NO861266L - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PYRIDAZINON DERIVATIVES. - Google Patents

Abstract

1. Pyridazinones of general formula I see diagramm : EP0196005,P30,F1 wherein X represents an oxygen or sulphur atom, R1 represents a saturated 5- to 7-membered alkyleneimino ring bonded via a nitrogen atom or a 5- to 7-membered saturated imino, N-alkylimino, N-phenylalkylimino, N-alkanoylimino or N-alkoxycarbonyliminoalkylene ring bonded via a carbon atom, whilst the above-mentioned rings may be substituted by one or two alkyl groups in the carbon structure and a methylene group in the 4-position of a 6- or 7-membered ring may be replaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl, imino, alkylimino, phenylalkylimino, alkoxycarbonylimino or alkanoylimino group, or R1 represents a saturated 5- to 7-membered alkyleneimino ring (optionally substituted by one or two alkyl groups) bonded via a nitrogen atom and in which a -CH2 CH2 - group is replaced by an -NH-CO group, the -CO- group in this -NH-CO- group being linked to the N-atom already present, or R1 represents a 5-membered heteroaromatic ring bonded via a nitrogen atom, which may additionally contain an oxygen or sulphur atom, one or two nitrogen atoms, or an oxygen or sulphur atom and a nitrogen atom and in which the heteroaromatic ring may be substituted by one or two alkyl groups, or in the case of a pyrazole, may alternatively be substituted by a hydroxy and an alkyl group, or R1 represents a 5- or 6-membered heteroaromatic ring bonded via a carbon atom, in which the heteroaromatic ring may contain an oxygen or sulphur atom, one, two or three nitrogen atoms, or an oxygen or sulphur atom and one or two nitrogen atoms, whilst the heteroaromatic rings may be substituted by one or two alkyl groups, by an amino or alkanoylamino group or, in the case of a pyridine, by one or two halogen atoms or by a halogen atom and an amino or morpholino group, and R2 represents a hydrogen atom or an alkyl group ; or X represents an imino group optionally substituted by an alkyl or phenylalkyl group, R1 represents a saturated 5- to 7-membered alkyleneimino ring bonded via a nitrogen atom or a 5- to 7-membered saturated imino, N-alkylimino, N-phenylalkylimino, N-alkanoylimino or N-alkoxycarbonyliminoalkylene ring bonded via a carbon atom, whilst the above-mentioned rings may be substituted by one or two alkyl groups in the carbon structure and a methylene group in the 4-position of a 6- or 7-membered ring may be replaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl, imino, alkylimino, phenylalkylimino, alkoxycarbonylimino or alkanoylimino group, or R1 represents a saturated 5- to 7-membered alkyleneimino ring (optionally substituted by one or two alkyl groups) bonded via a nitrogen atom and in which a -CH2 CH2 - groups is replaced by an -NH-CO group, the -CO- group in this -NH-CO- group being linked to the N-atom already present, and R2 represents a hydrogen atom or an alkyl group, whilst all the above-mentioned alkyl, alkanoyl or alkoxy groups may contain from 1 to 3 carbon atoms ; or X represents an imino group, R1 represents a 1-imidazolyl, 1-pyrazolyl, 3-methyl-1-pyrazolyl, 3-hydroxy-4-methyl-2-pyrazolyl or 1-[1.2.4]triazolyl group and R2 represents a methyl group in the 5-position ; or X represents an imino group, R1 represents a 2-chloro-6-morpholino-4-pyridyl group and R2 represents a hydrogen atom the optically active antipodes thereof, if R2 does not represent hydrogen, and the acid addition salts thereof.

Description

In tes* ydL^u^026 .-09^ and in the European patent

0.008.391 and tø.034.~7~4r3\ are described pyridazinones which have valuable pharmacological properties, especially cardiotonic,

an effect on blood pressure and/or antithrombotic effects.

It has now been found that the new pyridazinones with the general formula

which differ from the known pyridazinones by the saturated or aromatic heterocyclic residue in the 2-style bound over a nitrogen atom or over a carbon atom, and their acid addition salts, in particular their physiologically compatible acid addition salts with inorganic or organic acids, exhibit superior pharmacological properties, in particular antithrombotic

and cardiovascular characteristics.

In the above general formula I means

X an imino group optionally substituted with an alkyl or phenylalkyl group, an oxygen or sulfur atom,

one over a nitrogen atom bonded 5- to 7-membered alkyleneimino-

ring or one over a carbon atom bonded 5- to 7-membered, saturated imino-, N-alkyl-imino-, N-phenylalkylimino-, N-alkanolylimino-

or N-Alkoxycarbonylimino-alkylene ring, the above-mentioned rings in the carbon skeleton can be substituted with one or two alkyl groups, and a methylene group in the 4-position in a 6- or 7-

membered ring may be replaced by an oxygen or sulfur

atom, a sulfinyl-, sulfonyl-, imino-, alkylimino-, phenylalkyl-

imino, alkoxycarbonylimino or alkanoylimino group; an optionally with one or two alkyl groups above a nitrogen atom attached, saturated 5- to 7-membered alkylene ring, where a

-CH2CH2 group is replaced by a -NH-CO group, where this C0 group in this -NH-CO group is linked to the already present N atom; a 5-membered heteroaromatic ring bonded over a nitrogen atom which can also contain an oxygen

or sulfur atom, one or two nitrogen atoms, an oxygen or

important information

For archival reasons, the Norwegian Patent Office only has access to documents for this generally available patent application that contain handwritten notes, comments or crossing outs, or that may be stamped "Expired" or the like. We have therefore had to use these documents for scanning to create an electronic edition.

Handwritten remarks or comments have been part of the proceedings, and must not be used to interpret the content of the document.

Cross-outs and stampings with "Expired" etc. indicates that newer documents have been received during the proceedings to replace the earlier document. Such crossing out or stamping must not be understood as meaning that the relevant part of the document does not apply.

Please ignore handwritten remarks, comments or crossing outs, as well as any stamps with "Expired" etc. which have the same meaning. sulfur atom and a nitrogen atom, the heteroaromatic ring may be substituted with one or two alkyl groups, and for the pyrazoles also with a hydroxy group and an alkyl group; a 5- or 6-membered heteroaromatic ring bonded over a carbon atom which can contain an oxygen or sulfur atom, one, two or three nitrogen atoms, an oxygen or sulfur atom and one or two nitrogen atoms, the heteroaromatic rings can be substituted with one or two alkyl groups, with an amino or alkanoylamino group and, in the case of the pyridine, also with one or two halogen atoms or with a halogen atom and an amino or morpholino group, and

1*2 a hydrogen atom or an alkyl group, all of the above-mentioned alkyl, alkanoyl or alkoxy groups in each case may contain 1 to 3 carbon atoms.

Among the meanings given for the definition of the residues X, R, and above, e.g. in consideration: for X meaning an oxygen or sulfur atom, an imino-, methylimino-, ethylimino-, n-propylimino-, benzylimino-, 1-phenylethylimi.no- , 2-phenylethylimi.no- or 3-phenylpropylimino group,

for R^ the meaning 1-pyrroli.di.nyl-, pi.peri.di.no-, 1-hexa-hydroazepinyl-, 2-methyl-1-pyrrolidinyl-, 3-methyl-1-pyrrolidinyl-, 2- methyl -pi.peridino- , 2-n-propylpiperi.di.no- , 3-methyl-piperi.dino- , 4-methyl-piperidi.no- , 2-ethyl-piperi.di.no- , 4-ethyl- Piperidino-, 4-isopropyl-piperidino-, 2,6-dimethyl-piperidino-, 3,5-dimethyl-piperidino-, 1-piperazinyl, 4-methyl-l-piperazi .nyl-, 4-ethyl-l-piperazinyl-, 4-n-propyl-l-piperazinyl-, 4-benzyl-l-piperazinyl-, 4-formyl-l-piperazinyl-, 4-acetyl-l- piperazinyl-, 4-propionyl-1-piperazinyl-, 4-methoxycarbonyl-l-piperazinyl-, 4-ethoxycarbonyl-l-piperazinyl-, 2-pyrrolidinyl-, 3-pyrrolidinyl-, 2-piperidino-, 3 -piperidino-, 4-piperidino-, N-methyl-2-pyrrolidinyl-, N-methyl-3-pyrrolidinyl-, N-methyl-4-piperidino-, N-ethyl-4-pi.peridino-, N -isopropyl-4-piperidino-, N-formyl-4-piperidino-, N-acetyl-4-piperidino-, N-propi.onyl-4-piperidino-, morpholi.no-, thiomorpholi.no-, l -oxido-4-thiomorpholino-, 1,1-dioksi.do-4-ti.omorpholi.no-, 1,1-dioxide - 4-thiomorph olino-, imi.d-azolin-2-on-l-yl-, 2-methyl-2-imidazolin-1-yl-, imidazolin-2-on-4-yl-, 2-methyl-4 ,5-dihydro-imidazol-1-yl-, imidazolin-2-on-4-yl-, tetrahydrofuran-2-yl-, 4-methyl-2-piperazinyl-, 4-ethyl-2-

