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WO1999011629A1 - Nouveaux derives d'acide carboxylique, leur production et leur utilisation comme antagonistes mixtes des recepteurs d'endotheline eta et et¿b? - Google Patents

Nouveaux derives d'acide carboxylique, leur production et leur utilisation comme antagonistes mixtes des recepteurs d'endotheline eta et et¿b? Download PDF

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Publication number
WO1999011629A1
WO1999011629A1 PCT/EP1998/005354 EP9805354W WO9911629A1 WO 1999011629 A1 WO1999011629 A1 WO 1999011629A1 EP 9805354 W EP9805354 W EP 9805354W WO 9911629 A1 WO9911629 A1 WO 9911629A1
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Prior art keywords
alkyl
phenyl
halogen
alkoxy
haloalkoxy
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PCT/EP1998/005354
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German (de)
English (en)
Inventor
Wilhelm Amberg
Rolf Jansen
Dagmar Klinge
Hartmut Riechers
Stefan Hergenröder
Manfred Raschack
Liliane Unger
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Basf Aktiengesellschaft
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Priority claimed from DE19738578A external-priority patent/DE19738578A1/de
Priority claimed from DE1998111915 external-priority patent/DE19811915A1/de
Priority to BR9811631-2A priority Critical patent/BR9811631A/pt
Priority to SK152-2000A priority patent/SK1522000A3/sk
Priority to JP2000508669A priority patent/JP2001514254A/ja
Priority to IDW20000386D priority patent/ID25620A/id
Priority to AU95333/98A priority patent/AU748610B2/en
Priority to KR1020007002264A priority patent/KR20010023615A/ko
Application filed by Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Priority to NZ502660A priority patent/NZ502660A/en
Priority to HU0004935A priority patent/HUP0004935A3/hu
Priority to CA002302350A priority patent/CA2302350A1/fr
Priority to IL13427698A priority patent/IL134276A0/xx
Priority to EP98948859A priority patent/EP1009741A1/fr
Publication of WO1999011629A1 publication Critical patent/WO1999011629A1/fr
Priority to NO20001077A priority patent/NO20001077D0/no
Priority to BG104222A priority patent/BG104222A/xx

