WO1992012137A1

WO1992012137A1 - Novel 3(2h)-pyridazinones, pharmaceutical compositions containing them and process for preparing same

Info

Publication number: WO1992012137A1
Application number: PCT/HU1991/000054
Authority: WO
Inventors: Péter MÁTYUS; György RABLOCZKY; László JASZLITS; Judit KOSÁRY; Mária KÜRTHY; Ágnes PAPPNÉ BEHR; Dénesné ZÁRA; Egon Kárpáti; Anikó KOVÁCS; László Sebestyén; Lajos Farkas; Klára Czakó; Ildikó VARGA; Sándor ELEK; Istvánné MAGÓ; György MÁTHÉ; Ferenc SZEDERKÉNYI; Andrea JEDNÁKOVITS; Ilona BÓDI; Benjamin PODÁNYI
Original assignee: Richter Gedeon Vegyeszeti Gyar RT
Current assignee: Richter Gedeon Vegyeszeti Gyar Nyrt
Priority date: 1990-12-27
Filing date: 1991-12-20
Publication date: 1992-07-23
Anticipated expiration: 1993-06-27
Also published as: HU908474D0; HU209388B; HUT60476A; EP0517877A1; CA2074261A1; JPH05504778A

Abstract

The invention relates to novel, racemic and optically active 3(2H)-pyridazinone derivatives of general formula (I), wherein R1 means hydrogen; a C¿1-4?alkyl group optionally substituted by an R?5R6¿N- group where R?5 and R6¿, being the same or different, stand for a C¿1-4?alkyl group or R?5R6¿N- together represents a 6-membered heterocyclic group optionally containing an oxygen or an R7N- moiety where R7 is a C¿1-4?alkyl optionally substituted by a phenyoxy group or a C3-5alkenyl optionally substituted by a phenyl group; or a C1-4alkyl group substituted by a mono- or polysubstituted phenyl, phenoxy or benzyloxy group; or a C3-5alkenyl or C3-5alkynyl optionally substituted by an unsubstituted or optionally substituted phenyl group; or a phenyl group; R?2¿ means hydrogen; or a C¿1-4?alkyl optionally substituted by a morpholino, pyridyl, 1,4-benzodioxanyl or an optionally substituted phenyl group; R?3¿ means hydrogen or an optionally substituted phenyl group; R4 means hydrogen; or R8CO- group where R8 is a C¿1-4?alkyl, phenyl or pyridyl group or an amino group substituted by a C1-4alkyl group; or an -SO3M moiety where M is hydrogen or an organic or inorganic cation; X means halogen; and n is 1, 2 or 3, with the proviso that R?1¿ is different from a C¿1-4?alkyl, alkenyl, aralkyl and phenyl group when n is 1, as well as their tautomers and the acid addition salts of these compounds. The invention further relates to pharmaceutical compositions containing as active ingredient a compound of general formula (I) as well as to a process for the preparation of compounds of general formula (I). The compounds of the invention possess a significant calmodulin-antagonizing effect, decrease the coronary resistance and are less toxic. Thus, these compounds are useful for treating cardiovascular diseases, particularly angina pectoris.

Description

NOVEL 3(2H)-PYRIDAZINONES, PHARMACUTICAL COMPOSITIONS CON- TAINING THEM AND PROCESS FOR PREPARING SAME

This invention relates to novel 3 (2H) -pyridazinones of the general formula (I),

wherein

R¹ means hydrogen; a C_1-4alkyl group optionally

substituted by an R⁵R⁶N- group where R⁵ and R⁶, being the same or different, stand for a C_1-4alkyl group or R⁵R⁶N- together represents a 6-membered heterocyclic group optionally containing an oxygen or an R⁷N- moiety where R⁷ is a C_1-4alkyl optionally substituted by a phenyoxy group or a C_3-5alkenyl optionally substituted by a phenyl grup; or a C₁_₄alkyl group substituted by mono- or polysubstituted phenyl, phenoxy or benzyloxy group; or a C_3-5alkenyl or C_3-5alkynyl optionally substituted by an unsubstituted or optionally

substituted phenyl group; or a phenyl group;

R² stands for: hydrogen; or a C_1-4alkyl optionally

substituted by a morpholino, pyridyl, 1,4-benzodioxanyl or an optionally substituted phenyl group;

R³ means hydrogen or an optionally substituted phenyl

group;

R⁴ means hydrogen; or R⁸CO- group where R⁸ is a C_1-4alkyl, phenyl or pyridyl group or an amino group substituted by a C_1-4alkyl group; or an -SO₃M moiety where M is hydrogen or an organic or inorganic cation;

X means halogen; and

n is 1, 2 or 3,

with the proviso that R¹ is different from a C_1-4alkyl, alkenyl, aralkyl and phenyl group when n is 1,

as well as their tautomers, racemic and optically optionally active forms, mixtures thereof and acid addition salts of these compounds as well as pharmaceutical compositions containing these compounds.

According to an other aspect of the invention, there is provided a process for the preparation of the new

compounds of general formula (I).

The compounds according to the invention are endowed with valuable therapeutical, chiefly cardiovascular,

particularly antianginal properties and have also a significant calmodulin-antagonizing effect.

A particularly preferred group of the compounds

according to the invention are compounds of the general formula (I), wherein: R¹ means a C_3-5alkenyl group substituted by an optionally substituted phenyl group; R² stands for a benzyl or 1,4-benzodioxanylmethyl group; R³ is

hydrogen or methoxy-substituted phenyl group; R⁴ represents hydrogen or pyridylcarbonyl group; X means chlorine or bromine; and n is 1, 2 or 3.

An other preferable group of the invention contains compounds of the general formula (I), wherein R¹ stands fo C_1-4alkyl group optionally substituted by an R⁵R⁶N- group where R⁵ and R⁶ are as defined above, or by a methoxy-substi- tuted phenyl or benzyloxy group; R² means benzyl group; R³ is hydrogen; R⁴ stands for hydrogen or an -SO₃M group where M is as defined above; X represents chlorine; and n is 1, 2 3.

The novel 4-(substituted amino)-3(2H)-pyridazinones are the members of a compound class, which has relatively less been studied up to the present.

