DK169720B1 - Fluorinated 1- (alpha-phenylalkyl) -1H-1,2,3-triazole compounds as well as their preparation and pharmaceutical preparations containing such compounds - Google Patents

Description

in DK 169720 B1

The invention relates to novel fluorinated 1- (a-phenylalkyl) -1H-1,2,3-triazole compounds of the general formula g Ph-alk-N 2 (I) ki kz wherein pH means a at the o-position with fluorine and optionally further with at least one additional halogen atom substituted phenyl group, alk means methylene or lower alkylidene, means hydrogen, lower alkyl or an unsubstituted or lower alkanoyl or lower alkyl substituted carbamyl group, and R2 represents an unsubstituted or lower alkanoyl or lower alkyl substituted carbamo group for the preparation of these compounds as well as pharmaceutical compositions containing compounds of formula (I).

For example, as additional halogen substituents in Ph, halogen atoms having an atomic number not exceeding 35, such as fluorine, chlorine or other bromine, may be mentioned. In total, there may be 5 halogen substituents, in addition to the o-fluoro substituent, for example, 1 or 2 chlorine atoms, 1 chlorine and 1 fluorine atom 25 or 1-3, e.g. 1 or 2 fluorine atoms. For example, a single additional halogen atom is bonded in the 4-, 5 or especially the 6-position.

The lower alkylidene is, for example, methylene or C2-4 alkylidene, especially methylene, ethylidene, 1,1-propylidene, 2,2-propylidene (isopropylidene) or 1,1-butylidene.

Low alkyl is, for example, C 1-4 alkyl, such as methyl or other ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but can also be a C 5-7 alkyl group, e.g. pentyl, hexyl or heptyl.

2 DK 169720 B1

Carbamyl substituted with lower alkanoyl or lower alkyl is especially monosubstituted with lower alkanoyl or disubstituted with lower alkyl and means, for example, N-C 1-7 alkanoylcarbamyl, primarily N-C2-5 alkanoylcarbamoyl such as acetyl or pivaloylcarbamoyl, or first and foremost N di-C 1-4 -alkylcarbamyl such as Ν, Ν-dimethylcarbamyl or Ν, Ν-diethylcarbamyl.

EP-A-114,347 discloses chlorinated 10 l-phenyllavalkyl-1H-1,2,3-triazole compounds having anticonvulsant activity. The fluorinated compounds of formula (I) have a surprisingly better anticonvulsant effect than the closely related known chlorinated compounds, as shown in the pharmacological data below.

15

The compounds of the invention have valuable pharmacological properties, in particular a pronounced anticonvulsant effect, which can be detected, for example, on mice by a clear metrazole antagonism in a dose range of from ca. 30 to approx.

300 mg / kg p.o. and in mice and rats by means of a pronounced protective effect against convulsions triggered by electroshock in a dose range of about 1 to approx. 50, in most cases from ca. 1 to approx. 25 mg / kg p.o. With this model, for example, the following values for the effective dose of ED, -q in 25 mg / kg p.o. (1 hour pre-application): 1- (2,6-Difluorobenzyl) -1H-1,2,3-triazole-4-carboxamide 17 (mouse) and 8 (rat), 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-fluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide: 7 (mouse) and 10 (rat), 1- (o-fluorobenzyl) - 1H-1,2,3-triazole-4,5-dicarboxamide: 6 (mouse) and 10 (rat), 1- (6-chloro-2-fluorobenzyl) -1H-1,2,3-triazole -4-carboxamide: 11 (mice) and 1- (2,5-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide: 6 (mice).

3 DK 169720 B1

The fluorinated 1- (α-phenylalkyl) -1H-1,2,3-triazole compounds of formula (I), as mentioned above, have a better anticonvulsant effect than analogous chlorine compounds known from EP Publication No. 114,347. reed effect. With the known analogous chlorine compounds, using the above model, for example, the following ED 50 values are obtained: 1- (o-chlorobenzyl) -1H-1,2,3-triazole-4-carboxamide: 26 (mouse) 10 and 25 (rat) and 1- (o-chlorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide: 40 (mouse) and 43 (rat).

Thus, the compounds of the invention are very suitable for the treatment of various convulsions, for example for the treatment of epilepsy, and they can be used as anticonvulsants, for example antiepileptic drugs.

The invention relates primarily to compounds of formula 20 I wherein Ph means one at the o-position with fluorine and optionally further with up to 3 halogen atoms having an atomic number of up to 35 substituted phenyl group, alk means methylene or C2-4 alkylidene, means hydrogen, C 1-4 alkyl, carbamyl, NC 1-6 alkanoylcarbamyl or N, N-di-C 1-4 alkylcarbamyl, and R2 means carbamyl, NC 1-6 alkanoylcarbamyl or N, N-di-C 1-4 alkylcarbamyl.

The invention preferably relates to compounds of formula I wherein Ph means an in-position with fluorine and optionally further with up to 2 chlorine atoms, 1 fluorine and 1 chlorine atom or up to 2 fluorine atoms substituted phenyl group such as o-fluorophenyl, 2.3 -, 2,4-, 2,5- or 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, further 2,4,6-trifluorophenyl, alk means methylene, ethylidene or 2,2-propylidene, R hydrogen, C1-4 alkyl such as methyl, carbamyl, N-C2-5 alkanoylcarbamyl, such as acetyl or pivaloylcarbamyl, or N, N-di-C1-4 alkylcarbamyl such as dimethylcarbamyl, and R2 means carbamyl, N- C2-5 alkanoylcarbamyl such as acetyl or pivaloylcarbamyl, or N, N-di-C1-4 alkylcarbamyl such as dimethylcarbamyl.

