Derivative 3(2h)-pyridazinone, pharmaceutical composition, method of treatment

 

(57) Abstract:

The invention relates to new derivatives of 3(2H)-pyridazinone General formula I, where R1is hydrogen, phenyl, methyl, substituted CH3O or CH3SO2NH, C2-C4-alkyl, substituted R8R9N; C3-C5alkenyl, substituted phenyl, which is optionally substituted by halogen, one of A and B is hydrogen and the other a group of formula II, where R2and R3is independently hydrogen, C1-C4-alkyl or together with the adjacent group-N(CH2)nN - form pieperazinove or homopiperazine ring; R4is hydrogen or C1-C4-alkyl, R5, R6and R7is hydrogen, C1-C4-alkoxy, CH3SO2NH, X is a simple valence bond, an oxygen atom or the group-CH= CH-, m = 0-1, n = 2-3; R8and R9- independently C1-C4-alkyl, or together with the nitrogen atom to which they are attached, form morpholino - or 4-R10- piperazinone, where R10- C1-C4-alkyl, substituted phenoxypropane, or C3-C5alkenyl, substituted phenyl group, or an acid additive salts, which possess antiarrhythmic activity, pharmaceutical compositions, sod what avicelase and/or fillers. Proposed method antiarrhythmic treatment, which consists in assigning the patient an effective amount of the compounds or its pharmaceutically acceptable salt. Connection with its activity superior to known drug, e.g., sotalol. 3 S. and 3 C.p. f-crystals, 1 Il., table 4.

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The invention relates to racemic or optically active new derivative 3(2H)-pyridazinone, to a method for producing them, to pharmaceutical compositions containing these derivatives, to the use of these derivatives 3(2H)-pyridazinone in the treatment of diseases and in obtaining pharmaceutical compositions suitable for the treatment of disease.

According to the features of the present invention offers a racemic or optically active new derivatives of 3(2H)-pyridazinone General formula I

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in which R1represents hydrogen, phenyl, methyl, optionally having benzyl, hydroxy-Deputy, C1-4-alkyl, optionally having a Deputy of the formula R8R9N-, in which R8and R9independently are C1-4-alkyl, or R8and R9form, together with the adjacent nitrogen atom, a 6-membered heterocyclic group, optionally codeline with phenoxy Deputy, or C3-5alkenyl having a phenyl substituent; in addition, the C1-4-alkyl optionally substituted with phenyl having a methoxy - or methanesulfonamido, Deputy, or C3-5alkenyl, optionally having halogen or halodefinitely deputies;

A and B denote hydrogen, halogen or a group of the General formula II

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in which R2and R3independently are hydrogen or C1-4-alkyl, or together with the adjacent N-(CH2)nN-group form pieperazinove or homopiperazine ring,

R4represents hydrogen, C1-4-alkyl or phenyl,

R5, R6and R7each represents hydrogen, C1-4-alkoxy or amino group, optionally having methanesulfonyl Deputy,

X is a simple valence bond, an oxygen atom or a group of formula-CH=CH-

m is 0 or 1, and

n is 2 or 3, provided that A and B are always different and if one of A and B is hydrogen or halogen, and the other denotes a group of General formula (II),

and their additive salt of the acid.

The invention includes all tautomeric forms of the compounds of General formula I

Compounds of the present invention possess price is for the description of the invention, refer to linear or razvetvlenno-chain saturated aliphatic hydrocarbon groups having the number of carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, etc. as "C3-5-alkenyl groups" are mentioned linear or razvetvlenno-chain alkeneamine group, for example, allyl, 2-methylallyl, 1-propenyl, 2-propenyl, 1-butenyl and so on, the Term "halogen atom" includes all four halogen atom (fluorine, chlorine, bromine, iodine).

Compounds in which R1denotes hydrogen, methyl or C1-4-alkyl, optionally substituted by diethylaminopropyl, A represents A chlorine or bromine attached to pyridazinedione cycle in position 4, and B denotes an optionally substituted 1-(3-phenyl-2-propen-1-yl)-pieperazinove group attached to pyridazinedione cycle in position 5, belong to a preferred group of compounds of General formula (I).

Compounds in which R1represents hydrogen or C1-4-alkyl, substituted diethylamino - or 1-(2-phenoxyethyl)-piperazinone, A denotes a halogen, B is a group of the General formula (II) in which R2, R4and R5represent hydrogen, R3denotes methyl, R6and R7

Particularly preferred representatives of the compounds of General formula (I) are the following derivatives:

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

4-chloro-2-[2-[N, N-diethylamino)-ethyl] -5-[4-(3- phenyl-2-propenyl)-1-piperazinil]-3(2H-pyridazine,

5-chloro-4-[3-[N-[2-(3,4-acid)-ethyl]-N-methylamino]- propylamino] -2-[2-morpholinoethyl]-3-(2H)-pyridazinone,

5-chloro-2-[2-(N, N-diethylamino)-ethyl] -4-[3-N-[2-(3,4 - acid)-ethyl]-N-methylamino]-propylamino]-3-(2H)-pyridazinone,

4-[3-[N-[2-(3,4-acid)-ethyl] -N-methylamino] - propylamino] -3(2H)-pyridazinone,

5-chloro-4-[3-[N-[2-(3,4-acid)-ethyl]-N-methylamino]- propylamino] -2-[4-[(methoxyphenyl)-amino]-benzyl]-3(2H)-pyridazinone,

5-chloro-4-[3-[N-2-[4-[(methylsulphonyl)-amino]-phenoxy-]-ethyl]-N - methylamino]-propylamino]-3(2H)-pyridazinone,

and pharmaceutically acceptable salts of them when joining acids.

New 3(2H)-pyridazinone of the present invention belong to the group of compounds that is (the group) are less well known in this field.

Patent application Japan N 78-casinono, structurally similar to the compounds of the present invention, which serve as intermediates in obtaining pyridazino-[4,5-b][1,4-]-oxazino exhibiting anti-inflammatory, antidepressant and analgesic activity.

The description of the patent Czechoslovakia N 223.432 relates to 2-(C1-3)-alkyl, 2-cycloalkyl, 2-aryl and 2-(optionally substituted)-aralkyl-5-chloro-3(2H)-pyridazinone containing alkyl, alkoxyalkyl, cyclooctylamino-, pyrrolidino or piperidino in position 4.

Description of the invention to the French patent N 2.124.164 is 2-phenyl-6-chloro-(or methoxy)-4-[4 -(- benzoylethyl)-1-piperazinil]- 3(2H)-pyridazinone exhibiting analgesic, sedative and hypotensive properties.

Published patent application Germany N 3.902.316 refers to A derivative piperazinil(alkylamino)-pyridazinone with activity in blocking alpha adrenoceptor, in which - in contrast to the compounds of the present invention is pieperazinove and pyridazinones cycles are not connected to each other directly, and join through alkylamino chain.

