EP0141847A1 - Pyridazinone, son procede de preparation et son utilisation, medicaments contenant de la pyridazinone - Google Patents

Pyridazinone, son procede de preparation et son utilisation, medicaments contenant de la pyridazinone

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Publication number
EP0141847A1
EP0141847A1 EP84901989A EP84901989A EP0141847A1 EP 0141847 A1 EP0141847 A1 EP 0141847A1 EP 84901989 A EP84901989 A EP 84901989A EP 84901989 A EP84901989 A EP 84901989A EP 0141847 A1 EP0141847 A1 EP 0141847A1
Authority
EP
European Patent Office
Prior art keywords
pyridazinone
aryl
carbon atoms
pyridazinones
general formula
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Withdrawn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
EP84901989A
Other languages
German (de)
English (en)
Inventor
Hermann Amschler
Wolf-Rüdiger Ulrich
Manfrid Eltze
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.)
Takeda GmbH
Original Assignee
Byk Gulden Lomberg Chemische Fabrik GmbH
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 Byk Gulden Lomberg Chemische Fabrik GmbH filed Critical Byk Gulden Lomberg Chemische Fabrik GmbH
Publication of EP0141847A1 publication Critical patent/EP0141847A1/fr
Withdrawn legal-status Critical Current

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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
    • C07D237/06—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
    • C07D237/14—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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
    • C07D237/18—Sulfur atoms

Definitions

  • the invention relates to pyridazinones, their preparation and use and medicaments containing pyridazinones.
  • 6-aryl-3- [2H] pyridazinones as starting materials or intermediates for the synthesis of pharmaceuticals and crop protection agents and processes for their preparation are described, for example, by Baddar et al. [J. Chem. Soc. 1965, 3342], Steck [J. Heterocycl. Chem. 11 (1974) 755, Albright et al. [J. Heterocycl. Chem. 15 (1978) 881], Schreiber et al. [Bull. Soc.Chim. France 2 (1973) 625], Pitarch et al. [Eur.J.Med.Chem.-Chimica Therapeutica 9 (1974) 644] and Curran et al. [J. Med. Chem. 17 (1974) 273] or are i.a. known from the following descriptions DE-OS 2435 244, DE-OS 2445681, DE-OS 2757923.
  • 6-Aryl-3 [2H] pyridazinones with certain effects are e.g. known from the following descriptions DE-OS 2427943, DE-OS 28 10 267, DE-OS 2845 220, EP-OS 8391, EP-OS 10 156, JA-OS 58008 015 and US-PS 4397854.
  • 6- (4-Methoxyphenyl) -3 [2H] pyridazinone is described by Steck; Pitarch et al .; in DE-OS 2435 244 and DE-OS 23 10 267.
  • 6- (4-n-butoxyphenyl) -3 [2H] pyridazinone is described in DE-OS 2435 144.
  • 6- (3-trifluoromethylphenyl) -3 [2H ] pyridazinone and 6- (4-trifluoromethylphenyl) -3 [2H] pyridazinone are described by Albright et al.
  • the invention relates to 6-aryl-3 [2H] pyridazinones of the general formula I.
  • one of the substituents R1 or R2 represents a hydrogen atom and the other represents an alkoxy group having 1 to 5 carbon atoms, an alkenyloxy group having 3 to 5 carbon atoms, an alkynyloxy group having 3 to 5 carbon atoms or a trifluoromethyl group and X represents an oxygen atom or a sulfur atom, and their pharmacologically acceptable salts with bases for use as a bronchospasmolytic.
  • Alkoxy, alkenyloxy and alkynyloxy are straight-chain or branched. The double bond or triple bond of alkenyloxy or alkynyloxy does not start from the carbon atom that binds to the oxygen atom.
