FI64150B - NYA VID FOEDELSEKONTONTLL AV DAEGGDJUR ANVAENDBARA 3,5-DISUBSTITUERADE 1H-1,2,4-TRIAZOLER - Google Patents

Description

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c (45) ”'n ie ::: 3 ^ ^ (51) Kv.ik? /int,ci.^ C O? D 249/08 ENGLISH —FlN LAN D (21) Patent application - Patentansöknlng 7 Ö13 3 9 (22) Application cloud - AntbknlnfSdag 28.0U.76 ^ ^ ^ (23) Home - Giltighetsdag 28.Oi.7 8 (41) to the public - Bllvlt offentlig qj ^ _ γβ

Patent and Registration Board, (44) N on the date of escape and issue. -

Patent- och registerstyreisen 'Ansakin utlagd och uil.skrlften publicerad -SO. 06. 83 (32) (33) (31) Privilege sought — Begird prlorltet 1) 6.09.77

England-England (GB) 19012/77 (71) Group Lcpet.i1. S.p.A. , via Durando, 38, 20198 Milan, Italy-Italy (IT) (72) Amedeo Omodei-Lale, Voghera (Pavia), Pietro Consonni, Milan,

Giulio Galliani, Monza (Mi), Leonard Lerner, Milan, Italy-

Italien (lT) (7 * 0 Munsterhielm Ky Kb (9U) New 3,8 "-disubstituted lI! -L, 2, H-triazoles useful in mammalian birth control -1,2,1-triazoler

The invention relates to novel 3,5-disubstituted strong 1H-1,2,> + triatoles of formula 2

H N --- N

rVn 'LTV "..... f 5x hh ri wherein R is hydrogen, (C1-1 +) alkyl, (C1-1 +) alkoxy, allyloxy, propargyloxy, trifluoromethyl, phenyl, fluoro, chloro or diamethylamino; R-, is ( C 1-4 alkyl group .;

Rp is. hydrogen, fluorine, chlorine, (C 1-1) alkyl, methoxy or ethoxy; R 1 is hydrogen, fluorine, chlorine, (C 1-1) alkyl or) alkoxy; or 2,64150 H and together form a methylenedioxy group; provided that when R, R 9 and R 2 are simultaneously hydrogen, there can be no methyl; and further provided that when R 2 and one of R and R 2 are simultaneously hydrogen, R 1 and one of R and R 2 may not simultaneously be methyl; as well as their salts with pharmaceutically acceptable acids.

The compounds have a birth-regulating property.

The term "(C 1 -C 4) alkyl" as used herein means a straight or branched alkyl radical which is methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, sec-butyl or tert-butyl. The term "(C 1-4) + alkoxy" as used means a straight or branched alkoxy radical which is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy or tert-butoxy.

A preferred group of compounds are those compounds of formula I wherein R is (C 1-4) alkyl, (C 1-6) alkoxy, allyloxy, fluoro, chloro or dimethylamino, R 1 is (C 1-6) alkyl, is hydrogen, methoxy or ethoxy, R 1 may be hydrogen, (C 1-6) alkoxy, fluorine or chlorine, or R and R 1 together form a methylenedioxy group, provided that when R 8 and R 2 are simultaneously hydrogen, R 1 and R 2 - ^ cannot be methyl at the same time; and salts thereof with pharmaceutically acceptable acids.

Another preferred group of compounds are those compounds of formula I wherein R is (C 1-4) alkoxy, allyloxy, fluoro or chloro, R 1 is (C 1-4) alkyl, R 2 is hydrogen, methoxy or ethoxy and R may be hydrogen or) alkoxy; and salts thereof with pharmaceutically acceptable acids.

The most preferred group of compounds are those compounds of formula I wherein R is methoxy, ethoxy, allyloxy, fluoro or chloro, R 1 is (C 1-6) alkyl), R 2 is hydrogen or methoxy and R 1 is hydrogen; and salts thereof with pharmaceutically acceptable acids.

It will be apparent to one skilled in the art that due to the high mobility of the hydrogen atom of the 1,2β-triazoles (see KT Potts, Chem. Rew., 6, 99, 1961 and KT Potts, J. Ghem. Soc. 3 * + 51, 195 ^ ) the compounds of the invention may also exist in the corresponding tautomeric forms in which a hydrogen atom is attached to one of the other two nitrogen atoms of the triazole atom group. Accordingly, said tautomeric forms are to be considered as part of the present invention. It is known that tautomeric forms change rapidly and are therefore in dynamic equilibrium.

3,64150

In all cases, in all lists, the 3,5-disubstituted 1H-1,2,3-triazole derivatives of this invention are numbered as in Formula I.