5

The invention relates primarily to compounds of formula I wherein Ph means a fluorine at the o-position and optionally further with 1 chlorine atom, 1 fluorine atom and 1 chlorine atom or up to 2 fluorine atoms substituted phenyl such as o-fluoro-phenyl, 2, 3-, 2,4-, 2,5- or 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, furthermore 2,4,6-trifluorophenyl, alk means methylene or C2-4 alkylidene, especially methylene, R represents hydrogen, C 1-4 alkyl, such as methyl, or a group R 2, and R 2 represents carbamyl or otherwise N-C 2-5 alkanoylcarbamyl such as acetylcarbamyl or N, N-di-C 1-4 alkylcarbamyl; such as dimethylcarbamyl, for example, compounds of formula I wherein Ph means o-fluorophenyl, 2,3-, 2,4-, 2,5- or 2,6-difluorophenyl or 6-chloro-2-fluoro-phenyl, alk means methylene , R 2 represents hydrogen or unsubstituted carbamyl, and R 2 represents unsubstituted carbamyl.

In particular, the invention relates to compounds of formula I wherein Ph means o-fluorophenyl or 2,6-difluorophenyl, alk means methylene, R 4 represents hydrogen or unsubstituted carbamyl, and R 2 means unsubstituted carbamyl.

The invention preferably relates to compounds of formula I wherein Ph is 2,6-difluorophenyl, alk is methylene, R 1 is hydrogen, C 1-6 alkyl, such as methyl, or a group R 2 N-C 2- 5 alkanoylcarbamyl, such as acetylcarbamyl, or N, N-di-C 1-4 alkylcarbamyl, such as dimethylcarbamyl.

The invention relates in the very first series of compounds of formula I wherein Ph means o-fluorophenyl, 2,5-difluoro-phenyl, 2,6-difluorophenyl or 2-chloro-6-fluoro-phenyl, alk means methylene, and R R 2 is both carbamyl, DK 169720 B 1 s and compounds of formula I wherein Ph is 2,6-difluorophenyl, alk is methylene, is hydrogen or carbamyl, and R 2 is carbamyl.

The compounds of formula I can be prepared using methods known per se. The process of the invention is characterized in that a) reacting a compound of formula 10 Ph - alk - N3 (II) with a compound of formula

R 1 - I = I - r 2 (iii) wherein Y 1 is hydroxy and Y 2 is hydrogen or Y 1 and Y 2 are the additional bond, or a salt and / or tautomer thereof, or b) reacting a compound of formula 20

Ph - alk - Z (IV) wherein Z is reactively esterified hydroxy, with a 1H-1,2,3-triazole derivative of formula 25] = * - Rz 30 or a salt thereof or c) in a compound of formula

Ph-alk- <H (VI) · = · -Υι * 35 i, wherein Y 1 represents a group YA which can be converted to unsubstituted or lower alkyl substituted carbamyl and represents a group R group Υβ which can be converted to unsubstituted or low alkyl substituted carbamyl, or Y4 represents a group R 2 and Y 1 represents a group Υ β which can be converted to unsubstituted or low alkyl substituted carbamyl, Y 2 and / or Υβ converted to unsubstituted or lower alkyl substituted carbamyl, if necessary, separates a formed isomer mixture into the components and isolates the isomer of formula I 10 and, if desired, converts a prepared compound into another compound of formula I and / or separates a prepared enantiomer or diastereomer mixture in the components .

As starting compounds of formula III by process a) and tautomers thereof, for example, compounds of formulas R1-C5C-R2 (IIa) and R1 -C (= O) -CH2 ~ R2 (Hib) can be used.

Salts thereof are, for example, alkali metal salts, e.g. sodium salts of the compounds of formula IIla which can be formed from these compounds and alkali metal alkanolates, e.g.

Sodium methanolate.

The reaction of compounds of formula II with compounds of formula III is carried out in the usual 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 tert-butoxymethane, tetrahydrofuran or dioxane.

30

Preferred embodiments of this process are, for example, the reaction of an azide of formula II with a compound of formula IIa in benzene or dioxane at temperatures of from ca. 60-120 ° C, preferably at boiling temperature.

35 0 7 DK 169720 B1

The starting compounds of formula III and partly also the starting compounds of formula II are known compounds. New starting compounds of formula II can be prepared analogously to the known compounds, e.g. by reacting 5 a compound of the formula Ph-alk-Z (IV) wherein Z is reactively esterified hydroxy such as halogen, e.g. chlorine, bromine or iodine, or sulfonyloxy, such as lower alkanesulfonyloxy, optionally substituted benzenesulfonyloxy, such as methane, ethane, benzene, p-toluene or p-bromobenzene sulfonyloxy, or fluorosulfonyloxy, with an alkali metal azide, e.g. . with sodium azide, for example, in dimethyl sulfoxide or dimethylformamide, or by reacting an alcohol (Z = hydroxy) in the presence of triphenylphosphine and an azodicarboxylic acid ester, e.g. azodicarboxylic acid diethyl ester, with hydrogen azide acid, e.g. in toluene.

