SU1313346A3 - Method for producing substituted 6-aryl-3(2a)-pyridazinones - Google Patents

Abstract

The invention relates to substituted pyridazinones (PPs), in particular the preparation of compounds of general formula 1: -C N-NH-C (0) -CHTTTCR, where (-t) means a double or single bond between two carbon atoms; , CHj; A (III-imidazol-1-yl in the 3rd or 4th position of phenyl or (4,5,6, 7-tetrahydro-1H-benzimidazol-1-yl) in the 4th position of phenyl, which show cardiotonic activity and can be used in medicine.The goal is to create compounds with better activity.PZ preparation is obtained from γ-oxobenzenebutanoic acid with the substituent A, indicated above, and hydrazine in the medium of an organic solvent at the boiling of the reaction mixture with the release of PZ, where (ttt) means a single bond. After dehydrogenation, a PP is isolated, where (ttt) is a double bond. PP show that they are compared with the known active amrinone of cardio- tonic action (50-100 times) Table 1 EA 1:.. 0 SAE SO 4 ;: about:

Description

one

The invention relates to a process for the preparation of new substituted 6-aryl-3 (2H) -pyridazinones with cardiotonic properties, and can be used in medicine.

The aim of the invention is synthesized substituted 6-aryl-3 (2H) -pyridazinones with improved cardiotonic properties.

Example 1. Preparation of methyl 4- (1H-imidazol-1-yl) -p-oxobenzene-propanoate.

A solution of 4- (1H-imidazol-1-yl) -acetophenone (24.2 g; 0.13 mol) in tetrahydrofuran (250 ml) is added to a suspension of 50% NaOH (6.7 g) in tetrahydrofuran (70 ml) with stirring. The solution was stirred at room temperature for 1 h. Dimethyl carbonate (30 ml) was added, after which the mixture was heated under reflux overnight. The solid is filtered, the residue is treated with water and neutralized with acetic acid. The solid obtained in this way is filtered and recrystallized from methanol-ether to obtain 15.0 g of methyl 4- (lH-imidazol-l-yl) - - | l-oxybenzene solution.

Example 2. Preparation of 4- (1H- -imidazol-1-yl) -oxobenzenebutanoic acid.

A solution of 4- (1H-imidazol-1-yl) - 3 oxo-benzene-propanoic acid methyl ester (6.1 g; 0.025 mol) in tetrahydrofuran (65 ml) is slowly added to a re-stirring suspension of 50% NaOH (1 , 2 g; 0.025 mol in tetrahydrofuran (20 ml) and the solution is re-mashed for 1 hour. Bromoacetic acid ethyl ester (4.5 g) is added, after which the mixture is heated under reflux for 7-8 hours. Tetrahydrofuran is removed The residue is taken up in water and the organic material is extracted with ether. The residue obtained after removal of the ether is hydrolyzed by heating with 6 N. HCl for 8 hours. The crude acid is finally crystallized from dimethylformamide, yielding 3.3 g of 4- (1H-imidazl-1-yl) -oxoobenzenebutanoic acid.

Example 3. Obtaining 4,5-dihydro-6- 4- (1H-imidazol-1-yl) -phenyl 3- (2H) -pyridazinone.

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A solution of 4.5 g of 4- (lH-imidazole-1-yl) -X-oxybenzoic acid in ethanol (60 ml) is heated under reflux with 85% hydrazinehydrate (2.5 ml) for 7 h. The alcohol is evaporated, the residue is treated with water and filtered. The crude product is finally crystallized from ethanol to obtain 3.5 g of 4,5-dihydro-6-4- (1H-IMI-dazol-1-yl) -phenyl 3 -3 (2H) -pyridazinone; m.p. 206-207 ° С (with decomposition).

Calculated,%: C 65.00; H 5.00; N 23.33.

15

C ,, H ,, N, 0.

20

Found,%: C 65.06; H 5.35; N 23.39.

Example 4. The reaction of 4- (1H- -benzimidazol-1-yl) -J-oxobenzene-butanoic acid with hydrazine hydrate according to the method of Example 1 gives 4,5-dihydro-6-4- (1H-benzimidazol-1-yl -phenyl-3 (2H) -pyridazinone (Zi), 2 tons. pl. 262-264s

Example 5. Preparation of 4,5-dihydro-6-4- (1H-imidazol-1-yl) -phenyl-5-methyl-3 (2H) -pyridazinone (LC).

