WO1999011629A1 - Novel carboxylic acid derivatives, their production and their use as mixed eta/etb endothelin-receptor antagonists - Google Patents

Novel carboxylic acid derivatives, their production and their use as mixed eta/etb endothelin-receptor antagonists Download PDF

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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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alkyl
phenyl
halogen
alkoxy
haloalkoxy
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PCT/EP1998/005354
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German (de)
French (fr)
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/en
Priority claimed from DE1998111915 external-priority patent/DE19811915A1/en
Priority to KR1020007002264A priority Critical patent/KR20010023615A/en
Priority to CA002302350A priority patent/CA2302350A1/en
Priority to JP2000508669A priority patent/JP2001514254A/en
Priority to NZ502660A priority patent/NZ502660A/en
Priority to IL13427698A priority patent/IL134276A0/en
Priority to SK152-2000A priority patent/SK1522000A3/en
Application filed by Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Priority to EP98948859A priority patent/EP1009741A1/en
Priority to HU0004935A priority patent/HUP0004935A3/en
Priority to BR9811631-2A priority patent/BR9811631A/en
Priority to AU95333/98A priority patent/AU748610B2/en
Priority to IDW20000386D priority patent/ID25620A/en
Publication of WO1999011629A1 publication Critical patent/WO1999011629A1/en
Priority to NO20001077A priority patent/NO20001077D0/en
Priority to BG104222A priority patent/BG104222A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • 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
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    • 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
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • 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
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    • 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
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    • 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
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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

The invention relates to carboxylic acid derivatives of formula (I) wherein the radicals are defined in the description, and to the use of these derivatives as ETA/ETB endothelin-receptor antagonists.

Description

NEUE CARBONSÄUREDERIVATE, IHRE HERSTELLUNG UND VERWENDUNG ALS GEMISCHTE ETA/ETB-ENDOTHELIN-REZEPTORANTAGONISTENNEW CARBONIC ACID DERIVATIVES, THEIR PRODUCTION AND USE AS MIXED ETA / ETB ENDOTHELINE RECEPTOR ANTAGONISTS
5 Beschreibung5 Description
Die vorliegende Erfindung betrifft neue Carbonsäurederivate, deren Herstellung und Verwendung.The present invention relates to new carboxylic acid derivatives, their preparation and use.
10 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 Isoformen von Endothelin. Endothelin ist ein potenter Vasokon-10 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. Hereinafter, "endothelin" or "ET" means one or all isoforms of endothelin. Endothelin is a potent vasocon-
15 striktor 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 Biochem. Biophys . Res. Commun., 154, 868-875, 1988).15 strict and has a strong effect on vascular tone. This vasoconstriction is known to be caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).
2020th
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-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.
25 viert. Dazu zählen: Hypertonie, akuter Myokardinfarkt, pulmonare Hypertonie, Raynaud-Syndrom, zerebrale Vasospasmen, Schlaganfall, benigne Prostatahypertrophie, Atherosklerose und Asthma (J. Vascular Med. Biology 2., 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature 3_£4, 114 (1990), N. Engl. j. Med. 322,25 fourth. These include: hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostatic hypertrophy, atherosclerosis and asthma (J. Vascular Med. Biology 2., 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature 3, £ 4, 114 (1990), N. Engl. J. Med. 322,
30 205 (1989), N. Engl. J. Med. 222., 1732 (1993), Nephron ££, 373 (1994), Stroke 2_5_, 904 (1994), Nature 365. 759 (1993), J. Mol. Cell. Cardiol. 21, A234 (1995); Cancer Research 5£, 663 (1996)).30 205 (1989), N. Engl. J. Med. 222., 1732 (1993), Nephron ££, 373 (1994), Stroke 2_5_, 904 (1994), Nature 365, 759 (1993), J. Mol Cell. Cardiol. 21, A234 (1995); Cancer Research £ 5, 663 (1996)).
Mindestens zwei Endot elinrezeptorsubtypen, ETA- und ETB-Rezeptor, 35 werden zur Zeit in der Literatur beschrieben (Nature 348. 730 (1990), Nature 348, 732 (1990)). Demnach sollten Substanzen, die die Bindung von Endothelin an die beiden Rezeptoren inhibieren, physiologische Effekte von Endothelin antagonisieren und daher wertvolle Pharmaka darstellen.At least two endoteline receptor subtypes, 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.
4040
In WO 96/11914 wurden Carbonsäurederivate beschrieben, die jedoch mit hoher Affinität an den ETA-Rezeptor, und mit einer wesentlich geringeren Affinität an den ETB-Rezeptor binden (sog. ETA-spezifische Antagonisten) .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).
45 Als ETA-spezifische Antagonisten bezeichnen wir hier solche Antagonisten, deren Affinität zum ETA-Rezeptor mindestens zehnfach höher ist als ihre Affinität zum ETB-Rezeptor .45 We refer to 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.
Es bestand die Aufgabe, Endothelinrezeptorantagonisten bereitzustellen, die mit ungefähr gleicher Affinität an den ΞTA- und den ETB-Rezeptor binden (sog. gemischte Antagonisten) .The task was to provide endothelin receptor antagonists that bind to the ΞT A and ET B receptors with approximately the same affinity (so-called mixed antagonists).
Ungefähr gleiche Affinität zu den Rezeptoren besteht, wenn der Quotient der Affinitäten größer 0,1 und kleiner 10 ist.There is approximately the same affinity for the receptors if the quotient of the affinities is greater than 0.1 and less than 10.
Gegenstand der Erfindung sind Carbonsäurederivate der Formel I Carbonsäurederivate der Formel IThe invention relates to carboxylic acid derivatives of the formula I carboxylic acid derivatives of the formula I.
Figure imgf000004_0001
wobei die Substituenten die folgende Bedeutung besitzen:
Figure imgf000004_0001
where the substituents have the following meaning:
R Tetrazol oder eine GruppeR tetrazole or a group
00
^C II Ri^ C II Ri
R1 ein Rest OR7, worin R7 bedeutet:R 1 is a radical OR 7 , where R 7 is:
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, Ci-Cg-Alkyl,C 3 -C 8 cycloalkyl, Ci-Cg-alkyl,
CH2-Phenyl gegebenenfalls substituiert,CH 2 phenyl optionally substituted,
C3-Ce-Alkenyl- oder eine C3-Cg-Alkinylgruppe gegebenfalls substituiert oderC 3 -C e alkenyl or a C 3 -Cg alkynyl group optionally substituted or
Phenyl gegebenfalls substituiert.Phenyl optionally substituted.
R2 Wasserstof f , Hydroxy, NH2 , NH (Cι-C4-Alkyl ) , N (Cι-C4-Alkyl ) 2 / Halogen, Cι-C4-Alkyl , C2-C4-Alkenyl , C2-C4-Alkinyl , Cχ-C -Halogenalkyl , Cι~C -Alkoxy, Cι-C -Halogenalkoxy oderR 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, Cχ-C -haloalkyl, -C ~ C -alkoxy, Cι-C -haloalkoxy or
Cι-C -Alkylthio , oder CR2 ist mit CR10 wie unten angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft ; oder , falls Het einen Fünfring darstellt, kann CR2 zusammen mit CR3 einen 5- oder 6-gliedrigen Alkenyl- oder Alkylenylring, der gegebenenfalls substituiert sein kann, darstellen;-C -Alkylthio, 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;
X Stickstoff oder Methin;X nitrogen or methine;
Y Stickstoff oder Methin;Y nitrogen or methine;
W Stickstoff oder CR10, worin R10 Wasserstoff oder Cι-4-Alkyl bedeutet oder CR10 zusammen mit CR2 oder CR3 einen 5- oder 6-gliedrigen Alkylen- oder Alkenylenring bildet, der gegebenenfalls substituiert sein kann, und worin jeweils eine oder mehrere Methylengruppen durch Sauerstoff, Schwefel, -NH oder -N(Cι_C4_Alkyl) , ersetzt sein können;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);
R3 Wasserstoff, Hydroxy, NH2, NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl) 2, Halogen, Cι-C4-Alkyl, C2-C4-Alkenyl, C2-C4-Alkinyl , Cι-C -Halogenalkyl , Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy, Cι-C4-Alkylthio; oder CR3 ist mit CR10 wie oben angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft;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, Cι-C haloalkyl, Cι-C 4 -alkoxy, C 4 haloalkoxy, Cι-C4-alkylthio; or CR 3 is linked to CR 10 to a 5- or 6-membered ring as stated above;
R4 und R5 (die gleich oder verschieden sein können) :R 4 and R 5 (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 S0 -, NH- oder N-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 -, NH or N-alkyl group
C3-C8-Cycloalkyl gegebenenfalls substituiert;C 3 -C 8 cycloalkyl optionally substituted;
R6 Wasserstoff, Ci-Cs-Alkyl, C3-Cs-Alkenyl oder C3-Cs-Alkinyl, wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Halogen, Hydroxy, Mercapto, Carboxy, Nitro, Amino, Cyano, Cι-C4-Alkoxy, C-C6-Alkenyloxy, C-C6-Alkinyloxy, Cι-C4-Alkylthio, Cι-C4-Halogenalkoxy, Cι-C4-Alkylcarbonyl, Cι-C4-Alkoxycarbonyl, C3_8-Alkylcarbonyl- alkyl, NH(Cι-C4-Alkyl) , N(Cj.-C4-Alkyl ) 2, C3-C8-Cycloalkyl, Heteroaryloxy oder Heteroaryl, fünf- oder sechsgliedrig, enthaltend ein bis drei Stickstoffatome und/oder ein Schwefeloder Sauerstoffatom, 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, C1-C4-Halogen- alkyl, Cι~C4-Alkoxy, Cι-C4-Halogenalkoxy, Amino, NH(Ci-C -Alkyl) , N (Cι~C4-Alkyl ) 2 oder C ^-Alkylthio;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 and / or a sulfur or oxygen atom, phenoxy or phenyl, where the aryl radicals mentioned can in turn be substituted one or more times, for example one to three times by halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -halogen- alkyl, Cι ~ C 4 -alkoxy, C 4 haloalkoxy, amino, NH (Ci-C alkyl), N (Cι ~ C4 alkyl) 2, or C ^ -alkylthio;
Phenyl oder Naphthyl, die jeweils durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, Nitro, Cyano, Hydroxy, Amino, Ci-C4-Alkyl, Cι-C4~Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy, Phenoxy, Cι-C4-Alkylthio, Cι~C4-Alkylamino, C1-C4-DialkylaiTU.no, Dioxomethylen oder Dioxoethylen;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, Cι-C4 alkoxy, Cι- C 4 -haloalkoxy, phenoxy, Cι-C 4 alkylthio, Cι ~ C 4 alkylamino, C 1 -C 4 -DialkylaiTU.no, dioxomethylene or Dioxoethylen;
ein fünf- oder sechsgliedriger Heteroaromat, enthaltend ein bis drei Stickstoffatome und/oder ein Schwefel- oder Sauerstoffatom, welcher ein bis vier Halogenatome und/oder einen bis zwei der folgenden Reste tragen kann: Cι-C4-Alkyl, Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy,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, Cι-C 4 -alkoxy, C 4 haloalkoxy,
Cι-C4-Alkylthio, Phenyl, Phenoxy oder Phenylcarbonyl, wobei die Phenylreste ihrerseits ein bis fünf Halogenatome und/oder einen bis drei der folgenden Reste tragen können: Cι-C4-Alkyl , Cι-C4-Halogenalkyl, Cι~C4-Alkoxy, Cι-C4-Halogenalkoxy und/oder Cι-C4-Alkylthio;Cι-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: Cι-C 4 -alkyl, C 4 haloalkyl, Cι ~ C 4 -alkoxy, C 4 -haloalkoxy and / or Cι-C 4 alkylthio;
C3-Cg-Cycloalkyl, wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Halogen, Hydroxy, Mercapto, Carboxy, Nitro, Cyano, Cι-C4-Alkyl, C2-C4-Alkenyl, C2-C -Alkinyl, Cι-C4-Alkoxy, C!-C4-Alkylthio, Cι-C4-Halogen- alkoxy; 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;
Z Schwefel oder Sauerstoff;Z sulfur or oxygen;
B C2-C4 AlkylenBC 2 -C 4 alkylene
Het ein heterozyklischer Rest der allgemeinen Formel la oder IbHet a heterocyclic radical of the general formula la or Ib
Figure imgf000006_0001
la Ib mit T = 0, S, NR8
Figure imgf000006_0001
la Ib with T = 0, S, NR 8
R8 CI-C6 Alkyl bedeuten, sowie die physiologisch verträglichen Salze, und die enantiomerenreinen Formen.R 8 CI-C 6 alkyl mean, as well as the physiologically acceptable salts, and the enantiomerically pure forms.
