NO834770L - PROCEDURE FOR THE PREPARATION OF NEW ARALKYLTRIAZOL COMPOUNDS - Google Patents

Description

The invention relates to a process for the preparation of new aralkyltriazole compounds, in particular 1-phenyl lower alkyl-1H-1,2,3-triazole compounds with the formula

in which Ph means lower alkyl, halogen and/or trifluoromethyl substituted phenyl, alk means lower alkylidene, means hydrogen, lower alkyl, lower alkyloxy or an unsubstituted or with acyl, lower alkyl or lower alkylene, respectively aza-, oxa- or thialeverealkylene substituted amino- or carbamyl group and R 2 stands for an unsubstituted or with acyl, lower alkyl or lower alkylene, respectively aza-, oxa- or thialaverealkylene substituted carbamyl group or gets cyano if it denotes an unsubstituted or medacyl, lower alkyl or lower alkylene, respectively aza- .

Phenyl residues Ph contain, for example, even three, especially one or two of the aforementioned substituents.

The invention relates, for example, to the preparation of such compounds with the formula I, in which Ph means i2-position with lower alkyl, halogen or trifluoromethyl and optionally further with lower alkyl or halogen, which are found, for example, in the 3-, 4- or 6-position, preferably in 3- or 6-position, substituted phenyl, alk denotes the lower alkylidene, R^ denotes hydrogen, lower alkyl, lower alkoxy or an unsubstituted or lower alkyl substituted amino or carbamyl group and R£ stands for unsubstituted or lower alkyl substituted carbamyl or for cyano, if R^ denotes unsubstituted or with lower

alkyl substituted amino.

Optionally with acyl, lower alkyl, lower alkylene, respectively aza-, oxa- or thialaverealkylene substituted amino is for example amino, physiologically easily cleavable acylamino, lower alkylamino, dilaverealkylamino, 5- to 7-membered lower alkyleneamino, respectively aza-, oxa- or thialaverealkyleneamino. Likewise, correspondingly substituted carbamyl is, for example, carbamyl, physiologically easily cleavable acylcarbamyl, N-lower alkylcarbamyl, N,N-dilower alkylcarbamyl, N,N-lower alkylene-respectively N,N-(asa-, oxa- or thia)-lower alkylenecarbamyl with 4 to 6 ring members in the lower alkylene-respectively aza-, oxa-, respectively thia lower alkylene part.

In a physiologically easily cleavable acylamino or acylcarbamyl group, acyl is derived, in particular from a lower alkanoic acid optionally substituted with lower alkoxy or lower alkylene amino, a lower alkanesulfonic acid or an aliphatic half-ester or half-amide of carboxylic acid and means, for example, lower alkanoyl, e.g. . formyl, acetyl, propionyl, butyryl, isobutyryl, valeroyl or pivaloyl, lower alkoxy-lower alkanoyl, e.g. methoxy- or ethoxyacetyl, diloweralkylaminoloweralkanoyl, e.g. N,N-Dimethylcyclyl, lower alkane sulfonyl, e.g. methane or ethanesulfonyl, lower alkoxycarbonyl, e.g. methoxy-, ethoxy-, isopropuloxy- or tertiarybutyloxycarbonyl, ureido, 3-lower alkyl- or 3,3-di-lower alkyl ureido or 3,3-lower alkylene-respectively 3,3-(asa-, oxa- or thia)-lower alkylene ureido.

Above and below, the term "lower" organic groups and compounds shall be understood, for example, as those which contain up to and including 7, especially up to and including 4 carbon atoms (C atoms).

Lower alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl, further one of the isomeric pentyl, hexyl or heptyl groups. Halogens are, for example, those with atomic numbers up to and including 35, such as fluorine, chlorine or bromine.

The lower alkylidene is, for example, the 1,1-lower alkylidene with

even 4 C atoms, such as methylene, aethylidene, 1,1-propylidene, 1,1-butylidene, but may also be isopropylidene,

1,1-isobutylidene or a 1,1-pentylidene, 1,1-hexylidene or 1,1-heptylidene group.

Lower alkoxy is, for example, methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, secondary butyloxy or tertiary butyloxy, further one of the isomeric pentyloxy, hexyloxy or heptyloxy groups.

Lower alkylamino as well as those in 3-lower alkylureido are, for example, straight-chain lower alkylamino with up to and including 4 C atoms, such as methyl, ethyl, propyl or butylamino,

but may also be branched lower alkylamino with up to 4 C atoms, such as isopropyl, isobutyl or tertiary butylamino, or a pentylamino, hexylamino or heptylamino group. The lower alkylamino as well as those in 3,3-di-lower alkyl ureido are, for example, straight-chain dilower alkylamino with up to 4 C atoms each, such as dimethylamino, diethylamino, methyl-ethyl-amino, dipropylamino or dibutyl-amino, or can also be single branched dilower alkylamino with each up to 4 C atoms, such as methyl-isopropyl-amino. 5- to 7-membered lower alkyleneamino, respectively aza-, oxa- or thialeverealkylenamino, also as a component of corresponding ureido groups are, for example, pyrrolidino, piperidino, piperasino, respectively N'-lower alkyl-, such as N'-methylpiperasino, morpolino or thiomorpolino.

N-lower alkylcarbamyl is, for example, straight-chain N-lower alkylcarbamyl with up to 4 C atoms in the lower alkyl part, such as N-methyl-, N-ethyl-, N-propyl- or N-butylcarbamyl,

but may also be branched N-lower alkylcarbamyl with up to 4 lower alkyl C atoms, such as N-isopropyl-, N-

isobutyl, N-secondarybutyl or N-tertiarybutylcarbamoyl or a pentylcarbamoyl, hexylcarbanoyl or heptylcarbamoyl group. N,N-didilower alkylcarbamyl is, for example, straight-chain N,N-dilower alkylcarbamyl with each up to and including 4 C atoms in the lower alkyl parts, such as N,N-dimethyl-, N,N-diethyl-, N-ethyl-N-methyl-, N ,N-dipropyl- or N,N-dibutyl-carbamyl, but can also be single branched N,N-dilower alkylcarbamyl with each up to 4 C atoms in the lower alkyl parts, such as N-isopropyl-N-methyl- or N-isobutyl-N-methylcarbamyl, or an N,N-dipentyl, N,N-dihexyl, or N,N-diheptylcarbamoyl group. N,N-lower alkylene- or N,N-(asa-, oxa- or thia)-lower alkylenecarbamyl is for example pyrrolidinocarbonyl, piperidinocarbonyl, piperazino-respectively N<1->lower alkyl-, such as N'-methylpiperazinocarbonyl, morpholinocarbonyl or thiomorpholinocarbonyl.

Salt-forming compounds with the formula are, for example, such

in which an azalaverealkylene-substituted amino group or/or carbamyl R 1 and/or R 2 contains such an amino group. As salts of such compounds, their pharmaceutically usable acid addition salts with strong acids, such as mineral acids, for example salts of hydrohalic acids, above all hydrochloric or hydrobromic acids, i.e. hydrogen halide, above all hydrogen chloride and hydrogen bromide, or sulfuric acid salts come into consideration in particular , i.e. hydrogen sulphate and sulphates, being salts with suitable organic acids, such as dicarboxylic acids or organic sulphonic acids, for example maleinate, furmarates, maleates, tartrates or methanesulphonates, further N-cyclohexyl sulphonates.

The new compounds have valuable pharmacological properties, in particular a pronounced anticonvulsant effect, which can be demonstrated, for example, in mice due to a clear metrasol antagonism in the dose range from approx. 30 to 300 mg/kg p.o. as well as on mice and rats due to a pronounced protective effect against electroshock-triggered convulsions in the dose range from approx. 10-100 mg/kg p.o. (mouse) respectively from approx. 5-50 mg/kg p.o. (roots). The compounds of formula I are therefore excellently suitable for the treatment of convulsions of various kinds, for example for the treatment of epilepsy.

They can therefore be used as anticonvulsants, for example anti-epileptic drug active substances.

