CS195293B2 - Method of producing novel derivatives of pyridazine - Google Patents

Description

The present invention relates to a process for the preparation of novel pyridazine derivatives of the general formula

where

R1 represents a hydrogen atom, a trifluoromethyl group, an alkyl group having 1 to 5 carbon atoms, a free mercapto group or an alkylmercapto group having 1 to 3 carbon atoms or a phenyl radical optionally substituted by a fluorine atom, methyl, hydroxyl, methylmercapto, methylsulfinyl, methylsulfonyl or a dimethylamino group or one to three methoxy groups,

A represents a hydrogen atom,

B represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or

A and B together form another bond,

R2 represents a hydrogen atom or a lower alkyl radical having 1 to 3 carbon atoms, or

R2 together with D form another bond, and

R3 represents a chlorine atom, a methylamino, a morpholino or a 4-methylpiperazine group or, in the case where R2 represents a hydrogen atom or a lower alkyl radical having 1 to 3 carbon atoms,

R 3 together with D denotes an oxygen atom as well as their physiologically tolerable salts with inorganic or organic acids.

Compounds of formula I and their physiologically tolerated compounds. addition salts with inorganic or organic acids have valuable pharmacological properties, especially blood pressure lowering effects, antithrombotic and cardiotonic effects.

The 3-oxopyridazine derivatives of the formula I are prepared by the process according to the invention by reacting a compound of the formula II

198293

195203 where

A, B and R 1 are as defined above, or an ester thereof, in reaction with a compound of formula III

HžN — ΝΉ — R2 (ΠΙ), where

R2 is as defined above.

The reaction is conveniently carried out in a solvent such as glacial acetic acid, ethanol, isopropanol or an excess of the compound of formula III used at elevated temperatures, for example at temperatures between 50 and 150 ° C. However, the reaction can also be carried out without solvents.

The compound of formula I obtained according to the invention wherein D and R3 together represent an oxygen atom is then optionally converted, for example by heating with the appropriate phosphorus oxyhalide, phosphorus halide or thionyl chloride to temperatures between 80 and 150 ° C, to the corresponding halogen compound and thus the halogen compound obtained can then, for example, be converted to the corresponding amino compound by heating with the corresponding amine at temperatures between 100 and 250 ° C, optionally in a solvent such as ¹ in ethanol, isopropanol, glycol, dimethylsulfoxide, dimethylformamide, or by hydrolysis, for example , is converted to the corresponding 3-qx compound.

Compounds of formula I wherein A and B are hydrogen atoms may optionally be additionally dehydrogenated to a compound of formula I wherein A and B together form a carbon-carbon bond. The dehydrogenation can be carried out with bromine in glacial acetic acid, phosphorus pentachloride, sodium 3-nitrobenzenesulfonic acid, chromium trioxide, bromosuccinimide, hydrogen peroxide or sodium nitrite using known procedures. Compounds of formula I wherein R 1 is a phenyl radical substituted with a methylsulfinyl or methylsulfonyl group can be obtained from the corresponding methylmercaptophenyl compounds by oxidation in a known manner. Methylsulfinyl residues are obtained, for example, by oxidation with hydrogen peroxide at room temperature, the methylsulphoryl compound is obtained by oxidation with hydrogen peroxide at a temperature of about 70 ° C. ·

Compounds of formula I wherein R 1 is a phenyl radical substituted with a hydroxyl group can then be methylated. The methylation is conveniently carried out in a solvent such as ethanol, methyl iodide or dimethylsulfate in the presence of an inorganic base or diazomethanein, preferably at temperatures between 0 and 25 ° C.

Compounds of formula I wherein R 1 is mercapto may be converted with alkylating agents such as methyl iodide, dimethyl sulfate, isopropyl bromide, optionally in the presence of bases such as sodium bicarbonate / potassium tert-butyl alcohol, sodium amide or sodium hydride, optionally in a solvent such as dimethylformamide , dimethylsulfoxide, ethanol, isopropanol or glycol dimethyl ether, to the corresponding alkyl meth compounds.

The compounds of the formula I obtained can, if desired, be converted into their physiologically tolerated salts with inorganic or organic acids. Examples of suitable acids have been shown to be hydrochloric, hydrobromic, sulfuric, phosphoric, fumaric, succinic, nile, citric, tartaric or rialialic acid.

