CH630909A5 - New 3,5-disubstituted-1H-1,2,4-triazoles - Google Patents

Description

The present invention relates to novel 3,5-disubstituted 1H-1.2.4-triazoles of formula

630 909

in which:

R is chosen from: hydrogen, alkoxy (CM), alkoxy (CM), ailyloxy, propargyloxy, trifluoromethyl, phenyl, fluoro, chloro and dimethylamino; is

R represents an alkyl group (ClJ ();

R2 is chosen from: hydrogen, fluoro, chloro, alkyl (C] _4),

methoxy and ethoxy;

R3 is chosen from: hydrogen, fluoro, chloro, alkyl (C] _4) and alkoxy (C | _4); : o

R and R3 taken together represent a methylenedioxy group; provided that when R, R, and R3 simultaneously represent hydrogen, R] is not the methyl group. and also provided that when R2 and one of the groups R and R3 represent hydrogen. Ri and the other of the groups R and R3 are not simultaneously the methyl group,

and their salts obtained with pharmaceutically acceptable acids. The compound of formula I in which R 1 is the methyl group when R, R and R 3 simultaneously represent hydrogen is known from K.T. Potts, "J.C.S.", 1954. p. 3461. The compound of? O formula I in which R! and one of the groups R and R3 are simultaneously the methyl group when R, and the other of the groups R and R3 represent hydrogen is known from D.R. Liljegren, "J.C.S.", 1961, p. 518.

The new compounds of formula I have anti-reproductive properties and are active on the central nervous system.

The expression alkyl (Ci_4) as used herein denotes straight or branched alkyl radicals chosen from: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert.-butyl. The term alkoxy (C, _4) as used herein denotes straight or branched alkoxy radicals chosen from: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tert.-butoxy.

Preferred, among the compounds of formula I. those in which R is chosen from the groups: a! Coyl (Cj.4). alkoxy (C1-4), ailyloxy, fluoro, chloro and dimethylamino, R, represents an alkyl group-45 (C, .4). R2 is chosen from: hydrogen, methoxy and ethoxy, R3 can be hydrogen. alkoxy (CN4), fluoro or chloro, R and R3 taken together represent a methylenedioxy group, provided that. when R2 and R3 simultaneously represent hydrogen, R and R, are not simultaneously the methyl group, and their salts with? ” pharmaceutically acceptable acids.

Among the compounds of formula I, those in which R is chosen from the groups: alkoxy (Ci 2 4), ailyloxy, fluoro and chloro, R! represents an alkyl group (C, .4), R; is chosen from: hydrogen, methoxy and ethoxy, and R3 can be hydrogen or alkoxy (CM), and their salts obtained with pharmaceutically acceptable acids.

One will prefer to all the others, among the compounds of formula 1,

those in which R is chosen from: methoxy, ethoxy, ailyloxy,

fluoro and chloro. R, is an alkyl group (CM), R2 represents ""

hydrogen or the methoxy group and R, is hydrogen, and their salts obtained with pharmaceutically acceptable acids.

It will be obvious to any person skilled in the art that, as a result of the great mobility of the hydrogen atom of 1,2,4-triazoles (see KT Potts, "Chem. Rev.". 61, 99, 1961 and also KT Potts, "J. Chem." "Soc.". 3451, 1954), the compounds which are the subject of the invention can exist in the corresponding tautomeric forms, in which the hydrogen atom is located on one of the other two nitrogen atoms in the triazole ring. Consequently, the aforementioned tautomeric forms should be considered to be part of the invention.

We know that the tautomeric forms quickly transform one into the other and are, therefore, in a state of dynamic equilibrium.

In all cases, throughout the specifications, the 3,5-disubstituted derivatives of 1 H-1,2,4-triazoles which are the subject of the invention will be numbered as in formula I.

The process for preparing the 3,5-disubstituted 1H-1,2,4-triazoles which is the subject of the invention comprises the reaction, at a temperature of 80 to 200 ° C. for a period of 15 to 30 h. of a compound of formula

A-C

AT

NH-NH,

(II)

Y

or a salt obtained with an acid, for example the hydrochloride, with a compound of formula

B-CX

(III)

where A is the group or A is the group and B is the group and B is the group

/

H,

In the above formulas, the radicals R, R ,. R, and R3 have the same meanings as previously, CX is a functional group chosen from: carboxy, dithiocarboxy. carbonyl halide, carboxyl anhydride, orthoester, imidate. thioimidate, imidoyl halide, amidino and cyano, Y is an NH group and, when the CX group contains a nitrogen atom, it represents oxygen or sulfur.

