see below! ] methyl] acetate (approx. 0.028 mol) is dissolved in 1500 ml of acetone and the solution is stirred at room temperature within 30 minutes with 7.20 ml (corresponding to 0.019 mol of chromium trioxide) oxidation solution according to Jones, which by Dissolve 66.8 g of chromium trioxide in 57.5 ml of conc. Sulfuric acid and supplement with water to 250 ml is prepared, added dropwise «The color of the reaction mixture changes from initially yellow to reddish-brown to deep Dark green. When the addition is complete, the reaction mixture is stirred one hour at room temperature and then evaporated to half in vacuo at 30 °. so ice and saturated potassium bicarbonate solution are added until the pH value is 8, and the mixture is extracted twice with Ethyl acetate. The combined organic phases are three times with 2-n. Acid solution extracted. The watery, Hydrochloric acid extracts are mixed with ice and enough potassium bicarbonate until the pH value 8 is reached. The precipitated base is taken up in ethyl acetate. The organic phase is washed twice with water and once with saturated sodium chloride solution, dry it over sodium sulfate and evaporate it to dryness in a vacuum. The crude I [1- (2-benzoyl-4-chlorophenyl) -5- (dimethylamino) methyl] -IH-1,4-triazol-3-yl] methyl] acetate is obtained as a pale yellow oil.

509881/1096

A sample of the crude product is dissolved in ether and mixed with ethereal hydrogen chloride solution until the pH value 3 is reached. The crystalline hydrochloride obtained is filtered off with suction and shows after drying a m.p. of 166-170 °.

The raw material is produced as follows:

a) A solution of 16.0 g (0.040 mol) 1- (2-benzoyl-4-chlorophenyl) -5-f (dimethy! amino) -methyl] -IH-1,2,4-triazole-3-carboxylic acid methyl ester [see. Example 2] in 320 ml of tetrahydrofuran and 320 ml of methanol is taken at room temperature 9.1 g (0.24 mol) of sodium borohydride are added in portions while stirring. The temperature of the reaction solution rises to 40 °. The reaction mixture is then heated one hour to 50 °, it is then mixed with 100 ml of ice water and evaporated in vacuo most of the tetrahydrofuran and des Methanol. The aqueous residue is washed twice with ethyl acetate extracted. The organic phase is washed once with 1-n. Sodium hydroxide solution and then extracted it three times 2-n. Salt marrow solution o The aqueous, hydrochloric acid extracts are used mixed with sodium carbonate until the pH value 10 is reached. The precipitated base is dissolved in ethyl acetate, the solution Washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate and in vacuo evaporated. The residue is rubbed with ether and hexane,

509881/1096

The reaction product precipitates in crystalline form. After sucking off and drying in vacuo gives 1-12- (a-hydroxybenzyl) -4 ~ chlorophenyl] -5 - [(dimethylamino) methyl] -IH-1, 2,4-triazole-3-methanol from m.p. 121-123 °,

b) To the solution of 11.18 g (0.030 mol) 1-12- (a-hydroxy benzyl) -4-chlorophenyl] -5- [(dimethylarnino) methyl] -1H-1,2,4-triazo1-3-methanol a solution of 3.0 ml is added dropwise to 80 ml of methylene chloride and 10 ml of pyridine at 0 ° over the course of 10 minutes (0.0318 mol) acetic anhydride in 5 ml methylene chloride, and then stirred for 20 hours at room temperature. then a further 1.1 ml (0.012 mol) of acetic anhydride are added and the mixture is stirred for a further 4 hours at room temperature. The reaction mixture is evaporated in vacuo and the residue still evaporated to dryness twice with toluene. The amorphous residue is dissolved in ethyl acetate and the organic one is washed Phase twice with water and once with saturated sodium chloride solution. After drying over sodium sulfate and Evaporation in vacuo gives the amorphous [1- [2- (a-hydroxybenzyl) -4-chlorophenyl] -5 - [(dimethylamino) methyl] -1H-1,2,4-triazol-3-yl] methyl ]-acetate, which is used directly in the next stage. For characterization, a sample of the crude product is dissolved in acetone and

50988 1/1 096

mixed with a saturated solution of oxalic acid in acetone, until the pH value 3 is reached «The crystallized oxalate is suction filtered and hot acetone recrystallized. After drying, the oxalate melts at 185-186 ° with decomposition.

