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EP0517877A1 - Novel 3(2h)-pyridazinones, pharmaceutical compositions containing them and process for preparing same - Google Patents

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

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Publication number
EP0517877A1
EP0517877A1 EP92901821A EP92901821A EP0517877A1 EP 0517877 A1 EP0517877 A1 EP 0517877A1 EP 92901821 A EP92901821 A EP 92901821A EP 92901821 A EP92901821 A EP 92901821A EP 0517877 A1 EP0517877 A1 EP 0517877A1
Authority
EP
European Patent Office
Prior art keywords
group
optionally substituted
general formula
phenyl
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP92901821A
Other languages
German (de)
French (fr)
Inventor
Péter MATYUS
György RABLOCZKY
László JASZLITS
Judit Kosary
Mária KÜRTHY
Agnes Pappne Behr
Dénesné ZARA
Egon Karpati
Anikú KOVACS
Lászlú SEBESTYAN
Lajos Farkas
Klára CZAKO
Ildikó VARGA
Sándor ELEK
Istvánné MAGO
György MATHE
Ferenc Szederkenyi
Andrea Jednakovits
Ilona Bodi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Richter Gedeon Vegyeszeti Gyar Nyrt
Original Assignee
Richter Gedeon Vegyeszeti Gyar RT
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Richter Gedeon Vegyeszeti Gyar RT filed Critical Richter Gedeon Vegyeszeti Gyar RT
Publication of EP0517877A1 publication Critical patent/EP0517877A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/22—Nitrogen and oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to novel 3 (2H) -pyridazinones of the general formula (I),
  • R 1 means hydrogen; a C 1-4 alkyl group optionally
  • R 5 and R 6 being the same or different, stand for a C 1-4 alkyl group or R 5 R 6 N- together represents a 6-membered heterocyclic group optionally containing an oxygen or an R 7 N- moiety where R 7 is a C 1-4 alkyl optionally substituted by a phenyoxy group or a C 3-5 alkenyl optionally substituted by a phenyl ; or a C 1 _ 4 alkyl group substituted by mono- or polysubstituted phenyl, phenoxy or benzyloxy group; or a C 3-5 alkenyl or C 3-5 alkynyl optionally substituted by an unsubstituted or optionally
  • R 2 stands for: hydrogen; or a C 1-4 alkyl optionally
  • R 3 means hydrogen or an optionally substituted phenyl
  • R 4 means hydrogen; or R 8 CO- group where R 8 is a C 1-4 alkyl, phenyl or pyridyl group or an amino group substituted by a C 1-4 alkyl group; or an -SO 3 M moiety where M is hydrogen or an organic or inorganic cation;
  • X means halogen
  • n 1, 2 or 3
  • R 1 is different from a C 1-4 alkyl, alkenyl, aralkyl and phenyl group when n is 1,
  • the compounds according to the invention are endowed with valuable therapeutical, chiefly cardiovascular,
  • R 1 means a C 3-5 alkenyl group substituted by an optionally substituted phenyl group
  • R 2 stands for a benzyl or 1,4-benzodioxanylmethyl group
  • R 3 is
  • R 4 represents hydrogen or pyridylcarbonyl group
  • X means chlorine or bromine
  • n is 1, 2 or 3.
  • An other preferable group of the invention contains compounds of the general formula (I), wherein R 1 stands fo C 1-4 alkyl group optionally substituted by an R 5 R 6 N- group where R 5 and R 6 are as defined above, or by a methoxy-substi- tuted phenyl or benzyloxy group; R 2 means benzyl group; R 3 is hydrogen; R 4 stands for hydrogen or an -SO 3 M group where M is as defined above; X represents chlorine; and n is 1, 2 3.
  • 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 1-3 alkyl-, 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
  • 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.
  • 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.
  • beta-adrenergic blocking agents 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.
  • 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)].
  • R 2 , R 3 and n are as defined above,
  • R 4 stands for hydrogen and R 1 , R 2 , R 3 , X and n are as defined above; or
  • R 4 means hydrogen
  • R 1 is as defined above, except hydrogen
  • R 2 , R 3 , X as well as n are as defined above, with an agent being suitable to
  • R 8 is as defined above, to obtain compounds of the general formula (I), wherein R 4 stands for R 8 CO- group, R 1 is as defined above, except hydrogen, and R 2 , R 3 , X, n and R 8 are as defined above; or
