CS236683B2 - Manufacturing process of basic substituted pyridazines - Google Patents

Description

The present invention relates to a process for the preparation of pharmacologically valuable, basically substituted pyridazines of the formula I

R '

RR ‘w

O-CH 2 CH-CH 2 NH-CH 2 CH 2 Cl 2. OH 'N-R (1) wherein

R ^{* 1} , R ² and R ³ are each independently hydrogen, fluoro, chloro, bromo, hydroxy, nitro, trifluoromethyl, C 1 -C 8 alkyl, C 2 -C 6 alkoxyalkyl, C 1 -C 6 alkenyl; C 6 -C 6 alkynyl, C 5 -C 8 cycloalkyl, C 5 -C 8 cycloalkenyl, phenyl, C 1 -C 8 alkoxy, C 2 -C 6 hydroxyalkoxy carbon atoms, alkoxyalkoxy of up to 8 carbon atoms, alkenyloxy of up to 6 carbon atoms, alkynyloxy of up to 6 carbon atoms, cycloalkoxy of 5 to 8 carbon atoms in the ring, benzyloxy, phenethyloxy, alkanoyl of 1 to 6 carbon atoms, acylamino up to 11 carbon atoms in the acyl radical, -NH-CO-R ⁹ in which

R ⁹ is morpholino, piperidino or 1-pyrrolidinyl, furthermore ureido, ureido in the 3-position is mono-substituted with 5 or 6 carbon cycloalkyl, or ureido in the 3-position mono- or disubstituted with 1 to 1 alkyl 6 carbon atoms and / or a (C 3 -C 6) alkenyl group,

R ⁴ represents hydrogen or alkyl with 1 to 4 carbon atoms,

W represents hydrogen, chlorine or bromine, as well as their acid addition salts.

The compounds of formula I have an asymmetric carbon atom in the alkanolamine side chain and can therefore exist in racemic and optically active forms. For the purposes of the present invention, the compounds of the formula I are understood to include the possible stereoisomers and optically active compounds and mixtures thereof, in particular the racemate.

Substituents listed for R ^1, R ² and R ³ are in addition hydrogen, fluoro, chloro and bromo, hydroxy, nitro, trifluoirmethylové groups and phenyl groups in particular the following meanings:

C 1 -C 8 alkyl, preferably C 1 -C 4, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n- pentyl, isopentyl, neopentyl, t-pentyl, n-hexyl, iso hexyl, n-heptyl and n-octyl;

alkenyl of up to 6 carbon atoms, preferably of 3 or 4 carbon atoms, for example vinyl, allyl, 1-propenyl, isopropenyl, methallyl, tert-butyl, 2-pentenyl, 2-hexenyl;

alkynyl of up to 6 carbon atoms, preferably of 3 or 4 carbon atoms, for example propargyl;

cycloalkyl having 5 to 8 ring members, preferably 5 or 6 ring carbon atoms, for example cyclopentyl and cyclohexyl;

a cycloalkenyl group having 5 to 8 ring members, preferably 5 or 6 ring carbon atoms, for example a cyclopentenyl group;

(C 8-C) alkoxy, for example, methoxy, ethoxy, propoxy, butoxy, isopropoxy, isohexyloxy, m-heiptyloxy, n-octyloxy, pentyloxy;

cycloalkoxy of 5 to 8 carbon atoms in the cycloalkyl moiety, preferably cyclopentyloxy and cyclohexyloxy;

alkenyloxy of up to 6 carbon atoms, preferably of 3 or 4 carbon atoms, for example allyloxy, methallyloxy, crotyloxy, 2-hexenyloxy, alkynyloxy of up to 6 carbon atoms, preferably of 3 or 4 carbon atoms, for example propargyloxy;

alkanoyl group having 1 to 6 carbon atoms such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group ^isovalerate yl ° ^C ase, pivaloyl alkoxyalkoxy having a total of up to 8 carbon atoms, the Alkoxyalkoxy portion corresponds to the formula R ⁶ O-R ⁵ O and R ⁵ are C 2 -C 7 alkylene, R ^e is C 1 -C 6 alkyl, and the radicals R ⁵ and / or R ⁶ having 3 or more carbon atoms can also be branched. Examples of suitable alkoxyalkoxy groups include:

2-methoxyethoxy,

2-ethoxyethoxy,

3-methoxy-n-propoxy,

2-methoxy-n-propoxy,

4-methoxy-n-butoxy,

3-ethoxy-n-propoxy,

2-ethoxy-n-propoxy,

4-ethoxy-n-butoxy,

3-ethoxy-n-butoxy,

2-ethoxy-n-butoxy,

2.2-dimethyl-2-ethoxyethoxy,

3- (n-propoxy) -n-propoxy,

2- (n-propoxy) -n-propoxy,

3- (isopropoxy) n-propoxy,

2- (isopropoxy) -n-propoxy,

2- (n-propoxy) ethoxy,

2- (isopropoxy) ethoxy,

4- (n-propoxy) -n-butoxy,

3- (n-propoxy) n-butoxy,

2- (n-butoxyethoxy),

2- (sec.butoxy is ethoxy),

2- (tert-butoxy) ethoxy,

3- (n-butoxy) -N-proxy;

2- (n-butoxy) n-propoxy,

3- (isobutoxy) -n-propoxy,

3- (sec-butoxy) n-propoxy,

3- (tert-butoxy) -n-propoxy,

4- (n-butoxy) -n-butoxy,

3- (n-butoxy) -n-butoxy,

2- (n-butoxy) -n-butoxy,

4- (isobutoxy) -n-butoxy,

3- [isobutoxy] -n-butoxy,

2- (sec-butoxy) n-butoxy,

2,2-dimethyl-2- (n-butoxy) ethoxy,

2- (n-butoxy) -1-methylethoxy,

2- (isobutoxy) -2-methylethoxy,

5-methoxy-n-pentyloxy,

4-methoxy-n-pentyloxy,

3-methoxy-n-pentyloxy,

5-ethoxy-n-pentyloxy,

4-ethoxy-n-pentyloxy,

3-ethoxy-n-pentyloxy,

5- (n-proxy) -n-pentyloxycycline,

5- (isopropoxy) -n-pentyloxy, 6-methoxy-n-hexyloxy,

5-methoxy-n-hexyloxy,

4-methoxy-n-hexyloxy,

6-ethoxy-n-hexyloxy,

3-ethoxy-n-hexyloxy,

7-methoxy-n-heptyloxy; (C 2 -C 6) alkoxyalkyl, wherein the alkoxyalkyl group is of the formula R ⁸ O-R ⁷ - and R ⁸ is an alkyl group, and R ⁷ is an alkylene group, the radicals R ⁸ and / or R ⁷ when they contain more than 3 carbon atoms can also be branched, such as

63

S methoxymethyl, ethoxymethyl, n-proporymethyl, isopropoxymethyl, n-butoxymethyl, n-pentyloxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-n-propoxyethyl, 2-isopropoxyethyl,

2- n -butoxyethyl,

3-methoxy-n-propyl,

3-ethoxy-n-propyl,

3-n-propoxy-n-propyl,

2-methyioxy-2-methylethyl,

2-ethoxy-1-methylethyl,

2-n-propoxy-2-methylethyl,

2-isopropoxy-1-methylethyl,

4-methoxy-n-butyl,

4-ethoxy-n-butyl group,

5-methoxy-n-pentyl;

(C 2 -C 6) hydroxyalkyloxy, for example

2-hydroxyethoxy,

3-hydroxy-n-propoxy,

4-hydroxy-n-butoxy, pin,

3-hydroxy-n-butoxy,

5-hydroxy-n-pentyloxy,

4-hydroxy-n-hexyloxy,

2-hydroxy-n-hexyloxy,

2-hydroxy-n-propoxy;

phenalkyloxy, for example phenethyloxy, in particular benzyloxy;

an ureido or ureido group which is substituted at the 3-position with a C 1 -C 6 alkyl group, preferably a C 1 -C 4 alkyl group, a C 3 -C 6 alkenyl group or a C 5 or C 6 cycloalkyl group, wherein alkyl or / and alkenyl groups as substituents also disubstituted. Examples of suitable ureido groups include:

ureido group,

3-methylureido,

3-ethylureido,

3-propylureido,

3-isopropylureido,

3-allylureido,

3-cyclopentylureido,

3-cyclohexylureido,

3.3-dimethylureido,

3.3- diethylureido.

Further, the group -NH-CO-R ^{9 is} to be mentioned, wherein R ⁹ is morpholino, piperidino or 1-pyrrolidinyl.

For the acylamino group R ¹ and / or R ² and / or R ³ , the term "acyl" means an aryl, arylalkyl or alkyl-substituted carbonyl radical of up to 11 carbon atoms, which is derived from an aromatic, aromatic-aliphatic or aliphatic carboxylic acid acid. Suitable acylamino groups are, for example, acetamino, propionylamino, butyrylamino, benzoylamino, α- and (S-naphthoylamino, phenylacetylamino, preferably acetamino and benzoylamino).

