DE2708187A1 - Piperazinyl-(hydroxy)propyl derivs. of pyrido-pyridazine cpds. - with hypotensive activity and effects on heart rate and cardiac contraction - Google Patents

Abstract

Pyrido-pyridazine derivs. of formula (I) and their suitable acid addn. salts are new. In the formula, X is a nitrogen atom in the 1-, 2-, 3- or 4-position of the phenyl nucleus; R1 is 2-, 3- or 4-pyridyl opt. substd. by a halogen atom, or is phenyl opt. mono- or disubstd. by halogen, NO2, CF3, 1-3C alkyl and/or 1-3C alkoxy; R2 is H or OH; and R3 is H, halogen or 2-5C carbalkoxy. (I) have a hypotensive effect on arterial blood pressure. They also reduce heart rate and cardiac contractility. (I) are useful for the treatment of hypertension and coronary disease. Typical cpd. is 6- 3- 4-(2-pyridly)-1-piperazinyl -2-hydroxypropyl -pyrido 2,3-d pyridazin-5(6H)-one.

Description

The present invention relates to new pyrido-pyridazin-ones of the general formula I, and their physiologically compatible acid addition salts with inorganic or organic acids, which have valuable pharmacological properties, in particular central hypotensive effects, and processes for their preparation.

In the above general formula I means

N is a nitrogen atom in the 1-, 2-, 3- or 4-position of the phenyl nucleus,

R [deep] 1 is a 2-, 3- or 4-pyridyl group optionally substituted by a halogen atom or a phenyl group which can be mono- or disubstituted by a halogen atom, a nitro, trifluoromethyl, alkyl and / or alkoxy group, where the alkyl and alkoxy groups can each contain 1 to 3 carbon atoms,

R [deep] 2 is a hydrogen atom or the hydroxyl group and

R [deep] 3 is a hydrogen or halogen atom or a carbalkoxy group having 2 to 5 carbon atoms.

The present application thus relates to pyrido [2,3-d] pyridazin-5 (6H) -ones, pyrido [4,3-d] pyridazin-7 (6H) -ones, pyrido [3,4-d] pyridazin- 4 (5H) -ones and pyrido [3,2-d] pyridazin-8 (7H) -ones of the above general formula I.

For the alkyl and alkoxy radicals mentioned in the definition of the radical R [deep] 1, the meaning of the methyl, ethyl, propyl, methoxy, ethoxy or propoxy group comes in particular, for which in the definition of the radicals R [deep] 1 and R [deep] 3 halogen atoms mentioned the meaning of the chlorine or bromine atom and for the carbalkoxy group mentioned in the definition of the radical R [deep] 3 the meaning of the carbomethoxy, carbethoxy, carbopropoxy or carbobutoxy group into consideration.

Preferred compounds of general formula I are thus those in which

R [deep] 1 a 2-, 3- or 4-pyridyl group optionally substituted by a chlorine or bromine atom, a phenyl, methylphenyl, dimethylphenyl, chlorophenyl, trifluoromethylphenyl, nitrophenyl or methoxyphenyl group,

R [deep] 2 is a hydrogen atom or the hydroxyl group and

R [deep] 3 represents a hydrogen or chlorine atom or the carbomethoxy group. Here comes for R [deep] 1 in particular the meaning of 2-pyridyl, 3-pyridyl, 4-chloro-3-pyridyl, 4-pyridyl, phenyl, 2-methylphenyl, 2,6-dimethylphenyl , 2-chlorophenyl,

4-chloro-phenyl, 3-trifluoromethylphenyl, 2-nitrophenyl, 4-nitrophenyl, 2-methoxyphenyl or 4-methoxyphenyl groups are suitable.

The new pyridopyridazin-ones of the above general formula I are obtained according to the invention by the following process:

a) Implementation of a compound of the general formula II, in the

R [deep] 2, R [deep] 3 and N are as defined at the beginning,

X represents a nucleophilically exchangeable group such as a halogen atom or X together with R [deep] 2 represents an oxygen atom, with a piperazine derivative of the general formula III, in the

R [deep] 1 is as defined at the beginning.

The reaction is optionally carried out in a solvent, for example in isopropanol, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide, optionally in the presence of an acid-binding agent such as an alcoholate or an alkali hydroxide or alkali carbonate at temperatures between 50 and 200 ° C, but preferably at temperatures between 80 and 140 ° C. However, the reaction is particularly advantageously carried out using an excess of the piperazine derivative of the general formula III used as solvent.

b) reaction of a pyridine carboxylic acid of the general formula IV, in the

N and R [deep] 3 are as defined at the outset and

Y represents a halogen atom, or their reactive derivatives with a hydrazine derivative of the general formula V, in the

R [deep] 1 and R [deep] 2 are as defined at the outset.

The reaction is optionally carried out in a solvent, for example in methanol, ethanol, isopropanol, dioxane or dimethylformamide, optionally in the presence of an acid-binding agent such as pyridine, an alcoholate, an alkali hydroxide or alkali carbonate, at temperatures between 40 and 200 ° C, but preferably at temperatures between 60 and 140 ° C. c) Implementation of a pyrido-pyridazin-one of the general formula VI, in the

N and R [deep] 3 are as defined at the outset, or its alkali metal salts with a piperazine derivative of the general formula VII, in the

R [deep] 1 and R [deep] 2 are as defined at the outset and

Z represents a nucleophilically exchangeable group such as a chlorine, bromine or iodine atom.

The reaction is expediently carried out in a solvent such as isopropanol, dimethylformamide or dimethyl sulfoxide, preferably in the presence of a basic condensing agent such as sodium amide, potassium tert-butoxide, sodium hydroxide or sodium carbonate at temperatures between 0 and 100 ° C, but preferably at temperatures between 15 and 30 ° C . However, the reaction is particularly advantageously carried out in the melt.

The resulting new pyridopyridazin-ones of the general formula I can then, if desired, be converted into the physiologically acceptable salts with inorganic or organic acids. Examples of acids are hydrochloric acid, hydrobromic acid chemical acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, oxalic acid or maleic acid.

Some of the compounds of the general formulas II to VII used as starting materials are known from the literature or can be prepared by processes known from the literature.

For example, a pyridopyridazin-one of the general formula VI is obtained by reacting a corresponding o-dichloromethylene-pyridine-carboxylic acid with hydrazine hydrate in ethanol at reflux temperature (see DE Ames et al. In J. Chem. Soc. 1972, 709 ), by reacting the hydrazine of 3-ketocarboxylic acid-pyridine-2-carboxylic acid with concentrated sulfuric acid in methanol (see J. Matsuura et al. in Chem. Pharm. Bull 14, 1010 (1966), by subliming the abovementioned hydrazide (see p . Kamimoto et al. In Bull. Soc. Japan 40, 153 (1967)) or by reacting 3-formyl-pyridine-2-carboxylic acid with hydrazine hydrochloride (see F. Bottari in Gazz. Chim. Ital. 86, 990 (1956)), the pyridopyridazin-one obtained in this way can then be converted into a compound of the general formula II by reaction with a 1-chloro-3-prompropane or epibromohydrin.

