EP1037883A1 - NOVEL HETEROCYCLICALLY SUBSTITUTED $g(a)-HYDROXYCARBOXLIC ACID DERIVATIVES, METHOD FOR PRODUCING THE SAME AND THEIR USE AS ENDOTHELIN RECEPTOR ANTAGONISTS - Google Patents

NOVEL HETEROCYCLICALLY SUBSTITUTED $g(a)-HYDROXYCARBOXLIC ACID DERIVATIVES, METHOD FOR PRODUCING THE SAME AND THEIR USE AS ENDOTHELIN RECEPTOR ANTAGONISTS

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Publication number
EP1037883A1
EP1037883A1 EP98958900A EP98958900A EP1037883A1 EP 1037883 A1 EP1037883 A1 EP 1037883A1 EP 98958900 A EP98958900 A EP 98958900A EP 98958900 A EP98958900 A EP 98958900A EP 1037883 A1 EP1037883 A1 EP 1037883A1
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Prior art keywords
alkyl
substituted
phenyl
oxygen
sulfur
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EP98958900A
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German (de)
French (fr)
Inventor
Wilhelm Amberg
Rolf Jansen
Heinz Hillen
Stefan Hergenröder
Manfred Raschack
Liliane Unger
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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
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • 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
    • 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
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/12—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/36—One oxygen atom
    • C07D263/38—One oxygen atom attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2

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 Bioche. 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 ____, 2868 (1990), Nature 344, 114 (1990), N. Engl. J. Med. 122, 205 (1989), N. Engl. J. Med.
  • ET A and ET B receptor At least two endothelin receptor subtypes, ET A and ET B receptor, are currently described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990)). Accordingly, 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 task was to provide endothelin receptor antagonists that bind to the ET A and / or the ET B receptor.
  • the invention relates to heterocyclically substituted ⁇ -hydroxycarboxylic 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 1 -C 4 -alkylammonium or the ammonium ion;
  • R 5 can also be a phenyl radical which can carry one to five halogen atoms and / or one to three of the following radicals: nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy, C 1 -C 4 alkoxy , Mercapto, C 1 -C 4 alkylthio, amino, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2 .
  • 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 alkyl or one to two C 1 -C alkoxy groups.
  • a group such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which can carry one to two halogen atoms, or one to two C 1 -C alkyl or one to two C 1 -C alkoxy groups.
  • k can take on the values 0, 1 and 2
  • p can take on the values 1, 2, 3 and 4 and R 6 for
  • -C-C 4 alkyl C 3 -C 8 cycloalkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl or phenyl, which can be mono- to trisubstituted by: halogen, nitro, cyano, C ⁇ -C-alkyl, hydroxy, C ! -C 4 -alkoxy, C alkylthio, amino, NH (C ⁇ -C4 alkyl), N (C ⁇ -C alkyl) 2, mercapto.
  • R 7 means:
  • R 2 and R 3 (which may be the same or different): Phenyl or Nap hyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, C ⁇ -C-alkyl, C 2 -C alkenyl, C 2 -C alkynyl, C ⁇ -C_Halogenalkyl , C ⁇ -C 4 alkoxy, phenoxy, C ⁇ -C 4 haloalkoxy, C ⁇ -C 4 alkylthio, amino, NH (C ⁇ -C 4 alkyl), N (C ⁇ -C 4 alkyl) 2 or phenyl, that C ⁇ -C may be mono- substituted or polysubstituted, for example mono- to trisubstituted by halogen, nitro, cyano, C _ alkyl, C ⁇ -C haloalkyl, C ⁇ -C4-alkoxy, C ⁇ -4 -haloalkoxy or C
  • Phenyl or naphthyl which are ortho-linked 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;
  • C 5 -C 6 cycloalkyl where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 1 -C 4 -alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -alkynyl, -CC alkoxy, -CC 4 -alkylthio, -C 4 -haloalkoxy.
  • R 4 and R 11 (which may be the same or different):
  • CR 4 forms together with CR 11 a 5- or 6-membered alkylene or alkenylene ring, which may optionally be substituted, and in each case one or more methylene groups by oxygen, sulfur, -NH or -N (-CC 4 alkyl ), can be replaced.
  • R 8 is hydrogen, -CC 8 -alkyl, C 3 -C 8 -alkenyl or C 3 -C 8 -alkynyl, -C-C 5 -alkylcarbonyl, where these radicals can each be mono- or polysubstituted by: halogen, hydroxy , Mercapto, carboxy, nitro, amino, cyano, C 1 -C 4 alkoxy, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, C 1 -C 4 alkylthio, C 1 -C 4 haloalkoxy, C ⁇ -C 4 -alkoxycarbonyl, C 3 -C 8 -alkylcarbonyl-alkyl, NHfCx ⁇ -alkyl), N (C ! -C 4 -alkyl) 2 , C 3 -C 8 -cycloalkyl,
  • Phenoxy or phenyl where the aryl radicals mentioned can in turn be mono- or polysubstituted, for example mono- to three times by halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 4 -alkyl, C haloalkyl, C ⁇ -C 4 -alkoxy, C 4 haloalkoxy, amino, NH (C ⁇ -C 4 - Alkyl), N (-CC 4 -alkyl) 2 , phenyl, or -CC 4 -alkylthio;
  • Phenyl or naphthyl each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, C ⁇ -C alkyl, C ⁇ -C 4 haloalkyl, C 1 -C 4 - alkoxy, C ⁇ - C -haloalkoxy, phenoxy, -CC 4 alkylthio, NH (-C 4 alkyl), N (-C 4 alkyl) 2 , dioxomethylene or dioxoethylene;
  • C 8 -C 8 cycloalkyl where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 4 -C 4 alkyl, C 2 -C 4 alkenyl,
  • R 8 forms together with R 9 a to form a ring closed-sene C 3 -C 7 -alkylene chain which may be mono- or polysubstituted with C ⁇ -C 4 -alkyl, C 4 alkylthio, C ⁇ -C 4 -Alkoxy, -C-C 4 haloalkyl, C] _- C 4 haloalkoxy, and in which an alkylene group can be replaced by oxygen or sulfur, such as - (CH2.4-.
  • R 9 is hydrogen, -CC 4 alkyl
  • R 9 is linked to R 8 to form a ring, as indicated under R 8 .
  • R 10 are hydrogen, C 8 alkyl, C 3 -C 8 -alkenyl or C 3 -C 8 alkynyl, where these radicals in each case may be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, amino, cyano, C 4 alkoxy, C 3 -C 6 alkenyloxy, C 3 -CG-alkynyloxy, C ⁇ -C 4 alkylthio, C ⁇ -C4-haloalkoxy, C ⁇ -C 4 alkoxycarbonyl, C 3 - C 8 -alkylcarbonylalkyl, carboxamide, CONH (-C-C 4 -alkyl), CON (C ⁇ -C 4 -alkyl) 2 , CONRiSRie, NH (C ⁇ -C 4 -alkyl), N (C ⁇ -C 4 -alkyl) 2 , C ß -Cs cycloalkyl, heteroaryloxy or hetero
  • Phenyl or naphthyl each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, C ⁇ -C 4 -alkyl, C 4 haloalkyl, C ⁇ -C4 alkoxy, C ⁇ - C 4 haloalkoxy, phenoxy, -C 4 alkylthio, NH (-C 4 alkyl), N (-C 4 alkyl) 2 , dioxomethylene or dioxoethylene;
  • C 3 -Cg cycloalkyl where these radicals can each be mono- to trisubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C -Alkynyl, -C-C 4 alkoxy, -C-C 4 alkylthio, -C-C 4 -haloalkoxy.
  • R 12 is hydrogen, -CC 4 alkyl; or NR 12 forms together with CR 4 a 5- or 6-membered alkylene or alkenylene ring which can be substituted one to three times with C 1 -C 4 -alkyl, and in which one or more methylene groups can be replaced by oxygen or sulfur .
  • R 13 is hydrogen, halogen, -CC 4 alkyl, C 2 -C alkenyl, where these radicals can be substituted with halogen.
  • R 14 is hydrogen, -CC 4 alkyl.
  • R 15 and R 16 together form a closed C 3 -C 7 alkylene or C 4 -C 7 alkenylene chain, to which a phenyl ring is fused, which can be substituted one to three times by halogen, C 1 -C 4 -alkyl, C 4 alkylthio, C 1 -C 4 -alkoxy, C 4 haloalkyl, C ⁇ -C4-haloalkoxy, hydroxy, carboxy, amino.
  • R 19 C ⁇ -C 4 -alkyl, C 4 alkylthio, C! -C 4 -alkoxy, which carry one of the following radicals: hydroxy, carboxy, -C-C 4 -alkoxycarbonyl, amino, NH (-C-C 4 -alkyl), N (-C-C 4 -alkyl) 2 , carboxamide or CON (-C-C 4 alkyl) 2nd
  • An alkali metal is e.g. Lithium, sodium, potassium;
  • An alkaline earth metal is, for example, calcium, magnesium, barium;
  • C 3 -C 8 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
  • C 1 -C 4 -Halogenalkyl 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 1 -C 4 -Halogenalkoxy can be linear or branched such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2, 2-difluoroethoxy, 1, 1, 2, 2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy , 2-chloro-1, 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;
  • C 2 -C 4 alkenyl can be linear or branched, such as, for example, ethenyl, l-propen-3-yl, l-propen-3-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1- Butenyl or 2-butenyl;
  • C 2 -C 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 ⁇ _C 4 alkoxy can be linear or branched such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1-dimethylethoxy;
  • C 3 -C 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 1 -C 4 -Alkylthio can be linear or branched such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1, 1-dimethylethylthio;
  • C 1 -C 4 -alkylcarbonyl can be linear or branched, such as acetyl, ethylcarbonyl or 2-propylcarbonyl;
  • C ⁇ -C 4 alkoxycarbonyl can be linear or branched such as Methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;
  • C 3 -C 8 alkylcarbonylalkyl can be linear or branched, for example 2-oxo-prop-1-yl, 3-oxo-but-1-yl or 3-oxo-but-2-yl;
  • C ⁇ -C 8 alkyl can be linear or branched such as -CC 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).
  • prodrugs in which the release takes place under conditions such as those in certain body compartments, e.g. in the stomach, intestines, bloodstream, liver, predominate.
  • the invention further relates to the use of the abovementioned carboxylic acid derivatives for the production of medicaments, in particular for the production of inhibitors for ET A and ET B receptors.
  • the compounds I and also the intermediates for their preparation, e.g. II, can have one or more asymmetrically substituted carbon atoms.
  • Such compounds can exist as pure enantiomers or pure diastereomers or as a mixture thereof.
  • the use of an enantiomerically pure compound as the active ingredient is preferred.
  • WO 96/11914 can be called.
  • the compounds Ia according to the invention in which A is C 1 -C 4 -alkyl, azido, SR 10 or OR 10 and the other substituents have the meaning given under the general formula I can be prepared, for example, in such a way that the carboxylic acid derivatives of the general formula Ha, in which the substituents have the meaning given, with compounds of the general formula III to react.
  • R 17 is halogen or R 18 -S0 2 , where R 18 can be C 1 -C 4 -alkyl, C ⁇ -C 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 Ha, in a temperature range from room temperature to the boiling point of the solvent.
  • 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.
  • an alkali or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, e.g. 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 metal such as lithium diisopropylamide or lithium amide.
  • Carboxylic acids ie compounds of formula I in which R 1 is a group COOM, where M is an alkali metal cation or can be the equivalent of an alkaline earth metal cation.
  • RW is a conventional nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or, where appropriate, aryl- or alkylsulfonyl substituted by halogen, alkyl or haloalkyl, such as, for example, toluenesulfonyl and methylsulfonyl or another equivalent leaving group.
  • the preparation of the compounds I according to the invention requires the use of generally known protective group techniques.
  • R 10 4-hydroxyphenyl
  • the hydroxy group can first be protected as benzyl ether, which is then cleaved at a suitable stage in the reaction sequence.
  • 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 and R 3 (which may be the same or different):
  • Phenyl or naphthyl which can be substituted by one or more of the following radicals: halogen, cyano,
  • -C 4 alkyl -CC-haloalkyl, -C-C 4 alkoxy, -C-C-haloalkoxy or Cj_-C 4 alkylthio; or Phenyl or naphthyl, which are ortho-bonded via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 2 , NH or N (-C 4 alkyl) group
  • C 5 -C 6 cycloalkyl where these radicals can each be mono- to trisubstituted by: halogen, -CC 4 -alkyl, -C-C 4 -alkoxy, -C-C 4 -alkylthio, -C-C 4 -haloalkoxy .
  • R 4 and R 11 (which may be the same or different):
  • CR 4 forms together with CR 11 a 5- or 6-membered alkylene or alkenylene ring which can be mono- to trisubstituted with C 1 -C 4 -alkyl and in which one to three methylene groups can be replaced by oxygen or sulfur.
  • R 8 is hydrogen, C 1 -C 8 -alkyl, C 1 -C 5 -alkylcarbonyl, where these radicals can each be mono- to trisubstituted by: halogen, hydroxy, carboxy, amino, C 1 -C 4 -alkoxy, Cj_-C 4 - alkyl thio, C ⁇ -C4-haloalkoxy, C ⁇ -C alkoxycarbonyl, NH (C ⁇ -C4 alkyl), N (C 1 -C 4 alkyl) 2, C 5 -C 6 cycloalkyl, phenoxy or phenyl , where the aryl radicals mentioned 4-halo turn may be substituted once to three times by halogen, hydroxy, C ⁇ -C 4 -alkyl, C 4 haloalkyl, C ⁇ -C 4 -alkoxy, C alkoxy, amino, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2 ,
  • Phenyl or naphthyl which can each be mono- to trisubstituted by halogen, hydroxy, amino, C 1 -C 4 -alkyl, C ! -C 4 -haloalkyl, C 1 -C 4 -alkoxy, -C-C 4 -haloalkoxy, phenoxy, Cx-d-alkylthio, NH (C ⁇ -C 4 -alkyl), N (-C-C 4 -alkyl) 2 , Dioxomethylene or dioxoethylene;
  • C 3 -C 8 cycloalkyl where these radicals can each be mono- to trisubstituted by: halogen, C ⁇ -C-alkyl, C ⁇ -C-alkoxy, C ⁇ -C 4 alkylthio, C ⁇ -C-haloalkoxy; or R 8 forms together with R 9 to form a ring closed a C 4 -C 6 -alkylene chain which can be mono- to trisubstituted substituted with C ⁇ -C 4 -alkyl, C 4 haloalkyl, and in which an alkylene group by Oxygen or sulfur can be replaced, such as - (CH 2 ) 4 -, - (CH 2 ) 5 -, - (CH 2 ) 6 -, - (CH 2 ) 2 -0- (CH 2 ) 2 -, - ( CH 2 ) 2 -S- (CH 2 ) 2 -.
  • R 9 is hydrogen, -CC 4 alkyl
  • R 9 is linked to R 8 to form a ring, as indicated under R 8 .
  • R 10 is hydrogen, -CC 8 -alkyl, C 3 -C 8 -alkenyl or C 3 -C 8 -alkynyl, where these radicals can each be mono- to trisubstituted by: halogen, hydroxyl, mercapto, carboxy, amino, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 4 -C 4 -haloalkoxy, C-C 4 -alkoxycarbonyl, carboxamide, CONH (C ⁇ -C 4 -alkyl), CON (C ⁇ -C - alkyl) 2 , CONR 15 R 16 , NH (C 1 -C 4 alkyl), N (-C-C 4 alkyl) 2 , C 5 -C 5 - cycloalkyl, phenoxy or phenyl, the aryl radicals in turn being mono- to trisubstituted can by halogen, hydroxy, -C-C
  • Phenyl or naphthyl which in each case may be substituted one to three times by: halogen, hydroxy, amino, C ⁇ -C 4 -alkyl, C 4 haloalkyl, C ⁇ -C 4 -alkoxy, halogen-C alkoxy, C 1 -C 4 alkylthio, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2 , dioxomethylene or dioxoethylene;
  • R 12 is hydrogen, methyl
  • NR 12 forms a 5- or 6-membered alkyl ring which can be mono- to trisubstituted by methyl.
  • R 13 is hydrogen, halogen, -CC 4 alkyl, where these radicals can be mono- to trisubstituted by halogen.
  • R 14 is hydrogen, methyl.
  • R 15 and R 16 are hydrogen, methyl.
