HU211487A9 - 3(2h)-pyridazinone derivatives and process for the preparation thereof - Google Patents

Description

The present invention relates to novel 3 (2H) -pyridazinone derivatives, to processes for their preparation and to pharmaceutical compositions containing them. The invention also relates to the use of said 3 (2H) -pyridazinone derivatives for the preparation of a medicament for the treatment of diseases and for the treatment of diseases.

The present invention relates to novel 3 (2H) -pyridazinone derivatives of formula (I) and their acid addition salts. In the formula

R ¹ is hydrogen; phenyl; a methyl group optionally substituted by a benzyloxy group; C 1-4 alkyl optionally substituted with one of R ⁸ R ⁹ N- wherein R ⁸ and R ⁹ are independently C 1-4 alkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached, optionally oxygen or R Forms a six-membered heterocyclic group containing N, wherein R ¹⁰ is C 1 -C 4 alkyl which may be optionally substituted by a phenoxy group or substituted by a phenyl group

C3-C5 alkenyl; and the C 1-4 alkyl group may be substituted by a phenyl substituted by a methoxy or methanesulfonylamino group; or a C 3 -C 5 alkenyl group optionally bearing a phenyl or halophenyl group;

A and B are hydrogen, halogen or a group of formula II,

Rt where

R ² and R ³ each independently represent a hydrogen atom or a C 1 -C 4 alkyl group, or R ² and R ^{3 taken} together with the -N- (CH ₂ ) _n N group to which they are attached form a piperazine or homopiperazine ring;

R ⁴ is hydrogen, C 1-4 alkyl, or phenyl;

R ⁵ , R ⁶ and R ⁷ each independently represent a hydrogen atom, a C 1-4 alkoxy group, or an amino group optionally substituted with a methanesulfonyl group:

X is a single bond, oxygen or -CH = CH;

m is 0 or 1 and n is 2 or 3;

with the proviso that A and B cannot have the same meaning at the same time, and when one of A and B is hydrogen or halogen, the other can be only a group of formula II. The invention also encompasses all tautomers of the compounds of formula (I).

The compounds of the invention exhibit valuable antiarrhythmic activity

As used herein, the terms "C 1-4 alkyl" and "C 14 alkenyl" refer to saturated aliphatic hydrocarbon radicals having the specified number of carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, and the like. "C 3 -C 5 alkenyl" refers to straight or branched chain alkenyl groups, e.g. allyl, 2-methylallyl, 1-propenyl, 2-propenyl, 1-butenyl, and the like. The term "halogen" includes all four halogens (fluorine, chlorine, bromine and iodine).

A preferred group of compounds of the present invention are those compounds of formula I wherein R ^{1 is} hydrogen, methyl or C 1-4 alkyl optionally substituted with diethylamino, A is chloro linked to the 4-position of the pyridazinone ring. or a bromine atom, and B is an optionally substituted 1- (3-phenyl-2-propen-1-yl) piperazino group attached to the 5-position of the pyridazinone ring.

Another preferred group of compounds of the present invention are those compounds of formula I wherein R ¹ is hydrogen, C 1-4 alkyl substituted with diethylamino or 1- (2-phenoxyethyl) piperazino, A is halogen. , B is a group of formula (Π) wherein R ² , R ⁴ and R ⁵ are hydrogen, R ³ is methyl, R ⁶ and R ^{7 are} methoxy, X is a single bond, m is 1 and n is 3, and A is attached to the 5-position of the pyridazinone ring, B to the 4-position of the pyridazinone ring.

Particularly preferred compounds of the formula I are the following:

5-chloro-4- {3- [N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methylamino] -propylamino} -3 (2H) -pyridazinone,

4-chloro-2- [2- (N, N-dimethylamino) ethyl] -5- {4- (3-phenyl-2-propenyl) -1-piperazinyl} -3 (2H) -pyridazinone,

5-Chloro-4- {3- [N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methylamino] -propylamino} -2- [2-morpholinoethyl] -3 ( 2H) -pyridazinone,

5-chloro-2- [2-N, N-diethylamino) ethyl] -4- {3N [2- (3,4-dimethoxyphenyl) ethyl] -N-methylamino] propyl amino} -3 (2H) -pyridazinone,

4- {3- [N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methylamino] propylamino} -3 (2H) -pyridazinone,

5-Chloro-4- {3- [N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methylamino} propylamino} -2- {4 - [(methylsulfonyl) amino] ] benzyl} -3 (2H) -pyridazinone,

5-Chloro-4- {3- [N2- [4- (methylsulfonyl) amino] phenoxy] ethyl] -N-methylamino) -propylamino} -3 (2H) -pyridazinone; suitable acid addition salts thereof.

HU 211 487 A9

The novel 3 (2H) -pyridazinone derivatives of the present invention belong to a group of compounds that has so far been little studied.

No. 7,812,880. Japanese Patent Application No. 5,684,500 discloses related 5-and 4- (2-hydroxyethyl) amino-3 (2H) pyridazinone compounds of 2-alkyl, 2-alkenyl, 2-aralkyl and

Discloses 2-aryl derivatives thereof which are pyridazino [4,5-b] [1,4] -oxazines having anti-inflammatory, antidepressant and analgesic properties.

No. 223,432. Czechoslovakian Patent Specification has 2- (C 1 -C 3) alkyl, 2-cycloalkyl, 2-aryl having insecticidal and acaricidal activity at the 4-position containing alkyl, alkoxyalkyl, cycloalkylamino, pyrrolidino or piperidino; and 2- (optionally substituted) aralkyl-5-chloro-3 (2H) -pyridazinones.

No. 2,124,164. French patent specification

2-Phenyl-6-chloro (or methoxy) -4- [4- (toobenzoylalkyl) -1-piperazinyl] -3 (2H) -pyridazinone has analgesic, sedative and antihypertensive properties.

No. 3,902,316 A. German Patent Publication No. 4,193,198 relates to alpha-adrenoceptor blocking piperazinyl (alkylamino) pyridazinone derivatives in which, unlike the compounds of formula (I), the piperazine and pyridazinone rings are not linked directly to one another, but via an alkylene amino chain.

No. 320 032 A; European Patent Publication No. 3,684,123 discloses 3- (phenylaminoalkyl) amino and 3- [4- (phenoxyalkyl) piperazino] pyridazines and their 6-hydroxy and 6-chloro derivatives. The compounds have antiviral activity

No. 54,946. European Patent Application Publication No. 4,198,198 relates to 4-chloro-5- [2- (3-phenoxy-2-hydroxypropylamino) ethyl] amino) -3 (2H) -pyridazinone derivatives having a structure different from the compounds of the present invention. Although the compounds described are attributed to alpha- and beta-receptor blocking effects, the experimental results only confirm the antihypertensive effect.

