CS250689B2 - Method of pyridazine's derivatives production substituted in position 3 by substituted aminogroup - Google Patents

Abstract

The invention relates to a process for the preparation of derivatives pyridazine substituted in the 3-position carboxyalkylamino and their carboxyalkylamino group acid addition salts. These compounds have central effects nervous system and can therefore be used as active ingredients in pharmaceutical compositions. The compounds of the invention may be illustrated formula (I)

Description

The invention relates to a process for the preparation of 3-substituted pyridazine derivatives with carboxyalkylamino as well as their acid addition salts.

These compounds have central nervous system activity and can therefore be used as active ingredients in pharmaceutical compositions.

The compounds of the invention can be represented by the general formula I

in which

R 1 represents hydrogen, C 1 -C 4 alkyl, phenyl, phenyl monosubstituted with halogen or nitro or C 1 -C 4 alkyl or C 1 -C 4 alkoxy or hydroxyl, phenyl disubstituted with halogen, naphthyl radical , cyclohexyl, thien-2-yl or thien-3-yl,

R 2 is hydrogen, C 1 -C 4 alkyl or phenyl,

R3 is hydrogen, (C1-C4) alkyl, phenyl or cyano,

R 4 represents a carboxyl group and alk represents a (CH 2) _n group wherein n is an integer of 2, 3 or 4.

The compounds of formula I provide addition salts with mineral or organic acids. It is also within the scope of the invention to prepare addition salts of compounds of formula I with pharmaceutically acceptable acids.

The process according to the invention for the preparation of the compounds of the general formula I is characterized in that the correspondingly substituted 3-chloropyridazine of the general formula II

(l / l in which

R1, R2 and R3 are as defined above, reacted with an excess of hydrazine hydrate NH2-NH2, the resulting hydrazino derivative of formula III

II // 1 in which

R 1, R 2 and R 3 are as defined above, catalytically hydrogenated and the resulting amino derivative of general formula (IV)

R 1, R 2 and R 3 are as defined above, reacted with a ω-halogenated compound of formula V

X — Alk — R4 ‘(V) in which

X represents a halogen atom, preferably bromine,

RT stands for a COO-alkyl group having 1 to 4 carbon atoms in the alkyl moiety and alk is as defined above, and the resulting ester of formula Γ

^N-1 where Fy ') wherein

R1, R2, R3, R4 ^! and Alk are as defined above, saponified, whereupon the compound of formula I obtained is optionally converted into its acid addition salt.

The process of the invention can be illustrated by the following reaction scheme:

X-AIK-R ^ (IYI ⁾

N ~ N f / 0 ^(4! = COO-alkyl having 1 to 4 carbon atoms in the alkyl]

z in / dal-OL ·

R _f 1 *

N ~ N (t)

A ík - COC

The starting material is a pyridazine of the formula II, chlorinated in the 3-position, which is converted to the corresponding 3-aminopyridazine of the formula IV. Since in practice the direct route to obtain the amino derivative is difficult, the hydrazinated intermediate of formula III is obtained, which is obtained in good yield by boiling chlorinated pyridazine (IIJ under reflux with excess hydrazine hydrate). in the presence of a catalyst such as Raney nickel, the amino derivative of formula (IV) is prepared.

Treatment of the amino derivative of formula IV with a ω-halogenated ester of formula V yields a compound of formula Γ. The reaction is carried out by heating the reactants in a solvent medium such as dimethylformamide at a temperature of 50 to 100 ° C.

Compounds of formula I wherein R 4 is -COOH are obtained from compounds of formula Γ in which Rd 'is -COO-C 1 -C 4 alkyl in the alkyl moiety, by saponification in an acidic medium, preferably by heating with hydrohalic acid, for example with hydrochloric or hydrobromic acid, in an acetic acid medium at a temperature of 20 to 100 ° C. The resulting acid is isolated by evaporating the reaction mixture to dryness directly as the salt corresponding to the hydrohalic acid used.

