CS203084B2 - Method of producing new substituted 6-aryl -4h-s-triazolo/3,4-c/thieno/2,3-e/-1,4-diazepines - Google Patents

Description

The present invention relates to a process for the preparation of novel substituted 6-aryl-4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diazepines of formula I

(N group each having 3 to 6 carbon atoms, a five or six membered saturated or unsaturated ring containing one oxygen atom, one sulfur atom or one nitrogen atom, the nitrogen ring optionally being substituted on the nitrogen by a methyl group and when R1 is an atom is also a hydrogen atom or an alkyl or hydroxyalkyl group having 1 to 4 carbon atoms, as well as their physiologically acceptable acid addition salts.

The novel compounds of the formula (I) and their acid addition salts can be obtained according to the invention by:

R1 is hydrogen, chlorine or. a bromine atom or an alkyl group of 1 to 4 carbon atoms,

R2 represents a hydrogen, fluorine, chlorine or bromine atom, a nitro group or a trifluoromethyl group, and

R3 denotes an alkoxy group or an alkyknercapto group each having 1 to 3 carbon atoms, an cycloalkyl or a cycloalkenyl group

where

R 1 and R 2 are as defined above, with an acid of formula V

R3-UOOH (V) wherein

1R 3 is as defined above, or a functional derivative thereof, and the optionally obtained compound of formula (I) is converted into a physiologically acceptable acid addition salt.

The reaction is carried out using the free acid of formula (V) or a suitable 'functional' derivative thereof.

A functional derivative (acids of formula V is for example:

an orthoester of the formula R 5 -C 1 (OR ‘) 3, an iminoetheir of the formula

R 3 -Q (= NH) -OR 4, an amidine of formula

R ₃ = -O (= ΝΉ) -NH 2, an amide of formula

R3-CONH2, a thioamide of formula R3- * CSNHa ester of formula

R 5 -COOR ", for example methyl, ethyl or nitrophenyl ester, anhydride of formula (R3-CO) 2O, halide of formula

R 5 = COhal or also a nitrile of the general formula

R3-CN.

In the general formulas, R3 has the above-mentioned meaning, while

R ‘denotes a lower alkyl group α

R 'is a residue of an aliphatic, arallphatic or aromatic alcohol.

The imino ethers and amidines can usually be used in the form of their mineral acid salts, for example as hydrochlorides.

The reaction conditions may vary depending on the derivative (acid) employed. In general, the reaction may be carried out without or with a solvent, for example in methanol, ethanol, chloroform, tetrahydrofuran, benzene, toluene or mixtures of these solvents, without catalyst or in the presence catalyst, for example hydrochloric, sulfuric, phosphoric, polyphosphoric acid, acetic acid, propionic benzensulfanové or toluene. also, the presence of a base such as 2-methylimidazole as a catalyst is useful. the reaction temperature is between 0 and 300 ° C, preferably between 20 and 180 ^Q C.

Special variations of this procedure are as follows:

Method I

In this case, the acid derivative of formula V is an orthoester of formula

R 3 —d (OR ‘) 3 wherein

R 3 and R 3 have the meanings given above.

The reaction is usually carried out in the presence of an excess of orthoestel, which also serves as a solvent, at temperatures between 90 and 10 (0 ° C or in the presence of the catalysts mentioned above), at temperatures between room temperature and reflux temperature.

Method II

In this case, the acid derivative of formula V is an iminoether of formula

R ₃ - * G (= N'H) -OR ', where

R; and R‘ are as defined above.

The reaction is conveniently carried out in the solvents mentioned above at temperatures between room temperature and the reflux temperature of the reaction mixture.

Method III

In that case, the acid derivative of the general formula (V) is an amidine of the general formula

R 5 -O (= NH 1 -NH 2 where

R3 is as defined above.

The reaction is conveniently carried out in the presence of a basic catalyst, such as 2-methylimidazole, at an elevated temperature of between 150 and 250 ° C. Celsius. If the temperature is lower, for example, if the reaction is carried out at room temperature, the intermediate of formula (VIII) is formed first

in which

R1, R2 and R3 are as defined above.

This intermediate can be isolated and subjected to subsequent cyclization by heating to 15 (0 to 250 ° U). However, its isolation is not in any case (if necessary).