A suspension of RCN (6.6 g in 8 ml of water) is slowly added to a stirred solution of a mixture of 4- (1H-imidazol-1-yl) benzaldehyde (17.2 g), p-toluene sulfonic acid (19 g) and morpholine ( 11.4 g) in dioxane (100 ml). The mixture is heated under reflux for 3 hours, concentrated to half its volume and poured into a saturated solution of KjCOj. The oil is extracted with the extract, washed with water, dried and evaporated to give an oil, which is filtered through silica gel. The oil is finally crystallized from ether.

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To the transported solution of the indicated 4- (1H-imidazol-1-yl) -phenyl-4-morpholineacetonitrile in Ti, trahydrofuran (120 ml) is added 30 drops of 30% KOH in methanol followed by

 by slow addition of crotononitrile (4.2 g) over a 15-minute period, and the resulting mixture was stirred at room temperature for 90 minutes. Reaction mixture

55 are concentrated under vacuum, the residue is treated with water and the oil is extracted. Methylichloride extract is washed with water, dried: watered and

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concentrated, having obtained a high ecu resin.

It is dissolved in 30 ml of 6N. HCI and heated on the steam bath for 6 hours. The reddish solution is evaporated to dryness under vacuum, the residue is taken up in 150 ml of absolute alcohol, heated on the steam bath for 15 minutes and cooled. The inorganic salts are filtered off and the filtrate is used directly in the next stage. The filtrate is heated under reflux with 85% hydrazine hydrate (4 mp) for 4 hours. The solution is cooled, diluted with water and filtered. The solid is crystallized from ethano-lattetrahydrofuran to give 2.8 g of 4,5-dihydro-6-4- (1H-imidazol-1-yl) -phenylJ-5-methyl-3 (2H) -pyridazinone (3k), mp, 197-198 ° C,

Calculated,%: C 66.12; H 5.55; N22.04.

c ,, H,; N40.

Found,%: C 66.12; H 5.54; N 21.05.

Example 6. Pol.uda 4,5-di-hydro-6-1 3- (1H-imidazod-1 -yl) -phenyl-3 (2H) -pyridazinone.

A solution of 5.2 g of 3- (lH-imidazole-1-yl) -V-oxybenzene acid in ethanol (60 ml) is heated under reflux with 85% hydrazine hydrate (1.8 g) for 4 h. Alcohol evaporated, the residue is treated with water and filtered. The crude product is finally crystallized from ethanol to obtain 2.9 g of 4,5-dihydro-6-3- (1H-imidazol-1-yl) -phenyl-3 (2H) -pyridazino, m.p. 190-190, 5 ° C.

Calculated,%: C 64.98; H 5.03; N 23.39.

C, 3H, 2N40.

Found,%: C 65.02; H 5.08; N 23.33,

Example 7 Preparation of 4- (4,5 6,7-tetrahydro-III-benzimidazol-1-yl) -X-oxobenzene butanoic acid.

A solution of 4-fluoro-hydroxybenzene-butanoic acid (20 g; 0.1 mol) and 5,6,7,8-tetrahydrobenzimidazole (12.2 g; 0.1 mol) in DMSO (50 ml) is added drops to a suspension of 50% NaOH (9.6; 0.2 mol) in toluene (20 ml) with stirring, the temperature being maintained at about 30 ° C. At this point, add 33464

a large amount of DMSO (50 ml) and the mixture is stirred at room temperature overnight, after which it is heated at 100-110 ° C for 5 hours for 18 hours. The solution is cooled, extracted with ether and the aqueous solution is adjusted to pH 5. The thus obtained solid the substance is filtered off, washed with water and crystallized from dimethylformamide, to obtain 10 g of 4- (4,5,6,7-tetrahydro-1H-benzimidazol-1-yl) y-oxobenzene-butanoic acid, t, mp, 234 -235 C. Example 8, Preparation of 4,5-di-5-hydro-6- 4- (4,5,6,7-tetrahydro-1H-benzimidazol-1-yl) -phenyl-3 (2H) -pi readazinone.