A process for the preparation of 3 ', 5-disubstituted 1H-1H-triazoles of the invention comprises the compound of formula II nh-nh2

A-C ^ II

or by reacting an acid salt thereof, e.g. the hydrochloride, with a compound of formula III

B-CX III

in the formulas / = \ A is a group L,,) - and B is a group // - h * J / R1 or 3 v = \ / = \ A is a group \ _ and B is a group / \ _

In the above formulas, the radicals R 1, R 2, R 2 and R 2 have the same meaning as above, CX is a functional group which is carboxy, dithiocarboxy, carbonyl halide, carboxyanhydride, orthoester, imidate, thioimidate, imidoyl halide, amidine or cyano; Y is an NH group, and when the CX group contains a nitrogen atom, it is oxygen or sulfur. When the CX group is an imidate, thioimidate, imidoyl halide or amidine, the capped compound of formula III can also be used as the corresponding acid salt.

The process leading to the 1H-triazoles of this invention is a condensation reaction in which, depending on the nature of the reactive groups Y and CX, water, hydrogen sulfide, hydrogen halide, ammonia, alkanols, mercaptans, carboxylic acids and and mixtures thereof. These by-products can be eliminated during the reaction or removed at the end of the condensation by conventional methods.

In practice, the condensation reaction is carried out by heating, while stirring, the formulas II and Γ. The reagent of 11 is a solvent of> * · 64150 without solvent, at a temperature of about 80 to 200 ° C for a period of about 15 to 30 hours. It may be useful to use a slight molar excess of a compound containing a CX group compared to a compound of formula II. The CX function is preferably an imidate group of the formula "C 1-6 alkyl" C 1-4 alkyl

NH

wherein the alkyl may be methyl, ethyl or propyl so that the low boiling alcohol formed during condensation, e.g. methanol, ethanol or propanol, automatically evaporates from the reaction medium. Optionally, a suitable vacuum may be used to accelerate the removal of the alcohol. It has also been found that the presence of an acid catalyst can promote the condensation reaction and therefore a catalytic amount of hydrochloric or hydrobromic acid, or p-toluenesulfonic acid can optionally be added to the reaction mixture. This addition is not necessary when the corresponding acid salts are used as reagents. Finally, if during the heating the reaction mass tends to solidify, it may be useful to add a small amount of an organic solvent such as n-butanol, n-pentanol or the like to the mass. This solvent is evaporated off in vacuo at the end of the reaction.

The final products are then recovered according to known methods. For example, the reaction mixture is dissolved in a suitable organic solvent, preferably diethyl ether, and the organic solution is extracted several times with dilute sodium hydroxide. The alkaline extracts are combined and, if necessary, treated with carbon to remove impurities. Filter To explain, the pH of the filtrate is adjusted to 6-7 by the addition of dilute hydrochloric acid. The product stands out, it can be solid or oily. Depending on its nature, it can be recovered by filtration or extraction as a suitable organic solvent, such as, for example, diethyl ether or methylene chloride. Said solvent is then evaporated off to leave a solid crystalline residue. Further purification by column chromatography may sometimes be necessary. Finally, the desired 3,5-disubstituted 1H-1,2, h-triazole derivatives are recrystallized from suitable organic solvents such as hexane, methylene chloride, chloroform, diisopropyl ether, benzene, cyclohexane or mixtures thereof.

Il 5 64150

As mentioned above, the 3,5-disubstituted 1H-1,2, U-triazoles of the present invention have antireproductive properties, in particular they have a very interesting post-coital-post-implantation-inhibitory activity when administered in various pharmacological forms to laboratory animals, for example, rats, hamsters, dogs, monkeys, and baboons. Furthermore, the infertility activity of these new compounds has not been associated with other biological effects, which is common with hormonal agents.

Fertility can usually be adjusted in many different ways by the administration of hormonal agents. These include ovulation inhibition, ovum transport, fertilization, fertilization of a fertilized ovum, fetal resorption, or abortion. Only ovulation inhibition has evolved into a successful method that is clinically applicable.

The compounds of this invention allow for an entirely new attitude that a non-hormonal compound may be administered parenterally, orally, or intravaginally once or several times, as needed, after an "missed period" or to terminate a more advanced pregnancy. To determine the infertility activity, experiments were performed using Syrian female gold hamsters weighing 100 to 130 g. The animals were allowed to mate and the presence of semen in the vagina was considered an indication that mating had occurred. The day on which the semen was detected was considered to be the first day of pregnancy, as it has been found in the laboratories of the applicant and other researchers that 90-100% of the animals that have mated on the basis of the semen in the vagina are pregnant. Pregnancy was later confirmed at necropsy based on fetuses or implantation sites in the uterus. Even in the event that an animal loses a fetus, implant scars remain, indicating that the animal has been pregnant.

