CS244682B2 - Production method of new pyridazinylhydrazone derivatives - Google Patents

Abstract

Process for preparing novel pyridazinylhydrazone derivatives of formula (I) R CH 2 COOR 1 X as well as their physiologically acceptable addition salts salts with acids, with the hydrazine derivative of formula II (I) is reacted with an ether of formula III R-C = C-COOR 1 (III) and the resulting base is optionally converted by reaction with a pharmaceutically acceptable acid addition salt acid salt. Produced compounds have

Description

R

CH 2 COOR ¹

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

is reacted with an ether of formula III

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

The compounds produced have a significant blood pressure lowering effect.

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

R

X ~ in which

X represents a chlorine atom or a morpholino group,

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

In a book by S. M. Rapaport Med. Biochemistry, publ. VEB-Verlag Volk und Gesundheit, Berlin, 1965, p. 720 states that noradrenaline is primarily a blood pressure regulator in both the human and higher animal organisms. It is further mentioned in a book by O. Sohier and A. Marxer Arzneimittelforschung, publ. Birkháuser, Basel, 1969, Vol. 13, p. 107 that abnormally high blood pressure can be reduced by inhibiting noradrenaline biosynthesis; in this biosynthesis, tyrosine is hydrolyzed in the first step, the reaction being catalyzed by the enzyme tyrosine hydroxylase, the third step of this biosynthesis is dopamine β-hydroxylation, wherein the dopamine-γ-hydroxylase enzyme is used as the catalyst.

It has now been found that the novel pyridazinylhydrazone derivatives prepared by the process according to the invention are surprisingly characterized by an inhibitory effect on both the above-mentioned enzymes - tyrosine hydroxylase and also dopamine-γ-hydroxylase, thereby inhibiting noradenaline biosynthesis so that significant and sustained blood pressure lowering effect.

Accordingly, the present invention provides a process for the preparation of novel pyridazinylhydrazone derivatives of the formula I or physiologically acceptable acid addition salts thereof, which process is characterized in that the hydrazine derivative of the formula II

in which X is as defined above, is reacted with an ester of formula III

R-CMC-COOR ¹ (III) wherein

R a r! are as defined above, and the resulting base is optionally converted by treatment with a pharmaceutically acceptable acid into an acid addition salt.

In particular, medicaments having a predominantly blood pressure-lowering effect can be prepared by the process according to the invention by at least one of the novel pyridazinylhydrazone derivatives of the formula I or a physiologically acceptable acid addition salt thereof, optionally together with other pharmacologically active compounds and / or with conventional carriers or auxiliary substances, in a known manner, into pharmaceuticals in the form of tablets, suppositories, injectable solutions, emulsions, suspensions and the like.

From the starting materials of formula II used in the process according to the invention, the following are known from the literature: 3-chloro-pyridazin-6-yl-hydrazine (Yakugaku Zasshi, 75, 1955, p. 779, or Chemical Abstracts 5Q, 1956, p. 4 970b). 4-hydrazino-3,6-dichloropyridazine (Pharm. Bull., J5, 1957, p. 376); pyridin-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, amino-substituted pyridazinylhydrazines (e.g., J. Med. Chem., 18_, 1975, p. 741)). pyridazinylhydrazines not previously described.

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

To prepare acid addition salts of the compounds of formula I, the free base is conveniently dissolved in a solvent such as ether, methanol, ethanol or isopropyl alcohol, and a methanolic, ethanolic or ethereal solution of the inorganic acid is added dropwise with cooling or a solution is added. organic acids in methanol, ethanol, isopropyl alcohol ether or acetone. The precipitated salt is filtered off and recrystallized.

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

The in vitro tyrosine hydroxylase inhibition effect of the compounds of the invention was determined by the Nagatsu method (Anal. Biochem, p. 122 fl964j) on a rat adrenal homogenate. Radioactive tyrosine was purified according to the method of Ikeda (J. Biol. Chem., 241, p.4522, 1966j). The tyrosine hydroxylase activity of the rat adrenal homogenate was 0.64 ± 0.08 nmol / mg of egg white for 1 hour. Dopamine-β-hydroxylase activity was determined on a partially purified bovine adrenal preparation using a somewhat modified Nagatsu method (Β B. B. Acta, 139, 319 [1967]). The bovine adrenal preparation had a specific activity of 780 + 50 nmoles / mg egg white and 1 hour.

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

Table I

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

Table I continued

Example compound

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 blood pressure lowering effect of the compounds of the invention was investigated in spontaneously hypertensive rats (Wistar-Okamoto) (Arzn. Forsch., 6, p. 222 [Ϊ95δ]). Systolic eye blood pressure in the tail artery of non-sleeping animals was measured by the indirect method 4, 24, 48 and 72 hours after oral administration of the test compounds. Effect of several compounds according to

The invention for reducing blood pressure is shown in Table II. Table II Lowering blood pressure 4 hours 24 hours after application Acute toxicity of LD _{5 ()} on mice (mg / kg po) Compound from the example Dose mg / kg 1 50 -25 -11 , 200 2 50 -25 -25 530 3 50 -18 -23 > 200 acid fusarová 50 -33 0 80 (i.p.)

The results of biochemical and pharmacological experiments show that a long-term and significant decrease in blood pressure occurs concomitantly with an inhibitory effect on the action of the enzyme. The therapeutically effective daily dose of the compounds of formula I is 50 to 3000 mg / kg.

The invention is illustrated by the following examples.

Example 1

1,2-bis- (methoxycarbonyl) ethylidene- (3-chloropyridazin-6-yl) hydrazine.

To a mixture of 14.45 g (0.1 mol) of 3-chloropyridazin-6-yl-hydrazine with 100 ml of dioxane is added dropwise 14.21 g (0.1 mol) of acetylendicarboxylic acid dimethyl ester in 75 ml at room temperature with stirring at room temperature. ml dioxane. After stirring for a further 5 hours, the dioxane was evaporated under reduced pressure and the residue was recrystallized from alcohol. Yield 19.5 g (68.5%), m.p. 138-141 ° C.

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

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 tetrolic acid ester, 20 ml of ethanol and 2 drops of a 10% ethanolic hydrochloric acid solution is stirred and refluxed for 5 hours. The mixture is allowed to boil overnight and then evaporated to dryness under reduced pressure. The evaporation residue is triturated with ether, filtered and dried. Yield 0.98 g (38.5%). Melting point 124-126 ° C.

Example 3

2-Ethoxycarbonyl-et-1-ylidene- (3-chloropyridazin-6-yl) hydrazine

The procedure is as in Example 1, but starting from ethyl propiolic acid. Yield 65%, mp 115-117 ° C.

Example 4

2-ethoxycarbonyl-et-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 propiolic acid ethyl ester.

Yield 43%, mp 180-184 ° 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.