WO1998027091A1 - Antagonistes de recepteurs de l'endotheline utilises comme pesticides - Google Patents

Antagonistes de recepteurs de l'endotheline utilises comme pesticides Download PDF

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Publication number
WO1998027091A1
WO1998027091A1 PCT/EP1997/007047 EP9707047W WO9827091A1 WO 1998027091 A1 WO1998027091 A1 WO 1998027091A1 EP 9707047 W EP9707047 W EP 9707047W WO 9827091 A1 WO9827091 A1 WO 9827091A1
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WO
WIPO (PCT)
Prior art keywords
ylmethyl
benzothiadiazol
pyrazole
carboxylic acid
formula
Prior art date
Application number
PCT/EP1997/007047
Other languages
German (de)
English (en)
Inventor
Werner Mederski
Mathias Osswald
Dieter Dorsch
Claudia Wilm
Maria Christadler
Claus Jochen Schmitges
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
Priority to AU57583/98A priority Critical patent/AU5758398A/en
Publication of WO1998027091A1 publication Critical patent/WO1998027091A1/fr

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    • 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 I.
  • R is unsubstituted or mono-, di- or trisubstituted by R 3, R 4 or R 5 substituted phenyl, or unsubstituted or monosubstituted by R 2 2,1,3-benzothiadiazolyl,
  • R 1 A in which 1-7 H atoms can be replaced by F, -SA, -OA, unsubstituted or simply substituted by R 3, phenyl, alkylene-phenyl or unsubstituted or simply substituted by R 3 ,
  • R 3 , R 4 , R 5 each independently of one another A, -OA, -SA, -O-alkylene-COOH, -alkylene-COOH or COOH,
  • R 3 and R 4 together also -O-CH 2 -O- and
  • the object of the invention was to find new compounds with valuable properties, in particular those which can be used for the production of medicaments.
  • the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability.
  • they show endothelin receptor-antagonistic properties and can therefore be used to treat diseases such as hypertension, heart failure, coronary heart disease, renal, cerebral and myocardial ischemia, renal failure, cerebral infarction, subarachnoid hemorrhage, arteriosclerosis, pulmonary high pressure, inflammation, endahyroidism, asthma Shock and complications after the administration of substances such as Cyclosporin, as well as other diseases associated with endothelin activities.
  • connections show i.a. a high affinity for the endothelin
  • Subreceptors ET A and ET B have an affinity for the endothelin subtype receptor B.
  • a suitable method for determining the hypotensive effect is e.g. B. described by M.K. Bazil et al., J. Cardiovasc. Pharmacol. 22, 1993, 897-905 and J. Lange et al., Lab Animal
  • the compounds of the formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for the prophylaxis and / or therapy of cardiovascular and vascular diseases, especially hypertension and heart failure.
  • the invention relates to the compounds of the formula I and their salts and to a process for the preparation of these compounds and their salts,
  • R 1 and R 2 have the meaning given in claim 1, and A denotes alkyl having 1-4 C atoms or benzyl,
  • A is alkyl and has 1 to 7, preferably 1, 2, 3, 4, 5 or 6 carbon atoms.
  • 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-,
  • R 1 is alkyl
  • alkyl also has the following preferred meanings in addition to the preferred meanings mentioned:
  • Trifluoromethyl pentafluoroethyl, heptafluoropropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • Alkylene preferably means methylene, ethylene, propylene, butylene, furthermore pentylene or hexylene.
  • Alkylene-phenyl is especially benzyl or phenethyl.
  • O-A preferably means e.g. Methoxy, ethoxy, propoxy or butoxy, also isopropoxy or tert-butoxy.
  • R 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-methoxyphenyl, o-, m- or p- ethoxyphenyl, o-, m- or p-carboxyphenyl, o-, m- or p-methylthiophenyl, o-, m- or p-carboxymethoxyphenyl, o-, m- or p-carboxymethylphenyl, 2,3-, 2,4-2,5 -
  • the compounds of the formula I can have one or more chiral centers and therefore exist in various stereoisomeric forms.
  • 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.
  • R 4 or R 5 substituted phenyl and R 1 A, in which 1-7 H atoms can be replaced by F,
  • R 3 , R 4 , R 5 each independently represent A, -OA, -SA, -O-CH 2 -COOH, -CH 2 -COOH or COOH;
  • R 4 or R 5 substituted phenyl
  • R 1 is methyl, ethyl, propyl, butyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, unsubstituted or simply substituted by R 3, phenyl, benzyl or thienyl
  • R, R, R each independently of one another A, -OA, -SA,
  • 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.
  • Compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III and then cleaving the ester.