When the CX group represents: imidate. thio-imidate, imidoyl halide or amidino, the compound of formula III can also be used in the form of the corresponding salt obtained with an acid.

The process which leads to the 1,2,4-triazoles which are the subject of the invention is a condensation reaction during which, depending on the nature of the reactive groups Y and CX. water, hydrogen sulfide, hydrogen halide, ammonia, alcohols. mercaptans, carboxylic acids or mixtures of these bodies are formed as by-products. These by-products can be removed during the reaction or removed at the end of the condensation by means of conventional methods. In practice, the condensation reaction is carried out by heating, with stirring, the two reagents of formula II and III, generally in the absence of solvent, at a temperature between approximately 80 and approximately 200 C, for a period of approximately 15 at approximately 30:00. It will be advantageous to use a slight excess relative to the molar proportion of the compound containing the CX function on the compound of formula II. Preferably, the CX function is an imidate group of formula

^, 0-alkyl

-VS

%

NH

in which the alkyl can be methyl, ethyl or propyl, so that the low boiling alcohol which forms during condensation, for example methanol, ethanol or propanol, evaporates automatically from the reaction medium. Atin to speed up

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elimination of alcohol, a moderate vacuum can be applied without inconvenience. It has also been observed that the presence of a catalyst can promote the condensation reaction and therefore a catalytic amount of hydrochloric or hydrobromic acid, or p-tuuènesulfonique acid. can be added without disadvantage to the reaction mixture. This addition is not necessary when the reactants are used in the form of their salts of these acids. Finally, if, during heating, the reaction mass tends to solidify, it may be useful to add to this mass a small amount of an organic solvent such as, for example, n-butanol, n-pentanol. and their analogs. This solvent is removed by evaporation under vacuum at the end of the reaction.

The final products are then recovered according to known methods. By way of example, the reaction mixture is taken up with a suitable organic solvent, preferably ethic ether, and the organic solution is extracted several times with dilute sodium hydroxide. The alkaline extracts are combined and, if necessary, treated with activated carbon so as to separate the impurities. After filtration through celite, the filtrate is brought to a pH value of approximately 6-7 by addition of dilute hydrochloric acid. A product separates, which can be solid or oily. Depending on its nature, it can be recovered by filtration or extracted with an appropriate organic solvent, for example ethyl ether or methylene chloride. This solvent is then removed by evaporation. leaving a solid crystalline residue. Additional purification by column chromatography may sometimes be necessary. Finally, the 3,5-disubstituted 1H-1,2,4-triazoles are recrystallized from suitable organic solvents such as, for example, hexane, methylene chloride, chloroform, isopropyl ether. ie benzene, cyclohexane or mixtures thereof.

The 3,5-disubstituted 1H-1,2,4-triazoles object of the present invention have anti-reproductive properties and utility as CNS-depressant.

CNS-depressive activity was studied using the Irvvin method. More precisely, we studied the ability of the compounds which are the subject of the invention to alter motor coordination, rectifying reflex, spontaneous activity and muscle tone in laboratory animals, that is to say parameters which are directly linked to sedative, hypnotic and muscle relaxant effects. Representative experiments have shown that amounts between about 10 and about 300 mg, kg i.p. have the effect of appreciably altering the above parameters when they are tested in mice. However, the most important biological aspect of the compounds forming the object of the invention resides in the fact that they have a remarkable anti-reproductive utility. More specifically. they show postcoital contraceptive and postnational activity when administered by different phartna-logical routes to laboratory animals, for example rats, hamsters, dogs, monkeys and baboons.

In addition, the contraceptive activity of these new compounds is not associated with other biological effects often encountered with hormonal substances.

