CS236684B2 - Manufacturing process of basic substituted pyridazines - Google Patents

Description

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

in which

R ^{@ 1} , R ^{@ 2} and R @ ³ are each independently hydrogen, C1-C8alkyl, C1-C8alkoxy, C1-C6alkoxyalkoxy, and 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.

The substituents given for R @ ¹ , R @ ² and R @ ³ have, in particular, the following meanings in addition to hydrogen: an alkyl group having 1 to 8 carbon atoms, preferably having 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, n-hexyl, isohexyl, n-heptyl and n-octyl group;

(C 1 -C 8) alkoxy group, for example methoxy, ethoxy, propoxy, butoxy, isopropoxy, isohexyloxy, n-heptyloxy, n-octyloxy, pentyloxy;

C 1 -C 6 -alkoxyalkyloxy, preferably C 3-C 4ϋ, preferably with 3 or 4 carbon atoms, for example allyloxy, methallyloxy, crotyloxy, 2-hexenyloxy.

Preferred are compounds of formula I or their acid addition salts, in which only one of R ^1, R ² or R ³ is other than hydrogen.

Particularly preferred are those compounds having two or more of the above-mentioned advantageous properties. For R @ ¹ , R @ ² and R @ ³ , those radicals 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 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.

According to the invention, the compounds of formula (I) are prepared by base-substituted pyridazine of formula (Ia)

in which

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

W represents chlorine or bromine and

Y is hydrogen or a hydrogenolytically cleavable residue, hydrogenated with hydrogen in a solvent or dispersant in the presence of a hydrogenation catalyst.

The selective exchange of the chlorine or bromine atom of W, which is attached to the pyridazine ring, is carried out in a simple manner by a smooth hydrogenation reaction. As a rule, another solution or dispersion of the substance in a solvent or dispersant is treated with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel or a finely dispersed platinum group metal on a suitable support, such as palladium on carbon.

Particularly preferably, lower alkanols having 1 to 4 carbon atoms, water or mixtures of water and alkanols are used as solvents or dispersants. To capture the hydrogen halide formed in the hydrogenation, the reaction is carried out in the presence of a base such as a tertiary amine, magnesium oxide, an alkali metal acetate or an alkali metal hydroxide.

Conducting such exchange reactions by hydrogenation has been extensively studied and described, such as in Houben-Weyl, 4th edition (1965), Vol. V / 4, p. 773 et al. IV. ic, p. 364 et seq.

Preferably, the compounds of the formula (I) are used as starting materials in the process of the invention

in which

W represents chlorine or bromine and Y represents a hydrogenolytically cleavable residue a

R ^1, R ² and R ³ have the abovementioned meanings. In the hydrogenation of these compounds in a manner known per se, the chlorine or bromine atom W and the hydrogenolytically cleavable residue Y can be replaced by hydrogen in one and the same reaction step.

23BB84

In order to prepare compounds of formula Ia in which W is chlorine or bromine which are used as starting materials, a compound of formula V is reacted

in which

R ¹ , R ² and R ³ have the meanings given above, Z is -CH-CH 2 -Z o or -CH-CH 2 -Hal

AND

OH wherein Hal is a halogen atom, especially chlorine or bromine, with a compound of formula IV

in which

W · represents chlorine or bromine,

Y is hydrogen or a hydrogenolytically cleavable moiety, and the present hydrogenolytic cleavage moiety is then cleaved from the compound obtained by hydrogenolysis and the compound obtained is optionally converted by treatment with an acid into an acid addition salt.

Numerous hydrogenolytically cleavable residues have been known for a long time and serve very well, for example, in the field of peptide synthesis. Instructive papers and reviews have been published in particular by R. A. Boissonnas and G. Preitner, Helvetica Chimica Acta, Vol. 36, p. 875 (1953) and R.A. Boissonnas, Advances in Órganic. Chemistry vol. 3, p. 159 et seq. (1963) with numerous references to the original literature.

Examples of hydrogenolytically cleavable radicals include, in particular, in the phenyl core, a methyl, methoxy, chlorine or phenylazosubstituted benzyl group.