Published patent application Europe N 320.032 describes A 3-(phenylamino-alkyl)-is given antiviral activity.

Published description of the invention the European patent N 54.946 provides derivatives of 4-chloro-5-[2-(3-phenoxy-2-oxypropylene)-ethyl] -amino - 3(2H)-pyridazinone, structurally different from 3(2H)-pyridazinones of the present invention. Although alpha - and beta-receptor-blocking, anti-arrhythmic and anti-hypertensive effects and are attributed to these compounds, only hypotensive activity is proved by the test results.

According to additional features of the present invention, it is proposed a method of obtaining a racemic or optically active derivatives of 3(2H)-pyridazinone General formula I, which includes:

a) to obtain compounds of General formula I, in which one of A and B is not hydrogen, and R1has the above specified values, the reaction of compounds of General formula III

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in which R1has the above specified values,

and Hal represents halogen,

with an amine of General formula IV

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in which R2, R3, R4, R5, R6, R7, X, m and n have the same above a certain value, or

b) to obtain compounds of General formula I, in which R1is not hydrogen or a phenyl, A, B, and R3are not hydrogen, and R1
is hydrogen, and R3is not hydrogen, and R2, R4, R5, R6, R7, X, m and n are defined in the introductory part, with the compound of General formula R1Z, in which R1is defined in the introductory part is, except that he may not denote hydrogen or phenyl, and Z is a leaving group, or

to obtain compounds of General formula I in which A and B are defined in the introductory part of the value, R2and R3are the same or different and represent hydrogen or C1-4-alkyl, and R1, R4, R5, R7, R6, X, m and n are defined in the introductory part of the value, the reaction of compounds of General formula V

(V)

in which R1is defined in the introductory part is,

C and D are hydrogen or halogen atom or a group of the General formula VI

(VI)

in which R2is hydrogen or C1-4-alkyl,

Z denotes a leaving group,

and n is defined in the introductory part is, provided that one of C and D is always hydrogen or halogen, and with the additional condition that if one of them is hydrogen or halogen, the other is oredom or C1-4-alkyl,

R4, R5, R6, R7, X and m are defined in the introductory part of the value, or

g) to obtain compounds of General formula I, in which R1is not hydrogen, and A and B are defined in the introductory part of the value, the reaction of compounds of General formula VIII

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in which R1and n are defined in the introductory part of the value,

Y represents hydrogen or halogen, provided that one of Y and-N(R2)-(CH2)n-NH(R3-the group is always attached to pyridazinedione cycle in position 4, and the other(s) attached to the same loop in position 5,

with a compound of General formula IX

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in which R4, R5, R6, R7, X and m are defined in the introductory part of the value,

Z is a leaving group, or

d) to obtain compounds of General formula I, in which R1is hydrogen, and A and B are defined in the introductory part of the value, the processing of compounds of General formula I, in which R1means benzyloxyethyl group, and A and B are defined in the introductory part, with tribromide boron, or

e) to obtain compounds of General formula I, in which one of A and B is hydrogen, and R11is defined in the introductory part is, A and B represent halogen or a group of General formula II, provided that if one of A and B is halogen, the other represents a group of General formula II,

and, if necessary, the conversion of compounds of General formula I obtained according to the variant of the method a) to (e), its salt accession acid and/or separation of optically active isomers.

According to a preferred implementation variant of the method a), to obtain compounds of General formula I in which A denotes a group of General formula II, B is defined in the introductory part of the value derived from 4,5-diploid-3(2H)-pyridazinone General formula III is subjected to reaction with the amine of General formula IV in a non-polar solvent such as dioxane or toluene, at temperatures between 50oC and the boiling point of the solvent. Amin used in double-a ten-fold excess relative to one mole of the compounds of General formula III.

According to a preferred implementation variant of the method a), to obtain compounds of General formula I, in which B is a group of General formula II, and is defined in the introductory part is, the compound of General formula III ACC at a temperature between 50oC and the boiling point of the solvent. Amin used in double-a tenfold excess, calculated per one mol of the compounds of General formula III.

According to a preferred implementation variant of the method b), the compound of General formula I, in which R1represents hydrogen, is subjected to reaction with a compound of General formula R1Z, in which Z is preferably chlorine or bromine, in an aprotic solvent, preferably in dipolar-aprotic solvent such as dimethylformamide, in the presence of binders acid, such as potassium carbonate, at temperatures between 25oC and the boiling point of the solvent.

According to a preferred implementation variant of the method), the compound of General formula V is subjected to reaction with the amine of General formula VII or without using any solvent or in a solvent, preferably in dipolar-aprotic solvent such as dimethylformamide, at a temperature between 50 and 150oC. the amine is used in double-a ten-fold excess relative to one mole of the compounds of General formula V.

According to a preferred implementation variant of the method d), the connection abseil bromine, without using any solvent or in a solvent, preferably in dipolar-aprotic solvent such as dimethylformamide, optionally in the presence of binders acid, any organic or inorganic base, at a temperature between 25oC and 120oC.

According to a preferred implementation variant of the method d), the compound of General formula I, in which R1means benzyloxyethyl group, is subjected to reaction with tribromide boron in a solvent inert to the reacting substances, such as benzene or toluene, at room temperature.

According to a preferred implementation variant of the method (e), the compound of General formula I in which A and B are not hydrogen, is treated either with gaseous hydrogen, or a substance-hydrogen donor in the presence of a catalyst suitable for dehalogenase, such as palladium on charcoal, and optionally in the presence of binders acid, preferably inorganic bases, such as ammonia, at atmospheric pressure.

The reaction mixture obtained according to any one of the above options the way, can (optionally under vacuum) and the residue is extracted and/or subjected to chromatography and/or crystallization. Thus obtained compound of General formula I is optionally purified, for example by chromatography and/or recrystallization, moreover, and if it is possible and desirable, it can be converted into a salt with accession acids, which can be, if necessary, purified by recrystallization.

Compounds of General formula I containing a strongly basic group, can be converted into a salt with accession acid. To this end, the base is dissolved in an appropriate solvent, and the corresponding acid or its solution in an appropriate solvent is added to a solution of the base with stirring. Thus obtained reaction product is separated by filtration or crystallization, followed by evaporation of the solvent, and optionally purified, for example by recrystallization. The acid can be used organic and inorganic acids, preferably pharmaceutically acceptable acid, for example sulfuric acid, hydrogen chloride, fumaric or citric acid. The solvent can be used such as alcohols, esters, ethers and/or ketones. The salt formation is carried out at a temperature between 0 and 80occhialino at a temperature between 50 and 80oC.

Compounds of General formula I, in which R1and/or R2means(ut) hydrogen, can also exist in tautomeric forms. These compounds also belong to the scope of the present invention.