Method IV

In this case, the acid derivative of the formula V is an amide or a thioamide of the formula

R 5 - CONHa or

R3-CSNHss, where

R3 has the previously mentioned meanings.

The reaction can be carried out in a solvent with or without a solvent and with or without a catalyst at temperatures of 0 to 300 ° C.

Method

Here, the acid derivative of formula V is an ester of formula

R3-COOR, anhydride of formula (R3CO) 2O, halide of formula

R3-OOC1, or nit-ril of formula

R3-cn, where

R3 and R1 have the previously mentioned meanings.

First, an intermediate of formula (VII) is formed, and ring closure can be carried out in a conventional manner.

The final compounds of the formula I can be converted into physiologically harmless acid addition salts, as appropriate, in addition to those having a 1 or 6-membered saturated or unsaturated ring containing one sulfur atom at the 1-position. hydrogen halide, sulfuric acid, phosphoric acid, nitric acid, cyclohexylsulfamic acid, citric acid, tartaric acid, ascorbic acid, maleic acid, formic acid, salicylic acid or methane- or toluene-sulfoic acid and the like.

The starting compounds of formula (V) are known from the literature. While the production of the compound of formula (VIII) in the previous embodiment can be ignored, the production of the compound of formula (IV) is described below.

The hydrazine derivatives of formula (IV) may be prepared by reacting compounds of formula (II)

where

R1, R1 and X are as defined above, with hydrazine. This reaction may be carried out in one of the abovementioned solvents, and optionally one of the abovementioned catalysts may be used. The temperature may conveniently be between room temperature and reflux temperature of the reaction liquid.

The compounds of the formula I and, where appropriate, their acid addition compounds, have valuable therapeutic properties. They have been shown to be effective anxiolytically, relieve tension and have a muscle-relaxant effect, and an intense anti-onvulsive effect using various pharmacology test methods. They also have the property of substantially increasing food intake in mammals. Their remarkably low toxicity is also noteworthy. The known thieno-1,4-diazepines without an additional triazole ring, which are known, for example, from the publications DOS 2 155 403 and 2 221 623, in particular their very strong anti-convulsant effect, which is very strongly indicated in the so-called pentetrazole test, -alkyl-6-arylthieno [12,3-e] -4H-s-triazolo [3,4-c] -1,4-diazepines from DOS 2,229,845, but having an activity of more than Compounds and, where appropriate, acid addition salts thereof in which R 1 is a bromine atom, R 2 is a chloro-203084 or a bromine atom and R 3 is a methyl, cycloalkyl, tetrahydropyranyl, tetrahydrothiopyranyl or an optionally substituted plperidyl group, especially

8-Broim-6-o-chlorophenyl-1-cyclohexyl-4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diazepine (R1 = Br, R2 = Cl, R3 = CeHn),

8-bromo-6-o-broimiphenyl-4-cyclohexyl-4H-s-triazololo [3,4-e] thieno [2,3-e] -1,4-diazepine (R 1 -Br, R 2 = Br, R 5 = CeHii),

8-bromo-6-o-chlorophenyl-1-cyclobutyl-4H-s-triazolo [3,4-c] thienoph 2,3-e] -1,4-diazepine (R 1 = Br, R 2 = Cl, R 3 = C4H7),

8-Bromo-6-o-chlorophenyl-1-cycloipentyl-4H-s-triazole [3,4-cycleno-2,3-e] -1,4-idiazepine (R1 = Br, R2-Cl, R3) = C5H9],

8-bromo-6-o-chlorophenyl-1-cyclopropyl-4H-s-triazolo [3,4-c] thieno] 2,3-e] -1,4-palzepine (R1 = Br, R2 = Cl, R3 = C3H5),

8-bromo-6-o-chlorophenyl-1-methyl-4H-s-triazolo [3,4-c] thieno [2,3-e] 1,4-diazepine (R 1 = Br, R 2 = Cl, R 3 = CH3),

8-bromo-6-o-chlorophenyl-1-hydroxy-ethyl-4H-s-triazodo [3,4-c] thieno [2,3-e] -1,4-diazepine (R 1 = Br, R 2 = Cl , R 3 = CH 2 —CH 3 OH),

8-bromo-6-o-chlorophenyl-1-tetrahydropyranyl- (4) -4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diazepine (R1 = Br, R2) = Cl, R 5 = CSH 10),

