EP0796250A1 - Pyridazinones utiles comme antagonistes du recepteur de l'endotheline - Google Patents

Pyridazinones utiles comme antagonistes du recepteur de l'endotheline

Info

Publication number
EP0796250A1
EP0796250A1 EP96933341A EP96933341A EP0796250A1 EP 0796250 A1 EP0796250 A1 EP 0796250A1 EP 96933341 A EP96933341 A EP 96933341A EP 96933341 A EP96933341 A EP 96933341A EP 0796250 A1 EP0796250 A1 EP 0796250A1
Authority
EP
European Patent Office
Prior art keywords
pyridazin
methyl
dihydro
tetrahydro
dimethoxyphenyl
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Withdrawn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
EP96933341A
Other languages
German (de)
English (en)
Inventor
Dieter Dorsch
Mathias Osswald
Werner Mederski
Claudia Wilm
Claus Jochen Schmitges
Maria Christadler
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.)
Merck Patent GmbH
Original Assignee
Merck Patent 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 Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP0796250A1 publication Critical patent/EP0796250A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention relates to compounds of the formula
  • R 4 , R 4 each independently of one another are H, A or unsubstituted or simply substituted by alkoxy phenyl or benzyl,
  • n 1 or 2
  • a suitable method for determining the hypotensive effect is e.g. B. described by MK Bazil et al., J. Cardiovasc. Pharmacol. 22, 1993, 897-905 and J. Lange et al., Lab Animal 20, 1991, Appl. Note 1016.
  • the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for the prophylaxis and / or therapy of cardiac, circulatory and vascular diseases, especially hypertension and heart failure.
  • Q is Cl, Br, I or a free or reactively functionally modified OH group
  • A has 1 to 6, preferably 1, 2, 3 or
  • A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, further also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1,2 - or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1 -, 2-, 3- or 4-methylpentyl, 1, 1 -, 1, 2-, 1, 3-, 2,2-, 2,3 - or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2-, 1,2,2-trimethylpropyl, furthermore trifluoromethyl or pentafluoroethyl .
  • A also means cycloalkyl, especially cyclopropyl.
  • E is preferably O, furthermore CH 2 or S.
  • D is preferably CH 2 , carbonyl is also preferred.
  • n is preferably 1, further preferably 2.
  • Hal is preferably F, Cl or Br, but also I.
  • Alkoxy preferably means methoxy, furthermore ethoxy, propoxy, butoxy or pentyloxy.
  • Ar is unsubstituted, preferably - as indicated - monosubstituted phenyl, in particular preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o -, m- or p- isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-trifluoromethylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) pheny
  • Het is preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-
  • Benzopyrazolyl 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzthiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1, 3-oxadiazolyl, 2-, 3-, 4-, 5-, 6 -, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.
  • heterocyclic radicals can also be partially or completely hydrogenated.
  • Het can, for. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2 - or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1 -, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1 -, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1 -, -2 - or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydr
  • the radical R 2 is preferably Ar, 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,
  • R 2 further preferably denotes 2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl, further preferably 2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-
  • the radical R 3 preferably denotes carbomethoxy, carboethoxy, carbopropoxy, carbobutoxy, carbobenzyloxy, furthermore cyan, 1 H-tetrazol-5-yl or carboxy, but phenylsulfonamidocarbonyl or 4-alkylphenylsulfonamidocarbonyl is particularly preferred.
  • R 4 , R 4 or R 5 may be the same or different, ie are independent of each other.
  • the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.
  • Some preferred groups of compounds can be expressed by the following partial formulas Ia to Ih, which correspond to the formula I and in which the radicals which are not described in more detail than those in the formula
  • inlc Y is -CH 2 -S-;
  • R z represents a group
  • R 2 represents Ar
  • R 3 is CONHSO 2 R 5 ;
  • ⁇ - group and O R 3 is CONHSO 2 R;
  • the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.
  • Q preferably denotes Cl, Br, I or a reactively modified OH group such as alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl or p- Tolylsulfonyloxy).
  • the reaction is usually carried out in an inert solvent
  • an acid-binding agent preferably an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium, calcium or cesium.
  • an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or an excess of the phenol component of the formula II or the alkylation derivative of the formula III can also be favorable.
  • the reaction time is between a few minutes and 14 days, the reaction temperature is between about 0 ° and 150 °, normally between 20 ° and 130 °.
  • Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether,
  • Tetrahydrofuran (THF) or dioxane Tetrahydrofuran (THF) or dioxane
  • Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Sulfur carbon; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.
  • the new compounds can be prepared by methods known per se. For example, 6- (2,4-dimethoxyphenyl) -2,3-dihydropyridazin-3-one by reacting 4- (2,4-dimethoxyphenyl) -4-oxobutanoic acid with hydrazine and then reacting the 6- (2nd , 4-
  • Dimethoxyphenyl) -2,3,4,5-tetrahydropyridazin-3-ones are obtained with bromine.
  • Suitable inert solvents are those already mentioned above.
  • a compound of formula I into another Ver ⁇ compound of the formula I by converting one or more radical (s) R 1, R 2 and / or R 3 in one or more other radicals R 1, R 2 and / or R 3 , for example by hydrolyzing an ester group to a carboxy group and / or converting a carboxy group to a sulfonamidocarbonyl group.
  • free amino groups can be acylated in the usual way with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, advantageously in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine at temperatures between 60 and
