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EP0000113A1 - Dihydropyridazones, their preparation and medicines containing them and dihydropyridazones for use in medical treatments - Google Patents

Dihydropyridazones, their preparation and medicines containing them and dihydropyridazones for use in medical treatments Download PDF

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Publication number
EP0000113A1
EP0000113A1 EP78100001A EP78100001A EP0000113A1 EP 0000113 A1 EP0000113 A1 EP 0000113A1 EP 78100001 A EP78100001 A EP 78100001A EP 78100001 A EP78100001 A EP 78100001A EP 0000113 A1 EP0000113 A1 EP 0000113A1
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formula
methyl
dihydropyridazone
alkyl radical
atoms
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German (de)
French (fr)
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EP0000113B1 (en
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).
  • R 1 is hydrogen or an alkyl radical having 1 to 3 C atoms and R 2
  • R 1 is a hydrogen atom
  • Alkyl radicals for R 1 are in particular methyl, ethyl and propyl.
  • Halogen radicals substituted alkyl radicals for R 2 when R 1 represents a hydrogen atom, are, for example, 2-chloro-ethyl-2-bromoethyl, 2-fluoroethyl, 2-iodoethyl, 1-chloropropyl, 1-bromoropyl, 1-fluoropropyl, 1- Iodopropyl, 2-chloropropyl, 3-chloropropyl, 3-bromopropyl, 3-fluoropropyl, 3-iodopropyl, 1-chloroisopropyl, 1-bromoisopropyl, 1-iodoisopropyl, a-chloroisopropyl, 2-bromopropyl, 1-chlorobutyl, 1-bromobutyl, 1-fluorobutyl, 4-chlorobutyl, 4-bromobuty
  • R 2 may also have, for example, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl or 1-iodoethyl.
  • R 1 is hydrogen or methyl and R 2 , when R 1 is hydrogen, is an alkyl radical having 3 or 4 C atoms or a ⁇ -halogenoethyl radical substituted by a halogen atom, in particular a chlorine or bromine atom, or, if R 1 is methyl, means an alkyl radical with 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
  • Halogen radicals substituted alkyl radicals for R 2 when R 1 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-bromobutyl, 4-fluorobutyl,
  • 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 C 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 the formula I can be prepared by endowing a compound of the formula II
  • the compounds of the formula I are prepared by using a compound of the formula IV, in which R has the meanings given above, 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 ar restroomn acyl compound V cyclized with hydrazine.
  • 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
  • R 1 is not hydrogen
  • the present invention is intended to include the enantiomers.
  • the new compounds of the formula I and, moreover, also compounds of the formula I in which, when R 1 is hydrogen, R 2 is a halogenomethyl or an ⁇ -halogenoethyl radical have a strong antiplatelet activity and an antihypertensive effect Award effect. They are suitable as antihypertensives and for the prophylaxis and therapy of thrombo-embolic diseases.
  • Groups of 4 - 8 male spontaneously hypertensive Okamotv rats (270-340g) are administered orally.
  • the systolic blood pressure is measured without blood using piezocrystal recorders.
  • the ED 20% is determined taking into account the values of untreated control animals, the dose which 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 somewhat 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 compounds mentioned as an active ingredient, and the use of these compounds for therapeutic purposes.
  • the therapeutic agents or preparations are prepared in a known manner with the usual carriers or diluents and the commonly used pharmaceutical-technical auxiliaries in accordance with 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 lactose, 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 to achieve the depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate, can be obtained.
  • the tablets can also consist of several layers.
  • coated tablets can be coated by cores produced analogously to the tablets with agents commonly used in coated tablet coatings, for example Kollidon or ⁇ shellac, gum arabic, talc, titanium dioxide or sugar, ⁇ . getting produced.
  • the coated tablet 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 ingredient 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 rubbed again through a 1.0 mm sieve.
  • the granules obtained in this way are nesium stearate mixed and into coated tablets; pressed
  • the Dragurk are a der that is made in the usual way with a cover and essentially consists of sugar and talc.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

Die Erfindung betrifft 6-(p-Acylaminophenyl)-4,5-dihydropyridazone -(3) der Formel I <IMAGE> in eer für R¹ Wasserstoff oder ein Alkylrest mit 1 bis 3 C-Atomen steht und R², wenn für R¹ ein Wasserstoffatom steht, einen durch ein Halogenatom substituierten Alkylrest mit 3 bis 6 C-Atomen oder einen β-Halogenäthylrest oder, wenn für R¹ ein Alkylrest mit 1 bis 3 C-Atomen steht, einen durch ein Halogenatom substituierten Alkylrest mit 1 bis 6 C-Atomen bedeutet, ihre Herstellung und therapeutische Mittel, die eine Verbindung der Formel I als Wirkstoff, wobei R² auch einen Halogenmethyl- oder -Halogenäthylrest bedeutet für den Fall, daß R¹ Wasserstoff ist, enthalten. Diese Verbindungen sind als Anti-hypertensiva und zur Prophylaxe und Therapie thrombo-embolischer Erkrankungen geeignet.The invention relates to 6- (p-acylaminophenyl) -4,5-dihydropyridazone - (3) of the formula I <IMAGE> in which R 1 is hydrogen or an alkyl radical having 1 to 3 C atoms and R 2 when R 1 is a hydrogen atom is an alkyl radical substituted by a halogen atom with 3 to 6 C atoms or a β-haloethyl radical or, when R 1 is an alkyl radical having 1 to 3 C atoms, means an alkyl radical substituted by a halogen atom with 1 to 6 C atoms , their preparation and therapeutic agents which contain a compound of formula I as an active ingredient, where R² also denotes a halogenomethyl or haloethyl radical in the case where R¹ is hydrogen. These compounds are suitable as anti-hypertensives and for the prophylaxis and therapy of thrombo-embolic diseases.

Description

Die Erfindung betrifft 6-(p-Acylaminophenyl)-4,5-dihydropyridazone-(3), ihre Herstellung und pharmazeutische Zubereitungen, die 6-(p-Acylaminophenyl)-4,5-dihydropyridazone-(3) enthalten.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).

Es wurde gefunden, daß im Acylrest durch ein Halogenatom substituierte 6-(p-Acylaminophenyl)-.4,5-dihydropyridazone--(3) der Formel I

Figure imgb0001
in der für R1 Wasserstoff oder ein Alkylrest mit 1 bis 3 C-Atomen steht und R2, wenn für R1 ein Wasserstoffatom steht, einen durch ein Halogenatom substituierten Alkylrest mit 3 bis 6 C-Atomen oder einen ß-Halogenäthylrest oder, wenn für R1 ein Alkylrest mit 1 bis 3 C-Atomen steht, einen durch ein Halogenatom-substituierten Alkylrest mit 1 bis 6 C-Atomen bedeutet, wertvolle pharmakologische Eigenschaften aufweisen.It was found that 6- (p-acylaminophenyl) -. 4,5-dihydropyridazone - (3) of the formula I. Substituted in the acyl radical by a halogen atom
Figure imgb0001
 in which R 1 is hydrogen or an alkyl radical having 1 to 3 C atoms and R 2 , when R 1 is a hydrogen atom, an alkyl radical having 3 to 6 C atoms or a β-halogenoethyl radical substituted by a halogen atom or, if R 1 represents an alkyl radical with 1 to 3 C atoms, means an alkyl radical with 1 to 6 C atoms substituted by a halogen atom, and have valuable pharmacological properties.

