DD245874A5 - METHOD FOR PRODUCING FLUORIZED BENZYLTRIAZOL COMPOUNDS - Google Patents

Abstract

New fluorinated 1- (a-phenylalkyl) -1H-1,2,3-triazole compounds of the formula (I) in which Ph represents a phenyl radical which is substituted in the o-position by fluorine and optionally additionally by at least one further halogen atom, alk is lower alkylidene, R 1 represents hydrogen, lower alkyl or an unsubstituted or lower alkanoyl or lower alkyl substituted carbamyl group, and R 2 represents an unsubstituted or lower alkanoyl or lower alkyl substituted carbamyl group, have anticonvulsant properties and are useful as pharmaceuticals. They are prepared by reacting a compound of the formula (VI) in which Y 4 is esterified carboxy and Y 5 is hydrogen, lower alkyl or likewise esterified carboxy with an excess of ammonia or a di-lower alkylamine and, if desired, a compound obtainable by the process in which R 2 and optionally R 1 unsubstituted carbamyl is R 2 and optionally R 1 is lower alkanolated.

Description

- J - CtJ O / t

Field of application of the invention

The invention relates to a process for the preparation of novel 1- (a-phenyl-lower alkyl) -1H-1,2,3-triazole compounds having valuable pharmacological properties, in particular having anticonvulsant activity. The compounds prepared according to the invention are used as medicines, for example for the treatment of epilepsy.

Characteristic of the known technical solutions

There are already known compounds having an anticonvulsant action, for example 1 - (o-chlorobenzyl) -iH-1,2,3-triazole-4-carboxamide and i-io-chlorobenzyD-IH-i ^^ - triazole- ^ B- dicarboxamide.

Object of the invention

The aim of the invention is the provision of new compounds with stronger anticonvulsant activity.

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

According to the invention, new fluorinated 1- (a-phenylalkyl) -1H-1,2,3-triazole compounds of the formula

M = r · N

Ph-alk-N

^R l ^R 2

in which Ph is a phenyl radical substituted in the o-position by fluorine and optionally additionally by at least one further halogen atom, alk is lower alkylidene, Ri is hydrogen, lower alkyl or an unsubstituted or lower alkanoyl or lower alkyl-substituted carbamyl group, and R _{2 is} an unsubstituted or substituted by Lower alkanoyl or lower alkyl substituted carbamyl group.

As additional halogen substituents of Ph, for example, halogen atoms of atomic number up to and with 35, such as fluorine, chlorine or, secondarily, bromine, into consideration. In total up to and including 5 halogen substituents may be present, in addition to the o-fluoro substituent, for example, 1 or 2 chloro (s), 1 chloro and 1 fluoro or 1 to 3, e.g. 1 or 2 fluorine atom (s). A single additional halogen atom is, for example, in the 4-, 5- or especially 6-position

bound. , ,

Lower alkylidene is, for example, C 1 -C ₄ -alkylidene, in particular methylene, furthermore ethylidene, 1,1-propylidene, 2,2-propylidene (isopropylidene) or 1,1-butylidene.

Lower alkyl is, for example, C 1 -C ₄ -alkyl, such as methyl or, secondarily, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tert-butyl, but may also be a C ₅ -C ₇ -alkyl, such as butyl, hexyl or heptyl group his.

Carbamoyl substituted by lower alkanoyl or lower alkyl is in particular mono-substituted by lower alkanoyl or disubstituted by lower alkyl and is, for example, C -C -alkanoylcarbamyl, in particular N-C 1 -alkanoylcarbamyl, such as acetyl- or pivaloylcarbamoyl, or especially N, N-di-C 1 -C 4 AIkylcarbamyl, such as Ν, Ν-dimethylcarbamyl or N, N-Diäthylcarbamyl.

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 From about 1 to about 50, in most cases from about 1 to about 25 mg / kg po, convulsions in the Dos's range. In this model, for example, the following values for effective dose ED _{50 were obtained} in mg / kg po (1 h

Pre-application):.

1- (2,6-Difluorobenzyl) -1H-1,2,3-triazole-4-carboxamide: 17 (mouse) and 8 (rat), respectively; 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4-carboxamide: 17 (mouse, rat);

1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide: 4 (mouse, rat);

1- (6-chloro-2-fluoro-phenyl) -1H-1,2,3-triazole-4,5-dicarboxamide: 7 (mouse) and 10 (rat), respectively; 1- (o-fluorophenyl) -1H-1,2,3-triazole-4,5-dicarboxamide: 6 (mouse) and 10 (rat), respectively; 1- (6-chloro-2-fluoro-phenyl) -1H-1,2,3-triazole-4-carboxamide: 11 (mouse);

1- (2,5-Difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide: 6 (mouse).

The fluorinated 1- (a-phenylalkyl) -1H-1,2,3-triazole compounds of the formula (I) provided according to the invention have their chlorine analogues, which are known to be effective as anticonvulsant, in comparison to the advantage of improved activity. So resulted in the above model z. B. the following ED ₅₀ values:

1- (o-chlorobenzyl) -1H-1,2,3-triazole-4-carboxamide: 26 (mouse) or 25 (rat) and! - (o-chlorobenzyD-IH-i ^^ - triazole ^ S) dicarboxamide ^ of mouse) or 43 (rat).

Accordingly, the compounds provided according to the invention are excellently suitable for the treatment of convulsions of various origins, for example for the treatment of epilepsy and can be used as anticonvulsant, for example antiepileptic, active agents.