The Japanese patent specification (published patent application) No. 78-12880 relates to 2-alkyl, 2-alkenyl, 2-aralkyl and 2-aryl derivatives of structurally related 5- and 4-[(2-hydroxyethyl)amino]-3(2H)-pyridazinone compounds, which are the intermediates of antiinflammatory, analgetic and antidepressive pyridazino[3,4-b] [1,4]oxazine derivatives.

The Czechoslovakian patent specification No. 223,432 discloses 2-C_1-3alkyl-, 2-cycloalkyl-, 2-aryl- and 2-(optionally substituted) aralkyl-5-chloro-3 (2H) -pyridazinones containing an alkyl, alkoxyalkyl cycloalkylamino, pyrrolidino or piperidino group in 4-position. These compounds are insecticidally and acaricidally active. The preparation of hydroxyl-substituted alkylamino derivatives does not fall within the scope of this invention. The compounds falling within the scope of the invention are prepared by reacting 4,5-dichloro-3(2H)-pyridazinones with a little excess of the respective (appropriate) amino compound in an inert solvent at an elevated temperature. Essentially the same class of compounds is described in an article of Konecny et al. [Coll. Czech. Chem. Comm. 50, pages 492-502 (1985)]. In this

relation, the relative reactivity of the chlorine atoms of 4,5-dichloro-3(2H)-pyridazinones was also investigated: it has been stated that the exchange reaction of the 4-chlorine atom is favourized by using a little excess of the amine and toluene as solvent; whereas the use of a polar protic solvent promotes the exchange reaction of the 5-chlorine atom, although the isomer ratio depends also upon the

substitutents. Though the reaction of the 5-chlorine atom can be made practically predominant by the suitable choice of conditions and the yields are also good, the preparative yield of the product formed by the substitution of the 4- chlorine atom is usually very low, particularly when a secondary amine is employed as reagent.

It is known that cardiovascular diseases are the leading causes of death in several countries of the world. Angina pectoris, a disease affecting a very wide population also belongs to these disorders. The therapeutically used nitrate compounds, beta-adrenergic blocking agents and calcium

channel inhibitors are not in each case effective, even when used in combination; in addition, their use is not rarely restricted or even contraindicated by their side effects or accompanying diseases.

The syndrome of angina pectoris occurs, when the actual oxygen demand of the myocardium (heart muscle) exceeds the oxygen supply. Due to hypoxia, the disturbed balance induces the ischaemia of myocardium together with all severe sequels (anaerobic metabolism, chest pain, alteration in the ST segment). The medicinal intervention is aimed at restoration of the balance and elimination (abolishment) of the hypoxic periods (episodes). A usual way of increase in the oxygen supply consists e.g. in the decrease of resistance of the cronary vessels, and switching over of the local regulation of circulation. In spite of the attempts of medicinal therapy since more than hundred years, the medicinal treatment of angina pectoris has not been solved up to the present.

In the cases of nitrates addiction, vertigo, headache and the exacerbation of symptoms at an abrupt deprivation of the drug have mainly to be considered, however, hypotension and bradycardia may also develop.

When using beta-adrenergic blocking agents, dis- advantageous effects exerted on the serum lipid level as well as a myocardium infarction eventually occurring at the abrupt deprivation of the drug should be taken in account inter alia.

The most important side effects of the calcium channel inhibitors are headache, constipation and peripheral edema.

Based on recent results, an antianginal effect can be expected also from calmodulin antagonists, particularly by the recognition that a number of "lipophilic calcium anta- gonists" such as e.g. prenylamine and fendiline have been proved to possess also calmodulin-antagonizing action [Mannhold: Drugs of Future 9, pages 677-690 (1984)].

It has surprisingly been found during our investiga- tions that the novel 3(2H)-pyridazinones of the general formula (I), wherein R¹, R², R³, R⁴, X and n are as defined above, possess an excellent antianginal and calmodulin- antagonistic action without causing any notable side effect.

According to the invention the compounds of general formula (I) are prepared by

a) reacting a compound of general formula (II),

wherein R¹ and X are as defined above, with an amine of the general formula (III),

wherein R², R³ and n are as defined above,

to obtain compounds of the general formula (I), wherein

R⁴ stands for hydrogen and R¹, R², R³, X and n are as defined above; or

b) treating a compound of the general formula (I),

wherein R⁴ means hydrogen, R¹ is as defined above, except hydrogen, and R², R³, X as well as n are as defined above, with an agent being suitable to

introduce an R⁸CO- group, where R⁸ is as defined above, to obtain compounds of the general formula (I), wherein R⁴ stands for R⁸CO- group, R¹ is as defined above, except hydrogen, and R², R³, X, n and R⁸ are as defined above; or

c) treating a compound of the general formula (I), wherein R⁴ means hydrogen, R¹ is as defined above, except hydrogen, and R², R³, X and n are as defined above, with chlorosulfonic acid or with a complex of sulfur trioxide being suitable to introduce the sulfonic acid group, then, if desired, transforming the compound thus obtained to its salt by reacting it with an organic or inorganic base,

to obtain compounds of the general formula (I), wherein R⁴ represents an -SO₃M group, R¹ is as defined above, except hydrogen and R², R³, X, n and M are as defined above,

and, if desired, transforming a base of the general formula (I), wherein R¹, R², R³, R⁴, X and n are as defined above, obtained by any of the above processes a) to c), to its acid addition salt in a manner known per se and/or, if desired, transforming one of its acid addition salts to an other acid addition salt and/or, if desired, liberating a base of the general formula (I) from its salt.

According to a preferred embodiment of process a) of the invention a 4,5-dihalo-3 (2H)-pyridazinone derivative of the general formula (II) is reacted with a 3- to 10-fold molar excess of the amine of general formula (III) in a melt state at a temperature betwen 80 °C and 140 °C. In this case the time of reaction is relatively short and the 4-(hydroxy- alkyl) amino derivative can be separated in a pure form.

According to an other preferred embodiment of process a) of the invention, this reaction is carried out by using a high, suitably 5- to 15-fold, particularly suitably 10-fold molar excess of the amine in an apolar aprotic solvent, preferably in dioxane and/or toluene or in a less polar aprotic solvent, e.g. tertiary, iso- or n-butanol, at a temperature between 50 °C and the boiling point of the reaction mixture, preferably at the boiling point.