Alkylreste für R1 sind insbesondere Methyl, Äthyl und Propyl. Durch Halogen substituierte Alkylreste für R2, wenn für R1 ein Wasserstoffatom steht, sind beispielsweise 2-Chlor- Ethyl- 2-Bromäthyl, 2-Fluoräthyl, 2-Jodäthyl, 1-Chlorpropyl, 1-Bromoropyl, 1-Fluorpropyl, 1-Jodpropyl, 2-Chlorpropyl, 3-Chlorpropyl, 3-Brompropyl, 3-Fluorpropyl, 3-Jodpropyl, 1-Chlorisopropyl, 1-Bromisopropyl, 1-Jodisopropyl, a-chlorisopropyl, 2-Bromisopropyl, 1-Chlorbutyl, 1-Brombutyl, 1-Fluorbutyl, 4-Chlorbutyl, 4-Brombutyl, 4-Fluorbutyl, 1-Chlorisobutyl, 1-Bromisobutyl, 2-Chlorisobutyl, 1-Chlor-sec-butyl, 1-Brom-sec-butyl, 3-Chlor-sec-butyl, Chlortertiärbutyl, Bromtertiärbutyl, 1-Chloramyl, 1-Bromamyl, 5-Brcmamyl, 1-Äthyl-1-chlorpropyl, 1-Äthyl-1-brompropyl.Alkyl radicals for R 1 are in particular methyl, ethyl and propyl. Halogen radicals substituted alkyl radicals for R 2 , when R 1 represents a hydrogen atom, are, for example, 2-chloro-ethyl-2-bromoethyl, 2-fluoroethyl, 2-iodoethyl, 1-chloropropyl, 1-bromoropyl, 1-fluoropropyl, 1- Iodopropyl, 2-chloropropyl, 3-chloropropyl, 3-bromopropyl, 3-fluoropropyl, 3-iodopropyl, 1-chloroisopropyl, 1-bromoisopropyl, 1-iodoisopropyl, a-chloroisopropyl, 2-bromopropyl, 1-chlorobutyl, 1-bromobutyl, 1-fluorobutyl, 4-chlorobutyl, 4-bromobutyl, 4-fluorobutyl, 1-chloroisobutyl, 1-bromoisobutyl, 2-chloroisobutyl, 1-chloro-sec-butyl, 1-bromo-sec-butyl, 3-chloro-sec- butyl, chlorotertiary butyl, bromotertiary butyl, 1-chloramyl, 1-bromamyl, 5-bromamyl, 1-ethyl-1-chloropropyl, 1-ethyl-1-bromopropyl.

Für den Fall, daß für R1 ein Alkylrest steht, kommen für R2 reben den oben genannten Bedeutungen noch beispielsweise Chlormethyl, Brommethyl, Fluormethyl, Jodmethyl, 1-Chloräthyl, 1-Bromäthyl, 1-Fluoräthyl oder 1-Jodäthyl in Betracht.In the event that R 1 is an alkyl radical, R 2 may also have, for example, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl or 1-iodoethyl.

Die bevorzugten Verbindungen sind solche, in denen R1 Wasserstoff oder Methyl und R2, wenn R1 Wasserstoff ist, einen durch ein Halogenatom, insbesondere ein Chlor- oder Bromatom, substituierten Alkylrest mit 3 oder 4 C-Atomen oder einen ß-Ealogenäthylrest, oder, wenn R1 Methyl ist, einen durche ein Halogenatom, insbesondere ein Chlor- oder Brom- atom substituierten Alkylrest mit 1 bis 4 C-Atomen bedeutet.The preferred compounds are those in which R 1 is hydrogen or methyl and R 2 , when R 1 is hydrogen, is an alkyl radical having 3 or 4 C atoms or a β-halogenoethyl radical substituted by a halogen atom, in particular a chlorine or bromine atom, or, if R 1 is methyl, means an alkyl radical with 1 to 4 C atoms which is substituted by a halogen atom, in particular a chlorine or bromine atom.

Die Verbindungen der Formel I können hergestellt werden, Indem man eine Verbindung der Formel II

Figure imgb0002
Durch Halogen substituierte Alkylreste für R2, wenn für R1 ein Wasserstoffatom steht, sind beispielsweise 2-Chlorathy-, 2-Bromäthyl, 2-Fluoräthyl, 2-Jodäthyl, 1-Chlorpropyl, 1-Brompropyl, 1-Fluorpropyl, 1-Jodpropyl, 2-Chlorpropyl, 3-Chlorpropyl, 3-Brompropyl, 3-Fluorpropyl, 3-Jodpropyl, 1-Chlorisopropyl, 1-Bromisopropyl, 1-Jodisopropyl 2-Chlorisopropyl, 2-Bromisopropyl, 1-Chlorbutyl, 1-Brombutyl, 1-Fluorbutyl, 4-Chlorbutyl, 4-Brombutyl, 4-Fluorbutyl, 1-Chlorisobutyl, 1-Bromisobutyl, 2-Chlorisobutyl, 1-Chlor-sec-butyl, 1-Brom-sec-butyl, 3-Chlor-sec-butyl, Chlortertiärbutyl, Bromtertiärbutyl, 1-Chloramyl, 1-Bromamyl, 5-Brcmamyl, 1-Äthyl-1-chlorpropyl, 1-Äthyl-1-brompropyl.The compounds of formula I can be prepared by using a compound of formula II
Figure imgb0002
 Halogen radicals substituted alkyl radicals for R 2 , when R 1 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-bromobutyl, 4-fluorobutyl, 1-chloroisobutyl, 1-bromoisobutyl, 2-chloroisobutyl, 1-chloro-sec-butyl, 1-bromo-sec-butyl, 3-chloro-sec-butyl, Chlorotertiary butyl, bromotertiary butyl, 1-chloramyl, 1-bromamyl, 5-bromamyl, 1-ethyl-1-chloropropyl, 1-ethyl-1-bromopropyl.

Für den Fall, daß für R1 ein Alkylrest steht, kommen für R2 neben den oben genannten Bedeutungen noch beispielsweise Chlormethyl, Brommethyl, Fluormethyl, Jodmethyl, 1-Chloräthyl, 1-Bromäthyl, 1-Fluoräthyl oder 1-Jodäthyl in Betracht.In the event that R 1 is an alkyl radical, 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.