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;An alkaline earth metal is e.g. Calcium, magnesium, barium;
C3-Cs-Cycloalkyl ist z.B. Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl oder Cyclooctyl;C 3 -Cs cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
Cχ-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;Cχ-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;
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-l , 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-l, 1, 2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;
Cι-C4-Alkyl kann linear oder verzweigt sein wie z.B. Methyl, Ethyl, 1-Propyi, 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;
C-C4-Alkenyl kann linear oder verzweigt sein wie z.3. Ethenyl, l-Propen-3-yl, l-Propen-2-yl, 1-Propen-l-yl, 2-Methyl-1-propenyl, 1-Butenyl oder 2-Butenyl;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;
C2-C4-Alkinyl kann linear oder verzweigt sein wie z.B. Ethinyl , 1-Pro in-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-pro-in-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;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;
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;
C-C6~Alkinyloxy kann linear oder verzweigt sein wie z.B. 2-Propin-l-yloxy, 2-Butin-l-yloxy oder 3-Butin-2-yloxy; Cι-C4-Alkylthio kann linear oder verzweigt sein wie z.B. Methyl- thio, Ethylthio, Propylthio, 1-Methylethylthio, Butylthio, 1-Methylpropylthio, 2-Methylpropylthio oder 1, 1-Dimethylethyl- thio;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;
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;
Cι-C4-Alkoxycarbonyl kann linear oder verzweigt sein wie z.B. Methoxycarbonyl, Ethoxycarbonyl, n-Propoxycarbonyl, i-Propoxy- carbonyl oder n-Butoxycarbonyl ;C 1 -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, 3-0xo-but-l-yl oder 3-Oxo-but-2-ylC 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-Cδ-Alkyl kann linear oder verzweigt sein wie z.B. Cι-C4-Alkyl, Pentyl , Hexyl , Heptyl oder Octyl ;Ci-C δ alkyl can be linear or branched such as -CC 4 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.
Die Verbindungen und auch die Zwischenprodukte zu ihrer Herstellung, wie z.B. II, III und IV, können ein oder mehrere asymmetrisch substituierte Kohlenstoffatome besitzen. Solche Verbindungen können als reine Enantiomere bzw. reine Diastereo- mere oder als deren Mischung vorliegen. Bevorzugt ist die Ver- wendung einer enantiomerenreinen Verbindung als Wirkstoff.The compounds and also the intermediates for their preparation, e.g. II, III and IV, 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.
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. Die erfindungsgemäßen Verbindungen eignen sich besonders als gemischte Antagonisten, wie sie eingangs definiert wurden .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.
Die Herstellung der Verbindungen mit der allgemeinen Formel IV, in denen Z Schwefel oder Sauerstoff ist, kann - auch in enantiomerenreiner Form - wie in WO 96/11914 beschrieben, erfolgen. OHThe compounds of the general formula IV in which Z is sulfur or oxygen can be prepared - also in enantiomerically pure form - as described in WO 96/11914. OH
Figure imgf000009_0001
Figure imgf000009_0001
Verbindungen der allgemeinen Formel III sind entweder bekannt oder können z.B. durch Reduktion der entsprechenden Carbonsäuren bzw deren Ester, oder durch andere allgemein bekannte Methoden synthetisiert werden.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.
Die erfindungsgemäßen Verbindungen, in denen die Substituenten die unter der allgemeinen Formel I angegebenen Bedeutung haben, können beispielsweise derart hergestellt werden, daß man die Carbonsäurederivate der allgemeinen Formel IV, in denen die Substituenten die angegebene Bedeutung haben, mit Verbindungen der allgemeinen Formel V zur Reaktion bringt.The compounds according to the invention in which the substituents have the meaning given under the general formula I can be prepared, for example, by reacting the carboxylic acid derivatives of the general formula IV in which the substituents have the meaning given with compounds of the general formula V. brings.
IV + Rii - Het ► IIV + Rii - Het ► I
VV
In Formel V bedeutet R11 Halogen oder R1-S02-, wobei R12 In formula V, R 11 is halogen or R 1 -S0 2 -, where R 12
Cι~C-Alkyl, Cχ-C-Halogenalkyl oder Phenyl sein kann. Ferner ist mindestens eines der Ringglieder X oder Y oder Z Stickstoff. Die Reaktion findet bevorzugt in einem inerten Lösungs- oder Verdünnungsmittel unter Zusatz einer geeigneten Base, d.h. einer Base, die eine Deprotonierung des Zwischenproduktes IV bewirkt, in einem Temperaturbereich von Raumtemperatur bis zum Siedepunkt des Lösungsmittels statt.C ~ ~ C-alkyl, Cχ-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.
Verbindungen des Typs I mit R = COOH lassen sich weiterhin direkt erhalten, wenn man das Zwischenprodukt IV, in dem R COOH bedeutet, mit zwei Equivalenten einer geeigneten Base deprotoniert und mit Verbindungen der allgemeinen Formel V 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 I with R = COOH can furthermore be obtained directly if the intermediate IV, in which R is COOH, is deprotonated with two equivalents of a suitable base and reacted with compounds of the general formula V. 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 Kohlenwasserstoffe, 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 Bei- spiel Diisopropylether, Dibutylether, Methyl-tert. -Butylether, Propylenoxid, Dioxan und Tetrahydrofuran, Nitrile, wie zum Beispiel Acetonitril und Propionitril, Säureamide, wie zum Beispiel Dimethylformamid, Dimethylacetamid und N-Methylpyrrolidon, Sulfoxide und Sulfone, wie zum Beispiel Dimethylsulfoxid und Sulfolan.Examples 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, Ether, such as play 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, dimethylformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfones, such as, for example, dimethyl sulfoxide and sulfolane.
Verbindungen der Formel V sind bekannt, teilweise käuflich oder können nach allgemein bekannter Weise hergestellt werden.Compounds of the formula V are known, some are commercially available or can be prepared in a generally known manner.
Als Base kann ein Alkali- oder Erdalkalimetallhydrid wie Natriumhydrid, Kaliumhydrid oder Calciumhydrid, ein Carbonat wie Alkali- metallcarbonat, z.B. Natrium- oder Kaliumcarbonat, ein Alkalioder Erdalkalimetallhydroxid wie Natrium- oder Kaliumhydroxid, eine metallorganische Verbindung wie Butyllithium oder einAs 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 a
Alkaliamid wie Lithiumdiisopropylamid oder Lithiumamid dienen.Alkali amide such as lithium diisopropylamide or lithium amide are used.
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- halogenid, ein Anhydrid oder Imidazolid überführt und dieses dann mit einer entsprechenden HydroxylVerbindung HÖR7 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 beispielsweise auch dadurch vereinfachen, daß man die Carbonsäure in Gegenwart eines wasserabspaltenden Mittels wie eines Carbodiimids auf die HydroxylVerbindung einwirken läßt.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 HÖR 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.
Außerdem können Verbindungen der Formel I auch dadurch hergestellt werden, daß man von den Salzen der entsprechenden Carbonsäuren ausgeht, d. h. von Verbindungen der Formel I, in denen R1 für eine Gruppe COR und R für OM stehen, wobei M ein Alkali- metallkation oder das Equivalent eines Erdalkalimetallkations sein kann. Diese Salze lassen sich mit vielen Verbindungen der Formel R-A zur Reaktion bringen, wobei A eine übliche nucleofuge Abgangsgruppe bedeutet, beispielsweise Halogen wie Chlor, Brom, Iod oder gegebenenfalls durch Halogen, Alkyl oder Halogenalkyl substituiertes Aryl- oder Alkylsulfonyl wie z.B. Toluolsulfonyl und Methylsulfonyl oder eine andere äquivalente Abgangsgruppe. Verbindungen der Formel R-A mit einem reaktionsfähigen Substi- tuenten A sind bekannt oder mit dem allgemeinen Fachwissen leicht zu erhalten. Diese Umsetzung läßt sich in den üblichen Lösungs- mitteln durchführen und wird vorteilhaft unter Zugabe einer Base, wobei die oben genannten in Betracht kommen, vorgenommen. 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:In addition, 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. 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. Compounds of the formula RA with a reactive substituent A 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 abovementioned being possible. 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:
R1 COOR7, worin R7 bedeutet:R 1 COOR 7 , wherein R 7 means:
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, Ci-Cg-Alkyl,C 3 -C 8 cycloalkyl, Ci-Cg-alkyl,
CH2-Phenyl gegebenenfalls substituiert,CH 2 phenyl optionally substituted,
C3-Cg-Alkenyl- oder eine C3-Cg-Alkinyigruppe gegebenfalls substituiert oderC 3 -Cg alkenyl or a C 3 -Cg alkynyl group optionally substituted or
Phenyl, gegebenfalls substituiert.Phenyl, optionally substituted.
