IE51012B1

IE51012B1 - Benzoxazolyl dihydropyridazinone derivatives

Info

Publication number: IE51012B1
Application number: IE343/81A
Authority: IE
Original assignee: Thomae Gmbh Dr K
Priority date: 1980-02-22
Filing date: 1981-02-20
Publication date: 1986-09-03
Also published as: NZ196313A; DK73781A; NO157895C; DK151018C; ES8302700A1; ZA811130B; JPS6334154B2; AU543524B2; PH21232A; JPS56131581A; EP0034743A1; NO810586L; CA1166252A; DK151018B; IE810343L; ES499378A0; ES509533A0; GR74154B; ES8302699A1; AU6751981A

Abstract

1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL Benzoxazoles of general formula see diagramm : EP0034743,P9,F2 in which R1 represents a hydrogen atom ; a straight or branched alkyl group with 1 to 7 carbon atoms which can be substituted by an alkoxy group with 1 to 3 carbon atoms ; a cycloalkyl group with 3 to 7 carbon atoms ; an alkyl group with 1 to 3 carbon atoms substituted by a phenyl group which can be substituted by one or two alkoxy groups with 1 to 3 carbon atoms ; or a phenyl group which can be substituted by an alkyl or alkoxy group each with 1 to 3 carbon atoms, by a trifluormethyl, nitro or cyano group or by a fluorine, chlorine or bromine atom ; and in addition one of the mono-substituted phenyl groups mentioned above can be substituted by one or two alkyl groups with 1 to 3 carbon atoms or by an alkoxy group with 1 to 3 carbon atoms or by a fluorine, chlorine or bromine atom ; and R2 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms ; and their optically active antipodes as well as their physiologically compatible acid addition salts with inorganic or organic acids. 1. Claims for the Contracting State : AT Process for producing benzoxazoles of general formula see diagramm : EP0034743,P10,F4 in which R1 represents a hydrogen atom ; a straight or branched alkyl group with 1 to 7 carbon atoms which can be substituted by an alkoxy group with 1 to 3 carbon atoms ; a cycloalkyl group with 3 to 7 carbon atoms ; an alkyl group with 1 to 3 carbon atoms substituted by a phenyl group which can be substituted by one or two alkoxy groups with 1 to 3 carbon atoms ; or a phenyl group which can be substituted by an alkyl or alkoxy group each with 1 to 3 carbon atoms, by a trifluormethyl, nitro or cyano group or by a fluorine, chlorine or bromine atom ; and additionally one of the mono-substituted phenyl groups mentioned above can be substituted by one or two alkyl groups with 1 to 3 carbon atoms or by an alkoxy group with 1 to 3 carbon atoms or by a fluorine, chlorine or bromine atom ; and R2 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms ; and their optically active antipodes as well as their physiologically compatible acid addition salts with inorganic or organic acids characterised in that see diagramm : EP0034743,P11,F1 in which R1 and R2 are as defined in the introduction, X represents a mercapto, alkylmercapto, arylmercapto or aralkylmercapto group, and Y represents a hydrogen atom or an acyl radical, is cyclised ; or b) a carboxylic acid of general formula see diagramm : EP0034743,P11,F3 in which R1 and R2 are as defined in the introduction, or its amides, esters, thioester or halides, is reacted with hydrazine ; and if desired a compound of general formula I, in which R1 represents a hydrogen atom, obtained according to processes a) or b) is subsequently converted by means of alkylation into a corresponding compound of general formula I, in which R1 is defined as in the introduction with the exception of the hydrogen atom and the phenyl radicals mentioned in the introduction, and/or a racemate obtained, of general formula I, is separated by means of racemate separation into its optically active antipodes, and/or a compound obtained, of general formula I, is converted into its physiologically compatible acid addition salts with inorganic or organic acids.

Description

This invention relates to new benzoxazoles and benzothiazoles, to process for their preparation and to pharmaceutical compositions containing them.

According to one feature of the present invention there are provided compounds of general formula I, wherein R.j represents a hydroxy or mereapto group; an alkoxy or alkylmercapto group with 1 to 6 carbon atoms; an alkenyloxy or alkenylmercapto group with 3 to 6 carbon atoms; a phenylalkoxy or phenylalkylmercapto group wherein the alkyl moiety contains 1 to 3 carbon atoms and wherein the phenyl nucleus may optionally be substituted by from 1 to 3 substituents selected from alkoxy groups with 1 to 3 carbon atoms, halogen atoms and amino groups; an alkyl group with 1 to 3 carbon atoms (optionally substituted by a phenyl group); a phenyl group (optionally substituted by a methoxy or cyano group or a halogen atom); or a group of formula -N (in which 51013 - 3R2 represents a hydrogen atom; a straight-chain or branched alkyl group with 1 to 7 carbon atoms (optionally substituted by an alkoxy group with 1 to 3 carbon atoms); a cycloalkyl group with 3 to 7 carbon atoms; a phenylalkyl group wherein the alkyl moiety contains 1 to 3 carbon atoms and wherein the phenyl nucleus may optionally be substituted by one or two alkoxy groups with 1 to 3 carbon atoms; a phenyl group (optionally substituted by an alkyl or alkoxy group with 1 to 3 carbon atoms, a trifluoromethyl, nitro or cyano group or a fluorine, chlorine or bromine atom,the said mono-substituted phenyl groups being optionally further substituted by one or two alkyl groups with 1 to 3 carbon atoms, by an alkoxy group with 1 to 3 carbon atoms or by a fluorine, chlorine or bromine atom); or an alkoxycarbonyl group with 2 to 4 carbon atoms ; and R^ represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms]; R^ and R^, which may be the same or different, each represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms; and X represents an oxygen or sulfur atom, and salts thereof with inorganic or organic acids or bases.

The new compounds according to the invention exhibit interesting pharmacological properties and in particular cardiovascular activity, i.e. cardiotonic, hypotensive and/or antithrombotic activity. It will be appreciated that, for pharmaceutical use, the salts referred to above will be physiologically compatible. 4Other salts may, however, find use for example in the preparation of compounds of general formula I and their physiologically compatible salts.