Die bevorzugten Verbindungen sind solche, in denen R1 Wasserstoff oder Methyl und R2, wenn R1 Wasserstoff ist, einen durch ein Halogenatom, insbesondere ein Chlor- oder Bromatom, substituierten Alkylrest mit 3 oder 4 C-Atomen oder einen ß-Halogenäthylrest, oder, wenn R1 Methyl ist, einen durch ein Halogenatom, insbesondere ein Chlor- oder Bromatom, substituierten Alkylrest mit 1 bis 4 C-Atomen bedeutet.The preferred compounds are those in which R 1 is hydrogen or methyl and R 2 , when R 1 is hydrogen, is an alkyl radical having 3 or 4 C atoms or a β-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.

die Verbindungen der Formel I können hergestellt werden, Endem man eine Verbindung der Formel II

Figure imgb0003
Figure imgb0004
 the compounds of the formula I can be prepared by endowing a compound of the formula II
Figure imgb0003
Figure imgb0004

Demnach werden gemäß einer weiteren Ausführungsform die Verbindungen der Formel I hergestellt, indem man eine Verbindung der Formel IV, in der R die oben angegebenen Bedeutungen hat, mit einem Acylierungsmittel der Formel III

Figure imgb0005
in der R2 und Y die oben angegebenen Bedeutungen haben, unter den oben angegebenen Bedingungen acyliert und die arhaltene Acylverbindung V
Figure imgb0006
mit Hydrazin cyclisiert.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 above, with an acylating agent of the formula III
Figure imgb0005
 in which R 2 and Y have the meanings given above, acylated under the conditions given above and the arhaltigen acyl compound V
Figure imgb0006
 cyclized with hydrazine.

Diese Ringschlußreaktion mit Hydrazin oder Hydrazinhydrat und vorteilhaft mit einer äquimolekularen Menge Hydrazin in einem Lösungsmittel, insbesondere einem niederen Alkool, wie Methanol, Äthanol oder Propanol, einem cyclischen Ether, wie Dioxan, oder einem Dialkylformamid, wie Dimethylformamid, bei Temperaturen von 60 bis 150°C, vorzugsweise 80 bis 120°C, durchgeführt.This ring closure reaction with hydrazine or hydrazine hydrate and advantageously 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 carried out.

Die als Ausgangssubstanzen verwendeten Verbindungen der Formel II und auch der Formel IV sind bekannt oder können unter den beispielsweise in den DT-OS 16.70 158 und 21 50 436 oder den US-PS 3 824 271 und 3 888 901 beschriebenen Bedingungen hergestellt werden.The compounds of the formula II and also of the formula IV used as starting substances are known or can be prepared under the conditions described, for example, in DT-OS 16.70 158 and 21 50 436 or US Pat. Nos. 3,824,271 and 3,888,901.

Es wird darauf hingewiesen, daß die Verbindungen, in denen R1 ungleich Wasserstoff ist, ein asymmetrisches C-Atom in 5-Stellung aufweisen und als Racemate vorliegen. Die vorliegende Erfindung soll die Enantiomeren mit einschließen.It should be noted that the compounds in which R 1 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.

Falls eine Trennung gewünscht wird, wird diese zweckmäßigerweise auf der Stufe einer Verbindung der Formel II nach an sich üblichen Verfahren mit einer optisch aktiven Säure, wie Dibenzoylweinsäure oder Campher-10-sulfonsäure, über die Bildung diastereomerer Salze durchgeführt.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.

Nach den genannten Verfahren werden neben den in den Ausführungsbeispielen angegebenen Verbindungen beispielsweise erhalten:

  • 6-(p-Bromacetylaminophenyl)-4,5-dihydropyridazon-(3);
  • 6-(p-Bromacetylaminophenyl)-5-methyl-4,5-dihydropyridazon-(3);
  • 6-(p-Fluoracetylaminophenyl)-5-methyl-4,5-dihydropyridazon-(3 ) ;
  • 6-(p-Jodacetylaminophenyl)-5-methyl-4,5-dihydropyridazon--(3);
  • 6-[p-(3-Brommronionylamino)-phenyl -5-methyl-4,5-dihydropyridazon-(3);
  • 6- [p- (3-Fluorpropionylamino) -Phenyl -5-methyl-4, 5-dihydropyridazon-(3);
  • pyridazon-(3);
  • 6-[p- (2-Chlorbutyrylamino) -Phenyl] -4, 5-dihydropyridazon-(3):
  • 6-[p-(2-Chlorbutyrylamino)-phenyl]-5-methyl-4,5-dihydropyridazon-(3);
  • 6-[P-(3-Chlorbutyrylamino)-Phenyl]-5-methyl-4,5-dihydropyridazon- (3) ;
  • 6-[p-(2-Bromvalerylamino)-phenyl]-5-methyl-4,5-dihydropyridazon-(3);
  • 6-[p-(2-Bromisovalerylamino)-phenyl] -5-methyl-4,5-dihydropyridazon-(3);
  • 6-[p-(2-Äthyl-2-brombutyrylamino)-phenyl] -5-methyl-4,5-dihydropyridazon-(3);
In addition to the compounds specified in the exemplary embodiments, the processes mentioned give, for example:
  • 6- (p-bromoacetylaminophenyl) -4,5-dihydropyridazone- (3);
  • 6- (p-bromoacetylaminophenyl) -5-methyl-4,5-dihydropyridazone- (3);
  • 6- (p-fluoroacetylaminophenyl) -5-methyl-4,5-dihydropyridazone- (3);
  • 6- (p-iodoacetylaminophenyl) -5-methyl-4,5-dihydropyridazone - (3);
  • 6- [p- (3-Bromomionylamino) phenyl -5-methyl-4,5-dihydropyridazone- (3);
  • 6- [p- (3-Fluoropropionylamino) phenyl -5-methyl-4,5-dihydropyridazone- (3);
  • pyridazone- (3);
  • 6- [p- (2-Chlorobutyrylamino) phenyl] -4, 5-dihydropyridazone- (3):
  • 6- [p- (2-Chlorobutyrylamino) phenyl] -5-methyl-4,5-dihydropyridazone- (3);
  • 6- [P- (3-Chlorobutyrylamino) phenyl] -5-methyl-4,5-dihydropyridazone- (3);
  • 6- [p- (2-Bromovalerylamino) phenyl] -5-methyl-4,5-dihydropyridazone- (3);
  • 6- [p- (2-Bromoisovalerylamino) phenyl] -5-methyl-4,5-dihydropyridazone- (3);
  • 6- [p- (2-Ethyl-2-bromobutyrylamino) phenyl] -5-methyl-4,5-dihydropyridazone- (3);

Weiterhin wurde gefunden, daß die neuen Verbindungen der Formel I und darüber hinaus auch Verbindungen der Formel I in denen, wenn R1 Wasserstoff ist, R2 einen Halogenmethyl-oder einen α-Halogenäthylrest bedeutet, sich durch eine starke thrombozytenaggregationshemmende Wirkung und durch eine blutdrucksenkende Wirkung auszeichnen. Sie sind als Antihypertensiva und zur Prophylaxe und Therapie thrombo-embolischer Erkrankungen geeignet.Furthermore, it has been found that the new compounds of the formula I and, moreover, also compounds of the formula I in which, when R 1 is hydrogen, R 2 is a halogenomethyl or an α-halogenoethyl radical, have a strong antiplatelet activity and an antihypertensive effect Award effect. They are suitable as antihypertensives and for the prophylaxis and therapy of thrombo-embolic diseases.