  • the reaction is usually carried out in an inert solvent or solvent mixture, preferably in the presence of e.g. of glacial acetic acid Depending on the conditions used, the reaction time is between a few minutes and 14 days, the reaction temperature between about 0 ° and 160 °, normally between 20 ° and 140 °.
  • 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, methyl tert-butyl ether, 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, dimethylace
  • R, R 1 , R 2 and A have the meaning given in claim 1.
  • the compounds of formula II can be prepared by methods known per se. For example, ethyl 3- (2,1, 3-benzothiadiazol-5-ylmethyl) -2-methoxyimino-4-oxo-octanoate by reacting 5-bromomethyl-2,1, 3-benzothiadiazole with 2-methoxyimino-4-oxo - ethyl octanoate (WT Ashton and GA Doss in J. Heterocyclic Chem.
  • an acid-binding agent preferably an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt weak acid of the alkali or alkaline earth metals, preferably the Potassium, sodium, calcium or cesium
  • an organic base such as triethylamine, dimethylaniline, pyridine or quinoline can also be favorable.
  • Suitable inert solvents are those already mentioned above.
  • Esters can e.g. are saponified with acetic acid or with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.
  • An acid of the formula I can be converted with a base into the associated acid addition salt, for example by reacting equivalent amounts of the acid and the base in an inert solvent such as ethanol and then evaporating.
  • Bases that provide physiologically acceptable salts are particularly suitable for this implementation.
  • the acid of formula I can be converted with a base (e.g. sodium or potassium hydroxide or carbonate) into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salt.
  • a base e.g. sodium or potassium hydroxide or carbonate
  • 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 polybasic carboxylic, sulfonic or sulfuric acids, eg 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, nicotinic acid, isonicotinic acid, methanoic acid or Ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-to
  • the invention furthermore relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.
  • 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 for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical use for parenteral use 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 auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, Contain buffer substances, coloring, flavoring and / or several other active ingredients, for example one or more vitamins.
  • auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, Contain buffer substances, coloring, flavoring and / or several other active ingredients, for example one or more vitamins.
  • the compounds of formula I and their physiologically acceptable salts can be used in the control of diseases, in particular
  • Hypertension and heart failure can be used.
  • 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 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, on the rate of excretion and on the combination of drugs and severity of the respective disease to which the therapy applies. Oral application is preferred.
  • 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 jar 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 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 sterile. Each ampoule contains 10 mg of active ingredient.

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

Abstract

Nouveaux composés de formule (I) dans laquelle R représente phényle non substitué ou mono-, di- ou trisubstitué par R3, ou substitué par R5 ou 2,1,3-benzothiadiazolyle non substitué ou substitué uniquement par R2; R1 est A, 1 à 7 atomes de H pouvant être remplacés par F, -S-A, -O-A, phényle non substitué ou substitué uniquement par R3, -alkylène-phényle ou thiényle non substitué ou uniquement substitué par R3; R2 est A, F, Cl, Br ou -O-A; R?3, R4, R5¿ sont indépendamment A, -O-A, -S-A, -O-alkylène-COOH, -alkylène-COOH ou COOH; R3 et R4 ensemble peuvent être aussi -O-CH¿2?-O- et A est alkyle C1-7, ainsi que leurs sels, qui possèdent des propriétés antagonistes de récepteurs de l'endothéline.
PCT/EP1997/007047 1996-12-19 1997-12-15 Antagonistes de recepteurs de l'endotheline utilises comme pesticides WO1998027091A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU57583/98A AU5758398A (en) 1996-12-19 1997-12-15 Endothelin receptor antagonists as pesticides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19653024.5 1996-12-19
DE19653024A DE19653024A1 (de) 1996-12-19 1996-12-19 Endothelin-Rezeptor-Antagonisten