The invention further relates to a process for the preparation of a racemic or optically active 3 (2H) -pyridazinone derivative of formula (I)

a) for the preparation of compounds of formula I wherein one of A and B is other than hydrogen and R ¹ is a compound of formula III as defined above

(wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X, m and n are as defined above), or

b) for the preparation of compounds of formula I wherein R ¹ is other than hydrogen and phenyl, and A, B and R ³ are other than hydrogen, and R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X, m and n is a compound of formula (I) as defined above wherein R ¹ is hydrogen and R ³ is other than hydrogen, and R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X, m and n are in the introduction with a compound of formula R'Z, wherein R 'is as defined in the introduction, other than hydrogen and phenyl, and Z is a leaving group, or

c) for the preparation of compounds of formula I wherein A and B are as defined in the introduction, and R ² and R ^{3 are the} same or different and are selected from hydrogen or C 1 -C 4 alkyl, and R ¹ , R ⁴ , R ⁵ , R ⁷ , X, m and n are as defined in the introduction, a compound of formula (V)

wherein R * is as defined in the introduction, C and D are hydrogen or halo or a group of formula VI

Z- (CH ₂ ) _n -ΝH where R ² is hydrogen or C 1 -C 4 alkyl, Z is a leaving group and n is as defined in the introduction, with the proviso that one of C and D is always hydrogen or halogen. and, when one is hydrogen or halogen and the other is only (VI) is a group of formula may, with an amine of formula (VII) wherein R is as defined above, Hal is halogen, with an amine of formula (IV) _R 5 R * r 3 ^ -X- (CH ₂ , _m -CH-N- (CH ₂ ) _n -1 H) (IV)

R 7 wherein R ³ is hydrogen or C 1 -C 4 alkyl, Z, R ⁴ , R ⁵ , R ⁶ , R ⁷ , X as defined in the introduction to today; obsession

HU 211 487 A9

d) for the preparation of compounds of formula I wherein R is other than hydrogen and A and B are as defined in the introduction, a compound of formula VIII:

R 1 -N- X ₂ -N- (CH ₂ ) _n -NH wherein R ¹ and n are as defined in the introduction, and Y is hydrogen or halogen, with the proviso that Y and -N (R ² ) - One of the (CH 2) _n NH (R ³ ) groups is always attached to the 4-position of the pyridazinone ring and the other to the 5 position of the pyridazine ring, with a compound of formula IX

(wherein R ⁴ , R ⁵ , R ⁶ , R, X and m are as defined in the introduction and Z is a leaving group); obsession

e) for the preparation of compounds of formula I wherein R ¹ is hydrogen and A and B are as defined in the introduction, a compound of formula II wherein R ¹ is benzyloxymethyl and A and B are as defined in the introduction. treated with boron tribromide; obsession

f) for the preparation of compounds of formula (I) wherein one of A and B is hydrogen and R ¹ is a compound of formula (I) prepared in any of the introductory variants of process (a) to (e) wherein R is in the introduction, A and B are halogen or a group of formula (II), provided that when one of A and B is a halogen, the other is only a group of formula (II), is dehalogenated; and, if desired, converting the compounds of formula (I) obtained by the above processes (a) to (f) into an acid addition salt and / or separating the optically active isomers.

According to a preferred embodiment of the process (a) of the present invention, a compound of formula (I) wherein A is (Π) and B is the 4,5-dihalo-3 ( The 2H-pyridazinone derivative is reacted with the amine of formula IV in a non-polar solvent such as dioxane or toluene at a temperature between 50 ° C and the boiling point of the solvent. The amine is used in a molar excess of 2 to 10 times per mol of the compound of formula (III)

In a preferred embodiment of the process (a) of the present invention, a compound of formula (I) wherein B is a group of formula (Π), A is as defined above, a compound of formula (III) is a compound of formula (IV) with an amine in a polar solvent (e.g. ethanol or ethanol-water mixture) at a temperature between 50 ° C and the boiling point of the solvent.

In a preferred embodiment of process b) of the invention, the compound of formula I wherein R ¹ is hydrogen, the compound of formula R'Z where Z is preferably chlorine or bromine, in the presence of an acid scavenger such as potassium carbonate, in an aprotic solvent, preferably a dipolar aprotic solvent such as dimethylformamide, at a temperature between 25 ° C and the reflux temperature of the solvent.

In a preferred embodiment of process c), the compound of formula V is reacted with an amine of formula VB either in a solvent or in a solvent, preferably a dipolar aprotic solvent such as dimethylformamide, at a temperature between 50 and 15 ° C. . The amine is used in a molar excess of two to ten times the molar amount of compound of formula (V).

In a preferred embodiment of process d), the compound of formula VIII is reacted with a compound of formula IX, wherein Z is preferably chlorine or bromine, without solvent or in a solvent, preferably a dipolar aprotic solvent such as dimethylformamide. in the presence of an acid scavenger, such as an organic or inorganic base, at a temperature between 25 ° C and 120 ° C.

In a preferred embodiment of process (e) of the present invention, the compound of formula (I) wherein R ¹ is benzyloxymethyl is reacted with boron tribromide in a reaction-inert solvent such as benzene or toluene at room temperature.

In a preferred embodiment of process (f) of the present invention, the compound of formula I wherein A and B are other than hydrogen is a catalyst suitable for dehalogenation with hydrogen gas or a hydrogen source, preferably palladium on carbon and optionally an acid scavenger, preferably an inorganic base. , for example in the presence of ammonia, at atmospheric pressure.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is further illustrated with reference to Figure 1, which shows the duration (s / min) of the compound of Example 1, Sotalol, and the control in an in vivo reperfusion antiarrhythmic model.

The reaction mixture obtained as a result of the processes described above may be worked up by methods conventionally used in organic chemistry, for example, excess reagent and / or solvent may optionally be removed in vacuo and the residue extracted and / or chromatographed and / or crystallized.

HU 211 487 A9. The compound of formula (I) thus obtained can be purified, if desired, for example by chromatography and / or recrystallization and, if desired and possible, converted into its acid addition salt which, after isolation, may be purified by recrystallization if desired.

The compounds of formula (I) obtained by the process of the present invention which contain a sufficiently strong basic group can be converted into acid addition salts. The conversion is accomplished by dissolving the base in a suitable solvent and adding the appropriate acid or a solution of the acid in a solvent with stirring. The product obtained is isolated by filtration or after evaporation of the solvent by crystallization and, if desired, purified by recrystallization. Suitable acids are organic or inorganic acids, preferably pharmaceutically acceptable acids such as hydrochloric acid, sulfuric acid, fumaric acid or boric acid. Suitable solvents are, for example, alcohols, esters and / or ketones. The salt formation is carried out at a temperature between 0 'C and 80' C, preferably between 0 and 20 'C for mineral acids and between 50 and 80' C for organic acids.