Regulation of fertility can usually be achieved in several ways by the administration of hormonal substances. These may relate to inhibition of ovulation, egg transport, fertilization, implantation of the zygote, resorption of the fetus or abortion. It is only with inhibition of ovulation that a clinically useful method has been successfully developed. The subject matter compounds of this invention allow a completely new approach to this problem, in that a non-hormonal compound can be administered parenterally, orally or intravaginally, one or more times as necessary after a period of lack or to cause the end of a more advanced gestation. Representative experiments to assess contraceptive activity were carried out on females of Syrian golden hamsters weighing 100 to 130 g. The animals were mated and the presence of semen in the vagina was taken as proof of mating. The day sperm was detected was considered the first day of gestation since in our laboratories and in those of other researchers, 90 to 100% of females who mate, as the presence of sperm in the vagina proves, in the making.

The gestation was then confirmed at the autopsy by the presence of s fetuses or implantation sites in the uterus. Even if an animal loses the fetus through abortion, implantation scars remain and prove that the animal was pregnant.

The compounds which are the subject of the invention, which have a high solubility in the pharmaceutical vectors commonly used! were dissolved in sesame oil and administered subcutaneously in doses of 10 mg kg daily for 5 d starting on the fourth day of gestation (days 4-8). The animals were autopsied on the fourteenth day of gestation and the uteri were examined for evidence of gestation (implantation sites, resorption of fetuses or live fetuses), hemorrhage and evidence of abnormalities of the uterus, placenta or fetus. A compound was considered active if there was a reduction in live fetuses in at least 60% of the treated animals and if the presence of the implantation sites proved that the animals had been pregnant. In representative experiments, the compounds of Examples 1, 4, 6-8 and 10-17 were found to be active according to the above-mentioned criteria.

The compounds were then studied to establish the dose / activity relationships, and the corresponding ED50 values, that is to say; s 100% of activity (absence of live fetus) in 50% of the animals, were also determined. Table I gives the ED; 0 values obtained with a few representative compounds which are the subject of the invention.

Table I

1 „

j Consists of

ED 50 in mg / kg

! Example No.

s.c. (hamsters)

| 1

0.08

i 4

0.5

10

0.07

! not

0.25

13

0.04

! 14

0.1

The same criteria and experimental conditions as above were also applied when the anti-reproductive activity of the compounds forming the object of the invention was tested in other species of animals such as, for example, rats, dogs, monkeys and baboons. In representative experiments, Sprague-Davvley rats weighing 200 to 300 g were treated subcutaneously with a dose of 20 mg / kg of weight compound, dissolved in sesame oil, for 5 consecutive d beginning on the sixth day of pregnancy. The rats were killed and autopsied on the sixteenth day and the uteri were examined as seen above for hamsters. Also in this experiment, the compounds of Examples 1.4, 6-8 and 10-17 caused a reduction in living fetuses in at least 60% of the treated rats. The EDS0 values of the compounds of Examples 1 and ^ 13 were determined and are reported in Table II:

Table II

Composed of example N °

EDfn in mg, kg s.c. (rates)

1

13

1

0.7

Favorable results were also obtained by administering the compounds which are the subject of the invention by the oral route. Experiments to assess this property were carried out on hamsters

according to the same methods as above, with the exception that, obviously, the compounds were administered by the oral route instead of the subcutaneous route.

The reduction of approximately 60% of living fetuses was observed for an oral dosage of 10 mg / kg with the compounds of Examples 1.4, 6-8 and 10-17. The ED50 values of the compounds of Examples 1 and 13 were also determined and are reported in Table III:

Table III

Composed of

ED5 „in mg / kg example N °

p.o. (hamsters)

1

5

13

5

Finally, the compounds which are the subject of the invention reveal a very low toxicity. In fact, their LD50 values, determined according to Lichtfield and Wilcoxon, "Journ. Pharm. Expt. Ther. ”, 96.99.1949,: o are never lower than 600 mg / kg when administered to mice intraperitoneally.

The fact that the compounds which are the subject of the invention have an eminent antireproductive activity, even when administered orally, and that they are very soluble in the vectors n? Usual pharmaceuticals are undoubtedly important additional properties. For example, the high solubility means that the compounds are easily absorbable and can be incorporated into suitable and more tolerable injectable dosage forms, which have less disadvantages than the corresponding forms, in which the active ingredient is suspended in the carrier medium. . On the other hand, the oral activity also allows the compounds to be included in more acceptable pharmaceutical preparations. It will also be noted that apart from oral contraceptives which are however substances of steroidal nature and manifest their activity there by blocking ovulation, no other compound in anti-reproductive preparation is known to be active per os.