8-bromo-6-o-chlorophenyl-1-tetrahydropyranyl- (3) -4H-s-triazolo [3,4-c] thiemi [2,3-e] -1,4-diiazepine (R 1 = Br , R2 = Cl,

R 3 = O 3 H 10 O),

8-bromo-6-o-chlorophenyl-1-tetrahydrofuran-1- (12) -4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diazepine (R1 = Br , R2 = Cl, R3 = C4H7O),

8-bromo-6-o-bromophenyl-1-tetrahydrofuranyl- (2) -4H-s-itriazolo [3,4-c] thieeno [2,3-e] -1,4-diazepine (R1 = Br, R2) = Br, R 3 - = C 4 H 7 O),

8-bromo-6-o-chlorophenyl-1- [N-methylpiperidyl- (3)] -4H-s-triazolo [3,4-c] thieno [2,3-e] [1,4] diazepine (R1 = Br , R 2 = Cl, R 5 = CH 3 -N (C 5 H 10),

8-Broim-6-o-chlorophenyl-1-tetrahydrothiopyrans 1- (2) -4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diazepine (R1 = Br , R 2 = Cl, R 3 - C 5 H 10 S) and

8-Broimi-6-o-chlorophenyl-1-methoxy-4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diazepine (R1 = Br, R2 = Cl, R3 = OCH 3) and their acid addition salts.

White mice weighing 20-25 g or white rats FW 49 weighing 140-200 g were used for the tests. Except for the Geller conflict test, 10 animals were used for each dose. Geller's conflict test was performed with 4 animals for each dose. The test substances were suspended in olive oil and in all cases introduced into the stomach by a pharynx probe.

1. Pentetrazole antagonism:

Dose that abolishes the lethal effect of 125 mg / kg pentylentetrazole in 50% of animals administered intraperitoneally 1 hour after the dose of the test substance [Μ. I. Gluckmann, Curr. Ther. Res., 7,721 (1905)].

2. Geller test:

A dose at which animals in conflict will press a round-shaped object ten times to obtain a pill of food, although at the same time a signal on it will announce that they will be punished in the form of an electric wound together with the food pill. [J. Geller, Arch. Int. Pharmacodyn., 149, 243 (1964)].

3. Mouse fighting test:

Dose at which aggressiveness ceases in 50% of animals. It is determined in adult males who were kept in the dark during 3-4 weeks of isolation against young male mice. [Wirth, Gosswald, Horlein, Riss and Kreiskott, Arch. Int. Pharmacodyn. 115: 1-31 i (1958) j.

4. LD50:

Dose that survives 50% of the animals. [Litchfield and Wilcoxon, J. Pharmacol. Exptl. Therap. 98.99 (1949)].

The values were determined graphically in all tests. The test results are shown in the following table:

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203094

A single dose of the compounds of the invention is 0.05 to 50 mg, preferably 0.1 to 25 mg (orally) and 5 to 130 mg as a daily dose.

The compounds obtainable according to the invention can be used alone or in mixtures with other compounds according to the invention or also in combination with other pharmacologically active substances, such as spasmolytics or β-receptor blocking agents. Suitable dosage forms are. for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders. The tablets may, for example, be prepared by mixing the active ingredient (s) with known excipients, for example, inert diluents such as calcium carbonate, calcium phosphate or milk sugar, disintegrants such as corn starch, alginic acid, binding agents, such as starch or gelatin, glidants such as magnesium stearate or talc and / or depot effecting agents such as carboxypolymethylene, carboxymethylcellulose, acetylcellulose phthalate or polyvinyl acetate. Tablets may consist of multiple layers.

Correspondingly, dragees can be obtained by coating cores obtained analogously to the tablets by conventional means used for this purpose, for example collidone or shellac, gum arabic, talc ¹ , titanium dioxide or sugar. consisting of multiple layers. Likewise, the dragee coating may be of multiple layers, with the auxiliaries already mentioned in the preparation of tablets being used.

Juices of the compounds of the invention, or combinations thereof (may also additionally contain sweetening agents such as saccharin, cyclamate, glycerin or sugar, as well as flavorings such as flavoring agents such as vanillin or orange extract. thickening agents such as sodium carboxymethylcellulose, wetting agents, for example, condensation products of higher aliphatic alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Injectable solutions are prepared by conventional means, for example with the addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali salts of ethylenediaminetetraacetic acid, and are then filled into vials or ampoules.

