CS244682B2 - Process for preparing novel pyridazinylhydrazone derivatives - Google Patents

Abstract

A method for the preparation of novel pyridazinylhydrazone derivatives of the general formula I R CH^COOR1 X as well as their physiologically acceptable acid addition salts, wherein a hydrazine derivative of the general formula II (I) is reacted with an ether of the general formula III R-C=C-COOR1 (III), and the resulting base is optionally converted into an acid addition salt by reaction with a pharmaceutically acceptable acid. The compounds produced have

Description

R

CH^COOR ¹

X as well as their physiologically acceptable acid addition salts, wherein the hydrazine derivative of the general formula II

reacts with an ether of general formula III

RC=C-COOR ¹ (III), and the resulting base is optionally converted into an acid addition salt by reaction with a pharmaceutically acceptable acid.

The compounds produced have a significant effect on lowering blood pressure.

The invention relates to a process for the production of novel pyridazinylhydrazone derivatives of the general formula I

R

X ~ in which

X represents a chlorine atom or a morpholine group,

R represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or an alkoxycarbonyl group with 1 to 3 carbon atoms in the alkoxy moiety and R1 represents an alkyl group with 1 to 4 carbon atoms, as well as addition salts thereof with physiologically acceptable acids.

In the book by S. M. Rapaport Med. Biochemie, published by VEB-Verlag Volk und Gesundheit, Berlin, 1965, p. 720, it is stated that in the human organism and in the organism of higher animals, noradrenaline is mainly the regulator of blood pressure. It is further stated in the book by O. Sohier and A. Marxer Arzneimittelforschung, published by Birkháuser, Basel, 1969, vol. 13, p. 107, that it is possible to reduce abnormally high blood pressure by inhibiting the biosynthesis of noradrenaline; in this biosynthesis, tyrosine is hydrolyzed in the first stage, which reaction is catalyzed by the enzyme tyrosine hydroxylase, the third stage of this biosynthesis is the β-hydroxylation of dopamine, in which the enzyme dopamine-γ-hydroxylase serves as a catalyst.

It has now been found that the new pyridazinylhydrazone derivatives, prepared by the method according to the invention, are surprisingly characterized by an inhibitory effect on both the above-mentioned enzymes - tyrosine hydroxylase and dopamine-γ-hydroxylase, whereby the biosynthesis of noradrenaline can be inhibited, so that these new compounds of general formula I achieve a very significant and lasting effect in lowering blood pressure.

The subject of the invention is therefore a process for the production of new pyridazinylhydrazone derivatives of the general formula I, or their physiologically acceptable acid addition salts, which process is characterized in that a hydrazine derivative of the general formula II is

in which X has the above meaning, is reacted with an ester of general formula III

R-CMC-COOR ¹ (III), in which

R and r have the meanings given above, and the resulting base is optionally converted into an acid addition salt by reaction with a pharmaceutically acceptable acid.

The method according to the invention can be used to prepare, in particular, drugs with an effect mainly on lowering blood pressure by converting at least one of the obtained new pyridazinylhydrazone derivatives of the general formula I or its physiologically acceptable acid addition salt, optionally together with other pharmacologically active compounds and/or with conventional carriers or excipients, in a known manner into drugs in the form of tablets, suppositories, injection solutions, emulsions, suspensions, etc.

The following starting materials of the general formula II used in the process according to the invention are known from the literature: 3-chloro-pyridazin-6-yl-hydrazine (Yakugaku Zasshi, 75, 1955, p. 779, or Chemical Abstracts 50, 1956, p. 4970b). 4-hydrazino-3,6-dichloropyridazine (Pharm. Bull., J5,, 1957, p. 376) j pyrida2in-3-yl-hydrazine (Bull. Soc. Chim. France,

1959, p. 1793); 3-methylpyridazin-6-yl-hydrazine (J. Pharm. Soc. Jap., 1955, p. 776);

3-cyanopyridazin-6-yl-hydrazine (Hungarian Patent No. 165,304 and in addition pyridazinylhydrazines substituted with an amino group (e.g. J. Med. Chem., 18_, 1975, p. 741). The examples given below also discuss pyridazinylhydrazines, which have not been described so far.

Esters of the general formula III, used as starting materials, are generally prepared by reacting the acetates of alkyltriphenylphosphoranilides with acid chlorides and subjecting the resulting acyl ylides to pyrolysis (Liebigs Annalen 1977, p. 282).

To prepare the acid addition salts of the compounds of the general formula I, the free base is conveniently dissolved in a solvent, e.g. in ether, methanol, ethanol or isopropyl alcohol, and to the resulting solution is added dropwise, under cooling, a methanolic, ethanolic or ethereal solution of the corresponding inorganic acid, or a solution of an organic acid in methanol, ethanol, isopropyl alcohol, ether or acetone. The precipitated salt is filtered off and recrystallized.

As inorganic acids, hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid are preferably used, as organic acids, tartaric acid, maleic acid, fumaric acid, methanesulfonic acid, ethanesulfonic acid or 4-toluenesulfonic acid are preferably used.

