CA2074261A1 - 3(2h)-pyridazinones, pharmaceutical compositions containing them and process for preparing same - Google Patents

Abstract

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

Abstract The invention relates to novel, racemic and optically active 3(2H)-pyridazinone derivatives of the general formula (I), (I) wherein R1 means hydrogen; a C1-4alkyl group optionally substituted by an R5R6N- group where R5 and R6, being the same or different, stand for a C1-4alkyl group or R5R6N- together represents a 6-membered heterocyclic group optionally containing an oxygen or an R7N- moiety where R7 is a C1-4alkyl optionally substituted by a phenyoxy group or a C3-5alkenyl optionally substituted by a phenyl grup; 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;
R2 means hydrogen; or a C1-4alkyl 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 C1-4alkyl, 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 R1 is different from a C1-4alkyl, 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 com-positions containing as active ingredient a compound of the general formula (I) as well as to a process for the prepara-tion of compounds of the 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

2~7~
NOVEL 3 ~2H) -PYRIDP~ZINONE8, P~{ARP5ACUTICAL COMPO8ITION8 CON-TAINIWG TNEPI ~ID PROCE38 Fo~a PREPAR~NG 8AME
:
This invention relates to novel 3~2H)-pyridazinones of the general formula ~

R~ R3 O
R~ N- (C1-12)l~-CI-I- OR ' o ` N~X

wherein - R1 means hydrogen; a C1_4alkyl group optionally ~ sùbstituted by an R5R~N- group where R5 and R6, being the same or~different, stand for a C1_4alkyl group or R~R6N- together represents a 6-membered heterocyclic group optionally containing an oxygen or an R7N-:moiety~
where R7 is a C1_~alkyl optionally substituted by a ~ phenyoxy group or a C3_salkenyl optionally substituted:
~ ~ by a phenyl grup; or a C1 4a1kyl group~substituted by a : mono- or polysubstituted phenyl, phenoxy or benzyloxy~
: ~ . group; or a C3_5alkeny1 or C3 5alkyny1 optionally ~: sub~tituted ~y an unsubstituted or optionally substituted phenyl group; or a phenyl group;
R2 stands for: hydrogen; or a C1_4alkyl optionally : substltuted by a morphol1no, pyridyl, 1,4-benzodioxanyl 7410--67-lF/Km0 .

~. - : : ~

~07~
or`an optionally substituted phenyl group;
R3 means hydrogen or an optionally substituted phenyl group;
R4 means hydrogen; or R8C0- group where R8 i9 a Ci_4alkyl, phenyl or pyridyl group or an amino grcup substituted by a C1_4alkyl group; or an -S03M 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 ~rom a C1_4alkyl, alkenyl, aralkyl and phenyl group when n is 1, : -as well as their tautomers, racemic and optically optionally~
: active ~orms, mixtures thereof and acid addition salts of these compounds as well as~pharmaceutlcal 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, particùlarly antianginal properties and have also a signi- :
:ficant calmodulin-antagonizing effect.
A particularly preferred group of the compounds :
according to the invention are compounds of the general formula (I), ~herein: R1 means a C3_5alkenyl group ~ubsti-tuted 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 .
:

- -3- 2~37~a~

, ~
~ 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), whereln R1 stands for a C1_4alkyl group optionally substituted by an ~5R6N- group where R5 and R6 are as defined above, or by a methoxy-su~sti-tuted phenyl or benzyloxy group; R2 means benæyl group; R3 is hydrogen; R4 stands for~hydrogen or an -S03M group where M
~ is as defined above; X represents chlorine; and n is 1,~ 2 or 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 specificatlon (published patent - 15application) No. 78-12880 relates to 2-alkyl, 2-alkenyl, 2--aralkyl and 2-aryl derivatlves of structurally related 5-and 4-[(2-hydroxyethyl)aminQ]-3(2H)-pyridazinone compounds, which are the intermediates of antiinflammatory, analgetic ~ and antidepressive pyridazino[3,4-b][1,4]oxazine derivatives.
20~~ The Czechoslovakian patent specification No. 223,432 discloses 2-C1_3alkyl-, 2-cycloalkyl-, 2-aryl- and 2-(op-tionally 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 hvdroxyl-substituted alkylamino derivatives does not fall within the scope of this inVentiQn. The compounds falling within the scope of the invention are prepared by reacting 2~7~b~
. _ 4 -- 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 compouhds is described in an article of Konecny et al. [Coll.
Czech. Che~. Comm. 50, pages 492-502 (1985)]. In this relation, the relative reactivity of ~he chlorine atoms of 4,5-dichloro-3(2H)~pyridazinones was also lnvestigated: it has been stated that the exchange reaction of the 4-chlorine atom is favourlzed 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-chlorinè atom, although the isomer ratio depends also upon the substitutents. Though the reaction of the 5-chlorine atom can be made practlcally 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 lead-- 20 ing 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 2~7~