The compounds used as starting materials of formulas II and III are in part known in the literature or are obtained by methods known in the literature. The preparation of the starting compounds of formula II is described in the examples.

As already mentioned, the novel compounds of the formula I have valuable pharmacological properties, in particular blood pressure lowering effects, antithrombotic and cardiotonic effects. As an example, the biological effects of the following compounds were investigated:

A = 2-methyl-5 (6) - (3-oxo-4,5-dihydric-2H-6-pyridazinyl) benzimidazolium hydrochloride;

B == 2-methyl-5 (6) - (3-oxo-2H-6-pyridazinyl) benzimidazole hydrochloride

C = 2- (2,4-dimethoxyphenyl) -5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridinyl) benzimidazole,

D = 2-methyl-5 (6) - (3-morpholino-6-pyridazinyl) benzimidazole,

E = 2- (2-fluorophenyl) -5 (6) - (3-oxo-4,5-dihydro: 2H-6-pyridazinyl) benzimidazole hydrochloride,

F = 2-trifluoromethyl-5 (6) - (3-oxo-4,5; dihydro-2H-6-pyridazinyl) benzimidazole,

G = 2-methyl-5 (6) - (2-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole hydrochloride,

H = 5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole;

1- 2- (4-Methoxyphenyl) -5 (6) - ( ³ -oxo-4,5-dihydro-2H-6-pyrldazinyl) benzimidazole and

K = 2- (4-methoxyphenyl) -5 (6) - (3-oxo-2H-6-pyridazinyl) methanesulfonate henzinildazole. - - ............. 7

1. Detection of thrombocyte aggregation according to Born and Gross [J. Physiol. 170, 397 (1964)]

Thrombocyte aggregation was measured in platelet rich plasma of healthy

(B)

188393 subjects attempted. The optical density drop was measured after the addition of industrial collagen produced from Sigma, St. Petersburg. St. Louis (United States of America), which contains 1 mg of collagen fibrils per ml and the decrease in optical density was measured photometrically and registered. Depending on the angle of inclination of the density curve, the conclusion of the aggregation speed (V _max ) is made. The point of the curve at which the greatest light transmittance occurred was used to calculate the optical density (O. Η.). Approximately 0.01 ml of collagen solution per ml of platelet-rich plasma was added to induce maximal aggregation.

The following table shows the values found.

Table

Compound Attenuation after addition

10-4 mbl / 1

O.H.

2. Determination of blood pressure lowering effect

The blood pressure lowering effect was determined on a mixed sex dog of both sexes weighing between 19 and 26 kg, who were anesthetized with both chloralose / urethane (34 + 270 mg / kg intravenously) and Nembutal (10 mg / kg intravenously). Arterial blood pressure was measured in the Arteria femoralis with a pressure transducer (Statham P 23 De) and registered with a polygraph (Grass), while the test substances were injected into the veins in aqueous solution into the Vena saphena.

The following table shows the average of 3 experiments.

AND

(B)

D

F

H

AND

Substance

100% 100% 89% 100% 100% 100 O / o

Table

Dose mg / kg Reduction of blood pressure in the vein Pa

3. Determination of positive inotropic effect

Determination of the positive inotropic effect was performed as an effect on the contractility of the isolated, spontaneously striking guinea pig atrium. To this end, freshly extracted guinea pigs were transferred to an organ bath of 100 ml, which was filled with Tyrode's solution at a temperature of 30 ° C. The mixture was then bubbled through the mixture (95 ^l % oxygen and 5% carbon dioxide). Spontaneous contractions were registered isometrically on a polygraph (Grass via Grass-Force-Displacement-Transducer FT 03 C). Elongation atria amounted to 1 g. After equilibration period, 20 to 30 minutes with the test compound added at a concentration of 10- ⁵ g / ml.

The following table shows mean values from at least five different atria.

0,25 933/1200

1,00 3466/5066.