  • R 15 and R 16 together form a closed ring
  • Phenyl ring is annelated, such as 7-aza-bicyclo [4.2.0] -octa-1, 3, 5-triene, 2, 3-dihydroindole, indole,
  • R 19 is methyl, ethyl, methoxy or ethoxy, any of the following
  • R 2 and R 3 (which may be the same or different):
  • Phenyl or naphthyl which in each case may be substituted one to three times by: halogen, hydroxy, C ⁇ -C 4 -alkyl, C 4 haloalkyl, C ⁇ -C 4 -alkoxy, C 4 -haloalkoxy, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2, phenoxy or phenyl which is C ⁇ -C may be substituted up to three times by halogen, 4 -alkyl, C haloalkyl, C ⁇ -C 4 -alkoxy or -CC haloalkoxy; or
  • Phenyl or naphthyl which are ortho-linked via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0, NH or N (-C 4 -alkyl) group;
  • R 4 and R 11 (which may be the same or different): Hydrogen, halogen, -CC 4 alkyl, trifluoromethyl, hydroxymethylene, -C 4 alkoxy, -C 4 alkylthio, N (-C 4 alkyl) 2 ;
  • CR 4 together with CR 11 forms a 5- or 6-membered alkylene or alkenylene ring which can be mono- to disubstituted by methyl and in which one methylene group can be replaced by oxygen;
  • R 8 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 alkylcarbonyl, where these radicals can each be mono- to trisubstituted by: halogen, hydroxy, carboxy, amino, C 1 -C 4 -alkoxy, C 1 -C 4 -Alkylthio, C !
  • Phenyl which can be mono- to trisubstituted by halogen, hydroxy, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, dioxomethylene or dioxoethylene;
  • C 5 -C 6 cycloalkyl where these radicals can each be mono- to trisubstituted by: halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy;
  • R 8 together with R 9 forms a closed CC 6 alkylene chain which can be mono- to trisubstituted with C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and in which an alkylene group can be replaced by oxygen , such as - (CH 2 ) 4 -, - (CH 2 ) 5 -, - (CH 2 ) 6 -, - (CH 2 ) 2 -0- (CH 2 ) 2 -.
  • R 9 is hydrogen, -CC alkyl
  • R 9 is linked to R 8 as a ring under R 8 .
  • R 10 is hydrogen, C 1 -C 4 -alkyl, where these radicals can each be mono- to trisubstituted by: halogen, hydroxy, carboxy, C 1 -C 4 -alkoxy, C ⁇ -C-alkoxycarbonyl, carboxamide, CONH (C ⁇ -C -Alkyl), CON (C ! -C 4 -alkyl) 2 , CONR 15 R 16 ,
  • Phenyl mono- the C ⁇ -C C 1 -C C ⁇ C ⁇ -C-C may be substituted up to three times by halogen, hydroxy, 4 alkyl, 4 haloalkyl, 4 alkoxy, 4 alkylthio, NH (C ⁇ -C alkyl ), N (-C 4 alkyl) 2 , dioxomethylene or dioxoethylene;
  • R 13 is hydrogen, halogen, -CC 4 alkyl, trifluoromethyl.
  • R 15 and R 16 together form a C 3 -C 7 alkylene chain which is closed to a ring and to which a phenyl ring is fused, such as 2, 3-dihydroindole, indole, 1, 3-dihydroisoindole, 1, 2, 3, 4- Tetra-hydroquinoline, 1, 2, 3, 4-tetrahydroisoquinoline, where the phenyl ring can be substituted one to three times by halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy;
  • R 19 methoxy or ethoxy, which carry one of the following radicals: hydroxy, carboxy, -CC 4 alkoxycarbonyl, amino, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2 , carboxamide or CON (-C 4 alkyl) 2 .
  • 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, atheros - toxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and by-pass surgery, benign prostate hyperplasia, ischemic and intoxication-related kidney failure or hypertension, metastasis and growth of mesenchymal tumors such as prostate cancer, contrast agents induced kidney failure, pancreatitis, gastrointestinal ulcers.
  • 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 calcium antagonists such as verapamil.
  • 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 application form 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 12 medium (Gibco, No. 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022) , 1 M 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. After that, with medium neutralized and the cells collected by centrifugation at 300 xg.
  • the cells were adjusted to a concentration of 10 8 cells / ml buffer (50 M 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 , 40 mg / ml bacitracin and 0.2% BSA) in a concentration of 50 ⁇ g Protein suspended per test batch and incubated at 25 ° C with 25 pM [125J] ETi (ET A receptor test) or 25 pM [125J] -ET 3 (ET B receptor test) in the presence and absence of test substance.
  • the non-specific binding was determined to be 10 ⁇ 7 ME i.
  • 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.
  • 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, intraperitoneally). 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 100 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, solid or liquid, e.g. as tablets, film-coated tablets, capsules, powders, granules, dragees, 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.

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Abstract

The invention relates to carboxylic acid derivatives of formula (I) wherein A represents NR<8>R<9>, azido, OR<10>, SR<10> or C1-C4 alkyl, R<1> represents tetrazole or a group (1), wherein R has the following meaning: a) a radical OR<5>; b) a 5-membered heteroaromat bonded by a nitrogen atom; c) a group (2); d) a radical (3), and the remaining substituents have the meanings given in the description. The invention also relates to production of the inventive derivatives and to their use as endothelin receptor antagonists.

Description

Neue heterocyclisch substituierte α-Hydroxycarbonsäurederivate, ihre Herstellung und Verwendung als Endothelinrezeptorantago- nistenNew heterocyclically substituted α-hydroxycarboxylic acid derivatives, their production and use as endothelin receptor antagonists
Beschreibungdescription
Die vorliegende Erfindung betrifft neue Carbonsäurederivate, deren Herstellung und Verwendung.The present invention relates to new carboxylic acid derivatives, their preparation and use.
Endothelin ist ein aus 21 Aminosäuren aufgebautes Peptid, das von vaskulärem Endothel synthetisiert und freigesetzt wird. Endothelin existiert in drei Isoformen, ET-1, ET-2 und ET-3. Im folgenden bezeichnet "Endothelin" oder "ET" eine oder alle Iso- formen von Endothelin. Endothelin ist ein potenter Vasokonstrik- tor und hat einen starken Effekt auf den Gefäßtonus. Es ist bekannt, daß diese Vasokonstriktion von der Bindung von Endothelin an seinen Rezeptor verursacht wird (Nature, 332 , 411-415, 1988; FEBS Letters, 231, 440-444, 1988 und Bioche . Biophys. Res. Commun., 154, 868-875, 1988).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 Bioche. Biophys. Res. Commun., 154, 868-875, 1988).
Erhöhte oder abnormale Freisetzung von Endothelin verursacht eine anhaltende Gefäßkontraktion in peripheren, renalen und zerebralen Blutgefäßen, die zu Krankheiten führen kann. Wie in der Literatur berichtet, ist Endothelin in einer Reihe von Krankheiten invol- viert. Dazu zählen: Hypertonie, akuter Myokardinfarkt, pulmonäre Hypertonie, Raynaud Syndrom, zerebrale Vasospasmen, Schlaganfall, benigne Prostatahypertrophie, Atherosklerose, Asthma und Prostatakrebs (J. Vascular Med. Biology 2 , 207 (1990), J. Am. Med. As- sociation ____, 2868 (1990), Nature 344. 114 (1990), N. Engl. J. Med. 122, 205 (1989), N. Engl. J. Med. ____, 1732 (1993), Nephron __ , 373 (1994), Stroke 25» 904 (1994), Nature , 759 (1993), J. Mol. Cell. Cardiol. 21, A234 (1995); Cancer Research __\, 663 (1996), Nature Medicine 1, 944,(1995)).Increased or abnormal release of endothelin causes persistent vascular contraction in peripheral, renal, and cerebral blood vessels, which can lead to disease. As reported in the literature, 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 ____, 2868 (1990), Nature 344, 114 (1990), N. Engl. J. Med. 122, 205 (1989), N. Engl. J. Med. ____, 1732 (1993), Nephron __, 373 ( 1994), Stroke 25: 904 (1994), Nature, 759 (1993), J. Mol. Cell. Cardiol. 21, A234 (1995); Cancer Research __ \, 663 (1996), Nature Medicine 1, 944, ( 1995)).
Mindestens zwei Endothelinrezeptorsubtypen, ETA- und ETB Rezeptor, werden zur Zeit in der Literatur beschrieben (Nature 348. 730 (1990), Nature 348, 732 (1990)). Demnach sollten Substanzen, die die Bindung von Endothelin an einen oder an beide Rezeptoren in- hibieren, physiologische Effekte von Endothelin antagonisieren und daher wertvolle Pharmaka darstellen.At least two endothelin receptor subtypes, ET A and ET B receptor, are currently described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990)). Accordingly, 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.
Es bestand die Aufgabe, Endothelinrezeptorantagonisten bereitzustellen, die an den ETA- und/oder den ETB-Rezeptor binden. Gegenstand der Erfindung sind heterocyclisch substituierte α-Hy- droxycarbonsäurederivate der Formel IThe task was to provide endothelin receptor antagonists that bind to the ET A and / or the ET B receptor. The invention relates to heterocyclically substituted α-hydroxycarboxylic acid derivatives of the formula I.
wobei R1 steht für Tetrazol oder für eine Gruppewhere R 1 stands for tetrazole or for a group
0 II0 II
C —R in der R folgende Bedeutung hat:C —R in which R has the following meaning:
a) ein Rest OR5, worin R5 bedeutet:a) a radical OR 5 , in which R 5 denotes:
Wasserstoff, das Kation eines Alkalimetalls, das Kation eines Erdalkalimetalls, ein physiologisch verträgliches organisches Ammoniumion wie tertiäres Cι-C-Alkylammonium oder das Ammoniumion;Hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically compatible organic ammonium ion such as tertiary C 1 -C 4 -alkylammonium or the ammonium ion;
C3-C8-Cycloalkyl, Ci-Cg-Alkyl, CH2-Phenyl, das durch einen oder mehrere der folgenden Reste substituiert sein kann: Halogen, Nitro, Cyano, Cι-C-Alkyl, Cι-C-Halogenalkyl, Hydroxy, Cι-C-Alkoxy, Mercapto, Cι-C-Alkylthio, A ino, NH(Cι-C4-Alkyl) , N(Cι~C4-Alkyl ) 2;C 3 -C 8 cycloalkyl, Ci-Cg-alkyl, CH 2 -phenyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, -C-C-alkyl, -C-C-haloalkyl, hydroxy , -C -C alkoxy, mercapto, -C -C alkylthio, A ino, NH (-C -C 4 alkyl), N (-C ~ C 4 alkyl) 2 ;
eine C3-C8-Alkenyl - oder eine C3-C8-Alkinylgruppe, wobei diese Gruppen ihrerseits ein bis fünf Halogenatome tragen können;a C 3 -C 8 alkenyl or a C 3 -C 8 alkynyl group, these groups in turn being able to carry one to five halogen atoms;
R5 kann weiterhin ein Phenylrest sein, welcher ein bis fünf Halogenatome und/oder ein bis drei der folgenden Reste tragen kann: Nitro, Cyano, Cι-C-Alkyl, Cι-C4-Halogenalkyl, Hydroxy, Cι-C4-Alkoxy, Mercapto, Cι-C-Alkylthio, Amino, NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl ) 2.R 5 can also be a phenyl radical which can carry one to five halogen atoms and / or one to three of the following radicals: nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy, C 1 -C 4 alkoxy , Mercapto, C 1 -C 4 alkylthio, amino, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2 .
b) ein über ein Stickstoffatom verknüpfter 5 gliedriger Heteroaromat wie Pyrrolyl, Pyrazolyl, Imidazolyl und Triazolyl, welcher ein bis zwei Halogenatome, oder eins bis zwei Cι-C- Alkyl oder eins bis zwei Cι-C-Alkoxygruppen tragen kann. c) eine Gruppeb) 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 alkyl or one to two C 1 -C alkoxy groups. c) a group
in der k die Werte 0, 1 und 2, p die Werte 1, 2, 3 und 4 an- nehmen kann und R6 fürin which k can take on the values 0, 1 and 2, p can take on the values 1, 2, 3 and 4 and R 6 for
Cι-C4-Alkyl, C3-C8-Cycloalkyl , C3-C8-Alkenyl, C3-C8-Alkinyl oder Phenyl steht, der ein- bis dreifachsubstituiert sein kann durch: Halogen, Nitro, Cyano, Cχ-C-Alkyl, Hydroxy, C!-C4-Alkoxy, Cι-C-Alkylthio, Amino, NH(Cι-C4-Alkyl) , N(Cι-C -Alkyl)2, Mercapto.-C-C 4 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl or phenyl, which can be mono- to trisubstituted by: halogen, nitro, cyano, Cχ -C-alkyl, hydroxy, C ! -C 4 -alkoxy, C alkylthio, amino, NH (Cι-C4 alkyl), N (Cι-C alkyl) 2, mercapto.
d) ein Restd) a rest
00
IIII
—N S R7 —NSR 7
HH
OO
worin R7 bedeutet:where R 7 means:
Cι-C-Alkyl, C3-C8-Alkenyl, C3-C8-Alkinyl, C3-C8-Cycloalkyl, wo- bei diese Reste einen Cι-C-Alkoxy, Cχ-C-Alkylthio- und/oder einen Phenylrest wie unter c) genannt tragen können;C 1 -C 8 -alkyl, C 3 -C 8 -alkenyl, C 3 -C 8 -alkynyl, C 3 -C 8 -cycloalkyl, these radicals being a C 1 -C 8 -alkoxy, Cχ-C-alkylthio and / or can carry a phenyl radical as mentioned under c);
Cι-C-Halogenalkyl oder Phenyl, der wie unter c) genannt substituiert sein kann.-C-C-haloalkyl or phenyl, which can be substituted as mentioned under c).
Die übrigen Substituenten haben die folgende Bedeutung:The other substituents have the following meaning:
A NR8R9, Azido, ORiO, SRio oder Cx-C-Alkyl.A NR8R9, Azido, ORiO, SRio or C x -C alkyl.
X Sauerstoff, Schwefel, CR11 oder NR12; mit der Maßgabe, falls X = CR11, dann Y = Sauerstoff oder Schwefel oder NR14.X is oxygen, sulfur, CR 11 or NR 12 ; with the proviso that if X = CR 11 , then Y = oxygen or sulfur or NR 14 .
Y Sauerstoff, Schwefel, CR13 oder NR14; mit der Maßgabe, falls Y = Sauerstoff oder Schwefel oder NR14, dann X = CR11.Y is oxygen, sulfur, CR 13 or NR 14 ; with the proviso that if Y = oxygen or sulfur or NR 14 , then X = CR 11 .
R2 und R3 (die gleich oder verschieden sein können) : Phenyl oder Nap hyl , die durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, Nitro, Cyano, Hydroxy, Mercapto, Cχ-C-Alkyl, C2-C-Alkenyl , C2-C-Alkinyl , Cι-C_Halogenalkyl, Cχ-C4-Alkoxy, Phenoxy, Cι-C4-Halogenalkoxy, Cι-C4-Alkylthio, Amino, NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl ) 2 oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, Cι_C-Alkyl, Cι-C -Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy oder Cι-C-Alkylthio; oderR 2 and R 3 (which may be the same or different): Phenyl or Nap hyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, Cχ-C-alkyl, C 2 -C alkenyl, C 2 -C alkynyl, Cι-C_Halogenalkyl , Cχ-C 4 alkoxy, phenoxy, Cι-C 4 haloalkoxy, Cι-C 4 alkylthio, amino, NH (Cι-C 4 alkyl), N (Cι-C 4 alkyl) 2 or phenyl, that Cι-C may be mono- substituted or polysubstituted, for example mono- to trisubstituted by halogen, nitro, cyano, C _ alkyl, Cι-C haloalkyl, Cι-C4-alkoxy, Cι-4 -haloalkoxy or C Alkylthio; or
Phenyl oder Naphthyl, die orthoständig über eine direkte Bindung, eine Methylen-, Ethylen- oder Ethenylengruppe, ein Sauerstoff- oder Schwefelatom oder eine S02 , NH oder N(Cχ- C4-Alkyl) -Gruppe miteinander verbunden sind;Phenyl or naphthyl, which are ortho-linked via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 2 , NH or N (Cχ-C 4 -alkyl) group;
C5-C6 Cycloalkyl, wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Halogen, Hydroxy, Mercapto, Carboxy, Nitro, Cyano, Cι-C-Alkyl, C2-C4-Alkenyl, C2-C4-Alkinyl, Cι-C -Alkoxy, Cι-C4-Alkylthio, Cι-C4-Halogen- alkoxy.C 5 -C 6 cycloalkyl, where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 1 -C 4 -alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -alkynyl, -CC alkoxy, -CC 4 -alkylthio, -C 4 -haloalkoxy.