Zur Untersuchung der pharmakodynamischen Eigenschaften der erfindungsgemäßen Produkte wurden folgende Methoden verwendet:

  • 1. Hemmung der durch Collagen induzierten Aggregation von Thrombozyten des Menschen in vitro
    • Thrombozytenreiches Plasma wird durch Zentrifugation (300 g, 10 min Dauer bei 4°C) von vernösem Citratblut gewonnen. Die photometrische Messung der Thrombozytenaggregation erfolgt unter Zusatz von MgCl2 (Endkonzentration 10 mmol/1) und von Collagen Stago (Endkonzentration 0,02 mg/ml) im Born-Aggregometer Mk 3. Als Aggregationsmaß findet die maximale Extinktionsänderung/sec Verwendung.
    • Die Prüfung der aggregationshemmenden Wirksamkeit der Substanzen wird nach einer Inkubationszeit-von 10 min vorgenommen.
    • Als EC 50 % wird die Konzentration bestimmt, welche eine 50 %ige Hemmung der Aggregation verursacht.
  • 2. Hemmung der durch Collagen induzierten Aggregation von Thrombozyten der Ratte ex vivo
    • Die Substanzen werden Gruppen von 10 - 15 männlichen Sprague- Dawley-Ratten (200 - 250 g) oral appliziert. 2 - 4 Stunden nach der Application wird in Aether-Narkose Blut entnommen und durch Zentrifugation thrombozytenreiches Plasma gewonnen. Die Messung der Aggregation nach Collagen erfolgt wie oben angegeben.
    • Als ED 33 % wird die Dosis bestimmt, welche die durch Collagen induzierte Thrombozytenaggregation um 33 % hemmt.
  • 3. Blutdrucksenkende Wirkung an der narkotisierten Ratte Zur Testung der blutdrucksenkenden Wirkung erhalten Gruppen von 3 - 5 männlichen Sprague-Dawley-Ratten (240 - 280 g) in Urethan-Narkose (1,78 mg/kg i.p.) die Substanzen intraperitoneal appliziert. Die Messung des Blutdrucks in der A.carotis erfolgt über Statham-Transducer. Als ED 20 % wird die Dosis bestimmt, welche den mittleren Carotisblutdruck um 20 % senkt.
  • 4. Antihypertensive Wirkung an spontan nypertonen Ratten
The following methods were used to investigate the pharmacodynamic properties of the products according to the invention:
  • 1. Inhibition of collagen-induced aggregation of human platelets in vitro
    • Platelet-rich plasma is obtained by centrifugation (300 g, 10 min duration at 4 ° C) of citrated blood. The platelet aggregation is measured photometrically with the addition of MgCl 2 (final concentration 10 mmol / 1) and collagen Stago (final concentration 0.02 mg / ml) in the Born aggregometer Mk 3. The maximum absorbance is found as the aggregation measure tion change / sec usage.
    • 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%.
  • 2. Inhibition of collagen-induced aggregation of platelets in rats ex vivo
    • The substances are administered orally to groups of 10-15 male Sprague-Dawley rats (200-250 g). 2 - 4 hours after 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%.
  • 3. Hypotensive effect on the anesthetized rat To test the hypotensive effect, groups of 3-5 male Sprague-Dawley rats (240-280 g) were given the substances intraperitoneally in urethane anesthesia (1.78 mg / kg ip). The blood pressure in the carotid artery is measured using a Statham transducer. The ED 20% is the dose which lowers the mean carotid blood pressure by 20%.
  • 4. Antihypertensive effect on spontaneously hypertensive rats

Gruppen von 4 - 8 männlichen spontan hypertonen Okamotv- Ratten (270 - 340g) werden die Substanzen oral appliziert.Groups of 4 - 8 male spontaneously hypertensive Okamotv rats (270-340g) are administered orally.

Vor und 2 Stunden nach der Applikation wird der systolische Blutdruck unblutig mit Hilfe von Piezokristallaufnehmem gemessen.Before and 2 hours after the application, the systolic blood pressure is measured without blood using piezocrystal recorders.

Als ED 20 % wird unter Berücksichtigung der Werte unbehandelter Kontrolltiere die Dosis bestimmt, welche den systolischen Druck um 20 % senkt.The ED 20% is determined taking into account the values of untreated control animals, the dose which reduces the systolic pressure by 20%.

Die Berechnung der wirksamen Dosen bzw. Konzentrationen erfolgte aus den linearen Beziehungen zwischen den Logarithmen der Dosen bzw. Konzentrationen und der Wirkung mit Hilfe der Regressionsanalyse.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.

Als Referenzsubstanz für die Hemmung der Thrombozytenaggregation diente Acetylsalicylsäure, für die blutdrucksenkende Wirkung Dihydralazin.

Figure imgb0007
Figure imgb0008
 Acetylsalicylic acid served as the reference substance for inhibiting platelet aggregation, and dihydralazine for the hypotensive effect.
Figure imgb0007
Figure imgb0008

Die Ergebnisse (Tabelle 1) zeigen für die erfindungsgemäßen Verbindungen eine außerordentlich starke Hemmung der durch Collagen induzierten Aggregation von Thrombozyten des Menschen. Die Wirkung ist 291 - 15 900mal stärker als die des bekannten aggregationshemmenden Pharmakons Acetylsalicylsäure.The results (Table 1) show an extraordinarily strong inhibition of the aggregation of platelets in humans induced by collagen for the compounds according to the invention. The effect is 291 - 15 900 times stronger than that of the well-known aggregation-inhibiting drug acetylsalicylic acid.

┌Außer der Hemmung der Thrombozytenaggregation tritt eine ┐ blutdrucksenkende Wirkung von unterschiedlicher Stärke auf. Die Verbindung Beispiel Nr. 5 und Nr. 7 wirken 43 bzw. 7,6mal stärker blutdrucksenkend als das bekannte Antihypertonikum Dihydralazin. Eine Reihe weiterer Verbindungen (Beispiele 1, 3, 4, 8, 12 und 16) sind etwa ebenso aktiv wie Dihydralazin. Bei Verbindung 9 und 17., besonders aber bei Beispiel 6 ist die blutdrucksenkende Wirkung gering. Hier liegt eine hohe Spezifität der thrombozytenaggregationshemmenden Wirkung vor. Pharmakotherapeutisch sind Ver-, bindungen mit thrombozytenaggregationshemmender und blutdrucksenkender Wirkung ebenso wünschenswert wie solche die thrombozytenaggregationshemmend wirken und den Blutdruck nur wenig beeinflussen.Ußer In addition to the inhibition of platelet aggregation, there is an ┐ hypotensive effect of various strengths. The compound Example No. 5 and No. 7 have 43 and 7.6 times more hypotensive effects than the well-known antihypertensive dihydralazine. A number of other compounds (Examples 1, 3, 4, 8, 12 and 16) are approximately as active as dihydralazine. With compounds 9 and 17, but especially with example 6, the blood pressure lowering effect is low. There is a high specificity of the antiplatelet activity. Pharmacotherapeutically, compounds with antiplatelet and antihypertensive effects are just as desirable as those which inhibit platelet aggregation and have little influence on blood pressure.

An der Verbindung des Beispiels 5 (Tab. 2) wird nachgewiesen, daß die sehr starke Hemmung der Thrombozytenaggregation auch nach oraler Applikation festzustellen ist. Die Substanz senkt außerdem in der niedrigen oralen Dosis von 1,2 mg/kg den Blutdruck spontan hypertensiver Ratten um 20 %. Die akute Toxizität von Beispiel'5 ist etwas geringer als die von Acetylsalizylsäure und Dihydralazin.The compound of Example 5 (Table 2) 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 somewhat less than that of acetylsalicylic acid and dihydralazine.