The invention relates in the first place to the preparation of compounds of the formula (I) in which Ph is an o-position substituted by fluorine and optionally additionally by up to and 3 halogen atoms of the atomic number up to and including 35, alk for dC ₄ -alkylidene R _{1 is} hydrogen, C ₁ -C ₄ -alkyl, carbamyl, N-C ₁ -cyclo-alkanoylcarbamyl or N, N-di-C ₁ -C ₄ -alkylcarbamyl and R _{2 is} carbamyl, NC ₁ -C ₇ -alkanoylcarbamyl or N , N-di-C | -C ₄ alkylcarbamyl. The invention preferably relates to the preparation of compounds of the formula (I) in which in the o-position by fluorine and optionally additionally up to and with 2 chlorine atoms, 1 fluorine and 1 chlorine atom or up to and with 2 fluorine atoms substituted phenyl, such as o-fluorophenyl , 2,3- 2,4-, 2,5- or 2,6-difluorophenyl, 2-chloro-6-fluof-phenyl, further 2,4,6-trifluorophenyl, alkC ^ Cj-alkylidene, as Methylene, furthermore ethylidene or 2,2-propylidene, R ₁ denotes hydrogen, C ₁ -C ₄ -alkyl, such as methyl, carbamyl, N-C ₁ -C ₄ -alkanoylcarbamyl, such as acetyl- or pivaloylcarbamyl, or Ν, Ν- Di-C ₁ -C ₄ alkylcarbamyl, such as dimethylcarbamyl, and R _{2 is} carbamyl, NC ₂ -C ₅ -alkanoylcarbamyl, such as acetyl or pivaloylcarbamyl, or N ₁ N-di-C ₁ -C ₄ -alkylcarbamyl, such as dimethylcarbamyl ,

The invention relates in particular to the preparation of compounds of the formula (I) in which Ph in the o-position is substituted by fluorine and optionally additionally by 1 chlorine atom, 1 fluorine and 1 chlorine atom or up to 2 fluorine-substituted phenyl, such as o-fluorophenyl, 2, 3, 2,4, 2,5 or 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, furthermore 2,4,6-trifluorophenyl, alk for C ₁ -C ₄ -alkylidene, in particular 1, R _{1 is} hydrogen, C ₁ -C ₄ -alkyl, such as methyl, or a radical R ₂ and R _{2 is} carbamyl or, secondarily, C ₁ -C 5 -alkanoylcarbamyl, such as acetylcarbamyl or N _{1 is} N-di-C ₁ -C ₄ -alkylcarbamyl, such as dimethylcarbamyl, for example compounds of the formula (I) in which Ph o-fluorophenyl, 2,3-, 2,4-, 2,5- or 2,6-difluorophenyl or 6-chloro-2-fluoro-phenyl, alk is methylene, Ri is hydrogen or unsubstituted carbamyl and R _{2 is} unsubstituted carbamyl.

More particularly, the invention relates to the preparation of compounds of formula (I) wherein Ph is o-fluorophenyl or 2,6-difluorophenyl, alk is methylene, R _{1 is} hydrogen or unsubstituted carbamyl and R _{2 is} unsubstituted carbamyl. · '

The invention preferably relates to the preparation of compounds of the formula (I) in which Ph is 2,6-difluorophenyl, alk is methylene, R _{1 is} hydrogen, C ₁ -C ₄ -alkyl, such as methyl, or a radical R ₂ and R is ₂ carbamyl or, secondarily, N, C 1 -C 6 alkanoylcarbamyl, such as acetylcarbamyl, or Ν, Ν-di-C 1 -C 4 -alkylcarbamyl, such as dimethylcarbamyl. The invention relates in the first place to the preparation of compounds of the formula (I) in which Ph is o-fluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl or 2-chloro-6-fluorophenyl, alk is methylene and R ₁ and R _{2 are} both carbamyl, furthermore compounds of the formula I, in which Ph is 2,6-difluorophenyl, alk is methylene, R _{1 is} hydrogen or carbamyl and R _{2 is} carbamyl.

The process for the preparation of the compounds of the formula (I) is based on methods known per se and is characterized in that

a Ph-alk-N ₃ (II)

with a compound of the formula Rl - C = C - R ₂

i;

(IN THE)

wherein Yi is hydroxy and Y _{2 is} hydrogen and Y ₁ and Y ₂ together signify an additional bond, or a salt and / or tautomer thereof or

b) 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) '

= '-R2

m ·

or a salt thereof or

c) in a compound of the formula

Ph-alk-ii. (Vl) ₁

wherein Y _{4 is} a radical unsubstituted or substituted by lower alkyl carbamoyl Y _A and Y _{5 is} a group Ri or in unsubstituted or lower alkyl substituted carbamyl convertible radical Y ₈ or Y _{4 is} a group R ₂ and Y _{5 is} an unsubstituted or lower alkyl Substituted carbamyl convertible radical Y _B , Y _A and / or the Y _{B converted} into unsubstituted or substituted by lower alkyl carbamyl, if necessary, a resulting mixture of isomers separated into the components and isolating the isomers of formula (I) and, if desired, the compound obtainable by the process into another Converted compound of formula (I) and / or splits a enantiomer or diastereomer mixture obtainable according to the method into the components.

Suitable starting materials of the formula (III) for process variant a) and tautomers thereof are, for example, compounds of the formulas R ₁ -C = CR ₂ (IIIa) and R ₁ -Cf = O) -CH ₂ -Ra (HIb). Salts thereof are, for example, alkali metal, e.g. For example, sodium salts of compounds of the formula (IM a), which consists of these and Alkalimetallalkanqlaten, z. B.

Sodium methoxide, can be obtained.

The reaction of compounds II and III 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, or ethers, such as tertiarybutoxymethane, tetrahydrofuran or dioxane.

Preferred embodiments of this process are for example the reaction of an azide of formula (II) with a compound of formula (IIIa) .in benzene or dioxane at about 60-120 ⁰ C, preferably boiling temperature.