The invention primarily relates to compounds of the formula I, in which Ph means lower alkyl, halogen and/or trifluoromethyl substituted phenyl, alk means lower alkylidene, means hydrogen, lower alkyl, lower alkoxy, amino, acylamino, N-lower alkyl-, N.N-di-lower alkyl- , N,N-lower alkylene- respectively N,N-(asa-, oxa- or thia)-lower alkylene-amino, carbamyl, N-acylcarbamyl or N-lower alkyl-,N,N-dilower alkyl-, N,N-lower alkylene- respectively N,N-(asa-, oxa- or thia)-lower alkylenecarbamyl and R2 stands for carbamyl, N-acylcarbamyl, N-lower alkyl-, N,N-dilower alkyl-, N.N-lower alkylene- respectively N,N-(asa-, oxa- or thia)-lower alkylenecarbamyl or gets cyano if R^ is amino, acylamino, N-lower alkyl-, N,N-dilower-alkyl-, N,N-lower alkylene- respectively N,N- (asa-, oxa- or thia)- lower alkyleneamino, respectively for hydrogen or lower alkyl if R^ means carbamyl, N-acylcarbamyl, N-lower alkyl-, N,N-dilower alkyl-, N,N-lower alkylene- respectively N,N-(asa-, oxa- or thia)-lower-alkylenecarbamyl, whereby acyl always denotes in particular lower-alkanoyl, lower-alkyl-lower-alkoxycarbonyl, di-lower-alkylamino-lower-alkanoyl, lower-alkanesulfonyl, lower-alkoxycarbonyl, ureido, 3-lower-alkyl-respectively

•3,3-dilower alkyl ureido or 3,3-lower alkylene-respectively 3,3-(asa-, oxa- or thia)-lower alkylene ureido and lower alkyl as well as lower alkyl in N-lower alkyl-respectively N,N-dilower alkylamino respectively- carbamyl, the lower alkoxy and the lower alkylidene contain, for example, even 7 C atoms and the lower alkylene, respectively the aza-, oxa- or thialeverealkylene contain, for example, 4

even 6 ring joints.

The invention primarily relates to the production of

for example compounds of the formula I, in which Ph means 2-halophenyl, 2-trifluoromethylphenyl, 2-lower alkylphenyl,

2, 3- respectively 2, 6-dihalophenyl, 2-halogen-3-lower alkyl-phenyl respectively 3-halogen-2-lower alkylphenyl, 2-halogen-6-lower alkyl-phenyl, 2,3- respectively 2,6-dilower alkylphenyl, 3-halo-2-trifluoromethyl-phenyl respectively 2-halo-3-trifluoromethylphenyl or 2-halo-6-trifluoromethylphenyl, alk denotes the 1,1-lower alkylidene R. means hydrogen, lower alkyl, lower alkoxy, amino, lower alkylamino, dilower alkylamino, carbamyl, N-lower alkylcarbamyl or N,N-dilower alkylcarbamyl and R2 means carbamyl, N-lower alkylcarbamyl or N,N-dilower alkylcarbamyl, whereby lower alkyl and lower alkyl in N-lower alkyl respectively N,N-dilower alkylamino respectively - carbamyl, lower alkoxy and the lower alkylidene contain for example to and with 7 C atoms.

The invention relates above all to compounds of the formula I, where Ph means phenyl substituted with up to 3 lower alkyl groups respectively halogen atoms, lower alkyl and halogen and/or trifluoromethyl, whereby lower alkyl contains up to 4 C atoms and is for example methyl, respectively halogen has the atomic number up to and including 35, that is, is fluorine, chlorine or bromine, which for example stands for 2-lower alkylphenyl, 2-respectively 3-halophenyl, 2-trifluoromethylphenyl, 2,3-respectively 2,6-dilower alkylphenyl or 2, 3-, 2,4- and 2,6-dihalophenyl respectively,

alk denotes 1,1-dilower alkylidene with up to 4 C atoms, for example methylene, ethylidene or 1,1-propylidene, R^ denotes amino, lower alkanoylamino with up to 7 C atoms, such as fornylamino, acetylamino or pivaloyamino, lower alkylamino or dilower alkylamino each with up to and including 4 C atoms in the alkyl part, for

for example acetylamino, methyl, ethyl or propylamino, dimethyl or diethylamino, and R2 is carbamyl, N-lower alkanoylcarbamyl with up to and including 7 C atoms, such as formyl, acetyl or pivaloylcarbamyl, N-lower alkyl, N,N -dilower alkyl- or N,N-lower alkylenecarbamyl with each up to and including 4 C atoms in the alkyl part respectively 4

even 6 ring members in the alkyl part, such as carbamyl, N-acetylcarbamyl, N-methylcarbamyl, N,N-dimethylcarbamyl1

or piperidinocarbonyl, or cyano.

The invention relates in particular to the preparation of compounds of the formula I, in which Ph means 2-halophenyl, such as 2-fluoro-, 2-chloro or 2-bromophenyl, 2-trifluoromethylphenyl, 2-lower alkylphenyl, such as 2-methyl- or 2-ethylphenyl, 2 ,3-or 2,6-dihalophenyl with lower alkyl substituents with up to and including 4 C atoms, for example methyl or ethyl, respectively halogen substituents with the atomic number up to and including 35, for example chlorine, ; for example 2,6-dichlorophenyl, or 2,3- or 2,6-dilower alkylphenyl, such as 2,3-dimethyl-phenyl, alk denotes the 1,1-lower alkylidene with up to 4 C atoms, for example methylene, ethylidene or 1,1-propylidene, stands for amino, lower alkylamino or dilower alkylamino each with up to 4 C atoms in the alkyl part, for example methyl, ethyl or propylamino, dimethyl or diethylamino and R2 means carbamyl or cyano.

Namely, the invention relates to the production of the compounds of formula I mentioned in the examples.

The process for preparing the new compounds of formula I is characterized by, for example, reacting an acid with the formula

with a connection with the formula

in which B.L denotes cyano or an unsubstituted or carcabyl group substituted with acyl, lower alkyl or lower alkylene, respectively aza-, oxa- or thilower alkylene,

Y 1 means one as indicated in substituted amino group or means hydrogen, lower alkoxy or unsubstituted or as indicated substituted carbamyl, if R 2 stands for an unsubstituted or with acyl, lower alkyl or lower alkylene respectively aza-, oxa- or thie-lower alkylene substituted carbamyl group, and Y 2 and Y 3 means together a further bond, or in which RI means cyano or an unsubstituted or with acyl, lower alkyl or lower alkylene respectively aza-, oxa- or thi-lower alkylene substituted carbamyl group, Y^ and Y2 together get imino and Y^ hydrogen, if necessary separate a formed isomer mixture in components with and isolates isomers with the formula I

and if desired forms a formed compound in another compound with the formula I.

Tautomers of the compound of the formula III are, for example, cyanacetyl tautomers of the formula N=C-CH2-R2(IIa) of ketimine compounds of the formula III, in which Y. i and Y A„ denote imino and Y^ is hydrogen.

Salts of compounds with the formula III are, for example, metal salts, such as alkali metal salts, of compounds with the formula III, in which Y₁ and Y₂ together denote imino and Y₂ is hydrogen, respectively tautomers of these with the formula Illa.

The reaction takes place in the usual way, advantageously in an inert solvent, if necessary in the presence of a condensing agent and/or at an elevated temperature. Inert solvents are, for example, aromatic or araliphatic hydrocarbons, such as benzene or toluene, or ethers, such as tertiary butoxymethane, tetrahydrofuran or dioxane, and for the reaction with compounds of the formula Illa is further alcohol, such as lower alkanol, for example methanol, ethanol or butanol. Condensing agents are, for example, for the reaction with compounds of the formula III, in which and Y2 together denote imino and Y^ is hydrogen, respectively retomers with the formula Illa, salt-forming condensing agents, such as metal alcoholate, for example sodium metallonate, sodium ethanolate, or other alkali metal lavereal alcoholate, metal amides, such as sodium amide, lithium diisopropylamide and the like, or organometallic compounds, such as lower alkyl magnesium halides or lower alkyl lithium compounds, for example methyl or butyl magnesium bromide or butyl lithium. Instead of working in the presence of one of the aforementioned condensation agents, the components with the formula III or Ill can also be used as a salt.

Preferred embodiments of this method are, for example, the reaction of an acid of the formula II with a compound of the formula III, in which Y^ is hydrogen or lower alkyl and Y^ and Y^ form an additional bond, in benzene or dioxane at approximately 60-120° C, preferably boiling temperatures, as well as reaction with compounds of the formula IIa in the presence of sodium methanolate respectively sodium ethanolate and methanol respectively ethanol as solvent at approx. 40 to 100°C, preferably at boiling temperature.

The starting materials with the formula III and partly with the formula II

are known. New starting materials with the formula II can be prepared analogously to the method for producing the known starting materials, for example by reacting a compound with the formula Ph-alk-X (IV), where X means reactive esterified hydroxy, such as halogen, for example chlorine, bromine or iodo, or sulfonyloxy, such as lower alkane sulfonyloxy, optionally substituted benzenesulfonyloxy,

such as methane, ethane, benzene, p-toluene or p-bromobenzenesulfonyloxy, or fluorosulfonyloxy, with an alkali metal acid, for example with sodium acid, for example in dimethylsulfoxide or dimethylformamide, or by bringing an alcohol with the formula IV (X = hydroxy), in the presence of triphenylphosphine and an adzodicarbonyl acid ester, for example azodicarboxylic acid diethyl ester, with nitric acid, for example in toluene.