In particular, R ^{@ 4} may, in addition to the hydrogen atom, be C1 -C4 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.

Preferred are compounds of formula I or their acid addition salts, in which R ⁴ is hydrogen, or in which only one of R ^1, R ² or R ³ is other than hydrogen or R ^1, R ² or R · R ³ they are hydroxy, alkoxyalkoxy, alkoxy, alkoxyalkyl or hydroxyalkoxy or halogen.

Particularly preferred are those compounds having two or more of the above-mentioned advantageous properties, i.e. those compounds wherein R ⁴ is hydrogen and one of R ¹ , R ² or R ³ is hydroxy, alkoxyalkyl, alkoxyalkoxy, alkoxy or hydroxyalkoxy or halogen and both are hydrogen. For R @ ¹ , R @ ² and R @ ³ , those which do not contain any asymmetric centers are usually preferred.

Inorganic and organic acids are suitable for the preparation of acid addition salts of the compounds of formula (I). Suitable acids are, for example, hydrochloric acid, hydrobromic acid, 1,5-naphthalenedisulfonic acid, phosphoric acid. nitric acid, sulfuric acid, oxalic acid, lactic acid, tartaric acid, acetic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid , malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid or adipic acid. Preferred are the pharmaceutically acceptable acid addition salts of these compounds. The acid addition salts are obtained in a conventional manner by mixing the components, suitably in a suitable diluent or dispersant.

The pyridazines of formula VI can be reacted to produce compounds of formula I

in which

W and R ⁴ are as defined above,

T is chlorine or bromine, with a diamine of formula IX

O-CH 2 CH-CH 2 NH-CH 2 CH 2 NN _Z

OH (tX) wherein

R ¹ , R ² and R ³ have the meanings given above, and the compound obtained is optionally converted by treatment with an acid into an acid addition salt.

The reaction of the compound of the formula VI with the compound of the formula IX is usually carried out in a suitable solvent or dispersant in which the reactants are dissolved or suspended, such as benzene, toluene, xylene, chloroform, methylene chloride, carbon tetrachloride, chlorobenzene, dioxane, ether, tetrahydrofuran, water, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, etc.

The reaction may be carried out at room temperature, or may be accelerated by the use of heat, or may be completed by the use of heat, for example by heating to a temperature between 80 and 120 ° C. The molar ratio between the compounds of formulas VI and IX may be 1: 1 to 1:10 and optionally even more. When equimolar amounts of compounds of formulas VI and IX are used, it is recommended to work in the presence of at least an equimolar amount of acid binder such as potassium carbonate, sodium carbonate, trimethylamine, etc. Without acid binders, the hydrohalides of the compounds of formula AND.

Also, the reaction of halopyridazines with amino-containing compounds and conveniently reaction conditions are also known per se. An overview and numerous references to literature are found in R. Elderfield, Heterocyclic Compounds (1957) vol. 6, p. 130. Other publications related to this reaction are disclosed, for example, in German Patent Specification 579 391 (CA 27, 4631 (1933)) and Meier, Ringier Druey, Helv. Chim Acta, vol 37, p. and 523 (1954).

In order to prepare the diamines of the general formula IX which are used as. starting material, it is possible to react a compound of formula II or III or a mixture of a compound of formula II with a compound of formula III

in which

R ^1, R ² and R ³ have the above meanings,

Hal represents a halogen atom, in particular chlorine or bromine, and in the case of a mixture of a compound of formula II with a compound of formula III, the compound of formula III in the phenyl core is substituted in the same manner with a compound of formula VII

HzN-CH ₂ -CH-NH-X (VII) wherein

X is hydrogen or a hydrolytically cleavable protecting group such as an acetyl group or another acyl group.

This reaction is usually carried out in a suitable solvent or dispersant by dissolving or suspending the reactants.

Such solvents or dispersants are, for example, water, aromatic hydrocarbons such as benzene, toluene, xylene; ketones such as acetone, methyl ethyl ketone; halogenated hydrocarbons such as chloroform, carbon tetrachloride, chlorobenzene, methylene chloride; ethers such as tetrahydrofuran and dioran; sulfoxides such as dimethyl sulfoxide; tertiary acid amides such as dimethylformamide and N-methylpyrrolidone.