piperazinyl-, 4-n-propyl-2-piperazinyl-, 1,4-dimethyl-2-piperazinyl-, 1,4-di.ethyl-2-piperazinyl-, l-ethyl-4-methyl-2- piperazinyl-, 1-pyrrolyl-, 2-pyrrolyl-, 3-pyrrolyl-, N-methyl-2-pyrrolyl-, N-ethyl-2-pyrrolyl-, N-methyl-3-pyrrolyl-, N-ethyl-3 -pyrrolyl-, 2-thienyl-, 3-thienyl-, 2-pyridyl-, 3-pyridyl-, 4-pyridyl-, 2-pyrazinyl-, 1-imidazolyl-, 2-methyl-1 -imidazolyl-, 4-methyl-1-imidazolyl-, 2-ethyl-1-imidazolyl-, 4-ethyl-1-imidazolyl-, 2-amino-5-pyridyl-, 2-formylami. no-5-pyridyl-, 2-acetylamino-5-pyridyl-, 2-propionylami.no-5-pyridyl-, 2,6-di.chloro-4-pyridyl-, 2-chloro-6- ami no-4-pyridyl-, 2-chloro-6-morph olino-4-pyridyl-, 2, 6-di.chloro-3-pyridyl-, 2-chloro-6-morpholi.no-3 -pyridyl-, 1-pyrazolyl-, 4-methyl-1-pyrazolyl-, 3-hydroxy-4-methyl-2-pyrazolyl-, 5-oxazolyl-, 4-methyl-5-oxazolyl-, 4-pyrazolyl -, 3-amino-4-pyrazolyl-, 1-[1.2.3]-triazolyl-, 1-[1.2.4]triazolyl-, 2-hydroxy-l-imidazolyl-, 4-hydroxy-l-imidazolyl-, 4-methyl-1-imidazolyl-, 2-imidazolyl-, imidazolidin-2-on-1-yl-, 2-pyrim idyl, 5-pyrimidyl, 4-pyrimidyl, 5-thiazolyl, 2-thiazolyl, 2-oxazolyl or triazol-3-yl group.

Preferred compounds of the general formula I are

those where

X means an imino group, an oxygen or sulfur atom,

one over a nitrogen atom bonded pyrrolidinyl-, piperidino-, 1-hexahydroazepi.nyl-, morpholi no-, thi.morpholi.no-, 1-oxyd-thiomorpholi.no-, 1,1-di.oxydthiomorpholino-, 1-piperazinyl -, 4-methyl-l-piperazinyl-, 4-acety1-1-piperazinyl-, 4-carbethoxy-l-piperazinyl-, 1-imidazolyl-, 1-pyrazolyl-, 1-[1.2.4]triazolyl-, i .midazolidin-2-on-1-yl or 3-hydroxy-2-pyrazolyl group or a piperidino-, N-acetyl-piperidino-, furyl-, thienyl-, pyrrolyl-, pyridyl-, amino-pyridyl-linked over a carbon atom -, acetyl-amino-pyridyl-, pyrimidyl-, pyrazinyl-, oxazolyl-, dihalo-pyridyl- or halogeno-morpholino-pyridyl group, all of the above-mentioned residues can be substituted in the carbon skeleton with a methyl group, and

R2 a hydrogen atom or a methyl group in the 5-position.

Particularly preferred compounds of the above general formula I are those where

X means an oxygen atom or an imino group,

R-j^ denotes a 1-pyrrolidinyl-, 1-imidazolyl-, 2-furyl-, 3-

thienyl-, 1-piperazinyl-, 4-methyl-1-piperazinyl-, 4-carbethoxy-

1-piperazinyl-, 4-morpholino-, 4-thiomorpholino-, 1-oxido-4- jj thiomorpholi.no- and 4-pyridyl group, and

R2i 5-position means a methyl group.

According to the invention, the new compounds are produced by the following methods:

a) For the preparation of compounds with the general formula

In where R, means one of the initially indicated, over a

Carbon atom-bound residues: ring closure of a compound with the general formula, possibly formed in the reaction mixture

where

R2 is as initially stated,

one of the residues A or B means one

the other of the residues A or B means an amino group or a

where X is as initially stated, and

R^<1>means one of the residues indicated for R^ at the beginning which are bonded over a carbon atom,

Z 1 and Z 2 , which may be the same or different, mean nucleophilic leaving groups such as optionally substituted amino, alkoxy, phenyl alkoxy, phenoxy, alkyl mercapto, phenyl alkyl mercapto or phenylthio groups, or

Z^ and Z2 together mean an oxygen or sulfur atom, an optionally substituted imino group with an alkyl or phenylalkyl group, where the above-mentioned alkyl parts can in each case contain 1 to 3 carbon atoms, or an alkylenedioxy group with 2 or 3 carbon atoms, and have for Z .introductory meanings or an imidazolyl group, a chlorine, bromine or iodine atom.

For Z^ and Z2, e.g. i. in each case in consideration a methoxy, ethoxy, propoxy, benzyloxy, methyl mercapto, ethyl mercapto, propyl mercapto, phenyl mercapto or benzyl mercapto group, and

for Z^ a chlorine, bromine or iodine atom, a methoxy, ethoxy, phenoxy, methyl mercapto, ethyl mercapto, phenyl mercapto, benzyl mercapto or imidazolyl group.

The reaction is conveniently carried out in a solvent or a solvent mixture such as ethanol, isopropanol, glacial acetic acid, tetrahydrofuran, dioxane, benzene, toluene, xylene, chlorobenzene, glycol, glycol monomethyl ether, glycol dimethyl ether, diethylene glycol dimethyl ether, dimethylformamide, tetralin or sulfolane, possibly in the presence of a condensing agent such as

■ phosphorus oxychloride, thionyl chloride, sulphuryl chloride, hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, p-toluenesulfonic acid, glacial acetic acid, acetic anhydride, N,N1-dicyclohexyl carbodilimide, carbonyldiimidazole, potassium methylate or potassium tert-butylate, at temperatures between 0 and 300°C, preferably at the boiling temperature of the reaction mixture, e.g. at temperatures between 50 and 285°C. The turnover can also be made in. smelte.

If R denotes one of the residues mentioned at the outset which is bonded over a carbon atom, the reaction is carried out particularly advantageously in an excess of the acylating agent used for the preparation of a corresponding compound with the general formula II, e.g. by an excess of the nitrile, anhydride, ester, thioester, orthoester, amide, thioamide, halide or methoiodide used.

b) Reaction of a carboxylic acid with the general formula

where

R^ and R 2 are as indicated at the outset,

or reactive acid derivatives thereof, such as its esters, amides or halides, with hydrazine.

The reaction is conveniently carried out in a solvent such as methanol, ethanol, isopropanol, glacial acetic acid, propionic acid and/or in an excess of hydrazine or hydrazine hydrate,

at temperatures between 0 and 200°C, e.g. at temperatures between 20 and 150°C, preferably at the boiling temperature of the reaction mixture, and optionally in the presence of an acid such as sulfuric acid or p-toluenesulfonic acid as condensation agent. However, the reaction can also be carried out without a solvent. c) For the preparation of the general formula I where R-^ means one of the initially mentioned residues bonded over a nitrogen atom:

turnover of a compound with the general formula

where

R2 and X are as indicated above, and

Z 4 means a nucleophilic replaceable group such as a halogen atom, a sulfo group or a substituted mercapto group, e.g. a chlorine or bromine atom, a sulfo-, methylthio-, ethylthio-, phenylthio-, 2-nitrophenylthio-, 4-nitrophenylthio-, 2,4-dinitrophenylthio-, pyridinium-4-thio- or pyri. din-2-thio group, with an amine of the general formula

where

R^" means one of the residues initially mentioned for R-^ bonded over a nitrogen atom.

The reaction is carried out in a melt or in a suitable solvent such as tetrahydrofuran, dioxane, dimethylformamide or dimethylsulfoxide, optionally in the presence of an acid-binding agent such as potassium carbonate or pyridine, at elevated temperatures, e.g. at temperatures between 50 and 200°C, preferably at temperatures between 100 and 180°C.

d) For appearing. Ilation of compounds with the general formula I where X means an oxygen atom or an optionally with

an alkyl or phenylalkyl group substituted imino group: hydrogenation of a compound of the general formula

where

R 1 and R 2 are as indicated at the outset, and

X' means an oxygen atom or an imino group optionally substituted with an alkyl or phenylalkyl group, the alkyl part in each case may contain 1 to 3 carbon atoms.

