GB1579352A

GB1579352A - 3,5-disubstituted-1h-1,2,4-triazoles

Info

Publication number: GB1579352A
Application number: GB19012/77A
Authority: GB
Original assignee: Gruppo Lepetit SpA; Lepetit SpA
Current assignee: Gruppo Lepetit SpA
Priority date: 1977-05-06
Filing date: 1977-05-06
Publication date: 1980-11-19
Also published as: NO823654L; NO148525B; IT7822928A0; LU79601A1; YU41311B; PT68005B; DK149469B; FR2389615B1; IT1158700B; CA1100511A; DK149469C; SE444316B; NZ187181A; BE866728A; JPH0146513B2; HK26281A; JPS53137965A; DE2819372A1; FI64150C; FR2389615A1

Abstract

The 3,5-disubstitited-1H-1,2,4-triazoles <IMAGE> in which: R is chosen from: hydrogen, (C1-4)alkyl, (C1-4)alkoxy, allyloxy, propargyloxy, trifluoromethyl, phenyl, fluoro, chloro and dimethylamino; R1 represents a (C1-4)alkyl group; R2 is chosen from: hydrogen, fluoro, chloro, (C1-4)alkyl, methoxy and ethoxy; R3 is chosen from: hydrogen, fluoro, chloro, (C1-4)alkyl and (C1-4)alkoxy; R and R3, taken together, represent a methylenedioxy group; on condition that, when R, R2 and R3 simultaneously represent hydrogen, R1 is not the methyl group; and also on condition that, when R2 and one of the groups R and R3 represent hydrogen, R1 and the other of the groups R and R3 are not simultaneously the methyl group; and their salts obtained with pharmaceutically acceptable acids are described. These compounds have antireproductive properties and act on the central nervous system.

Description

(54) 3,5-DISUB STITUTED- lH- 1 2,4-TRIAZOLES (71) We, GRUPPO LEPETIT S.pA., an Italian Body Corporate, of Via Roberto Lepetit 8, Milan, Italy, do hereby declare the invention, for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention provides novel pharmacologically active 3,5 disubstituted - 1H - 1,2,4 - triazoles of the formula

wherein R, is C14 alkyl; R2 is hydrogen, fluorine, chlorine, C14 alkyl, methoxy or ethoxy; and either R3 is hydrogen, C14 alkyl, C14 alkoxy, allyloxy, propargyloxy, trifluoromethyl, phenyl, chlorine, fluorine or dimethylamino and R4 is hydrogen, C14 alkyl, C14 alkoxy, chlorine or fluorine or R3 and R4 together are methylenedioxy; and includes the pharmaceutically acceptable acid addition salts thereof. This invention excludes the compounds of formula I wherein R1 is methyl, R2 and R3 are each hydrogen and R4 is hydrogen or methyl.

"C14 alkyl" means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. "C14 alkoxy" means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy.

A preferred group of compounds of this invention comprises those compounds of formula I wherein R2 is hydrogen, methoxy or ethoxy and either R3 is C14 alkyl, C14 alkoxy, allyloxy, fluorine, chlorine or dimethylamino and R4 is hydrogen, C14 alkoxy, fluorine or chlorine or R3 and R4 together are methylenedioxy. More preferably, R2 is hydrogen, methoxy or ethoxy; R3 is C14 alkoxy, allyloxy, fluorine or chlorine and R4 is hydrogen or C14 alkoxy. Most preferably, R2 is hydrogen or methoxy; R3 is methoxy, ethoxy, allyloxy, fluorine or chlorine and R4 is hydrogen.

These groups include the pharmaceutically acceptable acid addition salts of the compounds.

It will be apparent to any person skilled in the art that, owing to the great mobility of the hydrogen atom of 1,2,4-triazoles (see K. T. Potts, Chem. Rew., 61, 99 (1961) and J. Chem. Soc. 3451(1954)), the compounds of the invention may exist in various tautomeric forms; the hydrogen atom may be located as shown in formula I or on one of the other two nitrogen atoms of the triazole nucleus. These tautomeric forms are included within this invention. It is known that tautomeric forms are in a state of dynamic equilibrium. In this specification, the compounds of the invention will be named as 1H-1,2,4-triazoles, following formula I.