Gegenstand der vorliegenden Erfindung sind demnach auch therapeutische Mittel oder Zubereitungen, die neben üblichen Träger-und Verdünnungsmitteln die genannten Verbindungen als Wirkstoff enthalten, sowie die Verwendung dieser Verbindungen zu therapeutischen Zwecken.The present invention accordingly also relates to therapeutic agents or preparations which, in addition to conventional carriers and diluents, contain the compounds mentioned as an active ingredient, and the use of these compounds for therapeutic purposes.

Es sei erwähnt, daß die Verbindungen 6-(p-Chloracetylamino- phenyl)-4,5-dihydropyridazon-(3) und 6-[P-(2-Chlorpropionyl- amino)- phenyl] -4,5-dihydropyridazon-(3) in der DT-OS 21 23 246 als Zwischenprodukte beschrieben werden. Für Acylaminophenyl-dihydropyridazone, die im Acyl nicht durch Halogen substituiert sind, sind entzündungshemmende und blut- ┌drucksenkende Eigenschaften beschrieben (vgl. DT-QS 16 70 158 und DT-OS 21 50 436). Die Hemmung der Thrombozytenaggregation durch die erfindungsgemäß zu verwendenden Verbindungen ist eine völlig unerwartete Wirkung.It should be noted that the compounds 6- (p-chloroacetylaminophenyl) -4,5-dihydropyridazone- (3) and 6- [P- (2-chloropropionylamino) phenyl] -4,5-dihydropyridazone- ( 3) are described as intermediate products in DT-OS 21 23 246. For acylaminophenyl-dihydropyridazones which are not substituted by halogen in the acyl, anti-inflammatory and blood- ┌ pressure-reducing properties described (see DT-QS 16 70 158 and DT-OS 21 50 436). The inhibition of platelet aggregation by the compounds to be used according to the invention is a completely unexpected effect.

Die therapeutischen Mittel oder Zubereitungen werden mit den üblichen Trägerstoffen oder Verdünnungsmitteln und den üblicherweise verwendeten pharmazeutisch-technischen Hilfsstoffen entsprechend der gewünschten Applikationsart mit einer geeigneten Dosierung in bekannter Weise hergestellt. Dabei kommen beim Menschen Dosen von 1 bis 100 mg in Betracht, wobei die orale Applikation bevorzugt ist.The therapeutic agents or preparations are prepared in a known manner with the usual carriers or diluents and the commonly used pharmaceutical-technical auxiliaries in accordance with the desired type of application with a suitable dosage. In humans, doses of 1 to 100 mg are possible, oral administration being preferred.

Darreichungsformen, die zur oralen Applikation geeignet sind, sind beispielsweise Tabletten, Filmtabletten, Dragees, Kapseln, Pillen, Pulver, Lösungen, Suspensionen oder Depotformen.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.

Zur praktischen Anwendung werden die erfindungsgemäß zu verwendenden Verbindungen mit den in der galenischen Pharmazie üblichen Trägerstoffen verarbeitet. Die entsprechenden Tabletten können beispielsweise durch Mischen des Wirkstoffs mit bekannten Hilfsstoffen, beispielsweise inerten Verdünnungsmitteln, wie Dextrose, Zucker, Sorbit, Polyvinylpyrrolidon, Mannit, Calciumcarbonat, Calciumphosphat oder Milchzucker, Sprengmitteln, wie Mais, Stärke, Alginsäure oder Polyvinylpyrrolidon, Bindemitteln wie Stärke oder Gelatine, Gleitmitteln, wie Magnesiumstearat oder Talkum, und/oder Mitteln zur Erzielung des Depoteffektes, wie Carboxypolymethylen, Carboxymethylcellulose, Celluloseacetatphthalat oder Polyvinylacetat, erhalten werden..Die Tabletten können auch aus mehreren Schichten bestehen.For practical use, 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 lactose, 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 to achieve the depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate, can be obtained. The tablets can also consist of several layers.

Entsprechend können Dragees durch überziehen von analog den Tabletten hergestellten Kernen mit üblicherweise in Dragee- überzügen verwendeten Mitteln, beispielsweise Kollidon oder ┌ Schellack, Gummi arabicum, Talk, Titandioxid oder Zucker, ┐ . hergestellt werden. Dabei kann auch die Drageehülle aus mehreren Schichten bestehen, wobei die oben bei den Tabletten erwähnten Hilfsstoffe verwendet werden können.Correspondingly, coated tablets can be coated by cores produced analogously to the tablets with agents commonly used in coated tablet coatings, for example Kollidon or ┌ shellac, gum arabic, talc, titanium dioxide or sugar, ┐. getting produced. The coated tablet can also consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.

Die Herstellung der neuen 6-(p-Acylaminophenyl)-4,5-dihydropyridazone-(3) wird durch die folgenden Beispiele näher erläutert.The preparation of the new 6- (p-acylaminophenyl) -4,5-dihydropyridazone- (3) is explained in more detail by the following examples.

Beispiel 1example 1

30,2 g (0,16 Mol) 6-(p-Aminophenyl)-4,5-dihydropyridazon-(3 ) werden mit 18,1 g (0,16 Mol) Chloracetylchlorid und 150 ml absolutem Benzol 2 Stunden unter Rückfluß gekocht. Man saugt bei Raumtemperatur ab, wäscht zuerst mit Benzol, dann mit Wasser und trocknet im Vakuum bei 80°C. Man erhält 34,6 g (81 % d.Th.) 6-(p-Chloracetylaminophenyl)-4,5-dihydrc- pyridazon-(3), beiger Festkörper, Schmelzpunkt 233°C (Zers.) (umkristallisiert aus Dimethylformamid/Wasser). Analyse für C12H12ClN3O2:

  • ber.: C 54,2 H 4,5 Cl 13,3 N 15,8 0 12,0 %
  • gef.: C 54,1 H 4,5 Cl 13,6 N 15,8 0 12,4 %
30.2 g (0.16 mol) of 6- (p-aminophenyl) -4,5-dihydropyridazone- (3) are refluxed with 18.1 g (0.16 mol) of chloroacetyl chloride and 150 ml of absolute benzene for 2 hours . It is suctioned off at room temperature, washed first with benzene, then with water and dried in vacuo at 80 ° C. 34.6 g (81% of theory) of 6- (p-chloroacetylaminophenyl) -4,5-dihydrc-pyridazone- (3), beige solid, melting point 233 ° C. (dec.) (Recrystallized from dimethylformamide / Water). Analysis for C 12 H 12 ClN 3 O 2 :
  • calc .: C 54.2 H 4.5 Cl 13.3 N 15.8 0 12.0%
  • found: C 54.1 H 4.5 Cl 13.6 N 15.8 0 12.4%