In the compounds according to the invention R^ may, for example, represent a hydroxy, methoxy, ethoxy, propoxy, lsopropoxy, butoxy, isobutoxy, tert.butoxy, pentoxy, neopentoxy, hexoxy, allyloxy, crotyloxy, pentenyloxy hexenyloxy, benzyloxy, methoxy-benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, mercapto, aethylaercapto, ethylmercapto, propylmercapto, isopropylmercapto, butylmercapto, isobutylaercapto, tert.butylmercapto, pentylmercapto, neopentylmeroapto, tert.pentylmereapto, hexylmercapto, allylmercapto, crotylmercapto, pentenylmercapto, hexenylmercapto, benzylraercapto, methoxybenzylmercapto, chloroben2ylmercapto, bromobenzylmercapto, dimethoxybenzylmercapto, 1-phenylethylmercapto, 2-phenylethylaercapto, 2-(methoxyphenyl)-ethylmercapto, 2-(dimethoxyphenyl)-ethylmercapto, 2-(chlorophenyl)-ethylmercapto, 2-(chloro-methoxyphenyl )-ethylmercapto, 2-(amino-dichlorophenyl)-ethylmercapto, 3-phenylpropylmeroapto, methyl, ethyl, propyl, isopropyl, benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, phenyl, methoxyphenyl, cyanophenyl, chlorophenyl, bromophenyl, fluorophenyl, amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert.butylamino, pentylamino, isopentylamino, neopentylamino, tert.pentylamino, hexylamino, heptylamino, dimethylamino, diethylamino, diisopropylamlno, methyl-ethylamino, methyl-propylamino, ethyl-isopropylamino, methylbutylamino, ethyl-pentylamino, methyl-heptylamino, methoxy-ethylamino, methoxy-propylamino, methoxybutylamino, methoxy-pentylamino, methoxy - heptylamino, ethoxy-ethylamino, propoxy-propylamino, - 5 N-methyl-ethoxyethylamino, N-ethyl-methoxypropylamino, cyclopropylami.no, cyclopentylami.no, cyclohexylami.no, cycloheptylami.no, N-methyl-cyclohexylami.no, N-ethylcyclohexylami.no, N-propyl-cyclohexylami.no, phenylaaino, aethylphenylasj.no, dimathylphenylamino, trimethylphenylamino, efcaylphenylamino, propylphenylaaino, isopropylphenylaai.no, aethoxyphenylamino, dimethoxyphenylamino, iaopropoxyphenylaaino, iluorophenylaaino, diiluorophenylamino, chlorophenylaaino, dichlorophenylaaino, broaophenylamino, dibromophenylaaino, trifluoroaethyl phenylaaino, nitrophenylaaino, cyanophenylaaino, aethyl-fluorophenylamino, methyl-chlorphenylaaino, methoxy-chlorophenylaaino, methoxy-broaophenylamino, methoxy-cyanophenylamino, methoxy-trifluoromethyl-phenylaaino, methoxy-nitrophenylamino, ethoxy-nitrophenylamino, propoxy-nitrophenylamino, benzylamine, 1-phenylethylamino, 2-phenylethylamino, 3-phenylpropylamino, methoxybenzylamino, dimethoxybenzylamino, 2-(dimethoxyphenyl)ethylamino, 2-(diethoxyphenyl)ethylami.no, 2-(dipropoxyphenyl)ethylamino, 2-(methoxy-ethoxyphenyl)-ethylamino, N-methyl phenylaaino, N-ethyl-methylphenylamino, N-methyl aethoxyphenylamino, N-ethyl-dimethoxyphenylaaino, N-aethyl-benzylaaino, N-ethyl-2-phenylethylamino or N-methyl-methoxybenzylaaino group , and may each represent a hydrogen atom or a methyl, ethyl, propyl or isopropyl group. When R^ and R^ are different the compounds according to the invention may exist in the form of an optically active antipode as well as mixtures thereof due to the optically active carbon in the 5-position of the pyridazinone ring. All such forms are within the scope of the present invention.

Preferred compounds are those wherein: - 6 represents a hydroxy or mercapto group; an alkoxy or alkylmercapto group with 1 to 3 carbon atoms; an allyloxy or allylraecapto group; a hexylmercapto, methoxybenzylmercapto or 2-(amino-dichlorophenyl)5 ethylmercapto group; an alkyl group with 1 to 3 carbon atoms (optionally substituted by a phenyl group); a cyanophenyl, amino or dimethylamino group; an alkylamino group with 1 to 5 carbon atoms (wherein the alkyl moiety is optionally substituted by a methoxy group); a phenyl10 amino group (wherein the phenyl nucleus is optionally substituted by a methyl, methoxy, trifluoromethyl, cyano or nitro group or by a chlorine or bromine atom); or a dichlorophenylamino, dibromophenylamino, dimethoxyphenylamino , methoxy-nitrophenylamino, trimethylphenylamino, cyclohexylamino, dimethoxyphenylethylamino or ethoxycarbonylamino group ; represents a hydrogen atom or a methyl group; and R^ represents a methyl group: and more particularly those wherein the pyridazino group is in position 5 of the benzoxazole or benzothiazole ring.

Especially preferred compounds are those of general formula la, wherein Rj represents a mercapto, methylmercapto, hydroxy, ethoxy, 2-(4-amino-3,5-dichloro- . phenyl)ethylmercapto, amino, dimethylamino or cyclohexylamino group; an alkylamino group with 1 to 5 carbon atoms; or a phenylamino group (optionally substituted by one or two methoxy groups); and X represents a sulfur atom or more especially an oxygen atom; and their salts with acids or bases.

In the above compounds of general formula la and their salts, Rj may more especially represent a hydroxy, mercapto, ethylamino, n-butylamino, cyclohexylamino or 4-methoxyphenylamino group.

Particularly preferred compounds according to the invention are the following: -methyl-6-[2'-mercapto-benzoxazole-5’-yl]-4,5dihydro-3(2H)-pyridazinone and salts thereof, and -methyl-6-[2’-n-butylamino-benzoxazole-5’-yl)4,5-dihydro-3(2H)-pyridazinone and acid addition salts thereof.

The compounds of general formula I may, for example, be prepared by the following processes which processes constitute further features of the present invention:a) Cyclisation of a compound, optionally prepared in situ in the reaction mixture, of formula II, 1012 - 8 (wherein R^, R^, R^ and X are as hereinbefore defined, Y represents a hydrogen atom or an acyl group and Z represents a nucleophilically exchangeable group) whereby the desired compound of formula I is obtained.

Y^when an acyl group, may for example represent an acetyl, propionyl, benzoyl or £-toluenesulfonyl group.

Z may, for example, represent a chlorine or bromine atom or a hydroxy, methoxy, ethoxy, benzyloxy, mercapto, methylmercapto, ethylmercapto, propylmercapto, benzylmercapto, phenylmercapto or imidazolylcarbonyl group.

The cyclisation is conveniently carried out in the presence of a solvent such as e.g. tetrahydrofuran, dioxan, benzene, toluene, dimethylformamide, dimethyl ethylene glycol or sulfolane and optionally in the presence of a condensing agent such as e.g. N,N'-dicyclohexylcarbodiimide, carbonyldiimidazole, £-toluenesulfonic acid, phosphorus oxychloride, thionylchloride, hydrochloric acid, sulfuric acid, phosphoric acid or polyphosphoric acid. Reaction temperatures are conveniently from 25 to 300°C, but preferably the boiling temperature of the reaction mixture, e.g. at temperatures of from 50 to 285°C. The cyclisation can however, if desired, be carried out in the melt. (wherein Rp R^, Rg and X are as hereinbefore defined), or an anhydride, ester, thioester, amide, imidazolide or acid halide thereof, with hydrazine.

The reaction is conveniently carried out in the presence of a solvent such as e.g. methanol, ethanol, isopropanol, glacial acetic acid, propionic acid and/or in an excess of hydrazine or hydrazine hydrate. Preferred temperatures are from 0 to 200°C, e.g. at temperatures of from 20 to 150°C, most preferably, however, at the boiling temperature of the reaction mixture. Optionally the reaction may be carried out in the presence of an acid as condensing agent such as e.g. sulfuric acid or £-toluenesulfonic acid. The reaction can however, if desired, be carried out without a solvent. c) For the preparation of compounds of general formula I wherein R^ represents an alkoxy or alkylmercapto group with 1 to 6 carbon atoms; an alkenyloxy or alkenylmercapto group with 3 to 6 carbon atoms; a phenylalkoxy or phenylalkylmercapto group wherein the alkyl moiety contains 1 to 3 carbon atoms and wherein the phenyl nucleus may optionally be substituted by from 1 to 3 substituents selected from alkoxy groups with 1 to 3 carbon atoms, halogen atoms and amino groups; or a group of formula R, ‘2 n: '3 [in which R2 represents a hydrogen atom; a straightchain or branched alkyl group with 1 to 7 carbon atoms (optionally substituted by an alkoxy group with 1 to 3 carbon atoms); a cycloalkyl group with 3 to 7 carbon 1012 - 10 atoms; a phenylalkyl group wherein the alkyl moiety contains 1 to 3 carbon atoms and wherein the phenyl nucleus may optionally be substituted by one or two alkoxy groups with 1 to 3 carbon atoms; or an alkoxycarbonyl group with to 4 carbon atoms and R^ represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms]: Alkylation of a compound of formula I as hereinbefore defined (wherein R^ represents a hydroxy or mereapto group or a group of formula [in which R.a represents a hydrogen atom; a straightchain or branched alkyl group with 1 to 7 carbon atoms (optionally substituted by an alkoxy group with 1 to 3 carbon atoms); a cyeloalkyl group with 3 to 7 carbon atoms; a phenylalkyl group wherein the alkyl moiety contains 1 to 3 carbon atoms and wherein the pheryl nucleus may optionally be substituted by one or two alkoxy groups with 1 to 3 carbon atoms; or an alkoxycarbonyl group with 2 to 4 carbon atoms]) with a compound of formula IV, (IV) [wherein R ’ represents an alkyl group with 1 to 3 carbon atoms (optionally substituted by an alkoxy group with 1 to 3 carbon atoms or by a phenyl group itself optionally substituted by from 1 to 3 substituents selected from alkyl and alkoxy groups with 1 to 3 carbon atoms, halogen - 11atoms and amino groups); an alkyl group with 4 to 7 carbon atoms (optionally substituted by an alkoxy group with 1 to 3 carbon atoms); an alkenyl group with 3 to 6 carbon atoms; or a cycloalkyl group with 3 to 7 carbon atoms; and U represents a nucleophilically exchangeablegroup such as, for example, a halogen atom or a sulfonic acid ester radical, e.g. a chlorine, bromine or iodine atom or a methanesulfonyloxy, £-toluenesulfonloxy or methoxysulfonyloxy group, whereby the desired compound of formula I is obtained.