The 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 manner of formation of the known ones, for example by reacting a compound of the formula Ph-alk-Z (IV) in which Z is reactive esterified hydroxy, such as halogen, e.g. Chlorine, brorine or iodine, or sulfonyloxy, such as lower alkanesulfonyloxy, optionally substituted benzenesulfonyloxy, such as methane, ethane, benzene, p-toluene or p-bromobenzenesulfonyloxy, or fluorosulfonyloxy, with an alkali metal azide, e.g. B. with sodium azide, for example, in dimethyl sulfoxide or dimethyl sulfoxide or dimethylformamide, or by reacting an alcohol (Z = hydroxy), in the presence of triphenylphosphine and an azodicarboxylic acid ester, .z. B. of Azodicarbonsäurediäthylester, brings with hydrazoic acid for reaction, for example in toluene.

In starting materials IV according to process variant b), reactive esterified hydroxy is, for example, halogen,

z. For example, chlorine, bromine or iodine, or sulfonyloxy, such as Niederalkansulfonyloxy, optionally substituted benzenesulfonyloxy, such as methane, ethane, benzene, p-toluene or p-B / ombenzolsulfonyloxy, or fluorosulfonyloxy.

Salts of compounds (V) are, for example, alkali metal or alkaline earth metal salts thereof, such 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 a salt, if necessary with heating, preferably in a solvent or diluent. Basic condensing agents are exemplified by the component of formula (VJ) salt-forming basic condensing agents such as alkali metal alcoholates, e.g., sodium methoxide or sodium ethoxide, alkali metal or alkaline earth metal amides, e.g., sodium amide or lithium diisopropylamide. V) are advantageously carried out in advance in one of their salts, for example by reaction with one of the abovementioned bases. Solvents are preferably the corresponding alcohols for carrying out the reaction in the presence of an alkoxide and, for example, aprotic organic solvents, such as phosphoric acid lower alkylamides, when carrying out the reaction in the presence of amides. eg hexamethylphosphoric triamide, alkanoic acid amides, eg.

Dimethylformamide, or di-lower alkyl sulfoxides, e.g. For example, dimethyl sulfoxide. If appropriate, by-products of the isomers formed by the process are to be separated off from the desired compounds of the formula (I).

The starting materials (IV) and (V), if they are not already known, can usually be prepared. To obtain compounds of formula (IV) z. B., by esterifying a corresponding alcohol (IV, Z = hydroxy) reactive, z. B.

using thionyl chloride, phosphorus tribromide or a sulfonyl chloride. Compounds (V) can be prepared by reacting trimethylsilyl azide or hydrazoic acid with a compound of the formula

R ₁ -C = CR ₂ (IIIaJbZW.R ₁ -C) = O) -CH ₂ -R ₂ (IHb);

wherein R _{1 is} in particular unsubstituted or substituted by lower alkyl carbamyl, and in an optionally obtained I-Trimethylsilyltriazolderivat the silyl group, optionally after Niederalk (ano) ylierung of carbamyl R ₂ and / or Ri as indicated for compounds of formula I below, by mild Splits off hydrolysis. But you can also trimethylsilylazide with a compound of the formula

Y ₅ -C = CY ₄ (VIIa) or R ₁ -Cf = O) -CH ₂ -Y ₄ (VIIb)

wherein Y _{4 is} a carbamoyl unsubstituted or lower alkyl substituted radical Y _A , esterified carboxy such as lower alkoxycarbonyl, or cyano and Y _{5 is} hydrogen or preferably a unsubstituted or lower alkyl substituted carbamyl radical Y ₈ which is preferably identical to Y a , React and Ya and / or Y _{B converted} into unsubstituted or substituted by lower alkyl carbamyl, in the case of esterified carboxy example by ammonolysis (reaction with ammonia) or in the case of cyano, for example by hydrolysis, wherein the trimethylsilyl group is removed.

According to process variant c), unsubstituted or lower-alkyl-substituted carbamyl-transferable radicals Y _A and / or Y _B are, for example, carboxyl groups present in a salt or anhydride form, unsubstituted or lower alkyl-substituted amidino groups or esterified carboxy groups, and also cyano groups.

Esterified carboxy groups are, for example, carboxy groups esterified with a lower alkanol or lower alkyl mercaptan, i. Lower alkoxy or lower alkoxythiocarbonyl groups, but may also be reacted with any other alcohol or mercaptan, e.g. with an optionally substituted phenol or thiophenol.

Salt-form carboxyl groups are, for example, carboxy groups present in an ammonium salt form derived from ammonia or a di-lower alkylamine, further in metal, e.g. B. alkali or alkaline earth metal salt form present carboxy groups.

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

The conversion of said groups Y _A and / or Y _B into optionally lower-alkylated carbamyl is usually carried out starting from free, esterified or anhydride carboxy groups and unsubstituted or lower alkyl substituted aminidino groups by solvolysis, ie hydrolysis or ammonolysis or aminolysis ( Reaction with ammonia or a di-lower alkylamine).

By hydrolysis, for example, cyano groups in carbamyl or unsubstituted or substituted by lower alkyl amidino groups Y _A and / or Y _{8 can be converted} into unsubstituted or substituted by lower alkyl carbamyl. The hydrolysis of cyano groups, for example, in the presence of basic hydrolysis, such as alkali metal hydroxides, z. As sodium or potassium hydroxide, if necessary in the presence of peroxy compounds, ζ. B. hydrogen peroxide. The hydrolysis of amidino groups, for example, in the presence of an acidic hydrolysis agent, such as a mineral, sulfonic or carboxylic acid, ζ. Example of sulfuric acid, phosphoric acid, hydrochloric acid or other hydrohalic acid, p-toluenesulfonic acid or other organic sulfonic acid, or a lower alkanoic acid such as acetic acid, preferably in catalytic amounts carried out.