A pyridopyridazin-one of the general formula VI can also be obtained by reacting a corresponding o-pyridine-dicarboxylic acid with acetic anhydride and subsequent reaction with hydrazine hydrate corresponding dichloro compound, which in turn is then partially hydrolyzed and then dehalogenated with palladium / carbon (see Chem. Pharm. Bull 13, 586 (1965) and ibid 17, 2263 (1969)).

A pyridine-carboxylic acid of the general formula IV is obtained, for example, by halogenating a corresponding o-acetomethyl-pyridine-carboxylic acid in the presence of an alkali metal hydroxide.

As already mentioned at the beginning, the new pyridopyridazin-ones of the general formula I and their physiologically compatible acid addition salts with inorganic and organic acids have valuable pharmacological properties, in addition to a reduction in the heart rate and the contractility of the heart, in particular a hypotensive effect on arterial blood pressure .

For example, the connections were

A = 6- [3- [4- (2-pyridyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [2,3-d] pyridazin-5 (6H) -one,

B = 6- [3- [4- (2-pyridyl) -1-piperazinyl] -propyl] -pyrido [2,3-d] pyridazine-5 (6H) -one-oxalate,

C = 6- [3- [4- (2-methoxyphenyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [2,3-d] pyridazin-5 (6H) -one.

D = 6- [3- [4- (2-methylphenyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [2,3-d] pyridazin-5 (6H) -one,

E = 6- [3- [4- (4-chlorophenyl) -1-piperazinyl] propyl] pyrido [2,3-d] pyridazine-5 (6H) -one oxalate,

F = 6- [3- [4- (Phenyl) -1-piperazinyl] -propyl] -pyrido [2,3-d] pyridazine-5 (6H) -one-oxalate,

G = 6- [3- [4- (3-chlorophenyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [2,3-d] pyridazin-5 (6H) -one,

H = 7- [3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl] pyrido [3,2-d] pyridazine-8 (7H) -one oxalate,

I = 7- [3- [4- (2-pyridyl) -1-piperazinyl] -propyl] -pyrido [3,2-d] pyridazine-8 (7H) -one-oxalate,

J = 5-carbomethoxy-7- [3- [4- (2-pyridyl) -1-piperazinyl] -propyl] -pyrido [3,2-d] pyridazine-8 (7H) -one-oxalate,

K = 7- [3- [4- (2-methylphenyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [3,2-d] pyridazin-8 (7H) -one,

L = 5-carbomethoxy-7- [3- [4- (4-chlorophenyl) -1-piperazinyl] propyl] pyrido [3,2-d] pyridazin-8 (7H) -one and

M = 5-carbomethoxy-7- [3- [4- (2-methoxyphenyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [3,2-d] pyridazine-8 (7H) -one oxalate

examined for their biological properties:

1.) Effect on the circulation:

The circulatory tests were carried out on dogs weighing 19-30 kg under chloralose-urethane-nembutal anesthesia (54 + 270 + 10 mg / kg i.v.). After opening the thorax in the 4th left intercostal space, the animals were ventilated with room air using a Harvard respirator.

The arterial blood pressure was determined in a carotid artery with a Statham pressure transducer, the heart rate was determined electronically from the sequence of the R-waves of the electrocardiogram, and the blood flow in the legs was determined by means of an electromagnetic flow meter inserted into the severed and cannulated femoral artery.

All parameters were registered by means of a direct writer. To inhibit coagulation, the animals received 10 mg / kg of sodium polyethylene sulfonic acid dissolved intravenously in 20% polydiol. The substances to be examined were administered intravenously to 4-6 dogs.

2.) Determination of the acute toxicity:

The acute toxicity of the substances to be examined was determined in mice (observation time: 14 days) after oral or intravenous administration. The LD [low] 50 was calculated from the percentage of animals that died after different doses within the observation period:

In addition, it should be noted that no toxic side effects occurred with any of the applied doses of the substances to be examined.

The new compounds of the general formula I are therefore particularly suitable for the treatment of hypertension and pre-sonar diseases.

For pharmaceutical use, the compounds of general formula I prepared according to the invention can optionally be incorporated into the customary pharmaceutical preparation forms such as tablets, coated tablets, powders, suspensions, solutions or suppositories in combination with other active substances. The single dose for adults is 50 to 250 mg.

The following examples serve to explain the invention in more detail; the chemical structure of the new compounds was ensured by means of IR, UV and NMR spectra:

example 1

6- [3- [4- (2-pyridyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [2,3-d] pyrimidin-5- (6H) -one

a) 6- (2,3-Epoxypropyl) -pyrido [2,3-d] pyridazin-5 (6H) -one

4.4 g (29.9 mM) of pyrido [2,3-d] pyridazin-5 (6H) -one are dissolved in 60 ml of dimethyl sulfoxide with warming. After cooling to room temperature, 4 g (29.9 mM + 20%) potassium tert-butoxide are added, the potassium salt precipitating after about 10 minutes. 5 ml of epibromohydrin are now added and the mixture is stirred until the reaction has ended. It is poured onto ice water and extracted with ethyl acetate. The extract is washed with 2N sodium hydroxide solution and water, dried over sodium sulfate, evaporated to dryness and the residue obtained is recrystallized from ethyl acetate / ether.

Yield: 3.9 g (65% of theory),

Melting point: 100-104 ° C.

b) 6- [3- [4- (2-Pyridyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [2,3-d] pyridazin-5 (6H) -one

3.9 g (19.2 mM) 6- (2,3-epoxypropyl) -pyrido [2,3-d] pyridazin-5 (6H) -one are mixed with 5 ml 1- (2-pyridyl) -piperazine 2 Heated to 120 ° C for hours. After cooling, the crude product obtained in this way is purified with a silica gel column (300 g) (particle size: 0.2-0.5 mm; eluent: chloroform / methanol = 19: 1) and crystallized from acetone / ether.

Yield: 4.6 g (66% of theory),

Melting point: 105-108 ° C.

C [deep] 19H [deep] 22N [deep] 6O [deep] 2 (366.4)

Calc .: C 62.27 H 6.05 N 22.94

Found: C 62.00 H 6.11 N 23.11

Example 2

6- [3- [4- (2-Pyridyl) -1-piperazinyl] propyl] pyrido [4,3, -d] pyridazin-7 (6H) -one

a) 6- (3-Chloropropyl) pyrido [4,3-d] pyridazin-7 (6H) -one

4.8 g (32.6 mM) of pyrido [4,3-d] pyridazin-7 (6H) -one are dissolved in 65 ml of dimethyl sulfoxide and treated with 4.4 g (32.6 mM + 20%) of potassium tert .butoxide and 5 ml of 1-bromo-3-chloropropane implemented analogously to Example 1a.

Yield: 5.7 g (78% of theory),

Melting point: 90-92 ° C (from ethyl acetate / ether).

C [deep] 10H [deep] 10N [deep] 3OCl (223.67)

Calc .: C 53.70 H 4.51 N 18.79

Found: C 53.55 H 4.47 N 18.30

b) 6- [3- [4- (2-Pyridyl) -1-piperazinyl] propyl] pyrido [4,3-d] pyridazin-7 (6H) -one

3 g (13.4 mM) 6- (3-chloropropyl) -pyrido [4,3-d] pyridazin-7 (6H) -one are mixed with 2.5 g (15.3 mM) 1- (2-pyridyl ) -piperazine heated to 120 ° C for 3 hours. The melt is taken up in chloroform and washed with concentrated ammonia. After evaporation to dryness, the crude product is purified with a silica gel column (200 g) (particle size: 0.2-0.5 mm; eluent chloroform / methanol = 50: 1 or = 19: 1) and crystallized from acetone / ether.