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 (episodesj. 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 medlcinal 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 "lipoph~ilic calcium anta-gonists" such as e.g. prenylamine and fendiline have been proved to possess also ca1mcdulln-antagonizing action ~. , ~7l~a~

- ~Mannhold: Drugs of Future 9, pages 677-690 (1984)].
It has surprisingly been found during our investiga-tions that the novel 3t2Hj-pyridaælnones of the general formula (I) ! wherein Rl, 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), .
O ~.
~ R, ~X ~II) ~wherein Rl and X are as defined above, with an amine of . ~the general formula (III), R2NH(CH2)n-CHOH (III) wherein R2, R3 and n are as defined above, to obtain compounds of the general formula (I~, wherein : ~4 stands for hydrogen and Rl, R2, R3, X and n are as defined above; or b) treating a compound of the general formula (I), wherein R4 means hydrogen, Rl is as defined above, except hydrogen, and R2, R3, X as vell as n are as _ 7 _ 2~

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 R8C0- group, Rl is as defined above, except hydrogen, and R2, R3, X, n and R8 are as de~ined above; or c) treating a compound of the general formula (I), wherein R4 means hydrogen,~Rl is as defined~above, except hydrogen, and R2, R3, X and n are as deflned above, . lO with chlorosulfonic acid or with a complex of sulfur trioxide being suitable to introduce the sulfonic acid group, then, if desiredj transforming the compound thus obtained to its salt by reacting it with an organic or inorganic base, to obtain compounds of thè~general formula (I), wherein R4 represents an -S03M group, R1 is as de~inPd 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 Rl, R2, R3, R4, X and n are as defined above, obtained by any of the above processe-~ a) to c), to its a id addition salt in a manner:known ~er se andjor, 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 reactsd with a 3- to 10-fold . ~
. . .

' ' '~ , . : .

- ` - 8 - 20~

.
- molar excess of the amine of genèral formula (III) in a melt state at a temperatùre betwen 80 C and 140 ~C. In this case-~
the time of raaction lS 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, thls reaction is carried out by using~a high, suitably 5- to 15-fold, particularly suitably 10-fold molar excess of the amine in an a~polar aprotic solvent, preferably in dioxane~andjor toluene or in a less polar aprotic solvent~, e.g. tertlary, iso- or n-butanol, at a temperature between 50 C and ~he boiling point of the reaction mixture, preferably at the boiling point.
An advantageous ambodiment of process b) of the invention or 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 temperaturP
between 0 C and 70 Cj 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 pOiht of the reaction mixture.
The process c) according to the invention for preparing derivatives containing an -S03M group as R4 can preferably 2 ~ 7 ~r ~
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 tempera-ture 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 L~_Li~_ to its salt, preferably e.g. to i s sodium salt. ~ -According to an other preferred embodiment of processc) of the invention a compound of the general formula (I~ is treated with a complex of sulfur trioxide, preferably with .
the complex formed with pyrldine, 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, lf 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 o~ 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 genernl formula (I) may be purified e.g. by chromatography and/or recrystallization; furthermore, it may optionally be~
transformed ~o an acid addition salt, which in turn can be 25 ~purified by recrystallization, lf desired, after separatlon.
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. Thls~trans-- j ~

- 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 deYired, purifled 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 andlor ketones may be used as solvents. The salt formation is carried out at a temperature range of 0 C
to 80 C, preferably between 0 C and 20 C when using mineral acids and preferably between 50 C and 80 oc when .
using organic acids.
The compounds of general formula (I), wherein the meaning of R1 andjor 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) centra(s) of asymmetryj can exist also i~
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); Bullo SOc~ Chim. France, page 2124 (1964);
J. Heterocyclic Chem. 21, page 481 (1984); Farmaco Ed. Sci.

