EP1196394A1 - Neue carbonsäurederivate mit 5,6 substituiertem pyrimidinring, ihre herstellung und verwendung als endothelin rezeptorantagonisten - Google Patents

Neue carbonsäurederivate mit 5,6 substituiertem pyrimidinring, ihre herstellung und verwendung als endothelin rezeptorantagonisten

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Publication number
EP1196394A1
EP1196394A1 EP00953009A EP00953009A EP1196394A1 EP 1196394 A1 EP1196394 A1 EP 1196394A1 EP 00953009 A EP00953009 A EP 00953009A EP 00953009 A EP00953009 A EP 00953009A EP 1196394 A1 EP1196394 A1 EP 1196394A1
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Prior art keywords
alkyl
alkoxy
phenyl
alkylthio
hydroxy
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German (de)
English (en)
French (fr)
Inventor
Wilhelm Amberg
Georg Kettschau
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Abbott GmbH and Co KG
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BASF SE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • 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
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
    • 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
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to new carboxylic acid derivatives, their preparation and use.
  • Endothelin is a 21 amino acid peptide that is synthesized and released by vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. In the following, "endothelin” or “ET” denotes one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a strong effect on vascular tone. This vasoconstriction is known to be caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).
  • endothelin causes persistent vascular contraction in peripheral, renal, and cerebral blood vessels, which can lead to disease.
  • endothelin is involved in a number of diseases. These include: hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostate hypertrophy, atherosclerosis, asthma and prostate cancer (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 164 , 2868 (1990), Nature 344, 114 (1990), N. Engl. J. Med. 122, 205 (1989), N. Engl. J. Med.
  • ET ⁇ and ET ß receptor At least two endothelin receptor subtypes, ET ⁇ and ET ß receptor, are currently described in the literature (Nature 348, 730 (1990), Nature 3_48, 732 (1990)). Therefore substances that inhibit the binding of endothelin to one or both receptors should antagonize the physiological effects of endothelin and should therefore be valuable pharmaceuticals.
  • the invention relates to carboxylic acid derivatives of the formula I.
  • R 1 stands for tetrazole or for a group
  • Hydrogen the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically compatible organic ammonium ion such as tertiary C 4 -C 4 alkyl ammonium or the ammonium ion;
  • R 7 may furthermore be a phenyl radical which one to five halogen atoms and / or can carry one to three of the following radicals: nitro, cyano, C 4 -alkyl, C 4 haloalkyl, hydroxy, C: ⁇ C 4 -Alkoxy, mercapto, -CC 4 alkylthio, amino, NH (-C 4 -alkyl), N (-C 4 -alkyl) 2 ; b) a 5-membered heteroaromatic linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which can carry one to two halogen atoms, or one to two C 1 -C 4 alkyl or one to two C 1 -C 4 alkoxy groups;
  • -C-C 4 alkyl C 3 -C 8 cycloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl or phenyl, which can be substituted by one or more, for example one to three of the following radicals : halogen, nitro, cyano, C 4 -alkyl, C 4 haloalkyl, hydroxy, C ⁇ -C 4 -alkoxy, C ⁇ 4 alkylthio, mercapto, amino, NH (C ⁇ -C alkyl), N (-C 4 alkyl) 2 ;
  • R 9 means:
  • Phenyl which can be substituted by one to three of the following radicals: halogen, nitro, cyano, C 1 -C 4 alkyl, C : -C haloalkyl, hydroxy, C 1 -C 4 alkoxy, C 3 -C 4 alkylth .io, mercapto, amino, NH (C ⁇ -C alkyl), N (C ⁇ -C4 alkyl). 2