The in vitro tyrosine hydroxylase inhibitory activity of the compounds prepared by the method of the invention was determined by the method of Nagatsuho (Anal. Biochem, p. 122, 1964) on rat adrenal homogenate. Radioactive tyrosine was purified by the method of Ikeda (J. Biol. Chem., 241, p. 4452, 1966). The tyrosine hydroxylase activity of the rat adrenal homogenate was 0.64 ± 0.08 nmol/mg protein and 1 hour. The dopamine-α-hydroxylase activity was determined on a partially purified preparation of bovine adrenal using a slightly modified method of Nagatsuho (Β. B. Acta, 139, p. 319 [1967]). The bovine adrenal preparation had a specific activity of 780 ± 50 nmol/mg protein and 1 hour.

The inhibitory effect of several compounds of the invention is shown in the following Table I.

Table I

Compound from the example Compound Concentration (mol/liter) Inhibitory effect on the action tyrosine- hydroxylases dopamine-/^- hydroxylase (%> 10- ⁴ 36 50 1 10- ⁵ 10 0 10 ⁴ 100 100 2 50 87 10 ⁵ 10 ^-4 - 73 3 10 ^-5 - 44

Table I continued

Compound from the example

Compound concentration (mol/liter)

Inhibitory effect on the action of tyrosine-dopamine-^hydroxylase hydroxylase (%)

10' ⁴ 0 100 fusaric acid

10 ^-5 0 100

DL-/-methyl- 10

-4-hydroxyphenylalanine 10

100 0

0

The effect of the compounds according to the invention on lowering blood pressure was investigated in spontaneously hypertensive rats (Wistar-Okamoto) (Arzn. Forsch. , _6_, p. 222[Ϊ95δ]). Systolic blood pressure in the tail artery of the awake animals was measured by the indirect method 4, 24, 48 and 72 hours after oral administration of the compounds under investigation. The effect of several compounds according to

of the invention for lowering blood pressure is shown in Table II. Table II Blood pressure reduction 4 hours 24 hours after application Acute toxicity LD ₅₀ (mg/kg po) in mice Compound from the example Dose mg/kg 1 50 -25 -11 ,200 2 50 -25 -25 530 3 50 -18 -23 >200 acid fusarium 50 -33 0 80 (i.p.)

The results of biochemical and pharmacological experiments demonstrate that a long-term and significant reduction in blood pressure occurs simultaneously with an inhibitory effect on the enzyme activity. The therapeutically effective daily dose of the compounds of general formula I is 50 to 3,000 mg/kg.

The invention is further illustrated by the following examples.

Example 1

1,2-Bis-(methoxycarbonyl)ethylidene-(3-ochloropyridazin-6-yl)hydrazine.

To a mixture of 14.45 g (0.1 mol) of 3-chloropyridazin-6-yl-hydrazine in 100 ml of dioxane, 14.21 g (0.1 mol) of acetylenedicarboxylic acid dimethyl ester in 75 ml of dioxane were added dropwise over 30 minutes while stirring at room temperature. The mixture was stirred for a further 5 hours, after which the dioxane was evaporated under reduced pressure and the residue was recrystallized from alcohol. The yield was 19.5 g (68.5%), melting point 138-141 °C.

3-Ethoxycarbonylprop-2-ylidene-(3-chloropyridazin-6-yl)hydrazine (Example 2) was prepared in 38.5% yield by the same procedure.

Example 2

3-ethoxycarbonyl-prop-2-ylidene-(3-chloropyridazin-6-yl)hydrazine

A mixture of 1.45 g (10 mmol) of 3-chloro-6-pyridazinylhydrazine, 1.12 g (10 mmol) of ethyl tetrolate, 20 ml of ethanol and 2 drops of a 10% ethanolic hydrochloric acid solution is heated to reflux for 5 hours with stirring, then left to stand overnight and then evaporated to dryness under reduced pressure. The residue after evaporation is triturated with ether, filtered and dried. Yield 0.98 g (38.5%). Melting point 124-126 °C.

Example 3

2-ethoxycarbonyl-ethyl-1-ylidene-(3-chloropyridazin-6-yl)hydrazine

The procedure is as in Example 1, except that ethyl propiolate is used as the starting material. The yield is 65%, melting point 115-117°C.

Example 4

2-ethoxycarbonyl-ethyl-1-ylidene-(3-morpholinopyridazin-6-yl)hydrazine

The procedure is as in Example 1, except that 3-morpholinopyridazin-6-yl-hydrazine is used as the starting compound, which is reacted with ethyl propioic acid ester.

The yield is 43%, the melting point is 180 to 184 °C.

Claims (1)

A process for the preparation of novel pyridazinylhydrazone derivatives of the general formula I = c in which X represents a chlorine atom or a morpholino group, R is hydrogen, C 1 -C 4 alkyl or C 1 -C 3 alkoxycarbonyl in the alkoxy moiety; and R ¹ represents a C 1 -C 4 alkyl group and their physiologically acceptable acid addition salts, characterized in that the hydrazine derivative of the general formula II NH-NHo in which X is as defined above, reacted with an ester of formula III R-CsC-COOR ¹ (II) (III) In which R @ 1 and R @ 2 are as defined above, and the resulting base is optionally converted by treatment with a pharmaceutically acceptable acid into an acid addition salt.