A mixture of 9 g of 4- (4,5,6,7-tetrahydro-β-Sh-benzimidazol-1-yl) -y-oxobenzol-0 butanoic acid and 3.5 g of hydrazine hydrate in 80 ml of ethanol is heated under reflux in a for 6 h. The reaction mixture is allowed to cool and filtered. The crude pro-5 product is finally crystallized from 2-methoxyethanol to obtain 4.5 g of 4,5-dihydro-6-4- (4,5,6,7-tetrahydro-1H-benzimidazol-1-yl-phenyl -3 (2H) -pyridazinone, t, pl. 296- 297 ° С-.

Calculated,%: C 68.88; H 6.14; N 18.90.

0.1

.J5 Found,%: C 68.84; H 6.40; N 18.50.

Example 9. Preparation of - (1H-imidazol-1-yl) -phenyl-3 (2H) -pyridazinone (13a).

0 Bromine (1.6 ml) is added dropwise to a solution of 4,5-dihydro-6-t4- (1Nimidazol-1-yl) -phenyl-3 (2H) -pyridazinone (3.5 g) in acetic acid (25 ml) at 80 C. The mixture is heated in

5 for 6 hours to complete the reaction. The solid is filtered off, washed with ether and converted to the free base, which is recrystallized from ethanol to obtain 1.1 g (III imidazl-1-yl-phenyl-3 (2H) -pyridazinone, mp 244- 245 s.

Calculated,%: C 64.56; H 4.30; N 23.17; HjO 1.39.

C, 3H, oN40, 1/5, Found,%: C 64.30; H 4.36; N, 04; 1.11,

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Example 10 Preparation of - (1H-imidazol-1-yl) -phenyl-5-methyl -3 (2H) -11Iridazinone (3i).

A solution of 3.6 g of 4,5-dihydro-6- 4- - (IL-imidazol-1-yl) -phenyl-5-methyl-3 (2H) -pyridazinone in a mixture of dioxane (100 ml) and S , K-dimethylformamide (25 ml) is heated with 12 g of MnO during EO B overnight. The temperature is raised to 105 ° C and maintained there for 4 hours. The inorganic solid is filtered and washed thoroughly with hot dioxane. The filtrate and the washes are mixed under vacuum and the residue is crystallized from methanol and tetrahydrofuran to give 2.1 g of (III-imidazol-1-yl) -phenyl-5-methyl-3 (2H) -pyridazinone, t. pl, 284-286 C.

Calculated,%: C 66.65; H 4.79; N 22.21.

C ,, H ,,

Found,%: C 66.22; H 4.59; N 22.06.

Example 11. Obtaining - (W-imidazol-1-yl) -phenyl-3 (2H) - pyridazinone,

A solution of bromine (0.7 ml) in acetic acid (20 ml) is added dropwise to a solution of 2.6 g of 4,5-dihydro-6-z- (III-imidazol-yl) -phenyl-3 ( 2H) -Glyridazinone in acetic acid (85 ml at 90-95 ° C. The reaction mixture is heated under reflux for 3.5 hours. After cooling, the solid is filtered off, washed with ether and converted into the free base, which is crystallized from ethanol, to obtain 1.3 g of 6- 3- (1H-imidazol-1-yl) -phenyl 3 -3 (2H) pyridazone, t, pl. 234.5-236.5 ° C,

Calculated,%: C 65.53; H 4.23; N 23.52.

C, jH ,, N40.

Found,%: C 65.44; H 4.66; N 23.73.

Example 12. Preparation of - (4,5,6,7-tetrahydro-III-benzimidazol-1-yl) phenyl-3 (2H) -pyridazinone

A solution of bromine (1 g) in 10 ml of acetic acid is added dropwise to a solution of 1.6 g of 4,5-dihydro-6-4- (4, 5,6., 7-tetrahydro-1H-benzimidazol-1 - yl) -phenyl-3 (2H) -pyridazinone in 40 ml of acetic acid at 86-88 ° C. The mixture is then heated at 100 ° C for 4-5 hours. The reaction mixture is cooled, the solid is filtered 68

Happen, washed with ether and dried in air. The hydrobromide salt thus obtained is converted into the free base,

which is crystallized from ethanol to obtain 0.6 g of the product - (4,5,6, 7-tetrahydro-1H-benzimidazol-1-yl) -phenyl-3 (2H) -pyridazinone, t, pl. 266-267 ° C.