6,64150

The compounds of the invention having high solubility in commonly used pharmaceutical excipients were dissolved in sesame oil and administered subcutaneously in daily doses of 10 mg / kg for five days, starting on the fourth day of pregnancy (days 4-8). Animals were necropsied at gestation. day and the uteri were examined for pregnancy (implantation sites, fetal resorptions or live fetuses), bleeding and malformations in the uterus, placenta or fetuses. A compound was considered active if the number of live fetuses had decreased by at least 60%. treated animals and the presence of implantation sites indicated that the animal had been pregnant. In typical experiments, the compounds of Examples 1, * 4-7 and 9-16 were found to be effective according to the above criteria.

The dose-activity relationships of the compounds and the corresponding ED 2 values were then examined, i. $ 100 activity (absence of live fetuses) was determined in 50 # of animals. The following table shows the ED 2 Q values of some typical compounds of the invention:

TABLE

The compound of the example ED 2 Q mg / kg s.c. hamsters 1 0.08 1+ 0.5 9 0.07 10 0.25] 2 0.0 ^ 13 0.1

The same criteria and experimental conditions set forth above were applied when the anti-reproductive activity of the compounds of the invention was studied in other animal species, such as, for example, rats, dogs, monkeys and baboons. In typical experiments, female Sprague-Dawley rats weighing 200-300 g were treated subcutaneously with 20 mg / kg of test compound dissolved in sesame oil for five consecutive days, starting on the sixth day of pregnancy. Rats were sacrificed and necropsy was performed on day 16 and uteri were examined as described above for hamsters. Also in this experiment, the compounds of Examples 1, k-7 and 9-16 caused a reduction in the number of live fetuses of at least $ 60 from treated animals. The EDf values of the compounds of Examples 1 and Ί 2 were determined; 7 *. «Ι.« 6 415 0 and are shown in the following table:

TABLE II

Example compound ED ^ g s.c. rats 1 1 12 0.7

Good results were also obtained by administering the compounds of the invention orally. Experiments to investigate this property were performed in hamsters using the same method as described above, with the sole exception that the compounds were administered orally and not subcutaneously.

At an oral dose of 10 mg / kg of the compounds of Examples 1, 4-7 and 9-16, a reduction in the number of live fetuses was found by about 60%. The ED, .n values of the compounds of Examples 1 and 12 were determined and are shown in the following table:

D U

TABLE III

Example compound ^ D50 p.o. hamsters 1 5 12 5

Finally, the compounds of the invention have very low toxicity. In fact, their LD ^ g values, determined according to Lichtfield and Wilcoxon, Journ. Pharm. Expt. Ther., 9 £, 99, 1949, are never lower than 600 mg / kg when the compounds were administered to mice intraperitoneally.

VERTAILUKOESELITYS

The birth control activity of the compounds of this invention compared to known compounds is clearly apparent from the following experimental description. The following compounds were tested: Compound A: 3- (3-methoxyphenyl) -5- (2-methylphenyl) -1H-1,4,4-triazole ”B: 3- (2-methoxyphenyl) -S- (2-methylphenyl ) -1H-1,2,4-triazole "C: 3- (3-ethoxyphenyl) -5- (2-methylphenyl) -1H-1,2,4-triazole D: 3- (3-allyloxyphenyl) -5- (2-methylphenyl) -1H-1,2,4-triazole "E: 5- (2-ethylphenyl) -3- (3-methoxyphenyl) -1H-1,2,4-triazole 8 64150

Compound F: 3- (3-allyloxyphenyl) -5- (2-ethylphenyl) -1H--1,2,4-triazole "G: 3- (3-ethoxyphenyl) -5- (2-ethylphenyl) -1H- 1,2,4-Triazole "H: 5- (2-ethylphenyl) -3- (4-methoxyphenyl) -1H-1,2,4-triazole" 1H: 5- (2-ethylphenyl) -3- (3-fluorophenyl) -1H-1,2,4-triazole "5-: 2-ethylphenyl) -3- (3,4-methylenedioxyphenyl) -1H-1,2,4-triazole" 5- (2-ethylphenyl) -3- (3,4-dimethoxyphenyl) -1H--1,2,4-triazole "L: 5- (2,4-dimethylphenyl) -3-phenyl-1H-1,2 , 4-triazole "M: 5- (2,4-dimethylphenyl) -3- (3-methoxyphenyl) -1H--1,2,4-triazole" N: 5- (4-chloro-2-methylphenyl) -3-phenyl-1H-1,2,4-triazole "0: 5- (4-chloro-2-methylphenyl) -3- (3-methoxyphenyl) -1H-1,2,4-triazole" P : 5- (5-chloro-2-methylphenyl) -3- (3-methoxyphenyl) -1H-1,2,4-triazole "Q: 5- (4-methoxy-2-methylphenyl) -3- (3 -methoxyphenyl) -1H-1,2,4-triazole MR: 3- (3-methoxyphenyl) -1-methyl-5- (2-methylphenyl) -1H-1,2,4-triazole "S: 3 , 5-diphenyl-1H-1,2,4-triazole ”T: 1-methyl-5- (2-methyl phenyl) -3- (3-methylphenyl) -1H-1,2,4-triazole-N- (3,4,5-trimethoxyphenyl) -1-methyl-5- (2-methylphenyl) - 1H-1,2,4-triazole "N: 5- (3-chlorophenyl) -1-methyl-3- (2-methylphenyl) -1H-1,2,4-triazole" N: 5- (3 -chlorophenyl) -3- (2-methylphenyl) -1H-1,2,4-triazole