In starting compounds of formula IV by process b), reactively esterified hydroxy means, for example, halogen, e.g. chlorine, bromine or iodine, or sulfonyloxy, such as lower alkanesulfonyloxy, optionally substituted benzenesulfonyloxy, such as methane, ethane, benzene, p-toluene or p-bromobenzene sulfonyloxy, or fluorosulfonyloxy.

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

The reaction is carried out in the usual manner, e.g. in the presence of a basic condensing agent or advantageously, using the compound of formula V as salt, if necessary during heating, preferably in a solvent or diluent. For example, basic condensing agents are those which form salts with the compound of formula V such as alkali metal alcoholates, e.g. sodium methanolate or sodium ethanolate, alkali metal or alkaline earth metal amides, e.g. sodium amide or lithium diisopropylamide. As mentioned, the conversion of compound 5 of formula V into a salt thereof is advantageously preceded by the reaction, e.g. by reaction with one of the bases mentioned. Solvents, when carrying out the reaction in the presence of an alcoholate, are preferably similar to alcohols and when carried out in the presence of amides, for example, aprotic organic solvents such as phosphoric acid-lower alkyl amides, e.g. hexamethylphosphoric triamide, alkanoic acid amides, e.g. dimethyl fomamide, or dilavalkyl sulfoxides, e.g. dimethyl sulfoxide. Isomers formed by the process of the invention as by-products can optionally be separated from the desired compounds of formula I.

If the starting compounds of formulas IV and V are not known compounds, they can be prepared in a manner known per se. For example, the compounds of Formula IV can be prepared by reacting esterified with a corresponding alcohol (IV, Z = hydroxy), e.g. by means of thionyl chloride, phosphorus tribromide or a sulfonyl chloride. Compounds of formula V can be prepared by reacting trimethylsilylazide or hydrogen azide acid with a compound of formula

R 1 -C = C-R 2 (IIa) or R 1 -C (* O) -CH 2 -R 2 (Hib) wherein R 1, in particular, means unsubstituted or lower alkyl substituted carbamyl, and in an optionally formed 1-trimethylsilyl triazole derivative , if desired after low alk (ano) ylation of carbamyl R2 and / or R1 as set forth below for compounds of formula I, by mild hydrolysis.

However, it is also possible to react trimethylsilylazide with a compound of the formula 0 Y5-C = C-Yi * (Vila) or Ri-C (= O) -CH2-Yi, (V11b) wherein Y4 represents a group YA which can be converted to unsubstituted or lower alkyl substituted carbamyl, e.g. esterified carboxy, such as lower alkoxycarbonyl, or cyano, and Y 5 represents hydrogen or preferably a group Υβ which can be converted to unsubstituted or lower alkyl substituted carbamyl and which is preferably identical to Y

A

10 to Yst and / or Y_ to unsubstituted or lower alkyl substituted carbamyl, in the case of esterified carboxy, for example, by ammonolysis (reaction with ammonia) or in the case of cyano, for example, by hydrolysis, thereby also decomposing the trimethylsilyl group.

15

Groups YA and / or Υβ, which according to process c) can be converted to unsubstituted or low-alkyl-substituted carbamyl, are, for example, free or in a salt or anhydride form, carboxyl groups, unsubstituted or low-alkyl substituted amidino groups or esterified carboxy groups, or further.

Esterated carboxy groups are, for example, carboxy groups esterified with a low alkanol or a low alkyl mercaptan, ie.

25 lower alkoxy or lower alkylthiocarbonyl groups, but they may also be esterified with any other alcohol or mercaptan, e.g. with an optionally substituted phenol or thiophenol.

For example, a carboxy group present in salt form is an ammonium salt form derived from an ammonia or a dilavalkylamine carboxy group, furthermore on metal salts of worm, e.g. alkali metal or alkaline earth metal salt form, present carboxy group.

For example, in anhydride form, there are carboxy groups present in a halide form such as chlorocarbonyl, but may also be anhydrided with a reactive carboxylic acid and, for example, may mean alkoxycarbonyloxycarbonyl 5 or trifluoroacetoxycarbonyl.

The conversion of said groups and / or Υβ to optionally low alkylated carbamyl is carried out in the usual manner from free, esterified or in anhydride form, carboxy groups and unsubstituted or low alkyl substituted amidino groups by solvolysis, i.e. hydrolysis or ammonolysis or aminolysis (reaction with ammonia or a dilavalkylamine).

For example, by hydrolysis, cyano groups can be converted to carbamyl or unsubstituted or low-alkyl substituted amidino groups Y and / or Y_ to unsubstituted or low-A3 alkyl-substituted carbamyl. The hydrolysis of cyano groups is carried out, for example, in the presence of basic hydrolysis agents such as alkali metal hydroxides, e.g. sodium or potassium hydroxide, if necessary in the presence of peroxy compounds, e.g. hydrogen peroxide. The hydrolysis of amidino groups is carried out, for example, in an acidic hydrolyzing agent such as a mineral acid, a sulfonic acid or a carboxylic acid, e.g.

Sulfuric acid, phosphoric acid, hydrochloric acid or another hydrogen halide acid, p-toluenesulfonic acid or other organic sulfonic acid, or a low alkanoic acid such as acetic acid, preferably in catalytic amounts.