  • R 2 is hydroxy, NH 2 , NH (-CC alkyl), N (-C 4 alkyl) 2 , -C 4 alkyl,
  • R 3 is hydroxy, NH 2 , NH (-CC alkyl), N (-C ⁇ C 4 alkyl) 2 , halogen, -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C alkynyl , C 3 -C 6 alkenyloxy,
  • R 4 and R 5 (which may be the same or different)
  • Phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, C ⁇ -C 4 -alkyl, C 4 haloalkyl, C ⁇ -C 4 -alkoxy, C 4 - Haloalkoxy, phenoxy, C 1 -C 4 -alkylthio, amino, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2 ; or
  • Phenyl or naphthyl which are linked to one another via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO, NH or N-alkyl group;
  • R 6 is hydrogen
  • Phenyl or naphthyl which in each case by one or more of the following radicals can be substituted halogen, nitro, cyano, hydroxy, amino, C ⁇ -C 4 -alkyl, C 4 haloalkyl, C: -C4 alkoxy, C ⁇ -C 4 -haloalkoxy, phenoxy, -C-C 4 alkylthio, NH (-C 4 alkyl), N (-C 4 alkyl) or dioxo ethylene or dioxoethylene;
  • a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom, which can carry one to four halogen atoms and / or one or two of the following radicals: -CC 4 alkyl, -C-C 4 - haloalkyl, C ⁇ -C 4 -alkoxy, C 4 haloalkoxy, C ⁇ -C 4 alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals or may carry one to three of the following radicals in turn one to five halogen atoms and / a: C ⁇ -C 4 alkyl, -C-C 4 haloalkyl, C ⁇ -C 4 alkoxy, C ⁇ -C haloalkoxy and / or C ⁇ -C 4 alkylthio;
  • R 10 -C 4 alkyl, -C 4 alkylthio, C ! -C 4 -alkoxy which carry one of the following radicals: hydroxy, carboxy, amino, NH (-C-C 4 alkyl), N (-C-C-alkyl) 2 , carboxa id or CON (C ! -C alkyl) ) 2 ;
  • An alkali metal is e.g. Lithium, sodium, potassium;
  • alkaline earth metal is e.g. Calcium, magnesium, barium;
  • Organic ammonium ions are protonated amines such as e.g. Ethanol-a in, diethanolamine, ethylenediamine, diethylamine or piperazine;
  • C 3 -C cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyciohexyl or cycloheptyl;
  • -C-C 4 haloalkyl can be linear or branched such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 2,2, 2-trifluoroethyl, 2-chlorine -2, 2-difluoroethyl, 2, 2-dichloro-2-fluoroethyl, 2, 2, 2-trichloroethyl or pentafluoroethyl;
  • C ⁇ -C 4 haloalkoxy can be linear or branched such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoro-ethoxy, 2, 2-difluoroethoxy, 1, 1, 2, 2-tetrafluoroethoxy, 2,2,2-tri-fluoroethoxy , 2-chloro-l, 1, 2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;
  • C 1 -C 4 -alkyl can be linear or branched, such as methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl;
  • CC 4 -alkenyl can be linear or branched, such as, for example, ethenyl, 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1-butenyl or 2 butenyl;
  • CC 4 ⁇ alkynyl can be linear or branched, such as, for example, ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;
  • C 1 -C 4 -alkoxy can be linear or branched such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1-dimethylethoxy;
  • CC 6 ⁇ alkenyloxy can be linear or branched, for example allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;
  • C 3 -C 6 ⁇ alkynyloxy can be linear or branched, such as 2-propyn-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy;
  • C ⁇ _C 4 alkylthio can be linear or branched such as methyl thio, ethyl thio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1, 1-dimethylethylthio;
  • -C ⁇ C 4 alkylcarbonyl can be linear or branched such as acetyl, ethylcarbonyl or 2-propylcarbonyl;
  • Alkoxycarbonyl can be linear or branched such as
  • C 3 -C 8 -alkylcarbonylalkyl can be linear or branched, for example 2-0xo-prop-l-yl, 3-0xo-but-l-yl or 3-oxo-but-2-yl
  • C 1 -C 8 alkyl can be linear or branched, such as C 1 -C 4 alkyl, pentyl, hexyl, heptyl or octyl;
  • Halogen is e.g. Fluorine, chlorine, bromine, iodine.
