EP1000044A1 - Benzothia(oxa)diazol derivatives and their use as endothelin-receptor antagonists - Google Patents

Benzothia(oxa)diazol derivatives and their use as endothelin-receptor antagonists

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Publication number
EP1000044A1
EP1000044A1 EP98939552A EP98939552A EP1000044A1 EP 1000044 A1 EP1000044 A1 EP 1000044A1 EP 98939552 A EP98939552 A EP 98939552A EP 98939552 A EP98939552 A EP 98939552A EP 1000044 A1 EP1000044 A1 EP 1000044A1
Authority
EP
European Patent Office
Prior art keywords
formula
benzothiadiazol
methoxyphenyl
compounds
dimethoxybenzyl
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Withdrawn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
EP98939552A
Other languages
German (de)
French (fr)
Inventor
Dieter Dorsch
Mathias Osswald
Werner Mederski
Claudia Wilm
Maria Christadler
Claus Jochen Schmitges
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 EP1000044A1 publication Critical patent/EP1000044A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/14—Thiadiazoles; Hydrogenated thiadiazoles condensed with carbocyclic rings or ring systems
    • 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
    • A61P11/06—Antiasthmatics
    • 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
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • 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
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to compounds of the formula
  • R 2 , R 3 , R 5 , R 6 each independently of one another H, Hai, A, OA or R 4 ,
  • Alkyl with 1-6 C atoms, in which one or two CH 2 groups can be replaced by O or S atoms or by -CR 5 CR ° groups and / or 1-7 H atoms by F,
  • R 5 and R 5 ' are each independently of one another H, F or A.
  • the invention was based on the task of finding 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 hypertension, inflammatory conditions, asthma, prosthma for complications after the administration of substances such as cyciosporin, as well as other diseases associated with endothelin activities.
  • the compounds show, among other things, a high affinity for the endothelin subreceptors ET A and ET 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 20, 1991, Appl. Note 1016.
  • 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 compounds of the formula according to claim 1 and their salts, characterized in that
  • R 1 , R 5 , R 6 and X have the meaning given in claim 1, and A denotes alkyl having 1-4 C atoms or benzyl, with a compound of the formula
  • R 2 , R 3 , R 4 have the meaning given in claim 1,
  • A is alkyl and has 1 to 5, preferably 1, 2, 3 or 4, carbon atoms.
  • A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore 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 3rd , 3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2- or 1, 2,2-trimethylpropyl, furthermore trifluoromethyl, pentafluoroethyl, Allyl or Crotyl.
  • Cycloalkyl is preferably cyclopropy
  • R 1 preferably denotes H, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, propoxy, methoxymethyl, nitro, amino, formamido, acetamido, sulfonamido, methylsulfonamido, N-methylsulfonamido, cyan and also formyl.
  • R 2 , R 3 , R 5 , R 6 each independently represent H. fluorine, chlorine,
  • the compounds of the formula I can have one or more chiral centers and therefore exist in various stereoisomeric forms.
  • Formula I encompasses all of these 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.
  • Some preferred groups of compounds can be expressed by the following sub-formulas la to le, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
  • R 2 , R 3 , R 4 , R 5 each independently of one another OA
  • R 4 denotes cycloalkyl with 3-6 C atoms
  • R 2 , R 3 , R 4 , R 5 each independently of one another H, Hai, A or
  • R 4 means cycloalkyl with 3-6 C atoms.
  • 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, preferably in the presence of a base.
  • the base is e.g. a potassium or sodium alcoholate such as potassium or sodium methylate, ethylate or tert-butoxide.
  • the underlying alcohols are particularly preferred as solvents.
  • 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 e.g. 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, ethanoi, isopropanoi, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl 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, dimethylacetamide or dimethylformamide (DM
  • the starting compounds of formula II are usually new, while those of formula III are generally known.
  • the compounds of formula II can be prepared by methods known per se.
  • ethyl 2- (2,1, 3-benzothiadiazol-5-yl) -4- (4-methoxyphenyl) -4-oxo-butanoate can be prepared by reacting 2- (2,1, 3-benzothiadiazol-5-yl) ethyl acetate with 2'-bromo-4-methoxyacetophenone in an inert solvent with the addition of an acid-binding agent, preferably an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali metal or alkaline earth metals, preferably potassium, sodium, calcium or cesium can be obtained.
  • an organic base such as triethylamine, dimethylaniline, pyridine or quinoiin can also be favorable.
  • Suitable inert solvents are those already mentioned above.
  • the compound 2- (7-methyl-2, 1, 3-benzothiadiazol-5-yl) -acetic acid methyl ester can e.g. can be prepared from 4,6-dimethyl-2,1,3-benzothiadiazole as follows:
  • 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 °.
  • 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.
  • 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, 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, isotonic acid, nicotinic acid, nicotinic acid - Or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p
  • compounds of formula I with bases can be converted into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salts.
  • 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.
  • 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 auxiliaries 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, for example one or more vitamins.
  • auxiliaries 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, 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.
  • 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,
  • 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
  • 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 sterile. Each ampoule contains 10 mg of active ingredient.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Pulmonology (AREA)
  • Neurology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • Vascular Medicine (AREA)
  • Neurosurgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The invention relates to novel compounds of formula (I), wherein R represents group (1), X stands for O or S, and R1, R2, R3, R4, R5 and R6 have the meaning cited in Claim 1, or a tauomeric cyclized form. The invention further relates to (E) isomers and their salts. Said novel derivatives exhibit endothelin-receptor antagonistic properties.

Description

BENZ0THIA(0XA)DIAZ0LDERIVATE UND IHRE VERWENDUNG ALS ENDOTHELIN-REZEPTOR -ANTAGONISTENBENZ0THIA (0XA) DIAZOOL DERIVATIVES AND THEIR USE AS ENDOTHELINE RECEPTOR ANTAGONISTS
Die Erfindung betrifft Verbindungen der FormelThe invention relates to compounds of the formula
NN
XX
NN
R worinR where
X O oder S,X O or S,
R1 H, Hai, OA or A,R 1 H, shark, OA or A,
R2, R3, R5, R6 jeweils unabhängig voneinander H, Hai, A, OA oder R4,R 2 , R 3 , R 5 , R 6 each independently of one another H, Hai, A, OA or R 4 ,
R4 -O-(CH2)n-Cy,R 4 -O- (CH 2 ) n -Cy,
Cy Cycloalkyl mit 3-8 C-Atomen,Cy cycloalkyl with 3-8 C atoms,
Alkyl mit 1-6 C-Atomen, worin eine oder zwei CH2-Gruppen durch O- oder S-Atome oder durch -CR5=CR° -Gruppen und /oder 1-7 H-Atome durch F ersetzt sein können,Alkyl with 1-6 C atoms, in which one or two CH 2 groups can be replaced by O or S atoms or by -CR 5 = CR ° groups and / or 1-7 H atoms by F,
R5 und R5' jeweils unabhängig voneinander H, F oder A.R 5 and R 5 'are each independently of one another H, F or A.
Hai Fluor, Chlor, Brom oder lod, n 0, 1 oder 2Shark fluorine, chlorine, bromine or iodine, n 0, 1 or 2
bedeutet,means
oder eine tautomere ringgeschlossene Form, sowie die (E)-Isomeren und die Salze aller Isomeren.or a tautomeric ring-closed form, as well as the (E) isomers and the salts of all isomers.
Die tautomere ringgeschlossene HydroxylactonformThe tautomeric ring-closed form of hydroxylactone
liegt vor, wenn die Verbindungen der Formel I als Carbonsäuren isoliert werden. Fallen die Verbindungen der Formel I als Salze (Carboxylate) an, so erhält man das offenkettige Tautomere. is when the compounds of formula I are isolated as carboxylic acids. If the compounds of the formula I are obtained as salts (carboxylates), the open-chain tautomer is obtained.
Ähnliche Verbindungen sind aus WO 95/05376 bekannt.Similar compounds are known from WO 95/05376.