R2 Wasserstoff, Hydroxy, Halogen, N(Cχ-C4-Alkyl )2, d-C4-Alkyl, Cι-C-Alkoxy, Cι-C-Alkylthio, Cι-C4-Halogenalkyl, Cι-C4-Halogenalkoxy, oder CR2 ist mit CR10 wie unten angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft; oder, falls Het einen Fünfring darstellt, kann CR2 zusammen mit CR3 einen 5- oder 6-gliedrigen Alkenyl- oder Alkylenylring, der gegebenenfalls substituiert sein kann, darstellen;R 2 is hydrogen, hydroxy, halogen, N (Cχ-C 4 -alkyl) 2 , dC 4 -alkyl, -C-C-alkoxy, Cι-C-alkylthio, Cι-C 4 -haloalkyl, Cι-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;
X Stickstoff oder Methin;X nitrogen or methine;
Y Stickstoff oder Methin;Y nitrogen or methine;
W Stickstoff oder CR10, worin R10 Wasserstoff oder Cι_4-Alkyl bedeutet oder CR10 zusammen mit CR2 oder CR3 einen 5- oder 6-gliedrigen Alkylen- oder Alkenylenring bildet, der durch eine oder zwei Methylgruppen substituiert sein kann und worin jeweils eine Methylengruppe durch Sauerstoff oder Schwefel ersetzt sein kann wie -CH2-CH2-0-, -CH2-CH2-CH2-0-, -CH=CH-0-, -CH=CH-CH20-, -CH(CH3 ) -CH (CH3) -0-, -CH=C (CH3) -0-, -C(CH3)=C(CH3)-0-, oder -C(CH3) =C(CH3) -S;W nitrogen or CR 10 , wherein R 10 is hydrogen or Cι_ 4 alkyl or CR 10 together with CR 2 or CR 3 forms a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two methyl groups and in which in each case one methylene group can be replaced by oxygen or sulfur, such as -CH 2 -CH 2 -0-, -CH 2 -CH 2 -CH 2 -0-, -CH = CH-0-, -CH = CH-CH 2 0 -, -CH (CH 3 ) -CH (CH 3 ) -0-, -CH = C (CH 3 ) -0-, -C (CH 3 ) = C (CH 3 ) -0-, or -C ( CH 3 ) = C (CH 3 ) -S;
Mindestens eines der Ringglieder X, Y oder W ist Stickstoff.At least one of the ring members X, Y or W is nitrogen.
R3 Wasserstoff, Hydroxy, Halogen, N(Cχ-C4-Alkyl )2, Cι-C -Alkyl, Cι-C4-Alkoxy, Cι-C4-Alkylthio, Cι-C-Halogenalkyl, Cι-C4-Halogenalkoxy, oder CR3 ist mit CR10 wie oben angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft; oder, falls Het einen Fünfring darstellt, kann CR2 zusammen mit CR3 einen 5- oder 6-gliedrigen Alkenyl- oder Alkylenylring, der gegebenenfalls substituiert sein kann, darstellen;R 3 is hydrogen, hydroxy, halogen, N (Cχ-C 4 -alkyl) 2 , -C-C-alkyl, Cι-C 4 -alkoxy, Cι-C 4 -alkylthio, Cι-C-haloalkyl, Cι-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;
R4 und R5 (die gleich oder verschieden sein können) :R 4 and R 5 (which may be the same or different):
Phenyl oder Naphthyl, die durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, Nitro, Cyano, Hydroxy, Mercapto, Amino, Cι~C4-Alkyl, Cι-C4-Halogenalkyl , Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy, Phenoxy, Cχ-C4-Alkylthio, NH(C -C4-Alkyl) oder N(Cχ-C4-Alkyl) 2 oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, Cι-C4-Alkyl, Cχ-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy oder Cι-C4-Alkylthio; oderPhenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, amino, Cι ~ C 4 -alkyl, C 4 haloalkyl, Cι-C4-alkoxy, Cι -C 4 -haloalkoxy, phenoxy, Cχ-C 4 -alkylthio, NH (C -C 4 -alkyl) or N (Cχ-C 4 -alkyl) 2 or phenyl, which can be mono- or polysubstituted, for example mono- to trisubstituted by halogen, nitro, cyano, C 4 alkyl, Cχ-C4-haloalkyl, Cι-C 4 -alkoxy, C 4 -haloalkoxy or Cι-C 4 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-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-alkyl group
C3-C8-Cycloalkyl;C 3 -C 8 cycloalkyl;
R6 C3-C8-Cycloalkyl, wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Halogen, Hydroxy, Mercapto, Carboxy, Nitro, Cyano, Cι-C4-Alkoxy, Cι-C4-Alkyl, C2-C-Alkenyl, C2-C4-Alkinyl, C3-C6-Alkenyloxy, C3-C6-Alkinyl- oxy, Cι-C4-Alkylthio, Cι-C4-Halogenalkoxy, Cι-C4-Alkylcarbonyl, Cι-C4-Alkoxy-carbonyl, NH(Cι-C -Alkyl) , N(Cχ-C -Aikyl ) 2 oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, Ci-C4-Alkyl, Cι-C-Halogenalkyl, Cι-C4-Alkoxy, C1-C-Halogenalkoxy oder Cχ-C4-Alkylthio;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, Cι-C 4 alkylthio, Cι-C4-haloalkoxy, Cι-C 4 -Alkylcarbonyl, -CC 4 -alkoxy-carbonyl, NH (-CC-alkyl), N (Cχ-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, Cι-C 4 alkoxy, C 1 -C -haloalkoxy or Cχ-C4-alkylthio;
Phenyl oder Naphthyl, die jeweils durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, Nitro, Mercapto, Carboxy, Cyano, Hydroxy, Amino, Cχ-C-Alkyl, C2-C4-Alkenyl, C2-C4-Alkinyl , C3-C6-Alkenyloxy, Cι-C4-Halogen- alkyl, C3-C6-Alkinyloxy, C1-C4-Alkylcarbonyl, Cχ-C4-Alkoxy- carbonyl, Cι-C4-Alkoxy, Cι-C -Halogenalkoxy, Phenoxy,Phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, mercapto, carboxy, cyano, hydroxy, amino, Cχ-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, Cχ-C 4 -alkoxy-carbonyl, Cι-C 4 - Alkoxy, -C-C haloalkoxy, phenoxy,
Cι-C4-Alkylthio, NH (C -C -Alkyl ) , N(C -C4-Alkyl) 2 , Dioxo- methylen, Dioxoethylen oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, Cχ-C4-Alkyl, Cι-C4-Halogenalkyl, Cι-C-Alkoxy, Cι-C-Halogenalkoxy oder C-C4-Alkylthio; ein fünf- oder sechsgliedriger Heteroaromat, enthaltend ein bis drei Stickstoffatome und/oder ein Schwefel- oder Sauerstoffatom, welcher ein bis vier Halogenatome und/oder einen bis zwei der folgenden Reste tragen kann: Cχ-C4-Alkyl, Cχ-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy,-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, Cχ-C 4 -alkyl, Cι-C 4 -haloalkyl, Cι-C-alkoxy, Cι-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: Cχ-C 4 -alkyl, Cχ-C 4 - haloalkyl, Cι-C 4 -alkoxy, C 4 haloalkoxy,
Cχ-C4-Alkylthio, Phenyl, Phenoxy oder Phenylcarbonyl, wobei die Phenylreste ihrerseits ein bis fünf Halogenatome und/oder einen bis drei der folgenden Reste tragen können: Cχ-C4-Alkyl, Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy und/oder Cι-C4-Alkylthio;Cχ-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: Cχ-C 4 -alkyl, C 4 haloalkyl, Cι-C 4 -alkoxy, C 4 -haloalkoxy and / or Cι-C 4 alkylthio;
Z Schwefel oder Sauerstoff;Z sulfur or oxygen;
B C -C4 AlkylenBC -C 4 alkylene
Het eine heterozyklische Gruppe der Formel la oder Ib mit T = 0, S.Het a heterocyclic group of formula la or Ib with T = 0, S.
