EP0000113B1 - Dihydropyridazones, procédé pour leur préparation et médicaments les contenant, et dihydropyridazones utilisables dans le traitment médical - Google Patents

Dihydropyridazones, procédé pour leur préparation et médicaments les contenant, et dihydropyridazones utilisables dans le traitment médical Download PDF

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Publication number
EP0000113B1
EP0000113B1 EP78100001A EP78100001A EP0000113B1 EP 0000113 B1 EP0000113 B1 EP 0000113B1 EP 78100001 A EP78100001 A EP 78100001A EP 78100001 A EP78100001 A EP 78100001A EP 0000113 B1 EP0000113 B1 EP 0000113B1
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EP
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Prior art keywords
formula
methyl
compound
dihydropyridazone
phenyl
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Expired
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EP78100001A
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German (de)
English (en)
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EP0000113A1 (fr
Inventor
Rolf Dr. Lebkuecher
Marco Dr. Thyes
Horst Dr. Koenig
Hans Dieter Dr. Lehmann
Josef Dr. Gries
Dieter Dr. Lenke
Johannes Dr. Kunze
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BASF SE
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BASF SE
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    • 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
    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to 6- (p-acylaminophenyl) -4,5-dihydropyridazone- (3), its preparation and pharmaceutical preparations which contain 6- (p-acylaminophenyl) -4,5-dihydropyridazone- (3).
  • Alkyl radicals for R ' are in particular methyl, ethyl and propyl.
  • Halogen radicals substituted alkyl radicals for R 2 when R 'represents a hydrogen atom are, for example, 2-chloroethyl, 2-bromoethyl, 2-fluoroethyl, 2-iodoethyl, 1-chloropropyl, 1-bromopropyl, 1-fluoropropyl, 1-iodopropyl, 2-chloropropyl, 3-chloropropyl, 3-bromopropyl, 3-fluoropropyl, 3-iodopropyl, 1-chloroisopropyl, 1-bromoisopropyl, 1-iodoisopropyl, 2-chloroisopropyl, 2-bromoisopropyl, 1-chlorobutyl, 1-bromobutyl, 1- Fluorobutyl, 4-chlorobutyl, 4-bromobut
  • R 2 may also contain, for example, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl or 1-iodoethyl in addition to the meanings mentioned above.
  • R 1 is hydrogen or methyl and R 2 , when R 1 is hydrogen, is an alkyl radical having 3 or 4 carbon atoms or a ⁇ -halogenoethyl radical which is substituted by a halogen atom, in particular a chlorine or bromine atom, or, if R 1 is methyl, means an alkyl radical having 1 to 4 C atoms which is substituted by a halogen atom, in particular a chlorine or bromine atom.
  • the compounds of formula I can be prepared by using a compound of formula II in which R 1 has the meanings given for formula I, with an acylating agent of the formula III in which R 2 has the meanings given for formula I and represents Y OH, chlorine, bromine, a lower alkoxy radical or OCOR 2 , in a manner known per se.
  • appropriate acylating agents are the corresponding carboxylic acids, carboxylic acid halides, in particular chlorides and bromides, carboxylic esters, in particular methyl and ethyl esters, and the corresponding carboxylic anhydrides.
  • the acylation is carried out under conditions which are customary per se.
  • using at least an equimolar amount of the acylating agent advantageously in the presence of a solvent and, if appropriate, in the presence of an auxiliary base at temperatures between 0 ° C. and 160 ° C. optionally at the boiling point of the reaction mixture and optionally using pressure.
  • Suitable solvents are solvents which are inert under the reaction conditions, such as aromatic hydrocarbons, for example benzene or toluene, cyclic aliphatic ethers, such as dioxane, or dialkylformamides, such as dimethylformamide.
  • aromatic hydrocarbons for example benzene or toluene
  • cyclic aliphatic ethers such as dioxane
  • dialkylformamides such as dimethylformamide.
  • Auxiliary bases as acid-binding agents are expediently inorganic bases, such as sodium or potassium carbonate, sodium or potassium hydrogen carbonate, or tertiary organic amines, such as triethylamine.
  • the preparation of the 6- (p-acylaminophenyl) -4,5-dihydropyridazone- (3) of the formula is illustrated by the following formula scheme: Accordingly, in a further embodiment, the compounds of the formula I are prepared by using a compound of the formula IV in which R 'has the meanings given for formula I with an acylating agent of the formula III in which R 2 and Y have the meanings given above, acylated under the conditions given above and the acyl compound V obtained cyclized with hydrazine.
  • This ring closure reaction with hydrazine or hydrazine hydrate is advantageously carried out with an equimolecular amount of hydrazine in a solvent, in particular a lower alcohol, such as methanol, ethanol or propanol, a cyclic ether, such as dioxane, or a dialkylformamide, such as dimethylformamide, at temperatures from 60 to 150 ° C, preferably 80 to 120 ° C, performed.
  • a solvent in particular a lower alcohol, such as methanol, ethanol or propanol, a cyclic ether, such as dioxane, or a dialkylformamide, such as dimethylformamide