Der Erfindung lag die Aufgabe zugrunde, neue Verbindungen mit wertvollen Eigenschaften aufzufinden, insbesondere solche, die zur Herstellung von Arzneimitteln verwendet werden können.The invention was based on the task of finding new compounds with valuable properties, in particular those which can be used for the production of medicaments.
Es wurde gefunden, daß die Verbindungen der Formel I und ihre Salze bei guter Verträglichkeit sehr wertvolle pharmakologische Eigenschaften besitzen. Insbesondere zeigen sie Endothelinrezeptor-antagonistische Eigenschaften und können daher zur Behandlung von Krankheiten wie Hypertonie, Herzinsuffizienz, koronare Herzerkrankung, renale, cerebrale und myocardiale Ischämie, Niereninsuffizienz, Hirninfarkt, subarachnoidale Hämorrhagie, Arteriosklerose, pulmonaler Hochdruck, Entzündungen, Asthma, Prostatahyperplasie, endotoxischer Schock und bei Komplikationen nach der Verabreichung von Substanzen wie z.B. Cyciosporin, sowie anderen, mit Endothelin-Aktivitäten assoziierten Krankheiten eingesetzt werden. Die Verbindungen zeigen u.a. eine hohe Affinität zu den Endothelin- Subrezeptoren ETA und ETB. Diese Wirkungen können nach üblichen in vitro- oder in vivo-Methoden ermittelt werden, wie z.B. beschrieben von P.D. Stein et al., J. Med. Chem. 37, 1994, 329-331 und E. Ohistein et al., Proc. Natl. Acad. Sei. USA 9 _, 1994, 8052-8056.It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability. In particular, 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 hypertension, inflammatory conditions, asthma, prosthma for complications after the administration of substances such as cyciosporin, as well as other diseases associated with endothelin activities. The compounds show, among other things, a high affinity for the endothelin subreceptors ET A and ET B. These effects can be determined by conventional in vitro or in vivo methods, as described, for example, by PD Stein et al., J. Med. Chem. 37, 1994, 329-331 and E. Ohistein et al., Proc. Natl. Acad. Be. USA 9_, 1994, 8052-8056.
Eine geeignete Methode zur Bestimmung der blutdrucksenkenden Wirkung wird z. B. beschrieben von M.K. Bazil et al., J. Cardiovasc. Pharmacol. 22, 1993, 897-905 und J. Lange et al., Lab Animal 20, 1991 , Appl. Note 1016.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 20, 1991, Appl. Note 1016.
Die Verbindungen der Formel I können als Arzneimittelwirkstoffe in der Human- und Veterinärmedizin eingesetzt werden, insbesondere zur Prophylaxe und/oder Therapie von Herz-, Kreislauf- und Gefäßkrankheiten, vor allem von Hypertonie und Herzinsuffizienz.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.
Gegenstand der Erfindung sind die Verbindungen der Formel I und ihre Salze sowie ein Verfahren zur Herstellung von Verbindungen der Formel nach Anspruch 1 sowie ihrer Salze, dadurch gekennzeichnet, daß manThe invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula according to claim 1 and their salts, characterized in that
eine Verbindung der Formel IIa compound of formula II
worin wherein
R1, R5, R6 und X die in Anspruch 1 angegebene Bedeutung haben, und A Alkyl mit 1-4 C-Atomen oder Benzyl bedeutet, mit einer Verbindung der FormelR 1 , R 5 , R 6 and X have the meaning given in claim 1, and A denotes alkyl having 1-4 C atoms or benzyl, with a compound of the formula
FTFT
worin wherein
R2, R3, R4 die in Anspruch 1 angegebene Bedeutung haben,R 2 , R 3 , R 4 have the meaning given in claim 1,
umsetzt,implements
Und anschließend den Ester spaltet, U nd then the ester splits,
und/oder eine Base oder Säure der Formel I in eines ihrer Salze umwandelt.and / or converts a base or acid of the formula I into one of its salts.
Für alle Reste, die mehrfach auftreten, wie z. B. R3, R4 oder R5 gilt, daß deren Bedeutungen unabhängig voneinander sind.For all residues that occur several times, such as B. R 3 , R 4 or R 5 applies that their meanings are independent of each other.
Vor- und nachstehend haben die Reste bzw. Parameter R, X, R1, R2, R3, R4, R5, R6, A, und n die bei den Formeln I bis III angegebenen Bedeutungen, falls nicht ausdrücklich etwas anderes angegeben ist.Above and below, the radicals or parameters R, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, and n have the meanings given in the formulas I to III, unless expressly stated otherwise specified.
In den vorstehenden Formeln bedeutet A Alkyl und hat 1 bis 5, vorzugsweise 1 , 2, 3 oder 4 C-Atome. A bedeutet vorzugsweise Methyl, weiterhin Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sek.-Butyl oder tert.-Butyl, ferner auch Pentyl, 1-, 2- oder 3-Methylbutyl, 1 ,1- , 1 ,2- oder 2,2-Dιmethylpropyl, 1-Ethylpropyl, Hexyl, 1- , 2- , 3- oder 4-Methylpentyl, 1 ,1- , 1 2- , 1 ,3- , 2,2- , 2,3- oder 3,3-Dimethylbutyl, 1- oder 2-Ethylbutyl, 1-Ethyl-1-methylpropyl, 1-Ethyl-2-methylpropyl, 1 ,1 ,2- oder 1 ,2,2-Trimethylpropyl, weiterhin Tri- fluormethyl, Pentafluorethyl, Allyl oder Crotyl. Cycloalkyl ist vorzugsweise Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl oder Cyclooctyl.In the above formulas, A is alkyl and has 1 to 5, preferably 1, 2, 3 or 4, carbon atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore 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 3rd , 3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2- or 1, 2,2-trimethylpropyl, furthermore trifluoromethyl, pentafluoroethyl, Allyl or Crotyl. Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
Hai bedeutet vorzugsweise F, Cl oder Br, aber auch I.Shark preferably means F, Cl or Br, but also I.
R1 bedeutet vorzugsweise H, Fluor, Chlor, Brom, lod, Methoxy, Ethoxy, Propoxy, Methoxymethyl, Nitro, Amino, Formamido, Acetamido, Sulfon- amido, Methylsulfonamido, N-Methylsulfonamido, Cyan ferner auch Formyl.R 1 preferably denotes H, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, propoxy, methoxymethyl, nitro, amino, formamido, acetamido, sulfonamido, methylsulfonamido, N-methylsulfonamido, cyan and also formyl.