In particular, polar solvents such as alcohols are used as solvents. Suitable alcohols are, for example, methanol, ethanol, isopropanol, tert-butanol, etc.

The reaction is carried out at temperatures from 20 ° C to the reflux temperature of the solvent or dispersant used. The reaction is often carried out at temperatures from 60 to 100 ° C. It may be expedient to use the starting compounds of the formulas VII in a 1- to 10-fold or even higher molar excess and / or to add the reactants of the formulas II and III in dissolved or suspended state to dissolve or suspend the reactant VII. The molar ratio between the compounds of formulas II, III and VII, respectively, may be 1:

: 1 to 1:10 and possibly more. In the presence of a compound of formula III, the reaction can also be carried out in the presence of acid-binding agents such as potassium carbonate, sodium carbonate, etc. Without acid-binding agents, the hydrohalides of the compounds of the formula IX are usually obtained.

When a compound of formula (II) or (III) is reacted with a compound of formula (VII), X is a protecting group, then a compound of formula (X) is formed first

in which

R @ ¹ , R @ ² , R @ ³ and X have the above meanings, from which, by cleavage of the protecting group X by conventional methods, for example when X is an acyl group, by hydrolysis, the compound of formula IX is obtained.

The starting compounds of the formula (VI) are in part known or can be prepared in a manner known per se. Thus, starting materials in which W and T are chlorine or bromine can be prepared readily from hydrazine derivatives by reaction with mucochloric acid, mucobromic acid or the corresponding chloro-bromo derivative (cf. Katritzky, Bou.lton, Advaces in Heterocyclic Chemistry ( 1968, vol. 9, pp. 235-236 J. The following reaction scheme illustrates the reaction of mucochloric acid:

d-NH t ⁺ nh ₂

The starting compounds of formula VI in which W is hydrogen can be prepared, for example, according to the reaction scheme set forth in R. Elderfield, Heterocyclic Compounds (1957), et al. 6, p. 130 using 4,5-dibromopyridazin-3-one as starting material.

The compounds of formulas II and III can be prepared according to known methods, for example by reacting the corresponding phenol with epichlorohydrin.

The optically active forms of the alkylenediamines of formula I may be obtained by resolution of the corresponding racemic alkylenediamines of formula I by conventional methods, for example by treating the racemate of a compound of formula I with an optically active acid, followed by fractional crystallization of the diastereomeric salt mixture thus obtained. solvents, such as ethanol, finally the optically active alkylenediamine is selected from the salt by means of a base. Optically active compounds of formula I can also be obtained by using optically active starting compounds of formula III or IX. These optically active starting compounds are obtained in a known manner by resolution of the racemate from optically inactive compounds of formula III or IX.

The compounds of the formula I and their acid addition salts which are prepared by the process according to the invention have valuable pharmaceutical properties. In particular, they have a strongly pronounced [beta] 2-adrenalytic effect, which is additionally cardioselective, i.e.. that compounds have a higher degree of specificity in blocking cardiac O-receptors than peripheral β-receptors, such as bronchial β-receptors 11

and. u l) il d of her muscle. In addition, these compounds have, in part, potent α-lytic, antiarrhythmic and blood pressure lowering properties. It is therefore suitable, for example, for the treatment or prophylaxis of heart problems and heart diseases such as angina pectoris and cardiac arrhythmias, as well as for the treatment of high blood pressure without attacking the lungs in sensitive patients.

The compounds of the formula I produced by the process according to the invention have a surprising effect on their pharmaceutical activity. a distinct superiority over compounds known from DOS No. 19,629 and having a similar structure.

Thus, the pyridazines produced by the process of the invention may be administered to humans alone, in admixture with each other or in the form of pharmaceutical compositions which contain as an active ingredient an effective dose of at least one pyridazine or acid addition salt thereof in addition to conventional pharmaceutically acceptable carriers and additives.

Suitable carriers are, for example: water, vegetable oils, starch, gelatin, lactose, magnesium stearate, waxes, petrolatum, etc. As additives, for example, wetting agents, disintegrants, preservatives, etc. may be used.