An advantageous embodiment of process b) of the invention for the preparation of derivatives containing an alkyl or aryl group as R⁸ comprises reacting a compound of the general formula (I) containing hydrogen as R⁴ with a reactive carboxylic acid derivative, preferably the acyl chloride or acid anhydride in an inert solvent in the

presence of a tertiary amine base as solvent at a temperature between 0 °C and 70 °C, preferably between 20 °C and 50 °C. In order to obtain derivatives containing an alkylamino group as R⁸, a compound of the general formula (I) containing hydrogen as R⁴ is treated with the appropriate alkyl

isocyanate in an inert solvent, preferably benzene or dioxane at a temperature between 20 °C and the boiling point of the reaction mixture.

The process c) according to the invention for preparing derivatives containing an -SO₃M group as R⁴ can preferably be realized by reacting a compound of the general formula (I) containing hydrogen as R⁴ with chlorosulfonic acid in an inert solvent, preferably carbon tetrachloride at a temperature between 0 °C and 25 °C. During working up of the

reaction mixture, the sulfonic acid obtained is separated or, if desired, it is transformed in situ to its salt, preferably e.g. to its sodium salt.

According to an other preferred embodiment of process c) of the invention a compound of the general formula (I) is treated with a complex of sulfur trioxide, preferably with the complex formed with pyridine, in a suitable solvent, preferably in pyridine thereafter, if desired, the pyridine salt of the sulfonic acid derivative obtained is separated and/or, the sulfonic acid derivative is liberated and, if desired, transformed to an other sulfonic acid salt.

The reaction mixture obtained as a result of the

processes discussed above may be worked up by using the usual methods of the organic chemical practice, e.g. by extraction, chromatography and/or crystallization following the removal of the excess of the reagent and/or solvent optionally under reduced pressure. If desired, the resulting compound of the general formula (I) may be purified e.g. by chromatography and/or recrystallization; furthermore, it may optionally be transformed to an acid addition salt, which in turn can be purified by recrystallization, if desired, after separation.

The compounds of the general formula (I) according to the invention, which contain a sufficiently strong basic group, may be transformed to acid addition salts. This trans formation is carried out by dissolving the base in a suitable solvent and then portionwise adding the appropriate

(corresponding) acid or a solution of the acid in a solvent under stirring. The product thus obtained is separated by filtration or crystallization following evaporation of the solvent and, if desired, purified e.g. by recrystallization. Any organic or inorganic acid, preferably a pharmaceutically acceptable acid, such as hydrochloric, sulfuric, fumaric or tartaric acid may be used as acid compounent. E.g. alcohols, esters, ethers and/or ketones may be used as solvents. The salt formation is carried out at a temperature range of 0 ºC to 80 °C, preferably between 0 °C and 20 °C when using mineral acids and preferably between 50 °C and 80 °C when using organic acids.

The compounds of general formula (I), wherein the meaning of R¹ and/or R² is hydrogen, can exist in (an) additional tautomeric form(s). These compounds are also within the scope of the invention.

The compounds of the general formula (I), wherein R³ is different from hydrogen and/or the substituents R¹, R² and/or R⁴ contain(s) (a) centre(s) of asymmetry, can exist also in optically active forms. The invention relates both to the racemates as well as to the optically active isomers.

A part of the compounds of general formula (II) used as starting substances in the process a) of the invention are known from the literature [see e.g.: J. Am. Chem. Soc. 75, page 1909 (1953); Bull. Soc. Chim. France, page 2124 (1964); J. Heterocyclic Chem. 21, page 481 (1984); Farmaco Ed. Sci. 32, page 780 (1977); ibid 40, page 921 (1985); Chem. Zvesti 38, page 239 (1984); and Chem. Pharm. Bull. 18, page 147 (1970)]; the compounds of general formula (II) not described thereto can analogously be prepared to methods known from the literature. E.g. the novel compounds of general formula (II) containing an alkenyl group substituted by an optionally substituted phenyl group, or an alkyl group substituted by a 4-substituted-1-piperazinyl group or a dimethoxybenzyl group as R¹ are prepared by reacting a 4,5-dihalo-3 (2H)-pyridazinone with a suitable R¹Y reagent, wherein Y stands for a leaving group, such as e.g. an R¹ halide compound.

These methods will hereinafter be discussed in detail in the chapter "Preparation of the starting substances". An over- whelming majority of the R¹Y reagents are known [see e.g.: J. Chem. Soc., page 1266 (1940); ibid., page 2516 (1961); J.

Chem. Soc. B, page 590 (1966); J. Am. Chem. Soc. 83, page 3846 (1961); Chem. Ber. 30, page 810; Chem. Pharm. Bull. 25, page 1811 (1977)]; the new compounds can be prepared by methods described for or analogously to the preparation of known compounds.

A part of amino alcohols of the general formula (III) similarly used as starting substances in the process a) are also known from the literature [see e.g.: J. Am. Chem. Soc. 77, pages 633 and 636 (1955); Monatsh. 95, page 922 (1964); as well as the German patent specification No. 1,118,218]; the new compounds can be prepared analogously to the com- pounds described. Thus, 3-aminopropanols containing a 4-fluoro- or 3,4-dimethoxybenzyl group as R² can be achieved by the in situ reduction with sodium borohydride of the Schiff's base obtained from the reaction of the respective benzaldehyde with 3-amino-propanol; whereas 3-aminopropanol derivatives containing a benzyl group as R² and a 4-methoxyphenyl group as R⁴ can be obtained by reducing the respective, known aminoketone prepared according to the literature [J. Am. Pharm. Assoc. Sci. Ed. 67, page 77

(1958)]. The preparation of 3-aminopropanols containing a 2-morpholinoethyl group as R² will be illustrated on the preparation of 3-[(2-morpholinoethyl)amino]propanol by reacting 2-morpholinoethyl chloride with 3-aminopropanol. These methods will hereinafter be discussed in detail in the chapter entitled "Preparation of starting substances".

The compounds of the general formula (I) according to the invention possess valuable biological effects, more par- ticularly antianginal and calmodulin-antagonizing action.

The antianginal action of compounds according to the invention is supported by their advantageous effects exerted on the coronary blood flow and other characteristics (parameters) being important from the viewpoint of this action.

I. Investigation of the coronary blood flow on anaesthetized open-chest dogs

These examinations were carried out on mongrel dogs anaesthetized by 30 mg/kg of sodium pentobarbital (Nembutal^R) administered intravenously (i.v.).