Yield: 1.3 g (27.6% of theory),

Melting point: 125-128 ° C.

C [deep] 19H [deep] 22N [deep] 6O (350.4)

Calc .: C 65.12 H 6.33 N 23.98

Found: C 65.00 H 6.45 N 23.70

Example 3

6- [3- [4- (2,6-Dimethylphenyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [2,3-d] pyridazin-5 (6H) -one

Prepared analogously to Example 1 from 6- (2,3-epoxypropyl) -pyrido [2,3, -d] pyridazin-5 (6H) -one and 1- (2-pyridyl) -piperazine.

Yield: 49% of theory,

Melting point: 164-167 ° C (as oxalate).

C [deep] 24H [deep] 29N [deep] 5O [deep] 6 (483.5)

Example 4

6- [3- [4- (3-Trifluoromethylphenyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [2,3-d] pyridazin-5 (6H) -one

Prepared analogously to Example 1 from 6- (2,3-epoxypropyl) -pyrido [2,3-d] pyridazin-5 (6H) -one and 1- (3-trifluoromethyl-phenyl) -piperazine.

Yield: 63.5% of theory

Melting point: 154-156 ° C.

C [deep] 21H [deep] 22N [deep] 5F [deep] 3O [deep] 2 (433.5)

Calc .: C 58.19 H 5.12 N 16.15

Found: C 58.20 H 5.23 N 16.35

Example 5

6- [3- [4- (2-Methoxyphenyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [2,3-d] pyridazin-5 (6H) -one

Prepared analogously to Example 1 from 6- (2,3-epoxypropyl) -pyrido [2,3-d] pyridazin-5 (6H) -one and 1- (2-methoxyphenyl) -piperazine.

Yield: 64% of theory,

Melting point: 155-158 ° C.

C [deep] 21H [deep] 25N [deep] 5O [deep] 3 (395.5)

Calc .: C 63.78 H 6.37 N 17.71

Found: C 63.10 H 6.52 N 17.50

Example 6

6- [3- [4- (2-Methylphenyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [2,3-d] pyridazin-5 (6H) -one

Prepared analogously to Example 1 from 6- (2,3-epoxypropyl) -pyrido [2,3-d] pyridazin-5 (6H) -one and 1- (2-methylphenyl) -piperazine.

Yield: 80% of theory,

Melting point: 138 ° C.

C [deep] 21H [deep] 25N [deep] 5O [deep] 2 (379.5)

Calc .: C 66.47 H 6.64 N 18.48

Found: C 66.80 H 6.66 N 18.87

Example 7

6- [3- [4- (3-Chlorophenyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [2,3-d] pyridazin-5 (6H) -one

Prepared analogously to Example 1 from 6- (2,3-epoxypropyl) -pyrido [2,3-d] pyridazin-5 (6H) -one and 1- (3-chlorophenyl) -piperazine.

Yield: 78% of theory,

Melting point: 127-130 ° C.

C [deep] 20H [deep] 22N [deep] 5O [deep] 2Cl (399.9)

Calc .: C 60.07 H 5.54 N 17.51 Cl 9.87

Found: C 59.90 H 5.53 N 16.98 Cl 9.97

Example 8

6- [3- [4- (2-Pyridyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [4,3-d] pyridazin-7 (6H) -one

Prepared analogously to Example 1 from 6- (2,3-epoxypropyl) -pyrido [4,3-d] pyridazin-7 (6H) -one and 1- (2-pyridyl) -piperazine.

Yield: 23% of theory,

Melting point: 142-144 ° C.

C [deep] 19H [deep] 22N [deep] 6O [deep] 2 (366.4)

Calc .: C 62.27 H 6.05 N 22.94

Found: C 62.35 H 6.01 N 22.95

Example 9

6- [3- [4- (3-Methylphenyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [4,3-d] pyridazin-7 (6H) -one

Prepared analogously to Example 1 from 6- (2,3-epoxypropyl) -pyrido [4,3-d] pyridazin-7 (6H) -one and 1- (3-methylphenyl) -piperazine.

Yield: 19.1% of theory,

Melting point: 102-106 ° C (as oxalate).

C [deep] 23H [deep] 27N [deep] 5O [deep] 6 (469.5)

Calculated: C 56.66 H 5.99 N 14.36

Found: C 56.10 H 6.07 N 14.13

Example 10

6- [3- [4- (Phenyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [4,3-d] pyridazin-7 (6H) -one

Prepared analogously to Example 1 from 6- (2,3-epoxypropyl) -pyrido [4,3-d] pyridazin-7 (6H) -one and phenylpiperazine.

Yield: 11% of theory,

Melting point: 125-129 ° C.

C [deep] 20H [deep] 23N [deep] 5O [deep] 2 (365.4)

Calc .: C 65.73 H 6.34 N 19.16

Found: C 66.05 H 6.58 N 18.95

Example 11

5- [3- [4- (2-pyridyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [3,4-d] pyridazin-4 [5H) -one

Prepared analogously to Example 1 from 5- (2,3-epoxypropyl) -pyrido [3,4-d] pyridazin-4 (5H) -one and 1- (2-pyridyl) -piperazine.

Yield: 11% of theory,

Melting point: 165-168 ° C.

C [deep] 19H [deep] 22N [deep] 6O [deep] 2 (366.4)

Calc .: C 62.27 H 6.05 N 22.94

Found: C 62.70 H 6.19 N 22.60

Example 12

5- [3- [4- (2-pyridyl) -1-piperazinyl] -2-hydroxypropyl] -7-chloropyrido [3,4-d] pyridazin-4 (5H) -one

Prepared analogously to Example 1 from 5- (2,3-epoxypropyl) -7-chloropyrido [3,4-d] pyridazin-4 (5H) -one and 1- (2-pyridyl) -piperazine.

Yield: 62.5% of theory

Melting point: 180-182 ° C.

C [deep] 19H [deep] 21N [deep] 6O [deep] 2Cl (400.9)

Calc .: C 56.92 H 5.28 N 20.96 Cl 8.85

Found: C 56.70 H 5.23 N 20.56 Cl 9.03

Example 13

6- [3- [4- (2-Pyridyl) -1-piperazinyl] propyl] pyrido [2,3-d] pyridazin-5 (6H) -one

1.2 g (5.8 mM) 2-dichloromethyl-pyridine-3-carboxylic acid and 1.6 g (5.8 mM + 20%) 3- [4- (2-pyridyl) -piperazinyl] -propyl-hydrazine are refluxed in 15 ml of ethanol for 6 hours. After cooling, 0.4 g of sodium carbonate in 8 ml of water are added and extracted with chloroform. The extract is evaporated to dryness and the residue is purified with a silica gel column (particle size: 0.2-0.5 mm; eluent chloroform / methanol = 19: 1).

Yield: 0.4 g (16% of theory),

Melting point: 204-206 ° C (as oxalate).

