CS241093B2 - Process for preparing 3- [2- (3-oxo-4-morpholinyl) ethylamino] -4-methyl-6-phenylpyridazine - Google Patents

Abstract

The invention relates to a process for the preparation of 3-[2-(3-oxo-4-morpholinyl)ethylamino]-4-methyl]6-phenylpyridazine, which has an effect on the central nervous system.

Description

The invention relates to a method for preparing 3- [2- (3-oxo-4-morpholinyl) ethylamino] -4-methyl-6-PHENYL ^J having effect on the central nervous system.

It has been several years since ipyridazine derivatives have been proposed as pharmaceuticals. In most cases, these are substances which are effective on the cardiovascular system and which in particular have a hyipotensive and vasodilating effect. More often, anti-inflammatory and analgesic effects are mentioned in connection with these substances. Finally, French Patent 2,141,697 describes a group of substances corresponding to the following general formula

I; y

OF

R 2 is - (CH 2) _n -N

. Z wherein n is 2 or 3 and Y and Z are lower alkyl; or

Y

Z group —N \

Z forms a heterocyclic radical.

These compounds have a psychotropic effect of the psychostimulatory type.

A recent study of a compound of the above formula wherein R 1 is methyl, Ar is phenyl wherein

R 1 represents a hydrogen atom or a lower alkyl group,

Ar is an aromatic residue,

341093, which received the common international designation 'Minaprin', led to the recognition that this was a new type of psychotroipic activity, which was described as a '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 and biochemical properties as said minaprine, and moreover, they are less toxic and virtually devoid of convulsive side effects.

The present invention provides a process for the preparation of 3- [2- (3-oxo-4-morpholinyl) ethylamino] -4-methyl-6-phenylpyridazine of formula I

and acid addition salts thereof, characterized in that the compound of formula (II) is reacted

with a haloacetyl halide in an inert solvent in the presence of an alkaline reagent at a temperature of -10 ° C to 0 ° C, followed by treatment with an alkali metal alcoholate such as sodium methylate and optionally converting the compound of formula I to an acid addition salt acid.

Thus, the process of the invention starts from a compound of formula II and follows the following reaction scheme:

CH2 — CH2

Pyridazine-NH-CH2-CH2-NH

OH Hal — C — CH2 — Hal (Π)

CH2 — CH2

Pyridazine-NH — CH2 — CH2 —N OH \

C — CH2 — Hal, 11o

alkali metal alcoholate

3 * ·

Pyridazine

Λ ~ \

-NH-CCH / -O (1) (III) / Treatment of a halogenated acetyl halide in an inert solvent such as 31-chloromethane in the presence of an alkaline agent such as an aqueous solution of sodium carbonate at -10 to 0 ° C gives a tertiary amine of formula III. Reaction of this amine III with an alkali metal alcoholate, such as sodium methylate, in methanol at the boiling point of the solvent affords the compound of formula I. This compound can be isolated in the form of a salt, such as a chlorohydrate.

The compound of formula (I) may be converted to the salt by a conventional method of treating the warm base solution with an acid, such that a solvent is chosen to crystallize the salt obtained upon cooling.

The 3-chloropyridazine from which the starting compound II is prepared is obtained from the corresponding 2H-3-pyridazone by treatment with an excess of phosphorus oxychiloride.

Said 2H-3-pyridazone is a known compound 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- [2- (2-hydroxyethylamino) ethylamino] -4-methyl-6-phenylpyridazine; dichlorohydrate (CM 30 311).

A mixture of 7.7 g of 3-chloro-4-methyl-6-phenylpyridazine and 15 g of N- (2-hydroxyethyl) ethylenediamine in 50 ml of n-butanol is refluxed for 2 hours in the presence of 2 g of copper powder. The reaction mixture is then poured into 100 ml of water and extracted with ether.

The ether phase was extracted with a 5N sulfuric acid solution, while the aqueous phase was then basified by the addition of baking soda.

The crystals obtained are centrifuged and recrystallized from isopropyl ether-isopropanol. Melting point: 91 ° C.

Chlorhydrate

Dissolve 3.9 g of the base in warm isopropanol, then add 2.44 ml of concentrated hydrochloric acid solution. The chlorohydrate crystallizes by cooling. The product is centrifuged and recrystallized from isopropanol.

Melting point: 144 ° C.

If the procedure was as in Example 1, but replaced by N- (2-hydroxyethyl) ethylenediamine with an equivalent amount of Ni-ethyl-N- (2-hydroxyethyl) ethylenediamine, 3-2- [N-ethyl-2] was obtained in the same manner. - (2-hydroxyethylamino)] ethylamino-4-methyl-6-phenylpyridazine (SR 95 084) isolated in the form of dichlorohydrate.

The product is highly hygroscopic and decomposes at 140 ° C.