The birth-regulating activity of compounds A to S was studied in hamsters. Compounds A to Q are in accordance with this invention, Compound R, which is a 1-methyl analog of Compound A, is disclosed in U.S. Patent 4,119,635 and Compound S is disclosed by Raines in J. Pharm. Sci., £ 0, 597, 1961.

Il 9 64150

Syrian female gold hamsters weighing 100-180 g were used in the experiments. The experiment was performed as described above. The compounds were dissolved in sesame oil containing 20% benzyl benzoate and administered subcutaneously in doses ranging from 0.0125 mg to 10 mg / kg.

The results obtained are shown in Table IV.

ED 1 values, i.e., the dose that terminates pregnancy in 50% of treated animals, were determined graphically.

TABLE IV

Compound Dose Animal lu- Animal ras- ED. » mg / kg / day amount of seasonal interruption m /) </ day s.c. tymis-% “p J s.c.

A 0.25 9 100 0.125 17 88.2 0.08 0.062 15 33.3 0.031 5 0 B 1.0 6 100 0.50 10 50 0.5 0.25 6 0 0.10 6 0 C 0.20 5 100 0.10 11 81.8 0.06 0.05 13 38.7 0.025 4 0 D 0.40 6 100 0.20 5 80 0.15 0.10 13 30.8 0, 05 3 0 E 0 .10 20 100 0.05 38 68.4 0.04 0.025 28 28.6 0.0125 10 0 F 0.20 15 100 0, 10 16 37.5 0, 12 0.05 4 0 G 0.10 5 100 0.05 14 71.4 0.04 0.025 22 13.6 H 0.25 5 100 0.20 9 77.8 0.15 0.15 6 50 0.10 22 9.1 I 0.80 5 100 0.40 6 50 0.40 0.20 11 0 0.10 12 0 ίο 64150 Table IV cont.

Compound Dose Animal lu- Animal ras- Εϋςη

Mg / kg / day amount of seasonal average mg / kg / day s · c · t%% · · · J 0.10 10 100 0.05 17 94.1 0.03 0.025 20 20 K 0.20 5 100 0.10 11 81.8 0.05 0.05 12 50 L 1.0 6 100 0.2 6 50 0.2 0.1 6 16.7 M 0.1 11 100 0.05 9 77.8 0 .04 0.025 10 10 N 0.40 6 100 0.20 9 77.8 0.14 0.10 12 25 0 0.10 5 100 0.05 9 77.8 0.04 0.025 18 5.6 P 0, 50 11 72.7 0.25 11 27.3 0.35 0.10 4 0 Q 0.40 6 100 0.20 6 50 0.20 0.10 4 0 R 10.0 4 0 »10

2.0 5 0 ^ ± U

S 10.0 8 87.5 5.0 17 41.2 6.0 2.0 7 0

The birth-regulating activity of compounds T, U, V and W was studied in rats. Compounds T, U, and V are disclosed in U.S. Patent 4,119,635, while W, a 1-demethyl analog of Compound V, is in accordance with this invention.

Female Spraque-Dawley rats were used in these experiments and the experiment was already performed as described above. The compounds were dissolved in sesame oil containing 20% benzyl benzoate and administered subcutaneously at doses of 25 mg / kg / day.

The results obtained are shown in Table V.

Il n 64150

TABLE V

Compound Number of animals% of completed females% of fetuses of live fetuses T 6 0 9U, 0 U 5 0 91.7 VH 0 96.5 W 6 100 0

Compound W, which was 100% effective in this experiment, was then tested as described above at doses of 1 mg and 5 mg / kg / day.

The results obtained are shown in Table VI.