The alkylation is carried out with an appropriate alkylating agent of formula IV such as e.g. a phenylalkyl halide, alkyl halide, dialkyl sulfate or trialkyloxoniumtetrafluoroborate. Such alkylating agents include for example benzyl chloride, phenylethyl bromide, methyl iodide, dimethyl sulfate, diethyl sulfate and ethyl bromide. The alkylation is conveniently carried out in the presence of a solvent such as e.g. methanol, ethanol, methanol/water, dimethylformamide or dioxan and optionally in the presence of a base such as e.g. sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium methylate or potassium carbonate. Preferred temperatures are up to the boiling temperature of the reaction mixture.

Due to the optically active carbon atom in position 5 of the pyridazinone ring, the compounds according to the invention wherein R. and R. are different can. if desired, be resolved into their optically active antipodes. This resolution is conveniently carried out by fractional crystallization of salts thereof with optically active acids such as e.g. tartaric acid, dibenzoyl tartaric acid, 1012 malic acid, camphoric acid or camphorsulfonic acid, or by chromatography using optically active adsorbents.

Morover, the compounds of general formula I can be converted, if desired, into their salts with inorganic or organic acids or bases. Suitable acids include for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.

The compounds of general formulae II and III, used as starting materials in the processes described above, may be obtained according to methods known from the literature. Thus, for example a compound of formula II can be obtained by reaction of a corresponding 3-(nitrohydroxybenzoyl) -butyric acid ester with hydrazine, subsequent reduction of the nitro group followed by reaction of the thus obtained compound with an appropriate carboxylic acid derivative.

A compound of formula III may be obtained by reaction of a compound of formula V, with malonic ester. The thus obtained compound is subsequently saponified, decarboxylated, the chlorine atom is replaced by a hydroxy or mercapto group, the nitro group is reduced and the thus obtained amino compound is cyclisized to the desired benzoxazole or -thiazole after reaction with an appropriate carboxylic acid derivative.

The compound of general formula I as well as their physiologically compatible salts exhibit, as already mentioned hereinbefore, interesting pharmacological properties and especially a cardiovascular activity, i.e. a cardiotonic, hypotensive and/or antithrombotic activity. These compounds are thus suitable for the treatment of chronic heart insufficiency or angina pectoris and/or for the prophylaxis of arterial occlusion and thrombosis.

For example the following compounds A » 5-Methyl-6-/J'-ethylaaino-benzoxazole-5'-yl7-4,5-dihydro3 (2H)-pyridazinone, B 5-Methyl-6-/2'-cyclohexylamino-benzoxazole-5'-yl74,5-dihydro-3(2H)-pyridazinone, C « 5-Methyl-6-/?'-n-hutylamino-beazoxazole-5,-yl7"^>5-dihydro-3(2H)-pyridazinone, D - 5-Methyl-6-/j?'-(4-methoxyphenylamino)-benzoxazole-5,-yl74,5-dihydro-3(2H)-pyridazinone, E - 5-Methyl-6-(2'-mercapto-benzoxazole-5*-yl)-4,5-dihydro3(2H)-pyridazinone, and F - 5-Methyl-6-(2'-hydroxy-benzoxazole-5’-yl)-4,5-dihydro3(2H)-pyridazinone were tested with regard to their biological properties.

The following tests were performed: - 14 1. Determination of the thrombocyte aggregation according to Born and Cross (J. Physiol. 170, 597 (1964)): The thrombocyte aggregation was measured in plateletrich plasma of healthy test persons. The decrease in optical density was measured photometrically and recorded after addition of commercial collagen of Messrs. Sigma, St. Louis, U.S.A., which contains 1 mg of collagenfibrils per ml. The velocity of aggregation (Vmax) was determined from the angle of inclination of the density eur10 ve . The point of the curve where the most light was transmitted, served for the determination of the optical den sity (o.d.). To provoke maximum aggregation approx. 0.01 ml of the collagen solution was added to 1 ml of platelet-rich plasma.

The following tabl® shows the results obtained: Table I: Compound ED^q in gmol/l A 1.4 P 0.4 2. Determination of the hypotensive and positive inotropic activity in the cat The tests were performed in cats, which were narcotisized 2c with pentobarbital sodium (40 mg/kg i.p.). The animals breathed spontaneously. The arterial blood pressure was measured in the aorta abdomlnalls by a Statham pressure transducer (P 23 Dc). The positive inotropic effect was determined by measuring the pressure in the left auricle by means of a catheter tipmanometer (miliar PC 350 A).

The contractility parameter dp/dtBax was registered by means of an analog differentiating circuit.

The substances under test were injected into the vena femoralls. Phyaiological saline solution or polydiol 200 was used as solvent. Each substance was tested in at least 3 cats, dose 0.1 or 2.0 mg/kg i.v.

The tested substances showed an activity lasting at least 45 minutes.

The following table contains the average values; Test Com- pound Dose mg/kg i.v. Change of blood pressure in mmHg Increase of dp/dt in % A 0.1 -40/33 + 79 B 0.1 -32/32 + 39 C 0.1 -27/27 + 62 D 2.0 -32/42 + 92 E 0.1 - 8/17 + 29 F 0.1 -18/19 + 65 3. Acute toxicity: The acute toxicity of the test compounds was determined in white mice after oral administration of a single dose (observation time: 14 days). - 16. Table III; rest compound acute toxicity mg/kg p.o. A > 300 (2 out of 6 animals died) B >300 (0 out of 6 animals died) C >300 (1 out of 6 animals died) D > 300 (0 out of 6 animals died) According to a yet further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient, at least one compound of formula I as hereinbefore defined or a physiogicaily compatible salt thereof in association with a pharmaceutical carrier or excipient.

For pharmaceutical administration the compound of 10 general formula I and their physiologically compatible salts may be incorporated into the conventional preparations in either solid or liquid form, optionally in combination with other active ingredients. The compositions may, for example, be presented in a form suitable for oral, rectal or parenteral administration. Preferred forms include, for example, plain tablets, coated tablets, powders, suspensions, suppositories and ampoules.

The active ingredient may be incorporated in excipients customarily employed in pharmaceutical compositions such as, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous 51013 - 17 s or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.

Advantageously the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Suitable dosage units for adults contain from 10 to 50 mg, preferably from 20 to 40 mg of active ingredient for intravenous administration and from 50 to 150 mg, preferably from 75 to 100 mg for oral administration. Such a dosage may, for example, be administered from 1 to 4 times per day. The following non-limiting examples serve to illustrate the present invention.