It therefore follows that the compounds which are the subject of the invention can be administered by different routes: oral, subcutaneous, intramuscular or intravaginal. -m

For oral administration, the substances are packaged in the form of lozenges, dispersible powders, capsules, granules, syrups, elixirs and solutions.

The compositions for oral use may contain one or more adjuvants such as, for example, sweetening agents, 4? perfumes, dyes, coating and preserving agents, so as to provide a preparation pleasing to the eye and to the taste. The lozenges may contain the active ingredient mixed with pharmaceutically acceptable excipients, for example inert diluents such as calcium carbonate, sodium carbonate, lactose and 5 "talc, granulating or disintegrating agents such as. for example, starch, alginic acid and sodium carboxymethyl cellulose, binding agents, for example starch, gum arabic, polyvinylpyrrolidone and lubricants, for example stearate magnesium, stearic acid and talc.

Syrups, elixirs and solutions are formulated according to the rules of the art. In addition to the active compound, they can contain suspending agents such as, for example, methylcellulose, hydroxyethyl ceilulose. tragacanth and sodium alainate, wetting agents, for example lecithin, polyoxyethylene stearates and polyoxvethylene sorbitolmonooleate, and the usual preservatives, sweeteners and buffers.

A capsule or lozenge may contain the active ingredient alone or mixed with an inert diluent solid such as, for example, calcium carbonate, calcium phosphate and kaolin.

In addition to the oral routes, other useful ways of administering the compounds which are the subject of the invention may suitably be

630 909

employed, such as, for example, subcutaneous or intramuscular administration.

The active ingredient is then included in the form of injectable doses. Such compositions are formulated according to the rules of the art and may contain suitable dispersing or wetting agents and suspending agents or buffers identical or similar to those mentioned above. Sesame oil, benzyl alcohol. benzvle benzoate. peanut oil and mixtures thereof can also be suitably used as carriers.

A vaginal tablet may also contain the active ingredient mixed with the usual carrier agents, for example gelatin.

adipic acid, sodium bicarbonate. lactose and their analogs.

The compounds which are the subject of the invention can also be administered in the form of their non-toxic salts obtained by addition of pharmaceutically acceptable acids. Such salts have the same degree of activity as the free bases from which they are easily prepared by reacting the base with an appropriate acid and, thus, they are included within the scope of the invention. Representative examples of such salts are the salts of mineral acids, such as, for example, the hydrochloride, brom-hydrate, sulfate and the like, and the salts of organic acids such as sulfur. benzoate, acetate, p-toluenesulfonate. benzenesulfonate. the maleate. tartrate. ie methanesulfonate, ie cyeiohexylsuil'onate and the like.

The dosage of active ingredients used to inhibit reproduction may vary between wide limits, depending on the nature of the compound.

Generally, good results are obtained when the compounds of the above-mentioned formula 1 are administered at a daily dose of approximately 0.8 to approximately 50 mg / kg of the animal's body weight.

The dosage units which achieve this goal generally contain from about 10 to about 600 mg of active compound mixed with a carrier or diluent agent, liquid or solid, pharmaceutically acceptable.

The following examples illustrate the process which is the subject of the invention and describe in detail some compounds of general formula I, without this limiting the scope of the invention.

Example 1:

3- (m-Methoxyphenyl) -5- (o-tolyl) -1 H-1,2,4-iriazole

A mixture of 3.0 g (0.02 mol) of the hydrazide of o-toluic acid and 4.83 g (0.027 mol) of the ethyl ester of m-methoxybenzimidic acid was heated on a oil bath with stirring for approximately 20 h, the bath temperature being maintained at approximately 125 ° C. After cooling, the reaction mass taken up in 100 ml of ethyl ether and the ethereal solution obtained was first extracted with 50 ml of a 5% aqueous solution of sodium hydroxide and then twice with 30 ml of water. The aqueous and alkaline extracts were combined, treated with activated charcoal to remove all impurities and very much on celite. The filtrate was brought to pH 7 by addition with stirring of 10% hydrochloric acid in water, which caused the separation of an oily substance which was extracted with ethyl ether. After drying over sodium sulfate, the ether was removed by evaporation in vacuo, and the residue obtained was re-crystallized in an isopropyl ether hexane mixture. Yield: 3.15 g. M.P. 100-102 C.