For example, by ammonolysis or aminolysis, free or saline or anhydride forms or esterified carboxy groups can be converted to unsubstituted or low-alkyl-substituted carbamyl. If necessary, the conversion is carried out in the presence of a condensing agent, advantageously in an inert solvent. Also used as condensing agents are basic condensing agents / primarily ammonia or amines used in excess in the anhydride form from an anhydride form, carboxy also alkali metal hydroxides or carbonates or tertiary organic nitrogen bases such as trilavalkylamines or tertiary alkyl amines nitrogen bases such as triethylamine or pyridine. Free carboxy groups can be converted to carbamyl during dehydration of the intermediate ammonium salts, e.g. by heating or acting on water-removing agents, such as acid anhydrides, e.g. phosphorus pentoxide, and the like, or carbodiimides, e.g. l ^ N'-dicyclohexylcarbodiimide.

A particularly preferred embodiment of this process is characterized by reacting a compound of formula VI wherein esterified is carboxy and Y 15 is hydrogen, lower alkyl or optionally esterified carboxy, with excess ammonia or a dilavalkylamine and, if desired, in a prepared compound wherein R 2 and optionally means unsubstituted carbamyl, lower alkanoylates R 2 and optionally R 2.

20

The starting compounds of formula VI may, in the case of novel compounds, be prepared in the usual manner, for example by reacting an azide of formula 25 Ph - alk - N3 (II) with a compound of formula

Ys-CsC-Yu (Vila) or Ri-C («O) -CH2-Yi, (Vllb), for example, in the same manner as described under process a). If necessary, primarily formed esters or nitriles of formula VI (Y 2 and optionally Υ β = esterified carboxy or cyano) can be hydrolyzed under basic conditions, e.g. by means of aqueous alcoholic sodium hydroxide solution, to the corresponding acid, and, primarily or by hydrolysis of corresponding esters or nitriles, acids of formula VI (Y Y and optionally Υβ = carboxy) are converted to the acid chloride, f .g. with thionyl chloride.

5

As conversion reactions for prepared compounds of formula I to other compounds of formula I, in particular, mention may be made of substitution reactions of N-unsubstituted or N-monolavalkylated carbamyl groups R 2 and / or the separation of prepared isomer mixtures.

Thus, in compounds of formula I, by treatment with a low alkanoylating agent, N-unsubstituted carbamyl can be converted to N-low alkanoylcarbamyl or by treatment with a low alkylating agent convert unsubstituted carbamyl to N, N-dilavalkyl carbamyl and / or N-monolavalkylcarbamyl , N-di-lower carbamyl. For example, N-monoalkyl derivatives of compounds of formula I may be prepared from corresponding starting compounds of formulas III, V or VI, especially VI.

20

Examples of low alkanoylating agents include low alkanoic carboxylic anhydrides such as acetic anhydride or the mixed anhydride of formic acid and acetic acid, or low alkanoic carboxylic acid chlorides such as acetyl chloride. The reaction with these 25 is carried out in the usual manner, if necessary in the presence of a base, e.g. triethylamine or pyridine, or in the case of reaction with acid anhydrides in the presence of a mineral acid, e.g. sulfuric acid.

Examples of low alkylating agents include reactive esters, such as hydrogen halide acid esters, sulfuric acid esters or sulfonic acid esters, of low alkanols such as low alkyl halides, e.g. methyl iodide, dilavalkyl sulfates, e.g. dimethyl sulfate, or low alkyl esters of aliphatic or aromatic sulfonic acids, especially of low alkanesulfonic acids or optionally substituted benzenesulfonic acids, e.g. low alkyl methanesulfonates, low alkyl ethanesulfonates, low alkyl benzene sulfonates or low alkyl p-toluenesulfonates. The low alkylation is carried out in the usual manner, for example under basic conditions, such as in the presence of an alkali metal hydroxide, e.g. potassium hydroxide, and advantageously a phase transfer catalyst, e.g. tetrabutylammonium bromide or benzyl trimethyl lammonium chloride.

The separation of isomer mixtures, which may be, for example, enantiomeric or diastereomeric mixtures of compounds of formula I having at least one asymmetric carbon atom as well as mixtures of compounds of formula I and isomers thereof formed by the process are carried out in the usual manner. For example, diastereomer isomer mixtures as well as mixtures of compounds of formula I and isomers thereof formed by the process can be separated due to the various physical properties of the components by conventional physical separation methods, e.g. by fractional crystallization, chromatography methods and the like. For example, for the separation of enantiomeric mixtures, fractional crystallization from an optically active solvent or chromatography on an optically active stationary and / or mobile phase is suitable. However, one can also convert an enantiomeric mixture, e.g. by reaction with an optically active acid chloride, to the corresponding diastereomeric acyl derivatives which are separated into the components from which the pure enantiomers are released, e.g. by mild acid treatment.

For example, the compounds of the invention of formula I may be used in the form of pharmaceutical compositions containing a therapeutically effective amount of the active compound, optionally together with inorganic or organic solid or liquid pharmaceutically useful carriers suitable for enteral, e.g. .g. oral, or parenteral administration. Thus, tablets or gelatin capsules, which contain the active substance together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and / or lubricants, e.g. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol.

