DD216456A5 - METHOD FOR PRODUCING NEW ARALKYLTRIAZONE COMPOUNDS - Google Patents

Abstract

The invention relates to a process for the preparation of 1-phenyl-lower alkyl-1H-1,2,3-triazole compounds for use as medicaments. The aim of the invention is the provision of new compounds with valuable pharmacological properties, in particular with anticonvulsant effect. According to the invention, compounds of the formula I are prepared in which Ph is phenyl which is substituted by lower alkyl, halogen and / or trifluoromethyl, alk is lower alkylidene, R 1 is lower, lower alkyl, lower alkoxy or an unsubstituted or lower alkyl or lower alkylene or aza, Oxo o. Thianiederalkylen substituted amino or carbamyl groups u. R deep2 represents an unsubstituted or substituted by lower alkyl or lower alkylene or aza-, oxa- or thi-lower alkylene carbamoyl group, or, if R deep 1 represents an unsubstituted or substituted by lower alkyl or lower alkyl or aza-, oxa- or thi-lower alkylene, cyano or, where R 1 is an unsubstituted or substituted by lower alkyl or lower alkyl or aza-, oxa- or thioweralkylene substituted carbamoyl group, is hydrogen or lower alkyl.

Description

Berlin, 4 «6, 84 AP C 07 D / 258 352 8 63 195 i8 / 38

Process for the preparation of new 1-phenyl-lower alkyl-IH-1,2,3-

- A nwendungsgebiet de _mi r invention

The invention relates to a process for preparing novel Aralkyltriazolverbindungen, in particular 1-Phenylniederalkyl-lH »l _i 2,3 ~ triazole compounds having valuable pharmacological properties, in particular with anticonvulsant action.

The compounds prepared according to the invention are used as medicaments «

Characteristic of known ^

There is no information available which compounds with anticonvulsant effect have been used so far. There is also no information on processes for the preparation of Aralkyltriazolverbindungen known »

The aim of the invention is the provision of new compounds with valuable pharmacological properties, in particular special anti-convulsive effect «

The invention is based on the object of finding new compounds with the desired properties and processes for their preparation.

According to the invention, new 1-phenyl-lower alkyl-IH-I, 2,3-triazole compounds of the formula

Ph-alk.

manufactured,

wherein Ph is phenyl which is substituted by lower alkyl, halogen and / or trifluoromethyl, alk is lower alkylidene, R.sup.2 is hydrogen, lower alkyl, lower alkoxy or an amino or carbamyl group which is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or azato, oxo or thiani lower alkylene and R _{2 is} an unsubstituted or substituted by acyl, lower alkyl or lower alkylene or aza-, oxa- or thi-lower alkylene-substituted carbarayl group or, if R _{1 is} an unsubstituted or substituted by acyl, lower alkyl or lower alkylene or, aza-, oxa- or thi-lower alkyls Represents amino group, for cyano or, if R _{1 is} an unsubstituted or substituted by acyl, lower alkyl or lower alkylene or aza-, oxa- or Thianiederalkylen substituted carbamyl group stands for hydrogen or lower alkyl, and the salts of salt-forming compounds of the formula I.

The phenyl radical Ph contains, for example, bis and with three, in particular one or two, of the abovementioned substituents.

The invention relates, for example, to the production of such

more compounds of formula I wherein Ph which position _# is in 2 »position by lower alkyl * halogen or Trifluorraethyl and optionally additionally by lower alkyl or halogen, for example, in 3 ~" 4 "or 6" is preferably in the 3- or 6-position _t R _{1 represents} hydrogen, lower alkyl, lower alkoxy or an unsubstituted or lower alkyl-substituted amino or carbamyl group and R p represents unsubstituted or lower alkyl-substituted carbamyl or R _{1 is} unsubstituted or lower alkyl-substituted amino, stands for cyano.

Optionally substituted by acyl _s lower alkyl, lower alkylene or, aza · * , oxa »or Thianiederalkylen substituted amino is for example amino, physiologically easily cleavable acylamino, lower alkylamino, di-lower alkylaraino, 5- to 7-membered lower alkyleneamino or» aza- , oxa- or Thianiederalkylenaminö * Like is appropriately substituted carbamyl for example Carbatnyl _f physM.ogisch easily cleavable Acylcarbamylf N-Niederalkylcarbamyli N, N ~ Diniederalkylcarbamyl _e N _t N-Niederalkylen ~ or _e N ₄ N ^ - (AZa, oxa or thia) -niederalkylencarbamyl with 4 to 6 Ring members in Niederalkylen- or Aza-Ä Oxa »or _e Thianiederalkylenteil,

In a physiologically readily cleavable acylamino or "Acylcarbamylgruppe is acyl derived in particular from an optionally substituted by lower alkoxy or lower alkylated amino substituted lower alkanoic acid, a lower alkanesulfonic or an aliphatic Halbester or semiamide of carbonic acid, and for example represents lower alkanoyl, z _e B _e formyl" Acetyl ^ propionyl _s Butyry * isobutyryl,

Valeroyl or pivaloyl, lower alkoxy-lower alkanoyl, e.g. B, methoxy or ethoxyacetyl, di-lower alkylamino lower alkanoyl, e.g. B. Ν, Ν-dimethylcyclyl, lower alkanesulfonyl, 2, B. methane or Aethansulfonyl, lower alkoxycarbonyl, 2. B. methoxy, ethoxy, isopropyloxy or Tertiarbutyloxycarbonyl, ureido, 3-Niederaikyl- b2w, 3,3-diiederalkylureido or 3,3-lower alkylene-b2w, 3,3- (A2a, oxa or thia) -n-lower alkylenureido ·

Above and below, "lower" organic groups and compounds are understood as meaning, for example, those having up to and including 7, in particular up to and including _9, carbon atoms (C atoms),

Lower alkyl is, for example, methyl, ethyl, propyl, isopropyl. Butyl, isobutyl, secondary butyl or tertiary butyl, furthermore one of the isomeric pentyl, hexyl or heptyl groups,

Halogen is, for example, of the atomic number up to and including 35, such as fluorine, chlorine or bromine.

Re-alkylidene is, for example, 1,1-lower alkylidene having up to and including 4 C atoms, such as methylene, ethylidene, 1,1-propylidene, 1,1-butylidene, but may also be isopropylidene, 1,1-isobutylidene or a 1,1- Be pentylidene, 1,1-hexylidene or 1,1-heptylidene group.

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

Lower alkylamino and also those in 3-lower alkylureido is, for example, straight-chain lower alkylamino having up to and including 4 C atoms, such as methyl, ethyl, propyl or butylamino, but may also be branched lower alkylamino having up to and including 4 C atoms, such as isopropyl, isobutyl or tert-butylamino, or a pentylamino, hexylamino or heptylamino group, di-lower alkylamino and also those in 3,3-di-lower alkylureido is, for example, straight-chain di-lower alkylamino having in each case up to and including 4-carbon atoms, such as dimethylamine, diethylamino, methyl-ethyl-amino, Dipropylamino or dibutylamino, but can also be simply branched Diniederalstylamino each with up to and with 4 C-atoms, such as methyl isopropylamino. 5 ~ to 7 ~ membered lower alkyleneamino or aza-, oxa »or thianethioalkyleneamino, also as constituents of corresponding ureido groups is, for example, pyrrolidino, piperidino, piperazine or _e N'-lower alkyl, such as N'-methylpiperazino, morpholine or thiomorpholino *

N-lower alkylcarbamyl is, for example, straight-chain N-lower-alkylcarbamyl having up to and including 4-carbon atoms in the lower alkyl moiety, such as N, methyl, N-ethyl, N-propyl or N-butylcarbamyl, but may also be branched N-lower alkylcarbamyl having up to and including 4 lower alkyl C atoms, such as N-isopropyl, N-isobutyl, N-secondary butyl or N-tert-butylcarbamoyl or a pentylcarbamoyl, hexylcarbamoyl or heptylcarbamoyl group, Ν, Ν-di-lower alkylcarbamyl is for example straight-chain Ν, Ν-Diniederalkylcarbämyl each with up to and 4 C atoms in the lower alkyl, such as N, N-dimethyl, N _f N ~ Di§thyl ~, N-ethyl-N-methyl, Ν, Ν -Dipropyl- or Ν, Ν-dibutylcarbamyl, but can also be simply branched Ν, Ν-Diniederalkylcarbamyl with each to and 4

C atoms in the lower alkyl moieties, such as N-isopropyl-N-methyl- or N-isobutyl-N-methyl-carbamyl, or a Ν, Ν-dipentyl, Ν, Ν-dihexyl or Ν, Ν-diheptylcarboxylic group « N, N-lower alkylene- or N ₁ N- (aza, oxa or thia) -nlederalkylencarbamyl is, for example pyrrolidinocarbonyl, piperidinocarbonyl, piperazino or "N'-lower alkyl, such as N-Methylpiperazinocarbonyl, morpholinocarbonyl or Thiomorpholinoearbonyl.

Salt-forming compounds of the formula I are, for example, * in which R- represents an azino-lower alkylene-substituted amino group and / or carbamyl R ₁ and / or R "has one. As salts of such compounds are in particular their pharmaceutically acceptable acid addition salts with strong acids, such as mineral acid, eg. As salts with hydrogen halides, especially hydrochloric or hydrobromic acid, ie hydrohalides, especially hydrochlorides and hydrobromides, or sulfuric acid salts, ie hydrogen sulfates and sulfates, further salts with suitable organic acids, such as dicarboxylic acids or organic sulfonic acids, eg. As maleates, fumarates, maleates, tartrates or methanesulfonates, further N-cyclohexylsulfaminates, into consideration.

The novel compounds have valuable pharmacological properties, in particular a pronounced anticonvulsant activity, which, for example, in mice on the basis of a clear metrazol antagonism in the dose range of about 30 to 300 mg / kg po and mouse and rat on the basis of a pronounced protective effect against induced by electroshock Convulsions in the dose range of about 10 - 100 mg / kg p <o. (Mouse) or from about 5-50 mg / kg p _e o. (Rat)

show. Accordingly, the compounds of the formula I are excellently suitable for the treatment of convulsions of various origins, for example for the treatment of epilepsy. Accordingly, they can be used as anticonvulsant, for example antiepileptic, active pharmaceutical ingredients.