Examples 2-6:

Following substantially the same methods as those described in Example 1, the following compounds were prepared.

Example 2:

j- (p-DimethvUimuwplu'iiyl / -> (u-iolyl i-I II-l, 2,4-lriJzole

From 2.55 g (0.017 mol) of the hydrazide of o-toluic acid and 4.26 g (0.021 mol) of the ethyl ester of p-dimethyl acid

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h aminobenzimide. Yield: 3.04 g. M.p. 173-175 C (recrystallized from isopropyl ether.

Example 3:

i-i o-Chlorophënyl> -5- (o-tolyl, -ÎH-l .2.4-! ria; ole

From 3.75 g (0.025 mI of the hydrazide of o-toluic acid and 5.5 g (0.03 mol) of the ethyl ester of o-chiorobenzimide acid. Yield : 4.26 g, PF 109-111: C (recrystallized from a hexane, methylene chloride mixture).

Example 4:

3- (o-Methoxyphenyl) -5-f o-tolyl j-1 H-1,2,4-triazole

From 6.75 g (0.045 mol) of the hydrazide of o-toluic acid and from 9.85 g (0.05 mol) of the ethyl ester of o-metho.xy-benzimidic acid . Yield: 4.81 g. M.p. 160-161 C (recrystallized from a hexane / isopropyl ether mixture).

Example 5:

3 -1 m-Chlorophênyl} -5-f o-tolyl i-I H-1.2,4-triazole

From 2.55 g (0.017 mol) of the hydrazide of o-toluic acid and from 4.1 g (0.0221 mol) of the ethyl ester of m-chloro-benzimidic acid. Yield: 2.34 g. M.p. 147-1481 C (recrystallized from a cyclohexane benzene l.

Example 6:

3-fm-Trifluoromethylphenyl) -5- n-tolyli-1H-1,2,4-triazole

A mixture of 2.55 g (0.017 mol) of the hydrazide of o-toluic acid and 4.8 g (0.0221 mol d of the ethyl ester of m-trifluoromethybenzimide acid was heated on a water bath. oil for 6 h with stirring, the bath temperature being maintained at approximately 125 C. A solid mass was formed, to which 15 ml of n-butanol were added and the resulting mixture was heated for approximately 19 h, the temperature of oil bath being maintained at approximately 125 C. During this time, the solid mass went completely into solution in butanol which was eliminated by evaporation under vacuum at the end of the reaction, bringing the temperature in oil bath to approximately 150; C. After cooling.! To the mass leaaionneile was taken up in ethyl ether, the ethereal solution was extracted with 120 ml of an aqueous solution of sodium hydroxide at 5 "i and then twice with 50 ml of water, and the aqueous and alkaline extracts were combined. After treatment with activated carbon to remove all impurities and f subsequent iltra tion on celitis. the filtrate was brought to pH 7 by addition, with stirring, of hydrochloric acid at 10 "in water. A precipitate formed, which was recovered and recrystallized from a cyclohexane benzene mixture. Yield: 2.55 g. PF 158-159 vs.

Examples 7-17:

These compounds were prepared as was substantially described in Example 6.

Eximpie 7:

3-'p-Fluorophenyli-5-i o-tolvl -IH-1.2.4-triazole

A. from 2.03 g (0.0135 months) of hydrazine of o-toluic acid and of 2. ° 5 ç (0. (i) 75 moli of ethyl ester of p-i acid 'uorobenzimidiuue- Yield' l.lx g PF 119-121 C irecnstai-lisè in a hexane ether isopropyliiiuej mixture.

Example ti:

3- p-Chlornphênyl'-5- o-tolyl, -l 11-1.2,4-irh: znh '

from 2.U3 g (0.0135 me) of the hyurazide of o-loiuic acid and 3.25 g (0.0175 mol of the ethyl ester of p-chlorobenziir.idic acid. Yield: Ì. 13 A. PF 150-151 Cireeristal-lise in isopropyl ether The compound contains a mixture of crystalline water.

Example V:

3-1 m-Ethoxyphenyl! -5- 'o-tolylj-1 II-1,2.4-i riazole

From 1.5 g (0.01 mol) of the hydrazide of o-toluic acid and .. from 2.12 g (0.0! 1 mol) of the ethyl ester of m-ethoxy acid -benzimide. Yield: 1.41 g. M.p. 84-86 C, crystallized from isopropyl ether).