The new compounds can further be prepared by reacting a compound with the formula

or a salt thereof, where Z means reactive before hydroxy, with a 1H-1,2,3-triazole derivative of the formula

if necessary, split a formed isomer mixture into the components and isolate the isomer with the formula I and, if desired, convert a formed compound into another compound with the formula I.

Reactive esterified hydroxy Z is, for example, halogen, for example chlorine, bromine or iodine, or sulfonyloxy, such as lower alkanesulfonyloxy, optionally substituted benzosulfonyloxy, such as methane-, ethane-, benzene-, p-toluene- or p-bromo-benzenesulfonyloxy, or fluorosulfonyloxy.

Salts of compounds with the formula V are, for example, alkali metal salts or alkaline earth metal salts thereof, such as their sodium, potassium or calcium salts.

The reaction takes place in the usual way, for example in the presence of a base condensing agent or similar, using the component with the formula V as a salt, if necessary under heating, preferably in a solvent or diluent. Basic condensing agents are, for example, salt-forming basic condensing agents with the components of the formula V, such as alkali metal alcoholate, for example sodium metallonate or sodium ethanoate, alkali metal or lower alkali metal amides, for example sodium amide or lithium diisopropylamide. As mentioned, the transfer of the component of formula V in one of their salts is preferably carried out in advance, for example by reaction with one of the aforementioned bases. The solvent for carrying out the reaction in the presence of an alcoholate is preferably the corresponding alcohols and when carried out in the presence of amides, for example aprotic organic solvents, such as phosphoric acid lower alkyl amides or di lower alkyl sulphoxides, for example hexamethyl phosphoric acid triamide or dimethyl sulphoxide.

The method is particularly suitable for the preparation of compounds, in which an animo group R. of the amino group respectively as a component of a carbamyl group R2 is at least N-mono-, preferably N,N-disubstituted, i.e. denotes acylamino, lower alkylamino or preferably lower alkyl -, lower alkylene- or (N'-lower alkyl) aza-, oxa- or thilower alkyleneamino.

The starting substances with formulas IV and V can be prepared in the usual way if they are not already known previously. Thus, compounds with the formula IV are obtained, for example, by reacting a corresponding alcohol with the formula IV (Z = hydroxy), for example by means of thionyl chloride, phosphorus tribromide or a sulphonyl chloride. Compounds of the formula V can be prepared by reacting trimethylsilyl azide or nitric acid with the compound of the formula

in which R2 denotes cyano or an unsubstituted or with acyl, lower alkyl or lower alkylene respectively aza-, oxa- or thialeweralkylene substituted carbamyl group, Y. denotes as indicated disubstituted amino groups or hydrogen, lower alkyl, lower alkoxy or unsubstituted or as indicated substituted carbamyl, if R^ stands for an unsubstituted or with acyl, lower alkyl or lower alkylene respectively aza-, oxa- or thiale-lower alkylene substituted carbamyl group, and Y2 and Y^ together denote a further bond, or in which RI means cyano or an unsubstituted or with acyl, lower alkyl or lower alkylene respectively asa- , oxa- or thialaverealkylene substituted carbamyl group, Y^ and Y^ together stand for imino and Y^ is hydrogen, or a tetomer and/or a salt thereof and if desired in the formed 1-trimethylsilyltriazole derivative acylates or lower alkylates an amino group R^ and /or carbamyl group R2hen-holdSsVis substituted with lower alkylene or aza-, oxal- lyes the thialaverealkylene and cleaves off the silyl group by mild hydrolysis. The new compounds can further be prepared by using a compound of the formula

in which Y^ means a residue Y^ and Y<- means a -group or a residue Y^ or Y^ means an R2~ group and Y^ means a residue Y ti , whereby YA._ means in unsubstituted or as indicated substituted carbamyl transferable residue or cyano transferable residue if Y^denotes optionally as indicated substituted amino R^and Y^denotes optionally as indicated isubstituted carbamyl transferable residue, or in a salt thereof, YAi is transferred to cyano or optionally as indicated in substituted carbamyl and/or transfers Yg in possibly as indicated substi-

tuated carbamyl, if necessary separates a formed isomer mixture into its components and isolates the isomer with formula I and, if desired, converts the formed compound into another compound with formula I.

Residues Y._ and Y according to the definition given above are, for example, free carboxy groups or in a salt or anhydride form, possibly N-lower alkylated respectively with lower alkylene or aza-, oxa- or thiale lower alkylene N,N-disubstituted amido groups or esterified carboxy groups, residues Y ri are further syanp groups.

Esterified carboxy groups are, for example, carboxy groups esterified with a lower alkanol or a lower alkyl mercaptan, i.e. a lower alkoxy or lower alkyl thiocarbonyl group, but can also be esterified with any other alcohol or mercaptan, for example with an optionally substituted phenol or thiophenol.

Carboxy groups present in salt form are, for example

in a carboxy group present in an ammonium salt form derived from ammonia or a mono- or dilave alkylamine, further in metal, for example alkali or alkaline earth metal salt form present carboxy groups.

Carboxy groups present in anhydrite form are, for example

carboxy group present in a halide form, such as chlorocarbonyl, but can also be anhydrous with a reactive carboxylic acid and means, for example, alkoxycarbonyloxycarbonyl or trifluoroacetoxycarbonyl.

Optionally lower alkylated or with lower alkylene or aza-, oxa- or thialeveralkylene N,N-substituted amidino groups are for example unsubstituted or N-mono-, N.N-di- or N,N'-dilower alkylene respectively with lower alkylene respectively aza-, oxa- or tialavere-

alkylene N,N-disubstituted amidino groups.

The transfer of the mentioned groups in cyano or optionally as indicated in substituted carbamyl respectively the transfer of Y in optionally as indicated substituted carbamyl takes place in the usual way, starting from free, esterified or in an anhydrite form present carboxyl groups and optionally N-lower alkylated respectively with lower alkylene respectively aza-, oxa- or thialeverealkylene N,N-disubstituted aminidino groups by solvolysis, i.e. hydrolysis or ammonolysis - respectively aminolysis (reaction with ammonia or a mono- or di-lower alkylamine, lower alkylene amine respectively aza-, oxa- or thialeverealkyleneamine).

By hydrolysis, one can for example optionally transfer the lower alkylene respectively with the lower alkylene respectively the aza-, oxa- or thialeverealkylene N,N-disubstituted amidino groups Y^ and/or Y,. in optionally corresponding substituted carbamyl and transfer cyano Y^in carbamyl. The hydrolysis is carried out, for example, in the presence of an acidic hydrolysing agent, such as a mineral, sulphonic or carboxylic acid, for example in the presence of sulfuric acid, phosphoric acid, hydrochloric acid or another halohydrogen acid, p-toluenesulphonic acid or another organic sulphonic acid, or in the presence sv a lower alkaline acid, such as acetic acid, preferably in catalytic amounts.

In the case of ammonolysis or aminolysis, for example, free or present in salt form or esterified carboxy groups can be transferred into unsubstituted or, as indicated, substituted carbamyl. Hereby, one works if necessary in the presence of a condensation agent, preferably in an inert solvent. Condensing agents are, for example, basic condensation agents based on carboxy present in anhydride form, such as alkali metal hydroxides or carbonates, or organic nitrogen bases, such as amines in excess corresponding to the amino group to be introduced, or tertiary organic nitrogen bases, such as trilower alkyl amines or tertiary heteroaromatic nitrogen bases, which triethylamine or pyridine, and acidic condensation agents based on esterified carboxy, such as mineral acid, such as halogenated hydrogen acids or the like. Free carboxy groups can be transferred by dehydration of the intermediately formed ammonium salts in possibly lower alkylated carbamyl, for example by heating or by the action of water extracting agents, such as acid anhydrides, for example phosphorus pentoxide, acetyl chloride and the like, or by the action of carbodiimide, for example N,N' -dicyclohexylcarbodiimide.

The starting substances with the formula VI can be prepared in the usual way if they are not previously known, for example by reacting an azide with the formula

with a connection with the formula

where Y is a group Yj. and Y and Y^ denote an additional bond or Y^ denotes hydrogen or lower alkyl, Y^

means hydroxy and Y^ means hydrogen or Y^ and Y^ together denote imino and Y^ is hydrogen, or a tetomer and/or salt thereof, for example as described for the reaction with corresponding compounds of the formula III.

Starting substances of the formula VI, in which Y,. is lower alkoxy

and Y4 is a group Y^, can further be prepared by reacting an acid of the formula II with an acid of the formula HOOC-CH2-YA (XI), or reacting an ester thereof, as a lower alkyl ester, for example with a malonic acid dilower alkyl ester, and /or a salt thereof, preferably in the presence of an alkali metal alkanolate and in:-..the formed 5-hydroxy-1-falk-4-YA-1H-1,1,3-triazole lower alkylates the hydroxy group, preferably by reaction with a reactive lower alkyl ester, such as dimethyl sulfate, in the presence of sodium hydroxide.