Example I N-Ethyl-N·-/2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyridazinone-6-vl) -phenyl7thlourea .Θ g (50 a mol) of 2-a«iao-4-(5-aethyl-4,5-dihydro-3(2H)pyridazinone-6-yl)-phenol were suspended In 250 si of tetrahydrofuran. The suspension obtained was mixed with 25 ml (0.29 mol) of ethyl isothiocyanate and the resultant mixture was refluxed for 3.5 hours·, whereby a clear solution formed after a short time. The mixture was then evaporated and the yellow oily residue obtained was crystallised by addition of ether. The precipitated product was filtered off with suction, washed with ether and dried at room temperature.

Yields 13.0 g (91.5 % of theory) M.p.: 137 - 139°C C14R18N4°2S (3θ6·4) Calc.: C 54.88 H 5.92 N 18.29 S 10.47 Found: 55.10 6.10 17.90 10.30 Example II 2-Ethylamlno-5-(3-methvl-4-oxo-hutyrlc acld-4-yl)-henzoxazole 3.24 g (10.0 b mol) of N-ethyl-N'-22-hydroxy-5-(3-methyl-4oxo-butyric acid-4-yl)-phenyl7thiourea were dissolved in 15C ml of tetrahydrofuran. The solution obtained was mixed with 4.17 g (20.0 m mol) of Ν,Ν’-dicyclohexylcarbodiimide and then refluxed for 5 hours. After refluxing, the resultant solution was evaporated to half its original volume, boiled again for a short time then cooled until crystals formed.

The obtained product was filtered off with suction, recrystallized from tetrahydrofuran and dried at room temperatu re.

Yield: 0.71 g (24.3 % of theory) M.p.; 160 - 162°C.

Example 1 -Methyl-6-/2·-aethylaaino-benzoxazole-5'-yl7-4»5-dihydro3(2H)-pyridazlnone 3.36 g (11.5 a aol) of N-aethyl-N'-/2-hydroxy-5-(5-aethyl5 4,5-dihydro-3(2H)-pyridazlnone-6-yl)-phenyl7thiourea were dissolved In 150 al of tetrahydrofuran. The solution was alxed with 3.13 g (15 a aol) of Ν,Ν'-dicyclohexylcarbodiimide and refluxed for 5 hours. After refluxing, the reaction mixture was evaporated to half its original volume, boiled again for a short time and cooled until crystals formed. The obtained product was filtered off with suction, reerystallized fran methanol and dried at rooa temperature.

Yield: 0.84 g (28.3 % of theory) M.p.: 241 - 242°C C13H14H4O2 (258.3) Calc.: C 60.46 H 5.46 N 21.69 Found: 60.28 5.61 21.50 Exaaple 2 -Methyl-6-/2’-n-butylaaino-benzoxazole-5'-yl7-4,5-dihydro20 3(2H)-pvrldazinone _______________ Prepared analogously to Example 1 from N-n-butyl-Ν'-/2-hydroxy5-(5-aethyl-4,5-dihydro-3(2H)-pyridazinone-6-yl)-phenyl7thiourea.

Yield: 39.7 * of theory M.p.: 186 - 188°C C16H2ON4O2 (300.4) Calc.: C 63.98 Η 6.7'1 N 18.65 Found: 63.99 6.96 18.54 S1012 - 20 Example 5 -Methyl-6-/Σ' -iaopropylamino-benzoxazole-5’-yl7>5-dihydro3(2H)-pyridazlnone Prepared analogously to Example 1 from N-iaopropyl-N15 /2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyridazinone-6-yl)phenyl/thiourea.

Yields 52 % of theory M.p.: 239 - 241°C C15H1qN402 (286.34) 10 Calc.s C 62.92 H 6.34 » 19.57 Founds 62.65 6.33 19.25 Example 4 -Methyl-6-25'~cyclohexylaE!ino-benzoxazole-5,-yl7-4,5-dihydro5(2H)-pyridazinone Prepared analogously to Example 1 from N-cyclohexyl-N’/2-hydroxy-5~(5-methyl-4,5-dihydro-3(2H)-pyrida2inone-6-yl)phenyl7thiourea.

Yields 59.1 % of theory M.p.s 235 - 237°C 20 C18H22N4°2 (326.4) Calc.s C 66.24 6.79 N 17.^6 Founds 66.CO 6.90 16.99 - 21 Example 5 - Methyl-6-/2' - (3,4-dimathoxyphenethylamino) -benzoxazole51-vl7-4.5-dlhydro-3(2H)-pyridazinone Prepared analogously to Example 1 from N-3»4-diaethoxyphenethyl5 N'-/J-hydroxy-5-(5-»ethyl-4,5-dihydro-3(2H)-pyridazinone6- yl)-phenyl/tbiourea. field: 48.2 % of theory M.p.: 70 - 72°C t'22H241,4°4 x JVdrochlerio acid (444.93) 10 Calc.: C 59.39 H 5.87 N 12.59 Cl 7-99 Pound: 59.40 5.69 12.89 8.00 Example 6 -Methyl-6-/2' -phenylamino-benzoxazole-5 ’ -yl7"4,5-dihydro3(2H)-pyridazinone ml of hydrazine hydrate (99 %) were added at approx. 20°C in portions to 20 ml of glacial acetic acid whilst stirring and ice cooling. Subsequently 6.5 g (20.0 m mol) of 2-phenylamino-5-(3-methyl-4-oxo-butyric acid-4-yl)-benzoxazole were added to the reaction mixture and the thus obtained suspen20 aion was refluxed. After 1 hour the suspension was cooled to room temperature and diluted with water. The precipitated product was filtered off with suction, washed with water and dried at 80°C.

Yield: 2.80 g (43.7 % of theory) M.p.: 214 - 217°C C18H1gN402 (320.34) Calc.: C 67.49 H 5.03 N 17.49 Found: 67.00 5.32 17.12 Example 7 -Methyl-6- 2Σ- -(2-chloroanilino)-benzoxazole-5’-yl7-4,5-dihydro-3(2H)-pyrldazinone_ Prepared analogously to Example 1 from N-2-chlorophenyl-N'5 /§-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyrldazinone-6-yl)phenyl/thiourea.

Yield: 33.9 % of theory M.p.: 193 - 195°C C18H15N4°2C1 (354.8) 10 Calc.: C 60.93 H 4.26 N 15-79 Cl 9.99 Found: 60.90 4.25 15.93 10.20 Example 8 - Methyl-6-/2'-(4-trifluoromethylphenylamino)-benzoxazole51 -yl7-4,5-dlhvdro-3 (2H) -pyrldazinone Prepared analogously to Example 1 from N-4-trifluoromethylphenyl-N'-/2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyridazinone 6- yl)-phenyl7thiourea.

Yield: 57.3 % of theory M.p.: 249 - 251 °C C19H15N402F5 (388.36) Calc.: C 58.76 H 3.89 N 14.42 Found: 59.00 4.13 14.31 Example 9 -Methyl-6-/2' - (3,4-dichlorophenylamino)-benzoxazole-5'-yl725 4,5-dlhydro-3(2H)-pyrldazinone Prepared analogously to Example 1 from N-3,4-dichloro»henylNi-/2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyridazinone-6-yl)phenyl/thiourea.

Yield: 73.5 % of theory M.p.: 253 - 256°C ^8^4^4^2^2 (389.3) Calc.: C 55.54 H 3.63 Cl 18.22 Found: 55.40 3.83 18.14 Exanpie 10 -Methyl-6-/Σ'-(4-bromophanylamino)-benzoxazole-5’-yj7"4,5dlhvdro-3(2H)-pyridazinone Prepared analogously to Example 1 from N-4-bromophenyl-H'10 2J-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyridazinone-6-yl) phenyl/thiourea.