Compounds of General formula I, in which R4is not hydrogen, and/or the substituents R1, R2and/or R3contain one or more of the center(s) asymmetry may exist in optically active forms. The present invention includes both the racemic and optically active forms of compounds of General formula I.

Some of the compounds of General formula I used as starting substances for option a), are known in this field, for example, J. Am. Chem. Soc. 75, 19098 (1953) Bull. Chem. Soc. France, 1964, 2124, J. Heterocyclic Chem 21, 481 (1984) Farmaco Ed. Sci. 32, 239 (1984), Chem. Pharm. Bull. 18, 147 (1970). Those compounds of General formula III, which are not described hitherto in the literature, can be obtained by similar methods. Thus, compounds of General formula III in which R1represents alkenyl having optionally substituted phenyl substituent, or an alkyl having 4-substituted 1-piperazinilnom Deputy, can be obtained by the reaction of 4,5-diploid-3(2H)-pyridazino the nom. Most of reagents of General formula R1Z used in the reaction of the present invention, are known in the art [for example, J. Chem. Soc. 1940, 1266, ibid 1961, 2516. In 1966 590 J. Am. Chem. Soc. 83, 3846 (1961) Chem. Ber. 30, 810, Chem. Pharm. Bull 25 1811 (1977), other compounds of General formula R1Z can be obtained by similar methods. Compounds of General formula III in which R1denotes 4-(methanesulfonyl-amino)-benzyl, can be obtained from compounds containing 4-nitrobenzyl as Deputy R1.

Some of the derivatives of 1,2-academia and 1,3-propandiamine and 1-substituted piperazines of General formula IV used for the variant of method (a) as starting substances are known in the art [for example, the description of the invention the European patent N 344.577, the description of the patent Belgium N 523.902, J. Med. Chem. 11, 804 (1986). The new compounds of General formula IV can be obtained by similar methods. Chloride 2-[4-[(methanesulfonamido)-phenoxy]-ethyl and its predecessors, are necessary to obtain 1 [2-[4-(methanesulfonamido)-phenoxy]-)ethyl]-piperazine, can be obtained as described in the description of the invention the European patent N 245.997 and the description of the patent Belgium is under the heading "acquisition of the initial substances" (paragraphs 1 and 2).

Alkylating funds General formula R1Z used as starting substances for the variant of the method b), are known in the art (see above) or can be obtained by similar methods.

Synthesis of new derivatives of 3(2H)-pyridazinone used as starting substances for the variant of the method), discussed below under the heading "acquisition of the initial substances" (paragraph 3). Preparation of amines of General formula VII is known in the literature [Chem. Ber. 31, 11958, J. Am. Chem. Soc. 62 922 (1940)].

Obtaining compounds of General formula VIII used as starting substances for the variant of method g), is presented below under the heading "acquisition of the initial substances" (paragraph 4).

Compounds of General formula I possess valuable pharmaceutical properties. More specifically, they show excellent antiarrhythmic activity.

In the treatment of rhythm disorders that cause pain to a significant portion of the population, medical treatment is a very common method of treatment. The sudden death of the patient with cardiac disease, representing the main cause of death in many countries of the world, can be attributed to ant the arrhythmia, however, only compounds belonging to class III (see: Classification Williams of Vaughan for antiarrhythmic drugs, J. Clin. Pharmacol 24, 129 (1989), are effective, due to the mechanism of their activity, and only some of these compounds are available in Commerce. The ingredients belonging to class I, representing the majority of commercially available antiarrhythmic drugs are, at the same time, practically inactive. That is why there is a great demand for new and safe antiarrhythmic agent belonging to the class III of the above classification.

Strikingly found that the new 3(2H)-pyridazinone General formula I of the present invention, when they are subjected to in vitro cytological electrophysiological experiments, cause significant prolongation of the duration of the peak potential (ARD90) characteristic of antiarrhythmic drugs belonging to class III. In addition, it appears that they have an excellent antiarrhythmic activity in various in vivo tests. Thus, compounds of General formula I of the present invention can be used either during treatment or in the prevention of several tick fibrillation (flickering) of the Atria (atrial fibrillation and ventricular fibrillation.

The activity of compounds of General formula I is represented by the following in vitro electrophysiological experiments and in vivo models of induced arrhythmia.

I. Intracellular electrophysiological studies on isolated dog Purkinje fibres: study of characteristics and duration of peak potential

Half-dogs of both sexes weighing 8-22 kg, anaesthetize intravenous pentobarbital sodium, 30 mg/kg (NembutalR). Surface Purkinje fibers cut from the heart and placed in a plastic tub for bodies containing solution Tyrode (147,0 mm Na+, "6 4.0 mm K+, 133,3 mm Cl-1, 2.0 mm Ca2+, 22,0 mm HCO3-, 0.9 mm H2PO4-, 5.0 mm glucose). The perfusion solution (solution Tyrode) hairout a mixture of 95% CO2and 5% O2. The temperature of the bodies is 37,0 0,5oC pH 7,3 0,5. Fiber Purkinje incubated for 1-2 hours La to avoid sudden changes in the duration of peak capacity, which is often observed within a short period of time after preparation. The usual method of using glass microelectrode use to measure vnutricletocny connected to the amplifier, neutralizing high resistive input capacity, through Ag-AgCl connection. Another electrode placed in the bath for bodies as a reference electrode. The maximum rate of depolarization (Vmaxmeasure e-differentiating device. Intracellular pulses observed in the two channel oscilloscope using the microcomputer in the mode line. Evaluate the following parameters: resting potential, the maximum potential amplitude, 50% and 90% repolarization, maximum rate of depolarization. Drugs stimulate through silver electrodes, insulated with polytetrafluoroethylene (PTFE). The parameters of the stimuli were rectangular pulses with a duration of 1 msec with double intensity threshold. Cycles basal (located at the base) stimuli change in the range between 200 MS and 1000 MS.

Those compounds that are able to prolong the duration of the peak potential, are considered as potential antiarrhythmic agent. Action of the compounds studied at a concentration of 5 mg/L. According to our research, the compounds of General formula (I) significantly prolong the duration of peak potential at 90% repostories typical results are presented in table. 1 (see the end of the description). Sotalol, N-[4-[1-hydroxy-2-[1-methyl-ethyl)-amino]-phenyl]-methanesulfonamide, used as a reference substance.

The above data show that the new compounds of General formula (I) of the present invention prolong the duration of peak potential at 90% repolarization.

II. Extracellular electrophysiological studies on isolated heart of rabbit (the study of the pharmacological effect on the effective refractory period)

Young male new Zealand white rabbits, weighing 1-2 kg death blow to the back of the head. Remove the heart and prepare the right ventricular shell and put them in the tub for bodies containing solution Tyrode. The perfusion solution hairout with 95% CO2. Temperature is 36 0,5oC, pH 7,4 0,5. After a period of equilibrium (60 min) using bipolar electrodes to annoy drugs. The parameters of the stimuli were rectangular pulse duration of 2 msec with double intensity threshold, when the cycle length of 1000 MS.