Publications (1)

Publication Number Publication Date
WO1998027091A1 true WO1998027091A1 (fr) 1998-06-25

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PCT/EP1997/007047 WO1998027091A1 (fr) 1996-12-19 1997-12-15 Antagonistes de recepteurs de l'endotheline utilises comme pesticides

Country Status (4)

Country Link
AR (1) AR008716A1 (fr)
AU (1) AU5758398A (fr)
DE (1) DE19653024A1 (fr)
WO (1) WO1998027091A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003039539A2 (fr) * 2001-11-09 2003-05-15 Merck Patent Gmbh Utilisation d'antagonistes du recepteur de l'endotheline dans le traitement de maladies tumorales
US8748442B2 (en) 2010-06-30 2014-06-10 Ironwood Pharmaceuticals, Inc. sGC stimulators
US9061030B2 (en) 2010-11-09 2015-06-23 Ironwood Pharmaceuticals, Inc. sGC stimulators
US9139564B2 (en) 2011-12-27 2015-09-22 Ironwood Pharmaceuticals, Inc. 2-benzyl, 3-(pyrimidin-2-yl) substituted pyrazoles useful as sGC stimulators

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0526708A1 (fr) * 1991-06-13 1993-02-10 F. Hoffmann-La Roche Ag Sulfonamide, sa préparation et son usage comme médicament et intermédiaire
WO1993008799A1 (fr) * 1991-11-05 1993-05-13 Smithkline Beecham Corporation Antagonistes recepteurs de l'endotheline
EP0617001A1 (fr) * 1993-03-19 1994-09-28 Merck & Co. Inc. Dérivés d'acide phénoxyphénylacétique
WO1996012706A1 (fr) * 1994-10-24 1996-05-02 Roussel Uclaf Nouveaux derives de pyrazolones et pyrazoles acides utiles comme antagonistes pour les recepteurs a l'endotheline

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0526708A1 (fr) * 1991-06-13 1993-02-10 F. Hoffmann-La Roche Ag Sulfonamide, sa préparation et son usage comme médicament et intermédiaire
WO1993008799A1 (fr) * 1991-11-05 1993-05-13 Smithkline Beecham Corporation Antagonistes recepteurs de l'endotheline
EP0617001A1 (fr) * 1993-03-19 1994-09-28 Merck & Co. Inc. Dérivés d'acide phénoxyphénylacétique
WO1996012706A1 (fr) * 1994-10-24 1996-05-02 Roussel Uclaf Nouveaux derives de pyrazolones et pyrazoles acides utiles comme antagonistes pour les recepteurs a l'endotheline

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003039539A2 (fr) * 2001-11-09 2003-05-15 Merck Patent Gmbh Utilisation d'antagonistes du recepteur de l'endotheline dans le traitement de maladies tumorales
WO2003039539A3 (fr) * 2001-11-09 2003-11-06 Merck Patent Gmbh Utilisation d'antagonistes du recepteur de l'endotheline dans le traitement de maladies tumorales
US8748442B2 (en) 2010-06-30 2014-06-10 Ironwood Pharmaceuticals, Inc. sGC stimulators
US10189809B2 (en) 2010-06-30 2019-01-29 Ironwood Pharmaceuticals, Inc. SGC stimulators
US9061030B2 (en) 2010-11-09 2015-06-23 Ironwood Pharmaceuticals, Inc. sGC stimulators
US9139564B2 (en) 2011-12-27 2015-09-22 Ironwood Pharmaceuticals, Inc. 2-benzyl, 3-(pyrimidin-2-yl) substituted pyrazoles useful as sGC stimulators

Also Published As

Publication number Publication date
AR008716A1 (es) 2000-02-09
AU5758398A (en) 1998-07-15
DE19653024A1 (de) 1998-06-25

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