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
    • C07D233/70—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D263/44—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to new carboxylic acid derivatives, their preparation and use.
  • Endothelin is a peptide made up of 21 amino acids that is synthesized and released by vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3.
  • endothelin or “ET” means one or all isoforms of endothelin.
  • Endothelin is a potent vasocon-
  • vasoconstriction is known to be caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).
  • endothelin causes persistent vascular contraction in peripheral, renal, and cerebral blood vessels, which can lead to disease.
  • endothelin is involved in a number of diseases.
  • ET A and ET B receptor 35 are currently described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990)). Accordingly, substances that inhibit the binding of endothelin to the two receptors should antagonize the physiological effects of endothelin and should therefore be valuable pharmaceuticals.
  • WO 96/11914 describes carboxylic acid derivatives which, however, bind with a high affinity to the ET A receptor and with a substantially lower affinity to the ET B receptor (so-called ET A -specific antagonists).
  • ET A -specific antagonists here as antagonists whose affinity for the ET A receptor is at least ten times higher than their affinity for the ET B receptor.
  • the task was to provide endothelin receptor antagonists that bind to the ⁇ T A and ET B receptors with approximately the same affinity (so-called mixed antagonists).
  • the invention relates to carboxylic acid derivatives of the formula I carboxylic acid derivatives of the formula I.
  • R 1 is a radical OR 7 , where R 7 is:
  • R 2 hydrogen f, hydroxy, NH 2 , NH (-C 4 alkyl), N (-C 4 alkyl) 2 / halogen, -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -alkynyl, C ⁇ -C -haloalkyl, -C ⁇ C -alkoxy, C ⁇ -C -haloalkoxy or
  • CR 2 is linked with CR 10 as given below to a 5- or 6-membered ring; or, if Het represents a five-membered ring, CR 2 together with CR 3 may represent a 5- or 6-membered alkenyl or alkylenyl ring which may optionally be substituted;
  • W is nitrogen or CR 10 , wherein R 10 is hydrogen or C 4 alkyl or CR 10 together with CR 2 or CR 3 forms a 5- or 6-membered alkylene or alkenylene ring, which may optionally be substituted, and in each case one or more methylene groups can be replaced by oxygen, sulfur, -NH or -N (-CC 4 _alkyl);
  • R 3 is hydrogen, hydroxy, NH 2 , NH (-C 4 alkyl), N (-C 4 alkyl) 2 , halogen, -C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, C ⁇ -C haloalkyl, C ⁇ -C 4 -alkoxy, C 4 haloalkoxy, C ⁇ -C4-alkylthio; or CR 3 is linked to CR 10 to a 5- or 6-membered ring as stated above;
  • R 4 and R 5 (which may be the same or different):
  • Phenyl or naphthyl optionally substituted, or
  • R 6 is hydrogen, Ci-Cs-alkyl, C 3 -Cs-alkenyl or C 3 -Cs-alkynyl, where these radicals can each be substituted one or more times by: halogen, hydroxy, mercapto, carboxy, nitro, amino, cyano , -C-C 4 alkoxy, CC 6 -alkenoxy, CC 6 -alkynyloxy, -C-C 4 -alkylthio, -C-C 4 -haloalkoxy, -C-C 4 -alkylcarbonyl, -C-C 4 -alkoxycarbonyl, C 3 _ 8 -Alkylcarbonyl- alkyl, NH (-C-C 4 alkyl), N (Cj.-C 4 alkyl) 2 , C 3 -C 8 cycloalkyl, heteroaryloxy or heteroaryl, five- or six-membered, containing one to three nitrogen atoms
  • Phenyl or naphthyl each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, Ci-C 4 -alkyl, C ⁇ 4 haloalkyl, C ⁇ -C4 alkoxy, C ⁇ - C 4 -haloalkoxy, phenoxy, C ⁇ -C 4 alkylthio, C ⁇ ⁇ C 4 alkylamino, C 1 -C 4 -DialkylaiTU.no, dioxomethylene or Dioxoethylen;
  • a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom, which can carry one to four halogen atoms and / or one or two of the following radicals: -CC 4 alkyl, -C-C 4 - haloalkyl, C ⁇ -C 4 -alkoxy, C 4 haloalkoxy,
  • C ⁇ -C 4 alkylthio phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals or may carry one to three of the following radicals in turn one to five halogen atoms and / a: C ⁇ -C 4 -alkyl, C 4 haloalkyl, C ⁇ ⁇ C 4 -alkoxy, C 4 -haloalkoxy and / or C ⁇ -C 4 alkylthio;
  • C3 -CG-cycloalkyl where these radicals may each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C -alkynyl, -CC 4 alkoxy, C ! -C 4 -Alkylthio, -C-C 4 haloalkoxy;