  • alk ⁇ xy, alkenyloxy and alkynyloxy are n-butoxy, n-propoxy, ethoxy, methoxy, 2,2-dimethylpropyloxy, isopentyloxy, isobutoxy, sec-butoxy, isopropoxy, buten-2-yloxy, allyloxy, methallyloxy, propyne -2-yloxy; preferred alkoxy are n-propoxy, isopropoxy and isobutoxy.
  • Suitable salts are salts with inorganic and organic bases.
  • the cations of the alkali metals or alkaline earth metals are primarily used as cations for salt formation, but the corresponding cations of organic nitrogen bases, such as amines or aminoalkanols, amino sugars, etc., are also used.
  • One embodiment of the invention are 6-aryl-3 [2H] pyridazinones of the general formula Ia
  • R1a is a hydrogen atom
  • R2a is an alkoxy group with 1 to 4 carbon atoms or an alkenyloxy group with 3 or 4 carbon atoms and
  • Xa represents an oxygen atom or sulfur atom, and their pharmacologically acceptable salts with bases for use as
  • R1b is an alkoxy group with 1 to 4 carbon atoms or an alkenyloxy group with 3 or 4 carbon atoms
  • R2b is a hydrogen atom
  • Xb represents an oxygen atom or a sulfur atom, and their pharmacologically acceptable salts with bases for use as a bronchospasmolytic.
  • Preferred representatives of embodiment Ia are those in which R2a is a
  • Methoxy, n-propoxy, isopropoxy, n-butoxy or isobutoxy group means.
  • Preferred representatives of embodiment Ib are those in which R1b represents an n-propoxy or trifluoromethyl group, the meaning of sulfur atom over oxygen atom being preferred for Xb.
  • the invention also relates to the new compounds of the general formula Ic
  • R1c ' or R2c represents a hydrogen atom and the other an alkoxy group with 1 to 5 carbon atoms, an alkenyloxy group with 3 to 5 carbon atoms, an alkynyloxy group with 3 to 5 carbon atoms or a trifluoromethyl group and
  • Xc represents an oxygen atom or a sulfur atom, wherein Xc is not an oxygen atom when R1c is a hydrogen atom and R2c is a methoxy, n-butoxy or trifluoromethyl group or when R1c is a trifluoromethyl group and R2c is a hydrogen atom, and their pharmacologically acceptable salts with bases.
  • Preferred representatives of the configuration lc are those in which R1c is hydrogen, R2c n-propoxy, isopropoxy or isobutoxy and Xc is an oxygen atom, or R1c is hydrogen, R2c methoxy or 3-methylbutoxy and Xc is a sulfur atom, or R1c n-propoxy or trifluoromethyl, R2c is hydrogen and Xc is a sulfur atom.
  • the invention further relates to a process for the preparation of the 6-aryl-3 [2H] pyridazinones of the general formula I and their pharmacologically tolerable salts with bases, which is characterized in that
  • the oxidation (dehydrogenation) according to process variant a) takes place according to methods known to the person skilled in the art. For example, dehydration with bromine in glacial acetic acid [Steck et al. J.Amer. Chem.Soc. 75 (1953) 1117]; in the presence of precious metals of subgroup 8, e.g. Palladium or platinum [DE-OS 27 57 923]; with chromium trioxide [Overend et al. J.Chem.Soc. 1947, 239] with nitrobenzenesulfonic acids or nitronaphthalenesultonic acids, preferably with their sodium or ammonium salts [GB-PS 1, 168,291].
  • process variant b) is carried out analogously to Schreiber et al. [Bull. Soc.chim. France 2 (1973) 625].
  • the morpholinobutyric acid III is reacted with hydrazine hydrate under reflux in a lower alkanol, for example n-butanol.
  • this can be done by Reaction of the corresponding acetophenone with glyoxylic acid and morpholine obtained morpholinium salt of compound III in acidic solution with hydrazine hydrate.
  • process variant c) takes place according to methods known to the person skilled in the art.