0,5 2400/3333

1,0 4400/4266

0,25 2266/1867

1,0 4400/5866

Table

Substance Increasing contractility in ° / o

AND 30 ·: ··. (B) 20 May · '·'; . ·. C 12 E 15 Dec G 13 TO 33 4. Acute toxicity

The acute toxicity of the test substances was determined in white mice by oral administration of a single dose administered orally (observation period 14 days):

The acute toxicity for the substance listed under D is 250 mg / kg orally (none of the 5 animals died).

The novel compounds of formula (I) may be formulated in conventional formulations such as tablets, dragees, suppositories, ampoules or drops, in combination with other active ingredients, in a single dose of 25 to 200 mg, preferably 50 to 150 mg.

Since the compounds of formula (I) may exist in the tautomeric forms of 1 H and 3 H respectively, the substitution point on the benzimidazole nucleus is indicated by the numbers 5 (6).

The following examples illustrate the invention in greater detail.

He did

2-Isopropyl-5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole

a) 4- (3-Amino-4-isobutyrylaminophenyl) -4-hexobutyric acid methyl ester

15.5 g of 4- (3-nitro-4-isobutyrylaminophenyl) -4-oxobutyric acid methyl ester is reduced in 480 ml of ethanol at room temperature and 50 kPa of hydrogen to 4 g of palladium on carbon. It is suctioned off, taken up with hot ethanol, filtered and crystallized. Melting point 178 ° C.

b) 2-Isopropyl-5 (6) - (3-ethoxycarbonyl-1-oxo-1-propyl) benzimidazole hydrothehloride g 4- (3-Amino-4-isobutyrylaminophenyl) -4-oxobutyric acid methyl ester was heated in 100 ml of ethanol. solution of hydrochloric acid under reflux for 1 hour. After cooling, the product was precipitated with ether and used in the next step without further purification

c) 2-Isopropyl-5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole 2-isopropyl-5 (6) - (3-ethoxycarbonyl-1-oxo-1) hydrochloride -propyl) benzimidazole and 10 g of hydrazine hydrate were refluxed in 10 ml of isopropanol for 1/2 hour. After isopropanol is distilled off, it is boiled off with water, the insoluble matter is filtered off and, after cooling, the product obtained is boiled off with acetone.

Melting point 230 ° C.

Example 2

2- (4-Methoxyphenyl) -5 (6) - (3-oxo-4,5-dihydro-2H-6-pyrldazinyl) benzimidazole

a) 2- (4-Methoxyphenyl) -5 (6) - (3-ethoxycarbonyl-1-oxo-1-propyl) benzimidazole hydrochloride g methyl 4- (3-nitro-4- (4-methoxybenzoylamino) phenyl) methyl ester The 4-oxobutyric acid is reduced in 500 ml of ethanoil at room temperature and a pressure of 600 kPa in the presence of 5 g of palladium on carbon for 3/4 hours. The precipitated mixture consisting of catalyst and 4- [3-amino-4- (4-methoxybenzoylamino) phenyl] -4-oxobutyric acid methyl ester was suspended in 1600 ml of ethanol and heated under reflux for 1 hour with the addition of hydrogen chloride gas. The catalyst is filtered off and the product is precipitated from the filtrate with ether.

Mp 240 ° C.

b) 2- (4-Methoxyphenyl) -5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole

12.6 g of 2- (4-methoxyphenyl) -5 (6) - (3-ethoxycarbonyl-1-oxo-1-pentyl) benzimidazole hydrochloride are heated in a mixture of 50 ml of isopropanol and 25 g of 80% hydrazine hydrate for 1/2 hour under reflux. After isopropanol was distilled off, the remaining crystalline precipitate was washed with cold isopropanol and boiled again with water. Melting point 174 ° C.

Example 3

2-Phenyl-5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole

2.5 g of 2-phenyl-5 (6) - (3-ethoxycarbonyl-1-oxo-1-propyl) benzimidazole hydrochloride are dissolved in 70 ml of ethanol, mixed with 40 ml of 80% hydrazine hydrate and refluxed for 1/2 hour. cooler. After cooling, it is poured into 400 ml of water, the precipitated product is filtered off with suction and recrystallized from methanol and a small amount of water.

Melting point 265 ° C.

Example 4

2- (4-Methylphenyl) -5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole

Prepared in analogy to Example 3 from 2- (4-methylphenyl) -5 (6) - (3-ethoxycarbonyl-1-oxo-1-propyl) benzimidazole hydrochloride.