The invention relates especially to compounds of formula I wherein Ph represents by lower alkyl, halogen and / or Trifluorraethyl substituted phenyl, alk lower alkylidene, R ₁ is hydrogen, lower alkyl _s lower alkoxy, amino, acylamino, N-lower alkyl, Ν, Ν- Di-lower alkyl, Ν, Ν-lower alkylene «· or N, N (Aza ~, oxa- or thia) ~ lower alkyleneamino, garbamyl, N-acylcarbamyl or NN-alkylthio, Ν, Din-di-lower alkyl, N, N-lower alkyl N-, N- (Aza-, Oxa- or Thia) -n-lower alkylenecarbamyl and R _{2 is} carbarayl, N-acylcarbamyl, N-lower-alkyl, N-lower alkylene, N, N-lower alkylene. N, N- (aza, oxa) or thia) lower alkylene carbarnyl or, if R _{1 is} amino, acylamino _{t is} N-lower alkyl, N, N-lower alkyl, Ν, Ν-lower alkylene or N, N- Aza-, Oxa or Thia) -niederaikylenamino is, for cyano or _e , if R 'carbamyl, N ~ acylcarbamyl, N-lower alkyl, Ν, Din-di-lower alkyl, Ν, Ν-lower alkylene or N, N (Aza-, Oxa- or ThiaJ-niederalkylencarbamyl, represents acyl in particular in particular Niederaikanoyl, Niederalkoxyniederalkoxycarbonyl, di-lower alkylaminolower alkynoyl, Niederalkansulfonyl, Niederalkoxycarbonyl, Ureido, 3-lower alkyl or 3,3-diiederalkylureido or 3,3- Niederalkylen- or 3,3 ~ (Aza-, Oxa or Thia) -niederalkylenureido and lower alkyl and lower alkyl in N-lower alkyl or, N, N-DiniederaH <ylamino or, carbamyl,

Lower alkoxy and lower alkylidene ζ, B. bis and with 7 C-atoms and lower alkylene or, aza-, oxa- or Thianiederalkylen z. B, 4 to and having 6 ring members.

The invention relates in the first place to the preparation of z, B, of compounds of the formula I in which Ph is 2-halophenyl, 2-trifluoromethylphenyl, 2-lower alkylphenyl, 2,3- or 2,6-dihalophenyl, 2-halogen-3 lower alkylphenyl or, 3-halo-2-lower alkylphenyl, 2-halo-6-lower alkylphenyl, 2,3- or 2,6-di-lower alkylphenyl, 3-halo-2-trifluoromethyl-phenyl or 2-halo 3-trifluoromethylphenyl or 2-halo-6-trifluoromethylphenyl, alk is 1,1-lower alkylidene, R ₁ is hydrogen, lower alkyl, lower alkoxy, amino, lower alkylamino, Oiniederalkylamino, carbamoyl, N-lower alkylcarbamoyl or Ν, Ν-Diniederalkylcarbarayl and R ₂ Carbamyl, N-lower alkylcarbamyl or N, N-di-lower alkyl · carbamyl, wherein lower alkyl and lower alkyl in N-lower alkyl or, Ν, Ν-Oiniederalkylamino and -carbamyl, lower alkoxy and lower alkylidene z, B, to and with 7 carbon atoms eufweisen ,

The invention relates in particular to compounds of the formula I in which Ph has up to and lower alkyl groups or halogen atoms, lower alkyl and halogen and / or trifluoromethyl, where lower alkyl having up to and including 4 carbon atoms and z. B is methyl, or halogen has the atomic number up to and including 35, ie, fluorine, chlorine or bromine, substituted phenyl, the ζ. B. for 2-lower alkylphenyl, 2-resp. 3-halophenyl, 2-trifluoromethylphenyl, 2,3- or 2,6-di-lower alkylphenyl or 2,3-, 2,4- or 2,6-dihalogeno

phenyl, alk 1,1-lower alkylidene with bis and with 4 C atoms, ζ. B, methylene, ethylidene or 1,1-propylidene, R. Amino, lower alkanoylamino having up to and including 7 C atoms, such as formylamine, acetylamino or pivaloylamino, lower alkylamino or di-lower alkylamino, each with up to and including 4-C Atoms in the alkyl moiety, z is "B * acetylamino, methyl, ethyl" or propylamino, dimethyl or di-ethylaraino, and R _{2 is} carbamyl, N-lower alkanoylcarbamyl having up to and containing 7 carbon atoms, such as formyl, acetyl or pivaloylcarbamyl , N-lower alkyl, Ν, Ν-di-lower alkyl or N, N-lower alkylenecarbamyl having in each case up to and including 4 C atoms in the alkyl or 4 to and 6 ring members in the alkyl moiety, such as carbamyl, N-acetylcarbamyl, N- Methylcarbamyl, N, N-dimethylcarbamyl or piperidinocarbonyl, or cyano.

The invention relates in particular to the production of

compounds of the formula I in which Ph is lower alkyl or halogen substituents lower alkyl having bis and 4-C atoms, z. B, methyl or ethyl, or halogen of the atomic number to and with 35, z. B, chloro-containing 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, z, B, 2,6-dichlorophenyl, or 2,3- or 2,6-di-lower alkylphenyl, such as 2,3-dimetylphenyl _# , alk 1,1-lower alkylidene having up to and including 4 C atoms, z, B * is methylene, ethylidene or 1,1-propylidene, R _{1 is} amino, lower alkylamino or di-lower alkylamino having in each case up to and including 4-C atoms in the alkyl moiety, eg. Ö, methyl, ethyl or propylamino, dimethyl or Diäthylamino means and Rp carbamyl or cyano means.

The invention relates in particular to the preparation of the compounds of the formula I mentioned in the examples.

The process for the preparation of the novel compounds of the formula I is characterized in that, for example, an azide of the formula

Phalk - N ₃ (II)

with a compound of the formula

Y ₁ - C = C - R 1 (III),

YY ^Y 2 -3

ivorin Ri is cyano or an unsubstituted or by acyl, or lower alkylene Uiederalkyl or aza-, oxa- or thia-lower alkylene is substituted carbamyl, Y * as indicated a disubstituted amino group or, if i '. \ for an unsubstituted or by acyl' is lower alkyl or lower alkylene or aza-, oxa- or thio-lower alkylene-substituted carbamyl group, hydrogen, lower alkoxy or unsubstituted or substituted as indicated carbamyl, and Y ₂ and Y, together represent an additional bond, or wherein R 'is cyano or an unsubstituted or acyl, lower alkyl or lower alkylene t.::v. Aza, oxa or substituted Thiäniederalkylen carb εmylgruppe represents, Y. and Y ₂ together represent imino and Y is hydrogen, or a tautomer and / or salt thereof, if necessary, an obtained Isomerenciemisch is separated into its components and the isomer of Formula I isolated and, if desired, the method according to the method

converts available compound into another compound of formula 1,

Tautomers of compounds of the formula III are, for example, cyanoacetyl-tautomers of the formula NaC-CH ₂ -R '(IIIa) of ketimine compounds of the formula III, in which Y ₁ and Y 1 represent imino and Y _{3 is} hydrogen.

Salts of compounds of formula III are for example metal salts, such as alkali metal salts, of compounds of formula III, wherein Y ₁ and Y "together represent imino, and Y ₃ is hydrogen, or dter tautomers of formula IIIa thereof.

The reaction is carried out in a customary manner, advantageously in an inert solvent, if necessary in the presence of a condensing agent and / or at elevated temperature. Inert solvents are, for example, aromatic or araliphatic hydrocarbons, such as benzene or toluene, ocier ethers, such as Tertiärbutoxymethan, tetrahydrofuran or dioxane, and for the reaction with compounds of the formula IHa furthermore alcohols such as lower alkanols, z. As methanol, ethanol or butanol. Condensation agents are, for example, for the reaction with compounds of formula III, wherein Y and Y _{2 are} common einin imino and Y _{3 is} hydrogen, or whose tautomers of the formula IIIa salt-forming condensing agents such as metal alkoxides, ζ. Sodium methoxide, sodium ethoxide, or other alkali metal lower alkanolates, metal amides such as sodium amide, lithium diisopropylarcide and the like, or organometallic compounds such as lower alkyl magnesium halides or lower alkyl lithium compounds, e.g. As methyl or butylmagnesium bromide or butyl lithium. Instead of working in the presence of one of the condensation agents mentioned, it is also possible to use the component of the formula III or IIIa as salt.

Preferred embodiments of this method are at "represent game, the reaction of an azide of formula IX with a compound of formula III, wherein Y * is hydrogen or lower alkyl and Y, and Y ₃ is an additional bond, in benzene or dioxane at about 60-120 ⁰ C, preferably boiling temperature, and with compounds of the formulas IIIa in the presence of sodium methoxide or sodium ethoxide and methanol or ethanol as solvent at about 40 to 100 ⁰ G, preferably at the boiling point.

Starting materials of the formula III and partially of the formula II are known. Novel starting materials of the formula II can be obtained in analogy to the mode of formation of the known, for example by reacting a compound of the formula Ph-alk-X; IV), in which X is reactive esterified hydroxy, such as halogen, for. For example, chlorine, bromine or dod, or sulfonyloxy, such as Niederalkansulfonyloxy, optionally substituted benzenesulfonyloxy, such as methane, ethane, benzene, p-toluene or p ~ bromobenzenesulfonyloxy, or fluorosulfonyloxy, with an alkali metal azide, z. As sodium azide, for example, in Oimethylsulfoxid or dimethylformamide, or by reacting an alcohol of the formula IV (X = hydroxy), in the presence of triphenylphosphine and a Azodicarbonsäureesters, z. B, of diethyl azodicarboxylate, with hydrazoic acid for reaction, for example in toluene.

The novel compounds can be further prepared by reacting a compound of the formula

Ph - alk - Z (IV),

wherein Z is reactive esterified hydroxy, with a 1H-1,2,3-triazole derivative of the formula

(V)

or a salt thereof,

if necessary, a isomer mixture obtained is separated into the components and the isomer of the formula I is isolated and, if desired, the compound obtainable according to the method is converted into another compound of the formula I.