,:

::

1 1 2 ~

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 o~ general formula (II) containing an alkenyl group substituted by an optionally substituted phenyl group, or an alkyl group substituted by a 4-substituted-l-piperazinyl group or a dlmethoxybenzyl group ~as R1 are prepared by reacting a 4,5~dihalo-3(2H)--pyridazinone with a suitable RlY reagent, wherein Y stands for a leaving group, such as e.g. an Rl 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); lbid., page 2516 (1961~; J.
Chem. Soc. ~, page 590 (1966); J. Am. Chem. 50c. 83, page 3a46 (1961); Chem. ~er. 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 o~
known compounds.
~ A part of amino alcohols of the general formula (III3 similarly used as starting substances in the process a) are also kno-n from the literature Isee 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--fl~oro- or 3,4-dimethoxybenzyl group as R2 can be achieved :

- 12 - 207~

by the ln 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 pre-. .
paration 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 low and other charàcteristics (para-~
meters) being important from the viewpoint of this action.
I~ Investig~tio~ of~the coron~ry blood ~low on ~o~-~
- ~ thetizea open-chest dog~
These examinations were carried out on mongrel dogs anaesthetized by 30 mg/kg of sodium pentobarbital (NembutalRj administered intravenously (i.v.).
The animals were art1ficially ventilated by a Harvard 612 A type respirator of variable phase through a tracheal tube by perform1ng a thoracotomy through the fifth inter-:

' ~ ' ' ' .

~ - 13 2~7 ~ a~1 -- 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 electro-magnetic 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 iO 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 1eft ve~tricle, 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 ~unction of time (dP/dt) of the ascending branch of the le~ft ventricular pressure wave, respecti~ely, gave informations about the contractile state of the heart.
.
The systemic~arterial blo~d pressure was determined by uslng a catheter inserted to the femoral artery and joined to a Statham P 23 Pb type pressure transducer and an electro-.

manometer. The heart rate was also measured by using a cardiotachometer controlled by the pressuré wave.
In order to determlne the myocardial reactivity, 0.2~g/kg of isoproterenol was intravenously administered before giving the compounds under test. When given in this dose, ' 2~7~b~
isoproterenol as a beta-adrenergic stimulant exerts a tempo-~rary, reversible effect increasing the myocardial contractile force and strengthening the coronary flow. In our experi-ments, 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 coronàry 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 ~orm 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 experiméntal period.
II. I~hibitio~ o~ th~ ~T ~egment el~Yation i~ducca b7 va~o~
-~ pr-Rsi~ o~ a~a-~thctized r~ts ~
These investigations were carried out on male CFY rats ` with a body-weight of 200 to 250 gO After anaesthetizing the animals by 1 g/kg~of intraperitoneally (i.p.) adminlstered urethane, ECG records were taken up by using limb leads. Sub-sequently, 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 ~ - 15 - 2~7~

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 ~25-336 (1981)].
Fendiline [chemically N-(3,3-diphenylpropyl)-N~
-methylbenzyl)amine] and nicorandil [chemically N-(2-nitro-oxyethyl)-3-pyridlnecarboxamide] were used as reference drugs.
T~blo I
Ef~ect of co~pounds of the general for~ula (I) o~ the coronary resi ta~ce 2nd vasopr-s~ induced 8T e~me~t ~ . , .
: ~elevatioD ~fter i.v. administration ' Compound Change in coronary Inhibition of ST
15 (Example) resistanca (%) after elevation after - No. -~1 ma!ka dose _ 5 mq/kq dose 7 -25.8 -53 25.4 ~ -81 - 13 -31.7 -100 ~20 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 druq) :
It is obvious from the data of Table 1 that the ~`' coronary resistance is significantly decreased and the ~, ,~ ' .

.. . .

