CS196336B2 - Method of producing novel 3-substituted 1-/o-benzoylphenyl/-5-/tertiary aminomethyl/-1h-1,2,4,-triazoles - Google Patents

Abstract

PROCESS FOR THE PRODUCTION OF NEW TRIAZOLE DERIVATIVES The invention relates to processes for the production of new triazole derivatives of the general formula (I) wherein R represents straight-chain alkyl having 2 or 3 carbon atoms. These new substances possess valuable pharmacological properties. In particular they have an anticonvulsive activity and are useful as active substances for therapeutic preparations for the treatment of epilepsy and of conditions of tension and of agitation. - 1a

Description

The present invention relates to a process for the preparation of novel 3-substituted 1- (o-benzoyl-phenyl) -5- (tert-aminomethyl) -1H-1,2,4-triazoles and their acid addition salts, which compounds have valuable pharmacological properties.

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

CONHR

The triazole derivatives of the formula I and their addition salts with inorganic and organic acids have valuable formacological properties. In particular, they are anticonvulsant, as can be demonstrated, for example, in mice in the pentetrazole-induced convulsion test after oral dosing of about 0.3 mg / kg, in the strychnine-induced convulsion test and in the electric shock test after administration. oral doses of about 1 mg / kg N-propyl-1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5 - [(dimethylamino) methyl] -1H-1,2,4-triazole-3- carboxamide or N-ethyl-1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5 - [(dimethylamino) methyl] -1H-1,2,4-triazole-3-carboxamide. In addition, the triazole derivatives of formula I and their acid addition salts also have moderate central nervous system depressant activity. However, these effects as well as atactic properties are mild in relation to the strong anticonvulsant and anxiolytic effects. These and other types of effects that can be affected by selected standard experiments [cf. W. Theobald and H.A. Kunz, Arzneimittelforsch. 13, 122 (1963) and W. Theobald et al., Arzneimittelforsch. 17, 561 (1967)] as well as good compatibility are characterized by the triazole derivatives of formula I and their pharmaceutically usable inorganic addition salts and wherein R represents a non-branched alkyl group having 2 or 3 carbon atoms.

The invention also relates to the preparation of inorganic and organic acid addition salts of the triazole derivatives of the formula I.

In the triazole derivatives of formula I, R is ethyl or propyl.

ganic acids as active substances for anticonvulsants and anxiolytic agents (tranquillizers), with a maximum of a low sedative effect, which are useful, for example, for the treatment of epilepsy and tension and arousal conditions.

The above data also applies to the addition salts of the triazole derivatives of the formula I with inorganic and organic acids, in particular the pharmaceutically acceptable acid addition salts.

The novel triazole derivatives of the formula I and their acid addition salts are prepared according to the invention by the carboxylic acid of the formula II

COOH

or reacting a functional derivative thereof with a compound of formula III,

NH 2 -R, (III) wherein R is as defined in Formula I, or a reactive functional derivative of such a compound, whereupon the optionally obtained triazole derivative of Formula I is converted into an inorganic or organic acid addition salt.

For example, to carry out the process of the invention, a carboxylic acid of formula II is reacted with a compound of formula III in the presence of a carbodiimide such as dicyclohexylcarbodiimide in an inert solvent such as tetrahydrofuran. It is further possible to react the carboxylic acid of formula II with ethyl or propyl isocyanate or isothiocyanate as a reactive functional derivative of the compound of formula III and heat the immediate reaction product until the evolution of carbon dioxide or carbonyl sulfide is complete.

Suitable reactive functional derivatives of the carboxylic acid of the formula II are, for example, its lower alkyl esters which react partially with the compounds of the formula III already at room temperature or optionally with heating and optionally in a closed vessel, depending on the reactivity or the boiling point of the compound of the formula III . The reaction medium used can be, for example, a lower alkanol such as methanol or ethanol, or also another inert organic solvent such as tetrahydrofuran or dioxane, optionally together with an excess to react the compound of the formula III to be used.