The new compounds can further be prepared by starting from a compound with the formula

where Yg means a cleavable residue, cleave H-Yg and, if necessary, separate a formed mixture of isomers into the components and isolate the isomer with the formula I and, if desired, convert the formed compound into another compound with the formula i.

Cleavable residues Y^ are, for example, hydroxy, lower alkoxy or optionally substituted amino groups, whereby lower alkoxy is preferably identical to lower alkoxy and optionally substituted amino is preferably identical to free or substituted amino R^.

The cleavage of H-Yg generally occurs spontaneously, in some cases the supply of thermal energy or the presence of an acidic or basic agent, such as a mineral acid, for example sulfuric or hydrochloric acid, or a carboxylic or sulphonic acid, for example acetic or p -toluenesulfonic acid, or an alkali metal hydroxide or alcoholate, for example sodium methanolate, be advantageous.

The starting materials of the formula IX are preferably prepared

in situ and further reacted without isolation, for example by reacting a compound with the formula

with a compound of the formula in which R 2 denotes cyano or an unsubstituted or with lower alkyl or lower alkylene respectively aza-, oxa- or thi-lower alkylene substituted carbamyl group, Y 1 and Y 2 means lower alkyloxy or optionally substituted amino , Y^ means hydrogen and Y^ and Yg means a further bond or Y^, Y2 and Y^ means lower alkoxy and Y^ and Yg means hydrogen or Y^ and Y2 mean together oxo, Yj means hydrogen or lower alkyl and Y^ and Yg means hydrogen, or a tautomer and/or salt thereof, for example with a compound of the formula Y*-C(= 0)-Cr^-R^ (Xa; Y.j = hydrogen or lower alkyl), Y1-C(Y2)=CH-R2(Xb; Y1 and Y2= lower-oxy or in the suspension from each other is unsubstituted or as for R^indicated substituted amino), or Y^-C(Y2){ Y^)~ CH2-R2(Xc; Y1, Y2 andY^= lower alkoxy). Compounds with the formula I, in which R^ means lower alkoxy, can further be prepared by using a compound with the formula; transfers the hydroxy group into lower alkoxy and, if necessary, separates a formed isomer plant into its components and isolates the isomer with the formula I and, if desired, converts the formed compound into another compound with the formula I. The transfer of hydroxy into lower alkoxy takes place, for example, by reaction with a reactive lower alkyl ester, as with a halohydrogen, such as chloro, bromo or hydroiodo acid ester, a sulfuric acid ester, i.e. a dilave alkyl sulfate, or a sulfonic acid ester, such as a lower alkane or optionally substituted benzenesulfonic acid ester, for example methane-, benzene, p-toluene- or p -bromobenzenesulfonic acid ester of a lower alkanol, advantageously in the presence of a basic agent, such as an alkali metal hydroxide, carbonate or alcoholate, for example sodium or potassium hydroxide, potassium carbonate or sodium metallonate, or a tertiary organic nitrogen base, such as a trilower alkylamine, for example triethylamino, or pyridine. The starting materials with the formula XII can, for example, be obtained by reacting an acid with the formula; ; with an acid of the formula HOOC-Cr^-F^(XI) or an ester thereof, for example a lower alkyl ester, for example as indicated for the reaction with compounds of the formula Illa. Compounds obtainable by the method can be transferred into other compounds with the formula I, transferring one or more variables with the general formula I into others. Thus, cyano can be hydrolysed to carbamyl, for example under basic conditions, such as in the presence of an alkali metal hydroxide. But cyano can also be transferred in N-lower alkyl-respectively N,N-dilower alkyl-carbamyl, for example by first transferring the nitrile with the formula I, for example by treatment with a lower alkanol, phenol or any other alcohol in an iminoether, react this with a mono- or di-alkylamine and hydrolyze the resulting amidine, preferably under mildly acidic conditions. Conversely, carbamyl R^ can be dehydrated to cyano, for example by treatment with a water-extracting agent, for example an acid anhydride, such as phosphorus pentoxide or phosphorus oxychloride, with a cyclic silasane or with dichlorocarbene or with trichloromethane in the presence of approx. 40% sodium hydroxide solution and a phase transfer catalyst, for example benzine-trimethylammonium chloride. ;Furthermore, one can transfer primary amino into acylamino, mono- or dilower alkylamino or transfer lower alkylene - respectively aza-, oxa- or thialaverealkylamino, similarly monolower realylamino into dilower alkylamino. The acylation takes place, for example, by reaction with a corresponding acid anhydride or chloride, such as acetic anhydride, the mixed anhydride of acetic and formic acid, a chloro or bromoformic acid lower alkyl ester, methanesulfonyl chloride or dimethylcarbamoyl chloride, the presence of a base, for example triethylamine or pyridine, is necessary , or in the presence of an acid, for example sulfuric acid. The lower alkylation takes place, for example, with a reactive ester of a lower alkane diol, respectively aza-moxa- or thial lower alkane diol, as a lower alkyl (endi) halide, for example -bromide or -iodide, lower alkyl (endi)sulfonate, for example - methanesulfonate or -p-toluenesulfonate, or with a dilave alkyl sulfate, for example dimethyl sulfate, preferably under basic compounds such as in the presence of caustic soda or potassium hydroxide and preferably in the presence of a phase transfer catalyst, such as tetrabutylammonium bromide or benzyltrimethylammonium chloride. In a completely analogous way, one can also transfer carbamyl R2 and/or R1 to N-acylcarbamyl, N-mono- or N,N-dilower alkylcarbamyl, respectively N,N-lower alkylenecarbamyl or N-N-(asa-, oxa- or thia)-lower- alkylenecarbamyl, one can likewise transfer N-monolower real alkylcarbamyl into N,N-dilower alkylcarbamyl, whereby particularly strong basic condensing agents may be necessary, such as alkali metal amides or alcoholates, for example sodium amide or sodium methanolate. The new compounds can, depending on the choice of the starting materials and working methods, exist in the form of one of the possible isomers, for example with regard to the position of R^; and R2, or as mixtures of these, depending on the number of asymmetric carbon atoms can the new compounds also exist as optical isomers, as antipodes or as mixtures of these, as racemates, diastereomer mixtures or racemate mixtures. Such mixtures of positional isomers as well as diastereomixtures and racemate mixtures can be split in a known manner into the pure positional isomers, diastereomers or racemates due to the physical-chemical differences of the components, for example by chromatography and/or fractional crystallization. The racemate content can be further cleaved in the optical antipodes according to known methods, for example by recrystallization of an optically active solvent, with the help of microorganisms or by reaction of an acidic precursor, for example by the formula VI (Y^ and/or Y^= carboxyl), with an optically active alcohol which with racemic acid forms an ester, and separation of the ester formed in this way into the diastereomers, for example due to their different solubilities, of which the antipodes can be released by the action of suitable agents. Preferably, the most effective of the two antipodes is isolated. Compounds of the formula I which form salt-forming racemates can also be cleaved by reaction with an optically active auxiliary compound in diastereomixtures, for example with an optically active acid in a mixture of diastereomers. acid addition salts and separation of these into the diastereomers, which enantiomers can be liberated in the usual way. For this purpose, common optically active acids are suitable, for example D- or L-tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic acid, camphorsulfonic acids or quinoic acid. Furthermore, free salt-forming compounds formed can be transferred in a manner known per se into acid addition salts, for example by reacting a solution of the free compound in a suitable solvent or solvent mixture with one of the above-mentioned acids or with a solution thereof, or with a suitable anion exchanger. Formed acid addition salts can be converted into the free compounds in a manner known per se, for example by treatment with a base, such as an alkali metal hydroxide, a metal carbonate or hydrogen carbonate, or ammonia, or by treatment with a suitable anion exchanger. Formed acid addition salts can, in a manner known per se, be transferred into other acid addition salts, for example by treating a salt of an organic acid with a suitable metal salt, such as a sodium, barium or silver salt, an acid in a suitable solvent, in which a formed inorganic salt is insoluble and is thus separated from the reaction mixture. The compounds include their salts can also be obtained in the form of their hydrates or include the solvent used for crystallization. Due to the close relationship between the new compounds, in free form and in the form of their salts, in the above and subsequently stated free compounds or their salts, the corresponding salts or free compounds should also be understood as appropriate. The invention also relates to such embodiments of the method after which one starts from any step of the method as an intermediate and similar compound and carries out the missing steps or uses a starting material in the form of a salt or forms a starting material in particular under the reaction conditions. Thus, all intermediate products