The animals were artificially ventilated by a Harvard 612 A type respirator of variable phase through a tracheal tube by performing a thoracotomy through the fifth inter costal space. Subsequently, the pericardium was opened and the descending branch of the left coronary artery (LAD) was exposed distally at 1.5 cm from its origin. An electromagnetic flow meter head was placed on the blood vessel which was joined to a Narcometic RT-500 type electromagnetic flow- measuring equipment. In this way the volume of the blood (ml/min) flowing through the exposed blood vessel section could be determined.

The myocardial contractile force (MCF) was measured by two methods. In a part of our experiments a strain gauge arch was placed on the epicardial surface of the left ventricle according to the method of Walton and Brodie [J. Pharm. Exp. Ther. 90, page 26 (1947)], whereas in other experiments a millar-tip catheter was introduced to the left ventricle, which made possible to measure the left ventricular pressure. The change in the tension of the strain gauge arch and the values obtained from the first derivative as a function of time (dP/dt) of the ascending branch of the left ventricular pressure wave, respectively, gave informations about the contractile state of the heart.

The systemic arterial blood pressure was determined using a catheter inserted to the femoral artery and joined to a Statham P 23 Pb type pressure transducer and an electromanometer. The heart rate was also measured by using a cardiotachometer controlled by the pressure wave.

In order to determine the myocardial reactivity, 0.2 μg/kg of isoproterenol was intravenously administered before giving the compounds under test. When given in this dose, isoproterenol as a beta-adrenergic stimulant exerts a temporary, reversible effect increasing the myocardial contractile force and strengthening the coronary flow. In our experiments, isoproterenol was used for testing the myocardial reactivity of the experimental animals and not as a reference drug.

In our experiments the change elicited by the compounds in the amplitude of the reactive hyperaemia (extreme increase in the coronary flow) following the occlusion of the

descending branch of the left coronary artery for one minute was measured. The inhibition of the reactive hyperaemia indicates an advantageous effect of the compound under test on the myocardial microcirculation.

The compounds under test were administered in the form of a bolus injection through the femoral vein.

The measurement characteristics (parameters) discussed above in detail were continuously registered on a Beckman 612 R type polygraph during the whole experimental period.

II. Inhibition of the ST segment elevation induced by vasopressin on anaesthetized rats

These investigations were carried out on male CFY rats with a body-weight of 200 to 250 g. After anaesthetizing the animals by 1 g/kg of intraperitoneally (i.p.) administered urethane, ECG records were taken up by using limb leads. Subsequently, a coronary spasm was induced by 3 IU/kg of vaso¬pressin administered intravenously, which appeared as an elevation of the ST segment on the ECG record. The eventual inhibition of the vasopressin-induced ST segment elevation by an intravenous pretreatment of the animals with the compounds according to the invention was investigated. The inhibition proves the abolishment of hypoxia, an antianginal effect [J. Pharm. Methods 5, pages 325-336 (1981)].

Fendiline [chemically N-(3,3-diphenylpropyl)-N-(α-methylbenzyl)amine] and nicorandil [chemically N-(2-nitro- oxyethyl)-3-pyridinecarboxamide] were used as reference drugs.

Table I

Effect of compounds of the general formula (I) on the coronary resistance and vasopressin-induced ST segment elevation after i.v. administration

Compound Change in coronary Inhibition of ST

(Example) resistance (%) after elevation after

No. 1 mg/kg dose 5 mg/kg dose

7 -25.8 -53

11 -25.4 -81

13 -31.7 -100

15 -26.8 -36

16 -14.3 -53

22 -28.9 -84

28 -37.5

32 -38.5 -72

34 -25.8 -20

Nicorandil -80.0 -60

(reference drug)

Fendiline -27.3 -100

(reference drug)

It is obvious from the data of Table 1 that the

coronary resistance is significantly decreased and the vasopressin-induced ST segment elevation is significantly inhibited by the compounds of the invention, whereas these compounds have no significant influence either on the blood pressure or the heart rate and do not possess any negative inotropic effect; in addition, they inhibit the reactive hyperaemia. On this basis, the compounds of general formula (I) according to the invention are useful for the treatment of cardiovascular diseases, especially angina pectoris.

All those discussed above are supperted by the significant calmodulin-antagonizing effect of the compounds, which was determined as follows.

Determination of the calmodulin-antagonizing effect For measuring the baseline activity of phosphodiesterase enzyme I [prepared as described in: Methods in Enzymology 102, page 39 (1983)], which can be activated by calcium-calmodulin, 0.9 ml volume of the reaction mixture contained 40 mmol of Tris, 40 mmol of imidazole, 5 mmol of magnesium acetate, 1.2 mmol of cyclic adenosine monophosphate (cAMP), alkaline phosphotase and phosphodiesterase enzyme I in a buffer solution of pH 7.5. On determination of the enzyme activated by calcium-calmodulin, the above reaction mixture contained also 100 μmol of calcium chloride and 5.7 × 10^-9 mol of calmodulin. The enzyme reaction was arrested by adding 0.1 ml of 55 % trichloroacetic acid after incubation for 30 miutes and after centrifuging, the amount of inorganic phosphate formed was determined in the supernatant according to a method known from the literature [Anal. Biochem. 135, page 233 (1983)]. The IC₅₀ values were determined from the regression curve of log concentration/% inhibition, based on the results of two parallel samples measured in five various concentrations. The results are summarized in Table 2.

Table 2

Calmodulin-antagonizing effect of compounds of the general formula (I)

Compound ^IC50

(Example) (μM)

No.

7 5.2

13 5.5

15 3.7

33 3.1

Fendiline (reference drug. 5.6

Based on the above data, the compounds of general formula (I) according to the invention possess a significant calmodulin-antagonizing effect and therefore, these compounds can be expected to have a very advantageous therapeutical use, particularly as antianginal agents on the basis of this inhibitory action, too.

The toxicity of these compounds is usually low. All these properties provide a valuable specftrum of effects as well as a therapeutic safety. For therapeutical use, a daily dose of the active agents according to the invention is usually in the range of about 0.2 mg/kg of body-weight up to about 10 mg/kg of body-weight, optionally administered in divided daily doses by considering also the conditions of resorption.

For therapeutical use, the active compounds of the invention are suitably formulated to pharmaceutical compositions by mixing them with non-toxic, inert, solid or liquid carriers and/or additives which are appropriate for enteral or parenteral administration and are commonly used in the therapeutical industry. E.g. water, gelatin, lactose, starch, pectin, magnesium starate, stearic acid, talc and vegetable oils are suitable carriers. As additives preserving, wetting (surface active), emulsifying or dispersing, buffering and aromatizing agents may be used.