Beispiel 2Example 2

  • a) 20 g (103 mMol) ß-(p-Aminobenzoyl)-propionsäure und 12,9 g (114 mMol) Chloracetylchlorid werden mit 200 ml absolutem Toluol 4 Stunden bei 80°C gehalten. Man saugt bei 10°C ab, wäscht mit Wasser und trocknet im Vakuum bei 50°C. Man isoliert 25,1 g (90 % d.Th.) ß-(p-Chloracetylaminobenzoyl)-propionsäure, hellbraune Kristalle, Schmelzpunkt 184 - 185°C (umkristallisiert aus Aceton).
    Analyse für C12H12ClNO4 :
    • ber.: C 53,4 H 4,5 Cl 13,1 N 5,2 %
    • L gef.: C 53,6 H 4,6 Cl 1:3,0 N 5,2 %
    a) 20 g (103 mmol) of β- (p-aminobenzoyl) propionic acid and 12.9 g (114 mmol) of chloroacetyl chloride are kept at 80 ° C. for 4 hours with 200 ml of absolute toluene. It is suctioned off at 10 ° C., washed with water and dried in a vacuum at 50 ° C. 25.1 g (90% of theory) of β- (p-chloroacetylaminobenzoyl) propionic acid, light brown crystals, melting point 184-185 ° C. (recrystallized from acetone) are isolated.
    Analysis for C 12 H 12 ClNO 4 :
    • calc .: C 53.4 H 4.5 Cl 13.1 N 5.2%
    • L found: C 53.6 H 4.6 Cl 1: 3.0 N 5.2%
  • ┌b) 4,0 g (14,8 mMol)
    ß-(p-Chloracetylaminobenzoyl)-propionsaure werden mit 0,74 g (14,8 mMol) Hydrazonhydrat und 70 ml Äthanol 3 Stunden am Rückfluß gehalten. Nach dem Absaugen bei 10°C und dem Trocknen im Vakuum bei 50°C erhält man 3,3 g (84 % d.Th.) 6-(p-Chloracetylamino- phenyl)-4,5-dihydropyridazon-(3), hellgelbe Kristalle (identisch mit der Verbindung aus Beispiel 1; Schmelzpunkt, IR, NMR).    ┌b) 4.0 g (14.8 mmol)
    ß- (p-Chloroacetylaminobenzoyl) -propionic acid are refluxed with 0.74 g (14.8 mmol) of hydrazone hydrate and 70 ml of ethanol for 3 hours. After suction at 10 ° C. and drying in vacuo at 50 ° C., 3.3 g (84% of theory) of 6- (p-chloroacetylaminophenyl) -4,5-dihydropyridazone- (3) are obtained, light yellow crystals (identical to the compound from Example 1; melting point, IR, NMR).
Beispiel 3Example 3

6,4 g (31,5 mMol) 6-(p-Aminophenyl)-5-methyl-4,5-dihydropyridazon-(3) und 4,2 g (37,1 mMol) Chloracetylchlorid werden in 150 ml absolutem Benzol 4 Stunden am Rückfluß-gehalten. Man saugt bei 0°C ab, wäscht mit Wasser und kristallisiert aus Äthanol/Wasser um. Man erhält 3,8 g (43 % d.Th.) 6-(p-Chloracetylaminophenyl)-5-methyl-4,5-dihydropyridazon-(3), hellgelbe Kristalle, Schmelzpunkt 235,5 bis 236,5°C. Analyse für C13H14ClN3O2:

  • ber.: C 55,8 H 5,0 Cl 12,7 N 15,0 0 11,4 %
  • gef.: C 55,8 H 5,1 Cl 12,4 N 15,2 0 11,9 %
6.4 g (31.5 mmol) of 6- (p-aminophenyl) -5-methyl-4,5-dihydropyridazone- (3) and 4.2 g (37.1 mmol) of chloroacetyl chloride are dissolved in 150 ml of absolute benzene 4 Hours reflux-held. It is suctioned off at 0 ° C., washed with water and recrystallized from ethanol / water. 3.8 g (43% of theory) of 6- (p-chloroacetylaminophenyl) -5-methyl-4,5-dihydropyridazone- (3), light yellow crystals, melting point 235.5 to 236.5 ° C. Analysis for C 13 H 14 ClN 3 O 2 :
  • calc .: C 55.8 H 5.0 Cl 12.7 N 15.0 0 11.4%
  • found: C 55.8 H 5.1 Cl 12.4 N 15.2 0 11.9%

Beispiel 4Example 4

47,2 g (0,25 Mol) 6-(p-Aminophenyl)-4,5-dihydropyridazon-(3) werden mit 35,6 g (0,28 Mol) 2-Chlorpropionylchlorid und 250 ml absolutem Benzol 2 Stunden unter Rückfluß gekocht. Man saugt bei 10°C ab, wäscht zuerst mit Benzol, dann mit Wasser und trocknet im Vakuum bei 100°C. Man erhält 64,8 g (93 % d.Th.) 6-[P-(2-Chloropropionylamino)-phenyl]-4,5-dihydropyridazon-(3), beiger Festkörper, Schmelzpunkt 243 bis 244°C (Zers.) (umkristallisiert aus Propanol).47.2 g (0.25 mol) of 6- (p-aminophenyl) -4,5-dihydropyridazone- (3) are mixed with 35.6 g (0.28 mol) of 2-chloropropionyl chloride and 250 ml of absolute benzene for 2 hours Reflux cooked. It is suctioned off at 10 ° C., washed first with benzene, then with water and dried in a vacuum at 100 ° C. 64.8 g (93% of theory) of 6- [P- (2-chloropropionylamino) phenyl] -4,5-dihydropyridazone- (3), beige solid, melting point 243 to 244 ° C. (dec. ) (recrystallized from propanol).

Analyse für C13H14ClN3O2 : L

  • ┌ber. : C 55,8 H 5,0 Cl 12,7 N 15,0 'J 11,4 %
  • gef.: C 55,2 H 4,9 Cl 13,1 N 14,9 0 11,9 %
Analysis for C 13 H 14 ClN 3 O 2 : L
  • About. : C 55.8 H 5.0 Cl 12.7 N 15.0 'J 11.4%
  • found: C 55.2 H 4.9 Cl 13.1 N 14.9 0 11.9%

Beispiel 5Example 5

6,0 g (29,6 mMol) 6-(p-Aminophenyl)-5-methyl-4,5-dihydropyridazon-(3) und 4,1 g (32,3 mMol) 2-Chlorpropionylchlorid werden mit 100 ml absolutem Toluol 4 Stunden bei 80°C gehalten. Man saugt bei 10°C ab. wäscht mit Wasser und trocknet im Vakuum bei 50°C. Man isoliert 7,9'g (91 % d.Th.) 6-[p-(2-Chlorpropionylamino)-phenyl] -5-methyl-4,5-dihydropyridazon-(3), beige Kristalle, Schmelzpunkt 215 bis 217°C (umkristallisiert aus Methanol).6.0 g (29.6 mmol) of 6- (p-aminophenyl) -5-methyl-4,5-dihydropyridazone- (3) and 4.1 g (32.3 mmol) of 2-chloropropionyl chloride are mixed with 100 ml of absolute Toluene held at 80 ° C for 4 hours. It is suctioned off at 10 ° C. washes with water and dries in vacuo at 50 ° C. 7.9 g (91% of theory) of 6- [p- (2-chloropropionylamino) phenyl] -5-methyl-4,5-dihydropyridazone- (3), beige crystals, melting point 215 to 217, are isolated ° C (recrystallized from methanol).