R4 und R11 (die gleich oder verschieden sein können) :R 4 and R 11 (which may be the same or different):
Wasserstoff, Halogen, Cι-C-Alkoxy, Cι-C4-Halogenalkoxy, C3-C6- Alkenyloxy, C3-C6-Alkinyloxy, Cι-C4-Alkylthio,Hydrogen, halogen, -C-alkoxy, -C-C 4 -haloalkoxy, C 3 -C 6 -alkenoxy, C 3 -C 6 -alkynyloxy, -C-C 4 -alkylthio,
Cι-C4-Alkylcarbonyl, Cχ-C-Alkoxycarbonyl, Hydroxy, NH2, NH(Cι-C -Alkyl) , N(Cι-C4-Alkyl ) 2 C 1 -C 4 -alkylcarbonyl, Cχ-C-alkoxycarbonyl, hydroxy, NH 2 , NH (Cι-C-alkyl), N (Cι-C 4 alkyl) 2
Cι-C4-Alkyl, C2-C4-Alkenyl, C2-C-Alkinyl, wobei diese Reste substituiert sein können durch Halogen, Hydroxy, Mercapto, Carboxy, Cyano;C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C -alkynyl, where these radicals can be substituted by halogen, hydroxy, mercapto, carboxy, cyano;
oder CR4 bildet zusammen mit CR11 einen 5- oder 6-gliedrigen Alkylen- oder Alkenylenring, der gegebenenfalls substituiert sein kann, und worin jeweils eine oder mehrere Methylengruppen durch Sauerstoff, Schwefel, -NH oder -N(Cι-C4-Alkyl) , ersetzt sein können.or CR 4 forms together with CR 11 a 5- or 6-membered alkylene or alkenylene ring, which may optionally be substituted, and in each case one or more methylene groups by oxygen, sulfur, -NH or -N (-CC 4 alkyl ), can be replaced.
R8 Wasserstoff, Cι-C8-Alkyl, C3-C8-Alkenyl oder C3-C8-Alkinyl, Cι-C5-Alkylcarbonyl, wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Halogen, Hydroxy, Mercapto, Carboxy, Nitro, Amino, Cyano, Cι-C4-Alkoxy, C3-C6-Alkenyloxy, C3-C6-Alkinyloxy, Cι-C4-Alkylthio, Cι-C-Halogenalkoxy, Cι-C4-Alkoxycarbonyl, C3-C8-Alkylcarbonyl- alkyl, NHfCx^-Alkyl) , N(C!-C4-Alkyl ) 2, C3-C8-Cycloalkyl,R 8 is hydrogen, -CC 8 -alkyl, C 3 -C 8 -alkenyl or C 3 -C 8 -alkynyl, -C-C 5 -alkylcarbonyl, where these radicals can each be mono- or polysubstituted by: halogen, hydroxy , Mercapto, carboxy, nitro, amino, cyano, C 1 -C 4 alkoxy, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, C 1 -C 4 alkylthio, C 1 -C 4 haloalkoxy, Cι-C 4 -alkoxycarbonyl, C 3 -C 8 -alkylcarbonyl-alkyl, NHfCx ^ -alkyl), N (C ! -C 4 -alkyl) 2 , C 3 -C 8 -cycloalkyl,
Phenoxy oder Phenyl, wobei die genannten Arylreste ihrerseits ein- oder mehrfach substituiert sein können, z.B. ein- bis dreifach durch Halogen, Hydroxy, Mercapto, Carboxy, Nitro, Cyano, Cι-C4-Alkyl, Cι-C -Halogenalkyl , Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy, Amino, NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl) 2, Phenyl, oder Cι-C4-Alkylthio;Phenoxy or phenyl, where the aryl radicals mentioned can in turn be mono- or polysubstituted, for example mono- to three times by halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 4 -alkyl, C haloalkyl, Cι-C 4 -alkoxy, C 4 haloalkoxy, amino, NH (Cι-C 4 - Alkyl), N (-CC 4 -alkyl) 2 , phenyl, or -CC 4 -alkylthio;
Phenyl oder Naphthyl, die jeweils durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, Nitro, Cyano, Hydroxy, Amino, Cι-C-Alkyl, Cι-C4-Halogenalkyl, C1-C4- Alkoxy, Cι-C -Halogenalkoxy, Phenoxy, Cι-C4-Alkylthio, NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl ) 2, Dioxomethylen oder Dioxo- ethylen;Phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, Cι-C alkyl, Cι-C 4 haloalkyl, C 1 -C 4 - alkoxy, Cι- C -haloalkoxy, phenoxy, -CC 4 alkylthio, NH (-C 4 alkyl), N (-C 4 alkyl) 2 , dioxomethylene or dioxoethylene;
C -C8-Cycloalkyl, wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Halogen, Hydroxy, Mercapto, Carboxy, Nitro, Cyano, Cχ-C4-Alkyl, C2-C4-Alkenyl,C 8 -C 8 cycloalkyl, where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 4 -C 4 alkyl, C 2 -C 4 alkenyl,
C2-C -Alkinyl, Cι-C -Alkoxy, d-C4-Alkylthio, Cι-C4-Halogen- alkoxy;C 2 -C 4 -alkynyl, C 1 -C 4 -alkoxy, dC 4 -alkylthio, C 1 -C 4 -haloalkoxy;
oder R8 bildet gemeinsam mit R9 eine zu einem Ring geschlos- sene C3-C7-Alkylenkette, die ein- oder mehrfach substituiert sein kann mit Cι-C4-Alkyl, Cι-C4-Alkylthio, Cι-C4-Alkoxy, Cι-C4-Halogenalkyl, C]_-C4-Halogenalkoxy, und in der eine Alkylengruppe durch Sauerstoff oder Schwefel ersetzt sein kann, wie -(CH2.4-. -(CH2)5-, -(CH )6-, -(CH2)7-, -(CH2)2-0-(CH2)2-, -(CH2)2-S-(CH2)2-.or R 8 forms together with R 9 a to form a ring closed-sene C 3 -C 7 -alkylene chain which may be mono- or polysubstituted with Cι-C 4 -alkyl, C 4 alkylthio, Cι-C 4 -Alkoxy, -C-C 4 haloalkyl, C] _- C 4 haloalkoxy, and in which an alkylene group can be replaced by oxygen or sulfur, such as - (CH2.4-. - (CH 2 ) 5 -, - ( CH) 6 -, - (CH 2 ) 7 -, - (CH 2 ) 2 -0- (CH 2 ) 2-, - (CH 2 ) 2 -S- (CH 2 ) 2 -.
R9 Wasserstoff, Cι-C4-Alkyl;R 9 is hydrogen, -CC 4 alkyl;
oder R9 ist wie unter R8 angegeben mit R8 zu einem Ring ver- knüpft.or R 9 is linked to R 8 to form a ring, as indicated under R 8 .
R10 Wasserstoff, Cι-C8-Alkyl, C3-C8-Alkenyl oder C3-C8-Alkinyl, wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Halogen, Hydroxy, Mercapto, Carboxy, Nitro, Amino, Cyano, Cι-C4-Alkoxy, C3-C6-Alkenyloxy, C3-Cg-Alkinyloxy, Cι-C4-Alkylthio, Cι-C4-Halogenalkoxy, Cι-C4-Alkoxycarbonyl , C3-C8-Alkylcarbonylalkyl, Carboxamid, CONH(Cι-C4-Alkyl) , CON(Cι-C4-Alkyl)2, CONRiSRie, NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl ) 2, Cß-Cs-Cycloalkyl, Heteroaryloxy oder Heteroaryl, fünf- oder sechsgliedrig, enthaltend ein bis drei Stickstoffatome und/ oder ein Schwefel- oder Sauerstoffatom, Phenoxy oder Phenyl, wobei alle genannten Arylreste ihrerseits ein- oder mehrfach substituiert sein können, z.B. ein- bis dreifach durch Halogen, Hydroxy, Mercapto, Carboxy, Nitro, Cyano, Cι-C-Alkyl, Cι-C4-Alkylcarboxy, R19, Cι-C-Halogenalkyl, Cι-C -Alkoxy, Cι-C4-Halogenalkoxy, Amino, NH(Cι-C4-Alkyl) , N(Cι-C -Alkyl ) 2, Phenyl, oder Cι-C4-Alkylthio;R 10 are hydrogen, C 8 alkyl, C 3 -C 8 -alkenyl or C 3 -C 8 alkynyl, where these radicals in each case may be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, amino, cyano, C 4 alkoxy, C 3 -C 6 alkenyloxy, C 3 -CG-alkynyloxy, Cι-C 4 alkylthio, Cι-C4-haloalkoxy, Cι-C 4 alkoxycarbonyl, C 3 - C 8 -alkylcarbonylalkyl, carboxamide, CONH (-C-C 4 -alkyl), CON (Cι-C 4 -alkyl) 2 , CONRiSRie, NH (Cι-C 4 -alkyl), N (Cι-C 4 -alkyl) 2 , C ß -Cs cycloalkyl, heteroaryloxy or heteroaryl, five- or six-membered, containing one to three nitrogen atoms and / or a sulfur or oxygen atom, phenoxy or phenyl, where all said aryl radicals can in turn be substituted one or more times, for example one - up to three times by halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkylcarboxy, R 19 , C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, Cι-C 4 haloalkoxy, amino, NH (Cι-C4 alkyl), N (Cι-C alkyl) 2, phenyl, or Cι-C 4 alkylthio;
Phenyl oder Naphthyl, die jeweils durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, Nitro, Cyano, Hydroxy, Amino, Cι-C4-Alkyl, Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy, Phenoxy, Cι-C4-Alkylthio, NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl ) 2, Dioxomethylen oder Dioxo- ethylen;Phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, Cι-C 4 -alkyl, C 4 haloalkyl, Cι-C4 alkoxy, Cι- C 4 haloalkoxy, phenoxy, -C 4 alkylthio, NH (-C 4 alkyl), N (-C 4 alkyl) 2 , dioxomethylene or dioxoethylene;
C3-Cg-Cycloalkyl, wobei diese Reste jeweils ein- bis dreifach substituiert sein können durch: Halogen, Hydroxy, Mercapto, Carboxy, Nitro, Cyano, Cι-C-Alkyl, C2-C4-Alkenyl, C2-C-Alkinyl, Cι-C4-Alkoxy, Cι-C4-Alkylthio, Cι-C4-Halogen- alkoxy.C 3 -Cg cycloalkyl, where these radicals can each be mono- to trisubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C -Alkynyl, -C-C 4 alkoxy, -C-C 4 alkylthio, -C-C 4 -haloalkoxy.
R12 Wasserstoff, Cι-C4-Alkyl; oder NR12 bildet zusammen mit CR4 einen 5- oder 6-gliedrigen Alkylen- oder Alkenylenring, der ein- bis dreifach mit Cι-C4-Alkyl substituiert sein kann, und worin jeweils eine oder mehrere Methylengruppen durch Sauerstoff oder Schwefel ersetzt sein können.R 12 is hydrogen, -CC 4 alkyl; or NR 12 forms together with CR 4 a 5- or 6-membered alkylene or alkenylene ring which can be substituted one to three times with C 1 -C 4 -alkyl, and in which one or more methylene groups can be replaced by oxygen or sulfur .
R13 Wasserstoff, Halogen, Cι-C4-Alkyl, C2-C-Alkenyl, wobei diese Reste mit Halogen substituiert sein können.R 13 is hydrogen, halogen, -CC 4 alkyl, C 2 -C alkenyl, where these radicals can be substituted with halogen.
R14 Wasserstoff, Cι-C4-Alkyl .R 14 is hydrogen, -CC 4 alkyl.
R15 und Riß;R 15 and crack;
R15 und R16 bilden gemeinsam eine zu einem Ring geschlossene C3-C7-Alkylen- oder C4-C7-Alkenylenkette, an die ein Phenylring anneliiert ist, der ein bis dreifach substituiert sein kann durch Halogen, Cι-C4-Alkyl, Cι-C4-Alkylthio, C1-C4-Alkoxy, Cι-C4-Halogenalkyl, Cι-C4-Halogenalkoxy, Hydroxy, Carboxy, Amino.R 15 and R 16 together form a closed C 3 -C 7 alkylene or C 4 -C 7 alkenylene chain, to which a phenyl ring is fused, which can be substituted one to three times by halogen, C 1 -C 4 -alkyl, C 4 alkylthio, C 1 -C 4 -alkoxy, C 4 haloalkyl, Cι-C4-haloalkoxy, hydroxy, carboxy, amino.
R19 Cι-C4-Alkyl, Cι-C4-Alkylthio, C!-C4-Alkoxy, die einen der folgenden Reste tragen: Hydroxy, Carboxy, Cι-C4-Alkoxycarbonyl, Amino, NH(Cι-C4-Alkyl) , N(Cι-C4-Alykl) 2, Carboxamid oder CON(Cι-C4-Alkyl)2.R 19 Cι-C 4 -alkyl, C 4 alkylthio, C! -C 4 -alkoxy, which carry one of the following radicals: hydroxy, carboxy, -C-C 4 -alkoxycarbonyl, amino, NH (-C-C 4 -alkyl), N (-C-C 4 -alkyl) 2 , carboxamide or CON (-C-C 4 alkyl) 2nd
Hierbei und im weiteren gelten folgende Definitionen:The following definitions apply here and below:
Ein Alkalimetall ist z.B. Lithium, Natrium, Kalium;An alkali metal is e.g. Lithium, sodium, potassium;
Ein Erdalkalimetall ist z.B. Calcium, Magnesium, Barium; C3-C8-Cycloalkyl ist z.B. Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl oder Cyclooctyl;An alkaline earth metal is, for example, calcium, magnesium, barium; C 3 -C 8 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
Cι-C4-Halogenalkyl kann linear oder verzweigt sein wie z.B. Fluormethyl, Difluormethyl, Trifluormethyl , Chlordifluormethyl , Dichlorfluormethyl, Trichlormethyl , 1-Fluorethyl, 2-Fluorethyl, 2,2-Difluorethyl, 2 , 2, 2-Trifluorethyl, 2-Chlor 2 , 2-difluorethyl, 2, 2-Dichlor-2-fluorethyl, 2 , 2 , 2-Trichlorethyl oder Pentafluorethyl ;C 1 -C 4 -Halogenalkyl 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;
Cι-C4-Halogenalkoxy kann linear oder verzweigt sein wie z.B. Difluormethoxy, Trifluormethoxy, Chlordifluormethoxy, 1-Fluor- ethoxy, 2 , 2-Difluorethoxy, 1, 1, 2 , 2-Tetrafluorethoxy, 2,2,2-Tri- fluorethoxy, 2-Chlor-1, 1, 2-trifluorethoxy, 2-Fluorethoxy oder Pentafluorethoxy;C 1 -C 4 -Halogenalkoxy can be linear or branched such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2, 2-difluoroethoxy, 1, 1, 2, 2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy , 2-chloro-1, 1, 2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;
Cι-C4-Alkyl kann linear oder verzweigt sein wie z.B. Methyl, Ethyl, 1-Propyl, 2-Propyl, 2-Methyl-2-propyl, 2- Methyl-1-propyl, 1-Butyl oder 2-Butyl;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;
C2-C4-Alkenyl kann linear oder verzweigt sein wie z.B. Ethenyl, l-Propen-3-yl, l-Propen-3-yl, 1-Propen-1-yl, 2-Methyl-1-propenyl, 1-Butenyl oder 2-Butenyl;C 2 -C 4 alkenyl can be linear or branched, such as, for example, ethenyl, l-propen-3-yl, l-propen-3-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1- Butenyl or 2-butenyl;
C2-C4-Alkinyl kann linear oder verzweigt sein wie z.B. Ethinyl, 1-Propin-l-yl, l-Propin-3-yl, l-Butin-4-yl oder 2-Butin-4-yl;C 2 -C 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;
Cι_C4-Alkoxy kann linear oder verzweigt sein wie z.B. Methoxy, Ethoxy, Propoxy, 1-Methylethoxy, Butoxy, 1-Methylpropoxy, 2-Methylpropoxy oder 1, 1-Dimethylethoxy;Cι_C 4 alkoxy can be linear or branched such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1-dimethylethoxy;
C3-C6-Alkenyloxy kann linear oder verzweigt sein wie z.B. Allyl- oxy, 2-Buten-l-yloxy oder 3-Buten-2-yloxy;C 3 -C 6 alkenyloxy can be linear or branched, for example allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;
C3-C6-Alkinyloxy kann linear oder verzweigt sein wie z.B. 2-Propin-l-yloxy, 2-Butin-l-yloxy oder 3-Butin-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;
Cι-C4-Alkylthio kann linear oder verzweigt sein wie z.B. Methyl- thio, Ethylthio, Propylthio, 1-Methylethylthio, Butylthio, 1-Me- thylpropylthio, 2-Methylpropylthio oder 1, 1-Dimethylethylthio;C 1 -C 4 -Alkylthio can be linear or branched such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1, 1-dimethylethylthio;
Cι-C4-Alkylcarbonyl kann linear oder verzweigt sein wie z.B. Acetyl, Ethylcarbonyl oder 2-Propylcarbonyl;C 1 -C 4 -alkylcarbonyl can be linear or branched, such as acetyl, ethylcarbonyl or 2-propylcarbonyl;
Cχ-C4-Alkoxycarbonyl kann linear oder verzweigt sein wie z.B. Methoxycarbonyl, Ethoxycarbonyl , n-Propoxycarbonyl , i-Propoxycar- bonyl oder n-Butoxycarbonyl ;Cχ-C 4 alkoxycarbonyl can be linear or branched such as Methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;
C3-C8-Alkylcarbonylalkyl kann linear oder verzweigt sein, z.B. 2-Oxo-prop-l-yl, 3-Oxo-but-l-yl oder 3-Oxo-but-2-yl;C 3 -C 8 alkylcarbonylalkyl can be linear or branched, for example 2-oxo-prop-1-yl, 3-oxo-but-1-yl or 3-oxo-but-2-yl;
Cχ-C8-Alkyl kann linear oder verzweigt sein wie z.B. Cι-C-Alkyl, Pentyl , Hexyl, Heptyl oder Octyl ;Cχ-C 8 alkyl can be linear or branched such as -CC alkyl, pentyl, hexyl, heptyl or octyl;
Halogen ist z.B. Fluor, Chlor, Brom, Jod.Halogen is e.g. Fluorine, chlorine, bromine, iodine.