The pharmaceutical preparations may be, for example, in the form of tablets, capsules, aqueous or oily solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions, dispersible powders or aerosol mixtures. The pharmaceutical preparations may also contain, in addition to the compounds of formula (I), one or more other pharmaceutically active substances, for example tranquillizers such as Luminal, Meprobamat, Chlorpromazine and benzodiazepine sedatives such as Diazepam or Chlordiazepoxide;

vasodilators such as glycerin trinitrate, pentaerythrittetranitrate and carbochromes;

diuretics such as chlorothiazide;

heart ionizing agents such as digital preparations;

hypotensives such as rauwolfie alkaloids and Guanethidine;

bronchodilators and sympathomimetic agents such as isoprenaline, osciprenaline, adrenaline and ephedrine;

α-adrenergic blockers such as Phentolamine;

cardiac membrane stabilizing agents (antiarrhythmics) such as Chlnidine and catecholamines such as noradremaline.

The following examples illustrate the preparation of the compounds of formula (I).

Example 1 a d 11

4.9 g of N- [3- (o-chlorophenoxy) -2-hydroxypropyl-ethylenediamine of formula (CH) CH-CH2-NH2-Cl2CH3]

Cl oti '2. ^NH 2 is dissolved in 50 ml of ethanol. A solution of 3.3 g of 4,5-dichloropyridazin-3-one of formula (I) is then added to the obtained solution

hours to reflux. Then the reaction mixture is concentrated in vacuo, the residue is digested with a small amount of ethyl acetate, the ethyl acetate is separated by decantation and the residue is finally recrystallized from ethanol. There was thus obtained N- [3- (o-chlorophenoxy) -2-hydroxypropyl] -N- [4-chloro-3-oxo-5-pyridazyl] ethylenediamine hydrochloride of the formula in 50 ml of ethanol and the mixture was then heated

HCl id • Melting point: 219 ° C.

Analysis for C15H19Cl3N4O3:

calculated:

44.0% C, 4.6% H, 26.0% Cl, 13.7% N, 11.7% O, found:

44.4% C, 4.8% H, 27.7% Cl, 13.5% N,

12.2% O.

Yield: 78%.

The N- [3- (o-chlorophenoxy) -2-hydroxypropyl] ethylenediamine used as starting material can be prepared as follows:

120 g of ethylenediamine are dissolved in 150 ml of ethanol. To this solution is added a solution of 20 g of o-chlorophenylglycidyl ether of the formula of K. Dôry, Angew. Chemie 77, 282, (1965)].

Example 2

5.1 g of N- [3- (o-ethoxyphemoxy) -2-hydroxypropyl] ethylenediamine of the formula

The OH is dissolved in 50 ml of toluene and 3 g of potassium carbonate are added. A solution of 3.6 g of 2-methyl-4,5-dichloropyridazin-3-one of formula (I) is then added with stirring at room temperature

Qo-CH ₂ -CH = CH ₂ Cl ⁰ in 40 ml ethanol and the mixture was heated for 20 hours under reflux. Excess ethylenediamine and ethanol are then distilled off in vacuo and the residue is then distilled under vacuum.

Thus - N- [3- (o-chlorophenoxy) -2-hydroxypropyl] ethylene diamine as an oil which can be distilled at a boiling point of 190 ³ C / 53.3 Pa. The 4,5-dichloropyridazin-3-one used as starting material can be prepared by reacting mucochloric acid with hydrazine in a known manner [e.g.

in 50 ml of toluene and then the mixture is heated under reflux for 17 hours with stirring. The reaction mixture was allowed to cool to room temperature, the inorganic residue was filtered off and the filtrate was concentrated in vacuo. The residual oil which solidifies after a short time is recrystallized from ethyl acetate.

There was thus obtained N- [3- (o-ethoxyphenoxy) -2-hydroxypropyl] -N- [2-methyl-3-oxo-4-chloropyridaz-5-yl] ethylenediamine. formulas

O-CH 2 CH-CH 2 NHOH

OC _Z H _S

- Melting point: 120 ^C C.

Calcd for C18H25ClN4O4:

54.5% C, 6.3% H, 9.0% Cl, 14.1% N,

16.1% O, found *

54.7% C, 6.3% H, 9.1% Cl, 13.8% M,

16.4% O.

Yield: 84%.

Starting materials can be prepared in analogy to the procedures described in Example 1.

Example 3

5.85 g of N- [3- (p-pentyloxyphenoxy) -2-hydroxypropyl] ethylenediamine of the formula

OH-O-O-O and 5.0 g of 4,5-dibromopyridazin-3-one are refluxed in 60 ml of ethanol for 10 hours. The solution is then filtered and the filtrate is concentrated to leave a viscous oil. The oily residue is stirred with 100 ml of water and 5 to 10 ml of ethyl acetate and aqueous 2 N carbonate solution.

mp 173-175 ° C.