with the formula IX can be formed in situ according to the process variants for reacting compounds with the formulas II and X and can be further reacted without isolation. New starting materials with the formulas II, V, VI, IX and XII, which were especially developed for the production of the compounds according to the invention, especially the starting materials which lead to the above as preferred characterizing compounds with the formula I, the method for their preparation and their applications as intermediate products as it is also the subject of the invention. ;The new compounds with the formula I can> find application; for example in the form of pharmaceutical preparations containing a therapeutically effective amount of active substance, optionally together with inorganic or organic, solid or liquid, pharmaceutically usable carriers that are suitable for an enteral, for example, oral or parenteral administration. Thus, tablets or gelatin capsules are used which contain the active substance together with a diluent, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, and/or a lubricant, for example silicon iodine, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets may also contain binders, for example magnesium aluminum silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatins, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrants, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or soft drinks or adsorbents, colourings, flavorings and sweeteners. Furthermore, the new compounds of formula I can be used in the form of parenterally administrable preparations or in the form of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, whereby these can be prepared before use, for example lyophilized preparations containing the active substance alone or together with a carrier material, for example mannitol. The pharmaceutical preparations may be sterilized and/or contain auxiliary substances, for example preservatives, stabilisers, wetting and/or emulsifying agents, solubility mediators, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical preparations, which, if desired, can contain additional pharmacologically active substances, are produced in a manner known per se, for example by means of conventional mixing, granulation, dragging, solubility or lyophilization methods, and contain from about. 0.1% to 100%, especially from approx. 1% to approx. 50%, lyophilisate contains up to 100% of the active substance. The compounds of formula I are preferably used in the form of pharmaceutical preparations. The dosage may depend on various factors, such as method of application, species, age and/or individual condition. The daily dose that can be administered is for oral application between approx. 5 and 50 mg/kg and for warm-blooded beings with a weight of approx. 0.5 g and about 5.0 g. The following examples serve to illustrate the invention; Temperatures are indicated in degrees Celsius. Example 1: 23 g (1 mol) of sodium are dissolved in 1 1 of ethyl alcohol and then 101 g (1.2 mol) of cyanoacetamide are added. 167.5 g (1 mol) of o-chlorobenzyl azide are added to this suspension at 40-50°C and heated for 2 hours at reflux. After cooling to 30°C, 1000 ml of water is added, the precipitated product is sucked off and washed several times with warm water. After recrystallization from dioxane and toluene, 5-amino-1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide is thus obtained in the form of colorless crystals at melting point 206°-207°. Example 2: In an analogous manner, 2,6-dichlorobenzyl azide is obtained starting from the 5-amino-1-(2,6-dichlorobenzyl)-1H-1,2,3-triazole-4-carboxamide, m.p. 243-245°C (after crystallization from methanol). The starting material can, for example, be produced in the following way. ;To a suspension of 7.2 g (0.11 mol) of sodium acid in 50 ml of dimethylsulfoxide, 24 g (0.1 mol) of 2,6-dichlorobenzyl bromide in 50 ml of dimethylsulfoxide are added at room temperature and left to stir for 2 hours at room temperature. It is then diluted with 250 ml of water, extracted with cyclohexane and the organic phase is washed several times with water. After drying over sodium sulfate, cyclohexane is distilled off at 50°C in a vacuum. 2,6-dichlorobenzyl azide is obtained as a colorless liquid. It is used without further purification. Example 3: In an analogous manner as described in example 2, starting from o-methylbenzyl chloride over a-azido-o-xylene, 5-amino-1-(o-methylbenzyl)-1H-1,2,3-triazole is obtained The -4-carboxamide melting point 227-228°C (after crystallization from dioxal/ethanol). Example 4: In an analogous manner as described in example 1, starting from o-fluorobenzyl azide 5-amino-1-(o-fluorobenzyl)-1H-1,2,3-triazole-4-carboxamide, melting point 189- 190°C /of methanol). Example 5: In an analogous manner to that described in example 1, starting from o-bromobenzyl azide 5-amino-1-(o-bromobenzyl)-1H-1,2,3-triazole-4-carboxamide is obtained, melting point 211 -213°; (of ethanol). Example 6: In an analogous manner as described in example 1, starting from o-trifluoromethylbenzyl azide 5-amino-1-(o-trifluoromethylbenzene)-1H-1,2,3-triazole-4-carboxamide is obtained, melting point 197-198 °C (of methanol). The starting material can, for example, be prepared in the following way: To a solution of 26.2 g (0.1 mol) of triphenylphosphine in 260 ml of toluene, at 10-20° C, a solution of 17, 4 g (0.1 mol) azodicarboxylic acid diethyl ester in 50 ml toluene and then at 5-10° C a solution of 17.6 g (0.1 mol) o-trifluoromethylbenzyl alcohol in 120 ml of a 1-normal solution of nitric hydrogen acids in toluene and leave to stir for 2 hours at room temperature. The precipitated hydrazine dicarboxylic acid ester is filtered off, the toluene solution is evaporated and the residue is treated with cyclohexane. The cyclohexane solution is decanted from the insoluble parts, fed through a small silica part and evaporated at 50°C in a vacuum. The o-trifluoromethyl-benzyl azide is thus obtained as a colorless liquid. Example 7: In an analogous way as described in example 6, starting from 2,3-dimethylbenzyl alcohol over 2,3-dimethyl-benzyl azide 5-amino-1-(2,3-dimethylbenzyl)-1H-1,2,3 -triazole-4-carboxamide, melting point 217°-219° C (from acetic acid ethyl ester). Example 8: In an analogous manner as described in example 2, starting from 1-(o-chlorophenyl)-phenethyl chloride over 1-(o-chlorophenyl)-ethyl azide 5-amino-1-phenyl-(o-chlorophenyl ) -ethylj-1H-1,2,3-triazole-4-carboxamide, m.p. 202°-204°C (of ethanol). Example 9: In an analogous manner to that described in example 2, starting from 1-(o-chlorophenyl)-propyl chloride over 1-(o-chlorophenyl)-propylazide, 5-amino-1-£-chlorophenyl)-propyl]J- The 1H-1,2,3-triazole-4-carboxamide, melting point 152-153°C (of ethanol). Example 10: In an analogous manner as described in example 6, starting from 1-(o-chlorophenyl)-butanol over 1-(o-chlorophenyl)-butylazide 5-amino-1-|l-(o-chlorophenyl ) -butyl} 1 H-1,2,3-triazole-4-carboxamide, melting point 150-152°C (of methanol). Example 11: 25.2 g (0.1 mol) of 5-amino-1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide is dissolved in 100 ml of dimethylformamide added dropwise while stirring at 0°C with 30.6 g (0.2 mol) phosphorus oxychloride. It is then quickly heated until the reaction mixture has reached 80°C and then immediately cooled again to 20°C. At this temperature, 100 ml of n-hydrochloric acid is added dropwise, then quickly heated and held back for 5 minutes. The hot reaction solution is diluted with 400 ml of water and the precipitated product is suctioned off. After washing several times with water and subsequent crystallization of ethyl alcohol, 5-amino-1'.-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid nitrile is thus obtained, melting point 174-176°C. ;Example 12; A solution of 11.7 g (0.05 mol) of 5-amino-1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid and 21.3 g; (0.15 mol) methyl iodide in 250 ml of acetonitrile is added dropwise at 20-25°C to a stirred suspension of 11.2 g of powdered potassium hydroxide and 1.6 g (0.005 mol) of tetrabutylammonium bromide in 100 ml of acetonitrile. After 1 hour, the inorganic material is decanted and the acetonitrile is evaporated in a vacuum. The residue is dissolved in diethyl ether, filtered off from undissolved material and the ether solution filtered through silica gel. After evaporation of the ether, 1-(o-chlorobenzyl)-5-dimethylamino-1H-1,2,3-triazole-4-carbonic acid nitrile is obtained with a melting point of 64-67°C. Example 13: To a solution of 13.1 g (0.05 mol) 1-(o-chlorobenzyl)-5-dimethylamino-1H-1,2,3,4-triazole-4-carboxylic acid in 300 ml ethanol and 25 ml of 5n caustic soda are added dropwise to 25 ml of a 30% hydrogen peroxide solution at 40-50°C. After completion of the dripping, the mixture is stirred for a further 2 hours at 40-50°C, then diluted with 600 ml of water and the precipitated product is suctioned off. After washing with water and crystallization from 70% ethanol, 1-(o-chlorobenzyl)-5-dimethylamino-1H-1,2,3-triazole-4-carboxamide is obtained, melting point 164-166°C. Example 14: 93 g (0.03 mol) of 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester is dissolved in 250 ml of methanol and saturated with ammonia at 50 °C. After this has remained for 3 days at 60°C, it is cooled, the crystallized product is suctioned off and washed with methanol. Thus, 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide with melting point 222-224°C is obtained. The starting material can be prepared, for example, in the following way: A solution of 8 g (0.054 mol) acetylene