  • the compounds IV are reacted analogously to DE-OS 24 45 681 in the presence of basic compounds, such as alkali metal carbonates or hydroxides or lower alkanolates or tertiary amines, with methanol or aqueous methanol at room temperature or slightly elevated temperature, from the salt formed the acid is released and heated with 1 to 1.5 mol of hydrazine hydrate, at least one neutral, but preferably acidic medium being maintained.
  • basic compounds such as alkali metal carbonates or hydroxides or lower alkanolates or tertiary amines
  • the 6-aryl-3 [2H] pyridazinones I are converted into the salts by methods known to those skilled in the art.
  • the inorganic or organic base whose salt is desired is used as the alkaline reactant.
  • the salts are obtained, for example, by reacting the pyridazinones I with the stoichiometric equivalent of an appropriate base, for example sodium hydroxide or sodium methanol, or converting readily soluble salts into poorly soluble salts by double reaction.
  • an appropriate base for example sodium hydroxide or sodium methanol
  • R1c and R2c have the meaning given above, used.
  • the compounds II, III and IV are known or can be prepared by known processes.
  • Example 1 6- (4-n-propoxyphenyl) -3 [2H] pyridazinone a) 28 g of 5- (4-n-propoxyphenyl) -2,3,4,5-tetrahydro-pyridazin-3-one are combined in one Solution of 24.2 g of caustic soda and 35.4 g of sodium metanitrobenzenesulfonate in 400 ml of water are heated under reflux for 2 hours. Activated carbon is added, the reaction solution is filtered while hot and cooled to room temperature. By adding more concentrated. Hydrochloric acid, the solution is acidified to pH 1-2; the solid is suction filtered, washed acid-free with water and dried. 25.2 g (90.9% of theory) of the title compound are obtained with an mp of 166-168 °. After recrystallization from ethanol the mp rises to 169 °
  • 6- (3-ethoxyphenyl) -2,3,4,5-tetrahydropyridazin-3-one; Mp 117 °: 6- (3-n-propoxyphenyl) -2,3,4,5-tetrahydropyridazin-3-one; Mp 90 °; 6- (3-allyloxyphenyl) -2,3,4,5-tetrahydropyridazin-3-one, m.p. 113-114 °;
  • Example 3 6- (3-trifluoromethylphenyl) -3 [2H] pyridazinone 12.2 g of glyoxylic acid monohydrate are dissolved in 20 ml of ethanol while boiling; after cooling, 23.0 g of morpholine and 25.0 g of 3-trifluoromethylacetophenone are added with cooling and the mixture is stirred at 50 ° for 16 hours. The reaction mixture is evaporated in vacuo, the residue is taken up in 300 ml of water and acidified to pH 4.5 with acetic acid. The oil which separates is separated off, taken up in 150 ml of n-butanol and 8 hours with 14 g of 100% hydrazine hydrate Reflux cooked.
  • reaction solution is then evaporated in vacuo, the residue is boiled with 200 ml of 2N hydrochloric acid, cooled, the crystal mass which forms is filtered off with suction and dried. 18.0 g (56.6% of theory) of the title compound of mp. 206-212 ° are obtained. After recrystallization from dimethylformamide / water, the compound melts at 217-218 °.
  • Example 5 6- (4-methoxyphenyl) -3 [2H] pyridazinthione a) 22 g of 3-chloro-6- (4-methoxyphenyl) pyridazine are refluxed with 11 g of thiourea in 100 ml of ethylene glycol monoethyl ether for 8 hours. After cooling, the mixture is diluted with 500 ml of water and extracted three times with chloroform. The chloroform phase is dried over sodium sulfate and evaporated. The backlog is out
  • the 6-aryl-3 [2H] pyridazinones of the general formula I and those of the embodiments Ia, Ib or lc have valuable properties which make them commercially usable. Surprisingly, they are characterized by a bronchospasmolytic effect, some of that of theophylline. significantly exceeds. In addition, they have a higher organic effect compared to theophylline.
