WO1990001479A1 - 4,5-dihydro-3(2h)-pyridazinones, process for producing them and their use - Google Patents

Abstract

4,5-Dihydro-3(2H)-pyridazinones of general formula (I), wherein R denotes hydrogen, alkyl with 1 to 3 carbon atoms or hydroxymethyl and R1 denotes a phenyl residue of formula (II) or an indolyl residue of formula (III), R2 being pyridyl, thiazolyl, imidazolyl, linked via an oxygen, nitrogen or sulphur atom or via a sulfinyl or sulfonyl group with the phenyl or indolyl residue, or imidazolyl, in which the thiazolyl and imidazolyl residues can possibly be substituted by alkyl with 1 to 3 carbon atoms, halogen, nitro, amino, alkylcarbonylamino with 1 to 3 carbon atoms in the alkyl moiety, mono- or dialkylamino with 1 to 3 carbon atoms per alkyl moiety or alkoxycarbonylamino with 1 to 3 carbon atoms in the alkyl moiety, R3 being hydrogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, hydroxy or halogen, and R4 being hydrogen, alkyl with 1 to 5 carbon atoms, alkylcarbonyl with 1 to 4 carbon atoms in the alkyl moiety, phenylcarbonyl, alkoxycarbonyl with 1 to 4 carbon atoms in the alkyl moiety or phenalkoxycarbonyl with 1 to 4 carbon atoms in the alkyl moiety, as well as their producible, pharmaceutically acceptable acid addition salts, in which when R1 is a phenyl residue, R2 cannot be a pyridyl or imidazolyl residue linked via a nitrogen atom, are useful pharmacological active ingredients.

Description

 4,5-dihydro-3 (2H) pyridazinones. Procedure to their

 Manufacture and its use

The present invention relates to 4,5-dihydro-3 (2H) pyridazinones of the general formula I.

 wherein

 R is hydrogen, alkyl having 1 to 3 carbon atoms or

Hydroxymethyl

R ^{1 is} a phenyl radical of the formula

or an indolyl radical of the formula

R ² pyridyl, thiazolyl, imidazolyl, which has an oxygen, nitrogen or sulfur atom or a sulfinyl or sulfonyl group with the phenyl or

 Indolylrest are linked, or imidazolyl, the thiazolyl and imidazolyl radicals optionally by alkyl having 1 to 3 carbon atoms, halogen, nitro, amino, alkylcarbonylamino having 1 to 3 carbon atoms in the

Alkyl part, mono- or dialkylamino with 1 to 3 carbon atoms per alkyl part or alkoxycarbonylamino with 1 to 3 carbon atoms in the alkyl part may be substituted,

R ^{3 is} hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or

Halogen and R ^{4 is} hydrogen, alkyl having 1 to 5 carbon atoms, alkylcarbonyl having 1 to 4 carbon atoms in the alkyl part, phenylcarbonyl, alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl part or phenalkoxycarbonyl having 1 to 4 carbon atoms in the alkyl part

mean, and their pharmaceutically acceptable acid addition salts which can be prepared, where in the case where R ^{1 is} a phenyl radical, R ² cannot be a pyridyl or imidazolyl radical linked via a nitrogen atom.

The invention also relates to processes for the preparation of the compounds of the general formula I and their use as pharmacological active ingredients.

R is preferably hydrogen, methyl or hydroxymethyl.

The pyridyl, thiazolyl and imidazolyl radicals mentioned in the definition of R ² can be linked via all ring carbon atoms, imidazolyl radicals also via a ring nitrogen atom.

Thiazolyl residues are preferably linked via the 2-position, imidazolyl residues via the 1- or 2-position. The thiazolyl and imidazolyl radicals are preferably unsubstituted or substituted by methyl or nitro.

Particularly preferred radicals R are 2-pyridyl mercapto or 3-pyridyloxy, 4-pyridylamino, 2-thiazolylmercapto, 5-nitro-thiazol-2-yl-amino, imidazol-1-yl, 1- Methyl-imidazol-2-yl-mercapto, the 1-methyl-imidazol-2-yl-sulfinyl and the 1-methyl-imidazol-2-yl-sulfonyl radical, the 4-pyridylamino radical not being attached to one of R ¹ standing phenyl radical can be bound. The R ² radicals can be linked to all ring carbon atoms of a phenyl radical representing R ¹ . Prefers a radical R ^{2 is} bound to the 4-position of the phenyl radical. The R ² radicals on an indolyl radical representing R ¹ can be linked to all carbon atoms of the six-membered ring. A linkage at the 5 position is preferred.

An indolyl radical representing R ¹ can be connected to the pyridazinone via the 2- or the 3-position. The 3-position is preferred.

Halogen R ³ preferably denotes fluorine, chlorine or bromine.

R ³ and R ^{4 are} preferably hydrogen.

The compounds of general formula I are analogous to the preparation of other 4,5-dihydro-3 (2H) -pyridazinones by reacting a carboxylic acid or a carboxylic acid derivative of general formula II

wherein R and R ^{1 have} the meanings given above and

X represents -COOH, -COCl, -CO-O-CO-R ⁵ , -COOR ⁵ or -CN, where R ⁵ denotes an organic radical,

accessible with hydrazine. The organic radical representing R ⁵ is preferably a

Alkyl radical with 1 to 4 carbon atoms. R ⁴ particularly preferably denotes methyl or ethyl. The hydrazine can also be used in the form of the hydrate or a salt in the presence of a base.

The reaction is advantageously carried out in the liquid phase, for which the presence of an inert solvent or diluent is generally necessary.

Suitable solvents or diluents are e.g. Alcohols, especially those with 1 to 6 carbon atoms, e.g. Methanol, ethanol, i- and n-propanol, i-, sec- and tert-butanol, n-, i-, sec-, tert-pentanol, n-hexanol, cyclopentanol, cyclohexanol; Ethers, especially those with 2 to 8 carbon atoms in the molecule, such as e.g. Diethyl ether, methyl ethyl ether, di-n-propyl ether, di-isopropyl ether,

Methyl n-butyl ether, ethyl propyl ether, di-butyl ether, tetrahydrofuran; 1,4-dioxane, 1,2-dimethoxyethane, bis-β-methoxyethyl ether; Polyethers such as Polyethylene glycols with a molecular weight of up to approx. 600; Oligoethylene glycol dimethyl ether, e.g. Pentaglyme; Crown ether, i.e. Cyclic polymers of ethylene glycol of the formula

(-OCH ₂ CH ₂ ) _p , where p is a number, for example from 4 to 10, it being possible for one or more benzene rings to be fused onto the ring; Aza and thia crown ethers (coronand amines and coronand sulfides); Glycols and partially etherified glycols, such as, for example, ethylene glycol, propylene glycol, trimethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether; aliphatic hydrocarbons, such as gasolines, low and high boiling petroleum ethers; aromatic hydrocarbons such as benzene, toluene, o-, m- and p-xylene, pyridine; halogenated aliphatic or aromatic hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, ethylene chloride, chlorobenzene, dichlorobenzene; Nitriles such as acetonitrile; Amides, such as, for example, dimethylformamide, N-methylpyrrolidone; Sulfoxides such as dimethyl sulfoxide; Water. Mixtures of different solvents or diluents can also be used.

The reaction of the compounds of general formula II with hydrazine is advantageously carried out at temperatures between room temperature and the boiling point of the solvent or diluent used.

The compounds of the general formula II can be prepared by various processes known per se, for example by acylating the compounds R ¹ -H with

R-maleic anhydride and subsequent hydrogenation of the unsaturated compound obtained, e.g. after in

J.Med. Chem. 17, 273 ff., (1974), described methods, further by Mannich reaction of ketones of the formula

R ¹ -CO-CH ₂ -R with formaldehyde / dimethylamine to Mannich bases R ¹ -CO-CH (R) -CH ₂ -N (CH ₃ ) ₂ and subsequent exchange of the

Amine residue, for example via the quaternary iodine compound against cyano, compounds R ¹ -CO-CH (R) -CH ₂ -CN and, if desired, compounds thereof from hydrolysis

R ¹ -CO-CH (R) -CH ₂ -COOH can be obtained. This sequence of reactions is described, for example, in J.Org. Chem. 38, 4044 ff., (1973).

The compounds of the general formula II with X = CN can, for example, also be acylated by compounds of the formula R ¹ -H with 2-R-3-chloro-propionic acid chloride

DE-OS 33 28 286 produce, initially creating compounds of the formula R ¹ -CO-CH (R) -CH ₂ -Cl, in which the

Chlorine e.g. exchanged with NaCN or KCN for CN.

Compounds of the general formula II with X = CN provide the compounds directly in the reaction with hydrazine of the general formula I when the reaction is carried out in an aqueous medium or in the presence of water. When the reaction is carried out in an anhydrous medium, the ketimines of the compounds of the general formula I are first formed, which are then hydrolyzed to the compounds of the general formula I in a manner known per se.

Starting compounds of the general formula II with X = CN can easily be converted into starting compounds of the general formula II with other meanings of X by processes known per se. Starting compounds of the general formula II with X = COOR ⁵ can easily be analogous to J. Org. Chem. 52, 304

(1987) by alkylating the corresponding ketones with

Prepare bromoacetic acid esters.

Another possibility is the reaction of compounds R ¹ -H with dialkylamides of the general formula III

wherein R ^{5 has} the meaning given above and R ⁶ for

Alkyl, preferably methyl,

according to the Vilsmeier method (analogous to J. Org. Chem. 25, 2049 (1960).

The compounds of the general formula III can easily be prepared from the activated carboxylic acid or the carboxylic acid chloride with secondary amines by methods known from the literature. Compounds of general formula II with X = COOH can be obtained by reaction of the corresponding halogen ketones with malonic esters or Meldrum acid (2, 2-dimethyl-1,3-dioxane-4, 6-dione) after saponification and decarboxylation (e.g. FR 2524-463).

 In an alternative process, compounds of the general formula I according to the invention can also be obtained by reacting hydroxy-, amino- or mercapto-substituted phenylpyridazinones with heterocycles which have a leaving group in a nucleophilic substitution reaction.

Such heterocycles are, for example, 2-bromopyridine or 5-nitro-2-bromothiazole.

If the compounds of the general formula I contain basic radicals, they form acid addition salts with acids. Inorganic and organic acids are suitable for the formation of such acid addition salts. Suitable

Acids are, for example: hydrogen chloride, hydrogen bromide, naphthalenedisulfonic acids, in particular 1,5-naphthalenedisulfonic acid, phosphoric, nitric, sulfuric, oxalic, milk, wine, vinegar, salicylic, benzoic, ant, propionic, Pivaline, diethyl vinegar, malone, amber, pimeline, fumaric, maleic, apple, sulfamine, phenylpropione, gluconic, ascorbic, isonicotine, methane sulfonic, p-toluenesulfonic, lemon or Adipic acid. Pharmacologically acceptable acid addition salts are preferred. The acid addition salts can be prepared as usual by combining the components, advantageously in a suitable solvent or diluent.

The compound of the general formula I is expediently dissolved in an organic solvent and mixed with a solution of the desired acid. For example, the hydrochlorides of the pyridazinones of the general formula I according to the invention can be obtained by dissolving the free compound in alcohol and the alcoholic solution with an equivalent amount of a solution of hydrogen chloride in

Diethyl ether is added. The 4, 5-dihydro-3 (2H) -pyridazinone derivatives according to the invention of the general formula I and their pharmacologically acceptable salts show pronounced antithrombotic, antiplatelet, antianginal, cardiotonic and hypotensive effects. They are ideal for the treatment and prevention of diseases of the heart and circulatory system, including thromboembolic disorders. They show excellent effectiveness in various tests, e.g. Platelet aggregation according to Born, Nature 194, p. 927, (1961); Arachidonic acid mortality in rabbits,

Science 193, p. 1085, (1974); arterial and venous

Prevention of thrombosis in rabbits, favorable hemodynamic profile after per os application on the awake dog. Testing in the abovementioned and a number of further tests reveals that the compounds of the general formula I according to the invention surprisingly have a particularly favorable activity profile with low toxicity, which is considerably superior to the known compounds.

The 4, 5-dihydro-3 (2H) -pyridazinones of the general formula I and their pharmaceutically acceptable acid addition salts according to the invention can therefore be administered to humans as a remedy on their own, in mixtures with one another or in the form of pharmaceutical preparations which are enteral or parenteral Application allowed ten and as an active ingredient contain an effective dose of at least one compound of general formula I or an acid addition salt thereof, in addition to the usual pharmaceutically acceptable carriers and additives.

The remedies can be administered orally, e.g. in the form of pills, tablets, coated tablets, dragees, hard and soft gelatin capsules, granules, solutions, syrups, elixirs, emulsions or suspensions or aerosol mixtures. However, administration can also be rectal, e.g. in the form of suppositories, or parenterally, e.g. in the form of solutions for injection, or percutaneously, e.g. in the form of ointments or tinctures.

The pharmaceutical preparations are made in a manner known per se, e.g. by stretching the active ingredients with pharmaceutically acceptable inorganic and / or organic carriers and / or solvents. The pharmaceutical preparations can also contain two or more compounds of the general formula I or their pharmacologically acceptable acid addition salts. The pharmaceutical preparations normally contain the therapeutically active compounds or the mixture of therapeutically active compounds in a concentration of approximately 0.5 to 90% by weight of the total mixture.

For the production of pills, tablets, dragees, hard and soft gelatin capsules or granules, the carrier materials can be, for example, natural stone powder, such as talc, clay, kaolin, chalk, synthetic stone powder, such as silicates, silica, sugar, such as invert or grape , Milk, malt, fruit or cane sugar, starch or starch derivatives such as corn starch, potato starch, gelatin. As carriers for soft gelatin capsules and suppositories are, for example

Fats, waxes, paraffins, e.g. Petroleum fractions, natural oils, e.g. Peanut or sesame oil, hardened oils, semi-solid and liquid polyols etc. are suitable. Suitable carriers for the production of solutions and syrups are e.g. Water, alcohols, sucrose, invert sugar, glucose, polyols etc. For example, suitable carriers for the production of injection solutions are Water, alcohols, glycols, glycerin, polyols, vegetable oils etc.

In addition to the active substances and carriers, the pharmaceutical preparations can also contain additives, such as e.g. Fillers, stretchers, explosives, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives. Contains sweeteners, coloring, flavoring or flavoring agents, thickening agents, diluents, additives, buffer substances, furthermore solvents, auxiliary solvents or solubilizers or agents for achieving a depot effect, as well as salts for changing the osmotic pressure, coating agents or antioxidants.

The daily dosage can be within wide limits, e.g. vary from 0.01 mg / kg body weight to 20 mg / kg body weight and must be adapted to the individual circumstances in each individual case.

Depending on the type of application, one moves within the dosage range mentioned in order to take into account the different absorption conditions in a known manner. For intravenous administration, one more dose is selected in the lower part of the specified dosage range. In general, daily amounts of about 0.01 to 1 mg / kg, preferably about 0.05 to 0.5 mg / kg of body weight, are achieved with intravenous administration deliver effective results. In the case of oral administration, the daily dosage is generally about 0.1 to 5 mg / kg, preferably 0.1 to 2 mg / kg of body weight. It may be necessary to deviate from the quantities mentioned. When administering larger quantities, it is advisable to divide the daily dose into several, for example two or three, partial administrations distributed over the course of the day.

In addition to the compounds of the general formula I, the pharmaceutical preparations can also contain one or more other pharmaceutically active substances, for example agents which promote blood circulation, such as dihydroergocristine, nicergoline, buphenine, nicotinic acid and its esters, pyridylcarbinol, bencyclane, cinnarizine, naftidrofuryl, raubasine and vincamine; positively inotropic compounds such as digoxin, acetyldigoxin, metildigoxin and lanato glycosides; Coronary dilators such as carbocromes, dipyridamoles, nifedipines and perhexilines; antianginal compounds such as isosorbide dinitrate, isosorbide mononitrate, glycerol trinitrate, molsidomine and verapamil;

(3-blockers such as propranolol, oxprenolol, atenolol,

Metoprolol and Penbutolol and oogen metabolic agents such as Pirilinol contain.

The following examples illustrate the composition of preparations of the 4,5-dihydro-3 (2H) -pyridazinones according to the invention. Example A

Tablets

 per tablet

Active ingredient (finely ground) 50 mg

 Milk sugar 150 mg

 Corn starch, white 230 mg

 Polyvinylpyrrolidone 15 mg

Magnesium stearate 5 mg

 450 mg

 Example B

Iniection solution active ingredient 4 mg

 Sodium chloride 0.7 mg

Water for injections ad 1 ml

Example C

 Rectal drug

Active ingredient 20 mg suppository base mass ad 2 g

Example D

Emulsions active ingredient 60 mg

 Glycerin, pure 0.2 - 2.0 g polyethylene stearate q.s.

Neutral oil q. s.

Taste corrections q.s.

Desalinated water to 100 ml Example E

 Active ingredient solutions

Active ingredient 8 mg

 Polyethylene glycol 1.5 mg

 Glycofurol ad 4 ml

Diluens:

 Water for injections 6 ml

The following examples relate to the preparation of the compounds of the general formula I according to the invention

Example 1 :

4,5-dihydro-5-methyl-6- (4- (2-pyridylmercapto) phenyl) -3 (2H) pyridazinone

10.6 g (0.03 mol) of 4- (4- (2-pyridylmercapto) phenyl) -4-oxo-3-methylbutyric acid hydrochloride and 3.5 ml (0.07 mol) of hydrazine hydrate are dissolved in 150 ml of ethanol heated under reflux for 8 hours. After cooling, the product is filtered off with suction, chromatographed on a silica gel column (mobile phase: methylene chloride: methanol = 99: 1 to 95: 5) and recrystallized from ethyl acetate.

Yield: 3.5 g (41% of theory)

Melting point: 147-149 ° C

Elemental analysis: C ₁₆ H ₁₅ N ₃ OS (297.38)

Calc .: C 64.6 H 5.1 N 14.1 0 5.4

Found: 64.3 5.2 13.9 5.4 Example 2:

4,5-dihydro-5-methyl-6- (4- (3-pyridyloxy) phenyl) -3 (2H) pyridazinone

14.6 g (0.047 mol) of 4- (4- (3-pyridyloxy) phenyl) -4-oxo-3-methylbutyric acid ethyl ester and 2.4 g (0.047 mol) of hydrazine hydrate are refluxed in 150 ml of ethanol for 5 hours heated. After concentration, the mixture is chromatographed on a silica gel column and recrystallized from isopropanol / ether.

Yield: 6.7 g (51% of theory)

Melting point: 139-141 ° C

Elemental analysis: C ₁₆ H ₁₅ N ₃ O ₂ (281.32)

Calculated: C 68.3 H 5.4 N 14.9 0 11.4

Found: 68.1 5.4 15.1 11.3

Example 3

4,5-dihydro-6- (4- (3-pyridyloxy) phenyl) -3 (2H) -oyridazinone 5.4 g (0.02 mol) 4- (4- (3-pyridyloxy) phenyl) - 4-oxo-butyric acid and 1.1 ml (0.023 mol) of hydrazine hydrate are refluxed in 100 ml of isopropanol for 6 hours. After cooling, the product is filtered off with suction and recrystallized from ethanol.

Yield: 3.2 g (60% of theory)

Melting point: 145-147 ° C

Elemental analysis: C ₁₅ H ₁₃ N ₃ O ₂ (267.29) Calc .: C 67.4 H 4.9 N 15.7 0 12.0

Found: 67.5 5.2 15.7 11.7 Example 4

4,5-dihydro-5-hydroxymethyl-6- (4- (3-pyridyloxy) phenyl) -3 (2H) pyridazinone

2.8 g (0.01 mol) of 4- (4- (3-pyridyloxy) phenyl) carbonylybutyrolactone, 1 ml (0.02 mol) of hydrazine hydrate and

 1 drop of glacial acetic acid is stirred in 40 ml of ethanol and 5 ml of dimethylformamide for 30 minutes at room temperature and for 17 hours at 80 ° C. After cooling, the mixture is diluted with 300 ml of water, filtered off with suction and recrystallized from isopropanol and methanol / methylene chloride (1: 1). Yield: 1.5 g (50% of theory)

 Melting point: 186-189 ° C

Elemental analysis: C ₁₆ H ₁₅ N ₃ O ₃ (297.31)

Calculated: C 64.6 H 5.1 N 14.1 0 16.1

Found: 64.6 5.4 14.1 16.0

Example 5

4,5-Dihvdro-5-methyl-6- (4- (2-thiazolylmercapto) phenyl) -3 (2H) pyridazinone

13 g (0.039 mol) of 4- (4- (2-thiazolylmercapto) phenyl) -4-oxo-3-methylbutyric acid ethyl ester, 3.4 ml (0.07 mol) of hydrazine hydrate and 1 ml of glacial acetic acid in 150 ml of ethanol are used for 12 hours heated under reflux. After concentration, the mixture is stirred with a little methylene chloride, suction filtered and chromatographed on a short silica gel column (mobile phase: methylene chloride). Yield: 6.4 g (54% of theory)

Melting point: 164-165 ° C

Elemental analysis: C ₁₄ H ₁₃ N ₃ OS ₂ (303.44)

Calculated: C 55.4 H 4.3 N 13.8 0 5.3 S 21.1

Found: 55.6 4.6 13.4 5.0 21.4

Example 6

4, 5-Dihydro-5-methyl-6- (4- (5-nitrothiazol-2-yl) amino) phenyl) -3 (2H) pyridazinone 4.1 g (0.02 mol) 6- ( 4-aminophenyl) -4,5-dihydro-5-methyl-3 (2H) -pyridazinone and 2.1 g (0.01 mol) of 2-bromo-5-nitrothiazole are stirred in 10 ml of dimethyl sulfoxide for 3 hours at room temperature. After adding 100 ml of water, the product is filtered off with suction and recrystallized from dimethylformamide.

Yield: 2.9 g (88% of theory)

 Melting point:> 280 ° C

Elemental analysis: C ₁₄ H ₁₃ N ₅ O ₃ S (331.36)

Calc .: C 50.7 H 4.0 N 21.1 0 14.5 S 9.7

Found: 51.3 4.2 20.7 14.7 9.5

Further compounds according to the invention can be prepared analogously to the examples given:

Example 7

4,5-Dihydro-5-methyl-6- (4- (1-methylimidazol-2-yl-mercapto) phenyl) -3 (2H) pyridazinone Example 8

4,5-dihydro-5-methyl-6- (4- (1-methylimidazol-2-yl-sulfinyl) phenyl) -3 (2H) pyridazinone

 M.p .: 187-189 ° C

Example 9 4,5-Dihydro-5-methyl-6- (4- (2-pyridylsulfonyl) phenyl) -3 (2H) pyridazinone

Example 10

4,5-dihydro-6- (5- (imidazol-1-yl) indol-3-yl) -3 (2H) pyridazinone

 Mp:> 265 ° C Example 11

4,5-Dihydro-6- (5- (imidazol-1-yl) indol-3-yl) -5-methyl-3 (2H) pyridazinone Example 12

4,5-dihydro-5-methyl-6- (5- (3-pyridyloxy) indol-3-yl) -3 (2H) pyridazinone

Example 13

4,5-Dihydro-5-methyl-6- (5- (2-pyridylmercapto) indol-3-yl-3 (2H) pyridazinone Example 14

4,5-dihydro-5-methyl-6- (5- (4-pyridylamino) indol-3-yl-3 (2H) pyridazinone Example 15

4,5-dihydro-5-methyl-6- (4- (4-pyridyloxy) phenyl) -3 (2H) pyridazinone

 M.p .: 176-177 ° C

Example 16 4,5-Dihydro-5-methyl-6- (4- (2-pyridyloxy) phenyl) -3 (2H) pyridazinone

Example 17 4,5-Dihydro-5-methyl-6- (4- (2-thiazolylsulfonyl) phenyl) -3 (2H) pyridazinone

M.p .: 168-172 ° C

The 4,5-dihydro-3 (2H) -pyridazinone derivatives according to the invention show a therapeutically particularly valuable combination of antithrombotic, cardiotonic and antianginal effects with low blood pressure reduction even in low doses. Tables 1 to 3 below show the activity data of compounds according to the invention obtained in various in vivo and in vitro tests.

The values of the venous thrombosis protection given in Table 1 were determined on the vena cava of the rat according to the method of Kumada et al, (Thrombosis Res. 18, 189-203 (1980)), that of the arterial thrombosis protection on the carotid artery of rabbits a modification (Just, 23rd Angiological Symposium, Kitzbühel, 1988, in press) of Harbauer's method ("Attempts to develop a standardized venous thrombosis model in rabbits", 17th Angiological Symposium in Kitzbühel, 1982). The values of the inhibition of platelet aggregation given in Table 2 were determined on human platelets in vitro according to the method of Born (J. Physiol. 162, 67 P (1962)) using arachidonic acid, thrombin, collagen, PAF (platelet activating factor) and of

 Adenosine diphosphate (ADP) determined as an aggregating agent.

To demonstrate the antianginal effect of the compounds according to the invention, tests were carried out on bastard dogs of both sexes in pentobarbital anesthesia (30 to 40 mg / kg iv) or in urethane-chloralose anesthesia (3 ml / kg urethane-chloralose mixture iv = 20 mg / kg Chloralose and 250 mg / kg urethane). The animals were ventilated with a Bird Mark 7 respirator. The final expiratory carbon dioxide content (measured with an ultraviolet absorption recorder) was between 4.5 and 5% by volume. During the entire experiment, the animals with pentobarbital anesthesia received a continuous infusion of pentobarbital IV. = 4 mg (in 6 ml) / kg / h to ensure a constant depth of anesthesia. The animals with urethane chloralose received no continuous infusion. The infusion was given through the cephalic vein. After the test animal had been prepared, it was waited approx. 1 h until all hemodynamic parameters had set (steady state). Then the actual experiment was started.

Systolic and diastolic blood pressure were measured peripherally in the femoral artery using a Statham pressure transducer. A Millar-Tip catheter pushed into the left ventricle via the carotid artery delivered the signal for the left ventricular end-diastolic pressure (= LVEDP) and the heart rate (= HF). In addition, the rate of pressure increase in the left

Ventricle determined as a measure of the contractility of the heart. The results obtained are shown in Table 3.

The reference substance listed in the tables is amrinone.

Table 1

Influencing experimental thrombosis in vivo

Compound dose thrombosis protection (%) of the example mg / kg i.p venous + arterial ++ No. (rat) (rabbit)

1 10 67 * 50 *

 2 3 - 63 *

 10 64 *

 3 10 52 * 75 *

 5 10 77 * 50 *

 6 10 55 * 0

 7 10 69 * -

8 10 65 * 43

 15 10 75 * 38

 Comparative substance 10 23 25

 30 36 * -

+ The values indicate the percentage reduction in the thrombus protein content; the mean values of 8 treated and 8 control animals were compared with each other in the Student's t-test.

++ The values give the percentage of inhibition of the

 Thrombosis incidence of a group of 8 treated animals versus 8 control animals. Statistical comparison: Fisher exact test.

At least p <0.05 Table 2

Inhibition of platelet aggregation in vitro

Ic ₅₀ , μmol / 1

Platelet agonist

 Compound A B C D E of Example No.

 1 4 30 7 20 40

2 0, 4 10 0.8 4 5

3 6 - - 30 40

4 5 - - - -

5 1 20 5 3 8

6 5 10 1 6 -

7 4 30 10 10 20

8 20 - - - -

10 4 200 15 - -

15 0.2 - - - -

17 5 40 15 - -

Comparative substance 9> 100 - 55 100

In the table above mean:

 A: induced by 0.36 mmol / 1 arachidonic acid

 B: by 10 (imol / 1 ADP (adenosine diphosphate)

 induced

C: by 0.2 - 0.4 N.J.H. (National Institutes of Health)

Units / ml thrombin induced

D: by 0.1 μmol / 1 PAF (platelet activating factor)

 induced

E: induced by 5 μg / ml collagen.

The pre-incubation of platelets with test substance at 37 ° C was 2 minutes. Table 3

Cardiovascular screening in the normotonic, anesthetized dog

VerbinDose ΔBd (mmHg) ΔLVEDP Δ HF ΔdP / dt dung des (mg / kg) syst.diast. (mmHg) (S / min) (mmHg / s) example

No.

 1 1.0 i.d. -5 -8 -4 +20 +2200

2 0.3 i.d. -15 -20 -2 +15 +2200

3 1.0 i.v. -25 -20 -4 +15 +1375

5 1.0 i.d. -30 -15 -4.5 +20 +850

6 0.3 i.d. -35 -20 -5 +20 +600

Comparative substance 1.0 i.v. -10 -15 -1 +15 +750

In the table above mean:

 ΔBd = change in systolic and diastolic

 Blood pressure

ΔLVEDP = change in left ventricular end-diastolic pressure

ΔHF = change in heart rate in bpm =

 Beats / min

ΔdP / dt = change in the rate of pressure rise

 in the left ventricle as a measure of the

Contractility of the heart

Claims

Claims 4,5-dihydro-3 (2H) -pyridazinones of the general formula I.

 wherein  R is hydrogen, alkyl having 1 to 3 carbon atoms or Hydroxymethyl R ^{1 is} a phenyl radical of the formula

or an indolyl radical of the formula

R ² pyridyl, thiazolyl, imidazolyl, which have a  Oxygen, nitrogen or sulfur atom or via a sulfinyl or sulfonyl group with the phenyl or Indolyl radical are linked, or imidazolyl, the thiazolyl and imidazolyl radicals optionally being substituted by alkyl having 1 to 3 carbon atoms, halogen, nitro, amino, alkylcarbonylamino having 1 to 3 carbon atoms in the alkyl part, mono- or dialkylamino having 1 to 3 carbon atoms per alkyl part or alkoxycarbonylamino can be substituted with 1 to 3 carbon atoms in the alkyl part, R ^{3 is} hydrogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, hydroxy or Halogen and R ^{4 is} hydrogen, alkyl having 1 to 5 carbon atoms, Alkylcarbonyl with 1 to 4 carbon atoms in the alkyl part, phenylcarbonyl, alkoxycarbonyl with 1 to 4 carbon atoms in the alkyl part or phenalkoxycarbonyl with 1 to 4 carbon atoms in the alkyl part mean, and their pharmaceutically acceptable acid addition salts which can be prepared, where in the case where R ^{1 is} a phenyl radical, R ² cannot be a pyridyl or imidazolyl radical linked via a nitrogen atom. 2. 4,5-dihydro-3 (2H) -pyridazinone according to claim 1, characterized in that R is hydrogen, methyl or hydroxymethyl. 3. 4,5-dihydro-3 (2H) -pyridazinones according to claim 1 and / or 2, characterized in that R ³ and / or R ^{4 are} hydrogen 4. 4,5-dihydro-3 (2H) -pyridazinones according to one or more of claims 1 to 3, characterized in that an indolyl radical for R ^{1 is} linked via the 3-position to the pyridazinone. 5. 4,5-dihydro-3 (2H) -pyridazinones according to one or more of claims 1 to 4, characterized in that the radical R ² with a phenyl radical for R ¹ above its 4-position and with one for R ¹ standing indolyl radical is linked via its 5-position. 6. 4,5-dihydro-3 (2H) -pyridazinones according to one or more of claims 1 to 5, characterized in that the thiazolyl and imidazolyl radicals are unsubstituted or substituted by methyl or nitro. 7. 4,5-dihydro-3 (2H) -pyridazinones according to one or more of claims 1 to 6, characterized in that R ² 2-pyridylmercapto, 3-pyridyloxy, 4-pyridylamino, 2-thiazolylmercapto, 5-nitro-thiazol-2-yl-amino, imidazol-1-yl, 1-methyl-imidazol-2-yl-mercapto, 1-methyl- means imidazol-2-yl-sulfinyl or 1-methyl-imidazol-2-yl-sulfonyl, where the pyπdylamino radical cannot be bound to a phenyl radical representing R ¹ . 8. Process for the preparation of 4,5-dihydro-3 (2H) -pyridazinones of the general formula I

 wherein  R is hydrogen, alkyl having 1 to 3 carbon atoms or Hydroxymethyl R ^{1 is} a phenyl radical of the formula

or an indolyl radical of the formula

R ² pyridyl, thiazolyl, imidazolyl, which have a  Oxygen, nitrogen or sulfur atom or via a sulfinyl or sulfonyl group with the phenyl or Indolyl radical are linked, or imidazolyl, the thiazolyl and imidazolyl radicals optionally being alkyl with 1 to 3 carbon atoms, halogen, nitro, amino, alkylcarbonylamino with 1 to 3 carbon atoms in the alkyl part, mono- or dialkylamino with 1 to 3 carbon atoms per alkyl part or substituted alkoxycarbonylamino with 1 to 3 carbon atoms in the alkyl part could be, R ^{3 is} hydrogen, alkyl having 1 to 4 carbon atoms, Alkoxy with 1 to 4 carbon atoms, hydroxy or Halogen and R ^{4 is} hydrogen, alkyl having 1 to 5 carbon atoms, Alkylcarbonyl with 1 to 4 carbon atoms in the alkyl part, Phenylcarbonyl, alkoxycarbonyl with 1 to 4 carbon atoms in the alkyl part or phenalkoxycarbonyl with 1 to 4 carbon atoms in the alkyl part mean, where, in the case that R ^{1 is} a phenyl radical, R ^{2 is} not a linked via a nitrogen atom May be pyridyl or imidazolyl, characterized in that a carboxylic acid or a carboxylic acid derivative of the general formula II

wherein R and R ^{1 have} the meanings given above and X represents -COOH, -COC1, -CO-O-CO-R ⁵ , -COOR ⁵ or -CN, where R ⁵ denotes an organic radical, is reacted with hydrazine. 9. Use of a 4,5-dihydro-3 (2H) -pyridazinone of the general formula I

wherein  R is hydrogen, alkyl having 1 to 3 carbon atoms or Hydroxymethyl R ^{1 is} a phenyl radical of the formula

or an indolyl radical of the formula

R ² pyridyl, thiazolyl, imidazolyl, which have a  Oxygen, nitrogen or sulfur atom or via a sulfinyl or sulfonyl group with the phenyl or Indolyl radical are linked, or imidazolyl, the thiazolyl and imidazolyl radicals optionally being substituted by alkyl having 1 to 3 carbon atoms, halogen, nitro, amino, alkylcarbonylamino having 1 to 3 carbon atoms in the alkyl part, mono- or dialkylamino having 1 to 3 carbon atoms per alkyl part or alkoxycarbonylamino can be substituted with 1 to 3 carbon atoms in the alkyl part, R ^{3 is} hydrogen, alkyl with 1 to 4 carbon atoms, Alkoxy with 1 to 4 carbon atoms, hydroxy or  Halogen and R ^{4 is} hydrogen, alkyl having 1 to 5 carbon atoms, alkylcarbonyl having 1 to 4 carbon atoms in the alkyl part, Phenylcarbonyl, alkoxycarbonyl with 1 to 4 carbon atoms in the alkyl part or phenalkoxycarbonyl with 1 to 4 Carbon atoms in the alkyl part mean, or a pharmaceutically acceptable acid addition salt thereof which can be prepared, where in the case where R ^{1 is} a phenyl radical, R ² cannot be a pyridyl or imidazolyl radical linked via a nitrogen atom, for the preparation of a medicament for the treatment and prevention of diseases of the heart and of Circulatory system including thromboembolic disorders. 10. Pharmaceutical preparation, characterized in that it contains one or more of the 4,5-Dihydro¬3 (2H) -pyridazinones of the general formula I as active ingredient

wherein  R is hydrogen, alkyl having 1 to 3 carbon atoms or Hydroxymethyl R ^{1 is} a phenyl radical of the formula

or an indolyl radical of the formula

R ² pyridyl, thiazolyl, imidazolyl, which have a Oxygen, nitrogen or sulfur atom or via a sulfinyl or sulfonyl group with the phenyl or Indolyl radical are linked, or imidazolyl, the thiazolyl and imidazolyl radicals optionally being substituted by alkyl having 1 to 3 carbon atoms, halogen, nitro, amino, alkylcarbonylamino having 1 to 3 carbon atoms in the alkyl part, mono- or dialkylamino having 1 to 3 carbon atoms per alkyl part or alkoxycarbonylamino can be substituted with 1 to 3 carbon atoms in the alkyl part. R ^{3 is} hydrogen, alkyl having 1 to 4 carbon atoms, Alkoxy with 1 to 4 carbon atoms, hydroxy or  Halogen and R ^{4 is} hydrogen, alkyl having 1 to 5 carbon atoms, Are alkylcarbonyl having 1 to 4 carbon atoms in the alkyl part, phenylcarbonyl, alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl part or phenalkoxycarbonyl having 1 to 4 carbon atoms in the alkyl part, or a pharmaceutically acceptable acid addition salt thereof which can be prepared, in the case where R ^{1 is} a phenyl radical, R ² cannot be a pyridyl or imidazolyl radical linked via a nitrogen atom, together with a pharmaceutically acceptable carrier and optionally pharmaceutically acceptable  Contains additives and optionally one or more other pharmacological active ingredients.