SU1486061A3 - Method of producing derivatives of pyridazinone or their salts - Google Patents

Description

The invention relates to heterocyclic compounds, in particular the production of derivatives of pyridazinone formula

one

The invention relates to a method for producing new derivatives of pyridazinone or their salts, which are stimulants of cardiac activity, exhibiting a vasodilator effect _; and having the ability to lower blood pressure.

The aim of the invention is a method of obtaining derivatives of pyridazinone or their salts, having a prolonged cardiotonic action and exceeding in its biological activity known substances of the same action.

EXAMPLE 1 6- ^ 4- [4- (4-Methoxybenzyl) -1-piperazinyl-carbonylZ-fe-

where K ,, K _g and 1 < ₃ - H or C _A -C ₄ -alkoxygroup, ^- Cd-C4-C ₄ -alkyl group, or their salts, which are stimulants of cardiac activity. The goal is to identify new, more active compounds. Their preparation is carried out by the interaction of the corresponding carboxylic acid with the amine of formyl _g

.¾

where K,, K _g and Kz indicated above. The process is carried out with the selection of the target product in free form or in the form of a salt. 1 tab.

Nile ^ -4,5-dihydro-5-methyl-3 (2H) -pyridazinone (hydrochloride)

; 0Η ₃ 0 - @ - € Η ₂ -ΝθΝ- with

ch ₃

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511 „„ 1486061

A mixture of 0,, 23 g of 4- (1,4,5,6-tetragvdro — 4-methyl-6-oxo-3-pyridazinyl) benzl carboxylic acid, 0.5 ml of a solution of triethylamine in tetrahydrofuran (containing .0.10 g triethylamine), 4 ml of,-dimethylformamide and 6 ml of tetrahydrofuran are cooled to (-20) (, -30) ° C. After cooling

3

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A solution of ethyl chloroformic acid in tetrahydrofuran (containing 0.11 g of ethyl chloroformic acid) is added in about 1 minute. After the addition and additional stirring (20 min) at the indicated temperature, add 3 ml of a solution of 0.21 x ’p-methoxbysyl piperazine in dichloromethane at the same temperature. Then the temperature is gradually raised to room temperature and after 1 h, 10 ml of tetrahydrofurap with methanol (1: 1) are added until a homogeneous mixture is formed, and 1 g of silica gel is added in addition. After that, concentrate to dryness in an evaporator.

Silica gel with the adsorbed product is placed in a column filled with 20 DU 30 g of silica gel and purified by column chromatography with a mixture of chloroform and methanol (from chloroform alone to a ratio of 10: 1). Fractions containing the desired product ,. 25 is evaporated and dissolved in 5 ml of, Ν-dimethylformamide and 10 ml of ethanol, to which 1.5 ml of 1N is added. hydrochloric acid in ethanol. An additional 30 ml of this ~ ash ether and 50 ml of n-hexane are then added. The precipitated crystals are collected by filtration and dried, which gives the hydrochloride salt of the desired 6- [4- [4- (4-methoxybenzyl-1) -piperaeiyl-carbonyl] -phenyl "^ -4,5-dihydro-5-methyl-3 (2H ) pyridazinone in the amount of 0.26 g (58% yield). 'IR: 1635 cm *', mp.242244 ° C.

PRI mme R 2. 6- £ 4- [4- (2,3,4-trimethoxybenzyl) -1-piperazinyl-carbonyl ^ -phenyl ^ -4,5-dihydr o-5-methyl-3 (2H ) pyridazion (hydrochloride)

ch ₃

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A mixture of 0.23 I "4- (1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl) benzene of carboxylic acid, 0.5 ml of solution, triethylamine in tetrahydrofuran (containing 0 , 10 g of triethylamine),

4 ml of Ν, Ν-dimethylformamide and 6 ml of te'hydrogen furan are cooled to (-20) (-30) · C. After cooling to 55, with stirring, a solution of ethyl chloroformate in tetrahydrofuran (containing 0.11 g of ethyl chloroformate kis ^0Η 3θ ~ @ ^"0Η 2" ^Ν Ο ^Ν

ch ₃ oon _h

lots) in about 1 min. After additional stirring (20 minutes) at the same temperature, add 3 ml of a solution of 0.27 g of 2,3,4-trimethoxybenzylpiperazine in dichloromethane at the same temperature. Then the temperature is gradually raised to room temperature and after 1 h, 10 ml of a mixture of tetrahydrofuran and methanol (1: 1) are added dropwise until a homogeneous mixture is formed, and 1 g of silica gel is added, followed by concentration to dryness in an evaporator.