  • the invention further relates to those compounds from which the compounds of the formula I can be released (so-called prodrugs). Preference is given to those prodrugs in which the release takes place under conditions which prevail in certain body compartments, for example in the stomach, intestine, bloodstream, liver.
  • the compounds and also the intermediates for their preparation, e.g. II and IV, can have one or more asymmetric substituted carbon atoms.
  • Such compounds can exist as pure enantiomers or pure diastereomers or as a mixture thereof. It is preferred to use an enantiomerically pure compound as the active ingredient.
  • the invention further relates to the use of the above-mentioned carboxylic acid derivatives for the production of medicaments, in particular for the production of inhibitors for endothelin receptors.
  • Compounds of general formula III are either known or can e.g. can be synthesized by reducing the corresponding carboxylic acids or their esters, or by other generally known methods.
  • enantiomerically pure compounds of the formula IV can be obtained by carrying out a classic racemate resolution with suitable enantiomerically pure bases with racemic or diastereomeric compounds of the formula IV.
  • bases are e.g. 4-chlorophenylethylamine and the bases mentioned in WO 96/11914.
  • R 11 is halogen or R 12 -S0 2 -, wherein R 12 is C -C 4 -alkyl, C may be 4 -haloalkyl or phenyl.
  • the reaction preferably takes place in an inert solvent or diluent with the addition of a suitable base, ie a base which brings about a deprotonation of the intermediate IV, in a temperature range from room temperature to the boiling point of the solvent.
  • R : is an ester
  • solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, each of which may optionally be chlorinated, such as, for example, hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichlorethylene, Ethers such as diisopropyl ether, dibutyl ether, methyl tert.
  • chlorinated such as, for example, hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichlorethylene
  • Ethers such as diisopropyl ether, dibutyl ether, methyl tert.
  • nitriles such as, for example, acetonitrile and propionitrile
  • acid amides such as, for example, dimethylformamide, dimethylacetamide and N-methylpyrrolidone
  • sulfoxides and sulfones such as, for example, dimethyl sulfoxide and sulfolane.
  • An alkali or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, for example sodium or potassium carbonate, an alkali or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium or an alkali amide such as lithium diisopropylamide can serve as the base.
  • compounds of the formula I can also be prepared by starting from the salts of the corresponding carboxylic acids, ie from compounds of the formula I in which R 1 represents a group COOM, where M can be an alkali metal cation or the equivalent of an alkaline earth metal cation.
  • R 1 represents a group COOM
  • M can be an alkali metal cation or the equivalent of an alkaline earth metal cation.
  • R 7 -A where A is a customary nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl which may be substituted by halogen, alkyl or haloalkyl, for example Toluenesulfonyl and methylsulfonyl or other equivalent leaving group.
  • the preparation of the compounds I according to the invention requires the use of generally known protective group techniques.
  • R 5 is 4-hydroxyphenyl
  • the hydroxy group can first be protected as a benzyl ether, which is then cleaved at a suitable stage in the reaction sequence.
  • Compounds of the formula I in which R 1 is tetrazole can be prepared as described in WO 96/11914.