Analysis calculated for C 20 H 25 BrNiO 1:

C 51.14%, H 6.2%, H 11.9%, O 13.6%, Br 17.0%, sodium were adjusted to pH 9.0. This solution was stirred until the oil crystallized completely and the solid product obtained was filtered off. The residue (5.4 g, 58% of theory) is recrystallized from ethanol to give 4.2 g of N- [3- (o-pentyloxyphenoxy) -2-hydroxypropyl] -N '- [3-oxy-4- bromopyridaz-5-yl] ethylenediamine of formula found:

H, 6.3; N, 11.5; O, 13.9; Br, 16.8.

Example 4

4.13 g of N- (3-phenoxy-2-hydroxy-propyl-ethylenediamine) of the formula (I) -.

The OH and 5.0 g of 4,5-dibromopyrazin-3-one were refluxed in 80 ml of anhydrous ethanol for 30 hours. The solution obtained is filtered and the filtrate is evaporated. A semi-solid residue remains, which is stirred with 100 ml of water and 10 ml of ethyl acetate. This mixture is now treated by the addition of aqueous 2 N carbonate solution.

OH, m.p. 165 DEG C., yield 3.9 g (52% of theory).

For C15H19BrN4O3 calculated:

47.0% C, 5.0% H, 14.6% N, 12.5% O, 20.9% Br, sodium citrate to pH 9.0, the reaction product slowly solidifying.

The solid product was filtered off and recrystallized from ethanol. There was thus obtained N- (3-phenoxy-2-hydroxypropyl) -N- [-3-oxo-4-bromopyridaz-5-yl] ethylenediamine of the formula:

46.8% C, 4.7 O / o H, N 14.6%, O 12.9%,

20.8% Br.

Example 5

4.9 g of N- [3- (o-chlorophenoxy) -2-hydroxypropyl] ethylenediamine of the formula

O-CH = CH <H ^ NH <^ H _of the NH

OH

Dissolve Cl in 50 mL of ethanol. To this solution is added a solution of 3.5 g of 5-bromopyridazin-3-one of formula

in 50 ml of ethanol and the reaction mixture is refluxed for a further 12 hours. The mixture was then concentrated in vacuo, the residue digested with a small amount of ethyl acetate, then filtered and the residue washed again with a small amount of fresh ethyl acetate. For further purification, the crystalline product is triturated in a mortar with 25 ml of a 2 N sodium carbonate solution and then digested at room temperature for 1 hour. The suspension was then stirred with 50 ml of ethyl acetate for 10 minutes using a high speed stirrer, allowed to settle and the organic phase separated. The ethyl acetate solution obtained was washed twice with distilled water and dried over anhydrous magnesium sulfate. The reaction product is precipitated in the form of the hydrochloride by dropwise addition of alcoholic hydrogen chloride to the dried ethyl acetate solution. The precipitate obtained is filtered off, washed with a small amount of ethyl acetate and recrystallized twice from ethanol.

5.3 g of N- [3- (o-chlorophenoxy) -2-hydroxypropyl] -N- [3-oxopyridaz-5-yl] ethylenediamine hydrochloride of the formula I are thus obtained.

HCt

Melting point: 219 ° C.

Calcd for C15H20ClN3O3:

C 48.0%, H 5.4%, Cl 18.9%, N 14.9%,

12.8% O

ΠΑίθΖΒΠΟ *

C, 48.3; H, 5.6; Cl, 18.5; N, 14.5.

12.5 ° / o O.

Yield: 70%.

The 5-bromopyridazin-3-one used above as starting material can be prepared according to the data contained in Example 5 of Spanish patent 454136 by reacting hydrazine hydrate with methyl ester of β-bromo-, d-formylacrylic acid in glacial acetic acid as solvent at temperature rooms.

Example 6

4.9 g of N- [3- (o-chlorophenoxy) -2-hydroxypropyl ethylenediamine of formula

^O-Z CHjCW l _of ortho · dissolved in 50 ml of ethanol. To this solution was added a solution of 2.9 g of 2-methyl-5-chloropyridazin-3-one of formula

in 50 ml of ethanol and the reaction mixture is then heated at reflux for 12 hours. Then the mixture is concentrated in vacuo, the residue is digested with a small amount of ethyl acetate, the ethyl acetate is filtered off and the residue on the filter is washed again with a small amount of fresh ethyl acetate. The crystalline product is recrystallized twice from ethanol for further purification. 5.7 g of N- [3- (o-chlorophenoxy) -2-hydroxypropyl] -N- [2-methyl-3-oxopyridaz-5-yl] ethylenediamine hydrochloride of the formula I are thus obtained.