The catalytic hydrogenation is carried out in a solvent such as methanol, ethanol, acetic acid ethyl ester, glacial acetic acid or dimethylformamide, with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/coal, at temperatures between 0 and 75° C, preferably at room temperature, and at a hydrogen pressure of 1 to 5 bar.

If one prepares a compound of the general formula I where R contains an imino and/or amino group,

this can be transferred by alkanoylation to the corresponding compound of the general formula I, where R^ contains an alkanoyl, mi.no- and/or alkanoylamino group, or a compound of the general formula I where R^ means one bonded over a carbon atom, with halogen atoms substituted pyridine residue, this can be transferred by catalytic dehalogenation and hydrogenation to a compound of the general formula I where R^ denotes a piperidin residue bonded over a carbon atom, or

a compound of the general formula I where R^ means a pyridine residue which is bonded over a carbon atom and substituted by one or two halogen atoms, can be transferred by halogen replacement to a corresponding compound of the general formula I where R^ means a pyridine residue bonded over a carbon atom which is substituted with an amino or morpholino group and optionally with a halogen atom.

The subsequent alkanoylation is conveniently carried out in a solvent such as methylene chloride, chloroform, diethyl ether, tetrahydrofuran, dioxane, benzene, acetonitrile or dimethylformamide, with a suitable ester, anhydride or acid halide, optionally in the presence of an acid binding agent such as sodium carbonate or pyridine, or with a suitable alkanoic acid in the presence of an acid-activating agent or a water-attracting agent, e.g. in the presence of chloroformate ethyl ester, thionyl chloride, phosphorus trichloride, N,N'-dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole or N,N<1->thionyldiimidazole, at temperatures between 0 and 200°C, preferably at temperatures between 20 and 100°C .

The subsequent dehalogenation and hydrogenation is carried out

1 a solvent such as methanol, ethanol, acetic acid ethyl ester, glacial acetic acid or dimethylformamide, with hydrogen in the presence of a hydrogenation catalyst such as platinum or palladium/charcoal, at temperatures between 0 and 75°C, preferably at room temperature, and at a hydrogen pressure of 1 to 5 bars.

The subsequent halogen replacement is carried out with ammonia or morpholine, suitably in a solvent such as dioxane or dimethylformamide, optionally in a pressure vessel at temperatures between 50 and 150°C.

They thus achieved connections with the general

formula I, due to its optically active carbon atom in position 4 or 5 in the pyridazinone ring, if R2 is an alkyl group, can be separated into its optically active antipodes by racemate resolution.

The racemate cleavage is conveniently carried out by fractional crystallization of the appropriate salt with optically active acids, such as tartaric acid, dibenzoyltartaric acid, malic acid, camphoric acid or camphorsulphonic acid, or by chromatography on optically active adsorptive agents.

Furthermore, the obtained compounds with the general formula I can be transferred to their acid addition salts, especially for pharmaceutical use to their physiologically compatible salts with inorganic or organic acids. As acids, e.g. considering hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

The compounds with the general formulas II to VI used as starting materials are obtained by methods known from the literature, or the compounds from which such are known. the literature.

Thus one achieves e.g. a suitable o-diami.no compound of the general formula II by reaction of a suitable 3-(3-ni.tro-4-acylamino-benzoyl)-propionic acid with hydrazine and subsequent reduction of the nitro group (see US Patent 4,026. 891), a suitable o-hydroxy-acylamino- or o-mercapto-acylamino compound of the general formula II by reaction of a suitably substituted 3-benzoyl-propionic acid with hydrazine, optionally subsequent reduction of the nitro group and subsequent acylation of the amino compound thus obtained.

A compound of the general formula III used as starting material is obtained by reacting a suitable p,a-dihalo-acetophenone with a suitable malonic acid ester. The thus obtained, suitably substituted 3-benzoyl-propionic acid derivative is then saponified, decarboxylated, nitrated, the halogen atom replaced by an amino, hydroxy or mercapto group, the nitro group reduced and the amino compound thus obtained after reaction with a suitable carboxylic acid derivative is converted into the desired compound of the general formula III.

A compound with the general formula IV used as a starting material gives, for example, by cyclization of a suitable thiourea or by reaction of a suitable o-amino-hydroxy compound with potassium ethyl xanthogenate and subsequent reaction of the thus obtained 2-mercaptobenzoxazole with a suitable electrophile, e.g. with an alkyl halide or a nitrohalobenzene.

A compound of the general formula VI used as starting material is obtained by reacting a suitable acrylic acid derivative with hydrazine.

The new compounds of the general formula I, their optically active antipodes and their acid addition salts, in particular their physiologically compatible acid addition salts with inorganic or organic acids, exhibit, as mentioned at the outset, valuable pharmacological properties, in particular cardiovascular effects, namely a cardiotonic and/or blood pressure-

lowering and an anti-thrombotic effect.

As examples were the compounds

A= 5-methyl-6-[2-(1-imidazolyl)-benzoxazol-5-yl]-4,5- oxa- op

dihydro-3(2H)-pyridazinone,

B = 5-methyl-6-[2-(1-piperazinyl)-benzoxazol-6-yl]-4,5-'-f<4>/

dihydro-3 (2H)-pyridazinone,

C = 5-methyl-6-[2-(4-carbethoxy-1-piperazinyl)-benzoxazole-~

6-yl]-4,5-dihydro-3(2H)-pyridazinone,

D = 5-methyl-6-[2-(1-pyrrolidinyl)-benzimidazol-5-yl]-4,5-

dihydro-3(2H)-pyridazinone,

E = 5-methyl-6-[2-(4-thiomorpholi.no)-benzimi.dazol-5-yl] - —4T ^i

4, 5-dihydro-3 (2H)-pyridazinone and

F = 5-methyl-6-[2-(1-imidazolyl)-benzimidazol-5-yl] - ^- 0

4,5-dihydro-3(2H)-pyridazinone

examined for its biological properties as follows:

1. Determination of platelet aggregation according to Born and

Cross (J. Physiol. 170, 397 (1964)):

Platelet aggregation was measured in platelet-rich plasma

from healthy subjects. Below was the course of the reduction of the optical density after the addition of commercial

ordinary collagen from the company Sigma, St. Louis/USA, which contains 1 mg of collagen fibrils per ml, measured photometrically and recorded.

On the basis of the slope angle of the density curve, the aggregation rate (Vmax) was calculated. The point on the curve where the highest light transmission occurred served to calculate the "optical density" (O.D.). For maximum aggregation release, approx. 0.01 ml of the collagen solution was added to 1 ml of platelet-rich plasma.

The following table contains the found value:

Table I

£ D ?

Connection/?*~50

A 3.1 x 10<-8>mol/l

2. Determination of blood pressure-lowering and positive inotropic effect on anesthetized cats: The investigations were carried out on cats anesthetized with pentobarbital sodium (40 mg/kg i.p.). The animals breathed spontaneously. Arterial blood pressure was measured in the abdominal aorta with a Statham pressure transducer (P 23 Dc). To find the positive inotropic effect, the pressure in the left heart chamber was measured with a catheter tip manometer (Milliar PC-350 A). On this basis, the contractility parameter dp/dtmax was calculated with the help of an analogue dlfferentiator. The test compound was injected into a femoral vein. The solvent used was polydiol 200. The compound was tested on 3 cats, dose 0.1 i.v..

The following table contains the mean values:

In this context, it should be noted that no toxic side effects were observed for the compounds during the biological investigations.

Due to their pharmacological properties, the compounds of the general formula I prepared according to the invention and their optically active antipodes and their physiologically compatible acid addition salts with inorganic or organic acids are suitable for the treatment of chronic heart failure or angina pectoris and/or for the prevention of arterial thromboembolism and arterial occlusion disorders.

For these purposes, the new/compounds, possibly in combination with other active substances and the like, can be incorporated into the usual pharmaceutical application forms such as tablets, dragees, powders, suspensions, suppositories or ampoules. The single dose is here for adults 1-4 times a day for intravenous administration 1-50 mg, preferably 2-40 mg, and for oral administration 5-150 mg, preferably 5-10i) mg.

The following examples further illustrate the invention: Example 1

5-methyl-6-[2-(2,6-dichloro-4-pyridyl)-benzimidazol-5-yl]-..4,.5-dihydro-3(2H).-pyridazinone

4.0 g (10.2 mmol) N-[2-amino-4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-2,6-dichloro -pyridine-4-carboxylic acid amide is dissolved in 50 ml of glacial acetic acid, heated for 5 minutes to 100°C, then cooled to room temperature, the precipitated product is filtered off with suction, washed with diethyl ether and dried in air.