The compounds of the invention may be prepared either by reacting a compound of the formula

with a compound of the formula

or by reacting a compound of the formula

with a compound of the formula

The compound of formula II, i.e. IIa or IIb, may be used in the form of an acid salt thereof, e.g. the hydrochloride. In the above formulae, the radicals R1,R2, R3 and R4 have the same meanings as before, CX is a functional group selected from carboxy, dithiocarboxy, carbonyl halide, carboxy anhydride, orthoester, imidate, thioimidate, imidoyl halogenide, amidino and cyano; and Y is NH or, if the group CX contains a nitrogen atom, oxygen or sulfur.

When the group CX represents imidate, thioimidate, imidoyl halogenide or amidino, also the compound of formula III may be employed as the corresponding acid salt.

The process which leads to the 1,2,4-triazoles of the invention is a condensation reaction during which, depending on the nature of the reacting groups Y and CX, water, hydrogen sulfide, hydrogen halide, ammonia, alkanols, mercaptans, carboxylic acids or mixtures thereof are formed as the by-products.

These by-products can be eliminated during the course of the reaction or are removed at the end of the condensation by means of usual procedures.

In practice, the condensation reaction is carried out by heating under stirring the pair of reactants of formulae II and III, generally in the absence of solvent, at a temperature of from 80 to 2000C for a time varying from 15 to 30 hours. A slight molar excess over the compound of formula II of the compound containing the CX function may be advantageously employed. Preferably, the CX function is an imidiate group of formula -CNH-OAlkyl wherein Alkyl may be methyl, ethyl or propyl, so that the low boiling alcohol which forms during the condensation, e.g. methanol, ethanol or propanol, automatically evaporates from the reaction medium. In order to speed up the removal of the alcohol, a moderate vacuum may be conveniently applied. It has also been observed that the presence of an acidic catalyst may favor the condensation reaction and, therefore, a catalytic amount of hydrochloric, hydrobromic, or ptoluenesulfonic acid may be conveniently added to the reaction mixture. This addition is not necessary when the reactants are employed as the corresponding acid salts. Finally, if during the heating the reaction mass tends to solidify, it may be advantageous to add the mass of small amount of an organic solvent such as, for instance, n-butanol or n-pentanol. This solvent is evaporated off in vacuo at the end of the reaction.

The final products are then recovered according to known procedures. As an example, the reaction mixture is taken up with a suitable organic solvent, preferably diethylether, and the organic solution is extracted several times with dilute sodium hydroxide. The alkaline extracts are combined together and, if necessary, treated with charcoal in order to remove impurities. After filtering on Celite (Registered Trade Mark), the filtrate is brought to a pH value of about 6-7 by adding dilute hydrochloric acid. A product separates which may be solid or oily.

Depending on its nature, it may be recovered by filtration or extracted with a suitable organic solvent, as an example diethylether or methylene-chloride. Said solvent is then evaporated off leaving a solid crystalline residue.

A further purification by column chromatography may be sometimes necessary. Finally, the desired 3,5 - disubstituted - 1H - 1,2,4 - triazole derivatives are recrystallized from suitable organic solvents, such as, for instance, hexane, methylene chloride, chloroform, diisopropyl ether, benzene, cyclohexane or mixtures thereof.

The following Examples (1 to 17) illustrate the process of the invention and describe in detail some compounds of the general formula I without limiting the scope of the invention.

Example 1 3-(m-Methoxyphenyl)-5-(o-tolyl)- I H- 1,2,4-triazole A mixture of 3.0 g. (0.02 mole) of the hydrazide of o-toluic acid and 4.83 g.

(0.027 mole) of m-methoxybenzimidic acid methyl ester was heated on an oil bath under stirring for about 20 hours, keeping the temperature of the bath at about 125 C. After cooling, the reaction mass was taken up with 100 ml. of diethyl ether and the obtained ether solution was first extracted with 50 ml of 5 /" aqueous sodium hydroxide and then twice with 30 ml of water. The water and alkaline extracts were combined together, treated with charcoal to remove any impurity and filtered on Celite. The filtrate was brought to pH 7 by adding under stirring 10% aqueous hydrochloric acid whereby an oily substance separated which was extracted with diethyl ether. After drying over sodium sulfate, the ether was evaporated off in vacuo and the obtained residue was recrystallized from diisopropyl ether/hexane. Yield 3.15 g. M.p. 1002 C.