Two bipolar extracellular platinum electrode localize (d = 0.1 mm) on the surface of the right ventricular membrane along trabeculectomy 8-12 mm from each other, then register two phase induced extracellular peak potentials. Peak potentials appear first on nearby electrodes, then the other electrodes, the difference of time between the electrodes is considered as time impulsive excitation. Amplified signals (signs) (Experimetria GMK) display on the monitor (Medicor VM 62 A). The duration of the cycle varies between 200 and 2000 msec. The measurements are carried out during a full adaptation to the new cycle length. The threshold is measured at each new cycle time as follows: intensity of stimuli is gradually reduced to twice the threshold intensity up until the tensile peak potentials are induced. The connection is used at a concentration of 10 mg/ml. the Results shall be summarized in a table. 2 (see the end of the description).

These results are similar to those obtained with intracellular electrophysiological tests, and confirm antiarrhythmic efficacy of the compounds.

The action of the compounds of Example 1 study on the model of in vivo reperfusion arrhythmias. This experiment is carried out as follows:

Shot rats weighing 400-500 g (anesthetic: 60 mg/kg of Nembutal, VNU the clamp (5 minutes occlusion), and after cessation of occlusion induce reperfusion arrhythmias (ventricular paroxysmal tachycardia and fibrillation), which is recorded ECG monitoring (abstraction from limb). At the same time determine the diastolic (minimum) and systolic (maximum) blood pressure (invasive method: through the carotid artery) and measure the speed of the pulse. Before occlusion control register electrocardiogram (ECG), and note duration postocclusive paroxysmal ventricular tachycardia, and ventricular fibrillation. Sotalol is used as a reference compound. As the test substance, compound No. 1, and the reference substance is administered intravenously in doses of 10 mg/kg the Results are presented in the drawing, which shows the average duration of ventricular paroxysmal tachycardia and/or ventricular fibrillation in a minute.

The results of this experiment, the compound of Example 1 is significantly more effective than sotalol.

According to another features of the present invention, offers a pharmaceutical composition comprising as an active ingredient pharmaceutically effect of tautomers and/or salts when joining acids, together with one or more pharmaceutically acceptable, carrier(s), diluent(s) and/or excipient(s).

The pharmaceutical compositions of the present invention can be prepared according to known methods by mixing the active ingredient with suitable inert solid or liquid carriers, diluents and/or excipients and bring the mixture to the galenical forms.

The pharmaceutical compositions of the present invention may be suitable for oral (e.g. tablet, pills, coated pills, coated tablets, hard or soft gelatin capsule, solution, emulsion or suspension), parenteral (e.g., solution for injection) or rectally (e.g., suppository) purpose.

As a carrier for the preparation of tablets, coated tablets, dragées and hard gelatin capsules can be used, for example, lactose, corn starch, potato starch, talc, magnesium carbonate, magnesium stearate, calcium carbonate, stearic acid or its salts, etc. as a carrier for soft gelatin capsules can be used, for example, vegetable oils, fats, waxes and polyols (polyhydric alcohols) a suitable consistency. the ol), sucrose or glucose. Solutions for injection may include, for example, water, alcohols, polyols, glycerine and vegetable oil as a carrier. Suppositories can be prepared using, for example, oils, waxes, fats or polyols suitable consistency.

In addition, the pharmaceutical compositions can also include ancillary tools, commonly used in the pharmaceutical industry, for example, wetting, sweeteners, flavouring agents, salts, causing the change of osmotic pressure, buffers, etc.

Because of the magnitude of the toxicity of the compounds of General formula I are generally low, spectrum of activity and therapeutic reliability of the compositions of the present invention are very favorable.

Daily dose of the compounds of General formula I can vary within wide limits depending on several factors, for example, the activity of the active ingredient, the condition of the patient and his age, the severity of the disease, etc. Oral daily dose is in most cases between 0.2 mg/kg and 25 mg/kg, preferably between 0.2 mg/kg and 10 mg/kg However, I must emphasize that these values doses are only of informative nature of the items of the present invention provides the use of compounds of General formula I, their tautomers and/or salts when joining acids for the preparation of pharmaceutical compositions having, in particular, anti-arrhythmic activity.

According to still further features of the present invention, it is proposed a method antiarrhythmic treatment, which involves giving the patient an effective amount of compounds of General formula I, its tautomer or a pharmaceutically acceptable salt.

The invention is illustrated further by the following non-limiting Examples of nature. The melting points are not corrected.

Examples 1 and 2

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

(Method a1)

The solution 3,63 g (22 mmol) of 4,5-dichloro-3-(2H)-pyridazinone and 13,88 g (55 mmol) of N-[2-(3,4-acid)-ethyl] -N-methyl-1,3-propandiamine in 80 ml of anhydrous dioxane is boiled for 10 hours under stirring and cooling under reflux. Then the solution is evaporated under vacuum, the residue is subjected to chromatography on a column of silica gel using a solvent mixture of 9: 1: 0.5, the mixture utilized shall be to the above solvent mixture, with the exception of direct note data. Fractions with Rf = 0,54 are combined and evaporated. Thus 2,99 g (36%) 4-isomer, melting at 92-94oC as the reaction product of Example 1. The melting point of its fumarata is 94-96oC. With continued chromatography using the above solvent mixture, and when combined and evaporation of the fractions with Rf = 0,42 obtained 4.09 g (49%) of 5-isomer as the reaction product of Example 2. So pl.: 98-101oC.

It monochlorotoluene salt melts at 108-110oC.