Other suitable reactive functional carboxylic acid derivatives of formula II. are its halides, especially chlorides, especially in the form of their hydrohalides, such as hydrochlorides. These are preferably prepared immediately prior to further reaction with the compounds of formula III from the free carboxylic acid and suitable acid halides such as thionyl chloride, oxalyl chloride or phosphorus tribromide, and are used without further purification for the next reaction. The carboxylic acid halides or their hydrohalides are reacted with the compounds of formula III preferably in the presence of at least an equivalent amount or at least twice the equivalent amount of an acid binding agent, for example a strong tertiary organic base such as triethylamine, N-ethyldlisopropylamine, pyridine or s-collidine. the excess may also serve as a solvent or an appropriate excess to react the compound of formula III used in the presence or absence of an inert organic solvent such as dioxane, tetrahydrofuran, benzene or dimethylformamide at temperatures between about 0 ° C and 100 ° C, optionally the boiling point of the reaction medium if this temperature is lower. Under analogous reaction conditions, mixed carboxylic acid anhydrides of the formula II, in particular mixed anhydrides with semi-esters of carbonic acid, obtained, for example, by reaction of alkali metal carboxylic acid salts with chloroformic esters, preferably lower alkyl chloroformates .

Further reactive functional derivatives of the carboxylic acid of the formula II are, for example, reactive esters, such as p-nitrophenyl esters and cyanomethyl esters, which are reacted with the compounds of the formula III in inert organic solvents, optionally with heating. Under the same conditions, the 1-imidazolides of the carboxylic acid of formula II are not reacted with the compounds of formula III.

The carboxylic acid of formula II and its ethyl ester can be prepared, for example, from 6- (o-chlorophenyl) -8-chloro-4H-s-triazolo [1,5-a] [1,4] benzodiazepine-2-carboxylic acid as described in DOS No. 2,159,527, optionally from its ethyl ester as described in DOS 2,234,552 and 2,304,307 by treatment with formaldehyde and formic acid, or from 1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5- (chloromethyl) -1H-1,2,4-triazole-2-carboxylic acid, optionally from its ethyl ester, also described in the above-mentioned DOS, by reaction with dimethylamine, for example in the presence of a small amount of lidu sodium. Other lower alkyls, swabs, such as the methyl ester, and other reactive functional derivatives can be obtained, for example, from the free carboxylic acid in a manner known per se.

Ethyl and propyl isocyanates and -isothiocyanates have already been mentioned as reactive functional derivatives of the compounds of formula III. The reactions of these compounds with the carboxylic acid of the formula II can be carried out in the presence or absence of an inert organic solvent of sufficiently high boiling point or boiling range, for example in toluene or xylene or in a mixture of xylenes. Further reactive functional derivatives of the compounds of formula III further include, for example, N-tri- [(lower) alkyl] silyl derivatives obtained by reaction of the above compounds with tri [(lower) alkyl] silyl chlorides such as trimethylsilyl chloride in inert anhydrous organic solvents. Their reaction with reactive functional carboxylic acid derivatives of the formula II in inert organic solvents leads to the N-tri [(lower] alkyl) carboxyamides of formula I from which the desired carboxamides are liberated by decomposition with water or lower alkanols.

Depending on the reaction conditions and the starting materials used, the final compounds are obtained in the free form or in the form of acid addition salts, which are also within the scope of the invention, or optionally also in the form of acid addition salt hydrates. The acid addition salts of the novel compounds of the formula I can be converted into the free bases in a manner known per se, for example by treatment with basic agents such as alkalis or ion exchangers. On the other hand, the compounds of the formula I obtained by the process according to the invention can be converted into their addition salts with inorganic or organic acids, if appropriate in the usual manner. For example, an acid corresponding to the desired salt component is added to a solution of the compound of formula I in an organic solvent. Preferably, organic solvents are chosen for this reaction in which the salt formed is difficult to dissolve, so that it can be separated by filtration. Such solvents are, for example, ethyl acetate, methanol, ethers, acetone, methyl ethyl ketone, a mixture of acetone and ether, a mixture of acetone and ethanol, a mixture of methanol and ether, or a mixture of ethanol and ether.

For use as medicaments, pharmaceutically usable acid addition salts, i.e. salts with those acids whose anions are not, can be used instead of the free bases. at doses that are considered toxic. It is further preferred that the salts to be used as medicaments are well crystallizable and are not hygroscopic or are only very hygroscopic. For example, the following acids can be used to form salts with the compounds of formula (I): hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, acetic, lactic, succinic, fumaric, maleic, malic, tartaric, citric, benzoic, salicylic, phenylacetic, almond and embon.

