FI74463B - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA 3-AMINO-4-METYL-6-FENYLPYRIDAZINDERIVAT. - Google Patents

Description

1 74463

Process for the preparation of therapeutically useful 3-amino-4-methyl-6-phenylpyridazine derivatives

Separated by application 822767 5

The invention relates to the preparation of 3-amino-4-methyl-6-phenylpyridazine derivatives; the compounds obtained are drugs acting on the central nervous system.

Several years ago, pyridazine derivatives were proposed for use as drugs. A large number of cases have involved cardiovascular agents, which have had a particularly antihypertensive and vasodilatory effect. Less frequently, these derivatives have been reported to have anti-inflammatory and analgesic properties. FR Patent No. 2,141,697 describes a group of compounds of the formula Ar 1 -N 2 -NH 2 -R 2 - = j / having hydrogen or a lower alkyl group;

Ar is an aromatic radical;

25 Y

R 2 is a group “(CH 2) -N <where n = 2 or 3 and Y and

\ Z Y

Z represents a lower alkyl group or forms a heterocyclic radical.

Recent studies with a compound with R 1 = CH 3, Ar = phenyl and R 2 = CH 2 CH 2 -N 2 O, under the trade name "Minaprine", have shown that question 35 has a new type of psychotropic effect, defined as non-inhibitory in nature. In addition, when administered orally at doses greater than 100 mg / kg, this compound has been shown to cause seizures.

It has now been found that certain 6-phenyl-4-methyl-3-aminopyridazines have the same pharmacological and biochemical properties as "minaprin" and that, in addition, they are less toxic and have virtually no anticonvulsant activity.

The present invention relates to a process for the preparation of therapeutically useful 3-amino-4-methyl-6-phenylpyridazines of the formula (I) CH3 f / // \\ (I) V 7 Λ / nh2

Jv — r / '' N — N7

15 R

wherein R is H or OH

and pharmaceutically acceptable acid addition salts thereof.

According to the invention, a 3-hydrazino derivative is prepared by reacting the corresponding 3-chloro compound under reflux with a large excess of hydrazine. When the compound thus obtained is hydrogenated in the presence of Raney nickel in a suitable solvent, a derivative of formula (I) is obtained.

These reactions can be illustrated by the following scheme: CH ^ ”-« 00- “··

R

CH3:>! * 74463

When the phenyl group in the 6-position of the pyridazine ring is substituted with an OH group (R = OH), it is preferable to prepare a compound of formula (I) in which the phenyl group is substituted in the same position by alkoxy by the method described above and then dealkylate the obtained compound by a known method. , for example by reaction with hydrobromic acid in acetic acid and refluxing.

The compound of formula (I) thus obtained can be converted into a salt in a classical manner by reacting the acid with a hot solution of the base, the solvent being selected so that the salt crystallizes on cooling.

The starting 3-chloro-4-methyl-6-phenyl-pyridazine derivative can be prepared from 2H-pyridazin-3-one by reaction with an excess of phosphorus oxychloride.

2H-Pyridazin-3-ones are known compounds or can be prepared by known methods such as by reacting hydrazine with Y-keto acid or a derivative thereof.

The compounds of the invention were subjected to pharmacological studies to determine their effect on the central nervous system and their toxicity.

Acute toxicity

Test compounds were administered intraperitoneally in increasing doses to 10 batches of mice. Mortality from the 25 products studied was found 24 hours after administration.

Based on the results obtained, a 50% lethal dose was determined for each of the compounds tested, i.e., the lowest possible dose that caused death in 50 to 30% of the animals tested.

During the same experiments, the limit dose of the anticonvulsant effect of the compound, i.e. the lowest possible dose at which the anticonvulsant effect begins to occur, was also observed.

The results obtained are summarized in Table I. This table also shows the results for comparison of the two compounds described in the aforementioned FR patent 2,141,697.

Οί3 ^ 'y * ^ ^ NH CH2CH2 N O Minaprine (DCI) ch3 H3CO \ / J- NH — CH „CH - = - / o CM 30073 J \ - / N = N * 1 \ _i 10

Table I

Compound DL50 Convulsive effect (mg / kg; i.p.) cut-off dose 15 (mg / kg; i.p.)

Minaprine 63 (52 - 77) 35 CM 30073 19 (11 - 35) 5 20 CM 30465 226 200 SR 95087> 200 200: 25

The numerical values shown in Table I show that the convulsive effect and toxicity of the compounds according to the invention are much lower than those of the reference compounds. Antidepressant effect 30 Despair reaction This test was performed on female mice weighing 18-23 g by the method described by CDI (Charles River) Porsolt (Archives Internationales de Pharmacodymie, 1977, 229-327-336).

35 The principle of this test is as follows: when the mouse is placed in a narrow container filled with water, it initially rattles 74463 and after about 2-4 minutes stops moving and floats on its stomach with its back round, its hind paws under its body making only some necessary movements to keep its head afloat. This is called the despair reaction.

Certain psychotropics, especially antidepressants, prolong the time a mouse flicks.

The following test procedure was chosen: the test products were administered i.p. hours before the test. For this test, the animals were placed in a narrow container (10 x 10 x 10 cm) filled with water up to a height of 6 cm, at which time the water temperature was 24 ° C ± 2 ° C. The animals were left in the water for 6 minutes and the time during which the animal was immobile between the second and sixth minutes was measured. The shorter the ly-15 this time, the more active the test substance.

Each substance was tested in batches of 10 mice. The results are the averages of at least two experiments.