Examples 3 and 4

2-Benzoyloxymethyl-5-chloro-4-[3-[N-[2-(3,4-acid) -ethyl] -N-methylamino] -propylamino]-3(2H)-pyridazinone(4-isomer) and 2-benzyl-oxymethyl-4-chloro-5-[3-[N-[2-(3,4-acid)- ethyl] -N-methylamino] -propylamino] -3(2H)-pyridazinone (5-isomer)

(Method a2)

This method begins by using 1.2 g (4.2 mmol) of 2-benzoyloxymethyl-4,5-dichloro-3(2H)-pyridazinone (obtaining this compound is described below under the heading "raw materials") and 2.66 g (10,54 mmol) N-[2-(3,4-acid)-ethyl] -N-methyl-1,3-propandiamine and is carried out according to the method of a1with the difference that instead of dioxane is used anhydrous toluene and prodolzhitelnost (the reaction product of example 3, Rf = 0.7), 0.87 g (41%) of 5-isomer (the reaction product of example 4, Rf = 0,4)

Examples 5 and 6

5-Chloro-4-[3-[[N-[2-(3,4-acid)-ethyl]-N-methylamino - propylamino] ] 2-(4-methoxybenzyl)-3(2H)-pyridazinone (4-isomer) and 4-chloro-5-[3-[[N-[2-(3,4-acid)-ethyl] -N-methyl - aminopropylene] ] -2-(4-methoxybenzyl)-3(2H)-pyridazinone (5-isomer)

(Method a3)

The method begins by using 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-acid)-ethyl] -N-methyl-1,3-propanediamine and is carried out according to the method of a1with the difference that instead of dioxane is used anhydrous n-butanol. Duration of response: 12 hours. Thus out of 0.85 g (27%) 4-isomer (the reaction product example 5, Rf = 0,4, it fumarate melts at 56-57oC) and 0.97 g (31%) 5-isomer (the reaction product

Example 6, Rf = 0,2)

Example 7

4-Chloro-5-[1-(1,4-)-disallowable-4-(3-phenyl-2-propenyl)]-3- (2H)-pyridazinone (5-isomer)

(Method a4)

In 16 ml of ethanol dissolve of 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)-disallocation and 1.5 ml (11 mmol) of triethylamine. The solution is boiled for 3 hours under stirring and cooling under reflux. The mixture is further cooled, section(53%) of target compound. So pl.: 176-178oC. It monochlorotoluene salt melts at 193-194oC.

When using the appropriate starting compounds and implementing methods for a1-a4are obtained compounds of General formula (I) described in the following table. 3 (see the end of the description).

If necessary, the isomeric forms of the compounds of Examples 31, 32, 36 and 38 are separated by evaporation of the reaction mixture and subjecting the remainder of the purification column chromatography.

Example 39

4-Chloro-5-[3-[N-2-(3,4-acid)-ethyl] -N-methylamino]- propylamino] -2-[3-(4-forfinal)-2-propenyl-3(2H)-pyridazinone

(Method b)

To a suspension of 5.7 g (15 mmol) 4-chloro-5-[3-[N-[2-(3,4-acid)-ethyl]-N-methylamino]- propylamino]-3(2H)-pyridazinone (obtained according to Example 2) and 10.2 g (74 mmol) of anhydrous potassium carbonate in 15 ml of anhydrous dimethylformamide was added dropwise with stirring a solution 2,73 g (16 mmol) of the chloride of 3-(4-forfinal)-2-propenyl in 3 ml of anhydrous dimethylformamide, maintaining the internal temperature at 10-15oC. the Reaction mixture was stirred at room temperature for days. Then under vacuum dimethylformamide is evaporated, to the residue is added a small amount of water and obtained about stillsuits of diethyl ether. Thus 3,24 g (42%) of target compound. So pl.: 84-85oC.

Example 40

5-Chloro-4-[3-[N-[2-(3,4-acid)-ethyl]-N-methylamino]- propylamino] -2-[3-(4-forfinal)-2-propenyl)]-3(2H)-pyridazinone

Proceeding from compounds of Example 1 and acting according to method b, is obtained target compound with a yield of 39%, Rf = 0,5 (EtOAc - MeOH = 9 : 1), his monochlorotoluene salt melts at 126-127oC.

Example 41

5-Chloro-2-methyl-4-[3-[N-(3-methyl-2-propyl)-N-methylamino] - propylamino]-3(2H)-pyridazinone

(Method)

A mixture of 1.77 g (7.5 mmol) of 5-chloro-4-(3-chloropropylamine)-2-methyl-3-(2H)-pyridazinone obtained as described below under the heading "raw materials", and 3.75 g (25 mmol) of N-dimethylphenylethylamine is melted at a temperature of 120oC for 5 hours. Then it is cooled, is added 20 ml of water and the solution extracted with ethyl acetate. The extract is cooled and evaporated and the crude reaction product is purified using column chromatography. Thus 1,67 g (64%) of target compound. Rf = 0.5 in. His fumaric salt melts at 128-129oC.

Example 42

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

Based on 5-Loznica, the melting is carried out at 140oC for 2.5 hours, the target compound is obtained with a yield of 34%, Rf = 0,6.

Example 43

4-Chloro-2-methyl-5-[4-(3-phenyl-2-propenyl)-1-piperazinil]- 3(2H)-pyridazinone

(Method g1)

In 5 ml of anhydrous dimethylformamide suspendered 0.75 g (3.3 mmole) of 4-chloro-2-methyl-5-(1-piperazinil)-3(2H)-pyridazinone obtained as described below under the heading "acquisition of the initial substances, and of 0.91 g (6.6 mmol) of anhydrous potassium carbonate. Then the suspension prikapivatsya a solution of 0.5 g (3.3 mmole) of 3-phenyl-2-propenyl chloride in 5 ml of anhydrous dimethylformamide, and the reaction mixture was stirred at room temperature for 24 hours. The dimethylformamide is evaporated under vacuum, to the residue is added a small amount of water and the solution thus obtained, extracted by eliterelatos. The organic phase is dried and evaporated, and the residue is crystallized from ethanol. Thus obtained 0.55 g (49%) of target compound. So pl.: 98-100oC. It monochlorotoluene salt melts at 218-220oC.

Example 44

2-Benzoyloxymethyl-5 - chloro-[3-[N-[2-[4-[(methylsulphonyl)-amino] phenoxy] -ethyl]-N-methylamino]- propylamino]-3(2H)-pyridazinone

(Nona, of 3.56 g (of 14.25 mmol) chloride 4-[(methylsulphonyl)-amino] - phenoxyethyl and 2 ml of 14.25 mmol) of triethylamine is melted at a temperature of 80oC for 16 hours. She then purified using column chromatography using first ethyl acetate then 9: 1: 0.5 mixture of ethyl acetate-methanol-ammonia. Thus obtained 1.8 g (69%) of target compound.

Rf = 0,7.

Example 45

5-Chloro-4-[3-[N-[2-[4-[(methylsulphonyl)-amino]-phenoxy]- ethyl]-N-methylamino]-propylamino]-3(2H)-pyridazinone

(Method d)

In 53 ml of anhydrous benzene are dissolved 2,69 g (4,88 mmole) of the compound of Example 44. To a solution of prikapivatsya 2,92 ml trichromate boron so that the temperature of the reaction mixture did not exceed 20oC. the thus Obtained suspension is stirred at room temperature for half an hour. Then, under stirring and cooling with ice water prikapivatsya 40 ml of methanol with such speed that the internal temperature did not exceed 25oC. the Reaction mixture is evaporated, the residue is boiled with 68 ml of distilled water for 1 hour, the solution is cooled, diluted with 100 ml of distilled water, the pH is brought to neutral by using solid potassium bicarbonate and ramoso column chromatography. Thus obtained 1.01 g (48%) of target compound, Rf = 0.45 in. It monochlorotoluene salt melts at 181-183oC.