By ammonolysis or aminolysis, for example, free or present in a salt or anhydride form or esterified carboxy groups in unsubstituted or substituted by lower alkyl carbamyl. If necessary, the reaction is carried out in the presence of a condensing agent, advantageously in a single-solvent. Condensing agents are basic condensing agents, especially ammonia or amines used for the aminolysis in excess, starting from present in anhydride form carboxy further alkali metal hydroxides or carbonates or tertiary organic nitrogen bases, such as Triniederalkylamine or tertiary heteroaromatic nitrogen bases, such as triethylamine or pyridine. Free carboxy groups can be obtained by dehydration of the intermediately formed ammonium salts, ζ. Β. by heating or exposure to dehydrating agents such as acid anhydrides, e.g. Phosphorus pentoxide, and the like, or of garbodiimides, e.g. B. N ^ -Dicyclohexylcarbodiimid converted into carbamyl. A particularly preferred embodiment of this process variant is characterized in that reacting a compound of formula VI, wherein Y _{4 is} esterified carboxy and Y _{5 is} hydrogen, lower alkyl or esterified carboxy, with an excess of ammonia or a di-lower alkylamine and, if desired, in a procedure according to available compound wherein R ₂ and optionally R ₁ unsubstituted carbamyl is R ₂ and optionally R ₁ lower alkanoylated.

The starting materials (Vl), if they are not known, can be prepared in a customary manner, for example by reacting an azide of the formula

Ph-alk-N ₃ "". (II)

with a compound of the formula

Y ₅ -C = CY ₄ (Vila) or R ₁ -Cf = O) -CH ₂ -Y ₄ (VIIb)

reacted, for example in an analogous manner as described under process variant a). If necessary, primarily obtained esters or nitriles of the formula (VI, Y _A and optionally Y _B = esterified carboxy or cyano) under basic conditions, for. B. by means of aqueous-alcoholic sodium hydroxide solution, hydrolyzed to the corresponding acid and primary or obtained by hydrolysis of corresponding esters or nitriles acids of the formula (Vl, Y _A and optionally Yb = carboxy), for example with thionyl chloride, are converted into the acid chloride.

In particular, substitution reactions on N-unsubstituted or N-mono-lower alkylated carbamoyl groups R ₂ and / or R ₁ and the separation of isomer mixtures obtainable according to the method are to be mentioned as conversion reactions of compounds obtainable according to the method into other compounds of the formula (I).

Thus, in compounds of formula (I) by treating with a lower alkanoylating agent N-unsubstituted carbamyl in N-lower alkanoylcarbamyl or by treatment with a Niederalkylierungsmittel unsubstituted carbamyl in Ν, Ν-Diniederalkylcarbamyl and / or N-Mononiederalkyicarbamyl in Ν, Ν-Diniederalkylcarbamyl convict. N-Mono-lower alkyl derivatives of compounds of the formula (I) can be obtained, for example, starting from corresponding starting materials of the formulas (III), (V) or (VI), in particular (VI).

Lower alkanoylating agents are, for example, lower alkanecarboxylic acid anhydrides, such as acetic anhydride or the mixed anhydride of formic and acetic acid, and lower alkanecarboxylic acid chlorides, such as acetyl chloride. The reaction with these is carried out usually, if necessary in the presence of a base, e.g. of triethylamine or pyridine, or in the case of the reaction with acid anhydrides in the presence of a mineral acid, e.g. of sulfuric acid. Lower alkylating agents are, for example, reactive esters, such as hydrohalic acid, sulfuric acid or sulfonic acid esters of lower alkanols, such as lower alkyl halides, e.g. Methyl iodide, di-lower alkyl sulfates, e.g. As dimethyl sulfate, or lower alkyl esters of aliphatic or aromatic sulfonic acids, in particular of lower alkanesulfonic acids or optionally substituted benzenesulfonic acids, ζ.B. Niederalkylmethansulfonate, -äthansulfonate, -benzolsulfonateoder-p-tuluolsulfonate. The lower alkylation is carried out in a customary manner, for example under basic conditions, such as in the presence of an alkali metal hydroxide, for. Example of potassium hydroxide, and advantageously a phase transfer catalyst, for. B. of tetrabutylammonium bromide or benzyltrimethylammonium chloride.

The separation of isomer mixtures, which are, for example, enantiomer or diastereomer mixtures of compounds of the formula (I) having at least one asymmetric carbon atom and mixtures of compounds of the formula (I) and isomers thereof to be mentioned according to the process, is carried out in customary manner. Diastereoisomer mixtures and mixtures of compounds of the formula (I) and isomers thereof formed according to the process can be synthesized, for example, by virtue of the different physical properties of the components by customary physical separation processes, ζ. Β. fractionated by fractional crystallization, chromatography method and the like. For example, fractional crystallization from an optically active solvent or chromatography on an optically active stationary and / or mobile phase are suitable for the separation of enantiomer mixtures. But you can also a Enantiomerengemisch, z. B. by reaction with an optically active acid chloride, convert into the corresponding diastereomeric Acylderiväte, this split into the components and from these, z. B. by mild acid treatment, the pure enantiomers release.

New starting materials, e.g. of the formulas (V) and (VI) which have been specially developed for the preparation of the compounds according to the invention, in particular the starting material which leads to the compounds of the formula (I) indicated at the outset, which form processes for their preparation and their use as intermediates also an object of the invention.

The new compounds of formula (I) may, for. B. are used as a form of pharmaceutical preparations containing a therapeutically effective amount of the active substance, optionally together with inorganic or organic, solid or liquid, pharmaceutically acceptable excipients which are suitable for enteral, eg oral or parenteral administration. Thus, one uses tablets or gelatin capsules containing the active ingredient together with diluents, for. As lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and / or lubricants, for. For example, 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, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, 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 parenterally administrable preparations or 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 adjuvants, eg. As konsevier, stabilizer, wetting and / or emulsifying agents, 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, granulating, confectioning, dissolving or lyophilising ^1, and contain from about 0.1% to 100%, in particular from about 1% to about 50%, of lyophilisates up to 100% of the active ingredient.