Examples 2-5 Following substantially the same procedures described in Example 1, the following compounds were prepared.

Example 2 3-(p-Dimethylaminophenyl)-5-(o-tolyl)- I H- 1,2,4-triazole from 2.55 g. (0.017 mole) of the hydrazine of o-toluic acid and 4.26 g. (0.021 mole) of p-dimethylaminobenzimidic acid ethyl ester. Yield 3.04 g. M.p. 173--750C (from diisopropyl ether).

Example 3 3-(o-Chlorophenyl)-5-(o-tolyl)- I H-I 2,4-triazole from 3.75 g. (0.025 mole) of the hydrazide of o-toluic acid and 5.5 g. (0.03 mole) of o-chlorobenzimidic acid ethyl ester. Yield 4.26 g. M.p. 109-ll0C (from hexane/methylene chloride).

Example 4 3-(o-Methoxyphenyl)-5-(o-tolyl)- I H- 1,2,4-triazole from 6.75 g. (0.045 mole) of the hydrazide of o-toluic acid and 9.85 g. (0.05 mole) of o-methoxybenzimidic acid ethyl ester. Yield 4.81 g. M.p. 160--61"C (from hexane/diisopropyl ether).

Example 5 3-(m-Chlorophenyl)-5-(o-tolyl)- 1 H- 1 ,2,4-triazole from 2.55 g. (0.017 mole) of the hydrazide of o-toluic acid and 4.1 g. (0.0221 mole) of m-chlorobenzimidic acid ethyl ester. Yield 2.34 g. M.p. 147--48"C (from cyclohexane/benzene).

Example 6 3-(m-Trifluoromethylphenyl)-5-(o-tolyl)- 1 H- 1 ,2,4,-triazole A mixture of 2.55 g. (0.017 mole) of the hydrazide of o-toluic acid and 4.8 g.

(0.0221 mole) of m-trifluoromethylbenzimidic acid ethyl ester was heated on an oil bath for 6 hours under stirring, keeping the temperature of the bath at about 125"C.

A solid mass formed which was added with 15 ml of n-butanol, and the resulting mixture was heated for about- 19 hours keeping the temperature of the oil bath at about 125"C.

During this period, the solid mass completely dissolved in the butanol which, at the end of the reaction, was evaporated off in vacuo, bringing the temperature of the oil bath to about 1500C. After cooling, the reaction mass was taken up with diethyl ether, the ether solution was extracted with 120 ml of 5% aqueous sodium hydroxide and then twice with 50 ml of water and the water and alkaline extracts were combined together. After treatment with charcoal to remove any impurity and subsequent filtration on Celite, the filtrate was brought to pH 7 by adding, under stirring, 10% aqueous hydrochloric acid. A precipitate formed, which was collected and recrystallized from cyclohexanelbenzene. Yield 2.55 g. M.p. 158 59"C.

Examples 7-17 These compounds were prepared substantially as described in Example 6 Example 7 3-(p-Fluorophenyl)-5-(o-tolyl)- 1 H- 1 ,2,4-triazole from 2.03 g (0.0135 mole) of the hydrazide of o-toluic acid and 2.95 g. (0.0175 mole) of p-fluorobenzimidic acid ethyl ester. Yield 1.18 g. M.p. 119--21"C (from hexane/diisopropyl ether).

Example 8 3-(p-Chlorophenyl)-5-(o-tolyl)- 1 H- 1 2,4-triazole from 2.03 g. (0.0135 mole) of the hydrazine of o-toluic acid and 3.25 g. (0.0175 mole) of p-chlorobenzimidic acid ethyl ester. Yield 1.13 g. M.p. 150--151"C (from diisopropyl ether). The compound contains half molecule of crystallization water.

Example 9 3-(m-Ethoxyphenyl)-5-(o-tolyl)- I H. 1 2,4,-triazole from 1.5 g. (0.01 mole) of the hydrazide of o-toluic acid and 2.12 g. (0.011 mole) of m-ethoxybenzimidic acid ethyl ester. Yield 1.41 g. M.p. 84860C (from diisopropyl ether).