By using the above carriers and additives, the acive substances of the invention may be formulated to the usual pharmaceutical compositions, e.g. solid forms (such as tablets, capsules, pills and suppositories) or liquid forms (such as aqueous or oily solutions, suspensions, emulsions, syrups) as well as to injectable solutions, suspensions and emulsions.

The invention also relates to a method for treating heart or circulation (cardiovascular) diseases, particularly angina pectoris. This process comprises administering a therapeutically effective amount of an active ingredient of the general formula (I) to the patient.

The invention is illustrated in detail by the aid of the following non-limiting Examples.

The compounds of general formula (I) given as examles, their (uncorrected) melting points or R_f values, respective ly of oils as well as the yield and method of preparation are given in the Examples and in Tables 3 and 4.

Example 1

Preparation of 5-chloro-4-[N-(2-hydroxyethyl)-N-methyl- amino]-2-(3-phenyl-2-propen-l-yl)-3(2H)-pyridazinone (method A₁)

A solution containing 2.81 g (0.01 mol) of 4,5-dichloro-2-(3-phenyl-2-propen-1-yl)-3(2H)-pyridazinone

[described hereinafter in the chapter entitled "Preparation of starting substances" method a₁)] and 2.25 g (0.03 mol) of 2-(N-methylamino)ethanol in 30 ml of anhydrous dioxane was boiled under reflux while stirring for 45 hours. After evaporating the solvent under reduced pressure, 30 ml of water were added to the residue and the pH value of the emulsion formed was adjusted to 7 by adding 10 % aqueous hydrochloric acid. After extracting the aqueous solution with ethyl acetate, the organic phase was dried and then evaporated. The residue was subjected to column chromatography on silica gel by using chloroform/ethyl acetate mixtures with increasing polarity as eluent. The fractions showing an R_f value of 0.56 (ethyl acetate) were combined to give the title compound in a yield of 1.00 g (34 %).

Example 2

Preparation of 5-chloro-4-[(3-hγdroxypropyl)amino]-2-(3-phenyl-2-propen-1-yl)-3(2H)-pyridazinone

(method A₂)

The above method A₁) was followed by using 4.00 g

(0.014 mol) of 4,5-dichloro-2-(3-phenyl-2-propen-1-yl)-3(2H)- pyridazinone and 3.20 g (0.042 mol) of 3-aminopropanol, except that n-butanol was used instead of dioxane and the reaction lasted for 10 hours to obtain 2.12 g (47 %) of the title compound, m.p.: 95-96 °C

Example 3

Preparation of 2-allyl-4-[N-benzyl-N-(3-hydroxypropyl)amino]-5-chloro-3(2H)-pyridazinone

(method A₃)

The mixture of 3.33 g (0.01 mol) of 2-allyl-4, 5- -dichloro-3(2H)-pyridazinone with 6.61 g (0.04 mol) of 3-(N-benzylamino)propanol was stirred at 130 °C for 90 minutes. After cooling down, 40 ml of water were added to the reaction mixture, the pH was adjusted to 7 and the solution was extracted with ethyl acetate. After drying and evaporation, the crude product was purified according to method A₂ to obtain 0.66 g (20 %) of title product, R_f = 0.62 (by developing with an 1:1 mixture of chloroform/ethyl acetate on silica gel).

Example 4

Preparation of 2-benzyl-4-[N-benzyl-N-(3-hydroxy- propyl) amino] -5-chloro-3(2H)-pyridazinone

(method A₄)

Method A₁ was followed by using 2.55 g (0.01 mol) of 2-benzyl-4,5-dichloro-3(2H) -pyridazinone and 24.78 g (0.15 mol) of 3-(N-benzylamino)propanol, except that toluene was employed instead of dioxane and the reaction lasted for 24 hours. In this way 1.53 g (40 %) of title product were obtained, R_f = 0.33 (by developing with a 9:1 mixture of toluene/methanol on silica gel).

Example 5

Preparation of 4-{N-benzyl-N-[3-hydroxy-1-(-methoxyphenyl)]amino}-5-chloro-2-(3-phenyl-2-propen-1-yl)-3(2H)-pyridazinone (method A₅)

Method A₁ was followed by using 3.10 g (0.011 mol) of 4,5-dichloro-2-(3-phenyl-2-propen-1-yl)-3(2H)-pyridazinone and 7.50 g (0.028 mol) of 3-(N-benzylamino)-1-(4-methoxyphenyl)propanol, except that water was employed instead of dioxane to yield 0.65 g (11 %) of title product, R_f = 0.44 (by developing with a 9:1 mixture of toluene/methanol on silica gel).

The compounds of Examples 6 to 30 were prepared by using the suitable starting substances and following methods A₁ to A₅. These compounds are summarized in Table 3.

Example 31

Preparation of 4-{N-[3-(benzyloxy)propyl]-amino}-5-chloro-2-(3-phenyl-2-propen-1-yl)-3(2H)-pyridazinone

(method B)

0.23 g (1.7 mmol) of benzoyl chloride was dropwise added to a solution of 0.50 g (1.5 mmol) of 5-chloro-4-[N-hydroxypropyl)amino]-2-(3-phenyl-2-propen-1-yl)-3(2H)-pyridazinone in 5 ml of pyridine at 10 °C under stirring and cooling by ice. The reaction mixture was stirred at 50 °C for 6 hours and then poured into 20 ml of ice-water. The solution was extracted with ethyl acetate and after washing the organic phase with 4 % hydrochloric acid and then with water, the organic phase was dried and evaporated. The evaporation residue was crystallized with ether to obtain 0.46 g (73 %) of title product, m.p.: 77-78 °C.

The compounds of Examples 32 and 33 were prepared from the suitable starting substances by using method B. The compound of Example 33 was purified by column chromatography. These compounds are summarized in Table 4.

Example 34

Preparation of 4-[N-(3-acetyloxγpropyl)-N-benzyl-amino]-5-chloro-2-(3-phenyl-2-propen-1-yl)-3(2H)-pyridazinone

Method B was followed by using 0.61 g (1.5 mmol) of the compound of Example 13 and 0.35 g (3.4 mmol) of acetic anhydride to obtain 0.65 g (97 %) of title product, R_f = = 0.88 (by developing with an 1:1 mixture of chloroform/ethyl acetate on silica gel).