Example 21

A solution of 8.26 g (approx. 0.020 mol) of crude I H- (2-Benzoyl-4-chlorophenyl) -5 - [(dimethylamino) methyl] -1H-1,2,4-triazol-3-yl ] methyl] acetate (cf. Example 20) in 250 ml of methanol and 115 ml of water are mixed with 60 ml of 1N sodium hydroxide solution (0.060 mol) at room temperature while stirring. The temperature of the reaction solution rises to 33 ° '. The reaction mixture is stirred for one hour at room temperature and then evaporated in vacuo. Water is added to the residue and the mixture is extracted twice with ethyl acetate. The combined organic phases are three times with 2-n. Hydrochloric acid solution extracted The aqueous, hydrochloric acid extracts are mixed with ice and enough sodium carbonate until the pH value is reached. “The precipitated base is taken up in ethyl acetate. The organic phase is washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The crude 1- (2-benzoyl-4-chlorophenyl) -5- [(jimethylamino) methyl] -lH-1,2,4-triazole-3-methanol is obtained as a solidified foam.

BÖ9881 / 1096

■ A sample of the crude product is dissolved in ether and mixed with ethereal hydrogen chloride solution until the pH 3 is reached. The crystalline hydrochloride obtained is filtered off with suction and, after drying, melts at 198-200 ° with decomposition »

Example 22

A solution of 3.0 g (0.008 mol) of crude 1- (2-benzoyl-4-chlorophenyl) -5-Γ (dimethylamino) methyl] -IH-I, 2,4-triazole-3-methanol (cf. example 21) in 670 ml of acetone is added dropwise at 0 to 5 ° with stirring with 2.63 ml (corresponding to 0.007 mol of chromium trioxide) Oxidation solution according to Jones [cf. Example 20)]. The reaction mixture, which after some time a Tiefgrtirie Color takes on 2 hours at room temperature

stirred and then evaporated to half in vacuo. Now you add ice and saturated sodium carbonate solution until the pH value 9 is reached, and extracted twice with ethyl acetate. Washes the combined organic phases it is washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated dry them in a vacuum. The residue is dissolved in ethyl acetate-isopropanol (4: 1) and the chromatographed Solution on a column of 200 g of silica gel. As an elution

$ 09881/1096

medium is ethyl acetate-isopropanol (4: 1). the Fractions containing the desired aldehyde are combined and evaporated. The crude 1- (2-benzoyl-4-chlorophenyl) -5 - [(dimethylamino) methyl] -1H-1,2,4-triazole-3-carboxaldehyde is obtained as frozen foam.

A sample of the aldehyde is dissolved in acetone and mixed with a saturated solution of oxalic acid in acetone, until the pH value 3 is reached. The oxalate precipitates in crystalline form. It is sucked off, well with acetone and Washed with ether and dried in vacuo. M.p. 178-181 ° with foaming.

Example 23

'A solution of 3.79 g (0.001 mol) 1- [2- (a-hydroxy-

benzyl) -4-chlorophenyl] -5-ί (dimethylamino) methyl] -3-methanol in 740 ml of acetone at 0 ° with stirring, 5.1 ml (corresponding to 0.0136 mol of chromium trioxide) of Jones oxidation solution (cf. Example 20) are added, and after When the addition is complete, the mixture is stirred for a further 30 minutes at room temperature. The grline reaction mixture is then evaporated in the Vacuum to half, add ice water and saturated sodium carbonate solution until pH 9 is reached, and extracted twice with Aethy! acetate The combined organic

509881/1096

The phases are washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated them in a vacuum. The amorphous residue is dissolved in ethyl acetate-isopropanol (4: 1) and the solution is chromatographed on an acid of 250 g of silica gel. Used as an eluent one ethyl acetate-isopropanol (4: 1) ο the fractions which the: the desired aldehyde are combined and evaporated. The residue is dissolved in acetone and a saturated solution is added of oxalic acid in acetone until the pH value 3 is reached. The resulting crystalline oxalate is filtered off with suction and washed with acetone and ether washed. After drying, 1- (2-benzoyl-4-chlorophenyl) -5 - [(dimethylamine) methyl] -lH-1,2,4-triazole-3-carboxaldehyde oxalate is obtained from m.p. 178-181 ° with foaming »

509881/1096

Example 24

To the solution of 2.0 g (0.005 mol) of crude 1- (2- benzoyl-4-chlorophenyl) ~ 5- [(diraethylamino) methyl J -1H-1,2,4-triazole-3-methanol a solution is added dropwise to 66 ml of dry methylene chloride and 1.33 ml of triethylamine at 0 ° with stirring of 0.78 ml (0.01 mol) of methanesulfonic acid chloride in 8 ml dry methylene chloride and then stirred without further cooling for one hour. The reaction mixture is added one with ice water and 120 ml of methylene chloride, the aqueous phase is separated off, and the organic phase is washed twice with ice-cold potassium bicarbonate solution and twice with saturated Sodium solution. After drying over magnesium sulfate and Evaporation of the solvent in vacuo leaves the crude methar sulfonic acid ester of the starting material.