Reactive esterified hydroxy Z is, for example, halogen, e.g. B. chloro, bromo or Dod, or sulfonyloxy, such as Niederalkansulfonyloxy, optionally substituted benzenesulfonyl, such as methane, ethane, benzene, p-toluene or p-bromobenzenesulfonyloxy, or fluorosulfonyloxy ·

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

The reaction is carried out in a customary manner, for example in the presence of a basic condensing agent or, advantageously, by using the component of the formula V as salt, if necessary with heating, preferably in a solvent or diluent. Basic condensing agents are, for example, with the component

the formula V salt-forming basic condensing agents, such as alkali metal alcoholates «z. B, sodium methoxide or sodium ethoxide. Alkali metal or alkaline earth metal amides, e.g. B. matriumamide or lithium diisopropylamide. As mentioned, the conversion of the component of the formula V into one of its salts is advantageously carried out in advance, z, B, by reaction with one of the bases mentioned. Solvents are preferably the corresponding alcohols for carrying out the reaction in the presence of an alcoholate and, for example, aprotic organic solvents such as phenylsulfuric acid or dimethylbenzenesulfides, eg. As hexamethylphosphoric triamide or dimethyl sulfoxide.

The method is particularly suitable for the preparation of compounds in which an amino group R * or the amino group as part of a carbamyl group R _{2 is} at least 11-mono-, preferably Ν, Ν-disubstituted, ie acylamino, fjiaderalkylamino or preferably di-lower alkyl, Niederialkyien or (N'-lower alkyl) represents aza, oxa or thian-lower alkylene-amino ·

Pie starting materials of the formula IV and V can, if they are not already known, were prepared in the usual way. To obtain compounds of formula IV z. Example, by esterifying a corresponding alcohol of formula IV (Z = hydroxy) reactive, z, B. by means of thionyl chloride, phosphorus tribromide or a sulfonyl chloride. Compounds of the formula V can be prepared by

trimethylsiliacid or hydrazoic acid having a formula

Y ₁ - C = C - R £ (III),

YY ^Y 2 ^Y 3

in which R * is cyano or a carbamoyl group which is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or aza-, oxa- or thia-lower alkylene, Y _{1 is} a disubstituted amino group as indicated or, if R p is an unsubstituted or acyl, lower alkyl or lower alkylene or Aza, Oxa or Thianiederalkylen substituted carbamoyl group, hydrogen, lower alkyl, lower alkoxy or unsubstituted or substituted as indicated carbamyl, and Y "and Y ₃ together represent an additional bond, or wherein Ro cyano or an unsubstituted or acyl, lower alkyl or Lower alkylene or aza, oxa or Thianiederalkylen substituted carbamyl, Y * and ¹ Yg together represent imino and Y, is hydrogen, or a tautomer and / or salt thereof and, if desired, in the resulting 1-Trimethylsilyltriazolderivat an amino group R ₁ and / or carbamyl group R ₂ acylated or lower alkylated substituted by lower alkylene or Aza-, Oxa- or Thianiederalkylen and cleaves the silyl group by mild hydrolysis.

The novel compounds can be further prepared by reacting in a compound of formula

Ph-alk-N

^Y 4

(VI),

^Y 5

Y. is a radical Y. and Y _{5 is} an R ^ group or a radical / ₃ or Y _{4 is} an Rp group and Y _{5 is} a radical Y _β , where Y. is unsubstituted or substituted as indicated carbamyl or, if Y, - optionally substituted R ₁ as indicated, in cyano and Y _ß in optionally as indicated substituted Garbamyl Überführbären radical, or in a salt thereof Y _A in cyano or optionally as indicated substituted carbamyl and / or Y _ß in optionally as indicated substituted carbamyl, if necessary, a resulting isomer mixture is separated into the components and the isomer of the formula I is isolated and if desired (the process according to the invention obtainable compound is converted into another compound of formula I,

Radicals Y. and _Y.sup.β according to the above definition are, for example, carboxy groups which are free or present in a salt or anhydride form, optionally N-lower-alkylated or by lower-alkylene or -azo, oxa or thianethylene-alkylene, Ν-disubstituted amidino groups or esterified carboxy groups, Radicals Y _β furthermore cyano groups,

Esterified carboxy groups are, for example, carboxy groups esterified with a lower alkanol or a lower alkyl mercaptan, i. h, lower alkoxy or lower alkylthiocarbonyl groups, but may also be esterified with any other alcohol or mercaptan, ζ, B. with an optionally substituted phenol or thiophenol.

In salt form, carboxy groups are for example: Ln one of ammonia or a mono- or di-lower alkyl

amine-derived ammonium salt form present carboxy groups, further in metal, z. B. alkali or alkaline earth metal salt form present carboxy groups.

Anhydride carboxy groups are, for example, carboxy groups present in a halide form, such as chlorocarbonyl, but may also be anhydrided with a reactive carboxylic acid and may be, for example, alkoxycarbonyloxycarbonyl or trifluoroacetoxycarbonyl.

Optionally lower alkylated or by lower alkylene or aza-, oxa- or thioweralkylene Ν, Ν-substituted amidino groups are, for example, unsubstituted or N-mono-, N, N-di- or N, N-D-lower alkylated or, by lower alkylene or aza- , Oxa or thia-lower alkylene N, N-disubstituted amidino groups

The conversion of said Y. in cyano or optionally substituted carbamyl as indicated or Y ₅ in optionally substituted as indicated carbamyl in the usual manner, starting from free, esterified or present in an anhydride form carboxy groups and optionally N-nxederalkylierten or by lower alkylene or aza-, oxa- or thi-lower alkylene N, N-disubstituted amidino groups by solvolysis, ie hydrolysis or ammonia or aminolysis (reaction with ammonia or a mono- or di-lower alkylamine, lower alkyleneamine or aza-, oxa- or thioweralkyleneamine).

By hydrolysis, for example, optionally

lower alkylated or _e by lower alkylene or "Aza, Oxa" or Thianiederalkylen Ν, Ν-disubstituted amidino Y. and / or Y ₅ in optionally substituted carbamyl and cyano Y _g in carbamyl, Oie hydrolysis example, in the presence of an acidic hydrolysis, such as a mineral, sulfonic or carboxylic acid, for example, sulfuric acid, phosphoric acid, hydrochloric acid or another hydrohalic acid, p-toluenesulfonic acid or another organic sulfonic acid, or a lower alkanoic acid, such as acetic acid, preferably in catalytic amounts.

By means of ammonia or aminolysis, it is possible for example to convert free or present in a salt form or esterified carboxy groups into unsubstituted or substituted carbamyl as indicated. In this case, if necessary, working in the presence of a condensing agent, advantageously in an inert solvent, condensing agents are starting from present in anhydride form carboxy example, basic condensing agents such as alkali metal hydroxides or carbonates, or organic nitrogen bases, such as the oinzuführenden amino group corresponding amines in excess or tertiary organic nitrogen bases, such as Triniederalkylamine or tertiary heteroaromatic nitrogen bases, ivio triethylamine or pyridine, and starting from esterified em carboxy acid condensing agent, such as mineral acids, such as hydrohalic acids and the like. Free carboxy groups may be obtained by dehydration of the intermediately formed ammonium salts, e.g., by heating or by the action of nascent agents, such as acid anhydrides, z, B, phosphorus pentoxide, acetyl chloride and the like, or

Carbodiimides, ζ. As NjN'-dicyclohexylcarbodiimide, be converted into optionally lower alkylated carbamyl.

The starting materials of the formula VI can, if they are not known, be prepared in the usual manner, for example by reacting an azide of the formula

t.

Ph - * alk - N ₃ (II)

with a compound of the formula

Y ₁ - C = C- Y ₄ (VII)

YY ^Y 2 ^Y 3

wherein Y is a group Y ₅ and Y p and Y ₃ represent an additional bond or Y is or ₁ is hydrogen or lower alkyl, Y ₂ is hydroxy and Y ₇ is hydrogen, Y ₁ and Y ₂ together represent imino, and Y ₃ is hydrogen or a tautomer _t and / or salt thereof, for example, as described for the reaction with corresponding compounds of formula III.

Starting materials of the formula VI in which Y ₅ is lower alkoxy and Y is a group Y _A can furthermore be prepared by reacting an azide of the formula II with an acid of the formula H00C-CH ₂ -Y _A (XI), or an ester, such as lower alkyl esters thereof, z, B, with a Nalonsaurediniederalkylester, and / or a salt thereof, preferably in the presence of a Alkalimetallalkanolates and in the formed 5-hydroxy-l-Phalk-4-Y _A -lH-l, 2,3 Triazole the hydroxy group niederalkyliert

preferably by reaction with a reactive lower alkyl ester, such as dimethyl sulfate "in the presence of sodium hydroxide.

The novel compounds can be further prepared by reacting a compound of the formula

N Ph -alk-N

R ₂ (IX),

^Y 6 ^H

in which _{Y.sup.β is} a leaving group which is cleavable, H-Yg is split off and if necessary a separated isomer mixture is separated into the components and the isomer of the formula I is isolated and, if desired, the compound obtainable according to the process is converted into another compound of the formula I.