dicarboxylic acid dimethyl ester in 25 ml is added dropwise to a reflux boiling solution of 8.4 g (0.05 mol) 0-chlorobenzyl azide in 50 ml benzene benzene. After a further hour at reflux, it is diluted with 75 ml of cyclohexane and, after cooling, the crystallized substance is suctioned off. After washing with a mixture of diethyl ether and hexane (1:1), 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester with melting point 88-91 C. is thus obtained; Example 15: 2.7 g (10 mM) of 1-(o-chlorobenzyl)-5-methoxy-1H-1,2,3-triazole-4-carboxylic acid is heated for 30 minutes at reflux with 15 ml of thionyl chloride. The excess thionyl chloride is distilled off at 60°C in a vacuum and the remaining 1-(o-chlorobenzyl)-5-methoxy-1H-1,2,3-triazole-4-carboxylic acid chloride is dissolved in 20 ml of toluene. This toluene solution is added dropwise to 20 ml of a concentrated aqueous ammonia solution at 0-5°C. The precipitated product is suctioned off and washed several times with water. The 1-(o-chlorobenzyl)-5-netoxy-1H-1,2,3-triazole-4-carboxamide with melting point 185-187°C is obtained. The starting material can, for example, be prepared in the following way: To a solution of 1.15 g (50 mM) sodium in 50 ml ethanol is added a mixture of 8.4 g (50 mM) o-chlorobenzyl azide, ;8 g (50 mol) malonic acid ethyl ester in 25 ml of ethanol and leave to stand for 20 hours at room temperature. Then, 6.3 (50 mM) dimethylsulphate is added dropwise at 10-20°C and after one hour at 25°C evaporated in a vacuum. The residue is dissolved in ethyl acetate, washed with n-sodium hydroxide solution and then with water and re-evaporated. The remaining oil is brought to crystallization with 50 ml of diethyl ether. The 1-(o-chlorobenzyl)-5-methoxy-1H-1,2,3-triazo1-4-carboxylic acid ethyl ester with a melting point of 118-120°C is thus obtained. ;3,3 (11.2 mM) 1-(o-chlorobenzyl)-5-methoxy-1H-1,2,3-triazole-4-carboxylic acid ethyl ester is dissolved in 50 ml of hot ethanol and heated for 1 hour at reflux after addition of ml n-sodium lye. The precipitated sodium salt is brought into solution by adding 250 ml of water and then acidified with 15 ml of 2N hydrochloric acid. The precipitated product is suctioned off and washed with water. One thus obtains 1-(o-chlorobenzyl)-5-methoxy-1H-1,2,3-triazole-4-carboxylic acid with a melting point of 130-135° (during decarboxylation). Example 16: 6.4 g (27 mM) of 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid is heated for 1 hour at reflux with 50 ml of thionyl chloride. The excess thionyl chloride is then distilled off under vacuum, the remaining 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid chloride is dissolved in 50 ml of toluene and this solution is added dropwise to 50 ml of a concentrated aqueous ammonia solution at 5-10°C. The precipitated product is filtered off, washed with water and recrystallized from dioxal/ethanol. One thus obtains 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide with a melting point of 237-239°C. In an analogous way, 1-(o-chlorobenzyl)-1H-1,2,3-triazole-5-carboxamide with a melting point of 155-158°C can also be prepared. The starting materials can, for example, be prepared in the following way: A solution of 16.75 g (100 mM) o-chlorobenzyl azide, 7.35 g (100 mM) propionic acid and 200 ml toluene is stirred for 24 hours at 50°C. After cooling to room temperature, the precipitated product is filtered off with suction and first washed with toluene and then with diethyl ether. This gives 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid with a melting point of 175°C (initial cleavage). After evaporation of the filtrate and washing of the evaporation residue with a little toluene, 1-(o-chlorobenzyl)-1H-1,2,3-5-carboxylic acid with a melting point of 120°C (initial cleavage) remains. Example 17: A mixture of 25.2 g (100 mM) 1-(o-chlorobenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid and 100 ml of thionyl chloride is heated at reflux for 30 minutes. The excess thionyl chloride is then extracted in vacuo and the remaining 1-(o-chlorobenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid chloride dissolved in 100 ml of toluene. This solution is added dropwise to 100 ml of a concentrated aqueous ammonia solution at 5-10°C, the precipitated product is suctioned off and washed with water. After crystallization from ethanol, 1-(o-chlorobenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide with melting point 181-183°C is thus obtained. The starting material can, for example, be prepared as follows: To a solution of 2.53 g (110 mM) sodium in 100 ml of ethanol, 14.3 g (110 mM) ethyl acetate and 16.8 g (100 mM) o- chlorobenzyl azide and then heated 20 hours at reflux. ;After adding 100 ml of n-sodium lye, it is further heated for 2 hours at reflux and then acidified with hydrochloric acid, while it is still hot. The precipitated product is suctioned off and washed with water. After crystallization from ethanol, 1-(o-chlorobenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid with melting point 186-187°C (during decarboxylation) is thus obtained. Example 18: A solution of 14.7 g (100 mM) o-methylbenzyl azide and 8.3 g (100 mM) But-2-i-carboxamide in 20 ml of dioxane is heated for 16 hours at 100°C. After evaporation of the dioxane, the isomers are separated by column chromatography. One thus obtains 1-(o-methylbenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide with melting point 185-187° (of ethanol) and a by-product which is discarded. ;Example 19: In an analogous way as described in example 1; by reacting o-chlorobenzyl azide with 2-cyano-N-methyl-acetamide 5-amino-1-(o-chlorobenzyl)-1H-1,2,3 -triazole-4-(N-methyl)-carboxamide with melting point 140-142°C (from acetonitrile). Example 20: In an analogous manner to that described in example 1, reaction of o-chlorobenzyl azide with 2-cyano-N,N-dimethylacetamine yields 5-amino-1-(o-chlorobenzyl)-1H-1, The 2,3-triazole-4-(N,N-dimethyl)-carboxamide with melting point 143-145°C; (from acetonitrile). Example 21: In an analogous manner to that described in example 2, reaction of 2,3-dichlorobenzyl azide with cyanacetamide gives 5-amino-1-(2,3-dichlorobenzyl)-1H-1,2,3- triazo1-4-carboxamide, m.p. 224-226°C (of ethanol). The starting material can be prepared starting from 2,3-dichlorobenzyl alcohol by halogenation, for example with phosphorus tribromide and reaction with sodium acid. Example 22: 10.4 g raw, approx. 65% 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester is suspended in 50 ml of a 4n solution of ammonia in methanol and stirred for 1 hour at 50° C. The less soluble 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide is allowed to cool, filtered off and dissolved in dioxane from the filter cake. It is precipitated by evaporation and cooling of the dioxane solution in the form of crystals with a melting point of 222-224°C. The starting material can, for example, be prepared as follows: 1.15 g (50 mM) sodium is dissolved in 100 ml methanol. 9.25 g (50 mM) 1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester and 8.05 g (50 mM) o-chlorobenzyl chloride are added and heated for 24 hours by boiling. It is then evaporated until crystallization begins, allowed to cool and filtered off. The residue can be used after drying without cleaning. Example 23: In an analogous manner as described in example 6, starting from 2,4,6-trimethylbenzene alcohol over 2,4,6-trimethylbenzyl azide 5-amino-1-(2,4,6-trimethylbenzyl)-1H- The 1,2,3-triazole-4-carboxamide with melting point 195-196°C (of acetic acid ethyl ester). Example 24: In an analogous manner as described in example 6, starting from 5-chloro-2-methyl-benzyl alcohol over 5-chloro-2-methyl-benzyl azide 5-amino-1-(5-chloro-2-methyl) is obtained -benzy1)-1H-1,2,3-triazole-4-carboxamide with melting point 247-248°C (acetic acid). Example 25: In an analogous manner as described in example 1, starting from o-chlorobenzyl azide and cyanoacetic acid piperidide, 5-amino-1-(o-chlorobenzyl)-1H-1,2,3-triazo1-4-carboxylic acid is obtained the piperidide with melting point 138-140°C (ethanol). Example 26: In an analogous manner as described in example 2, starting from m-chlorobenzyl chloride over m-chlorobenzyl azide, 5-amino-1-(m-chlorobenzyl)-1H-1,2,3-triazole-4-carboxa- the mide with melting point 196-198°C (of ethanol). Example 27: In an analogous manner as described in example 2, starting from m-trifluoromethylbenzyl chloride over m-trifluoromethylbenzyl azide, 5-amino-1-(m-trifluoromethylbenzyl)-1H-1,2,3-triazole-4-carboxamide is obtained with melting point 206-207°C (of ethanol). Example 28: In an analogous manner as described in example 16, starting from 11.8 g (50 mmol) 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid is obtained over the acid chloride by treatment of this with piperidine (50 mmol) 1 -(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid piperidide with melting point 141-142°C; (from ethanol) and by treatment with dimethylamine (50 mmol) The 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid-N,N-dimethylamide with melting point 120-121°C (of ethanol). Example 29: In an analogous manner as described in example 1, starting from m-Methylbenzyl azide 5-amino-1-(m-methyl-benzyl)-1H-1,2,3-triazole-4-carboxamide with melting point 200 is obtained -202°C (from ethanol).; Example 30: In an analogous manner as described in example 16; starting from m-chlorobenzyl azide above 1 -(m-chlorobenzyl)-1H-1,2,3-triazole-* 4 -carboxylic acid with melting point 174-176 C (decomposition) 1-(m-chlorobenzyl)-r 1H— 1 , 2 , 3-triazole-4-carboxamide with melting point 223-224°C (from ethanol).