Silica gel containing the target product adsorbed on it is placed in a column filled with 30 g of silica gel and subjected to column chromatography using a mixture of chloroform and methanol (from chloroform alone to a 10: 1 ratio). The fractions containing the desired product are evaporated, the product obtained is dissolved in 5 ml of, -dimethylformamide and 10 ml of ethanol, to which 1.5 ml of 1N is added. a solution of hydrochloric acid in ethanol, and an additional 50 ml of ethyl ether and 50 ml of n-hexane. The precipitated crystals are collected by filtration and dried. Get the hydrochloride salt of the target 6- £ ί- (2,3,4-trimethoxybenzyl) -1-piperazinyl-carbonyl) -phenyl ^ -4,5-dihydro-5-methyl-3 (2H) -pyridazininone in the amount of 0 , 21 g (yield 41/0, t. Pl. 180-182 ° C. IR: 1635 cm · ¹ '.

Example 6- [4- [4- (2,3,4 -Trimethoxybenzyl) -1-piperazinyl-carbonshk] -phenyl} -4,5-dihydro-5-methyl-3 (2H) -pyridzionium

MeO ОИе / СШ

me-^ y-sn ^ -X ^ -c -CoU- 0 = 0

⁰ ............. '(III)

A mixture of 4.71 g of 4- (1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl) benzene carboxylic acid, 2.83 ml of trimethylamine, 120 ml of tetrahydrofuran and 80 ml of, Ν- dimethylformamide is cooled to (-20) - (- 30) ° C. After cooling, add 1.4 ml of ethyl chloroformate with stirring. After adding and subsequent mixing-. 20 ml of a solution of 5.4 g of 2,3,4-trimethoxybenzylpiperazine in dichloromethane at the same temperature is added over 20 minutes at the same temperature.

5 1486061

Then the temperature is gradually brought to room temperature, after 19 hours the solvent is evaporated and the residue is extracted with ethyl acetate and dried over sodium sulfate. The extract is concentrated. The residue is chromatographed with chloroform: methanol at a ratio of 10: 1. The fractions containing the expected product were evaporated and the resulting solid vesche- ₁₀ GUSTs perekristallieovyvayut from ethanol. 5.11 g of the title compound are obtained (yield 52.5 ^).

The suitability of the compounds obtained in examples 1 and 2, as 15

stimulants of cardiac activity are shown by pharmacological tests carried out according to standard methods, for example, by observing a significant increase in the contraction of the papillary muscle (tizsi11 ratNagaz) recovered from the dog and the muscle of the left atrium recovered from the guinea pig. In addition, a significant increase in heart muscle contraction is observed in an anesthetized dog.

Pharmacological tests carried out as follows.

A method for using an isolated 30 papillary muscle preparations in the ventricles of the heart with transverse circulation obtained from a dog.

The papillary preparation isolated and provided with transverse circulation __

about 5

Howling muscles in the ventricles of the heart, obtained from a dog, are prepared according to the method of Endo and Hashimoto. The compound dissolved in the solvent is injected intraarterially by injection into the preparation and the papillary muscle contraction in the ventricles of the heart is recorded.

The method of use of the drug isolated left atrial of the guinea pig.