  • a functionally modified amino and / or hydroxy group in a compound of the formula I can be liberated by solvolysis or hydrogenolysis by customary methods.
  • a compound of the formula I which contains an NHCOR 4 or a COOR 4 group can be converted into the corresponding compound of the formula I which instead contains an NH 2 or a HOOC group.
  • COOR 4 groups can be saponified, for example, with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.
  • a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
  • acids that provide physiologically acceptable salts are suitable for this implementation.
  • inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or poly-based carbon atoms.
  • Sulfonic or sulfuric acids for example formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, methonic acid or nicotinic acid, nicotinic acid, nicotinic acid Ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates can be used for the isolation and / or purification of the compounds of the formula I.
  • Racemates obtained can be separated into their enantiomers mechanically or chemically by methods known per se. Diastereomers are preferably formed from the racemic mixture by reaction with an optically active release agent.
  • optically active compounds of the formula I by the methods described above by using starting materials which are already optically active.
  • Active ingredients are brought into a suitable dosage form.
  • the invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts.
  • Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, Benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly.
  • Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used in particular for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants for which are used for parenteral use topical application ointments, creams or powder.
  • the new compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injectables.
  • the specified preparations can be sterilized and / or contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, eg one or more vitamins.
  • auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, eg one or more vitamins.
  • the substances according to the invention are generally preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit.
  • the daily dosage is preferably between about 0.02 and 10 mg / kg of body weight.
  • the specific dose for each patient depends on a wide variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, and on the rate of excretion , Drug combination and severity of the respective disease to which the therapy applies. Oral application is preferred.
  • customary work-up means: if necessary, water is added and, if necessary, the pH is adjusted to between 2 and 10, depending on the constitution of the end product, extracted with
  • Ethyl acetate or dichloromethane separates, dries the organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization.
  • Mass spectrometry (MS): El (electron impact ionization) M + FAB (Fast Atom Bombardment) (M + H) +
  • 6-phenyl-2,3-dihydro-pyridazin-3-one-2 5-phenyl-6-methyl-2,3-dihydro-pyridazin-3-one-2 4-phenyl-6-methyl-2,3-dihydro-pyridazin-3-one-2
  • 6-cyclopropyl-2,3-dihydro-pyridazin-3-one-2 means.
  • 6- (4-carboxyphenyl) -2,3-dihydro-pyridazin-3-one-2 6- (2,5-dimethoxyphenyl) -2,3-dihydro-pyridazin-3-one-2 6- (3.4 -dimethoxyphenyl) -2,3-dihydro-pyridazin-3-one-2 6- (thien-2-yl) -2,3-dihydro-pyridazin-3-one-2 6- (furan-2-yl) - 2,3-dihydro-pyridazin-3-one-2
  • 6- (4-carboxyphenyl) -2,3-dihydro-pyridazin-3-one-2 6- (2,5-dimethoxyphenyl) -2,3-dihydro-pyridazin-3-one-2 6- (3.4 -dimethoxyphenyl) -2,3-dihydro-pyridazin-3-one-2 6- (thien-2-yl) -2,3-dihydro-pyridazin-3-one-2 6-phenyl-4-methyl-2, 3-dihydro-pyridazin-3-one-2
  • 6- (4-methoxyphenyl) -2,3,4,5-tetrahydro-pyridazin-3-one-2, mp 213 ° 6- (4-chlorophenyl) -2,3,4,5-tetrahydro-pyridazine- 3-one-2 6- (4-carboxyphenyl) -2,3,4,5-tetrahydro-pyridazin-3-one-2 6-carboxy-2,3,4,5-tetrahydro-pyridazin-3-one 6 - (2,5-dimethoxyphenyl) -2,3,4,5-tetrahydro-pyridazin-3-one-2
  • 6- (3,4-dimethoxyphenyl) -2,3,4,5-tetrahydro-pyridazin-3-one-2 6- (2,4-dimethoxyphenyl) -2,3,4,5-tetrahydro-pyridazin-3 -one 6- (thien-2-yl) -2,3,4,5-tetrahydro-pyridazin-3-one-2 6-phenyl-4-methyl-2,3,4,5-tetrahydro-pyridazin-3 -on-2 6- (4-methoxyphenyl) -4-methyl-2,3,4,5-tetrahydro-pyridazin-3-one-2
  • 6- (4-carboxyphenyl) -2,3,4,5-tetrahydro-pyridazin-3-one-2 6-carboxy-2,3,4,5-tetrahydro-pyridazin-3-one 6- (2.5 -dimethoxyphenyl) -2,3,4,5-tetrahydro-pyridazin-3-one-2 6- (3,4-dimethoxyphenyl) -2,3,4,5-tetrahydro-pyridazin-3-one-2 6- (2,4-dimethoxyphenyl) -2,3,4,5-tetrahydro-pyridazin-3-one
  • 6- (4-chlorophenyl) -5-methyl-2,3-dihydro-pyridazin-3-one 6- (4-carboxyphenyl) -4-methyl-2,3-dihydro-pyridazin-3-one-2 6- (2,5-dimethoxyphenyl) -4-methyl-2,3-dihydro-pyridazin-3-one-2 6- (3,4-dimethoxyphenyl) -4-methyl-2,3-dihydro-pyridazin-3-one -2 6- (thien-2-yl) -4-methyl-2,3-dihydro-pyridazin-3-one-2
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile . Each injection glass contains 5 mg of active ingredient.
  • a mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • a solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH 2 PO 4 .2H 2 O, 28.48 g of Na 2 HPO 4 .12H 2 O and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
  • Example D ointment
  • 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • Example E tablets A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient .
  • Example F coated tablets
  • Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • Example G capsules
  • each capsule contains 20 mg of the active ingredient.
  • a solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pulmonology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne de nouveaux composés de la formule (I) où R<1>, R<2>, R<3> et Y ont la signification donnée dans la revendication 1. L'invention concerne également leurs sels. Lesdits nouveaux composés ont des propriétés antagonistes du récepteur de l'endothéline.
EP96933341A 1995-10-09 1996-09-19 Pyridazinones utiles comme antagonistes du recepteur de l'endotheline Withdrawn EP0796250A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19537548 1995-10-09
DE19537548A DE19537548A1 (de) 1995-10-09 1995-10-09 Endothelin-Rezeptor-Antagonisten
PCT/EP1996/004111 WO1997013758A1 (fr) 1995-10-09 1996-09-19 Pyridazinones utiles comme antagonistes du recepteur de l'endotheline