Yield: 65.4 % of theory M.p.: 243 - 245°C C18H15N4°2Br (390.27) Calc.: C 55.40 H 3-87 N 14.36 Br 20.48 Found: 55.00 4.05 13.95 20.76 Example 11 - Methyl-6-/J'-(4-methoxyphenylamino)-benzoxazole-5'-yl7~ 4,5-dihvdro-3(2H)-pyridazinone Prepared analogualy to Example 1 from N-4-methoxyphenylN'-/2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyridazinone6- yl)-phenyl7thiourea.

Yield: 40.3 % of theory M.p.: 220 - 222°C 25 C19H18N403 (350.4) Calc.: C 65.13 H 5.18 N 15.99 Found: 65.30 5.20 15.83 Example 12 -Methyl-6-/2'-(2-nethoxy-4-nitrophenylaaino)-bsnzoxazole5-yl7-4.5-dlhydro-3(2H)-pyridazinone Prepared analogously to Example 1 from N-2-methoxy-4-nitro5 phenyl-N *-/l-hydroxy-5-(5-®ethyl-4,5-dihydro-3(2H)-pyridazinone-6-yl)-phenyl/thiourea.

Yield: 65.6 % of theory M.p.: 223 - 225°C C19H17N5O5 (395.4) Calc.: C 57.82 H 4.33 N 17.71 Found: 58.27 4.25 18.17 Example 13 -Methyl-6-/Σ' - (4-methylphenylami.no)-benzoxazole-5' -yl/4,5-dihydro-3(2H)-pyridazinong---------15 Prepared analogously to Example 1 from N-4-methylphenyl-N’/2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyridazinone-6-yl)phenyl7thiourea.

Yield: 52.1 % of theory M.p.: 273 - 275°C C19H18N402 (334.39) Calc.: C 68.25 H 5.43 N 16.76 Found: 68.10 5.59 16.88 Example 14 -Methyl-6-/2'-(2,4,6-trimethylphenylamino)-henzoxazole25 51-yl7-4,5-dlhydro-3(2H)-pyridazinone Prepared analogously to Example 1 from N-2,4,6-trimethylphenyl-N'-/2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyridazinone-6-yl)-phenyl7thiourea. - 25 Yield: 76.4 % of theory M.p.: 225 - 228°C c2ih22M4°2 (362.4) Calc.: C 69.59 H 6.12 »15.46 Found: 69.79 6.37 15.65 Example 15 -Methy1-6-/21-(4-cyanophenylamino)-benzoxazole-51-yl74.5- dlhydro-3 (2Hϊ-pyrldazinone______.

Prepared analogously to Example 1 from M-4-cyanophenyl-N’10 /2-hydroxy-5-(5-«ethyl-4,5-dihydro-3(2H)-pyridazinone-6-yl)phenyl7thiourea.

Yield: 59.7 % of theory M.p.: 318 - 320°C C19H15»502 (345.37) 15 Calc.: C 66.08 H 4.38 N 20.28 Found: 66.14 4.58 20,03 Example 16 -Methyl-6-/J'-ethoxyoarbonylamino)-benzoxazole-5’-yl74.5- dihvdro-3(2H)-pyridazinone 20 Prepared analogously to Example 1 from N-ethoxycarhonyl-N'/2-hydroxy-5-(5-mathyl-4,5-dihydro-3(2H)-pyridazinone-6-yl)phenyl/thiourea.

Yield: 19.8% of theory M.p.: 235 - 239°C C15W4 · (316.33) Calc.: C 56.95 H 5.10 N 17.71 Found: 55.81 5-14 17.08 Example 17 -Methyl-6-/2'-n-peatylamino-benzoxazole-5’-yl7-4,5-dihvdro-3 (2H) -pyridazlnonePrepared analogously to Exanple 1 from N-n-pentyl-N’5 /2-hydroxy-5-(5-aethyl-4,5-dihydro-3(2H)-pyridazinone-6-yl)phenyl7thiourea.

Yields 52.3 % of theory M.p.s 154 - 155°C C17H22N4°2 Calc.8 C 64.95 H 7.05 N 17.82 Found! 65.26 7.12 17.88 Example 18 -Methyl-6-/2’-ethylamiao-benzoxazole-5’-yl7-4,5-dihydro3 (2H) -pyridazlnone Prepared analogously to Example 1 from N-ethyl-Ν'-/2-hydroxy -(5-methyl-4,5-dihydro-3(2H)-pyridazinone-6-yl)-phenyi7thio urea.

Yields 71.9 % of theory M.p.s 244 - 246°C C14H16W4O2 (272.3) Calo.s C 61.75 H 5.92 N 20.57 Founds 61.95 5.98 20.85 gjcgmglejg, -Methyl-6-/2'-(3-methoxypropylamino)-benzoxazole-5 *-yl7~ 4.5-dlhydro-3(2H)-pyridazlnone Prepared analogously to Example 1 from N-3-methoxypropyl-N1/2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyrida2inone-6-yl)phenyl7thiourea. 5101 Yield: 55.5 % of theory M.p.: 153 - 154°C C16H2ON4°3 (316·4) Calc.: C 60.75 H 6.37 M 17.71 Found: 61.00 6.40 17.56 Exanple 20 -Methyl-6-/2’-amino-benzoxazole-5'-yl7-4,5-dihydro-3(2H)— pyridazinone Prepared analogously to Example 1 from N-/2-hydroxy-5-(5-methyl 4,5-dihydro-3(2H)-pyridazinone-6-yl)-phenyl7thiourea.

Yield: 42.1 # of theory M.p.: 285 - 287°C Example 21 ,5-Dimethyl-6-/2'-(*-phenylethyl)-benzoxazole-5’-yl7-4,5-di15 hydro-3(2H)-pyrldazlnone_ a) 4-(4-Chlorophenyl)-3.5-dimethyl-4-oxo-butvric acid g (0.688 mol) of sodium hydride (50 % oil suspension) were added at root temperature to 1200 ml of absolute tetrahydrofuran and the mixture was stirred for 15 minutes.

After addition of 52 g (0.228 mol) of 4-(4-chlorophenyl)3-methyl-4-oxo-butyric acid in small portions, the reaction mixture was refluxed for 2 hours. Subsequently the mixture was cooled to 40°C and 64 ml (1.02 mol) of methyl iodide were added dropwise. After refluxing fora further 3 hours and subsequent cooling to room temperature, the reaction mixture was added to water with stirring and the organic phases were distilled off in a rotary evaporator. The aqueous alkaline solution was washed twice with petroleum ether and then acidified by means of cono. hydrochloric acid. The oil thus obtained crystallised on further S1012 stirring. The crystals were filtered off with suction, washed with water and dried.

Yields 52 g (94.7 % of theory) M.p.s 95 - 97°C. b) 4-(4-Chloro-3-nitrophenyl)-3»3-dimethyl-4-oxo-butyric acid g (0.2 mol) of 4-(4-chlorophenyl)-3,3-dimethyl-4-oxobutyric aoid were added in portions at -15°C and -10°C to 500 al of fuming nitric acid whilst stirring. After stirring for 30 minutes at -10°C, the reaction mixture was poured on ice water. The precipitated product was filtered off with suction, washed neutral with water and dried. Yields 47.5 g (83.1 % of theory) M.p.s 118 - 120°C. c) 2-Nitro-4-(5,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone6-yl)-chlorobenzene__________________ ml of hydrazine hydrate (99 %) were added in portions at approx. 20°C to 400 ml of glacial acetic acid whilst stirring and ice-cooling. Subsequently 43 g (0.15 mol) of 4-(4-chloro-3-nitrophenyl)-5»5-dimethyl-4-oxo-butyric acid were added and the reaction mixture was refluxed for 1 hour. After cooling, the reaction mixture was diluted with water. She precipitated product was filtered off with suction, washed again with water and dried.