  • the excellent effectiveness of the 6-aryl-3 [2H] pyridazinones enables their use in human and veterinary medicine, whereby they are used for the treatment and prophylaxis of diseases which are based on diseases of the bronchi.
  • bronchitis chronic obstructive respiratory diseases of various origins
  • the invention therefore furthermore relates to a process for the treatment of mammals which are suffering from one of the abovementioned diseases.
  • the method is characterized in that the sick mammal is administered a therapeutically effective and pharmacologically tolerable amount of one or more of the compounds of the formula I.
  • the invention further relates to medicaments which contain one or more of the 6-aryl-3 [2H] pyridazinones of the general formula I or
  • the medicaments are produced by processes known per se, in which compounds are used as such or, if appropriate, in combination with suitable pharmaceutical carriers. If the new pharmaceutical preparations contain pharmaceutical carriers in addition to the active ingredients, the active ingredient content of these mixtures is 0.5 to 95, preferably 15 to 75 percent by weight of the total mixture.
  • the active ingredients or the medicinal products are used in any suitable formulation, provided that the training or maintenance of sufficient active ingredient levels is ensured. can, for example, by oral or parenteral administration in suitable doses
  • the pharmaceutical preparation of the active ingredient is usually in the form of unit doses which are tailored to the desired administration.
  • a unit dose can be, for example, a tablet, a dragee, a capsule, a suppository or a measured volume of a powder, a granulate, a solution, an emulsion or a suspension.
  • unit dose is understood to mean a physically determined unit which contains an individual amount of the active ingredient in combination with a pharmaceutical carrier, the active ingredient content of which corresponds to a fraction or a multiple of a single therapeutic dose.
  • a single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half, a third or a quarter of a daily dose. If only a fraction, such as half or a quarter, of the unit dose is required for a single therapeutic administration, the unit dose is advantageously divisible. e.g. in the form of a tablet with a score line.
  • compositions according to the invention when in unit doses and for oral administration e.g. are intended for humans, contain about 10 to 500 mg, advantageously 50 to 300 mg and in particular 100 to 300 mg of active ingredient.
  • Parenteral preparations can contain about 2 to 40 mg, advantageously 4 to 30 mg and in particular 10 to 25 mg of active ingredient.
  • the active ingredient (s) when administered orally in a daily dose of 0.1 to 12, preferably 1 to 8, in particular 2 to 4 mg / kg body weight, optionally in the form of several, preferably 1 to administer 3 individual doses to achieve the desired results.
  • a single dose contains the active ingredient (s) in amounts of 0.1 to 6, preferably 0.5 to 4, in particular 1 to 3 mg / kg body weight.
  • the Active ingredients it has proven advantageous to use the Active ingredients to be administered in a daily dose of 0.5 to 10 mg, preferably 1 to 8 mg, in particular 2 to 5 mg, optionally in the form of several, preferably 1 to 3, single doses.
  • Preparations for intravenous administration are primarily for acute treatment, e.g. Emergency treatment, appropriate.
  • the therapeutic administration of the pharmaceutical preparation can take place 1 to 4 times a day at fixed or varying times, e.g. before meals and / or in the evening. However, it may be necessary to deviate from the doses mentioned, depending on the type, body weight and age of the individual to be treated, the type and severity of the disease, the type of preparation and administration of the drug, and the period or Interval within which the administration takes place. In some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient has to be exceeded. In acute cases, a higher dose is administered at the start of treatment. After the desired effect occurs, the dose is reduced to a lower dose.
  • the optimum dosage and type of application of the active ingredients required in each case can be determined by any specialist on the basis of his specialist knowledge.
  • the pharmaceutical preparations generally consist of the active compounds according to the invention and non-toxic, pharmaceutically acceptable pharmaceutical carriers which are used as admixtures or diluents in solid, semi-solid or liquid form or as enveloping agents, for example in the form of a capsule, a tablet coating, a bag or another container, for the therapeutically active ingredient.