Yg removable radicals are for example hydroxy "lower alkoxy or optionally substituted amino groups, lower alkoxy lower alkoxy is preferably identical to R ₁ and optionally substituted amino preferably by free or substituted amino R. ₁

The elimination of HY ^ is generally spontaneous, in some cases, the supply of thermal energy or the presence of an acidic or basic agent «such as a mineral acid, z, B, sulfuric or hydrochloric« or a carboxylic or sulfonic acid «z , B. of acetic or p-toluenesulfonic acid, or an alkali metal hydroxide or alcoholate, e.g. As sodium methoxide, be beneficial «

The starting materials of the formula IX are preferably prepared in situ and reacted further without isolation, for example

by adding a compound of the formula

Ph - alk - N ₃ (II)

with a compound of the formula

YY ^Y 7 ^Y 8

Y ₁ -CC- R · (X),

^Y 2 ^Y 3

wherein R * represents cyano or a carbamoyl group which is unsubstituted or substituted by lower alkyl or lower alkylene or aza- , oxa- or thia-lower alkylene, Y. and Y _{2 are} lower alkoxy or optionally substituted amino R ₁ , Y is hydrogen and Y ₇ and Y _{g are} an additional bond or ^Y l ^{f Y} 2 ^{unci Y} 7 ^Never deralkoxy ^{and Y} 3 and Y _{Q is} hydrogen or Y. and Yp together oxo, Y _{7 is} hydrogen or FJiederalkyl and Y ₃ and Yg is hydrogen or a tautomer and / or salt thereof, for example with a compound of the formula Y ^ -C (= O) -CH ₂ -R ^ (Xa; Y ^ s hydrogen or lower alkyl), Y ₁ -C (Y ₂ ) SCH-R ^ (Xbs Y ₁ and Y ₂ lower alkoxy or independently of one another unsubstituted or substituted as specified for R. amino), or Y ₁ -C (Y ₂ X (Y ₇ J-CH ₂ -R ₂ (Xc; Y ₁ , Y ₂ and Y ₇ = lower alkoxy)).

Compounds of the formula I in which R _{1 is} lower alkoxy can also be prepared by reacting in a compound of the formula

Ph-alk-

N__

(XII)

^R 2

HO

the hydroxy group is converted into lower alkoxy and, if necessary, a resulting mixture of isomers is separated into the components and the isomer of the formula I is isolated and if desired the compound obtainable by the process is converted into another compound of the formula I.

The conversion of hydroxy into lower alkoxy is carried out, for example, by reaction with a reactive lower alkyl ester, such as a hydrogen halide such as hydrochloric, hydrobromic or hydriodic acid ester, a sulfuric acid ester, üV-h. a di-lower alkyl sulfate, or a sulfonic acid ester, such as a lower alkane or optionally substituted benzenesulfate ester, ζ, Β. Methane, benzene, p-toluene or p-Brombenzolsulfonsäureester a lower alkanol, advantageously in the presence of a basic agent such as an alkali metal hydroxide, carbonate or alcoholate, for. Example of sodium or potassium hydroxide, potassium carbonate or sodium, or a tertiary organic nitrogen base, such as a Triniederalkylamine * z. B, of triethylamino, or of pyridine.

The starting materials of the formula XII can be obtained, for example, by reacting an azide of the formula

Ph - alk - N ₃ (II)

with an acid of the formula HOQC-CHL-Rp (XI) or an ester, e.g. B, a lower alkyl ester thereof, e.g. B, as indicated for the reaction with compounds of the formula IUa «

Compounds obtainable by the process can be converted into other compounds of the formula I by converting one or more variables of the general formula I into others.

Thus, cyano R ₂ can be hydrolyzed to carbamyl, for example under basic conditions, such as in the presence of an alkali metal hydroxide. "Cyano can also be converted into N-lower alkyl or N, N-di-lower alkyl-» carbamyl, for example by reacting the nitrile of the formula I first, z, B. converted by treatment with a lower alkanol, phenol or any other alcohol in an imino ether, reacting this with a mono- or di-lower alkylamine, and hydrolysing the amidine formed, preferably under mildly acidic conditions,

Conversely, one can dehydrate carbamyl R ₂ to cyano, for example by treatment with a dehydrating agent, for. B, an acid anhydride, such as phosphorus pentoxide or phosphorus oxychloride, with a cyclic silazane or with dichlorocarbon or with trichloromethane in the presence of about 40% sodium hydroxide solution and a phase transfer catalyst, for. B. before benzyltrimethylammonium chloride *

Furthermore, you can primary amino R ₁ in acylamino, mono- or di-lower alkylamino or lower alkylene or »Aza, Oxa»

or Thianiederalkylenamino, as well Mononiederalkylainino R ₁ in Diniederalkylamino convert. The acylation takes place ζ. 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 Bromameisensäureniederalkylester, methanesulfonyl chloride or dimethylcarbamoyl chloride, if necessary in the presence of a base, for. From triethylamine or pyridine, or an acid, e.g. B. of sulfuric acid. The lower alkylation is carried out z, B. Kit a reactive ester of a lower alkanediol or aza-, Cxa- or Thianiederalkandiols, such as a lower alkyl (endi) -nalogenid, z. B. bromide or iodide, lower alkyl (endi) sulfonate, z. For example, methanesulfonate or p-toluenesulfonate, or a Diniederalkylsulfat, ζ. Β. Dimethyl sulfate, preferably under basic conditions, such as in the presence of sodium hydroxide or potassium hydroxide, and advantageously a phase transfer catalyst such as tetrabutylammonium bromide or benzyltrimethylammonium chloride * In a very similar manner can also Carbamyl Rp and / or R * in N-acylcarbamyl, N-Monooder N , N-di-lower alkylcarbamyl or Ν, Ν-Niederalkylencarbrmyl or NN- (Aza-, Oxa or ThiaJ-niederalkylencarbamyl, as well as N-Mono-lower alkylcarbamyl in N, N-di-lower alkylcarbamyl, but mean more basic Kondensationsini, tt el, such as alkali metal amides or - Alcohols, z "B, sodium amide or sodium methoxide, may be required.

The new compound can, depending on the choice of starting materials and procedures, in the form of one of the possible isomers, eg. B. respect to the position of R. and R _2, or as mixtures thereof, depending on the number of asymmetric carbonic

furthermore, as optical isomers, such as antipodes, or as mixtures of these, such as racemates, diastereoisomeric mixtures or racemic mixtures.

Obtained mixtures of positional isomers and diastereomer mixtures and racemate mixtures can be separated in a known manner in the pure position isomers, diastereomers or Raceraate due to the physico-chemical differences of the constituents, for example by chromatography and / or fractional crystallization. "Racemates obtained can also be prepared by known methods decompose into the optical antipodes «, for example, by recrystallization from an optically active solvent, by means of microorganisms or by reaction of an acidic precursor, for. B. of the formula VI (Y and / or Y ₅ 'is carboxyl) with a forming with the racemic ester optically active alcohol and separation of the ester thus obtained, Eg on the basis of their different solubilities, into the diastereomers , from which the antipodes can be released by the action of suitable agents, decomposed. Advantageously one isolates the more effective of the two antipodes.

Racemates of salt-forming compounds of the formula I can also be prepared by reaction with an optically active auxiliary compound in diastereomeric mixtures, for example with an optically active acid in mixtures of diastereomeric acid addition salts, and separation of these into the diastereomers from which the enantiomers are liberated in the usual manner can be split.

For this purpose, common optically active acids are, for. For example, D- or L-tartaric acid, di-o-toluyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acids or quinic acid.

Furthermore, obtained free salt-forming compounds can be converted in a conventional manner in acid addition salts, for. 3. by reacting a solution of the free compound in a suitable solvent or Lösungsraiertgamisch with one of the aforementioned acids or with a solution thereof, or with a suitable anion exchanger ·

Obtained 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 bicarbonate, or ammonia, or with a suitable anion exchanger.

Acid addition salts obtained can be converted in a conventional manner into other acid addition salts, for. 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 forming inorganic salt is insoluble and thus precipitates out of the reaction mixture.

The compounds, including their salts, may also be obtained in the form of the hydrates or include the solvent used for crystallization.

Owing to the close relationship between the new compounds in free form and in the form of their salts,

gene and useful hereinafter also understand the appropriate salts or free compounds among the free compounds or their salts.

The invention also relates to those embodiments of the process according to which one proceeds from a compound obtainable as an intermediate at any stage of the process and performs the missing steps or uses a starting material in the form of a salt or forms in particular under the reaction conditions.

Thus, all intermediates of formula IX according to the process variant of the reaction of compounds of formulas II and X can be formed in situ and further reacted without isolation.

Heue starting materials of the formulas II, V, VI, IX and XII, which were developed specifically for the preparation of the compounds of the invention, in particular the starting material selection leading to the compounds of the formula I indicated at the outset, the processes for their preparation and their use as intermediates also form an object of the invention,

The novel compounds of formula I can, for. B, in the form of pharmaceutical preparations which contain a therapeutically effective amount of the active substance, optionally together with inorganic or organic, solid or liquid, pharmaceutically acceptable excipient which are suitable for enteral, z, B, oral, or parenteral administration. How to use tablets

or gelatin capsules containing the active ingredient together with diluents, e.g. As lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and / or lubricant ,, z, B, silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol have. Tablets may also bind, e.g. Magnesium aluminum silicate, starches, such as corn, i / eizen. Rice or arrowroot starch, gelatin, tragacanth, i'iethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. For example, starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners. Furthermore, the novel compound of the formula I can be used in the form of preparations which can be administered by paraffin or of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these z. As in lyophilized preparations containing the active substance alone or together with a carrier material, for. As mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and / or excipient * 3, z. B, preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations, which, if desired, may contain other pharmacologically active substances are prepared in a conventional manner, for. Example by means of conventional mixing, granulation, coating, solution or lyophilization, prepared and contain from about 0.1 % to XOO %, in particular from about 1 % to about 50 %, lyophilizates ö:, 8 to 100 % of active ingredient.

The compounds of the formula I are preferably used in the form of pharmaceutical preparations. The dosage may depend on various factors, such as the mode of administration, species, age and / or individual condition. The doses to be administered daily are between about 5 and 50 mg / kg for oral administration and about 0.5 g for warm-blooded animals weighing about 70 kg, and about 5.0 g.

Au sfü _{i i} h _i run _i 9 _{i i} e sb _ii isP _i) i el _i

The following examples serve to illustrate the invention; Temperatures are given in degrees centigrade »

EXAMPLE 1 23 g (1 mol) of sodium are dissolved in 1 l 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 at 40 ° -50 ° to this suspension and heated to reflux for 2 hours. After cooling to 30 ° is added 1000 ml of water, the precipitated product is filtered off and washed several times with warm water. Recrystallization from dioxane and toluene gives 5-amino-1- (o-chlorobenzyl) -

in the form of colorless crystals from

Mp 206 ° - 207 °

2: In an analogous manner, starting from

2,6-dichlorobenzyl azide, 5-amino-1- (2,6-dichlorobenzyl) -1H-1,2,3-triazole-4-carboxamide, mp, 243-245 ° (after crystallization from methanol).