6

Tablets may further contain binders, e.g. magnesium aluminum silicate, starch such as corn, wheat, rice or pile herb starch, gelatin, tragacanth, methyl cellulose, sodium carboxyl methyl cellulose and / or polyvinylpyrrolidone, and, if desired, disintegrating agents, e.g. starch, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, dyes, flavors and sweeteners. Furthermore, the compounds of the invention may be used in the form of parenteral administration preparations or in the form of infusion solutions. Such solutions are preferably isotonic. aqueous solutions or suspensions, these can be prepared before use, e.g. by lyophilized preparations containing the active substance alone or together with a carrier material, e.g. mannitol. The pharmaceutical compositions may be sterilized and / or contain adjuvants, e.g. preservatives, stabilizers, wetting agents and / or emulsifiers, solubility promoting agents, salts for controlling the osmotic pressure and / or buffers. The present pharmaceutical compositions, which if desired may contain other pharmacologically active compounds, are prepared in a manner known per se, e.g. using conventional mixing, granulating, coating, dissolving or lyophilization methods, and containing from ca. 0.1 to 100%, especially from ca. 1 to

uO

ca. 50%, lyophilisates up to 100% active substance.

The invention also relates to pharmaceutical compositions containing compounds of formula I together with common excipients. The dosage may depend on various factors such as mode of application, species age and / or individual condition.

DK 169720 B1 0 15

The daily dose for oral application is between approx. l and approx.

50 mg / kg in single doses of approx. 1 to 25 mg / kg and for humans or warm blooded animals with a body weight of approx. 70 kg preferably in daily doses of approx. 0.070 g to approx. 3.5 g.

5

The invention is further illustrated by the following examples.

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. The solution is added to an autoclave in which 250 g of ammonia is pressurized and the autoclave is left at 100 ° C for 24 hours. Cooling is then carried out, the crystallized product is extracted, washed with methanol and recrystallized from dioxane / toluene. There is obtained 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, m.p. 197-199 ° C.

For example, the starting material can be prepared as follows: To a solution of 41.5 g (0.275 mole) of o-fluorobenzyl azide in 50 ml of toluene heated to a solution of 40 g (0.282 mole) of acetylenedicarboxylic acid dimethyl ester in 500 ml toluene. After an additional 5 hours at 90 ° C, the toluene is removed and upon cooling, the crystallized substance is suctioned off. Thus, after recrystallization from a mixture of diethyl ether and petroleum ether (lsl), 1- (o-fluoro-benzyl) -1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester is obtained, m.p. 49-51 ° C.

30

Example 2.5 59 g (0.26 mol) of 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4-carboxylic acid are heated with 300 ml of thionyl chloride for 1 hour to reflux. Excess thionyl chloride is distilled off in vacuo, the remaining 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4-carboxylic acid chloride is dissolved in 500 ml of toluene and this solution is added dropwise at 5 -10 ° C to 500 ml of concentrated aqueous ammonia solution. The precipitated product 5 is aspirated, washed with water and recrystallized from ethanol.

In this way, 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4-carboxamide is prepared, m.p. 220-222 ° C.

The starting material may be prepared, for example, in the following manner: A solution of 50 g (0.33 mol) of o-fluorobenzyl azide, 23.1 g (0.33 mol) of propynecarboxylic acid and 400 ml of toluene is stirred for 24 hours at 70 ° C. The precipitated product is aspirated after cooling to room temperature, then washed with toluene and then with diethyl ether. In this way, 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4-carboxylic acid is prepared with m.p.

151 ° C (dec.).

Example 3

Analogous to the procedure 20 described above in Example 1, is prepared from 2,6-difluorobenzyl azide and acetylenedicarboxylic acid dimethyl ester over 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester (mp 62 -65 ° C) 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, m.p. 203-205 ° C (from methanol).

25

Example 4

Analogous to the process described in Example 2, is prepared from 2,6-difluorobenzyl azide over 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4-carboxylic acid, m.p. 160-162 ° C (from acetonitrile, decomposition) 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4-carboxamide, m.p. 237-240 ° C (from ethanol).

35

Example 5 17 DK 169720 B1

Further, by analogy to the process described in Examples 1-4, the following compounds may be prepared: 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

Analogous to the procedure described in Example 2, is prepared from 1- (6-chloro-2-fluoro-benzyl) -1H-1,2,3-triazole-4-carboxylic acid 1- (6-chloro-2-fluoro -benzyl) -1H-1,2,3-triazole-4-carboxamide, m.p. 274-276 ° C (from glacial acetic acid).

The starting material can be prepared, for example, as follows: A mixture of 98 g (0.678 mole) of 6-chloro-2-fluoro-toluene, 91.5 g (0.678 mole) of sulfuryl chloride and 0.2 g of dibenzoyl peroxide is stirred for 3 hours at 100 ° C. 110 ° C, then distilled. This gives 6-chloro-2-fluoro-benzyl chloride, b.p. = 78-82 ° C.

To a suspension of 47 g (0.722 mole) of sodium azide in 400 ml of dimethyl sulfoxide is added dropwise at 20-40 ° C 123 g (0.687 mole) of 6-chloro-2-fluoro-benzyl chloride. After stirring for 4 hours at room temperature, the mixture is diluted with 1 liter of ice water and extracted with cyclohexane. After distilling off the solvent, the residue is distilled. This gives 6-chloro-2-fluoro-benzyl azide, bp15 = 99-100 ° C.

27.5 g (0.15 mol) of 6-chloro-2-fluoro-benzyl azide and 10.5 g (0.15 mol) of propynecarboxylic acid in 300 ml of toluene are heated at 90 ° C for 3 hours. After cooling, the crystals which are recrystallized from acetonitrile are suctioned off. This gives 1- (6-chloro-2-fluoro-benzyl) -1H-1,2,3-triazole-4-carboxylic acid with m.p. 182 ° C (dec.).