Example 46

Dichlorhydrate 4-[3-[N-2-(3,4-acid)-ethyl]-N-methylamino] propylamino]-3(2H)-pyridazinone

(Method e)

In a mixture of 20 ml ethanol and 1.25 ml conc. (? cc) ammonium hydroxide is dissolved 0.52 g (1,36 mmole) of 5-chloro-4-[3-[N-[2-(3,4-acid)-ethyl]-N-methylamino] -propylamino] -3(2H)-pyridazinone obtained in Example 1. The solution is subjected to hydrogenation at atmospheric pressure in the presence of 0.3 g of 10% palladium catalyst on charcoal using a Parr apparatus. When reaching the necessary absorption of hydrogen, the catalyst was filtered and the filtrate evaporated. The residue is dissolved in a small amount of methylene chloride and the solution filtered. The clear solution is evaporated, the residue dissolved in 3 ml of ethanol, and the solution, thus obtained, is brought to pH 2 with a solution of anhydrous gaseous hydrogen chloride in ethanol under stirring and cooling with ice. The solution is left to stand overnight at -10oC, then the precipitated crystals are filtered, washed and dried. Thus 0,42 g (74%) target the DN (e), get other compounds enumerated in table. 4 ( see the end of the description).

Obtaining salts accession acids

Fumarate 5-chloro-4-3-N-(2-phenylethyl)/N-methylamino)-propylamino - 3(2H)-pyridazinone

To a solution of 0.9 g (to 21.8 mmole) from Example 14 in 8 ml of ethanol prikapivatsya at a temperature of 70oC a solution of 0.33 g (2.8 mmole) of fumaric acid in 6 ml of ethanol, obtained at the same temperature 70oC, under stirring. The mixture is left to stand over night - 10oC, the precipitated crystals are filtered, washed and dried. Thus obtained 1.01 g (83%) of target compound. So pl.: 164-167oC.

Dichlorhydrate-4-chloro-2-[2-N,N-diethylamino)-ethyl]-5-[4-[(2- [4-[methylsulphonyl)-amino]-phenoxy]-ethyl]-1-piperazinil]-3-(2H)- pyridazinone

A suspension of 0.8 g (1.5 mmole) from Example 30 in 11 ml of anhydrous acetone is brought to pH 2 by introducing anhydrous gaseous hydrogen chloride under stirring and cooling with ice. The solution is left to stand overnight at -10oC. Then, the precipitated crystals are filtered, washed and dried. Thus 0,82 g (91%) of target compound. So pl.: 171-173oC.

Obtaining initial substances

< / BR>
Dichlorhydrate 4,5-dichloro-2-[2-[4-(2-phenoxyethyl)-1 - piperazinil]-ethyl]-3(2H)-pyridazinone

To a solution 0,69 g (30 mmol) of metallic sodium in 20 ml of anhydrous ethanol is added at room temperature and under stirring of 1.65 g (10 mmol) of 4,5-dichloro-3(2H)-pyridazinone. The mixture is stirred for 15 minutes, then added to 3.41 g (10 mmol) of dichlorhydrate 2-[4-(2-phenoxyethyl)-1-piperazinil)-ethyl chloride, and the reaction mixture is boiled for 2 hours under stirring and cooling under reflux. Precipitated sodium chloride is filtered and the filtrate is transformed into a salt with a solution of anhydrous gaseous hydrogen chloride in ethanol. Yield: 73%,

so pl.: 208-210oC.

Dichlorhydrate 4,5-dichloro-2-[2-[4-(3-phenyl-2-propenyl)-1 - piperazinil]-ethyl]-3(2H)-pyridazinone

the steps of the above method, but using the appropriate substituted alkyl chloride, obtained target compound with a yield of 66%. So pl.: 238-240oC.

Method ii)

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

of 1.65 g (10 mmol) of 4,5-Dichloro-3(2H)-pyridazinone converted into the potassium salt with an equimolar amount of potassium hydroxide dissolved in methanol, and the methanol is removed under aquamanile in 30 ml of toluene, then added 0.6 g (1.8 mmole) of tetrabutylammonium bromide. The reaction mixture is boiled for 3 hours while cooling under reflux and evaporated to dryness under vacuum. The residue is dissolved in water, then the solution is extracted with ethyl acetate, dried and evaporated. The crude reaction product thus obtained, optionally purified using column chromatography on silikagelevye column, using ethyl acetate as solvent. Thus 1,17 g (41%) of target compound. So pl.: 117-120oC.

2-Benzoyloxymethyl-4,5-dichloro-3(2H)-pyridazinone

The steps of the above method, but using chloride benzoyloxymethyl chloride instead of 4-methoxybenzyl, it turns out the target connection with the release of 60%. So pl.: 60-64oC.

Method iii)

4,5-Dichloro-2-(3-phenyl-2-propenyl)-3(2H)-pyridazinone

To 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 is added dropwise under stirring and cooling at a temperature below 15oC solution of 16.8 g (110 mmol) of the chloride of 3-phenyl-2-propenyl in 5 ml of anhydrous dimethylformamide. The reaction mixture was perimentally filtered are washed with water, dried and optionally purified by treatment with alumina in a solution of benzene. Thus 24,9 g (859%) of target compound. So pl.: 98-99oC.

Method iv)

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

In 150 ml of 99.5%-aqueous solution of acetic acid is dissolved 4.5 g (15 mmol) of 4,5-dichloro-2-(4-nitrobenzyl)-3(2H)-pyridazinone (obtained in accordance with method III, but using 4-nitrobenzylidene instead of 3-phenyl-2-propylchloride) (so pl. 128-130oC). Then to the solution is added 7.5 g of iron powder with such a rate that the temperature did not exceed 20oC, and the suspension is stirred at room temperature for 8 hours. By treating the reaction mixture in the usual way it turns out 3,15 g (77%) of 2-(4-aminobenzyl)-4,5-dichloro-3(2H)-pyridazinone, melting at 187-189oC, which is dissolved in 34 ml of anhydrous pyridine. To a solution of prikapivatsya with stirring and cooling to 1.24 ml (16 mmol) of methane-sulfochloride such a rate that the internal temperature remained between 0oC and 5oC. the mixture is Then stirred at room temperature for 4 hours and poured into water. The precipitated crystals are filtered and promisesand piperazines and 1-substituted (1,4)-diazocyclopropane General formula (IV) can be obtained via the following methods:

Method (i)

1-[3-(4-Forfinal)-2-propenyl]-piperazine

To the boiling solution 32,4 g (376 mmol) of anhydrous piperazine in 45 ml of anhydrous ethanol prikapivatsya under stirring and cooling under reflux within 1 hour a solution of 6.3 g (37 mmol) of the chloride of 3-(4-forfinal)-2-propenyl in 60 ml of anhydrous ethanol. The solvent is removed under vacuum, the residue is dissolved in chloroform and washed with water to get rid of piperazine. The organic phase is dried, evaporated and the crude reaction product, if necessary, distilled under vacuum. Thus 5,4 g (66%) of target compound. So pl.: 148oC/80 PA.