The starting material can be prepared as follows.

- 30 -.

To a suspension of 7.2 g (0.11 mol) of sodium azide in 50 ml of Oimethylsulfoxyd be added at room temperature, 24 g (U ₁ I mol) of 2,6-dichlorobenzyl bromide in 50 ml of dimethyl sulfoxide and allowed to stir for 2 hours at room temperature. It is then diluted with 250 ml of water, extracted with cyclohexane and the organic phase washed several times with water. After drying over sodium sulfate, the cyclohexane is distilled off at 50 ° in vacuo. The 2,6-dichlorobenzyl azide is obtained as a colorless liquid. It is used without further purification,

Example 3t In a manner analogous to that described in Example 2, starting from o-methylbenzyl chloride, 5-amino-1- (o-methylbenzyl) -1H-1,2,3-triazole-4 is obtained via N-azido-o-xylene carboxamide, mp 227-228 ° (after crystallization from dioxane / ethanol).

Example 4; In a manner analogous to that described in Example 1, starting from o-fluorobenzyl azide, the 5-amino-1- (o-fluorobenzyl) -1H-1,2,3-triazole-4-carboxamide, mp, 189 190 ° (from methanol).

Example 5; In an analogous manner as described in Example 1, starting from o-bromobenzyl azide, the 5-amino-l- (a-.bromobenzyl) -LH-l, 2,3-triazole-4-carboxamide, mp. 211 - 213 ° ν from ethanol) ·

Example 6: In a manner analogous to that described in Example 1, starting from o-trifluoromethylbenzyl azide, the 5-amino-1- (o-trifluoromethylbenzyl) -1H-1,2,3-triazole-4-carboxamide, mp, 197 - 198 ° (from methanol),

The starting material may, for example, be prepared as follows:

To a solution of 26.2 g (0.1 mol) of triphenylphosphine in 260 ml of toluene is added dropwise at 10 - 20 ° initially a solution of 17.4 (o _e l Hol) Azodicarbonsäurediäthylester in 50 ml of toluene and then at 5-10 ° Add a solution of 17.6 g (0.1 mol) of o-trifluoromethylbenzyl alcohol in 120 ml of a! Normal solution of Stickstoffv / acid acids in toluene and allowed to stir for 2 hours at room temperature. The precipitated hydrazino-dicarboxylic acid ester is filtered off with suction, the toluene solution is evaporated and the residue is treated with cyclohexane. The cyclohexane solution is decanted from the insoluble parts, filtered through a little silica gel and evaporated at 50 ° in vacuo. This gives the o-trifluoromethyl benzyl azide as a colorless liquid.

Example 7: In a manner analogous to that described in Example 6, starting from 2,3-dimethylbenzyl alcohol over 2,3-dimethylbenzyl azide, 5-amino-1- (2,3-dimethylbenzyl) -1H-1,2, 3-triazole-4-carboxamide, m.p. 217-219 (from ethyl acetate).

Example 8t In analogous manner as described in Example 2, starting from 1- (o »chlorophenyl) -phenyläthylchlorid over l- (o-chlorophenyl) ethyl azide, the 5-amino-1- ^ 1«. (o-chlorophenyl) ethyl J7 -HH-1,2,3-triazole-4-carboxamide, mp, 202-204 ° (from ethanol).

B EISP iel 9s In analogous manner as described in Example 2, but starting from l- (o »chlorophenyl) ~ -propylchlo

on l- (o-chlorophenyl) propyl azide, the 5-amino-1-1 / 2 "1- (oo-fluoro-phenyl) -propyl- _i 7'-lH-1,2,3-triazole-4-carboxamide, m.p. -153 ° (from ethanol).

Example 10: In a manner analogous to that described in Example 6, starting from 1- (o-chlorophenyl) butanol via 1- (o-chlorophenyl) -butyl azide, the 5-amino-1- (~ l- (o-) chlorophenyl) -

Mp. 150 - 152 ° (off

Methanol).

EXAMPLE 11 25.2 g (0.1 mol) of 5-aminol-1- (o-chlorobenzyl) -1H-1,2,3-triazole-4-carboxamide are dissolved in 100 ml of dimethylformamide and stirred at 0 added dropwise with 30.6 g (0.2 mol) of phosphorus oxychloride. Then it is heated rapidly until the reaction mixture has reached 80 ° and then cooled immediately to 20 °. At this temperature, 100 ml of n-hydrochloric acid are added dropwise, then heated rapidly and heated to reflux for 5 minutes. The hot reaction solution is diluted with 400 ml of water and the precipitated product is filtered off with suction. After repeated washing with water and subsequent crystallization from ethyl alcohol to give the 5-amino-l- (o-chlorobenzyl) -IH-1,2,3-triazole-4-carbonitrile, mp. 174-176 °.

EXAMPLE 12 A solution of 11.7 g (0.05 mol) of 5-amino-1- (10-chlorobenzyl) -1H-1,2,3-triazole-4-carbonitrile and 21.3 g ( 0.15 mol) of methyl iodide in 250 ml of acetonitrile. at 20 - 25 ° added dropwise in 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 decanted nan from the inorganic material and evaporates the acetonitrile in vacuo. The residue is dissolved in diethyl ether, filtered from the undissolved material and the ether solution filtered through silica gel. After evaporation of the ether gives the 1- (o »chlorobenzyl) -5 ~ dimethylamino ~ lH-l, 2 _i 3-tria2ol-4-carbonitrile, mp. 64- 67 °,

Example 13 _{i iii:} To a solution of 13.1 g (0.05 mole) of l ~ (ochlorbenzyl) -5-dimethylamino «lH» l, 2,3,4-triazol-4 ~ carbons8U-renitril in 300 ml of ethanol and 25 ml of 5N sodium hydroxide solution are added dropwise at 40-50 25 ml of 30% hydrogen peroxide solution. After completion of the dropwise addition is stirred for 2 hours at 40 - 50, then diluted with 600 ml of water and the precipitated product is filtered off with suction. After washing with water and crystallization from 70% ethanol, the 1- (o-chlorobenzyl) -dimethylamine-1,1,3,3-triazole-4-carboxamide, mp 164-166 °, is obtained.

Example 14 i 93 g (0.03 mol) of l ~ (o-chlorobenzyl) -IH-I, 2,3-triazole-4,5-dicarboxylic acid dimethyl ester are dissolved in 250 ml of methanol and saturated with ammonia at 50 °. After standing for 3 days at 60 is cooled, the crystallized product is filtered off with suction and washed with methanol. This gives the 1- (o-chlorobenzyl) -1H, 1,3-triazole-4,5-dicarboamide of mp 222-224 °.

The starting material may be prepared, for example, as follows:

To a refluxing solution of 8.4 g (0.05 mol)

o-Chloro-benzyl azide in 50 ml of benzene is added dropwise a solution of 8 g (0.054 mol) of dimethyl acetylenedicarboxylate in 25 ml of benzene. After a further hour at reflux, it is diluted with 75 ml of cyclohexane and, after cooling, the crystallized substance is filtered off with suction. After washing with a mixture of diethyl ether and hexane (Isi), the 1- (o-chlorobenzyl) -1H-1,2 is obtained. Dimethyl 3-triazole-4,5-dicarboxylate of mp, 88-91 °.

Example 15: 2.7 g (10 mM) of 1- (o-chlorobenzyl) -5-methoxy-1H-1,2,3-triazole-4-carboxylic acid are refluxed with 15 ml of thionyl chloride for 30 minutes. The excess thionyl chloride is distilled off at 60 ° in vacuo and the residual l- (o-chlorobenzyl) -5-methoxy-lH-l, 2,3-triazole-4-sarbonsäurechlorid dissolved in 20 ml of toluene. This toluene solution is added dropwise at 0-5 ° to 20 ml of a concentrated aqueous ammonia solution. The precipitated product is filtered off with suction and washed several times with water. 185-187 °, the l- (o-chlorobenzyl) -5-methoxy-lH-l, 2,3-triazole-4-carboxamide, mp.

The exit material can z. B, made as follows:

To a solution of 1.15 g (50 mM) of sodium in 50 ml of ethanol is added a mixture of 8.4 g (50 mmol) of o-chlorobenzyl azide, 8 g (50 mol) of malonic acid diethyl ester in 25 ml of ethanol and allowed to stand for 20 hours stand at room temperature.

Oanη be added dropwise at Io - 20 ° 6.3 g (50 mM) of dimethyl sulfate and evaporated after one hour at 25 ° in vacuo.

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. This gives the 1-> (o-chlorobenzyl) -5-methoxy-1H-1,2,3-triazole-4-carboxylic acid ethyl ester of melting point 118-120 °.

3.3 g (11.2 mM) of ethyl (O-chlorobenzyl) - S-methoxy-1H-1-triazole-4-carboxylate are dissolved in 50 ml of warm ethanol and, after addition of 15 ml of 1N sodium hydroxide solution, for 1 hour The precipitated sodium salt is brought into solution by addition of 250 ml of water and then acidified with 15 ml of 2N hydrochloric acid, the precipitated product is filtered off with suction and washed with water to give the 1- (o-chlorobenzyl) -5- Methoxy-lH-l, 2,3-triazole-4-carboxylic acid, mp. 130 - 135 ° (with decarboxylation).

Example 16; 6.4 g (27 mM) of 1- (o-chlorobenzyl) -1H-1,2,3-triazole-4-carboxylic acid are refluxed with 50 ml of thionyl chloride for 1 hour. Then distilling the excess thionyl chloride in vacuo, 2 _f 3-triazol-4 "carboxylic acid chloride dissolves the remaining l- (o-chlorobenzyl) ~ lH-l, in 50 ml of toluene and added dropwise to this solution at 5 - 10 ° to 50 ml of a concentrated aqueous ammonia solution. The precipitated product is filtered off, washed with water and recrystallized from dioxane / ethanol. This gives the 1- (o-chlorobenzyl) -1H-1,2,3-triazole-4-carboxamide, mp. 237-239 °.