Ein weiterer Gegenstand der Erfindung sind solche Verbindungen, aus denen sich die Verbindungen der Formel I freisetzen lassen (sog. Prodrugs) .The invention further relates to those compounds from which the compounds of the formula I can be released (so-called prodrugs).
Bevorzugt sind solche Prodrugs, bei denen die Freisetzung unter solchen Bedingungen abläuft, wie sie in bestimmten Körperkompar- timenten, z.B. im Magen, Darm, Blutkreislauf, Leber, vorherrschen.Preference is given to those prodrugs in which the release takes place under conditions such as those in certain body compartments, e.g. in the stomach, intestines, bloodstream, liver, predominate.
Gegenstand der Erfindung ist weiter die Verwendung der oben genannten Carbonsäurederivate zur Herstellung von Arzneimitteln, insbesondere zur Herstellung von Hemmstoffen für ETA und ETB Rezeptoren.The invention further relates to the use of the abovementioned carboxylic acid derivatives for the production of medicaments, in particular for the production of inhibitors for ET A and ET B receptors.
Die Verbindungen I und auch die Zwischenprodukte zu ihrer Herstellung, wie z.B. II, können ein oder mehrere asymmetrisch substituierte Kohlenstoffatome besitzen. Solche Verbindungen können als reine Enantiomere bzw. reine Diastereomere oder als deren Mischung vorliegen. Bevorzugt ist die Verwendung einer enantiomerenreinen Verbindung als Wirkstoff.The compounds I and also the intermediates for their preparation, e.g. II, can have one or more asymmetrically substituted carbon atoms. Such compounds can exist as pure enantiomers or pure diastereomers or as a mixture thereof. The use of an enantiomerically pure compound as the active ingredient is preferred.
Die Herstellung der Verbindungen mit der allgemeinen Formel Ha in der A Cι-C4-Alkyl, Azido, SR10 oder OR10 bedeutet, kann wie in WO 96/11914, DE 19614533.3 oder DE 19726146.9 beschrieben, erfolgen.The compounds having the general formula Ha in which A is -C 4 alkyl, azido, SR 10 or OR 10 can be prepared as described in WO 96/11914, DE 19614533.3 or DE 19726146.9.
R4R4
I H A—C C OH Ha R5 RlIHA — CC OH Ha R 5 R 1
Verbindungen der Formel Ilb in denen A SR10 oder OR10 bedeutet kann man in enantionmerenreiner Form über eine sauer katalysierte Umetherung erhalten, wie dies in DE 19636046.3 beschrieben wurde. Weiterhin kann man enantiomerenreine Verbindungen der Formel II erhalten, indem man mit racemischen bzw. diastereomerenCompounds of the formula IIb in which A is SR 10 or OR 10 can be obtained in enantiomerically pure form via an acid-catalyzed transetherification, as described in DE 19636046.3. Furthermore, enantiomerically pure compounds of formula II can be obtained by using racemic or diastereomeric
Verbindungen der Formel II eine klassische RacematSpaltung mit geeigneten enantiomerenreinen Basen durchführt. Als solche Basen eigenen sich z.B. 4 Chlorphenylethylamin und die Basen, die inCompounds of formula II carries out a classic racemate resolution with suitable enantiomerically pure bases. As such bases are e.g. 4 chlorophenylethylamine and the bases used in
WO 96/11914 genannt werden.WO 96/11914 can be called.
Die erfindungsgemäßen Verbindungen Ia, in denen A Cι~C4-Alkyl, Azido, SR10 oder OR10 bedeutet und die übrigen Substituenten die unter der allgemeinen Formel I angegebenen Bedeutung haben, können beispielsweise derart hergestellt werden, daß man die Carbonsäurederivate der allgemeinen Formel Ha, in denen die Substituenten die angegebene Bedeutung haben, mit Verbindungen der allgemeinen Formel III zur Reaktion bringt.The compounds Ia according to the invention in which A is C 1 -C 4 -alkyl, azido, SR 10 or OR 10 and the other substituents have the meaning given under the general formula I can be prepared, for example, in such a way that the carboxylic acid derivatives of the general formula Ha, in which the substituents have the meaning given, with compounds of the general formula III to react.
IIIIII
In Formel III bedeutet R17 Halogen oder R18-S02 , wobei R18 Cι-C4-Alkyl, Cχ-C4-Halogenalkyl oder Phenyl sein kann. Die Reaktion findet bevorzugt in einem inerten Lösungs oder Verdünnungsmittel unter Zusatz einer geeigneten Base, d.h. einer Base, die eine Deprotonierung des Zwischenproduktes Ha bewirkt, in einem Temperaturbereich von Raumtemperatur bis zum Siedepunkt des Lösungsmittels statt.In formula III, R 17 is halogen or R 18 -S0 2 , where R 18 can be C 1 -C 4 -alkyl, Cχ-C 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 Ha, in a temperature range from room temperature to the boiling point of the solvent.
Verbindungen des Typs Ia mit R1 = COOH lassen sich auf diese Weise direkt erhalten, wenn man das Zwischenprodukt Ha, in dem R1 COOH bedeutet, mit zwei Equivalenten einer geeigneten Base deprotoniert und mit Verbindungen der allgemeinen Formel III zur Reaktion bringt. Auch hier findet die Reaktion in einem inerten Lösungsmittel und in einem Temperaturbereich von Raumtemperatur bis zum Siedepunkt des Lösungsmittels statt.Compounds of type Ia with R 1 = COOH can be obtained directly if the intermediate Ha, in which R 1 is COOH, is deprotonated with two equivalents of a suitable base and reacted with compounds of the general formula III. Here too, the reaction takes place in an inert solvent and in a temperature range from room temperature to the boiling point of the solvent.
Beispiele für solche Lösungsmittel beziehungsweise Verdünnungsmittel sind aliphatische, alicyclische und aromatische Kohlen- Wasserstoffe, die jeweils gegebenenfalls chloriert sein können, wie zum Beispiel Hexan, Cyclohexan, Petrolether, Ligroin, Benzol, Toluol, Xylol, Methylenchlorid, Chloroform, Kohlenstofftetra- chlorid, Ethylchlorid und Trichlorethylen, Ether, wie zum Beispiel Diisopropylether, Dibutylether, Methyl tert. Butylether, Propylenoxid, Dioxan und Tetrahydrofuran, Nitrile, wie zum Beispiel Acetonitril und Propionitril, Säureamide, wie zum Beispiel Dirnethylformamid, Dimethylacetamid und N Methylpyrrolidon, Sulfoxide und Sulfone, wie zum Beispiel Dimethylsulfoxid undExamples of such 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. Butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitriles, such as, for example, acetonitrile and propionitrile, acid amides, such as, for example, dimethyl formamide, dimethylacetamide and N methylpyrrolidone, Sulfoxides and sulfones, such as dimethyl sulfoxide and
Sulfolan.Sulfolan.
Verbindungen der Formel III sind bekannt oder können nach allge- 5 mein bekannter Weise hergestellt werden wie z.B.:Compounds of the formula III are known or can be prepared in a generally known manner, for example:
H. Erlenmeyer, G. Bischoff Helv. Chim. Acta, 21, 280-283, 1946, G. Kjellin, J. Sandström Acta Chim. Scand. 23., 2879 1969, E. R. Buchmann, A. O. Reims, H. Sargent J. Org. Chem., , 764 766, 1941, F. C. James, H. D. Krebs, Aust. J-. Chem., 15, 385 391, 10 1982, G. R. Humphrey, S. H. B. Wright, J. Heterocyclic Chem., 26., 23, 1989.H. Erlenmeyer, G. Bischoff Helv. Chim. Acta, 21, 280-283, 1946, G. Kjellin, J. Sandström Acta Chim. Scand. 23, 2879 1969, E. R. Buchmann, A. O. Reims, H. Sargent J. Org. Chem.,, 764 766, 1941, F. C. James, H. D. Krebs, Aust. J-. Chem., 15, 385 391, 10 1982, G.R. Humphrey, S.H.B. Wright, J. Heterocyclic Chem., 26., 23, 1989.
Als Base kann ein Alkali- oder Erdalkalimetallhydrid wie Natriumhydrid, Kaliumhydrid oder Calciumhydrid, ein Carbonat wie Alkali- 15 metallcarbonat, z.B. Natrium oder Kaliumcarbonat, ein Alkali oder Erdalkalimetallhydroxid wie Natrium oder Kaliumhydroxid, eine metallorganische Verbindung wie Butyllithium oder ein Alka- liamid wie Lithiumdiisopropylamid oder Lithiumamid dienen.As a base, an alkali or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, e.g. 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 metal such as lithium diisopropylamide or lithium amide.
20 Verbindungen der Formel Ilb können analog der in DE 19726146.9 beschrieben Methoden zu den Verbindungen Ib umgesetzt werden.20 compounds of the formula IIb can be reacted analogously to the methods described in DE 19726146.9 to give the compounds Ib.
Ilb IbIlb Ib
3030
Verbindungen der Formel I können auch dadurch hergestellt werden, daß man von den entsprechenden Carbonsäuren, d. h. Verbindungen der Formel I, in denen R1 COOH bedeutet, ausgeht und diese zunächst auf übliche Weise in eine aktivierte Form wie ein Säure-Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, ie compounds of the formula I in which R 1 is COOH, and first converting them into an activated form in the usual way, such as an acid
35 halogenid, ein Anhydrid oder Imidazolid überführt und dieses dann mit einer entsprechenden HydroxylVerbindung HÖR5 umsetzt. Diese Umsetzung läßt sich in den üblichen Lösungsmitteln durchführen und erfordert oft die Zugabe einer Base, wobei die oben genannten in Betracht kommen. Diese beiden Schritte lassen sich beispiels-35 halide, an anhydride or imidazolide and this is then reacted with a corresponding hydroxyl compound HÖR 5 . This reaction can be carried out in the customary solvents and often requires the addition of a base, the above-mentioned being possible. These two steps can be
40 weise auch dadurch vereinfachen, daß man die Carbonsäure in40 also simplify it by adding the carboxylic acid in
Gegenwart eines wasserabspaltenden Mittels wie eines Carbodiimids auf die Hydroxylverbindung einwirken läßt.Presence of a water-releasing agent such as a carbodiimide on the hydroxyl compound.
Außerdem können Verbindungen der Formel I auch dadurch herge- 45 stellt werden, indem man von den Salzen der entsprechendenIn addition, compounds of the formula I can also be prepared by using the salts of the corresponding
Carbonsäuren ausgeht, d. h. von Verbindungen der Formel I, in denen R1 für eine Gruppe COOM stehen, wobei M ein Alkalimetallkation oder das Equivalent eines Erdalkalimetallkations sein kann. Diese Salze lassen sich mit vielen Verbindungen der Formel R-W zur Reaktion bringen, wobei W eine übliche nucleofuge Abgangsgruppe bedeutet, beispielsweise Halogen wie Chlor, Brom, Iod oder gegebe- nenfalls durch Halogen, Alkyl oder Halogenalkyl substituiertes Aryl- oder Alkylsulfonyl wie z.B. Toluolsulfonyl und Methylsulfonyl oder eine andere äquivalente Abgangsgruppe. Verbindungen der Formel R-W mit einem reaktionsfähigen Substituenten W sind bekannt oder mit dem allgemeinen Fachwissen leicht zu erhalten. Diese Umsetzung läßt sich in den üblichen Lösungsmitteln durchführen und wird vorteilhaft unter Zugabe einer Base, wobei die oben genannten in Betracht kommen, vorgenommen.Carboxylic acids, ie compounds of formula I in which R 1 is a group COOM, where M is an alkali metal cation or can be the equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds of the formula RW, where W is a conventional nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or, where appropriate, aryl- or alkylsulfonyl substituted by halogen, alkyl or haloalkyl, such as, for example, toluenesulfonyl and methylsulfonyl or another equivalent leaving group. Compounds of the formula RW with a reactive substituent W are known or are easy to obtain with the general specialist knowledge. This reaction can be carried out in the customary solvents and is advantageously carried out with the addition of a base, the above-mentioned being suitable.
In einigen Fällen ist zur Herstellung der erfindungsgemäßen Verbindungen I die Anwendung allgemein bekannter Schutzgruppentechniken erforderlich. Soll beispielsweise R10 = 4-Hydroxyphenyl bedeuten, so kann die Hydroxygruppe zunächst als Benzylether geschützt sein, der dann auf einer geeigneten Stufe in der Reaktionssequenz gespalten wird.In some cases, the preparation of the compounds I according to the invention requires the use of generally known protective group techniques. For example, if R 10 = 4-hydroxyphenyl, the hydroxy group can first be protected as benzyl ether, which is then cleaved at a suitable stage in the reaction sequence.
Verbindungen der Formel I, in denen R1 Tetrazol bedeutet, können wie in WO 96/11914 beschrieben, hergestellt werden.Compounds of the formula I in which R 1 is tetrazole can be prepared as described in WO 96/11914.
Im Hinblick auf die biologische Wirkung sind Carbonsäurederivate der allgemeinen Formel I - sowohl als reine Enantiomere bzw. reine Diastereomere oder als deren Mischung - bevorzugt, in denen die Substituenten folgende Bedeutung haben:With regard to the biological action, 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:
A NR8R9, Azido, OR10, SR10 oder Cι-C-Alkyl .A NR 8 R 9 , azido, OR 10 , SR 10 or -CC alkyl.
X Sauerstoff, Schwefel, CR11 oder NR12; mit der Maßgabe, falls X - CR11, dann Y = Sauerstoff oder Schwefel oder NR14.X is oxygen, sulfur, CR 11 or NR 12 ; with the proviso, if X - CR 11 , then Y = oxygen or sulfur or NR 14 .
Y Sauerstoff, Schwefel, CR13 oder NR14; mit der Maßgabe, falls Y = Sauerstoff oder Schwefel oder NR14, dann X = CR11.Y is oxygen, sulfur, CR 13 or NR 14 ; with the proviso that if Y = oxygen or sulfur or NR 14 , then X = CR 11 .