The invention also relates to the use of the compounds of the formula (I), preferably in the form of pharmaceutical preparations. The dosage may depend on various factors, such as route of administration, species, age and / or individual condition. The daily doses to be administered by oral administration are between about 1 and about 50 mg / kg in single doses of about 1 to 25 mg / kg and for warm-blooded animals weighing about 70 kg, preferably in daily doses of about 0.070 g and about 3, 5g.

embodiment

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

Example 1: 73.5 g (0.25 mol) of 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester are dissolved in 1000 ml of methanol. Then it is pressed in an autoclave 250g ammonia and leaving for 24 hours at 100 ⁰ C. It is then cooled, the crystallized product filtered off with suction, washed with methanol and recrystallized from dioxane / toluene. The 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, mp. 197-199 ° C. '.

The starting material can be prepared, for example as follows: To a warmed at 9O ⁰ C solution of 41.5 g (0.275 mol) of o-Fluorbenzylazid in 50 ml of toluene, a solution of 40g (0.282 mol) dimethyl acetylenedicarboxylate was added dropwise in 500 ml of toluene. After 5 more hours at 90 ° C, the toluene is removed and sucked off after cooling the crystallized substance. After recrystallization from a mixture of diethyl ether and petroleum ether (1: 1) to give the 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxylic acid Dimethylestervompp. 49-51 ⁰ C.

Example 2: 59 g (0.26 mol) of 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4-carboxylic acid are refluxed with 300 ml of thionyl chloride for 1 hour. Then distilling the excess thionyl chloride in vacuo, the back bleibene i- (o-fluorobenzyl) -1H-1,2,3-triazole solves-4-carboxylic acid chloride in 500mlToluol and this solution dropwise at 5-10 ⁰ C to 500 ml of a concentrated aqueous ammonia solution. The precipitated product is filtered off, washed with water and recrystallized from ethanol. This gives the 1- (o-Ffuorbenzyl) -1H-1,2,3-triazole-4-carboxamide, mp. 220-222 ° C. The starting material can be prepared, for example, as follows: A solution of 50 g (0.33 mol) of o-fluocbenzyl azide, 23.1 g (0.33 mol) of propenoic acid and 400 ml of toluene is stirred for 24 hours at 70.degree. The precipitated product is filtered off with suction after cooling to room temperature and washed first with toluene and then with diethyl ether. We obtain the l- (o-fluorobenzyl) -1 H-1,2,3-triazole-4-carboxylic acid, mp. 151 ⁰ C (dec.)

Example 3: Analogously to Example 1, 2,6-difluorobenzyl azide and dimethyl acetylenedicarboxylate are obtained via dimethyl 1- (2,6-difluorobenzyl) -1H-1,2,3-trifluoro-4,5-dicarboxylate (Mp. 62-65 ⁰ C), the 1- (2,6 ^: Difluorbenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, mp 203-205 ⁰ C (from methanol).

Example 4: In an analogous manner as described in Example 2, starting from 2,6-difluorobenzyl azide over 1- (2,6-difluorobenzene / l) -1H-1,2,3-triazole-4-carboxylic acid of the mp. 160-162 ⁰ C (from acetonitrile; dec.) 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4-carboxamide 237-240 ⁰ C, mp (from ethanol)..

Example 5: In a manner analogous to that described in Example 1, 4, it is also possible to prepare: 1- (2,3-difluorobenzyl) -1H-1,2,3-triazole-4-carboxamide, 1- (2,4-) Difluorobenzyl) -1H-1,2,3-triazole-4-carboxamide and 1- (2,5-difluorobenzyl) -1H-1,2,3-triazole-4-carboxamide

EXAMPLE 6 Analogously to Example 2, the 1- (6-chloro-2-fluorobenzyl) -1H-1,2,3-triazole-4-carboxylic acid is obtained from 1- (6-chloro-2-benzyl) -1H-1,2,3-triazole-4-carboxylic acid. 2-fluoro-benzyl) -1H-1,2,3-triazole-4-carboxamide, mp. 274-276 ⁰ C (from glacial acetic acid). The starting material may, for. A mixture of 98 g (0.688 mol) of 6-chloro-2-fluoro-toluene, 91.5 g (0.678 mol) of sulfuryl chloride and 0.2 g of dibenzoyl peroxide is stirred for 3 hours at 100-110 ° C and then distilled. Is obtained so that 6-chloro-2-fluoro-benzyl chloride b.p. ₁₅ = 78-82 ⁰ C.

To a suspension of 47 g (0.722) of sodium azide in 400 ml of dimethyl sulfoxide is added dropwise at 20-40 ⁰ C 123g (0.687 mol) of 6-chloro-2-fluoro-benzyl chloride added. After 4 hours of stirring at room temperature, diluted with 1 liter of ice water and extracted with cyclohexane. After distilling off the solvent, the residue is distilled. This gives the 6-chloro-2-fluorobenzylazide; Kpi5 = 99-100 ⁰ C.

27.5 g (0.15 M) of 6-chloro-2-fluoro-benzyl azide and 10.5 g (0.15 M) Propincarbonsäure in 300 ml of toluene is heated for 3 hours at 90 ⁰ C. After cooling, the crystals filtered off and crystallized from acetonitrile. This gives the 1- (6-chloro-2-fluoro-benzyl) -1H-1,2,3-triazole-4-carboxylic acid of mp. 182 ⁰ C (dec.).

Example 7: In an analogous manner as described in Example 1, starting from 6-chloro-2-fluoro-benzyl azide and. Acetyl-dicarboxylic acid dimethyl ester on the! - (B-chloro-i-fluoro-benzylMH-I ^ S-triazole-Aodicarbonsäuredimethylester (mp 88-9O ⁰ C) the i-ie-chloro-fluoro-benzyO-IH-I ^ S-triazole ^ o-dicarboxamide, mp. 214-216 ⁰ C (from glacial acetic acid).

Example 8: In an analogous manner as described in Example 1, obtained from 2,5-difluorobenzyl azide (bp ₁₅ = 82-84 ° C) over 1- (2,5-difluorobenzyl) -1H-1,2,3-triazole -4,5-dicarboxylic acid dimethyl ester, the 1- (2,5-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, mp. 191-192 ° C (from dioxane / toluene).