The crude methanesulfonic acid ester obtained above is in a mixture of 4.6 ml (0.03 mol) of 30% ethanol Dimethylamine solution and 60 ml of methanol and dissolved in Left to stand at room temperature for 16 hours. The reaction mixture is then evaporated to dryness in vacuo, added to Residue ice water and enough saturated sodium carbonate solution, that the pH value 10 is reached, and extracted three times with ethyl acetate. The organic phase is washed

once with water and then extracted three times with 2-n. Hydrochloric acid solution. The hydrochloric acid aqueous extracts are mixed with sodium carbonate until the pH value 10 is reached and then extracted twice with ethyl acetate.

509881/1096

The combined ethyl acetate solutions are mixed twice with water and once with saturated sodium chloride solution washed, dried over magnesium sulfate and filtered. So much ethereal hydrogen chloride solution is added to the filtrate, that the pH value 3 has been reached. The product, which precipitates out in crystalline form, is suction filtered and thoroughly mixed with it Washed ethyl acetate and ether. After drying in vacuo, 1- (2-benzoyl-4-chlorophenyl) -3,5-bis- [ (dime thy lamino) methyl] -IH-1,2,4-triazole dihydrochloride from the snip. 90 ° (with gradual decomposition).

509881/1096

Example 25

A mixture of 4.18 g (0.01 mol) 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] ~ 5 - [(dimethylamino) methyl] -IH-1, 2,4-triazol-3 -carboxamide and 2.86 g (0.015 mol) of p-toluenesulfonic acid chloride in 2.42 ml of pyridine and 24 ml of N, N-dimethylformamide is stirred for 2 hours at room temperature. It changes the initially yellow color of the reaction mixture over green to red-brown. The reaction solution is poured into ice water and extracted twice with ether. The organic phase is washed three times with water and once with saturated sodium chloride solution, dry them over sodium sulfate and evaporate them to dryness in a vacuum. The residue is crystallized out Isopropanol. After suction filtration and drying, the 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- [(dimethylamino) - · methylI-IH-1,2 ^ -triazole-S-carbonitrile of m.p. 117-119 °.

In an analogous way one obtains

from 3.84 g CO, 01 mol) 1- (2-benzoyl-4-chlorophenyl) -5 - [(dimethylamino) methyl} -lH-l, 2,4-triazole-3-carboxamide the amorphous 1- ( 2-Benzoyl-4-chlorophenyl) -5 - [(dimethylamino) methyl] -1H-1,2,4-triazole-3-earbonitrile. This is mixed in an ethereal solution with a solution of hydrogen chloride in ether, whereby the crystalline hydrochloride precipitates. It is suction filtered and washed with ether and hexane. After drying, the 1- (2-benzoyl-4-chlorophenyl) -5 - [(dimethylamine) -methyl 1-lH-1,2,4-triazole-3-carbonitrile hydrochloride obtained melts at 216-219 ° with decomposition .

509881/1096

150 ml of isopropanol are saturated with ammonia gas at 0 °. 2.45 g (0.05 mol) of sodium cyanide are added to this solution at 0 ° with stirring and, after 5 minutes, a solution of 3.69 g (0.01 mol) of crude 1- (2-benzoyl-4-chlorophenyl) -5 - [(dimethylamine) -methyl] -lH-l, 2,4-triazole- · 3-carboxaldehyde in 30 ml of isopropanol. Two portions of 8.70 g (0.10 mol) of manganese dioxide each are then added at 0 ° at intervals of 10 minutes, and the reaction mixture is stirred at 0 ° _{3 for 4 hours}

The reaction mixture is then boiled at 250 ml Diluted methylene chloride and filtered through diatomaceous earth. The clear filtrate is evaporated to dryness in vacuo. The residue is dissolved in ethyl acetate-methanol (4: 1) and the solution is chromatographed on a 300 g column Silica gel. Ethyl acetate-methanol is used as the eluent (4: 1) ο The fractions which contain the desired product are combined and evaporated. The The amorphous residue is dissolved in 50 ml of ethyl acetate and an ethereal hydrogen chloride solution is added up to the Congo acidic solution Reaction. The crystalline hydrochloride obtained is filtered off with suction and washed with ethyl acetate and ether. To The 1- (2-benzoyl-4-chlorophenyl) -5 - {(dimethylamino) methyl] -IH-1,4-triazole-3-carboxamide hydrochloride obtained melts on drying at 250 ° with decomposition.

The aldehyde required as a starting material can be prepared according to Example 22 or 23.