Yield: 86% of the theoretical,

m.p.: 260-264°C,

<C>17<H>13C12N5° <374'2)

Example 2

5-methyl-6-[2-(2-pyrazinyl)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from N-[2-amino-4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-pyrazine-2-carboxylic acid amide analogously to Ex. 1.

Yield: 47.7% of the theoretical,

m.p.: > 300°C.

Example 3

6-[2-(2-furyl)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from N-[2-amino-4-(4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-furan-2-carboxylic acid amide analogously to Ex. 1. Yield: 36.7% of the theoretical,

m.p.: > 300°C.

Example 4

6-[2-(2-thienyl)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazirion

Prepared from N-[2-amino-no-4-(4,5-dihydro-3 (2H)-pyridazinon-6-yl)-phenyl]-thiophene-2-carboxylic acid amide analogously to Ex p. 1.

Yield: 29.8% of the theoretical,

m.p.: 170-174°C.

Example 5

5-methyl-6-[2-(3-thienyl)-benzimidazol-5-yl]-4,5-dihydro-. 3 (2H)-pyr.idaz.inone

Prepared from N-[2-amino-4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-thiophene-3-carboxylic acid amide analogously to Ex. 1.

Yield: 71% of the theoretical,

m.p.: 184-186°C.

Example 6

6-[2-(3-thienyl)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-

pyridazinone

Prepared from N-[2-amino-4-(4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-thiophene-3-carboxylic acid amide analogously to Ex. 1. Yield: 73% of the theoretical,

m.p.: 176-178°C.

Example 7

5-methyl-6-[2-(2-furyl)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from N-[2-amino-4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-furan-2-carboxylic acid amide analogously to Ex. 1.

Yield: 24.7% of the theoretical,

m.p.: 264-266°C.

Example 8 5-methyl-6-[2-(3-pyridyl)-benzoxazol-5-yl]-4,5-dihydro-3 (2H)-pyrida z.i.none 2 g (6.0 mmol) N- [2 -hydroxy-5-(5-methyl-4,5-dlhydro-3(2H)-pyridazinon-6-yl)-phenyl]-pyridine-3-carboxylic acid amide is suspended in 40 ml of glacial acetic acid and heated for 40 hours in .a steel bomb with a glass lining to 150°C. The acetic acid is then distilled off, the residue is stirred with water, then suctioned off and dried. Further purification takes place by chromatography over silica gel (eluent: dichloromethane + 6% ethanol). Yield: 38.3% of the theoretical, m.p.: 223-225°C.

Example 9

5-methyl-6-[2-(4-pyridyl)-benzoxazol-5-yl]-4,5-dihydro-3 (2H)-pyridazinone

Prepared from N-[2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-pyridine-4-carboxylic acid amide analogously to Ex. 8.

Yield: 39.9% of the theoretical,

m.p.: 238-240°C.

Example 10

5-methyl-6-[2-(2-acetamido-5-pyridyl)-benzoxazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from N-[2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-2-acetaminopyri.di.n-5-carboxylic acid amide analogous to Ex. 8.

Yield: 20.7% of the theoretical,

m.p.: 299-300°C.

Example 11

5-methyl-6-[2-(2-furyl)-benzoxazol-5-yl]-4,5-dihydro-.3. (2H)-pyridazinone

Prepared from N-[2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-furan-2-carboxylic acid amide analogously to Ex. 8.

Yield: 22.2% of the theoretical,

m.p.: 204-205°C.

Example 12

5-methyl-6-[2-(2-thienyl)-benzoxazol-5-yl]-4,5-dihydro-.3. ( 2H)-pyri.daz i.non

Prepared from N-[2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-thiophene-2-carboxylic acid amide analogously to Ex. 8.

Yield: 50.5% of the theoretical,

m.p.: 214-215°C.

Example 13

5-methyl-6-[2-(3-thienyl)-benzoxazol-5-yl]-4,5-dihydro-..3. (2H).-pyridazinone

Prepared from N-[2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-thiophene-3-carboxylic acid amide analogously to Ex. 8.

Yield: 22.3% of the theoretical,

mp: 222-224°C.

Example 14

6-[2-(4-methyl-oxazol-5-yl)-benzoxazol-5-yl]-4,5-dihydro-3.(2H)-pyr j dazinone

Prepared from N-[2-hydroxy-5-(4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-4-methyl-oxazole-5-carboxylic acid amide analogously to Ex. 8.

Yield: 12.7% of the theoretical,

m.p.: 238-240°C.

Example 15

6-[2-(3-thienyl)-benzoxazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from N-[2-hydroxy-5-(4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-thiophene-3-carboxylic acid amide analogously to Ex.8. Yield: 15% of the theoretical,

m.p.: 262-263°C.

Example 16

5-methyl-6-[2-(2-thienyl)-benzthiazol-5-yl]-4,5-dihydro-3 (2H)-pyridazinone

1.7 g (4.9 mmol) N-[2-mercapto-5-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-thiophene -2-carboxylic acid amide is melted until no more gas evolution is observed. The product thus obtained is purified by column chromatography over 200 g of silica gel (eluent: dichloromethane + 5% ethanol). Yield: 11% of the theoretical,

m.p.: 203-204°C,

C,fiH,-.N..OS..(327.4)

Example 17

5-methyl-6-[2-(2-furyl)-benzthiazol-5-yl]-4,5-dihydro-

.3 (2H)-pyr i.dazinone Prepared from N-[2-mercapto-5-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl]-furan-2-carboxylic acid amide analogous to Example 16. Yield: 28% of the theoretical, m.p.: 223-224°C.

Example 18

5-methyl-6-[2-(1-piperazinyl)-benzoxazol-5-yl]-4,5-dihydro-3.(2H)-pyridazinon

1.5 g (5.4 mmol) of 5-methyl-6-(2-methylthio-benzoxazol-5-yl)-4,5-dihydro-3(2H)-pyridazinone are mixed with 10 g of piperazine and heated for 2 hours to 160°C. The reaction mixture is then stirred with approx. 300 ml of water, the undissolved product is suctioned off and washed with water. The purification is carried out by column chromatography (basic aluminum oxide, eluent: methylene chloride + 2% ethanol).

Yield: 44.4% of the theoretical,

m.p.: 215-216°C

C16H19N5°2<313'4>-

Example 19

5-methyl 1-6-[2-(1-pyrrolidinyl)-benzoxazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from 5-methyl-6-(2-methylthio-benzoxazol-5-yl)-4,5-dihydro-3(2H)-pyridazinone and pyrrolidine analogously to Ex. 18. Yield: 59.4% of the theoretical,

m.p.: 230-231°C.

Example 20

5-methyl-6-[2-(1-imidazolyl)-benzoxazol-5-yl]-4,5-

. dihydro- 3. (2H)-pyridaz in non

Prepared from 5-methyl 1-6-(2-methylthio-benzoxazol-5-yl)-4,5-dihydro-3(2H)-pyridazinone and imidazole analogously to Ex. 18. Yield: 31.4% of the theoretical,

m.p.: 236-238°C.

Example 21

5-methyl-6-[2-(4-methyl-1-piperazinyl)-benzoxazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from 5-methyl-6-(2-methylthio-benzoxazol-5-yl)-4,5-dihydro-3(2H)-pyridazinone and 1-methyl-piperazine analogously to Ex. 18.

Yield: 58.8% of the theoretical,

m.p.: 230-231°C.

Example 22 5-methyl 1-6-[2-(2-methyl 1-1-imidazolyl)-benzoxazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone Prepared from 5-methyl- 6-(2-methylthio-benzoxazol-5-yl)-4,5-dihydro-3 (2H)-pyridazinone and 2-methyl-imidazole in dimethylsulfoxide by heating for 3 hours to 150°C analogously to Ex.18 . Yield: 18.8% of the theoretical, mp: 214-216°C.

Example 23

6-[ 2-(2-methyl-1-imidazolyl)-benzoxazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from 6-(2-methylthio-benzoxazol-5-yl)-4,5-dihydro-3(2H)-pyridazinone and 2-methylimidazole analogously to Ex. 18.

Yield: 54.2% of the theoretical,

m.p.: 242-243°C.

Example 24

5-methyl-6-[2-(4-methyl-1-pyrazolyl)-benzoxazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from 5-methyl-6-(2-methylthio-benzoxazol-5-yl)-4,5-dihydro-3(2H)-pyridazinone and 4-methyl-pyrazole analogously to Ex. 18.

Yield: 16.6% of the theoretical,

m.p.: 255-257°C.