Example 9: In an analogous manner as described in Example 1, obtained from 2,4-difluorobenzyl azide (Kpi ₅ = 80-83 ⁰ C) on the 1- (2,4-difluorobenzyl) -1H-1,2,3- triazole-4,5-dicarboxylic acid dimethyl ester of m.p. 75-76 ° C (from cyclohexane), the 1- (2,4-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide m.p. 183-185 ⁰ C (from dioxane / toluene).

EXAMPLE 10 Analogously to Example 1, reaction with dimethylamine gives 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxylic acid di (N, N-dimethyl) amide of melting point 130 ⁰ -133 C (ausTertiärbutoxymethan).

EXAMPLE 11 Analogously to Example 1, 2,3-difluorobenzyl azide and dimethyl acetylenedicarboxylate are exchanged for 1- (2,3-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester in the 1- (2,3- Difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, mp. 183-185 ⁰ C (from ethyl acetate / benzene).

EXAMPLE 12 Analogously to Example 2, 1- (2,6-difluorobenzyl) -5-methyl-1H-1,2,3-triazole-4-carboxylic acid gives 1- (2,6-difluorobenzyl) -5-methyl- 1 H-1,2,3-triazole-4-carboxamide, mp. 208-210 ° C (from methanol) The starting material is prepared as follows:

Dissolve 2 ^ 53g (0.11 mol) of sodium in 60 ml of alcohol, then add a mixture of 16.9 g (0.1 mol) of 2,6-difluorobenzyl azide and 14.3 g (0.11 mol) of acetoacetic ester in 60 ml of alcohol and heated for 18 hours to reflux. After addition of 120 ml of n-sodium hydroxide solution is allowed to boil for a further 2 hours at reflux, diluted with 200 ml of water and acidified with cooling to pH 1 with hydrochloric acid. The precipitated product is filtered off with suction, washed first with water, then with ether and dried. This gives the 1- (2,6-difluorobenzyl) -5-methyl-1H-1,2,3-triazole-4-carboxylic acid, mp. 166-167 ° C.

EXAMPLE 13 Analogously to Example 1, 1- [1- (2,6-dimethyl) -1- [1,2- (2,6-difluorophenyl) ethyl] -1H-1,2,3-triazole-4-carboxylate is obtained. Difluorophenyl) ethyl] -1H-1,2,3-triazole-4-carboxamide, mp. 205-207 ⁰ C (from methanol).

The starting material is prepared as follows:

Reduction of 10.2 (66mM) 2,6-difluoroacetophenone with 2.5g (65mM) lithium aluminum hydride in ether gives 1- (2,6-difluorophenyl) ethanol as a colorless oil.

Dissolve 10g (63mM) of 1- (2,6-difluorophenyl) ethanol in 150ml of hydrazoic acid solution (1.2n in toluene), add 22.8g (200mM) of trifluoroacetic acid and allow to stand at room temperature for 24 hours. After dilution with 300 ml of hexane is washed first with water, then with sodium bicarbonate acid-free, dried over sodium sulfate and the solvents are removed at 40-50 ⁰ C under reduced pressure. The residue is dissolved in 100 ml of hexane, filtered through 50 g of silica gel and evaporated again. This gives the 1- (2,6-difluorophenyl) ethyl azide as a colorless oil.

6.5 g (35 mmol) of 1- (2,6-difluorophenyl) ethyl azide and 2.45 g (35 mmol) of propenoic acid in 50 ml of toluene are heated to 60-70 ° C. for 24 hours. After cooling, the mixture is extracted with 100 ml of η-sodium hydroxide solution and, after acidification with hydrochloric acid, the 1- [1-2,6-difluorophenyl) ethyl] -1H-1,2,3-triazole-4-carboxylic acid of the mp. 135- 138 ° C (decomp.).

7.1 g (26.6 mM) of 1- [1- (2,6-difluorophenyl) ethyl] -1H-1,2,3-triazole-4-carboxylic acid are heated to reflux for 10 hours with 150 ml of ethanol and 1 ml of sulfuric acid , After work-up gives the 1- [1- (2,6-difluorophenyl) ethyl] 1H-1,2,3-triazol-4-carbonsäureäthylestervom mp. 118-121 ⁰ C.

Example 14 Analogously to Example 1, from 1- {2- [2- (2,6-difluorophenyl) propyl]} - 1H-1,2,3-triazole-4-carboxylic acid ethyl ester the 1- {2- [2- ( 2,6-Difluorophenyl) propyl]} - 1H-1,2,3-triazole-4-carboxamide, mp. 203-205 ⁰ C (from methanol).

The starting material is prepared as follows:

To 28g (15OmM) 2,6-Difluorbenzoesäureäthylester in 200 ml of ether is added dropwise 120 ml of a 3molaren solution of methylmagnesium chloride in tetrahydrofuran added. After 1 hour of reflux and workup with 10% ammonium chloride solution gives the 2- (2,6-difluorophenyl) propan-2-ol of Κρ ·, ₂ = 74-76 ° C.

20.6 g (12OmM) of 2- (2,6-difluorophenyl) -propan-2-ol are dissolved in 300 ml of hydrazoic acid solution (n in benzene) and treated with 22.8 g (20OmM) of trifluoroacetic acid. After 24 hours at room temperature, it is diluted with 500 ml of hexane, washed with water and then with sodium bicarbonate solution acid-free, dried with sodium sulfate, the solvents evaporated and the residue is distilled. This gives the 2- (2,6-difluorophenyl) -2-azido-propane of Kp ₁₅ = 85-87 ⁰ C.