  • R 8 CI-C 6 alkyl mean, as well as the physiologically acceptable salts, and the enantiomerically pure forms.
  • An alkali metal is e.g. Lithium, sodium, potassium;
  • alkaline earth metal is e.g. Calcium, magnesium, barium;
  • C 3 -Cs cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
  • C ⁇ -C 4 haloalkyl can be linear or branched such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2, 2, 2-trifluoroethyl, 2-chlorine -2, 2-difluoroethyl, 2, 2-dichloro-2-fluoroethyl, 2, 2, 2-trichloroethyl or pentafluoroethyl;
  • C 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-l, 1, 2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;
  • C 1 -C 4 -alkyl can be linear or branched, such as methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl;
  • CC 4 alkenyl can be linear or branched, such as 3. Ethenyl, l-propen-3-yl, l-propen-2-yl, 1-propen-l-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-pro-in-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;
  • C 1 -C 4 -alkoxy can be linear or branched such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1-dimethylethoxy;
  • C 3 -C 6 alkenyloxy can be linear or branched, for example allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;
  • CC 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, for example, 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 1 -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, 3-0xo-but-1-yl or 3-oxo-but-2-yl
  • Ci-C ⁇ alkyl can be linear or branched such as -CC 4 alkyl, pentyl, hexyl, heptyl or octyl;
  • Halogen is e.g. Fluorine, chlorine, bromine, iodine.
  • the invention further relates to those compounds from which the compounds of the formula I can be released (so-called prodrugs).
  • 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 compounds and also the intermediates for their preparation can have one or more asymmetrically substituted carbon atoms.
  • Such compounds can exist as pure enantiomers or pure diastereomers or as a mixture thereof. Preference is given to using an enantiomerically pure compound as the active ingredient.
  • 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 according to the invention are particularly suitable as mixed antagonists as defined at the outset.
  • Compounds of general formula III are either known or can e.g. can be synthesized by reducing the corresponding carboxylic acids or their esters, or by other generally known methods.
  • R 11 is halogen or R 1 -S0 2 -, where R 12
  • C ⁇ ⁇ C-alkyl, C ⁇ -C-haloalkyl or phenyl can be. Furthermore, at least one of the ring members X or Y or Z is nitrogen.
  • the reaction preferably takes place in an inert solvent or diluent with the addition of a suitable base, i.e. a base, which brings about a deprotonation of the intermediate IV, takes place 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, Ether, such as play 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, Ether, such as play diisopropyl ether, dibutyl ether, methyl tert
  • nitriles such as, for example, acetonitrile and propionitrile
  • acid amides such as, for example, dimethylformamide, dimethylacetamide and N-methylpyrrolidone
  • sulfoxides and sulfones such as, for example, dimethyl sulfoxide and sulfolane.
  • an alkali or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride
  • a carbonate such as alkali metal carbonate, 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 a
  • Alkali amide such as lithium diisopropylamide or lithium amide are used.
  • 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 converting them first in the usual manner into an activated form such as an acid halide, an anhydride or Imidazolid transferred and then reacted with a corresponding hydroxyl compound H ⁇ R 7 .
  • 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 also be simplified, for example, by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a water-releasing agent such as a carbodiimide.
  • compounds of the formula I can also be prepared by starting from the salts of the corresponding carboxylic acids, ie from compounds of the formula I in which R 1 is a group COR and R is OM, where M is an alkali metal cation or the Can be equivalent to an alkaline earth metal cation.
  • R 1 is a group COR and R is OM
  • M is an alkali metal cation or the Can be equivalent to an alkaline earth metal cation.