Reserpine-induced hanging eyelid deposition effect This test described by GOURET (Journal de Pharmacologie (Paris), 1973, 4 ^ (1), 105-128) was performed on female CDI mice weighing 20 ± 1 g (Charles River). Reserpine causes drooping of the duodenum 1 hour after intravenous administration; some antidepressant agents resist this deposition.

The following test procedure was chosen: test substances were administered i.p. Reserpine was co-administered intravenously at a dose of 2 mg / kg. One hour after reserpine administration, the number of animals that did not show deposition was observed.

This test was performed in batches of 10 mice and results are expressed as the percentage of animals that did not show deposition and are all means of at least two experiments.

The results obtained with the compounds of the invention are summarized in Table II. For comparison, the results obtained with the known compounds, Minaprine and CM 30073, are also shown.

Table II

Antidepressant effect 5 Compound Reserpine-induced "Behavioral Despair" antihypertensive effect anti-immobility effect percentage decrease (DE50, mg / kg; i.p.) * *

Minaprine 5 (4 - 7) 10 mg / kg: - 35% 10 CM 30073 1 mg / kg: 30% 5 mg / kg: 60% _ at higher doses the compound is too toxic 15 CM 30465 8.6 (8.3 - 9) 10 mg / kg: - 24%

Dopamine Mimetic Activity The dopamine mimetic activity of the compounds of the invention was studied in mice with dopaminergic receptors in the strands of the brain as described by J. PROTAIS and J. COSTENTIN in Journal de Pharmacologien (Paris) 7, 251-255 (1976).

25 Unilateral injury to black-striped dopaminergic neurons causes hypersensitivity to striatal dopamine receptors. The resulting asymmetry manifests itself in that the animal rotates in the opposite direction to the more strongly stimulated receptors.

30 After intraperitoneal administration of the test products to the animals, the spins performed by the animal over a period of two minutes were calculated.

The results are expressed as percentage changes from control animals that did not receive any of the test compounds.

The results obtained with the compounds according to the invention are summarized in Table III, which also shows the two comparators; Results for Minaprine and CM 30073.

Table III

Compounds Doses moles / kg Ipsilateral wheel-5 i.p. number of operations 2 min.

% of control animals

Minaprine 5.3 - 91% 10 CM 30073 5.3 0% CM 30465 5.3 - 89% 15

It is apparent from Tables I, II and III that the representative compounds of this invention, taken as a whole, have antidepressant and dopamine-mimetic activity of the same order of magnitude as Minaprine.

Compared to Minaprine, and in particular to CM 30073, the representative compounds of the present invention are much less toxic and have virtually no anticonvulsant activity.

Thus, the novel compounds of this invention can be used to treat all psychomotor behavioral disorders.

These may include prescribing hyperkinesia in children, latent depression in adults, major depressive disorder, old-age depression, and memory impairment and aging-related disorders.

These compounds can be administered orally or by injection. Therapeutic preparations may be solid or liquid and may be, for example, tablets, capsules, granules, suppositories or injectables.

35 The dosage can vary within wide limits depending on the type and severity of the condition being treated and the route of administration. When administered orally to an adult, the dose of 74463 nos is most often 0.010 to 0.500 g and may be divided into several administrations if desired.

Example of a galenic preparation:

Extrudate 5 CM 30465 200 mg

Microcrystalline cellulose 100 mg

Lactose 197 mg

Magnesium stearate 3 mg 500 mg 10

The following embodiment illustrates the invention.

Example 3-Amino-4-methyl-6-phenylpyridazine (hydrochloride) (CM 30465)

15 (I) R = H

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 was refluxed. After 1 hour and 30 minutes, the reaction mixture was allowed to cool. The separated solid product was separated and washed with a small amount of water. The product was recrystallized from a mixture of isopropanol and isopropyl ether, weight 4.5 g. Mp: 162 ° C.

b) CM 30465 25 6.5 g of the derivative obtained above were dissolved in as little methanol as possible and 2.5 g of Raney nickel were added. Hydrogenated at 5 atmospheres for 48 hours. The catalyst was filtered off and the filtrate was evaporated to dryness. The residue was recrystallized from a mixture of isopropanol and isopropyl ether. Weight 5.25 g; M.p .: 130-132 ° C.

Hydrochloride. 2 g of base were dissolved in as little isopropanol as possible, and 1.2 equivalents of gaseous hydrochloric acid were added to the solution, and the product was precipitated by adding ether. There was thus obtained a white powder (1.7 g), m.p .: 172-174 ° C.

Following the procedure of Example a) using 74463 starting from 3-chloro-4-methyl-6- (4-methoxyphenyl) pyridazine, the corresponding 3-hydrazino derivative was obtained. This was treated as in the example in b) to give the corresponding 3-amino derivative.

Finally, demethylation of the obtained compound by refluxing under cooling in a 2: 1 mixture of 48% hydrobromic acid and acetic acid gave 3-amino-4-methyl-6- (4-hydroxyphenyl) pyridazine (SR 95087), which was separated from the hydrobromic acid. dina; M.p .: 260 ° C (decomposes).

Claims (1)

Claim _. . A process for the preparation of therapeutically useful 3-amino-4-methyl-6-phenylpyridazine derivatives of the formula (I) - / CH 3 10 y = JN = NR wherein R is H or OH, and pharmaceutically acceptable acid addition salts thereof. characterized in that a 3-chloro-4-methyl-6-phenylpyridazine derivative of formula (II) CH3 ft \ - (j \ -Cl (II) N = N , OH or alkoxy is reacted with an excess to give the 3-hydrazinopyridazine-25 derivative corresponding to hydrazine, which is hydrogenated in the presence of Raney nickel in a solvent and, when R 'is alkoxy, the alkyl group is cleaved off and, if desired, converted into a pharmaceutically acceptable acid addition salt. .