10 g (51 mM) of 2- (2,6-difluorophenyl) -2-azido-propane are reacted with 3.6 g (51 mM) of propenoic acid in 100 ml of toluene and worked up as described in Example 12. This gives the 1- {2- [2- (2,6-difluorophenyl) propyl]} - 1H-1,2,3-triazole-4-carboxylic acid, mp. 173 ° C (dec.).

After esterification of this acid with 50 ml of ethanol and 0.5 ml of concentrated sulfuric acid to give the 1- {2- [2- (2,6-difluorophenyl) propyl]} - 1 H-1,2,3-triazole-4-carboxylic acid ethyl ester as pale yellow viscous oil, which can be used without further purification for the reaction with ammonia.

EXAMPLE 15 Analogously to Example 1, starting from 2- (2,6-difluorophenyl) -2-azido-propane and dimethyl acetylenedicarboxylate, over the 1- {2- [2- (2,6-difluorophenyl) propyl]} - 1H- 1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester (m.p. 100-102) the 1- {2- [2- (2,6-difluorophenyl) propyl]} - 1H-1,2,3-triazole-4 , 5-dicarboxamide, mp. 177-178 ° C (from ethyl acetate / hexane),

Example 16: 16.9 g (0.1 mol) of 2,6-difluorobenzyl azide and 8.3 g (0.1 moles) of but-2-in-carboxamide are heated in 20 ml of dioxane 16 hours at 100 ⁰ C. After evaporation of the dioxane, the desired isomer is separated by column chromatography. This gives the 1- (2,6-difluorobenzyl) -5-methyl-1H-1,2,3-triazole-4-carboxamide, mp. 208-210 ⁰ C (from methanol).

Example 17: 2.81 g (10 mM) of 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, 20 ml of acetic anhydride and 2 drops of sulfuric acid are heated at 80 ° C. for 3 hours , After cooling, it is stirred with 100 ml of water for 1 hour at 20-25 ⁰ C, the precipitated product is filtered off and washed with water. After recrystallization from 75 ml of methanol, this gives the. 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-di (n-acetyl) carboxamidvomSmp. 136-138 ⁰ C.

Example 18: Analogously to Example 17, the 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4- (N-acetyl) -carboxamide of mp 205-207 is also obtained ⁰ C (from dioxane-toluene).

Example 19: 1.4 g (12,5mMol) Acetylendicarbonsäurediamid are dissolved at 60 ⁰ C in 10 ml of dimethyl sulfoxide. Are added 1.69 g (1OmMoI) of 2,6-difluorobenzyl azide and stirred for 16 hours at 80 ⁰ C stir. Then diluted with 25 ml of water, filtered off with suction, stirred with 50 ml of water, allowed to stir for 30 minutes at 50-60 ⁰ C, sucks again, dried and crystallized from dioxane / ethanol to. The 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, mp. 203-205 ° C.

Example 20 Tablets containing in each case 50 mg of 1- (o-fluorobenzyD-1H-1 ^, S-triazole-carboxamide can be prepared as follows:

Composition (10000 tablets) 500.0 g active substance 500.0 g lactose 352.0 g potato starch 8.0 g gelatin 60.0 g talc 10.0 g magnesium stearate 20.0 g Silica (highly dispersed) q-s ethanol

The active ingredient is mixed with the lactose and 292 g potato starch, the mixture is moistened with an alcoholic solution of gelatin and granulated through a sieve. After drying, the remainder of the potato starch, talc, magnesium stearate and fumed silica are mixed and the mixture is compressed into 145.0 mg weight tablets and 50.0 mg active ingredient, optionally with partial scores for finer dose adjustment can.

Example 21: Lacquered tablets, containing in each case 100 mg of 1-) o-fluorobenzyl) -1H-1,2,3-triazole-4-carboxamide, can be prepared as follows:

Composition (for 1 000 tablets)

Active ingredient 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 0.64g

Water q.s.

Methylene chloride q.s.

The active substance, the lactose and 40 g of the corn starch are mixed and moistened with a paste made 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 this is painted with a solution of the hydroxypropylmethylcellulose and the shellac in methylene chloride; the final weight of the coated tablet is 283mg.

Example 22: In a manner analogous to that described in Examples 20 and 21, tablets or coated tablets containing another compound according to Examples 1-19 can also be prepared.

Claims (24)