Example 10 3-(m-Allyloxyphenyl)-5-(o-tolyl)- I H- 1,2,4-triazole from 1.5 g. (0.01 mole) of the hydrazide of o-toluic acid and 2.26 g. (0.011 mole) of m-alloxybenzimidic acid ethyl ester. Yield 1.89 g. M.p. 72--75"C (from diisopropyl ether).

Example 11 3-( 1, '-Biphenyl-4-yl)-5-(o-tolyl)- 1 H-I 2,4-triazole from 0.99 g. (0.0066 mole) of the hydrazide of o-toluic acid and 1.68 g. (0.0075 mole) of p-phenyl-benzimidic acid ethyl ester. Yield 1.47 g. M.p. 165-670C (from cyclohexane/benzene).

Example 12 5-(o-Ethylphenyl)-3-(m-methoxyphenyl)- I H- 1,2,4-triazole from 4.87 g. (0.03 mole) of the hydrazide of o-ethylbenzoic acid and 5.35 g. (0.03 mole) of m-methoxy-benzimidic acid ethyl ester. Yield 5.36 g. M.p. 72-750C (from diisopropyl ether/hexane). The hydrochloride melts at 175-1770C (from ethanol/ethyl ether).

Example 13 3-(m-Allyloxyphenyl)-5-(o-ethylphenyl)- I H- 1,2,4-triazole from 1.64 g (0.01 mole) of the hydrazide of o-ethylbenzoic acid and 2.26 g. (0.011 mole) of m-allyloxy-benzimidic acid ethyl ester. Yield 2.73 g. M.p. (as the hydrochloride) 130--32"C (from ethanol).

Example 14 3-(p-Chlorophenyl)-5-(o-ethylphenyl)- I H- 1,2,4-triazole from 1.64 g. (0.01 mole) of the hydrazide of o-ethylbenzoic acid and 2.01 g. (0.011 mole) of p-chlorobenzimidic acid ethyl ester. Yield 1.32 g. M.p. 1 l8-l200C (from diisopropyl ether/hexane).

Example 15 5-(o-Isopropylphenyl)-3-phenyl- I H- 1,2,4-triazole from 1.25 g. (0.007 mole) of the hydrazide of o-isopropylbenzoic acid and 1.15 g.

(0.0077 mole) of benzimidic acid ethyl ester. Yield 1.38 g. M.p. 165-670C (from diisopropyl ether/light petroleum).

Example 16 5-(o-Isopropylphenyl)-3-(m-methoxyphenyl)- 1 H- 1 ,2,4-triazole from 1.78 (0.01 mole) of the hydrazide of o-isopropylbenzoic acid and 1.97 g. (0.011 mole) of m-methoxy-benzimidic acid ethyl ester. Yield 2.27 g. M.p. 125-260C (from diisopropyl ether/light petroleum).

Example 17 5-(o-Ethylphenyl)-3-phenyl- 1 H- 1 ,2,4-triazole from 1.64 g. (0.01 mole) of the hydrazide of o-ethylbenzoic acid and 1.49 g. (0.01 mole) of benzimidic acid ethyl ester. Yield 1.77 g. M.p. 124--26"C (from diisopropyl ether/hexane).

The starting benzimidic acid ethyl ester derivatives were prepared according to literature methods (Pinner, "Die Imido ther und Ihre Derivative"; R.

Oppenheim, Berlin, 1892; L. Weintraub et al. J. Org. Chem., Vol. 33, No. 4, page 1679, 1968).

The starting hydrazides of o-toluic, o-ethylbenzoic and o-isopropylbenzoic acid were prepared according to Stolle and Stevens, J. Pr[2], 69, 368 (see also Beilstein, Vol. 9, page 467, J. Springer Verlag, Berlin, 1926).