Melting point 266 ° C (from ethyl acetate). Example 5

2- (4-Methylmercaptophenyl) -5 (6) - (3-oxo ^L -4,5-dihydro-2H-6-pyridazinyl) benzimidazole

(a) 2- (4-Methyl-mercaptophenyl) -5 (6) - (3-methoxycarbonyl-1-oxo-1-propyl) -benzimidazole hydrochloride

13S293 ^; -2.5 g iiitro 0V3-4- ^{(4-méthylmerkaptoben;} žóýlámlno) phenyl / -4,5-dihydro-3 (2H) -pyridazinone ^'ďazínonu in 200 ml of methanolic hydrochloric acid at room temperature and at a pressure 500 kPa was reduced with hydrogen in the presence of 2.5 g of palladium on carbon to 6- [3-amino-4- (4-methylmercaptobenzoylamino) phenyl] -4,5-dihydrO-3 (2H) -pyridazinone. The product is partially precipitated and suctioned off together with the catalyst, another part is obtained by concentrating the mother liquors; The two fractions were combined without separation of the catalyst, suspended in 100 ml of methanol and heated at reflux for 1 1/2 hours with the addition of hydrogen chloride. It is filtered while hot, the cooled product is filtered off with suction, washed with ethanol and ether and further dried directly after drying.

b) 2- (4-Methylmercaptophenyl) -5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzlimidazole

6.8 g of 2- (4-methylmercaptophenyl) -5 (6) - (3-methoxycarbonyl-1-oxo-1-propyl) benzimidazole hydrochloride were heated for 1 hour in a mixture of 80 ml of glacial acetic acid and 10 ml of hydrazine hydrate. to reflux. It is poured onto ice and the precipitated product is purified on silica gel (eluent: chloroform / methanol 19: 1).

Mp 248 ° C.

Example 6

2- (4-Dimethylaminophenyl) -5 (6) - (3-oxo-4,5-dihydro-2H-6-pyrldazinyl) benzimidazole

Prepared in analogy to Example 5 from 6- [3-nitro-4- (4-dimethylaminobenzoylamino) phenyl] -4,5-dihydro-3 (2H) -pyridazinone. The crude product precipitates from methanolic ammonia solution with water.

•

Mp 246-249 ° C.

Example 7

2- (3,4,5-Trimethoxyphenyl) -5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole

Prepared in analogy to Example 2b from 2- (3,4,5-trimethoxyphenyl) -5 (6) - (3-ethoxycarbonyl-1-oxo-1-propyl) -benzimldazole hydrochloride.

Melting point 310 ° C,

Example

2- (2-methoxyphenyl) -5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole hydrochloride

Prepared in analogy to Example 3 from 2- (2-methoxyphenyl) -5 (6) - (3-ethoxycarbonyl-1-oxo-1-propyl) benzimidazole hydrochloride. The hydrochloride is precipitated from ethanol with an ethereal hydrochloric acid solution.

Melting point 263 ° C.

Example 9

2- (3,4-Dimethoxyphenyl) -5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole

It was prepared analogously to Example 2b from 2- (3,4-dimethoxyphenyl) -5 (6) - (3-ethoxycarbonyl-1-oxo-1-propyl) benzimidazole hydrochloride.

Melting point 167 ° C.

Example 10

2- (3-Methoxyxyphenyl) -5 (6) - (3-oxo-4,5-dihydro-2H-pyridazinyl) benzimidazole

2.0 g of 2- (3-methoxyphenyl) -5 (6) - (3-ethoxycarbonyl-1-oxo-1-proipyl) benzimidazole hydrochloride was heated to reflux with 10 ml of 80% hydrazine hydrate for 10 minutes. It is then mixed with water and the precipitate is recrystallized from acetone.

Melting point 260 ° C.

Example 11

2- (2,4-Dimethoxyphenyl) -5 (6) - (4-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole hydrochloride

Prepared in analogy to Example 3 from 2- (2,4-dimethoxyphenyl) -5 (6) - (3-ethoxycarbonyl-1-oxo-1-butyl) benzimidazole hydrochloride. The hydrochloride is precipitated from a 1: 1 mixture of chloroform and methanol with ethereal hydrochloric acid.