TABLE VI

Dose mg / kg / day Animal lu- Finished Live si- ΕΠ s.c.

number of pregnancies $ P, ... ..

%% mg / kg / day δ 6 66.7 δ, H> 1 <5 1 H 25 25.2

The fact that the compounds of the invention have considerable anti-reproductive activity even when administered orally and that they are highly soluble in ordinary pharmaceutical carriers are undoubtedly still important properties.

For example, due to their high solubility, the compounds are readily absorbed and can be combined with suitable and good injectable dosage forms which have fewer negative aspects than similar formulations in which the active ingredient is suspended in a carrier. On the other hand, the fact that the compound is also active when administered orally allows the compounds to be formulated into more acceptable pharmaceutical preparations. It should also be noted that, with the exception of oral contraceptives, which, however, are steroidal in nature and exhibit activity in inhibiting ovulation, no other antireproductive compounds or preparations are known which are active per os.

Consequently, the compounds of the invention may be administered in various ways: orally, subcutaneously, intramuscularly or intravaginally. For oral administration, the substances are formed into tablets, dispersing powders, capsules, granules, syrups, elixirs and solutions. Compositions for oral use may contain one or more conventional excipients, such as sweetening, flavoring, coloring, coating and preservative agents, to provide an elegant and tasty preparation. Tablets may contain the active ingredient in admixture with conventional pharmaceutically acceptable excipients, for example, inert diluents, cutin sodium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents such as starch, alginic acid and sodium carboxymethylcellulose, for example starch, alginic acid and sodium carboxymethylcellulose. and lubricants, for example magnesium stearate, s thyric acid and talc.

Syrups, elixirs and solutions are prepared according to the prior art. They may contain, together with the active ingredient, suspending agents such as methyl cellulose, hydroxyethylcellulose, tragacanth and sodium malginate, wetting agents such as lecithin, polyoxyethylene stearates and polyoxyethylene sorbitan monooleate and conventional preservatives, preservatives.

The capsule or tablet may contain the active ingredient as such or in admixture with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin.

Apart from orally, the compounds of the invention may conveniently be administered by other routes, such as intravenously or intramuscularly. The active ingredient is then formulated into an injectable dosage form. Such compositions are prepared using known techniques and may contain suitable dispersing or wetting agents and suspending or buffering agents, which are identical or similar to those mentioned above.

As the carrier, sesame oil, benzyl alcohol, benzyl benzoate, peanut oil and mixtures thereof can be suitably used.

li 13 641 50

The compound for vaginal administration may also contain the active ingredient in admixture with a conventional carrier, for example, gelatin, adipic acid, sodium bicarbonate, lactose or the like.

The compounds of the invention may also be administered in the form of their non-toxic, pharmaceutically acceptable acid addition salts. Such salts have the same degree of activity as the free bases, from which they are readily prepared by reacting the base with a suitable acid, and are therefore within the scope of the invention. Typical such salts include mineral acid salts such as, for example, hydrochloride, hydrobromide, sulfate and the like, and organic acid salts such as succinate, benzoate, acetate, p-toluenesulfonate, benzenesulfonate, maleate, tartrate, methanesulfonate, cyclohexylate, cyclohexylhexylhexyl.

The dose of active ingredient used to prevent proliferation can vary within wide limits depending on the nature of the compound. In general, good results are obtained by administering the compounds of formula I mentioned above in daily doses of about 0.8 to 50 mg / kg per kg of body weight of the animal.

Dosage forms suitable for this purpose generally contain from about 10 to 600 mg of active ingredient in admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.

The following examples illustrate the process of the invention and illustrate in detail certain compounds of general formula I, without limiting the invention.

Example 1 3- (m-methoxyphenyl) -5- (o-tolyl) -1H-1,2,2-triazole

A mixture of 3.0 g (0.02 moles) of o-toluic acid hydrazide and k-, 83 g (0.027 moles) of m-methoxybenzimidic acid ethyl ester was heated in an oil bath while stirring for about 20 hours, maintaining the bath temperature at about 125 ° C. agarose. After cooling, the reaction mass was dissolved in 100 ml of diethyl ether and the resulting 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, treated with charcoal to remove impurities and filtered to explain. The pH of the filtrate was adjusted to 7 by adding, with stirring, aqueous hydrochloric acid from LO # to separate an oily substance which was extracted with diethyl ether. Dry over sodium sulfate, evaporate the ether in vacuo and recrystallize the residue from diisopropyl ether / hexane. Yield 3.15 g. Mp 100-102 ° C.