Typical compounds which can be prepared according to the procedures described in the above Examples are as follows: 5-(o-Ethylphenyl)-3-(m-fluorophenyl)- IH- 1,2,4-triazole 5-(o-Ethylphenyl)-3-(2,3-dimethylphenyl)- 1H- 1,2,4-triazole 5-(o-Ethylphenyl)-3-(2,3-dimethoxyphenyl)- lH- 1 ,2,4-triazole 5-(o-Ethylphenyl)-3-(3 , 5-dimethoxyphenyl)- 1H- 1 2,4-triazole 5-(o-Ethylphenyl)-3-(3,4-methylenedioxyphenyl)- lH- H-1,2,4-triazole 3-Phenyl-5-(o-propylphenyl)- lH- 1 ,2,4-triazole 3-(m-Methoxyphenyl)-5-(o-propylphenyl)- IH- 1,2,4-triazole 5-(o-Butylphenyl)-3-phenyl- lH- 1 ,2,4-triazole 5-(o-Butylphenyl)-3-(m-methoxyphenyl)- lH- 1,2,4-triazole 5-(2,4-Dimethylphenyl)-3-phenyl- lH- 1 ,2,4-triazole 5-(2,4-Dimethylphenyl)-3-(m-methoxyphenyl)- lH- 1 ,2,4-triazole 5-(2,5-Dimethylphenyl)-3-phenyl- 111-1 ,2,4-triazole 5-(2,5-Dimethylphenyl)-3-(m-methoxyphenyl)- lH- 1,2,4-triazole 5-(2,6-Dimethylphenyl)-3-phenyl- lH- 1 2,4-triazole 5-(2,6-Dimethylphenyl)-3-(m-methoxyphenyl)- IH- 1 ,2,4-triazole 5-(4-Chloro-2-methylphenyl)-3-phenyl- lH- 1 ,2,4-triazole 5-(4-Chloro-2-methylphenyl)-3-(m-methoxyphenyl)- lH- 1 ,2,4-triazole 5-(5-Chloro-2-methylphenyl)-3-phenyl- lH- 1,2,4-triazole 5-(5-Chloro-2-methylphenyl)-3-(m-methoxyphenyl)- lH- 1 ,2,4-triazole 5-(4-Methoxy-2-methylphenyl)-3-phenyl- IH- 1,2,4-triazole and 5-(4-Methoxy-2-methylphenyl)-3-(m-methoxyphenyl)- 1H-1,2,4-triazole The compounds of this invention possess anti-reproductive and CNS depressant activity.

The CNS-depressant activity was investigated by means of the Irwin method.

More exactly, the ability of the compounds of the invention to impair, in the laboratory animals, the motor cohordination, the righting reflex, the spontaneous activity and the muscular tone, i.e., parameters which are directly related to sedative, hypnotic and miorelaxing effects, was investigated. Representative experiments have shown that amounts from about 10 to about 300 mg/kg i.p. are effective in impairing significantly the above parameters when tested in mice.

However, the most important biological aspect of the compounds of the invention lies in that they possess remarkable anti-reproductive utility. More particularly, they show post-coital-post-implantation antifertility activity when administered by different pharmacological routes, to laboratory animals, e.g. rats, hamsters, dogs, monkeys and baboons.

Moreover, the antifertility activity of these new compounds is not associated with other biological effects which are usual with hormonal substances.

Fertility regulation can usually be achieved in a number of ways through the administration of hormonal substances. These can involve ovulation inhibition, ova transport, fertilization, implantation of the zygote, resorption of the fetus or abortion. Only with ovulation inhibition has there developed a successful method that is clinically useful.

The compounds of this invention allow an entirely new approach to this problem in which a non-hormonal compound can be administered parenterally, orally or by intravaginal route once or more times as needed after a "missed period" or to induce termination of a more advanced pregnancy.

Representative experiments for assessing antifertility activity were carried out with female Syrian golden hamsters weighing 100 to 130 g. The animals were mated and the presence of sperm in the vagina was taken as evidence of mating. The davy sperm was detected was considered day one of pregnancy, since in our laboratories and those of other investigators 90 to 100% of animals that mate as evidenced by vaginal sperm are pregnant.

Pregnancy was later confirmed at the time of autopsy by presence of fetuses or implantation sites in the uterus.

Even if an animal aborts the fetus, implantation scars still remain as evidence that the animal has been pregnant.