DK 169720 B1 18

Example 7

Analogous to the procedure described in Example 1, is prepared from 6-chloro-2-fluoro-benzyl azide and acetylenedi-carboxylic acid dimethyl ester over 1- (6-chloro-2-fluoro-benzyl) -1H-1,2,3-triazole -4,5-dicarboxylic acid dimethyl ester (mp 88-90 ° C) 1- (6-chloro-2-fluoro-benzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, m.p. 214-216 ° C (from glacial acetic acid).

Example 8

Analogous to the procedure 10 described above in Example 1, is prepared from 2,5-difluorobenzyl azide (bp = 82-84 ° C) over 1- (2,5-difluorobenzyl) -1H-1,2,3-triazole -4,5-dicarboxylic acid dimethyl ester 1- (2,5-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, m.p. 191-192 ° C (from dioxane / toluene).

Example 9 Analogous to the procedure described in Example 1, is prepared from 2,4-difluorobenzyl azide (bp = 80-83 ° C) over 1- (2,4-difluorobenzyl) -1H-1,2,3-triazole -4,5-dicarboxylic acid dimethyl ester with m.p. 75-76 ° C (from cyclohexane) 1- (2,4-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, m.p.

203-185 ° C (from dioxane / toluene).

Example 10

Analogous to the procedure described in Example 1, is prepared by reaction with dimethylamine 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxylic acid di (Ν, Ν-dimethyl) -25 amide with mp. 130-133 ° C (from tert-butoxymethane).

Example 11

Analogous to the procedure described in Example 1, is prepared from 2,3-difluorobenzyl azide and acetylenedicarboxylic acid dimethyl ester over 1- (2,3-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester 1- (2,3-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, m.p. 183-185 ° C (from ethyl acetate / benzene).

DK 169720 B1 19

Example 12

Analogous to the procedure described in Example 2, is prepared from 1- (2,6-difluorobenzyl) -5-methyl-1H-1,2,3-triazole-4-carboxylic acid 1- (2,6-difluorobenzyl) -5 -methyl-1H-5,2,3-triazole-4-carboxamide, m.p. 208-210 ° C (from methanol).

The starting material is prepared as follows: 2.53 g (0.11 mol) of sodium is dissolved in 60 ml of alcohol, to which is added a mixture of 16.9 g (0.1 mol) of 2,6-difluorobenzyl azide and 14.3 g ( 0.11 mole) of acetic acid ester in 60 ml of alcohol and the mixture is heated for 18 hours to reflux. After adding 120 ml of 1 N sodium hydroxide solution, the mixture is boiled for a further 2 hours at reflux, diluted with 200 ml of water and acidified under cooling with hydrochloric acid to pH 1. The precipitated product is filtered off, washed with 15 water, then ether. dried. There is thus obtained 1- (2,6-difluorobenzyl) -5-methyl-1H-1,2,3-triazole-4-carboxylic acid, m.p. 166-167 ° C.

Example 13

Analogous to the procedure 20 described above in Example 1, is prepared from 1- [1- (2,6-difluorophenyl) ethyl] -1H-1,2,3-triazole-4-carboxylic acid ethyl ester 1- [1- (2, 6-difluorophenyl) ethyl] -1H-1,2,3-triazole-4-carboxamide, m.p. 205-207 ° C (from methanol).

The starting material is prepared as follows: By reducing 25.2 g (66 mmol) of 2> 6-difluoroacetophenone with 2.5 g (65 mmol) of lithium aluminum hydride in ether, 1- (2,6-difluorophenyl) ethanol in of a colorless oil.

10 g (63 mmol) of 1- (2,6-difluorophenyl) ethanol are dissolved in 150 ml of hydrogen azide acid solution (1.2 N in toluene), and 22.8 g (200 mmol) of trifluoroacetic acid are added and the mixture is left for 24 hours at room temperature. After dilution with 300 ml of hexane, wash first with water, then with sodium hydrogen carbonate solution for acid-free reaction, then the solution is dried with sodium sulfate and the solvent is removed under reduced pressure at 40-50 ° C. The residue is dissolved in 100 ml of hexane, the solution is filtered through 50 g of silica gel and then evaporated again. This gives 1- (2,6-difluoro-phenyl) ethyl azide in the form of a colorless oil.

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

7.1 g (26.6 mmol) of 1- [1- (2,6-difluorophenyl) ethyl] -1H-1,2,3-triazole-4-carboxylic acid are heated with 150 ml of ethanol and 1 ml of sulfuric acid for 10 hours. hours for reflux. After working up, 1- [1- (2,6-difluorophenyl) ethyl] -1H-1,2,3-triazole-4-carboxylic acid ethyl ester is obtained, m.p. 118-121 ° C.

Example 14 Analogously to the procedure described in Example 1, is prepared from 1- {2- [2- (2,6-difluorophenyl) propyl]} - 1Η-1,2,3-triazole-4-carboxylic acid ethyl ester 1- {2- [2- (2,6-difluorophenyl) propyl]} -1H-1,2,3-triazole-4-carboxamide, m.p. 203-205 ° C (from methanol).

The starting material is prepared as follows: To 28 g (150 mmol) of 2,6-difluorobenzoic acid ethyl ester in 200 ml of ether is added dropwise and slowly 120 ml of 3-M solution of methyl magnesium chloride in tetrahydrofuran. After 1 hour refluxing and working up with 10% ammonium chloride solution 30, 2- (2,6-difluorophenyl) -propan-2-ol with bp = 74-76 ° C is obtained.