Besonders bevorzugt sind Verbindungen der Formel I - sowohl als reine Enantiomere bzw. reine Diastereomere oder als deren Mischung - in denen die Substituenten folgende Bedeutung haben:Compounds of the formula I are particularly preferred - both as pure enantiomers or pure diastereomers or as a mixture thereof - in which the substituents have the following meaning:
R' COOH;R 'COOH;
X,Y N;X, Y N;
W CR10 ; R2,R3 Wasserstoff, Hydroxy, NH2, NH(C -C4-Alkyl) , N(C -C4-Alkyl) 2, Halogen, C-C4-Alkyl, C2-C -Alkenyl, C2-C-Alkinyl, Cχ-C4-Halogenalkyl, Cι~C -Alkoxy, Cι-C -Halogenalkoxy oder Cχ-C4-Alkylthio, oder CR2 ist mit CR10 wie unten angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft oder, falls Het einen Fünfring darstellt, kann CR2 zusammen mit CR3 einen 5- oder 6-gliedrigen Alkylen oder Alkylenylring, der gegebenenfalls substituiert sein kann, darstellen;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, Cχ-C 4 -haloalkyl, Cι-C -alkoxy, Cι-C -halalkalkoxy or Cχ-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;
R4 Phenyl, das durch einen oder mehrere der folgenden Reste sub- stituiert sein können: Halogen, Nitro, Cyano, Hydroxy,R 4 is phenyl which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy,
Mercapto, Amino, Cχ-C-Alkyl, Cι-C4-Halogenalkyl, Cχ-C4-Alkoxy, Cι-C-Halogenalkoxy, Phenoxy, Cχ-C-Alkylthio, NH(Cχ-C4-Alkyl) oder N(Cχ-C4-Alkyl) oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, C -C-Alkyl, Cι-C4-Halogenalkyl , Cι-C4-Alkoxy, C-C4-Halogenalkoxy oder Cι-C4-Alkylthio; oderMercapto, amino, Cχ-C-alkyl, Cι-C 4 haloalkyl, Cχ-C 4 alkoxy, Cι-C-haloalkoxy, phenoxy, Cχ-C-alkylthio, NH (Cχ-C 4 alkyl) or N ( Cχ-C 4 alkyl) or phenyl which may be mono- or polysubstituted, for example mono- to trisubstituted by halogen, nitro, cyano, C -C alkyl, Cι-C4-haloalkyl, Cι-C 4 alkoxy , CC 4 -haloalkoxy or -CC 4 alkylthio; or
R5 Phenyl oder 3 , 4-DimethoxyphenylR 5 is phenyl or 3, 4-dimethoxyphenyl
R6 C5-C7-Cycloalkyl, wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Cχ-C4-Alkoxy, Cχ-C4-Alkyl, Cχ-C4-Alkylthio, Halogen, Hydroxy, Carboxy, Cyano, Trifluormethyl, Acetyl, oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Cyano, Cχ-C4-Alkyl, Cχ-C4-Halogenalkyl, Cι-C-Alkoxy, Cι-C-Halogenalkoxy oder Cχ-C4-Alkylthio;R 6 C 5 -C 7 cycloalkyl, where these radicals can each be mono- or polysubstituted by: Cχ-C 4 alkoxy, Cχ-C 4 alkyl, Cχ-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, Cχ- C 4 alkyl, Cχ-C 4 haloalkyl, -C-C alkoxy, Cι-C-haloalkoxy or Cχ-C 4 alkylthio;
Phenyl oder Naphthyl, die jeweils durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, Nitro, Mercapto, Carboxy, Cyano, Hydroxy, Amino, Cχ-C4-Alkyl, Cι-C4-Halogenalkyl, Acetyl, Cχ-C4-Alkoxycarbonyl, Cι-C-Alkoxy, Cι-C4-Halogenalkoxy, Phenoxy, Cχ-C4-Alkylthio, NH (Cχ-C -Alkyl ) , N(C -C4-Alkyl) , Dioxomethylen, Dioxoethylen oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, Cχ-C4-Alkyl, Cχ-C4-Halogenalkyl, Cχ-C4-Alkoxy, Cι-C4-Halogenalkoxy oder Cι-C4-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, Cχ-C 4 alkyl, Cι-C 4 haloalkyl, acetyl, Cχ-C 4 -alkoxycarbonyl, -C-C-alkoxy, Cι-C 4 -haloalkoxy, phenoxy, Cχ-C 4 -alkylthio, NH (Cχ-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, Cχ-C 4 haloalkyl, Cχ-C 4 alkoxy, Cι-C 4 haloalkoxy or -C-C 4 alkylthio;
ein fünf- oder sechsgliedriger Heteroaromat, enthaltend ein bis drei Stickstoffatome und/oder ein Schwefel- oder Sauer- stoffatom, welcher ein bis vier Halogenatome und/oder einen bis zwei der folgenden Reste tragen kann: Cχ-C-Alkyl, Cι-C-Halogenalkyl, Cχ-C4-Alkoxy, Trifluormethoxy, Cχ-C-Alkyl- thio, Phenyl oder Phenoxy, wobei die Phenylreste ihrerseits ein bis fünf Halogenatome und/oder einen bis drei der folgenden Reste tragen können: Cι-C4-Alkyl, Cχ-C4-Halogen- alkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy und/oder Cι-C -Alkyl- thio;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, Cι-C- Haloalkyl, Cχ-C 4 -alkoxy, trifluoromethoxy, Cχ-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, Cχ-C 4 -haloalkyl, -C-C 4 alkoxy, Cι-C 4 -haloalkoxy and / or Cι-C alkyl thio;
Z Schwefel oder Sauerstoff;Z sulfur or oxygen;
B C3-AlkylenBC 3 alkylene
Het la mit R2 und R3 Methyl und T = 0, S.Het la with R 2 and R 3 methyl and T = 0, S.
Die Verbindungen der vorliegenden Erfindung bieten ein neues therapeutisches Potential für die Behandlung von Hypertonie, pul- monalem Hochdruck, Myokardinfarkt , Angina Pectoris, akutem/chronischem Nierenversagen, Niereninsuffizienz, zerebralen Vaso- spasmen, zerebraler Ischämie, Subarachnoidalblutungen, Migräne, Asthma, Atherosklerose, endotoxischem Schock, Endotoxin-induziertem Organversagen, intravaskulärer Koagulation, Restenose nach Angioplastie, benigne Prostata-Hyperplasie, ischämisches und durch Intoxikation verursachtes Nierenversagen bzw. Hypertonie, metastasierung und Wachstum mesenchymaler Tumoren, Kontrastmit- tel-induziertes Nierenversagen, Pankreatitis, gastrointestinale Ulcera. Ein weiterer Gegenstand der Erfindung sind Kombinationspräparate aus Endothelinrezeptorantagonisten der Formel I und Inhibitoren des Renin-Angiotensin Systems. Inhibitoren des Renin-Angiotensin- Systems sind Reninhemmer, Angiotensin-II-Antagonisten und vor allem Angiotensin-Converting-Enzyme (ACE) -Hemmer.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.
Diese Kombinationspräparate eigenen 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 mM 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- haltiger 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 mM glutamine (Gibco No. 25030-024), 100 U / ml penicillin and 100 μg / 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.
Für die Membranpräparation wurden die Zellen auf eine Konzentration von 108 Zellen/ml Puffer (50 mM Tris-HCL Puffer, pH 7.4) eingestellt und danach durch Ultraschall desintegriert (Branson Sonifier 250, 40-70 Sekunde /constant/Output 20).For the membrane preparation, 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).
BindungstestsBinding tests
Für den ETA- und ETB-Rezeptorbindungstest wurden die Membranen in Inkubationspuffer (50 mM Tris-HCl, pH 7,4 mit 5 M MnCl2, 40 μg/ml Bacitracin und 0,2 % BSA) in einer Konzentration von 50 μg Protein pro Testansatz suspendiert und bei 25°C mit 25 pM [125J]-ETχ (ETA-Rezeptortest) oder 25 pM [125J]-ET3 (ETB-Rezeptortest) in Anwesenheit und Abwesenheit von Testsubstanz inkubiert. Die unspezifische Bindung wurde mit 10-7 M ETx 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 M MnCl 2 , 40 μg / 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] -ETχ (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. After 30 min, 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.
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 katheti- siert.Male SD rats weighing 250-300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and despinalized. The carotid artery and jugular vein were cathetized.
In Kontrolltieren führt die intravenöse Gabe von 1 μg/kg ET1 zu einem deutlichen Blutdruckanstieg, der über einen längeren Zeitraum anhält.In control animals, intravenous administration of 1 μg / kg ET1 leads to a significant increase in blood pressure that persists over a longer period of time.
Den Testtieren wurde 30 min vor der ET1 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 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.
p.o. - Testung der gemischten ETA- und ETB-Antagonisten:po - testing of mixed ET 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 carotid artery (for measuring blood pressure) and the jugular vein (application of big endothelin / endothelin 1) are catheterized.
Nach einer Stabilisierungsphase wird big Endothelin (20 μg/kg, Appl. Vol. 0.5 ml/kg) bzw. ETl (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 TestSubs anzen 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, intrapero- 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, intraperotonically). 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 tägliche Wirkstoffdosis zwischen etwa 0,5 und 50 mg/kg Körpergewicht bei oraler Gabe und zwischen etwa 0,1 und 10 mg/kg Körper- gewicht 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 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.
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, Füllstoffen, Konservierungsmitteln, Tablettensprengmitteln, Fließreguliermitteln, Weichmachern, Netzmitteln, Dispergiermitteln, Emulgatoren, Lösungsmitteln, Retardierungsmitteln, Anti- oxidantien 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 (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.
SynthesebeispieleSynthesis examples
Beispiel 1:Example 1:
2 , 3-Epoxy-3 , 6-diphenylhexansäuremethylester2,3-Epoxy-3,6-diphenylhexanoic acid, methyl ester
Zu einer Lösung aus 4 g (17,8 mmol) 1, 4-Diphenyl-l-butanon,To a solution of 4 g (17.8 mmol) of 1,4-diphenyl-1-butanone,
2,7 ml (31 mmol) Chloressigsäuremethylester in 60 ml THF wurden portionsweise über 8 Stunden 1,4 g (31 mmol) 50prozentiges Natriumhydrid zugegeben. Nachdem das Keton abreagiert hatte, wurde die Reaktionsmischung auf Eiswasser gegeben und mit Ether extrahiert. Die organische Phase wurde über Magnesiumsul at getrocknet und, nachdem das Lösungsmittel abdestilliert worden war, konnnten 5, 5 g eines Öls isoliert werden, welches weiter umgesetzt wurde.2.7 ml (31 mmol) of methyl chloroacetate in 60 ml of THF were added in portions over 8 hours to 1.4 g (31 mmol) of 50 percent sodium hydride. After the ketone had reacted, the reaction mixture was poured onto ice water and extracted with ether. The organic phase was dried over magnesium sulfate and, after the solvent had been distilled off, 5.5 g of an oil could be isolated, which was reacted further.
Beispiel 2 :Example 2:
2-Hydroxy-3-methoxy-3, 6-diphenylhexansäuremethylester2-Hydroxy-3-methoxy-3, 6-diphenylhexanoic acid methyl ester
In 20 ml Dichlormethan wurden 2 g (6,75 mmol) 2 , 3-Epoxy-3 , 6-di- phenylhexansäuremethylester mit 0,5 ml Methanol vorgelegt und 5 Tropfen Bortrifluoridetherat zugegeben. Nach 2 Stunden wurde der Ansatz eingeengt und der Rückstand mittels MPLC (cyclo-Hexan/ Essigester-Gradient) gereinigt, wobei 530 mg des einen Diastereo- meren, 720 mg des zweiten Diastereomeren und 800 mg einer Mischfraktion isoliert wurden. Beispiel 3 :2 g (6.75 mmol) of methyl 2,3-epoxy-3,6-diphenylhexanoate with 0.5 ml of methanol were placed in 20 ml of dichloromethane and 5 drops of boron trifluoride etherate were added. After 2 hours, the mixture was concentrated and the residue was purified by means of MPLC (cyclo-hexane / ethyl acetate gradient), 530 mg of one diastereomer, 720 mg of the second diastereomer and 800 mg of a mixed fraction being isolated. Example 3:
2-Hydroxy-3-methoxy-3 , 6-diphenylhexansäure (ein Diastereomer, Stereochemie unbekannt)2-hydroxy-3-methoxy-3, 6-diphenylhexanoic acid (a diastereomer, stereochemistry unknown)
Das zweite Diastereomer (720 mg, 2,2 mmol) wurde in 9 ml Dioxan gelöst und mit 4,5 ml IN Natronlauge versetzt. Das Gemisch wurde 16 Stunden gerührt, anschließend mit Wasser versetzt und mit Ether extrahiert. Die wässrige Phase wurde mit Zitronensäure an- gesäuert, mit Ether extrahiert, die organische Phase mit über Magnesiumsulfat getrocknet und das Lösungsmittel abdestilliert. Es wurden 936 mg eines Öls isoliert, welches direkt weiter umgesetzt wurde.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.