Compounds of formula I wherein R and / or R ² are hydrogen may exist in further tautomeric forms. These compounds are also within the scope of the invention.

Compounds of formula (I) wherein R ⁴ is other than hydrogen and / or one or more centers of asymmetry in the substituents R ¹ , R ² and / or R ³ may exist in optically active forms. Both racemic compounds and optically active isomers are within the scope of the invention.

Some of the compounds of formula (III) used as starting materials in process (a) of the invention are known in the literature (e.g., J. Am. Chem. Soc. 75, 1909 (1953); Bull. Chem. Soc. Francé 1964, 2124; Heterocyclic Chem., 19, 481, 481 (1984); Farmaco Ed. Sci., 32, 239 (1984); Chem. Fharm. Bull., 18, 147, (1970). le, can be prepared by analogous methods. for example, substituted phenyl-substituted alkenyl or 4substituted piperazinyl group szuszbtituált novel compounds of formula alkyl (III) corresponding 4,5-dihalo-3 (2H) -pyridazinone, where ^R1 is optionally It is prepared by reaction with R'Z, where Z is a leaving group, such as halogen, etc. Most of the R'Z reagents used in the reaction are known (see, for example, J. Chem. Soc. 1940, 1266; ibid., 1961, 2516). ; J. Chem. Soc. B 1966, 590; J. Am. Chem. Soc. 83, 3846 (1961): Chem. 30, 810; Chem. Pharm. Bull. 25, 1811 (1977); the other compounds of formula R'Z may be prepared by analogous methods. Compounds of formula ¹ when R is 4- (methylsulfonyl) benzyl group (III) can be prepared from compounds containing the 4-nitrobenzyl group, R ¹ is].

Some of the 1,2-ethanediamine of formula IV, 1,3-propanediamine derivatives and 1-substituted piperazines used as starting materials in process (a) of the present invention are known in the art [e.g. 0 344 577 European and 523,902. Belgian patents; J. Med. Chem. 11, 804 (19681). The novel compounds of formula (IV) may be prepared analogously. 2- [4 - [(Methanesulfonylamino] -phenoxy) -ethyl chloride and its precursors are needed for the preparation of 1- [2- [4- (methanesulfonylamino) -phenoxy] -ethyl] -piperazine. European Patent Nos. 797,623 and Belgian Patent Nos. 797,623.

Examples of the preparation of new starting materials used in process a) are given in Sections 1 and 2 of the section entitled "Preparation of starting materials".

The alkylating agents of formula R'Z used as starting materials in process (b) of the invention are known in the literature (see above) or may be prepared in an analogous manner.

The synthesis of the new 3 (2H) -pyridazinone derivatives of formula (V) used as starting material in process (c) according to the invention is described in Section 3, Preparation of starting materials. The preparation of amines of formula (VE) is known in the literature (Chem. Bér. 31, 1195; J. Am. Chem. Soc. 62, 922 (1940)).

The preparation of new compounds of formula VIII used as starting material in process d) of the present invention is described in Section 4, Preparation of Starting Materials.

The compounds of the formula I have a valuable therapeutic effect. In particular, they have excellent antiarrhythmic effects.

The antiarrhythmic activity of the compounds of formula I is demonstrated by in vitro electrophysiological studies and in vivo induced arrhythmia models.

I. Intracellular Cardiac Electrophysiology Studies on Isolated Canine Purkinjerost Preparation: Effect on Configuration and Duration of Action Potential.

Male and female mongrel dogs (8-22 kg) 30 mg / kg

iv anesthetized with pentobarbital sodium (Nembutal ^R ). Surface Purkinje Fibers were prepared from their hearts and placed in a Plexiglas bath with Tyrode's solution (Na * 147.0 mM; K * 4.0 mM; Cl 133.3 mM; Ca ² * 2.0 mM; HCO ₃ - 22.0 mM). Η ₂ ΡΟ ₄ “0.9 mM; glucose 5.0 mM). The medium was continuously bubbled through with carbogen gas (95% CO ₂ ). The temperature in the test bath was 37, heated at 0.5 ° C, pH 7.3ChtO, 5. To avoid the spontaneous action often observed after a short set-up potential duration changes, Purkinje-fiber preparations were incubated for 1 to 2 hours prior to measurement, intracellular action potentials were discharged by conventional glass capillary microelectrode technique, electrodes were charged with 3, KCl and resistivity was 5-15 Microelectrodes were fed through a Ag-AgCl connection into a high-input capacitance neutralizing amplifier.

EN 211 487 A9 served as a true electrode. The maximum rate of depolarization (v ^) was measured using an electronic differentiation unit: The intracellular signals were tracked on a two-channel oscilloscope and visualized online using a microcomputer. The following parameters were measured: resting potential, action potential, amplitude, 50% and 90% repolarization, maximum depolarization rate. The preparations were stimulated with Teflon-insulated silver electrodes with a double pacing threshold of 1 msec square pulses. The basal pacing cycle lengths were varied within 200-1000 msec

Compounds that are capable of prolonging the action potential in this assay are considered to be potentially antiarrhythmic. The compounds were tested at 5 mg / L. In our study, the compounds of formula I of the present invention significantly prolonged the action potential duration at 90% repolarization time (APD?), While practically no effect on depolarization rate (Vmax) was observed. Some characteristic data are shown in Table 1. N- [4- [1-hydroxy-2 - [(1-methylethyl) amino] ethyl] phenyl] methanesulfonamide (sotalol) was used as reference.

Table 1 Effect of compounds of formula (/) on action potential

Example number of compound APD _9O (msec) Duration Increase (%) before treatment after treatment First 259.3 ± 8.9 318 l ± 10.4 ** 22.7 12th 209.1 + 6.2 262.2 ± 3.7 * 25.4 18th 248.3 ± 6.5 307 ± 8 l, l ** 23.7 22nd 221.2 ± 19.2 272.0 ± 22.8 * 22.9 24th 248.4 ± 5.2 316.4 ± 7.5 * 27.4 26th 246.4 + 8.1 318.7 ± 13.4 ** 29.3 34th 253.1 ± 11.1 354.6 ± 25.2 * 39.9 35th 246.5 ± 6.9 289.1 ± 5.3 ** 17.3 45th 248.2 ± 10.4 329.1 ± 9.7 32.6 46th 243.6 ± 16.6 313.6 ± 21.8 28.7 sotalol 272.8 + 4.3 320.0 ± 8.5 ** 17.3

* <5%, ** p <l%.

From the above data it is evident that the compounds of formula I according to the invention significantly prolong the action potential at 90% repolarization.