Example 14

6- [3- [4- (2-Pyridyl) -1-piperazinyl] propyl] pyrido [2,3-d] pyridazin-5 (6H) -one

Prepared analogously to Example 2 from 6- (3-chloropropyl) -pyrido [2,3, -d] pyridazin-5 (6H) -one and 1- (2-pyridyl) -piperazine.

Yield: 25% of theory,

Melting point: 205-207 ° C (as oxalate).

C [deep] 20H [deep] 24N [deep] 6O [deep] 5 (440.5)

Calc .: C 57.26 H 5.49 N 19.08

Found: C 57.30 H 5.61 N 18.94

Example 15

6- [3- [4- (4-Methoxyphenyl) -1-piperazinyl] propyl] pyrido [2,3-d] pyridazin-5 (6H) -one

Prepared analogously to Example 2 from 6- (3-chlorophenyl) pyrido [2,3-d] pyridazin-5 (6H) -one and 1- (4-methoxyphenyl) piperazine.

Yield: 25% of theory,

Melting point: 190-192 ° C (as oxalate).

C [deep] 23H [deep] 27N [deep] 5O [deep] 6 (469.5)

Calc .: C 58.84 H 5.79 N 14.92

Found: C 58.90 H 5.66 N 14.95

Example 16

6- [3- [4- (4-Chlorophenyl) -1-piperazinyl] propyl] pyrido [2,3-d] pyridazin-5 (6H) -one

Prepared analogously to Example 2 from 6- (3-chloropropyl) pyrido [2,3-d] pyridazin-5 (6H) -one and 1- (2-chlorophenyl) piperazine.

Yield: 28% of theory,

Melting point: 225-228 ° C (as oxalate).

C [deep] 22H [deep] 24N [deep] 5O [deep] 5Cl (473.9)

Calc .: C 55.75 H 5.10 N 14.78 Cl 7.48

Found: C 56.20 H 5.13 N 15.27 Cl 7.45

Example 17

6- [3- [4- (Phenyl) -1-piperazinyl] propyl] pyrido [2,3-d] pyridazin-5 (6H) -one

Prepared analogously to Example 2 from 6- (3-chloropropyl) pyrido [2,3-d] pyridazin-5 (6H) -one and phenylpiperazine.

Yield: 38% of theory,

Melting point: 209-211 ° C (as oxalate).

C [deep] 22H [deep] 25N [deep] 5O [deep] 5 (439.5)

Calc .: C 60.12 H 5.73 N 15.94

Found: C 61.00 H 5.81 N 16.28

Example 18

6- [3- [4- (3-Methylphenyl) -1-piperazinyl] propyl] pyrido [2,3-d] pyridazin-5 (6H) -one

Prepared analogously to Example 2 from 6- (3-chloropropyl) pyrido [2,3-d] pyridazin-5 (6H) -one and 1- (3-methylphenyl) piperazine.

Yield: 28% of theory,

Melting point: 165-167 ° C (as oxalate).

C [deep] 23H [deep] 27N [deep] 5O [deep] 5 (453.5)

Calculated: C 60.91 H 6.00 N 15.44

Found: C 61.00 H 6.26 N 16.02

Example 19

6- [3- [4- (2,6-Dimethylphenyl) -1-piperazinyl] propyl] pyrido [4,3-d] pyridazin-7 (6H) -one

Prepared analogously to Example 2 from 6- (3-chloropropyl) pyrido [4,3-d] pyridazin-7 (6H) -one and 1- (2,6-dimethylphenyl) piperazine.

Yield: 12% of theory,

Melting point: 140-142 ° C.

C [deep] 22H [deep] 27N [deep] 5O (377.5)

Calc .: C 70.00 H 7.21 N 18.55

Found: C 70.30 H 7.25 N 18.40

Example 20

6- [3- [4- (2-pyridyl) -1-piperazinyl] propyl] pyrido [4,3-d] pyridazin-7 (6H) -one

Prepared analogously to Example 2 from 6- (3-chloropropyl) pyrido [4,3-d] pyridazin-7 (6H) -one and 1- (2-pyridyl) piperazine.

Yield: 27.6% of theory

Melting point: 125-128 ° C

C [deep] 19H [deep] 22N [deep] 6O (350.4)

Calc .: C 65.12 H 6.38 N 23.98

Found: C 65.00 H 6.45 N 23.70

Example 21

6- [3- [4- (2-Methoxyphenyl) -1-piperazinyl] propyl] pyrido [4,3-d] pyridazin-7 (6H) -one

Prepared analogously to Example 2 from 6- (3-chloropropyl) pyrido [4,3-d] pyridazin-7 (6H) -one and 1- (2-methoxyphenyl) piperazine.

Yield: 12% of theory,

Melting point: 140-142 ° C.

C [deep] 21H [deep] 25N [deep] 5O [deep] 2 (379.5)

Calc .: C 66.47 H 6.67 N 18.47

Found: C 66.50 H 6.62 N 18.30

Example 22

5- [3- [4- (2-pyridyl) -1-piperazinyl] propyl] pyrido [3,4-d] pyridazin-4 (5H) -one

Prepared analogously to Example 2 from 5- (3-chloropropyl) pyrido [3,4-d] pyridazine and 1- (2-pyridyl) piperazine.

Yield: 25% of theory,

Melting point: 193-201 ° C (as oxalate).

C [deep] 21H [deep] 24N [deep] 6O [deep] 5 (440.5)

Calc .: C 57.26 H 5.49 N 19.08

Found: C 56.50 H 5.57 N 18.65

Example 23

6- [3- [4- (Phenyl) -1-piperazinyl] propyl] pyrido [2,3-d] pyridazin-5 (6H) -one

1.47 g (10 mM) of pyrido [2,3-d] pyridazin-5 (6H) -one are dissolved in 25 ml of dimethyl sulfoxide, 1.34 g (10 mM + 20%) of potassium tert-butoxide are added and up to stirred for the formation of the potassium salt (~ 10 minutes) at room temperature. 3.4 g (10 mM + 20%) 3- (4-phenyl-piperazinyl) -propyl-bromide are then added and the mixture is stirred until the reaction has ended. The reaction mixture is poured into ice water, extracted with ethyl acetate and the ethyl acetate extract is evaporated to dryness after washing with water and drying over sodium sulfate. After purification with a silica gel column (particle size: 0.2-0.5 mm; eluent chloroform / methanol = 19: 1), 1.2 g (35% of theory) of pure product are obtained from the crude product.

Yield: 1.2 g corresponds to 35% of theory,

Melting point: 208-210 ° C (as oxalate).

Example 24

4-Chloro-6- [3- [4- (2-pyridyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [4,3-d] pyridazin-7 (6H) -one

Prepared analogously to Example 1 from 4-chloro-6- (2,3-epoxypropyl) -pyrido [4,3-d] pyridazin-7 (6H) -one and 1- (2-pyridyl) -piperazine.

Yield: 10% of theory,

Melting point: 120-122 ° C.

C [deep] 19H [deep] 21N [deep] 6O [deep] 2 (400.9)

Calc .: C 56.92 H 5.28 N 20.96 Cl 8.85

Found: C 56.80 H 5.43 N 21.80 Cl 9.18

Example 25

5- [3- [4- (4-Methoxyphenyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [3,4-d] pyridazin-4 (5H) -one

Prepared analogously to Example 1 from 5- (2,3-epoxypropyl) -pyrido [3,4-d] pyridazin-4 (5H) -one and 1- (4-methoxyphenyl) -piperazine.