  • R 4 represents an -SO 3 M group
  • R 1 is as defined above, except hydrogen and R 2 , R 3 , X, n and M are as defined above,
  • 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.
  • the time of reaction is relatively short and the 4-(hydroxy- alkyl) amino derivative can be separated in a pure form.
  • 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 apolar aprotic solvent preferably in dioxane and/or toluene or in a less polar aprotic solvent, e.g. tertiary, iso- or n-butanol
  • An advantageous embodiment of process b) of the invention for the preparation of derivatives containing an alkyl or aryl group as R 8 comprises reacting a compound of the general formula (I) containing hydrogen as R 4 with a reactive carboxylic acid derivative, preferably the acyl chloride or acid anhydride in an inert solvent in the
  • 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 -SO 3 M group as R 4 can preferably be realized by reacting a compound of the general formula (I) containing hydrogen as R 4 with chlorosulfonic acid in an inert solvent, preferably carbon tetrachloride at a temperature between 0 °C and 25 °C.
  • 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.
  • 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 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.
  • 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
  • the compounds of the general formula (I), wherein R 3 is different from hydrogen and/or the substituents R 1 , R 2 and/or R 4 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.
  • 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 R 1 are prepared by reacting a 4,5-dihalo-3 (2H)-pyridazinone with a suitable R 1 Y reagent, wherein Y stands for a leaving group, such as e.g. an R 1 halide compound.
  • 3-aminopropanols containing a 4-fluoro- or 3,4-dimethoxybenzyl group as R 2 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 R 2 and a 4-methoxyphenyl group as R 4 can be obtained by reducing the respective, known aminoketone prepared according to the literature [J. Am. Pharm. Assoc. Sci. Ed. 67, page 77
  • the compounds of the general formula (I) according to the invention possess valuable biological effects, more par- ticularly antianginal and calmodulin-antagonizing action.
  • 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.
  • LAD left coronary artery
  • 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 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.
  • isoproterenol was intravenously administered before giving the compounds under test.
  • isoproterenol as a beta-adrenergic stimulant exerts a temporary, reversible effect increasing the myocardial contractile force and strengthening the coronary flow.
  • isoproterenol was used for testing the myocardial reactivity of the experimental animals and not as a reference drug.
  • 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.
  • Fendiline chemically N-(3,3-diphenylpropyl)-N-( ⁇ -methylbenzyl)amine
  • nicorandil chemically N-(2-nitro- oxyethyl)-3-pyridinecarboxamide
  • the compounds of general formula (I) according to the invention are useful for the treatment of cardiovascular diseases, especially angina pectoris.
  • the above reaction mixture contained also 100 ⁇ mol 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 IC 50 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • water, gelatin, lactose, starch, pectin, magnesium starate, stearic acid, talc and vegetable oils are suitable carriers.
  • additives preserving, wetting (surface active), emulsifying or dispersing, buffering and aromatizing agents may be used.
  • 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.
  • solid forms such as tablets, capsules, pills and suppositories
  • liquid forms such as aqueous or oily solutions, suspensions, emulsions, syrups
  • 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.
  • Example 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.
  • 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.
  • Example using method a 2 is the compound named hereinafter, which was prepared as described above by using the appropriate R 1 -Cl compound instead of 2-[4-(2-phenoxy- ethyl)-1-pyperazinyl]ethyl chloride dihydrochloride:

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  • Animal Behavior & Ethology (AREA)
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Abstract

Nouveaux dérivés racémiques et optiquement actifs de 3(2H)-pyridazinone répondant à la formule générale (I), dans laquelle R1 représente hydrogène; un groupe alkyle C1-4 éventuellement substitué par un groupe R5R6N- où R5 et R6 sont identiques ou différents et représentent un groupe alkyle C1-4 ou R5R6N- représente ensemble un groupe hétérocyclique hexagonal éventuellement contenant un oxygène ou une fraction R7N- où R7 représente un alkyle C1-4 éventuellement substitué par un groupe phénozy ou un alcényle C3-5 éventuellement substitué par un groupe phényle; ou un groupe alkyle C1-4 substitué par un groupe phényle, phénoxy ou benzyloxy mono- ou polysubstitué; ou bien un alcényle C3-5 ou un alcynyle C3-5 éventuellement substitué par un groupe phényle non substitué ou éventuellement substitué; ou un groupe phényle; R2 représente hydrogène; ou un alkyle C1-4 éventuellement substitué par morpholino, pyridyle, 1,4-benzodioxanyle ou un groupe phényle éventuellement substitué; R3 représente hydrogène ou un groupe phényle éventuellement substitué; R4 représente hydrogène; ou un groupe R8CO- où R8 représente un groupe alkyle C1-4, phényle ou pyridyle ou un groupe amino substitué par un groupe alkyle C1-4; ou une fraction -SO3M où M représente hydrogène ou un cation organique ou inorganique; X représente halogène; et n est 1, 2 ou 3; à condition que R1 ne représente pas un groupe alkyle C1-4, alcényle, aralkyle ou phényle lorsque n est 1; ainsi que leurs tautomères et les sels d'addition avec les acides de ces composés. On a également prévu des compositions pharmaceutiques contenant à titre d'ingrédient actif un composé répondant à la formule (I), ainsi qu'un procédé de préparation des composés répondant à la formule (I). Lesdits composés présentent un effet antagoniste sensible contre la calmoduline, diminuent la résistance coronarienne et sont moins toxiques. De ce fait, ils sont utiles au traitement des maladies cardio-vasculaires, notamment l'angine de poitrine.New racemic and optically active derivatives of 3 (2H) -pyridazinone corresponding to the general formula (I), in which R1 represents hydrogen; a C1-4 alkyl group optionally substituted by a group R5R6N- where R5 and R6 are identical or different and represent a C1-4 alkyl group or R5R6N- together represents a hexagonal heterocyclic group optionally containing an oxygen or a fraction R7N- where R7 represents C1-4 alkyl optionally substituted with a phenozy group or C3-5 alkenyl optionally substituted with a phenyl group; or a C1-4 alkyl group substituted by a mono- or polysubstituted phenyl, phenoxy or benzyloxy group; or a C3-5 alkenyl or a C3-5 alkynyl optionally substituted with an unsubstituted or optionally substituted phenyl group; or a phenyl group; R2 represents hydrogen; or C1-4 alkyl optionally substituted with morpholino, pyridyl, 1,4-benzodioxanyl or an optionally substituted phenyl group; R3 represents hydrogen or an optionally substituted phenyl group; R4 represents hydrogen; or a group R8CO- where R8 represents a C1-4 alkyl, phenyl or pyridyl group or an amino group substituted by a C1-4 alkyl group; or a fraction -SO3M where M represents hydrogen or an organic or inorganic cation; X represents halogen; and n is 1, 2 or 3; with the proviso that R1 does not represent a C1-4 alkyl, alkenyl, aralkyl or phenyl group when n is 1; as well as their tautomers and the addition salts with acids of these compounds. Pharmaceutical compositions are also provided which contain, as active ingredient, a compound corresponding to formula (I), as well as a process for preparing the compounds corresponding to formula (I). Said compounds have a significant antagonistic effect against calmodulin, reduce coronary resistance and are less toxic. Therefore, they are useful in the treatment of cardiovascular diseases, especially 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 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 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 stands for: 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, 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 C3-5alkenyl 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 C1-4alkyl 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-C1-3alkyl-, 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 (NembutalR) 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 Rf 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 Rf 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, Rf = 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, Rf = 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, Rf = 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, Rf = = 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, Rf = 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

Claims
1. Racemic and optically active 3(2H)-pyridazinone derivatives of the general formula (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.
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 C1-4allkyl group optionally
substituted by an R5R6N- group where R5 and R6, being the same or different, stand for a C1-4allkyl group or R5R6N- together represents a 6-membered heterocyclic group optionally containing an oxygen or an R7N- moiety where R7 is a C1-4allkyl optionally substituted by a phenyoxy group or a C3-5alkenyl optionally substituted by a phenyl grup; or a C1-4allkyl group substituted by a mono- or polysubstituted phenyl, phenoxy or benzyloxy group; or a C3-5alkenyl or C3-5alkenyl optionally substituted by an unsubstituted or optionally
substituted phenyl group; or a phenyl group;
R2 means hydrogen; or a C1-4allkyl 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 C1-4allkyl, 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 addition salts of these compounds, which comprises
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.
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)
EP92901821A 1990-12-27 1991-12-20 Novel 3(2h)-pyridazinones, pharmaceutical compositions containing them and process for preparing same Withdrawn EP0517877A1 (en)

Applications Claiming Priority (2)

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HU847490 1990-12-27
HU908474A HU209388B (en) 1990-12-27 1990-12-27 Process for producing new 3/2h/-pyridazinones and pharmaceutical compositions comprising same

Publications (1)

Publication Number Publication Date
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020016681A1 (en) * 2000-03-31 2002-02-07 Sean Ekins Single point interaction screen to predict IC50
HU227237B1 (en) * 2001-09-27 2010-12-28 Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag Substituted alkylpyridazinone derivatives, process for their preparation, pharmaceutical compositions containing them

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CS223432B1 (en) * 1982-01-07 1983-10-28 Vaclav Konecny Substituted 5-chlor-3-oxo-2h-pyridazins and method of preparation thereof
US4666902A (en) * 1983-06-20 1987-05-19 Cassella Aktiengesellschaft Tetrahydropyridazinone derivatives, processes for their preparation and their use
DE3934436A1 (en) * 1989-06-01 1991-04-18 Thomae Gmbh Dr K 2-HYDROXY-N-PROPYLAMINES, MEDICAMENTS CONTAINING SUCH COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF

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Title
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HUT60476A (en) 1992-09-28

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