Depending on the choice of starting materials and processes, the novel compounds may be in the form of optical antipodes or racemates, if such compounds contain at least two symmetrical carbon atoms, also in the form of mixtures of isomers (mixtures of racemates). The mixtures of isomers obtained (mixtures of racemates) can be separated on the basis of the physicochemical differences of the components in a known manner into the two stereoisomeric (diastereomeric) pure racemates, for example by chromatography and / or fractional crystallization.

The racemates obtained can be decomposed into diastereoisomers by known methods, for example by recrystallization from an optically active solvent, by means of microorganisms or by reaction with an optically active acid forming a racemic salt compound, and by resolution of the salts thus obtained, e.g. the antipodes can be released by treatment with suitable agents. Particularly useful optically active acids are, for example, the D- and L-forms of tartaric, di-o-toluyltartaric, malic, mandelic, camphorsulfonic or quinic acids. Preferably, the more effective of both antipodes is isolated.

The novel active compounds are administered orally, rectally or parenterally. The dose depends on the route of administration, the condition, age and individual behavior of the patient. Daily dosages of the free bases or pharmaceutically acceptable acid addition salts thereof are between 0.1 mg / kg and 3 mg / kg for warm-blooded. Suitable unit dosage forms, such as dragees, tablets, suppositories or ampoules, preferably contain 0.5 to 50 mg of the active ingredient according to the invention.

Dosage unit forms for oral administration preferably contain, as active ingredient, between 0.5 and 50% of a compound of formula I or a pharmaceutically acceptable salt thereof. For the preparation thereof, the active ingredient is combined with, for example, solid, powdered carriers such as lactose, sucrose, sorbitol, mannitol; starches such as potato starch, corn starch or amylopectin, laminar powder or citrus fruit pulp powder; further with cellulose derivatives or with gelatin, optionally with the addition of lubricants, such as magnesium or calcium stearate or polyethylene glycols, and tablets or dragee cores are prepared. Dragee cores are coated, for example, with concentrated sugar solutions which contain, for example, gum arabic, talc and / or titanium dioxide, or they are coated with a lacquer which is dissolved in readily volatile organic solvents or solvent mixtures. These coatings may additionally contain the addition of coloring agents, for example to distinguish different doses of active ingredient.

Other unit dosage forms for oral administration include push-fit capsules of gelatin as well as soft, sealed capsules of gelatin and a plasticizer, such as glycerin. The push-fit capsules contain the active ingredient preferably in the form of a granulate, for example in admixture with fillers such as corn starch, and / or lubricants such as. talc or magnesium stearate, and optionally stabilizers such as sodium metabisulfite (Na 2 S 2 O 5) or ascorbic acid. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as liquid polyethylene glycols, and stabilizers may also be added.

Like forms. For example, suppositories which are a combination of the active ingredient with a suppository base are suitable for unit dose administration for rectal administration. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Gelatin rectal capsules which are a combination of the active ingredient with the matrix are also suitable. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons. Ampoules for parenteral, especially intramuscular administration, preferably contain the water-soluble salt of the active ingredient in a concentration of preferably 0.2 to 5%, optionally together with suitable stabilizers and buffers, in aqueous solution.

The following regulations are intended to further clarify the manufacture of tablets, dragees, suppositories, and ampoules:

(a) 50.0 g of N-propyl-1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5H (dimethylaminomethyl) -1H-1H-triazole-6-carboxamide are mixed with 500 g of lactose and 292 g g of potato starch, moistened with an alcoholic solution of 8 g of gelatin and granulated with a sieve After drying, the mixture is mixed with 60 g of potato starch, 60 g of talc, 10 g of magnesium stearate and 20 g of highly dispersed silica. The tablets are compressed into 10,000 tablets, each weighing 105.0 mg and containing 5.0 mg of active ingredient, optionally with grooves for finer dose adjustment.

b) 2.50 g of N-ethyl-1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5 - [(dimethylamino) methyl] -1H-1H-triazole-5-carboxamide is well mixed with 16 g of corn starch and 6 g of highly dispersed silica are moistened with a solution of 2 g of stearic acid, 6 g of ethylcellulose and 5 g of stearin in about 70 ml of isopropyl alcohol and granulated with a sieve III (Ph. Helv. V). It is dried for about 14 hours and then passed through a sieve III to III.Then 16 g of corn starch, 16 g of talc and 2 g of magnesium stearate are admixed and the mixture is pressed into 1000 dragee cores which are coated with 2 g of concentrated syrup. shellac, 7.5 g of gum arabic, 0.15 g of dye, 2 g of highly disperse silica, 25 g of talc and 53.35 g of sugar, and the coating is dried. 5 mg of the active substance.