Yield! 33 g (78.1 % of theory) M.p.; 193 - 194°C. d) 2-Nitro-4-(5»5-dimethyl-4,5-dihydro-3(2H)-pyridazinone6-yl)-phenol g (0.1 mol) of 2-nitr0-4-(5,5-dimethyl-4,5-dihydro3(2H)-pyridazinone-u-yl)-chlorobenzene were suspended in 750 al of glycol and the suspension was mixed with a - 29 solution of 40 g of powdered potassium hydroxide in 250 ml of glycol. The solution thus obtained was heated for 2 hours at 16O°C. After cooling to room temperature the solution was poured into approx. 3 1 of ice-water and acidified by means of cone, hydrochloric acid. The precipitated product was filtered off with suction. The filtrate was extracted 4 times with 250 ml aliquots of ethyl acetate, The organic phase was dried with sodium sulfate and evaporated. The residue and the solid product were ccobined, triturated with water, filtered with suction and dried. Yield: 20 g (76 % ot theory) M.p.: 211 - 213°C. e) 2-Amino-4-(5,5-dimethyl-4,5-dihydro-3(2Ά) -pyridazinone6-yl)-phenol g (0.076 mol) of 2-nitro-4-(5»5-dimethyl-4,5-dihydro3(2H)-pyridazinone-6-yl)-phenol in 600 ml of dimethyl formamide were reduced in a Parr apparatus at room temperature with hydrogen (5 bar) and 2 g of palladiua/charcoal (10 %) as catalyst. When the hydrogen absorption was finished the catalyst was filtered off with suction and the filtrate was evaporated. A solid product was obtained, which was triturated with ether. After filtering off with suction, the product was washed with ether and dried.

Yield: 17 g (96 % of theory) M.p.j 260 - 263°C. f) 2-(2-Phenylpropionylamino)-4-(5>5-dimethyl-4,5-dihydro5(2H)-pvrldazinone-6-vl)-phenol 2.8 g (0.012 mol) of 2-amiro-4-(5,5-dimethyl-4,5-dihydro3(2H)-pyridazinone-6-yl)-phenol were suspended in 40 ml of absolute tetrahydrofuran and 40 ml of absolute dimethylformamide. 3.03 g (0.018 mol) of 2-phenylpropionic acid chloride were added dropwise at room temperature. After 1.5 hours the reaction mixture was stirred into water and extracted several times with ethyl acetate. The SiOl2 - 30 organic phases were dried with sodium sulfate and evaporated. The product obtained was purified by column chromatography (silica gel, grain size: 0.05 - 0...20 mgi, eluant: chloroform/ethanol 1 %). The product thus obtained 5 was reacted further in crude form.

Yields 1.7 g (38.8 % of theory. g) 5,5-Dimethyl-6-/2'-(ef-phenylethyl)-benzoxazole-5*-yl74,5-dihydro-3(2H)-pyridazinone 1.7 g (0.0046 mol) of 2-(2-phenylpropionylamino)-410 (5,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone-6-yl)phenol were suspended in 12 ml of sulfolane and the suspension was refluxed for 5 hours. Subsequently the hot reaction mixture was stirred into ice-water. The precipitated oily product was extracted with ethyl acetate.

The organic phase was dried with sodium sulfate and evaporated. The obtained residue was purified by means of column chromatography (silica gel, grain size: 0.05 to 0.20 mm, eluant: chloroform/ethanol 1 %). The corresponding fractions were combined, filtered via charcoal and evaporated. The residue was an oil, which was crystallized with petroleum ether.

Yield: g (62.5 % of theory) M.p.: 131 - 135°C C21H21N3°2 (347.4) Calc.: C 72.61 H 6.09 N 12.10 Found: 72.18 6.30 11.91 Example 22 ,5-Dimethyl-6-(2'-amino-benzoxazole-5’-yl)-4,5-dihydro3(2H)-pyrldazinone 2.1 g (0.0072 mol) of ii-/5-hydroxy-5-(5,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone-6-yl)-phenyl7thiourea (prepared by alkaline hydrolysis of Ν'-benzoyl-N-/£-hydroxy-5-(5,5-di - 31 methyl-4,5-dihydro-3(2H)-pyridazinone-6-yl)-phenyl7-thiourea) were dissolved in 40 ol of absolute tetrahydrofuran. 2.05 g (0.01 mol) of N,N'-dicyclohexylcarbodiimide were added and the reaction aixture was refluxed for 2 hours whilst stirring. After cooling to room temperature, the precipitated product was filtered off with suction and washed with tetrahydrofuran. The reaction product was suspended in 1 H ammonia, stirred for 50 minutes, filtered1'off with suction, washed with water and dried.

Yield: 1.0 g (54 % of theory) M.p.: > 250°C C13H14M4O2 (258.3) Calc.: C 60.45 H 5.46 N 21.69 Found: 60.67 5.41 21.44 Example 23 -Methyl-6-/2·-dimethylamino-benzothiazole-5’-yl7-4,5-dihydro-3(2H)-pyrldazinone a) 4-(3-Amino-4-mercaptophenyl)-5-methyl-4-oxo-butyrlc acid g (0.1 mol) of 4-(3-nitro-4-chlorophenyl)-3-methyl4-oxo-butyric acid were added to a solution of 72 g (0.3 mol) of sodium sulfide x 9 H20 in 500 ml of water and the mixture was heated for 35 hours on a steam bath. After cooling to 10°C, the reaction mixture was adjusted to pH 4.5 by means of glacial acetic acid. Subsequently the reaction mixture was extracted -several times with ethyl acetate. The organic phase was dried with sodium sulfate and evaporated. The residue obtained was reacted further in crude form.

Yield: 27.5 (approx, 100 % of theory). b) 5-Methyl-6-/2'-dimethylaminobenzothiazole-5'-yl7-4,5-dihydro-5(2H)-pyrldazinone 2.2 g (0.018 mol) of dimethylthiocarbamoyl chloride were added at room temperature to a solution of 2.8 g (0.012 mol) - 32 of 2-amlno-4-(5-methyl-4,5-dihydro-3(2H)-pyridazlnone6-yl)-thiophenol (prepared by reaction of 4-(3-amino4- meroaptopheayl)-3-methyl-4-oxo-butyric acid and hydrazine) in 40 ml of absolute tetrahydrofuran whilst stirring.

After 20 hours the precipitated product was filtered off. The filtrate was diluted with water and extracted twice with ethyl acetate. Subsequently the aqueous phase was made alkaline by means of 2 N sodium hydroxide solution and extracted with chloroform. The organic phase was dried with sodium sulfate and evaporated. An oily product was obtained, which crystallized while standing overnight. The obtained crude product (1 g) was purified by column chromatography (silica gel, grain size: 0.05 to 0.20 mm, eluant: chiorofora/ethanol 1 %).

Yield: 550 mg (16 % of theory) M.p.: 177 - 184°C C14H16N4OS (288.4) Calc.: C 58.51 H 5.59 N 19.43 S 11.12 Found: 58.41 5.69 19.12 11.02 20 Example 24 - Methyl-6-/5'-(4-cyanophenyl)-benzoxazole-51-yl74,5-dihydro-3(2H)-pyridazlnone 2.07 g (5.3 m mol) of 1-acetoxy-2-(4’-cyanobenzoylamino)4-(5-methyl-4,5-dlhydro-3(2H)-pyridazinone-6-yl)-benzene 25 in 50 ml of sulfolane were mixed with 0.5 ml of 10 % hydrochloric acid. After heating for 4 hours to 240°C, the mixture was stirred into 150 ml of water and the precipitate obtained was filtered off with suction. 'Mie' product was purified by column chromatography (silica gel, chloroform 30 + 1 % ethanol).

Yield: 145 mg (8.3 % of theory) M.p.: 278 - 280°C.

