NO823654L - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVITIES NEW 3,5-DISUBSTITUED 1H-1,2,4-TRIAZOLE DERIVATIVES - Google Patents

Description

The present invention relates to the production of new 3,5-disubstituted-1H-1,2,4-triazoles with the formula:

wherein R is selected from hydrogen, (C 1-4 )alkyl, (C 1-4 )alkoxy, allyloxy, triflubromethyl, phenyl, fluorine, chlorine and dimethylamino; is a (C 1-4 )alkyl group; with the proviso that when R is hydrogen, R^ cannot be methyl; provided further that when R is hydrogen, R 1 and R 2 cannot simultaneously be methyl;

as well as pharmaceutically acceptable salts thereof.

The compounds of formula I have CNS activity.

The term "(C 4 )alkyl" used means straight or branched alkyl radicals selected from methyl, ethyl, propyl, isopropyl, butyl, isopropyl, sec-butyl and tert-butyl. The term "(C 1-4 ) alkoxy" means straight or branched alkoxy radicals selected from methoxy, ethoxy, propoxy, iso-propoxy, butoxy, isobutyloxy and tert-butoxy.

A preferred group of compounds comprises those compounds of formula I, where R is selected from (C 1-4 )alkyl, (C 1-4 ) alkoxy, allyloxy, fluorine, chlorine and dimethylamino, R 1 is

(C 1-4 )alkyl.

Another preferred group of compounds comprises compounds of formula I, where R is selected from (C₄₄) alkoxy, allyloxy, fluorine and chlorine, R is (C₄₄)alkyl, as well as salts thereof with pharmaceutically acceptable acids.

The most preferred group of compounds comprises compounds of formula I, where R is selected from methoxy, ethoxy, allyloxy, fluorine and chlorine, R 1 is a (C 1 4 )alkyl group, as well as salts thereof with pharmaceutically acceptable acids.

Because of the great mobility of the hydrogen atom in 1,2,4-triazoles (cf. K.T. Potts, Chem, Rew., 61, 99, 1961 and K.T. Potts, J.Chem. Soc. 3451, 1954), the compounds with formula I also exist in the corresponding tautomeric forms, where the hydrogen atom is located on one of the other two nitrogen atoms in the triazole nucleus. The tautomeric compounds are therefore covered by the invention.

It is known that tautomeric forms rapidly change into each other and are therefore in a state of dynamic equilibrium. In all cases, the 3,5-disubstituted-1H-1,2,4-triazole derivatives, which are prepared according to the invention, will be numbered as shown in formula I.

The process for the preparation of the 3,5-disubstituted-1H-1,2,4-triazole compounds comprises reacting a compound with the formula:

or an acid salt thereof, e.g. the hydrochloride, with a compound of the formula: where A is the group ^ and B is or A is the group and B is the group

In the formulas given above, the radicals R and R-^ have the same meanings as above, CX' is a functional group selected from carboxy, dithiocarboxy, carbonyl halide, carboxylic anhydride, orthoester, imidate, thioimidate, imidoyl halide, amidino and cyano; Y is NH and when the group CX contains a nitrogen atom, Y is oxygen or sulfur. When the group CX represents imidate, thioimidate, imidoyl halide or amidino, the compound of formula III can also be used as the corresponding acid salt.

The process leading to the 1,2,4-triazoles is a condensation reaction whereby, depending on the type of reacting groups Y and CX, water, hydrogen sulphide, hydrogen halide, ammonia, alkanols, mercaptans, carboxylic acids or mixtures are formed hence as by-products. These by-products can be eliminated during the course of the reaction or removed at the end of the condensation using conventional methods.

In practice, the condensation reaction is carried out by heating with stirring the compounds of formula II and III, usually in the absence of a solvent, at a temperature in the range of 80-200°C for a period of time in the range of 15-30 hours. A small molar excess in relation to the compound of formula II of the compound containing the CX function can be advantageously used. The CX function is preferably an imidate group of the formula:

where the alkyl group may be methyl, ethyl or propyl, so that the low-boiling alcohol which is formed; during the condensation, e.g. methanol, ethanol or propanol, automatically evaporates from the reaction medium. To speed up the removal of the alcohol, a moderate vacuum can be used. It has also been observed that the presence of an acidic catalyst can promote the condensation reaction and therefore a catalytic amount of hydrochloric acid or hydrobromic acid, or p-toluenesulfonic acid can suitably be added to the reaction mixture. This addition is not necessary when the reactants are used as the corresponding acid salts. If the reaction mass tends to solidify during heating, a small amount of an organic solvent, such as

e.g. n-butanol, n-pentanol and analogues. This solvent is evaporated in vacuum at the end of the reaction.