  • These salts can be reacted with many compounds of the formula RA, where A is a customary nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl optionally substituted by halogen, alkyl or haloalkyl, such as toluenesulfonyl and methylsulfonyl or one other equivalent leaving group.
  • A is a customary nucleofugic leaving group, for example hal
  • R 1 COOR 7 wherein R 7 means:
  • R 2 is hydrogen, hydroxy, halogen, N (C ⁇ -C 4 -alkyl) 2 , dC 4 -alkyl, -C-C-alkoxy, C ⁇ -C-alkylthio, C ⁇ -C 4 -haloalkyl, C ⁇ -C 4 -haloalkoxy, or CR 2 is linked to CR 10 to a 5- or 6-membered ring as indicated below; or, if Het represents a five-membered ring, CR 2 together with CR 3 may represent a 5- or 6-membered alkenyl or alkylenyl ring which may be substituted;
  • At least one of the ring members X, Y or W is nitrogen.
  • R 3 is hydrogen, hydroxy, halogen, N (C ⁇ -C 4 -alkyl) 2 , -C-C-alkyl, C ⁇ -C 4 -alkoxy, C ⁇ -C 4 -alkylthio, C ⁇ -C-haloalkyl, C ⁇ -C 4 - Haloalkoxy, or CR 3 is with CR 10 as indicated above linked into a 5- or 6-membered ring; or, if Het represents a five-membered ring, CR 2 together with CR 3 may represent a 5- or 6-membered alkenyl or alkylenyl ring which may be substituted;
  • R 4 and R 5 (which may be the same or different):
  • Phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, amino, C ⁇ ⁇ C 4 -alkyl, C 4 haloalkyl, C ⁇ -C4-alkoxy, C ⁇ -C 4 -haloalkoxy, phenoxy, C ⁇ -C 4 -alkylthio, NH (C -C 4 -alkyl) or N (C ⁇ -C 4 -alkyl) 2 or phenyl, which can be mono- or polysubstituted, for example mono- to trisubstituted by halogen, nitro, cyano, C 4 alkyl, C ⁇ -C4-haloalkyl, C ⁇ -C 4 -alkoxy, C 4 -haloalkoxy or C ⁇ -C 4 alkylthio; 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 2 -, NH or N-alkyl group
  • R 6 is C 3 -C 8 -cycloalkyl, where these radicals in each case may be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 4 -alkoxy, C 4 alkyl, C -C 2 -alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 alkenyloxy, C 3 -C 6 -alkynyl oxy, C ⁇ -C 4 alkylthio, C ⁇ -C4-haloalkoxy, C ⁇ -C 4 -Alkylcarbonyl, -CC 4 -alkoxy-carbonyl, NH (-CC-alkyl), N (C ⁇ -C -alkyl) 2 or phenyl, which can be substituted one or more times, for example one to three times by halogen, nitro, cyano, Ci-C 4 -alkyl, C haloalkyl, C ⁇
  • Phenyl or naphthyl each of which can be substituted by one or more of the following radicals: halogen, nitro, mercapto, carboxy, cyano, hydroxy, amino, C ⁇ -C-alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -Alkynyl, C 3 -C 6 -alkenyloxy, -C-C 4 -halo-alkyl, C 3 -C 6 -alkynyloxy, C 1 -C 4 -alkylcarbonyl, C ⁇ -C 4 -alkoxy-carbonyl, C ⁇ -C 4 - Alkoxy, -C-C haloalkoxy, phenoxy,
  • -C-C 4 alkylthio NH (C -C alkyl), N (C -C 4 alkyl) 2 , dioxomethylene, dioxoethylene or phenyl, which can be substituted one or more times, for example one to three times by Halogen, nitro, cyano, C ⁇ -C 4 -alkyl, C ⁇ -C 4 -haloalkyl, C ⁇ -C-alkoxy, C ⁇ -C-haloalkoxy or CC 4 -alkylthio; a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom which can carry one to four halogen atoms and / or one or two of the following radicals: C ⁇ -C 4 -alkyl, C ⁇ -C 4 - haloalkyl, C ⁇ -C 4 -alkoxy, C 4 haloalkoxy,
  • C ⁇ -C 4 alkylthio phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals or may carry one to three of the following radicals in turn one to five halogen atoms and / a: C ⁇ -C 4 -alkyl, C 4 haloalkyl, C ⁇ -C 4 -alkoxy, C 4 -haloalkoxy and / or C ⁇ -C 4 alkylthio;
  • W CR 10 W CR 10 ;
  • R 2 , R 3 hydrogen, hydroxy, NH 2 , NH (C -C 4 alkyl), N (C -C 4 alkyl) 2 , halogen, CC 4 alkyl, C 2 -C alkenyl, C 2 - C-Alkynyl, C ⁇ -C 4 -haloalkyl, C ⁇ -C -alkoxy, C ⁇ -C -halalkalkoxy or C ⁇ -C 4 -alkylthio, or CR 2 is linked to CR 10 as given below to a 5- or 6-membered ring or, if Het represents a five-membered ring, CR 2 together with CR 3 may represent a 5- or 6-membered alkylene or alkylenyl ring which may be optionally substituted;
  • R 4 is phenyl which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy,
  • R 5 is phenyl or 3, 4-dimethoxyphenyl
  • R 6 C 5 -C 7 cycloalkyl where these radicals can each be mono- or polysubstituted by: C ⁇ -C 4 alkoxy, C ⁇ -C 4 alkyl, C ⁇ -C 4 alkylthio, halogen, hydroxy, carboxy, cyano, trifluoromethyl, acetyl, or phenyl, which can be substituted one or more times, for example one to three times by halogen, cyano, C ⁇ - C 4 alkyl, C ⁇ -C 4 haloalkyl, -C-C alkoxy, C ⁇ -C-haloalkoxy or C ⁇ -C 4 alkylthio;