609881/109 6

Example 27

To the solution of 5.37 g (0.01 mol) of crude [2- (dimethylamino) acetamido] - [2- (o-Chlorobenzoyl) -4-chlorophenylazo] malonic acid diethyl ester 40 ml of 1N are added to 60 ml of methanol. Sodium hydroxide solution and heats the Reaction mixture with stirring at 50 ° for 3 hours. The methanol is then evaporated off in vacuo and the residue is diluted with 50 ml of water and add 1 g of activated charcoal. After filtering off The clear filtrate is treated with 2-n over purified diatomaceous earth. Acid solution added until the pH 7 and washed once with methylene chloride. The aqueous phase is then evaporated to dryness in vacuo and the residue was evaporated twice more with methanol-toluene (1: 1) in vacuo at 40 ° to dry it completely. The residue is then boiled with methanol. The undissolved inorganic salts are separated by filtration over purified diatomaceous earth and the clear filtrate is evaporated to dryness. The residue consists of raw 1- [2- (o-chlorobenzoy ^^ - chlorphenylJ-S-ßdimethylamine ^ -methylJ · lH-l, 2,4-triazole-3-carboxylic acid, if desired directly to the next stage, the conversion into the methyl ester, which in turn serves as the starting material for example 15 can be used.

509881/1096

A sample is used to convert it into the hydrochloride the carboxylic acid in ethanol is mixed with a saturated solution of hydrogen chloride in ether until the pH of the mixture is reached after adding water 3 reached. After adding ethyl acetate, the salt crystallizes out. It is sucked off and washed with ethyl acetate and hexane. After drying, the 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- (dimethylamino-methyl) -IH-1,4-triazole-3-carboxylic acid hydrochloride obtained melts at 220 ° with decomposition.

For conversion into the methyl ester already mentioned a solution of 2.08 g (0.005 mol) of crude 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- (dimethylamino-methyl) -IH-1,2,4-triazole-3-carboxylic acid in 30 ml of methanol with 10 ml of a 6-n. Solution of hydrogen chloride in methanol and 16 hours refluxed. The reaction mixture is then evaporated in vacuo. Water is added to the residue and the mixture is extracted twice with methylene chloride. The organic phase is washed twice with ice-cold 1-n. Sodium bicarbonate solution and twice with saturated sodium chloride solution, dry it over sodium sulfate and evaporate it to dryness in a vacuum. Of the The residue crystallizes out when rubbed with ether. After filtering off with suction and drying in vacuo, the pure one is obtained Methyl 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- (dimethylamino-methyl) -1H-1,4-triazole-3-carboxylate of m.p. 133-135 °.

The starting material for the first stage (ring closure) is produced as follows:

509881/1096

a) A solution of 5.02 g (0.02 mol) (2-chloroacetamido) -maIonsäurediethylester [see. Ajay Kumar Böse, J. Indian Chem. Soc. 31, 108-110 (1954)] and 4.50 g (0.03 mol) of sodium iodide in 100 ml of acetone is refluxed for 30 minutes. The reaction mixture is then evaporated in vacuo. To the arrears water is added and the mixture is extracted twice with methylene chloride. The organic phase is washed once with dilute aqueous Sodium bisulfite solution and twice with saturated sodium chloride solution, dry them over sodium sulfate and evaporate them in vacuo a. The residue is recrystallized from methylene chloride-hexane. After suction filtration and drying in vacuo, one obtains the (2-Jodaqetamido) malonic acid diethyl ester with a melting point of 95 ° -97 °.

b) A mixture of 5.16 g (0.015 mol) of (2-iodoacetamido) -ma ionic acid diethyl ester and 8.0 ml (0.045 mol) of 33% strength ethanol Dime thy lamin solution in 50 ml of ethanol is used for 16 hours Room temperature stirred. The reaction solution is then evaporated in vacuo, the residue is mixed with water and extracted twice with ether. The organic phase is washed twice with ice water and once with saturated sodium chloride solution, dry them over sodium sulfate and evaporate them to dryness in a vacuum. The residue, a viscous oil, provides practically pure [2- (dimethylamino) acetamido] malonic acid diethyl ester and is used directly for the next stage.

509881/1096

c) A solution of 4.53 g (0.017 mol) of 2-amino-2 ', 5-dichloro-benzophenone [cf. LH Sternbach et al. , J.0rg ". Chem. 26 , 4448 (1961)] in 21 ml of concentrated glacial hydrochloric acid (4: 1) is stirred at room temperature with 3.4 ml (0.014 mol) of 5 molar aqueous sodium nitrite Lb ' The resulting diazonium salt solution is cooled to 10 °, 9 g of ice are added and a solution of 4.43 g (0.017 mol) of crude [2- (dimethylamine) acetamido] malonic acid diethyl ester in 44 ml of acetone is added dropwise A saturated aqueous potassium carbonate solution is then added dropwise at 5-10 ° in the course of 15 minutes until the pH value is 6. The mixture is stirred for a further hour at room temperature and then 150 ml of ether are added. The ether layer is separated off and twice with ice water and washed once with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo.The residue, a yellow-brown oil, consists of practically pure [2- (dimethylamine) acetamido] - [2- (o-chlorobenzoyl) -4-chlorophenylazo ] -malonic acid diethyl ester The compound points to silica gel thin Layered plates have an Rf value of 0.36 in the toluene-ethyl acetate system (1: 1).