Example 31: In an analogous way as described in example 16

starting from m-trifluoromethylbenzyl azide over 1-(m-trifluoromethylbenzyl)-1H-1,2,3-triazole-4-carboxylic acid with melting point 171°C (decomposition) 1-(m-trifluoromethylbenzyl)-1H-1,2 The ,3-triazole-4-carboxylic acid amide with melting point 193-195°C (from ethanol).

Example 32: In an analogous way as described in example 1

by reacting o-chlorobenzyl azide and cyanoacetic acid-(4-methyl)-piperazide 5-amino-1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid-(4-methyl)- piperaside with a melting point of 114-116°C. The methanesulfonate melts at 208-210°C

(of acetone).

Example 33: Into a mixture of 30.7 g of acetic anhydride and 0.1 ml of sulfuric acid heated at 60° C, 10.1 g of 5-amino-1-(o-chlorobenzyl)-1H-1,2, 3-triazole-4-carboxamide. The ether is allowed to stir for 30 minutes at 60-70°C, preferably in 250 ml of ethanol, heated for 30 minutes at reflux, evaporated under reduced pressure to dryness and finely divided with 250 ml of ethyl ester. The quickly formed crystalline precipitate is sucked off and recrystallized by eddiester. 5-acetylamino-1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide with melting point 181-183°C is obtained.

The vinegar-ester mother liquor is combined and evaporated to dryness. The residue is purified and a silica gel column with toluene/acetic acid eluant. The crude eluate is evaporated and recrystallized from toluene. The 5-acetyl-amino-1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-(N-acetyl)carboxamide with melting point 140-142°C is obtained.

Example 34: In an analogous way as described in the examples

1-33 can be further produced:

1-(o-chlorobenzyl)-5-formylamino-1H-1,2,3-triazole-4-carboxamide, 1-(o-chlorobenzyl)-5-formylamino-1H-1,2,3-triazole-4- (N-formyl)-carboxamide, 5-ethoxycarbonylamino-1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide, 1-(o-chlorobenzyl)-5-(3,3-dimethylureido )-1H-1,2,3-triazole-4-carboxamide, 1 -(o-chlorobenzyl)-5-(N J N'-dimethylglycyamino)-1H-1,2,3-triazole-4-carboxamide, 5- ethoxyacetylamino-1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide, 1-(o-chlorobenzyl)-5-(4-methylpiperazinecarbonylamino)-1H-1,2,3-triazole- 4-carboxamide.

Example 35: Tablets each containing 50 mg of 5-amino-1-(o-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide can be prepared as follows.

The active substance is mixed with lactose and 292 g of potato starch, the mixture is moistened with an alcoholic gelatin solution and granulated through a sieve. After drying, the rest of the potato starch, the talc, the magnesium stearate and the highly dispersed silicon dioxide are mixed and the mixture is pressed into tablets with a weight of 145.0 mg and 50.0 mg active substance content, which, if desired, can be provided with full slits for better adaptation of the dosage .;

Example 36: Lacquer tablets each containing 100 mg of 5-amino-1-(o-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide can be prepared as follows:

The active substance, the lactose and 40 g of the corn starch are mixed and moistened and granulated with a paste made from 15 g of corn starch and water (while heating). The granulate is dried, the rest of the cornstarch, the talc and the calcium stearate are added and mixed with the granulate. The mixture is pressed into tablets (starting weight: 280 mg)

and these are lacquered with a solution of hydroxypropyl methyl cellulose and shellac in methyl chloride; final weight of the varnish tablets: 283 mg.

Example 37: In an analogous way as described in the examples

35 and 36 can also be made into tablets or lacquer tablets which contain another compound according to examples 1-34.

Example 38: The compound according to example 11 can also

can be obtained in the following other way:

1.15 sodium is dissolved in 50 ml of ethanol. A mixture of 8.4 g of o-chlorobenzyl azide, 3.3 g of malodinitrile and 50 ml of ethanol is then added, allowed to stand for 24 hours at room temperature and the solvent is distilled off under reduced pressure. The residue is shaken with 50 ml of 2n-hydrochloric acid and 100 ml of acetic acid ethylene ester, an organic phase separated, evaporated and the residue recrystallized twice from ethanol. Thus, 5-amino-1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid nitrile with melting point 174-176°C is likewise obtained.

Claims (10)

