DK149530B - Analogy process for preparing 3-amino-4-methyl-6- phenylpyridazine derivatives or pharmaceutically acceptable acid addition salts thereof - Google Patents

Description

1A953Q

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The present invention relates to an analogous process for the preparation of novel 3-amino-4-methyl-6-phenyl-pyridazine azine derivatives of the formula / CH 3 / - + - -NH 2 (I)

V.-jW N = N

R

Wherein R is H or OH, or pharmaceutically acceptable acid addition salts thereof.

The compounds of formula (I) have effect on the central nervous system.

Pyridazine derivatives have been used for many years as pharmaceuticals.

In many cases, these are compounds that act on the cardiovascular system and in particular have hypotensive or vasodilatory effects. In rarer cases, the pyridazin derivatives have anti-inflammatory and analgesic effects. French Patent No. 2,141,697 also discloses pyridazine compounds of the formula rYR1

Ar- V \ -NH-R2 Ni = rN

where hydrogen or a lower alkyl group means. Ar represents an aromatic group and R 2 represents the group - (CH 2) -N where n is 2 or 3 and Y and 2 means Z y 1 in a lower alkyl group, or -N means a heterocyclic group.

The characteristic of these known compounds is a psychotropic effect of the psychostimulatory type.

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On closer examination of the compound where / - \ CH 2, Ar represents phenyl, and R 2 means -CH 2 CH 2 ~ N ^ which has been given the international common name "Minaprine", it has been shown that this is a psychotropic effect of a new type, referred to as "disinhibitory" action. Moreover, at doses greater than 100 mg / kg orally, this compound is convulsive.

It has now been found that the compounds of formula (I) have the same pharmacological and biochemical properties as "Minaprine" 10 while being less toxic and practically without convulsive action.

The process of the invention is characterized by reacting a 3-chloro-4-methyl-6-phenyl-pyridazine derivative of the formula _ / CH3 β \ - ^ - Cl (II) VJ __ / N = NR * wherein R 'means H , OH or alkoxy, with a large excess of hydrazine to form a corresponding 3-hydrazine-pyridazine derivative which is hydrogenated in the presence of Raney nickel in a solvent and, when -R 20 corresponding alkyl group, whereupon the compound formed is optionally converted into a pharmaceutically acceptable acid addition salt thereof.

For the preparation of compounds of formula I wherein the phenyl group at the 6-position of the pyridazine ring is substituted by an OH group (R = OH), it is preferred to dealkylate the corresponding alkoxy compound in known manner, e.g. by the action of hydrogen bromide in acetic acid under reflux.

The compounds of formula (I) can be converted into acid addition salts in the conventional manner by the action of an acid on a hot solution of the compound of formula (I), the solvent being selected such that the acid addition salt crystallizes upon cooling.

The 3-chloro-4-methyl-6-phenyl-pyridazine derivatives used 5 as starting products can be prepared from corresponding 2H-3-pyridazones by the action of an excess of phosphorus oxychloride. The 2H-3-Pyridazones are known or can be prepared by known methods, e.g. effect of hydrazine on γ-ketonic acids or derivatives thereof.

The process of the invention is further illustrated in the Examples below.

Example 1 3-Amino-4-methyl-6-phenyl-pyridazine (hydrochloride) (CM 30465) a) 3-Hydrazino-4-methyl-6-phenyl-pyridazine A mixture of 5 g of 3-chloro-4 methyl 6-phenyl-pyridazine and 12 ml of hydrazine hydrate are heated to reflux. After 1.5 hours, the reaction mixture is allowed to cool. A solid is separated which is centrifuged and washed with a small amount of water. The solid is recrystallized from a mixture of isopropanol and isopropyl ether. Yield: 4.5 g, m.p. 162 ° C.

b) 3-Amino-4-methyl-5-phenyl-pyridazine 6.5 g of the compound prepared under (a) is dissolved in a minimum of methanol and 2.5 g of Raney nickel are added. It is hydrogenated under a pressure of 5 atm. for 48 hours. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue is recrystallized from a mixture of isopropanol and isopropyl ether. Yield: 5.25 g, mp: 130-132 ° C.

Hydrochloride: To 2 g of the compound prepared under b) dissolved in a minimum of isopropanol, 1.2 equivalents of 35 gaseous hydrogen chloride are added and then precipitated by the addition of ether. A white powder (1.7 g) is obtained, mp: 172-174 ° C.

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Example 2 3--ιηίηο-4-πβ1 ± .ν1-6- (4-hydroxyphenyl) -pyridazine (hydrobromide) Proceeding in the manner described in Example 1a) from 3-chloro-4-methyl-6- (4-methoxy-phenyl) -pyridazine, the corresponding 3-hydrazino derivative is obtained. By reacting this in the manner described in Example 1b) the corresponding 3-amino-4-methyl-6- (4-methoxyphenyl) pyridazine is obtained, which is demethylated by refluxing in a mixture of 48% hydrogen bromic acid. and acetic acid in the 2: 1 volume ratio. There is obtained 3-amino-4-methyl-6- (4-hydroxy-phenyl) -pyridazine, hydrobromide (SR 95087), mp: 260 ° C (dec.).

The present compounds are subjected to pharmacological tests to determine their effect on the central nervous system and their toxicity.

Acute toxicity

The test compounds are administered intraperitoneally in increasing doses to groups of 10 mice. Mortality is noted for the first 24 hours after the compound is administered.