Analyse für C14H16ClN3O2:

  • ber.: C 57,2 H 5,5 Cl 12,1 N 14,3 0 10,9 %
  • gef.: C 57,1 H 5,5 Cl 12,1 N 14,6 0 11,2 %
Analysis for C 14 H 16 ClN 3 O 2 :
  • calc .: C 57.2 H 5.5 Cl 12.1 N 14.3 0 10.9%
  • found: C 57.1 H 5.5 Cl 12.1 N 14.6 0 11.2%

Beispiel 6Example 6

18,9 g (0,10 Mol) 6-(p-Aminophenyl)-4,5-dihydropyridazon-(3) werden mit 15,2 g (0,12 Mol) 3-Chlorpropionylchlorid und 90 ml absolutem Benzol.2 Stunden am Rückfluß gehalten Man saugt bei 10°C ab, wäscht zuerst mit Benzol, dann mit Wasser und trocknet im Vakuum bei 100°C. Man erhält 27,2 g (97 % d.Th.) 6-[p-(3-Chlorpropionylamino)-phenyl]--4,5-dihydropyridazon-(3), farblose Substanz, Schmelzpunkt 226 bis 2270C (Zers.) (umkristallisiert aus Dimethylformamid/ Wasser).18.9 g (0.10 mol) of 6- (p-aminophenyl) -4,5-dihydropyridazone- (3) are mixed with 15.2 g (0.12 mol) of 3-chloropropionyl chloride and 90 ml of absolute benzene for 2 hours held at reflux, suction filtered at 10 ° C., washed first with benzene, then with water and dried in vacuo at 100 ° C. This gives 27.2 g (97% of theory) of 6- [p- (3-chloropropionylamino) phenyl] - 4,5-dihydropyridazon- (3), colorless substance, melting point 226-227 0 C (dec .) (recrystallized from dimethylformamide / water).

Analyse für C13H14ClN3O2:

  • ber.: C 55,8 H 5,0 Cl 12,7 N 15,0 0 11,4 %
  • gef.: C 56,0 H 5,3 Cl 12,7 N 15,0 0 11,4
Analysis for C 13 H 14 ClN 3 O 2 :
  • calc .: C 55.8 H 5.0 Cl 12.7 N 15.0 0 11.4%
  • Found: C 56.0 H 5.3 Cl 12.7 N 15.0 0 11.4

Beispiel 7Example 7

6,0 g (29,6 mMol) 6-(P-Aminophenyl)-5-methyl-4,5-dihydropyridazon-(3) und 4,1 g (32,3 mMol) 3-Chlorpropionylchlorid-Terden mit 100 ml absolutem Toluol 4 Stunden bei 80°C geruhrt. Man saugt bei 10°C ab, wäscht mit Wasser und trocknet im Vakuum bei 50°C. Man erhält 5,8 g (67 % d.Th.) 6-[p-(3-Chlorpropionylamino)-pheny] -5-methyl-4, 5-dihydropyridazon-(3), beige Kristalle, Schmelzpunkt 221 bis 223°C (Zers.) (umkristallisiert aus Methanol).6.0 g (29.6 mmol) of 6- (P-aminophenyl) -5-methyl-4,5-dihydropyridazone- (3) and 4.1 g (32.3 mmol) of 3-chloropropionyl chloride- Terden with 100 ml of absolute toluene stirred at 80 ° C for 4 hours. It is suctioned off at 10 ° C., washed with water and dried in a vacuum at 50 ° C. 5.8 g (67% of theory) of 6- [p- (3-Chloropropionylamino) pheny] -5-methyl-4, 5-dihydropyridazone- (3), beige crystals, melting point 221 to 223 ° C (dec.) (Recrystallized from methanol).

Analyse für C14H16ClN3O2:

  • ber.: C 57,2 H 5,5 Cl 12,1 N 14,3 0 10,9
  • gef.: C 57,2 H 5,6 Cl 12,0 B 14,4 0 11,6 %
Analysis for C 14 H 16 ClN 3 O 2 :
  • calc .: C 57.2 H 5.5 Cl 12.1 N 14.3 0 10.9
  • found: C 57.2 H 5.6 Cl 12.0 B 14.4 0 11.6%

Beispiel 8Example 8

6,0 g (29,6 mMol) 6-(p-Aminophenyl)-5-methyl-4,5-dihydropyridazon-(3) und 4,6 g (32,6 mMol) 4-Chlorbutyrylchlorid werden mit 100 ml absolutem Toluol 6 Stunden bei 80°C gehalten. Man saugt bei 10°C ab, wäscht mit Wasser und trocknet im Vakuum bei 50°C. Man erhält 8,5 g (93 % d.Th.) 6-[p-(4-Chlorbutyrylamino)-phenyl -5-methyl-4,5-dihydropyridazon-(3), beige Kristalle, Schmelzpunkt 176 bis 178°C (umkristallisiert aus Methanol).6.0 g (29.6 mmol) of 6- (p-aminophenyl) -5-methyl-4,5-dihydropyridazone- (3) and 4.6 g (32.6 mmol) of 4-chlorobutyryl chloride are mixed with 100 ml of absolute Toluene kept at 80 ° C for 6 hours. It is suctioned off at 10 ° C., washed with water and dried in a vacuum at 50 ° C. 8.5 g (93% of theory) of 6- [p- (4-chlorobutyrylamino) phenyl -5-methyl-4,5-dihydropyridazone- (3), beige crystals, melting point 176 to 178 ° C. are obtained (recrystallized from methanol).

Analyse für C15H18ClN3O2:

  • ber.: C 58,6 H 5,9 Cl 11,5 N 13,7 0 10,4 %
  • gef.: C 58,4 H 5,9 Cl 11,4 N 13,8 0 10,9 %
Analysis for C 15 H 18 ClN 3 O 2 :
  • calc .: C 58.6 H 5.9 Cl 11.5 N 13.7 0 10.4%
  • found: C 58.4 H 5.9 Cl 11.4 N 13.8 0 10.9%

In der folgenden Tabelle sind weitere Ausführungsbeispiele zusammengestellt. Die Herstellung dieser Dihydropyridazone erfolgte nach der in Beispiel 7 beschriebenen Methode.

Figure imgb0009
Figure imgb0010
Figure imgb0011
 Further exemplary embodiments are compiled in the following table. These dihydropyridazones were prepared by the method described in Example 7.
Figure imgb0009
Figure imgb0010
Figure imgb0011

Formulierungsbeispiele, die in üblicher Weise hergestellt werden:

Figure imgb0012
Formulation examples that are produced in the usual way:
Figure imgb0012

Der Wirkstoff wird mit Polyvinylpyrrolidon in 10%iger wäßriger Lösung befeuchtet, durch ein Sieb mit der lichten Maschenweite 1,0 mm getrieben und bei 50°C getrocknet. Dieses Granulat wird mit Polyäthylenglykol (mittl. M.G. 4 000), Hydroxypropylmethylcellulose, Talkum und Magnesiumstearat vermischt und zu Tabletten à 240 mg verpreßt.