Example 10:

] „3-i m-Allyloxyphhiyh-5-i o-toh l, -IH-'i.2.4-triazole

From 1.5 g (0.01 mol) of the hydrazide of o-toluic acid and 2.26 g (0.011 mol) of the ethyl ester of m-allyloxy-benzimidic acid. Yield: 1.89 g. M.p. 72-75 C (recrystallized from isopropyl ether).

15

Example 11:

3- f 1.1'-Biphenyl-4-yl) -5- / o-tolyl 1-1 H-1.2,4-triazole

From 0.99 g (0.0066 mol) of the hydrazide of o-toluic acid and from 1.68 g (0.0075 mol) of the ethyl ester of p-phenylbenzimidic acid . Yield: 1.47 g. M.p. 165-167 'C (recrystallized from cyclohexane / benzene).

Example 12:

25 5- (o-Ethvlphènyll-3- (m-methoxyphenylj-1 H-1,2,4-triazole

From 4.87 g (0.03 mol) of the hydrazide of o-ethyl-benzoic acid and 5.35 g (0.03 mol) of the ethyl ester of m-methoxvbenzimidic acid. Yield: 5.36 g. M.p. 72-75 ° C (recrystallized in an ethanol / ethyl ether mixture. Mp of methane sulfonate: 104 C.

Example 13:

3- ■ m-Allyhxyphenyl> -5- o-ethylphenylj-1 Hl, 2,4-triazole: •> From 1.64 gl 0.01 mol) of hydrazide of o-ethylbenzoic acid and 2.26 g (0.011 me) of the ethyl ester of m- allyloxybenzimidic acid. Yield: 2.73 g. F.F. (as hydrochloride) 130-132 C (recrystallized in rethanol).

Example 14:

3-i p-Chlorophenyl i-5-i o-ethylphënyh-111-1.2 4-trlazole

From 1.64 g (0.01 mol) of the hydrazide of o-ethyl benzoic acid and from 2.01 g (0.011 mol) of the ethyl ester of p-chlorobenzimidic acid. Yield: 1.32 g. M.P. 118-120 Cirecristal (in a mixture of isopropyl ether hexane).

Example 15:

> ■ o-hopropylphenyl i-3-phenyl-I H-1,2,4-triazole

:> From 1.25 g (0.007 mol) of the acid hydrazide

2-isopropylbenzoic acid and 1.15 g (0.0077 mol) of the ethyl ester of benzimidic acid. Yield: 1.38 g. M.p. 165-167 C (recrystallized in a mixture of isopropyl ether and petroleum ether).

Example 16:

5-1 o-Isopropylphenyli-3-t m-méttlwxyphinxl -! II - !. 2.4-tnazole

From 1.78 g (0.OI mol) of the hydrazide of 2-isopropyl-henzoic acid and 1.97 g (0.011 mol) of the ethyl ester of m-nicthoxybenzimidic acid. Yield: 2.27 P.F. 125-126 C (recrystallized in a mixture of isopropyl ether and petroleum etiler).

Example H:

ii-EtiivIphenyii-3-phcnvl-1H-l, 2.4-triiizoU-

"i From l.64g (0. () l mol) of the acid hydrazide o-

èihyiben / .oique el ile 1,4l) g (0,01 mol) of the ethyl ester of ben / imidic acid. Yield: 1.77 g. l'K 124-126 C trecristallisè in a mixture of isopropyl ether hexane).

The ethyl esters of the starting benzimide acids were prepared according to methods published in the literature (Pinner, "Die Imidoäther und ihre Derivative"; R. Oppenheim, Berlin, 1892: L. Weintraub and ed. "J. Org. Chem. Vol. 33, No. 4, p. 1679, 1968). Hydrazides of o-toluic acids. o-ethylbenzoic acid and o-

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isopropylbenzoic starter were prepared according to Stolle and Stevens, "J. Pr. " 2. 69. 368 (see also Beilslein, vol. 9. p. 467. J. Springer Verlag, Berlin. 1926).