In an analogous manner, the. - (o-chlorobenzyl) -LH-l, 2,3-triazole-5-carboxamide of mp, 155-158 ° can be prepared.

The starting materials can ζ. B, are prepared as follows:

Lino solution of 16.75 g (100 mM) of o-chlorobenzyl azide, 7.35 g (100 mM) of propenoic acid and 200 ml of toluene is stirred at 50 ° for 24 hours. The precipitated product is filtered off with suction after cooling to room temperature and washed first with toluene and then with diethyl ether. This gives the 1 "(o-chlorobenzyl) -1H-1,2,3-triazole-4-carboxylic acid of mp ₄ 175 (dec.). After evaporation of the filtrates and washing of the residue with a little toluene, the l- (o-chlorobenzyl) -LH ~ l _? 2,3,5-carboxylic acid of mp. 120 ° (dec.) Back.

Ba ispiel 17: A mixture of 25.2 g (100 mM) .l- (o-chlorobenzyl) -5-methyl-1H-1,2,3-triazole-4-carboxylic acid and 100 ml of thionyl chloride is refluxed for 30 minutes The excess thionyl chloride is then stripped off in vacuo and the residual 1- (o-chlorobenzyl) -5-methyl-1H-1,2,3-triazole-4-carbonyl chloride is dissolved in 100 ml of toluene. This solution is added dropwise at 5-10 to 100 ml of a concentrated aqueous ammonia solution, the precipitated product is filtered off with suction and washed with water, s. After crystallization from ethanol, the 1- (o-chlorobenzyl) -5-methyl-1H-1,2,3-triazole-4-methylcarboxamide, mp 181 ° -183 °, is obtained in this way.

The starting material may, for. B. be prepared as follows,

To a solution of 2.53 g (110 mM) of sodium in 100 ml of ethanol are added 14.3 g (110 mM) of ethyl acetoacetate and 16.8 g (100 mM) of o-chlorobenzyl azide and then heated for 20 hours

to reflux.

After addition of 100 ml of η-sodium hydroxide solution is heated to reflux for a further 2 hours and then acidified while still warm with hydrochloric acid. The precipitated product is filtered off with suction and washed with water. After crystallization from ethanol, the l- (o- <

acid of mp, 186-187 ° (with decarboxylation).

Example 18 : A solution of 14.7 g (100 mM) of o-methyl-benzyl azide and 8.3 g (100 mM) of but-2-ynecarboxamide in 20 ml of dioxane is heated at 100 ° for 16 hours. After evaporation of the dioxane, the isomers are separated by column chromatography.

Thus, the L- (o-methylbenzyl) -5-methyl-IH-I, 2,3-triazole-4-carboxamide, mp. 185 -'Ii a by-product which is discarded.

triazole-4-carboxamide of mp. 185-187 ° (from ethanol) as well as

Example 19: In a manner analogous to that described in Example 1, the reaction of o-chlorobenzyl azide with 2-cyano-N-methyl-acetamide gives 5-amino-1- (o-chlorobenzyl) -1H-1,2,3 triazole-4- (Ni acetonitrile).

triazole-4- (N-methyl) -carboxamide, mp. 140 - 142 ° (aus

Example 2Qi ₁ In a manner analogous to that described in Example 1, the reaction of o-chlorobenzyl azide with 2-cyano-N, M-dimethyl-acetamide gives 5-amino-1- (o-chlorobenzyl) -1H-1, 2,3- "triazole-4- (N, N-dimethyl) -carboxamide, mp 143 145 ° (from acetonitrile).

Example 21: In analogous manner as described in Example 2, the reaction of 2,3-dichlorobenzyl azide with cyanoacetamide gives 5-amino-1- (2,3-dichlorobenzyl) -LH-!, S-triazole ^ -carboxamide, mp. 224-226 ° (from ethanol). The starting material can be prepared starting from 2,3-dichlorobenzyl alcohol by halogenation, eg. B. be prepared with phosphorus tribromide and reaction with sodium azide.

Example 22t 10.4 g of crude, about 65% l- (o-chlorobenzyl) -iH-l, 2,3-triazole-4,5-dicarboxylic acid dimethyl ester are suspended in 50 ml of a 4N solution of ammonia in methanol and 1 Stirred at 50 °. It is allowed to cool, filtered off with suction and dissolved in dioxane moderately soluble l- (o-chlorobenzyl) -LH-l, 2,3-triazole-4,5 ~ dicarboxamide with dioxane from the Nutsch cake out. It precipitates during concentration and cooling of the dioxane solution in the form of crystals of mp 222-224.

The starting material may, for. B. be prepared as follows:

1.15 g (50 mM) of sodium are dissolved in 100 ml of methanol,. 9.25 g (50 mM) of l, 2,3-triazole-4 _s -dimethyl dicarboxylate and 8.05 g (50 mmol) of o-chlorobenzyl chloride are added and the mixture is heated for 24 hours. Then it is concentrated to the onset of crystallization one, allows to cool and sucks. The residue can be used after drying without purification.

BOiSP ₁₁ Ie I 25: In an analogous manner as described in Example 6, starting from 2,4,6-trimethylbenzyl alcohol over 2,4i6-trimethylbenzyl azide, the 5-amino-l- (2,4,6 ~ tri ~

methylbenzyl) -lH-i, 2,3-triazole-4-carboxamide, mp 195 196 ° (from ethyl acetate),

Example 24: In a manner analogous to that described in Example 6, starting from 5-chloro-2-methylbenzyl alcohol over S-chloro-methyl-benzyl azide, the 5-amino-1- (5-chloro-2-methyl) benzyl) -LH-l _l 2,3-triazole «4-carboxamide, mp. 247 248 ° (acetic acid).

Example 25: In a manner analogous to that described in Example 1, starting from o-chlorobenzyl azide and cyanoacetic acid piperidide, the 5-amino-i- (o-chlorobenzyl) -IH-1,2,3-triazole-4-carboxylic acid piperidide of the mp, 138-140 ° (ethanol),

Bei pi el 26 In an analogous manner as in Example 2, but starting from m-chlorobenzyl chloride over m-Chlorbenzylazid the 5-amino-l- (m-chlorobenzyl) -IH-1,2,3-triazol-4- carboxamide of mp, 196-198 ° (from ethanol),

Example 27; In a manner analogous to that described in Example 2, starting from m-trifluoromethylbenzyl chloride over m-trifluoromethylbenzyl azide, the 5-amino-1- (m-trifluoromethylbenzyl) -1H-1,3,3-triazole-4-carboxamide of the mp, 206 - 207 ° (from ethanol).

Example 28: In an analogous manner as described in Example 16, starting from 11.8 g (50 mmol) of 1- (o-chlorobenzyl) -1H-l, 2,3-triazole-4-carboxylic acid over the acid chloride by treatment of the same with piperidine (50 mmol), the 1- (o-chlorobenzyl) -1H-1,2,3-triazole-4-carboxylic acid piperidide

, - 40 -

from mp, 141-142 ° (from ethanol) and by treatment with dimethylamine (50 mmol) the 1- (o-chlorobenzyl) -1H-1,2,3-triazole-4-carbonyl ethanol).

4-Carboxylic acid-N, N-dimethylamide, mp. 120 - 121 ° (from

Example 29: In an analogous manner as described in Example 1, starting from m-methylbenzyl azide, the 5-amino-lim-methylbenzyl) -LH-l, 2,3-triazole-4-carboxamide, mp. 200 202 ° (from ethanol)

Example 30: In a manner analogous to that described in Example 16, starting from m-chlorobenzyl azide, over the 1- (m-chlorobenzyl) _r lH-l, 2,3-triazole-4-carboxylic acid, mp. 174-176 ° ( Dec.). The l- (m-chlorobenzyl) -LH ~ l, 2,3 ~ triazole-4-carboxamide, mp 223-224 ° (from ethanol). "

Example 31: In a manner analogous to that described in Example 16, starting from m-trifluoromethylbenzyl azide, there is obtained the 1- (ni-trifluoromethylbenzyl) -1H-1,2,3-triazole-4-carboxylic acid of mp 171 ) Zers.) The l- (m-tpifluoromethylbenzyl) lH-l, 2,3 ~ triazole-4-carboxamide, mp. 193-195 ° (from ethanol).

Example 32: In a manner analogous to that described in Example 1, the reaction of o-chlorobenzyl azide and cyano-8-acetic acid (4-methyl) piperazide gives 5-amino-1- (o-chlorobenzyl) -NH-1 , 2, 3-1-riazole-4-carboxylic acid- (4-methyl) -piperazide of mp 114-116 °. The methanesulfonate melts at 208-210 ° (from acetone).

Example 33: Into a mixture of 30.7 g heated to -60 °

Acetic anhydride and 0.1 ml of sulfuric acid are added in portions with stirring 10.1 g of 5-amino-l- (o ~ cblorbenzyl) -LH-l, 2,3- «triazole-4-carboxamide entered. The mixture is stirred for 30 minutes at 60-70 °, poured into 250 ml of ethanol, heated to reflux for 30 minutes, evaporated to dryness under reduced pressure and digested with 250 ml of ethyl acetate. The crystalline precipitate formed immediately is filtered off with suction and recrystallized from ethyl acetate. This gives 5-acetylamino-1- (o-chlorobenzyl) -1H-1,2,3-triazole-4-carboxamide, mp. 181-183 °.

The ethyl acetate-mother liquors are combined and evaporated to dryness. The residue is purified by chromatography on a silica gel column using toluene / ethyl acetate as eluent. The crude product is evaporated and recrystallised from toluene. The 5-acetylamino-1- (o-chlorobenzyl) -1H-1,2,3-triazole-4- (N-acetyl) carboxamide of mp 140-142 ° is obtained.

Example 34: In a manner analogous to that described in Examples 1, it is also possible to prepare:

l- (o-ChlorbenzylJ-5-formylamino-IH-1,2,3-triazole-4-carboxamide,

1- (o-chlorobenzyl) -5-formylamino-lH-i, 2,3-triazol-4- (ω-methyl) -ca-rboxamide,

5-Äthoxycarbonylamino-l- (o-chlorobenzyl) -lH-l, 2,3-triazol-4-carboxamide,

4-carboxamide,

l- (o-chlorobenzyl) -5- (N ', N'-dimethylglycylamino) -lH-l, 2,3-triazol-4-carboxamide,

5-Ä \ thoxyacetylamino-l- (o-chlorbehzyl) -lH-l, 2,3-triazol-4-carboxamide.