II. Extracellular cardiac electrophysiological studies in rabbit heart preparation. (Examination of the effect on the effective refractory period (ERP))

Young male New Zealand white rabbits (1-2 kg) were sacrificed by necrosis, the heart and the free right ventricle wall were prepared and placed in an organ bath containing Tyrode's solution. The medium was continuously bubbled with carbogen gas. The temperature was 36 ± 0.5 ° C and the pH was 7.4 ± 0.5. After equilibration (60 min), the preparations were stimulated with a bipolar electrode with 2 msec, two pacesecond pulses of 1000 msec cycle length. To measure conduction time

At 100 mM from the excitatory electrode and 8-12 mM from each other, 2 bipolar extracellular drainage platinum electrodes (d = 0.1 mM) were placed on the right ventricle surface along the trabelular muscle fibers and triggered biphasic extracellular action potentials We recorded. Action potentials first appeared on the nearer and later on the distal electrode, which was considered a time difference in conduction time. The amplified signals (Experimetria GMK) were displayed on an oscilloscope screen (Medicor VM 62 A). The cycle lengths were varied between 200 and 2000 msec cycle length limits. Measurements were always made when the adaptation was complete for the new cycle length. For each new cycle length, the pacing threshold was measured by gradually decreasing the pacing intensity from the double pacing threshold until propagating action potentials could be elicited. The test compound was used at a concentration of 10 mg / L. The results are summarized in Table 2.

Table 2 Effect of Compounds of Formula (1) on Effective Refractory Area (ERP)

Example number of compound ERP (msec) before treatment after treatment First 116.0 ± 6.7 152.0 ± 3.7 ** 18th 107.0 ± 7.6 136.0 + 14.0 * 26th 105.0 ± 9.5 127.5 ± 10.3 * 35th 104.8 ± 13.2 135 ± O ll, l ** sotalol 86.9 + 9.8 110.3 ± 9.0 * '

* p <5%, ** p <1%.

These results are similar to intracellular cardiac electrophysiological data and confirm the antiarrhythmic efficacy of these compounds.

The antiarrhythmic activity of the compound of Example 1 was also tested in an in vivo reperfusion arrhythmia model. The method is excellent for EH. class antiarrhythmics. The experiment was carried out as follows.

In anesthetized rats weighing 400-500 g (anesthetized with 60 mg / kg iv Nembutal), after opening the chest (artificial ventilation), the left coronary artery (LAD) was temporarily suppressed (5 min occlusion), and then released after reperfusion arrhythmia ( tachycardia and fibrillation), which was monitored by continuous ECG monitoring (limb drainage). Diastolic and systolic blood pressure (invasively, through the carotid artery) and heart rate were simultaneously measured. The control ECG recorded prior to suppression was used to measure the duration of post-suppression reperfusion arrhythmia, i.e. ventricular tachycardia, and ventricular fibrillation. Sotalol was used as reference. Both the compound of Example 1 and the reference compound were administered at a dose of 10 mg / kg iv. dosing. The results are shown in Figure 1. * * (Figure 1 illustrates the average time to ventricular tachycardia and / or ventricular fibrillation per minute).

HU 211 487 A9

The results of this study show that the compound of Example 1 is significantly more potent than the reference sotalol.

The present invention further provides pharmaceutical compositions comprising as active ingredient at least one racemic or optically active compound of formula (I), a tautomer and / or an acid addition salt thereof, and one or more pharmaceutically acceptable carriers, diluents and / or excipients.

The pharmaceutical compositions of the present invention may be prepared by methods known per se by mixing the active ingredient with the appropriate inert solid or liquid carriers, diluents and / or excipients and bringing the mixture into a galenic form.

The pharmaceutical compositions of the invention may be suitable for oral (e.g., tablets, pills, coated pills, dragees, hard or soft gelatine capsules, solution, emulsion or suspension), parenteral (e.g., injection solution) or rectal (e.g., suppository) administration.

Suitable carriers for tablets, coated tablets, dragees and hard gelatine capsules are e.g. lactose, corn starch, potato starch, magnesium carbonate, magnesium stearate, calcium carbonate, stearic acid or its salts, etc. They can be used. Carriers for soft gelatine capsules are e.g. vegetable oils, fats, waxes or polyols of appropriate consistency. Carriers for solutions and syrups are e.g. water, polyols (polyethylene glycol), sucrose or glucose. Injectable solutions include, e.g. water, alcohols, polyols, glycerol or vegetable oils. The suppositories are e.g. oils, waxes, fats or polyols of appropriate consistency.

In addition, pharmaceutical formulations include auxiliaries commonly used in the pharmaceutical industry, e.g. wetting agents, sweetening agents, flavoring agents, salts for the production of osmotic pressure, buffers, etc. contain.

As the toxicity of these compounds is generally low, this together represents a valuable spectrum of action and therapeutic safety.

The daily dose of the compounds of the formula I may vary within wide limits, depending on a number of factors (e.g., the activity of the active ingredient, the condition and age of the patient, and the severity of the disease. The daily oral dose is generally 0.2 mg / kg to 25 mg / kg However, it should be emphasized that these dosage values are for information only and that the dosage administered will always be determined by the attending physician.

The present invention also relates to the use of compounds of the formula I, their tautomers and / or their acid addition salts, in particular for the preparation of medicaments having antiarrhythmic activity.

The present invention further provides an antiarrhythmic treatment method comprising administering to a patient an effective amount of a compound of Formula I, a tautomer thereof, or a pharmaceutically acceptable acid addition salt thereof.

The invention is illustrated by the following examples, without limiting the scope of the invention to the examples. The melting points are uncorrected.

Examples 1 and 2

5-Chloro-4- (3- [N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methylamino] -propylamino] -3 (2H) -pyridazinone (4-isomer) ) and 4-chloro-5- [3- [N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methylamino] -propylamino] -3 (2H) -pyridazinone (5- isomer) (Method A)

3.63 g (22 mmol) of 4,5-dichloro-3 (2H) -pyridazinone and 13.88 g (55 mmol) of N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-1 A solution of 3-propanediamine in 80 ml of anhydrous dioxane was heated at reflux for 10 hours. The solution was concentrated in vacuo and the residue was purified on a silica gel column with ethyl acetate-methanol. ammonia = 9: 1: 0.5 (hereinafter, unless otherwise stated, both column and thin layer chromatography data refer to the above solvent mixture). The fractions R _f = 0.54 were combined and evaporated to give 2.99 g (36%) of the 4-isomer (m.p. 92-94 ° C) (product of Example 1). Melting point of fumarate: 94-96 'C. Chromatography afforded 4.09 g (149%) of the 5-isomer (m.p. 98-101 ° C (product of Example 2). M.p. 108: 110'C.