R2, R3, R5, R6 bedeuten jeweils unabhängig voneinander H. Fluor, Chlor,R 2 , R 3 , R 5 , R 6 each independently represent H. fluorine, chlorine,
Brom, lod, Hydroxy, Methoxy, Ethoxy, Propoxy, Butoxy, Peπtyloxy, Hexyl- oxy, Alkyl wie z.B. Methyl, Ethyl, Propyl oder Isopropyl, weiterhin Hydroxy, Nitro, Amino, N-Methylamino, Dimethylamino, Benzyloxy, Phenethyloxy, Methylthio, Ethylthio, Methylsulfinyl, Ethylsulfinyl, Methylsulfonyl, Ethyl- sulfonyl, Phenylsulfinyl, Phenylsulfonyl, Nitro, Amino, Methylamino, Ethyl- amino, Dimethylamino, Diethylamino, Formamido, Acetamido, N-Methyl- acetamido, N-Ethylacetamido, N-Propylacetamido, N-Butylacetamido, Propionylamino, Butyrylamino, Methylsulfonamido, Ethylsulfonamido, Propylsulfonamido, Butylsulfonamido, N-Methyl-methylsulfonamido, N-Bromine, iodine, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, alkyl such as e.g. Methyl, ethyl, propyl or isopropyl, furthermore hydroxy, nitro, amino, N-methylamino, dimethylamino, benzyloxy, phenethyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, phenylsulfinyl, phenylsulfonyl, nitro, amino, methylamino - amino, dimethylamino, diethylamino, formamido, acetamido, N-methyl-acetamido, N-ethylacetamido, N-propylacetamido, N-butylacetamido, propionylamino, butyrylamino, methylsulfonamido, ethylsulfonamido, propylsulfonamido, nylsulfonamido, butylsulfonamido, butylsulfonamido, butylsulfonamido
Methyl-ethylsulfonamido, N-Ethyl-methylsulfonamido, N-Ethyl-ethylsulfon- amido, N-Propyl-methylsulfonamido, N-Propyl-ethylsulfonamido, N-Butyl- methylsulfonamido, N-Butyl-ethylsulfonamido, Phenylsulfonamido, (4- Methylphenyl)-sulfonamido, Ureido, Methylureido, Pheπylureido, Methoxy- carbonylamino, Ethoxycarbonylamino, Formyl, Hydroxymethyl, Methoxymethyl, Ethoxymethyl, Anilino, Phenoxycarbonylamino, Benzyloxycarbonyl- amino, Benzylsulfonamido, N,N-Dimethylureido, 1-Piperidinyl-CONH-, 1- Pyrrolidinyl-CONH, Hydroxyethoxycarbonylamino, Methoxyethoxycarbonyl- amino, Carboxymethoxy, Carboxyethoxy, Methoxycarbonylmethoxy, Methoxycarbonylethoxy, Hydroxyethoxy, Methoxyethoxy, Carboxy,Methyl-ethylsulfonamido, N-ethyl-methylsulfonamido, N-ethyl-ethylsulfonamido, N-propyl-methylsulfonamido, N-propyl-ethylsulfonamido, N-butyl-methylsulfonamido, N-butyl-ethylsulfonamido, phenylsulfonamido, (4-methylphenyl) - sulfonamido, ureido, methylureido, phenylureido, methoxycarbonylamino, ethoxycarbonylamino, formyl, hydroxymethyl, methoxymethyl, ethoxymethyl, anilino, phenoxycarbonylamino, benzyloxycarbonylamino, benzylsulfonamido, N, N-dimethylureido, 1-piperidynyl-CONH , Hydroxyethoxycarbonylamino, methoxyethoxycarbonylamino, carboxymethoxy, carboxyethoxy, methoxycarbonylmethoxy, methoxycarbonylethoxy, hydroxyethoxy, methoxyethoxy, carboxy,
Methoxycarbonyl, Ethoxycarbonyi, Carboxymethyl, Methoxycarbonylmethyl oder Ethoxycarbonylmethyl.Methoxycarbonyl, ethoxycarbonyl, carboxymethyl, methoxycarbonylmethyl or ethoxycarbonylmethyl.
Die Verbindungen der Formel I können ein oder mehrere chirale Zentren besitzen und daher in verschiedenen stereoisomeren Formen vorkommen. Die Formel I umschließt alle diese Formen. Besonders bevorzugt sind die Z-Isomeren der Formel I, d.h. die Verbindungen, in denen die C=C-Doppelbindung im Rest R in der Z- Konfiguration vorliegt.The compounds of the formula I can have one or more chiral centers and therefore exist in various stereoisomeric forms. Formula I encompasses all of these forms. The Z isomers of the formula I are particularly preferred, ie the compounds in which the C =C double bond in the R radical is in the Z configuration.
Dementsprechend sind Gegenstand der Erfindung insbesondere diejenigen Verbindungen der Formel I, in denen mindestens einer der genannten Reste eine der vorstehend angegebenen bevorzugten Bedeutungen hat. Einige bevorzugte Gruppen von Verbindungen können durch die folgenden Teilformeln la bis le ausgedrückt werden, die der Formel I entsprechen und worin die nicht näher bezeichneten Reste die bei der Formel I angegebene Bedeutung haben, worin jedochAccordingly, 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 sub-formulas la to le, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
n la R1 H,n la R 1 H,
X s,X s,
R2, R3, R4, R5 jeweils unabhängig voneinar OA,R 2 , R 3 , R 4 , R 5 each independently of one another OA,
A Alkyl mit 1-6 C-Atomen undA alkyl with 1-6 C atoms and
R4 Cycloalkyl mit 3-6 C-Atomen bedeutet,R 4 denotes cycloalkyl with 3-6 C atoms,
in Ib R1 H,in Ib R 1 H,
X O,X O,
R2, R3, R4, R5 jeweils unabhängig voneinander H, Hai, A oderR 2 , R 3 , R 4 , R 5 each independently of one another H, Hai, A or
OA,OA,
A Alkyl mit 1-6 C-Atomen undA alkyl with 1-6 C atoms and
R4 Cycloalkyl mit 3-6 C-Atomen bedeutet.R 4 means cycloalkyl with 3-6 C atoms.
Die Verbindungen der Formel I und auch die Ausgangsstoffe zu ihrer Herstellung werden im übrigen nach an sich bekannten Methoden hergestellt, wie sie in der Literatur (z.B. in den Standardwerken wie Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart) beschrieben sind, und zwar unter Reaktionsbedingungen, die für die ge- nannten Umsetzungen bekannt und geeignet sind. Dabei kann man auch von an sich bekannten, hier nicht näher erwähnten Varianten Gebrauch machen.The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart) are described, namely under reaction conditions which are known and suitable for the reactions mentioned. You can also do that make use of variants which are known per se and are not mentioned here.
Die Ausgangsstoffe können, falls erwünscht, auch in situ gebildet werden, so daß man sie aus dem Reaktionsgemisch nicht isoliert, sondern sofort weiter zu den Verbindungen der Formel I umsetzt. Verbindungen der Formel I können vorzugsweise erhalten werden, indem man Verbindungen der Formel II mit Verbindungen der Formel III umsetzt, und anschließend den Ester spaltet.If desired, 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.
Die Umsetzung erfolgt in der Regel in einem inerten Lösungsmittel, vorzugsweise in Gegenwart einer Base. Als Base dient z.B. ein Kalium- oder Natriumalkoholat wie Kalium- oder Natriummethylat, -ethylat oder -tert- butylat. Als Lösungsmittel sind besonders die zugrundeliegenden Alkohole bevorzugt.The reaction is usually carried out in an inert solvent, preferably in the presence of a base. The base is e.g. a potassium or sodium alcoholate such as potassium or sodium methylate, ethylate or tert-butoxide. The underlying alcohols are particularly preferred as solvents.
Die Reaktionszeit liegt je nach den angewendeten Bedingungen zwischen einigen Minuten und 14 Tagen, die Reaktionstemperatur zwischen etwa 0° und 150°, normalerweise zwischen 20° und 130°.Depending on the conditions used, 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 °.
Als inerte Lösungsmittel eignen sich z.B. Kohlenwasserstoffe wie Hexan, Petrolether, Benzol, Toluol oder Xylol; chlorierte Kohlenwasserstoffe wie Trichlorethylen, 1 ,2-Dichlorethan, Tetrachlorkohlenstoff, Chloroform oder Dichlormethan; Alkohole wie Methanol, Ethanoi, Isopropanoi, n-Propanol, n-Butanol oder tert.-Butanol; Ether wie Diethylether, Diisopropylether, Tetrahydrofuran (THF) oder Dioxan; Glykolether wie Ethylenglykolmono- methyl- oder -monoethylether (Methylglykol oder Ethylgiykol), Ethylen- glykoldimethylether (Diglyme); Ketone wie Aceton oder Butanon; Amide wie Acetamid, Dimethylacetamid oder Dimethylformamid (DMF); Nitrile wie Acetonitril; Sulfoxide wie Dimethylsulfoxid (DMSO); Schwefelkohlenstoff; Carbonsäuren wie Ameisensäure oder Essigsäure; Nitroverbindungen wie Nitromethan oder Nitrobenzol; Ester wie Ethylacetat oder Gemische der genannten Lösungsmittel.Suitable inert solvents are e.g. 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, ethanoi, isopropanoi, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl 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, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide; 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.
