GB2034710A - 1H-1,2,4-triazoles - Google Patents

Abstract

Compounds of the formula <IMAGE> (wherein either R is hydrogen or methyl and R1 is hydrogen or C1-4 alkyl or CHROR, is formyl; R2 is hydrogen, chlorine, fluorine, bromine, C1-4 alkyl or C1-4 alkoxy; and either R3 is C1-4 alkyl, C1-4 alkoxy, allyloxy, propargyloxy, trifluoromethyl, phenyl, chlorine, fluorine, bromine or dimethylamino and R4 is hydrogen, chlorine, fluorine, bromine, C1-4 alkyl or C1-4 alkoxy or R3 and R4 together are methylenedioxy; or a pharmaceutically acceptable acid addition salt thereof) have anti- reproductive acitivity.

Description

SPECIFICATION 1 H-1.2.4-Triazoles 5-(cu-Hydroxytolyl)- 1 H-1,2,4-triazoles, including such compounds having a 3-phenyl or 3nitrophenyl substitutent, are described in Belgian Patent Specification No. 786,562. That specification also discloses 1 -alkyl-3,5-disubstituted-1 ,2,4-triazoles having CNS depressant activity.

The novel compounds of this invention have the formula

wherein either R is hydrogen or methyl and R, is hydrogen or C 1-4 alkyl or CHROR, is formyl; R2 is hydrogen, chlorine, fluorine, bromine, C14 alkyl or C14 alkoxy; and either R3 is C14 alkyl, C14 alkoxy, allyloxy, propargyloxy, trifluoromethyl, phenyl, chlorine, fluorine, bromine or dimethylamino and R4 is hydrogen, chlorine, fluorine, bromine, C14 alkyl or C14 alkoxy or R3 and R4 together are methylenedioxy; and includes pharmaceutically acceptable acid addition salts thereof.

"C1~4 alkyl" may represent a straight or branched alkyl radical and means methyl, ethyl, propyl, iscpropyl, butyl, isobutyl, sec-butyl or tert-butyl. "C1~4 alkoxy" represents a straight or branched alkoxy radical and means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy.

It will be clear to anyone skilled in the art that, owing to the great mobility of the hydrogen atom of 1,2,4-triazoles (see Potts, Chem. Rev., 61 (1961) 99 and J.C.S. (1954) 3451), the compounds of this invention may exist in any of three tautomedc forms. These tautomeric forms are in a state of dynamic equilibrium and it is intended that all such forms should fall within the scope of this invention although, for convenience, the compounds will be represented in the form shown in formula I.

The compounds of the invention in which R and R1 are hydrogen may be prepared by rearrangement of hydrazones of formula 11, i.e. of substituted benzaldehydes with 4-hydrazino-1 H-2,3benzoxyazines

In practice, the rearrangement is carried out, following the procedure described in J. Heterocyclic Chemistry 9 (1972) 58, simply by refluxing the hydrazone in a high boiling inert organic solvent such as xylene, a halogenated aromatic hydrocarbon or dimethylformamide, for 30 to 120 minutes, and recovering the product by filtration.

Compounds of formula I in which CHROR1 is formyl may be obtained from those in which R and R1 are each hydrogen by oxidation with an oxidising agent such as manganese dioxide, chromic acid, chromic anhydride and pyridine, lead tetraacetate or a ceric salt.

Compounds of formula I in which R is methyl and R1 is hydrogen may be obtained from those in which R and R1 are each hydrogen by a Grignard reaction, using methyl-magnesium iodide in an inert organic solvent and hydrolysing the organomagnesium compound which is obtained.

Compounds of formula I in which Rand/or R1 is alkyl can be obtained from the corresponding compounds in which R and/or R1 is hydrogen by conventional etherification procedures.

The following Examples 1 to 4 illustrate how the compounds of the invention may be prepared.

Example 1 5-(2-Hydroxymethylphenyl )-3-(3-methoxyphenyl)-1 H-l 2,4-triazole A suspension of 16 g of 4-[2-(3-methoxybenzyliden)hydrazino]-1H-2,3-benzoxazine in 160 cc of anhydrous xylene is refluxed for 45 minutes and then cooled in an ice bath. The solid which precipitates is recovered by filtration and recrystallized from ethanol yielding 14.7 g of the title compound. M.p.

1 57-590C.

Example 2 3-(4-Chlorophenyl)-5-(2-hydroxymethylphenyl)-1 )-1 2,4-triazole The compound of the title is prepared following the procedure described in the foregoing Example starting from 4-[2-(4-chlorobenzyliden)hydrazino]-1 H-2,3-benzoxazine. Yield 57%. M.p. 252-540C (from ethanol).