Yield: 7% of theory,

Melting point: 144-147 ° C.

C [deep] 21H [deep] 25N [deep] 5O [deep] 3 (395.5)

Calc .: C 63.78 H 6.37 N 17.71

Found: C 64.30 H 6.73 N 17.00

Example 26

5- [3- [4- (4-Chlorophenyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [3,4-d] pyridazin-4 (5H) -one

Prepared analogously to Example 1 from 5- (2,3-epoxypropyl) -pyrido [3,4-d] pyridazin-4 (5H) -one and 1- (4-chlorophenyl) -piperazine.

Yield: 3% of theory,

Melting point: 151-154 ° C (as hydrochloride).

C [deep] 20H [deep] 23N [deep] 5O [deep] 2Cl [deep] 2 (399.9)

Calc .: C 55.05 H 5.31 N 16.05 Cl 16.25

Found: C 55.25 H 5.11 N 15.33 Cl 17.32

Example 27

5- [3- [4- (3-Trifluoromethyl-phenyl) -1-piperazinyl] -propyl] -pyrido [3,4-d] pyridazin-4 (5H) -one

Prepared analogously to Example 2 from 5- (3-chloropropyl) pyrido [3,4-d] pyridazin-4 (5H) -one and 1- (3-trifluoromethylphenyl) piperazine.

Yield: 17% of theory,

Melting point: 183-186 ° C (as oxalate).

C [deep] 23H [deep] 24N [deep] 5O [deep] 5F [deep] 3 (507.48)

Calc .: C 53.48 H 4.87 N 13.56

Found: C 53.45 H 4.76 N 12.98

Example 28

5- [3- [4- (3-Chlorophenyl) -1-piperazinyl] propyl] pyrido [3,4-d] pyridazin-4 (5H) -one

Prepared analogously to Example 2 from 5- (3-chloropropyl) pyrido [3,4-d] pyridazin-4 (5H) -one and 1- (3-chlorophenyl) piperazine.

Yield: 45% of theory,

Melting point: 187-190 ° C (as oxalate).

C [deep] 22H [deep] 24N [deep] 5O [deep] 5Cl (473.9)

Calc .: C 53.70 H 5.32 N 14.23 Cl 7.20

Found: C 53.80 H 5.10 N 13.63 Cl 9.80

Example 29

5- [3- [4- (2-Methylphenyl) -1-piperazinyl] propyl] pyrido [3,4-d] pyridazin-4 (5H) -one

Prepared analogously to Example 2 from 5- (3-chloropropyl) pyrido [3,4-d] pyridazin-4 (5H) -one and 1- (o-tolyl) piperazine.

Yield: 49% of theory,

Melting point: 175-178 ° C.

C [deep] 23H [deep] 27N [deep] 5O [deep] 5 (453.5)

Calc .: C 59.72 H 6.00 N 15.14

Found: C 59.50 H 5.94 N 14.95

Example 30

6- [3- [4- (3-pyridyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [2,3-d] pyridazin-5 (6H) -one

Prepared analogously to Example 1 from 6- (2,3-epoxypropyl) -pyrido [2,3-d] pyridazin-5 (6H) -one and 1- (3-pyridyl) -piperazine.

Yield: 40% of theory,

Melting point: 167-168 ° C.

C [deep] 19H [deep] 22N [deep] 6O [deep] 2 (366.4)

Calc .: C 62.27 H 6.05 N 22.94

Found: C 61.70 H 6.03 N 22.90

Example 31

6- [3- [4- (4-Pyridyl) -1-piperazinyl] propyl] pyrido [4,3-d] pyridazin-7 (6H) -one

Prepared analogously to Example 2 from 6- (3-chloropropyl) pyrido [4,3-d] pyridazin-7 (6H) -one and 1- (4-pyridyl) piperazine.

Yield: 15% of theory,

Melting point: 208-210 ° C.

Example 32

7- [3- [4- (2-pyridyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [3,2-d] pyridazin-8 (7H) -one

a) 7- (2,3-Epoxypropyl) -pyrido [3,2-d] pyridazin-8 (7H) -one

1.8 g (12.2 mmol) of pyrido [3,2-d] pyridazin-8 (7H) -one are dissolved in 30 ml of dimethyl sulfoxide with warming. After cooling to room temperature, 1.65 g (12.2 mmol + 20%) potassium tert. butoxide added, the potassium salt precipitating after about 10 minutes. 1.8 ml of epibromohydrin are now added and the mixture is stirred until the reaction has ended. It is poured onto ice water and extracted with ethyl acetate. The extract is washed with 2N sodium hydroxide solution and water, dried over sodium sulfate and evaporated to dryness.

Yield: 0.3 g (12% of theory),

Melting point: 173-175 ° C (from ethyl acetate)

C [deep] 10H [deep] 9N [deep] 3O [deep] 2 (203.2)

Calc .: C 59.10 H 4.46 N 20.30

Found: C 58.60 H 4.44 N 20.60

b) 7- [3- [4- (2-Pyridyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [3,2, -d] pyridazin-8 (7H) -one

1.2 g (5.9 mmol) of 2,3- (epoxypropyl) -pyrido [3,2-d] pyridazin-8 (7H) -one are mixed with 0.96 g (5.9 mmol) of 1- (2 -Pyridyl) -piperazine melted at 120 ° C for 5 minutes. After cooling, the crude product obtained in this way is purified with a silica gel column (100 g) (particle size: 0.2-0.5 mm, eluent: chloroform / methanol = 19: 1) and crystallized from acetone.

Yield: 1.2 g (55.5% of theory),

Melting point: 145-148 ° C

C [deep] 19H [deep] 22N [deep] 6O [deep] 2 (366.43)

Calc .: C 62.27 H 6.05 N 22.94

Found: C 62.45 H 6.17 N 23.00

Example 33

5-Carbomethoxy-7- [3- [4- (2-pyridyl) -1-piperazinyl] -propyl] -pyrido [3,2-d] pyridazin-8 (7H) -one

a) 5-Carbomethoxy-7- (3-chloropropyl) -pyrido [3,2-d] pyridazin-8 (7H) -one

1.35 g (6.6 mmol) of 5-carbomethoxypyrido [3.2-d] pyridazin-8 (7H) -one are added to a suspension of 350 mg (6.6 mmol + 10%) sodium hydride (55% in oil) in 20 ml of absolute dimethylformamide and stirred at 60 ° C. for 30 minutes. After cooling to room temperature, 6.7 ml of 1-bromo-3-chloropropane are added and the mixture is stirred until the reaction has ended. Now the solvent is drawn off, the residue is taken up in water and extracted with chloroform. The chloroform extract is dried over sodium sulfate and concentrated to dryness.