  • a carrier can serve, for example, as a mediator for the absorption of medicinal products by the body, as a formulation aid, as a sweetener, as a taste corrector, as a colorant or as a preservative.
  • tablets, coated tablets, hard and soft capsules for example made of gelatin, dispersible powders, granules, aqueous and oily suspensions, emulsions, solutions or syrups can be used.
  • Tablets can contain inert diluents, e.g. Calcium carbonate, calcium phosphate, sodium phosphate or lactose; Granulating and distributing agents, e.g. Corn starch or alginates; Binders, e.g. Starch, gelatin or acacia; and lubricants, e.g. Aluminum or magnesium stearate, talc or silicone oil. They can additionally be provided with an overlay which can also be designed in such a way that it causes a delayed dissolution and absorption of the drug in the gastrointestinal tract, so that e.g. better tolerance, protracting or retardation is achieved.
  • Gelatin capsules can mix the drug with a solid, e.g. Calcium carbonate or kaolin, or an oily, e.g. Olive, peanut or paraffin oil, thinners included.
  • Aqueous suspensions which can optionally be prepared at short notice.
  • Suspending agents e.g. Sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium alginate, polyvinylpyrrolidone tragacanth or acacia
  • Dispersing and wetting agents e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate or lecithin
  • Preservatives e.g. Methyl or propyl hydroxybenzoates
  • Flavoring agents Sweeteners, e.g. Sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup.
  • oily suspensions can e.g. Peanut, olive, sesame, coconut or paraffin oil and thickeners such as e.g. Beeswax, hard paraffin or cetyl alcohol; also sweeteners, flavoring agents and antioxidants.
  • Powders and granules dispersible in water can contain the medicinal substances in mixtures with dispersing, wetting and suspending agents, for example those mentioned above, and with sweeteners, flavoring agents and colorants.
  • Emulsions can contain, for example, olive, peanut or paraffin oil in addition to emulsifiers, such as, for example, acacia, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweeteners and flavoring agents.
  • Suppositories are used for rectal application of the medicinal products, which are produced with the help of binders melting at rectal temperature, for example cocoa butter or polyethylene glycol.
  • sterile injectable aqueous suspensions for the parenteral use of the drugs, sterile injectable aqueous suspensions, isotonic saline solutions or other solutions, the dispersants or wetting agents and / or pharmacologically acceptable diluents, e.g. Propylene or butylene glycol.
  • the inhalative application of the compounds according to the invention is also preferred. These are administered either directly as a powder or by nebulizing the solutions or suspensions containing the compounds according to the invention.
  • the nebulization can take place in a conventional manner, for example by compressed air nebulizers or ultrasound nebulizers.
  • Administration from spray cans, in particular those with a conventional metering valve (metering aerosols) is particularly advantageous.
  • Dosing aerosols make it possible to provide a defined amount of active ingredient per spray. So-called synchronous inhalers are particularly advantageous here, with which the release of active substance can take place synchronously with inhalation. Suitable synchronous inhalation devices are e.g. disclosed in DE-PS 1945 257, DE-PS 19 17 911 and DE-OS 20 55 734.
  • the active ingredients are preferably used in micronized form, particle sizes of less than 10 ⁇ m being advantageous.
  • the active ingredients are used in the usual way Dispersed blowing agents, preferably with the aid of a dispersant.
  • Dispersed blowing agents preferably with the aid of a dispersant.
  • Mixtures of trichlorofluoromethane (Frigen ® 11) and dichlorodifluoromethane (Frigen ® 12) are particularly suitable as blowing agents, it being possible to replace trichlorofluoromethylthane in whole or in part with 1, 1,2-trichlorotrifluoroethane (Frigen ® 113).
  • Particularly suitable dispersants are the sorbitan esters (Spane ® from Atlas GmbH) and lecithin which are customary for this purpose.