Melting point 200-205 ° C (decomposition). Calcd for C19H22Cl2N4O3:

H, 5.70; H, 18.2; N, 14.4.

12.3% O, found ·

49.5% C, 5.5 θ / ο H, 18.5% Cl, 14.0% N,

12.1 ° / o O.

The 2-methyl-5-chloropyridazin-3-one used as starting material can be prepared according to the data reported by Torizo Takahashi et al., Yakugaku Zasshi 66 (12), pp. 1168-1172 (1966).

Using the appropriate procedure as described in Examples 1 to 6, the compounds listed in the following table were prepared:

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The substantial technical predominance of the compounds produced by the process of the invention compared to a typical representative of known products commercially available with the same type of action and with a similar chemical structure, i.e. Metoprolol, is evident from the following pharmacological comparative tests.

Formulas of compounds to be compared:

A compound of the invention

OH

2. Metoprolol

H-C-O-CH-CH-CH3-O-CH-CH-CH-NH-CH (CHfa OH

1. Effect on blood circulation of anesthetized dog

1.1 Blockade of 5-receptors

In a pentobarbital-narcotized dog, the compound of the invention suppresses the increase in contractility and isoprenaline-induced heart rate increase with an ED 50 of 0.003 mg / kg i.v., while the corresponding value for Metoprolol is 0.14 mg / kg. Thus, the compound of the invention is about 40 times more potent than Metoprolol (and eleven times more potent than Propranolol) on the heart.

Comparison of cardiac / 3-receptor suppression with β-receptor suppression of blood vessels ED50 (heart) to ED50 (blood vessel), which can be viewed as a measure of cardioselectivity, gives a 1: 76 ratio for a compound of the invention and 1: 18 for Metoprolol. . Thus, the compound of the invention has a clear cardioselective effect.

1.2 Hemodynamics

The hemodynamic effect of a compound of the invention on a dog anesthetized with pentobarbital is characterized by a marked decrease in blood pressure (—4665.5 Pa at 0.05 mg / kg iv, Metoprolol 66666.5 Pa], left ventricular diastolyi pressure drop (LVEDP -266, 6 Pa), Metoprolol (266.6 Pa) and a decrease in total peripheral resistance (TPR-1191 dyn. Cm- ⁵ , Metoprolol-135 dyn. S.cmr ⁵ ) without being accompanied by a decrease in heart contractility, which in Metoprolol, especially at higher doses, it occurs significantly.

A decrease in contractility and cardiac output is prevented for the compound of the invention by its own mild sympathomimetic effect (ISA), which represents about 1/3 of the value of Pindolol.

Thus, the compound of the invention has a more favorable hemodynamic effect than Metoprolol since, despite a decrease in the TPR value, it reduces both the subsequent load and, on the other hand, the preliminary heart load without causing a negative inotropic effect.

2. Effect on the waking dog with renal hypertonia

Metoprolol at a dose of 3.0 mg / kg po has virtually no ability to acutely lower blood pressure in a waking dog with renal hypertension (Δ BD _S 800 800 Pa, Δ BD _d 400 400 Paj, while the compound of the invention already at 0.2 mg / kg po reduces systolic blood pressure by –3733 Pa and diastolic blood pressure by - 2000 Pa.

Testing, which was carried out in an analogous manner, yielded for the other compounds of the invention and for a structurally comparable compound of the formula:

known from DOS 2,819,629, the values of pharmacological effects are shown in the following table.

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Ri R2 r3 r4 w Blockade / Si receptors Cardioselectivity LVEDP TPR

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The intrinsic sympathomimetic activity (ISA) values reported in the above table are reported relative to Pindolol, which serves as a standard.

The pharmacological data show that the compounds according to the invention are distinguished by a particularly well-balanced spectrum of action, in comparison with the closest known compounds. In addition to improved blockade / h-receptor efficacy, which is at least 100% higher than compounds known from DOS 2,819,629, these compounds have a beneficial effect on acute blood pressure reduction and in particular have a very balanced intrinsic sympathomimetic activity (ISA) which, on the other hand, prevents a decrease in contractility but, on the other hand, does not yet lead to an undesirable increase in heart rate, which properties make the use of the compounds of the invention particularly advantageous.

A further advantage of the compounds produced by the process according to the invention, in particular in comparison with the compounds known from DOS No. 2,819,629, is their better tissue compatibility. Thus, for example, local irritation can be largely avoided when administered intravenously.