Instead of a uniform compound of formula V, a mixture of a compound of formula II with a compound of formula III can also be used

O-CH 2 CH — CH 2 ^O (II)

OH (IH) wherein the compound of formula III is substituted in the phenyl ring with the same substituents as the compound of formula II, and

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

Hal represents a halogen atom, especially chlorine or bromine.

The reaction of the compounds of formulas IV and V is usually carried out in a suitable solvent or dispersant in which the reactants are dissolved or suspended. 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 dioxane; 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. Alcohols having 1 to 4 carbon atoms are preferred. 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 of from 60 to 100 ° C. It may be expedient to use the starting compound of formula (IV) in up to 10-fold or, optionally, in even higher molar excess and / or to add the reactants of formula (II) and (III) in dissolved or suspended state to the dissolved or suspended reagent of formula (IV). Thus, the molar ratio between the compounds of the formulas II, III and IV, respectively, may be 1: 1 to 1: 10 and optionally even 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 carbonate236684 »

and the like. Without acid-binding agents, then usually hydrohalides are obtained when Y = hydrogen of the compounds of formula I.

The reaction of epoxides or halohydrins with compounds containing amino groups and the conditions from which this reaction is conveniently carried out are known per se. Comprehensive data can be found in the publication

Houben-Weyl, 4th edition (1965), vol. XI / 1, pp. 24 to 74, and 1314 to 326.

In the reaction of the compounds of formula (IV) and (V), Y is obtained when, in formula (IV), Y represents a hydrogenolytically cleavable radical, for example a benzyl radical or a benzoxycarbonyl radical of a compound of the general formula Ia, 2. R

OH Y

(And also in which

R ^1, R ^2, R ³ and W Maija above meanings and

Y represents a hydrogenolytically cleavable residue.

Hydrohalides of the compounds of formula (Ia) are obtained using compounds of formula (III) and in the absence of acid-binding agents.

The starting materials of the formula IV can be prepared by reacting the compounds of the formula VI

(Vil in which

W is as defined above, and

T is chloro or bromo, with a compound of formula VII

H2N — CH2 — CH2 — NH — X (VII) wherein

X represents a hydrolytically cleavable radical or Y (= hydrogen or a hydrogenolytically cleavable radical).

The hydrolytically cleavable radical is, for example, an acetyl radical or another acyl radical, i.e. a radical derived from an aliphatic, aromatic or araliphatic carboxylic acid by cleavage of the hydroxyl group.

The hydrogenolytically cleavable radical is, for example, a benzyl radical or a benzoxycarbonyl radical.

The reaction of the compounds of the formula VI with the compounds of the formula VII is usually carried out in a suitable solvent or dispersant in which the reactants are dissolved or suspended, such as benzene, xylene, chloroform, methylene chloride, carbon tetrachloride, diethyl ether, dioxane, tetrahydrofuran, dimethylsulfoxide, acetone. , methyl ethyl ketone, dimethylformamide, N-methylpyrrolidone, etc. The molar ratio between compounds of formulas VI and VII may be 1: 1 to 1:10 and optionally even more. The reaction may be carried out at room temperature or may be accelerated by the use of heat or may be terminated by the use of heat, for example by heating to a temperature of 80 to 110 ° C.

When X is hydrogen in the reaction of the compound of the formula VI with the compound of the formula VII, the compound of the formula VII is expediently used in excess, in some cases also as a solvent. When X is a hydrolytically or hydrogenolytically cleavable protecting group in the reaction of VI and VII, and both reactants are used in equimolar amounts, the reaction is conveniently carried out in the presence of acid binders such as potassium carbonate, sodium carbonate, triethylamine, etc.

When X is a protecting group in the reaction of a compound of formula VI with a compound of formula VII, a compound of formula VIII is formed first

X and W 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, or when X is a hydrogenolytically cleavable group, by hydrogenolysis, a compound of formula IV 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 by reaction with mucochloric acid, mucobromic acid or the corresponding chloro-bromo derivative (cf. Katritzky, Boulton, Advances in Heterocyclic Chemistry (1968, vol. 9, pp. 235-236) By way of example, mucochloric acid can be illustrated by the following reaction scheme.

