Classifications

• • 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)
• Hematology (AREA)
• Diabetes (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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Publications (2)

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• 1977
  • 1977-06-18 DE DE19772727481 patent/DE2727481A1/de not_active Withdrawn
• 1978
  • 1978-06-01 EP EP78100001A patent/EP0000113B1/de not_active Expired
  • 1978-06-01 DE DE7878100001T patent/DE2861089D1/de not_active Expired
  • 1978-06-16 JP JP7226978A patent/JPS549289A/ja active Granted
  • 1978-06-16 ZA ZA00783464A patent/ZA783464B/xx unknown
  • 1978-06-16 CA CA305,625A patent/CA1108614A/en not_active Expired
  • 1978-06-16 AT AT441178A patent/AT361494B/de not_active IP Right Cessation
• 1980
  • 1980-04-11 AT AT0198680A patent/AT363489B/de not_active IP Right Cessation
• 1981
  • 1981-01-14 US US06/224,939 patent/US4376771A/en not_active Expired - Fee Related

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