The compounds of the invention, which possess a high solubility in the commonly employed pharmaceutical vehicles, were dissolved in sesame oil and administered subcutaneously in doses of 10 mgikg daily for 5 days beginning on day, 4 of pregnancy (days 4-8). The animals were autopsied on day 14 of pregnancy and the uteri were examined for evidence of pregnancy (implantation sites, fetal resorptions or live fetuses), hemorrage, and evidence of abnormalities of the uterus, placenta orxfetuses. A compound was considered to be active if there was a reduction of live fetuses in at least 60% of the treated animals and the presence of implantation sites proves the animal to have been pregnant. In representative experiments the compounds of Examples 1, 4 to 7 and 9 to 16 prove to be active according to the above criteria.

The compounds were then studied for dose-activity relationships and the corresponding ED50 values i.e., 100% activity (absence of live fetuses) in 50% of the animals, were also determined. The following table reports the EDso values of some representative compounds of the invention: TABLE I Compound ED50(mg/kg of Example s.c. hamsters) 1 0.08 4 0.5 9 0.07 10 0.25 12 0.04 13 0.1 The same criteria and experimental conditions as above were also applied when the anti-reproductive activity of the compounds of the invention was investigated in other animal species such as, for instance, rats, dogs, monkeys and baboons. In representative experiments, female Sprague-Dawley rats weighing from 200 to 300 g. were treated subcutaneously with a dosage of 20 mg/kg of the compound to be tested, dissolved in sesame oil, for five consecutive days starting from day 6 of pregnancy. The rats were killed and autopsied on day 16 and the uteri were examined as seen above for hamsters. Also in this experiment the compounds of Example 1,4 to 7 and 9 to 16 caused a reduction of live fetuses in at least 60 /n of the treated rats. The ED50 values of the compounds of Examples I and 12 were determined and are reported in the following Table: TABLE II Compound ED50(mg/kg of Example s.c. rats) 1 I 12 0.7 Favourable results were also obtained by administering the compounds of the invention by oral route. The experiments for assessing this property were carried out on hamsters following the same procedure as above, with the obvious exception that the compounds were administered orally instead of subcutaneously.

The reduction of about 60 /n of live fetuses was observed at an oral dosage of 10 mg/kg with compounds of Examples 1, 4 to 7 and 9 to 16. The ED50 values of the compounds of Examples 1 and 12 were also determined and are reported in the following table: TABLE III Compound of ED50(mg/kg Example p.o. hamsters) 1 5 12 5 Finally, the compounds of the invention display a very low toxicity. In fact, their LD50-values, determined according to Lichtfield and Wilcoxon, Journ.

Pharm. Expt. Ther., 96, 99, 1949, are never lower than 600 mg/kg, when administered to mice by intraperitoneal route.

The facts that the compounds of the invention possess outstanding antireproductive activity even when administered by the oral route and are very soluble in the common pharmaceutical carriers represent undoubtedly further important properties. As an example, the high solubility causes the compounds to be readily absorbable and incorporable into suitable and more tolerable injectable dosage forms which possess less drawbacks than corresponding forms wherein the active ingredient is suspended in the carrier. Further, the oral activity allows the compounds to be embodied into more acceptable pharmaceutical preparations. It is also to be noted that, apart from oral contraceptives which however are substances of steroidal nature and display their activity by blocking the ovulation, no other anti-reproductive compounds or preparations are known to be active per os.

It follows, therefore, that the compounds of the invention may be administered by various routes: orally, subcutaneously, intramuscularly or intravaginally.

For oral administration the substances are compounded in such forms as tablets, dispersible powders, capsules, granules, syrups, elixirs and solutions.

The compositions for oral use may contain one or more conventional adjuvants, such as, for instance, sweetening agents, flavoring agents, coloring agents, coating and preservative agents, in order to provide an elegant and palatable preparation.

Tablets may contain the active ingredient admixed with conventional pharmaceutical acceptable excipients, e.g. inert diluents such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, such as, for instance, starch, aliginic acid and sodium carboxymethylcellulose, binding agents, e.g. starch, gelatin, gum-arabic and polyvinylpyrrolidone and lubricating agents, e.g. magnesium stearate, stearic acid and talc.

Syrups, elixirs and solutions are formulated as known in the art. Together with the active compound they may contain suspending agents, such as, for instance, methyl cellulose, hydroxyethylcellulose, tragacanth aand sodium aligate, wetting agents, e.g. lecithin, polyoxyethylene stearates and polyoxyethylene sorbitan monooleate, and the common preservative, sweetening and buffering agents.