The starting compounds of formula VI in which W is hydrogen can be prepared, for example, according to the reaction scheme of R. Elderfield, Heterocyclic Compound (1957), Vol. 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 traction crystallization of the diastereomeric salt mixture thus obtained. solvents, such as ethanol, and finally the optically active alkylenediamine is liberated from the salt with a base. Optically active compounds of formula I can also be obtained by using optically active starting compounds of formula III. These optically active starting compounds are obtained in a known manner by resolution of the racemate from optically inactive compounds of formula III.

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 strong β-adrenalytic effect, which is additionally cardioselective, i.e. the compounds have a higher degree of specificity in blocking cardiac / β-receptors than peripheral β-veceptors, for example β-receptors of the bronchial 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.

Surprisingly, the compounds of the formula (I) produced by the process according to the invention have a distinct advantage over their pharmaceutical activity over the compounds known from DOS 28 19 629 and having a similar structure.

Thus, the pyridazines produced by the process of the invention can 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 of the invention or its acid addition salt 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. In addition to the compounds of formula (I), the pharmaceutical preparations may also contain one or more other pharmaceutically active substances, for example tranquillizers such as Luminal, Meprobamat, Chlorpromazine and benzodiazepine sedatives such as Diazepam or Chlorodiazepoxide;

vasodilators such as glycerin trinitrate, pentaerythrittetranitrate and carbochromes;

diuretics such as chlorothiazide; heart ionizing agents such as diaitalic 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 quinidine and catecholamines such as noradrenaline.

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

• Example 1

3.0 g of N- (3-phenoxy-2-hydroxypropoxyl) 12

-N * - [--chloro-3-oxopyridaz-5-yl] ethylenediamine hydrochloride of formula ·

Oy-O-C ^CH-CH ^ fí-CH ^ NH-H ^N-HCl

The OH was dissolved in 100 mL of a 5% (w / w) sodium hydroxide solution and 0.3 g of 10% palladium on carbon was added. Hydrogenation in a shaking duck with hydrogen at atmospheric pressure is then carried out at room temperature until no more hydrogen is consumed and the reaction mixture is allowed to stand overnight at room temperature.

The reaction mixture thus obtained is filtered, the residue on the filter Z 1 consisting essentially of the catalyst is left and the filtrate is evaporated to dryness.

Shake the residue well with 50 ml of water and filter the resulting suspension. A residue on filter Z2 is thus obtained.

The residue on filter Z 1 is shaken with heating with 50 ml of ethanol and the catalyst is filtered off from the obtained suspension. The filtrate (alcoholic) was evaporated, the residue was combined with the residue on the Z 2 filter and both were recrystallized together from water. 2.0 g (about 82% of theory) of N- (3-phenoxy-2-hydroxypropyl) -N- [3-oxopyridaz-5-yl] ethylenediamine of the formula I are obtained.

Melting point 151-153 ° C.

Calcd for C15H20N1O3:

% C, 59.18;% H, 6.63;% N, 18.41;% O, 15.78;

H, 6.2; N, 18.4; O, 16.0.

Example 1 and d 2

4.2 g of N- [3- (2-ethoxyphenoxy) -2-hydroxyprop-1-yl] -N '- [4-chloro-3-oxopyridaz-5-yl) ethyleindiamine hydrochloride CH 2 CH-CH 2 NH-CH 2 CH 2 NH- 1 H 2.

HCl

The OH was dissolved in 1000 ml of water, and 0.3 g platinum oxide was added to the solution. Hydrogenation is then carried out at room temperature in a shaking duck under atmospheric pressure with hydrogen until hydrogen uptake takes place and then the reaction mixture is left still at room temperature overnight.

The reaction mixture thus obtained is filtered, the residue on the R 1 filter, which essentially consists of a catalyst, is stored, and the filtrate is evaporated to dryness. Evaporate the evaporation residue with 50 ml of a 1 N solution of sodium carbonate in water and filter the resulting suspension. The residue on filter R2 is obtained.