R2 und R3 (die gleich oder verschieden sein können) :R 2 and R 3 (which may be the same or different):
Phenyl oder Naphthyl, die durch einen oder mehrere der fol- genden Reste substituiert sein können: Halogen, Cyano,Phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, cyano,
Hydroxy, Mercapto, Amino, C!-C-Alkyl, Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy, Phenoxy, Cι-C4-Alkylthio, NH(Cι-C4-Alkyl) oder N(Cι-C4-Alkyl) 2 oder Phenyl, das ein- bis dreifach substituiert sein kann durch Halogen, Cyano, C!-C4-Alkyl, Cι-C-Halogenalkyl , Cι-C4-Alkoxy, Cι-C-Halogen- alkoxy oder Cj_-C4-Alkylthio; oder Phenyl oder Naphthyl, die orthoständig über eine direkte Bindung, eine Methylen-, Ethylen- oder Ethenylengruppe, ein Sauerstoff- oder Schwefelatom oder eine S02-, NH- oder N(Cι-C4-Alkyl) -Gruppe miteinander verbunden sindHydroxy, Mercapto, Amino, C ! -C-alkyl, -C-C 4 -haloalkyl, -C-C 4 -alkoxy, -C-C 4 -haloalkoxy, phenoxy, Cι-C 4 -alkylthio, NH (-C-C 4 -alkyl) or N (Cι-C 4- alkyl) 2 or phenyl, which can be mono- to trisubstituted by halogen, cyano, C ! -C 4 alkyl, -CC-haloalkyl, -C-C 4 alkoxy, -C-C-haloalkoxy or Cj_-C 4 alkylthio; or Phenyl or naphthyl, which are ortho-bonded via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 2 , NH or N (-C 4 alkyl) group
C5-C6-Cycloalkyl, wobei diese Reste jeweils ein- bis dreifach substituiert sein können durch: Halogen, Cι-C4-Alkyl, Cι-C4-Alkoxy, Cι-C4-Alkylthio, Cι-C4-Halogenalkoxy.C 5 -C 6 cycloalkyl, where these radicals can each be mono- to trisubstituted by: halogen, -CC 4 -alkyl, -C-C 4 -alkoxy, -C-C 4 -alkylthio, -C-C 4 -haloalkoxy .
R4 und R11 (die gleich oder verschieden sein können) :R 4 and R 11 (which may be the same or different):
Cx-C-Alkyl, wobei diese Reste substituiert sein können durch Halogen, Hydroxy;C x -C-alkyl, where these radicals can be substituted by halogen, hydroxy;
Wasserstoff, Halogen, Cι-C-Alkoxy, Cι-C-Halogenalkoxy, Cι-C-Alkylthio, Hydroxy, NH2, NH (Cι-C4-Alkyl) , N(Cι-C4-Alkyl)2;Hydrogen, halogen, -CC alkoxy, -CC haloalkoxy, -C-alkylthio, hydroxy, NH 2 , NH (-C 4 alkyl), N (-C 4 alkyl) 2 ;
oder CR4 bildet zusammen mit CR11 einen 5- oder 6 gliedrigen Alkylen- oder Alkenylenring, der ein- bis dreifach substituiert sein kann mit Cι-C4-Alkyl und worin jeweils ein bis drei Methylengruppen durch Sauerstoff oder Schwefel ersetzt sein können.or CR 4 forms together with CR 11 a 5- or 6-membered alkylene or alkenylene ring which can be mono- to trisubstituted with C 1 -C 4 -alkyl and in which one to three methylene groups can be replaced by oxygen or sulfur.
R8 Wasserstoff, Cι-C8-Alkyl, Cι-C5-Alkylcarbonyl, wobei diese Reste jeweils ein- bis dreifach substituiert sein können durch: Halogen, Hydroxy, Carboxy, Amino, Cι-C-Alkoxy, Cj_-C4-Alkyl- thio, Cι-C4-Halogenalkoxy, Cι-C-Alkoxycarbonyl, NH(Cι-C4-Alkyl) , N(C1-C4-Alkyl ) 2, C5-C6-Cycloalkyl, Phenoxy oder Phenyl, wobei die genannten Arylreste ihrerseits ein- bis dreifach substituiert sein können durch Halogen, Hydroxy, Cι-C4-Alkyl, Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogen- alkoxy, Amino, NH (C1-C4-Alkyl ) , N(C1-C4-Alkyl) 2, Phenyl oder Cι-C-Alkylthio;R 8 is hydrogen, C 1 -C 8 -alkyl, C 1 -C 5 -alkylcarbonyl, where these radicals can each be mono- to trisubstituted by: halogen, hydroxy, carboxy, amino, C 1 -C 4 -alkoxy, Cj_-C 4 - alkyl thio, Cι-C4-haloalkoxy, Cι-C alkoxycarbonyl, NH (Cι-C4 alkyl), N (C 1 -C 4 alkyl) 2, C 5 -C 6 cycloalkyl, phenoxy or phenyl , where the aryl radicals mentioned 4-halo turn may be substituted once to three times by halogen, hydroxy, Cι-C 4 -alkyl, C 4 haloalkyl, Cι-C 4 -alkoxy, C alkoxy, amino, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2 , phenyl or C 1 -C 4 alkylthio;
Phenyl oder Naphthyl, die jeweils ein- bis dreifach substituiert sein können durch Halogen, Hydroxy, Amino, Cι-C4-Alkyl, C!-C4-Halogenalkyl, C1-C4-Alkoxy, Cι-C4-Halogenalkoxy, Phenoxy, Cx-d-Alkylthio, NH (Cι-C4-Alkyl) , N(Cι-C4-Alkyl) 2 , Dioxomethy- len oder Dioxoethylen;Phenyl or naphthyl, which can each be mono- to trisubstituted by halogen, hydroxy, amino, C 1 -C 4 -alkyl, C ! -C 4 -haloalkyl, C 1 -C 4 -alkoxy, -C-C 4 -haloalkoxy, phenoxy, Cx-d-alkylthio, NH (Cι-C 4 -alkyl), N (-C-C 4 -alkyl) 2 , Dioxomethylene or dioxoethylene;
C3-C8-Cycloalkyl, wobei diese Reste jeweils ein- bis dreifach substituiert sein können durch: Halogen, Cχ-C-Alkyl, Cι-C-Alkoxy, Cι-C4-Alkylthio, Cχ-C-Halogenalkoxy; oder R8 bildet gemeinsam mit R9 eine zu einem Ring geschlossene C4-C6-Alkylenkette, die ein- bis dreifach substituiert sein kann mit Cι-C4-Alkyl, Cι-C4-Halogenalkyl, und in der eine Alkylengruppe durch Sauerstoff oder Schwefel ersetzt sein kann, wie -(CH2)4-, -(CH2)5-, -(CH2)6-, - (CH2) 2-0- (CH2) 2-, -(CH2)2-S-(CH2)2-.C 3 -C 8 cycloalkyl, where these radicals can each be mono- to trisubstituted by: halogen, Cχ-C-alkyl, Cι-C-alkoxy, Cι-C 4 alkylthio, Cχ-C-haloalkoxy; or R 8 forms together with R 9 to form a ring closed a C 4 -C 6 -alkylene chain which can be mono- to trisubstituted substituted with Cι-C 4 -alkyl, C 4 haloalkyl, and in which an alkylene group by Oxygen or sulfur can be replaced, such as - (CH 2 ) 4 -, - (CH 2 ) 5 -, - (CH 2 ) 6 -, - (CH 2 ) 2 -0- (CH 2 ) 2 -, - ( CH 2 ) 2 -S- (CH 2 ) 2 -.
R9 Wasserstoff, Cι-C4-Alkyl;R 9 is hydrogen, -CC 4 alkyl;
oder R9 ist wie unter R8 angeben mit R8 zu einem Ring verknüpft .or R 9 is linked to R 8 to form a ring, as indicated under R 8 .
R10 Wasserstoff, Cι-C8-Alkyl, C3-C8-Alkenyl oder C3-C8-Alkinyl, wobei diese Reste jeweils ein- bis dreifach substituiert sein können durch: Halogen, Hydroxy, Mercapto, Carboxy, Amino, Cι-C4-Alkoxy, Cι-C4-Alkylthio, Cχ-C4-Halogenalkoxy, Cι-C4-Alkoxycarbonyl, Carboxamid, CONH(Cι-C4-Alkyl) , CON(Cι-C - Alkyl)2, CONR15R16, NH (C1-C4-Alkyl ) , N(Cι-C4-Alkyl) 2, C5-C5- Cycloalkyl, Phenoxy oder Phenyl, wobei die genannten Arylreste ihrerseits ein- bis dreifach substituiert sein können durch Halogen, Hydroxy, Cι-C4-Alkyl, Cι-C4-Alkylcarboxy, Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, Cj.-C-Halogenalkoxy, Amino, NH (C1-C4-Alkyl ) , N(C;ι_-C4-Alkyl ) 2, Phenyl, Cι-C4-Alkylthio oder Rl9;R 10 is hydrogen, -CC 8 -alkyl, C 3 -C 8 -alkenyl or C 3 -C 8 -alkynyl, where these radicals can each be mono- to trisubstituted by: halogen, hydroxyl, mercapto, carboxy, amino, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 4 -C 4 -haloalkoxy, C-C 4 -alkoxycarbonyl, carboxamide, CONH (Cι-C 4 -alkyl), CON (Cι-C - alkyl) 2 , CONR 15 R 16 , NH (C 1 -C 4 alkyl), N (-C-C 4 alkyl) 2 , C 5 -C 5 - cycloalkyl, phenoxy or phenyl, the aryl radicals in turn being mono- to trisubstituted can by halogen, hydroxy, -C-C 4 alkyl, -C-C 4 alkylcarboxy, Cι-C 4 haloalkyl, Cι-C 4 alkoxy, Cj.-C-haloalkoxy, amino, NH (C 1 -C 4 Alkyl), N (C 1 -C 4 -alkyl) 2 , phenyl, C 1 -C 4 -alkylthio or R 19 ;
Phenyl oder Naphthyl, die jeweils ein- bis dreifach substituiert sein können durch: Halogen, Hydroxy, Amino, Cι-C4-Alkyl, Cι-C4-Halogenalkyl , Cχ-C4-Alkoxy, Cι-C-Halogen- alkoxy, Cι-C4-Alkylthio, NH(Cι-C4-Alkyl) , N(Cι-C -Alkyl)2, Dioxomethylen oder Dioxoethylen;Phenyl or naphthyl, which in each case may be substituted one to three times by: halogen, hydroxy, amino, Cι-C 4 -alkyl, C 4 haloalkyl, Cχ-C 4 -alkoxy, halogen-C alkoxy, C 1 -C 4 alkylthio, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2 , dioxomethylene or dioxoethylene;
C3-C8-Cycloalkyl, wobei diese Reste jeweils ein- bis dreifach substituiert sein können durch: Halogen, Cι-C4-Alkyl, Cι-C-Alkoxy, Cι-C4-Halogenalkyl.C 3 -C 8 -cycloalkyl, where these radicals may in each case be substituted once to three times by: halogen, Cι-C 4 -alkyl, C alkoxy, Cι-C 4 haloalkyl.
R12 Wasserstoff, Methyl; oderR 12 is hydrogen, methyl; or
NR12 bildet zusammen mit CR4 einen 5- oder 6 gliedrigen Alky- lenring, der ein- bis dreifach mit Methyl substituiert sein kann.Together with CR 4, NR 12 forms a 5- or 6-membered alkyl ring which can be mono- to trisubstituted by methyl.
R13 Wasserstoff, Halogen, Cι-C4-Alkyl, wobei diese Reste ein- bis dreifach mit Halogen substituiert sein können.R 13 is hydrogen, halogen, -CC 4 alkyl, where these radicals can be mono- to trisubstituted by halogen.
R14 Wasserstoff, Methyl. R15 und R16 :R 14 is hydrogen, methyl. R 15 and R 16 :
R15 und R16 bilden gemeinsam eine zu einem Ring geschlosseneR 15 and R 16 together form a closed ring
C3-C7-Alkylenkette oder C -C7-Alkenylenkette, an die einC 3 -C 7 alkylene chain or C -C 7 alkenylene chain to which a
Phenylring anneliiert ist, wie 7-aza-bi- cyclo [4.2.0] -octa-1, 3 , 5-trien, 2 , 3-Dihydroindol, Indol,Phenyl ring is annelated, such as 7-aza-bicyclo [4.2.0] -octa-1, 3, 5-triene, 2, 3-dihydroindole, indole,
1, 3-Dihydroisoindol, 1,2,3, 4-Tetrahydrochinolin,1,3-dihydroisoindole, 1,2,3,4-tetrahydroquinoline,
1, 2 , 3 , 4-Tetrahydroisochinolin, wobei jeweils der Phenylring ein- bis dreifach substituiert sein kann durch Halogen, Cχ-C -1, 2, 3, 4-tetrahydroisoquinoline, where the phenyl ring can be substituted one to three times by halogen, Cχ-C -
Alkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkyl, Cι-C4-Halogenalkoxy.Alkyl, Cι-C 4 -alkoxy, C 4 haloalkyl, Cι-C 4 haloalkoxy.
R19 Methyl, Ethyl, Methoxy oder Ethoxy, die einen der folgendenR 19 is methyl, ethyl, methoxy or ethoxy, any of the following
Reste tragen: Hydroxy, Carboxy, Cι-C4-Alkoxycarbonyl, Amino,Wear residues: hydroxy, carboxy, -C 4 alkoxycarbonyl, amino,
NH (Cι-C4-Alkyl ) , N(Cι-C4-Alkyl) 2, Carboxamid oderNH (-C 4 alkyl), N (-C 4 alkyl) 2 , carboxamide or
CON(Cι-C -Alkyl)2;CON (-C-alkyl) 2 ;
Besonders bevorzugt sind Verbindungen der Formel I - sowohl als reine Enantiomere bzw. reine Diastereomere oder als derenCompounds of the formula I are particularly preferred - both as pure enantiomers or pure diastereomers or as their
Mischung - in denen die Substituenten folgende Bedeutung haben:Mixture - in which the substituents have the following meaning:
A NR8R9, Azido, OR10, SR10 oder Cι-C4-AlkylA NR 8 R 9 , azido, OR 10 , SR 10 or -CC 4 alkyl
X Sauerstoff, Schwefel oder CR11; mit der Maßgabe, falls X = CR11, dann Y = Sauerstoff oder Schwefel.X is oxygen, sulfur or CR 11 ; with the proviso that if X = CR 11 , then Y = oxygen or sulfur.
Y Sauerstoff, Schwefel oder CR13; mit der Maßgabe, falls Y = Sauerstoff oder Schwefel, dann X = CR11.Y is oxygen, sulfur or CR 13 ; with the proviso that if Y = oxygen or sulfur, then X = CR 11 .
R2 und R3 (die gleich oder verschieden sein können) :R 2 and R 3 (which may be the same or different):
Phenyl oder Naphthyl, die jeweils ein- bis dreifach substituiert sein können durch: Halogen, Hydroxy, Cι-C4-Alkyl, Cι-C4-Halogenalkyl , Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy, NH (C1-C4-Alkyl ) , N (C1-C4-Alkyl) 2, Phenoxy oder Phenyl, das ein bis dreifach substituiert sein kann durch Halogen, Cι-C4-Alkyl, Cι-C-Halogenalkyl, Cι-C4-Alkoxy oder Cι-C-Halogenalkoxy; oderPhenyl or naphthyl, which in each case may be substituted one to three times by: halogen, hydroxy, Cι-C 4 -alkyl, C 4 haloalkyl, Cι-C 4 -alkoxy, C 4 -haloalkoxy, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2, phenoxy or phenyl which is Cι-C may be substituted up to three times by halogen, 4 -alkyl, C haloalkyl, Cι-C 4 -alkoxy or -CC haloalkoxy; or
Phenyl oder Naphthyl, die orthoständig über eine direkte Bindung, eine Methylen-, Ethylen- oder Ethenylengruppe, ein Sau- erstoff- oder Schwefelatom oder eine S0-, NH- oder N(Cι-C4-Alkyl) -Gruppe miteinander verbunden sind;Phenyl or naphthyl, which are ortho-linked via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0, NH or N (-C 4 -alkyl) group;
Cyclohexyl .Cyclohexyl.