A capsule or a tablet may contain the active ingredient alone or admixed with an inert solid diluent, such as, for instance, calcium carbonate, calcium phosphate and kaolin.

Besides the oral route, other useful ways for administering the compounds of the invention may be suitably employed, such as, for instance, the subcutaneous or the intramuscular administration.

The active ingredient is thus embodied into injectable dosage forms. Such compositions are formulated according to the art and may contain appropriate dispersing or wetting agents and suspending or buffering agents identical or similar to those mentioned above.

Sesame oil, benzyl alcohol, benzyl benzoate, peanut oil and their mixtures may also be suitably employed as vehicles.

A vaginal insert may also contains the active ingredient in admixture with the common carriers e.g. gelatin, adipic acid, sodium bicarbonate, lactose and analogs.

The compounds of the invention may also be administered in the form of their non-toxic pharmaceutically acceptable acid addition salts. Such salts possess the same degree of activity as the free bases, from which they are readily prepared by reacting the base with an appropriate acid and accordingly, are included within the scope of the invention. Representative of such salts are the mineral acid salts, such as, for instance, the hydrochloride, hydrobromide and sulfate salts and the organic acid salts such as the succinate, benzoate, acetate, p-toluenesulfonate, benzenesulfonate, maleate, tartrate, methanesulfonate and cyclohexylsulfonate salts.

The dosage of active ingredient employed for inhibiting reproduction may vary within wide limits, depending on the nature of the compound.

Generally, good results are obtained when the compound of formula I is administered at a daily dosage of 0.8 to 50 mg/kg animal body weight. The dosage forms useful for this purpose generally contain from 10 to 600 mg of the active ingredient in admixture with a solid or liquid pharmaceutically acceptable diluent or carrier.

The following Examples illustrate compositions of the invention.

Example 18 A vial for injectable use is prepared from: 3-(m-methoxyphenyl)-5-(o-tolyl)- IH- 1,2,4-triazole 30 mg.

Benzyl benzoate 250 mg.

Sesame oil q.s. 2 ml.

Example 19 A vial for injectable use is prepared from: 3-(m-Ethoxyphenyl)-5-(o-tolyl)- IH- 1,2,4-triazole 30 mg.

Benzyl alcohol 100 mg.

Peanut oil q.s. 2 ml.

Example 20 A vial for injectable use is prepared from: 5-(o-Ethylphenyl)-3-(m-methoxyphenyl)- lH- 1,2,4 triazole 20 mg.

Benzyl alcohol 80 mg.

Castor oil q.s. 2 ml.

Example 21 A sugar coated tablet is prepared from: 3-(m-Methoxyphenyl)-5-(o-tolyl)- IH-1,2,4-triazole 100 mg.

Sodium carboxymethylcellulose 5 mg.

Magnesium stearate 5 mg.

Gelatin 10 mg.

Starch 10 mg.

Saccharose 25 mg.

gum arabic, lactose, titan dioxide, aluminium lac according to conventional procedures.

Example 22 A capsule is prepared from: 5-(o-Ethylphenyl)-3-(m-methoxyphenyl)- lH- 1,2,4 triazole 60 mg.

Talc 5 mg.

Lactose 5 mg.

Sodium carboxymethylcellulose 5 mg.

Starch q.s. 150 mg.

Example 23 A tablet is prepared from: 3-(m-Methoxyphenyl)-5-(o-tolyl)- lH- 1,2,4-triazole 100 mg.

Levilite 100 mg.

Starch 80 mg: Magnesium stearate 10 mg.

We make no claim herein to the compounds 3 - phenyl - 5 - (o - tolyl) 1H-1,2,4 - triazole, 3,5 - bis(o - tolyl) - 1H - 1,2,4 - triazole, 3 - (m - tolyl) - 5 (o - tolyl) - 1H - 1,2,4 - triazole and 3 - (p - tolyl) - 5 - (o - tolyl) - lH - 1,2,4 triazole, and the pharmaceutically acceptable acid addition salts thereof.

Subject to the foregoing disclaimer.