The residue on filter R1 is shaken with 50 ml of ethanol with heating and the suspension obtained is filtered to separate the catalyst. The alcoholic filtrate is evaporated, the residue is combined with the residue on filter R2 and both are recrystallized together from water. Thus, 2.75 g (about 79% of theory) of N- [3- (2-ethoxyphenoxy) -2-hydroxyprop-1-yl] -N- [3-oxopyridaz-5-yl] ethylenediamine of the formula I are obtained.

ÁJ

AND·*

Melting point 124-126 ° C. Analysis for C17H21N4O4 calculated:

% C, 58.59;% H, 6.95;% N, 16.08;% 18.38.

% H, 7.0%; N 16.0%; O 18.41%.

When 4.2 g of N- [3- (2-ethoxyphenoxy) -2-hydroxyprop-1-yl] -N'- [4-chloro-3-oxopyridaz-5-yl] ethylenediamine hydrochloride is replaced in the above example 4.7 g of N- [3- (2-ethoxyphenoxy) -2-hydroxyprop-1-yl] -N-benzyl-N '- [4-chloro-3-oxopyridaz-5-yl] ethylenediamine of the formula

or 5.1 g of its hydrochloride and otherwise work accurately. in the same manner as above, 2.61 g (about 75 percent of theory) of N- [3- (2-ethoxyphenoxy) -2-hydroxyprop-1-yl] -N'- [3-oxopyridaz-5- yl] ethylenediamine.

Melting point: 125-126 ° C.

Calcd for C17H24N4O4:

% H, 6.95;% N, 16.08;% O, 18.38.

H, 7.02; N, 16.1; O, 18.40. Example 3

3.8 g of N- [3- (2-ethoxyphenoxy) -2-hydroxyprop-1-yl] -N- (4-chloro-3-oxopyridaz-5-yl) ethylenediamine of the formula

C 1 -c-ch-ch ₂ nh-ch ₂ N

O

The OH was dissolved in 100 mL of methanol and 2 mL of 40% aqueous potassium hydroxide, and 0.3 g of 10% palladium on carbon was added to the solution. Hydrogenation is then carried out at room temperature in a shaking duck under atmospheric pressure with hydrogen until there is no further uptake of hydrogen, and then the reaction mixture is left overnight at room temperature.

The reaction mixture thus obtained is filtered, the residue on filter R1, which consists essentially of a catalyst, is saved, and the filtrate is evaporated to dryness. The residue R2 is thus obtained.

The residue on filter R1 is shaken with 50 ml of methanol while heating and the catalyst is filtered off. The methanolic filtrate was evaporated, the residue was combined with the residue R2 and both were recrystallized together from water.

2.5 g (i.e. about 72% of theory) of N- [3- (2-ethoxyphenoxy) -2-hydroxyprop-1-yl) -N- [3-oxopyridaz-5-yl] ethylenediamine of formula ltt are obtained.

OCj-k

O-CH 2 CH-CH 2 NH-CH 2 CH 2 NHOH o

Melting point: 125-126 ° C. Calcd for C17H11NiO4:

H, 6.95; N, 16.08; O, 18.38. Found:

58.52% C, 7.0 _0/0 H, 16.15% N, 18.40% O.

Example 1 a d 4

4.1 g of N- [3- (4-butoxyphenoxy) -2-hydroxyprop-1-yl] -N- [4-chloro-3-oxopyridaz-5-yl] ethylenediamine of the formula

OH

Dissolve in 100 ml of methanol and 2 ml of a 38% w / w aqueous solution of potassium hydroxide, to which 0.3 g of palladium on carbon is added. Hydrogenation with hydrogen is then carried out at room temperature in a shaking duck at atmospheric pressure until no further uptake of hydrogen occurs. The reaction mixture was then allowed to stand overnight at room temperature.

The reaction mixture thus obtained is filtered, the residue on filter R1, which consists essentially of a catalyst, is stored, and the filtrate is evaporated to dryness. A residue Rz is thus obtained.

The filter residue Rt is shaken with 50 ml of methanol while heating and the catalyst is removed by filtration. Evaporate the methanolic filtrate, combine the residue with R 2 and recrystallize the two from water. 2.7 g (i.e., about 75% of theory) of N- (3- (4-butoxyphenoxy) -2-hydroxyprop-1-yl) -N'- [3-oxopyridaz-5-yl] ethylenediamine of formula (C10-10) are obtained. ch ^ ch-ch ^ nh-ch ^ ci ^ nhA ^ n

OH

Melting point of hydrochloride 247-249 ° C.

found:

60.5% C, 7.55% H, 14.9% N, 17.1% O.