-. - 42 -

1- (o-chlorobenzyl) -5- (4-methylpiperazinocarbonylamino) -1H-l _< 2,3-tria2ol-4-carboxamide _<>

In section 35: tablets containing 50 mg each of 5-amino-1- (ethylbenzyl) -1H-1,2,3-triazole-4-carboxamide _# can be prepared as follows.

Composition (10000 tablets)

active substance 500.0 g lactose 50O ₉ o g potato starch 352.0 g gelatin 8.0 g talc 60.0 g magnesium stearate 10.0 g Silica (highly dispersed) 20.0 g / \ THANOL q.s.

g potato starch, the mixture is moistened with an alcoholic solution of gelatin and granulated through a sieve. After dehydration, the remainder of the potato starch, talc, magnesium stearate and fumed silica are mixed and the mixture is compressed to give tablets each of 145.0 mg in weight and 50.0 mg of active ingredient, optionally with partial scores to finely adjust the dosage could be"

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

- 43 composition (for 1000 tablets)

active substance 100.00 g lactose 100.00 g corn starch 70.00 g talc 8.50 g calcium stearate 1.50 g Hydroxypropyl methylcellulose 2:36 shellac o, 64g water q.s. methylene chloride q.s.

The active ingredient, the lactose and 40 g of the corn starch are mixed and moistened with a paste prepared from 15 g of corn starch and water (with heating) and granulated. The granules are dried, the remainder of the corn starch, the talc and the calcium stearate are added and mixed with the granules. The mixture is compressed into tablets (weight: 280 mg) and coated with a solution of the hydroxypropylmethylcellulose and the shellac in methylene chloride t final weight of the coated tablet: 283 mg.

Example 37: In a manner analogous to that described in Examples 35 and 36, tablets or coated tablets containing another compound according to Examples 1-34 can also be prepared.

Example 38: The compound according to Example 11 can also be obtained in the following ways:

1.15 g of sodium are dissolved in 50 ml of ethanol. Then a mixture of 8.4 g of o-chlorobenzyl azide, 3.3 g of malodi,

nitrll. and 50 ml of ethanol, 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 ethyl acetate, the organic phase separated, evaporated and the residue recrystallized twice from ethanol. This also gives the 5-amino [i ~ (o-chlorobenzyl) -IH-1,2,3-triazole-4-carbonitrile of the Srap * 174-176 °.

Claims (49)