  • carboxylic acid derivatives of the general formula I - both as pure enantiomers or pure diastereomers or as a mixture thereof - are preferred, in which the substituents have the following meaning:
  • R 2 hydroxy, N (-CC 4 -alkyl) 2 , C ⁇ -C 4 -alkyl-, -C-C 4 -haloalkyl-, C ⁇ -C -alkoxy-, C ⁇ -C 4 -haloalkoxy-, C ⁇ -C 4 -Alkylthio or CR 2 forms together with CR 3 a 5- or 6-membered alkylene or alkenylene ring, which can be substituted by one or two C ⁇ -C 4 alkyl groups, and in each case one or more methylene groups by oxygen, sulfur , -NH or -N (C ⁇ -C-alkyl) can be replaced;
  • R 3 is hydroxy, N (C -C 4 alkyl) 2 , CC 4 alkyl, C -C haloalkyl, C ⁇ -C alkoxy, C ⁇ -C haloalkoxy, C ⁇ -C alkylthio, halogen or CR 3 forms, as indicated under R 2 , together with CR 2 a 5- or 6-membered ring;
  • R 4 and R 5 are phenyl or naphthyl, which can be substituted by one or more, for example one to three, of the following radicals: halogen, cyano, hydroxy, mercapto, amino, C ⁇ -C 4 -alkyl, C ⁇ -C -haloalkyl, C ⁇ -C 4 alkoxy, C ⁇ -C 4 haloalkoxy, C ⁇ -C alkylthio, NH (C -C 4 alkyl) 2 , N (C -C 4 alkyl) 2 , C ⁇ -C 4 alkylcarbonyl, C - C 4 ⁇ alkoxycarbonyl;
  • Phenyl or naphthyl which are connected to one another via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 2 , NH or N (C ⁇ -C 4 -alkyl) group
  • R 6 C ⁇ -C 3 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl or C 3 -C 8 cycloalkyl, where these radicals can each be substituted one or more times by: halogen, hydroxy, cyano , C ⁇ -C 4 alkoxy, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, C ⁇ -C 4 alkylthio, C ⁇ -C 4 haloalkoxy, C ⁇ -C 4 alkylcarbonyl, hydroxycarbonyl,
  • C ⁇ -C 4 -alkoxycarbonyl NH (C ⁇ -C-alkyl) 2 , N (C ⁇ -C 4 -alkyl) 2 , phenoxy or phenyl, it being possible for the aryl radicals mentioned to be substituted one or more times, for example one to three times by Halogen, C ⁇ -C 4 -alkyl, C ⁇ -C 4 -haloalkyl, C ⁇ -C -alkoxy, C ⁇ -C 4 -haloalkoxy, R 10 , C ⁇ _C 4 _alkoxycarbonyl, dioxomethylene, dioxoethylene, C ⁇ -C 4 -alkylthio phenyl or phenoxy; Phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, C ⁇ -C-alkyl, C ⁇ -C -haloalkyl, C ⁇ ⁇ C-alkoxy
  • a five- or six-membered heteroaro containing one to three nitrogen atoms and / or a sulfur or oxygen atom which can carry one to four halogen atoms and / or one or two of the following radicals: -CC 4 alkyl, C ⁇ -C 4 -Halogenalkyl, C ⁇ -C -alkoxy, C ⁇ -C 4 -haloalkoxy, C ⁇ -C 4 -alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals themselves can carry one to five halogen atoms and / or one to three of the following radicals: C ⁇ -C 4 alkyl, C ⁇ -C 4 haloalkyl, C ⁇ -C 4 alkoxy, C ⁇ -C 4 haloalkoxy and / or C -C alkyl thio;
  • R 10 C ⁇ -C 4 alkyl, C ⁇ -C 4 alkoxy, which carry one of the following radicals: hydroxy, carboxamide or C0N (C ⁇ -C 4 alkyl) 2 ;
  • R 2 C ⁇ -C 4 alkyl, C ⁇ -C 4 alkoxy, especially methyl, ethyl,
  • Methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy or CR 3 forms, as indicated under R 2 , together with CR 2 a 5-membered ring;
  • R 4 and R 5 are phenyl (identical or different), which can be substituted by one or more, for example one to three of the following radicals: halogen, hydroxy, C 1 -C 4 -alkyl, C ⁇ -C 4 -alkoxy, C ⁇ -C 4 alkylthio or R 4 and R 5 are phenyl groups, which are ortho-linked via a direct bond, a methylene, ethylene or ethylene group, an oxygen or sulfur atom or an S0 2 , NH or N (C ⁇ -C 4 -alkyl) group are connected to each other; or
  • R 4 and R 5 are cyclohexyl
  • R 6 C ⁇ -C 8 alkyl, C 3 -C 6 alkenyl or C 3 -C 8 cycloalkyl, where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, cyano, C ⁇ -C 4 alkoxy , C 3 -C 6 -alkenyloxy, C ⁇ -C 4 -alkylthio, phenoxy or phenyl, where the aryl radicals mentioned can be substituted one or more times, for example one to three times by C 1 -C 4 -alkyl, C ⁇ -C 4 -alkoxy, dioxomethylene, dioxoethylene, C ⁇ -C 4 -alkylthio;