Yield: 1.6 g (86% of theory).

b) 5-Carbomethoxy-7- [3- [4- (2-pyridyl) -1-piperazinyl] -propyl] -pyrido [3,2-d] pyridazin-8 (7H) -one

1 g (3.5 mmol) of 5-carbomethoxy-7- (3-chloropropyl) -pyrido [3,2-d] pyridazin-8 (7H) -one are mixed with 1 g (6.1 mmol) 1- (2 -Pyridyl) -piperazine heated to 120 ° C for one hour. The melt obtained in this way is purified with a silica gel column (100 g) (particle size: 0.2-0.5 mm, eluent: chloroform / methanol 50: 1 or 19: 1). The product obtained after evaporation is dissolved in acetone and precipitated as an oxalate with ethereal oxalic acid.

Yield: 350 mg (20% of theory),

Melting point: 158-160 ° C

C [deep] 23H [deep] 26N [deep] 6O [deep] 7 (498.5)

Calc .: C 55.41 H 5.26 N 16.86

Found: C 55.00 H 5.21 N 16.65

Example 34

7- [3- [4- (2-pyridyl) -1-piperazinyl] propyl] pyrido [3,2-d] pyridazin-8 (7H) -one

a) 7- (3-Chloropropyl) pyrido [3,2-d] pyridazin-8 (7H) -one

11.5 g (78 mmol) of pyrido [3,2-d] pyridazin-8 (7H) -one are dissolved in 200 ml of dimethyl sulfoxide with heating and with 14.5 g (129 mmol) of potassium tert-butoxide and 15 , 8 ml of 1-bromo-3-chloropropane reacted in the manner described in Example 1a.

The crude product is purified over a silica gel column (300 g) (particle size: 0.2-0.4 mm, eluent: chloroform / acetone = 19: 1).

Yield: 8.9 g (50.9% of theory).

b) 7- [3- [4- (2-Pyridyl) -1-piperazinyl] -propyl] -pyrido [3,2-d] pyridazin-8 (7H) -one

2 g (8.94 mmol) of 7- (3-chloropropyl) pyrido [3,2-d] pyridazin-8 (7H) -one are mixed with 1.5 g (9.19 mmol) of 1- (2-pyridyl ) -piperazine heated to 120 ° C for 10 minutes. The melt obtained in this way is purified with a silica gel column (150 g) (particle size: 0.2-0.5 mm, eluent: chloroform / methanol = 50: 1 or = 19: 1). The product obtained after evaporation is dissolved in acetone and precipitated as an oxalate with ethereal oxalic acid.

Yield: 0.6 (15.2% of theory),

Melting point: 212-215 ° C (from methanol) (as oxalate)

C [deep] 21H [deep] 24N [deep] 6O [deep] 5 (440.46)

Calc .: C 57.26 H 5.49 N 19.08

Found: C 57.20 H 5.56 N 18.95

Example 35

7- [3- [4- (4-Chlorophenyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [3,2-d] pyridazin-8 (7H) -one

Prepared analogously to Example 32 from 7- (2,3-epoxypropyl) -pyrido [3,2-d] pyridazin-8 (7H) -one and 1- (4-chlorophenyl) -piperazine.

Yield: 50.8% of theory

Melting point: 173-175 ° C

C [deep] 20H [deep] 22N [deep] 5O] deep] 2Cl (399.9)

Calc .: C 60.07 H 5.54 N 17.51 Cl 8.87

Found: C 59.70 H 5.58 N 17.75 Cl 9.20

Example 36

7- [3- [4- (2-Methylphenyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [3,2-d] pyridazin-8 (7H) -one

Prepared analogously to Example 32 from 7- (2,3-epoxypropyl) -pyrido [3,2-d] pyridazin-8 (7H) -one and 1- (o-tolyl) -piperazine.

Yield: 56.2% of theory

Melting point 94-96 ° C

C [deep] 21H [deep] 25N [deep] 5O [deep] 2 (379.47)

Calc .: C 67.47 H 6.64 N 18.48

Found: C 67.80 H 6.70 N 18.60

Example 37

7- [3- [4- (4-chloro-3-pyridyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [3,2-d] pyridazin-8 (7H) -one

Prepared analogously to Example 32 from 7- (2,3-epoxypropyl) pyrido [3,2-d] pyridazin-8 (7H) -one and 1- (4-chloro-3-pyridyl) piperazine.

Yield: 23.1% of theory,

Melting point: 108-112 ° C

C [deep] 19H [deep] 21N [deep] 6O [deep] 2Cl (400.89)

Calc .: C 56.92 H 5.28 N 20.96 Cl 8.84

Found: C 56.70 H 5.50 N 20.00 Cl 9.13

Example 38

7- [3- [4- (2-Methoxyphenyl) -1-piperazinyl] propyl] pyrido [3,2-d] pyridazin-8 (7H) -one

Prepared analogously to Example 34 from 7- (3-chloropropyl) pyrido [3,2-d] pyridazin-8 (7H) -one and 1- (2-methoxyphenyl) piperazine.

Yield: 15.7% of theory

Melting point: 118-120 ° C (as oxalate)

C [deep] 23H [deep] 27N [deep] 5O [deep] 6 (469.5)

Calculated: C 56.66 H 5.99 N 14.36

Found: C 56.30 H 5.57 N 13.79

Example 39

7- [3- [4- (4-Pyridyl) -1-piperazinyl] propyl] pyrido [3,2-d] pyridazin-8 (7H) -one

Prepared analogously to Example 34 from 7- (3-chloropropyl) pyrido [3,2-d] pyridazin-8 (7H) -one and 1- (4-pyridyl) piperazine.

Yield: 3.2% of theory,

Melting point: 177-179 ° C (as oxalate)

C [deep] 23H [deep] 26N [deep] 6O [deep] 9 (530.5)

Calc .: C 52.07 H 4.94 N 15.85

Found: C 51.60 H 4.92 N 15.15

Example 40

5-carbomethoxy-7- [3- [4- (2-pyridyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [3,2-d] pyridazin-8 (7H) -one

Prepared analogously to Example 33 from 5-carbomethoxy-7- (2,3-epoxypropyl) -pyrido [3,2-d] pyridazin-8 (7H) -one and 1- (2-pyridyl) -piperazine.

Yield: 24.7% of theory

Melting point: 180-183 ° C

C [deep] 21H [deep] 24N [deep] 6O [deep] 4 (424.45)

Calculated: C 59.42 H 5.70 N 19.80

Found: C 59.50 H 5.72 N 20.20

Example 41

5-carbomethoxy-7- [3- [4- (2-methoxyphenyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [3,2-d] pyridazin-8 (7H) -one

Prepared analogously to Example 33 from 5-carbomethoxy-7- (2,3-epoxypropyl) -pyrido [3,2-d] pyridazin-8 (7H) -one and 1- (2-methoxyphenyl) -piperazine.

Yield: 22.5% of theory

Melting point: 80-82 ° C (as oxalate)

C [deep] 25H [deep] 29N [deep] 5O] deep] 9 (543.5)

Calc .: C 55.24 H 5.38 N 12.89

Found: C 55.65 H 5.77 N 13.27

Example 42

5-carbomethoxy-7- [3- [4- (4-pyridyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [3,2-d] pyridazin-8 (7H) -one

Prepared analogously to Example 33 from 5-carbomethoxy-7- (2,3-epoxypropyl) -pyrido [3,2-d] pyridazin-8 (7H) -one and 1- (4-pyridyl) -piperazine.