Examples 2-5 Using the procedures outlined in Example 1, the following compounds were prepared:

Example 2 3- (p-Dimethylaminophenyl) -5- (o-tolyl) -1H-1,2,4-triazole was prepared from 2.55 g (0.017 mol) of o-toluic acid hydrazide and 4.26 g ( 0.021 mol) of p-dimethylaminobenzimidic acid ethyl ester. Yield 3.04 g. Melting point, 173-175 ° C (from diisopropyl ether).

Example 3 3- (o-Chlorophenyl) -5- (o-tolyl) -1H-1,2,4-triazole was prepared from 3.75 g (0.025 moles) of o-toluic acid hydrazide and 5.5 g (0 .03 moles) of ethyl ester of o-chlorobenzimidic acid. Yield 4.26 g. Mp 109-111 ° C (from hexane / methylene chloride).

Example 4 3- (o-Methoxyphenyl) -5- (o-tolyl) -1H-1,2,4-triazole was prepared from 6.75 g (0.045 moles) of o-toluic acid hydrazide and 9.85 g ( 0.05 moles) of o-methoxybenzimidic acid ethyl ester. Yield 4.81 g. Mp 160-161 ° C (from hexane / diisopropyl ether).

Example 5 3- (m-Chlorophenyl) -5- (o-tolyl) -1H-1,2,4-triazole was prepared from 2.55 g (0.017 mol) of o-toluic acid hydrazide and 4.1 g ( 0.0221 moles) of m-chlorobenzimidic acid ethyl ester. Yield 2.34 g. Mp 147-148 ° C (from cyclohexane / benzene),

Example 6 3- (m-Trifluoromethylphenyl) -5- (o-tolyl) -1H-1,2,4-triazole A mixture of 2.55 g (0.017 mol) of o-toluic acid hydrazide and 4.8 g (0 .2221 moles) of m-trifluoromethylbenzimidic acid ethyl ester was heated in an oil bath for 6 hours, while stirring, the bath temperature was maintained at about 125 ° C. A solid mass formed, 15 ml of n-butanol was added and the mixture thus obtained was heated for about 19 hours, the temperature of the oil bath being maintained at about 125 ° C. During this time, the solid mass completely dissolved in butanol, which at the end of the reaction was evaporated off in vacuo by raising the temperature of the oil bath.

II

15,641 50 to about 150 ° C. After cooling, the reaction mass was dissolved in diethyl ether, the ether solution was extracted with 120 ml of 5% aqueous sodium hydroxide and then twice with 50 ml of water, water and alkaline extracts were combined. The solution was treated with charcoal to remove impurities and then immediately filtered to explain, the pH of the filtrate was adjusted to 7 by the addition, while stirring, of aqueous hydrochloric acid from $ 10. A precipitate formed which was collected and recrystallized from cyclohexane / benzene. Yield 2.55 g. Mp 158-159 ° C.

Examples 7-17 These compounds were prepared essentially as shown in Example 6.

Example 7 3- (p-Fluorophenyl) -5- (o-tolyl) -1H-1,2,9-triazole was prepared from 2.03 g (0.0135 moles) of o-toluic acid hydrazide and 2.95 g: (0.0175 moles) of p-fluorobenzimidic acid ethyl ester. Yield 1.18 g. Mp 119-121 ° C (from hexane / diisopropyl ether).

Example 8 3- (p-Chlorophenyl) -5- (o-tolyl) -1H-1,2,9-triazole was prepared from 2.03 g (0.0135 moles) of o-toluic acid hydrazide and 3.25 g of: (0.0175 moles) of p-chlorobenzimidic acid ethyl ester. Yield 1.13 g-m.p. 150-151 ° C. (Diisopropyl ether). The compound contains half a molecule of water of crystallization.

Example 9 3- (m-Ethoxyphenyl) -5- (o-tolyl) -1H-1,2,9-triazole was prepared from 1.5 g (0.01 mol) of o-toluic acid hydrazide and 2.12 g of: (0.011 mol) of m-ethoxybenzimidic acid ethyl ester. Yield 1.9-1 g. Mp 89-86 ° C (from diisopropyl ether).

Example 10 3- (m-Allyloxyphenyl) -5- (o-tolyl) -1H-1,2k-triazole was prepared from 1.5 g (0.01 mol) of o-toluic acid hydrazide and 2.26 g of: (0.011 mol) of m-allyloxy-benzimidic acid ethyl ester. Yield 1.89 g. Mp 72-75 ° C (from diisopropyl ether).

Example 11 3-O, 1,1'-Biphenyl-9-yl) -5- (o-tolyl) -1H-1,9-triazole was prepared from 1 n of 0.99 g (0 , 0066 mol.ia) o-toluic acid hydrazide and 1.68 g (0.0075 mol) of p-phenyl 1 -bon tr. 1 mi d i acid ethyl 1 I <> s Tor 1M. Yield 1.9-7 g. Mp 165-167 ° C (from cyclohexane / benzene).