Die Ausgangsverbindungen der Formel II sind in der Regel neu, während die der Formel III in der Regel bekannt sind. Die Verbindungen der Formel II können aber nach an sich bekannten Methoden hergestellt werden. So kann z.B. 2-(2,1 ,3-Benzothiadiazol-5-yl)- 4-(4-methoxyphenyl)-4-oxo-butansäureethyiester durch Umsetzung von 2- (2,1 ,3-Benzothiadiazol-5-yl)-essigsäureethylester mit 2'-Brom-4-methoxy- acetophenon in einem inerten Lösungsmittel unter Zusatz eines säurebindenden Mittels, vorzugsweise eines Alkali- oder Erdalkalimetall-hydroxids, -carbonats oder -bicarbonats oder eines anderen Salzes einer schwachen Säure der Alkali- oder Erdalkalimetalle, vorzugsweise des Kaliums, Natriums, Caiciums oder Cäsiums, erhalten werden. Auch der Zusatz einer organischen Base wie Triethylamin, Dimethylanilin, Pyridin oder Chinoiin kann günstig sein.The starting compounds of formula II are usually new, while those of formula III are generally known. However, the compounds of formula II can be prepared by methods known per se. For example, ethyl 2- (2,1, 3-benzothiadiazol-5-yl) -4- (4-methoxyphenyl) -4-oxo-butanoate can be prepared by reacting 2- (2,1, 3-benzothiadiazol-5-yl) ethyl acetate with 2'-bromo-4-methoxyacetophenone in an inert solvent with the addition of an acid-binding agent, preferably an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali metal or alkaline earth metals, preferably potassium, sodium, calcium or cesium can be obtained. The addition of an organic base such as triethylamine, dimethylaniline, pyridine or quinoiin can also be favorable.
Vorzugsweise arbeitet man bei Temperaturen zwischen 0° und 150°. Als inerte Lösungsmittel eignen sich die schon oben erwähnten.Preferably one works at temperatures between 0 ° and 150 °. Suitable inert solvents are those already mentioned above.
Die Verbindung 2-(7-Methyl-2, 1 ,3-benzothiadiazol-5-yl)-essigsäure- methylester kann z.B. aus 4,6-Dimethyl-2,1 ,3-benzothiadiazol wie folgt hergestellt werden:The compound 2- (7-methyl-2, 1, 3-benzothiadiazol-5-yl) -acetic acid methyl ester can e.g. can be prepared from 4,6-dimethyl-2,1,3-benzothiadiazole as follows:
1. Regioselektive Deprotonierung mit Lithiumdiisopropylamid und 1 ,3-1. Regioselective deprotonation with lithium diisopropylamide and 1, 3-
Dimethyl-tetrahydro-pyrimidin-2-on in THF. 2. Umsetzung mit CO2.Dimethyl-tetrahydro-pyrimidin-2-one in THF. 2. Implementation with CO 2 .
3. Veresterung mit Methyliodid und Kaliumcarbonat in DMF.3. Esterification with methyl iodide and potassium carbonate in DMF.
Ester können z.B. mit Essigsäure oder mit NaOH oder KOH in Wasser, Wasser-THF oder Wasser-Dioxan bei Temperaturen zwischen 0 und 100° verseift werden.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 °.
Eine Base der Formel I kann mit einer Säure in das zugehörige Säureadditionssalz übergeführt werden, beispielsweise durch Umsetzung äquivalenter Mengen der Base und der Säure in einem inerten Lösungsmittel wie Ethanol und anschließendes Eindampfen. Für diese Umsetzung kommen insbesondere Säuren in Frage, die physiologisch unbedenkliche Salze liefern. So können anorganische Säuren verwendet werden, z.B. Schwefelsäure, Salpetersäure, Halogenwasserstoffsäuren wie Chlorwasserstoffsäure oder Bromwasserstoffsäure, Phosphorsäuren wie Ortho- phosphorsäure, Sulfaminsäure, ferner organische Säuren, insbesondere aliphatische, alicyclische, araliphatische, aromatische oder heterocyclische ein- oder mehrbasige Carbon-, Sulfoπ- oder Schwefelsäuren, z.B. Ameisensäure, Essigsäure, Propionsäure, Pivalinsäure, Diethylessigsäure, Malonsäure, Bernsteinsäure, Pimelinsäure, Fumarsäure, Maleinsäure, Milchsäure, Weinsäure, Äpfelsäure, Citronensäure, Gluconsäure, Ascorbinsäure, Nicotinsäure, Isonicotinsäure, Methan- oder Ethansulfon- säure, Ethandisulfonsäure, 2-Hydroxyethansulfonsäure, Beπzolsulfon- säure, p-Toluolsulfonsäure, Naphthalin-mono- und disulfonsäuren, Lauryl- schwefelsäure. Salze mit physiologisch nicht unbedenklichen Säuren, z.B. Pikrate, können zur Isolierung und /oder Aufreinigung der Verbindungen der Formel I verwendet werden.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. In particular, acids that provide physiologically acceptable salts are suitable for this implementation. Thus, 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, 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, isotonic acid, nicotinic acid, nicotinic acid - Or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and / or purification of the compounds of the formula I.
Andererseits können Verbindungen der Formel I mit Basen (z.B. Natriumoder Kaliumhydroxid oder -carbonat) in die entsprechenden Metall-, insbesondere Alkalimetall- oder Erdalkalimetall-, oder in die entsprechenden Ammoniumsalze umgewandelt werden.On the other hand, compounds of formula I with bases (e.g. sodium or potassium hydroxide or carbonate) can be converted into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salts.
Gegenstand der Erfindung ist ferner die Verwendung der Verbindungen der Formel I und/oder ihrer physiologisch unbedenklichen Salze zur Herstellung pharmazeutischer Zubereitungen, insbesondere auf nicht-chem- ischem Wege. Hierbei können sie zusammen mit mindestens einem festen, flüssigen und/oder halbflüssigen Träger- oder Hilfsstoff und gegebenenfalls in Kombination mit einem oder mehreren weiteren Wirkstoffen in eine geeignete Dosierungsform gebracht werden.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.
Gegenstand der Erfindung sind ferner pharmazeutische Zubereitungen, enthaltend mindestens eine Verbindung der Formel I und/oder eines ihrer physiologisch unbedenklichen Salze.The invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts.
Diese Zubereitungen können als Arzneimittel in der Human- oder Veteri- närmedizin verwendet werden. Als Trägerstoffe kommen organische oder anorganische Substanzen in Frage, die sich für die enterale (z.B. orale), parenterale oder topische Applikation eignen und mit den neuen Verbindungen nicht reagieren, beispielsweise Wasser, pflanzliche Öle, Benzyl- alkohole, Alkylenglykole, Polyethylenglykole, Glycerintriacetat, Gelatine, Kohlehydrate wie Lactose oder Stärke, Magnesiumstearat, Talk, Vaseline. Zur oralen Anwendung dienen insbesondere Tabletten, Pillen, Dragees, Kapseln, Pulver, Granulate, Sirupe, Säfte oder Tropfen, zur rektalen Anwendung Suppositorien, zur parenteralen Anwendung Lösungen, vorzugsweise ölige oder wässrige Lösungen, ferner Suspensionen, Emulsionen oder Implantate, für die topische Anwendung Salben, Cremes oder Puder. Die neuen Verbindungen können auch lyophilisiert und die erhaltenen Lyo- philisate z.B. zur Herstellung von Injektionspräparaten verwendet werden. Die angegebenen Zubereitungen können sterilisiert sein und/oder Hilfsstoffe wie Gleit-, Konservierungs-, Stabilisierungs- und/oder Netzmittel, Emulgatoren, Salze zur Beeinflussung des osmotischen Druckes, Puffersubstanzen, Färb-, Geschmacks- und /oder mehrere weitere Wirkstoffe enthalten, z.B. ein oder mehrere Vitamine.These preparations can be used as medicinal products in human or veterinary medicine. 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, coated tablets, Capsules, powders, granules, syrups, juices or drops, for rectal use suppositories, for parenteral use solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, for topical 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 contain auxiliaries 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, for example one or more vitamins.