After striking the head of a male guinea pig with a body weight of 200300 g, the left atrium is immediately removed. The left atrioventricular opening is fixed at the bottom of the bath for parts of the body, filled with 30 ml of Krebs-Henseleit solution, kept at 35 C. The gaseous mixture (95 ^ oxygen and 5% carbon dioxide) is passed through the solution by Krebs-Henseleit, which is in the bath. Isometric voltage is measured by attaching the thread to the left atrium of the heart, and the other end

threads - to the transducer sensor. The drug is loaded with a residual voltage of 0.5 g. Then two plate electrodes are attached to the drug and electrically actuated, delivering rectangular pulses with a duration of 1 ms and 1.5 to a threshold voltage at a rate of twice per second. After the drug has stabilized for 30 minutes, the compound is added to the bath, dissolved in a solvent, and the effect is recorded.

Method of use of anesthetized dogs.

Male or female "mangrel" dogs weighing 8-15 kg are used. The dogs are anesthetized with 30 mg / kg pentobarbital sodium (intravenous injection) and an artificial respirator is attached. Produce thoracotomy between the left fourth and fifth ribs and the fifth rib is removed. Near-heart bag is cut to expose the heart. The blood flow through the aorta is measured by attaching a probe of an electromagnetic device for measuring the speed of current to the ascending aorta, which is used as an approximate indicator of the work of the produced heart (CO). Left ventricular pressure is measured by immersing a catheter connected to a pressure transducer to the left ventricle. Electrically measure the rate of increase in left ventricular pressure (άρ /). Contractions of the right ventricular wall (Sopo) are determined using a strain gauge attached to the wall of the right ventricle. Systemic blood pressure is measured from the left femoral artery. The number of heartbeats (per minute) is measured by an electrocardiogram (stroke P). The compound dissolved in the solvent is administered as a therapeutic agent intravenously along the left femoral vein.

As a result of carrying out the described pharmacological tests, it turned out that all drugs that stimulate heart activity cause an increase in the contraction of the nipple muscle of the dog, as well as the left atrial muscle of the guinea pig; in addition, the maximal rate of increase in left ventricular pressure (<1С / <1 _кс ), SOPG and CO is enhanced, i.e. gain reduction7

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Niya cardiac muscle anesthetized dogs.

The table shows the rate of increase of the papillary muscle contraction in the ventricles of the heart in a dog when administered with the proposed compound for an amount of 30 μg, the amplification rate of the contraction of the left atrium of the guinea pig when administered with a therapeutic aim of 10 ~ ^? g / ml and the rate of increase in L / Sop and CO in an anesthetized dog when administered with a therapeutic goal of 10 and 30 µg / kg, as well as 15 results of comparative tests of the proposed compounds (I-XII) with known compounds:

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The proposed table shows the degree of increase in each measured value in percent during anesthesia of dogs.

The proposed compounds tested 45 for toxicity when administered intravenously to mice:

Connection P ^ 5P "mg / kg

I 148.2

II * 114.0

they can be classified as low-toxic.

Pyridazinone derivatives or. their salts, suitable as a means of stimulating heart activity, also have an active effect on the expansion of the lumen of blood vessels and lower blood pressure.

Claims (1)

Claim 20 The method of obtaining pyridazinone General formula where K, K ₄ and 1C is hydrogen or C, -C ₄ -alkoxy, * 4-C ₍ -C4 is an alkyl group, or their salts, characterized in that the carboxylic acid of the General formula · where 1C has the indicated meanings, is reacted with an amine of the general formula , and 3 ^ dn _g - <> ^{n g} Sat where K,, and K.3 have the indicated meanings, with the selection of the target product in free form or in salt form. 9 1486061 1 o Compound Papillary muscle contraction in the ventricles dog heart (30 µg intraarterially) Contraction of the left atrial muscle in a guinea pig (10 ” ^? G / ml) Anesthetized dog. Vine, µg / kg intravenously ^a P ^{/ c} m m <w * Sop £ WITH I 23.0 41.7 ten 28.7 28.7 13.2 thirty 60.2 68.4 21, 3 II 22.1 27.4 ten 26,8 31.5. 12.1 III ' - - thirty 70.2 78.6 22.4 IV - - 100 66.6 37.1 17.1 V - - 300 28.7 36.1 13.8 VI - - 100 29.1 64.3 8.1 VII - - 100 33.3 45.1 20.2 !