1-(3-phenyl-2-propenyl)-(1,4)-disallowable.

Acting on the above method, but using 1,4-disallowable instead of piperazine chloride and 3-phenyl-2-propenyl chloride instead of 3-(4-forfinal)-2-propenyl obtained target compound with a yield of 91%. Rf = 0.25 in

Monohydrate 1-[2-[(4-(methylsulphonyl)-amino]-phenoxy]-ethyl] piperazine

Steps visheukazannogo method, but using chloride 2-[4-[(methylsulphonyl)amino] -phenoxy] -ethyl chloride instead of 3-(4-forfinal)-2-propenyl obtained target compound with a yield of 40%. So pl. 212-214o
Method (i)

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

In 35 ml of water are dissolved 3.58 g (20 mmol) 4,5-dichloro-2-methyl-3(2H)-pyridazinone and 3.76 g (50 mmol) 3-aminopropanol. The mixture is boiled for 4 hours under stirring and cooling under reflux, then it is cooled and extracted with 200 ml of chloride methanol. The organic phase is dried, evaporated and the crude reaction product is purified using chromatography on silikagelevye column. Thus obtained 0.84 g (19%) of target compound. So pl.: 65-66oC, Rf = 0,7.

By the above method can be also obtained 2-benzoyloxymethyl-5-chloro-4-[N-(3-oksipropil-)-amino]-3(2H)-pyridazinone. In this case, as the starting material is 2-benzoyloxymethyl-4,5-dichloro-3(2H)-pyridazinone. Yield: 28%. Rf = 0.75 in. So pl.: 54-56oC.

Method ii)

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

In 5 ml of methylene chloride is dissolved to 0.48 g (2.2 mmole) of 5-chloro-4-[N-(3-oksipropil)-amino] -2-methyl-3(2H)-pyridazinone and to the solution prikapivatsya of 2.1 ml (28.8 mmol) of chloride tiomila. The mixture is then boiled for 3 hours under stirring and cooling under reflux. The solvent vyparivaya obtained 0,38 g (73%) of target compound. So pl.: 91-92oC.

According to the above method, but using the appropriate source materials, can also be obtained 2-benzoyloxymethyl-5-chloro-[4-[N-(3-chlorpropyl)-amino]-3 - 3(2H)-pyridazinone. Yield: 70%. So pl.: 42-46oC.

4 New 3(2H)-pyridazinone General formula (VIII) can be obtained, for example, via the following methods:

Method (i)

4-Chloro-2-methyl-5-(1-piperazinil)-3(2H)-pyridazinone

The solution 4,48 g (25 mmol) of 4,5-dichloro-2-methyl-3(2H)-pyridazinone and 17.2 g (200 mmol) of piperazine in 45 ml of anhydrous ethanol is boiled for 4 hours under stirring and cooling under reflux. The solvent is evaporated under vacuum and the residue dissolved in a mixture of water and methylene chloride. The organic phase is washed with water, dried and evaporated. The residue is ground into powder with ether. Thus 3,44 g (50%) of target compound. So pl.: 83-87oC.

Method ii)

2-Benzoyloxymethyl-5-chloro-4-[N-(3-(methylamino)-propyl] -amino] - 3(2H)-pyridazinone

In 40 ml of ethanol containing 33% methylamine, dissolved 5.35 g (15,63 mmol) 2-benzoyloxymethyl-5-chloro-4-[N-(3-chlorpropyl)-amino]- 3(2H)-pyridazinone [which can be obtained according to the method 3ii]. The solution is kept at 100oC in those who tsya chromatography on silikagelevye column. Thus 4,19 g (80%) of target compound. Rf = 0.35 in.

Example 50. Tablet containing 25 mg of active ingredient.

One tablet has the following composition:

Active ingredient - 15,0 mg

Corn starch - 97,0 mg

Polyvinylpyrrolidone - 175,0 mg

Magnesium stearate - 3.0 mg

Total: 300,0 mg

The tablet will receive the following way:

The active ingredient and the corn starch are mixed, then moisten 10-15 wt.% aqueous solution of polyvinylpyrrolidone and a mixture granularit, and then dried at a temperature of from 40 to 50oC. the Dry granules are forced through a sieve, mixed with talc and magnesium stearate and the resulting mixture is produced tablets.

The weight of one tablet is 300 mg.

Example 51. Tablet containing 250 mg of active ingredient.

One tablet has the following composition:

Active ingredient - 250.0 mg

Lactose - 270,0 mg

Corn starch is 75.0 mg

Magnesium stearate - 5.0 mg

Total: 600,0 mg

The tablet will receive the following way:

The active ingredient, lactose and corn starch moisten and mix granularit, and then dried at a temperature of from 40 to 50oC. Dry gr who have tablets.

The weight of one tablet is 600,0 mg.

Example 52. Tablets containing 25 mg of active ingredient.

The core of the bean has the following composition:

Active ingredient - 25.0 mg

Corn starch - 245,0 mg

Talc - 18,0 mg

Gelatin - 8.0 mg

Magnesium stearate 4.0 mg

Total: 300,0 mg

The active ingredient and the corn starch are mixed, then moistened with 10 wt. % aqueous solution of gelatin and of the wet mixture to produce pellets, then the pellets are dried at a temperature of from 40 to 50oC. the Dry granules are forced through a sieve, homogenized with talc and magnesium stearate and the resulting mixture is compressed core tablets with core 300,0 mg

Example 53. Tablets containing 50.0 mg of active ingredient.

The core of the bean has the following composition:

Active ingredient 50.0 mg

Lactose - 97,0 mg

Polyvinylpyrrolidone - 2.0 mg

Magnesium stearate 1.0 mg

Total: 150,0 mg

Granules are produced in the same way as described above. The mass of a single core tablets is 150,0 mg

The core tablets covered with a layer containing sugar and talc using a known method. Received pills paint non-toxic food & rsquo; s the second ingredient.

Active ingredient 5.0 mg

Corn starch - 40,0 mg

Aerosil - 3.0 mg

Magnesium stearate - 2.0 mg

Total: 50.0 mg

The components are homogenized and fill them gelatine capsules of suitable size.

Example 55. Gelatin capsule containing 25.0 mg of the active ingredient.

Active ingredient - 25.0 mg

Corn starch - 265,0 mg

Aerosil - 6.0 mg

Magnesium stearate 4.0 mg

Total: 300,0 mg

The components are homogenized and fill them gelatine capsules of suitable size.