Example 3 2-[5-(3-Methoxyphenyl)-1 H-l .2,4-triazol-3-yl]benzaldehyde 5 g of 5-(2-hydroxymethylphenyl)-3-(3-methoxyphenyl)-1 H-1,2,4-triazole are added to a suspension of 25 g of manganese dioxide in 500 cc of anhydrous benzene and the mixture is stirred at room temperature for 6 hours. Then four portions of manganese dioxide, 5 g each, are added at intervals of one hour and, when the reaction, which is followed by thin layer chromatography, is completed, the mixture is filtered through Celite. While the filtrate is concentrated to dryness, yielding 0.78 g of the compound of the title, the residue is taken up with water and brought to pH 10 by means of 10% sodium hydroxide. After stirring at room temperature for 20 minutes the mixture is filtered again through Celite and the filtrate is adjusted to pH 6 by addition of 8% hydrochloric acid.A precipitate forms which is recovered by filtration and dried, yielding 3.34 g of the compound of the title. The two crops, 0.78 g plus 3.34 g, are gathered together and recrystallized from isopropyl ether/methylene chloride, yielding 3 g of pure compound. M.p. 1 63-650C.

Example 4 2-[5-(4-chlorophenyi)-1 H-1,2,4-triazol-3-yl)] benzaldehyde Following substantially the same procedure of the foregoing Example and starting from the corresponding 3(4-chlorophenyl)-5-(2-hydroxymethylphenyl)-iH-i ,2,4-triazole, the compound of the title is obtained in 84% yield. M.p. 1 98-2000C.

Typical compounds which can be prepared according to the procedures described in the above Examples are as follows: 3-(3-ethoxyphenyl)-5-(2-hydroxymethylphenyl)- 1 H- 1 2,4-triazole 3-(3-allyloxyphenyl)-5-(2-hydroxymethylphenyl)- I H- 1 ,2,4-triazole 2-[5-(3-ethoxyphenyl)- 1 H-l ,2,4-triazol-3-yl]benzaldehyde 3-(3-ethoxyphenyl)-5-[2-( 1 -hydroxyethyl)phenyl]- 1 H- 1 ,2, 4-triazole 5-(2-hydroxymethylphenyl)-3-(3-propargyloxyphenyl)- 1 H- ,2,4-triazole 5-(2-hydroxymethylphenyl)-3-(4-trifluoromethylphenyl)- 1 H- ,2,4-triazole 5-[2-( 1 -hydroxyethyl)phenyl]-3-(3-methoxyphenyl)- 1 H- ,2,4-triazole 3-(4-fluorophenyl)-5-(2-hydroxymethylphenyl)- 1 H- 1,2,4-triazole 5-(2-hydroxymethylphenyl)-3-(4-biphenylyl)- 1 H- ,2,4-triazole 2-[5-(4-biphenylyl)-1 H-1 ,2,4-triazol-3-yl]benzaldehyde 5-(2-hydroxymethylphenyl)-3-(4-methylphenyl)- 1 H- ,2,4-triazoie 5-(2-hydroxymethylphenyl)-3-(3,4-methylenedioxyphenyl)- 1H-1,2,4-triazole 5-(2-hydroxymethylphenyl)-3-(3,5-dimethoxyphenyl)- 1 H- 2,4-triazole 5-(2-hydroxymethylphenyl)-3-(3 ,4-di methoxyphenyl)- 1 H-1,2,4-triazole 2-[5-(3,5-dimethoxyphenyl)-1H-1,2,4-triazol-3-yl]benzaldehyde 5-(4-chloro-2-hydroxymethylphenyl)-3-(3-methoxyphenyl)- 1 H- ,2,4-triazole 5-(2-hydroxymethyl-4-methylphenyl)-3-(3-methoxyphenyl)- 1 H- ,2,4-triazole 5-(2-hydroxymethyl-6-methylphenyl)-3-(3-methoxyphenyl)- 1 H- 2,4-triazole 5-(2-hydroxymethyl-4-methoxyphenyl)-3-(3-methoxyphenyl)- 1 H-1,2,4-triazole 3-methoxy-6-[5-(3-methoxyphenyl)- 1 H- ,2,4-triazol-3-yl)]-benzaldehyde 5-(2-hydroxymethyl-4-methoxyphenyl)-3-(2-methylphenyl)- 1 H- 2,4-triazole 5-(2-hydroxymethyl-4-chlorophenyl)-3-(o-tolyl)- 1 H- 2,4-triazole 5-[2-(a-hydrnxyethyl)-4-methoxyphenyl]-3-(o-tolyl) 1 H-1 ,2,4-triazole 5-[o-(hydroxymethyl)phenyl]-3-(2,4-xylyl)- 1 H- 2,4-triazole 5-[o-(hydroxymethyl)phenyl]-3-(2,4-dichlorophenyl )- 1 H- 1,2,4-triazole 5-[o-(methoxymethyl)phenyl]-3-(m-methoxyphenyl)- 1 H- 1,2,4-triazole 5-[o-(methoxymethyl)phenyl]-3-(m-ethoxyphenyl)- 1 H- 2,4-triazole.