20.6 g (120 mmol) of 2- (2,6-difluorophenyl) propan-2-ol are dissolved in 300 ml of hydrogen azide acid solution (1 N in benzene), to which 22.8 g (200 mmol) is added. trifluoroacetic acid. After 24 hours at room temperature, dilute with 500 ml of hexane, then wash with water and then with sodium hydrogen carbonate solution for acid-free reaction, then dry with sodium sulfate, evaporate the solvent and distill the residue. In this way 2- (2,6-difluoro-phenyl) -2-azido-propane is obtained having bp = 5 = 85-87 ° C.

10 g (51 mmol) of 2- (2,6-difluorophenyl) -2-azido-propane are reacted with 3.6 g (51 mmol) of propynecarboxylic acid in 100 ml of toluene, and the reaction mixture is worked up in the same manner as described in Example 12. There is obtained 1- {2- [2- (2,6-difluorophenyl) propyl]} -1H-1,2,3-triazole-4-carboxylic acid, m.p. 173 ° C (dec.).

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

Example 15

Analogous to the procedure 20 described above in Example 1, is prepared from 2- (2,6-difluorophenyl) -2-azido-propane and acetylenedicarboxylic acid dimethyl ester over 1- {2- [2- (2,6-difluorophenyl) propyl]} - 1Η-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester (mp 100-102 ° c) 1- {2- [2- (2,6-difluorophenyl) propyl]} -1H-1, 2,3-triazole-4,5-dicarboxamide, m.p.

257-178 ° C (from ethyl acetate / hexane).

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

Example 17 DK 169720 B1 22 2.81 g (10 mmol) 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 to 80 ° c for 3 hours. After cooling, the mixture is stirred with 100 ml of water for 1 hour at 20-25 ° C, the precipitated product is suctioned off and washed with water. After recrystallization from 75 ml of methanol, 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-di (N-acetyl) carboxamide is obtained, m.p. 136-138 ° C.

Example 18 Analogously to the process described in Example 17, 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4- (N-acetyl) carboxamide is also prepared with m.p. 205-207 ° C (from dioxane / toluene).

Example 19 Dissolve 1.4 g (12.5 mmol) of acetylenedicarboxylic acid diamide at 15 ° C in 10 ml of dimethyl sulfoxide. 1.69 g (10 mmol) of 2,6-difluorobenzyl azide is added and the mixture is stirred for 16 hours at 80 ° C. The mixture is then diluted with 25 ml of water, then suction filtered, the product is stirred with 50 ml of water, the stirring is continued for 30 minutes at 50-60 ° C, suctioned again and the product is dried and recrystallized from dioxane / ethanol. 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide is obtained, m.p. 203-205 ° C.

Example 20

Tablets containing 50 mg of 1- (o-fluorobenzyl) -1H-1,2,3-25 triazole-4-carboxamide per tablet can be prepared as follows:

Composition (10,000 tablets)

Active substance 500.0 g

Lactose 500.0 g Potato starch 352.0 g

Gelatin 8.0 g

Talc 60.0 g DK 169720 B1 23

Magnesium stearate 10.0 g • Silica (high dispersion) 20.0 g

Ethanol q.s.

The active substance is mixed with lactose and 292 g of potato starch, the mixture is moistened with an alcoholic solution of the gelatin and granulated through a sieve. After drying, the remainder of the potato starch, talcum, magnesium stearate and the high-dispersed silica are mixed and the resulting mixture is pressed into tablets of 145.0 mg 10 with an active substance content of 50.0 mg. If desired, the tablets may be provided with splits for finer adjustment of dosage.

Example 21

Lactate tablets containing 100 mg of 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4-carboxamide per tablet can be prepared as follows:

Composition (for 1000 tablets)

Active substance 100.00 g

Lactose 100.00 g 20 Corn starch 70.00 g

Talc 8.50 g

Calcium stearate 1.50 g

Hydroxypropyl methyl cellulose 2.36 g

Shellac 0.64 g 25 Water q.s.

Methylene chloride q.s. '

The active substance, lactose and 40 g of corn starch are mixed and the mixture is wetted with an adhesive made from 15 g of corn starch and water (under heating) and the mixture is granulated. The granulate is dried, the rest of the corn starch, talcum and calcium stearate are added and mixed with the granulate. The mixture is pressed into tablets (weight: 280 mg), which is lacquered with a solution of hydropropylmethyl cellulose and shellac DK 169720 B1 24 in methylene chloride. The final lactate tablet has a final weight of 283 mg.

Example 22 In the same way as described in Examples 20 and 21, tablets or lacquer tablets containing another compound of Examples 1-19 can also be prepared.