1. Process for the preparation of new 1-phenyl-lower-alkyl-1H-1,2,3-triazole compounds of the formula in which Ph means lower alkyl, halogen and/or trifluoromethyl substituted phenyl, alk means lower alkylidene, R means hydrogen, lower alkyl, lower alkoxy or an unsubstituted or with acyl, lower alkyl or lower alkylene respectively aza-, oxa- or thialeverealkylene substituted amino - or carbamyl group and R^ stands for an unsubstituted or with acyl, 'lower alkyl or lower alkylene respectively aza-, oxa- or thialeweralkylene substituted carbamyl group or gets cyano, if R^ denotes an unsubstituted or with acyl, lower alkyl or lower alkylene respectively aza-, oxa- or thialaverealkylene substituted amino group, respectively R2 stands for hydrogen or lower alkyl if R^ means an unsubstituted or with acyl, lower alkyl or lower alkylene, respectively aza-, oxa- or thialaverealkylene substituted carbamyl group, and salts of salt-forming compounds with the formula I, characterized by reacting an acid with the formula with a connection with the formula in which R^ denotes cyano or an unsubstituted or acyl, lower alkyl or lower alkylene respectively aza-, oxa- or thialeweralkylene substituted carbamyl group, Y.j denotes a disubstituted amino group or hydrogen, lower alkyl, lower alkoxy or unsubstituted or as indicated substituted carbamyl, if RL stands for an unsubstituted or with acyl, lower alkyl or lower alkylene, respectively aza-, oxa- or thialeverealkylene substituted carbamyl group, and Y2 and Y^ together denote an additional bond, or in which R^ denotes cyano or an unsubstituted or lower alkyl or lower alkylene, respectively aza-, oxa- or thialaverealkylene substituted carbamyl group stpr Y^ and Y2 together for imino and Y^ is hydrogen, or a tautomer and/or salt thereof, or. reacts a compound with the formula wherein Z is vetyr reactive ester hydroxy, with a 1-H-1,2,3-triazole derivative of the formula or a salt thereof, or in a compound of the formula in which Y^ denotes a residue Y^ and Y^ denotes an R^ group or a residue YB or Y^ denotes an R,, group and Yj. denotes a residue ■ Yg, whereby Y^ means an in unsubstituted or as indicated substituted carbamyl or in cyano transferable residue if Y^ denotes optionally as indicated substituted amine R. i and Y_B, means an in optionally as indicated substituted carbamyl transferable residue , or in a salt thereof, transfers Y in cyano or optionally as indicated substituted carbamyl and/or transfers Y0 in optionally as indicated substituted carbamyl or of a compound of the formula wherein Yg means a cleavable residue, of cleavage H-Yg or in a compound of the formula transfers the hydroxy group in lower alkoxy and -if necessary separates a formed isomer mixture into its components and isolates the isomer with the formula I and, if desired, converts the formed compound into another compound with the formula I and/or transfers a formed free compound in a salt or transfers a formed salt in the free compound. 2. Process according to claim 1, characterized in that one starts from a compound obtainable as an intermediate product at any stage of the process and carries out the missing steps or uses a starting material in the form of a salt or in particular forms a starting material under the reaction conditions, for example when reacting a compound with the formula with a compound of the formula in which R^ denotes cyano or an unsubstituted or with lower alkyl or lower alkylene respectively aza-, oxa- or thialaverealkylene substituted carbamyl group, and Y2 means lower alkoxy or optionally substituted amino, Y^ means hydrogen and Y^ and Yg means a further bond, or Y^ , Y and Y^ means lower alkoxy and Y^ and Yg means hydrogen or Y^ and Y^ together mean oxo, Y-j means hydrogen or lower alkyl and Y^ and Yg means hydrogen, or a tautomer and/or salt thereof and reacts the reaction product with the formula (IX) further without isolation. 3. Method according to one of claims 1 and 2. characterized by preparing compounds with the formula I, in which Ph means lower alkyl, halogen and/or trifluoromethyl substituted phenyl, alk means lower alkylidene, R^ means hydrogen, lower alkyl . -lower alkyl-, N,N-dilower alkyl-,N,N-lower alkylene-respectively N,N-(asa-,oxa- or thia)-lower alkylenecarbamyl and R2 stands for carbamyl, N-acylcarbamyl, N-lower alkyl-, N, N-dilower alkyl-, N,N-lower alkylene-respectively N,N-(asa-, oxa- or thia)-lower alkylenecarbamyl or, gets cyano if R^ is amino, acylamino, N-lower alkyl-, N,N-dilower alkyl- , N,N-lower alkylene- respectively N,N-(asa-, oxa- or thia)-lower alkyleneamino, respectively R2 stands for hydrogen or lower alkyl if R^ means carbamyl, N-acylcarbamyl, N-lower alkyl-, N,N- dilavere-alk yl, N,N-lower alkylene- respectively N,N- (asa-, oxa- or thia)-lower alkylenecarbamyl, whereby acyl in particular denotes lower alkanyl, lower lakoxy, lower alkoxycarbamyl, diloweralkylamino- lower alkanoyl, lower alkanesylphonyl, lower alkoxycarbamyl, ureido . dilower alkylamino respectively - carbamyl, lower alkoxy and lower alkylidene contain, for example, up to and including 7 C atoms and the lower alkylene, respectively aza-, oxa or thialavere alkylene contain, for example, 4 to and including 6 ring members, or salt of a salt-forming compound of the type defined above. 4. Process according to one of claims 1 and 2, characterized in that compounds of the formula I are prepared in which Ph means 2-halophenyl, 2-trifluoromethylphenyl, 2-lower alkylphenyl, 2,3- and 2,6-dihalophenyl, 2- halogen-3-lower alkyl-phenyl-respectively 3-halogen-2-lower alkylphenyl, 2-halogen-6-lower alkylphenyl, 2,3-respectively 2,6-lower alkylphenyl, 3-halogen-2-trifluoromethyl-phenyl respectively 2-halogen- 3-trifluoromethylphenyl or 2-halo-6-trifluoromethylphenyl, alk denotes 1,1-lower alkylidene, R. means hydrogen, lower alkyl, lower alkoxy, amino, lower alkylamino, dilower alkylamino, carbamyl, N-lower alkylcarbamyl or N,N-dilower alkylcarbamyl and R2 means carbamyl . 5. Process according to one of claims 1 and 2, characterized in that compounds with the formula I are prepared, in which Ph means with up to and including 3 lower alkyl groups respectively the halogen atom, lower alkyl and halogen and/or trifluoromethyl, whereby lower alkyl contains up to and including 4 C atoms, respectively halogen has the atomic number up to and including 35, substituted phenyl, alk denotes the 1,1-lower alkylidene with up to and including 4 C atoms, R^ means amino, lower alkanoylamino with up to and including 7 C atoms, lower alkylamino respectively diloweralkylamino with each up to and including 4 C atoms in the alkyl part and R2 denotes carbamyl, N-loweralkanoylcarbamyl with up to and including 7 C atoms, N-loweralkyl-, N,N-diloweralkyl- or N,N-loweralkylene-carbamyl with each up to and including 4 C atoms in the alkyl part respectively contains 4 up to and including 6 ring members in the alkylene part or means cyano. 6. Method according to one of claims 1 and 2, characterized in that compounds with the formula I are prepared, in which Ph means 2-halophenyl, 2-trifluoromethylphenyl, 2-lower alkylphenyl, or 2,6-dihalophenyl or 2,3-or 2,6-diloweralkylphenyl with lower alkyl substituents with up to and including 4 C atoms, respectively halogen substituents with the atomic number of and with 35, alk denotes the 1,1-lower alkylidene with up to and including 4 C atoms, R 1 stands for amino, lower alkyl aquino or di lower alkylamino with each up to and including 4 C atoms in the alkyl part and R 2 means carbamyl. 7. Method according to one of claims 1 and 2, characterized in that compounds with the formula I are prepared, in which Ph means 2-halophenyl, 2-trifluoromethylphenyl, 2-lower alkylphenyl, or 2,6-dihalophenyl or 2,3-or 2,6-diloweralkylphenyl with lower alkyl substituents with up to and including 4 C atoms or halogen substituents with the atomic number up to and including 35 , alk denotes the 1,1-lower alkylidene with up to and including 4 C atoms, R^ stands for amino, lower alkylamino or dilower alkylamino with each up to and including 4 C atoms in the alkyl part and R 2 means carbamyl or cyano. 8. Method according to one of claims 1 and 2, characterized in that 5-amino-1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide is produced. 9. Method according to one of claims 1 and 2, characterized in that 5-amino-1-(2,6-dichlorobenzyl)-1H-1,2,3-triazole-4-carboxamide, 5-amino- 1-(o-methylbenzyl)-1H-1,2,3-triazo1-4-carboxamide, 5-amino-1-(o-fluorobenzyl)-1H-1,2,3-triazo1-4-carboxamide, 5- amino-1-(o-bromobenzyl)-1H-1,2,3-triazole-4-carboxamide, 5-amino-1-(o-trifluoromethylbenzyl)-1H-1,2,3-triazole-4-carboxamide, 5-amino-1-(2,3-dimethylbenzyl)-1H-1,2,3-triazole-4-carboxamide, 5-amino-1-tho-(o-chlorophenyl)-ethyl)-1H-1, 2 , 3-triazole-4-carboxamide, 5-amino-1-{*-(o-chlorophenyl)-propylj -1H-1,2,3-triazole-4-carboxamide, 5 amino-1- £1 -( o-chlorophenyl)-buty]J - 1H-1,2,3-triazo1-4-carboxamide,5-amino-1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid, 1 -(o-chlorobenzyl)-5-dimethylamino-1H-1,2,3-triazole-4-carboxylic acid nitrile, 1 -(o-chlorobenzyl)-5-dimethylamino-1H-1 ,2,3-triazole-4- carboxamide, 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide, 1 -(o-chlorobenzyl)-5-methoxy-1H-1,2,3-triazole-4-carboxamide, 1 -(o-chlorobenzyl)-1H-1,2,3-triazo1-4-carboxamide, 1 - (o-chlorobenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide, 1-(o-methylbenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide, 5-amino-1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-(N-methyl)-carboxamide, 5-amino-1-(o-chlorobenzyl)-1H-1,2, 3-triazole-4-(N jN-dimethyl)-carboxamide or 5-amino-1-(2,3-dichlorobenzyl)-1H-1,2,3-triazo1-4-carboxamide. 10. Process according to one of claims 1 and 2, characterized in that 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide, 5-amino-1-(2 ,4,6-trimethylbenzyl)-1H-1,2,3-1triazole-4-carboxamide, 5-amino-1-(5-chloro-2-methylbenzyl)-1H-1,2,3-triazole-4- carboxamide, 5-amino-1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid piperidide, 5-amino-1-(m-chlorobenzyl)-1H-1,2,3- triazole-4-carboxamide, 5-amino-1-(m-trifluoromethylbenzyl)-1H-1,2,3-triazole-4-carboxamide,1 -(o-chlorobenzyl)-1H-1,2,3-triazole- 4-carboxylic acid piperidide, 1 -(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid-N,N-dimethylamide, 5-amino-1-(m-methylbenzyl)-1H-1,2, 3-triazole-4-carboxamide, 1-(m-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide, 1-(m-trifluoromethylbenzyl)-1H-1,2,3-triazole-4- carboxamide 5-amino-1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid-(4-methyl)-piperazide 1-(o-chlorobenzyl)-5-formylamino-1H-1, 2,3-triazole-4-carboxamide, 1-(o-chlorobenzyl)-5-formylamino-1H-1,2,3-triazole-4-(N-formyl)-carboxamide, 5-ethoxycarbony lamino-1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide, 1 -(o-chlorobenzyl)-5-(3,3-dimethylureido)-1H-1,2,3-triazo1-4-carboxamide, 1 -(o-chlorobenzyl)-5-(n; N <1-> dimethylglycylamino)-1H-1,2,3-triazole-4-carboxamide or 5- ethoxyacetylamino-1-(o-chlorobenzyl)-1H-1,2,3-triazo1-4-carboxamide, 1-(o-chlorobenzyl)-5-(4-methylpiperazinocarbonylamino)-1H-1,2, 3-triazole-4-carboxamide or an acid addition salt thereof.