Examples 3 and 4

2-Benzyloxymethyl-5-chloro-4- {3- [N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methylamino] -propylamino} -3 (2H) pyridazinone (4 isomer) and 2- (benzyloxymethyl) -4-chloro-5- (3- [N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methylamino] propylamino} -3 ( 2H) pyridazinone (5-isomer) (Method A ₂ )

1.2 g (14.2 mmol of 2-benzyloxymethyl) -4,5-dichloro-3 (2H) -pyridazinone (the preparation of which is described in the "Preparation of Starting Materials"), and

Starting from 2.66 g (10.54 mmol) of N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-1,3-propanediamine and proceeding according to method a, except using anhydrous toluene instead of dioxane and a reaction time of 5 hours. The separation of the isomers is carried out according to method a). 0.53 g (25%) of the 4-isomer (product of Example 3; R _f = 0.4) is obtained.

Examples 5 and 6

5-Chloro-4- (3- [N- (2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-amino) propyl-amino} -2- (4-methoxybenzyl) 3 (2H) -pyridazinone (4-isomer) and 4-chloro-5- (3- [N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methylamino] propylamino} -2- (4-Methoxybenzyl) -3 (2H) pyridazinone (5-isomer) (Method ₂ )

1.8 g (6.3 mmol) of 4,5-dichloro-2- (4-methoxybenzyl) 3 (2H) -pyridazinone and 4 g, 15.8 mmol) of N- [2- (3,4- starting from dimethoxyphenyl) ethyl] -N-methyl-1,3-propanediamine and proceeding according to method a, except that anhydrous n-but

We use A9 women. Reaction time: 12 hours. 0.85 g (27%),

4-isomer (product of Example 5; Rf = 0.4; fumarate melting point 56-57 ° C) and 0.97 g (31%) of 5-isomer (product of Example 6; R _f = 0.2). we get

Example 7

4-Chloro-5- [1- (1,4) -diaza-cycloheptyl-4- (3-phenyl-2-pmpenyl)] - 3 (2H) -pyridazinone (5-isomer) (Method ₄ )

1.65 g (10 mmol) of 4,5-dichloro-3 (2H) -pyridazinone,

21.6 g (10 mmol) of 1- (3-phenyl-2-propenyl) - (1,4) -diaza10 cycloheptane and 1.5 ml (11 mmol) of triethylamine are dissolved in 16 ml of ethanol. The solution was heated to reflux for 3 hours with stirring and reflux. The reaction mixture is cooled, the precipitate is filtered off, washed with ethanol and then with diethyl ether. 1.83 g (53%) of the title compound are obtained. Mp: 176-178 ° C. Melting point of its monohydrochloride salt: 193-194 ° C.

Suitable starting materials in the same procedure _I -A ₄ are prepared using an additional compound (I) of the formula which are described in Table 3

Table 3

Example Y R ¹ R ² R ³ R ⁵ R ⁶ n m X Mode- agent Yield (%) Op./C or R _f 8th 5-Cl c ₆ h ₅ H Me OMe OMe 3 1 - Ai 7 107113 ^a 9th 4-Cl c ₆ h ₅ H Me OMe OMe 3 1 - al 7 77-8 10th 5-C1 c ₆ h ₅ ch = chch ₂ H Me OMe OMe 3 1 - THE, 23 38-40® 11th 4-C1 c ₆ h ₅ ch = chch ₂ H Me OMe OMe 3 1 - THE, 11 68-70® 12th 5-C1 C _t H ₅ 0 (CH ₂ ) ₂ H H Me OMe OMe 3 1 - THE, 49 187-9 ^b 13th 4-C1 H Me OMe OMe 3 1 - ^A 1 26 204-6 ^b 14th 5-C1 H H Me OMe OMe 2 1 - THE, 26 102-4 15th 4-Cl H H Me OMe OMe 2 1 - ^A 1 16 116-9 16th 5-Cl H H Me OMe OMe 3 1 - ^A 1 50 117-9 17th 4-C1 H H Me OMe OMe 3 1 - ^A ] 31 156-8 18th 5-C1 (Et) ₂ N (CH ₂ ) ₂ H Me OMe OMe 3 1 - a ₂ 46 183-4 ^{° C} 19th 4-C1 (Et) ₂ N (CH ₂ ) H Me OMe OMe 3 1 - a ₂ 22 0.4 ^d 20th 5-C1 Me H Me OMe OMe 3 1 - ^In Figure 2 60 142-4® 21st 4-C1 Me H Me OMe OMe 3 1 - a ₂ 33 85-91 22nd 5-Cl MeSO ₂ NHC ₆ H ₄ CH ₂ H Me OMe OMe 3 1 - a ₂ 45 125- 6; 158160® 23rd 4-C1 MeSO ₂ NHC ₆ H ₄ CH ₂ H Me OMe OMe 3 1 - a ₂ 21 0.56 ^d 24th 5-Br H H Me OMe OMe 3 1 - a ₂ 41 95-6; 178-9 ^e 25th 4-Br H H Me OMe OMe 3 1 - a ₂ 38 0.3 ^d 26th 5-Cl ο \ καιρ ₂ H Me OMe OMe 3 1 - ₃ 28 240-2 ^c

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Example Y R ¹ R ² R ³ R ⁵ R ⁶ n m X Mode- agent Yield (%) OpZC or R _f 27th 4-Cl H Me OMe OMe 3 1 - ^In Figure 3 47 73 28th 5-C1 C ^ tjObOOIjN .MPHpl H Me OMe OMe 3 1 - ^In Figure 3 25 182-6 ^f 29th 4-C1. C ^ PI OOyf H Me OMe OMe 3 1 - ₃ 33 217-221 ^f 30th 4-C1 (Et) ₂ N (CH ₂ ) _{2 CH2-CH2} H NHSO ₂ Me 2 1 0 ₄ 38 146-7 31st 4-Cl cTVc ^. ch ₂ -ch ₂ H H 2 0 CH = CH ₄ 8.5 225-6 ^c 32nd 4-Cl (Et) ₂ N (CH ₂ ) ₂ CH ₂ -CH ₂ -CH ₂ H H 2 0 CH = CH A4 67 0.46 ^d 33rd 4-C1 H ch ₂ -ch ₂ H H0 2 1 SHE In _{Figure 4} 44 149- 150 34th 4-C1 H ch ₂ -ch ₂ H H 2 0 CH = CH ₄ 74 209- 211; 158 160 ' (In) 35th 4-C1 (Et) ₂ N (CH ₂ ) ₂ ch ₂ -ch ₂ H H 2 0 CH = CH ₄ 44 87-9; 221-3 ^C 36th 5-C1 (Et) ₂ N (CH ₂ ) ₂ ch ₂ -ch ₂ H H 2 0 CH = CH ₄ 21 212-14 ^c 37th 4-C1 (Et) ₂ N (CH ₂ ) ₂ ch ₂ -ch ₂ H F 2 0 CH = CH ₄ 32 174-5 38th 5-C1 (Et) ₂ N (CH ₂ ) ₂ ch ₂ -ch ₂ H F 2 0 CH = CH ₄ 10 0.75 ^d

a: fumarate; B: 2H ₂ O 3HC1 salt; c; 2HCl salt; d: R 1 (EtOAc: MeOH: cc.NH ₃ -9: 1: 0.5) e: HCl salt; f: 3HCl salt