S0988 1/1 096

Example 28

A solution of 5.37 g (0.01 mol) of crude [2- (dimethylamino) acetamido] - [2- (o-chlorobenzoyl) -4-chlorophenylazo] malonic acid diethyl ester [see. Example 27 a) to c)] and 50 ml of conc. aqueous ammonia solution in 100 ml of methanol is 16 hours stirred at room temperature. The reaction mixture is then evaporated in vacuo. Water is added to the residue and the mixture is extracted twice with methylene chloride. The organic phase is washed twice with ice-cold 1-n. Hydrochloric acid extracted. To the sour one aqueous extraction is added 5-n. Sodium hydroxide solution, up to pH 11 is reached and the resulting dispersion of the reaction product is extracted twice with methylene chloride. The organic phase is washed twice with water and once with saturated sodium chloride solution, and it is dried over Sodium sulfate and evaporated it to dryness in a vacuum. The residue crystallizes out after trituration with ether. To " Removing and drying in vacuo is obtained in the same way The process of decarbethoxylation, ring closure and ammonolysis of the remaining ester group, 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5 - [(dimethylamino) -methyl) -IH-1,2 , 4-triazole-3-carboxamide of m.p. 178-180 °.

509881/1096

Claims (1)

- 97 claims: in which R, hydrogen, lower alkyl, optionally esterified or etherified hydroxymethyl, optionally acetalized formyl, optionally functionally modified carboxy or optionally mono- or disubstituted aminomethyl,
Lower alkyl and Hydrogen or lower alkyl, wherein R 'and R ~ may be linked as a lower alkyl, directly or in / 3- or 7-position via oxygen, sulfur or the imino or a Niederalkyliminorest, and the rings A and B independently of one another can be unsubstituted or substituted, and their addition salts with inorganic and organic acids. 509881/1096 2. Triazole derivatives of the general formula I given in claim 1, in which R ,, R ^ and R- the have given meaning in claim 19 and the rings A and B independently of one another unsubstituted or by halogen up to atomic number 35, trifluoromethyl, nitro, Lower alkyl or lower alkoxy are substituted, and their Addition salts with inorganic and organic acids. 3., triazole derivatives of the general formula I given in claim 1, in which R, hydrogen, lower alkyl, hydroxymethyl, lower alkanoyloxymethyl, lower alkoxymethyl, formyl carboxyj-lower alkoxycarbonyl, cyano, optionally mono- or disubstituted carbamoyl or optionally mono- or disubstituted aminomethyl, R " and R ₃ have the meaning given in the claim and the rings A and B are independently unsubstituted or substituted by halogen up to atomic number 35, trifluoromethyl, nitro, lower alkyl or lower alkoxy, and their addition salts with inorganic and organic acids. 4 '. Triazole derivatives of claim 1 given general formula I, in which R, 509881/1096 - QQ - _ has the meaning of hydrogen, hydroxymethyl, lower alkanoyloxymethyl, formyl, carboxy, lower alkoxycarbonyl cyano or optionally mono- or disubstituted carbamoyl or optionally mono- or disubstituted aminomethyl, where the substituents present are monovalent hydrocarbon radicals with at most 10 carbon atoms each, which, if there are two Lower alkyl is, also between each other directly or in β- or 7-position also via oxygen, sulfur, the imino radical or a lower alkylimino radical, R «and R, which have the meaning given in claim 1 and the rings A and B independently of one another unsubstituted or substituted by halogen up to atomic number 35, trifluoromethyl or nitro, and their addition salts with inorganic and organic acids. 5. Triazole derivatives of the general formula I given in claim 1, in which R, hydrogen, hydroxymethyl, Lower alkanoyloxymethyl, formyl, carboxy, lower alkoxycarbonyl, Represents cyano or a group of the partial formula I aa, C-N (I aa) in which X is oxygen or two hydrogen atoms and R ^ and R _{5 are} hydrogen or in claim 19 for 509881/109 6 R ₂ and R ₃ have the meaning given, R "and R- have the meaning given in claim 1 and the rings A and B are independently unsubstituted or substituted by halogen up to atom number 35, trifluoromethyl or nitro, and their addition salts with inorganic and organic acids 6. Triazole derivatives of those specified in claim 1 of the general formula I, in which R, hydrogen, hydroxymethyl, Niederallcanoyloxymethyl, formyl, carboxy, Represents lower alkoxycarbonyl, cyano or a group of the sub-formula I aa, C-N in which X oxygen E or two hydrogen atoms and R, and R, -independent from each other hydrogen, lower alkyl with a maximum of 3 carbon atoms or together with the adjacent nitrogen atom Morpholino or Alkylenimirio with 5 to 6 ring members mean R "and R- lower alkyl with a maximum of 2 carbon atoms, or together with the adjacent nitrogen atom are morpholino or alkylenimino with 5 to 6 ring members and which Rings A and B independently of one another unsubstituted or through Halogen up to atomic number 35, trifluoromethyl or nitro substituted and their addition salts with inorganic and organic acids. 