The 3-chloropyridazines used as starting materials are known compounds or can be prepared by known methods, in particular by treating excess 2H-pyridaz-3-ones with an excess of phosphorus oxychloride.

The invention is illustrated by the following examples. "Preparations 1 to 23" describes the preparation of intermediates of formula (I) in which R 4 * is a group of formula -COO-alkyl of 1 to 4 carbon atoms in the alkyl moiety, from which the corresponding compounds of formula (I) are then hydrolyzed.

Preparation 1

3- (3-ethoxycarbonylpropylamino) -4-methyl-6- (naphth-1-yl) -pyridazine hydrochloride of the formula:

R 2 = H R 3 = CH 3

Alk = (CH 2) 3 R f ‘= COOC 2 H 5

and)

3-Hydrazino-4-methyl-6- (naphth-1-yl) -pyridazine

A mixture of 6.0 g of 3-chloro-4-methyl-6- (naphth-1-yl) pyridazine with 4.8 g of hydrazine hydrate is heated at reflux for 4 hours, and a precipitate is formed which is filtered off with suction Mp 206 ° C.

(b)

3-Amino-4-methyl-6- (naphth-1-yl) -pyridazine

To a solution of 5.0 g of the hydrazine derivative prepared according to a) in methanol was added 2 g of Raney nickel and the mixture was hydrogenated at room temperature under 100 psi for 72 hours. The catalyst was then filtered off and the solvent was evaporated to dryness under reduced pressure. The residue was recrystallized from methanol. Melting point 110 ° C.

C)

3- (3-Ethoxycarbonylpropylamino) -4-methyl-6- (naphth-1-yl) -pyridazine hydrochloride

1.18 g of the amino derivative prepared in (b1) are dissolved in as little dimethylformamide as possible, followed by the addition of 1.46 g of ω-bromobutyrate. The mixture was heated for 3 hours ^and at 80 DEG C. After cooling the reaction was diluted with water, basified with 1 N NaOH and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and evaporated to dryness under reduced pressure. The oily residue was taken up with a small amount of methanol and hydrogen chloride gas was bubbled through the resulting solution until the solution had an acidic reaction. Anhydrous ether is then added and the precipitate formed is filtered off with suction. After recrystallization from isopropanol, it has a melting point of 168 degrees Celsius.

Preparations 2 to 23

Using the procedure described above, but using different starting 3-chloropyridazines and / or halogenated esters, the compounds of the general formula Γ shown in Table I are prepared.

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230683

Example 1

4- (4-Methyl-6- (naphthyl) pyridazine) hydrochloride of formula (I), wherein:

R ₂ = H R 3 = CH 3

Alk = (CH 2) 3 R 4 = COOH

1.8 g of the ester prepared according to "Preparation 1" are dissolved in a mixture of 81 ml of acetic acid with 9 ml of concentrated hydrochloric acid. The mixture was heated at 100% for 9 hours and then evaporated to dryness under reduced pressure. The solid residue is recrystallized from isopropianol to give the title product, m.p. 260 ° C.

Example ^ y 2 and ^ 23 '

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250889

Example 24

3- (3-Carboxypropylamino) -4-methyl-6- (4-hydroxyphenyl) pyridazine hydrobromide of formula (I) in which:

R 2 = H R 3 = CH 3

Alk = (CH 2) 3 R 1 = COOH

A solution of 2 g of the acid of Example 4 in 20 ml of 48% hydrobromic acid was heated under reflux for 15 hours. After cooling, the resulting solid is filtered off with suction and washed first with isopropanol, then with ether, and then dried at 70 DEG C. under reduced pressure.

2 g of the title compound of melting point &gt; 260 DEG C. are obtained.

The compounds of the invention were tested to determine their central nervous system activity.

Effect of replacing χ-aminobutyric acid at its post-synaptic receptor.

Method:

The neurochemical activity of the compounds produced by the method of the invention on the GAM-ergic system is evaluated by the results of the substitution of χ-aminobutyric acid (GAM) at its post-synaptic receptor.