For example, one or more active ingredients, or active ingredient combinations comprising capsules, can be prepared by mixing the active ingredients with inert carriers such as milk sugar or sorbitol and filling them in gelatin capsules.

Suitable suppositories can be prepared, for example, by mixing suitable carriers such as neutral fats or polyethylene glycol or derivatives thereof.

Example 1

8-Broin-6-o-chlorophenyl-1-methyl-4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diazepine and 11.5 g of 7-broim-5- o-chlorophenyl-3H- [2,3-e] thieno-1,4-diazepin-2-one (see DOS

221 623 J are heated with 100 ml of absolute pyridine and 6.5 g of phosphorus pentasulphide for 4 hours with stirring at 55 to 00 ° C, then allowed to cool and poured into 100 ml of ice-cold sodium chloride solution. The precipitate is filtered off with suction and washed with water, dissolved in 100 ml of methylene chloride, the solution is dried, evaporated, and the residue is mixed with methylene chloride. After ¹ suction, 6 g of brown crystals of 7-bromo-5-o-chlorophenyl-3H- [2,3-e] thieno-1,4-diazepine-2-thione of the formula IIa, m.p. 214 DEG C., are obtained. C (decomposition).

bj 6.0 g of the above compound was suspended in 100 ml of tetrahydrofuran and stirred at room temperature for 20 minutes with 1.2 g of hydrazine hydrate. After concentration to approximately 10 ml, 20 ml of ether are added and the crystals are added.

Yield: 5.2 g of 74bromo-5-t- (o-brickphenyl) -2-hydrazino-OH- [2,3-e] thleno-1,4-diazepine, m.p. 300 DEG C. (decomposition) of formula IV .

5.2 g of the above compound are suspended in 50 ml of triethyl ortho-acetic acid and heated to 80 ° C. After about 30 minutes, a clear solution is formed at this temperature, from which colorless crystals later precipitate. Allow to cool, filter off the crystals and wash with ether.

Yield: 5 g of the title compound, m.p. 211 DEG-213 DEG.

Example 2

8-Chloro-6-o- (o-chlorophenyl) -1- [tetrahydrofuran- (2j) -4H-s-triazolo [3,4-c] thienol-2,3-e] -1,4- diazepim

0.01 mol, i.e. 3.25 g of 7-brick-5- (OH-chlorophenyl) -2-hydrazino-3- [2,3-e] thieno-1,4-diazepine, produced by reacting the corresponding thienodiazepintlone with hydrazine (m.p. 236 DEG C., decomposition) was suspended in 100 ml of tetrahydrofuran and 1.0 ml of tetrahydrofuran-2-carboxylic acid chloride was added. The mixture was refluxed for 5 hours, the solvent was evaporated and the solvent was evaporated, as described in Example 1a.

1.3 g of 1j are thus obtained. 32% of theory, colorless crystals, m.p. 191 ° C.

Further, the end products listed in the following examples included in the table were obtained according to the above procedure.

Table

Example R1 R1 number

R3 Temperature Melting point hydrazide ° C of formula VII ° C

3 Br Cl N 212—213 236 (decomposition) 4 Br Cl OC2H5 144—146 5 Br Cl -Ό 190—191 110 (decomposition) 6 Br Cl > 192—193 oil. substance 7 Cl Cl OCH3 160—162 - 8 Cl Cl XE> 188—189 177 (decomposition) 9 C2H5 Cl XE) 128—129 203 10 H H XE) 178-180 oil. substance 11 H Cl 0CH3 184—185 - 12 C2H5 Cl 0CH3 oil - 13 H H 0CH3 167—168 - 14 Br Cl 0- 145—147 - 15 Dec Br Cl 190—191 212 (decomposition) 16 Br Cl 187—188 200 (decomposition) 17 H H 138—140 - 0- (1 'mol 18 Br Br 0 CH3OH) 242 - 19 Dec C2H5 Cl 174—175 197 (decomposition) 20 May Br Cl cx 171—180 217—1218 1 (decomposition) 21 Br Cl E 260—262 217 (decomposition)