  • Phenyl or naphthyl which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, C ⁇ -C 4 -alkyl, C ⁇ -C 4 -haloalkyl, C ⁇ -C 4 -alkoxy, C ⁇ -C -Haloalkoxy, phenoxy, C ⁇ -C 4 -alkylthio, C ⁇ -C -kylamino or C ⁇ -C 4 -dialkylamino;
  • a five- or six-membered heteroaromatic containing a nitrogen atom and / or a sulfur or oxygen atom which can carry one to four halogen atoms and / or one or two of the following radicals: C ⁇ -C 4 -alkyl, C ⁇ -C 4 -haloalkyl, C ⁇ -C alkoxy, C ⁇ -C alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals in turn can carry one to five halogen atoms and / or one to three of the following radicals: C ⁇ -C 4 alkyl, C ⁇ -C -Haloalkyl, C ⁇ -C 4 -alkoxy and / or C ⁇ -C -alkylthio;
  • the compounds of the present invention offer new therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, arrhythmia, acute / chronic kidney failure, chronic heart failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, athma, athma, athma endotoxic shock, endotoxin-induced
  • the invention further relates to combinations of endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotensin system.
  • Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists and angiotensin converting enzyme (ACE) inhibitors.
  • Combinations of endothelin receptor antagonists of the formula I and ACE inhibitors are preferred.
  • the invention further relates to combinations of endothelin receptor antagonists of the formula I and beta-blockers.
  • the invention further relates to combinations of endothelin receptor antagonists of the formula I and diuretics.
  • the invention further relates to combinations of endothelin receptor antagonists of the formula I and substances which block the action of VEGF (vascular endothelial growth factor).
  • VEGF vascular endothelial growth factor
  • substances which block the action of VEGF are, for example, antibodies directed against VEGF or specific binding proteins or also low molecular weight substances which can specifically inhibit VEGF release or receptor binding.
  • the combinations mentioned above can be administered simultaneously or sequentially in time. They can be used both in a single pharmaceutical formulation or in separate formulations.
  • the form of administration can also be different, for example the endothelin receptor antagonists can be administered orally and VEGF inhibitors parenterally.
  • the ET A or ET B receptor expressing CHO cells were in DMEM NUT MIX F 1 medium (Gibco, No. 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022) , 1 mM glutamine (Gibco No. 25030-024), 100 U / ml penicillin and 100 ⁇ g / ml Streptomycin (Gibco, Sigma No. P-0781) increased. After 48 hours, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS at 37 ° C for 5 minutes. The mixture was then neutralized with medium and the cells were collected by centrifugation at 300 ⁇ g.
  • the cells were adjusted to a concentration of 10 8 cells / ml buffer (50 mM Tris-HCl buffer, pH 7.4) and then disintegrated by ultrasound Branson Sonifier 250, 40-70 seconds / constant / output 20).
  • the membranes were incubated in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl 2 ,
  • endothelin antagonists are applied to other preparations in the same vessel 15 min before the endothelin dose-response curve begins.
  • the effects of endothelin are calculated in% of the K + contracture. With effective endothelin antagonists, the endothelin dose-response curve is shifted to the right. Testing the ET antagonists in vivo:
  • test animals were given the test compounds i.V. 30 min before the ETI administration. injected (1 ml / kg). To determine the ET antagonistic properties, the blood pressure changes in the test animals were compared with those in the control animals.