Publications (1)

Publication Number Publication Date
EP0796250A1 true EP0796250A1 (fr) 1997-09-24

Family

ID=7774384

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96933341A Withdrawn EP0796250A1 (fr) 1995-10-09 1996-09-19 Pyridazinones utiles comme antagonistes du recepteur de l'endotheline

Country Status (16)

Country Link
US (1) US5883090A (fr)
EP (1) EP0796250A1 (fr)
JP (1) JPH10511118A (fr)
CN (1) CN1168137A (fr)
AR (1) AR004689A1 (fr)
AU (1) AU7211996A (fr)
BR (1) BR9606668A (fr)
CA (1) CA2207243A1 (fr)
CZ (1) CZ176897A3 (fr)
DE (1) DE19537548A1 (fr)
HU (1) HUP9801879A3 (fr)
NO (1) NO972612L (fr)
PL (1) PL320638A1 (fr)
SK (1) SK73597A3 (fr)
WO (1) WO1997013758A1 (fr)
ZA (1) ZA968483B (fr)

Families Citing this family (10)

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Publication number Priority date Publication date Assignee Title
US6187920B1 (en) 1998-03-26 2001-02-13 Sumitomo Chemical Co., Ltd. Pyridazinone derivatives
US6670362B2 (en) * 2000-09-20 2003-12-30 Pfizer Inc. Pyridazine endothelin antagonists
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NO972612L (no) 1997-08-08
CN1168137A (zh) 1997-12-17
CZ176897A3 (en) 1997-10-15
MX9704262A (es) 1997-09-30
WO1997013758A1 (fr) 1997-04-17
AR004689A1 (es) 1999-03-10
BR9606668A (pt) 1997-09-30
SK73597A3 (en) 1998-05-06
AU7211996A (en) 1997-04-30
US5883090A (en) 1999-03-16
PL320638A1 (en) 1997-10-13
CA2207243A1 (fr) 1997-04-17
ZA968483B (en) 1997-05-20
HUP9801879A2 (hu) 1999-06-28
JPH10511118A (ja) 1998-10-27
DE19537548A1 (de) 1997-04-10
NO972612D0 (no) 1997-06-06
HUP9801879A3 (en) 1999-07-28

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