- 1~ - 2~

vasopressin-induced ST segment elevation is significantly inhibited by the compounds of the invention,~whereas these compounds have no s~gni~icant 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 compoùnds of general formula (I) according to the invention are useful for the treatment of cardlovascular diseases, especially angina pectoris.
~ ~ All those discussed above are supperted by the sig ~ -nificant calmodulin-antagonizing effect of~the compounds, which was determined as follows.
Determin~tio~ of ehe c~lmodulin-a~tago~izi~g effeot For measuring the baseline activity of phospho-diesterase en~yme 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 monopho~phate ~ (cAMP), alkaline phosphotase and phosphodiestexase enzyme I
in a buffer solution o~ pH 7.5. On determination of the enz~ne activated by calcium-calmodulin, the above reaction mixture contained also 100 ~mol of calcium chloride and 5.7 x x 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 . .

- 17 - 2~7~

regression curve of log concentration/% inhibltion,~ based on the results of two parallel samples measured in five various concentrations. The results are summarized in Table 2.
~able 2 Calmodulin-antagonizing effect of compounds of the general formula (I) Compound : IC50 tExamp~ M) No.

5.2 15 ~ 3.7 33 3.1 15 Fendiline (reference druq~ 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 valuabla 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 mglkg of body-weight up to about 10 mg/kg of body-weight, optLonally admlnistered in ~ .

, ,~ 2~

~ivided daily doses by considering also the conditions of resorption.
For therapeutical use, the active compounds of tha in-vention are suitably formulated to pharmaceutical composi-tions by mixing them with non-toxic, inert, solid or liquid carriers and/or additives which are appropriate for enteral or parenteral administrat1on and are commonly used in the .
therapeutical industry. E.g. water, gelatinj lactose, starch, - ~ :
pectin, magnesium starate, stearic acid, talc and vegetable , - lO oils are suitable carriers. As addit1ves preserving,~wetting (sur~ace act1ve), 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. ~ ;
20 ~ The invention also relates to a method for treating heart or circulation (cardiovascular) diseases, particularly angina pectoris. This process comprises administering a the-;~ rapeutically effective amount of an active ingredient of the general formulà (I) to the patient.
25The invention is illustrated in detail by the aid o~
the following non-limiting Examples.
The compounds of genera1 formula (I) given as examles, their tuncorrected) melting points or Rf values, respective-.
:

- 19 ~ 2 ~
ly of oils as well as the yield and method of preparation are given in the Examples and in Tables 3 and 4.
ExaMpls 1 Préparation Or 5-~hloro-4-t~-(2-hy~ro~yethyl3-N-m~thyl~
amino~-2-(3-phenyl-2-prope~ yl)-~2~-py~iaazi~one tDIethod Al) A solution containing 2.81 g (O.Ol mol) of 4,5-: -dichloro-2-(3-phenyl-2-propèn-l-yl)-3(2H)-pyridaz1none [described hereinafter in the chapter entitled "Preparation : 10 of starting substances" method al)] and 2.25 g ~0.03 mol) of ~ -2-(N-methylam.ino)~ethanol in 30 ml of anhydrous dioxane was boiled under reflux while stirring for 45 hours. After evap-orat1ng 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 lO % 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 ~y using chloroform/ethyl acetate mixtures with increasing polarity as eluent. The fractions showing:an Rf value of 0.56 :
(ethyl acetate~ were combined to give the title compound in a . yield of l.00 y ~34 %).
Ex~pl~ 2 Preparation of 5-ohloro-4-~(3-hydroxypropyl~mi~0]-2 - 25 -(3-phenyl-2-propen-l-ylj-3(2H)-pyrid~zino~e:
~metho~ Az) The above method Al) was followed by using 4.00 g ~0.~014 mol) of 4,5-dichIoro-2-(3-phenyl-2-prop-n-l-yl)-3~zH)-' .

- - 20 - 2~7~

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 oc Example 3 Prepar~tion of 2-~llyl-~-tN-be~yl-N-53-hyaroxy-propyljamino~-5-chloro~-3(2H~-pyrid~z~i~one~
l~ethod 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 ~O 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 puri~ied according to method A2 to o~tain 0.66 g (20 ~j of title product, Rf = 0.62 (by develop-ing with an 1:1 mixture of chloroform/ethyl acetate on silica gel).
Bx~ple 4 ~ Prep~ratio~ of 2-ben~yl-~-r~-be~z~l-N-(3-~ydroxy--propyl~ino]-5-chloro-3~2~)-pyri~azi~o~o ~etho~ A~j Method Al 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 - 25 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, Rf = 0.33 (by developing wlth a 9:1 mixture of .