The end products are obtained using known methods. As an example, the reaction mixture can be taken up in a suitable organic solvent, preferably diethyl ether, and the organic solution extracted several times with dilute sodium hydroxide. The alkaline extracts are combined and, if necessary, treated with charcoal to remove impurities. After filtration on celite, the filtrate is brought to a pH value of around 6-7 by adding hydrochloric acid. This results in the separation of a product which may be solid or oily. It can, depending on its nature, be recovered by filtration or extracted with a suitable organic solvent, e.g. diethyl ether or methylene chloride. This solvent is then evaporated leaving a solid crystalline residue.

Further purification by column chromatography may sometimes be necessary. The desired 3,5-disubstituted-1H-1,2,4-triazole derivatives are finally recrystallized from suitable organic solvents, such as e.g. hexane, methylene chloride, chloroform, diisopropyl ether, benzene, cyclohexane or mixtures thereof.

The prepared 3,5-disubstituted-1H-1,2,4-triazoles have CNS depressant activity.

The CNS depressant activity was investigated using Irwin's method (cf. Psychopharmacology (Berl.) 13, 222-257

(1968)). More specifically, the ability of the compounds to weaken laboratory animals' motor coordination ability, directional reflex, spontaneous activity and muscle tension, i.e. parameters that are directly related to sedative, hypnotic and muscle relaxant effects, was investigated. Representative trials have shown that amounts of from approx. 10 to approx. 300 mg/kg i.p. are effective with respect to a significant weakening of the above-mentioned parameters when tested on mice.

The compounds of formula I can thus be administered in different ways: orally, subcutaneously, intramuscularly or intravaginally.

For oral administration, the substances are placed in forms such as

tablets, dispersible powders, capsules, granules, syrups, elixirs and solutions.

The preparations for oral use may contain one or more conventional additives, such as e.g. sweeteners, flavourings, colourants, coating agents and preservatives, to provide an appealing and edible preparation.

Tablets may contain the active ingredient mixed with conventional pharmaceutically acceptable excipients, e.g. inert diluents, such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, such as e.g. starch, alginic acid and sodium carboxymethyl cellulose; binders, e.g. starch, gelatin, gum arabic and polyvinylpyrrolidone; and lubricants, e.g. magnesium stearate, stearic acid and talc.

Syrups, elixirs and solutions are formulated in a known manner. Together with the anti-compounds, they can contain suspending agents, such as e.g. methyl cellulose, hydroxyethyl cellulose, tragacanth and sodium alginate; wetting agents, e.g. lecithin, polyoxyethylene stearates and polyoxyethylene sorbitan monooleate; and common preservatives, sweeteners and buffers.

A capsule or a tablet can contain the active ingredient eels or mixed with an inert, solid diluent, such as e.g. calcium carbonate, calcium phosphate and kaolin.

In addition to oral administration, other useful routes of administration for the compounds of formula I can be used, such as e.g. subcutaneous and intramuscular administration.

The active ingredient is thus introduced in injectable dosage forms. Such preparations are formulated in a known manner and may contain suitable dispersing or wetting agents and suspending and buffering substances similar to those mentioned above. Sesame oil, benzyl alcohol, benzyl benzoate, peanut oil and mixtures thereof can also be suitably used as carriers.

A vaginal preparation can also contain the active ingredient mixed with common carriers, e.g. gelatin, adipic acid, sodium bicarbonate, lactose and similar substances.

The compounds of formula I 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 can easily be prepared by reacting the base with a suitable acid. Representative examples of such salts are the mineral acid salts, such as e.g. the hydrochloride, the hydrobromide, the sulfate, and the like, and organic acid salts, such as the succinate, the benzoate, the acetate, the p-toluene sulfonate, the benzene sulfonate, the maleate, the tartrate, the methane sulfonate, the cyclohexyl sulfonate, and the like.

The dose of active ingredient used to inhibit reproduction can vary within wide limits depending on the compound used. In general, good results are obtained when the compounds of formula I are administered in daily doses of from approx. 0.8 to approx. 50 mg/kg body weight.

The dosage forms that are useful for this purpose usually contain from approx. 10 to approx. 600 mg of active ingredient in admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.

The following examples illustrate the invention.