509881/1006 7 triazole derivatives of the general formula I given in claim 1, in which IU is hydroxymethyl, lower alkanoyloxymethyl, formyl, carboxy, lower alkoxycarbonyl, cyano or a group of the sub-formula I aa, ίί / C-N (I aa) I> in which X is oxygen or two hydrogen atoms and R, and R ^ independently of one another are hydrogen, lower alkyl with a maximum of 3 carbon atoms or, together with the adjacent nitrogen atom, morpholino or alkylenimino with 5 to 6 ring members, R _? and R ~ is lower alkyl with a maximum of 2 carbon atoms, or together with the attached nitrogen atom is morpholino or alkylenimino with 5 to 6 ring members, ring A in position 4 to the triazole ring by halogen up to atom number 35, in particular chlorine, or substituted by nitro and ring B. unsubstituted or substituted by halogen up to atomic number 35, in particular by fluorine or chlorine in the ortho position, and their addition salts with inorganic and organic acids 8. Triazole derivatives of the general formula I given in claim 1, in which R ^ carboxy or lower alkoxycarbonyl means R2 and R-j as indicated in claim 7 Have meaning and the rings A and B, as in 509881/1096 Claim 7 indicated, can be substituted, and their addition salts with inorganic and organic acids. 9. Triazole derivatives of the general formula I given in claim 1, in which R-. a group the sub-formula I represents aa, CN
I. ^R 5 in which X, Ra ^{un <^ R5} ^ ^e * - ^m claim have the meaning indicated 7, Rj and R 'are also as defined in claim 7 have, and the rings A and B, as set out in claim 7 can be substituted, and their addition salts with inorganic and organic acids. 10. The compounds of general formula I described in the examples and their addition salts with inorganic ones and organic acids. ΪΓ. Me l- (2-Benzoyl-4-chlorophenyl) -5 - [(dimethylamino) methylJ-lH-l ^^ - triazole-S-carboxylic acid, its methyl ester and their addition salts with inorganic and organic acids. 509881/1096 12. The 1- (2-benzoyl-4-chlorophenyl) -5- [(dimethylami.no) - methyl} -lH-1,2,4-triazole-3-carboxamide and its addition salts with inorganic and organic acids. "- 13 ..- The 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5 - [(dimethyl- amino) -methyl] -IH-I, 2,4-triazole-3-carboxylic acid, its methyl ester and their addition salts with inorganic and organic acids. . -. ' 14. The l- (2-benzoyl-4-chlorophenyl) -5- (morpholinomethyl) - lH-l, 2,4-triazole-3-carboxylic acid, its methyl ester and its Addition salts with inorganic and organic acids. 15- The 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- (morpholino- methyl) -IH-I, 2,4-triazole-3-carboxamide and its addition salts with inorganic and organic acids. · \ -. 16. The N, N-dimethyl-1- [2- (o-fluorobenzoyl) -4-chlorophenyl] - 5-1 (dime thy! Amino) -methyl] -lH-l, 2,4-triazole-3-carboxamide and its addition salts with inorganic and organic acids. 17. The 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -3,5-bis- I (dimethylamino) methyl] -lH-l, 2,4-triazole and its addition salts with inorganic and organic acids. 509881/1096 18. Process for the preparation of new triazole derivatives of the general formula I, (D in which R, hydrogen, lower alkyl, optionally esterified or etherified hydroxymethyl, forrayl, optionally functionally modified carboxy or optionally mono- or disubstituted aminomethyl, R ₂ lower alkyl and Ro denotes hydrogen or lower alkyl, where R ₂ and R ₃ as lower alkyl can be connected directly or in β- or 7-position also via oxygen, sulfur or the imino or a lower alkylimino radical, and the rings A and B independently of one another can be unsubstituted or substituted,
509881/1096 and their addition salts with inorganic and organic acids, characterized in that one a) a reactive ester of a compound of the general formula II, R ₁ CH ₂ -OH (II) in which R, has the meaning given under formula I, and the rings A and B, as indicated here can be substituted, with a compound of general formula III, H-N / ^R 2 (III) In which R «and R-, which have the meaning given under the formula I, or reacts with an alkali metal derivative of such a compound with R ~ other than hydrogen, or 509881/1096 b) for the preparation of compounds of general formula I in which R ₂ and R «are methyl, while R, which has the meaning given under formula I, is a compound of general formula IV, (IV) in which R has the meaning given under formula I, and the rings A and B, as indicated therein can be substituted, is reacted with formaldehyde and formic acid, or c) for the preparation of compounds of the general formula I in which R, the meaning given under the formula I with the exception of hydroxymethyl, and R ₂ and R- have the meaning given under the formula I, a compound of the general formula V, 509881/1096 (V) in which R-, R ₂ and Ro have the meaning given under the formula I and the rings A and B, as indicated there, can be substituted, oxidized, or d) for the preparation of compounds of the general formula I ₉ in which