Beispiel 4:Example 4:
2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3-methoxy-3 , 6-diphenyl- hexansäure (ein Diastereomer)2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3-methoxy-3, 6-diphenyl-hexanoic acid (a diastereomer)
In 20 ml DMF wurden 195 mg (4,4 mmol) 50 prozentiges Natriumhydrid, 465 mg (1,5 mmol) 2-Hydroxy-3-methoxy-3 , 6-diphenylhexan- säure und 291 mg (1,5 mmol) 3 , 4-Dimethyl-2-methylsulfonpyrimidin zusammengegeben und 2 Stunden bei Raumtemperatur gerührt. Das Reaktionsgemisch wurde auf 100 ml Eiswasser gegeben, mit Zitronen- säure angesäuert und mit Ether extrahiert. Die organische Phase wurde mit Magnesiumsulfat getrocknet und das Lösungsmittel abdestilliert. Der Rückstand wurde mittels MPLC (cyclo-Hexan/Essig- ester-Gradient) gereinigt und es wurden 103 mg eines Diastereo- mers isoliert.195 mg (4.4 mmol) of 50 percent sodium hydride, 465 mg (1.5 mmol) of 2-hydroxy-3-methoxy-3, 6-diphenylhexanoic acid and 291 mg (1.5 mmol) 3 were added to 20 ml of DMF , 4-Dimethyl-2-methylsulfonpyrimidin combined and stirred for 2 hours at room temperature. The reaction mixture was added to 100 ml of ice water, acidified with citric acid and extracted with ether. The organic phase was dried with magnesium sulfate and the solvent was distilled off. The residue was purified by means of MPLC (cyclo-hexane / ethyl acetate gradient) and 103 mg of a diastereomer were isolated.
IH-NMR (200 MHz, CDC13): 7.1-7.5 ppm (10 H, m), 6.2 (1 H, s), 5.6 (1 H, s), 3.8 (3 H, s), 3.3 (3 H, s), 2.5-2.8 (3 H, m) , 2.3 (3 H, s), 2.0 (1 H, m), 1.5-1.8 (2 H, m) .IH-NMR (200 MHz, CDC13): 7.1-7.5 ppm (10 H, m), 6.2 (1 H, s), 5.6 (1 H, s), 3.8 (3 H, s), 3.3 (3 H, s), 2.5-2.8 (3 H, m), 2.3 (3 H, s), 2.0 (1 H, m), 1.5-1.8 (2 H, m).
ESI-MS: M+ = 436ESI-MS: M + = 436
Beispiel 5:Example 5:
2 , 3-Epoxy-3-phenyl-6- (3 , 4-methoxyphenyl)hexansäuremethylester (Diastereomerengemisch) :2,3-Epoxy-3-phenyl-6- (3,4-methoxyphenyl) hexanoic acid methyl ester (mixture of diastereomers):
Es wurden 12 , 6 g (44 mmol) l-Phenyl-4- (3 , 4-dimethoxy)phenylbu- tan-l-on zusammen mit 8,3 g Chloressigsäuremethylester in 50 ml DMF gelöst und bei Raumtemperatur innerhalb von einer Stunde 3,7 g 50prozentige Natriumhydridsuspension portionsweise zugegeben. Nach insgesamt 1,5 Stunden hatte das Edukt abreagiert und die Reaktionslösung wurde auf 300 ml Eiswasser gegeben. Die wässrige Phase wurde mit Zitronensäure angesäuert, mehrmals mit Ether extrahiert, die abgetrennte organische Phase gewaschen und über Magnesiumsulfat getrocknet. Das Lösungsmittel wurde abdestilliert und es wurden 13 g eines Öls isoliert, welches gleich weiter um- gesetzt werden konnte.12.6 g (44 mmol) of l-phenyl-4- (3, 4-dimethoxy) phenylbutan-l-one were dissolved together with 8.3 g of methyl chloroacetate in 50 ml of DMF and at room temperature within one hour 3 , 7 g 50 percent sodium hydride suspension added in portions. After a total of 1.5 hours, the starting material had reacted and the reaction solution was added to 300 ml of ice water. The watery The phase was acidified with citric acid, extracted several times with ether, the separated organic phase was washed and dried over magnesium sulfate. The solvent was distilled off and 13 g of an oil were isolated, which could be reacted immediately.
Beispiel 6 :Example 6:
2-Hydroxy-3- (2- (3 , 4-dimethoxy- phenyl )ethoxy) -3-phenyl-6- (3 , 4-dimethoxyphenyl)hexansäuremethyle- ster2-Hydroxy-3- (2- (3, 4-dimethoxyphenyl) ethoxy) -3-phenyl-6- (3, 4-dimethoxyphenyl) hexanoic acid methyl ester
Eine Mischung aus 3,6 g (10 mmol) 2, 3-Epoxy-3-phenyl-6- (3 , 4-meth- oxyphenyDhexansäuremethylester, 1,8 g (10 mmol) 2- (3 , 4-dimeth- oxy)ethanol und 100 mg p-Toluolsulfonsäure wurden in 50 mlA mixture of 3.6 g (10 mmol) of 2,3-epoxy-3-phenyl-6- (3,4-methoxyphenyhexanoic acid methyl ester, 1.8 g (10 mmol) of 2- (3,4-dimethoxy) ) ethanol and 100 mg of p-toluenesulfonic acid were in 50 ml
Dichlormethan bei Eiskühlung eine Stunde gerührt. Die Reaktionslösung wurde auf gesättigte Natriuhydrogencarbonatlösung gegeben, die organische Phase wurde abgetrennt und über Magnesiumsulfat getrocknet. Das Lösungsmittel wurde abdestilliert und 4,7 g Rückstand mittels MPLC (Gradient: cyclo-Hexan/Essigster) gereinigt. Es wurden 750 mg eines Diastereomerengemisches isoliert.Dichloromethane stirred for one hour while cooling with ice. The reaction solution was added to saturated sodium bicarbonate solution, the organic phase was separated off and dried over magnesium sulfate. The solvent was distilled off and 4.7 g of residue were purified by means of MPLC (gradient: cyclo-hexane / ethyl acetate). 750 mg of a mixture of diastereomers were isolated.
Beispiel 7 :Example 7:
2-Hydroxy-3- (2- (3 , 4-dimethoxy- phenyl)ethoxy)-3-phenyl-6- (3 , 4-dimethoxyphenyl) exansäure2-Hydroxy-3- (2- (3, 4-dimethoxyphenyl) ethoxy) -3-phenyl-6- (3, 4-dimethoxyphenyl) exanoic acid
Zu 750 mg (1,4 mmol) 2-Hydroxy-3- (2- (3 , 4-dimethoxy- phenyl )ethoxy) -3-phenyl-6- (3 , 4-dimethoxyphenyl )hexansäuremethyle- ster gelöst in 4,2 ml Dioxan wurden 2,1 ml IN Natronlauge gegeben und bei Raumtemperatur 16 Stunden gerührt. Das Gemisch wurde mit 100 ml Wasser versetzt und mit Ether extrahiert. Anschließend wurde mit Salzsäure neutralisiert, die wässrige Phase mit Ether extrahiert, die Etherphase mit Magnesiumsulfat getrocknet und das Lösungsmittel abdestilliert. Es wurden 620 mg eines Öls isoliert, welches gleich weiter eingesetzt wurde.To 750 mg (1.4 mmol) of 2-hydroxy-3- (2- (3, 4-dimethoxyphenyl) ethoxy) -3-phenyl-6- (3, 4-dimethoxyphenyl) hexanoic acid methyl ester dissolved in 4, 2 ml of dioxane were added to 2.1 ml of 1N sodium hydroxide solution and stirred at room temperature for 16 hours. The mixture was mixed with 100 ml of water and extracted with ether. The mixture was then neutralized with hydrochloric acid, the aqueous phase was extracted with ether, the ether phase was dried with magnesium sulfate and the solvent was distilled off. 620 mg of an oil were isolated, which was used immediately.
Beispiel 8:Example 8:
2- (4, 6-dimethyl-pyrimidin-2-yloxy)-3-(2- (3 , 4-dimethoxy- phenyl) ethoxy) -3-phenyl-6- (3 , 4-dimethoxyphenyl) hexansäure2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3- (2- (3, 4-dimethoxy-phenyl) ethoxy) -3-phenyl-6- (3, 4-dimethoxyphenyl) hexanoic acid
In 10 ml DMF wurden 164 mg (3,42 mmol) Natriumhydrid, 600 mg (1,14 mmol) 2-Hydroxy-3- (2- (3 , 4-dimethoxy- phenyl) ethoxy) -3-phenyl-6- (3 , 4-dimethoxyphenyl) exansäure und 223 mg (1,2 mmol) 3 , 4-Dimethyl-2-methylsulfonpyrimidin zusammen- gegeben und 6 Stunden bei Raumtemperatur gerührt. Das Reaktionsgemisch wurde auf 100 ml Eiswasser gegeben, mit Zitronensäure angesäuert und mit Ether extrahiert. Die organische Phase wurde mit Magnesiumsulfat getrocknet und das Lösungsmittel abdestilliert. 5 Der Rückstand wurde mittels Flashchromatographie (cyclo-Hexan/Es- sigester-Gradient) gereinigt und es wurden 115 mg eines Diaste- reomers kristallin isoliert.164 mg (3.42 mmol) of sodium hydride, 600 mg (1.14 mmol) of 2-hydroxy-3- (2- (3,4-dimethoxyphenyl) ethoxy) -3-phenyl-6- were added to 10 ml of DMF. (3,4-dimethoxyphenyl) exanoic acid and 223 mg (1.2 mmol) 3,4-dimethyl-2-methylsulfone pyrimidine together - given and stirred for 6 hours at room temperature. The reaction mixture was poured onto 100 ml of ice water, acidified with citric acid and extracted with ether. The organic phase was dried with magnesium sulfate and the solvent was distilled off. 5 The residue was purified by means of flash chromatography (cyclo-hexane / ethyl acetate gradient) and 115 mg of a diastereomer were isolated in crystalline form.