Melting point 257-260 ° C.

Example 12

2- (4-Methoxyphenyl) -5 (6) - (4-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole

Prepared in analogy to Example 5b from 2- (4-methoxyphenyl) -5 (6) - (3-methoxycarbonyl-1-oxo-1-butyl) benzimidazoil hydrochloride. The product was purified by column chromatography (silica gel, chloroform / methanol 50: 1 to 19: 1), taken up in ethanol and precipitated with water.

Melting point 140-150 ° C.

S2 83

Example 13 ·

2- (4-Methoxyphenyl) -5 (6) - (2-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole

Prepared in analogy to Example 2b from 2- (4-methoxyphenyl) -5 (6) - (3-ethoxycarbonyl-1-oxo-1-propyl) benzimidazole hydrochloride and methylhydrazine hydrochloride.

90 DEG C. (2: 1 isopropanol / cyclohexane).

Example 14

2- (2-Methoxyphenyl) -5 (6) - (2-methyl-3-oxo-4,5-dihydro, -2H-6-pyridazinyl) benzimidazole hydrochloride

Prepared in analogy to Example 13 from 2- (2-methoxyphenyl) -5 (6) - (3-ethoxycarbonyl-1-oxo-1-propyl) benzimidazole hydrochloride. The hydrochloride is precipitated from isopropanol with ethereal hydrochloric acid.

Mp 282-284 ° C.

Example 15

2- (2-Fluorophenyl) -5 (6) - (2-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole hydrochloride

Prepared in analogy to Example 13 from 2- (2-fluorophenyl) -5 (6) - (3-ethoxycarbonyl-1-oxo-1-propyl) benzimldazole hydrochloride. The hydrochloride is precipitated from methanol with an ethereal hydrochloric acid solution.

Melting point 322 ° C.

Example 16

2- (4-Methoxyphenyl) -5 (6) - (2,4-dimethyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole

Prepared in analogy to Example 5b from 2- (4-methoxyphenyl) -5 (6) - (3-methoxycarbonyl-1-oxo-1-butyl) benzimldazole hydrochloride and methylhydrazine hydrochloride.

Melting point 120-130 ° C (from ethanol and water).

Example 17

2- (4-Methylsulfinylphenyl) -5 (6) - (3-oxo-4,5-dihydrol-2H-6-pyridazinyl) benzimidazole

0.6 g of 2- (4-methylmercaptophenyl) -5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole are dissolved in 100 ml of glacial acetic acid, mixed with 0, 4 g of 30% hydrogen peroxide and allowed to stand at room temperature for 2 days, poured onto 100 ml of ice water, basified with ammonia, extracted with ethyl acetate and purified by silica gel chromatography (eluent: ethyl acetate). Mp 291 ° C.

Example 18

2- (4-Methylsulfonylphenyl) -5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole 2- (4-methylmercaptophenyl) -5 (6) - (3) -oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole is dissolved in 200 ml of glacial acetic acid, mixed with 0.6 g of 30% hydrogen peroxide and heated at 70 ° C for 6 hours.

Melting point 280-284 ° C.

Example 19

2- (4-Methoxyphenyl) -5 (6) - (3-methylamino-6-pyridazinyl) benzimidazole

They were prepared analogously to Example 11. A 19: 1 to ¹ : ¹ mixture of chloroform and methanol was used as eluent.

Mp 87 ° C.

Example 20

2- (4-Methoxyphenyl) -5 (6) - (3-oxo-2H-6-pyridazinyl) benzimidazole

100 mg of 2- (4-methoxyphenyl) -5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole are mixed in portions with boiling glacial acetic acid (2 ml) in portions with 300 mg of chromium trioxide. It is then poured onto water, extracted with ethyl acetate and purified on a silica gel column (eluent: chloroform / methanol 9: 1).

Melting point 281 ° C.

Example 21

2- (4-Methoxyphenyl) -5 (6) - (3-oxo-2H-6-pyridazinyl) benzimidazole

100 mg of 2- (4-methoxyphenyl) -5 (6) - (3-oxo-4,5-dlhydro-2H-6-pyridazinyl) benzimidazole was suspended in 2 ml of chlorobenzene and after addition of 100 mg of N-bromosuccinimide, 30 minutes is heated under reflux. The solvent was then evaporated and the residue chromatographed on silica gel (eluent: chloroform / methanol 9: 1).

