CS241094B2 - Method of 4-methyl-6-phenylpyridazine derivatives preparation - Google Patents

Abstract

Process for preparing 4-methyl-6-phenylpyridazine derivatives of the general formula wherein R is hydrogen or a hydroxyl group consisting of the corresponding chloro derivative is reacted with excess hydrazine and the product obtained is hydrogenated in the presence of Raney nickel.

Description

The present invention relates to a process for the preparation of 4-methyl-6-phenylpyridazine derivatives having central nervous system activity.

It has been several years since pyridazine derivatives have been proposed as pharmaceuticals. In most cases, these are substances which are effective on the cardiovascular system and which have in particular a hypotensive and vasodilating effect. The anti-inflammatory and analgesic effect of these substances is sparse. Finally, French Patent 2,141,697 describes a group of substances corresponding to the general formula:

in which

1R1 is hydrogen or lower alkyl,

Ar is an aromatic residue,

R 2 represents a group

Wherein n is 2 or 3 and Y and Z are lower alkyl or

Y /

—N

Z forms a heterocyclic radical.

These compounds have a psyehotropic effect of the psychostimulatory type.

Recent studies of a compound of the formula wherein R 1 is methyl, Ar is phenyl, and Ra is a group which has received a common international designation "Minaprine" have led to the finding that this is a psychotropic effect of a new type that was labeled as 'deinhibitory effect'. Otherwise, the compound exhibits a convulsive effect at doses higher than 100 mg / kg orally.

It has now been found that some 6-phenyl-4-methylpyridazines have the same pharmacological, logical and biochemical properties as minaprine, and moreover, they are less toxic and virtually free of the side convulsive effect.

The invention relates to a group of pyridazine derivatives corresponding to the general formula I

wherein R represents a hydrogen atom or a hydroxyl group.

The invention also relates to acid addition salts of the compounds of formula I.

The present invention provides a process for the preparation of a compound of the formula (I), characterized in that it is a compound of the formula (I)

is reacted with an amount of hydrazine representing 5 times the theoretically necessary amount to form the 3-hydrazino pyridazine derivative, whereupon the compound obtained is hydrogenated with Raney nickel in a suitable solvent.

The process according to the invention thus consists in first preparing said 3-hydrazino derivative by refluxing the corresponding chloro derivative with a large excess of hydrazine, and then the 3-hydrazino derivative thus obtained is hydrogenated in the presence of Raney nickel in a suitable solvent with to form a compound of formula I.

This process can be illustrated by the following reaction scheme:

If the phenyl group at the poloze position of the pyridazine ring is substituted with a hydroxyl group (R = OH), it is preferable to prepare the corresponding compound of formula I, wherein the phenyl group carries an allkoxy substituent at the same position, by the above method, and the compound is then dealkylated by a method known per se, for example by treatment with hydrobromic acid in acetic acid at reflux temperature.

The compounds of formula (I) thus obtained can be converted into salts by the classical method of treating an acid with a warm solution of a base, the solvent being chosen to crystallize the salt obtained after cooling.

The 13-chloropyridazines used in the process of the invention as starting compounds are obtained from the corresponding 2H-3-pyridazones by treatment with an excess of phosphorus oxychloride.

Said 2H-3-pyridazones are known compounds and can be obtained by methods known per se, such as by the action of hydrazine on gamma-keto acids or derivatives thereof.

Example 1

3-Amino-4-methyl-6-phenylpyridazine

Chlorhydrate (CM 30 465)

Formula I: R = H

Step a) 3-Hydrazino-4-methyl-6-phenylpyridazine

A mixture of 5 g of 3-chloro-4-methyl-6-phenylpyridazine and 12 ml of hydrazine hydrate is heated to reflux. After 1 hour 30 minutes the reaction mixture was allowed to cool. The solid was collected by centrifugation and washed with a small amount of water. The product is then recrystallized from a mixture of isopropanol and isopropyl ether.

Yield of product: 4.5 g;

Melting point: 162 ° C.

Step b)

The product CM 30 465

6.5 g of the compound obtained in the previous reaction step are dissolved in a minimum amount of water, and 2.5 g of Raney nickel are added to the obtained solution. This mixture was hydrogenated at 0.5 MPa for 48 hours. The catalyst was filtered off and the filtrate was evaporated to dryness. The residue is recrystallized from a mixture of isopropanol and isopropyl ether.

Yield: 5.25 g;

Melting point: 130-132 ° C.

Chlorhydrate

To 2 g of the base dissolved in the minimum amount of isopropanol was added 1.2 equivalents of hydrogen chloride gas and the solution was precipitated by the addition of chlorine. A white powder is obtained.

Yield: 1.7 g;

Melting point: 172-174 ° C.

Example 1 a d 2

Starting from 3-chloro-4-methyl-6- (4-methoxyphenyl) pyridazine, the corresponding 3-hydrazino derivative was obtained, which was treated as in Example 1b to give the corresponding 3-amino derivative. .

Finally, demethylation gives 3-amino-4-methyl-6- (4-hydroxyphenyl) -pyridazine (SR).

Isolated in the form of bromohydrate. Melting point: 260 DEG C. (dec.).

The products produced by the method of the invention have been subjected to pharmacological tests to determine their central nervous system efficacy and toxicity. Acute toxicity

Study compounds were administered in241094 tr-aperitoneally at increasing doses to groups of 10 mice. Mortality induced by these compounds was monitored for 24 hours after administration of these compounds.

Based on the results obtained, a lethal dose of 50 is determined for each product tested, i.e., the dose that causes the death of 50% of the test animals.

At the same time, in determining acute toxicity, the threshold dose of these products giving rise to convulsive activity, i.e. the minimum dose of said products at which convulsions begin to occur, is also determined.