R4 und R11 (die gleich oder verschieden sein können) : Wasserstoff, Halogen, Cι-C4-Alkyl, Trifluormethyl, Hydroxyme- thylen, Cι-C4-Alkoxy, Cι-C4-Alkylthio, N(Cι-C4-Alkyl)2;R 4 and R 11 (which may be the same or different): Hydrogen, halogen, -CC 4 alkyl, trifluoromethyl, hydroxymethylene, -C 4 alkoxy, -C 4 alkylthio, N (-C 4 alkyl) 2 ;
oder CR4 bildet zusammen mit CR11 einen 5- oder 6-gliedrigen Alkylen- oder Alkenylenring, der ein- bis zweifach mit Methyl substituiert sein kann, und worin jeweils eine Methylengruppe durch Sauerstoff ersetzt sein kann;or CR 4 together with CR 11 forms a 5- or 6-membered alkylene or alkenylene ring which can be mono- to disubstituted by methyl and in which one methylene group can be replaced by oxygen;
R8 Wasserstoff, Cι-C4-Alkyl, Cι-C4-Alkylcarbonyl, wobei diese Reste jeweils ein- bis dreifach substituiert sein können durch: Halogen, Hydroxy, Carboxy, Amino, Cι-C4-Alkoxy, Cι-C4-Alkylthio, C!-C4-Halogenalkoxy, Cι-C4-Alkoxycarbonyl, NH (C1-C4-Alkyl ) , N (C1-C4-Alkyl ) 2, C5-C6-Cycloalkyl, Phenyl, der seinerseits ein- bis dreifach substituiert sein kann durch Halogen, Cι-C4-Alkyl, Cι-C-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy, Cι-C4-Alkylthio;R 8 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 alkylcarbonyl, where these radicals can each be mono- to trisubstituted by: halogen, hydroxy, carboxy, amino, C 1 -C 4 -alkoxy, C 1 -C 4 -Alkylthio, C ! -C 4 haloalkoxy, -C -C 4 alkoxycarbonyl, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2 , C 5 -C 6 cycloalkyl, phenyl, which in turn is a Cι Cι-C-C-C Cι Cι-C may be substituted up to three times by halogen, 4 -alkyl, C haloalkyl, 4 alkoxy, haloalkoxy 4, 4 -alkylthio;
Phenyl, das ein- bis dreifach substituiert sein kann durch Halogen, Hydroxy, Cι-C-Alkyl, Trifluormethyl, Cι-C4-Alkoxy, Cι-C4-Alkylthio, Dioxomethylen oder Dioxoethylen;Phenyl, which can be mono- to trisubstituted by halogen, hydroxy, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, dioxomethylene or dioxoethylene;
C5-C6-Cycloalkyl, wobei diese Reste jeweils ein- bis dreifach substituiert sein können durch: Halogen, Cι-C4-Alkyl, Cι-C4-Alkoxy;C 5 -C 6 cycloalkyl, where these radicals can each be mono- to trisubstituted by: halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy;
oder R8 bildet gemeinsam mit R9 eine zu einem Ring geschlossene C-C6-Alkylenkette, die ein- bis dreifach substituiert sein kann mit Cι-C -Alkyl, Cι-C4-Halogenalkyl, und in der eine Alkylengruppe durch Sauerstoff ersetzt sein kann, wie -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)2-0-(CH2)2-.or R 8 together with R 9 forms a closed CC 6 alkylene chain which can be mono- to trisubstituted with C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and in which an alkylene group can be replaced by oxygen , such as - (CH 2 ) 4 -, - (CH 2 ) 5 -, - (CH 2 ) 6 -, - (CH 2 ) 2 -0- (CH 2 ) 2 -.
R9 Wasserstoff, Cι-C-Alkyl;R 9 is hydrogen, -CC alkyl;
oder R9 ist wie unter R8 angeben mit R8 zu einem Ring ver- knüpft.or R 9 is linked to R 8 as a ring under R 8 .
R10 Wasserstoff, Cι-C4-Alkyl, wobei diese Reste jeweils ein- bis dreifach substituiert sein können durch: Halogen, Hydroxy, Carboxy, Cι-C4-Alkoxy, Cχ-C-Alkoxycarbonyl, Carboxamid, CONH (Cι-C -Alkyl ) , CON(C!-C4-Alkyl) 2, CONR15R16,R 10 is hydrogen, C 1 -C 4 -alkyl, where these radicals can each be mono- to trisubstituted by: halogen, hydroxy, carboxy, C 1 -C 4 -alkoxy, Cχ-C-alkoxycarbonyl, carboxamide, CONH (Cι-C -Alkyl), CON (C ! -C 4 -alkyl) 2 , CONR 15 R 16 ,
NH (C1-C4-Alkyl ) , N(Cι-C4-Alkyl)2, C5-C6-Cycloalkyl, Phenyl, der seinerseits ein- bis dreifach substituiert sein kann durch Halogen, Hydroxy, Cι-C4-Alkyl, Cι-C4-Alkylcarboxy, Trifluormethyl, C!-C4-Alkoxy, NH(Cι-C4-Alkyl) , R19, N(Cι-C -Alkyl) 2 , Phenyl oder Cι-C4-Alkylthio; Phenyl der ein- bis dreifach substituiert sein kann durch Halogen, Hydroxy, Cι-C4-Alkyl, C1-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Alkylthio, NH (Cι-C-Alkyl) , N(Cι-C4-Alkyl) 2, Dioxomethy- len oder Dioxoethylen;NH (C 1 -C 4 alkyl), N (Cι-C4 alkyl) 2, C 5 -C 6 -cycloalkyl, phenyl, which for its part may be mono- substituted to trisubstituted by halogen, hydroxy, Cι-C 4 -Alkyl, -CC 4 -alkyl carboxy, trifluoromethyl, C ! -C 4 alkoxy, NH (-CC 4 alkyl), R 19 , N (-C-alkyl) 2 , phenyl or -CC 4 alkylthio; Phenyl mono- the Cι-C C 1 -C Cι Cι-C-C may be substituted up to three times by halogen, hydroxy, 4 alkyl, 4 haloalkyl, 4 alkoxy, 4 alkylthio, NH (Cι-C alkyl ), N (-C 4 alkyl) 2 , dioxomethylene or dioxoethylene;
C3-C8-Cycloalkyl, wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Halogen, Cι-C4-Alkyl, C1-C4-Alkoxy.C 3 -C 8 -cycloalkyl, where these radicals may be substituted one or more times by: halogen, Cι-C 4 alkyl, C 1 -C 4 alkoxy.
R13 Wasserstoff, Halogen, Cι-C4-Alkyl, Trifluormethyl.R 13 is hydrogen, halogen, -CC 4 alkyl, trifluoromethyl.
Ris und Riß;Ris and riss;
R15 und R16 bilden gemeinsam eine zu einem Ring geschlossene C3-C7-Alkylenkette, an die ein Phenylring annelliert ist, wie 2, 3-Dihydroindol, Indol, 1, 3-Dihydroisoindol, 1, 2 , 3 , 4-Tetra- hydrochinolin, 1, 2 , 3 , 4-Tetrahydroisochinolin, wobei der Phenylring jeweils ein- bis dreifach substituiert sein kann durch Halogen, Cι-C4-Alkyl, Cι-C4-Alkoxy, Hydroxy;R 15 and R 16 together form a C 3 -C 7 alkylene chain which is closed to a ring and to which a phenyl ring is fused, such as 2, 3-dihydroindole, indole, 1, 3-dihydroisoindole, 1, 2, 3, 4- Tetra-hydroquinoline, 1, 2, 3, 4-tetrahydroisoquinoline, where the phenyl ring can be substituted one to three times by halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy;
R19 Methoxy oder Ethoxy, die einen der folgenden Reste tragen: Hydroxy, Carboxy, Cι-C4-Alkoxycarbonyl, Amino, NH (C1-C4-Alkyl ) , N (C1-C4-Alkyl ) 2, Carboxamid oder CON(Cι-C4-Alkyl)2.R 19 methoxy or ethoxy, which carry one of the following radicals: hydroxy, carboxy, -CC 4 alkoxycarbonyl, amino, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2 , carboxamide or CON (-C 4 alkyl) 2 .
Die Verbindungen der vorliegenden Erfindung bieten ein neues therapeutisches Potential für die Behandlung von Hypertonie, pulmonalem Hochdruck, Myokardinfarkt, Angina Pectoris, Arrhythmie akutem/chronischem Nierenversagen, chronische Herzinsuffizienz, Niereninsuffizienz, zerebralen Vasospasmen, zerebraler Ischämie, Subarachnoidalblutungen, Migräne, Asthma, Atherosklerose, endo- toxischem Schock, Endotoxin-induziertem Organversagen, intravas- kulärer Koagulation, Restenose nach Angioplastie und by-pass Operationen, benigne Prostata-Hyperplasie, ischämisches und durch Intoxikation verursachtes Nierenversagen bzw. Hypertonie, Meta- stasierung und Wachstum mesenchymaler Tumoren wie Prostatakarzinom, Kontrastmittel-induziertes Nierenversagen, Pankreatitis, gastrointestinale Ulcera.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, atheros - toxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and by-pass surgery, benign prostate hyperplasia, ischemic and intoxication-related kidney failure or hypertension, metastasis and growth of mesenchymal tumors such as prostate cancer, contrast agents induced kidney failure, pancreatitis, gastrointestinal ulcers.
Ein weiterer Gegenstand der Erfindung sind Kombinationen aus Endothelinrezeptorantagonisten der Formel I und Inhibitoren des Renin-Angiotensin Systems. Inhibitoren des Renin-Angiotensin- Systems sind Reninhemmer, Angiotensin-II-Antagonisten und Angio- tensin-Converting-Enzyme (ACE) -Hemmer . Bevorzugt sind Kombinationen aus Endothelinrezeptorantagonisten der Formel I und ACE-Hem- mern. Ein weiterer Gegenstand der Erfindung sind Kombinationen aus Endothelinrezeptorantagonisten der Formel I und Calciumantago- nisten wie Verapamil.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 calcium antagonists such as verapamil.
Ein weiterer Gegenstand der Erfindung sind Kombinationen aus Endothelinrezeptorantagonisten der Formel I und Beta-Blockern.The invention further relates to combinations of endothelin receptor antagonists of the formula I and beta-blockers.
Ein weiterer Gegenstand der Erfindung sind Kombinationen aus Endothelinrezeptorantagonisten der Formel I und Diuretika.The invention further relates to combinations of endothelin receptor antagonists of the formula I and diuretics.
Ein weiterer Gegenstand der Erfindung sind Kombinationen aus Endothelinrezeptorantagonisten der Formel I und Substanzen, die die Wirkung von VEGF (Vascular endothelial growth factor) blockieren. Solche Substanzen sind beispielsweise gegen VEGF gerichtete Antikörper oder spezifische Bindeproteine oder auch niedermolekulare Substanzen, die VEGF Freisetzung oder Rezeptorbindung spezifisch hemmen können.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). Such substances 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.
Die vorstehend genannten Kombinationen können gleichzeitig oder nacheinander zeitlich abgestuft verabreicht werden. Sie können sowohl in einer einzigen galenischen Formulierung oder auch in getrennten Formulierungen eingesetzt werden. Die Applikationsform kann auch unterschiedlich sein, beispielsweise können die Endothelinrezeptorantagonisten oral und VEGF-Hemmer parenteral verab- reicht werden.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 application form can also be different, for example the endothelin receptor antagonists can be administered orally and VEGF inhibitors parenterally.
Diese Kombinationspräparate eignen sich vor allem zur Behandlung und Verhütung von Hypertension und deren Folgeerkrankungen, sowie zur Behandlung von Herzinsuffizienz.These combination products are particularly suitable for the treatment and prevention of hypertension and its complications, as well as for the treatment of heart failure.
Die gute Wirkung der Verbindungen läßt sich in folgenden Versuchen zeigen:The good effects of the compounds can be shown in the following experiments:
RezeptorbindungsstudienReceptor binding studies
Für Bindungsstudien wurden klonierte humane ETA- oder ETB-Rezep- tor-exprimierende CHO-Zellen eingesetzt.Cloned human ET A or ET B receptor-expressing CHO cells were used for binding studies.
MembranpräparationMembrane preparation
Die ETA- oder ETB-Rezeptor-exprimierenden CHO-Zellen wurden in DMEM NUT MIX F12-Medium (Gibco, Nr. 21331-020) mit 10 % fötalem Kälberserum (PAA Laboratories GmbH, Linz, Nr. A15-022), 1 M Glutamin (Gibco Nr. 25030-024), 100 E/ml Penicillin und 100 μg/ml Streptomycin (Gibco, Sigma Nr P-0781) vermehrt. Nach 48 Stunden wurden die Zellen mit PBS gewaschen und mit 0,05 % trypsin-halti- ger PBS 5 Minuten bei 37°C inkubiert. Danach wurde mit Medium neutralisiert und die Zellen durch Zentrifugation bei 300 x g gesammelt.The ET A or ET B receptor-expressing CHO cells were in DMEM NUT MIX F 12 medium (Gibco, No. 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022) , 1 M glutamine (Gibco No. 25030-024), 100 U / ml penicillin and 100 μg / 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. After that, with medium neutralized and the cells collected by centrifugation at 300 xg.
Für die Membranpräpara ion wurden die Zellen auf eine Konzen- tration von 108 Zellen/ml Puffer (50 M Tris-HCL Puffer, pH 7.4) eingestellt und danach durch Ultraschall desintegriert Branson Sonifier 250, 40-70 Sekunden/constant/output 20).For the membrane preparation, the cells were adjusted to a concentration of 10 8 cells / ml buffer (50 M Tris-HCL buffer, pH 7.4) and then disintegrated by ultrasound (Branson Sonifier 250, 40-70 seconds / constant / output 20) .
BindungstestsBinding tests
Für den ETA- und ETB-Rezeptorbindungstest wurden die Membranen in Inkubationspuffer (50 mM Tris-HCl, pH 7,4 mit 5 mM MnCl2, 40 mg/ml Bacitracin und 0,2 % BSA) in einer Konzentration von 50 μg Protein pro Testansatz suspendiert und bei 25°C mit 25 pM [125J] ETi (ETA-Rezeptortest) oder 25 pM [125J]-ET3 (ETB Rezeptortest) in Anwesenheit und Abwesenheit von Test-substanz inkubiert. Die unspezifische Bindung wurde mit 10~7 M E i bestimmt. Nach 30 min wurde der freie und der gebundene Radioligand durch Filtration über GF/B Glasfaserfilter (Whatman, England) an einem Skatron- Zellsammler (Skatron, Lier, Norwegen) getrennt und die Filter mit eiskaltem Tris-HCl-Puffer, pH 7,4 mit 0,2 % BSA gewaschen. Die auf den Filtern gesammelte Radioaktivität wurde mit einem Packard 2200 CA Flüssigkeits-zintillationszähler quantifiziert.For the ET A and ET B receptor binding test, the membranes were incubated in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl 2 , 40 mg / ml bacitracin and 0.2% BSA) in a concentration of 50 μg Protein suspended per test batch and incubated at 25 ° C with 25 pM [125J] ETi (ET A receptor test) or 25 pM [125J] -ET 3 (ET B receptor test) in the presence and absence of test substance. The non-specific binding was determined to be 10 ~ 7 ME i. After 30 min the free and bound radioligand were separated by filtration through GF / B glass fiber filters (Whatman, England) on a Skatron cell collector (Skatron, Lier, Norway) and the filters with ice-cold Tris-HCl buffer, pH 7.4 washed with 0.2% BSA. Radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.
Testung der ET-Antagonisten in vivo:Testing the ET antagonists in vivo:
Männliche 250 - 300 g schwere SD-Ratten wurden mit Amobarbital narkotisiert, künstlich beatmet, vagotomisiert und despinali- siert. Die Arteria carotis und Vena jugularis wurden katheteri- siert.Male SD rats weighing 250-300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and despinalized. The carotid artery and jugular vein were catheterized.
In Kontrolltieren führt die intravenöse Gabe von 1 mg/kg ETI zu einem deutlichen Blutdruckanstieg, der über einen längeren Zeitraum anhält.In control animals, intravenous administration of 1 mg / kg ETI leads to a significant increase in blood pressure that persists over a longer period.