Example 25

6-[2-(N-acetyl-4-piperidinoto)-benzimidazol-5-yl]-4,5-Lyl dihydro-3. (2H)-pyridazinone hydrochloride id

450 mg of 6-[2-(4-piperidino)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone are suspended in 50 ml of ethyl acetate and 15 ml of glacial acetic acid. 15 ml of acetic anhydride are added to this mixture and heated for 2 hours at reflux temperature. The solvent is removed, and the residue is triturated in ether/acetone. It is then heated for a short time with water, and after removing the water, the residue obtained is dissolved in ethanol, activated charcoal is added and filtered. By adding ethereal hydrochloric acid to the filtrate, the desired product is obtained.

Yield: 210 mg (37% of the theoretical),

m.p.: from 237°C (acetone).

Ex empel 2 6 .

5-methyl-6-[2-(N-acetyl-4-piperidinbJ-benzimidazol-\5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from 5-methyl-6-[2-(4-piperidino)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone and acetic anhydride analogously to Ex. 25.

Yield: 16% of the theoretical,

m.p.: 245-248°C.

Example 27,

6-[2-(4-piperidiiroO-benzimidazol-5-yl]-4,5-dihydro-^,3(2H)-pyridazinone hydrochloride i d

3.6 g of 6-[2-(2,6-dichloro-4-pyridyl)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone are hydrogenated in 100 ml of methanol for 6 hours in a pressure vessel at 50°C and 5 bar hydrogen in the presence of palladium/charcoal. Filtration is then carried out, ether is added to the filtrate, and the precipitated crystals are suctioned off. The crude product obtained is dissolved in methanol, activated carbon is added and filtered. By adding ethereal hydrochloric acid to the filtrate, the desired product is obtained.

Yield: 2.05 g (61.4% of the theoretical),

mp.: sintering from 100°C.

Example 28

6-[2-(2-chloro-6-morpholyrro-4-pyridyl)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

900 mg of 6-[2-(2,6-dichloro-4-pyridyl)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone are suspended in 15 ml of morpholine and heated for 1 hour to 100 °C. The mixture is then cooled, filtered off, boiled 1x with water and dried well. The residue obtained is then dissolved in dimethylformamide, activated charcoal is added, filtered off, and the desired product is precipitated by adding petroleum ether.

Yield: 300 mg (29.2% of the theoretical),

m.p.: above 300°C.

Example 29

5-methyl-6-[2-(2-pyridyl)-benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridazinone

6.5 g (20 mmol) N-[2-hydroxy-4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-pyridine-2-carboxylic acid amide (prepared from pyridine-2-carboxylic acid, N,N'-carbonyldiimidazole and 2-hydroxy-4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-aniline) are introduced with stirring at 120 °C in 60 g of polyphosphoric acid and kept for 1 hour at this temperature. After cooling

the mixture is diluted with ice water, made alkaline with ammonia and extracted with methylene chloride. The extract is washed with water, dried with sodium sulfate, and the solvent is distilled off in vacuo. The residue is stirred with acetone, the precipitated crystals

filtered off and recrystallized from isopropanol/water.

Yield: 4.5 g (73.3% of the theoretical),

m.p.: 233°C.

Example 30

5-methyl-6-[2-(3-thienyl)-benzoxazol-6-yl]-4,5-dihydro-3.(2H)-pyridazinone

3.0 g (9.1 mmol) N-[2-(hydroxy-4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl]-thiophene-3-carboxylic acid amide (prepared from thiophene-3-carboxylic acid, N,N<1->carbonyldiimidazole and 2-hydroxy-4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-aniline) and 0, 5 g of p-toluenesulfonic acid dissolved in 50 ml of glacial acetic acid and heated for 8 hours to reflux temperature. The glacial acetic acid is then distilled off in vacuo, the residue is stirred with water and diisopropyl ether, filtered off and washed with water and then with acetone. The crude product is recrystallized from dioxane.

Yield: 1.6 g (56.4% of the theoretical),

m.p.: 2 35°C.

Example 31

5-methyl-6-[2-(2-furyl)-benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from N-[2-hydroxy-4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-furan-2-carboxylic acid amide and polyphosphoric acid analogously to Ex. 29.

Yield: 40% of the theoretical,

m.p.: 209°C.

Example 32

5-methyl-6-[2-(2-thienyl)-benzoxazol-6-yl]-4,5-. dihydro-3. (2H)-pyri.dazi.non

Prepared from N-[2-hydroxy-4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-thiophene-3-carboxylic acid amide and polyphosphoric acid at 130°C analogously to Ex. 29

Yield: 16.1% of the theoretical,

m.p.: 222°C.

Example 33

5-methyl-6-[2-(3-pyridyl)-benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from N-[2-hydroxy-4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-pyridine-3-carboxylic acid amide and polyphosphoric acid at 150°C analogously to Ex. 29.

Yield: 25% of the theoretical,

m.p.: 218°C.

Example 34

5-methyl-6-[2-(2-pyrazinyl)-benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from N-[2-hydroxy-4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-pyrazine-2-carboxylic acid amide and., poly-phospho oric acid analogous to Ex. 29.

Yield: 21.7% of the theoretical,

m.p.: 242°C.

Example 35

5-methyl-6-[2-(4-pyridyl)-benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from N-[2-hydroxy-4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-pyridinium-4-carboxylic acid amide and polyphosphoric acid analogue with Ex. 29.

Yield: 49.1% of the theoretical,

m.p.: 228°C.

Example 36

5-methyl-6-[2-(1-acetyl-4-piperidinp)-benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from N-[2-hydroxy-4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-1-acetyl-piperidine-4-carboxylic acid amide and polyphosphoric acid analogously to Ex. 29.

Yield: 60.3% of the theoretical,

m.p.: 199°C.

Example 37

5-methyl-6-[2-(4-methyl-5-oxazolyl)-benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from N-[2-hydroxy-4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-4-methyl-oxazole-5-carboxylic acid amide and polyphosphoric acid at 140 °C analogous to Ex. 29.

Yield: 28.2% of the theoretical,

m.p.: 217°C.

Example 38

5-methyl-6-[2-(5-pyrimidinyl)-benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from N-[2-hydroxy-4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-pyrimidine-5-carboxylic acid amide and polyphosphoric acid at 150°C analogously to Ex. 29.

Yield: 16.3% of the theoretical,

m.p.: 279°C.

Example 39

5-methyl-6-[2-(2-amino-5-pyridyl)-benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from N-[2-hydroxy-4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-6-acetamino-pyridine-3-carboxylic acid amide and polyphosphoric acid at 150°C analogous to Ex. 29. Yield: 8.2% of the theoretical,

mass spectrum: M+ = 321 m/e.

Example 40

6-[2-(2-pyridyl)-benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from N-[2-hydroxy-4-(4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-pyridine-2-carboxylic acid amide and polyphosphoric acid analogously to Ex. 29.

Yield: 29.1% of the theoretical,

m.p.: 282-283°C.

Example 41

6-[2-(2-furyl)-benzoxazol-6-yl]-4,5-dihydro-3 (2H)-pyridazinon

Prepared from N-[2-hydroxy-4-(4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-furan-2-carboxylic acid amide and polyphosphoric acid analogously to Ex. 29.

Yield: 31.3% of the theoretical,

m.p.: 261-262°C.

Example 42

5-Methyl-6-[2-(4-thiomorpholirito)-benzoxazol-6-yl]-.4,.5-dihydro-.3(2H).-pyridazinone. . Prepared from 5-methyl-6-(2-methylthio-benzoxazol-6-yl)-4,5-dihydro-3 (2H)-pyridazinone and thiomorpholine analogously to Ex. 18.

Yield: 56.5% of the theoretical,

m.p.: 218°C.

Example 4 3

5-methyl-6-[2-(1-piperidino)-benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from 5-methyl-6-(2-methylthio-benzoxazol-6-yl)-4,5-dihydro-3(2H)-pyridazinone and piperidine analogously to Ex. 18. Yield: 85.4% of the theoretical,

m.p.: 235°C.

Example 44

5- methyl-6- [2-(1-oxido-4-thiomorpholine*L)benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from 5-methyl-6-(2-methylthio-benzoxazol-6-yl)-4,5-dihydro-3 (2H)-pyridazinone and 1-oxido-thiomorpholine analogously to Ex. 18.

Yield: 6 5.3% of the theoretical,

m.p.: 257-260°C.

Example 45

56- - my.elt]y -4 1-, 65- -d[i2h- y(dlr,ol--d3 i(o2kHs)i-dpyo-ri4d-atiz.oimnoon rfoli.mr ^) -benzoxazole-< s>\*

Prepared from 5-methyl-6-(2-methylthio-benzoxazol-6-yl)-4,5-dihydro-3(2H)-pyridazinone and 1,1-dioxido-thiomorpholine analogously to Ex. 18.