Example number Rl R2 22nd Br Cl 23 Br Cl 24 Br Cl 25 Br Cl 26 Br Cl 27 Mar: Br Cl 28 H Cl 29 C2H5 Cl 30 Br Br 31 Br F 32 Br H 33 Br Cl 34 Br Cl 35 Br Br 36 Br Br 37 Br Cl 38 Br Cl 39 Br Cl 40 Br Cl 41 Br Cl 42 Br Cl 43 Br Cl 44 Br Cl 45 Br Cl

R3

O

U I / Ti

I ^ύ &

CH,

I ⁵ a

CH3

CH3

0H3

H

DC3H7

HOC2H4—

0CH3

SCH3

ΧΞ)

OC2H5

H-c-N H

Melting point ^q C of formula VII ° C

291—253 196 (decomposition) 223—225 215—220 (decomposition) 187—189 197—198 (decomposition) 231—2,33 215—218 (decomposition) 209—211 213 (decomposition) 260—261 204— 206 98—100 155 (roziklad) 120—122 1Θ5 — ú.6'8 (decomposition) 205—206 210 - 284 - 216—218 - 203—206 - ·

190—191 220 (decomposition)

140—141 172 (decomposition)

224—2) 26

198—200

158—160

179—180

144—146

140—142

211—212

257—258

240-241 hydrochloride

257—258 (decomposition)

Claims (6)