  • the dispersant is dissolved in the less volatile propellant component, which is refrigerated.
  • the micronized active ingredient or the micronized active ingredients are stirred into the solution.
  • the dispersion is filled into spray cans. After crimping, the more volatile blowing agent component is pressed on.
  • the active ingredient (s) can, if appropriate, also be formulated in microencapsulated form with one or more of the stated carriers or additives.
  • Tablets with 100 mg of 6- (4-n-propoxyphenyl) -3 [2H] pyridazinone, 40 kg of active ingredient, 24 kg of milk sugar and 16 kg of corn starch are granulated with 4 kg of polyvinylpyrrolidone (MW ⁇ 25,000) in 5.5 liters of water and passed through a sieve of 1.25 mm mesh size is pressed. After drying, 10 kg of carboxymethyl cellulose, 4 kg of talc and 2 kg of magnesium stearate are added. The granules are pressed on an eccentric machine into tablets of 9 mm in diameter, 250 mg in weight and a hardness of 4 to 5 kg.
  • Capsules containing 15 mg of 6- (4-isopropoxyphenyl) -3 [2H] pyridazinone, 150 mg of active ingredient, 845 mg of microcrystalline cellulose and 5 mg of amorphous silica are finely powdered, mixed well and filled into size 4 hard gelatin capsules.
  • the 6-aryl-3 [2H] pyridazinones of the general formula I have a bronchospasmolytic effect which in some cases that of theophylline. significantly exceeds. In addition, they have a higher organ-selective effect compared to theophylline, as the comparison of bronchospasmolysis on the isolated, spontaneously contracted tracheal chain of guinea pigs shows with regard to the positive inotropic effect on the electrically irritated left atrium of the rat.
  • Theophylline has long been used as a broncholytic in the treatment of bronchial asthma and other spastic conditions of smooth bronchial muscles. Its side effects, especially those on the cardiovascular system, are known [cf. Ehrhart / Ruschig, Medicines, Verlag Chemie Weinheim / Bergstrasse 1972, Vol. 1, Page 341, Vol. 2, Page 258; Schulze-Werner Haus Pharmakotherapie 4 (1981) 168 to 177].
  • Organs can be measured under isometric conditions by applying the
  • Test substance in a cumulative, semi-logarithmically increasing concentration e.g. 1x10 -6 + 2x10 -6 + 7x10 -6 + 2x10 -5 etc. mol / 1
  • a relaxation is brought about, whereby after each single dose of the test substance a constant relaxation response is waited before the next higher concentration is applied.
  • a complete dose-response curve of the test substance is thus obtained for a period of 20 to 30 minutes.
  • the respective relaxation is expressed as a percentage of the maximum relaxation that can be achieved by administration of (-) isoprenaline (10 -6 mol / 1).
  • the measure of the bronchodilatory activity is the concentration of the test substance, which causes 50% of the maximum achievable relaxation, expressed by the negative logarithm of the EC 50 mol / 1: -lg [EC 50 ].
  • Isometric contractions HSE force transducers K-30; Watanabe-Schreiber Linear Corder Mark 5
  • HSE stimulator 7 V, 3 ms, 2 Hz
  • the measure of the cardiotonic activity is the concentration of the test substance, which increases the contraction force of the atrium by 40% above the initial value [EC 40pot mol / 1], expressed by the negative logarithm of the [EC 40pot ]: - lg [EC 40pot ] .
  • the toxicity studies are carried out on female NMRI mice (body weight 23-30 g).
  • the animals (5 animals per dose) receive food and water ad libitum.
  • Different doses of the substances are administered once as a suspension in methocel by gavage.
  • the observation period is 7 days.
  • the dose tolerata (DJ) ie the highest dose at which no animals die yet, is determined by observation.
  • Table II shows the results of testing the inhibition of histamine-induced bronchospasm in anesthetized guinea pigs.