  • Phenyl or naphthyl each of which can be substituted by one or more of the following radicals: halogen, nitro, mercapto, carboxy, cyano, hydroxy, amino, C ⁇ -C 4 alkyl, C ⁇ -C 4 haloalkyl, acetyl, C ⁇ -C 4 -alkoxycarbonyl, -C-C-alkoxy, C ⁇ -C 4 -haloalkoxy, phenoxy, C ⁇ -C 4 -alkylthio, NH (C ⁇ -C-alkyl), N (C -C 4 -alkyl), dioxomethylene, dioxoethylene or phenyl , which can be mono- or polysubstituted, for example one to three times by halogen, nitro, cyano, C 4 -C 4 alkyl, C ⁇ -C 4 haloalkyl, C ⁇ -C 4 alkoxy, C ⁇ -C 4 haloalkoxy or -C-
  • a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom which can carry one to four halogen atoms and / or one or two of the following radicals: C:-C-alkyl, C ⁇ -C- Haloalkyl, C ⁇ -C 4 -alkoxy, trifluoromethoxy, C ⁇ -C-alkylthio, phenyl or phenoxy, where the phenyl radicals in turn can carry one to five halogen atoms and / or one to three of the following radicals: -C-C 4 alkyl, C ⁇ -C 4 -haloalkyl, -C-C 4 alkoxy, C ⁇ -C 4 -haloalkoxy and / or C ⁇ -C alkyl thio;
  • the compounds of the present invention offer new therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, acute / chronic renal failure, renal insufficiency, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, atherosclerosis, endotoxic Shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty, benign prostate hyperplasia, ischemic and intoxication-caused kidney failure or hypertension, metastasis and growth of mesenchymal tumors, contrast-induced kidney failure, pancreatitis, gastrointestinal.
  • the invention further relates to combination preparations 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, above all, angiotensin converting enzyme (ACE) inhibitors.
  • ACE angiotensin converting enzyme
  • 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 mM glutamine (Gibco No. 25030-024), 100 U / ml penicillin and 100 ⁇ g / ml streptomycin (Gibco, Sigma No. P-0781). After 48 hours, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 minutes at 37 ° C. The mixture was then neutralized with medium and the cells were collected by centrifugation at 300 ⁇ g.
  • the cells were adjusted to a concentration of 10 8 cells / ml buffer (50 mM Tris-HCl buffer, pH 7.4) and then disintegrated by ultrasound (Branson Sonifier 250, 40-70 seconds / constant / output 20).
  • the membranes were incubated in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 M MnCl 2 , 40 ⁇ g / 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] -ET ⁇ (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 with 10 -7 M ETx.
  • the free and the 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.
  • test animals were given the test compounds i.v. 30 min before the administration of ET1. 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, intraperotonically). It can also be applied with vapors or sprays through the nasopharynx.
  • the dosage depends on the age, condition and weight of the patient and on the type of application.
  • the daily dose of active ingredient is between about 0.5 and 50 mg / kg of body weight when administered orally and between about 0.1 and 10 mg / kg of body weight. weight with parenteral administration.
  • 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 (cf. H. Sucker et al. : Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1991).
  • the administration forms obtained in this way normally contain the active ingredient in an amount of 0.1 to 90% by weight.
  • the second diastereomer (720 mg, 2.2 mmol) was dissolved in 9 ml of dioxane and 4.5 ml of 1N sodium hydroxide solution were added. The mixture was stirred for 16 hours, then water was added and the mixture was extracted with ether. The aqueous phase was acidified with citric acid, extracted with ether, the organic phase was dried over magnesium sulfate and the solvent was distilled off. 936 mg of an oil were isolated, which was directly reacted further.
  • Diast. I IH-NMR (200 MHz, CDC13): 7.1-7.5 ppm (10 H, m), 6.9 (3 H, m), 6.25 (1 H, s), 5.75 (1 H, s), 4.45 (1 H, d), 4.35 (1 H, d), 3.9 (3 H, s), 3.85 (6 H, s), 2.4-2.7 (3 H,), 2.3 (6 H, s), 2.0-2.2 ( 1 H, m), 1.7-1.9 (2 H, m).
  • Diast. I IH-NMR (200 MHz, CDC13): 7.1-7.4 ppm (10 H, m), 6.6 (1 H, s), 6.55 (2 H, s), 6.3 (1 H, s), 6.2 (1 H, dtr), 5.9 (1 H, d), 4.0 4.2 (1 H, m), 3.85 (3 H, s), 3.8 (3 H, s), 3.75 (3 H, s), 3.4 (1 H , m), 2.4-2.7 (3 H, m), 2.3 (6 H, s), 2.0-2.1 (1 H, m), 1.5-1.7 (2 H, m).