Calcd for C18H28NiOd:

C 60.60, H 7.5%, N 14.88%, O 17.01%,

If the starting material used in Example 4 is replaced by 4.6 g of N- [3- (4-butoxyphenoxy) -2-hydroxyprop-1-yl] -N'- [4-bromo-3-oxopyridaz-5- yl] ethylenediamine of formula

and the rest was carried out as in Example 4 to give 2.9 g (about 77% of theory) of N- [3- (4-butoxyphenoxy) -2-hydroxyprop-1-yl] -N'- [ 247 DEG-249 DEG C. 3-oxopyridaz-5-yl] ethylenediamine.

Example 5

4.0 g of N- (3- (2,6-dimethoxyphenoxy) -2-hydroxypropyl) -N- [4-chloro-3-oxopyridaz-5-yl] ethylenediamine

The OCH ₃ was dissolved in 100 ml of methanol and 0.3% 10% palladium on carbon and 1 g of magnesium oxide were added. Hydrogenation with hydrogen is then carried out at room temperature in a shaking duck at atmospheric pressure until no more hydrogen is consumed, and then the mixture is left at room temperature overnight.

The reaction mixture thus obtained is filtered, the residue on filter R1, which essentially consists of a catalyst, is stored, the filtrate is evaporated to dryness to give a residue R2.

The residue on filter R1 is shaken with heating and 50 ml of methanol and the catalyst is filtered off from the obtained suspension. The methanolic filtrate was evaporated, the residue was combined with the residue R2 and the two residues were recrystallized together from water. 3.0 g (about 83 percent of theory) of N- [4- (2,6-dimethoxyphenoxy) -2-hydroxypropyl] -N- [3-oxopyridaz-5-yl] ethylenediamine of the formula are obtained.

OCt-L

O-CH 3 -CH-C 1 OH

OCH, m.p. 133-134 ° C.

Calcd for C17H24N4O5:

56.01% C, 6.64% H, 15.38% N, 21.97% O jjq _eZen i o *

H, 6.7; N, 15.5; O, 22.2.

If hydrogenation is carried out not at room temperature in a shaking duck but under vigorous stirring at reflux (67 ° C) under reflux, 2.8 g (about 77% of theory) of N- [3- (2) are obtained. 6-dimethoxyphenoxy) -2-hydroxypropyl] -N '- [3-oxopyridaz-5-yl] ethylenediamine, m.p. 134-135 ^° C.

Example 1 a d 6

3.8 g of N- [3- (2,3,5-trimethylphenoxy) -2-hydroxypropyl] -N- [4-chloro-3-oxopyridaz-5-yl] ethylenediamine of the formula

CH ₃ CH ₃ was dissolved in 100 ml methanol and 2 ml of 40% (percentage by weight) of potassium hydroxide, and, to the resulting solution are added 0.3 g of 10% palladium on carbon ^one. Hydrogenation with hydrogen was then carried out at room temperature in a shaking duck at atmospheric pressure until no more hydrogen was consumed and the reaction mixture was allowed to stand overnight at room temperature.

The irrigation mixture thus obtained is filtered, the residue on the R 1 filter, which consists essentially of a catalyst, is saved, and the filtrate is evaporated to dryness. The residue R2 is thus obtained.

The filter residue R1 is now shaken with 50 ml of methanol while heating and the catalyst is filtered off from the obtained suspension. The methanol filtrate was evaporated, and residue are combined and both R radicals are common ² <V them recrystallized from ethanol and water. 2.8 g (about 82% of theory) of N- [3- (2,3,5-trimethylphenoxy) -2-hydroxypropyl] -N'- [3-oxopyridaz-5-yl] ethylenediamine of the formula:

CH>

£> -O-CH _of CH-CH-CH NM £ £ _CH2 -NH

Z \ OH

CH ₃ CH ₃

O

m.p. 284-286 ° C. Calcd for C18H28N4O3:

% C, 62.39;% H, 7.57;% N, 16.18;

% C, 62.45;% H, 7.60;% N, 16.10.

The same end product with the same melting point is obtained when the above starting material is changed

a) 5,0 'g of N- [3- (2,3,5-trimethylphenoxy-2-hydroxypropyl)] - N - (4-methoxybenzyl) -N' - [4-chloro-3-oxopyridaz-5-yl] ] ethylenediamine,

h) 4.8 g of N- [3- (2,3,5-trimethylphenoxy-2-hydroxypropyl)] -N- (4-methylbenzyl) -N '- [4-chloro-3-oxopyridaz-5-yl] ethylenediamine,

c) 5.1 g of N- [3- (2,3,5-trimethylphenoxy-2-hydroxypropyl)] - N - (3-chlorobenzyl) -N '- [4-chloro-3-oxopyridaz-5-yl] ] ethylenediamine of the formula

a] R = 4-OCH 3

b) R = 4-CH 3 or R = 3-Cl

The yields in these cases are as follows:

a) 2.7 g (78% of theory) bj 2.9 g (83% of theory)

c) 2.6 g (75% of theory).

In an analogous manner to that described above (the following compounds can also be prepared by the examples):

OH

149 ° C.

Yield: 85%.

OH

O '/ = \ I

V y -O-CH ^CH-CH ^H-CH ^CH ^NH - \N ^

OCH 2 CH-CH 2

Melting point: 154 ° C.

Yield: 62%.

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

O

-H

O-CH 2 CH-CH 2 NH-CH 2 CH 2 NH

OH

2. Metoprolol

H ₃ C-0-CH _of CTT - </)

1. Effect on blood circulation of anesthetized dog

1.1. Blocking of β-receptors

For dogs anaesthetized with pentobarbital suppresses the compound of the invention increase the contractility and heart rate increases conditional isoprenaline by ED ₅₀ of 0.009 mg / kg iv, while the corresponding value for Metoprolol is 0.14 mg / kg. Thus, the compound of the invention is about 15 times more potent on the heart than Metoprolol (and 3.6 times more potent than Propanolol).

1.2 Hemodynamics

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.

2. Effect on the waking dog with renal hypertension. -CH 2 CH-CH 3 NH-CH (CH 3)

OH

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 Pa, Δ BD _d - 400 Pa), whereas the compound of the invention already at 0.004 mg / kg iv decreases systolic blood pressure by - 3333 Pa and diastolic blood pressure by - 2666 Pa.

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 particular, these compounds have a beneficial effect on acute lowering of blood pressure and in particular have a very balanced intrinsic sympathomimetic activity (ISA) which, on the one hand, prevents a decrease in contractility but on the other hand does not lead to undesirable heart rate .

A further advantage of the compounds produced by the process according to the invention, in particular in comparison with the compounds known from DOS 2,819,629, is their improved tissue compatibility. Thus, for example, local irritation can be largely avoided when administered intravenously.

Based on the above-mentioned advantageous combination effects, the po23 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 application of the compounds according to the invention is preferably carried out orally or intravemously.

Claims (3)

The object of the invention A process for the preparation of basic substituted pyridazines of the general formula I wherein: R 1, R ² and R ³ are each independently hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkenyloxy, and acid addition salts thereof, characterized in that: is a base-substituted pyridazine of formula (Ia) wherein: R, R ² and R ³ have the above meanings, W represents chlorine or bromine, and Y is hydrogen or a hydrogenolytically cleavable moiety, hydrogenated with hydrogen in a solvent or dispersant in the presence of a hydrogenation catalyst, and optionally converted to an acid addition salt by treatment with an acid. 2. Method according to claim 1, characterized in that as the starting material used is a compound of formula Ia wherein Y is hydrogen and R ^1, R ^2, R ³ and W have the meanings given in point 1. 3. Process according to claim 1 or 2, characterized in that as the starting material used is a compound of formula Ia, in which only one of R ^1, R ² or R ³ is other than hydrogen and W and Y have the meanings referred to in point 1. Severography, n. P., Plant 7, Most