Den Testtieren wurde 30 min vor der ETI Gabe die TestVerbindungen i.v. injiziert (1 ml/kg) . Zur Bestimmung der ET-antagonistischen Eigenschaften wurden die Blutdruckänderungen in den Testtieren mit denen in den Kontrolltieren verglichen.The 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.
p.o. - Testung der gemischten E A- und ETB-Antagonisten:po - testing of the mixed E A and ET B antagonists:
Männliche 250-350g schwere normotone Ratten (Sprague Dawley, Janvier) werden mit den Testsubstanzen oral vorbehandelt. 80 Minuten später werden die Tiere mit Urethan narkotisiert und die A. carotis (für Blutdruckmessung) sowie die V. jugularis (Applikation von big Endothelin/Endothelin 1) katheterisiert .Male normotonic rats weighing 250-350 g (Sprague Dawley, Janvier) are pretreated orally with the test substances. 80 minutes later, the animals are anesthetized with urethane and the A. carotid (for blood pressure measurement) and the jugular vein (application of big endothelin / endothelin 1) catheterized.
Nach einer Stabilisierungsphase wird big Endothelin (20 μg/kg, Appl. Vol. 0.5 ml/kg) bzw. ETI (0.3 μg/kg, Appl. Vol. 0.5 ml/kg) intravenös gegeben. Blutdruck und Herzfrequenz werden kontinuierlich über 30 Minuten registriert. Die deutlichen und langanhaltenden Blutdruckänderungen werden als Fläche unter der Kurve (AUC) berechnet. Zur Bestimmung der antagonistischen Wirkung der Testsubstanzen wird die AUC der Substanzbehandelten Tiere mit der AUC der Kontrolltiere verglichen.After a stabilization phase, big endothelin (20 μg / kg, Appl. Vol. 0.5 ml / kg) or ETI (0.3 μg / 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.
Die erfindungsgemäßen Verbindungen können in üblicher Weise oral oder parenteral (subkutan, intravenös, intramuskulär, intraperi- toneal) verabfolgt werden. Die Applikation kann auch mit Dämpfen oder Sprays durch den Nasen-Rachenraum erfolgen.The compounds according to the invention can be administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). It can also be applied with vapors or sprays through the nasopharynx.
Die Dosierung hängt vom Alter, Zustand und Gewicht des Patienten sowie von der Applikationsart ab. In der Regel beträgt die tägli- ehe Wirkstoffdosis zwischen etwa 0,5 und 100 mg/kg Körpergewicht bei oraler Gabe und zwischen etwa 0,1 und 10 mg/kg Körpergewicht bei parenteraler Gabe.The dosage depends on the age, condition and weight of the patient and on the type of application. As a rule, the daily dose of active substance is between approximately 0.5 and 100 mg / kg body weight when administered orally and between approximately 0.1 and 10 mg / kg body weight when administered parenterally.
Die neuen Verbindungen können in den gebräuchlichen galenischen Applikationsformen fest oder flüssig angewendet werden, z.B. als Tabletten, Filmtabletten, Kapseln, Pulver, Granulate, Dragees, Suppositorien, Lösungen, Salben, Cremes oder Sprays. Diese werden in üblicher Weise hergestellt. Die Wirkstoffe können dabei mit den üblichen galenischen Hilfsmitteln wie Tablettenbindern, Füll- Stoffen, Konservierungsmitteln, Tablettensprengmitteln, Fließreguliermitteln, Weichmachern, Netzmitteln, Dispergiermitteln, Emulgatoren, Lösungsmitteln, Retardierungsmitteln, Antioxidantien und/oder Treibgasen verarbeitet werden (vgl. H. Sucker et al . : Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991) . Die so erhaltenen Applikationsformen enthalten den Wirkstoff normalerweise in einer Menge von 0,1 bis 90 Gew.-%.The new compounds can be used in the customary pharmaceutical application forms, solid or liquid, e.g. as tablets, film-coated tablets, capsules, powders, granules, dragees, 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.
SynthesebeispieleSynthesis examples
Beispiel 1:Example 1:
2-Methylsulfonyl-4, 5-dimethylthiazol2-methylsulfonyl-4,5-dimethylthiazole
Es wurden 2,7 g 2-Methylmercapto-4, 5-dimethylthiazol in Methylen- chlorid bei Eistemperatur vorgelegt und 5.9 g mCPBA zugegeben. Der Ansatz wurde bei Raumtemperatur 16 Stunden gerührt und anschließend einmal mit Natriumhydrogencarbonat-Lösung und mit Natriumthiosulfat-Lösung extrahiert. Die organische Phase wurde über Magnesiumsulfat getrocknet, das Lösungsmittel abdestilliert und 2,88 g Öl isoliert, die direkt weiter eingesetzt wurden.2.7 g of 2-methylmercapto-4,5-dimethylthiazole in methylene chloride were introduced at ice temperature and 5.9 g of mCPBA were added. The mixture was stirred at room temperature for 16 hours and then once with sodium hydrogen carbonate solution and with Extracted sodium thiosulfate solution. The organic phase was dried over magnesium sulfate, the solvent was distilled off and 2.88 g of oil were isolated, which were used directly.
iH- MR (200 MHz): 3.25 ppm (3 H, s), 2.50(3 H, s), 2.40 (3 H, s).iH-MR (200 MHz): 3.25 ppm (3 H, s), 2.50 (3 H, s), 2.40 (3 H, s).
ESI-MS: M+ = 191ESI-MS: M + = 191
Beispiel 2 :Example 2:
2-Methylmercapto-4 , 5-cyclopenteno-thiazol2-methylmercapto-4,5-cyclopentenothiazole
In Ethanol wurden 10,4 g Ammoniumdithiocarbamat vorgelegt und 7,5 g 2-Chlorocyclopentanon zugegeben. Nach 30 Minuten war die Reaktion beendet und die Reaktionsmischung wurde auf Wasser gegeben. Mit Natronlauge wurde die wäßrige Phase stark alkalisch gestellt, mit Methylenchlorid extrahiert und dann mit konzentrierter Salzsäure auf pH 2 eingestellt. Die wäßrige Phase wurde mit Essigester extrahiert, die organische Phase mit Magnesium- sulfat getrocknet und das Lösungsmittel abdestilliert. Der Rückstand wurde in Toluol aufgenommen, eine Spatelspitze p-Toluolsul- fonsäure zugegeben und bei 60°C das Lösungsmittel abdestilliert. 7,9 g Öl wurden in 75 ml Wasser und 2,4 g NaOH gelöst und zügig 5,7 ml Dimethylsulfat zugetropft. Nach einer Stunde war die Reak- tion beendet und das Gemisch wurde auf Wasser gegeben. Die wäßrige Phase wurde mit Ether extrahiert, die organische Phase mit Magnesiumsulfat getrocknet und das Lösungsmittel abdestilliert. Der Rückstand wurde ohne weitere Reinigung in der nachfolgenden Reaktion eingesetzt.10.4 g of ammonium dithiocarbamate were placed in ethanol and 7.5 g of 2-chlorocyclopentanone were added. After 30 minutes the reaction was complete and the reaction mixture was poured into water. The aqueous phase was made strongly alkaline with sodium hydroxide solution, extracted with methylene chloride and then adjusted to pH 2 with concentrated hydrochloric acid. The aqueous phase was extracted with ethyl acetate, the organic phase was dried with magnesium sulfate and the solvent was distilled off. The residue was taken up in toluene, a spatula tip of p-toluenesulfonic acid was added and the solvent was distilled off at 60.degree. 7.9 g of oil were dissolved in 75 ml of water and 2.4 g of NaOH and 5.7 ml of dimethyl sulfate were quickly added dropwise. After one hour the reaction was complete and the mixture was poured into water. The aqueous phase was extracted with ether, the organic phase was dried with magnesium sulfate and the solvent was distilled off. The residue was used in the subsequent reaction without further purification.
Beispiel 3 :Example 3:
2-Methylsulfonyl-4 , 5-cyclopenteno-thiazol2-methylsulfonyl-4,5-cyclopentenothiazole
Es wurden 1,9 g 2-Methylmercapto-4, 5-cyclopenteno-thiazol in1.9 g of 2-methylmercapto-4,5-cyclopentenothiazole were added
Methylenchlorid bei Eistemperatur vorgelegt und 7.3 g mCPBA zugegeben. Der Ansatz wurde bei Raumtemperatur 16 Stunden gerührt und anschließend einmal mit 1 N Natronlauge und mit Natriumthiosulfat-Lösung extrahiert. Die organische Phase wurde über Magnesium- sulfat getrocknet, das Lösungsmittel abdestilliert und 2,25 g Öl isoliert, die direkt weiter eingesetzt wurden.Methylene chloride submitted at ice temperature and 7.3 g of mCPBA added. The mixture was stirred at room temperature for 16 hours and then extracted once with 1 N sodium hydroxide solution and with sodium thiosulfate solution. The organic phase was dried over magnesium sulfate, the solvent was distilled off and 2.25 g of oil were isolated, which were used directly.
iH-NMR (200 MHz): 3.26 ppm (3 H, s), 3.05 (2 H, dd) , 2.95(2 H, dd) , 2.55 (2 H, dddd) . i H-NMR (200 MHz): 3.26 ppm (3 H, s), 3.05 (2 H, dd), 2.95 (2 H, dd), 2.55 (2 H, dddd).
ESI-MS: M+ 203 Beispiel 4 :ESI-MS: M + 203 Example 4:
2-Methylsulfonyl-4 , 5-dimethyloxazol2-methylsulfonyl-4,5-dimethyloxazole
Es wurden 3 g 2-Methylthio-4, 5-dimethyloxazol in 100 ml Methylenchlorid gelöst und bei Eistemperatur 13 g mCPBA zugegeben. Der Ansatz wurde drei Stunden gerührt und anschließend auf Natrium- thiosulfat-Lösung gegeben.Mit Natriumhydrogencarbonat wurde neutralisiert und das Produkt mit Methylenchlorid extrahiert. Nach dem Trocknen über Magnesiumsulfat wurde das Lösungsmittel abdestilliert und 2 g Rohprodukt isoliert, die direkt weiter eingesetzt werden konnten.3 g of 2-methylthio-4,5-dimethyloxazole were dissolved in 100 ml of methylene chloride and 13 g of mCPBA were added at ice temperature. The mixture was stirred for three hours and then added to sodium thiosulfate solution. The mixture was neutralized with sodium bicarbonate and the product was extracted with methylene chloride. After drying over magnesium sulfate, the solvent was distilled off and 2 g of crude product isolated, which could be used directly.
!H-NMR (200 MHz): 3.30 ppm (3 H, s), 2.35(3 H, s) , 2.15 (3 H, s) . ESI-MS: M+ = 175! H NMR (200 MHz): 3.30 ppm (3 H, s), 2.35 (3 H, s), 2.15 (3 H, s). ESI-MS: M + = 175
Beispiel 5 :Example 5:
(S)-2- (4 , 5-dimethylthiazol -2-yloxy) -3-methoxy-3 , 3-diphenylpro- pionsäure (1-1)(S) -2- (4,5-dimethylthiazol -2-yloxy) -3-methoxy-3,3-diphenylpropionic acid (1-1)
Zu einer Vorlage aus 1 g S-2-Hydroxy-3-methoxy-3 , 3-diphenylpro- pionsäure in 20 ml THF/ 20 ml DMF wurden 320 mg 55% NaH zugegeben und 15 Minuten nachgerührt. Zu dieser Mischung wurden 700 mg 2-Methylsulfonyl-4, 5-dimethylthiazol zugegeben und 16 Stunden bei Raumtemperatur gerührt. Anschließend wurde der Ansatz mit Wasser versetzt, mit Citronensäure angesäuert und das Produkt mit Ether extrahiert. Nach dem Trocknen über Magnesiumsulfat und dem Abde- stiellieren des Lösungsmittels wurde chromatographisch gereinigt und das Produkt aus Ether/n-Hexan auskristllisiert . Es wurden 522 mg Kristalle isoliert.320 mg of 55% NaH were added to a mixture of 1 g of S-2-hydroxy-3-methoxy-3, 3-diphenylpropionic acid in 20 ml of THF / 20 ml of DMF and the mixture was stirred for 15 minutes. 700 mg of 2-methylsulfonyl-4,5-dimethylthiazole were added to this mixture and the mixture was stirred at room temperature for 16 hours. The mixture was then mixed with water, acidified with citric acid and the product extracted with ether. After drying over magnesium sulfate and the solvent had been removed, the mixture was purified by chromatography and the product was crystallized from ether / n-hexane. 522 mg of crystals were isolated.
iH- MR (200 MHz): 7.35-7.20 ppm (10 H, m) , 6.25 (1 H, s) , 3.30 (3 H, s), 2.25(3 H, s) , 2.20 (3 H, s) . i H-MR (200 MHz): 7.35-7.20 ppm (10 H, m), 6.25 (1 H, s), 3.30 (3 H, s), 2.25 (3 H, s), 2.20 (3 H, s ).
ESI-MS: M+ = 383ESI-MS: M + = 383
Beispiel 6:Example 6:
2-(4, 5-Cyclopentenothiazol-2-yloxy)-3-(2-(3, 4 dimethoxy- phenyl) ethoxy) -3 , 3-diphenylpropionsäure (1-17 )2- (4, 5-Cyclopentenothiazol-2-yloxy) -3- (2- (3, 4 dimethoxyphenyl) ethoxy) -3, 3-diphenylpropionic acid (1-17)
XH-NMR (200 MHz): 7.30-7.20 ppm (10 H, m) , 6.80-6.60 (3 H, m) , 6.25 (1 H, s), 3.85 (3 H, s) , 3.80 (3 H, s) , 3.70-3.40 (2 H, m) , 2.9-2.6 (4 H, m) , 2.30-2.25 (2 H, m) . ES I-MS : M+ = 545 X H-NMR (200 MHz): 7.30-7.20 ppm (10 H, m), 6.80-6.60 (3 H, m), 6.25 (1 H, s), 3.85 (3 H, s), 3.80 (3 H , s), 3.70-3.40 (2 H, m), 2.9-2.6 (4 H, m), 2.30-2.25 (2 H, m). ES I-MS: M + = 545
2- (4 , 5-Dimethyloxazol-2-yloxy) -3- (2- (3 , 4 dimethoxy- phenyl) ethoxy) -3 , 3-diphenylpropionsäure (1-15)2- (4, 5-Dimethyloxazol-2-yloxy) -3- (2- (3, 4 dimethoxyphenyl) ethoxy) -3, 3-diphenylpropionic acid (1-15)
iH- MR (200 MHz): 7.30-7.20 ppm (10 H, m) , 6.80-6.60 (3 H, m) , 6.00 (1 H, s), 3.85 (3 H, s) , 3.80 (3 H, s) , 3.70-3.40 (2 H, m) , 2.80 (2 H, tr) , 2.10 (3 H, s), 1.90 (3 H, s). i H-MR (200 MHz): 7.30-7.20 ppm (10 H, m), 6.80-6.60 (3 H, m), 6.00 (1 H, s), 3.85 (3 H, s), 3.80 (3 H , s), 3.70-3.40 (2 H, m), 2.80 (2 H, tr), 2.10 (3 H, s), 1.90 (3 H, s).
ESI-MS: M+ = 517ESI-MS: M + = 517
(S)-2- (Benzothiazol -2-yloxy)-3-methoxy-3, 3-diphenylpropionsäure (1-6)(S) -2- (benzothiazol -2-yloxy) -3-methoxy-3, 3-diphenylpropionic acid (1-6)
!H-NMR (200 MHz): 7.70-7.50 (2 H, m) , 7.35-7.20 (12 H, m) , 6.50 (1 H, s) , 3.30 (3 H, s) . ! H-NMR (200 MHz): 7.70-7.50 (2 H, m), 7.35-7.20 (12 H, m), 6.50 (1 H, s), 3.30 (3 H, s).
ESI-MS: M+ = 405ESI-MS: M + = 405
(S)-2- (4, 5-Cyclopentenothiazol-2-yloxy)-3-methoxy-3, 3-diphenyl- propionsäure (1-5)(S) -2- (4,5-cyclopentenothiazol-2-yloxy) -3-methoxy-3,3-diphenylpropionic acid (1-5)
XH-NMR (200 MHz): 7.50-7.20 ppm (10 H, m) , 6.40 (1 H, s) , 3.30 (3 H, s), 2.80-2.60 (4 H, m) , 2.30 (2 H, m) . X H-NMR (200 MHz): 7.50-7.20 ppm (10 H, m), 6.40 (1 H, s), 3.30 (3 H, s), 2.80-2.60 (4 H, m), 2.30 (2 H , m).