Erf u ng sans P rue h .... · '' 1. A process for the preparation of new I-Phenylniederalkyl-IH «1,2,3-triazo.l compounds of the formula ^, N-N
Ph-alk-f / - _fr . R ₁ wherein Ph is phenyl which is substituted by lower alkyl, halogen and / or trifluorotiethyl, alk is lower alkylidene, R _{1 is} Valerof, lower alkyl, lower alkoxy or an unsubstituted or acyl, lower, alkyl or lower alkylene or aza, xxa And Rp is an unsubstituted or substituted by acyl, lower alkyl or lower alkylene or aza-, oxa- or Thianiederalkylen substituted carbyl or, if R _{1 is} an unsubstituted or acyl, lower alkyl or lower alkyl to or ~ aza, oxa represents ocTer thia-lower alkylene substituted .minogruppe, cyano or, where R ₁ is a u! or substituted by acyl, lower alkyl or alkylene Miede bziv. Aza-, oxa- or thia-lower alkylene subs ituierte carbamyl means represents hydrogen or lower alkyl, and salts of the salzbildei Verbindu strength aer formula I, characterized in that one Cass an A ^ id of the formula Ph - alk with a compound of the formula YY
^Y 2 3 in which R 'represents cyano or a carbamoyl group which is unsubstituted or substituted by acyl, lower alkyl or lower alkylene or aza, "oxa" or thia-lower alkylene, Y _{1 is} a disubstituted amino group as indicated or, if R' is an unsubstituted or acyl, lower alkyl or lower alkylene or «Aza-, Oxa or Thianiederalkylen substituted carbamyl group. Is hydrogen, lower alkyl, lower alkoxy or unsubstituted or substituted as indicated carbamyl and Y "and Y ₃ together represent an additional bond, or wherein Rp is cyano or an unsubstituted or substituted by lower alkyl or lower alkylene or aza-, oxa- or thioweralkylene carbamyl group, Y. and Y ₂ together represent imino, and Y ₃ is hydrogen, or a tautomer and / or salt thereof, or reacting a compound of formula Ph - alk - Z (IV), wherein Z is reactive esterified hydroxy, with a 1-H-1,2,3-T _r iazolderivat the formula (V) R ₂ ^R l or a salt thereof or in a compound of the formula NJU Ph-alk-f (VI) Rest Y _B means or a radical Y and Y _{5 is} an R ^ group or a an R ₂ ~ group and Y _{5 represents} a radical Y ", wherein Υ * represents an unsubstituted or substituted as indicated carbamyl or, if Y, - optionally substituted as indicated amino R *, in cyano and Y" one in optionally as indicated Substituted carbamyl convertible radical, or in a salt thereof Y ^ in cyano or optionally substituted as indicated substituted carbamyl and / or Y _ß in optionally substituted as / / substituted carbamyl or from a compound of formula wherein Y _{6 is} a leaving group, splits off HY ₆ or in a compound of the formula Ph-alk-N (XII) the hydroxy group is converted into lower alkoxy and, if necessary, a resulting isomer mixture is separated into the components and the isomer of formula I is isolated and if desired the compound obtainable by the process is converted into another compound of the formula I and / or a free compound obtainable by the process in a salt or a process according to the available Salt into the free compound, ^{2 3} wherein RL is cyano or a carbamoyl group which is unsubstituted or substituted by lower alkyl or lower alkylene or aza-, oxa- or thi-lower alkylene, Y ₁ and Y _{2 are} lower alkoxy or optionally substituted amino R ₁ , Y _{3 is} hydrogen and Y ₇ and Yg are an additional bond, or Y ₁ , Yp and Y _{7 are} lower alkoxy and Y ₃ and Yg are hydrogen or Y ₁ and Yp together are oxa, Y ₇  .-... '- 49 -'. ; Hydrogen or lower alkyl and Y ₃ and Yg are hydrogen, or a tautomer and / or salt thereof and the reaction product of the formula (IX) further reacted without isolation. Method according to item I _1, characterized by proceeding from a compound obtainable as an intermediate at any stage of the process and carrying out the missing steps or using a starting material in the form of a salt or, in particular, under the reaction conditions, for example by adding a compound the formula Phalk - N ₃ (II) with a compound of the formula ^Y 7 Y   ι Y ₁ - C - C - R £ (X) ₁ YY 3. Process according to one of the items 1 and 2, characterized in that compounds of the formula I in which Ph is phenyl which is substituted by lower alkyl, halogen and / or trifluoromethyl, alk is lower alkylidene, R _{1 is} hydrogen, lower alkyl, lower alkoxy, amino, Acylamino, N-lower alkyl, Ν, Ν-lower alkyl, -. Ν, Ν-lower alkylene or N, N- (Aza-, Oxa or Thia) -niederalkylenamino, carbamyl, N-acylcarbamyl or N-lower alkyl, N, N-di-lower alkyl, N, N-lower alkylene or N, N- (aza, oxa or thia) lower alkylene carbamyl and R _{2 is} carbamyl, N-acylcarbamyl, N-lower alkyl, N, N-di-lower alkyl, Ν, Ν-lower alkylene or N, N- (Aza-, Oxa or Thia) -niederalkylencarbamyl or, if R _{1 is} amino, acylamino, N-lower alkyl, N, N-di-lower alkyl, Ν, Ν-lower alkylene or N, N- (Aza-, Oxa- or thia) -niederalkylenamino, for cyano or, if R ₁ carbamyl, N-acylcarbamyl, N-lower alkyl, N, N-di-lower alkyl, Ν, Ν-lower alkylene or N, N- (Aza-, Oxa - or ThiaJ-niederalkylencarbamyl, is in particular lower alkanoyl, Niederalkoxyniederalkoxycarbonyl, Diniederalkylaminoniederalkanoyl, Niederalkansulfonyl, Niederalkoxycarbonyl, Ureido, 3-lower alkyl or, 3,3-diiederalkylureido or 3,3-Niederalkylen- or 3 , 3- (Aza-, Oxa- or T hia) -niederalkylenureido and lower alkyl and lower alkyl in N-lower alkyl or Ν, Ν-di-lower alkylamino or -carbamyl, lower alkoxy and lower alkylidene z. B. to and     · · · » having 7 C atoms and lower alkylene or, aza-, oxa- or thiower lower alkylene z, B. 4 to and having 6 ring members, or produces a salt of a salt-forming compound of the above defined type. 4., Process according to one of the items 1 and 2, characterized in that compounds of the formula I, wherein Ph 2-Haiogenphenyl, 2-Triflüormethylphenyl, 2-lower alkylphenyl ^ 2,3- or * 2,6-dihalogenophenyl, 2- Halogeno-3-lower-alkyl-phenyl or * 3-halo-2-lower-alkylphenyl, 2-halo-6-lower alkyl-phenyl, 2,3- or 2,6-di-lower alkylphenyi, 3-halo-2-trifluoromethyl-phenyl or 2-halo-3-trifluoromethylphenyl or 2-halo-6-trifluoromethylphenyl, alk is 1,1-lower alkylidene, R _{1 is} hydrogen, mxederalkyl, lower alkoxy, amino, lower alkylamino, di-lower alkylamino, carbamyl, N-lower alkylcarbamyl or N, N-lower alkylcarbamyl and R _{2 is} carbamyl, N-lower alkylcarbamyl or N, N-di-lower alkylcarbamyl, wherein lower alkyl and Nxederalkyl in H-lower alkyl or, N, N-di-lower alkylamino or -carbamyl, lower alkoxy and lower alkylidene z, B, to and with 7-C Have atoms, · 5. Process according to one of the items 1 and 2, characterized in that compounds of the formula I in which Ph is substituted by up to and including 3 lower alkyl groups or halogen atoms, lower alkyl and halogen and / or trifluoromethyl, where lower alkyl having up to and including 4 C atoms, or halogen having the atomic number up to and including 35, substituted phenyl, alk 1,1-lower alkylidene with bis and with 4 C atoms, R. Amino, lower alkanoylamino with bis and with 7 C atoms, Niederalkylarnino or Diniederalkylamino each with up to and with 4 C atoms in Älkylteil represents and R ₂ carbamyl, N-Niederalkanoylcarbamyl with bis and with 7 C atoms, N-lower alkyl, N, N-di-lower alkyl or Ν, Ν-Niederalkylencarbamyl having in each case up to and 4 C atoms in the alkyl or 4 to and 6 ring members in Älkylteil or cyano means produces. 6. The method according to any one of the items 1 and 2, characterized by reacting compounds of the formula I, wherein Ph as lower alkyl or halogen substituents lower alkyl having up to and with 4 C-atoms or halogen of the atomic number up to and 35 having 2- Halophenyl, 2-trifluoromethylphenyl, 2-lower alkylphenyl, or 2,6-dihalophenyl or 2,3- or 2,6-di-lower alkylphenyl, alk is 1,1-lower alkylidene having up to and including 4 C atoms, R. for amino, Ni ^ deralkylamino or Diniederalkylamino each having up to and 4 C atoms in the alkyl moiety and R "carbamyl or cyano means produces. 7, Method according to one of the items 1 and 2, characterized in that compounds of formula I, wherein Ph as lower alkyl or halogen substituents lower alkyl having up to 4 carbon atoms or Halogen of atomic number to 35 and having 2-halophenyl 2-trifluorothiethylphenyl, 2-lower alkylphenyl, or 2,6-dihalophenyl or 2,3- or 2,6-di-lower alkylphenyl * alk is 1,1-lower alkylidene having up to and including 4 C atoms, R _{1 is} amino, lower alkylamino or
Diniederalkylamino each having up to and 4 C atoms in the alkyl moiety and Rp carbamyl, prepared. 0. The method according to any one of items 1 and 2, characterized in that one prepares the 5-amino-l- (o-chlorobenzyl) -IH-I, 2,3-triazole-4-carboxamide. 9, Method according to one of the items 1 and 2, characterized in that one prepares the 5-amino-l- (2,6-dichlorobenzyl) -LH-i, 2j3-triazole-4-carboxamide. 10. The method according to any one of the items 1 and 2, characterized in that the 5-arnino-l- (o-methylbenzyl) -LH ~
i, 2,3-triazole-4-carboxamide. 11. The method according to any one of the items 1 and 2, characterized in that one prepares the 5-amino-l- (o-fluorobenzyl) lH-l, 2,3 ~ triazole-4-carboxamide. 12. The method according to any one of the items 1 and 2, characterized in that one prepares the 5-amxno-l- (o-bromobenzyl) -LH-l, 2,3-triazole-4-carboxamide. 13. The method according to any one of the items 1 and 2, characterized in that one prepares the 5-amino-l- (o-trifluoromethylbenzyl) -LH »l, 2,3-trlazol-4-carboxamide. 14. The method according to any one of items 1 and 2, characterized in that the 5-amino-1- (2,3-dimethylbenzyl) -LH-. l _# 2,3-triazole-4-carboxamide, 15. The method according to any one of the items 1 and 2, characterized in that the S-amino-l - ^ / fl-io-chloro-phenyl) -ethyl _- J7'-lH-l, 2,3-triazole-4-carboxamide manufactures. 16. The method according to any one of the items 1 and 2, characterized in that one prepares the 5-amino-l- / ~ * 1- (o »chlorophenyl) -propylJ7-lH-l, 2,3-triazole-4-carboxamide . 17. The method according to any one of the items 1 and 2, characterized in that one prepares the S-amino-l- ^ l- ^ o-chlorophenyl) -butyl__7 "-LH-l, 2,3" -triazole-4-carboxamide , 18. The method according to any one of the items 1 and 2, characterized in that the 5-amino-l- (o-chlorobenzyl) lH-l, 2,3-triazole-4-carbonitrile. manufactures. 19. The method according to any one of the items 1 and 2, characterized in that one prepares the 1- (o-chlorobenzyl) -5-dimethylaminolH-l, 2,3-triazole-4-carbonitrile. 20. Process according to one of the items 1 and 2, characterized in that the 1- (o-chlorobenzyl) -5-dimethylaminolH-1,2,3-triazole-4-carboxamide is prepared, 21. The method according to any one of the items 1 and 2, characterized in that one prepares the l- (o-chlorobenzylj-lH-l, 2,3-triazole-4,5-dicarboxamide. 22 ", process according to one of the items 1 and 2, characterized in that the l- (o-chlorobenzyl) -5-methoxy-> lH-l, 2,3-triazole-4-carboxamide is produced« 23. Method according to one of the items 1 and 2, characterized in that the 1- (o-chlprbenzyl) -IH- X, 2,3- triazole-4-carboxamide is prepared, 24. Process according to one of the items 1 and 2, characterized in that the 1- (o-chlorobenzyl) -5-methyl-1H-1,2,3-triazole-4-carboxamide is prepared, 25. The method according to any of the points 1 and 2, characterized in that _t the l- (o ~ methylbenzyl) -5-methyl-lH-1,2,3 ~ triazol-4-carboxamide prepared, 26. The method according to any one of the items 1 and 2, characterized in that one prepares the 5-amino-l- (O ~ chlorobenzyl) -1H-1 ₄ 2,3-triazole-4- (N ~ methyl) -carboxamid. 27. A process as claimed in one of the items 1 and 2, characterized in that the 5-amino-1- (o-chlorobenzyl) -H-1,2,3-triazole ~ 4 ~ (N, N-dimethyl) - carboxamide, 28. Method according to one of the items 1 and 2, characterized in that the 5-amino-1- (2,3-dichlorobenzyl) -1H-1,2,3-triazole-4-carboxamide is prepared, 29. Method according to one of the items 1 and 2, characterized in that the l- (o-chlorobenzyl) -LH-l, 2,3 "- triazole-4,5-dicarboxamide produces. 30. The method according to any one of the items 1 and 2, characterized in that the 5-amino-l- (2,4 # 6-tr'imethylbenzyl) ~
IH-I, 2,3-triazole-4-carboxamide produces. 31 »Process according to one of the items 1 and 2, characterized in that the 5-amino-1- (5-chloro-2-methylbenzyl) -IH-I, 2,3-triazole-4-carboxamide is prepared« 32. Process according to one of the items -1 and 2, characterized in that the 5-amino-1- (o-chlorobenzyl) -IH-1,2,3-triazole-4-carboxylic acid piperidide is prepared » 33. The method according to any one of items 1 and 2, characterized in that one prepares the 5-amino-l- (m-chlorobenzyl) -LH-l, 2,3-triazole-4-carboxamide. 34. The method according to any one of items 1 and 2, g * ekennzeichnet in that one prepares the 5-amino-l- (m-trifluoromethylbenzyl) -IH-I, 2,3-triazole-4-carboxamide. 35. The method according to any one of items 1 and 2, characterized in that one prepares the 1- (o-chlorobenzyl) -LH-l, 2,3-triazole-4-carboxylic acid piperidide. 36. The method according to any one of the items 1 and 2, characterized in that one prepares the 1- (o-chlorobenzyl) -LH-l, 2,3-triazole-4-carboxylic acid N, N-dimethylamide. 37 »Process according to one of the items 1 and 2, characterized in that the 5-amino-l- (m-raethylbenzyl) -LH-l, 2,3-triazole-4-carboxamide prepared. 38. Process according to one of the items 1 and 2, characterized in that the 1 - (m-chlorobenzyl) -LH-1 _f 2,3-triazole-4-carboxamide is prepared, 39 * Process according to one of the items 1 and 2, characterized in that the 1- (m ~ trifluoromethylbenzyl-1H- is prepared. 40. Method according to one of the items 1 and 2, characterized in that the 5-amino-1- (o-chlorobenzyl) -H-1,2,3-triazole-4-carboxylic acid- (4-methyl) piperazide or an acid addition salt thereof, 41. Method according to one of the items 1 and 2, characterized in that 5-acetylamino-1- (o-chlorobenzyl) -1H-1,2,3-triazole-4-carboxamide is prepared, 42. The method according to any one of items 1 and 2, characterized in that one prepares 5-formylamino-l- (o-chlorobenzyl) -LH-l, 2,3 ~ triazole-4-carboxamide. 43. Process according to one of the items 1 and 2, characterized in that S-ethoxycarbonylamino-1-io-chlorobenzyl) -: LH-1:, 2,3-triazole-4-carboxamide is prepared, 44. Process according to one of the items 1 and 2, characterized in that 5- (3,3-dimethylureido-1- (o-chlorobenzyl) -1H-1,2,3-triazole-4-carboxamide is prepared, 45. Method according to one of the items 1 and 2, characterized in that 5- (N ', N'-Dimethylglycylaitiino) -l- (ochlorbenzylJ-lH-l ^ S-triazole ^ -carboxamide produces. 46. The method according to any one of the items 1 and 2, characterized in that one prepares 5 ~ (4-methylpiperazinocarbonylamino) -1- (o ~ chlorobenzyl) -LH ~ l, 2,3-triazole-4-carboxamide. 47. A process as claimed in one of the items 1 and 2, characterized in that 5-ethoxyacetylamino-1- (o-chlorobenzyl) -1H-1,2,3-triazole-4-carboxamide is prepared, 48. The method according to any one of the items 1 and 2, characterized in that one prepares 5-acetylamino-l- (o-chlorobenzyl) -LH-l, 2 _f 3-triazole-4- (N-acetyl) carboxamide. 49. A process according to any one of items 1 and 2, characterized in that 5-formylamino-1- (o-chlorobenzyl) -1H-1,2,5-triazole-4- (N-formyl) carboxamide is prepared.