The compounds of this invention can have anti-reproductive activity. They can show particularly interesting post-coital-post-implantation anti-fertility activity when administered by various pharmacological routes to laboratory animals, e.g. rats, hamsters, dogs, monkeys and baboons.

Moreover, the anti-fertility activity of the new compounds can be substantially free of the other biological effects common with hormonal substances.

A pharmaceutical composition of this invention comprises a compound of the invention in association with a physiologically acceptable excipient.

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 nonhormonal 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 day 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 mg/kg 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), hemorrhage, and evidence of abnormalitites of the uterus, placenta or fetuses. 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 and 3 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., 1 00% 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 Compound of Example ED50mg/Kg s.c. hamsters 1 0.08 3 0.1 Favorable results were also obtained by administering the compounds of the invention orally. 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% of live fetuses was observed at an oral dosage of 20 mg/Kg with compounds of Examples 1 and 3. The ED50 values were also determined and are reported in the following table: Table II Compound ofExample ED50mg/Kg p.o. hamsters 10 3 > 10 < 20 The compounds of the invention display very low toxicity. In fact, their LD50 values, determined according to Lichtfield and Wilcoxon, Journ. Pharm. Expt. Ther., 96, 99, 1949, are often higher than 600 mg/Kg, when administered to mice intraperitoneally.

The facts that the compounds of the invention possess outstanding antireproductive activity even when administered orally 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 adsorbable 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 antireproductive compounds or preparations are known to be active per os.

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, alginic 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 compounds they may contain suspending agents such as, for instance, methylcellulose, hydroxyethylcellulose, tragacanth and sodium alginate, 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 carbonaie, calcium phosphate or kaolin.

Besides the oral route, other useful ways for administering the compounds of the invention may be suitably employed, such as, for instance, subcutaneous or 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 indentical 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 appropiate 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 or sulfate and the organic acid salts such as the succinate, benzoate, acetate, p-toluenesulfonate, benzenesulfonate, maleate, tartrate, methanesuifonate or cyclohexanesulfonate.

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 compounds of the above formula I are administered in a single dosage of from 0.8 to 50 mg/kg intramuscularly or in a multiple dosage (for from 5 to 10 days) of 1.0 to 50 mg/kg orally or intravaginally.

The dosage forms useful for this purpose generally contain from 10 to 600 mg of the active ingredient.

The following Examples 5 to 7 illustrate the compositions of this invention.

Example 5 A vial for injectable use is prepared from: 5-[o-(hydroxymethyl)phenyl]-3-(m-methoxyphenyl)- 1 H- ,2,4-triazole 20 mg Benzyl alcohol 100 mg Castor oil q.s. 2 ml Example 6 A vial for injectable use is prepared from: 2-[5-(m-methoxyphenyl )- 1 H- 1,2,4-triazol-3-yl]benzaldehyde 30 mg Benzyl benzoate 250 mg Sesame oil q.s. 2 ml Example 7 A capsule is prepared from: 5-[o-(hydroxymethyl)phenyl]-3(m-methoxyphenyl)-1 H- ,2,4-triazole 1 50 mg Stearic acid 30 mg Lactose 120 mg

Claims (7)

Claims

1. A compound of the formula

wherein either R is hydrogen or methyl and R1 is hydrogen or C1-4 alkyl or CHROR, is formyl R2 is hydrogen, chlorine, fluorine, bromine, C14 alkyl or C14 alkoxy; and either R3 is C1-4 alkyl, C14 alkoxy, allyloxy, propargyloxy, trifluoromethyl, phenyl, chlorine, fluorine, bromine or dimethylamino and R4 is hydrogen, chlorine, fluorine, bromine, C14 alkyl or C,~4 alkoxy or R3 and R4 together are methylenedioxy; or a pharmaceutically acceptable acid addition salt thereof.

2.5-[2-(Hydroxymethyl)phenyl]-3-(m-methoxyphenyl)- 1 H- ,2,4-triazole.

3. 2-[5-(m-Methoxyphenyl)- 1 H- 1,2,4-triazol-3-yl]-benzaldehyde.

4. A compound as claimed in claim 1 substantially as described in any of Examples 1 to 4.

5. A pharmaceutical composition comprising a compound as claimed in any preceding claim in association with a physiologically acceptable excipient.

6. A composition according to claim 5 in unit dosage form, each unit dosage comprising from 10 to 600 mg of the compound.

7. A composition according to claim 5 substantially as described in any of Examples 5 to 7.