  • the compounds of the formula in which R 'is not hydrogen have an asymmetric carbon atom in the 5-position and are present as racemates.
  • the present invention is intended to include the enantiomers. If a separation is desired, this is expediently carried out at the stage of a compound of the formula II using conventional methods using an optically active acid, such as dibenzoyltartaric acid or camphor-10-sulfonic acid, via the formation of diastereomeric salts.
  • Platelet-rich plasma is obtained by centrifugation (300 g, 10 min duration at 4 ° C) of venous citrate blood.
  • the platelet aggregation is measured photometrically with the addition of MgCl 2 (final concentration 10 mmol / l) and collagen Stago (final concentration 0.02 mg / ml) in the Born aggregometer Mk 3.
  • the maximum change in extinction / sec is used as the aggregation measure.
  • the aggregation-inhibiting activity of the substances is tested after an incubation period of 10 minutes.
  • the concentration which causes 50% inhibition of the aggregation is determined as EC 50%.
  • the substances are administered orally to groups of 10-15 male Sprague-Dawley rats (200-250 g). 2-4 hours after the application, blood is drawn under ether anesthesia and platelet-rich plasma is obtained by centrifugation. The collagen aggregation is measured as indicated above.
  • the ED 33% is the dose which inhibits the platelet aggregation induced by collagen by 33%.
  • Groups of 4-8 male spontaneously hypertensive Okamoto rats (270-340 g) are administered orally.
  • the systolic blood pressure is measured without blood using piezocrystal sensors.
  • the ED 20% is determined taking into account the values of untreated control animals, the dose that reduces the systolic pressure by 20%.
  • the effective doses or concentrations were calculated from the linear relationships between the logarithms of the doses or concentrations and the effect using the regression analysis.
  • Acetylsalicylic acid served as the reference substance for inhibiting platelet aggregation, and dihydralazine for the hypotensive effect.
  • Example 5 shows that the very strong inhibition of platelet aggregation can also be determined after oral administration.
  • the substance also lowers the blood pressure of spontaneously hypertensive rats by 20% in the low oral dose of 1.2 mg / kg.
  • the acute toxicity of Example 5 is slightly less than that of acetylsalicylic acid and dihydralazine.
  • the present invention accordingly also relates to therapeutic agents or preparations which, in addition to conventional carriers and diluents, contain the new compounds of the formula 1 as active ingredient, and also these compounds or else compounds of the formula I in which, when R 'is hydrogen, R 2 is a halomethyl or a-haloethyl radical, for use as antihypertensives and for the prophylaxis and therapy of thromboembolic disorders.
  • the therapeutic agents or preparations are prepared in a known manner with the usual carriers or diluents and the commonly used pharmaceutical-technical auxiliaries according to the desired type of application with a suitable dosage. In humans, doses of 1 to 100 mg are possible, oral administration being preferred.
  • Dosage forms that are suitable for oral administration are, for example, tablets, film-coated tablets, coated tablets, capsules, pills, powders, solutions, suspensions or depot forms.
  • the compounds to be used according to the invention are processed with the carriers customary in pharmaceutical pharmacy.
  • the corresponding tablets can be mixed, for example, by mixing the active ingredient with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, polyvinylpyrrolidone, mannitol, calcium carbonate, calcium phosphate or milk sugar, disintegrants such as corn starch, alginic acid or polyvinylpyrrolidone, binders such as starch or gelatin, lubricants , such as magnesium stearate or talc, and / or agents for achieving the depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate.
  • the tablets can also consist of several layers.
  • coated tablets can be produced by coating cores produced analogously to the tablets with agents conventionally used in coated tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the coated tablet cover can also consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.
  • the active ingredient is moistened with polyvinylpyrrolidone in 10% strength aqueous solution, passed through a sieve with a mesh size of 1.0 mm and dried at 50.degree. These granules are mixed with polyethylene glycol (mean MW 4,000), hydroxypropylmethyl cellulose, talc and magnesium stearate and pressed into tablets of 240 mg each.
  • the mixture of the active substance with lactose and corn starch is granulated with an 8% aqueous solution of the polyvinylpyrrolidone through a 1.5 mm sieve, dried at 50 ° C. and again passed through a 1.0 mm sieve.
  • the granules thus obtained are mixed with magnesium stearate and pressed to dragee cores.
  • the dragee cores obtained are coated in a conventional manner with a casing which consists essentially of sugar and talc.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (8)