Example 35

Preparation of 4-{N-benzyl-N-[3-(butylcarbamoyloxy)-propyl]amino}-5-chloro-2-(3-phenyl-2-propen-1-yl)-3(2H)-pyridazinone

After dropwise adding 0.60 g (6.06 mmol) of butyl isocyanate to 1.09 g (2.66 mmol) of the compound of Example 13 dissolved in 20 ml of benzene, the reaction mixture was boiled under reflux for 4 hours and then evaporated to dryness under reduced pressure. The residue was subjected to column chromatography on silica gel by using a solvent mixture of chloroform and ethyl acetate to obtain 0.74 g (55 %) of title product, R_f = 0.84 (by developing with an 1:1 mixture of cloroform/ethyl acetate on silica gel).

Example 36

Preparation of pyridinium-{3-[N-benzyl-N-[2-(3-phenyl-2-propen-1-yl)-5-chloro-3-oxo-4(2H)-pyridazinylamino]propyl}sulfate

After portionwise adding 0.32 g (2 mmol) of pyridine- sulfur trioxide complex to the solution of 0.40 g (1 mol) of the compound of Example 13 in 4 ml of anhydrous pyridine below 10 °C under stirring and cooling by ice, the reaction mixture was stirred for 1 hour, then evaporated to dryness at 40 °C under a pressure of 1.33 × 10² Pa and ether was twice distilled off from the oily residue. After taking up the residue in water and extracting with chloroform, the organic layer was washed with water and dried. The evaporation residue was suspended in ether, then petroleum ether,

filtered and dried to give 0.45 g (80 %) of title product, m.p.: 102-103 °C.

Example for the preparation of an acid addition salt Preparation of 5-chloro-2-(3-phenyl-2-propen-1-yl)-4-{3-[(3-pyridyl-carbonyloxy)propyl]amino}-3(2H)-pyridazinone hydrochloride

The pH value of a solution containing 0.45 g (1 mmol) of the base of Example 32 in 5 ml of anhydrous ether was adjusted to 3 by adding 20 % ethanolic hydrogen chloride solution. After standing overnight at 5 °C, the crystallin precipitate was filtered, washed and dried to give 0.44 g %) of title hydrochloride, m.p.: 115-119 °C. Preparation of 5-chloro-4-[N-(3-hydroxypropyl)-N-(2-morpholinoethyl)-amino]-2-(3-phenyl-2-propen-1-yl)-3(2H)-pyridazinone fumarate

A solution of 0.40 g (3.5 mmol) of fumaric acid in 9 ml of ethanol was dropwise added to a solution containing 1.50 g (3.5 mmol) of the base of Example 23 in 9 ml of ethanol at 70 °C while stirring. After stirring at the same temperature for 10 minutes, the solution was evaporated to constant weight under reduced pressure to obtain 1.90 g (100 %) 0f the title fumarate.

Preparation of starting substances

1. Examples for the preparation of novel 4,5-dihalo-3(2H)-pyridazinones of the general formula (II)

Method ax): Preparation of 4,5-dichloro-2-(3-phenγl-2-propen-1-yl)-3(2H)-pyridazinone

A solution of 16.8 g (0.11 mol) of cinnamyl chloride in 5 ml of anhydrous dimethylformamide was dropped to a suspension containing 16.5 g (0.10 mol) of 4,5-dichloro-3(2H)-pyridazinone and 150 g of anhydrous potassium carbonate in 100 ml of anhydrous dimethylformamide at a temperature below 15 °C under stirring. The reaction mixture was stirred at room temperature overnight and then poured into 600 ml of water while stirring. The crystalline precipitate was

filtered, washed with water, dried and if necessary, purified by treatment with aluminum oxide in benzene solution. In this way 25 g (89 %%) of the title compound were obtained, m.p. : 98-99 °C.

Further Examples using method ai are the compounds listed hereinafter, which were prepared as described above by using the appropriate R¹Cl compound instead of cinnamyl chloride:

4,5-Dichloro-2-[3-(4-fluorophenyl)-2-propen-1-yl]-3(2H)-pyridazinone, yield 59 %, m.p.: 124 °C.

4,5-Dichloro-2-[3-(4-methoxyphenyl)-2-propen-1-yl]-3(2H)-pyridazinone, yield 62 %%, m.p.: 156-157 °C.

4,5-Dichloro-2-(2-phenoxyethyl)-3(2H)-pyridazinone, yield 98 %, m.p.: 94-97 °C.

4,5-Dichloro-2-(3,4-dimethoxybenzyl)-3(2H)-pyridazinone, yield 54 %,, m.p.: 104-108 °C.

4,5-Dibromo-2-(3-phenyl-2-propen-1-yl)-3(2H)-pyridazinone (in this case 4,5-dibromo-3(2H)-pyridazinone was used instead of 4,5-dichloro-3(2H)-pyridazinone), yield 64 %, m.p.: 88-90 °C.

Method a₂): Preparation of 4,5-dichloro-2-{2-[4-(2-phenoxyethyl)-1-piperazinyl]ethyl}-3(2H)-pyridazinone

After portionwise adding 1.65 g (0.01 mol) of 4,5-dichloro-3(2H)-pyridazinone at room temperature to a

solution prepared from 0.69 g (0.03 mol) of sodium in 20 ml of anhydrous ethanol under stirring, the stirring was

continued for 15 minutes, then 3.41 g (0.01 mol) of 2-[4-(2-phenoxyethyl)-1-piperazinyl]ethyl chloride dihydrochloride were portionwise added. After boiling the reaction mixture under reflux and stirring for 2 hours, the precipitated sodium chloride was filtered and a salt was formed by adding ethanolic hydrogen chloride solution to the filtrate to obtain 3.43 g (73 %) of dihydrochloride of the title

compound, m.p.: 208-210 °C.

Further Example using method a₂ ) is the compound named hereinafter, which was prepared as described above by using the appropriate R¹-Cl compound instead of 2-[4-(2-phenoxy- ethyl)-1-pyperazinyl]ethyl chloride dihydrochloride:

4,5-Dichloro-2-{2-[4-(3-phenyl-2-propen-1-yl)-1-piperazinyl]ethyl}-3(2H)-pyridazinone, yield 66 %, m.p.: 238-240 °C (dihydrochloride).