C19H14N4°2 (330.35) Calc.: C 69.08 H 4.27 N 16.96 Found: 68.24 4.34 16.86 - 33 Example 25 -Methyl-6-(2’-hydroxy-benzoxazole-5'-yl)-4,5-dihydro-3(2H) pyridazinone 1.08 g (0.005 mol) of 2-aaino-4-(5-methyl-4,5-dihydro-3(2H)pyridazinone-6-yl)-phenol were suspended in 50 ml of absolute tetrahydrofuran and the suspension was mixed with 1 g (0.006 mol) of Ν, Ν'-carbonyl diimidazole whilst stirring.

After refluxing for 45 minutes, the reaction mixture was evaporated and the residue was stirred with water. The obtained crystals were filtered off with suction, washed with water and dried. Subsequently the crude product was dissolved in chloroform:methanol - 9:1» filtered hot via activated charcoal, and the filtrate was evaporated until crystals formed. The reaction product was cooled in an ice bath, The precipitated product was filtered off with sucticn, washed with ether and dried.

Yield: 0.55 g (44.7 % of theory) M.p.: 250 - 253°C (245.2) Calc.: C 58.77 H 4.52 N 17.13 Found: 58.77 4.46 17.22 Example 26 -Methyl-6-(2 *-ethoxy-benzoxazole-5’-yl)-4,5-dihydro-3(2H)pyrldazlnone 2.19 g (0.01 mol) of 2-amino-4-(5-methyl-4,5-dihydro-3(2H)pyridazinone-6-yl)-phenol were suspended in 10 ml of tetraethyl carbonate and 3 ol of dimethylformamide were added. After heating for 1 hour at 180°C (oil bath), the reaction mixture was cooled to room temperature. The precipitated product was filtered offiwith suctior and washed with ether. Subsequently the reaction product was recrystallized twice from IOC ml of ethanol by addition of activated charcoal.

Yields 900 mg (33 % of theory), M.p.5 193 - 194°C. ^14^15^3^3 (273.3) Calc.s C 61.53 H 5.53 N 15.38 Founds 61.59 5-52 15.65 Example 27 -Methyl-6-(2'-mercapto-benzoxa2ole-5'-yl)-4,5-dlhydro3(2H)-pyrlda2lnone g (0.1 aol) of 2-amino-4-(5-methyl-4,5-dihydro-3(2H)10 pyridazinone-6-yl)-phenol were suspended ln 500 ml of ethanol and 24 g (0.15 mol) of potassium ethylxanthogenate were added whilst stirring. After refluxing for 3 hours, the reaction mixture was cooled to room temperature. The precipitated product was filtered off with suction and washed with cold ethanol and ether. The potassium salt thus obtained was dissolved in 1000 ml of water, filtered via activated charcoal and the filtrate was neutralized with 2 N acetic acid. The precipitated product was filtered off with suction, washed with water and dried in a vacuum shelf dryer.

Yield: 15 g (57.7 % of theory) M.p.: >25O°C C^H^N^S (261.3) Calc.: C 55.16 H 4.24 N 16.08 S 12.27 Found: 55.09 4.16 15.93 12.10 Example 28 -Methyl-6-(21-methylmercapto-benzoxazole-5'-yl)-4,5-dihydro-3(2H)-pyrldazlnone 653 mg (0.0025 mol) 5-methyl-6-(2,-mercapto-benzoxazole-5lyl)-4,5-dihydro-3(2H)-pyridazinone were dissolved in 10 ml 5101 - 35 of absolute dimethylformamide and the solution was nixed with 210 mg (0.0025 mol) of sodium bicarbonate. After addition of 2 ml of methyl iodide the reaction mixture was stirred for 15 hours at 40°C. The reaction mixture was stirred Into water and extracted with ethyl acetate. The organic phase was dried with sodium sulfate and evaporated. The obtained solid residue was recrystallized from ethanol.

Yield: 340 mg (49.4 % of theory) 10 M.p .: 178 - 180°C.

C13H13N3°2S (275.3) Calc.: C 56.71 H 4.76 N 15.26 S 11.65 Found: 56.20 4.78 15.41 11.57 Exanple 29 15 5-Methyl-6-(2’-n-hexylmercapto-benzoxazole-5’-yl)-4,5-dihydro3(2H)-pyridazlnone 2.99 g (0,01 mol) of 5-methyl-6-(2’-mereapto-benzoxazole-5'-yl) 4,5-dihydro-3(2H)-pyridazinone-potassium salt were dissolved in 20 ml of absolute dimethylformamide. 1.5 ml of n-hexyl bromide were added whilst stirring and the reaction mixture was stirred for 1 hour at 40°C. Subsequently the reaction mixture was stirred into water and extracted with ethyl acetate. The organic phase was dried with eodium sulfate, and evaporated. The obtained residue was reerystallized from ethanol.

Yield: 2.4 g (69.6 of theory) M.p.: 119 - 121°C C18h23n3°2S (345.5) Calc.: C 62.57 H 6.71 N 12.16 S 9.28 Found: 62.65 6.79 12.17 9.05 Example 50 -Methyl-6-(2'-allylmercapto-benzoxazole-5 *-yl)-4,5-dihydro 3(2H)-pyridazinone Prepared analogously to Example 29 from 5-methyl-6-(2'-mer5 capto-benzoxazole-5'-yl)-4,5-dihydro-3(2H)-pyridazinonepotasslus salt and allyl bromide.

Yield: 73 % of theory M.p.: 113 - 114°C C15H15N3°2S (301.4) Calc.: C 59.78 H 5.02 N 13.94 S 10.63 Founds 60.01 5.21 14.28 10.50 Example 31 -Methyl-6-(21-p-methoxybenzylmercapto-benzoxazole-5'-yl)4,5-dlhvdro-3(2H)-pyridazinone 15 Prepared analogously to Example 29 from 5-methyl-6-(2'-mer· capto-benzoxazole-5'-yl)-4,5-dihydro-3(2H)-pyridazinonepotassium salt and g.-methoxybenzyl bromide.

Yield: 66.6 % of theory M.p.: 174 - 176°C Ο,,θΗ^Ο^ (381.5) Calc.: C 62.97 H 5.02 N 11.02 S 8.41 Found: 63.47 5.08 11.34 8.63 - 37 51012 Example 32 -Methyl-/2’ -/2-(4-amino-3,5-dichlorophenyl)-ethylmercapto7benzoxazole-51-yl7-4.5-dihydro-5(2H)-pyridazinone Prepared analogously to Example 29 from 5-methyl-6-(2*-mer5 capto-benzoxazole-5'-yl)-4,5-dihydro-3(2H)-pyridazinone potassium salt and 2-(4-amino-3,5-dichlorophenyl)-ethylbromide.

Yield: 52 % of theory M.p.: 205 - 208°C.

Example 33 -Methyl-/2,-methylbenzoxazole-5,-yl7-4,5-dihydro-3(2H)•pyridazlnone Prepared analogously to Example 21g from 2-acetylamino-4-(5methyl-4,5-dihydro-3(2H)-pyridazinone-6-yl)-phenol by heating in sulfolane.

Yield: 75.3 % of theory M.p.: 210 - 213°C.

Example 34 -Methyl-/2'-isopropylbenzoxazole-5'-yl7-4,5-dihydro-3(2H)pyrldazinone Prepared analogously to Example 21g from 2-isobutyrylamino4-(5-methyl-4,5-dihydro-3(2H)-pyridazinone-6-yl)-phenol by heating in sulfolane.

Yield: 52.5 # of theory M.p.: 1.60 - 162°C.

Example A Tablets containing 100 mg of 5-methyl-6-/2'-ethylaminobenzoxazole-5'-yl7-4,5-dlhvdro-3(2H)-pyrldazlnone Composition: 1 tablet contains: Active ingredient 100.0 mg Lactose 50.0 mg Polyvinyl pyrrolidone 5.0 mg Carboxymethyl cellulose 19.0 mg Magnesium stearate 1.0 mg 175.0 mg The active ingredient and the lactose were homogeneously moistened with an aqueous solution of the polyvinyl pyrrolidone.