Example 1: 3-(m-Methoxyphenyl)-5-(o-tolyl)-1H-1,2,4-triazole A mixture of 3.0 g (0.02 mol) of the hydrazide of o-toluene acid and 4, 83 g (0.027 mol) m-methoxybenzimidic acid ethyl ester was heated in an oil bath with stirring for about 20 hours, while the bath temperature was maintained at approx. 125°C. After cooling, the reaction mass was taken up 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 aqueous and alkaline extracts were combined, treated with charcoal to remove any impurities and filtered on celite. The filtrate was brought to pH 7 by adding, with stirring, 10% aqueous hydrochloric acid, whereby an oily substance was separated which was extracted with diethyl ether. After drying over sodium sulfate, the ether was evaporated in vacuo and the residue obtained was recrystallized from diisopropyl ether/hexane. Yield 3.15 g, m.p. 100-

102°C.

Examples 2-6

By using essentially the same method as described in example 1, the following compounds were prepared: Example 2: 3-(p-dimethylaminophenyl)-5-(o-tolyl) 1H-1,2,4-triazole from 2.55 g (0.017 mol) of the hydrazide of o-toluene acid and 4.26 g (0.021 mol) p-dimethylaminobenzimidic acid ethyl ester. Yield 3.04 g, m.p. 173-175°C (from diisopropyl ether).

Example 3: 3-(o-chlorophenyl)-5-(o-tolyl)-1H-1,2,4-triazole

from 3.75 g (0.025 mol) of the hydrazide of o-toluene acid and 5.5 g (0.03 mol) o-chlorobenzimidic acid ethyl ester. Yield 4.26 g,

m.p. 109-111°C (from hexane/methylene chloride).

Example 4: 3-(Methoxyphenyl)-5-(o-tolyl) 1H-1,2,4-triazole

from 6.75 g (0.045 mol) of the hydrazide of o-toluene acid and 9.85 g (0.05 mol) o-methoxybenzimidic acid ethyl ester. Yield 4.81 g, m.p. 160-161°C (from hexane/diisopropyl ether).

Example 5; 3-( m- chlorophenyl)- 5-( o- tolyl)- 1H- 1, 2, 4- triazole

from 2.55 g (0.017 mol) of the hydrazide of o-toluene acid and 4.1 g (0.0221 mol) of m-chlorobenzimidic acid ethyl ester. Yield 2.34 g, m.p. 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 the hydrazide of o-toluene acid and 4.8 g (0.0221 mol) of m-trifluoromethylbenzimidic acid ethyl ester was heated in an oil bath for 6 hours with stirring, the bath temperature being held at approx. 125°C. This gave a solid mass to which 15 ml of n-butanol was added and the resulting mixture was heated for about 19 hours, while the temperature of the oil bath was maintained at approx. 125°C.

During this time, the solid mass dissolved completely in the butanol, which was evaporated in a vacuum at the end of the reaction, as the temperature of the oil bath was brought to approx. 150°C. After cooling, the reaction mass was taken up in 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 aqueous and alkaline extracts were combined. After treatment with charcoal to remove any impurities and subsequent filtration on celite, the filtrate was brought to pH 7 by adding, with stirring, 10% aqueous hydrochloric acid. This gave a precipitate which was collected and recrystallized from cyclohexane/benzene. Yield 2.55 g, m.p. 158-159°C.

Examples 7-17

These compounds were prepared essentially as described in Example 6.

Example 7: 3-(p-fluorophenyl)-5-(o-tolyl)-1H-1,2,4-triazole

from 2.03 g (0.0135 mol) of the hydrazide of o-toluene acid and 2.95 g (0.0175 mol) of p-fluorobenzimidic acid ethyl ester. Yield 1.18 g, m.p. 119-121°C (from hexane/diisopropyl ether).

Example 8: 3-(p-chlorophenyl)-5-(o-tolyl)-1H-1,2,4-triazole

from 2.03 g (0.0135 mol) of the hydrazide of o-toluene acid and 3.25 g (0.0175 mol) p-chlorobenzimidic acid ethyl ester. Yield 1.13 g, m.p. 150-151°C (from diisopropyl ether). The compound contains half a molecule of crystal water.

Example 9: 3(m-ethoxyphenyl)-5-(o-tolyl)-1H-1,2,4-triazole

from 1.5 g (0.01 mol) of the hydrazide of o-toluene acid and 2.12 g (0.011 mol) of m-ethoxybenzimidic acid ethyl ester. Yield 1.41 g, m.p. 84-86°C (from diisopropyl ether).

Example 10: 3-(m-allyloxyphenyl)-5-(o-tolyl)-1H-1,2,4-triazole from 1.5 g (0.01 mol) of the hydrazide of o-toluene acid and 2.26 g (0.011 mol) m-allyloxybenzimidic acid ethyl ester. Dividend

1.89 g, m.p. 72-75°C (from diisopropyl ether).