, ~ 1 - 2 ~ 7 :' .
- toluene/methanol on silica gel).
Ex~pla s Prep~ration of i-CN-benzyl-N-t3-hydroxy-l-t-msth phenyl)]a~ino}-5-chloro-2-~3-phenyl-2-propen-1-yl)--3(2~)-pyridazinone ~metho~ A5) Method Al 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.sO g (0.028 mol) of 3-~N benzylamino)-1-(4-methoxy-~ phenyl)propanol, except~that water was employed instead of dioxane to yield 0~.65 g (ll %) of title product, Rf = 0.44 (by developing with a 9:1 mixture of toluene!methanol on .
slllca gel).
2he compounds of Examples 6 to 30 were prepared by using the suitable starting substances and following methods A1 to A5. These compounds are su~arized in Table 3.
~ Exa~ple 31 : ~ ~ 2reparatio~ o~ ~-{~-t3-tbenzyloxy)propyl]-~mino~
-s-~:hloro-2-t3-pbeny~ propon-l-yl)-3~2~ pyridazi:
5metbo~ B):-;
0~23 g (1.7 mmol) of benzoyl chloride was dropwise . added to a solution of 0.50 g (1.5 mmol) of S-chloro-4-[N-~3--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 Cofor 6 hours and then poured into 20 ml of ice-water. The solution , ~
was extracted wikh 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 -.

- 22 - 2~7~

residue was crystallized with ether to obtain 0.46 g ~73 %) of title product, m.p.: 77-7~ C.
The compounds of Examples 32 and 33 were prepared from~
the suitable star~ing substances by using method B. The compound of Example 33 was purifled by column chromatography.
These compounds are summarized in Ta~le 4.

, Ex~ple 34 ~repar~tio~ of 4-tN-(3-~cetylo~ypropyl)-N-benzyl--~mi~o~-S-chloro-2-~3-phenyl-2-propen-1-yl)-3(2~-~10 --pyrl~zinone 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~ =

= 0.88 (by developing with an 1:1 mixture of chloroform/ethyl acetate on silica gel).

,' ,. .
-' , ~:

~ ' ~

: . ' :
' :, .
., , - 23 - 207~

T~ble 3 Example ~1 R2 R3 X n M.p. rield Method No. (C)(~1 or Rf , 6 Et2NCH2cH2 CH3 ~ Cl 1 55 50 A

7 Cy C6H5CH2 H Cl 10.622 12 Al 8 CH3 C6H5CH2 H Cl 2o.402 28 A2 9 SC=C-C82 C6H5C~2 H C~ 20.262 6 A~
C6H5 C6H5CH2 H Cl 2O. 602 16 A2 11 4-CH3O-C6H4CH2 C6HSCH2 H Cl 20.482 13 A3 12 3,4-~eO)2C6H3cH2 C6H5CH2 H Cl 2o.392 21 2 13 Cy C6H5CH2 H Cl 2 83-84 49 A4 20 14 4-MeO-Cy C6H5CH2 H Cl 20.303 22 A3 .~ 15 4-F-Cy C6H5CH2 H Cl 20.343 19 A3 16 C6H5cH2~cH2 C6H5CH2 H Cl 2o.293 5 A
17 C6H5O~H2CH2 ~ C6HSCH2 H Cl 2o.442 17 A2 18 C6HsOCH2CH2N~_JN(cH2)2 C6H5CH2 H Cl 2 0.404 1,4 A2 19 Cy-N ~ N(CH2)2 C6H5CH2 H Cl 2 0.334 8 A~

Cy4-MeO-C6H4CH2 H Cl 2 o.5422~ A2 21 Cy4-F-C6H4CH2 H Cl 2 o,77227 A2 22 Cy~ ~ H C1 2 o,39224 A3 23 Cy I~H2CH2 H Cl 2 o.64236 A1 - 24 - 2~

~bl~ 3 ~cont~.~
:

Example Rl R2 R3 X n M.p. Yield Method 5 No. (C) (~
or ~f 24 CH3C6H5CH2 H Cl 3 65 70 11 ~5 CyC6H5CH2 H Cl 3 o.247 24 ~ ' ' ~26 ~ NCH2~CH2 C6H5CH2 H Cl 3 0.2B6 25 A5 ~

27 Cy C6HsCH2 H Br 2 ~ 82-86 20 A3 ~28 4-oH Cy C6H5C~2 H Cl 2 128-131 16 A4 1529 H .C6H5CH2 H Cl 2 ~64-65 22 :30 Cy ~3-pyridylmethyl H Cl 2 o.695 17 A3 : Note: The upper signs mean the following systems used for : ~ . determination of Rf values~ ethyl acetate; 2: :
.
: . chlorsform/ethyl acetate ~ 1:1; 3: toluene~methanol = ::-= 9:1; 4: ethyl acetate/methanol = 9:1; 5: ethyl acetate/methanol/NEt3 = 9:0.$:0.5; 6: ethyl acetate/ethanol = 4:1; 7: methylene chloride/ethyl - :
acetate = 95:5.
Cy: 3-phenyl-?-propen-1-yl group :: , ~: ' .

. ~

.
. . . .
, 2~7~

' Table 4 R ~ N- (CH?~,, C !~ 4 r~cl 13xample R1 R2 R3 R4 X M.p. Yield ~5ethod No . ~ C ) 10. or Rf : .
32 ~ Cy H H ~Cl ~ 81--82 ~ 68 B

33: Cy C6~5CE~2 H (CH3)2CHC0 Cl 0.802 9 B
.
-: E~ampla 35 ~repar~tio~ of 4-~N-b~ yl-N-~3~ utylaarlb~0yloxy~
2 0 ~ ~ -prOpy~ o} -5 ChlOro-2 - ~ 3 -ph~ yl-2 -prOpem ~ i-y - .
3i2~)-pyrid~ino~
After dropwise adding 0.60 g ~6.06 mmol~ of butyl isocyanate to 1.09 g (2.66 mmol) of the compound of Exa~ple 13 dissolved in 20 ml of benzene, the reaction mixture was ~oiled under re~lux for 4 hours and then evaporated to ~dryness under reduced pressure. The residue was~subjected ~o column chromatography on silica gel by using a solvent mixture of chloroform and ethyl acetate to ob~ain 0.74 g ~55 : %) of title product! Rf = 0.84 (by developing with an 1:1 :
:

:

, - 26 - 2~

mixture of cloroform/ethyl acetate on sllica gel~. :
Exa~ple 36 -Pr~par~tion of pyri~inium-{3-tN-be~zyl-N ~Z-~3-ph-nyl--2-propen-l-yl)-S-chloro-3-oxo-4i2~)-pyri~azinyl-~minolpropyl}sul~te 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 lO C under stirring and cooling by ice, the~reac~ion .~
mixture was stirred for 1 hour, then evaporated to dryness at ~.
, ~ . :
40 C under a pressure of 1.33 x 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 ~15 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.
~xample for the preparatio~ of ~n ~cid ~ddition s~lt Preparatio~ o~ 5-¢hloro-2-(3-phe~y1-2-propen-1-yl)~
3-t~3-pyridyl-c~rbo~ylo~y)propyl]a~iuo}-3(2 -pyri~a~i~o~ hy~rochlori~e : 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 crystalline precipitate was filtered, washed and dried to:give 0.44 g (9o %) o~ title hydrochloride, m.p.: 115-119 C.
.