Yield: 8% of theory,

Melting point: 90-93 ° C

Example 43

5-carbomethoxy-7- [3- [4- (4-chlorophenyl) -1-piperazinyl] propyl] pyrido [3,2-d] pyridazin-8 (7H) -one

Prepared analogously to Example 33 from 5-carbomethoxy-7- (3-chloropropyl) -pyrido [3,2-d] pyridazin-8 (7H) -one and 1- (4-chlorophenyl) -piperazine.

Yield: 24% of theory,

Melting point: 180-182 ° C

C [deep] 22H [deep] 24N [deep] 5O [deep] 3Cl (441.91)

Calc .: C 59.79 H 5.47 N 15.85 Cl 8.02

Found: C 60.00 H 5.48 N 15.95 Cl 8.52

Example 44

5-Carbomethoxy-7- [3- [4- (3-pyridyl) -1-piperazinyl] -propyl] -pyrido [3,2-d] pyridazin-8 (7H) -one

Prepared analogously to Example 33 from 5-carbomethoxy-7- (3-chloropropyl) pyrido [3,2-d] pyridazine and 1- (3-pyridyl) piperazine.

Yield: 7.5% of theory,

Melting point: 197-200 ° C (as oxalate)

C [deep] 25H [deep] 28O [deep] 11N [deep] 6 (588.5)

Calc .: C 51.02 H 4.85 N 14.38

Found: C 50.60 H 5.33 N 14.78

Example 45

5-Chloro-7- [3- [4- (2-pyridyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [3,2-d] pyridazin-8 (7H) -one

Prepared analogously to Example 32 from 5-chloro-7- (2,3-epoxypropyl) -pyrido [3,2-d] pyridazin-8 (7H) -one and 1- (2-pyridyl) -piperazine.

Yield: 42.4% of theory

Melting point: 123-125 ° C

C [deep] 19H [deep] 21N [deep] 6O [deep] 2Cl (400.88)

Calc .: C 56.92 H 5.28 N 20.96 Cl 8.86

Found: C 57.30 H 5.26 N 20.30 Cl 9.09

Example 46

6- [3- [4- (4-chloro-3-pyridyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [2,3-d] pyridazin-5 (6H) -one

Prepared analogously to Example 32 from 6- (2,3-epoxypropyl) pyrido [2,3-d] pyridazin-5 (6H) -one and 1- (4-chloro-3-pyridyl) piperazine.

Yield: 20% of theory,

Melting point: 136-138 ° C

C [deep] 19H [deep] 21N [deep] 6O [deep] 2Cl (400.89)

Calc .: C 56.92 H 5.28 N 20.96

Found: C 56.75 H 5.38 N 21.20

Example 47

6- [3- [4- (4-Pyridyl) -1-piperazinyl] propyl] pyrido [2,3-d] pyridazin-5 (6H) -one

Prepared analogously to Example 34 from 6- (3-chloropropyl) pyrido [2,3-d] pyridazin-5 (6H) -one and 1- (4-pyridyl) piperazine.

Yield: 10% of theory,

Melting point: 187-190 ° C (as oxalate)

C [deep] 23H [deep] 26N [deep] 6O [deep] 9 (530.5)

Calc .: C 52.07 H 4.94 N 15.84

Found: C 52.40 H 5.13 N 15.70

Example 48

8-chloro-6- [3- [4- (2-pyridyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [2,3-d] pyridazin-5 (6H) -one

Prepared analogously to Example 32 from 8-chloro-6- (2,3-epoxypropyl) -pyrido [2,3-d] pyridazin-5 (6H) -one and 1- (2-pyridyl) -piperazine.

Yield: 46% of theory,

Melting point: 100-103 ° C

C [deep] 19H [deep] 21N [deep] 6O [deep] 2Cl (400.9)

Calc .: C 56.92 H 5.28 N 20.96 Cl 8.86

Found: C 56.90 H 5.21 N 21.00 Cl 8.22

Example 49

5- [3- [4- (4-Pyridyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [3,4-d] pyridazin-4 (5H) -one

Prepared analogously to Example 32 from 5- (2,3-epoxypropyl) -pyrido [3,4-d] pyridazin-4 (5H) -one and 1- (4-pyridyl) -piperazine.

Yield: 3.9% of theory,

Melting point: 138-140 ° C (as dioxalate)

C [deep] 23H [deep] 26N [deep] 6O [deep] 10 (546.51)

Calc .: C 50.54 H 4.79 N 15.37

Found: C 50.85 H 5.38 N 14.08

Example 50

5- [3- [4- (4-chloro-3-pyridyl) -1-piperazinyl] propyl] pyrido [3,4-d] pyridazin-4 (5H) -one

Prepared analogously to Example 34 from 5- (3-chloro-propyl) -pyrido [3,4-d] pyridazin-4 (5H) -one and 1- (4-chloro-3-pyridyl) -piperazine.

Yield: 3.5% of theory,

Melting point: 108-110 ° C (as oxalate).

Example 51

6- [3- [4- (4-Nitrophenyl) -1-piperazinyl] propyl] pyrido [2,3, -d] pyridazin-5 (6H) -one

Prepared analogously to Example 2 from 6- (3-chloropropyl) pyrido [2,3-d] pyridazin-5 (6H) -one and 1- (4-nitrophenyl) piperazine.

Yield: 28.2% of theory

Melting point: 165-168 ° C

C [deep] 20H [deep] 22N [deep] 6O [deep] 3 (394.44)

Calculated: C 60.90 H 5.62 N 21.31

Found: C 60.75 H 5.67 N 21.00

Example 52

6- [3- [4- (2-Nitrophenyl) -1-piperazinyl] propyl] pyrido [2,3-d] pyridazin-5 (6H) -one

Prepared analogously to Example 2 from 6- (3-chloropropyl) pyrido [2,3-d] pyridazin-5 (6H) -one and 1- (2-nitrophenyl) piperazine.

Yield: 36.3% of theory

Melting point: 60-70 ° C (as hydrochloride)

C [deep] 20H [deep] 22N [deep] 6O [deep] 3. 2 HCl (467.4)

Calc .: C 51.40 H 5.17 N 17.98 Cl 15.87

Found: C 52.20 H 5.60 N 18.15 Cl 12.32

Example A.

Tablets of 100 mg 6- [3- [4- (2-pyridyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [2,3-d] pyridazin-5 (6H) -one

Composition:

Active ingredient 100.0 mg

Milk sugar 50.0 mg

Polyvinylpyrrolidone 5.0 mg

Carboxymethyl cellulose 19.0 mg

Magnesium stearate 1.0 mg

= 175.0 mg

Production method:

The active ingredient and the milk sugar are evenly moistened with an aqueous solution of polyvinylpyrrolidone and granulated. After drying, the granules are mixed with the remaining active ingredients and the mixture is pressed into tablets in the usual way.

Example B.

Suppositories containing 150 mg of 5- [3- [4- (2-pyridyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [3,4-d] pyridazin-4 (5H) -one

Composition:

Active ingredient 150.0 mg

Suppository mass 1,550.0 mg

= 1,700.0 mg

Production method:

The active ingredient is evenly stirred into the melted suppository mass and suspended and the liquid mixed poured into chilled suppository molds.