Example 11: 3-(1,1'-biphenyl-4-yl)-5-(o-tolyl)-1H-1,2,4-triazole from 0.99 g (0.0066 mol) of the hydrazide of o -toluene acid and 1.68 g (0.0075 mol) p-phenylbenzimidic acid ethyl ester. Yield 1.47 g, m.p. 165-167°C (from cyclohexane/benzene).

Example 12: 5-(o-ethylphenyl)-3-(m-methoxyphenyl)-1H-1,2,4-triazole

from 4.87 g (0.03 mol) of the hydrazide of o-ethylbenzoic acid and 5.35 g (0.03 mol) of m-methoxybenzimidic acid ethyl ester. Out-

exchange 5.36 g, m.p. 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

from 1.64 g (0.01 mol) of the hydrazide of o-ethylbenzoic acid and 2.26 g (0.011 mol) of m-allyloxybenzimidic acid ethyl ester. Yield 2.73 g, m.p. (as the hydrochloride) 130-132°C (from ethanol).

Example 14: 3-(p-chlorophenyl)-5-(o-ethylphenyl)-1H-1,2,4-triazole from 1.64 g (0.01 mol) of the hydrazide of o-ethylbenzoic acid and 2.01 g .(0.011 mol) p-chlorobenzimidic acid ethyl ester. Dividend

1.32 g, m.p. 118-120°C (from diisopropyl ether/hexane).

Example 15: 5-(o-isopropylphenyl)-3-phenyl-1H-1,2,4-triazole

from 1.25 g (0.007 mol) of the hydrazide of 2-isopropylbenzoic acid and 1.15 g (0.00 77 mol) of benzimidic acid ethyl ester. Yield 1.38 g, m.p. 165-167°C (from diisopropyl ether/light petroleum).

Example 16: 5-(o-isopropylphenyl)-3-(m-methoxyphenyl)-1H-1,2,4-triazole

from 1.78 g (0.01 mol) of the hydrazide of 2-isopropylbenzoic acid and 1.97 g (0.011 mol) of m-methoxybenzimidic acid ethyl ester. Yield 2.27 g, m.p. 125-126°C (from diisopropyl ether/light petroleum).

Example 17: 5-(o-ethylphenyl)-3-phenyl-1H-1,2,4-triazole

from 1.64 g (0.01 mol) of the hydrazide of o-ethylbenzoic acid and 1.49 g (0.01 mol) benzimidine ethyl ester. Yield 1.77 g, m.p. 124-126°C (from diisopropyl ether/hexane).

The benzimidic acid ethyl ester derivatives which were used as starting compounds were prepared according to methods in the literature (cf. Pinner, "Die Imidoather und Ihre Derivative"; R. Oppen-heim, Berlin, 1892; L. Weintraub et al. J. Org..Chem. , Vol. 33, No. 4, page 1679, 1968).

The hydrazides of o-toluene acid, o-ethylbenzoic acid and o-isopropylbenzoic acid which were used as starting materials 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 that can be prepared according to the methods in the examples above are:

Claims (2)

1. Analogous process for the preparation of therapeutically effective 3,5-disubstituted-1H-1,2,4-triazoles of the general formula: wherein R is selected from hydrogen, (C^^Jalkyl, (C1_4 ) alkoxy, allyloxy, trifluoromethyl, phenyl, fluorine, chlorine and dimethylamino; R1 is a (C1-4 )alkyl group; provided that when R is hydrogen, R .^ not be methyl; further provided that when R is hydrogen, R1 and R cannot simultaneously be methyl; as well as salts thereof with pharmaceutically acceptable acids, characterized in that a molar amount of a compound with the formula: or an acid salt thereof, is condensed with a small molar excess of a compound of the formula: or an acid salt thereof, wherein CX is a functional group selected from carboxy, dithiocarboxy, carbonyl halide, carboxylic anhydride, orthoester, imidate, thioimidate, imidoyl halide, amidino and cyano, Y is a group NH and, when the group CX contains a nitrogen atom, Y is oxygen or sulphur; and either A is the group and the B group or A is the group and B is the group where R and R^ have the above meaning, at a temperature of 80-200°C for a period of 15-30 hours, optionally in the presence of an acidic catalyst and an organic solvent, and, if desired, conversion of a compound thus obtained to a pharmaceutically acceptable acid addition s.all thereof. 2. Analogy method according to claim 1, characterized in that the group CX is the group where alkyl can be methyl, ethyl or propyl.