Melting point 281 ° C.

193293

Example 22

2- (4-Methoxyphenyl) -5 (6) - (3-oxo-2H-6-pyridazinyl) benzimidazole

100 mg of 2- (4-methoxyphenyl) -5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimldazole are dissolved in 2 ml. glacial acetic acid, add 0.2 ml of 30% hydrogen peroxide and reflux for 30 minutes. Pour into water, extract with ethyl acetate, evaporate and recrystallize from ethanol.

Melting point 281 ° C.

Example 1 a d 2 3

2- (4-Methoxyphenyl) -5 (6) - (3-oxo-2H-6-pyridazinyl) benzimidazole

100 mg of 2- (4-methoxyphenyl) -5 (6) - (3-oxo-4,5-dihydro-2H-pyridazinyl) benzimidazole are dissolved in 2 ml of glacial acetic acid and added dropwise to a solution of 100 mg of sodium nitrite ¹ in 2 ml of water. The mixture is then diluted with water for 60 minutes at 60 DEG C. and treated as usual.

Melting point 281 ° C.

Example 24

2- (4-Hydroxyphenyl) -5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole

Prepared in analogy to Example 2b from 2- (4-hydroxyphenyl) -5 (6) - (3-ethoxycarbonyl-1-oxo-1-propyl) benzimidazole hydrochloride.

Melting point 338 ° C,

Example 25

2- (4-Methoxyphenyl) -5 (6) - (3-oxo-2H-6-pyridazinyl) benzimidazole

0.05 g of 2- (4-hydroxyphenyl) -5 (6) - (3-oxol-2H-6-pyridinyl) benzimidazole is added to a solution of 0.025 g of sodium in 2 ml of ethanol. Then 0.2 ml of methyl iodide was added and stirred for 0.5 hour at room temperature. After concentration, water is added, extracted with ethyl acetate and purified by silica gel column chromatography (eluent: chloroform / methanol 19: 1).

Melting point: 281 ° C.

Example 26

2- (4-Methoxyphenyl) -5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole

Prepared in analogy to Example 25 from -2- (4-hydroxyphenyl) -5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole and dimethyl sulfate. . ^{? !} Melting point 174 ° C.

Example. 2 7

2-Methylmercapto-5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) -henzimidazole hydrochloride

4.93 g of 2-mercapto-5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole are dissolved in 250 ml of dimethylformamide, 1.7 g of sodium bicarbonate are added, and 1.8 g of methyl iodide and stirred at room temperature for 1 hour. After adding an additional 2.8 g of methyl iodide. is stirred for 1 hour at 40 to 50 ° C. Evaporate approximately half, pour into water and dissolve the product in boiling ^; ethanol. The hydrochloride is precipitated by the addition of an ethanolic hydrochloric acid solution and recrystallized from a mixture of ethanol and water.

Melting point above 300 ° C.

Example 28

2-Isoipropymercapto-5 (6) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole

It was prepared analogously to Example 27 from isopropyl bromide and sodium hydride as the base. After pouring into water, it is made alkaline with ammonia. Mp 224-227 ° C (from ethanol). Example 29

2-Methyl-5 (6) - (3-chloro-6-pyridazinyl) benzimidazole 2-methyl-5 (6) - (3-oxo-2H-6-pyridazinyl) benzimidazole is added portionwise to 250 ml of boiling oxychloride. phosphorous and then boil for another 2.5 hours. After the phosphorus oxychloride has been distilled off and the residue is decomposed with ice water, the insoluble hydrochloride is filtered off with suction and converted into the free base by digestion with 100 ml of concentrated ammonia.

Example 30

2-Methyl-5 (6) - (3-morpholino-6-pyridazinyl) benzimidazole

1.7 g of 2-methyl-1-5 (6) - (3-chloro-6-pyridazinyl) benzimidazole were heated with 13.1 g of morpholine in a pressure bottle at 190-200 ° C for 16 hours. Excess morpholine is distilled off

195> 93 15 under vacuum, the residue is triturated with water, filtered, boiled with water and recrystallized from a 2: 1 mixture of cyclohexane and isopropanol. The product still contains half a mole of crystalline water and melts at 148-151 ° C.