WHAT WE CLAIM IS: 1. A compound of the formula

wherein R1 is C14 alkyl; R2 is hydrogen, fluorine, chlor

Claims

**WARNING** start of CLMS field may overlap end of DESC **. Example 23 A tablet is prepared from: 3-(m-Methoxyphenyl)-5-(o-tolyl)- lH- 1,2,4-triazole 100 mg. Levilite 100 mg. Starch 80 mg: Magnesium stearate 10 mg. We make no claim herein to the compounds 3 - phenyl - 5 - (o - tolyl) 1H-1,2,4 - triazole, 3,5 - bis(o - tolyl) - 1H - 1,2,4 - triazole, 3 - (m - tolyl) - 5 (o - tolyl) - 1H - 1,2,4 - triazole and 3 - (p - tolyl) - 5 - (o - tolyl) - lH - 1,2,4 triazole, and the pharmaceutically acceptable acid addition salts thereof. Subject to the foregoing disclaimer. WHAT WE CLAIM IS:

1. A compound of the formula

wherein R1 is C14 alkyl; R2 is hydrogen, fluorine, chlorine, C14 alkyl, methoxy or ethoxy; and either R3 is hydrogen, C14 alkyl, C14 alkoxy, allyloxy, propargyloxy, trifluoromethyl, phenyl, fluorine, chlorine or dimethylamino and R4 is hydrogen, fluorine, chlorine, C14 alkyl or C14 alkoxy or R3 and R4 together are methylenedioxy; or a pharmaceutically acceptable acid addition salt thereof.

2. A compound as claimed in claim 1 wherein R2 is hydrogen, methoxy or ethoxy and either R3 is C14 alkyl, C14 alkoxy, allyloxy, fluorine, chlorine or dimethylamino and R4 is hydrogen, C14 alkoxy, fluorine or chlorine or R3 and R4 together are methylenedioxy.

3. A compound as claimed in claim 2 wherein R3 is C14 alkoxy, allyloxy, .fluorine or chlorine and R4 is hydrogen or C14 alkoxy.

4. A compound as claimed in claim 1 wherein R2 is hydrogen or methoxy; R3 is methoxy, ethoxy, allyloxy, fluorine or chlorine and R4 is hydrogen.

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

6. 3 - (m - Ethoxyphenyl) - 5 - (o - tolyl) - 1H - 1,2,4 - triazole.

7. 5 - (o - Ethylphenyl) - 3 - (m - methoxyphenyl) - 1H - 1,2,4 - triazole.

8. A process for preparing a compound as claimed in claim 1, which comprises condensing a molar proportion of a compound of the formula

or an acid salt thereof, with a slight molar excess of a compound of the formula

wherein CX is a functional group selected from carboxy, dithiocarboxy, carbonyl halide, carboxy anhydride, orthoester, imidate, thioimidate, imidoyl halogenide, amidino and cyano (provided that the compound of formula III may be in acid salt form if CX is imidate, thioimidate, imidoyl halogenide or amidino); Y is NH or, if the group CX contains a nitrogen atom, oxygen or sulfur; and R1, R2 R3 and R4 are as defined in claim 1, at from 80 to 2009C for from 15 to 30 hours.

9. A process for preparing a compound as claimed in claim 1, which comprises

condensing a molar proportion of a compound of the formula

or an acid salt thereof with a slight molar excess of a compound of the formula

wherein CX and Y are as defined in claim 8 and R1, R2, R3 and R4 are as defined in claim 1, at from 80 to 2000C for from 15 to 30 hours.

10. A process according to claim 8 or claim 9 which is conducted in the presence of an acidic catalyst.

11. A process according to any of claims 8 to 10 which is conducted in an organic solvent.

12. A process according to claim 11 wherein the organic solvent is n-butanol or n-pentanol.

13. A process according to any of claims 8 to 12 wherein the group CX is --CNHH-OAlkyl wherein Alkyl is methyl, ethyl or propyl.

14. A process for preparing a compound as claimed in claim 1 substantially as described in any of Examples 1 to 17.

15. A compound as claimed in claim 1 when prepared by a process according to any of claims 8 to 14.

16. A pharmaceutical composition comprising a compound as claimed in any of claims 1 to 7 and 15 in association with a physiologically acceptable excipient.

17. A composition according to claim 16 substantially as described in any of Examples 18 to 23.