Diast. I: 0 Smp. : 93-96°CDiast. I: 0 mp: 93-96 ° C
ESI-MS: M+ = 630ESI-MS: M + = 630
Beispiel 9 :Example 9:
5 2-(4, 6-dimethyl-pyrimidin-2-yloxy) -3- (3 , 4-dimethoxybenzy- loxy)-3-phenyl-6- (3 , 4-dimethoxyphenyl) hexansäure5 2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3- (3, 4-dimethoxybenzyloxy) -3-phenyl-6- (3, 4-dimethoxyphenyl) hexanoic acid
Diast. I: Smp. : 130-133°C 0 ESI-MS: M+ = 616Diast. I: mp: 130-133 ° C 0 ESI-MS: M + = 616
Beispiel 10:Example 10:
2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3- (4-methoxyphen- 5 oxy) -3-phenyl-6- (3 , 4-dimethoxyphenyl) exansäure2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3- (4-methoxyphen-5 oxy) -3-phenyl-6- (3, 4-dimethoxyphenyl) exanoic acid
Diast. I:Diast. I:
Smp. : 118-122°CM.p .: 118-122 ° C
ESI-MS: M+ = 572 0ESI-MS: M + = 572 0
Beispiel 11:Example 11:
2- (4, 6-dimethyl-pyrimidin-2-yl- oxy) -3-methoxy-3-phenyl-6- (3 , 4-dimethoxyphenyl) exansäure 52- (4, 6-dimethyl-pyrimidin-2-yl-oxy) -3-methoxy-3-phenyl-6- (3, 4-dimethoxyphenyl) exanoic acid 5
Diast. I:Diast. I:
Smp. : 135-138°CM.p .: 135-138 ° C
ESI-MS: M+ = 480ESI-MS: M + = 480
Q Diast. II: Q Diast. II:
Smp. : 128-134°C ESI-MS: M+ = 480M.p .: 128-134 ° C ESI-MS: M + = 480
Beispiel 12 : 5Example 12: 5
2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3-methoxy-3 , 6-dιphenylhexan- säure IH-NMR (200 MHz, CDC13 ) : 7.1-7.5 ppm (10 H, m) , 6.7 (1 H, s) , 5.S (1 H, s) , 3.3 (3 H, s), 2.5-2.7 (3 H, m) , 2.3 (6 H, s), 2.0-2.1 (1 H, m) , 1.6-1.8 (2 H, m) .2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3-methoxy-3, 6-diphenylhexanoic acid IH-NMR (200 MHz, CDC13): 7.1-7.5 ppm (10 H, m), 6.7 (1 H, s), 5.S (1 H, s), 3.3 (3 H, s), 2.5-2.7 (3 H, m), 2.3 (6 H, s), 2.0-2.1 (1 H, m), 1.6-1.8 (2 H, m).
ESI-MS: M+ = 420ESI-MS: M + = 420
Beispiel 13 :Example 13:
2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3-hex-3E-enoxy-3 , 6-diphenylhe- xansäure2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3-hex-3E-enoxy-3, 6-diphenylhexanoic acid
Diast. I: Smp. : 110-114°C ESI-MS: M+ = 488Diast. I: mp: 110-114 ° C ESI-MS: M + = 488
Diast. II: ESI-MS: M+ = 488Diast. II: ESI-MS: M + = 488
Beispiel 14:Example 14:
2- (4 , 6-dimethyi-pyrimidin-2-yloxy) -3- (2- (3 , 4-dimethoxy- phenyl ) ethoxy) -3 , 6-diphenylhexansäure2- (4, 6-dimethyipyrimidin-2-yloxy) -3- (2- (3, 4-dimethoxyphenyl) ethoxy) -3, 6-diphenylhexanoic acid
Diast. I: Smp. : 87-88°CDiast. I: mp: 87-88 ° C
ESI-MS: M+ = 570ESI-MS: M + = 570
Diast. II: Smp.: 87-88°C ESI-MS: M-r = 570Diast. II: mp: 87-88 ° C ESI-MS: M-r = 570
Beispiel 15:Example 15:
2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (3 , 4-dimethoxy- phenyl ) ethoxy) -3 , 6-diphenylhexansäure2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (3, 4-dimethoxyphenyl) ethoxy) -3, 6-diphenylhexanoic acid
Diast. I: Smp. : 141-142°C ESI-MS: M+ = 586Diast. I: mp: 141-142 ° C ESI-MS: M + = 586
Beispiel 16:Example 16:
2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3- (3 , 4-dimethoxybenzy- loxy) -3 , 6-diphenylhexansäure Diast . I :2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3- (3, 4-dimethoxybenzyloxy) -3, 6-diphenylhexanoic acid Diast. I:
IH-NMR (200 MHz, CDC13 ) : 7.1-7.5 ppm (10 H, m) , 6.9 (3 H, m),6.7 (1 H, s), 5.8 (1 H, s), 4.4 (1 H, d) , 4.3 (1 H, d) , 3.9 (3 H, s), 3.85 (3 H, s), 2.5-2.7 (3 H, m) , 2.3 (6 H, s) , 2.0-2.3 (1 H, m) , 1.7-1.9 (2 H, m) .IH-NMR (200 MHz, CDC13): 7.1-7.5 ppm (10 H, m), 6.9 (3 H, m), 6.7 (1 H, s), 5.8 (1 H, s), 4.4 (1 H, d), 4.3 (1 H, d), 3.9 (3 H, s), 3.85 (3 H, s), 2.5-2.7 (3 H, m), 2.3 (6 H, s), 2.0-2.3 (1 H, m), 1.7-1.9 (2 H, m).
ESI-MS: M- = 556ESI-MS: M- = 556
Beispiel 17:Example 17:
2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (3 , 4-dimethoxybenzy- loxy) -3 , 6-diphenylhexansäure2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (3, 4-dimethoxybenzyloxy) -3, 6-diphenylhexanoic acid
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): 7.1-7.5 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).
ESI-MS: M^ = 572ESI-MS: M ^ = 572
Beispiel 18:Example 18:
2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (2-thiophenyle- thoxy) -3 , 6-diphenylhexansäure2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (2-thiophenylthoxy) -3, 6-diphenylhexanoic acid
Diastereomerengemisch 3:1: Zers. : 85°C ESI-MS: M+ = 532Diastereomer mixture 3: 1: decomp. : 85 ° C ESI-MS: M + = 532
Beispiel 19:Example 19:
2- (4, 6-dimethyl-pyrimidin-2-yloxy)-3-(2-(3, 4, 5-trimethoxy- phenyl ) ethoxy) -3 , 6-diphenylhex.ansäure2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3- (2- (3, 4, 5-trimethoxy-phenyl) ethoxy) -3, 6-diphenylhexanoic acid
Diast. I:Diast. I:
IH-NMR (200 MHz, CDC13): 7.0-7.3 ppm (10 H, m) , 6.65 (1 H, m) , 6.4 (2 H, s), 5.75 (1 H, s), 3.9 (3 H, s), 3.85 (6 H, s), 3.5-3.7 (2 H, m) , 2.8-2.9 (2 H, m) , 2.3-2.5 (3 H, m) , 2.3 (6 H, s), 2.0-2.3 (1 H, m) , 1.5-1.7 (2 H, m) .IH-NMR (200 MHz, CDC13): 7.0-7.3 ppm (10 H, m), 6.65 (1 H, m), 6.4 (2 H, s), 5.75 (1 H, s), 3.9 (3 H, s), 3.85 (6 H, s), 3.5-3.7 (2 H, m), 2.8-2.9 (2 H, m), 2.3-2.5 (3 H, m), 2.3 (6 H, s), 2.0 -2.3 (1 H, m), 1.5-1.7 (2 H, m).
ESI-MS: M- = 600 Beispiel 20 :ESI-MS: M- = 600 Example 20:
2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (3 , 4, 5-trimethoxy- phenyl ) ethoxy) -3 , 6-diphenylhexansäure2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (3, 4, 5-trimethoxy-phenyl) ethoxy) -3, 6-diphenylhexanoic acid
Diast. I:Diast. I:
Smp. : 153-155°CM.p .: 153-155 ° C
ESI-MS: M+ = 616ESI-MS: M + = 616
Beispiel 21:Example 21:
2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3- (2- (4-hydroxy-3-methoxy- phenyl ) ethoxy) -3 , 6-diphenylhexansäure2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3- (2- (4-hydroxy-3-methoxyphenyl) ethoxy) -3, 6-diphenylhexanoic acid
Diast. I:Diast. I:
IH-NMR (200 MHz, CDC13 ) : 7.0-7.4 ppm (10 H, m) , 6.9 (1 H, dm), 6.6-6.75 (3 H, m) , 5.8 (1 H, s), 5.5 (OK), 3.9 (3 H, s), 3.85 (3 H, s), 3.5-3.7 (2 H, m) , 2.8-2.9 (2 H, tr) , 2.3-2.5 (3 H, m) , 2.3 (6 H, s), 2.0-2.3 (1 H, m) , 1.5-1.7 (2 H, m) .IH-NMR (200 MHz, CDC13): 7.0-7.4 ppm (10 H, m), 6.9 (1 H, dm), 6.6-6.75 (3 H, m), 5.8 (1 H, s), 5.5 (OK ), 3.9 (3 H, s), 3.85 (3 H, s), 3.5-3.7 (2 H, m), 2.8-2.9 (2 H, tr), 2.3-2.5 (3 H, m), 2.3 ( 6 H, s), 2.0-2.3 (1 H, m), 1.5-1.7 (2 H, m).
ESI-MS: M+ = 556ESI-MS: M + = 556
Diast. II: ESI-MS: M+ = 556Diast. II: ESI-MS: M + = 556
Beispiel 22:Example 22:
2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (4-hydroxy-3-meth- oxyphenyl ) ethoxy) -3 , 6-diphenylhexansäure2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (4-hydroxy-3-meth-oxyphenyl) ethoxy) -3, 6-diphenylhexanoic acid
Diast. I:Diast. I:
Smp.: 154-157°CM.p .: 154-157 ° C
ESI-MS: M+ = 572ESI-MS: M + = 572
Beispiel 23:Example 23:
2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3- (4-carboxybenzyloxy)-3, 6-di- phenylhexansäure2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3- (4-carboxybenzyloxy) -3, 6-di-phenylhexanoic acid
Diast. I:Diast. I:
IH-NMR (200 MHz, CDC13 ) : 8.0 (2 H, d) , 7.1-7.5 ppm (12 H, m) , 6.8 (1 H, m),6.8 (1 H, s), 4.6 (1 H, d) , 4.5 (1 H, d) , 2.5-2.7 (3 H, m) , 2.3 (6 H, s), 2.1-2.25 (1 H, m) , 1.5-1.7 (2 H, m) .IH-NMR (200 MHz, CDC13): 8.0 (2 H, d), 7.1-7.5 ppm (12 H, m), 6.8 (1 H, m), 6.8 (1 H, s), 4.6 (1 H, d), 4.5 (1 H, d), 2.5-2.7 (3 H, m), 2.3 (6 H, s), 2.1-2.25 (1 H, m), 1.5-1.7 (2 H, m).