Yield: 6 3.5% of the theoretical,

m.p.: 280°C.

Example 46

5-methyl-6-[2-(4-methyl-1-piperazinyl)-benzoxazole-. 6-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from 5-methyl-6-(2-methylthio-benzoxazol-6-yl)-4,5-dihydro^3 (2H)-pyridazinone and N-methyl-piperazine analogously to Ex. 18.

Yield: 61% of the theoretical,

m.p.: 198°C.

Example 47

5-methyl-6-[2-(4-carbethoxy-1-piperazinyl)-benzoxazol-.6-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from 5-methyl-6-(2-methylthio-benzoxazol-6-yl)-4,5-dihydro-3(2H)-pyridazinone and 4-carbethoxy-piperazine analogously to Ex. 18.

Yield: 72.7% of the theoretical,

m.p.: 239°C.

Example 48

5-methyl-6-[2-(1-pyrrolidinyl)-benzoxazol-6-yl]-..4,5-dihydro-3 (2H)-pyridazinone

Prepared from 5-methyl-6-(2-methylthio-benzoxazol-6-yl)-4,5-dihydro-3(2H)-pyridazinone and pyrrolidine analogously to Ex. 18. Yield: 73.8% of the theoretical,

m.p.: 234°C.

Example 49

5-methyl-6-[2-(1-piperazinyl)-benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from 5-methyl-6-(2-methylthio-benzoxazol-6-yl)-4,5-dihydro-3(2H)-pyridazinone and piperazine in melt analogously to Ex. 18.

Yield: 70.0% of the theoretical,

m.p.: 213°C.

Example 50

5-methyl-6-[2-(4-methyl-1-imidazolyl)-benzoxazole-

. 6-yl]-4., 5-dih.hydro.-3. (2.H)-pyridazinone

Prepared from 5-methyl 1-6-(2-methylthio-benzoxazol-6-yl)-4,5-dihydro-3(2H)-pyridazinone and 4-methyl-imidazole at 150°C analogously to Ex. 18.

Yield: 73.5% of the theoretical,

m.p.: 258°C.

Example 51 6-[2-(1-plperidino)-benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridaz inone Prepared from 6-(2-methylthio-benzoxazol-6-yl)-4 ,5-dihydro-3(2H)-pyridazinone and piperidine analogous to Ex. 18. Yield: 62% of the theoretical, mp: 198-199°C.

Example 52

6-[2-(4-morpholin^)-benzoxazol-6-yl]-4,5-dihydro-

3(2H)-pyridazinone

Prepared from 6-(2-methylthio-benzoxazol-6-yl)-4,5-dihydro-3(2H)-pyridazinone and morpholine analogously to Ex. 18. Yield: 73.3% of the theoretical,

m.p.: 240°C.

Example 53

6-[2-(1-pyrrolidinyl)-benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from 6-(2-methylthio-benzoxazol-6-yl)-4,5-dihydro-3(2H)-pyridazinone and pyrrolidine analogously to Ex. 18. Yield: 78.9% of the theoretical,

m.p.: 265-266°C.

Example 54

6-[2-(4-methyl-1-imidazolyl)-benzoxazol-6-yl]-. 4,5-dihydro-3(2H)-pyr r.i.daz inone

Prepared from 6-(2-methylthio-benzoxazol-6-yl)-4,5-dihydro-3(2H)-pyridazinone and 4-methyl-imidazole at 150°C analogously to Ex. 18.

Yield: 17% of the theoretical,

smr>. : 280-282°C.

Example 55

6-[2-(4-carbethoxy-1-piperazinyl)-benzoxazol-6-yl]-

. 4,5-dihydro-3(2H)-pyridazinone

Prepared from 6-(2-methylthio-benzoxazol-6-yl)-4,5-dihydro-3(2H)-pyridazinone and 4-carbethoxy-piperazine analogously to Ex. 18.

Yield: 50.1% of the theoretical,

m.p.: 242-243°C.

Example 56

6-[2-(1-piperazinyl)-benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridazinone ...

Prepared from 6-[2-methylthio-benzoxazol-6-yl)-4,5-dihydro-3(2H)-pyridazinone and piperazine (melt) analogously to Ex. 18.

Yield: 36.7% of the theoretical,

m.p.: 182-183°C.

Example 57

6-[2-(1-oxido-4-thiomorpholino)-benzoxazol-6-yl]-4,5-dihydro-3(.2H)-pyridazinone

Prepared from 6-(2-methylthio-benzoxazol-6-yl)-4,5-dihydro-3(2H)-pyridazinone and 1-oxido-thiomorpholine analogously to Ex. 18.

Yield: 39.1% of the theoretical,

m.p.: > 310°C.

Example 58

6-[2-(1,1-dioxido-4-thiomorpholino)-benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from 6-(2-methylthio-benzoxazol-6-yl)-4,5-dihydro-3(2H)-pyridazinone and 1,1-dioxido-thiomorpholine analogously to Ex. 18.

Yield: 33.3% of the theoretical,

mp: 298-299°C.

Example 59 6-[2-(4-methyl-1-piperazinyl)-benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridazinone Prepared from 6-(2-methylthio-benzoxazol-6-yl )-4,5-dihydro-3(2H)-pyridazinone and N-methyl-piperazine analogously to Ex. 18. Yield: 41.5% of the theoretical, mp: 247-248°C.

Example 60

6-[2-(4-thiomorpholino)-benzoxazol-6-yl]-4,5-dihy.chloro-3(2H)-pyridazinone

Prepared from 6-(2-methylthio-benzoxazol-6-yl)-4,5-dihydro-3(2H)-pyridazinone and thiomorpholine analogously to Ex. 18. Yield: 39.2% of the theoretical,

m.p.: 253-254°C.

Example 61

5-n-propyl-6-[2-(1-imidazolyl)-benzoxazol-5-yl]-4,5-dihydro-3. (2H)-pyridazinone

Prepared from 5-n-propyl-6-(2-methylthio-benzoxazol-5-yl)-4,5-dihydro-3 (2H)-pyridazinone and imidazole analogously to Ex. 18. Yield: 30.3% of the theoretical,

m.p.: 190-192°C.

Example 62

5-n-propyl-6-[2-(1-piperazinyl)-benzoxazol-5-yl]-. 4,5-dihydro-3(2H)-pyridazinone

Prepared from 5-n-propyl-6-(2-methylthio-benzoxazol-5-yl)-4,5-dihydro-3 (2H)-pyridazinone and piperazine analogously to Ex. 18. Yield: 65.2% of the theoretical,

m.p.: 162-164°C.

Example 63

5-methyl-6-[2-(1-imidazolyl)-benzoxazol-6-yl]-

. 4,5-dihydro-3. (2H)-pyridazinone

Prepared from 5-methyl-6-(2-methylthio-benzoxazol-6-yl)-4,5-dihydro-3(2H)-pyridazinone and imidazole at 160°C analogously to Ex. 18.

Yield: 17% of the theoretical,

m.p.: 219°C.

Example 64

5-methyl-6-[2-(4-morpholino)-benzoxazol-6-yl]-4,5-dihydro-3. (,2H)-pyr idazinone

Prepared from 5-methyl-6-(2-methylthio-benzoxazol-6-yl)-4,5-dihydro-3(2H)-pyridazinone and morpholine analogously to Ex. 18. Yield: 81.2% of the theoretical,

m.p.: 209°C.

Example 65

6-[2-(3-thienyl)-benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from N-[2-hydroxy-4-(4,5-dihydro-3 (2H)-pyridazinon-6-yl)-phenyl]-thiophene-3-carboxylic acid amide and glacial acetic acid/p-toluenesulfonic acid analogously to Ex. 30.

Yield: 22.2% of the theoretical,

m.p.: 272-273°C.

Example 66

5-methyl-6-[2-(2-acetamido-5-pyridyl)-benzoxazole-. 6-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from N-[2-hydroxy-4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-2-acetamino-pyridine-5-carboxylic acid amide and glacial acetic acid/p -toluenesulfonic acid analogous to Ex. 30.

Yield: 12% of the theoretical,

m.p.: > 300°C.

Example 67

5-methyl 1-6-[2-(2,6-dichloro-3-pyridyl)-benzoxazol-6-yl]-.4,5-dihydro-3 (2H)-pyridazinone ..

Prepared from N-[2-hydroxy-4-(5-methyl-4,5-dihydro-3(2H)-<pyr>ridazinone-6-vl)-phen<y>l]-2,6-dichloro- <py>ridin-3-carbox<y>lsvreamide and glacial acetic acid/p-toluenesulfonic acid analogously to Ex. 30. Yield: 40% of the theoretical,

m.p.: 268-270°C.