Example 39

4-Chloro-5- (3- [N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methylamino] propylamino-2- [3- (4- fluorophenyl) -2-propenyl J-3 (2H) -pyridazinone (Method B)

5.7 g (15 mmol) of 4-chloro-5- {3- [N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methylamino] -propylamino} -3 (2H) of pyridazinone 40 (compound of Example 2) and 10.2 g (74 mmol) of anhydrous potassium carbonate in 15 ml of anhydrous dimethylformamide with stirring at an internal temperature of 10 to 15 ° C, 2.73 g (16 mmol). A solution of 3- (4-fluorophenyl) -2-propenyl chloride in 3 ml of anhydrous dimethylformamide was added dropwise. The reaction mixture was stirred at room temperature for 1 day. The dimethylformamide was evaporated in vacuo, water was added to the residue, and the resulting emulsion was extracted with ethyl acetate. The organic layer was dried, evaporated and the residue was crystallized from diethyl ether. 3.24 g (42%) of the title compound are obtained. 84-85 ° C.

Example 40 55

5-Chloro-4- [1,3-N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methylamino] -propylamino-2- [3- (4-fluorophenyl) - 2-propenyl] -3- (2H) -pyridazinone

Starting from Example 1 and using Method b), the title compound 60 was obtained in 39% yield. R _f = 0.5 (EtOAc-MeOH = 9: 1, monohydrochloride salt 126-127 ° C).

Example 41

5-Chloro-2-methyl-4- {3- [N- (3-phenyl-2-propyl) -N-methylamino] -propylaminoph-3 (2H) -pyridazinone (Method c)

1.77 g (7.5 mmol) of 5-chloro-4- (3-chloropropylamino) 2-methyl-3 (2H) -pyridazinone (described in Preparation of Starting Materials) and A mixture of 3.73 g (25 mmol) of N, -dimethylphenylethylamine was melted at 120 ° C for 5 hours. After cooling, water (20 mL) was added to the reaction mixture, and the solution was extracted with ethyl acetate. After drying and evaporation, the crude product is purified by column chromatography. 1.67 g (64%) of the title compound are obtained. R _f = 0.5. Its fumarate has a melting point of 128-129 ° C.

Example 42

5-Chloro-2-methyl-4- {3- [N- [2- (3,4,5-trimethoxyphenyl) ethyl] -N-methylamino) propylamino} -3 (2H) -pyridazinone

Starting from 5-chloro-4- (3-chloropropylamino) -2-methyl-3 (2H) -pyridazinone and 3,4,5-trimethoxyphenylethylamine and proceeding according to method C, with the exception that the melting is carried out at 140 ° C for 2.5 hours. This gave the title compound in 34% yield. R _f = 0.6.

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Example 43

4-Chloro-2-methyl-5- [4- (3-phenyl-2-propenyl) -piperazinyl] -3 (2H) -pyridazinone (Method Dj)

0.75 g (3.3 mmol) of 4-chloro-2-methyl-5- (1-piperazinyl) 3 (2H) -pyridazinone (the preparation of which is described in the "Preparation of Starting Materials") and 0.91 g. Anhydrous potassium carbonate (6.6 mmol) was suspended in anhydrous dimethylformamide (5 mL). A solution of 0.5 g (3.3 mmol) of 3-phenyl-2-propenyl chloride in 5 ml of anhydrous dimethylformamide was added dropwise to the suspension while stirring at room temperature, and the reaction mixture was stirred at room temperature for 24 hours. The dimethylformamide was evaporated in vacuo, water was added to the residue, and the resulting solution was extracted with ethyl acetate. The organic phase is dried and evaporated, and the residue is crystallized from ethanol to give 0.55 g (49%) of the title compound, m.p. 98-100 ° C. Melting point of its monohydrochloride salt: 218-220'C.

Example 44

2- (Benzyloxy) -5-chloro-4- / 3- [N- [2- [4- [Imetilszulfonil) amino] phenoxy] ethyl] -N-methylamino] propylamino) - 3 (2H) -pyridazinone (Method d ₂ )

3.2 g (9.5 mmol) of 2- (benzyloxymethyl) -5-chloro-4- [3- (N-methylamino) propylamino] - (2H) -pyridazinone,

A mixture of 3.56 g (14.25 mmol) of 4 - [(methylsulfonyl) amino] phenoxyethyl chloride and 2 mL (14.25 mmol) of triethylamine was stirred for 16 hours at 80 ° C. The reaction mixture was subjected to column chromatography, first with ethyl acetate and then with ethyl acetate-methanol. ammonia = 9: 1: 0.5 solvent mixture. This gave 1.8 g (69%) of the title compound. R _f = 0.7.

Example 45

5-Chloro-4- / 3- [N- [2- [4 - [(methylsulfonyl) amino] phenoxy] ethyl) -N-methylamino] -propylamino} -3 (2H) pyridazinone (Method E)

Example 44 (2.69 g, 4.88 mmol) was dissolved in anhydrous benzene (53 mL). While stirring and cooling with ice water, add dropwise to the solution

2.92 mL (3.16 mmol) of boron tribromide so that the temperature of the reaction mixture did not rise above 20 ° C. The resulting slurry was stirred for half an hour at room temperature and then methanol (40 mL) was added dropwise with stirring and cooling with ice-water at a rate such that the internal temperature did not rise above 25 ° C. The reaction mixture was evaporated, the residue was refluxed with 68 ml of distilled water for 1 hour, the solution was cooled, diluted with 100 ml of distilled water and neutralized with solid potassium bicarbonate and extracted with chloroform. The organic phase is dried and evaporated, and the residue is purified by column chromatography. 1.01 g (48%) of the title compound are obtained. R _f = 0.45. Melting point of its monohydrochloride salt: 181-183 ° C.