The typical compounds which can be prepared according to the methods described in Examples 2 to 17 are the following:

-1H-1,2,4-triazole

P.F. (C)

EDS0 (mg / kg) s.c. (hamsters)

5- (o-Ethylphenyl) -3- (m-fluorophenyl) -

112-14

0.4

5- (o-Ethylphenyl) -3- (2,3-dimethylphenyl) -

154-55

5- (o-Ethylphenyl) -3- (2,3-dimethoxyphenyl) -

139-41

5- (o-Ethylphenyl) -3- (3,5-dimethoxyphenyl) -

133-35

5- (o-Ethylphenyl) -3- (3,4-methylenedioxyphenyl) -

108-10

0.03

3-Phenyl-5- (o-propylphenylel-

3- (m-Methoxyphenyl) -5- (o-propylpheny! E) -

5- (o-Butylphenyi) -3-phenyl-

121-22

5- (o-Butylphenyl) -3- (m-methoxyphenyl) -

101-02

5- (2,4-Dimethylphenyl) -3-phenylI-

139-41

0.2

5- (2,4-Dimethylphenyl) -3- (m-methoxyphenyl) -

106-08

0.04

5- (2,5-Dimethylphenvl) -3-phenyl-

147-49

5- (2,5-Dimethylphenyl) -3- (m-methoxyphenyl) -

127-30

5- (2,6-Dimethylphenyl) -3-phenyl-

5- (2,6-Dimethylphenyl) -3- (m-methoxyphenyl) -

5- (4-Chloro-2-methylphenyl) -3-phenyl-

135-36

0.14

5- (4-Chloro-2-methylphenyl) -3- (m-methoxyphenyia) -

137-39

0.04

5- (5-Chloro-2-methylphenyl) -3-phenyl-

170-72

5- (5-Chloro-2-methylphenyl) -3- (m-methoxyphenyl) -

169-71

0.35

5- (4-Methoxy-2-methylphenyl) -3-phenyl-

152-53

5- (4-Methoxy-2-methylphenyl) -3- (m-methoxyphenyl) -

121-22

0.2

3- (m-Ethoxyphényi l-5- (o-ethylphenyle) -

84-86

0.04

5- (o-Elhyiphenyl) -3- (3,4-dimethoxyphenyl) -

57-60

0.05

5- (o-Ethylphenyl) -3- (p-methoxyphenyl) -

128-29

0.15

Example 19:

A vial for injection is prepared with

3-m (methoxyphenyl) -5- (o-tolyl) -1 H-1,2,4-triazole 30 mg benzyl benzoate 250 mg sesame oil q.s.p. 2 ml

Example 20:

A vial for injection is prepared with 3- (m-ethoxyphenyl) -5- (o-tolyl) -1 H-1,2,4-triazole 30 mg benzyl alcohol 100 mg peanut oil q.s.p. 2 ml

Example 21:

A vial for injection is prepared with 5- (o-ethylphenyn-3- (m-methoxyphenyl) -1 H-1.2.4-triazoie 20 mg benzyl alcohol 80 mg castor oil q.s.p. 2 ml

Example 22:

A sugar-coated lozenge is prepared with

3- (m-methoxyphenyI) -5- (o-tolyl) -1 H-1,2,4-triazole 100 mg sodium carboxymethylcellulose magnesium stearate gelatin starch sucrose

5 mg 5 mg 10 mg 10 mg 25 g gum arabic, lactose, titanium dioxide, alumina lacquer according to traditional methods.

Example 23:

One capsule is prepared with

5- (o-ethylphenyl) -3- (m-methoxyphenyl) -1 H-1,2,4-

triazole talc lactose carboxymethylcellulose sodium starch q.s.p.

Example 24:

A lozenge is prepared with 3- (m-methoxyphenyl) -5- (o-tolyl) -1 H-1,2,4-triazole levilite starch maanesium stearate

60 mg 5 mg 5 mg 5 mg 150 ma

100 mg 100 mg 80 mg 10 ma

R

Claims (8)