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Abstract

L'invention concerne des dérivés d'acide carboxylique correspondant à la formule (I) dans laquelle les restes correspondent à la définition donnée dans la description, ainsi que l'utilisation de ces dérivés comme antagonistes mixtes des récepteurs d'endothéline ETA et ETB.
PCT/EP1998/005354 1997-09-04 1998-08-24 Nouveaux derives d'acide carboxylique, leur production et leur utilisation comme antagonistes mixtes des recepteurs d'endotheline eta et et¿b? WO1999011629A1 (fr)

Priority Applications (13)

Application Number Priority Date Filing Date Title
IL13427698A IL134276A0 (en) 1997-09-04 1998-08-24 Novel carboxylic acid derivatives, their production and their use as mixed eta/etb endothelin-receptor antagonists
EP98948859A EP1009741A1 (fr) 1997-09-04 1998-08-24 Nouveaux derives d'acide carboxylique, leur production et leur utilisation comme antagonistes mixtes des recepteurs d'endotheline et a? et et b?
NZ502660A NZ502660A (en) 1997-09-04 1998-08-24 Pyrimidyl- or (oxazolyl- or thiazolyl-)oxy substituted carboxylic acid derivatives useful as mixed ETA/ETB endothelin-receptor antagonists
JP2000508669A JP2001514254A (ja) 1997-09-04 1998-08-24 新規カルボン酸誘導体、その製造及び混合ｅｔａ／ｅｔｂエンドセリン受容体拮抗薬としてのその使用
IDW20000386D ID25620A (id) 1997-09-04 1998-08-24 Turunan-turunan asam karboksilat baru, pembuatannya dan penggunaannya sebagai campuran reseptor antagonis et a/et b
AU95333/98A AU748610B2 (en) 1997-09-04 1998-08-24 Novel carboxylic acid derivatives, their production and their their use as mixed ETa/ETb endothelin-receptor antagonists
KR1020007002264A KR20010023615A (ko) 1997-09-04 1998-08-24 신규 카르복실산 유도체, 그 제조 및 혼합 ｅｔａ/ｅｔｂ엔도텔린 수용체 길항제로서의 용도
BR9811631-2A BR9811631A (pt) 1997-09-04 1998-08-24 Derivado de ácido carboxìlico e uso do mesmo
SK152-2000A SK1522000A3 (en) 1997-09-04 1998-08-24 Novel carboxylic acid derivatives, their production and their use as mixed eta/etb endothelin-receptor antagonists
HU0004935A HUP0004935A3 (en) 1997-09-04 1998-08-24 Novel carboxylic acid derivatives, their production and their use as mixed eta/etb endothelin-receptor antagonists
CA002302350A CA2302350A1 (fr) 1997-09-04 1998-08-24 Nouveaux derives d'acide carboxylique, leur production et leur utilisation comme antagonistes mixtes des recepteurs d'endotheline eta et etb
NO20001077A NO20001077D0 (no) 1997-09-04 2000-03-02 Nye karboksylsyrederivater, deres fremstilling og anvendelse som blandete ETA/ETB-endothelin-reseptorantagonister
BG104222A BG104222A (en) 1997-09-04 2000-03-06 Novel carboxylic acid derivatives, their production and their use as mixed eta/etb endothelin-receptor antagonists

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE19738578.8 1997-09-04
DE19738578A DE19738578A1 (de) 1997-09-04 1997-09-04 Neue Carbonsäurederivate, ihre Herstellung und Verwendung als gemischte ET¶A¶/ET¶B¶-Rezeptorantagonisten
DE19811915.1 1998-03-18
DE1998111915 DE19811915A1 (de) 1998-03-18 1998-03-18 Neue Carbonsäurederivate, ihre Herstellung und Verwendung als gemischte ET¶A¶/ET¶B¶-Rezeptorantagonisten

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JP (1) JP2001514254A (fr)
KR (1) KR20010023615A (fr)
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AR (1) AR017052A1 (fr)
AU (1) AU748610B2 (fr)
BG (1) BG104222A (fr)
BR (1) BR9811631A (fr)
CA (1) CA2302350A1 (fr)
CO (1) CO4970738A1 (fr)
HR (1) HRP980484A2 (fr)
HU (1) HUP0004935A3 (fr)
ID (1) ID25620A (fr)
IL (1) IL134276A0 (fr)
NO (1) NO20001077D0 (fr)
NZ (1) NZ502660A (fr)
PL (1) PL338954A1 (fr)
SK (1) SK1522000A3 (fr)
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000073276A2 (fr) * 1999-06-01 2000-12-07 Basf Aktiengesellschaft Nouveaux derives d'acide carboxylique comprenant des heterocycles d'azote substitues par aryle, leur preparation et leur utilisation comme antagonistes du recepteur d'entholine
WO2007137980A1 (fr) * 2006-05-29 2007-12-06 Nicox S.A. Composés hétérocycliques nitrés en tant qu'antagonistes de récepteur de l'endothéline
US8703793B2 (en) 2008-03-05 2014-04-22 Boehringer Ingelheim International Gmbh Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation
US9029544B2 (en) 2010-02-19 2015-05-12 Boehringer Ingelheim International Gmbh Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation
US9150583B2 (en) 2011-08-17 2015-10-06 Boehringer Ingelheim International Gmbh Furo[3,4-c]quinoline derivatives, medicaments containing such compounds, their use and process for their preparation