Example 46

4- {3- [N- [2- (3,4-Dimethoxyphenyl) ethyl] -N-methylamino] -propylamino} -3 (2H) -pyridazinone dihydrochloride (Method F)

0.52 g (1.36 mmol) of 5-chloro-4- {3- [N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methylamino] -propylamino} -3 ( 2H) -pyridazinone (Example 1) in 20 mL of ethanol and

1.25 mL cc. dissolved in a mixture of ammonium hydroxide. The solution is hydrogenated in the presence of 0.3 g of 10% palladium on carbon at atmospheric pressure in a Paar apparatus until the desired hydrogen uptake is achieved. The catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in ethanol (3 mL) and the pH of the solution was adjusted to pH 2 with ethanolic hydrogen chloride gas solution with stirring and ice-cooling. The solution was allowed to stand overnight at -10 ° C, and the precipitated crystals were filtered, washed and dried. 0.42 g (74%) of the title compound is obtained. O. pp .: 169-171 'C.

Starting from the appropriate starting materials and following procedure f), the compounds listed in Table 4 below are prepared:

Table 4

Example R ¹ Mode- by school Yield O. p. (° C) 47th ^ / CUG / g f 62 228-230 ⁸ 48th (Et) ₂ N (CH 2) ₂ f 70 130134 ^a 49th PbO / CHg / gW W / CH2 / 2 f 56 157-159 ^b

a 2HCI Η2Ο b3HCl 2Η2Ο

Preparation of acid addition salts

5-Chloro-4- (3- [N- [2-phenethyl) -N-methylamino] -propylamino} -3 (2H) -pyridazinone fumarate

To a solution of the base of Example 14 (0.9 g, 2.8 mmol) in ethanol (8 mL) at 70 ° C was added fumaric acid (0.33 g, 2.8 mmol) in ethanol (70 mL) at 70 ° C. A solution of C is added dropwise. The reaction mixture was allowed to stand overnight at -10 ° C, and the precipitated crystals were filtered, washed, and dried. 1.01 g (83%) of the title product are obtained.

O. p .: 164-167 'C.

4-Chloro-2- (2- (N, N-diethylamino) ethyl] -5- {4- [2-14 [(methylsulfonyl) amino] phenoxy] ethyl-1-piperazinyl} -3 (2H) -pyridazinone dihydrochloride 0.8 g (1.5 mmol) of a suspension of the base of Example 30 in 11 ml of anhydrous acetone was stirred and ice-cooled with dry hydrogen chloride gas.

EN 211 487 A9 is set to 2. The solution was allowed to stand at -10 ° C overnight, the precipitated crystals were filtered, washed and dried. Yield: 0.82 g (91%). O. p .: 171-173 'C.

Preparation of starting materials

1. The novel 4,5-dihalo-3 (2H) -pyridazinones of formula (péld) in the Examples are prepared, for example, by the following methods:

(i) method

4,5-Dichloro-α- {α- [4- (2-phenoxyethyl) -N-piperazinyl] ethyl} -3 (2H) -pyridazinone dihydrochloride

To a solution of 0.69 g (30 mmol) of sodium metal in 20 ml of anhydrous ethanol was added with stirring at room temperature, 1.65 g (10 mmol) of 4,5-dichloro-3 (2H) pyridazinone and stirring was continued for 15 minutes. 2- [4- (2-Phenoxyethyl) -1-piperazinyl] ethyl chloride dihydrochloride (41 g, 10 mmol) was added. The reaction mixture was stirred and refluxed for 2 hours. The precipitated sodium chloride is filtered off and the filtrate is salted with ethanolic dry hydrogen chloride gas. Yield: 73%. M.p .: 208210 ° C.

4,5-Dichloro-2- (2- [4- (3-phenyl-2-propenyl)] - piperazinyl] -ethyl] -3 (2H) -pyridazinone dihydrochloride In all of the above steps but with appropriately substituted alkyl chloride to give the title product in 66% yield, m.p .: 238240C.

(ii) method

4,5-Dichloro-2- (4-methoxybenzyl) -3 (2H) -pyridazinone

Potassium salt of 1.65 g (10 mmol) of 4,5-dichloro-3 (2H) -pyridazinone in methanolic solution of equimolar potassium hydroxide was prepared and the methanol was evaporated in vacuo. A solution of 4-methoxybenzyl chloride (1.56 g, 10 mmol) in toluene (30 mL) was added dropwise to a suspension of the salt in toluene (30 mL) and tetrabutylammonium bromide (0.6 g, 1.8 mmol) was added dropwise. The reaction mixture was refluxed for 3 hours and then evaporated to dryness in vacuo. The residue was dissolved in water and the solution was extracted with ethyl acetate. After drying and evaporation, the crude product was chromatographed on a silica gel column, if necessary, with ethyl acetate. 1.17 g (414%) of the title compound are obtained. O. p .: 117-120 'C.

2- (Benzyloxymethyl) -4,5-dichloro-3 (2H) -pyridazinone Using the above procedure, but substituting 4-methoxybenzyl chloride for benzyloxymethyl chloride, the title compound is obtained in 60% yield. M.p .: 60-64 ° C.

iii) method

2- (3-Phenyl-2-propenyl) -4,5-dichloro-3 (2H) -pyridazinone

A suspension of 16.5 g (100 mmol) of 4,5-dichloro-3 (2H) -pyridazinone and 150 g (163 mmol) of anhydrous potassium carbonate in 100 ml of anhydrous dimethylformamide was stirred with cooling of cold water at a temperature below 15 ° C. A solution of 16.8 g (110 mmol) of 3-phenyl-2-propenyl chloride in 5 ml of anhydrous dimethylformamide was added dropwise. The reaction mixture was stirred at room temperature for 1 day and then poured into 600 ml of water with stirring. The precipitated crystals are collected, washed with water, then dried and, if necessary, purified by treatment with alumina in benzene solution. 24.9 g (89%) of the title compound are obtained.

(iv) method

4,5-Dichloro-2- (4 - [(methylsulfonyl) amino] benzyl} 3- (2H) -pyridazinone

4.5 g (15 mmol) of 4,5-dichloro-2- (4-nitrobenzyl) 3 (2H) -pyridazinone, which was prepared in Example iii. Prepared according to Method A, except that 4-nitrobenzyl chloride (p. 128-130 'C) was used in place of 3-phenyl-2-propenyl chloride, dissolved in 150 ml of 99.5% acetic acid. 7.5 g of iron powder are added to the solution while stirring and cooling, so that the temperature does not rise above 20 ° C, and the suspension is stirred for 8 hours at room temperature. The reaction mixture was worked up in the usual manner, 3.15 g (77%) of 2- (4-aminobenzyl) -4,5-dichloro-3 (2H) -pyridazinone (m.p.

187-189 'C) dissolved in 34 ml of anhydrous pyridine. To the solution, while stirring and cooling, 1.24 mL (16 mmol) of methanesulfonyl chloride was added dropwise so that the internal temperature of the reaction mixture was kept between 0 and 5 ° C. The reaction mixture was stirred at room temperature for 4 hours and then poured into water. The precipitated crystals are filtered off and washed with water. This gives 2.34 g (57%) of the title compound. O. pp .: 152-154 'C.