ESI-MS: M+ = 395ESI-MS: M + = 395
(S) -2- (4, 5-Dimethyloxazol-2-yloxy) -3-methoxy-3 , 3-diphenylpro- pionsäure (1-4)(S) -2- (4,5-dimethyloxazol-2-yloxy) -3-methoxy-3,3-diphenylpropionic acid (1-4)
!H-NMR (200 MHz): 7.50-7.20 ppm (10 H, m) , 6.10 (1 H, s) , 3.25 (3 H, s), 2.1 (3H, s), 1.90 (3 H, s). ! H-NMR (200 MHz): 7.50-7.20 ppm (10 H, m), 6.10 (1 H, s), 3.25 (3 H, s), 2.1 (3H, s), 1.90 (3 H, s).
ESI-MS: M+ = 367ESI-MS: M + = 367
2- (4, 5-Dimethylthiazol-2-yloxy) -3- (2- (3 , 4-dimethoxy- phenyl ) ethoxy) -3 , 3-diphenylpropionsäure ( 1-13 )2- (4, 5-Dimethylthiazol-2-yloxy) -3- (2- (3, 4-dimethoxyphenyl) ethoxy) -3, 3-diphenylpropionic acid (1-13)
XH-NMR (200 MHz): 7.30-7.20 ppm (10 H, m) , 6.70-6.50 (3 H, m) , 6.20 (1 H, s), 3.90 (3 H, s) , 3.85 (3 H, s) , 3.70-3.40 (2 H, m) , 2.80 (2 H, tr) , 2.20 (3 H, s), 1.15 (3 H, s). X H NMR (200 MHz): 7.30-7.20 ppm (10 H, m), 6.70-6.50 (3 H, m), 6.20 (1 H, s), 3.90 (3 H, s), 3.85 (3 H , s), 3.70-3.40 (2 H, m), 2.80 (2 H, tr), 2.20 (3 H, s), 1.15 (3 H, s).
ESI-MS: M+ = 533.ESI-MS: M + = 533.
Analog oder wie im allgemeinen Teil beschrieben lassen sich die Verbindungen in der Tabelle I herstellen. Tabelle IThe compounds in Table I can be prepared analogously or as described in the general part. Table I
tt
Beispi el 7Example 7
Gemäß dem oben beschriebenen Bindungstest wurden für die nachfol- gend aufgeführten Verbindungen Rezeptorbindungsdaten gemessen.According to the binding test described above, receptor binding data were measured for the compounds listed below.
Die Ergebnisse sind in Tabelle 2 dargestellt.The results are shown in Table 2.
Tabelle 2Table 2
Rezeptorbindungsdaten (Ki-Werte)Receptor binding data (Ki values)

Claims

Patentansprüche claims
1. Heterocyclisch substituierte α-Hydroxycarbonsäurederivate1. Heterocyclically substituted α-hydroxycarboxylic acid derivatives
0 wobei R1 Tetrazol oder eine Gruppe 0 where R 1 is tetrazole or a group
0 II C—R 5 in der R folgende Bedeutung hat:0 II C — R 5 in which R has the following meaning:
a) ein Rest OR5, worin R5 bedeutet:a) a radical OR 5 , in which R 5 denotes:
^ Wasserstoff, das Kation eines Alkalimetalls, das Kation eines Erdalkalimetalls oder ein physiologisch verträgliches organisches Ammoniumion;^ Hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal or a physiologically acceptable organic ammonium ion;
C3-C8-Cycloalkyl, Cx-C8-Alkyl, CH2-Phenyl, C3-C8-Alkenyl, 5 C3-C8-Alkinyl oder Phenyl jeweils gegebenfalls substituiert.C 3 -C 8 cycloalkyl, C x -C 8 alkyl, CH 2 phenyl, C 3 -C 8 alkenyl, 5 C 3 -C 8 alkynyl or phenyl are each optionally substituted.
b) ein über ein Stickstoffatom verknüpfter 5-gliedrigerb) a 5-member linked via a nitrogen atom
Heteroaromat. 0 c) eine GruppeHeteroaromatic. 0 c) a group
in der k die Werte 0, 1 und 2, p die Werte 1, 2, 3 und 4 annehmen kann und R6 für 0in which k can have the values 0, 1 and 2, p can have the values 1, 2, 3 and 4 and R 6 for 0
Cι-C4-Alkyl, C3-C8-Cycloalkyl, C3-C8-Alkenyl, C3-C8-Alkinyl oder gegebenenfalls substituiertes Phenyl steht.-C-C 4 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl or optionally substituted phenyl.
5 d) ein Rest5 d) a rest
OO
—N S - R7 —NS - R 7
H IIH II
00
worin R7 bedeutet :where R 7 means:
Cι-C-Alkyl, C3-C8-Alkenyl , C3-C8-Alkinyl, C3-C8-Cycloalkyl , wobei diese Reste einen Cι-C-Alkoxy , Cι-C4-Alkylthio- und/oder einen Phenylrest tragen können;C 1 -C 8 alkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 8 cycloalkyl, these radicals being a C 1 -C 8 alkoxy, C 1 -C 4 alkylthio and / or can carry a phenyl radical;
Cι-C-Halogenalkyl oder Phenyl, gegebenenfalls substituiert.-C-C haloalkyl or phenyl, optionally substituted.
A NR8R9, Azido, OR10, SR10 oder Cι-C4-AlkylA NR 8 R 9 , azido, OR 10 , SR 10 or -CC 4 alkyl
X Sauerstoff, Schwefel, CR11 oder NR12; mit der Maßgabe, falls X = CR11, dann Y = Sauerstoff oder Schwefel oder NR14;X is oxygen, sulfur, CR 11 or NR 12 ; with the proviso that if X = CR 11 , then Y = oxygen or sulfur or NR 14 ;
Y Sauerstoff, Schwefel, CR13 oder NR14; mit der Maßgabe, falls Y = Sauerstoff oder Schwefel oder NR14, dannY is oxygen, sulfur, CR 13 or NR 14 ; with the proviso if Y = oxygen or sulfur or NR 14 , then
X = CR11;X = CR 11 ;
R2 und R3 (die gleich oder verschieden sein können) :R 2 and R 3 (which may be the same or different):
Phenyl oder Naphthyl, gegebenenfalls substituiert, oderPhenyl or naphthyl, optionally substituted, or
Phenyl oder Naphthyl, die orthoständig über eine direkte Bindung, eine Methylen-, Ethylen- oder Ethenylengruppe, ein Sauerstoff- oder Schwefelatom oder eine S02-, NH- oder N(Cχ-C4- Alkyl ) -Gruppe miteinander verbunden sindPhenyl or naphthyl, which are ortho-linked via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 2 -, NH or N (Cχ-C 4 - alkyl) group
Cs-Cs-Cycloalkyl gegebenfalls substituiert;Cs-Cs-cycloalkyl optionally substituted;
R4 und R11 (die gleich oder verschieden sein können) :R 4 and R 11 (which may be the same or different):
Wasserstoff, Halogen, Cι-C4_Alkoxy, Cι-C4-Halogenalkoxy, C3-C6-Alkenyloxy, C3-C6-Alkinyloxy, Cι-C-Alkylthio, Cι-C-Alkylcarbonyl, C!-C4-Alkoxycarbonyl, Hydroxy, NH2, NH(Cι-C -Alkyl) , N(Cι-C4-Alkyl) 2 Ci-Cj-Alkyl, C2-C4-Alkenyl, C2-C-Alkinyl , wobei diese Reste gegebenenfalls substituiert sein können;Hydrogen, halogen, Cι-C 4 _Alkoxy, Cι-C 4 haloalkoxy, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, Cι-C-alkylthio, Cι-C alkyl-carbonyl, C! -C 4 -alkoxycarbonyl, hydroxy, NH 2 , NH (-CC alkyl), N (-C 4 alkyl) 2nd Ci-Cj-alkyl, C 2 -C 4 alkenyl, C 2 -C alkynyl, where these radicals can be optionally substituted;
oder CR4 bildet zusammen mit CR11 einen 5- oder 6- gliedrigen Alkylen- oder Alkenylenring, der gegebenfalls substituiert sein kann, und worin jeweils eine oder mehrere Methylengruppen durch Sauerstoff, Schwefel, -NH oder -N(Cι~C4-Alkyl) , ersetzt sein können;or CR 4 forms together with CR 11 a 5- or 6-membered alkylene or alkenylene ring, which may optionally be substituted, and in which one or more methylene groups each by oxygen, sulfur, -NH or -N (-C ~ C 4 alkyl ), can be replaced;
R8 Wasserstoff, Cι-C8-Alkyl, C3-C8-Alkenyl, C3-C8-Alkinyl ,R 8 is hydrogen, -CC 8 alkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl,
Cx-Cs-Alkylcarbonyl, wobei diese Reste gegebenenfalls substituiert sein können;Cx-Cs-alkylcarbonyl, where these radicals can optionally be substituted;
Phenyl oder Naphthyl, gegebenenfalls substituiert;Phenyl or naphthyl, optionally substituted;
gegebenenfalls substituiertes C3-C8-Cycloalkyl;optionally substituted C 3 -C 8 cycloalkyl;
oder R8 bildet gemeinsam mit R9 eine zu einem Ring geschlossene C3-C7-Alkylenkette, die gegebenenfalls substi- tuiert sein kann, und in der eine Alkylengruppe durchor R 8 forms, together with R 9, a C 3 -C 7 alkylene chain which is closed to form a ring, which may be substituted, and in which an alkylene group forms
Sauerstoff oder Schwefel ersetzt sein kann;Oxygen or sulfur can be replaced;
R9 Wasserstoff, Cι-C4-Alkyl;R 9 is hydrogen, -CC 4 alkyl;
oder R9 ist mit R8 wie unter R8 angegeben zu einem Ring verknüpft;or R 9 is linked to R 8 as stated under R 8 to form a ring;
R10 Wasserstoff, Cι-C8-Alkyl, C3-C8-Alkenyl, C3-C8.Alkinyl, wobei diese Reste gegebenenfalls substituiert sein können; Phenyl oder Naphthyl, gegebenenfalls substituiert;R 10 is hydrogen, -CC 8 alkyl, C 3 -C 8 alkenyl, C 3 -C 8 .alkynyl, where these radicals can be optionally substituted; Phenyl or naphthyl, optionally substituted;
gegebenenfalls substituiertes C3-C8-Cycloalkyl;optionally substituted C 3 -C 8 cycloalkyl;
R12 Wasserstoff, Cι-C4-Alkyl;R 12 is hydrogen, -CC 4 alkyl;
oder NR12 bildet zusammen mit CR4 einen 5- oder 6- gliedrigen Alkylen- oder Alkenylenring, der gegebenfalls substituiert sein kann, und worin jeweils eine oder mehrere Methylengruppen durch Sauerstoff oder Schwefel er- setzt sein können;or NR 12 forms together with CR 4 a 5- or 6-membered alkylene or alkenylene ring, which may be substituted and in which one or more methylene groups can be replaced by oxygen or sulfur;
R13 Wasserstoff, Halogen, Cι-C4-Alkyl, C2-C-Alkenyl,R 13 is hydrogen, halogen, -CC 4 alkyl, C 2 -C alkenyl,
C2-C4-Alkinyl, wobei diese Reste gegebenfalls substituiert sein können;C 2 -C 4 alkynyl, where these radicals can optionally be substituted;
R14 Wasserstoff, Cι-C4-Alkyl; bedeuten ,R 14 is hydrogen, -CC 4 alkyl; mean
sowie die pysiologisch verträglichen Salze, und die möglichen enantiomerenreinen und diastereoisomerenreinen Formen.as well as the physiologically acceptable salts, and the possible enantiomerically pure and diastereoisomerically pure forms.
2. Verwendung der heterocyclisch substituierten α-Hydroxycarbonsäurederivate I gemäß Anspruch 1 zur Behandlung von Krankheiten.2. Use of the heterocyclically substituted α-hydroxycarboxylic acid derivatives I according to claim 1 for the treatment of diseases.
3. Verwendung der Verbindungen I gemäß Anspruch 2 als Endothelin Rezeptorantagonisten .3. Use of the compounds I according to claim 2 as endothelin receptor antagonists.
4. Verwendung der heterocyclisch substituierten α-Hydroxycarbonsäurederivate I gemäß Anspruch 1 zur Herstellung von Arznei- mittein zur Behandlung von Krankheiten, bei denen erhöhte Endothelinspiegel auftreten.4. Use of the heterocyclically substituted α-hydroxycarboxylic acid derivatives I as claimed in claim 1 for the production of medicaments for the treatment of diseases in which elevated endothelin levels occur.
5. Verwendung der heterocyclisch substituierten α-Hydroxycarbonsäurederivate I gemäß Anspruch 1 zur Herstellung von Arznei- mittein zur Behandlung von Krankheiten, bei denen Endothelin zur Entstehung und/oder Progression beiträgt.5. Use of the heterocyclically substituted α-hydroxycarboxylic acid derivatives I according to claim 1 for the manufacture of medicaments for the treatment of diseases in which endothelin contributes to the development and / or progression.
6. Verwendung der heterocyclisch substituierten α-Hydroxycarbonsäurederivate I gemäß Anspruch 1 zur Behandlung von chro- nischer Herzinsuffizienz, Restenose, Bluthochdruck, pulmonalem Hochdruck, akutem/chronischen Nierenversagen, zerebraler Ischämie, Asthma, benigne Prostatahyperpiasie und Prostatakrebs .6. Use of the heterocyclically substituted α-hydroxycarboxylic acid derivatives I according to claim 1 for the treatment of chronic heart failure, restenosis, high blood pressure, pulmonary high pressure, acute / chronic renal failure, cerebral ischemia, asthma, benign prostatic hyperpiasia and prostate cancer.
7. Kombinationen aus heterocyclisch substituierten α-Hydroxycar- bonsäurederivaten I gemäß Anspruch 1 und einem oder mehreren Wirkstoffen, ausgewählt aus Inhibitoren des Renin-Angiotensin Systems wie Reninhemmer, Angiotensin-II-Antagonisten, Angio- tensin-Converting-Enzyme (ACE) -Hemmer, gemischten ACE/Neu- trale Endopeptidase (NEP) -Hemmern, ß-Blockern, Diuretika, Calciumantagonisten und VEGF-blockierenden Substanzen.7. Combinations of heterocyclically substituted α-hydroxycarboxylic acid derivatives I as claimed in claim 1 and one or more active substances, selected from inhibitors of the renin-angiotensin system such as renin inhibitors, angiotensin-II antagonists, angiotensin converting enzymes (ACE) inhibitors , mixed ACE / neutral endopeptidase (NEP) inhibitors, β-blockers, diuretics, calcium antagonists and VEGF-blocking substances.
8. ArzneimittelZubereitungen zur peroralen und parenteralen Anwendung, enthaltend pro Einzeldosis, neben den üblichen Arzneimittelhilfsstoffen, mindestens ein Carbonsäurederivat I gemäß Anspruch 1. 8. Pharmaceutical preparations for oral and parenteral use, containing, in addition to the usual pharmaceutical excipients, at least one carboxylic acid derivative I according to claim 1 per single dose.
9. Ein strukturelles Fragment der Formel9. A structural fragment of the formula
worin die Reste R1, R2, R3, R4, X und Y die in Anspruch 1 an- gegebene Bedeutung haben, als strukturelles Fragment in einem Endothelin-Rezeptorantagonisten. wherein the radicals R 1 , R 2 , R 3 , R 4 , X and Y have the meaning given in claim 1, as a structural fragment in an endothelin receptor antagonist.
Neue heterocyclisch substituierte α-Hydroxycarbonsäurederivate, ihre Herstellung und Verwendung als EndothelinrezeptorantagonistenNew heterocyclically substituted α-hydroxycarboxylic acid derivatives, their production and use as endothelin receptor antagonists
ZusammenfassungSummary
Die vorliegende Erfindung betrifft Carbonsäurederivate der Formel IThe present invention relates to carboxylic acid derivatives of the formula I.
wobei die Substituenten die in der Beschreibung erläuterte Bedeutung haben, die Herstellung und Verwendung als Endothelinrezeptorantagonisten. where the substituents have the meaning explained in the description, the preparation and use as endothelin receptor antagonists.
EP98958900A 1997-11-14 1998-11-04 NOVEL HETEROCYCLICALLY SUBSTITUTED $g(a)-HYDROXYCARBOXLIC ACID DERIVATIVES, METHOD FOR PRODUCING THE SAME AND THEIR USE AS ENDOTHELIN RECEPTOR ANTAGONISTS Withdrawn EP1037883A1 (en)

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