Die Verbindungen der Formel I und ihre physiologisch unbedenklichen Salze können bei der Bekämpfung von Krankheiten, insbesondere von Hypertonie und Herzinsuffizienz verwendet werden.The compounds of formula I and their physiologically acceptable salts can be used in the control of diseases, in particular hypertension and heart failure.
Dabei werden die erfindungsgemäßen Substanzen in der Regel vorzugsweise in Dosierungen zwischen etwa 1 und 500 mg, insbesondere zwischen 5 und 100 mg pro Dosierungseinheit verabreicht. Die tägliche Dosierung liegt vorzugsweise zwischen etwa 0,02 und 10 mg/kg Körpergewicht. Die spezielle Dosis für jeden Patienten hängt jedoch von den verschiedensten Faktoren ab, beispielsweise von der Wirksamkeit der eingesetzten speziellen Verbindung, vom Alter, Körpergewicht, allgemeinen Gesundheitszustand, Geschlecht, von der Kost, vom Verabrei- chungszeitpunkt und -weg, von der Ausscheidungsgeschwindigkeit,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. However, 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,
Arzneistoffkombination und Schwere der jeweiligen Erkrankung, welcher die Therapie gilt. Die orale Applikation ist bevorzugt.Drug combination and severity of the disease to which the therapy applies. Oral application is preferred.
Vor- und nachstehend sind alle Temperaturen in °C angegeben. In den nachfolgenden Beispielen bedeutet "übliche Aufarbeitung": Man gibt, falls erforderlich, Wasser hinzu, stellt, falls erforderlich, je nach Konstitution des Endprodukts auf pH-Werte zwischen 2 und 10 ein, extrahiert mit Ethylacetat oder Dichlormethan, trennt ab, trocknet die organische Phase über Natriumsulfat, dampft ein und reinigt durch Chromatographie an Kieselgel und /oder durch Kristallisation. Rf-Werte an Kieselgel; Laufmittel: Ethylacetat/Methanol 9:1. Massenspektrometrie (MS): El (Elektronenstoß-Ionisation) M+ All temperatures above and below are given in ° C. In the examples below, "customary work-up" means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, and the mixture is dried and dried organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization. Rf values on silica gel; Mobile solvent: ethyl acetate / methanol 9: 1. Mass spectrometry (MS): El (electron impact ionization) M +
FAB (Fast Atom Bombardment) (M+H)+ Beispiel 1FAB (Fast Atom Bombardment) (M + H) + Example 1
Zu einer Lösung von 34 mg Natrium in 10 ml Ethanol gibt man 0,368 g 4-To a solution of 34 mg sodium in 10 ml ethanol, add 0.368 g 4-
Cyclopentyloxy-3,5-dimethoxybenzaldehyd ("A") und 0,52 g 2-(2,1,3- Beπzothiadiazol-5-yl)-4-(4-methoxyphenyl)-4-oxo-butansäureethylester F. 89° (erhältlich durch Umsetzung von 5,5 g 2-(2,1 ,3-Benzothiadiazol-5-yl)- essigsäureethylester mit 5,5, g 2'-Brom-4-methoxyacetophenon und 4 g Kaliumcarbonat in 200 ml Aceton, 18 Stunden unter Rückfluß; 2-(2,1 ,3- Benzothiadiazol-5-yl)-essigsäureethylester, F. 40-41 ° erhält man durch Reaktion von 24,3 g 3,4-Diaminophenylessigsäureethylester und 26,9 ml Thionylaniiin in 80 ml Toluol, 4 Stunden unter Rückfluß) und erhitzt eine Stunde unter Rückfluß. Nach Zugabe von 1 ,4 ml Essigsäure wird weitere 16 Stunden erhitzt. Das Lösungsmittel wird entfernt und wie üblich aufgearbeitet. Man erhält 3-(2,1 ,3-Benzothiadiazol-5-yl)-4-(4-cyclopentyloxy-3,5- dimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-on, FAB 575.Cyclopentyloxy-3,5-dimethoxybenzaldehyde ("A") and 0.52 g of 2- (2,1,3-beπzothiadiazol-5-yl) -4- (4-methoxyphenyl) -4-oxo-butanoic acid ethyl ester F. 89 ° (obtainable by reacting 5.5 g of 2- (2,1, 3-benzothiadiazol-5-yl) ethyl acetate with 5.5, g of 2'-bromo-4-methoxyacetophenone and 4 g of potassium carbonate in 200 ml of acetone, 18 Hours under reflux; ethyl 2- (2,1, 3-benzothiadiazol-5-yl), mp 40-41 ° is obtained by reaction of 24.3 g ethyl 3,4-diaminophenylacetate and 26.9 ml thionylaniiine in 80 ml of toluene, 4 hours under reflux) and heated under reflux for one hour. After adding 1.4 ml of acetic acid, the mixture is heated for a further 16 hours. The solvent is removed and worked up as usual. This gives 3- (2,1, 3-benzothiadiazol-5-yl) -4- (4-cyclopentyloxy-3,5-dimethoxybenzyl) -5-hydroxy-5- (4-methoxyphenyl) -5H-furan-2- on, FAB 575.
Analog erhält man durch Umsetzung von "A"Analogously, by converting "A"
mit 2-(2, 1 ,3-Benzothiadiazol-5-yl)-4-(3-fluor-4-methoxyphenyl)-4-oxo- butansäureethylesterwith 2- (2, 1, 3-benzothiadiazol-5-yl) -4- (3-fluoro-4-methoxyphenyl) -4-oxo-butanoic acid ethyl ester
3-(2, 1 ,3-Benzothiadiazol-5-yl)-4-(4-cyclopentyloxy-3,5- dimethoxybenzyl)-5-hydroxy-5-(3-fluor-4-methoxyphenyl)-5H-furan-2-on;3- (2, 1, 3-Benzothiadiazol-5-yl) -4- (4-cyclopentyloxy-3,5-dimethoxybenzyl) -5-hydroxy-5- (3-fluoro-4-methoxyphenyl) -5H-furan 2-one;
mit 2-(2,1 ,3-Benzothiadiazol-5-yl)-4-(2,5-dimethoxyphenyl)-4-oxo- butansäureethylesterwith 2- (2,1, 3-benzothiadiazol-5-yl) -4- (2,5-dimethoxyphenyl) -4-oxo-butanoic acid ethyl ester
3-(2,1 ,3-Benzothiadiazol-5-yl)-4-(4-cyclopentyloxy-3,5- dimethoxybenzyl)-5-hydroxy-5-(2,5-methoxyphenyl)-5H-furan-2-on;3- (2,1, 3-benzothiadiazol-5-yl) -4- (4-cyclopentyloxy-3,5-dimethoxybenzyl) -5-hydroxy-5- (2,5-methoxyphenyl) -5H-furan-2- on;
mit 2-(7-Methyl-2, 1 ,3-Benzothiadiazol-5-yl)-4-(3-fluor-4-methoxyphenyl)-4- oxo-butansäureethylesterwith 2- (7-methyl-2, 1, 3-benzothiadiazol-5-yl) -4- (3-fluoro-4-methoxyphenyl) -4-oxo-butanoic acid ethyl ester
3-(7-Methyl-2,1 ,3-Benzothiadiazol-5-yl)-4-(4-cyclopentyloxy-3,5- dimethoxybenzyl)-5-hydroxy-5-(3-fluor-4-methoxyphenyl)-5H-furan-2-on, Fp. 159-160°; Analog erhält man durch Umsetzung von 3-Cyclopentyloxy-4,5- dimethoxybenzaldehyd3- (7-methyl-2,1, 3-benzothiadiazol-5-yl) -4- (4-cyclopentyloxy-3,5-dimethoxybenzyl) -5-hydroxy-5- (3-fluoro-4-methoxyphenyl) - 5H-furan-2-one, mp 159-160 °; Analog is obtained by reacting 3-cyclopentyloxy-4,5-dimethoxybenzaldehyde
mit 2-(2,1 ,3-Benzothiadiazol-5-yl)-4-(4-methoxyphenyl)-4-oxo- butansäureethylesterwith 2- (2,1, 3-benzothiadiazol-5-yl) -4- (4-methoxyphenyl) -4-oxobutanoic acid ethyl ester
3-(2, 1 ,3-Benzothiadiazol-5-yl)-4-(3-cyclopentyloxy-4,5- dimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-on, FAB 575.3- (2, 1, 3-Benzothiadiazol-5-yl) -4- (3-cyclopentyloxy-4,5-dimethoxybenzyl) -5-hydroxy-5- (4-methoxyphenyl) -5H-furan-2-one, FAB 575.