c) 10.0 g of N-propyl-1- (4-chlorobenzoyl) -4-chlorophenyl] -5 - [(dimethylamino) methyl 1-1H-1,2,2,4-triazole-3-carboxamide and 1990 g The finely ground suppository bases (such as cocoa butter) are thoroughly mixed, and the mixture is then melted, and from the melt, which is kept homogeneous by mixing, 1000 suppositories of 2 g are cast by pouring. substances.

d) A solution of 2.0 g of N-ethyl-1- (4-chlorobenzoyl) -4-chlorophenyl) -5- (dimethylamino) methyl] -0H-1,2,4-triazole-3- of carboxamide hydrochloride in 1 liter of water is filled into 1000 ampoules and sterilized. Each ampoule contains 2 mg of active substance as a 0.2% solution.

The following examples illustrate the preparation of the novel compounds of formula I as well as the hitherto unknown starting materials, without limiting the scope of the invention in any way.

Example

35.0 g (0.0835 mol) of 1- [2- (o-chlorobenzoyl) -4-chlorophenyl) -5 - ((dimethylamino) methyl] -1H-). The title compound was refluxed in 175 ml of thicyl chloride for 90 minutes, the clear solution was evaporated in vacuo at 40 ° C, and the residue was evaporated to complete the reaction. the removal of thionyl chloride was redissolved in 100 ml of absolute toluene and evaporated again, and the crude acid chloride hydrochloride obtained was dissolved in 350 ml of dioxane and 56.7 ml (0.417 mol) of a 33% ethanolic solution of ethylamine were added thereto with stirring. The reaction mixture was evaporated to dryness in vacuo, ice water was added to the residue, followed by 2N sodium hydroxide solution to pH 11. The separated crude product was taken up in methylene chloride. The extracts were washed twice with water and once with saturated sodium chloride solution, dried over MgSO4 bisulfate and evaporated in vacuo. The solid residue was recrystallized from 500 ml of isopropanol ·. After drying in vacuo, the obtained N-ethyl-1- [2- (c-chlorobenzyl) -4-chlorophenyl) -5 - ((dimethylamino) methyl] 10H11,2,4-thiazole-3-carboxamide melts at room temperature. Mp 131-133 ° C.

The starting material is prepared as follows:

To a suspension of 45.0 g (0.11 mol) ll [2- (clchlcrbenzcyl) -4-chlorophenyl] -5- (chloromethyl) llH-l 2,4ltriazcl 3-carboxylic acid ethyl ester ^J '(network. DOS 2,159,527 32) and · 0.5 g · (0.0033 mol) sodium iodide · In 250 · ml methanol · 310 ml (0.226 mol) ·

Of a 33% ethanolic dimethylamine solution and the mixture is stirred at room temperature for 6 hours. The clear reaction solution is evaporated in vacuo, the residue is dissolved in 200 ml of water and 2N hydrochloric acid solution is slowly added until pH 5 is reached. After stirring at 0-5 ° C for 16 hours, the precipitated amino acid is filtered off and washed well with water. and then ether. After drying, 1- [2- (o-chlorobenzoyl) -4 was obtained

-chlorophenyl] -5 - [(dimethylamino) methyl] -1H-1,2,4-triazole-3-carboxylic acid, m.p. 222-225 ° C with decomposition.

N-propyl-1- [2- (o-chlorobenzoyl) -4-chlorophenyl] -5 - [(dimethylamino) methyl] -1H-1,2,4-triazole-3-carboxaimide, m.p. Mp 110-113 ° C (from ether).

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of the novel 3-substituted 1- (o-benzoylphenyl) -5- (t-aminomethyl) -1H-1,2,4-triazoles of the formula I, СООЧ CONHR or a reactive functional derivative thereof is reacted with a compound of formula III NH2-R, (III) wherein R is an unbranched alkyl group having 2 or 3 carbon atoms, and their addition salts with inorganic and organic acids, characterized in that the carboxylic acid of formula II wherein R is as defined in formula I or with a reactive functional derivative of such a compound, whereupon the optionally obtained triazole derivative of the formula I is converted into an inorganic or organic acid addition salt.