Process for the preparation of novel substituted 6-aryl-4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diazepines of the general formula I (I) wherein: R1 represents a hydrogen, chlorine or bromine atom or a C1-C4 alkyl group, R @ 2 represents a hydrogen, fluorine, chlorine or bromine atom, a nitro group or a trifluoromethyl group and R 3 represents an alkoxy group or an alkylmercapto group having from 1 to 3 carbon atoms each, a cycloalkyl or cycloalkenyl group having from 3 to 6 carbon atoms, a five or six membered saturated or unsaturated ring containing one oxygen atom, one sulfur atom or one nitrogen atom, substituted on the nitrogen by a methyl group and, when R1 is a bromine atom, is also a hydrogen atom or an alkyl or hydroxyalkyl group having from 1 to 4 carbon atoms, as well as their physiologically acceptable acid addition salts, characterized in that a compound of formula IV wherein R 1 and R 2 are as defined above, with an acid of formula V R 5 -COOH (V), where VYNALEZU R 5 is as defined above, or by some functional acid derivative of the formula this R3-COOH (Va) R3 — C (= NH3 — OR) (Vb) R3-O (= NH3-MHz) (Ve) R3-CONHz (Vd) R3-CS-NH2; (Ve) R3 — COOR ” (Vf) R 3 - (CO) ₂ O (Vg) R3-COCl (Vhj or R3-CN (VI), in which samples R3 is as defined above, R ‘denotes a lower alkyl group and R 'denotes the remainder of aliphatic, ar, aliphatic! or an aromatic alcohol, and optionally the compound of formula I thus obtained is converted into a physiologically acceptable acid addition salt. . 2. The method of item 1, for the preparation of the new substituted 6-aryl-4H-s-triazolo [3,4-c] thienol-2,3-e] -1,4-diazepiines of the general formula Ia wherein: R 1 represents a bromine atom, R @ 2 denotes a fluorine, chlorine or bromine atom, a nitro group or a trifluoromethyl group and R 5 represents a hydrogen atom or a straight or branched alkyl or hydroxyalkyl group having 1 to 4 carbon atoms, as well as their physiologically acceptable acid addition salts, characterized in that the compound of formula (IVa): R1 and R2 are as defined above, with an acid of formula V R 3 -COOH m where R3 is as defined above or is a functional derivative of this selines of general formula R 3 - (OR ‘) 3 (Va) R _{3 -} IC (= NH) OR ' (Vb) R3-C (= NH) -NH2 (Vc) R 5 - CONH 2 (Vd) R 5 = CS-NH 2 (Ve) R3 — COOR ” (Vf) R 5 - (CO) 2 O (Vg) R3-COCl (Vh) or> R 5 - CN (Vi), in which formulas R3 is as defined above. R ‘denotes a lower alkyl group α R 'represents a residue of an aliphatic, araliphatic or aromatic alcohol, and optionally the compound of formula I thus obtained is converted into a physiologically acceptable acid addition salt. 3. The process of item 1, for producing the new substituted 6-aryl-4H-s-triazolo [3,4-c] thleno [2,3-e] -1,4-diazepines of the general formula Ib wherein: R1 represents a hydrogen, chlorine or bromine atom or an alkyl group of 1 to 4 carbon atoms, R @ 2 represents a hydrogen, fluorine, chlorine or bromine atom, a nitro group or a trifluoromethyl group and R3 represents a straight or branched alkoxy or alkylmercapto group having from 1 to 3 carbon atoms or a cycloalkyl or cycloalkenyl group having from 2 to 3 carbon atoms each, as well as their physiologically acceptable acid addition salts, characterized in that the compound of the formula IVb is R 1 and R 2 are as defined above, with an acid of formula V R3-COOH (V) wherein R 3 is as defined above, or some functional derivative of the acid of formula R3-CONH2 (Va) r ₃ —C (= NH) —OR ' (Vb) R3 - O (= NH3 - NH2); (Vc) R3C-ONHz (Vd) R3-CS-NH2; (Ve) Rs — COOR “ (Vf) Rs - (CO) ₂ O (Vg) R3-COCl (Vh) or R3-CN (Vij, in which samples R3 is as defined above, R ‘denotes a lower alkyl group α R 'represents a residue of an aliphatic, araliphatic or aromatic alcohol, and optionally the compound of formula I thus obtained is converted into a physiologically acceptable acid addition salt. 4. The process of hold 1, for producing a new substituted 6-aryl-4H-s-tr _; The azole 10 [3,4-c] thienoyl 2,3-e] -1,4-diazepines of formula Ie wherein: R1 represents a hydrogen, chlorine or bromine atom or an alkyl group of 1 to 4 carbon atoms, R @ 2 represents a hydrogen, fluorine, chlorine or bromine atom, a nitro group or a trifluoromethyl group and R 5 represents a five- or six-membered ring containing an oxygen atom, as well as their physiologically acceptable acid addition salts, characterized in that ss to the compound of the formula IVc wherein: R1 and R2 are as defined above, with an acid of formula V R 3 -COOH (V) wherein R 5 is as defined above, or some functional derivative thereof formula Rs-C (ORR) 3 (Va) R5-Q (= NH3-OR1 ⁾ (Vb) R3-C (—NH) -NH2 (Vc) Rs — CONHz (Vd) R3-CS-NH2; (Ve) Rs — COOR “ (Vf) R 3 - (CO) 2 O (Vg) R3-COCl (Vh) or R3-CN (Vi), in which samples R3 is as defined above, R ‘denotes a lower alkyl group α R 'represents a residue of an aliphatic, araliphatic or aromatic alcohol, and optionally the compound of formula I thus obtained is converted into a physiologically acceptable acid addition salt. 5. The poldle method of item 1, for producing new substituted. 6-aryl-4H-s-triazolo [3,4-c] thienol [2,3-e] -1,4-diazepines of formula Id wherein, R1 represents a hydrogen, chlorine or bromine atom or an alkyl group of 1 to 4 carbon atoms, R2 is hydrogen, fluoro, chloro or bromo, nitro or trifluoromethyl; R3 represents a five- or six-membered saturated or unsaturated nitrogen or sulfur-containing ring, the nitrogen ring optionally being substituted on the nitrogen by a methyl group, and their physiologically acceptable acid addition salts when R5 is a nitrogen ring, characterized in that: a compound of formula IVd wherein R1 and R2 are as defined above, with an acid of formula V R 5 —COOH (V) where R 3 is as defined above, or some functional derivative of the acid of formula R3-O (OR1) 3 (Va) R3—0 (= NH) —OR ‘ (Vb) R 3 - (= NH) - NH 2 (Vc) R3-CONH2 (Vd) Rj-CS-NH ₂ (Ve) R3 — COOR ” (Vfj R 3 - (CO) 2 O (Vg) R3-COCl (Vh) or R3-CN (Vi), (IVd) in which formulas R3 is as defined above, R1 represents a lower alkyl group and R1 represents a residue of an aliphatic, araliphatic or aromatic alcohol, and optionally the compound of formula I thus obtained is converted into a physiologically acceptable acid addition salt.