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* Cited by examiner, † Cited by third party
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EP2451786B1 (fr) * 2009-07-10 2014-01-22 Cadila Healthcare Limited Procédé amélioré de préparation d'ambrisentan et nouveaux intermédiaires associés

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WO1995026716A1 (fr) * 1994-03-31 1995-10-12 Basf Aktiengesellschaft Derives d'acide carboxylique de pyrimidine ou de triazine utilises comme medicaments
WO1996011914A1 (fr) * 1994-10-14 1996-04-25 Basf Aktiengesellschaft Nouveaux derives d'acide carboxylique, leur preparation et leur utilisation
WO1997028160A1 (fr) * 1996-02-01 1997-08-07 Smithkline Beecham Corporation Antagonistes des recepteurs de l'endotheline
WO1997038982A1 (fr) * 1996-04-12 1997-10-23 Basf Aktiengesellschaft Nouveaux derives d'acide carboxylique, leur preparation et leur utilisation
WO1998009953A2 (fr) * 1996-09-05 1998-03-12 Basf Aktiengesellschaft Derives d'acide azinyloxy et phenoxy-diaryl-carboxylique, leur preparation et leur utilisation en tant qu'antagonistes mixtes des recepteurs d'endotheline eta/et¿b?

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WO1996011914A1 (fr) * 1994-10-14 1996-04-25 Basf Aktiengesellschaft Nouveaux derives d'acide carboxylique, leur preparation et leur utilisation
WO1997028160A1 (fr) * 1996-02-01 1997-08-07 Smithkline Beecham Corporation Antagonistes des recepteurs de l'endotheline
WO1997038982A1 (fr) * 1996-04-12 1997-10-23 Basf Aktiengesellschaft Nouveaux derives d'acide carboxylique, leur preparation et leur utilisation
WO1998009953A2 (fr) * 1996-09-05 1998-03-12 Basf Aktiengesellschaft Derives d'acide azinyloxy et phenoxy-diaryl-carboxylique, leur preparation et leur utilisation en tant qu'antagonistes mixtes des recepteurs d'endotheline eta/et¿b?

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000073276A2 (fr) * 1999-06-01 2000-12-07 Basf Aktiengesellschaft Nouveaux derives d'acide carboxylique comprenant des heterocycles d'azote substitues par aryle, leur preparation et leur utilisation comme antagonistes du recepteur d'entholine
WO2000073276A3 (fr) * 1999-06-01 2001-05-10 Basf Ag Nouveaux derives d'acide carboxylique comprenant des heterocycles d'azote substitues par aryle, leur preparation et leur utilisation comme antagonistes du recepteur d'entholine
WO2007137980A1 (fr) * 2006-05-29 2007-12-06 Nicox S.A. Composés hétérocycliques nitrés en tant qu'antagonistes de récepteur de l'endothéline
US8703793B2 (en) 2008-03-05 2014-04-22 Boehringer Ingelheim International Gmbh Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation
US9029544B2 (en) 2010-02-19 2015-05-12 Boehringer Ingelheim International Gmbh Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation
US9150583B2 (en) 2011-08-17 2015-10-06 Boehringer Ingelheim International Gmbh Furo[3,4-c]quinoline derivatives, medicaments containing such compounds, their use and process for their preparation

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KR20010023615A (ko) 2001-03-26
CA2302350A1 (fr) 1999-03-11
AU748610B2 (en) 2002-06-06
AR017052A1 (es) 2001-08-22
NO20001077L (no) 2000-03-02
TR200000602T2 (tr) 2000-12-21
NO20001077D0 (no) 2000-03-02
IL134276A0 (en) 2001-04-30
HRP980484A2 (en) 1999-06-30
AU9533398A (en) 1999-03-22
PL338954A1 (en) 2000-12-04
TW546295B (en) 2003-08-11
CN1269792A (zh) 2000-10-11
BR9811631A (pt) 2000-09-26
ID25620A (id) 2000-10-19
BG104222A (en) 2001-02-28
EP1009741A1 (fr) 2000-06-21
HUP0004935A2 (hu) 2001-10-28
SK1522000A3 (en) 2000-08-14
NZ502660A (en) 2002-02-01
JP2001514254A (ja) 2001-09-11
CO4970738A1 (es) 2000-11-07
HUP0004935A3 (en) 2001-12-28

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