EP0517877A1 - Nouveaux 3(2h)-pyridazinones, compositions pharmaceutiques les contenant et procede de preparation - Google Patents

Nouveaux 3(2h)-pyridazinones, compositions pharmaceutiques les contenant et procede de preparation

Info

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Withdrawn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)
English (en)
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/fr
Withdrawn legal-status Critical Current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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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Cardiology (AREA)
  • Veterinary Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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.
EP92901821A 1990-12-27 1991-12-20 Nouveaux 3(2h)-pyridazinones, compositions pharmaceutiques les contenant et procede de preparation Withdrawn EP0517877A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
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
EP0517877A1 true EP0517877A1 (fr) 1992-12-16

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ID=10972641

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92901821A Withdrawn EP0517877A1 (fr) 1990-12-27 1991-12-20 Nouveaux 3(2h)-pyridazinones, compositions pharmaceutiques les contenant et procede de preparation

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EP (1) EP0517877A1 (fr)
JP (1) JPH05504778A (fr)
CA (1) CA2074261A1 (fr)
HU (1) HU209388B (fr)
WO (1) WO1992012137A1 (fr)

Families Citing this family (2)

* 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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Publication number Priority date Publication date Assignee Title
CS223432B1 (cs) * 1982-01-07 1983-10-28 Vaclav Konecny ) Substituované 5-chlór-3-oxo-2H-pyridazíny a sposob ich přípravy
US4666902A (en) * 1983-06-20 1987-05-19 Cassella Aktiengesellschaft Tetrahydropyridazinone derivatives, processes for their preparation and their use
DE3934436A1 (de) * 1989-06-01 1991-04-18 Thomae Gmbh Dr K 2-hydroxy-n-propylamine, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung

Non-Patent Citations (1)

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Title
See references of WO9212137A1 *

Also Published As

Publication number Publication date
HU908474D0 (en) 1991-07-29
HU209388B (en) 1994-05-30
HUT60476A (en) 1992-09-28
CA2074261A1 (fr) 1992-06-28
WO1992012137A1 (fr) 1992-07-23
JPH05504778A (ja) 1993-07-22

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