Figure imgb0013
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.
Figure imgb0013

Die Mischung der Wirkstoffsubstanz mit Lactose und Maisstärke wird mit einer 8%igen wäßrigen Lösung des Polyvinylpyrrolidons durch Sieb 1,5 mm granuliert, bei 50°C getrocknet und nochmals durch Sieb 1,0 mm gerieben. Das so erhaltene Granulat wird mit Mag-

Figure imgb0014
nesiumstearat gemischt un zu Drageekerne; verpreßt Die erhaltenen Dragurk are a der In üblicher Weise mit einer Hülle üherzogen eich wesentlichen aus Zucker und Talkum staht.
Figure imgb0015
Figure imgb0016
Figure imgb0017
The mixture of the active ingredient 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 rubbed again through a 1.0 mm sieve. The granules obtained in this way are
Figure imgb0014
nesium stearate mixed and into coated tablets; pressed The Dragurk are a der that is made in the usual way with a cover and essentially consists of sugar and talc.
Figure imgb0015
Figure imgb0016
Figure imgb0017

Claims (7)

1. 6-(p-Acylaminophenyl)-4,5-dihydropyridazone-(3) der Formel I
Figure imgb0018
in der für R1 Wasserstoff oder ein Alkylrest mit 1 bis 3 C-Atomen steht und R2, wenn für R1 ein Wasserstoffatom steht, einen durch ein Halogenatom substituierten Alkylrest mit 3 bis 6 C-Atomen oder einen ß-Halogenäthylrest oder, wenn für R1 ein Alkylrest mit 1 bis 3 C-Atomen steht, einen durch ein Halogenatom substituierten Alkylrest mit 1 bis 6 C-Atomen bedeutet.1. 6- (p-acylaminophenyl) -4,5-dihydropyridazone- (3) of the formula I.
Figure imgb0018
 in which R 1 is hydrogen or an alkyl radical having 1 to 3 C atoms and R 2 , when R 1 is a hydrogen atom, an alkyl radical having 3 to 6 C atoms or a β-halogenoethyl radical substituted by a halogen atom or, if R 1 represents an alkyl radical having 1 to 3 C atoms, an alkyl radical having 1 to 6 C atoms substituted by a halogen atom. 2. Verbindungen der Formel I, in denen R1 Wasserstoff oder Methyl und R2, wenn R1 Wasserstoff ist, einen durch ein Halogenatom substituierten Alkylrest mit 3 oder 4 C-Atomen oder einen ß-Halogenäthylrest oder, wenn R Methyl ist, einen durch ein Halogenatom substituierten Alkylrest mit 1 bis 4 C-Atomen bedeutet.2. Compounds of the formula I in which R 1 is hydrogen or methyl and R 2 , when R 1 is hydrogen, an alkyl radical having 3 or 4 carbon atoms or a β-halogenoethyl radical which is substituted by a halogen atom or, if R is methyl, one alkyl radical substituted by a halogen atom and having 1 to 4 carbon atoms. 3. 6-[p-(2-Chlorpropionylamino)-phenyl]-5-methyl-4,5-dihydropyridazon-(3).3. 6- [p- (2-Chloropropionylamino) phenyl] -5-methyl-4,5-dihydropyridazone- (3). 4. Verfahren zur Herstellung von Verbindungen der Formel I, dadurch gekennzeichnet, daß man eine Verbindung der Formel II
Figure imgb0019
in der R1 die oben angegebenen Bedeutungen hat, mit einem Acylierungsmittel der Formel III
Figure imgb0020
in der für Y OH, Chlor, Brom, ein niederer Alkoxyrest oder OCOR2 steht, gegebenenfalls in einem Lösungsmittel und gegebenenfalls in Gegenwart einer Base umsetzt.4. A process for the preparation of compounds of formula I, characterized in that a compound of formula II
Figure imgb0019
 in which R 1 has the meanings given above, with an acylating agent of the formula III
Figure imgb0020
 in which Y is OH, chlorine, bromine, a lower alkoxy radical or OCOR 2 , if appropriate in a solvent and if appropriate in the presence of a base. 5. Verfahren zur Herstellung von Verbindungen der Formel I, dadurch gekennzeichnet, daß man eine Verbindung der Formel V
Figure imgb0021
mit Hydrazon cyclisiert.5. A process for the preparation of compounds of formula I, characterized in that a compound of formula V
Figure imgb0021
 cyclized with hydrazone. 6. Therapeutisches Mittel, gekennzeichnet durch einen Gehalt an einer Verbindung der Formel I nach Anspruch 1 oder einer Verbindung der Formel I, in der, wenn R1 Wasserstoff ist, R2 einen Halogenmethyl- oder einen -Halogenäthylrest bedeutet als Wirkstoff neben üblichen Trägerstoffen und Verdünnungsmitteln.6. Therapeutic agent, characterized by a content of a compound of formula I according to claim 1 or a compound of formula I, in which, when R 1 is hydrogen, R 2 is a halomethyl or a -Halogenäthylrest as active ingredient in addition to conventional carriers and Thinners. 7. Therapeutisches Mittel, gekennzeichnet durch einen Gehalt an -6-[p-(2-Chlorpropionyl-amino)-phenyl]--5-methyl-4,5- dihydropyridazon-(3).7. Therapeutic agent, characterized by a content of -6- [p- (2-chloropropionylamino) phenyl] - 5-methyl-4,5-dihydropyridazone- (3).
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EP0089528A1 (en) * 1982-03-13 1983-09-28 BASF Aktiengesellschaft 6-Aryl-4,5-dihydro-3(2H)-pyridazinones, their preparation and use
US4410529A (en) * 1980-06-13 1983-10-18 Basf Aktiengesellschaft Novel dihydropyridazinones, their preparation and therapeutic agents containing these compounds
US4415571A (en) * 1980-06-13 1983-11-15 Basf Aktiengesellschaft Carbamate dihydropyridazinones, their preparation and therapeutic agents containing these compounds
US4965263A (en) * 1981-10-20 1990-10-23 Mitsui Toatsu Kagaku Kabushiki Kaisha 6-acylaminophenyl-5-alkyl-4,5-dihydro-3(2H)-pyridazinone compounds useful as blood pressure depressants, antithrombotic agents and in the treatment of heart disease

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EP0012338A1 (en) * 1978-12-15 1980-06-25 BASF Aktiengesellschaft Dihydropyridazinones, process for their preparation and therapeutical agents containing them
EP0012366A1 (en) * 1978-12-16 1980-06-25 BASF Aktiengesellschaft 3,4-Diaza-bicyclo(4.1.0)hepten-2-ones-5, process for their preparation and therapeutical compositions containing them
US4410529A (en) * 1980-06-13 1983-10-18 Basf Aktiengesellschaft Novel dihydropyridazinones, their preparation and therapeutic agents containing these compounds
US4415571A (en) * 1980-06-13 1983-11-15 Basf Aktiengesellschaft Carbamate dihydropyridazinones, their preparation and therapeutic agents containing these compounds
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EP0089528A1 (en) * 1982-03-13 1983-09-28 BASF Aktiengesellschaft 6-Aryl-4,5-dihydro-3(2H)-pyridazinones, their preparation and use

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ATA198680A (en) 1981-01-15
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