16,641 50

Example 12 5- (o-Ethylphenyl) -3- (m-methoxyphenyl) -111-1,2,3-triazole was prepared from 87 g (0.03 moles) of o-ethylbenzoic acid hydrazide and , 35 g (0.03 moles) of m-methoxybenzimidic acid ethyl ester. Yield 5.36 g. Mp 72-75 ° C (from diisopropyl ether / hexane). The hydrochloride melts at 175-177 ° C (from ethanol / ethyl ether).

Example 13 3- (m-Allyloxyphenyl) -5- (o-ethylphenyl) -1H-1,2,4-triazole was prepared from 1.6 * + g (0.01 mol) of o-ethylbenzoic acid hydrazide and 2, 26 g (0.011 mol) of m-allyloxy-benzimidic acid ethyl ester. Yield 2.73 g * M.p. (as hydrochloride) 130-132 ° C (from ethanol).

Example 11 * 3- (p-Chlorophenyl) -5- (o-ethylphenyl) -1H-1,2,3 * -triazole was prepared from 1.6 * + g (0.01 mol) of o-ethylbenzoic acid hydrazide and 2.01 g (0.011 mol) of p-chlorobenzimidic acid ethyl ester. Yield 1.32 g. Mp 18-120 ° C (from diisopropyl ether / hexane). Example 15 5- (o-Isopropylphenyl) -3-phenyl-1,1-1,2,2-triazole was prepared from 1.25 g (0.007 moles) of 2-isopropylbenzoic acid hydrazide and 1.15 g (0.0077 moles) of moles) of ethyl ester of benzimidic acid. Yield 1.38 g. Mp 165-167 ° C (from diisopropyl ether / petroleum ether). Example 16 5- (o-Isopropylphenyl) -3- (m-methoxyphenyl) -1H-1,2, + + triazole was prepared from 1.78 g (0.01 mol) of 2-isopropylbenzoic acid. hydrazide and 1.97 g (0.011 mol) of ethyl m-methoxybenzimidate. Yield 2.27 g. Mp 125-126 ° C (from diisopropyl ether / petroleum batches).

Example 17 5- (o-Ethylphenyl-1S-phenyl-1H-1H-triazole was prepared from 1.6 * + g (0.01 mol) of o-ethylbenzoic acid hydrazide and 1.9 g (0.01 mol) of moles) of benzimidic acid ethyl ester Yield 1.77 g.

Mp 12 DEG-126 DEG C. (from diisopropyl ether / hexane).

The ethyl ester derivatives of benzimidic acid used as starting materials were prepared according to methods mentioned in the literature (Pinner, "Die Imidoäther und Ihre Derivative"; R. Oppenheim, Berlin, 1892; L. Weintraub et al. J. Org. Chem., Vol. 33, No. h, page 1679, 1968).

The starting hydrazides of o-toluic acid, o-ethylbenzoic acid and 11,615,0 o-isopropylbenzoic acid were prepared according to the method of Stolle and Stevens. J. Pr. / 27 »69, 368 (see also Beilstein, Vol. 9, p. 467, J. Springer Verlag, Berlin, 1926).

Typical compounds that can be prepared according to the methods described in the above examples are as follows: ... Sul.p. EDcfl mg / kg s.c.

-1H-1,2,4-tetrazole r 50 C hamsters S- (o-ethylphenyl) -3- (m-fluorophenyl) -112-114 0.4 5- (o-ethylphenyl) -3- (2,3 -dimethylphenyl) -154-155 5- (o-ethylphenyl) -3- (2,3-dimethoxyphenyl) -139-141 5- (o-ethylphenyl) -3- (3,5-dimethoxyphenyl) -133-135 - (o-ethylphenyl) -3- (3,4-methylenedioxyphenyl) -108-110 0.03 3-phenyl-5- (o-propylphenyl) -3- (m-methoxyphenyl) -5- (o- propylphenyl) -5- (o-butylphenyl) -3-phenyl-121-122 5- (o-butylphenyl) -3- (m-methoxyphenyl) -101-102 5 -C (2,4-dimethylphenyl) -3-phenyl - 139-141 0.2 5- (2,4-dimethylphenyl) -3- (m-methoxyphenyl) - 106-108 0.04 5- (2,5-dimethylphenyl) -3-phenyl-147-149 5- (2,5-dimethylphenyl) -3- (m-methoxyphenyl) -127-130 5- (2,6-dimethylphenyl) -3-phenyl-5- (2,6-dimethylphenyl) -3- (m-methoxyphenyl) - 5- (4-chloro-2-methylphenyl) -3-phenyl-135-136 0.14 5- (4-chloro-2-methylphenyl) -3- (m-methoxyphenyl) -137-139 °, 04 5- (5-chloro-2-methylphenyl) -3-phenyl-170-172 5- (5-chloro-2-methylphenyl) -3- (m-methoxyphenyl) ) - 169-171 0.35 5- (4-methoxy-2-methylphenyl) -3-phenyl-152-153 5- (4-methoxy-2-methylphenyl) -3- (m-methoxyphenyl) -121 -122 0.2 3- (m-ethoxyphenyl) -5- (o-ethylphenyl) -84-86 0.04 5- (o-ethylphenyl) -3- (3,4-dimethoxyphenyl) -57-60 °, 05 5- (o-ethylphenyl) -3- (p-methoxyphenyl) -128-129 0.15 18 641 50