, - 27 - 2~7~

: Prepara~tion of 5-chloro-4-[N-~3-hydro~ypropyl)-N-~2--~orphollnoethyl)-ami~o~-2-~3-ph-nyl-2-propen-1-yl3--3(2~)-pyri~azinon- fum~rate 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 tbe base of Example 23 ln 9 ml of ethanol at 70 C while stirring. After stirring at the same temperatUrQ
for 10 mlnutes, the solution was evaporated ~o constant : :
weight under reduced pressure to obtain l.gO g (100 %) of the title fumarate. : : :
repar~tio~ of ~tarting sub~tan~es x2~plo~ for~the prepar~tion of novel 4,s-dihalo-3(2H)-.
-pyri~sinone~of the ge~er~l formu1 ~ethod ~ Preparatio~ of 4,5-dichloro-2-(3-phe~yl-2--prop~ yl)-3~2~)-pyrida~inone A solution of 16.a g (0.11 mol) of cinnamyl chloride in . 5 ml of anhydrous~dlmethylformamide was~dropped to a sus-~pension containing 16.5 g (0.10 mol) of 4,5-dichloro-3(2H)--pyrldazinone and 150 g of anhydrous potassium carbonate in 100 ml of anhydrous dimethylformamide at a temperature b low 15 C under stirring. The reaction mixture was stirred at room tèmperature 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 a1 are the compounds - 2 ~ 7 ~
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 S9 %, 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,$-Dichloro-2-(2-phenoxyethy~ 3(2H)-pyridazinone, : ~ yield 98 %, m.p.: 94-97:C.
10~ 4,5-Dichloro-2-(3,4-dimethoxybenzyl~-3(2H)-pyridazi-~none, yield 54 %, m.p.: 104-108 C. :
4,5-Dibromo-2-(3-phenyl-2-propen-1-yl)-3(2H)-pyridazi-none (in this case 4,5-dibromo-3(2H)-pyridazinone wa~ used instead of 4,$-dichloro-3(2H)-pyridazlnons), yl~ld 64 %, m.p.: 88-90 C.

. ~ethod a2): ~reparatio~ o~ 4~s-~ichloro-2-{2-t4-l2 ~-phe~o~yethyl)-l-pipera~i~yl~ethyl~--3S2~3 pyrlæa~inone -; 20 After portionwise adding 1.65 g (0.01 mol) of 4,5--dichloro-3(2~)-pyridazinone at room temperature to a - solution prepared from O.S9 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)-l-piperazinyl]ethyl chloride dihydrochloride were portionwise added. After boillng the reaction mixture under reflux and stirring for 2 hours, the precipitated sodium chloride was filtered and a salt was formed by adding .

2 ~ 7 ~

ethanolic hydrogen chloride solution to the ~iltrate to obtain 3.43 g (73 %) of dihydrochLoride of the titl 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 R1C1 compound instead of 2-[4-(2-phenoxy-ethyl)-l-pyperazinyl]ethyl chloride dihydrochloride:
4,5-Dichloro-2-{2-t4-(3-phenyl-2-propen-1-yl)-1--piperazinyl]ethyl}-3(2H)-pyridazinone, yield 66 %, m.p.: 238-240 oc (dihydrochloride). -~
~et~o~ a3)`: Prep2ratio~ o~ ~,5-~ichloro ~-~4-a~thoxy-benzyl)-3~2H)-pyridazino~e 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 andthen evaporating methanol under reduced pressure, the s~lt 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 silics gel by using ethyl acetate as eluent to give 1.16 g (41 %~ o~ title product, m.p.: 117-120 C.

- : ~2 ~ 7 ~
Metho~a43: Preparation o~ ~,S-~ichloro-2-[3-~4-hydroxy-p~nyl)-2-propen-1-yl]-3(2H)-pyr~zino~e To a solution containing 6.9 g (0.022 mol) of 4,5-di-chloro-2-[3-(4-~ethoxyph~nyl)-2-propèn-1-yl]-3(2H)-pyrida-zinone in 13~0 ml of 98 % methanesulfonic acid, 30.4 g (0.20mol) of methionine were portionwise added at room temperature under stirring. After the exothermic reactionj 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 ~10 adding concentrated ammonium hydroxide solution, the mixture was extracted~wlth~ethyl acetate and the organ1c phase was : ~ washed with water. After evaporation~and drying, the oily residue was boiled~under reflux with 92 ml of 2 N hydro- ~.
chloric acid under stirring for 2~hours. After`cooling down~
~15 the product was filtered, wa~hed until neutral and dried. The .
crude product obtained was purified by chromatography on ~
silica gel, using a 95:5 mixture of chloroformjethyl acetate ~ :
as eluent to yield 1.7g g (27 %) of title compound, m.p.:
1~3-195 C.