Moist screening: 1.5 mm Drying: in a circulation air drier at 50°C Dry screening: 1 mm The granulate and the remaining auxiliary products were mixed and pressed into tablets.

Weight of tablet: 175 mg Punch; 9 mm 0 Example B Coated tablets containing 50 mg of 5-methyl-6-/2’-ethylaminobenzoxazole-5'-vl7-4,5-dlhvdro-3(2H)-pyridazlnone coated tablet core contains: Active ingredient 50.0 mg Corn starch dried 20.0 mg Soluble starch 2.0 mg Carboxymethyl cellulose 7.0 mg Magnesium stearate 1.0 mg 80.0 mg The active ingredient and the starch were homogeneously moistened with an aqueous solution of the soluble starch. Moist screening: 1.0 nm Dry screening: 1.0 ma Drying: in a circulation air drier at 50°C The granulate and the remaining auxiliary products were mixed and pressed into cores.

Weight of core: 80 mg Punch: 6 mm Radius of curvature: 5 mm The finished cores were covered with a sugar coating in conventional manner.

Weight of coated tablet: 120 mg Example 0 Suppositories containing 75 mg of 5-methyl-6-/2'-ethylamino -benzoxazole-5 '-717-4, 5-dlhvdro-5(2H)-pvridazlnon.e suppository contains: Active ingredient: 75.0 mg Suppository mass (e.g. Witepsol H 19 and Witepsol W 45) 1625.0 mg 1700.0 mg Method of preparation: The suppository mass was melted. At 38°C the pulverized active ingredient was homogeneously dispersed in the melt.

The suppository mass was cooled to 35°C and poured into pre-cooled moulds.

Weight of suppository: 1.7 g situs Example D Ampoules containing 25 mg of 5-methyl-6-/5'-ethylaminobenzoxazole-51-vl7-4,5-dihvdro-3(2H)-pyridazinone Compositions 1 ampoule contains; Active ingredient Sodium chloride Polyethylene glycol 600 Dissolving intermediary (e.g. hydroxy-ethylated hydrated castor oil) Water for injection purposes ad .0 mg 45.0 mg 1.0 ml 0.5 ml 5.0 ml Method of preparation; The active ingredient was dissolved in a mixture of polyethylene glycol, dissolving intermediary and approx, half of the water in a suitable volume-calibrated vessel whilst stirring. The solution was mixed with the sodium chloride and made up with water to the given, volume.

Example E Suspension containing 75 mg of 5-methyl-6-/5'-ethylamino20 benzoxazole-5'-yl7-4,5-dlhydro-5(2H)-pyridazinone per 5 ml 100 ml of suspension contain; Active ingredient 1.5 g Carboxymethyl cellulose 0.1 g Methyl p-hydroxybenzoate 0.05 g Propyl p-hydroxybenzoate 0.03 g Cane sugar 10.0 g Glycerine 5.0 g Sorbit solution 70 % 20.0 g Aroma 0.3 g Water dist. 100.0 ml - 41 Method of preparation: Distilled water was heated up to 70°C, and methyl p-hydroxybenzoate, propyl g-hydroxybenzoate, glycerine, and carboxymethyl cellulose were dissolved therein whilst stirring.

This solution was cooled to rooa temperature, the active ingredient was added whilst stirring and homogeneously dispersed. Subsequently, the sugar, the sorblt solution, and the aroma were added and dissolved and the suspension was evaporated in vacuo whilst stirring.

Claims

CLAIMS 1. To 5 carbon atoms which can be substituted by a methoxy group; 10 a phenyl group which can be substituted by a methyl, methoxy, trifluoromethyl, cyano or nitro group or by a chlorine or bromine atom; a dichlorophenyl, dibromophenyl, dimethoxyphenyl, methoxynitrophenyl, trimethylphenyl, cyclohexyl or dimethoxyphenylethyl group; and R 2 represents a methyl group; 15 and their optically active antipodes as well as their physiologically compatible acid addition salts with inorganic or organic acids. 1 to 3 carbon atoms or by a fluorine, chlorine or bromine atom; and Rg represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms and their optically active antipodes as well as their physiologically compatible acid addition salts with inorganic or organic acids.

1. Benzoxazoles of general formula in which 5 R.] represents a hydrogen atom; a straight or branched alkyl group with 1 to 7 carbon atoms which can be substituted by an alkoxy group with 1 to 3 carbon atoms; a cycloalkyl group vith 3 to 7 carbon atoms; an alkyl group with 1 to 3 carbon atoms substituted by a phenyl group which can be substituted by one or two alkoxy groups 10 with 1 to 3 carbon atoms; or a phenyl group which can be substituted by an alkyl or alkoxy group each with 1 to 3 carbon atoms, by a trifluormethyl, nitro or cyano group or by a fluorine, chlorine or bromine atom; and in addition one of the mono-substituted phenyl groups mentioned above can be substituted by one or two 15 alkyl groups with 1 to 3 carbon atoms or by an alkoxy group with

2. Benzoxazoles of general formula in which Rj and R 2 are as defined in claim 1, and their optically active 5 antipodes as well as their physiologically compatible acid addition salts with inorganic or organic acids.

3. Benzoxazoles of general formula I according to claim 2 in which Rj represents a hydrogen atom; an alkyl group with

4. Benzoxazoles of general formula I according to claim 2 in which Rj represents ar alkyl group with 1 to 5 carbon atoms; the cyclohexyl group or a phenyl group optionally substituted by one or two 20 methoxy groups; and R 2 represents the methyl group; and their optically active antipodes as well as their physiologically compatible acid addition salts with inorganic or organic acids. 5. 5-Methy1-6-)/ 1 -ethyl ami no-benzoxazol-5 1 -yl]-4,5-di hydro3(2H)pyridazinone and its optically active antipodes as well as their acid addition salts. 6. 5-Methyl-6-[2'-cyclohexylamino-Denzoxazol-5'-yi]-4,5-dihydro5 3(2H)pyridazinone and its optically active antipodes as well as their acid addition salts. 7. 5-Methy1-6-^'-n-butylamino-benzoxazol-5'-yl] -4,5-dihydro3(2H)pyridazinone and its optically active antipodes as well as their acid addition salts. 10 8. Pharmaceutical preparations containing a compound according to claims 1 to 7 in addition to one or more inert carriers and/or diluents. 9. Use of a compound according to claims 1 to 7 for producing a pharmaceutical preparation for controlling cardiovascular diseases 15 in a non-chemical way. 10. Process for producing new benzoxazoles according to claims 1 to 7 and their optically active antipodes as well as their physiologically compatible acid addition salts with inorganic or organic acids, wherein 20 a) a thiourea of general formula and R 2 are as defined in the introduction, X represents a mercapto, alkylmercapto, arylmercapto or 5 aralkylmercapto group, and Y represents a hydrogen atom or an acyl radical, is cyclised; or b) a carboxylic acid of general formula in which 10 R·] and R 2 are as defined in the introduction, or its amides, esters, thioesters or halides, is reacted with hydrazine, and if desired a compound of general formula I, in which Ri represents a hydrogen atom, obtaired according to processes a) or b) is subsequently converted by means of alkylation into a corresponding compound of general formula I, 15 in which Ri is defined as in the introduction with the exception of the hydrogen atom and the phenyl radicals mentioned in the introduction, and/or a racemate obtained, of general formula I, is separated by means of racemate separation into its optically active antipodes, and/or a compound obtained, of general formula I, is converted into 20 its physiologically compatible acid addition salts with inorganic or organic acids. Π. A process for producing benzoxazoles as described herein with reference to Examples 1 to 34. 12. Benzoxazoles of formula I as defined in claim 1 whenever produced by a process as claimed in either claim 10 or 11.

5. 13. Pharmaceutical preparations substantially as described herein with reference to Examples A to E.