Example 31

2-Methyl-S (6) - [3- (4-methyl-1-piperazinyl)] -6-pyridazinyl / benzimidazole

Prepared in analogy to Example 30 from 2-methyl-5 (6) - (3-chloro-6-pyridazinyl) benzimidazole and 1-methylpiperazine.

Melting point 145-148 ° C.

Example 32

2-Methyl-5 (6) - (3-chloro-6-pyridazinyl) henzimidazole

1.32 g of 2-methyl-5 (8) - (3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole hydrochloride are stirred with a solution of 4.2 g of phosphorus pentachloride in 15 ml of phosphorus oxychloride and is heated at reflux for 7 hours. The phosphorus oxychloride is filtered off, the residue is treated with ice water, basified with ammonia, filtered off with suction and purified on a silica gel column (eluent: chloroform / methanol 9: 1).

Mp 253-255 ° C.

Example 33

2-Methyl-5 (6) - (3-oxo-2H-6-pyridazinyl) benzimidazole hydrochloride

0.25 g of 2-methyl-5- (8) - (3-chloro-6-1-yridazinyl) benzimidazole was heated in 10 ml of concentrated hydrochloric acid in a sealed tube at 120 ° C for 3 hours, then basified with ammonia and the precipitated base was _e leads straight to the hydrochloride as in example 2. Melting point 350 ° C.

Example 34

2- (4-Methoxyphenyl) -5 (6) - (3-chloro-6-pyridazinyl) benzimidazole hydrochloride

5.6 g of 2- (4-methoxyphenyl) -5 (6) - (3-oxo-2H-6-pyridazinyl) benzimidazole are heated in 400 ml of phosphorus oxychloride for 2 hours under reflux. Excess phosphorus oxychloride was distilled off, the residue was decomposed with ice water and the precipitated product was filtered off.

Mp 232 ° C.

Example 35

2- (4-Methoxyphenyl) -5 (6) - (3-morpholino-6-pyridazinyl) benzimidazole 2- (4-methoxyphenyl) -5 (6) - (3-chloro-6-pyridazinyl) of benzimidazole and 100 ml of morpholine are heated in 180 ml of isopropanol in a pressure bottle at 180 ° C for 5 hours. After distilling off the solvent, the residue is boiled with water, filtered off with suction and purified on a silica gel column (eluent: chloroform / methanol 19: 1 to 9: 1).

Melting point 197 ° C.

Claims (5)