1. Dérivés de la 6-(p-acylaminophényl)-4,5-dihydro-pyridazone-(3) de la formule générale 1
Figure imgb0025
dans laquelle le symbole R1 représente un atome d'hydrogène ou un radical alcoyle en C1 à C3 et le symbole R2 désigne un radical alcoyle en C3 à C6 substitué par un atome d'halogène ou un radical β-halo-éthyle, lorsque R' représente un atome d'hydrogène, ou un radical alcoyle en C1 à C6 substitué par un atome d'halogène, lorsque R1 représente un radical alcoyle en C1 à C3.
2. Dérivés de la formule générale I, dans laquelle R1 représente un atome d'hydrogène ou un radical méthyle et R2 un radical alcoyle en C3 ou C4 substitué par un atome d'halogène ou un radical β-halo-éthyle, si R1 désigne un atome d'hydrogène, ou un radical alcoyle en C1 à C4 substitué par un atome d'halogène, lorsque R' désigne un radical méthyle.
3. La 6-[p-(2-chloropropionylamino)-phényl]-5-méthyl-4,5-dihydropyridazone-(3).
4. Procédé de préparation de dérivés de la formule générale 1 suivant la revendication 1, caractérisé en ce que l'on fait réagir un composé de la formule Il
Figure imgb0026
dans laquelle R1 possède les significations définies pour la formule I, le cas échéant dans un solvant et éventuellement en présence d'une base, avec un agent d'acylation de la formule III
Figure imgb0027
dans laquelle R2 possède les significations définies pour la formule 1 et Y désigne un radical -OH, un atome de chlore ou de brome, un groupe alcoxy inférieur ou un groupe -OCOR2.
5. Procédé de préparation de dérivés de la formule générale I suivant la revendication 1, caractérisé en ce que l'on cyclise un composé de la formule V
Figure imgb0028
dans laquelle R1 et R2 possèdent les significations définies pour la formule I, par l'hydrazine.
6. Composition thérapeutique, caractérisée en ce qu'elle contient, à côté de véhicules et diluants usuels, un composé de la formule 1 suivant la revendication 1 comme principe actif.
7. Composition thérapeutique suivant la revendication 6, caractérisée en ce que le principe actif est la 6-[p-(2-chloropropionylamino)-phényl]-5-méthyl-4,5-dihydropyridazone-(3).
8. Composé de la formule 1 suivant la revendication 1 ou composé de la formule I, dans laquelle R' = H et R2 représente un radical halo-méthyle ou α-halo-éthyle, utilisé pour combattre l'hypertension et pour les traitements prophylactiques et thérapeutiques d'affections thrombo-emboliques.
EP78100001A 1977-06-18 1978-06-01 Dihydropyridazones, procédé pour leur préparation et médicaments les contenant, et dihydropyridazones utilisables dans le traitment médical Expired EP0000113B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19772727481 DE2727481A1 (de) 1977-06-18 1977-06-18 Dihydropyridazone und dihydropyridazone enthaltende therapeutische mittel
DE2727481 1977-06-18

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EP0000113A1 EP0000113A1 (fr) 1979-01-10
EP0000113B1 true EP0000113B1 (fr) 1981-09-16

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US (1) US4376771A (fr)
EP (1) EP0000113B1 (fr)
JP (1) JPS549289A (fr)
AT (2) AT361494B (fr)
CA (1) CA1108614A (fr)
DE (2) DE2727481A1 (fr)
ZA (1) ZA783464B (fr)