2. The novel 1-substituted piperazines of formula IV and the 1-substituted (1,4) diazacycloheptanes of formula IV may be prepared, for example, as follows:

(i) method

- Preparation of [3- (4-Fluorophenyl) -2-propenyl) piperazine

To a boiling solution of 32.4 g (376 mmol) of anhydrous piperazine in 45 ml of anhydrous ethanol was stirred and refluxed for 1 hour 6.3 g (37 mmol) of 3- (4-fluorophenyl) -2-propenyl chloride. of anhydrous ethanol solution was added dropwise. The solvent was evaporated in vacuo and the residue was dissolved in chloroform and washed with water to remove piperazine. The organic phase is dried, evaporated and the crude product is evaporated in vacuo if necessary. 5.4 g (66%) of the title compound are obtained. E p: 148 'C / 80 Pa.

1- (3-Phenyl-2-propenyl) - (1,4) diaza-cycloheptane

In all of the above steps, but using 1,4-diazacycloheptane instead of piperazine and 3-phenyl-2-propenyl chloride instead of 3- (4-fluorophenyl) 2-propenyl chloride, 91% yield of the title compound is obtained. product. R _f = 0.25.

HU 211 487 A9

1- {2- {4 - [(Methylsulfonyl) amino) phenoxy) ethyl} piperazine monohydrate

In all the above steps, but using 2- {4 - [(methylsulfonyl) amino] phenoxy} ethyl chloride instead of 3- (4-fluorophenyl) -2-propenyl chloride, the title compound is obtained in 40% yield. product. Mp: 212-214'C.

3. The novel 3 (2H) pyridazines of formula (V) in the embodiments are prepared, for example, by the following methods:

(i) method

4- [N- (Hydroxypropyl) amino] -5-chloro-2-methyl-3 (2H) -pyridazinone

4,5-Dichloro-2-methyl-3 (2H) -pyridazinone (3.58 g, 20 mmol) and 3-aminopropanol (3.76 g, 50 mmol) were dissolved in water (35 mL). The mixture was refluxed for 4 hours, cooled and extracted with dichloromethane (200 mL). The organic phase is dried, evaporated and the crude product is chromatographed on silica gel. 0.84 g (19%) of the title compound is obtained. M.p .: 65-66 ° C, _Rf = 0.7.

Prepared according to the above procedure starting from 2- (benzyloxymethyl) -4,5-dichloro-3 (2H) -pyridazinone

2- (benzyloxymethyl) -4- [N- (3-hydroxypropyl) amino] -3 (2H) -pyridazinone. Yield: 28%, _Rf = 0.75, mp: 54-56 ° C ii) Method

5-Chloro-4- [N- (3-chloropropyl) amino] -2-methyl-3 (2H) pyridazinone

Dissolve 5-chloro-4- [N- (3-hydroxypropyl) amino] -2-methyl-3 (2H) -pyridazinone (0.48 g, 2.2 mmol) in dichloromethane (5 mL) and add 2 , 1 mL (28.8 mmol) of thionyl chloride was added dropwise. The reaction mixture was stirred and refluxed for 3 hours. The solvent was evaporated and the crude product was triturated in ether to give 0.38 g (73%) of the title compound. O. p .: 91-92'C.

2- (Benzyloxymethyl) -5-chloro-4- [N- (3-chloropropyl) amino] -3 (2H) -pyridazinone is prepared from the appropriate starting materials as described above. Yield: 70%, m.p. 42-46 ° C.

4. The novel 3 (2H) -pyridazines of formula (VIII) in the Examples may be prepared, for example, by the following methods:

(i) method

4-Chloro-2-methyl-5 - (] - piperazinyl) -3 (2H) -pyridazinone

A solution of 4,5-dichloro-2-methyl-3 (2H) -pyridazinone (4.48 g, 25 mmol) and piperazine (17.2 g, 200 mmol) in anhydrous ethanol (45 mL) was heated at reflux for 4 hours. The solvent was evaporated in vacuo and the residue partitioned between water and dichloromethane. The organic phase is washed with water, dried and evaporated. The residue was triturated with ether to give 3.44 g (60%) of the title compound. M.p. 83-84 'C.

(ii) method

2-Benzyloxymethyl-5-chloro-4- (N- (3- (methylamino) pmpylamino) -3 (2H) pyridazinone

2.35 g (15.63 mmol) of 2- (benzyloxymethyl) -5-chloro-4- [N- (3-chloropropyl) amino) -3 (2H) -pyridazinone (prepared according to Step 3.ii). Example 4) is dissolved in 40 ml of ethanol containing 33% methylamine. The solution was kept in a pressure-resistant steel tube at 100 ° C for 5 hours. The solvent was evaporated and the residue was chromatographed on silica gel. 4.19 g (80%) of the title compound are obtained. R _f = 0.35.

PATENT CLAIMS

Claims (5)

PATENT CLAIMS 1. The following racemic or optically active 3 (2H) -pyridazinones: 5-Chloro-2- (2- (N, N-diethylamino) ethyl) -4- (3- (N- (2- (3,4-dimethoxyphenyl) ethyl) -N-methylamino) propylamino) -3 (2H) -pyridazinone, 5-chloro-4- (3- (N- (2- (3,4-dimethoxyphenyl) ethyl) -N-methylamino) propyl) -2- (4 - ((methylsulfonyl) - amino) benzyl) -3 (2H) -pyridazinone, or 5-chloro-4- (3- (N- (2- (4- (methylsulfonyl) amino) phenoxy) ethyl) -N-methyl-amino) propyl) -3 (2H) -pyridazinone The 3 (2H) -pyridazinone of claim 1 which is 5-chloro-2- (2- (N, N-diethylamino) ethyl) -4- (3- (N- (2 (3, 4-dimethoxyphenyl) -N-methylamino) -propylamino) -3 (2H) -pyridazinone. The 3 (2H) -pyridazinone of claim 1 which is 5-chloro-4- (3- [N- (2- (3,4-dimethoxyphenyl) ethyl) -N-methylamino) propyl- amino) -2- (4 - ((methylsulfonyl) amino) benzyl) -3 (2H) -pyridazinone The 3 (2H) -pyridazinone of claim 1 which is 5-chloro-4- (3- (N- (2 - ((methylsulfonyl) amino) phenoxy) ethyl) -N-methylamino) propylamino) -3 (2H) -pyridazinone 5. A racemic or optically active 3 (2H) -pyridazinone which is 5-chloro-4- (3- (N- (2- (3,4-dimethoxyphenyl) ethyl) -N-methylamino) propyl amino) -3 (2H) -pyridazinone.