ESI-MS: M+ = 540 Diast. II:ESI-MS: M + = 540 Diast. II:
Smp. : 160-I67°CM.p .: 160-I67 ° C
ESI-MS: M+ = 540ESI-MS: M + = 540
Beispiel 24:Example 24:
2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (4-carboxybenzy- loxy) -3 , 6-diphenylhexansäure2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (4-carboxybenzyloxy) -3, 6-diphenylhexanoic acid
Diast. I:Diast. I:
IH-NMR (200 MHz, CDC13 ) : 8.0 (2 H, d) , 7.1-7.5 ppm (12 H, m) , 6.2 (1 H, m),5.6 (1 H, s), 4.55 (1 H, d) , 4.45 (1 H, d) , 3.9 (3 H,s), 2.5-2.7 (3 H, m) , 2.3 (3 H, s) , 2.1-2.25 (1 H, m) , 1.6-1.8 (2 H, m) .IH-NMR (200 MHz, CDC13): 8.0 (2 H, d), 7.1-7.5 ppm (12 H, m), 6.2 (1 H, m), 5.6 (1 H, s), 4.55 (1 H, d), 4.45 (1 H, d), 3.9 (3 H, s), 2.5-2.7 (3 H, m), 2.3 (3 H, s), 2.1-2.25 (1 H, m), 1.6-1.8 (2 H, m).
ESI-MS: M+ = 556ESI-MS: M + = 556
Diast. II: ESI-MS: M- = 556Diast. II: ESI-MS: M- = 556
Beispiel 25:Example 25:
2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3- (4-methoxyphenoxy) -3 , 6-di- phenylhexansäure2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3- (4-methoxyphenoxy) -3, 6-di-phenylhexanoic acid
Diast. I:Diast. I:
IH-NMR (200 MHz, CDC13 ) : 7.1-7.5 ppm (10 H, m) , 6.5-6.8 (5 H, m),5.9 (1 H, s), 3.75 (3 H, s), 2.2-2.7 (4 H, m) , 2.3 (6 H, s),IH-NMR (200 MHz, CDC13): 7.1-7.5 ppm (10 H, m), 6.5-6.8 (5 H, m), 5.9 (1 H, s), 3.75 (3 H, s), 2.2-2.7 (4 H, m), 2.3 (6 H, s),
1.5-1.7 (2 H, m) .1.5-1.7 (2 H, m).
ESI-MS: M+ = 512ESI-MS: M + = 512
Diast. II: ESI-MS: M+ = 512Diast. II: ESI-MS: M + = 512
Beispiel 26:Example 26:
2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (4-methoxyphen- oxy) -3 , 6-diphenylhexansäure2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (4-methoxyphenoxy) -3, 6-diphenylhexanoic acid
Diast. I:Diast. I:
IH-NMR (200 MHz, CDC13 ) : 7.1-7.5 ppm (10 H, m) , 6.5-6.9 (4 H, m),6.2 (1 H, s), 5.75 (1 H, s), 3.8 (3 H, s), 3.75 (3 H, s),IH-NMR (200 MHz, CDC13): 7.1-7.5 ppm (10 H, m), 6.5-6.9 (4 H, m), 6.2 (1 H, s), 5.75 (1 H, s), 3.8 (3 H, s), 3.75 (3 H, s),
2.2-2.7 (4 H, m) , 2.3 (3 H, s) , 1.5-1.7 (2 H, m) .2.2-2.7 (4 H, m), 2.3 (3 H, s), 1.5-1.7 (2 H, m).
ESI-MS: M+ = 528 Diast. II: ESI-MS: M+ = 528ESI-MS: M + = 528 Diast. II: ESI-MS: M + = 528
Beispiel 27:Example 27:
2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3- (3- (3 , 4, 5-trimethoxy- phenyl )prop-2E-enoxy) -3 , 6-diphenylhexansäure2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3- (3- (3, 4, 5-trimethoxy-phenyl) prop-2E-enoxy) -3, 6-diphenylhexanoic acid
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) .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).
ESI-MS: M- = 612ESI-MS: M- = 612
Analog oder wie im allgemeinen Teil beschrieben lassen sich die in Tabelle 1 aufgeführten Verbindungen herstellen. The compounds listed in Table 1 can be prepared analogously or as described in the general part.
R6-R6-
Figure imgf000026_0001
Figure imgf000026_0001
R5 R5R5 R5
1010
Figure imgf000026_0002
Figure imgf000026_0002
υiυi
Figure imgf000027_0001
Figure imgf000027_0001
Figure imgf000028_0002
Figure imgf000028_0001
Figure imgf000028_0002
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000029_0001
1010
0000
Figure imgf000030_0001
Figure imgf000030_0001
t ot o
Figure imgf000031_0001
Figure imgf000031_0001
I oI o
Figure imgf000032_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000033_0001
l tl t
Figure imgf000034_0001
Figure imgf000034_0001
ω ωω ω
Figure imgf000035_0001
Figure imgf000035_0001
ωω
Figure imgf000036_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000037_0001
ω σ.ω σ.
Figure imgf000038_0001
Figure imgf000038_0001
u>u>
Figure imgf000039_0001
Figure imgf000039_0001
ω ooω oo
Figure imgf000040_0001
Figure imgf000040_0001
ω u>ω u>
Figure imgf000041_0001
Figure imgf000041_0001
oO
Figure imgf000042_0001
Figure imgf000042_0001
*»* »
RR
Figure imgf000043_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000044_0001
Figure imgf000044_0002
Figure imgf000044_0002
* 2 - ( 4, 5-dimethyloxazolyl ) * 2- (4, 5-dimethylthiazolyl) * 2 - (4,5-dimethyloxazolyl) * 2- (4,5-dimethylthiazolyl)
Beispiel 12Example 12
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 (Kj.-Werte)Receptor binding data (Kj. Values)
Figure imgf000045_0001
Figure imgf000045_0001

Claims

Patentansprüche claims
1. Carbonsäurederivate der Formel I1. Carboxylic acid derivatives of the formula I.
Figure imgf000046_0001
wobei die Substituenten folgende Bedeutung haben:
Figure imgf000046_0001
where the substituents have the following meaning:
R Tetrazol oder eine Gruppe 0R tetrazole or a group 0
^C Rl^ C Rl
R1 ein Rest OR7,R 1 is a residue OR 7 ,
worin R7 bedeutet:where R 7 means:
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, Cι-C8-Alkyl,C 3 -C 8 cycloalkyl, -CC 8 alkyl,
CH2-Phenyl gegebenenfalls substituiert,CH 2 phenyl optionally substituted,
C3-C6-Alkenyl- oder eine C3-C6-Alkinylgruppe gegebenfalls substituiert oderC 3 -C 6 alkenyl or a C 3 -C 6 alkynyl group optionally substituted or
Phenyl, gegebenfalls substituiert.Phenyl, optionally substituted.