Example 18

A vial for injection was prepared using 3- (m-methoxyphenyl) -5- (o-tolyl) -1H-1,2,4-triazole 30 mg benzyl benzoate 250 mg sesame oil q.s. To 2 ml.

Example 19

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

Example 20

A vial for injection was prepared using 5- (o-ethylphenyl) -3- (m-methoxyphenyl) -1H-1,2,2-triazole 20 mg benzyl alcohol 80 mg castor oil q.s. To 2 ml.

Example 21

The sugar-coated tablet was prepared using 3- (m-methoxyphenyl) -5- (o-tolyl) -1H-1,2,4-triazole 100 mg sodium carboxymethylcellulose 5 mg magnesium stearate 5 mg gelatin 10 mg starch 10 mg sucrose 25 mg gum arabic, lactose , titanium dioxide and aluminum milk according to conventional methods.

Example 22

The capsule was prepared using 5- (o-ethylphenyl) -3- (m-methoxyphenyl) -1H-1,2,4-triazole 60 mg talc 5 mg lactose 5 mg sodium carboxymethylcellulose 5 mg starch q.s. To 150 mg.

Example 23

A tablet was prepared using 3- (m-methoxyphenyl) -5- (o-tolyl) -1H-1,2,4-triazole 100 mg levilite 100 mg starch 80 mg magnesium stearate 10 mg.

of

Claims (6)

A 3,5-disubstituted 1H-1,2,3-triazoles of the formula 1 2 HN -N R 1 wherein R is hydrogen, (C 1-4 alkyl, (C 1-4 J) -alkoxy, allyloxy, propargyloxy, trifluoromethyl, phenyl, fluoro, chloro or dimethylamino; ethoxy; R 3 is hydrogen, fluorine, chlorine, (C 1 -C 4 alkyl) or (C 1 -C 4 alkoxy; or R and R 3 together form a methylenedioxy group; provided that when R, R 1 and R 2 are simultaneously hydrogen R R 1 cannot be methyl, and further that when R 1 and one of R 1 and R 2 are simultaneously hydrogen R 1 and the other of R 1 and cannot simultaneously be methyl, as well as their salts with pharmaceutically acceptable acids. A compound according to claim 1, wherein R is (C 1-4) alkyl, (C 1-4) alkoxy, allyloxy, fluoro, chloro or dimethylamino, R 1 is (C 1-4) alkyl, R 2 is hydrogen, methoxy or ethoxy, R 3 may be hydrogen, (C 1-1) alkoxy, fluorine or chlorine, R and R 8 together are a methylenedioxy group, provided that when R 2 and R 2 are simultaneously hydrogen, R and R 1 cannot simultaneously be methyl, and its salts with pharmaceutically acceptable acids. A compound according to claim 1, wherein R 1 is (C 1-6) alkoxy, allyloxy, fluorine or chlorine, R 1 is (C 1-4) alkyl, R 2 is hydrogen, methoxy or ethoxy and R 1 may be hydrogen or (C 1-4 alkoxy, and its salts with pharmaceutically acceptable acids. A compound according to claim 1, wherein R is methoxy, ethoxy, allyloxy, fluorine or chlorine, R 1 is a (C 1-4) alkyl group L). , R 2 is hydrogen or methoxy and R 1 is hydrogen, and salts thereof with pharmaceutically acceptable acids. A compound according to claim 1 which is 3- (m-methoxyphenyl) -5- (o-tolyl) -1H-1,2,4-triazole. A compound according to claim 1 which is 3- (m-ethoxyphenyl) -5- (o-tolyl) -1H-1,2,4-triazole. A compound according to claim 1 which is 5- (o-ethylphenyl) -3- (m-methoxyphenyl) -1H-1,2,3 * 4-triazole. claim;