pRedmSt A process for the preparation of novel pyridazine derivatives of the general formula I wherein R is hydrogen, trifluoromethyl, alkyl of 1 to 5 carbon atoms, a free merkaptpskupinu or alkylmercapto with 1 to 3 ¹ carbon atoms or a phenyl radical optionally substituovaVYNALEZU Nu fluorine, methyl, hydroxyl, methylmerkaptoskuplnou, methylsulphinyl, methylsulphonyl or dimethylamino or one to three methoxy groups. A represents a hydrogen atom, B represents a hydrogen atom or a C1-C3 alkyl group, or A together with B together form another bond, R2 represents a hydrogen atom or a lower alkyl radical having 1 to 3 carbon atoms, or R2 together with D forms a further bond, and R3 represents a chlorine atom, a methylamino, morpholine or 4-methylpiperazine group, or when R2 represents a hydrogen atom or lower (C 1 -C 3) -alkyl radical, R 5 together with D denotes an oxygen atom, and their physiologically tolerable salts with inorganic or organic acids, characterized in that for the production of the 3-oxopyridazine derivatives of the general formula I, where R 5 and D together form oxygen atom, compound of formula π 193293 A, B and R 1 are as defined above, or an ester thereof is reacted with a compound of formula III in a solvent H ₂ N-NH-R 2 (III) where R2 is as defined above and optionally the compound of formula I, wherein D and R3 together represent an oxygen atom, is converted to the corresponding halogenated compound with phosphorus oxyhalide, phosphorus halide or thionyl chloride, and optionally the halogenated compound is then converted to the corresponding halogenated compound the amino compound or by hydrolysis is converted to the corresponding oxo compound and / or the compound of formula I, wherein A and B are hydrogen, dehydrogenated and / or the compound of formula I, wherein R 1 is methylmercaptophenyl, is converted by oxidation to a compound of general formula I wherein R 1 is phenyl substituted with methylsulfinyl or methylsulfonyl and / or the compound of formula I is obtained, wherein R 1 is hydroxyphenyl or mercapto, optionally further methylated, optionally alkylated and / or recovered and the compound of formula (I) is converted into its physiologically tolerable salts with inorganic or organic acids. 2. The method of item 1, for producing R _2, A and D are as defined in paragraph 1 and B 'is hydrogen or together with A forms a bond dalšf, R 1 represents a hydrogen atom, a trifluoromethyl group, a C 1 -C 5 alkyl radical, or a phenyl radical optionally substituted by a fluorine atom or by one or two methoxy groups, and R 8 represents a chlorine atom, a morpholino group or a 4-methylpiperazino group, or when R ₂ represents a hydrogen atom or a lower alkyl radical having 1 to 3 carbon atoms, R'3 represents together with D an oxygen atom and their physiologically tolerable salts with inorganic or organic acids, characterized in that for the preparation of the 3-oxopyridazine derivative of the formula Ia, in which R'3 and D together represent an oxygen atom, the compound of the formula IIa A has the meaning given in 1 a B ‘and R‘, as defined in this point, are reacted in a solvent with a compound of formula IJI H ₂ N-NH-R ₂ (III) wherein R2 is as defined in 1, and optionally the obtained compound of formula I, wherein D and R'3 together represent an oxygen atom, is converted to the corresponding halogenated compound by means of phosphorus oxyhalide, phosphorus halide or thionyl chloride and optionally halogenated with an amine is converted to the corresponding amino compound or is hydrolyzed to the corresponding oxo compound and / or the compound of formula Ia, wherein A and B 'are hydrogen, dehydrogenated and / or the compound of formula Ia is converted into its physiologically tolerable salts with inorganic or organic acids. 3. The process according to item 1, for the preparation of novel pyridazine derivatives of the general formula Ib 165203 1β 20 where R2, A, Β and D have the meaning given in point 1, R 1 'is hydrogen, C 1 -C 3 alkyl, trifluoromethyl, free mercapto or C 1 -C 3 alkyl or C 1 -C 3 alkyl or phenyl radical optionally substituted by fluorine, methyl, hydroxyl, methylmercapto, methylsulfinyl, methylsulfonyl or dimethylamine a group or one to three methoxyl groups R3 'represents a chlorine atom, a methylamino group, a morpholino group, or 4-methylpiperazino, or when R2 is a hydrogen atom or a lower alkyl radical having 1 to 3 carbon atoms, R 3 'together with D represents an oxygen atom as well as their physiologically tolerable salts with inorganic or organic acids, characterized in that for the production of 3-oxopyrldazine derivatives of the general formula Ib, where R 3' and D together represent an oxygen atom, a compound of the general formula lib íí.f · 5-ch ~ ch <ooh (nb) where A, B and R1 'are as defined above, or an ester thereof, reacted in a solvent with a compound of formula III H2N1 — NH — R2 {ΠΙ3, where R2 is as defined in 1, and optionally the compound of formula Ib, where D and Rj 'together represent an oxygen atom, is converted to the corresponding halogenated compound with phosphorus oxyhalide, phosphorus pentachloride, and the halogenated compound thus obtained is optionally reacted with with an amine is converted to the corresponding amine compound or converted to the corresponding oxo compound by hydrolysis and / or A and B are hydrogen atoms, dehydrogenated and / or the compound of the formula Ib, where R 1 'represents a hydroxyphenyl radical by methylation, is converted to the corresponding methoxy compound and / the compound of formula Ib, wherein R 1 'is methylmercaptophenyl, is converted by oxidation with hydrogen peroxide to a methylsulphinyl or methylsulphonyl compound and / or the compound of formula Ib, where R 1' is a mercapto group, is alkylated to the corresponding alkylmerkaptosloučeninu Affairs and / or the resulting compound of formula Ib into its physiologically tolerated salts with inorganic or organic acids.