R is carboxy or lower alkoxycarbonyl, while R ₂ and R_ have the meaning given under the formula I, to a compound of the general formula VI, 509881/1096 CO-O-R, C-CO-O-R, (VI) in which R, means lower alkyl R "and R _{3 have} the meaning given under the formula I and the rings A and B, as stated there, can be substituted, a basic medium can act, and if desired one according to one of a) to d) given method compound I obtained in a Addition salt converted with an inorganic or organic acid , or if desired 509881/1098 e) for the preparation of compounds of the general formula I, in which R, optionally mono- or disubstituted carbamoyl, while R ~ and R., under the formula I have given meaning, a carboxylic acid of the general formula I e falling under the general formula I, CO-OH (I e) in which R "and R" are given under the formula I. Have meaning and the rings A and B, as indicated there, 509881/1096 may be substituted, or a reactive func tional derivative of such with a compound of general formula VII, H-N (VII) in which R, and Rr independently of one another are hydrogen or hydrocarbon radicals with a maximum of 10 carbon atoms each, which, if it is lower alkyl, are also linked directly or in β- or 7-position via oxygen, sulfur, the amino or a lower alkylimino radical can be, mean or with a reactive functional derivative of such a compound, or f) for the preparation of compounds of the general formula I in which R-, aminomethyl or mono- or disubstituted Is aminomethyl, while R2 and R- are those under the general Formula I have given meaning, a reactive 609881/1096 Ester of a compound of the general formula If falling under the general formula I,. CH ₂ -OH (if) in which R ^ and R «have the meaning given under the formula I and the rings A and B, as indicated there, can be substituted with a compound of the general formula VII given above, in which R, and R ₅ the under this formula have given meaning, or with an alkali metal derivative of such a compound, or g) for the preparation of a triazole derivative of the general formula I, in which R 1 denotes hydroxymethyl, while K ^ and R _{3 have} the meaning given under the formula I, a compound of the general formula VIII, 509881/1096 (VIII) in which Ac denotes the acyl radical of an organic acid, R «and R ~ have the meaning given under formula I and rings A and B, as indicated there, are substituted. can, solviated, or h) for the preparation of a triazole derivative of the general formula I, in which R 1 denotes formyl, while R ₂ and R "have the meaning given under the formula I, a compound of the general formula Ih, CH ₂ -OH (I h) CH ₂ -N 509881/1096 252569Ί in which R ^ and R_ the meaning given under the formula I. and the rings A and B, as indicated there, may be substituted, oxidized, or i) for the preparation of a triazole derivative of the general formula I, in which R 1 denotes cyano, while R 1 and R 1 denote have the meaning given under the formula I, a compound of the general formula I i, CO-NH, (I i) in which R "and R" have the meaning given under the formula I. and the rings A and B, as indicated there, may be substituted, dehydrated, or j) for the preparation of triazole derivatives of the general formula I, in which R ₁ optionally denotes mono- or disubstituted carbamoyl, while R ₃ and R _{3 have} the meaning given under the formula I, a compound of the general formula falling under the general formula I. Ij, $ 09881/1096 ■ - 114 - (i j) in which R «and R- have the meaning given under the formula I. and the rings A and B, as indicated there, may be substituted with a compound of the above given general formula VII, in which R, and R, - the under this formula have given meaning, in the presence of an alkali metal cyanide and a selective oxidizing agent implements and, if desired, one after one or several successive ones Process according to e) to j) obtained triazole derivative of the general formula I in an addition salt transferred with an inorganic or organic base. 509881/1096. 19. The method according to claim 18, characterized in, that one compounds of the general formula I in which R ,, R- and Pv- have the meaning given in claim 18 and the rings A and B, independently of one another, are unsubstituted or by halogen up to atomic number 35, trifluoromethyl, nitro, Lower alkyl or lower alkoxy are substituted, and their Manufactures addition salts with inorganic and organic acids. 20. The method according to claim 18, characterized in that compounds of the general formula I in which R-, Hydrogen, lower alkyl, hydroxymethyl, lower alkanoyloxymethyl, Lower alkoxymethyl, formyl, carboxy, Lower alkoxycarbonyl, cyano, optionally mono- or disubstituted carbamoyl or optionally mono- or disubstituted Aminomethyl means R- and R- in claim 18 have given meaning and the rings A and B independently of one another unsubstituted or by halogen up to atomic number 35, trifluoromethyl, nitro, lower alkyl or lower alkoxy and their addition salts with inorganic and organic acids. 