Example 2

3- (2- (3-oxo-4-morpholinyl) ethylamino] -4-methyl-6-phenylpyridazine chlorohydrate (CM 30 488).

5.4 of CM 30 311 (Example 1) was dissolved in 100 ml of water. The mixture is cooled to -5 to -10 ° C and 2.2 g of chloroacetyl chloride are added dropwise with vigorous stirring.

Stirring was continued for 12 hours and the mixture was evaporated to dryness. The residue was dissolved in 50 ml of anhydrous methanol, and to this solution was added sodium methylate solution obtained by mixing 0.46 g of sodium and 50 ml of methanol. The mixture was refluxed for 6 hours and then evaporated to dryness again. The residue was taken up in water and extracted with ethyl acetate.

The solution was dried and evaporated to dryness to give an oily product.

Chlorhydrate

The base was dissolved in a minimum amount of warm isopropanol and treated with an equivalent of aqueous concentrated hydrochloric acid. Ether was added to the mixture and the solution was allowed to crystallize.

Melting point: 190-191 ° C.

The products produced by the method of the invention were subjected to pharmacological tests to determine their central nervous system activity and their toxicity.

Acute toxicity

The study product was administered intraperitoneally at increasing doses to groups of 10 mice. The mortality of the experimental animals was monitored for 24 hours after administration of this product.

On the basis of the results obtained, a lethal dose of 50, i.e. the dose that causes 50% of the death of the test animals, is determined for the test product.

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

The results obtained are shown 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 30 488

Lethal dose Threshold convulsive

DL 50 (mg / kg, i.p.) dose (mg / kg, i.p.) (52-77) 35 (11-35) 5 greater than 300 300

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

Antidepressant efficacy

The 'surrender' reaction

This test was performed using female mice (CDI, Charles River) weighing 18-23 g, according to the method described by Persolt (Archives Internationales de Phartnacodynamle, 1977, 229, 327-336).

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 is known as the despair reaction.

Some psychotropic, especially antidepressant drugs, increase the amount of time the mouse is trying to vigorously keep it above water during the test.

The following method was used in this test:

The test product was administered i.p. 1 hour before the test. In this test, test mice were placed in a narrow vessel (10 X 10 X 10 cm) filled with water to a height of 6 cm, with a water temperature of + 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.

Groups of 10 mice were used in the test and the result obtained is the average of two experiments.

Reserpine-induced ptosis

This test was described by Guoret (Journal de Pharmacologie, Paris, 1973, 4 (1), 105-128) and was performed using female mice (CDI, Charles River) weighing 20 + 1 g). Reserpine induces the skin 1 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 test animals not showing the symptoms of ptosis was evaluated.

This test was performed with a group of 10 mice, the result being expressed as a percentage of the animals lacking the symptoms of said ptosis and the average of two measurements.

The results obtained are summarized in Table 2. The results obtained using two known compounds, minaprine and CM 30 073, are also shown for comparison.

.241093

Table 2

Antidepressant Efficacy Compound

Minaprin

CM 30 073

CM 30 488

Reserpine-induced ptosis (DE 50, mg / kg, i.p.) (4-7) mg / kg: 30% mg / kg: 60% at higher doses, the product is too toxic 20 (13-31)

'Surrender' response (percentage reduction in immobilisation time) mg / kg: —35 ° / o

Dopamimomimetric efficiency

The dopamimomimetric activity of the compounds prepared by the method of the invention was studied at the dopaminergic striastic mouse receptors by the technique described by P. Proitais and J. Costentin in the Journal de Pharmacologie (Paris), 7, 251-255 (1976).

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

After administration of the study product by intraperitoneal administration, the number of turns performed by the experimental 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 are summarized 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 ((Wmol / kg, i.p. in the ipsilateral sense over 2 minutes in% relative to control animals)

Minaprin 5.3 —91%

CM. 30,073 5.3 0%

CM 30 488 5.3

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

With respect to minaprine, and in particular to CM 30 073, the test products produced by the process of 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 symptoms of dementia.

These products may be administered orally or by injection. Therapeutic compositions containing these products may be ~ 90% 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 0.5 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:

Tablets compound 30 488 200 mg microcrystalline cellulose 100 mig lactose 197 mg magnesium stearate 3 mg

500 mg

Claims (1)

OBJECT OF THE INVENTION Process for the preparation of 3- [2- (3-oxo-4-morpholinyl) ethylamino] -4-methyl-6-phenylpyridazine and its acid addition salts, characterized in that the compound of the formula II and n is treated with a haloacetyl halide in an inert a solvent in the presence of an alkaline reagent, at a temperature of -10 ° C to 0 ° C, whereupon the product obtained is reacted with an alkali metal alcoholate such as sodium methylate and the compound of formula I is optionally converted into an acid addition salt by treatment with an acid.