This test is performed according to the method of ENNAs and SNYDER described in Brain Res., 100, pp. 81-97, 1975.

The replacement assay is performed in vitro on a suspension of synaptic membranes and tritiated χ-aminobutyric acid (GAM at a final concentration of 3.6 nM).

Results:

compound average effective concentration of Example (CE 50) in replacement of tritiated χ-aminobutyric acid

(in μΜj 14 2.8 15 Dec 1.34 1 2.9 16 10 10 0.70 8 1,25 4 5.0 19 Dec 2.4 18 10.5 24 3.0 20 May 0.83 7 7.0 6 3.2 11 0.71

Note:

The compounds produced by the process of the invention have the ability to replace χ-aminobutyric acid at its synaptic receptor.

This in vitro experiment is complemented by an in vivo experiment.

1] Effect on mouse motility

Method

The sedative-sedative effect of the compounds of the invention is determined by determining the spontaneous motility of mice in an actimetric assay (J. R, BOISSIER and P. SIMON, Arch. Int. Pharmacodyn, 1965, 158, pp. 212-2211).

The apparatus used in this test consists of Apelab-type actometric cages (26 cm long, 21.5 cm wide, 10 cm high) through which two beams of light striking the photoelectric cell pass.

The test animals are individually caged 45 minutes after administration of the test compound. Each interruption of the light beam shall be recorded by the appropriate computer. The number of interruptions within 10 minutes is determined, which interruptions correspond to the runs of the test animals. For testing a single dose of compound, groups of experimental animals consist of 12 mice.

2] Reserpine-induced ptosis antagonism

Method

The antidepressant activity of the compounds of the invention is evaluated according to a test for determining reserpine-induced ptosis antagonism in mice.

This test is performed on groups of 10 female mice weighing 20 + 1 g. The compounds of the invention are administered anthraperitoneally concomitantly with reserpine (2 mg. Kg ^-1 , intravenously). Mice are observed individually for 1 hour after administration of the test compound and reserpine. Animals that do not show ptosis within 15 seconds of observation are considered to be antagonized, and all control animals treated with vehicle and reserpine only develop ptosis, and the mean effective dose for inducing antagonism (DE 50) is determined by a sequential trial method.

3] Effect on mouse behavior manifested by swings after unilateral lesion of the annealed body (corpus striatumj with 6-hydroxydopamine)

The activity of the compounds of the invention on the central dopaminergic system is determined by the behavior of the swollen mouse after unilateral lesion of the annealed body (corpus striatum with 6-hydroxydopamine) (P. PROTAIS and J. COSTENTIN, J. Pharmacol, 7/2, p. 251). to 255, 1976).

Female Charles River CD1 mice weighing 20-24 g are pre-treated with unilateral lesions of the annealed body by stereotactic injection of 6-hydroxydopamine at 8 per animal experiment. One week after this procedure, the test compound is administered intraperitoneally to groups of 7 mice. One hour after application of the test compound, the number of turns was determined for 2 minutes. Rotations on the same side on which the lesion was made are counted positive, rotations on the opposite side are negative. The algebraic sum of turns in the group of test animals to which the test compound was administered is compared with the algebraic sum of turns in the control animals only (saline). The results obtained with one of the compounds of the invention, ie the compound of Example 17, are shown in Table III.

Table III dose (mg.kg “mouse motility effect reserpine-induced ptosis antagonism DEso (mg. Kg” ¹ ) mouse behavior manifested by swelling dose effect (mg. Kg “ ¹ ) —48 ° / o + + 29–33% + (26-32) +

100 +: p 0.05 + +: p 0.01

The results of these tests show that the compounds of the invention have an effect on the neuron by occupying the γ-aminobutyric acid reception site. They have pharmacological properties in animal experiments, so that they can be used in human medicine for the treatment of psychological neurological or neuromuscular diseases.