21. The method according to claim 18, characterized in that compounds of the general formula I in which R, 509881/1096 has the meaning of hydrogen, hydroxymethyl, lower alkanoyloxymethyl, formyl, carboxy, lower alkoxycarbonyl cyano or optionally mono- or disubstituted carbamoyl or optionally mono- or disubstituted aminomethyl, where the substituents present are monovalent hydrocarbon radicals with at most 10 carbon atoms each, which, if there are two Lower alkyl is also linked directly or in β- or 7-position via oxygen, sulphurous imino radicals or a lower alkylimino radical, R ₂ and R ~ have the meaning given in claim 18 and rings A and B are, independently of one another, unsubstituted or are substituted by halogen up to atomic number 35, trifluoromethyl or nitro, and their addition salts are prepared with inorganic and organic acids. 22. The method according to claim 18, characterized in that compounds of the general formula I in which R, hydrogen, Hydroxymethyl, lower alkanoyloxymethyl, formyl, carboxy, lower alkoxycarbonyl, Represents cyano or a group of the partial formula I aa, i - if "C ¹ aa) in which X is oxygen or two hydrogen atoms and.R ^ and R ^ are hydrogen or in claim 18 for 5 09881/1096 R and R ₃ have the meaning given, R ₂ and R _{3 have} the meaning given in claim 18 and the rings A and B are independently unsubstituted or substituted by halogen up to atomic number 35, trifluoromethyl or nitro, and their addition salts with inorganic and organic SMuren manufactures. 23. The method according to claim 18, characterized in that one compounds of the general formula I in which R, hydrogen. Hydroxymethyl, lower alkanoyloxymethyl, formyl, carboxy, Represents lower alkoxycarbonyl, cyano or a group of the sub-formula I aa, Il ^ ^R / C-N tt I X in which X is oxygen or two hydrogen atoms and R, and R_ are independently hydrogen, lower alkyl with a maximum of 3 carbon atoms or together with the attached nitrogen atom are morpholino or alkylenimino with 5 to 6 ring members, R "and R" are lower alkyl with at most 2 carbon atoms, or together with the attached nitrogen atom are morpholino or alkylenimino with 5 to 6 ring members and the rings A and B are independently unsubstituted or substituted by halogen up to atom number 35, trifluoromethyl or nitro, and their addition salts with inorganic and organic acids are produced. 509881/1096 24. The method according to claim 18, characterized in that compounds of the general formula I in which R. Hydroxymethyl, lower alkanoyloxymethyl, formyl, carboxy, lower alkoxycarbonyl, cyano or represents a group of the sub-formula I aa, C-N (I aa) in which X is oxygen or two hydrogen atoms and R. and R _c 4th independently of one another are hydrogen, lower alkyl with a maximum of 3 carbon atoms or together with the adjacent nitrogen atom are morpholino or alkylenimino with 5 to 6 ring members, R _? and R »is lower alkyl with a maximum of 2 carbon atoms, or together with the adjacent nitrogen atom is morpholino or alkylenimino with 5 to 6 ring members, ring A in position 4 to the triazole ring is substituted by halogen up to atom number 35, in particular chlorine, or by nitro and ring B is unsubstituted or is substituted by halogen up to atomic number 35, in particular by fluorine or chlorine in the ortho position, and prepares its addition salts with inorganic and organic acids. 25. The method according to claim 18, characterized in that compounds of the general formula I in which R-. Carboxy or lower alkoxycarbonyl, R2 and R _{3 denote} those in claim 24 S0Ö881 / 10Ö6 have given meaning and the rings A and B, as in Claim 24 indicated, can be substituted, and their addition salts with inorganic and organic acids manufactures. 26. The method according to claim 18, characterized in that compounds of the general formula I in which R, represents a group of Teilforir.el I aa X / R ₇
CN ¹ ^ R
5 in which X, R /, ^{un (} ^ ^ c have the meaning given in claim 24, R ~ and R- also have the meaning given in claim 24 and the rings A and B, as given in claim 24, can be substituted , and their addition salts with inorganic and organic acids. 27. Modification of the method according to claim 18, characterized in that marked that one can proceed to any one Stage terminates or starts from a compound occurring at any stage as an intermediate and the carries out missing steps or forms a starting material under the reaction conditions or optionally in the form of a salt used. 509881/109 6 28. The method according to claim 18, characterized in that that the compounds of general formula I described in the examples and their addition salts with inorganic and organic acids. 29. Pharmaceutical compositions for the treatment of epilepsy and states of tension and excitement, characterized by a content of a triazole derivative according to claims 1 to 17, or a pharmaceutically acceptable addition salt of such a triazole derivative with an inorganic or organic acid, together with pharmaceutical carriers. 509881/1096