Analog erhält man durch Umsetzung von 4-Cyclopropylmethyloxy-4,5- dimethoxybenzaldehydAnalog is obtained by reacting 4-cyclopropylmethyloxy-4,5-dimethoxybenzaldehyde
mit 2-(2, 1 ,3-Benzothiadiazol-5-yl)-4-(4-methoxyphenyl)-4-oxo- butansäureethylesterwith 2- (2, 1, 3-benzothiadiazol-5-yl) -4- (4-methoxyphenyl) -4-oxo-butanoic acid ethyl ester
3-(2, 1 ,3-Benzothiadiazol-5-yl)-4-(3-cyclopropylmethyloxy-4,5- dimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-on;3- (2, 1, 3-Benzothiadiazol-5-yl) -4- (3-cyclopropylmethyloxy-4,5-dimethoxybenzyl) -5-hydroxy-5- (4-methoxyphenyl) -5H-furan-2-one;
mit 2-(2, 1 ,3-Benzothiadiazol-5-yl)-4-(3-fluor-4-methoxyphenyl)-4-oxo- butansäureethylesterwith 2- (2, 1, 3-benzothiadiazol-5-yl) -4- (3-fluoro-4-methoxyphenyl) -4-oxo-butanoic acid ethyl ester
3-(2, 1 ,3-Benzothiadiazol-5-yl)-4-(4-cyclopropylmethyloxy-3,5- dimethoxybenzyl)-5-hydroxy-5-(3-fluor-4-methoxyphenyl)-5H-furan-2-on;3- (2, 1, 3-Benzothiadiazol-5-yl) -4- (4-cyclopropylmethyloxy-3,5-dimethoxybenzyl) -5-hydroxy-5- (3-fluoro-4-methoxyphenyl) -5H-furan 2-one;
mit 2-(2, 1 ,3-Benzothiadiazol-5-yl)-4-(2,5-dimethoxyphenyl)-4-oxo- butansäureethylesterwith 2- (2, 1, 3-benzothiadiazol-5-yl) -4- (2,5-dimethoxyphenyl) -4-oxo-butanoic acid ethyl ester
3-(2, 1 ,3-Benzothiadiazol-5-yl)-4-(4-cyclopropylmethyloxy-3,5- dimethoxybenzyl)-5-hydroxy-5-(2,5-dimethoxyphenyl)-5H-furan-2-on und3- (2, 1, 3-Benzothiadiazol-5-yl) -4- (4-cyclopropylmethyloxy-3,5-dimethoxybenzyl) -5-hydroxy-5- (2,5-dimethoxyphenyl) -5H-furan-2- on and
mit 2-(7-Methyl-2, 1 ,3-benzothiadiazol-5-yl)-4-(3-fluor-4-methoxyphenyl)-4- oxo-butansäureethylesterwith 2- (7-methyl-2, 1, 3-benzothiadiazol-5-yl) -4- (3-fluoro-4-methoxyphenyl) -4-oxo-butanoic acid ethyl ester
3-(7-Methyl-2,1 ,3-benzothiadiazol-5-yl)-4-(4-cyclopropylmethyloxy- 3,5-dimethoxybenzyl)-5-hydroxy-5-(3-fluor-4-methoxyphenyl)-5H-furan-2- on, Fp. 156-158°.3- (7-methyl-2,1, 3-benzothiadiazol-5-yl) -4- (4-cyclopropylmethyloxy-3,5-dimethoxybenzyl) -5-hydroxy-5- (3-fluoro-4-methoxyphenyl) - 5H-furan-2-one, mp 156-158 °.
Analog erhält man die Verbindung 3-(7-Methyl-2,1 ,3-benzothiadiazol-5-yl)- 4-(4-cyclohexyloxy-3,5-dimethoxybenzyl)-5-hydroxy-5-(3-fluor-4- methoxyphenyl)-5H-furan-2-on, Fp. 163-164°. Beispiel 2The compound 3- (7-methyl-2,1, 3-benzothiadiazol-5-yl) - 4- (4-cyclohexyloxy-3,5-dimethoxybenzyl) -5-hydroxy-5- (3-fluoro- 4-methoxyphenyl) -5H-furan-2-one, mp 163-164 °. Example 2
Zu einer Suspension von 30 mg 3-(2,1 ,3-Benzothiadiazol-5-yl)-4-(4- cyclopentyloxy-3,5-dimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H- furan-2-on in 1 ml Methanol gibt man äquimolare Mengen 0,1 N NaOH und rührt bei Raumtemperatur. Das Lösungsmittel wird entfernt, der Rückstand zwischen Wasser und Diethylether verteilt, und die wässrige Phase wird anschließend lyophilisiert. Man erhält 2-(2,1 , 3-Benzothiadiazol-5-yl)-3-(4- cyclopentyloxy-3,5-dimethoxybenzyl)-4-(4-methoxyphenyl)-4-oxo-2- butensäure Natriumsalz.To a suspension of 30 mg of 3- (2,1, 3-benzothiadiazol-5-yl) -4- (4-cyclopentyloxy-3,5-dimethoxybenzyl) -5-hydroxy-5- (4-methoxyphenyl) -5H- furan-2-one in 1 ml of methanol are given equimolar amounts of 0.1 N NaOH and stirred at room temperature. The solvent is removed, the residue is partitioned between water and diethyl ether, and the aqueous phase is then lyophilized. 2- (2,1, 3-Benzothiadiazol-5-yl) -3- (4-cyclopentyloxy-3,5-dimethoxybenzyl) -4- (4-methoxyphenyl) -4-oxo-2-butenoic acid sodium salt is obtained.