Invention claim: R ₁ R ₂ wherein Ph is a phenyl radical substituted in the o-position by fluorine and optionally additionally by at least one further halogen atom, alk is lower alkylidene, R 1 is hydrogen, lower alkyl or an unsubstituted or lower alkanoyl or lower alkyl-substituted carbamyl group and R _{2 is} an unsubstituted or lower alkanoyl or Lower alkyl substituted carbamyl group, characterized in that a) Ph-alk-N ₃ '(II), with a compound of the formula ^Y l ^Υ (III) wherein Y _{1 is} hydroxy and Y _{2 is} hydrogen, or Y ₁ and Y ₂ together represent an additional bond, or a salt and / or tautomer thereof or
b) a compound of the formula Ph-alk-Z (IV), wherein Z is reactive esterified hydroxy, with a 1 H-1,2,3-triazole derivative of the formula H-N \ <- R ₂ or a salt thereof or
c) in a compound of the formula Ph - alk - - γ (Vl), ^Y 5 wherein Y _{4 is} a substituted or substituted by lower alkyl carbamyl group Y _A 'md Y _{5 is} a ReStR ₁ or in unsubstituted or lower alkyl substituted carbamyl convertible radical Y ₆ or Y _{4 is} a radical R ₂ and Y _{5 is} an unsubstituted or by 'is lower alkyl substituted carbamyl convertible group Y _8, Y _Y and / or Y converted to unsubstituted or substituted by lower alkyl carbamyl _8, if necessary separating a resulting mixture of isomers into its components and the isomer of formula (I) is isolated and if desired, the process according obtainable compound in a converts another compound of the formula (I) and / or splits an enantiomer or diastereomer mixture obtainable according to the process into the components. 2. The method according to item 1, characterized in that reacting a compound of formula VI, wherein Y _{4 is} esterified carboxy and Y _{5 represents} hydrogen, lower alkyl or esterified carboxy, with an excess of ammonia or a di-lower alkylamine and, if desired, a method according to available Compound in which R ₂ and optionally R ₁ unsubstituted carbamyl means R ₂ and optionally R ₁ lower alkanoylated. 3. The method according to item 1 or 2, characterized by reacting compounds of formula (I), wherein Ph is a in o-position by fluorine and optionally additionally by to and with 3 halogen atoms of the atomic number to and 35 substituted phenyl, alkfür .ci-C ₄ is alkylidene, R ₁ is hydrogen, C ₁ -C ₄ -alkyl, carbamoyl, NC ₁ -C ₇ -Alkanoylcarbamyl or N, N-di-C ₁ -C ₄ alkylcarbamyl, R ₂ and carbamyl, NC ₁ -C ₇ alkanoylcarbamyl or N, N-di-C ₁ -C ₄ -alkylcarbamyl. 4. The method according to item 1 or 2, characterized by reacting compounds of formula (I) wherein Ph in o-position by fluorine and optionally additionally by up to and with 2 chlorine atoms, 1 fluorine or 1 chlorine atom or bis and with fluorine atoms substituted phenyl, alk Ci-C ₄ is alkylidene, R ₁ is hydrogen, Ci-C ₄ alkyl, carbamoyl, NC ₂ -C ₅ -Alkanoylcarbamyl or N, N-di-C ₁ -C ₄ alkylcarbamyl, and R _{2 is} carbamyl, NC is Cs-alkanoylcarbamyl or N is _1- N-di-C ₁ -C ₄ -alkylcarbamyl. · ' 5. The method according to item-1 or 2, characterized by reacting compounds of formula (I) wherein Ph in o-position by fluorine and optionally additionally by 1 chlorine atom, 1 fluorine and 1 chlorine atom or bis and with 2 fluorine atoms phenyl, alkfürCr-C ₄ is alkylidene, R, is hydrogen, C ₁ -C ₄ -A ^ yI or a radical R _2, and R ₂ is carbamyl or N, N-di-C ₁ -C ₄ alkylcarbamyl , manufactures. 6. The method according to item 1 or 2, characterized by reacting compounds of formula (I) wherein Ph o-fluorophenyl, 2,3-2,4-, 2,5- or 2,6-difluorophenyl or 6-chloro Is -2-fluoro-phenyl, alk is methyl, R _{1 is} hydrogen or carbamyl and R _{2 is} carbamyl. 7. Process according to item 1 or 2, characterized in that compounds of the formula (I) in which Ph is o-fluorophenyl or 2,6-difluorophenyl, alk is methylene, R _{1 is} hydrogen or carbamyl and R _{2 is} carbamyl, manufactures. 8. The method according to item 1 or 2, characterized in that compounds of the formula (I) wherein Ph is 2,6-difluorophenyl, alk is methylene, R-, hydrogen, C ₁ -C ₄ -A ^ yI or a R ₂ is and R _{2 is} carbamyl, NC ^ Cs-alkanoylcarbamyl or N ^ -Di-C ^ d-carbamyl, prepared. 9. The method according to item 1 or 2, characterized in that compounds in which Ph o-fluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl or 2-chloro-6-fluoro-phenyl, alk is methylene and R ₁ and R _{2 are} both carbamyl. 10. The method according to item 1 or 2, characterized in that one produces compounds of formula (I) wherein Ph is 2,6-difluorophenyl, alk methylene, R _{1 is} hydrogen or carbamyl and R _{2 is} carbamyl. 11. The method according to item 1 or 2, characterized in that one produces 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4-carboxarriid. 12. The method according to item 1 or 2, characterized in that one produces 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4-carboxamide. 13. The method according to item 1 or 2, characterized in that one produces 1- (0-fluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide. 14. The method according to Punkti or 2, characterized in that one produces 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide. 15. The method according to item 1 or 2, characterized in that one produces 1- (6-chloro-2-fluoro-benzyl) -1H-1,2,3-triazole-4-carboxamide. 16. The method according to item 1 or 2, characterized in that one produces 1- (6-chloro-2-fluoro-benzyl) -1H-1,2,3-triazole-4,5-dicarboxamide. 17. The method according to item 1 or 2, characterized in that one produces 1- (2,5-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide. 1-8. Process according to item 1 or 2, characterized in that 1- [1- (2,6-difluorophenyl) ethyl] -1H-1,2,3-triazole-4-carboxamide is prepared. , · 19. The method according to item 1 or 2, characterized in that one produces 1- (2,6-difluorobenzyl) -5-methyl-1H-1,2,3-triazole-4-carboxamide. 20. The method according to item 1 or 2, characterized in that one produces 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-di (N, N-dimethyl) -carboxamide. 21. The method according to item 1 or 2, characterized in that one prepares 1- [1- (2,6-difluorophenyl) ethyl] -1H-1,2,3-triazole-4-carboxamide. 22. The method according to item 1 or 2, characterized in that one produces 1- {2- [2- (2,6-difluorophenyl) propyl]} - 1H-1,2,3-triazole-4-carboxamide. 23. The method according to item 1 or 2, characterized in that one produces 1- {2- [2,6-Dif'uorphenyi) propyl]} - 1H-1,2,3-triazole-4,5-dicarboxamide. 24. The method according to item .1 or 2, characterized in that one produces 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4- (N-acetyOcarboxamid. 25. The method according to item 1 or 2, characterized in that one produces 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-di (N-acetyl) carboxamide. 26. The method according to item 1 or 2, characterized in that one produces 1- (2,3-difluorobenzyl) -1H-1,2,3-triazole-4-carboxamide. 27. Method according to item 1 or 2, characterized in that 1- (2,3-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide is prepared. 28. The method according to item 1 or 2, characterized in that one produces 1- (2,4-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide.