DE3826855A1 - 4,5-DIHYDRO-3 (2H) -PYRIDAZINONE, PROCESS FOR THEIR PREPARATION 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 R<1> denotes a phenyl residue of formula (II) or an indolyl residue of formula (III), R<2> 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, R<3> being hydrogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, hydroxy or halogen, and R<4> 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 R<1> is a phenyl residue, R<2> cannot be a pyridyl or imidazolyl residue linked via a nitrogen atom, are useful pharmacological active ingredients.

Description

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

wherein

R is hydrogen, alkyl of 1 to 3 carbon atoms or hydroxymethyl
R¹ is a phenyl radical of the formula

or an indolyl radical of the formula

R² pyridyl, thiazolyl, imidazolyl, which are linked via an oxygen, nitrogen or sulfur atom or via a sulfinyl or sulfonyl group with the phenyl or indolyl radical, or imidazolyl, wherein the thiazolyl and Imidazolylreste optionally substituted by alkyl having 1 to 3 Carbon atoms, halogen, nitro, amino, alkylcarbonylamino having 1 to 3 carbon atoms in the alkyl moiety, mono- or dialkylamino having 1 to 3 carbon atoms per alkyl moiety or alkoxycarbonylamino having 1 to 3 carbon atoms in the alkyl moiety,
R³ is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen and
R⁴ is hydrogen, alkyl having 1 to 5 carbon atoms, alkylcarbonyl having 1 to 4 carbon atoms in the alkyl moiety, phenylcarbonyl, alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety or phenalkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety, and their producible pharmaceutically acceptable acid addition salts, wherein in the case where R¹ is a phenyl radical, R² can not be a pyridyl or imidazolyl radical linked via a nitrogen atom.

The invention also relates to processes for the preparation of Compounds of the general formula I and their use as pharmacologically active substances.

R is preferably hydrogen, methyl or hydroxyme thyl.

The pyridyl, thia Zolyl and Imidazolylreste can over all ring carbons be linked atoms, imidazolyl also via a Ring nitrogen atom.

Thiazolyl residues are preferred over the 2-position ver attaches imidazolyl residues via the 1- or 2-position. The Thiazolyl and imidazolyl radicals are preferably unsubstituted substituted or substituted by methyl or nitro.

Particularly preferred radicals R 2 are the 2-pyridylmercapto the 3-pyridyloxy, the 4-pyridylamino, the 2-thiazolyl mercapto, the 5-nitro-thiazol-2-yl-amino-imidazole 1-yl, the 1-methyl-imidazol-2-yl-mercapto, the 1-Me thyl-imidazol-2-yl-sulfinyl and the 1-methyl-imidazole 2-yl-sulfonyl radical, wherein the 4-pyridylamino radical is not may be bonded to a standing phenyl for R¹.

The radicals R² can with all ring carbon atoms of a be linked to R¹ standing phenyl. Prefers  a radical R² is bound to the 4-position of the phenyl radical the.

On an indolyl radical R¹, the radicals R² linked to all carbon atoms of the six-membered ring his. Preferred is a link at the 5-position.

An indolyl radical R¹ may be substituted by the 2- or be connected via the 3-position with the pyridazinone. The 3-position is preferred.

For R³ standing halogen is preferably fluorine, chlorine or bromine.

R³ and R⁴ are preferably hydrogen.

The compounds of general formula I are in Analogy to the production of others 4,5-dihydro-3 (2H) -pyridazinone by reaction of a Carboxylic acid or a carboxylic acid derivative of general formula II

wherein R and R¹ have the meanings given above and X is -COOH, -COCl, -CO-O-CO-R⁵, -COOR⁵ or -CN, where R⁵ is an organic radical, accessible with hydrazine.

The organic radical R⁵ is preferably one Alkyl radical having 1 to 4 carbon atoms. Especially R⁵ is preferably methyl or ethyl.  

The hydrazine may also be in the form of the hydrate or a Salt can be used in the presence of a base.

The reaction is conveniently in the liquid phase which usually involves the presence of a inert solvent or diluent required is.

Suitable solvents or diluents are for. B. Alko hole, especially those with 1 to 6 carbon atoms, such as. As methanol, ethanol, i- and n-propanol, i-, sec- and tert-butanol, n-, i-, sec-, tert-pentanol, n-hexanol, cyclo pentanol, cyclohexanol; Ether, in particular those having 2 to 8 carbon atoms in the molecule, such as. For example, 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; Polyether, such as. B. Polyethylenglyko le with a molecular weight up to about 600; Oligoethylene glycol dimethyl ether, such as. Pentaglyme; Crown ether, ie cyclic polymers of ethylene glycol of the formula (-OCH₂CH₂) _p , where p is a number z. B. from 4 to 10, wherein one or more benzene rings may be condensed on the ring and; Aza- and thia-crown ethers (coronand-amines and coronand-sulfides); Glycols and partially etherified glycols, such as. As ethylene glycol, propylene glycol, trimethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol mono ethyl ether; aliphatic hydrocarbons, such as. For example, 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, chlorine benzene, dichlorobenzene; Nitriles, such as. For example acetonitrile; Amides, such as Dimethylformamide, N-methyl-pyrrolidone; Sulfoxides, such as. B. dimethyl sulfoxide; Water. It is also possible to use mixtures of different solvents or diluents.

The reaction of the compounds of general formula II with hydrazine takes place advantageously at temperatures between room temperature and boiling point of the used Solvent or diluent.

The compounds of general formula II can be manufacture by various methods known per se len, such as B. by acylation of the compounds R-H with R-maleic anhydride and subsequent hydrogenation of obtained unsaturated compound, for. B. after the im J. Med. Chem. 17, 273 et seq., (1974), further by Mannich reaction of ketones of the formula R¹-CO-CH₂-R with formaldehyde / dimethylamine to Mannich bases R¹-CO-CH (R) -CH₂-N (CH₃) ₂ and subsequent exchange of the Aminrestes, z. B. on the quaternary iodine compound against Cyan, wherein compounds R¹-CO-CH (R) -CH₂-CN and ge if desired, from this by hydrolysis compounds R¹-CO-CH (R) -CH₂-COOH can be obtained. This reaction sequence ge is z. As described in J. Org. Chem. 38, 4044 et seq., (1973).

The compounds of general formula II with X = CN read z. B. also by acylation of compounds of the formula R¹-H with 2-R-3-chloro-propionic acid chloride according to DE-OS 33 28 286 produce, wherein first compounds of the formula R¹-CO-CH (R) -CH₂-Cl are formed, in which the Chlorine z. B. with NaCN or KCN is replaced by CN.

Compounds of the general formula II with X = CN in the reaction with hydrazine directly the compounds  the general formula I, when the reaction in aqueous Medium or in the presence of water is performed. When carrying out the reaction in anhydrous medium Initially, the ketimines of the compounds of general formula I, which then be in be way known to the compounds of the general formula I be hydrolyzed.

Starting compounds of the general formula II where X = CN can be easily according to known methods in Starting compounds of general formula II with ande convert meanings of X.

Starting compounds of the general formula II where X = COOR⁵ can easily be prepared analogously to J. Org. Chem. 52, 304 (1987) by alkylation of the corresponding ketones with Bromoacetic acid esters produce.

Another possibility is the implementation of verbin R¹-H with dialkylamides of the general formula III

wherein R⁵ has the abovementioned meaning and R⁶ for Alkyl, preferably methyl, is, according to the Vilsmeier method (analogous to J. Org. Chem. 25, 2049 (1960).

The compounds of general formula III can be easily prepared by methods known in the literature from the activated carboxylic acid or the carboxylic acid chloride with secondary amines.

Compounds of general formula II with X = COOH can by reacting the corresponding halogenated ketones with malonic esters or Meldrum acid (2,2-dimethyl-1,3-di- oxan-4,6-dione) after saponification and decarboxylation be kept (eg FR 25 24-463).

In an alternative method can be inventive according to the compounds of general formula I by Reaction of hydroxy, amino or mercapto-substitu Phenylpyridazinonen with heterocycles, which a Have leaving group, in a nucleophilic Substi tion reaction received.

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

If the compounds of the general formula I are basic Containing radicals, they form acid additions with acids salts. To form such acid addition salts are inorganic and organic acids suitable. suitable Acids are, for example: hydrogen chloride, bromine water fabric, naphthalenedisulfonic acids, in particular 1,5-naphtha lindisulfonic acids, phosphoric, nitric, sulfuric, oxalic, Milk, wine, vinegar, salicylic, benzoin, ants, Pro pionine, pivaline, diethylacetic, malonic, succinic, pime lin, fumaric, maleic, malic, sulfamic, phenylpropionic, Glucone, ascorbic, isonicotin, methanesulfonic, p-toluene sulfonic, citric or adipic acid. Pharmacologically Acceptable acid addition salts are preferred. The acid addition salts can be added as usual by combining the Components, suitably in a suitable Lö or diluents.

Conveniently, while the connection of the general my formula I dissolved in an organic solvent  and added with a solution of the desired acid. So For example, the hydrochlorides of the Invention pyridazinones corresponding to the general formula I characterized to be obtained that the free compound in alcohol is dissolved and the alcoholic solution with an equi valent amount of a solution of hydrogen chloride in Diethyl ether is added.

The 4,5-dihydro-3 (2H) -pyridazinonderi invention vate of general formula I and their pharmacological acceptable salts show pronounced antithrombotic, antiplatelet, antianginal, cardio tone and hypotensive effects. They are suitable Excellent for the treatment and prevention of diseases including the heart and the circulatory system thromboembolic disorders. They show a ausge drew efficacy in various tests, such as z. B. Platelet aggregation according to Born, Nature 194, S. 927, (1961); Arachidonic acid lethality in rabbits, Science 193, p. 1085, (1974); arterial and venous Rabbit thrombosis prevention, favorable hemodyna Mixed profile after per os application on the awake dog. The exam in the mentioned and a number of others Tests show that the compounds of the invention of general formula I surprisingly at low Toxicity a particularly favorable effect profile aufwei That's far superior to the known compounds is.

The 4,5-dihydro-3 (2H) -pyridazinone of the invention general formula I and their pharmaceutically acceptable Acid addition salts can therefore be used on humans as Heilmit alone, in mixtures with each other or in Be administered form of pharmaceutical preparations, which allowed enteral or parenteral administration  and that as an active ingredient an effective dose at least one compound of general formula I or an acid addition salt thereof, besides usual pharma Zeutisch immaculate carriers and additives, enthal th.

The remedies can be administered orally, z. In the form of pills, Ta blots, coated tablets, dragees, hard and soft gelatin capsules, granules, solutions, syrups, elixirs, emulsions ions or suspensions or aerosol mixtures be enough. The administration can also be rectal, z. In the form of suppositories, or parenterally, e.g. In Form of injection solutions, or percutaneously, e.g. B. in shape ointments or tinctures.

The pharmaceutical preparations are known per se ter way, z. B. by stretching the active ingredients with pharmaceutically acceptable inorganic and / or organi made of carriers and / or solvents. The pharmaceutical preparations can also be two or more rere compounds of general formula I or their pharmacologically acceptable acid addition salts Normally, the pharmaceutical prep prepare the therapeutically active compounds or the Mixture of therapeutically active compounds in one Concentration of about 0.5 to 90 wt .-% of the total mixture.

For the production of pills, tablets, coated tablets, hard and soft gelatin capsules or granules can be as Carriers z. B. natural minerals such. B. valley kum, clays, kaolins, chalk, synthetic rocks flours, such as As silicates, silica, sugars, such as. B. Invert, grape, milk, malt, fruit or pipe sugar, starch or starch derivatives, such as. Corn starch, Potato starch, gelatin, use. As carriers  for soft gelatin capsules and suppositories are z. B. Fet te, waxes, paraffins such. B. petroleum fractions, natural Liche oils, such as. Peanut or sesame oil, hydrogenated oils, semi-solid and liquid polyols, etc. suitable. As a carrier materials for the production of solutions and syrups z. As water, alcohols, Saccachrose, invert sugar, Glucose, polyols, etc. As excipients for the Her Position of injection solutions are suitable for. Water, Alcohols, Glycols, Glycerin, Polyols, Vegetable Oils Etc.

The pharmaceutical preparations can be prepared in a known manner In addition to the active ingredients and carriers nor additives, such as z. Fillers, stretch, blast, tie, slip, mesh, Stabilizing, emulsifying, dispersing, preserving flavoring, sweetening, coloring, flavoring or flavoring, Thickening, diluents, aggregates, buffer sub punch, solvent, co-solvent or Solver or means for obtaining a depot effect, as well as salts for altering the osmotic Contain printing, coating or antioxidants.

The daily dosage can be within wide limits, z. From 0.01 mg / kg body weight to 20 mg / kg body weight vary per weight and is in each case the to adapt to individual circumstances.

Depending on the type of application you move within the said dosage range, in a known manner the take into account different absorption conditions gen. So one chooses with intravenous administration a Do more in the lower part of the indicated dosage range. In general, intravenous appli cation daily amounts of about 0.01 to 1 mg / kg, before preferably about 0.05 to 0.5 mg / kg body weight to Er  to deliver effective results. For oral Application is the daily dosage usually about 0.1 to 5 mg / kg, preferably 0.1 to 2 mg / kg of Kör pergewicht. If necessary, it may be necessary to deviate from the stated amounts. At the time of administration For larger quantities it is recommended to use the day dose into several, z. For example, two or three over the day distribute distributed partial administration.

In addition to the compounds of the general formula I, the pharmaceutical preparations may also contain one or more other pharmaceutically active substances, for example circulation-promoting agents such as dihydroergocristine, nicergoline, buphenin, nicotinic acid and its esters, pyridylcarbinol, bencyclan, cinnarizine, naftidro furyl, Raubasin and vincamine; positively inotropic compounds such as digoxin, acetyldigoxin, metildigoxin and lana to glycosides; Coronary dilators such as carbocromen, dipyramido, nifedipine and perhexiline; antianginal compounds such as isosorbide dinitrate, isosorbide mononitrate, glycerol trinitrate, molsidomine and verapamil; β- blockers such as propranolol, oxprenolol, atenolol, metoprolol and pen butolol, and oogenetic agents such as pirilinol.

The following examples illustrate the together tion of preparations of the 4,5-Dihy invention dro-3 (2H) -pyridazinone.

Example A tablets per tablet Active substance (finely ground) | 50 mg lactose 150 mg Cornstarch, white 230 mg polyvinylpyrrolidone 15 mg magnesium stearate  5 mg 450 mg

Example B injection Active ingredient | 4 mg sodium chloride 0.7 mg Water for injections ad 1 ml

Example C Rectal dosage form Active substance | 20 mg Suppository matrix 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. masking flavor q. s. Water desalted ad 100 ml

Example E active ingredient solutions Active substance | 8 mg polyethylene glycol 1.5 mg Glycofurol ad 4 ml diluent: @ Water for injection 6 ml

The following examples relate to the preparation of 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-methyl-butyric acid ethyl ester hydrochloride and 3.5 ml (0.07 mol) of hydrazine hydrate are dissolved in 150 ml of ethanol 8 Heated under reflux for hours. After cooling it will filtered off, chromatographed on a silica gel column (Eluent: 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: C₁₆H₁₅N₃OS (297.38)

Calc .: C, 64.6, H, 5.1, N, 14.1, O, 5.4;
Found: C, 64.3, H, 5.2, N, 13.9, O, 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- methyl-butyric acid ethyl ester and 2.4 g (0.047 mol) of hydra Carbohydrate is refluxed in 150 ml of ethanol for 5 hours heated river. After concentration is over a silica gel column chromatographed and from isopropanol / ether to crystallized.

Yield: 6.7 g (51% of theory)
Melting point: 139-141 ° C
Elemental analysis: C₁₆H₁₅N₃O₂ (281.32)

Calc .: C 68.3, H 5.4, N 14.9, O 11.4;
Found: C 68.1, H 5.4, N 15.1, O 11.3.

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

5.4 g (0.02 mol) of 4- (4- (3-pyridyloxy) -phenyl) -4-oxo butyric acid and 1.1 ml (0.023 mol) of hydrazine hydrate heated in 100 ml of isopropanol for 6 hours under reflux. After cooling, the product is filtered off with suction and converted from ethanol crystallized.

Yield: 3.2 g (60% of theory)
Melting point: 145-147 ° C
Elemental analysis: C₁₅H₁₃N₃O₂ (267.29)

Calc .: C, 67.4, H, 4.9, N, 15.7, O, 12.0;
Found: C 67.5, H 5.2, N 15.7, O 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) -carbonyl- γ- butyrolactone, 1 ml (0.02 mol) of hydrazine hydrate and 1 drop of glacial acetic acid are dissolved in 40 ml of ethanol and 5 ml of methylformamide for 30 minutes at room temperature and 17 h at 80 ° C stirred. After cooling, it is diluted with 300 ml of water, filtered off and recrystallized from isopropanol and methanol / methylene chloride (1: 1).

Yield: 1.5 g (50% d: theory)
Melting point: 186-189 ° C
Elemental analysis: C₁₆H₁₅N₃O₃ (297.31)

Calc .: C 64.6, H 5.1, N 14.11, O 16.1;
Found: C 64.6, H 5.4, N 14.11, O 16.0.

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

13 g (0.039 mol) of 4- (4- (2-thiazolylmercapto) -phenyl) -4- Ethyl oxo-3-methylbutyrate, 3.4 ml (0.07 mol) Hydrazine hydrate and 1 ml of glacial acetic acid are dissolved in 150 ml of ethanol Heated under reflux for 12 hours. After concentration is Stirred with a little methylene chloride, filtered off with suction and over a short silica gel acid (eluent: methylene chloride) Chromatograph.

Yield: 6.4 g (54% of theory)
Melting point: 164-165 ° C
Elemental analysis: C₁₄H₁₃N₃OS₂ (303.44)

Calc .: C 55.4, H 4.3, N 13.8, O 5.3, S 21.1
Found: C, 55.6, H, 4.6, N, 13.4, O, 5.0, S, 21.4.

Example 6 4,5-dihydro-5-methyl-6- (4- (5-nitrothiazole-2-yl) amino) - phenyl) -3 (2H) -pyridazinone

4.1 g (0.02 mol) of 6- (4-aminophenyl) -4,5-dihydro-5-methyl- 3 (2H) -pyridazinone and 2.1 g (0.01 mol) 2-bromo-5-nitro Thiazole be in 10 ml of dimethyl sulfoxide for 3 hours Room temperature stirred. After adding 100 ml of water is filtered off and recrystallized from dimethylformamide.

Yield: 2.9 g (88% of theory)
Melting point: <280 ° C
Elemental analysis: C₁₄H₁₃N₅O₃S (331.36)

Calc .: C 50.7, H 4.0, N 21.1, O 14.5, S 9.7;
Found: C 51.3, H 4.2, N 20.7, O 14.7, S 9.5.

Analogous to the examples given can be further produce compounds of the invention:

Example 7

4,5-dihydro-5-methyl-6- (4- (1-methyl-imidazol-2-yl mercapto) phenyl) -3 (2H) -pyridazinone.  

Example 8

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

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) indole-3-yl) -3 (2H) - pyridazinone.

Example 11

4,5-Dihydro-6- (5- (imidazol-1-yl) indole-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.

Claims (10)

1. 4,5-dihydro-3 (2H) -pyridazinone of the general formula I. whereinR is hydrogen, alkyl of 1 to 3 carbon atoms or hydroxymethyl
R¹ is a phenyl radical of the formula or an indolyl radical of the formula R² pyridyl, thiazolyl, imidazolyl, which are linked via an oxygen, nitrogen or sulfur atom or via a sulfinyl or sulfonyl group with the phenyl or indolyl radical, or imidazolyl, wherein the thiazolyl and Imidazolylreste optionally substituted by alkyl having 1 to 3 Carbon atoms, halogen, nitro, amino, alkylcarbonylamino having 1 to 3 carbon atoms in the alkyl moiety, mono- or dialkylamino having 1 to 3 carbon atoms per alkyl moiety or alkoxycarbonylamino having 1 to 3 carbon atoms in the alkyl moiety,
R³ is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen and
R⁴ is hydrogen, alkyl having 1 to 5 carbon atoms, alkylcarbonyl having 1 to 4 carbon atoms in the alkyl moiety, phenylcarbonyl, alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety or phenalkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety, and their producible, pharmaceutically acceptable acid addition salts, wherein, in the case where R¹ is a phenyl radical, R² can not be a nitrogen atom linked via a pyridyl or imidazolyl radical. 2. 4,5-dihydro-3 (2H) -pyridazinone according to claim 1, since characterized in that R is hydrogen, methyl or Hydroxymethyl means. 3. 4,5-dihydro-3 (2H) -pyridazinone according to claim 1 and / or 2, characterized in that R³ and / or R⁴ Mean hydrogen. 4. 4,5-dihydro-3 (2H) -pyridazinone after one or more Ren of claims 1 to 3, characterized in that a standing for R¹ Indolylrest on the 3-position with is linked to the pyridazinone. 5. 4,5-dihydro-3 (2H) -pyridazinone after one or more Ren of claims 1 to 4, characterized in that the radical R² with a standing for R¹ phenyl its 4-position and with a standing for R¹ Indolylrest linked via its 5-position. 6. 4,5-dihydro-3 (2H) -pyridazinone after one or more Ren of claims 1 to 5, characterized in that the thiazolyl and imidazolyl unsubstituted or are substituted by methyl or nitro. 7. 4,5-dihydro-3 (2H) -pyridazinone after one or more Ren of claims 1 to 6, characterized in that R²  2-pyridylmercapto, 3-pyridyloxy, 4-pyridylamino, 2-thia zolylmercapto, 5-nitro-thiazol-2-yl-amino, imidazol-1-yl, 1-methyl-imidazol-2-yl-mercapto, 1-methyl-imidazol-2-yl sulfinyl or 1-methyl-imidazol-2-yl-sulfonyl, wherein the pyridylamino radical is not one of R¹ may be bound to the phenyl radical. 8. A process for the preparation of 4,5-dihydro-3 (2H) -pyri dazinone of the general formula I. wherein
R is hydrogen, alkyl of 1 to 3 carbon atoms or hydroxymethyl
R¹ is a phenyl radical of the formula or an indolyl radical of the formula R² pyridyl, thiazolyl, imidazolyl, which are linked via an oxygen, nitrogen or sulfur atom or via a sulfinyl or sulfonyl group with the phenyl or indolyl radical, or imidazolyl, wherein the thiazolyl and Imidazolylreste optionally substituted by alkyl having 1 to 3 Carbon atoms, halogen, nickel, amino, alkylcarbonylamino having 1 to 3 carbon atoms in the alkyl moiety, mono- or dialkylamino having 1 to 3 carbon atoms per alkyl moiety or alkoxycarbonylamino having 1 to 3 carbon atoms in the alkyl moiety,
R³ is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen and
R⁴ is hydrogen, alkyl having 1 to 5 carbon atoms, alkylcarbonyl having 1 to 4 carbon atoms in the alkyl moiety, phenylcarbonyl, alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety or phenalkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety, in which case R¹ is a phenyl moiety R 2 can not be a pyridyl or imidazolyl radical linked via a nitrogen atom, since it is characterized in that a carboxylic acid or a carboxylic acid derivative of the general formula I wherein R and R¹ have the abovementioned meanings and X is -COOH, -COCl, -CO-O-CO-R⁵, -COOR⁵ or -CN, where R⁵ is 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 of 1 to 3 carbon atoms or hydroxymethyl
R¹ is a phenyl radical of the formula or an indolyl radical of the formula R² is pyridyl, thiazolyl, imidazolyl, which are linked via an oxygen, nitrogen or sulfur atom or via a sulfinyl or sulfonyl group to the phenyl or indolyl radical, or imidazolyl, where the thiazolyl and imidazolyl radicals, if appropriate, by alkyl having 1 to 3 Carbon atoms, halogen, nickel, amino, alkylcarbonylamino having 1 to 3 carbon atoms in the alkyl moiety, mono- or dialkylamino having 1 to 3 carbon atoms per alkyl moiety or alkoxycarbonylamino having 1 to 3 carbon atoms in the alkyl moiety,
R³ is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen and
R⁴ 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, or a producible, pharmaceutically acceptable acid addition salt thereof, wherein, when R¹ is phenyl, R² can not be pyridyl or imidazolyl linked through a nitrogen atom for the manufacture of a medicament for treating and preventing diseases of the heart and circulatory system including thromboembolic disorders. 10. Pharmaceutical preparation, characterized in that it contains as active ingredient one or more of the 4,5-dihydro-3 (2H) -pyridazinones of general formula I. wherein
R is hydrogen, alkyl of 1 to 3 carbon atoms or hydroxymethyl
R¹ is a phenyl radical of the formula or an indolyl radical of the formula R² pyridyl, thiazolyl, imidazolyl, which are linked via an oxygen, nitrogen or sulfur atom or via a sulfinyl or sulfonyl group with the phenyl or indolyl radical, or imidazolyl, wherein the thiazolyl and Imidazolylreste optionally substituted by alkyl having 1 to 3 Carbon atoms, halogen, nitro, amino, alkylcarbonylamino having 1 to 3 carbon atoms in the alkyl moiety, mono- or dialkylamino having 1 to 3 carbon atoms per alkyl moiety or alkoxycarbonylamino having 1 to 3 carbon atoms in the alkyl moiety,
R³ is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen and
R⁴ is hydrogen, alkyl having 1 to 5 carbon atoms, alkylcarbonyl having 1 to 4 carbon atoms in the alkyl moiety, phenylcarbonyl, alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety or phenalkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety, or a producible, pharmaceutically acceptable acid addition salt thereof in which, in the case where R¹ is a phenyl radical, R² may not be a pyridyl or imidazolyl radical linked via a nitrogen atom, together with a pharmaceutically acceptable carrier and optionally pharmaceutically acceptable additives and optionally one or more other pharmacologically active agents.