Claims (12)

Fluorinated 1- (α-phenylalkyl) -1H-1,2,3-triazole compounds, characterized in that they have the general formula Ph-alk-N 2 | (χ) kk 10 wherein Ph means a phenyl group optionally substituted with at least one additional halogen atom with fluorine and optionally further with at least one additional halogen atom; means an unsubstituted or lower alkanoyl or lower alkyl substituted carbamyl group. Compounds according to claim 1, characterized in that Ph is one at the o-position with fluorine and optionally 20 further with up to 3 halogen atoms having an atomic number of not more than 35 substituted phenyl group, alk means methylene or C2-4 alkylidene, R means hydrogen, C 1-4 alkyl, carb-arnyl, NC 1-6 alkanoylcarbamyl or N, N-di-C 1-4 alkylcarbamyl, and R 2 represents carbamyl, N-C 1-6 alkanoylcarbamyl or N, N-di-C 1-4 -alkylcarbamyl. Compounds according to claim 1, characterized in that Ph is one at the o-position with fluorine and optionally further with up to 2 chlorine atoms, 1 fluorine and 1 chlorine atom or up to 2 fluorine atoms substituted phenyl group, alk means C2 R R represents hydrogen, Cj ^alk alkyl, carbamyl, NC ^^ - alkanoylcarbamyl or N, N-di-C ^ _ alkyl alkyl carbamyl, and R₂ means carbamyl, N-C₂cj alkanoylcarbamyl or N, N-di -C 1-4 alkylcarbamyl. 35 Compounds according to Claim 1, characterized in that Ph is one further substituted with 1 chlorine, 1 fluorine and 1 chlorine atom or up to 2 fluorine atoms in the o-position with fluorine and optionally DK 169720 B1, alk means C2-4 alkylidene, represents hydrogen, C 1-4 alkyl or a group R 2 / and R 2 represents carbamyl or N, N-di-C 1-4 alkyl carbamyl. Compounds according to claim 1, characterized in that Ph means o-fluorophenyl, 2,3-, 2,4-, 2,5 or 2,6-difluorophenyl or 6-chloro-2-fluorophenyl, alk means methylene R 2 represents hydrogen or carbamyl and R 2 represents carbamyl. Compounds according to claim 1, characterized in that Ph means o-fluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl or 2-chloro-6-fluorophenyl, alk means methylene, and R 1 and R 2 are both means carbamyl. A compound according to claim 1, characterized in that it is 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide. Compound according to claim 1, characterized in that it is 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4-carboxamide. A compound according to claim 1, characterized in that it is 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, 1- (o-fluorobenzyl) -1H-1, 2,3-triazole-4-carboxamide, 1- (6-chloro-2-fluoro-benzyl) -1H-1,2,3-triazole-4-carboxamide, 1- (6-chloro-2-fluoro-benzyl) ) -1H-1,2,3-triazole-4,5-dicarboxamide, 1- (2,5-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, 1- [1- ( 2,6-difluorophenyl) ethyl] -1H-1,2,3-triazole-4-carboxamide 1- (2,6-difluorobenzyl) -5-methyl-1H-1,2,3-triazole -4-carboxamide, 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-di (Ν, Ν-dimethyl) -carboxamide, 1- [1- (2,6) -difluorophenyl) ethyl] -1H-1,2,3-triazole-4-carboxamide, 1- {2- [2- (2,6-difluorophenyl) propyl]} -1H-1,2,3-triazole-4 -carboxamide, 1- {2- [2- (2,6-difluorophenyl) propyl]} -1H-1,2,3-triazole-4,5-di-carboxamide, 1 difluorobenzyl) -1H-1,2,3-triazole-4- (N-acetyl) carboxamide / 1- (2,6-difluorobenzyl) -1H-1 / 2,3-triazole-4,5-di (N- acetyl) carboxamide, 1- (2,3-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide or 1- (2,4-difluorobenzyl) -1H-1 , 2,3-triazole-4,5-dicarboxamide. 15 Pharmaceutical compositions, characterized in that they contain a compound according to any one of claims 1-9 in addition to conventional pharmaceutical auxiliaries and / or carriers. 20 A process for the preparation of novel 1- (α-phenyllavalkyl) -1H-1,2,3-triazole compounds of the general formula Wherein Ph means an phenyl group optionally substituted by at least one additional halogen atom with fluorine and optionally 30 with at least one additional halogen atom, alk means methylene or lower alkylidene, means hydrogen, low 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, characterized in that a compound of the formula Ph - alk - N3 (II) 5 is reacted with a compound of the formula R1 - i = i - R2 (III) wherein Y1 is hydroxy and Y2 is hydrogen, or Y1-10 and Y1 together represent an additional bond, or a salt and / or tautomer thereof, or b) reacting a compound; wherein: Z is reactively esterified hydroxy, with a 1 H-1,2,3-triazole derivative of the formula "Π <v) Y = i-r 2 20 1 or a salt thereof or c) in a compound of the formula Ph-alk-N ^ J (VI) 25 '' i-Yi 'Ϊ5 wherein Y ^ represents a group Y ^ which can be converted to unsubstituted or lower alkyl substituted carbamyl and Y ^ represents a group ^ or a group Υβ which can be converted to unsubstituted or lower alkyl substituted carbamyl, or Y 1 represents a group R 2 and Y 5 represents a group or lower alkyl substituted carbamyl, if necessary, separates a formed isomer mixture into the components and isolates the isomer of formula I and, if desired, converts a compound of formula I to another compound of formula I. and / or separating a prepared enantiomeric or diastereomeric mixture into the components, the process being particularly characterized by reacting a compound of formula VI, wherein Y4 is esterified carboxy, and Y1. means hydrogen, lower alkyl or optionally esterified carboxy, with an excess of ammonia or a dilavalkylamine and, if desired, lower alkanoyls and optionally R 1 in a compound prepared wherein R 1 and optionally R 2 represent unsubstituted carbamyl. 10 15 20 25 30 35