Analog erhält man durch Behandlung der in Beispiel 1 genannten Furan- derivate mit NaOH die Natriumsalze der entsprechenden offenkettigen 4- Oxo-2-butensäurederivate:The sodium salts of the corresponding open-chain 4-oxo-2-butenoic acid derivatives are obtained analogously by treating the furan derivatives mentioned in Example 1 with NaOH:
2-(2,1 ,3-Benzothiadiazol-5-yl)-3-(4-cyclopentyloxy-3,5-dimethoxy- benzyl)-4-(3-fluor-4-methoxyphenyl)-4-oxo-2-butensäure Natriumsalz;2- (2,1, 3-benzothiadiazol-5-yl) -3- (4-cyclopentyloxy-3,5-dimethoxy-benzyl) -4- (3-fluoro-4-methoxyphenyl) -4-oxo-2- butenic acid sodium salt;
2-(2,1 ,3-Benzothiadiazol-5-yl)-3-(4-cyclopentyloxy-3.5-dimethoxy- benzyl)-4-(2,5-methoxyphenyl)-4-oxo-2-butensäure Natriumsalz;2- (2,1, 3-benzothiadiazol-5-yl) -3- (4-cyclopentyloxy-3.5-dimethoxybenzyl) -4- (2,5-methoxyphenyl) -4-oxo-2-butenoic acid sodium salt;
2-(7-Methyl-2,1 ,3-benzothiadiazol-5-yl)-3-(4-cyclopentyloxy-3,5- dimethoxybenzyl)-4-(3-fluor-4-methoxyphenyl)-4-oxo-2-butensäure Natriumsalz;2- (7-methyl-2,1, 3-benzothiadiazol-5-yl) -3- (4-cyclopentyloxy-3,5-dimethoxybenzyl) -4- (3-fluoro-4-methoxyphenyl) -4-oxo 2-butenoic acid sodium salt;
2-(2, 1 ,3-Benzothiadiazol-5-yl)-3-(3-cyclopentyloxy-4.5- dimethoxybenzyl)-4-(4-methoxyphenyl)-4-oxo-2-butensäure Natriumsalz;2- (2, 1, 3-Benzothiadiazol-5-yl) -3- (3-cyclopentyloxy-4.5-dimethoxybenzyl) -4- (4-methoxyphenyl) -4-oxo-2-butenoic acid sodium salt;
2-(2,1 ,3-Benzothiadiazol-5-yl)-3-(3-cyclopropylmethyloxy-4,5- dimethoxybenzyl)-4-(4-methoxyphenyl)-4-oxo-2-butensäure Natriumsalz;2- (2,1, 3-benzothiadiazol-5-yl) -3- (3-cyclopropylmethyloxy-4,5-dimethoxybenzyl) -4- (4-methoxyphenyl) -4-oxo-2-butenoic acid sodium salt;
2-(2, 1 ,3-Benzothiadiazol-5-yl)-3-(4-cyclopropylmethyioxy-3,5- dimethoxybenzyl)-4-(3-fluor-4-methoxyphenyl)-4-oxo-2-butensäure Natriumsalz; 2-(2, 1 ,3-Benzothiadiazol-5-yl)-3-(4-cyclopropylmethyloxy-3,5- dimethoxybenzyl)-4-(2,5-methoxyphenyl)-4-oxo-2-butensäure Natriumsalz und2- (2, 1, 3-Benzothiadiazol-5-yl) -3- (4-cyclopropylmethyioxy-3,5-dimethoxybenzyl) -4- (3-fluoro-4-methoxyphenyl) -4-oxo-2-butenoic acid sodium salt ; 2- (2, 1, 3-Benzothiadiazol-5-yl) -3- (4-cyclopropylmethyloxy-3,5-dimethoxybenzyl) -4- (2,5-methoxyphenyl) -4-oxo-2-butenoic acid sodium salt and
2-(7-Methyl-2,1 ,3-benzothiadiazol-5-yl)-3-(4-cyclopropylmethyloxy- 3,5-dimethoxybenzyl)-4-(3-fluor-4-methoxyphenyl)-4-oxo-2-butensäure2- (7-methyl-2,1, 3-benzothiadiazol-5-yl) -3- (4-cyclopropylmethyloxy-3,5-dimethoxybenzyl) -4- (3-fluoro-4-methoxyphenyl) -4-oxo 2-butenoic acid
Natriumsalz.Sodium salt.
Die nachfolgenden Beispiele betreffen pharmazeutische Zubereitungen:The following examples relate to pharmaceutical preparations:
Beispiel A: InjektionsgläserExample A: Injection glasses
Eine Lösung von 100 g eines Wirkstoffes der Formel I und 5 g Dinatrium- hydrogenphosphat wird in 3 I zweifach destilliertem Wasser mit 2 n Salzsäure auf pH 6,5 eingestellt, steril filtriert, in Injektionsgläser abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jedes Injektionsglas enthält 5 mg Wirkstoff.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.
Beispiel B: SuppositorienExample B: Suppositories
Man schmilzt ein Gemisch von 20 g eines Wirkstoffes der Formel I mit 100 g Sojalecithin und 1400 g Kakaobutter, gießt in Formen und läßt erkalten. Jedes Suppositorium enthält 20 mg Wirkstoff.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.
Beispiel C: LösungExample C: solution
Man bereitet eine Lösung aus 1 g eines Wirkstoffes der Formel I, 9,38 g NaH2PO4 • 2 H2O, 28,48 g Na2HPO4 • 12 H2O und 0,1 g Benzalkonium- chlorid in 940 ml zweifach destilliertem Wasser. Man stellt auf pH 6,8 ein, füllt auf 1 I auf und sterilisiert durch Bestrahlung. Diese Lösung kann in Form von Augentropfen verwendet werden.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.
Beispiel D: SalbeExample D: ointment
Man mischt 500 mg eines Wirkstoffes der Formel I mit 99,5 g Vaseline unter aseptischen Bedingungen. Beispiel E: Tabletten500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions. Example E: tablets
Ein Gemisch von 1 kg Wirkstoff der Formel I, 4 kg Lactose, 1 ,2 kg Kartoffelstärke, 0,2 kg Talk und 0,1 kg Magnesiumstearat wird in üblicher Weise zu Tabletten verpreßt, derart, daß jede Tablette 10 mg Wirkstoff enthält.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.
Beispiel F: DrageesExample F: coated tablets
Analog Beispiel E werden Tabletten gepreßt, die anschließend in üblicher Weise mit einem Überzug aus Saccharose, Kartoffelstärke, Talk, Tragant und Farbstoff überzogen werden.Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
Beispiel G: KapselnExample G: capsules
2 kg Wirkstoff der Formel I werden in üblicher Weise in Hartgelatinekapseln gefüllt, so daß jede Kapsel 20 mg des Wirkstoffs enthält.2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.
Beispiel H: AmpullenExample H: ampoules
Eine Lösung von 1 kg Wirkstoff der Formel I in 60 I zweifach destilliertem Wasser wird steril filtriert, in Ampullen abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jede Ampulle enthält 10 mg Wirkstoff. 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.

Claims

Patentansprücheclaims
1. Verbindungen der Formel I1. Compounds of formula I.
RR
NN
XX
NN
RR
worinwherein
O oder S,O or S,
R1 H, Hai, OA or A,R 1 H, shark, OA or A,
R2, R3, R5, R6 jeweils unabhängig voneinander H, Hai, A, OA oder R4,R 2 , R 3 , R 5 , R 6 each independently of one another H, Hai, A, OA or R 4 ,
R4 -0-(CH2)n-Cy,R 4 -0- (CH 2 ) n -Cy,
Cy Cycloalkyl mit 3-8 C-Atomen,Cy cycloalkyl with 3-8 C atoms,
A Alkyl mit 1-6 C-Atomen, worin eine oder zwei CH2- Gruppen durch O- oder S-Atome oder durch -CR5=CR5'-Gruppen und /oder 1-7 H-Atome durch F ersetzt sein können,A alkyl with 1-6 C atoms, in which one or two CH 2 groups can be replaced by O or S atoms or by -CR 5 = CR 5 ' groups and / or 1-7 H atoms by F. ,
R5 und R5' jeweils unabhängig voneinander H, F oder A, Hai Fluor, Chlor, Brom oder lod,R 5 and R 5 'are each independently of one another H, F or A, Shark fluorine, chlorine, bromine or iodine,
n 0, 1 oder 2n 0, 1 or 2
bedeutet,means
oder eine tautomere ringgeschlossene Form, sowie die (E)-Isomeren und die Salze aller Isomeren.or a tautomeric ring-closed form, as well as the (E) isomers and the salts of all isomers.