Based on the above-mentioned advantageous combined effects, the compounds of the invention are particularly suitable for the treatment and prophylaxis of myocardial infarction.

The daily dose for adult patients ranges from 5 to 30 mg as a single dose, or the dose may also be divided into 2 to 3 divided doses.

The compounds of the invention are preferably administered orally or intravenously.

Claims (10)

A process for the preparation of basic substituted pyridazines of the general formula I SUBJECT INVENTION in which R ¹ , R ² and R ³ are each independently hydrogen, fluoro, chloro, bromo, hydroxy, nitro, trifluoromethyl, C 1 -C 8 alkyl, C 2 -C 6 alkoxyalkyl, C 6 -C 6 alkenyl carbon atoms, alkynyl of up to 6 carbon atoms, cycloalkyl of 5 to 8 carbon atoms in the ring, cycloalkenyl of 5 to 8 carbon atoms in the ring, phenyl, alkoxy of 1 to 8 carbon atoms, hydroxyalkoxy of 2 to 6 atoms carbon, alkoxyalkoxy of up to 8 carbon atoms, alkenyloxy of up to 6 carbon atoms, alkynyloxy of up to 6 carbon atoms, cycloalkoxy of 5 to 8 carbon ring atoms, benzyloxy, phenethyloxy, alkanoyl of 1 to 6 carbon atoms, acylam 11 carbon atoms in the acyl radical, - NH - CO - R ⁹ , wherein R ⁹ is morpholino, piperidino or 1-pyrrolidinyl, furthermore ureido, ureido in the 3-position mono-substituted with 5 or 6 carbon cycloalkyl or ureido in the 3-position mono- or disubstituted with 1 to 6 alkyl carbon atoms and / or alkenyl of 3 to 6 carbon atoms, R ⁴ represents hydrogen or alkyl with 1 to 4 carbon atoms, W is hydrogen, chlorine or bromine, as well as their acid addition salts, characterized in that the compound of formula (VI): R ⁴ and W have the above meanings and T represents chlorine or bromine, with a compound of formula IX WO-CH 2 CH-CH 2 NH-C 2 C 4 N ₁ OH (ix) R ¹ , R ² and R ³ have the meanings given above, and the compound obtained is optionally converted by treatment with an acid into an acid addition salt. 2. Method according to claim 1, characterized in that as the starting material used is a compound of formula IX, wherein only one of R ^1, R ² or R ³ has a different point in one defined than hydrogen. 3. Process according to claim 1 or 2, characterized in that as the starting material used is a compound of formula VI, wherein R ⁴ is hydrogen and T and W have the meanings given in point 1. 4. Process according to claims 1-3, characterized in that as the starting material used is a compound of formula IX wherein one of R ^1, R ² or R ³ is fluorine, chlorine or bromine and the other two are hydrogen. 5. Process according to claims 1 to 4, characterized in that as the starting material used is a compound of formula IX, wherein R ¹ is 2-chloro, R ² is hydrogen and R ³ is hydrogen, and compounds of formula VI wherein R ⁴ is hydrogen and T and W are as defined in point 1. 6. Method according to claim 1 for the manufacture of compounds of formula I wherein R ^1, R ^2, R ³ and R ⁴ have the meanings given in point 1, W is chloro, as well as their addition salts with acids, characterized in that a compound of formula VI wherein R ⁴ and W are as defined above and T is chloro is treated with a compound of formula IX wherein R ¹ , R ² and R ³ are as defined above, and the compound obtained is optionally converted by treatment with of an acid to an acid addition salt. 7. A method according to claim 6, characterized in that as the starting material used is a compound of formula IX, wherein only one of R ^1, R ² or R ³ is other than hydrogen, wherein the meaning of this symbol is shown in section 1. 8. A process according to Claims 6 and 7, wherein the starting material is a compound of formula VI wherein R &lt; ^{4 &gt}; is hydrogen and T and W are as defined in point 6. 9. Process according to claims 6-8, characterized in that as the starting material used is a compound of formula IX wherein one of R ^1, R ² or R ³ is fluorine, chlorine or bromine and the other two are hydrogen. 10. A method according to claims 6-9, characterized in that as the starting material used is a compound of formula IX, wherein R ¹ is 2-chloro, R ² is hydrogen and R ³ is hydrogen, and compounds of formula VI wherein R ⁴ is hydrogen and T and W have the meanings given in point 6.