Example C

Coated tablets containing 50 mg of 6- [3- [4- (2-methylphenyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [2,3-d] pyridazin-5 (6H) -one

1 dragee contains:

Active substance 50.0 mg

Dried corn starch 20.0 mg

soluble starch 2.0 mg

Carboxymethyl cellulose 7.0 mg

Magnesium stearate 1.0 mg

= 80.0 mg

Production method:

The mixture is processed as described in Example A to form tablet cores, which are then coated with sugar and gum arabic.

Example D

Suspension with 250 mg 6- [3- [4- (2-pyridyl) -1-piperazinyl] -propyl] -pyrido [4,3-d] pyridazin-7 (6H) -one per 5 ml

100 ml suspension contain:

Active substance 5.0 g

Carboxymethyl cellulose 0.1 g

methyl p-hydroxybenzoate 0.05 g

Propyl p-hydroxybenzoate 0.01 g

Sugar 10.0 g

Glycerin 5.0 g

Sorbitol solution 70% 20.0 g

methyl p-hydroxybenzoate 0.05 g

Propyl p-hydroxybenzoate 0.01 g

Sugar 10.0 g

Glycerin 5.0 g

Sorbitol solution 70% 20.0 g

Flavor 0.3 g

distilled water ad 100.0 ml

Production method:

In the distilled water heated to 70 ° C., p-hydroxybenzoic acid methyl ester and propyl ester as well as glycerol and carboxymethyl cellulose are dissolved with stirring. The solution is cooled to room temperature and the active ingredient is added with stirring and dispersed homogeneously. After the sugar, the sorbitol solution and the aroma have been added and dissolved, the suspension is evacuated while stirring for deaeration.

Claims (16)

1. New pyrido-pyridazin-ones of the general formula I, in the N is a nitrogen atom in the 1-, 2-, 3- or 4-position of the phenyl nucleus, R [deep] 1 is a 2-, 3- or 4-pyridyl group optionally substituted by a halogen atom or a phenyl group which can be mono- or disubstituted by a halogen atom, a nitro, trifluoromethyl, alkyl and / or alkoxy group, where the alkyl and alkoxy groups can each contain 1-3 carbon atoms, R [deep] 2 is a hydrogen atom or the hydroxyl group and R [deep] 3 denotes a hydrogen atom or halogen atom or a carbalkoxy group having 2 to 5 carbon atoms, and their physiologically acceptable acid addition salts with inorganic or organic acids. 2. New pyrido-pyridazin-ones of the general formula I according to claim 1, in which N is a nitrogen atom in the 1-, 2-, 3- or 4-position of the phenyl nucleus, R [deep] 1 a 2-, 3- or 4-pyridyl group optionally substituted by a chlorine or bromine atom, a phenyl, methylphenyl, dimethylphenyl, chlorophenyl, nitrophenyl, trifluoromethylphenyl or methoxyphenyl group, R [deep] 2 is a hydrogen atom or the hydroxyl group and R [deep] 3 denotes a hydrogen or chlorine atom or the carbomethoxy group, and their physiologically acceptable acid addition salts with inorganic or organic acids. 3. New pyrido-pyridiazin-ones of the general formula I according to claim 1, in which N, R [deep] 2 and R [deep] 3 are as defined in claim 2 and R [deep] 1 the 2-pyridyl, 3-pyridyl, 4-chloro-3-pyridyl, 4-pyridyl, phenyl, 2-methylphenyl, 2,6-dimethylphenyl, 2-chlorophenyl, Represents 4-chlorophenyl, 3-trifluoromethylphenyl, 2-nitrophenyl, 4-nitrophenyl, 2-methoxyphenyl or 4-methoxyphenyl group, and their physiologically acceptable acid addition salts with inorganic or organic acids. 4. 6- [3- [4- (2-Pyridyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [2,3-d] pyridazin-5 (6H) -one and its acid addition salts. 5. 7- [3- [4- (2-Methoxyphenyl) -1-piperazinyl] propyl] pyrido [3,2-d] pyridazin-8 (7H) -one and its acid addition salts. 6. 7- [3- [4- (2-Pyridyl) -1-piperazinyl] propyl] pyrido [3,2, -d] pyridazin-8 (7H) -one and its acid addition salts. 7. 6- [3- [4- (2-Methoxyphenyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [2,3-d] pyridazin-5 (6H) -one and its acid addition salts. 8. 6- [3- [4- (2-Methylphenyl) -1-piperazinyl] -2-hydroxypropyl] -pyrido [2,3-d] pyridazin-5 (6H) -one and its acid addition salts. 9. Medicaments containing at least one compound of the above general formula I in addition to optionally one or more inert carriers and / or diluents. 10. Process for the preparation of new pyrido-pyridazin-ones of the general formula I. in the N is a nitrogen atom in the 1-, 2-, 3- or 4-position of the phenyl nucleus, R [deep] 1 is a 2-, 3- or 4-pyridyl group optionally substituted by a halogen atom or a phenyl group which can be mono- or disubstituted by a halogen atom, a nitro, trifluoromethyl, alkyl and / or alkoxy group, where the alkyl and alkoxy groups can each contain 1 to 3 carbon atoms, R [deep] 2 is a hydrogen atom or the hydroxyl group and R [deep] 3 denotes a hydrogen or halogen atom or a carbalkoxy group with 2 to 5 carbon atoms, as well as their physiologically acceptable acid addition salts with inorganic or organic acids, characterized in that a) a compound of the general formula II, in the R [deep] 2, R [deep] 3 and N are as defined at the beginning, X represents a nucleophilically exchangeable group such as a halogen atom or X together with R [deep] 2 represents an oxygen atom, with a piperazine derivative of the general formula III, in the R [deep] 1 as defined at the outset, is implemented or b) a pyridine carboxylic acid of the general formula IV, in the N and R [deep] 3 are as defined at the outset and Y represents a halogen atom, or their reactive derivatives with a hydrazine derivative of the general formula V, in the R [deep] 1 and R [deep] 2 are as defined at the outset, is implemented or c) a pyrido-pyridazin-one of the general formula VI, in the N and R [deep] 3 are as defined at the outset, or its alkali metal salts with a piperazine derivative of the general formula VII, in the R [deep] 1 and R [deep] 2 are as defined at the outset and Z represents a nucleophilically exchangeable group such as a chlorine, bromine or iodine atom, is reacted and, if desired, a compound of the general formula I obtained is then converted into its physiologically acceptable acid addition salts with inorganic or organic acids. 11. The method according to claim 10a, characterized in that the reaction is carried out in a solvent and at temperatures between 50 and 200 ° C, preferably at temperatures between 80 and 140 ° C. 12. The method according to claim 10a and 11, characterized in that the reaction is carried out in the presence of an acid-binding agent or in an excess of the amine of the general formula III used. 13. The method according to claim 10b, characterized in that the reaction is carried out in a solvent at temperatures between 40 and 200 ° C, preferably at temperatures between 60 and 140 ° C. 14. The method according to claim 10b and 13, characterized in that the reaction is carried out in the presence of an acid-binding agent. 15. The method according to claim 10c, characterized in that the reaction is carried out in a solvent and at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 30 ° C. 16. The method according to claim 10c and 15, characterized in that the reaction is carried out in the presence of an acid-binding agent.