Calculated,%: C 69.35; H 5.50;

N 19.03.

C, HIS, 0.1. Found,%: C 69.25; H 5.36; N 19.03.

Test for determining cardiac inotronic activity in anesthetized dog.

This way of checking is to determine the effect of increasing

intravenous doses of the compound per myocardial contractility (dp / dt maximum blood pressure of the left ventricle), heart rate and aortic blood pressure of the dog anesthetized with pentobarbital.

Adult mongrel dogs of both sexes are anesthetized with pentobarbipam - 35 mg / kg intravenously, and then

Anesthesia is maintained by continuous pentobarbitol injection of 3.5 mg / kg / h. The trache is intubated, but animals can breathe spontaneously. A cannula is inserted into the femoral vein to inject the test compounds. A catheter pressure sensor is inserted into the ascending aorta through the femoral artery to measure aortic blood pressure.

Millara (MiElar) or filled

liquid cat €; ter. The Millar catheter probe is passed into the left ventricle through the carotid artery to measure the blood pressure in the left ventricle. Needle electrodes are injected subcutaneously to record the course II of the electrocardiogram (ECG).

Blood pressure in the left ventricle and aortic blood pressure are recorded on a tape recorder. A heart rate is also recorded using a biotachometer triggered by an R-wave ECG, and the first derivative of blood pressure in the left ventricle (dp / dt), obtained using a differential amplifier, is recorded.

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pressure vessel. A period of at least 30 minutes is used to obtain control results before administration of the test compound,

Depending on the solubility, the compounds are dissolved in 0.9% saline solution either in dilute HC1 or in NaOH (0.1 or 1.0 N) and diluted to the required volume with normal saline. If necessary to make the appropriate dilutions then ethanol or dimethylacetamide can be used as solvents. Enter appropriate control media, when necessary,

Each dose of the test compound is administered in a volume of 0.1 ml / kg for 1 minute.

In tests using the described anesthetized dog, the compounds of the invention, when administered intravenously at a rate of about 0.01-0.31 kg / kg / min, cause a significant dose-dependent increase in cardinal contractility, which is accompanied only by small or minimal changes in heart rate and blood pressure.

The test results of 4,5-dihydro-6- 3- (1H-imidazol-1-yl) -phenyl--3 (2H) -pyridazinone (A.) and (III-imidazol-1-yl-phenyl-3 (2H) -pyridazinone (B.) using the technique with an anesthetized dog are presented in the table.

Peripheral vessel dilatation activity CI-9I4 (table) was analyzed in comparison with amrinos on anesthetized dogs using the forelimb prefusion method. CI-914 or amrinone is applied locally to the brachial artery in which the blood flow is kept constant. The results of this study caused a dose-dependent decrease in pressure in the brachial artery, while no significant effect on blood pressure in the arterial system was noted. Amrinon led to similar effects, but it was about 50-100 times

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weaker compared with the compounds according to the proposed method as regards the expansion of peripheral vessels.

Claims (1)

Invention Formula The method of obtaining substituted 6-aryl-3 (2H) -pyridazinones of the general formula R 15 (I) where is a double or single bond between two carbon atoms; R is hydrogen or methyl; A - (lH- and ffldazol-yl) in the 3- or 4-position of phenyl, or (4,5,6,7-tetrahydro-1H-benz-imidazol-1-yl) in the 4-position of phenyl, characterized in that - oxobenzenebutanoic acid of general formula thirty (Ii) 35 where A and R have the indicated meanings, are reacted with hydrazine of the formula HjN - NHj (Iii) in a medium with an organic solvent at the boiling point of the reaction mixture and the desired product is isolated with the general formula (I), where it means a single bond between two carbon atoms, or further dehydrogenation is carried out and the desired product is isolated General formula (I), where - means a double bond between two carbon atoms. Priority featured: 17.09.81 when R is hydrogen or methyl, A - (1H-imidazol-1-yl); 07.27.82 when R is hydrogen or methyl, A - (4, 5,6,7-tetrahydro-III-benzimidazol-1-yl),