Example 56. Gelatin capsule containing 250 mg of active ingredient.

Active ingredient: 250 mg

Lactose - 148,0 mg

Magnesium stearate - 2.0 mg

Total: 400,0 mg

The components are homogenized and fill them gelatine capsules of suitable size.

Example 57. Solution for injection containing 25.0 mg of the active ingredient.

One ampoule contains:

Active ingredient - 25.0 mg

Sodium chloride - 5.0 mg

Sodium chloride is dissolved in 5 cm3double-distilled water.

The active ingredient and the sodium chloride was dissolved in the required amount of double-distilled water for injection. The solution pewnego ingredient.

One ampoule contains:

Active ingredient 50.0 mg

Sodium chloride - 10.0 mg

The active ingredient and the sodium chloride was dissolved in the required amount of double-distilled water for injection, then poured into ampoules under sterile conditions.

Example 59. Candles containing 250.0 mg of the active ingredient.

Each suppository contains:

Active ingredient - 250.0 mg

The glycerides of the fatty acid - 750,0 mg

Total: 1000,0 mg

Example 60. Drops containing 5% active ingredient.

Active ingredient 50.0 mg

Sorbitol - 340,0 mg

The glycol - 100.0 mg

Citric acid 1.0 mg

Sodium citrate - 3.0 mg

Water that does not contain free ions - 1.0 cm3< / BR>
Flavor - 1.0 mg

Total: 505,0 mg

Sorbitol, active ingredient, citric acid and sodium citrate are dissolved in an aqueous solution of propylene glycol, then after the dissolution of solid materials add flavor. The solution is filtered and poured into bottles with pipettes.

1. Derivative 3(2H)-pyridazinone General formula I

< / BR>
where R1is hydrogen, phenyl, methyl, substituted benzyloxycarbonyl or phenyl group substituted by methoxy or methanesulfonic the config by phenyl, which is optionally substituted with halogen;

A or B - one means a hydrogen or halogen and the other represents a group of General formula II

< / BR>
where R2and R3independently are hydrogen or C1-C4-alkyl or together with the adjacent group-N(CH2)nN - form pieperazinove or homopiperazine ring;

R4is hydrogen or C1-C4-alkyl;

R5, R6and R7mean hydrogen, C1-C4-alkoxy, methanesulfonylaminoethyl;

X is a simple valence bond, an oxygen atom or a group of formula-CH=CH-;

m = 0 or 1;

n = 2 or 3;

R8and R9independently are C1-C4-alkyl, or R8and R9together with the nitrogen atom to which they are attached, form morpholinopropan or 4-R10-piperazinone, where R10means C1-C4-alkyl, substituted phenoxypropane, or C3-C5alkenyl, substituted phenyl group,

or their acid additive salt.

2. Compounds of General formula I on p. 1, wherein R1denotes hydrogen, methyl or C2-C4-alkyl, optionally substituted by diethylaminopropyl, A represents A chlorine or br is pen-1-yl)-piperazinone, attached to pyridazinone cycle in position 5.

3. Compounds of General formula I on p. 1, wherein R1represents hydrogen or C1-C4-alkyl, substituted diethylamino - or 1-(2-phenoxyethyl)-piperazinone, A denotes a halogen, B is a group of General formula II in which R2, R4and R5each represents hydrogen, R3denotes methyl, R6and R7are methoxy group, X is a simple valence bond, m = 1 and n = 3, moreover, A is attached to the loop in position 5, and B attached to the same loop in position 4.

4. The compound of General formula I on p. 1, characterized in that it is a compound selected from the group including

5-chloro-4-[3-[N-[2-(3,4-acid)-ethyl] -N-methylamino]-propylamino] -3(2H)-pyridazinone;

4-chloro-2-[2-(N, N-diethylamino)-ethyl] -5-[4-(3-phenyl-2-propenyl)-1-piperazinil]-3(2H)-pyridazinone;

5-chloro-4-[3-[N-[2-(3,4-acid)-ethyl] -N-methylamino]-propylamino] -2-[2-morpholinoethyl]-3(2H)-pyridazinone;

5-chloro-2-[2-(N,N-diethylamino)-ethyl] 4-[3-N-[2-(3,4-acid)-ethyl] -N-methylamino]-propylamino]-3(2H)-pyridazinone;

4-[3-[N-[2-(3,4-acid)-ethyl] -N-methylamino] -propylamino] -3(2H)-pyridazinone;

5-chloro-4-[3-[N-2-(3,4-dim is-[3-[N-[2-[4-[(methylsulphonyl)-amino] -phenoxy)]-ethyl]-N-methylamino]-propylamino]-3(2H)-pyridazinone.

5. Pharmaceutical composition having anti-arrhythmic activity, containing the active ingredient based on the derived pyridazinone, one or more pharmaceutically acceptable carrier, diluent and/or excipient, wherein the active ingredient it contains a compound of General formula I on p. 1 in an effective amount.

6. The way antiarrhythmic treatment, characterized in that prescribe the patient an effective amount of the compounds of General formula I under item 1 or a pharmaceutically acceptable salt.

 

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< / BR>
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R1unbranched or branched alkyl with 1 to 20 carbon atoms, unbranched or branched halogenated, cianelli, oxyalkyl, alkoxyalkyl or alkoxycarbonyl with 1 to 8 carbon atoms in each alkyl part, unbranched or branched alkenyl with 2 to 12 carbon atoms, unbranched or branched quinil with 2 to 12 carbon atoms or unsubstituted or once to six times substituted by alkyl cyclohexyl or cyclohexylmethyl, unsubstituted or once to fivefold substituted in the phenyl part of the same or different substituents phenyl, phenylalkyl or phenylalkyl with 1 to 12 carbon atoms in each unbranched or branched alkyl or alkenylphenol part, moreover, as substituents of the phenyl can be called a halogen atom, hydroxyl, cyano, formylamino, unbranched or branched alkyl, alkoxygroup with 1 to 4 carbon atoms, unbranched or branched girsvetlana or branched, dialkylamino, alkylsulphonyl, alkylcarboxylic, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, formylamino, alifornian;

R2a hydrogen atom or an unbranched or branched alkyl with 1 to 18 carbon atoms, unsubstituted or singly or multiply substituted by identical or different substituents from the group comprising hydroxyl group, a halogen atom, a cyano;

R1and R2together with the nitrogen atom to which they relate, signify unsubstituted or singly or multiply substituted, saturated five - to semicolony a heterocycle, which may contain in addition to the nitrogen atom, an oxygen atom and a Deputy may be alkoxycarbonyl with 1 to 4 carbon atoms;

R3, R4, R5and R6independently from each other mean a hydrogen atom, halogen atom, alkoxygroup with 1 to 6 carbon atoms

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