R2 Wasserstoff, Hydroxy, NH2, NH (Cχ-C -Alkyl ) , N(C-C4-Alkyl ) 2, Halogen, Cι-C4-Alkyl, C2-C-Alkenyl, C2-C4-Alkinyl, C!-C-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy oder C-C4-Alkylthio, oder CR2 ist mit CR10 wie unten angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft oder, falls Het einen Fünfring darstellt, kann CR2 zusammen mit CR3 einen 5- oder 6-gliedrigen Alkenyl- oder Alkylenylring, der gegebenenfalls substituiert sein kann, darstellen; X Stickstoff oder Methin;R 2 is hydrogen, hydroxy, NH 2 , NH (Cχ-C-alkyl), N (CC 4 -alkyl) 2 , halogen, Cι-C 4 alkyl, C 2 -C alkenyl, C 2 -C 4 alkynyl , C ! -C-haloalkyl, -CC 4 -alkoxy, -C-C 4 -haloalkoxy or CC 4 -alkylthio, or CR 2 is linked to CR 10 as indicated below to form a 5- or 6-membered ring or, if Het is 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; X nitrogen or methine;
Y Stickstoff oder Methin;Y nitrogen or methine;
W Stickstoff oder CR10, worin Rio Wasserstoff, Halogen oderW nitrogen or CR 10 , wherein Rio is hydrogen, halogen or
Cχ_4-Alkyl bedeutet oder CR10 zusammen mit CR2 oder CR3 einen 5- oder 6-gliedrigen Alkylen- oder Alkenylenring bildet, der gegebenenfalls substituiert sein kann, und worin jeweils eine oder mehrere Methylengruppen durch Sauerstoff, Schwefel, -NH oder -N(Cχ_C _Alkyl) , ersetzt sein können;Cχ_ 4 -alkyl means 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 which in each case one or more methylene groups by oxygen, sulfur, -NH or - N (Cχ_C _alkyl), can be replaced;
R3 Wasserstoff, Hydroxy, NH , NH(Cχ-C4-Alkyl) , N(Cχ-C -Alkyl)2, Halogen, C-C -Alkyl, C2-C-Alkenyl, C2-C -Alkinyl, Cι-C4-Halogenalkyl, C!-C4-Alkoxy, Cι_C4-Halogenalkoxy, Cχ-C4- lkylthio; oder CR3 ist mit CR10 wie oben angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft;R 3 is hydrogen, hydroxy, NH, NH (Cχ-C 4 -alkyl), N (Cχ-C-alkyl) 2 , halogen, CC-alkyl, C 2 -C-alkenyl, C 2 -C -alkynyl, Cι- C 4 haloalkyl, C ! -C 4 -alkoxy, Cι_C 4 -haloalkoxy, Cχ-C 4 - lkylthio; or CR 3 is linked to CR 10 to a 5- or 6-membered ring as stated above;
R4 und R5 (die gleich oder verschieden sein können) :R 4 and R 5 (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-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-alkyl group
C -Cg-Cycloalkyl gegebenenfalls substituiert;C -Cg cycloalkyl optionally substituted;
R6 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, Cχ-C4-Alkoxy, C-C6-Alkenyloxy, C3-C6-Alkinyloxy, Cχ-C-Alkylthio, Cχ-C-Halogenalkoxy, Cχ-C4-Alkylcarbonyl, Cχ-C4~Alkoxycarbonyl, C3_g-Alkylcarbonyl- alkyl, NH (C -C4-Alkyl ) , N(Cχ-C4-Alkyl) 2, C3-C8-Cycloalkyl,R 6 is hydrogen, -CC 8 -alkyl, C 3 -C 8 -alkenyl or C 3 -C 8 -alkynyl, where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, Amino, cyano, Cχ-C 4 -alkoxy, CC 6 -alkenyloxy, C 3 -C 6 -alkynyloxy, Cχ-C-alkylthio, Cχ-C-haloalkoxy, Cχ-C 4 -alkylcarbonyl, Cχ-C 4 ~ alkoxycarbonyl, C 3 _g-alkylcarbonyl-alkyl, NH (C -C 4 -alkyl), N (Cχ-C 4 -alkyl) 2 , C 3 -C 8 -cycloalkyl,
Heteroaryloxy oder Heteroaryl, fünf- oder sechsgliedrig, enthaltend ein bis drei Stickstoffatome und/oder ein Schwefeloder Sauerstoffatom, Phenoxy oder Phenyl, wobei die genannten Arylreste ihrerseits ein- oder mehrfach substituiert sein können, z.B. ein- bis dreifach durch Halogen, Hydroxy,Heteroaryloxy or heteroaryl, five- or six-membered, containing one to three nitrogen atoms and / or a sulfur or oxygen atom, phenoxy or phenyl, where the aryl radicals mentioned can themselves be mono- or polysubstituted, e.g. one to three times by halogen, hydroxy,
Mercapto, Carboxy, Nitro, Cyano, Cχ-C4-Alkyl, Cι-C4-Halogen- alkyl, Cχ-C4-Alkoxy, Cχ-C4-Halogenalkoxy, Amino, NH(Cχ-C4-Alkyl) , N (Cχ-C4-Alkyl ) 2 oder Cχ-C4-Alkylthiθ;Mercapto, carboxy, nitro, cyano, Cχ-C 4 -alkyl, Cι-C 4 -haloalkyl, Cχ-C 4 -alkoxy, Cχ-C 4 -haloalkoxy, amino, NH (Cχ-C 4 -alkyl), N (Cχ-C 4 alkyl) 2 or Cχ-C 4 alkylthiθ;
Phenyl oder Naphthyl, die jeweils durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, Nitro, Cyano, Hydroxy, Amino, Cχ-C4-Alkyl, Cχ-C-Halogenalkyl, Cχ-C4-Alkoxy, Cχ-C4-Halogenalkoxy, Phenoxy, Cχ-C4-Alkylthio, Cχ-C4-Alkylamino, Cχ-C4-Dialkylamino, Dioxomethylen oder Dioxoethylen;Phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, Cχ-C 4 -alkyl, Cχ-C-haloalkyl, Cχ-C4-alkoxy, Cχ-C 4 -haloalkoxy, phenoxy, Cχ-C 4 -alkylthio, Cχ-C 4 -alkylamino, Cχ-C 4 -dialkylamino, dioxomethylene or dioxoethylene;
ein fünf- oder sechsgliedriger Heteroaromat, enthaltend ein bis drei Stickstoffatome und/oder ein Schwefel- oder Sauerstoffatom, welcher ein bis vier Halogenatome und/oder einen bis zwei der folgenden Reste tragen kann: Cχ-C4-Alkyl, Cχ-C4-Halogenalkyl, Cχ-C4-Alkoxy, Cχ-C4-Halogenalkoxy, Cχ-C4-Alkylthio, Phenyl, Phenoxy oder Phenylcarbonyl, wobei die Phenylreste ihrerseits ein bis fünf Halogenatome und/oder einen bis drei der folgenden Reste tragen können: Cχ-C4~Alkyl, Cχ-C4-Halogenalkyl, Cχ-C4-Alkoxy, Cχ-C4-Halogenalkoxy und/oder Cχ-C4-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: Cχ-C 4 alkyl, Cχ-C4 haloalkyl , Cχ-C4-alkoxy, Cχ-C 4 -haloalkoxy, Cχ-C4-alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals themselves can carry one to five halogen atoms and / or one to three of the following radicals: Cχ-C4 ~ Alkyl, Cχ-C4 haloalkyl, Cχ-C 4 alkoxy, Cχ-C 4 haloalkoxy and / or Cχ-C 4 alkylthio;
C3-C8-Cycloalkyl, wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Halogen, Hydroxy, Mercapto, Carboxy, Nitro, Cyano, Cχ-C4-Alkyl, C -C4-Alkenyl, C -C4-Alkinyl, Cχ-C4-Alkoxy, Cχ-C4-Alkylthio, Cχ-C4-Halogen- alkoxy;C 3 -C 8 cycloalkyl, where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, Cχ-C4-alkyl, C -C 4 alkenyl, C -C 4 -Alkynyl, Cχ-C 4 -alkoxy, Cχ-C 4 -alkylthio, Cχ-C4-haloalkoxy;
Z Schwefel oder Sauerstoff;Z sulfur or oxygen;
B C2-C4 AlkylenBC 2 -C4 alkylene
Het ein heterozyklischer Rest der allgemeinen Formel la oder IbHet a heterocyclic radical of the general formula la or Ib
Figure imgf000048_0001
la ib mit T = 0, S, NR8
Figure imgf000048_0001
la ib with T = 0, S, NR 8
R8 Cχ-C6 AlkylR 8 Cχ-C 6 alkyl
bedeuten, sowie die physiologisch verträglichen Salze, und die enantiomerenreinen Formen.mean, as well as the physiologically acceptable salts, and the enantiomerically pure forms.
2. Verwendung der Carbonsäurederivate gemäß Anspruch 1 zur Herstellung von Arzneimitteln. 2. Use of the carboxylic acid derivatives according to claim 1 for the manufacture of medicaments.
PCT/EP1998/005354 1997-09-04 1998-08-24 Novel carboxylic acid derivatives, their production and their use as mixed eta/etb endothelin-receptor antagonists WO1999011629A1 (en)

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IDW20000386D ID25620A (en) 1997-09-04 1998-08-24 NEW CARBOXICATE ACID DERIVATIVES, THEIR PRODUCTION AND USE AS A MIXTURE OF ET A / ET B ANTAGONICAL RECEPTORS
EP98948859A EP1009741A1 (en) 1997-09-04 1998-08-24 Novel carboxylic acid derivatives, their production and their use as mixed et a?/et b? endothelin-receptor antagonists
JP2000508669A JP2001514254A (en) 1997-09-04 1998-08-24 Novel carboxylic acid derivatives, their preparation and their use as mixed ETA / ETB endothelin receptor antagonists
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
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
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
KR1020007002264A KR20010023615A (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 (en) 1997-09-04 1998-08-24 Novel carboxylic acid derivatives, their production and their use as mixed eta/etb endothelin-receptor antagonists
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BR9811631-2A BR9811631A (en) 1997-09-04 1998-08-24 Derivative of carboxylic acid and its use
NO20001077A NO20001077D0 (en) 1997-09-04 2000-03-02 Novel Carboxylic Acid Derivatives, Their Preparation and Use as Mixed ETA / ETB Endothelin Receptor Antagonists
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000073276A2 (en) * 1999-06-01 2000-12-07 Basf Aktiengesellschaft Carboxylic acid derivatives comprising aryl-substituted nitrogen heterocycles, their production and their use as endothelin receptor antagonists
WO2007137980A1 (en) * 2006-05-29 2007-12-06 Nicox S.A. Nitrated heterocyclic compounds as endothelin receptor antagonist
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
Publication number Priority date Publication date Assignee Title
EP2451786B1 (en) * 2009-07-10 2014-01-22 Cadila Healthcare Limited Improved process for the preparation of ambrisentan and novel intermediates thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995026716A1 (en) * 1994-03-31 1995-10-12 Basf Aktiengesellschaft Pyrimidine or triazine carboxylic acid derivatives to be used as medicaments
WO1996011914A1 (en) * 1994-10-14 1996-04-25 Basf Aktiengesellschaft New carboxylic acid derivatives, their preparation and their use
WO1997028160A1 (en) * 1996-02-01 1997-08-07 Smithkline Beecham Corporation Endothelin receptor antagonists
WO1997038982A1 (en) * 1996-04-12 1997-10-23 Basf Aktiengesellschaft Novel carboxylic acid derivatives, their production and use
WO1998009953A2 (en) * 1996-09-05 1998-03-12 Basf Aktiengesellschaft Azinyloxy-and phenoxy-diaryl-carboxylic acid derivatives, their preparation and use as mixed eta/etb endothelin receptor antagonists

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995026716A1 (en) * 1994-03-31 1995-10-12 Basf Aktiengesellschaft Pyrimidine or triazine carboxylic acid derivatives to be used as medicaments
WO1996011914A1 (en) * 1994-10-14 1996-04-25 Basf Aktiengesellschaft New carboxylic acid derivatives, their preparation and their use
WO1997028160A1 (en) * 1996-02-01 1997-08-07 Smithkline Beecham Corporation Endothelin receptor antagonists
WO1997038982A1 (en) * 1996-04-12 1997-10-23 Basf Aktiengesellschaft Novel carboxylic acid derivatives, their production and use
WO1998009953A2 (en) * 1996-09-05 1998-03-12 Basf Aktiengesellschaft Azinyloxy-and phenoxy-diaryl-carboxylic acid derivatives, their preparation and use as mixed eta/etb endothelin receptor antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RIECHERS H ET AL: "DISCOVERY AND OPTIMIZATION OF A NOVEL CLASS OF ORALLY ACTIVE NONPEPTIDIC ENDOTHELIN-A RECEPTOR ANTAGONISTS", JOURNAL OF MEDICINAL CHEMISTRY, vol. 39, no. 11, May 1996 (1996-05-01), pages 2123 - 2128, XP002034887 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000073276A2 (en) * 1999-06-01 2000-12-07 Basf Aktiengesellschaft Carboxylic acid derivatives comprising aryl-substituted nitrogen heterocycles, their production and their use as endothelin receptor antagonists
WO2000073276A3 (en) * 1999-06-01 2001-05-10 Basf Ag Carboxylic acid derivatives comprising aryl-substituted nitrogen heterocycles, their production and their use as endothelin receptor antagonists
WO2007137980A1 (en) * 2006-05-29 2007-12-06 Nicox S.A. Nitrated heterocyclic compounds as endothelin receptor antagonist
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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