  • mice Male normotonic rats weighing 250-350 g (Sprague Dawley, Jan-four) are orally pretreated with the test substances. 80 minutes later, the animals are anesthetized with urethane and the carotid artery (for measuring blood pressure) and the jugular vein (application of big endothelin / endothelin 1) are catheterized.
  • big endothelin (20 ⁇ g / kg, Appl. Vol. 0.5 ml / kg) or ETI (0.3 ⁇ g / kg, Appl. Vol. 0.5 ml / kg) is given intravenously. Blood pressure and heart rate are continuously recorded over 30 minutes. The significant and persistent changes in blood pressure are calculated as the area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC of the substance-treated animals is compared with the AUC of the control animals.
  • the compounds according to the invention can be administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperotonically). It can also be applied with vapors or sprays through the nasopharynx.
  • the dosage depends on the age, condition and weight of the patient and on the type of application.
  • the daily dose of active substance is between approximately 0.5 and 50 mg / kg body weight when administered orally and between approximately 0.1 and 10 mg / kg body weight when administered parenterally.
  • the new compounds can be used in the customary pharmaceutical application forms in solid or liquid form, for example as tablets, film-coated tablets, capsules, powders, granules, coated tablets, Suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way.
  • the active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et al. : Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1991).
  • the administration forms obtained in this way normally contain the active ingredient in an amount of 0.1 to 90% by weight.
  • the ether phases were extracted with IN KOH, the alkaline water phase again brought to pH 1 with 2N HC1 and extracted again with ether.
  • the ether phases thus obtained were dried over magnesium sulfate, filtered and the solvent removed in vacuo.
  • the yellowish residue (1.2 g) was mixed with 10 ml of diethyl ether for 3 hours at room temperature, then the precipitated solid was filtered off with suction and dried, giving 0.6 g of the target compound.

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EP00953009A 1999-07-20 2000-07-05 Neue carbonsäurederivate mit 5,6 substituiertem pyrimidinring, ihre herstellung und verwendung als endothelin rezeptorantagonisten Withdrawn EP1196394A1 (de)

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DE19933164 1999-07-20
DE19933164A DE19933164A1 (de) 1999-07-20 1999-07-20 Neue Carbonsäurederivate mit 5,6 substituiertem Pyrimidinring, ihre Herstellung und Verwendung als Endothelin Rezeptorantagonisten
PCT/EP2000/006293 WO2001005771A1 (de) 1999-07-20 2000-07-05 Neue carbonsäurederivate mit 5,6 substituiertem pyrimidinring, ihre herstellung und verwendung als endothelin rezeptorantagonisten

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KR (1) KR20020019550A (cs)
CN (1) CN1367778A (cs)
AR (1) AR030026A1 (cs)
AU (1) AU6561500A (cs)
BG (1) BG106321A (cs)
BR (1) BR0012592A (cs)
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SK (1) SK772002A3 (cs)
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AR030026A1 (es) 2003-08-13
DE19933164A1 (de) 2001-01-25
HUP0202646A2 (hu) 2003-02-28
PL353165A1 (en) 2003-10-20
NO20020254D0 (no) 2002-01-17
CN1367778A (zh) 2002-09-04
AU6561500A (en) 2001-02-05
HUP0202646A3 (en) 2003-03-28
BG106321A (en) 2002-08-30
TW555749B (en) 2003-10-01
MXPA02000616A (es) 2002-08-30
BR0012592A (pt) 2002-05-28
ZA200200333B (en) 2003-04-30
NO20020254L (no) 2002-02-20
SK772002A3 (en) 2003-01-09
KR20020019550A (ko) 2002-03-12
WO2001005771A1 (de) 2001-01-25
JP2003505377A (ja) 2003-02-12

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