  • Vmax e maximum flow rate of the breathing air during expiration
  • a method for the simultaneous registration of pharmacodynamic or toxic effects on inner sensitive receptors, on respiration and on the cardiovascular system of guinea pigs [U. Kilian, E. Müller, E. Ch. Dittmann and J. Hamacher, drug research 28 (II) 1699-1708, 1978].
  • the pneumotachogram arm was recorded on anesthetized (ethyl urethane 1.25 g / kg ip), monovagotomized, spontaneously breathing guinea pigs ( ⁇ , 350-450 g).
  • Column A shows how many out of 10 animals the latency more than doubled 30 minutes after application of the active ingredient. In brackets, how many out of 10 animals the latency more than tripled.
  • Latency is the time from the start of acetylcholine nebulization to the appearance of clear asthma symptoms.
  • Guinea pigs (250-350 g) are exposed to an acetylcholine mist (0.06% in 0.9% sodium chloride solution; ultrasonic nebulizer Heyer Use 77) twice in a sealed plexiglass cylinder (volume: 5 l) every 20 minutes. The time from the start of nebulization to the onset of significant breathing efforts (possibly more hypoxic
  • the latency period is measured and referred to as the latency period.
  • the latency is 2 minutes.
  • the test substance is administered orally using a pharyngeal tube (standard dose 100 ⁇ mol / kg, volume 1 ml 4% methocel suspension in 0.9% sodium chloride solution / kg).
  • the animals are again exposed to the acetylcholine mist and the latency times are measured. Extending the latency to at least twice the length is considered a protective effect.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La 6-aryle-3 AD2H BDpyridazinone de formula (I), où l'un des substituants R1 ou R2 représente un hydrogène et l'autre un alkoxy contenant de 1 à 5 C, un alcényloxy contenant de 3 à 5 C, un alcinyloxy contenant de 3 à 5 C ou CF3, et où X représente un oxygène ou un soufre, et ses sels pharmaceutiquement acceptables avec des bases conviennent pour une utilisation en tant que bronchospasmolytique. Procédé de préparation de ces composés et des médicaments correspondants.
EP84901989A 1983-05-11 1984-05-10 Pyridazinone, son procede de preparation et son utilisation, medicaments contenant de la pyridazinone Withdrawn EP0141847A1 (fr)

Applications Claiming Priority (2)

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CH2580/83 1983-05-11
CH258083 1983-05-11

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EP0141847A1 true EP0141847A1 (fr) 1985-05-22

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EP (1) EP0141847A1 (fr)
JP (1) JPS60501256A (fr)
DE (1) DE3417368A1 (fr)
IT (1) IT1173591B (fr)
WO (1) WO1984004522A1 (fr)

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DK159431C (da) * 1984-05-10 1991-03-18 Byk Gulden Lomberg Chem Fab 6-phenyl-3(2h)-pyridazinoner, fremgangsmaade til fremstilling deraf, laegemidler indeholdende disse samt anvendelse af forbindelserne til fremstilling af laegemidler
JPH06508842A (ja) * 1991-07-05 1994-10-06 ビイク　グルデン　ロンベルク　ヒエーミツシエ　フアブリーク　ゲゼルシヤフト　ミツト　ベシユレンクテル　ハフツング 置換ピリダジンの皮膚病に対する使用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2435244A1 (de) * 1974-07-22 1976-02-05 Lentia Gmbh Verfahren zur herstellung von 3-phenylpyridazonen
US4397854A (en) * 1981-05-14 1983-08-09 Warner-Lambert Company Substituted 6-phenyl-3(2H)-pyridazinones useful as cardiotonic agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8404522A1 *

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IT8420849A1 (it) 1985-11-09
WO1984004522A1 (fr) 1984-11-22
IT1173591B (it) 1987-06-24
JPS60501256A (ja) 1985-08-08
IT8420849A0 (it) 1984-05-09
DE3417368A1 (de) 1984-11-15

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