Method a₃): Preparation of 4,5-dichloro-2-(4-methoxy- benzyl)-3(2H)-pyridazinone

After transforming 1.65 g (0.01 mol) of 4,5-dichloro-3(2H)-pyridazinone to its potassium salt by adding an equi- molar amount of potassium hydroxide in methanol solution and then evaporating methanol under reduced pressure, the salt thus obtained was suspended in 30 ml of toluene, 1.56 g (0.01 mol) of 4-methoxybenzyl chloride dissolved in 30 ml of toluene were dropwise added under stirring, then 0.60 g

(0.0018 mol) of tetrabutylammonium bromide was added. After boiling under reflux for 3 hours, the reaction mixture was evaporated to dryness under reduced pressure, the residue was dissolved in water and the solution was extracted with ethyl acetate. After drying and evaporating, the crude product obtained was subjected to chromatography on silica gel by using ethyl acetate as eluent to give 1.16 g (41 %)) of title product, m.p.: 117-120 °C. Method a₄): Preparation of 4,5-dichloro-2-[3-(4-hydroxyphenyl)-2-propen-1-yl]-3(2H)-pyridazinone

To a solution containing 6.9 g (0.022 mol) of 4,5-dichloro-2-[3-(4-methoxyphenyl)-2-propen-1-yl]-3(2H)-pyridazinone in 13ύ0 ml of 98 % methanesulfonic acid, 30.4 g (0.2 mol) of methionine were portionwise added at room temperature under stirring. After the exothermic reaction, the mixture was maintained at 30 °C for 96 hours, then poured into 400 g of ice. The pH value of the solution was adjusted to 9 by adding concentrated ammonium hydroxide solution, the mixture was extracted with ethyl acetate and the organic phase was washed with water. After evaporation and drying, the oily residue was boiled under reflux with 92 ml of 2 N hydrochloric acid under stirring for 2 hours. After cooling down, the product was filtered, washed until neutral and dried. The crude product obtained was purified by chromatography on silica gel, using a 95:5 mixture of chloroform/ethyl acetate as eluent to yield 1.79 g (27 %) of title compound, m.p.:

193-195 °C.

2. Examples for the preparation of novel 3-(substituted amino)propanols of the general formula (III)

Method b₁): Preparation of 3-[N-(4-fluorobenzyl)amino]- propanol hydrochloride

7.60 g (0.10 mol) of 3-aminopropanol were dropped to a solution of 12.41 g (0.10 mol) of 4-fluorobenzaldehyden 50 ml of ethanol below 10 °C. The solution was stirred at room temperature overnight and subsequently 3.80 g (0.10 mol) of sodium borohydride were portionwise added below 10 °C. The reaction mixture was stirred at the same temperature for 1 hour, at room temperature overnight, then 10 ml of acetic acid were portionwise added below 10 °C and the mixture was stirred at room temperature for 1 hour. After filtering the reaction mixture, the filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in 100 ml of 20 % sodium hydroxide solution. The solution was extracted with ethyl acetate and after drying, 20 % ethanolic hydrogen chloride solution was added at 5 °C to adjust the pH value to 3. The crystalline precipitate was filtered and washed with ether to obtain 19.1 g (87 %) of the title compound,

m.p.: 136-137 °C.

Further Examples using method b₁) are the compounds listed hereinafter, which were prepared as described above by using the appropriate aldehyde instead of 4-fluorobenz- aldehyde:

3-[N-(3,4-Dimethoxybenzyl)amino]propanol, yield 54 %, b.p.: 198-200 °C/266 Pa.

3-[N-(4-Methoxybenzyl)amino]propanol, yield 70 %, m.p.: 140-141 °C(HCl).

3-[N-(3-Pyridylmethyl)amino]propanol, yield 65 %, m.p.: 163-165 °C(HC1).

Method b₂): Preparation of 3-(N-benzylamino)-1-(4-methoxyphenyl)-1-propanol

To a solution containing 3.00 g (0.01 mol) of -(N-benzylamino)-4-methoxypropiophenone in 130 ml of methanol, 5.50 g (0.15 mol) of sodium borohydride were portionwise added below 20 °C under stirring, then the reaction mixture was stirred at room temperature for 1 hour. Subsequently, 105 ml of 5 % acetic acid were dropped to the mixture, methanol was removed under reduced pressure, the residue was filtered and the filtrate was alkalinized by adding sodium carbonate. After extracting with ethyl acetate, the organic layer was washed with water, dried and evaporated. The residue was sus- pended in ether and after filtering, the crystals were dried to give 2.06 g (76 %) of the title compound, m.p.: 65-66 °C.

Method b₃): Preparation of 3-[N-(2-morpholinoethyl)-amino]propanol

A mixture of 9.30 g (0.05 mol) of 2-morpholinoethyl chloride hydrochloride with 15.0 g (0.20 mol) of 3-amino- propanol was stirred at 140 °C for 4 hours, then cooled to room temperature and 100 ml of water were added. After

extracting with chloroform, the organic phase was dried, evaporated and the residue was distilled under reduced

pressure to obtain 5.65 g (60 %) of the title compound, b.p.: 138-140 °C/200 Pa.

Claims

1. Racemic and optically active 3(2H)-pyridazinone derivatives of the general formula (I)

wherein

R¹ means hydrogen; a C_1-4alkyl group optionally

substituted by an R⁵R⁶N- group where R⁵ and R⁶, being the same or different, stand for a C_1-4alkyl group or R⁵R⁶N- together represents a 6-membered heterocyclic group optionally containing an oxygen or an R⁷N- moiety where R⁷ is a C_1-4alkyl optionally substituted by a phenyoxy group or a C_3-5alkenyl optionally substituted by a phenyl grup; or a C_1-4alkyl group substituted by a mono- or polysubstituted phenyl, phenoxy or benzyloxy group; or a C_3-5alkenyl or C_3-5alkynyl optionally substituted by an unsubstituted or optionally

substituted phenyl group; or a phenyl group;

R² means hydrogen; or a C_1-4alkyl optionally substituted by a morpholino, pyridyl, 1,4-benzodioxanyl or an optionally substituted phenyl group;

R³ means hydrogen or an optionally substituted phenyl group;

X means halogen; and

n is 1, 2 or 3,

as well as their tautomers and the acid addition salts of these compounds.