630 909 1. 1H-l.2,4-Triazoles 3.5-thénìpeutically active substitutes of formula fi) in which: R is chosen from: hydrogenated. alcoylfC]. 4). alkoxyfC | _4). allyl-oxy, propargyloxy, trifluoromethyl. phenyl. fluoro, chloro and dimethvlamino; R] represents an alkyl group (C | .4,); R; is chosen from: hydrogenated, fluoro, chloro, alkyl (CCl), methoxy and ethoxy; R3 is chosen from: hydrogen, fluoro, chloro, alkyl (C | _4) and alkoxvCC] ^); R and R, taken together represent a methylenedioxy group; provided that. when R. R, and R, represent hydrogen simultaneously. R, is not a methyl group; and also provided that. when R; and one of the groups R and R3 represent hydrogen, R, and the other of the groups R and R, are not simultaneously the methyl group, and their salts obtained with pharmaceutically acceptable acids. 2. Compound according to claim 1, in which R is chosen from: alkyl (C | 4), alkoxyfCj.j.j, ailyloxy, fluoro, chloro and dimethlamino. Rj represents an alkyl group (C | _4), R; is chosen from: hydrogen, methoxy and ethoxy. R, may be hydrogen. an alkoxy group (Ci_4J, fluoro or chloro. R and R3 taken together represent a methylenedioxy group. provided that, when R-. and R, represent simultaneously hydrogen, R and R (are not simultaneously the methyl group, and its salts obtained with pharmaceutically acceptable acids. 3. A compound according to claim 1. in which R is chosen from: alkoxy (CI, 4 ;. ailyloxy. Tiuoro and chloro, R, represents an alkoxylC 4 group). R: is chosen from: hydrogenated, methoxy and ethoxy and R3 may be hydrogen or an aleexyl group Cj_4j, and its salts obtained with pharmaceutically acceptable acids. 4. Compound according to claim 1. in which R is chosen from: methoxy, ethoxy. ailyloxy, fluoro and chloro. R, is an alkoxy group (C [.4), R2 represents hydrogen or a methoxy group and R, is hydrogen, and its salts obtained with pharmaceutically acceptable acids. 5. A compound according to claim 1, which is 3- (m-methoxy-phenyl) -5- (o-tolyl j-1 H-1,2,4-triazoie. oh. A compound according to claim 1. which is 3- (m-ethoxy-phenyl) -5- (o-tolvl) -l H-i, 2.4-triazole. Compound according to claim 1, which is 5-fo-ethylphenyl) -3-i m-methoxyphenyl) -1 H- i, 2.4-tria / ole. Process for preparing I H-l, 2.4-tria / oles 3.5-disubstitutes of formula in which: R is chosen from: hydrogen, aico \ liC | .4), alkoxyfC].,.,), Ailyloxy. propargyloxy. trifluoromethyl. phènyie, fluoro, chloro et dimethylamino: R represents a groupealcoyl (C> .4): R; is chosen from: hydrogen, fluoro, chloro, alkyl (C] .4), methoxy and ethoxy; R, is chosen from: hydrogen, fluoro, chloro, alcoylfC, .4) and alkoxy (C | .4j: R and R, taken together represent a methylenedioxy group; provided that when R, R, and R3 simultaneously represent hydrogen. R, is not a methyl group; also provided that. when R = and one of the groups R and Rs simultaneously represent hydrogen, R, and the other of the groups R and R, are not simultaneously the methyl group. and their salts obtained with pharmaceutically acceptable acids, which comprises the condensation of an amount of a compound of formula NH-NH, A-C AT (II) or a salt thereof obtained with an acid, with an amount in slight excess relative to the molar proportion of a compound of formula B-CX (III) or a salt thereof obtained with an acid, in which CX is a functional group chosen from: carboxy. dithiocarboxy, carbonyl halide. carboxyl anhydride, orthoester, imidate, thio-imidate. imidoyl, amidino and cyano halide, Y is an NH group and, when the CX group contains a nitrogen atom, it represents oxygen or sulfur and, if A is the / - group ^ AT . B is the group or. if \ / X / À is group A. y. B is, e group- * - R - "AL1 / in which R. R ,, R; and R, are defined as above, at a temperature between 80 and 200 C, for a period ranging from 15 to 30 h, optionally in the presence of an acid catalyst 1 and an organic solvent, and the recovery of 1H- l, 2.4-triazole 3.5-disubstituted as defined by formula I. 9. The method of claim S. wherein the group CX is the group O-aicovle / % NH in which the alcovle can be methyl, ethyl or propyl. 10. The method of claim *. in which the organic solvent is chosen from n-butanol and n-pentanol.