2. Verbindungen der Formel I gemäß Anspruch 12. Compounds of formula I according to claim 1
a) 2-(2, 1 ,3-Benzothiadiazol-5-yl)-3-(4-cyciopentyloxy-3,5- dimethoxybenzyl)-4-(4-methoxyphenyl)-4-oxo-2-butensäure; b) 2-(2,1 ,3-Benzothiadiazol-5-yl)-3-(4-cyclopentyloxy-3,5- dimethoxybenzyl)-4-(3-fluor-4-methoxyphenyl)-4-oxo-2- butensäure; c) 3-(2, 1 ,3-Benzothiadiazol-5-yl)-4-(4-cyclopentyloxy-3,5- dimethoxy-benzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan- 2-on; d) 3-(2, 1 ,3-Benzothiadiazol-5-yl)-4-(4-cyclopentyloxy-3,5- dimethoxybenzyl)-5-hydroxy-5-(3-fiuor-4-methoxyphenyl)-5H- furan-2-on; e) 3-(2, 1 ,3-Benzothiadiazol-5-yl)-4-(3-cyclopentyloxy-4,5- dimethoxybenzyl)-5-hydroxy-5-(3-fluor-4-methoxyphenyl)-5H- furan-2-on; f) 3-(7-Methyl-2, 1 ,3-benzothiadiazol-5-yl)-4-(4-cyclopentyloxy- 3,5-dimethoxybenzyl)-5-hydroxy-5-(3-fluor-4-methoxyphenyl)- 5H-furan-2-on;a) 2- (2, 1, 3-Benzothiadiazol-5-yl) -3- (4-cyciopentyloxy-3,5-dimethoxybenzyl) -4- (4-methoxyphenyl) -4-oxo-2-butenoic acid; b) 2- (2,1, 3-Benzothiadiazol-5-yl) -3- (4-cyclopentyloxy-3,5-dimethoxybenzyl) -4- (3-fluoro-4-methoxyphenyl) -4-oxo-2- butenoic acid; c) 3- (2, 1, 3-Benzothiadiazol-5-yl) -4- (4-cyclopentyloxy-3,5-dimethoxy-benzyl) -5-hydroxy-5- (4-methoxyphenyl) -5H-furan 2-one; d) 3- (2, 1, 3-Benzothiadiazol-5-yl) -4- (4-cyclopentyloxy-3,5-dimethoxybenzyl) -5-hydroxy-5- (3-fiuor-4-methoxyphenyl) -5H- furan-2-one; e) 3- (2, 1, 3-Benzothiadiazol-5-yl) -4- (3-cyclopentyloxy-4,5-dimethoxybenzyl) -5-hydroxy-5- (3-fluoro-4-methoxyphenyl) -5H- furan-2-one; f) 3- (7-Methyl-2, 1, 3-benzothiadiazol-5-yl) -4- (4-cyclopentyloxy-3,5-dimethoxybenzyl) -5-hydroxy-5- (3-fluoro-4-methoxyphenyl ) - 5H-furan-2-one;
sowie ihre Salze.as well as their salts.
3. Verfahren zur Herstellung von Verbindungen der Formel I nach Anspruch 1 sowie ihrer Salze, dadurch gekennzeichnet, daß man eine Verbindung der Formel II3. A process for the preparation of compounds of formula I according to claim 1 and their salts, characterized in that a compound of formula II
worin wherein
R1, R5, R6 und X die in Anspruch 1 angegebene Bedeutung haben, und A Alkyl mit 1-4 C-Atomen oder Benzyl bedeutet,R 1 , R 5 , R 6 and X have the meaning given in claim 1, and A denotes alkyl having 1-4 C atoms or benzyl,
mit einer Verbindung der Formel IIIwith a compound of formula III
R'R '
worin wherein
R2, R3, R4 die in Anspruch 1 angegebene Bedeutung haben,R 2 , R 3 , R 4 have the meaning given in claim 1,
umsetzt,implements
und anschließend den Ester spaltet,and then cleaves the ester,
und/oder eine Base oder Säure der Formel I in eines ihrer Salze umwandelt.and / or converts a base or acid of the formula I into one of its salts.
Verfahren zur Herstellung pharmazeutischer Zubereitungen, dadurch gekennzeichnet, daß man eine Verbindung der Formel I nach Anspruch 1 und/oder eines ihrer physiologischen unbedenklichen Salze zusammen mit mindestens einem festen, flüssigen oder halbflüssigen Träger- oder Hilfsstoff in eine geeignete Dosierungsform bringt.Process for the preparation of pharmaceutical preparations, characterized in that a compound of formula I according to Claim 1 and / or one of their physiologically acceptable salts together with at least one solid, liquid or semi-liquid carrier or auxiliary in a suitable dosage form.
5. Pharmazeutische Zubereitung, gekennzeichnet durch einen Gehalt an mindestens einer Verbindung der Formel I nach Anspruch 1 und/oder einem ihrer physiologisch unbedenklichen Salze.5. Pharmaceutical preparation, characterized in that it contains at least one compound of the formula I as claimed in claim 1 and / or one of its physiologically acceptable salts.
6. Verbindungen der Formel I nach Anspruch 1 und ihre physiologisch unbedenklichen Salze zur Bekämpfung von Hypertonie, Herzinsuffizienz, Niereninsuffizienz, Hirninfarkt, koronarer Herzerkrankung, renaler, cerebraler und myocardialer Ischämie, subarachnoidaler Hämorrhagie, Entzündungen, Asthma und endotoxischem Schock.6. Compounds of formula I according to claim 1 and their physiologically acceptable salts for combating hypertension, heart failure, kidney failure, cerebral infarction, coronary heart disease, renal, cerebral and myocardial ischemia, subarachnoid hemorrhage, inflammation, asthma and endotoxic shock.
7. Arzneimittel der Formel I nach Anspruch 1 und ihre physiologisch unbedenklichen Salze als Endothelin-Rezeptor-Antagonisten.7. Medicament of formula I according to claim 1 and their physiologically acceptable salts as endothelin receptor antagonists.
8. Verwendung von Verbindungen der Formel l nach Anspruch 1 und/oder ihre physiologisch unbedenklichen Salze zur Herstellung eines Arzneimittels.8. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts for the manufacture of a medicament.
9. Verwendung von Verbindungen der Formel I nach Anspruch 1 und/oder ihrer physiologisch unbedenklichen Salze bei der Bekämpfung von Hypertonie, Herzinsuffizienz, Niereninsuffizienz,9. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts in the fight against hypertension, heart failure, kidney failure,
Hirninfarkt, koronarer Herzerkrankung, renaler, cerebraler und myocardialer Ischämie, subarachnoidaler Hämorrhagie. Entzündungen, Asthma und endotoxischem Schock. Brain infarction, coronary heart disease, renal, cerebral and myocardial ischemia, subarachnoid hemorrhage. Inflammation, asthma and endotoxic shock.
EP98939552A 1997-07-23 1998-06-29 Benzothia(oxa)diazol derivatives and their use as endothelin-receptor antagonists Withdrawn EP1000044A1 (en)

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DE19731571A DE19731571A1 (en) 1997-07-23 1997-07-23 Endothelin receptor antagonists
DE19731571 1997-07-23
PCT/EP1998/003957 WO1999005132A1 (en) 1997-07-23 1998-06-29 Benzothia(oxa)diazol derivatives and their use as endothelin-receptor antagonists

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EP1130027A1 (en) * 2000-02-29 2001-09-05 Aventis Pharma Deutschland GmbH Memno peptides, process for preparation and use thereof
DE10155076A1 (en) * 2001-11-09 2003-05-22 Merck Patent Gmbh Use of endothelin receptor antagonists for the treatment of tumor diseases

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KR960703901A (en) * 1993-08-19 1996-08-31 로즈 암스트롱 Substituted 2 (5H) furanone, 2 (5H) thiophenone and 2 (5H) pyrrolone derivatives, methods for their preparation and their use as endothelin antagonists (Substituted 2 (5H) Furanone, 2 (5H) Thiophenone and 2 (5H) Pyrrolone Derivatives, Their Preparation and Their Use as Endothelin antagonists)
DE19509950A1 (en) * 1995-03-18 1996-09-19 Merck Patent Gmbh Endothelin receptor antagonists
DE19607096A1 (en) * 1996-02-24 1997-08-28 Merck Patent Gmbh Endothelin receptor antagonists

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TW461887B (en) 2001-11-01
SK512000A3 (en) 2000-07-11
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ZA986551B (en) 1999-09-20
AU8802298A (en) 1999-02-16
NO20000324D0 (en) 2000-01-21
CA2297315A1 (en) 1999-02-04
PL338070A1 (en) 2000-09-25
WO1999005132A1 (en) 1999-02-04
CN1265102A (en) 2000-08-30
KR20010022004A (en) 2001-03-15
AU733338B2 (en) 2001-05-10
HUP0003335A2 (en) 2001-07-30
AR010933A1 (en) 2000-07-12

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