2. A compound selected from the group consisting of 5-chloro-2-(3-phenyl-2-propen-1-yl)-4-{3-[(3-pyridylcarbonyl- oxy)propyl]amino}-3(2H)-pyridazinone,

4-[N-benzyl-N-(3-hydroxypropyl)amino]-5-chloro-2-(3-phenyl-2-propen-1-yl)-3(2H)-pyridazinone,

4-[N-benzyl-N-(3-hydroxypropyl)amino]-5-chloro-2-(4-methoxybenzyl)-3(2H)-pyridazinone

and the acid addition salts of these compounds.

3. A pharmaceutical composition, which comprises as active ingredient a ovel, racemic or optically active 3(2H)-pyridazinone derivative of the general formula (I), wherein R¹, R², R³, R⁴, X and n are as defined in claim 1, or a tautomer thereof or a pharmaceutically acceptable acid

addition salt thereof as defined in claim 1, in admixture with carriers and/or additives commonly used in the pharmaceutical industry.

4. A process for the preparation of the novel 3(2H) -pyridazinone dervatives of general formula (I)

wherein

R¹ means hydrogen; a C_1-4allkyl group optionally

substituted by an R⁵R⁶N- group where R⁵ and R⁶, being the same or different, stand for a C_1-4allkyl group or R⁵R⁶N- together represents a 6-membered heterocyclic group optionally containing an oxygen or an R⁷N- moiety where R⁷ is a C_1-4allkyl optionally substituted by a phenyoxy group or a C_3-5alkenyl optionally substituted by a phenyl grup; or a C_1-4allkyl group substituted by a mono- or polysubstituted phenyl, phenoxy or benzyloxy group; or a C_3-5alkenyl or C_3-5alkenyl optionally substituted by an unsubstituted or optionally

substituted phenyl group; or a phenyl group;

R² means hydrogen; or a C_1-4allkyl optionally substituted by a morpholino, pyridyl, 1,4-benzodioxanyl or an optionally substituted phenyl group;

R³ means hydrogen or an optionally substituted phenyl

group;

R⁴ means hydrogen; or R⁸CO- group where R⁸ is a C_1-4allkyl, phenyl or pyridyl group or an amino group substituted by a C_1-4alkyl group; or an -SO₃M moiety where M is hydrogen or an organic or inorganic cation;

X means halogen; and

n is 1, 2 or 3,

as well as their tautomers, racemic and optically active forms, mixtures thereof and acid addition salts of these compounds, which comprises

a) reacting a compound of general formula (II),

wherein R², R³ and n are as defined above,

to obtain compounds of the general formula (I), wherein

R⁴ stands for hydrogen and R¹, R², R³, X and n are as defined above; or

b) treating a compound of the general formula (I),

5. A process as claimed in process b) of claim 4, which comprises using as an active carboxylic acid derivative and optionally an acid binding agent, or an alkyl isocyanate as an agent being suitable to introduce an R⁸CO- group.

6. A process as claimed in claim 5, which comprises using an acyl chloride or acid anhydride as reactive carboxylic acid derivative and a tertiary amine as acid binding agent.

7. A procss for the preparation of a pharmaceutical composition, which comprises mixing as active ingredient a novel racemic or optically active 3(2H)-pyridazinone deriva- tive of the general formula (I), wherein R¹, R², R³, R⁴, X and n are as defined in claim 1, or a tautomer thereof or a pharmaceutically acceptable acid addition salt thereof as defined in claim 1, prepared by using process a), b) or c) claimed in claim 4, with carriers and/or additives commonly used in the pharmaceutical industry and transforming them to a pharmaceutical composition.

8. Method for treating mammals (including man)

suffering from angina pectoris, which comprises administering a therapeutically effective amount of a novel, racemic or optically active 3(2H)-pyridazinone derivative of the general formula (I), wherein R¹, R², R³, R⁴, X and n are as defined in claim 1, or a tautomer thereof or a pharmaceutically acceptable acid addition salt thereof as defined in claim 1, to a subject in need of such treatment. INTERNATIONAL SEARCH REPORT

International Application No PCT/HU 91/00054

I. CLASSIFICATION OF SUBJECT MATTER (It several classification symbols apply, Indicate all)•

According to International Patent Classification (IPC) or to both National Classiflcation and IPC

Int. Cl . : C 07 D 237/22 ; A 61 K 31/50

II. FIELDS SEARCHED

Minimum Documentation Searched ⁷

Classification System Classification Symbols

Int.Cl. C 07 D 237/00; A 61 K 31/00

Documentation Searched other than Minimum Documentation

to the Extent that such Documents are Included in the Fields Searched•

111. DOCUMENTS CONSIDERED TO BE RELEVANT *

Category * Citation of Document, " with Indication, where appropriate, of the relevant passages « i Relevant to Claim No. "

D,A CS, Bl, 223 432 (KONECNY et al . ) 15 March 1986 1 , 4

(15.03.86), see claims.

EP, Al, 0400 519 (THOMAE) 05 December 1990 1 , 3, 4 (05.12.90), see claims 1,3,7,10.

US, A, 4 666 902 (ZOLLER et al.) 19 May 1987 1 , 3 (19.05.87), see abstract.

* Special categories of cited documents: '• "T" later document published after the international filing date

"A" document defining the general state of the art which is not or priority date and not in conflict with the application but considered to be of particular relevance cited to understand the principle or theory underlying the invention

"E" earlier document but published on or after the International

filing date "X" document of particular relevance; the claimed invention cannot be considered novel or cannot be considered to

"L" document which may throw doubts on priority ciaim(s) or Involve an Inventive step

which is cited to establish the publication date of another

citation or other special reason (as specified) "Y" document of particular relevance;^' the claimed invention cannot be considered to Involve an inventive step when the

"0" document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docuother means ments, such combination being obvious to a person skilled

"P" document published prior to the international filing date but in the art.

later than the priority date claimed "*" document member ot the same patent family

IV. CERTIFICATION

Date of the Actual Completion of the International Search Date of Mailing of this International Search Report

18 March' 1992 ( 18.03.92) 01 April 1992 (01.04.92 )

International Searching Authority Signature ot Authorized Officer

AUSTRIAN PATENT OFFICE kru __- ^'

Form PCT/ISA/210 ⁽second sheet) (January 1W5)