:
2. ~xampl~ ~or the propar~tio~ o~ ~ovsl 3-~ubstitute~
aminolprop~nols o~ the gener.l ~orm~la ~ ~etho~ bl): Prep~r~tion o~ 3-~N-(4-fluorobe~zyl?ami~o~-- ~ : prop ol hydroohlori~e 7.60 g (0.10 mol~ of 3-aDinopropanol 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 ' ~
, ::

2 ~
reaction m~ixture was stirred at the same temperature for 1 hour, at room temperature overnighe~ then 10 ml of acetic acid were portionwise added below 10 oc and the mixture was stirred at room temperature Eor 1 hour. After filtering the reaction mixture, the filtrate was evaporated to dryness un-der reduced pressure and the residue was dissolved in lOO ml of zo~ sodlum hydroxide solution. The solution was extracted with ethyl acetate and after drying, 20 % ethanolic hydrogen ~: chlorlde solution was added at 5 C to adjust the pH value to : : 10 3. The crystalline precipitate was filtered and washed with ether to obtain 19.1 g (87 %) of the title compound, m.p.: 136-137 oc. ~ `
Further Examples using method b1) are the compounds listed her~inafter, 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 %, 20 ~ m.p.: 140-141 ~C(~Cl).~
3-tN-(3-Pyridylmethyl)amino]propanol, yield 65 %, m.p.: 163-165 C(HCl).
~ethod b2): Preparation of 3-~N-benzylami~o)-1-(4--methoxyphenyl~ prop~ncl 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 ~elow ~0 C under stirring, then the ~reaction mixture 2 ~ 7 ~
was stirred at room temperature for l 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 wer dried to give 2.06 g ~76 %) of th ~title~compoundj m.p.~: 65-66 C.
: ~ethod ~3): Prspar tion of 3-[N-32-morpholi~oethyl)~
~ ~amino]propanol : A mixture of 9.30 g-(0.05 mol) of 2-morpholinoethyl ::~
chloride hydrochlorlde with 15.0 g ~0.20 mol) of 3-amino-prbpanol was stirred a 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, : ~ evapor3ted and the residue was distilled under reduced pressure to ohtain 5.65 g (60 %) of the title compound,~b.p.: -138-140 C/200 Pa. ~ ~
~:
:
:
' ~ ' .

~' :

: ~

Claims (8)

Claims

1. Racemic and optically active 3(2H)-pyridazlnone derivatives of the general formula (I) (I) wherein R1 means hydrogen; a C1-4alkyl group optionally substituted by an R5R6N- group where R5 and R6, being the same or different, stand for a C1-4alkyl group or R5R6N- toaether represents a 6-membered heterocyclic group optionally containing an oxygen or an R7N- moiety where R7 is a C1-4alkyl optionally substituted by a phenyoxy group or a C3-5alkenyl optionally substituted by a phenyl grup; or a C1-4alkyl group substituted by a mono- or polysubstltuted 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;
R2 means hydrogen; or a C1-4alkyl 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 C1-4alkyl, 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 R1 is different from a C1-4alkyl, alkenyl, aralkyl and phenyl group when n is 1, 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-methoxy-benzyl)-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 deflned in claim 1, in admixture with carriers and/or additives commonly used in the pharma-ceutical industry.

4. A process for the preparation of the novel 3(2H)--pyridazinone dervatives of general formula (I) (I) wherein R1 means hydrogen; a C1-4alkyl group optionally substituted by an R5R6N- group where R5 and R6, being the same or different, stand for a C1-4alkyl group or R5R6N- together represents a 6-membered heterocyclic group optionally containing an oxygen or an R7N- moiety where R7 is a C1-4alkyl optionally substituted by a phenyoxy group or a C3-5alkenyl optionally substituted by a phenyl grup; 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;
R2 means hydrogen; or a C1-4alkyl optionally substituted by a morpholino, pyridyl, 1,4-benzodloxanyl 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 C1-4alkyl, 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 R1 is different from a C1-4alkyl, alkenyl, aralkyl and phenyl group when n is 1, as well as their tautomers, racemic and optically active forms, mixtures thereof and acid addltion salts of these compounds, which comprises a) reacting a comoound of general formula (II), (II) wherein R1 and X are as defined above, with an amine of the general formula (III), (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 sultable 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 dofined 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.

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 clalm 5, which comprises using an acyl chloride or acid anhydride as reactive carboxy-lic 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 op-tically 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.