The results obtained are summarized in Table 1 below. This table also shows the results obtained using the two comparative products described in French Patent 2,141,697;

Table 1

Compound

Minaprine CM 30 073

CM 30 465 SR 95 087

Lethal dose of DL50 (mg / kg, i

Threshold convulsive dose (mg / kg, i.p. (52-77) 19 (11-35)

226 higher than 200

200 higher than 200

The results shown in the above table show that the compounds prepared by the process of the invention have significantly less toxicity and a convulsive effect than said reference compounds.

Antidepressant efficacy

The "surrender -fate" reaction

This assay was performed using female mice (CDI, Charles Riverj weighing 18-23 g, according to the method described by Persolt (Archives Internationales de Pharmacodyne-Amie, 1977, 229, 327-366)).

The principle of this test is as follows: when placed in a narrow container filled with water, the mouse vigorously tries to keep it above water. Then, after about 2 to 4 minutes, it immobilizes and floats on the chest with a domed back and hind legs under the body, making only a few necessary movements to keep the head above the water. This reaction is referred to as the despair reaction.

Some psychotropic, especially antidepressant drugs, prolong the time during which the mouse is vigorously trying to keep it above water.

The following methods were used in this test:

Test products were administered i. Ρ. 1 hour before the test. In this test, experimental mice were placed in a narrow vessel (TO X 10 X 10 cm) filled with water to a height of 6 cm, with a reagent water temperature of 24 + 2 ° C. Mice were left in water for 6 minutes, measuring the time that the mice were stationary between 2 and 6 minutes. The shorter the time, the more effective the test product is.

Each compound was studied in a group of 10 mice and the results obtained are an average of at least two experiments.

Reserpine-induced ptosis

This test was described by Guoret (Journal de Pharm, acoloigie, Paris, 1973, 4 (1), 105-128) and was performed using female mice (CDI, Charles Riverj weighing 20 + 1 g). Reserpine induces ptosis 1 One hour after intravenous administration, some antidepressants antagonize this ptosis.

The following methods were used: test compounds were administered intraperitoneally. At the same time, reserpine was administered intravenously at a dose of 2 mg / kg. One hour after the administration of reserpine, the number of animals not showing symptoms of ptosis was evaluated.

This test was performed with a group of 10 mice, the results being expressed as a percentage of the animals not showing the symptoms of said ptosis and averaging at least two measurements.

The results obtained are summarized in Table 2 below. For comparison, the results obtained using two known comparative products, mine prine and product CM 30 073, are also shown.

Table 2 Antidepressant Efficacy Compound

Reserpine-induced ptosis (DE50, mg / kg, i.p)

'Surrender' (% reduction in immobilisation time)

Minaprin CM 30 073 (4–7) 10 mg / kg: —35% mg / kg: 30% mg / kg: 60% - at higher doses the product is too toxic

CM 30 465

8.6 (8.3—9) mg / kg: —24%

Dopamimomimetric effect

The dopamimomimetric effect of the products prepared by the method of the invention was studied at dopaminergic striatal receptors of mice by the technique described by P. Protais and J. Costentin in the Journal de Pharmacologie (Paris), 7, 251-255 (1976).

The unilateral lesion of dopaminergic nigrostriatal neurons results in hypersensitivity of the dopamine receptors. The resulting asymmetry results in the animal turning in a contralateral sense to the most intensively stimulated receptors.

Following intraperitoneal administration of study compounds, the number of turns performed by the test animal is counted over two minutes.

The results of the measurements shall be expressed as a percentage of changes relative to control animals not treated with the product under study.

The results obtained for the individual products are shown in Table 3 below, which also shows the results obtained using the comparative products: minaprine and CM 30 073.

Table 3

Compound Dose Average number of turns (µmol / kg, i.p.) in the ipsilateral sense over 2 min in ® / o relative to control animals

Minaprine CM 30 073

CM 30 465

5.3 —91%

5,3 0%

5.3 —89%

It follows from the preceding Tables 1, 2 and 3 that the compounds prepared by the process of the invention, which were selected for the above tests, generally have antidepressant and dopamimomimetric activity comparable to that of minaprine.

With respect to minaprine and in particular with respect to product CM 30 073, the test products produced by the process according to the invention are much less toxic and practically devoid of convulsive action.

Therefore, the novel compounds produced by the method of the invention can be used in the treatment of psychomotor disorders.

These products may be prescribed, inter alia, for the treatment of hyperkinesia in children, depression in adults, as well as for the treatment of severe depressive states, involutionary depression of the elderly. memory disorders and old age with symptoms of dementia.

These products may be administered orally or by injection. Therapeutic compositions containing these products may be solid or liquid and may be formulated, for example, as tablets, gelatin capsules, granules, suppositories, or injectables.

The dosage may vary within wide limits, particularly depending on the degree of disease being treated and the mode of administration. For adult and oral administration, this dose is most often equal to 0.01 to 0.5 g. This dose can optionally be taken several times.

By way of example of said pharmaceutical preparation, the following galenic preparation may be mentioned:

Claims (1)

SUBJECT Process for preparing 4-methyl-6-phenylpyridazino; A compound of formula I (I) wherein R is a hydrogen atom or a hydroxyl group, Tablets CM 30 465 200 mg microcrystalline cellulose 100 mg lactose 197 mg magnesium stearate 13 mg 500 mg of ynAlez in which R is as defined above are reacted with an amount of hydrazine representing a multiple of the theoretically necessary amount to give the 3-hydrazino-pyridaizine derivative and the product is hydrogenated in the presence of Raney nickel in a suitable solvent.