From the results obtained, DL ^ Q, i.e. the dose causing death in 50% of the test animals for each of the test compounds.

During the same experiment, the convulsive threshold dose of the compound, i.e. the minimum dose at which a convulsive activity begins to manifest.

The results obtained are summarized in Table I. This comparison includes two comparative compounds known from the aforementioned French Patent Specification No. 2,141,697.

5 149530 CH3 ft ^^ -NH-CH2CH2-n '^ 3 Minaprine (DCI) \ i —- J Ns = N \ _ / _ / CH3 H3CO- / \ _ ^ -NH-CH2CH2-N 0 CM 30073 \ = JN = N \ - /

Table I

Connective DLso Convulsive Threshold (mg / kg, i.p.) Threshold (mg / kg, i, p.)

Minaprine 63 (52-77) _35_ CM 30073 19 (11-35) _5_ CM 30465_226_ 200_ lO SR 95087_> 200_> 200_

The figures given in Table I above show that the compounds of this invention have a much lower toxicity and a much poorer convulsive activity than the corresponding comparison compounds.

Antidepressant activity "Despair reaction": This experiment is conducted with female mice of the species CDI (Charles River), weighing from 18 to 23 g, by the method described by Porsolt (Archives Internationales de Pharmacodynamie, 1977, 229, 327-336).

The test principle is as follows: When a mouse is placed in a narrow container filled with water, it peels until after 2-4 minutes it ceases to peel and floats on its stomach with curved back and the hind legs pulled up under it and only makes some necessary moves to keep its 25 head above the water. It is the so-called despair reaction.

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Certain psychoactive drugs, especially the antidepressants, prolong the time that the mouse is flushing.

The following test protocol is used: The test compounds are administered intraperitoneally for 1 hour before the test. In the experiment, the animals are placed in a narrow container (10 x 10 x 10 cm) filled with water at a height of 6 cm, the temperature of the water being 24 - 2 ° C. The animals are kept in the water for 6 minutes and the time period during which the animal is immobile is measured between the 2nd and 6th minutes. The shorter this time, the more active the connection is.

Each compound is examined in a group of 10 mice. The results are the average of at least two trials.

Antagonism against reserpine-induced ptosis.

This experiment, described by Gouret (Journal of Pharmacology (Paris), 1973, 4 (1), 105-128), is conducted with female mice of the species CDI (Charles River) weighing 20-1 g. -pain induces ptosis 1 hour after its intravenous administration.

Certain antidepressants counteract this ptosis.

The following test protocol is used: the test compounds are administered intraperitoneally. The reserpine is co-administered intravenously at a dose of 2 mg / kg. One hour after the administration of the reserpine, the number of animals not exhibiting ptosis is recorded.

This experiment is conducted with groups of 10 animals and the results are expressed as percentage of animals that do not exhibit ptosis and 25 they are the average of at least two trials.

The results obtained with the subject compounds are listed in Table II. For comparison, results obtained with the two known compounds, Minaprine and CM 30073, are also listed.

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Table II

Antidepressant activity

Combine Antagonism to Reserpine "Behavioral Hopelessness" Induced Ptosis% Reduction of Movement- 5 ^ DE50 'i.p.

Minaprine 5 (4-7) 10 mg / kg: - 35% CM 30073 1 mg / kg: 30% 5 mg / kg: 60%

The compound is too toxic for higher doses of Jtolc CM 30465 8.6 (8.3-9) 10 mg / kg: - · 24%

Dopamine-like activity

The dopamine-like activity of the compounds of this invention is investigated on the dopaminergic striped receptors in mice by the technique described by P. Protais and J. Costentin in Journal de Pharmacologie (Paris), 7, 251-255 (1976).

The single-sided lesion of the dark-streaked, dopaminergic neurons induces a hypersensitivity of the receptors to dopamine at the stripe level. The asymmetry resulting therefrom appears in the animal's rotations in the contralateral direction of the most intensely stimulated receptors.

After administration of the test compounds by intraperitoneal route, the number of turns performed by the animal is counted for a period of 2 minutes.

The results are expressed as percentage variations relative to the control animals that have not received the test compound.

The results obtained are listed in Table III below, where the results for the two comparison compounds are shown. Minaprine and CM 30073 are also listed.

Table III

Compound Dose ymol / kg, i.p. Average number of 2-minute homolateral rotations in% relative to control animals

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

It can be seen from Tables I, II and III that the compounds of this invention generally have an antidepressant activity and a dopamine-like activity of the same magnitude as Minaprine.

Compared to Minaprine and especially CM 30073, the 15 compounds in question have a very low toxicity and are virtually devoid of convulsive activity.

Thus, the compounds of this invention can be used for treatment of all disorders of psychomotor behavior.

They can include is prescribed for hyperkinesis in children, in masked depression in adults, in severe depressive conditions, in depression in the elderly as well as in memory disorders and in old age impairment.

The compounds may be administered by oral route or as injections.

The therapeutic compositions may be solid or liquid and e.g. available in the form of tablets, gelatinous pills, granules, suppositories or injectable preparations.

The dosage may vary within large quantities, especially depending on the nature and severity of the disorder to be treated, as well as the mode of administration. For oral administration to adults, it is usually between 0.010 and 0.500 g, possibly divided into several doses.