In particular, the compounds of the invention may be used for the treatment of mental or behavioral disorders such as depression, asthenia, Parkinson's disease, digestive disorders or insomnia.

The compounds of the invention may be administered orally or by injection. Pharmaceutical compositions containing them as active ingredient may be solid or liquid and have

0.5 -50% + + -62% + + in the form of, for example, tablets, pills, granules, suppositories, or injections.

The dosage may vary within wide limits, in particular depending on the type and severity of the disease and the mode of administration. For an adult, when administered orally, the daily dose is most often 0.50 to 0.500 g and can be divided, if desired, into several portions.

By way of example, the following galenic composition: pill compound of Example 17 100 mg

Aerosil 0.5 mg magnesium stearate 1.5 mg starch STA RX 1 500 40 mg

150 mg

Claims (4)

A process for the preparation of pyridazine derivatives substituted in the 3-position by a carboxyalkylamino group of the general formula I in which R 1 is hydrogen, C 1 -C 4 alkyl, phenyl, phenyl monosubstituted with halogen or nitro or C 1 -C 4 alkyl or hydroxy of C 1 -C 4, halogen-disubstituted phenyl, naphthyl , cyclohexyl, thien-2-yl or thien-3-yl, R 2 is hydrogen, C 1 -C 4 alkyl or phenyl, R3 is hydrogen, (C1-C4) alkyl, phenyl or cyano, R 4 represents a carboxyl group and Alk represents a (CH2) _{n group} , wherein n is an integer of 2, 3 or 4, as well as their addition salts with mineral or organic acids, pharmaceutically acceptable, well substituted 3-chloropyridazine of formula II 250639 in which R1, R2 and Ro are as defined above, reacted with an excess of hydrazine hydrate NH2-NH2, the resulting hydrazino derivative of formula (III). in which R 1, R 2 and R 3 are as defined above, catalytically hydrogenated and the resulting amino derivative of the general formula IV Γ 'Γ ^NH 2uv' in which R1, R2 and R3 as defined above are reacted with a ω-halogenated compound of formula V X — Alk — R 1 (V) in which X is halogen, preferably bromine and R ⁴ represents a COO-alkyl group having 1 to 4 carbon atoms in the alkyl moiety a Alk is as defined above, and the resulting ester of formula obecného wherein R1, R2, Ro, R4 &apos; and Alk are as hereinbefore defined, saponified, whereupon the compound of formula I obtained is optionally converted into a pharmaceutically acceptable acid addition salt thereof. 2. The process of item 1 for the preparation of a pyridazine derivative substituted in the 3-position with a carboxyalkylamino group of formula (I) wherein R 1 is a phenyl group optionally substituted as in 1 or a naphthyl group, R 2 is hydrogen, R 5 is hydrogen, alkyl C1-C4, phenyl, Rd represents a carboxyl group and Alk represents a (CH2) group, wherein 11 represents an integer of 2 or 3, as well as its addition salts with a pharmaceutically acceptable mineral or organic acid, characterized by: 3. A process according to claim 1, wherein the 3-chloropyridazine of formula II, wherein R1, R2 and R3 are as defined above, is reacted with an excess of hydrazine hydrate to form the hydrazino derivative of formula III in which R1, R2 and R3 are as defined above. , the resulting amino derivative of the general formula IV in which R1, R2 and R3 are as defined above, is reacted with a ω-halogenated a compound of formula V wherein Alk is as defined above and X and R 1 are as defined in point 1, and the resulting ester of formula Γ wherein R 1, R 2, R 3 and Alk are as defined above and R 4 ^! The compound of formula (I) is saponified, whereupon the compound of formula (I) obtained is optionally converted into its addition salt with a pharmaceutically acceptable acid. 3. The process according to claim 1, wherein the saponification is carried out in an acid medium. 4. The process according to claim 1, wherein the saponification is carried out by heating with a hydrohalic acid such as hydrochloric or hydrobromic acid or with acetic acid at a temperature of 20 to 100 degrees Celsius.