Example 68

5-n-propyl-6-[2-(4-pyridyl)-benzoxazol-5-yl]-..4,5-dihydro-3 (2H)-pyridazinone

Prepared from N-[2-hydroxy-5-(5-n-propyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-pyridine-4-carboxylic acid amide analogously to Ex. 8.

Yield: 40.1% of the theoretical,

m.p.: 200-202°C.

Example 69

5-methyl-6-[2-(2-chloro-6-morpholino-3-pyridyl)-benzoxazole-. 6-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from 5-methyl-6-[2-(2,6-dichloro-3-pyridyl)-benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridazinone and morpholine analogously to Ex. 28.

Yield: 22% of the theoretical,

m.p.: 236°C.

Example 70

5-methyl-6-[2-(1-imidazolyl)-benzi.midazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

a) 4-(2-chloro-benzimidazol-5-yl)-4-oxo-3-methyl-butyric acid methyl ester

12 g (46 mmol) of 4-(benzimidazol-2-on-5-yl)-4-oxo-3-methyl-butyric acid methyl ester are heated in 200 ml of phosphorus oxychloride for 1.5 hours under reflux. The excess phosphorus oxychloride is then distilled off in a vacuum, and the remaining residue is added to water under ice cooling. Neutralize with ammonia, extract with ethyl acetate, wash the ethyl acetate phase twice with water, pass it over magnesium sulphate and evaporate it to dryness. The residue is purified by chromatography (silica gel: 0.032-0.063 mm, eluent: ethyl acetate/petroleum ether = 2/1).

Yield: 7.9 g (61.2% of the theoretical),

m.p.: 135-136°C

b) 4-[2-(1-imidazolyl)-benzimidazol-5-yl]-4-oxo-3-methyl-butyric acid rethyl ester

1.5 g (5.3 mmol) 4-(2-chloro-benzimidazol-5-yl)-4-oxo-3-methyl-butyric acid methyl ester and 1.1 g (16 mmol) imidazole are mixed and heated for 1.5 hours to 130°C. You get a clear, tough melt which, after cooling, is added to water. Extract 3 times with ethyl acetate, wash the combined ethyl acetate solutions three times with water, dry them over magnesium sulphate and evaporate to dryness.

Yield: 1.5 g (90% of the theoretical),

m.p.: 130-140°C.

c) 5-methyl-6-[2-(1-imidazolyl)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

1.4 g (4.3 mmol) of 4-[2-(1-imidazolyl)-benzimidazol-5-yl]-4-oxo-3-methyl-butyric acid methyl ester is heated with 30 ml of acetic acid and 3.8 ml of 80% hydrazine hydrate for 1.25 hours at 105°C. After cooling, add approx. 100 ml of water, and the mixture is extracted three times with ethyl acetate. The combined ethyl acetate solutions are washed twice with water, dried over magnesium sulphate and evaporated. The residue is purified chromatographically (silica gel: 0.032-0.063 mm, eluent: methylene chloride/ethanol = 1:0 to 1:0.14).

Yield: 0.29 g (22.9% of the theoretical),

m.p.: 282-285°C (decomp.).

Example 71

5-methyl-6-[2-(4-methyl-1-piperazinyl)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from 4-[2-(4-methyl-1-piperazinyl)-benzimidazol-5-yl]-4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate

analogous to example 70c.

Yield: 6 7% of the theoretical,

m.p.: 317-320°C (decomp.).

Example 72

5-methyl-6-[2-(4-morpholinium)-benzimidazol-5-yl]-(4,5-dihydro-3(2H)-pyridazinone

Prepared from 4-[2-(4-morpholino)-benzimidazol-5-yl]-4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate analogously to Ex. 70c.

Yield: 51% of the theoretical,

mass spectrum: M+ 313 m/e

IR spectrum (methylene chloride): 1665 cm (carbonyl)

Example 73

5-methyl 1-6-[2-(1-pyrrolidinyl)-benzimidazol-5-yl]-

..4,5-dihydro-3(.2H)-pyridazinone

Prepared from 4-[2-(1-pyrrolidinyl)-benzimidazol-5-yl]-4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate analogously to Ex. 70c.

Yield: 75.3% of the theoretical,

m.p.: 233-236°C.

Example 74

5-methyl-6-[2-(4-thiomorpholino)-benzimidazol-5-yl]-.4,5-dihydro-3(2H)-pyridazinone

Prepared from 4-[2-(4-thiomorpholino)-benzimidazol-5-yl]-4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate analogously to Ex. 70c.

Yield: 73% of the theoretical,

UV spectrum (ethanol): 224 nm (0.18), 246 nm (0.28),

323 nm (0 .33) ,

IR spectrum (methylene chloride): 1665 cm 1 (carbonyl)

1625-1630 cm"<1>(C=N)

Example 75

5-methyl-6-[2-(2-pyrrolyl)-benzimidazol-5-yl]-. 4,5-dihydro-3 ( 2H) .-pyr in dazinone .....

Prepared from 4-[2-(2-pyrrolyl)-benzimidazol-5-yl]-4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate analogously to Ex. 70c.

Yield: 36% of the theoretical,

m.p.: 305-310°C (decomp.)

IR spectrum (methylene chloride): 1630 cm (carbonyl)

Example 76

5-methyl-6-[2-(1-oxido-4-thiomorpholino)-benzimidazol-5-y1]-4,5-dihydro-3(2H)-pyridazinone

Prepared from 4-[2-(1-oxido-4-thiomorpholino)-benzimidazol-5-yl]-4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate analogously to Ex. 70c.

Yield: 84% of the theoretical,

m.p.: 105°C (decomp.)

UV spectrum (ethanol): 221 nm (0.34), 245 nm (0.53),

319 nm (0.63),

IR spectrum (methylene chloride): 1655 cm (carbonyl)

Example 77

5-methyl-6-[2-(1-hexahydroazepinyl)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from 4-[2-(1-hexahydroazepinyl)-benzimidazol-5-yl]-4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate analogously to Ex. 70c.

Yield: 19% of the theoretical,

m.p.: 295-298°C (decomp.),

4.

mass spectrum: M : 325 m/e

Example 78

5-methyl-6-[2-(1-pyrazolyl)-benzimidazol-5-yl]-. 4,5-dihydro-3(2H)-pyridazinone

Prepared from 4-[2-(1-pyrazolyl)-benzimidazol-5-yl]-4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate analogously to Ex. 70c.

Yield: 37% of the theoretical,

m.p.: 290-292°C.

Example 79

5-methyl-6-[2-(4-acetyl-1-piperazinyl)-benzimidazole-. 5-y.l.] -.4.,5-dihydro-3(2H)-pyr.idazinone

Prepared from 4-[2-(4-acetyl-1-piperazinyl)-benzimidazol-5-yl]-4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate analogously to Ex. 70c.

Yield: 44% of the theoretical,

m.p.: 295-302°C.

Example 80

5-methyl-6-[2-(imidazolidin-2-on-1-yl)-benzimidazol-5-yl]-4,5-d in hydro -.3. (2H)-pyridazinone Prepared from 4-[2-(imidazolidin-2-on-1-yl)-benzimidazol-5-yl[-4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate analogously to Ex. 70c.

Yield: 7% of the theoretical,

m.p.: 285°C (decomp.),

mass spectrum: M+ = 312 m/e.

Example 81

5-methyl-6-[2-(1-piperidino)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from 4-[2-(1-piperidino)-benzimidazol-5-yl]-4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate analogously to Ex. 70c.

Yield: 49% of the theoretical,

m.p.: 185°C (decomp.),

mass spectrum: M<+>= 311 m/e.

Example 82

5-methyl-6-[2-(3-hydroxy-4-methyl-2-pyrazolyl)-benzimidazol-5-yl]-4,5-dihydro-3 (2H)-pyr.idazinone Prepared from 4-[2 -(3-hydroxy-4-methyl-2-pyrazolyl)-benzimidazol-5-yl]-4-oxo-3-methyl-butyric acid methyl ester and hydrazine hydrate analogous to Ex. 70c.

Yield: 67% of the theoretical,

m.p.: 260-265°C (decomp.),

mass spectrum: M+ = 324 m/e.

Example 83

5-methyl-6-[2-(4-morpholino)-benzimidazol-5-yl]-4,5-dihydr.o-3. (2H)-p.yri.daz inone

a) 4-[2-(4-morpholino)-benzimidazol-5-yl]-4-oxo-3-methyl-butyric acid morpholide

Prepared from 4-(2-sulfo-benzimidazol-5-yl)-4-oxo-3-methyl-butyric acid analogously to Ex. 70a.