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DE2854191A1 (de) * 1978-12-15 1980-07-03 Basf Ag Dihydropyridazinone, verfahren zu ihrer herstellung und diese verbindungen enthaltende therapeutische mittel
DE2854475A1 (de) * 1978-12-16 1980-07-03 Basf Ag Neue 3,4-diaza-bicyclo eckige klammer auf 4.1.0 eckige klammer zu hepten-(2)- one-(5), verfahren zu ihrer herstellung und diese verbindungen enthaltende therapeutische mittel
GR81309B (fr) 1980-06-13 1984-12-11 Basf Ag
DE3022176A1 (de) * 1980-06-13 1982-01-07 Basf Ag, 6700 Ludwigshafen Neue dihydropyridazinone, verfahren zu ihrer herstellung und diese verbindungen enthaltende therapeutische mittel
DE3124699A1 (de) * 1981-06-24 1983-01-13 Basf Ag, 6700 Ludwigshafen Neue 2-aryl-3,4-diaza-bicyclo(4.n.0.)alken-(2)-one-(5),verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
EP0107735B1 (fr) * 1981-10-20 1988-10-19 Mitsui Toatsu Kagaku Kabushiki Kaisha Nouveaux derives de pyridazinone
DE3209159A1 (de) * 1982-03-13 1983-09-15 Basf Ag, 6700 Ludwigshafen Neue 6-aryl-4,5-dihydro-3(2h)-pyridazinone, verfahren zu ihrer herstellung, diese verbindungen enthaltende therapeutische mittel und deren verwendung
DE3212304A1 (de) * 1982-04-02 1983-10-06 Nattermann A & Cie Imidazolylphenyl-tetrahydropyridazine, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische praeparate
DE3328286A1 (de) * 1982-08-07 1984-02-09 Basf Ag, 6700 Ludwigshafen Neue anilide, verfahren zu ihrer herstellung und ihre verwendung
DE3302021A1 (de) * 1983-01-22 1984-07-26 Basf Ag, 6700 Ludwigshafen 6-aryl-4,5-dihydro-3(2h)-pyridazinone, ihre herstellung und verwendung
JPH02119064A (ja) * 1988-10-28 1990-05-07 Matsushita Electric Ind Co Ltd 密閉形鉛蓄電池
US7772188B2 (en) 2003-01-28 2010-08-10 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
AU2006311577B2 (en) 2005-11-09 2013-02-07 Zalicus Inc. Methods, compositions, and kits for the treatment of medical conditions
US20100120694A1 (en) 2008-06-04 2010-05-13 Synergy Pharmaceuticals, Inc. Agonists of Guanylate Cyclase Useful for the Treatment of Gastrointestinal Disorders, Inflammation, Cancer and Other Disorders
US7879802B2 (en) 2007-06-04 2011-02-01 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
EP2321341B1 (fr) 2008-07-16 2017-02-22 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
MX357121B (es) 2011-03-01 2018-06-27 Synergy Pharmaceuticals Inc Star Proceso de preparacion de agonistas c de guanilato ciclasa.
WO2013106547A1 (fr) 2012-01-10 2013-07-18 President And Fellows Of Harvard College Composés promoteurs de réplication des cellules bêta et leurs procédés d'utilisation
CA2902348C (fr) 2013-02-25 2021-11-30 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et applications associees
EP2970384A1 (fr) 2013-03-15 2016-01-20 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
CA2905435A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
BR112015030326A2 (pt) 2013-06-05 2017-08-29 Synergy Pharmaceuticals Inc Agonistas ultrapuros de guanilato ciclase c, método de fabricar e usar os mesmos
WO2015021358A2 (fr) 2013-08-09 2015-02-12 Dominique Charmot Composés et procédés d'inhibition du transport de phosphate
US20200368223A1 (en) 2019-05-21 2020-11-26 Ardelyx, Inc. Methods for inhibiting phosphate transport

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US3822260A (en) * 1970-10-09 1974-07-02 American Cyanamid Co 6-(cyanophenyl)-4,5-dihydro-3(2h)-pyridazinones
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US3746712A (en) * 1971-06-08 1973-07-17 A Ross 6-(substituted-phenyl)-5-methyl-4,5-dihydro-3(2h)-pyridazinones
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Also Published As

Publication number Publication date
AT363489B (de) 1981-08-10
CA1108614A (fr) 1981-09-08
EP0000113A1 (fr) 1979-01-10
DE2727481A1 (de) 1979-01-11
US4376771A (en) 1983-03-15
JPS549289A (en) 1979-01-24
ZA783464B (en) 1979-07-25
DE2861089D1 (en) 1981-12-03
AT361494B (de) 1981-03-10
JPS6231708B2 (fr) 1987-07-09
ATA441178A (de) 1980-08-15
ATA198680A (de) 1981-01-15

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