Yield: 30% of the theoretical,

mass spectrum: M+ = 386 m/e.

b) 5-methyl-6-[2-(4-morpholino)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from 4-[2-(4-morpholino)-benzimidazol-5-yl]-4-oxo-3-methyl-butyric acid morpholide and hydrazine hydrate analogously to Ex. 70c.

Yield: 61% of the theoretical,

mass spectrum: M+ = 313 m/e.

Example 84

5-Methyl-6-[2-(1-[1.2.4]triazolyl)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

a) 4-[1-[1.2.4]triazolyl-benzimidazol-5-yl]-4-oxo-3-methyl-butyric acid methyl ester

260 mg (1 mmol) of 4-(2-chloro-benzimidazol-5-yl)-4-oxo-3-methyl-butyric acid methyl ester are heated with 9 80 mg (14 mmol) of 1,2,4-triazole in an oil bath to 160° C. After 45 minutes, the mixture is cooled and rubbed with 50 ml of hot methanol. After that

10 to 20 ml of methanol are distilled off, the resulting precipitate is suctioned off while hot and dried in air.

Yield: 0.22 g (74% of theoretical),

m.p.: 300-306°C (decomp.).

b) 5-methyl-6-[2-(1-[1.2.4]triazolyl)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

280 mg (1 mmol) 4-[1-[1.2.4]triazolyl-benzimidazol-5-yl]-4-oxo-3-methyl-butyric acid methyl ester is heated with 5 ml of ethanol and 1 ml of 98% hydrazine hydrate for 1 hour more 100°C. The solvent is then distilled off in a vacuum, water is added to the residue and extracted 3 times with ethyl acetate. The combined ethyl acetate phases are washed twice with water, dried over sodium sulphate and evaporated in vacuo. The obtained residue is purified by chromatography (silica gel, eluent: ethyl acetate). Yield: 107 mg (40% of the theoretical),

m.p.: 228-230°C.

Example 85

5-methyl-6-[2-(3-methyl-1-pyrazolyl)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared from 5-methyl-6-(2-chloro-benzimidazol-5-yl)-4,5-dihydro-3(2H)-pyridazinone and 3-methylpyrazole analogously to Ex. 84b.

Yield: 87% of the theoretical,

m.p.: 320-322°C (decomp.).

Example 86

5-methyl-6-[2-(1-pyrrolidinyl)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

295 mg (1 mmol) of 5-methyl-6-[2-(1-pyrrolidinyl)-benz-imidazol-5-yl]-3-(2H)-pyridazinone are dissolved in 20 ml of glacial acetic acid and hydrogenated at room temperature and 5 bar hydrogen in the presence of platinum dioxide. After completion of hydrogen absorption, the catalyst is filtered off, and the filtrate is evaporated to dryness in a vacuum. The residue is purified by chromatography (silica gel, eluent: methylene chloride/ethanol = 1:0 to 1:0.2).

Yield: 30% of the theoretical,

Claims (3)

1. Analogous method for the preparation of therapeutically active pyridazinones of the general formula where X means an ^even-t-uolt mod on alkyl—or- f-e^y4ra-3rk-y-l-g-rttppe —6 -ubctituortf imino group, an oxygen or sulfur atom, R1 means a saturated 5- to 7-membered alkylenimine ring attached to a nitrogen atom or a 5- to 7-membered saturated imino-, |-N alkyliminu-, N=TeTiy'l^I]^llr nriTvo -^ iMs- r N-alkanoylimino- traps -N-alkoxycarbonylimi-R o^alkyleneririg, j-hve-r—éet—rrevTvte^-i-nger—^k-an—vær-e—s-ubstd-tuertr-ar-k-ar-bonskj-elet^ — with—,1— e-l-l-e-r—r2—a-l-k-y-l-g-e-u-pped^ and a methylene group in the 4-position in a 6-fel-le-r—?4membered ring may be replaced by an oxygen or sulfur atom, a sulfinyl-, sulfonyL-, imino-, alkylimino-, ph4e«yl-a1 ky 1 im i no -|, alkoxycarbonylimino- or alkanoylimino group; a ^svontuolt with—l—e^Hber-^—arl-kylygrappigr— nitrogen atom bound saturated 5- to 7-membered alkylenimine ring, where a -Cl^CI^ group is replaced by a -NH-CO group, where C0 the -group in this -NH-CO group is linked to the already present N atom; a 5-membered heteroaromatic ring bonded over a nitrogen atom which can additionally contain a bk-sygen-1 o-l-lor cvovolatomfc one or two nitrogen atoms, Le-fe ^ksyg-ans^-elXe^^sAAw^jra-fcOffH^ Lom, { in that the heteroaromatic ring can be substituted with 1 |e-i-l-e-r-2-i alkyl groups, and in the case of the pyrazoles also with a hydroxy group and an alkyl group; a 5- or 6-membered heteroaromatic ring bonded over a carbon atom which may contain an oxygen or sulfur atom, etfjy^ o traps three-| nitrogen atoms, one oxygen-Ci&^ v'i clor ovovolatoml and one ^el-er two Nitrogen atom^cJ, the heteroaromatic rings may be substituted with 1 re-Hrer-2-\ alkyl group^, with an amino- or alkanoylamino group and for in the case of the pyridines also with one or two halogen atoms or with a halogen atom and a jtimino or morpholino group, and 1*2 means a hydrogen atom or an alkyl group, in that all the above-mentioned alkyl, alkanoyl or alkoxy groups can in each case contain 1-3 carbon atoms, their optically active antipodes, when R_ does not mean a hydrogen atom, and cteresVacid addition salts, characterized in that a) for the preparation of compounds with the general formula I where means one of the initially mentioned residues bonded over a carbon atom, one is optionally ring-closed in reaction the mixture formed compound with the general formula where R2 is as stated above, one of the residues A or B means one the other of the residues A and B means an amino group or a kj/ dU^ kji^ fv^ L Z 3 v)aAz>td°q mm/w R-^ ' means one of the residues specified for R^ above which is bonded over a carbon atom, Z^ and Z2 together mean an oxygen imrdaz olyl group T-e t—chloro-—br om—el-ler— iodine atom, or b) a carboxylic acid of the general formula where Rl 0<^ R2 is as indicated above, or its reactive acid derivatives are reacted with hydrazine, or c) for the preparation of compounds of the general formula I where means one of the above stated residues which is bonded over a nitrogen atom, a compound is reacted with the general formula where R2 and X are as indicated above, and Z 4 means a nucleophilic replaceable group, with an amine of the general formula where R^' means one of the residues indicated above for R^ bonded over a nitrogen atom, or d) for the preparation of compounds of the general formula I where X means a faXygen atom^el-l-«i_ari__eve^^ -jellej^_feny_1 a 1 kyl gr-uppe— substituted imino group-j[ hydrogenates a compound with the general formula $( oJ —P nv^n rf° H ( <vi> ) where R, and R„ are as indicated above, and X' means a bkGya& natom el Ler—e-n—even Lue-3rt—med~.e n alkyl-- or—-— v optionally, a thus prepared compound of the general formula I where R^ contains an imino and/or amino group is then transferred by alkanoylation to a corresponding compound of the general formula I where R^ contains an alkanoylimino and/or alkanoylamino group, or a thus prepared compound of the general formula I where R^ means a pyridine residue which is bonded over a carbon atom and substituted with halogen atoms, is transferred by catalytic dehalogenation and hydrogenation to a compound of the general formula I where R^ means a piperidinyl residue which is bonded over a carbon atom, or a thus prepared compound of the general formula I where R^ means a pyridine residue which is bonded over a carbon atom and substituted by one or two halogen atoms, is transferred by halogen replacement to a corresponding compound of the general formula I where R^ means a bonded over a carbon atom pyridine residue which is substituted with an amino or morpholi.no group and optionally with a halogen atom, or a thus prepared compound of the general formula I containing an optically active carbon atom in the 4- or 5-position of the pyridazinone ring, when R 2 means an alkyl group, is separated into its optically active antipodes by racemate resolution, or a thus prepared compound of the general formula I are transferred to their acid addition salts, especially their physiologically compatible salts with inorganic or organic acids. 2. Process according to claim 1, characterized in that 5-methyl-6-[2-(1-imidazolyl)-benzoxazol-5-yl]-4,5-dihydro-3 (2H)-pyridazinone is prepared, its optical ■ ^■^•2 active antipodes and its acid addition salts. 3. Process according to claim 1, characterized in that 5-methyl-6-[2-(1-piperazinyl)-benzoxazol-6-yl]-4,5-dihydro-3(2H)-pyridazinone is prepared, its optical - J^S.^ active antipodes and its acid addition salts.